BioMed Research International: Pharmacology The latest articles from Hindawi Publishing Corporation © 2014 , Hindawi Publishing Corporation . All rights reserved. Accumulation of Extracellular Hyaluronan by Hyaluronan Synthase 3 Promotes Tumor Growth and Modulates the Pancreatic Cancer Microenvironment Thu, 24 Jul 2014 18:42:37 +0000 Extensive accumulation of the glycosaminoglycan hyaluronan is found in pancreatic cancer. The role of hyaluronan synthases 2 and 3 (HAS2, 3) was investigated in pancreatic cancer growth and the tumor microenvironment. Overexpression of HAS3 increased hyaluronan synthesis in BxPC-3 pancreatic cancer cells. In vivo, overexpression of HAS3 led to faster growing xenograft tumors with abundant extracellular hyaluronan accumulation. Treatment with pegylated human recombinant hyaluronidase (PEGPH20) removed extracellular hyaluronan and dramatically decreased the growth rate of BxPC-3 HAS3 tumors compared to parental tumors. PEGPH20 had a weaker effect on HAS2-overexpressing tumors which grew more slowly and contained both extracellular and intracellular hyaluronan. Accumulation of hyaluronan was associated with loss of plasma membrane E-cadherin and accumulation of cytoplasmic β-catenin, suggesting disruption of adherens junctions. PEGPH20 decreased the amount of nuclear hypoxia-related proteins and induced translocation of E-cadherin and β-catenin to the plasma membrane. Translocation of E-cadherin was also seen in tumors from a transgenic mouse model of pancreatic cancer and in a human non-small cell lung cancer sample from a patient treated with PEGPH20. In conclusion, hyaluronan accumulation by HAS3 favors pancreatic cancer growth, at least in part by decreasing epithelial cell adhesion, and PEGPH20 inhibits these changes and suppresses tumor growth. Anne Kultti, Chunmei Zhao, Netai C. Singha, Susan Zimmerman, Ryan J. Osgood, Rebecca Symons, Ping Jiang, Xiaoming Li, Curtis B. Thompson, Jeffrey R. Infante, Michael A. Jacobetz, David A. Tuveson, Gregory I. Frost, H. Michael Shepard, and Zhongdong Huang Copyright © 2014 Anne Kultti et al. All rights reserved. Diagnostic and Prognostic Value of Soluble Syndecan-1 in Pleural Malignancies Thu, 24 Jul 2014 07:55:16 +0000 Background. The distinction between malignant and benign pleural effusions is a diagnostic challenge today and measuring soluble biomarkers could add to the diagnostic accuracy. Syndecan-1 is a proteoglycan involved in various cellular functions and is cleaved from the cell surface in a regulated manner. The shed fragment, which can be recovered in effusion supernatant and in serum, retains its binding capacities, but often with different functions and signalling properties than the cell-bound form. Aim. This study aimed to investigate the diagnostic and prognostic value of soluble syndecan-1 in pleural effusions and sera from patients with pleural malignancies. Study Design. Using two cohorts of patients, we assessed the diagnostic and prognostic value of soluble syndecan-1 in pleural effusions and sera, using enzyme-linked immunosorbent assays. Results. In pleural effusions, syndecan-1 distinguished malignant and benign diseases, with an odds ratio of 8.59 (95% CI 3.67 to 20.09). Furthermore, syndecan-1 in pleural effusions predicted a survival difference for patients with pleural metastatic disease and malignant mesothelioma of 11.2 and 9.2 months, respectively. However, no such effects were seen when syndecan-1 was measured in serum. Conclusion. Soluble syndecan-1 is a promising candidate biomarker for the cytopathological diagnosis and prognostication of malignant pleural effusions. Filip Mundt, Ghazal Heidari-Hamedani, Gustav Nilsonne, Muzaffer Metintas, Anders Hjerpe, and Katalin Dobra Copyright © 2014 Filip Mundt et al. All rights reserved. New Perspectives on Antiacne Plant Drugs: Contribution to Modern Therapeutics Thu, 24 Jul 2014 00:00:00 +0000 Acne is a common but serious skin disease, which affects approximately 80% adolescents and young adults in 11–30 age group. 42.5% of men and 50.9% of women continue to suffer from this disease into their twenties. Bacterial resistance is now at the alarming stage due to the irrational use of antibiotics. Hence, search for new lead molecule/bioactive and rational delivery of the existing drug (for better therapeutic effect) to the site of action is the need of the hour. Plants and plant-derived products have been an integral part of health care system since time immemorial. Therefore, plants that are currently used for the treatment of acne and those with a high potential are summarized in the present review. Most active plant extracts, namely, P. granatum, M. alba, A. anomala, and M. aquifolium exhibit minimum inhibitory concentration (MIC) in the range of 4–50 µg/mL against P. acnes, while aromatic oils of C. obovoides, C. natsudaidai, C. japonica, and C. nardus possess MICs 0.005–0.6 μL/mL and phytomolecules such as rhodomyrtone, pulsaquinone, hydropulsaquinone, honokiol, magnolol, xanthohumol lupulones, chebulagic acid and rhinacanthin-C show MIC in the range of 0.5–12.5 μg/mL. Novel drug delivery strategies of important plant leads in the treatment of acne have also been discussed. Priyam Sinha, Shruti Srivastava, Nidhi Mishra, and Narayan Prasad Yadav Copyright © 2014 Priyam Sinha et al. All rights reserved. Synthesis, Characterization and In Vitro Anticancer Activity of C-5 Curcumin Analogues with Potential to Inhibit TNF-α-Induced NF-κB Activation Thu, 24 Jul 2014 00:00:00 +0000 In a search of new compounds active against cancer, synthesis of a series of C-5 curcumin analogues was carried out. The new compounds demonstrated good cytotoxicity against chronic myeloid leukemia (KBM5) and colon cancer (HCT116) cell lines. Further, these compounds were found to have better potential to inhibit TNF-α-induced NF-κB activation in comparison to curcumin, which show their potential to act as anti-inflammatory agents. Some compounds were found to show higher cytotoxicity against cancer cell lines in comparison to curcumin used as standard. Amit Anthwal, Bandana K. Thakur, M. S. M. Rawat, D. S. Rawat, Amit K. Tyagi, and Bharat B. Aggarwal Copyright © 2014 Amit Anthwal et al. All rights reserved. Pinocembrin Protects Human Brain Microvascular Endothelial Cells against Fibrillar Amyloid- β1−40 Injury by Suppressing the MAPK/NF- κ B Inflammatory Pathways Wed, 23 Jul 2014 07:23:06 +0000 Cerebrovascular accumulation of amyloid-β (Aβ) peptides in Alzheimer’s disease (AD) may contribute to disease progression through Aβ-induced microvascular endothelial pathogenesis. Pinocembrin has been shown to have therapeutic effects in AD models. These effects correlate with preservation of microvascular function, but the effect on endothelial cells under Aβ-damaged conditions is unclear. The present study focuses on the in vitro protective effect of pinocembrin on fibrillar Aβ1−40 (fAβ1−40) injured human brain microvascular endothelial cells (hBMECs) and explores potential mechanisms. The results demonstrate that fAβ1−40-induced cytotoxicity in hBMECs can be rescued by pinocembrin treatment. Pinocembrin increases cell viability, reduces the release of LDH, and relieves nuclear condensation. The mechanisms of this reversal from Aβ may be associated with the inhibition of inflammatory response, involving inhibition of MAPK activation, downregulation of phosphor-IKK level, relief of IκBα degradation, blockage of NF-κB p65 nuclear translocation, and reduction of the release of proinflammatory cytokines. Pinocembrin does not show obvious effects on regulating the redox imbalance after exposure to fAβ1−40. Together, the suppression of MAPK and the NF-κB signaling pathways play a significant role in the anti-inflammation of pinocembrin in hBMECs subjected to fAβ1−40. This may serve as a therapeutic agent for BMEC protection in Alzheimer’s-related deficits. Rui Liu, Jin-ze Li, Jun-ke Song, Jia-lin Sun, Yong-jie Li, Si-bai Zhou, Tian-tai Zhang, and Guan-hua Du Copyright © 2014 Rui Liu et al. All rights reserved. Towards Understanding the Roles of Heparan Sulfate Proteoglycans in Alzheimer’s Disease Wed, 23 Jul 2014 07:04:48 +0000 Alzheimer’s disease (AD) is the most common form of dementia, characterized by progressive loss of memory and cognitive dysfunctions. A central pathological event of AD is accumulation and deposition of cytotoxic amyloid-β peptide (Aβ) in the brain parenchyma. Heparan sulfate proteoglycans (HSPGs) and the side chains heparan sulfate (HS) are found associated with Aβ deposits in the brains of AD patients and transgenic animal models of AD. A growing body of evidence from in vitro and in vivo studies suggests functional roles of HSPG/HS in Aβ pathogenesis. Although the question of “how and why HSPG/HS is codeposited with Aβ?” still remains, it is within reach to understand the mechanisms of the events. Recent progress by immunohistochemical examination with advanced antibodies shed light on molecular structures of HS codeposited with Aβ. Several recent reports have provided important new insights into the roles of HSPG in Aβ pathogenesis. Particularly, experiments on mouse models revealed indispensible functions of HSPG in modulating Aβ-associated neuroinflammation and clearance of Aβ from the brain. Application of molecules to interfere with the interaction between HS and Aβ peptides has demonstrated beneficial effects on AD mouse models. Elucidating the functions of HSPG/HS in Aβ deposition and toxicity is leading to further understanding of the complex pathology of AD. The progress is encouraging development of new treatments for AD by targeting HS-Aβ interactions. Gan-lin Zhang, Xiao Zhang, Xiao-min Wang, and Jin-Ping Li Copyright © 2014 Gan-lin Zhang et al. All rights reserved. -Tocotrienol Oxazine Derivative Antagonizes Mammary Tumor Cell Compensatory Response to CoCl2-Induced Hypoxia Tue, 22 Jul 2014 11:43:14 +0000 In response to low oxygen supply, cancer cells elevate production of HIF-1α, a hypoxia-inducible transcription factor that subsequently acts to stimulate blood vessel formation and promote survival. Studies were conducted to determine the role of δ-tocotrienol and a semisynthetic δ-tocotrienol oxazine derivative, compound 44, on +SA mammary tumor cell hypoxic response. Treatment with 150 µM CoCl2 induced a hypoxic response in +SA mammary tumor cells as evidenced by a large increase in HIF-1α levels, and combined treatment with compound 44 attenuated this response. CoCl2-induced hypoxia was also associated with a large increase in Akt/mTOR signaling, activation of downstream targets p70S6K and eIF-4E1, and a significant increase in VEGF production, and combined treatment with compound 44 blocked this response. Additional in vivo studies showed that intralesional treatment with compound 44 in BALB/c mice bearing +SA mammary tumors significantly decreased the levels of HIF-1α, and this effect was associated with a corresponding decrease in Akt/mTOR signaling and activation of downstream targets p70S6kinase and eIF-4E1. These findings demonstrate that treatment with the δ-tocotrienol oxazine derivative, compound 44, significantly attenuates +SA mammary tumor cell compensatory responses to hypoxia and suggests that this compound may provide benefit in the treatment of rapidly growing solid breast tumors. Suryatheja Ananthula, Parash Parajuli, Fathy A. Behery, Alaadin Y. Alayoubi, Sami Nazzal, Khalid El Sayed, and Paul W. Sylvester Copyright © 2014 Suryatheja Ananthula et al. All rights reserved. The Motile Breast Cancer Phenotype Roles of Proteoglycans/Glycosaminoglycans Tue, 22 Jul 2014 06:46:39 +0000 The consecutive stages of cancer growth and dissemination are obligatorily perpetrated through specific interactions of the tumor cells with their microenvironment. Importantly, cell-associated and tumor microenvironment glycosaminoglycans (GAGs)/proteoglycan (PG) content and distribution are markedly altered during tumor pathogenesis and progression. GAGs and PGs perform multiple functions in specific stages of the metastatic cascade due to their defined structure and ability to interact with both ligands and receptors regulating cancer pathogenesis. Thus, GAGs/PGs may modulate downstream signaling of key cellular mediators including insulin growth factor receptor (IGFR), epidermal growth factor receptor (EGFR), estrogen receptors (ERs), or Wnt members. In the present review we will focus on breast cancer motility in correlation with their GAG/PG content and critically discuss mechanisms involved. Furthermore, new approaches involving GAGs/PGs as potential prognostic/diagnostic markers or as therapeutic agents for cancer-related pathologies are being proposed. Dragana Nikitovic, Katerina Kouvidi, Kallirroi Voudouri, Aikaterini Berdiaki, Evgenia Karousou, Alberto Passi, and George N. Tzanakakis Copyright © 2014 Dragana Nikitovic et al. All rights reserved. The Nonglycemic Actions of Dipeptidyl Peptidase-4 Inhibitors Mon, 21 Jul 2014 07:51:53 +0000 A cell surface serine protease, dipeptidyl peptidase 4 (DPP-4), cleaves dipeptide from peptides containing proline or alanine in the N-terminal penultimate position. Two important incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), enhance meal-stimulated insulin secretion from pancreatic β-cells, but are inactivated by DPP-4. Diabetes and hyperglycemia increase the DPP-4 protein level and enzymatic activity in blood and tissues. In addition, multiple other functions of DPP-4 suggest that DPP-4 inhibitor, a new class of antidiabetic agents, may have pleiotropic effects. Studies have shown that DPP-4 itself is involved in the inflammatory signaling pathway, the stimulation of vascular smooth cell proliferation, and the stimulation of oxidative stress in various cells. DPP-4 inhibitor ameliorates these pathophysiologic processes and has been shown to have cardiovascular protective effects in both in vitro and in vivo experiments. However, in recent randomized clinical trials, DPP-4 inhibitor therapy in high risk patients with type 2 diabetes did not show cardiovascular protective effects. Some concerns on the actions of DPP-4 inhibitor include sympathetic activation and neuropeptide Y-mediated vascular responses. Further studies are required to fully characterize the cardiovascular effects of DPP-4 inhibitor. Na-Hyung Kim, Taeyang Yu, and Dae Ho Lee Copyright © 2014 Na-Hyung Kim et al. All rights reserved. Abarema cochliacarpos Extract Decreases the Inflammatory Process and Skeletal Muscle Injury Induced by Bothrops leucurus Venom Sun, 20 Jul 2014 12:06:45 +0000 Snakebites are a public health problem, especially in tropical countries. However, treatment with antivenom has limited effectiveness against venoms’ local effects. Here, we investigated the ability of Abarema cochliacarpos hydroethanolic extract (EAc) to protect mice against injection of Bothrops leucurus venom. Swiss mice received perimuscular venom injection and were subsequently treated orally with EAc in different doses. Treatment with EAc 100, 200, and 400 mg/kg reduced the edema induced by B. leucurus in 1%, 13%, and 39%, respectively. Although lower doses showed no antihypernociceptive effect in the Von Frey test, the higher dose significantly reduced hyperalgesia induced by the venom. Antimyotoxic activity of EAc was also observed by microscopy assessment, with treated muscles presenting preserved structures, decreased edema, and inflammatory infiltrate as compared to untreated ones. Finally, on the rotarod test, the treated mice showed better motor function, once muscle fibers were preserved and there were less edema and pain. Treated mice could stand four times more time on the rotating rod than untreated ones. Our results have shown that EAc presented relevant activities against injection of B. leucurus venom in mice, suggesting that it can be considered as an adjuvant in the treatment of envenomation. Jeison Saturnino-Oliveira, Daiana Do Carmo Santos, Adriana Gibara Guimarães, Antônio Santos Dias, Marcelo Amorim Tomaz, Marcos Monteiro-Machado, Charles Santos Estevam, Waldecy De Lucca Júnior, Durvanei Augusto Maria, Paulo A. Melo, Adriano Antunes de Souza Araújo, Márcio Roberto Viana Santos, Jackson Roberto Guedes da Silva Almeida, Rita de Cássia Meneses Oliveira, Aldeidia Pereira de Oliveira, and Lucindo José Quintans Júnior Copyright © 2014 Jeison Saturnino-Oliveira et al. All rights reserved. Obligatory Role for Endothelial Heparan Sulphate Proteoglycans and Caveolae Internalization in Catestatin-Dependent eNOS Activation Sun, 20 Jul 2014 11:38:31 +0000 The chromogranin-A peptide catestatin modulates a wide range of processes, such as cardiovascular functions, innate immunity, inflammation, and metabolism. We recently found that the cardiac antiadrenergic action of catestatin requires a PI3K-dependent NO release from endothelial cells, although the receptor involved is yet to be identified. In the present work, based on the cationic properties of catestatin, we tested the hypothesis of its interaction with membrane heparan sulphate proteoglycans, resulting in the activation of a caveolae-dependent endocytosis. Experiments were performed on bovine aortic endothelial cells. Endocytotic vesicles trafficking was quantified by confocal microscopy using a water-soluble membrane dye; catestatin colocalization with heparan sulphate proteoglycans and caveolin 1 internalization were studied by fluorimetric measurements in live cells. Modulation of the catestatin-dependent eNOS activation was assessed by immunofluorescence and immunoblot analysis. Our results demonstrate that catestatin (5 nM) colocalizes with heparan sulphate proteoglycans and induces a remarkable increase in the caveolae-dependent endocytosis and caveolin 1 internalization, which were significantly reduced by both heparinase and wortmannin. Moreover, catestatin was unable to induce Ser1179 eNOS phosphorylation after pretreatments with heparinase and methyl-β-cyclodextrin. Taken together, these results highlight the obligatory role for proteoglycans and caveolae internalization in the catestatin-dependent eNOS activation in endothelial cells. Sara Fornero, Eleonora Bassino, Roberta Ramella, Clara Gallina, Sushil K. Mahata, Bruno Tota, Renzo Levi, Giuseppe Alloatti, and Maria Pia Gallo Copyright © 2014 Sara Fornero et al. All rights reserved. Pharmacogenomics in Personalized Medicine and Drug Metabolism Thu, 17 Jul 2014 11:50:11 +0000 Wei-Chiao Chang Copyright © 2014 Wei-Chiao Chang. All rights reserved. Netrins and Their Roles in Placental Angiogenesis Thu, 17 Jul 2014 00:00:00 +0000 Netrins, a family of laminin-related proteins, were originally identified as axonal guidance molecules. Subsequently, netrins were found to modulate various biological processes including morphogenesis, tumorogenesis, adhesion, and, recently, angiogenesis. In human placenta, the most vascularized organ, the presence of netrins has also been reported. Recent studies demonstrated the involvement of netrins in the regulation of placental angiogenesis. In this review we focused on the role of netrins in human placental angiogenesis. Among all netrins examined, netrin-4 and netrin-1 have been found to be either pro- or antiangiogenic factors. These opposite effects appear to be related to the endothelial cell phenotype studied and seem also to depend on the receptor type to which netrin binds, that is, the canonical receptor member of the DCC family, the members of the UNC5 family, or the noncanonical receptor members of the integrin family or DSCAM. Mbarka Dakouane-Giudicelli, Nadia Alfaidy, and Philippe de Mazancourt Copyright © 2014 Mbarka Dakouane-Giudicelli et al. All rights reserved. Mesenchymal Stem Cell-Induced Doxorubicin Resistance in Triple Negative Breast Cancer Wed, 16 Jul 2014 15:49:42 +0000 Triple negative breast cancer (TNBC) is an aggressive histological subtype with limited treatment options and a worse clinical outcome compared with other breast cancer subtypes. Doxorubicin is considered to be one of the most effective agents in the treatment of TNBC. Unfortunately, resistance to this agent is common. In some drug-resistant cells, drug efflux is mediated by adenosine triphosphate-dependent membrane transporter termed adenosine triphosphate-binding cassette (ABC) transporter, which can drive the substrates across membranes against concentration gradient. In the tumor microenvironment, upon interaction with mesenchymal stem cells (MSCs), tumor cells exhibit altered biological functions of certain gene clusters, hence increasing stemness of tumor cells, migration ability, angiogenesis, and drug resistance. In our present study, we investigated the mechanism of TNBC drug resistance induced by adipose-derived MSCs. Upon exposure of TNBC to MSC-secreted conditioned medium (CM), noticeable drug resistance against doxorubicin with markedly increased BCRP protein expression was observed. Intracellular doxorubicin accumulation of TNBC was also decreased by MSC-secreted CM. Furthermore, we found that doxorubicin resistance of TNBC was mediated by IL-8 presented in the MSC-secreted CM. These findings may enrich the list of potential targets for overcoming drug resistance induced by MSCs in TNBC patients. Dar-Ren Chen, Dah-Yuu Lu, Hui-Yi Lin, and Wei-Lan Yeh Copyright © 2014 Dar-Ren Chen et al. All rights reserved. New Drugs on the Internet: The Case of Camfetamine Wed, 16 Jul 2014 15:48:37 +0000 Introduction. The number of new psychoactive substances (NPS) advertised for sale online is constantly increasing and it has become a phenomenon of global concern. Among NPS, Camfetamine has been rediscovered as recreational drug in 2011. Very little information is still available in the scientific literature on its nature and potential health risks. Methods. Data in scientific literature were integrated with a multilingual qualitative assessment of a range of online resources over the period of 32 months (May 2011–January 2014). Results. N-Methyl-3-phenyl-norbornan-2-amine (Camfetamine) may act as an indirect dopaminergic agonist in the central nervous system and may have mild-moderate opioid activity too. There are no current epidemiological data about recreational use of Camfetamine; our research shows that it is indeed used especially by individuals with a history of recreational polydrug misuse. It facilitates mental alertness, induces relaxation, and, unlike many other stimulants, seems not to be associated with severe physical effects. Valid causes for concern issued in our research may be Camfetamine intravenous or intramuscular administration as well as its use in conjunction with other psychoactive substances. Conclusions. It is here highlighted that more large-scale studies need to be carried out to confirm and better describe both the extent of Camfetamine misuse and possible psychotropic/adverse effects. Eduardo Cinosi, Ornella Corazza, Rita Santacroce, Matteo Lupi, Tiziano Acciavatti, Giovanni Martinotti, and Massimo di Giannantonio Copyright © 2014 Eduardo Cinosi et al. All rights reserved. Anti-Inflammatory Effect and Mechanism of the Green Fruit Extract of Solanum integrifolium Poir. Tue, 15 Jul 2014 12:04:31 +0000 The green fruit of Solanum integrifolium Poir. has been used traditionally as an anti-inflammatory and analgesic remedy in Taiwanese aboriginal medicine. The goal of this study is to evaluate the anti-inflammatory activity and mechanism of the green fruit extract of S. integrifolium. A bioactivity-guided fractionation procedure was developed to identify the active partition fraction. The methanol fraction (ME), with the highest phenolic content, exhibited the strongest inhibitory effect against LPS-mediated nitric oxide (NO) release and cytotoxicity in RAW264.7 macrophages. ME also significantly downregulated the expression of LPS-induced proinflammatory genes, such as iNOS, COX-2, IL-1β, IL-6, CCL2/MCP-1, and CCL3/MIP1α. Moreover, ME significantly upregulated HO-1 expression and stimulated the activation of extracellular-signal-regulated kinase 1/2 (ERK1/2). Pretreatment of cells with the HO-1 inhibitor zinc protoporphyrin and MEK/ERK inhibitor U0126 attenuated ME’s inhibitory activity against LPS-induced NO production. Taken together, this is the first study to demonstrate the anti-inflammatory activity of green fruit extract of S. integrifolium and its activity may be mediated by the upregulation of HO-1 expression and activation of ERK1/2 pathway. Lisu Wang, Shu-Yuan Chiou, Yi-Ting Shen, Fu-Tsun Yen, Hsiou-Yu Ding, and Ming-Jiuan Wu Copyright © 2014 Lisu Wang et al. All rights reserved. Novel Psychoactive Substances in Young Adults with and without Psychiatric Comorbidities Tue, 15 Jul 2014 08:45:49 +0000 Objective. Comorbidities between psychiatric diseases and consumption of traditional substances of abuse (alcohol, cannabis, opioids, and cocaine) are common. Nevertheless, there is no data regarding the use of novel psychoactive substances (NPS) in the psychiatric population. The purpose of this multicentre survey is to investigate the consumption of a wide variety of psychoactive substances in a young psychiatric sample and in a paired sample of healthy subjects. Methods. A questionnaire has been administered, in different Italian cities, to 206 psychiatric patients aged 18 to 26 years and to a sample of 2615 healthy subjects matched for sex, gender, and living status. Results. Alcohol consumption was more frequent in the healthy young population compared to age-matched subjects suffering from mental illness (79.5% versus 70.7%; ). Conversely, cocaine and NPS use was significantly more common in the psychiatric population (cocaine 8.7% versus 4.6%; ) (NPS 9.8% versus 3%; ). Conclusions. The use of novel psychoactive substances in a young psychiatric population appears to be a frequent phenomenon, probably still underestimated. Therefore, careful and constant monitoring and accurate evaluations of possible clinical effects related to their use are necessary. Giovanni Martinotti, Matteo Lupi, Tiziano Acciavatti, Eduardo Cinosi, Rita Santacroce, Maria Salvina Signorelli, Laura Bandini, Giulia Lisi, Diego Quattrone, Paola Ciambrone, Andrea Aguglia, Federica Pinna, Salvatore Calò, Luigi Janiri, and Massimo di Giannantonio Copyright © 2014 Giovanni Martinotti et al. All rights reserved. Sphingosine-1-Phosphate Transporters as Targets for Cancer Therapy Tue, 15 Jul 2014 08:25:31 +0000 Sphingosine-1-phosphate (S1P) is a pleiotropic lipid mediator that regulates cell survival, migration, the recruitment of immune cells, angiogenesis, and lymphangiogenesis, all of which are involved in cancer progression. S1P is generated inside cancer cells by sphingosine kinases then exported outside of the cell into the tumor microenvironment where it binds to any of five G protein coupled receptors and proceeds to regulate a variety of functions. We have recently reported on the mechanisms underlying the “inside-out” signaling of S1P, its export through the plasma membrane, and its interaction with cell surface receptors. Membrane lipids, including S1P, do not spontaneously exchange through lipid bilayers since the polar head groups do not readily go through the hydrophobic interior of the plasma membrane. Instead, specific transporter proteins exist on the membrane to exchange these lipids. This review summarizes what is known regarding S1P transport through the cell membrane via ATP-binding cassette transporters and the spinster 2 transporter and discusses the roles for these transporters in cancer and in the tumor microenvironment. Based on our research and the emerging understanding of the role of S1P signaling in cancer and in the tumor microenvironment, S1P transporters and S1P signaling hold promise as new therapeutic targets for cancer drug development. Masayuki Nagahashi, Kazuaki Takabe, Krista P. Terracina, Daiki Soma, Yuki Hirose, Takashi Kobayashi, Yasunobu Matsuda, and Toshifumi Wakai Copyright © 2014 Masayuki Nagahashi et al. All rights reserved. Molecular Mechanisms for Biliary Phospholipid and Drug Efflux Mediated by ABCB4 and Bile Salts Tue, 15 Jul 2014 06:26:19 +0000 On the canalicular membranes of hepatocytes, several ABC transporters are responsible for the secretion of bile lipids. Among them, ABCB4, also called MDR3, is essential for the secretion of phospholipids from hepatocytes into bile. The biliary phospholipids are associated with bile salts and cholesterol in mixed micelles, thereby reducing the detergent activity and cytotoxicity of bile salts and preventing cholesterol crystallization. Mutations in the ABCB4 gene result in progressive familial intrahepatic cholestasis type 3, intrahepatic cholestasis of pregnancy, low-phospholipid-associated cholelithiasis, primary biliary cirrhosis, and cholangiocarcinoma. In vivo and cell culture studies have demonstrated that the secretion of biliary phospholipids depends on both ABCB4 expression and bile salts. In the presence of bile salts, ABCB4 located in nonraft membranes mediates the efflux of phospholipids, preferentially phosphatidylcholine. Despite high homology with ABCB1, ABCB4 expression cannot confer multidrug resistance. This review summarizes our current understanding of ABCB4 functions and physiological relevance, and discusses the molecular mechanism for the ABCB4-mediated efflux of phospholipids. Shin-ya Morita and Tomohiro Terada Copyright © 2014 Shin-ya Morita and Tomohiro Terada. All rights reserved. Video Game Addiction in Gambling Disorder: Clinical, Psychopathological, and Personality Correlates Mon, 14 Jul 2014 08:54:07 +0000 Objective. We studied the prevalences of video game use (VGU) and addiction (VGA) in gambling disorder (GD) patients and compared them with subjects with non-video game use (non-VGU) in relation to their gambling behavior, psychopathology, and personality characteristics. Method. A sample of 193 GD patients (121 non-VGU, 43 VGU, and 29 VGA) consecutively admitted to our pathological gambling unit participated in the study. Assessment. Measures included the video game dependency test (VDT), symptom checklist-90-revised, and the temperament and character inventory-revised, as well as a number of other GD indices. Results. In GD, the observed prevalence of VG (use or addiction) was 37.3% (),VGU 22.3% (), and VGA 15% (). Orthogonal polynomial contrast into logistic regression showed positive linear trends for VG level and GD severity and other measures of general psychopathology. After structural equation modeling, higher VG total scores were associated with younger age, general psychopathology, and specific personality traits, but not with GD severity. Patients’ sex and age were involved in the mediational pathways between personality traits and VG impairment. Conclusions. GD patients with VG are younger and present more dysfunctional personality traits, and more general psychopathology. The presence of VG did not affect the severity of GD. Susana Jiménez-Murcia, Fernando Fernández-Aranda, Roser Granero, Mariano Chóliz, Melania La Verde, Eugenio Aguglia, Maria S. Signorelli, Gustavo M. Sá, Neus Aymamí, Mónica Gómez-Peña, Amparo del Pino-Gutiérrez, Laura Moragas, Ana B. Fagundo, Sarah Sauchelli, José A. Fernández-Formoso, and José M. Menchón Copyright © 2014 Susana Jiménez-Murcia et al. All rights reserved. Ligation Strategies for Targeting Liposomal Nanocarriers Mon, 14 Jul 2014 07:45:56 +0000 Liposomes have been exploited for pharmaceutical purposes, including diagnostic imaging and drug and gene delivery. The versatility of liposomes as drug carriers has been demonstrated by a variety of clinically approved formulations. Since liposomes were first reported, research of liposomal formulations has progressed to produce improved delivery systems. One example of this progress is stealth liposomes, so called because they are equipped with a PEGylated coating of the liposome bilayer, leading to prolonged blood circulation and improved biodistribution of the liposomal carrier. A growing research area focuses on the preparation of liposomes with the ability of targeting specific tissues. Several strategies to prepare liposomes with active targeting ligands have been developed over the last decades. Herein, several strategies for the functionalization of liposomes are concisely summarized, with emphasis on recently developed technologies for the covalent conjugation of targeting ligands to liposomes. Patricia Marqués-Gallego and Anton I. P. M. de Kroon Copyright © 2014 Patricia Marqués-Gallego and Anton I. P. M. de Kroon. All rights reserved. Erratum to “Involvement of Nrf2-Mediated Upregulation of Heme Oxygenase-1 in Mollugin-Induced Growth Inhibition and Apoptosis in Human Oral Cancer Cells” Mon, 14 Jul 2014 00:00:00 +0000 Young-Man Lee, Q-Schick Auh, Deok-Won Lee, Jun-Yeol Kim, Ha-Jin Jung, Seung-Ho Lee, and Eun-Cheol Kim Copyright © 2014 Young-Man Lee et al. All rights reserved. Collagen VI and Hyaluronan: The Common Role in Breast Cancer Mon, 14 Jul 2014 00:00:00 +0000 Collagen VI and hyaluronan are widely distributed extracellular matrix macromolecules that play a crucial role in tissue development and are highly expressed in cancers. Both hyaluronan and collagen VI are upregulated in breast cancer, generating a microenvironment that promotes tumour progression and metastasis. A growing number of studies show that these two molecules are involved in inflammation and angiogenesis by recruiting macrophages and endothelial cells, respectively. Additionally, collagen VI induces epithelial-mesenchymal transition that is correlated to increased synthesis of hyaluronan in mammary cells. Hyaluronan has also a specific role in cellular functions that depends mainly on the size of the polymer, whereas the effect of collagen VI in tumour progression may be the result of the intact molecule or the C5 peptide of α3(VI) chain, known as endotrophin. Collectively, these findings strongly support the parallel role of these molecules in tumour progression and suggest that they may be used as prognostic factors for the breast cancer treatment. Evgenia Karousou, Maria Luisa D'Angelo, Katerina Kouvidi, Davide Vigetti, Manuela Viola, Dragana Nikitovic, Giancarlo De Luca, and Alberto Passi Copyright © 2014 Evgenia Karousou et al. All rights reserved. Human Genetic Disorders and Knockout Mice Deficient in Glycosaminoglycan Sun, 13 Jul 2014 07:28:37 +0000 Glycosaminoglycans (GAGs) are constructed through the stepwise addition of respective monosaccharides by various glycosyltransferases and maturated by epimerases and sulfotransferases. The structural diversity of GAG polysaccharides, including their sulfation patterns and sequential arrangements, is essential for a wide range of biological activities such as cell signaling, cell proliferation, tissue morphogenesis, and interactions with various growth factors. Studies using knockout mice of enzymes responsible for the biosynthesis of the GAG side chains of proteoglycans have revealed their physiological functions. Furthermore, mutations in the human genes encoding glycosyltransferases, sulfotransferases, and related enzymes responsible for the biosynthesis of GAGs cause a number of genetic disorders including chondrodysplasia, spondyloepiphyseal dysplasia, and Ehlers-Danlos syndromes. This review focused on the increasing number of glycobiological studies on knockout mice and genetic diseases caused by disturbances in the biosynthetic enzymes for GAGs. Shuji Mizumoto, Shuhei Yamada, and Kazuyuki Sugahara Copyright © 2014 Shuji Mizumoto et al. All rights reserved. Therapeutic Efficacy of Vitamin E -Tocotrienol in Collagen-Induced Rat Model of Arthritis Thu, 10 Jul 2014 11:38:19 +0000 Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory disease primarily involving inflammation of the joints. Although the management of the disease has advanced significantly in the past three decades, there is still no cure for RA. The aim of this study was to determine the therapeutic efficacy of δ-tocotrienol, in the rat model of collagen-induced arthritis (CIA). Arthritis was induced by intradermal injection of collagen type II emulsified in complete Freund’s adjuvant. CIA rats were orally treated with δ-tocotrienol (10 mg/kg) or glucosamine hydrochloride (300 mg/kg) from day 25 to 50. Efficacy was assessed based on the ability to reduce paw edema, histopathological changes, suppression of collagen-specific T-cells, and a reduction in C-reactive protein (CRP) levels. It was established that δ-tocotrienol had the most significant impact in lowering paw edema when compared to glucosamine treatment. Paw edema changes correlated well with histopathological analysis where there was a significant reversal of changes in groups treated with δ-tocotrienol. The results suggest that δ-tocotrienol is efficient in amelioration of collagen-induced arthritis. Vitamin E delta-tocotrienol may be of therapeutic value against rheumatoid arthritis. Nagaraja Haleagrahara, Mirashini Swaminathan, Srikumar Chakravarthi, and Ammu Radhakrishnan Copyright © 2014 Nagaraja Haleagrahara et al. All rights reserved. Noninvasive and Quantitative Assessment of In Vivo Fetomaternal Interface Angiogenesis Using RGD-Based Fluorescence Thu, 10 Jul 2014 07:03:28 +0000 Angiogenesis is a key process for proper placental development and for the success of pregnancy. Although numerous in vitro methods have been developed for the assessment of this process, relatively few reliable in vivo methods are available to evaluate this activity throughout gestation. Here we report an in vivo technique that specifically measures placental neovascularization. The technique is based on the measurement of a fluorescent alpha beta 3 () integrin-targeting molecule called Angiolone-Alexa-Fluor 700. The integrin is highly expressed by endothelial cells during the neovascularization and by trophoblast cells during their invasion of the maternal decidua. Angiolone was injected to gravid mice at 6.5 and 11.5 days post coitus (dpc). The fluorescence was analyzed one day later at 7.5 and 12.5 dpc, respectively. We demonstrated that (i) Angiolone targets protein in the placenta with a strong specificity, (ii) this technique is quantitative as the measurement was correlated to the increase of the placental size observed with increasing gestational age, and (iii) information on the outcome is possible, as abnormal placentation could be detected early on during gestation. In conclusion, we report the validation of a new noninvasive and quantitative method to assess the placental angiogenic activity, in vivo. M. Keramidas, J. Lavaud, F. Sergent, P. Hoffmann, S. Brouillet, J.-J. Feige, J.-L. Coll, and N. Alfaidy Copyright © 2014 M. Keramidas et al. All rights reserved. Butylidenephthalide Blocks Potassium Channels and Enhances Basal Tension in Isolated Guinea-Pig Trachea Thu, 10 Jul 2014 00:00:00 +0000 Butylidenephthalide (Bdph, 30~300 μM), a constituent of Ligusticum chuanxiong Hort., significantly enhanced tension in isolated guinea-pig trachea. In this study, we investigate the mechanism(s) of Bdph-induced contraction in the tissue. Isolated trachea was bathed in 5 mL of Krebs solution containing indomethacin (3 μM), and its tension changes were isometrically recorded. Cromakalim (3 μM), an ATP-dependent K+ channel opener, significantly antagonized the Bdph-induced enhancement of baseline tension. Bdph (300 μM) also significantly antagonized cromakalim-induced relaxation. Bdph (300 μM) did not significantly influence the antagonistic effects of glibenclamide (GBC, 1 μM) and tetraethylammonium (TEA, 8 mM) against the cromakalim-induced relaxation. However, Bdph (300 μM) and 4-aminopiridine (4-AP, 5 mM), a blocker of Kv1 family of K+ channels, in combination significantly rightward shifted the log concentration-relaxation curve of cromakalim. The antagonistic effect of the combination almost equals the sum of the individual effects of Bdph and 4-AP, suggesting that the antagonistic mechanism of Bdph may be similar to that of 4-AP. All calcium channel blockers influenced neither the baseline tension nor antagonistic effect of Bdph against cromakalim. In conclusion, Bdph may be similar to 4-AP, a blocker of Kv1 family of K+ channels, to enhance the baseline tension of guinea-pig trachea. Hsin-Te Hsu, You-Lan Yang, Wan-Chen Chen, Chi-Ming Chen, and Wun-Chang Ko Copyright © 2014 Hsin-Te Hsu et al. All rights reserved. Rho/ROCK Signal Cascade Mediates Asymmetric Dimethylarginine-Induced Vascular Smooth Muscle Cells Migration and Phenotype Change Wed, 09 Jul 2014 12:37:31 +0000 Asymmetric dimethylarginine (ADMA) induces vascular smooth muscle cells (VSMCs) migration. VSMC phenotype change is a prerequisite of migration. RhoA and Rho-kinase (ROCK) mediate migration of VSMCs. We hypothesize that ADMA induces VSMC migration via the activation of Rho/ROCK signal pathway and due to VSMCs phenotype change. ADMA activates Rho/ROCK signal pathway that interpreted by the elevation of RhoA activity and phosphorylation level of a ROCK substrate. Pretreatment with ROCK inhibitor, Y27632 completely reverses the induction of ADMA on ROCK and in turn inhibits ADMA-induced VSMCs migration. When the Rho/ROCK signal pathway has been blocked by pretreatment with Y27632, the induction of ERK signal pathway by ADMA is completely abrogated. Elimination of ADMA via overexpression of dimethylarginine dimethylaminohydrolase 2 (DDAH2) and L-arginine both blocks the effects of ADMA on the activation of Rho/ROCK and extra cellular signal-regulated kinase (ERK) in VSMCs. The expression of differentiated phenotype relative proteins was reduced and the actin cytoskeleton was disassembled by ADMA, which were blocked by Y27632, further interpreting that ADMA inducing VSMCs migration via Rho/ROCK signal pathway is due to its effect on the VSMCs phenotype change. Our present study may help to provide novel insights into the therapy and prevention of atherosclerosis. Yi-ming Zhou, Xi Lan, Han-bin Guo, Yan Zhang, Li Ma, and Jian-biao Cao Copyright © 2014 Yi-ming Zhou et al. All rights reserved. Antidiabetic Effect of Sida cordata in Alloxan Induced Diabetic Rats Wed, 09 Jul 2014 11:50:43 +0000 Medicinal plants are efficient ameliorator of oxidative stress associated with diabetes mellitus. In this study, ethyl acetate fraction (SCEE) of Sida cordata was investigated for scientific validation of its folk use in diabetes. Antidiabetic effect of SCEE was confirmed by antihyperglycemic activity in normal glucose loaded and diabetic glucose loaded animals as well as normal off feed animals. Confirmation of antidiabetic activity and toxicity ameliorative role of S. cordata was investigated in a chronic multiple dose treatment study of fifteen days. A single dose of alloxan (120 mg/kg) produced a decrease in insulin level, hyperglycemia, elevated total lipids, triglycerides, and cholesterol and decreased the high-density lipoproteins. Concurrent with these changes, there was an increase in the concentration of lipid peroxidation (TBARS), H2O2, and nitrite in pancreas, liver, and testis. This oxidative stress was related to a decrease in glutathione content (GSH) and antioxidant enzymes. Administration of SCEE for 15 days after diabetes induction ameliorated hyperglycemia, restored lipid profile, blunted the increase in TBARS, H2O2, and nitrite content, and stimulated the GSH production in the organs of alloxan-treated rats. We suggested that SCEE could be used as antidiabetic component in case of diabetes mellitus. This may be related to its antioxidative properties. Naseer Ali Shah and Muhammad Rashid Khan Copyright © 2014 Naseer Ali Shah and Muhammad Rashid Khan. All rights reserved. The K–Cl Cotransporter KCC3 as an Independent Prognostic Factor in Human Esophageal Squamous Cell Carcinoma Wed, 09 Jul 2014 00:00:00 +0000 The objectives of the present study were to investigate the role of K–Cl cotransporter 3 (KCC3) in the regulation of cellular invasion and the clinicopathological significance of its expression in esophageal squamous cell carcinoma (ESCC). Immunohistochemical analysis performed on 70 primary tumor samples obtained from ESCC patients showed that KCC3 was primarily found in the cytoplasm of carcinoma cells. Although the expression of KCC3 in the main tumor (MT) was related to several clinicopathological features, such as the pT and pN categories, it had no prognostic impact. KCC3 expression scores were compared between the MT and cancer nest (CN), and the survival rate of patients with a score was lower than that of patients with a score. In addition, the survival rate of patients in whom KCC3 was expressed in the invasive front of tumor was lower than that of the patients without it. Furthermore, multivariate analysis demonstrated that the expression of KCC3 in the invasive front was one of the most important independent prognostic factors. The depletion of KCC3 using siRNAs inhibited cell migration and invasion in human ESCC cell lines. These results suggest that the expression of KCC3 in ESCC may affect cellular invasion and be related to a worse prognosis in patients with ESCC. Atsushi Shiozaki, Kenichi Takemoto, Daisuke Ichikawa, Hitoshi Fujiwara, Hirotaka Konishi, Toshiyuki Kosuga, Shuhei Komatsu, Kazuma Okamoto, Mitsuo Kishimoto, Yoshinori Marunaka, and Eigo Otsuji Copyright © 2014 Atsushi Shiozaki et al. All rights reserved. Sensitization of Cancer Cells through Reduction of Total Akt and Downregulation of Salinomycin-Induced pAkt, pGSk3β, pTSC2, and p4EBP1 by Cotreatment with MK-2206 Tue, 08 Jul 2014 12:16:08 +0000 MK-2206 is an inhibitor of Akt activation. It has been investigated as an anticancer drug in clinical trials assessing the potential of pAkt targeting therapy. The purpose of this study was to identify conditions that increase the sensitivity of cancer cells to MK-2206. We found that the treatment of cancer cells with a high concentration of salinomycin (Sal) reduced total Akt protein levels but increased activated Akt levels. When cancer cells were cotreated with MK-2206 and Sal, both pAkt and total Akt levels were reduced. Using microscopic observation, an assessment of cleaved PARP, FACS analysis of pre-G1 region, and Hoechst staining, we found that Sal increased apoptosis of MK-2206-treated cancer cells. These results suggest that cotreatment with MK-2206 and Sal sensitizes cancer cells via reduction of both pAkt and total Akt. Furthermore, cotreatment of cancer cells with Sal and MK-2206 reduced pp70S6K, pmTOR, and pPDK1 levels. In addition, Sal-induced activation of GSK3β, TSC2, and 4EBP1 was abolished by MK-2206 cotreatment. These results suggest that cotreatment using MK-2206 and Sal could be used as a therapeutic method to sensitize cancer cells through targeting of the PI3K/Akt/mTOR pathway. Our findings may contribute to the development of MK-2206-based sensitization therapies for cancer patients. Ae-Ran Choi, Ju-Hwa Kim, and Sungpil Yoon Copyright © 2014 Ae-Ran Choi et al. All rights reserved. Mallotus philippinensis Muell. Arg (Euphorbiaceae): Ethnopharmacology and Phytochemistry Review Tue, 08 Jul 2014 00:00:00 +0000 Mallotus philippinensis Muell. Arg (Euphorbiaceae) are widely distributed perennial shrub or small tree in tropical and subtropical region in outer Himalayas regions with an altitude below 1,000 m and are reported to have wide range of pharmacological activities. Mallotus philippinensis species are known to contain different natural compounds, mainly phenols, diterpenoids, steroids, flavonoids, cardenolides, triterpenoids, coumarins, isocoumarins, and many more especially phenols; that is, bergenin, mallotophilippinens, rottlerin, and isorottlerin have been isolated, identified, and reported interesting biological activities such as antimicrobial, antioxidant, antiviral, cytotoxicity, antioxidant, anti-inflammatory, immunoregulatory activity protein inhibition against cancer cell. We have selected all the pharmacological aspects and toxicological and all its biological related studies. The present review reveals that Mallotus philippinensis is a valuable source of medicinally important natural molecules and provides convincing support for its future use in modern medicine. However, the existing knowledge is very limited about Mallotus philippinensis and its different parts like steam, leaf, and fruit. Further, more detailed safety data pertaining to the acute and subacute toxicity and cardio- and immunotoxicity also needs to be generated for crude extracts or its pure isolated compounds. This review underlines the interest to continue the study of this genus of the Euphorbiaceae. Mayank Gangwar, R. K. Goel, and Gopal Nath Copyright © 2014 Mayank Gangwar et al. All rights reserved. Acetylated Hyaluronic Acid: Enhanced Bioavailability and Biological Studies Tue, 08 Jul 2014 00:00:00 +0000 Hyaluronic acid (HA), a macropolysaccharidic component of the extracellular matrix, is common to most species and it is found in many sites of the human body, including skin and soft tissue. Not only does HA play a variety of roles in physiologic and in pathologic events, but it also has been extensively employed in cosmetic and skin-care products as drug delivery agent or for several biomedical applications. The most important limitations of HA are due to its short half-life and quick degradation in vivo and its consequently poor bioavailability. In the aim to overcome these difficulties, HA is generally subjected to several chemical changes. In this paper we obtained an acetylated form of HA with increased bioavailability with respect to the HA free form. Furthermore, an improved radical scavenging and anti-inflammatory activity has been evidenced, respectively, on ABTS radical cation and murine monocyte/macrophage cell lines (J774.A1). Carmela Saturnino, Maria Stefania Sinicropi, Ortensia Ilaria Parisi, Domenico Iacopetta, Ada Popolo, Stefania Marzocco, Giuseppina Autore, Anna Caruso, Anna Rita Cappello, Pasquale Longo, and Francesco Puoci Copyright © 2014 Carmela Saturnino et al. All rights reserved. A Review on the Traditional Chinese Medicinal Herbs and Formulae with Hypolipidemic Effect Mon, 07 Jul 2014 08:02:50 +0000 Hyperlipidemia, characterized by the abnormal blood lipid profiles, is one of the dominant factors of many chronic diseases such as diabetes, obesity, and cardiovascular diseases (CVD). For the low cost, effectiveness, and fewer side effects, the popularity of using traditional Chinese medicine (TCM) to handle hyperlipidemia is increasing and its role in health care has been recognized by the public at large. Despite the importance of TCM herbs and formulations, there is no comprehensive review summarizing their scientific findings on handling hyperlipidemia. This review summarizes the recent experimental and clinical results of nine representative single Chinese herbs and seven classic TCM formulae that could improve lipid profiles so as to help understand and compare their underlying mechanisms. Most of single herbs and formulae demonstrated the improvement of hyperlipidemic conditions with multiple and diverse mechanisms of actions similar to conventional Western drugs in spite of their mild side effects. Due to increasing popularity of TCM, more extensive, well-designed preclinical and clinical trials on the potential synergistic and adverse side effects of herb-drug interactions as well as their mechanisms are warranted. Hyperlipidemic patients should be warned about the potential risks of herb-drug interactions, particularly those taking anticoagulants and antiplatelet drugs. Tung-Ting Sham, Chi-On Chan, You-Hua Wang, Jian-Mei Yang, Daniel Kam-Wah Mok, and Shun-Wan Chan Copyright © 2014 Tung-Ting Sham et al. All rights reserved. Adult Separation Anxiety and TCI-R Personality Dimensions in Patients with Anxiety, Alcohol Use, and Gambling: A Preliminary Report Thu, 03 Jul 2014 11:50:18 +0000 Background. Nowadays, adult separation anxiety disorder (ASAD) is an established diagnostic category but is little investigated in subjects with addictive behaviours. Objective. To assess the presence of ASAD among patients with addictive disorders in comparison with anxiety patients and measure the personality correlates in all these groups. Methods. 103 outpatients, meeting DSM-IV-TR criteria for anxiety disorders (38 patients), alcohol dependence (30 patients), or pathological gambling (35 patients), were assessed by the Structured Clinical Interview for Separation Anxiety Symptoms (SCI-SAS) and the Adult Separation Anxiety Checklist (ASA-27) for separation anxiety and by the Temperament and Character Inventory-Revised (TCI-R) for personality characteristics. Results. ASAD is detected in 34.2% of anxiety patients, 13.3% of alcoholics, and 11.4% of gamblers. Separation anxiety scores correlate positively with harm avoidance and negatively with self-directedness in all groups; further correlations are seen among addictive patients only, that is, self-transcendence for gamblers and cooperativeness for both alcoholics and gamblers. Conclusions. The prevalence of ASAD is lower among addictive patients than in those with anxiety disorders; correlations are found between separation anxiety and specific TCI-R dimensions, with some matching across the three diagnostic groups. Gino Pozzi, Angelo Bruschi, Andrea De Angelis, Marco Pascucci, Daniele Stavros Hatzigiakoumis, Paolo Grandinetti, Marco Di Nicola, Stefano Pini, and Luigi Janiri Copyright © 2014 Gino Pozzi et al. All rights reserved. Metabolism of Cartilage Proteoglycans in Health and Disease Thu, 03 Jul 2014 11:22:15 +0000 Cartilage proteoglycans are extracellular macromolecules with complex structure, composed of a core protein onto which a variable number of glycosaminoglycan chains are attached. Their biosynthesis at the glycosaminoglycan level involves a great number of sugar transferases well-orchestrated in Golgi apparatus. Similarly, their degradation, either extracellular or intracellular in lysosomes, involves a large number of hydrolases. A deficiency or malfunction of any of the enzymes participating in cartilage proteoglycan metabolism may lead to severe disease state. This review summarizes the findings regarding this topic. Demitrios H. Vynios Copyright © 2014 Demitrios H. Vynios. All rights reserved. 25C-NBOMe: Preliminary Data on Pharmacology, Psychoactive Effects, and Toxicity of a New Potent and Dangerous Hallucinogenic Drug Thu, 03 Jul 2014 07:37:45 +0000 Introduction. The use of novel psychoactive substances (NPSs) has rapidly increased as well as their online availability. The aim of this paper is to provide a comprehensive review of the nature and the risks associated with 25C-NBOMe, which has recently appeared in the drug market. Methods. A systematic analysis of the scientific literature and a qualitative assessment of online and media resources (e.g., e-newsgroups, chat-rooms, and e-newsletters) in 10 languages were carried out. Results. 25C-NBOMe is sold online as legal LSD or as research chemical with different designations such as “Boom,” “Pandora,” “Holland film,” or “N-bomb.” It is a partial agonist of 5-HT2A receptors. It is usually ingested orally/sublingually and, less commonly, nasally, through injection, vaginally, rectally, and smoked. Its effects include sublingual numbing, stimulation, “body high,” hallucinations, dissociation, and anxiety. 25C-NBOMe presents high risk of overdoses; acute toxicity and fatalities have been reported. Conclusions. 25C-NBOMe consumption represents an emerging phenomenon with potential harmful effects. Its use is increased by its online availability at low costs. Health and other professionals should be informed about this new trend of substance use. Francesco Saverio Bersani, Ornella Corazza, Gabriella Albano, Giuseppe Valeriani, Rita Santacroce, Flaminia Bolzan Mariotti Posocco, Eduardo Cinosi, Pierluigi Simonato, Giovanni Martinotti, Giuseppe Bersani, and Fabrizio Schifano Copyright © 2014 Francesco Saverio Bersani et al. All rights reserved. ADAMTS4 and ADAMTS5 Knockout Mice Are Protected from Versican but Not Aggrecan or Brevican Proteolysis during Spinal Cord Injury Thu, 03 Jul 2014 00:00:00 +0000 The chondroitin sulfate proteoglycans (CSPGs) aggrecan, versican, and brevican are large aggregating extracellular matrix molecules that inhibit axonal growth of the mature central nervous system (CNS). ADAMTS proteoglycanases, including ADAMTS4 and ADAMTS5, degrade CSPGs, representing potential targets for ameliorating axonal growth-inhibition by CSPG accumulation after CNS injury. We investigated the proteolysis of CSPGs in mice homozygous for Adamts4 or Adamts5 null alleles after spinal cord injury (SCI). ADAMTS-derived 50–60 kDa aggrecan and 50 kDa brevican fragments were observed in Adamts4−/−, Adamts5−/−, and wt mice but not in the sham-operated group. By contrast Adamts4−/− and Adamts5−/− mice were both protected from versican proteolysis with an ADAMTS-generated 70 kDa versican fragment predominately observed in WT mice. ADAMTS1, ADAMTS9, and ADAMTS15 were detected by Western blot in Adamts4−/− mice’ spinal cords after SCI. Immunohistochemistry showed astrocyte accumulation at the injury site. These data indicate that aggrecan and brevican proteolysis is compensated in Adamts4−/− or Adamts5−/− mice by ADAMTS proteoglycanase family members but a threshold of versican proteolysis is sensitive to the loss of a single ADAMTS proteoglycanase during SCI. We show robust ADAMTS activity after SCI and exemplify the requirement for collective proteolysis for effective CSPG clearance during SCI. Kadir Demircan, Vehap Topcu, Tomoyuki Takigawa, Sumeyya Akyol, Tomoko Yonezawa, Gulfer Ozturk, Veli Ugurcu, Rukiye Hasgul, M. Ramazan Yigitoglu, Omer Akyol, Daniel R. McCulloch, and Satoshi Hirohata Copyright © 2014 Kadir Demircan et al. All rights reserved. Drug Delivery Nanoparticles in Skin Cancers Wed, 02 Jul 2014 06:39:43 +0000 Nanotechnology involves the engineering of functional systems at nanoscale, thus being attractive for disciplines ranging from materials science to biomedicine. One of the most active research areas of the nanotechnology is nanomedicine, which applies nanotechnology to highly specific medical interventions for prevention, diagnosis, and treatment of diseases, including cancer disease. Over the past two decades, the rapid developments in nanotechnology have allowed the incorporation of multiple therapeutic, sensing, and targeting agents into nanoparticles, for detection, prevention, and treatment of cancer diseases. Nanoparticles offer many advantages as drug carrier systems since they can improve the solubility of poorly water-soluble drugs, modify pharmacokinetics, increase drug half-life by reducing immunogenicity, improve bioavailability, and diminish drug metabolism. They can also enable a tunable release of therapeutic compounds and the simultaneous delivery of two or more drugs for combination therapy. In this review, we discuss the recent advances in the use of different types of nanoparticles for systemic and topical drug delivery in the treatment of skin cancer. In particular, the progress in the treatment with nanocarriers of basal cell carcinoma, squamous cell carcinoma, and melanoma has been reported. Chiara Dianzani, Gian Paolo Zara, Giovanni Maina, Piergiorgio Pettazzoni, Stefania Pizzimenti, Federica Rossi, Casimiro Luca Gigliotti, Eric Stefano Ciamporcero, Martina Daga, and Giuseppina Barrera Copyright © 2014 Chiara Dianzani et al. All rights reserved. Efficacy of a Hypotonic Treatment for Peritoneal Dissemination from Gastric Cancer Cells: An In Vivo Evaluation Wed, 02 Jul 2014 00:00:00 +0000 The aim of the present study was to determine the efficacy of a hypotonic treatment for peritoneal dissemination from gastric cancer cells using an in vivo model. We firstly evaluated the toxicity of a peritoneal injection of distilled water (DW) (2 mL for 3 days) in mice. Macroscopic and microscopic examinations revealed that the peritoneal injection of DW did not severely damage the abdominal organs of these mice. MKN45 gastric cancer cells preincubated with NaCl buffer or DW for 20 minutes in vitro were then intraperitoneally injected into nude mice, and the development of dissemination nodules was analyzed. The total number, weight, and volume of the dissemination nodules were significantly decreased by the DW preincubation. We then determined whether the peritoneal injection of DW inhibited the establishment of peritoneal dissemination. After a peritoneal injection of MKN45 cells into nude mice, NaCl buffer or DW was injected into the abdominal cavity for 3 days. The total volume of dissemination nodules was significantly lower in DW-injected mice than in NaCl-injected mice. In conclusion, we demonstrated the safeness of a peritoneal injection of DW. Furthermore, the development of dissemination nodules from gastric cancer cells was prevented by a preincubation with or peritoneal injection of DW. Atsushi Shiozaki, Daisuke Ichikawa, Kenichi Takemoto, Yoshito Nako, Shingo Nakashima, Hiroki Shimizu, Maki Kitagawa, Toshiyuki Kosuga, Hirotaka Konishi, Shuhei Komatsu, Hitoshi Fujiwara, Kazuma Okamoto, Yoshinori Marunaka, and Eigo Otsuji Copyright © 2014 Atsushi Shiozaki et al. All rights reserved. Angiogenin Expression during Early Human Placental Development; Association with Blood Vessel Formation Tue, 01 Jul 2014 09:31:30 +0000 The placenta is a transient organ essential for fetal development. During human placental development, chorionic villi grow in coordination with a large capillary network resulting from both vasculogenesis and angiogenesis. Angiogenin is one of the most potent inducers of neovascularisation in experimental models in vivo. We and others have previously mapped angiogenin expression in the human term placenta. Here, we explored angiogenin involvement in early human placental development. We studied, angiogenin expression by in situ hybridisation and/or by RT-PCR in tissues and primary cultured trophoblastic cells and angiogenin cellular distribution by coimmunolabelling with cell markers: CD31 (PECAM-1), vascular endothelial cadherin (VE-cadherin), vascular endothelial growth factor receptor-2 (VEGF-R2), Tie-2, von Willebrand factor, CD34, erythropoeitin receptor (Epo-R), alpha-smooth muscle actin, CD45, cytokeratin 7, and Ki-67. Extravillous and villous cytotrophoblasts, isolated and differentiated in vitro, expressed and secreted angiogenin. Angiogenin was detected in villous trophoblastic layers, and structured and nascent fetal vessels. In decidua, it was expressed by glandular epithelial cells, vascular cells and macrophages. The observed pattern of angiogenin expression is compatible with a role in blood vessel formation and in cross-talk between trophoblasts and endothelial cells. In view of angiogenin properties, we suggest that angiogenin may participate in placental vasculogenesis and organogenesis. Nadine Pavlov, Jean-Louis Frendo, Jean Guibourdenche, Séverine A. Degrelle, Danièle Evain-Brion, and Josette Badet Copyright © 2014 Nadine Pavlov et al. All rights reserved. Prevalence and Correlates of Binge Drinking among Young Adults Using Alcohol: A Cross-Sectional Survey Mon, 30 Jun 2014 11:41:37 +0000 Background. Although binge drinking prevalence and correlates among young people have been extensively studied in the USA and Northern Europe, less is known for Southern Europe countries with relatively healthier drinking cultures. Objective. We aimed at analyzing prevalence and correlates of binge drinking in a representative sample of young adults in Italy. Methods. We conducted a cross-sectional survey among alcohol-consuming young adults. We carried out univariate and multivariate analyses to assess associations between recent binge drinking and candidate variables. Results. We selected 654 subjects, with 590 (mean age: 20.65 ± 1.90) meeting inclusion criteria. Prevalence for recent binge drinking was 38.0%, significantly higher for females than males. Multivariate analysis showed that high alcohol expectancies, large amount of money available during the weekend, interest for parties and discos, female gender, cannabis use, influence by peers, and electronic cigarettes smoking all were significantly associated with recent binge drinking, whereas living with parents appeared a significant protective factor. Conclusions. More than a third of young adults using alcohol are binge drinkers, and, in contrast with findings from Anglo-Saxon countries, females show higher risk as compared with males. These data suggest the increasing importance of primary and secondary prevention programmes for binge drinking. Francesco Bartoli, Daniele Carretta, Cristina Crocamo, Alessandro Schivalocchi, Giulia Brambilla, Massimo Clerici, and Giuseppe Carrà Copyright © 2014 Francesco Bartoli et al. All rights reserved. Molecular Mechanisms of Curcumin on Diabetes-Induced Endothelial Dysfunctions: Txnip, ICAM-1, and NOX2 Expressions Thu, 26 Jun 2014 10:50:10 +0000 We aim to investigate the effects of curcumin on preventing diabetes-induced vascular inflammation in association with its actions on Txnip, ICAM-1, and NOX2 enzyme expressions. Male Wistar rats were divided into four groups: control (CON), diabetic (DM; streptozotocin (STZ), i.v. 55 mg/kg BW), control-treated with curcumin (CONCUR; 300 mg/kg BW), and diabetes treated with curcumin (DMCUR; 300 mg/kg BW). 12th week after STZ injection, iris blood perfusion, leukocyte adhesion, Txnip, p47phox, and malondialdehyde (MDA) levels were determined by using laser Doppler, intravital fluorescent confocal microscopy, Western Blot analysis, and TBAR assay, respectively. The iris blood perfusion of DM and DMCUR was decreased significantly compared to CON and CONCUR . Plasma glucose and HbA1c of DM and DMCUR were increased significantly compared to CON and CONCUR . Leukocyte adhesion, ICAM-1, p47phox expression, and MDA levels in DM were increased significantly compared to CON, CONCUR, and DMCUR . Txnip expression in DM and DMCUR was significantly higher than CON and CONCUR . From Pearson’s analysis, the correlation between the plasma MDA level and the endothelial functions was significant. It suggested that curcumin could ameliorate diabetic vascular inflammation by decreasing ROS overproduction, reducing leukocyte-endothelium interaction, and inhibiting ICAM-1 and NOX2 expression. Natchaya Wongeakin, Parvapan Bhattarakosol, and Suthiluk Patumraj Copyright © 2014 Natchaya Wongeakin et al. All rights reserved. Carum copticum L.: A Herbal Medicine with Various Pharmacological Effects Wed, 25 Jun 2014 08:36:00 +0000 Carum copticum L. commonly known as “Ajwain” is cultivated in many regions of the world including Iran and India, states of Gujarat and Rajasthan. Traditionally, C. copticum has been used in the past for various therapeutic effects including bloating, fatigue, diarrhea, abdominal tumors, abdominal pain, respiratory distress, and loss of appetite. It has other health benefits such as antifungal, antioxidant, antibacterial, antiparasitic, and hypolipidemic effects. This plant contains different important components such as carbohydrates, glucosides, saponins and phenolic compounds (carvacrol), volatile oils (thymol), terpiene, paracymene and beta-pinene, protein, fat, fiber, and minerals including calcium, phosphorus, iron, and nicotinic acid (niacin). In the previous studies, several pharmacological effects were shown for C. copticum. Therefore, in this paper, the pharmacological effects of the plant were reviewed. Mohammad Hossein Boskabady, Saeed Alitaneh, and Azam Alavinezhad Copyright © 2014 Mohammad Hossein Boskabady et al. All rights reserved. Obsessive-Compulsive Aspects and Pathological Gambling in an Italian Sample Wed, 25 Jun 2014 07:32:01 +0000 Introduction. Gambling behaviour appears as repetitive and difficult to resist and seems to be aimed at neutralizing or reducing negative feelings such as anxiety and tension, confirming its similarities with the obsessive-compulsive spectrum. Aims. Estimating the prevalence of gambling behaviour in an Italian sample and assessing the effects of sociodemographic variables and the correlations between gambling behaviour and obsessive-compulsive features. Methods. A sample of 300 Italian subjects was evaluated based on gambling behaviours and obsessive-compulsive attitudes. The assessment was carried out in small centers in Italy, mainly in coffee and tobacco shops, where slot machines are located, using the South Oaks Gambling Screen (SOGS) and the MOCQ-R, a reduced form of Maudsley Obsessional-Compulsive Questionnaire. Results. A negative correlation between SOGS and MOPQ-R, with reference to the control and cleaning subscales, was evidenced in the majority of the examined subjects. Both evaluating instruments showed reliability and a good discriminative capacity. Conclusions. Our study evidenced that the sample of gamblers we analysed did not belong to the obsessive-compulsive disorders area, supporting the validity of the model proposed by DSM-5 for the classification of PG. These data confirm the importance of investing in treatments similar to those used for substance use disorders. Filippo Petruccelli, Pierluigi Diotaiuti, Valeria Verrastro, Irene Petruccelli, Maria Luisa Carenti, Domenico De Berardis, Felice Iasevoli, Alessandro Valchera, Michele Fornaro, Giovanni Martinotti, Massimo Di Giannantonio, and Luigi Janiri Copyright © 2014 Filippo Petruccelli et al. All rights reserved. Bioactivity-Guided Fractionation Identifies Amygdalin as a Potent Neurotrophic Agent from Herbal Medicine Semen Persicae Extract Tue, 24 Jun 2014 07:40:13 +0000 Herbal medicine Semen Persicae is widely used to treat blood stasis in Chinese medicine and other oriental folk medicines. Although little is known about the effects of Semen Persicae and its active compounds on neuron differentiation, our pilot study showed that Semen Persicae extract promoted neurite outgrowth in rat dopaminergic PC12 cells. In the present study, we developed a bioactivity-guided fractionation procedure for the characterization of the neurotrophic activity of Semen Persicae extract. The resultant fractions were assayed for neurite outgrowth in PC12 cells based on microscopic assessment. Through liquid-liquid extraction and reverse phase HPLC separation, a botanical glycoside amygdalin was isolated as the active compound responsible for the neurotrophic activity of Semen Persicae extract. Moreover, we found that amygdalin rapidly induced the activation of extracellular-signal-regulated kinase 1/2 (ERK1/2). A specific ERK1/2 inhibitor PD98059 attenuated the stimulatory effect of amygdalin on neurite outgrowth. Taken together, amygdalin was identified as a potent neurotrophic agent from Semen Persicae extract through a bioactivity-guided fractional procedure. The neurotrophic activity of amygdalin may be mediated by the activation of ERK1/2 pathway. Chuanbin Yang, Jia Zhao, Yuanyuan Cheng, Xuechen Li, and Jianhui Rong Copyright © 2014 Chuanbin Yang et al. All rights reserved. Inhibitory Potential of Turbinaria ornata against Key Metabolic Enzymes Linked to Diabetes Tue, 24 Jun 2014 05:42:38 +0000 One of the therapeutic approaches in treating diabetes is to reduce postprandial hyperglycemia by inhibiting major carbohydrate hydrolyzing enzymes. In the present study, crude extracts of marine seaweed, Turbinaria ornata, were tested for their antidiabetic potential using enzyme inhibitory assays (α-amylase, α-glucosidase, and dipeptidyl peptidase-IV). Among the tested extracts, methanol and acetone extracts showed significant inhibitory effects on α-amylase ( 250.9 μg/mL), α-glucosidase (535.6 μg/mL), and dipeptidyl peptidase-4 (55.2 μg/mL), respectively. Free radical scavenging activity of these extracts was analyzed using DPPH assay (65%). Extracts were tested for in vitro toxicity using DNA fragmentation assay, haemolytic assay, and MTT assay. None of the extracts showed toxicity in tested models. Furthermore, GC-MS analysis of lead extracts showed the presence of major compounds, hentriacontane, z, z-6, 28-heptatriactontadien-2-one, 8-heptadecene, and 1-heptacosanol. Our findings suggest that Turbinaria ornata can be used as a potential source for further in vivo studies in controlling hyperglycemia. P. S. Unnikrishnan, K. Suthindhiran, and M. A. Jayasri Copyright © 2014 P. S. Unnikrishnan et al. All rights reserved. Affective Dependence and Aggression: An Exploratory Study Mon, 23 Jun 2014 11:01:01 +0000 Introduction. Emotionally dependent subjects may engage in controlling, restrictive, and aggressive behaviours, which limit their partner’s autonomy. The underlying causes of such behaviours are not solely based on levels of aggression, but act as a mean of maintaining the subject’s own sense of self-worth, identity, and general functioning. Objective. The aim of the paper is to explore the correlation between affective dependency and reactive/proactive aggression and to evaluate individual differences as predisposing factors for aggressive behaviour and emotional dependency. Methods. The Spouse-Specific Dependency Scale (SSDS) and the Reactive Proactive Questionnaire (RPQ) were administered to a sample of 3375 subjects. Results. In the whole sample, a positive correlation between emotional dependency and proactive aggression was identified. Differences with regard to sex, age group, and geographical distribution were evidenced for the scores of the different scales. Conclusion. A fundamental distinction between reactive and proactive aggression was observed, anchoring proactive aggression more strictly to emotional dependency. Sociocultural and demographical variables, together with the previous structuring of attachment styles, help to determine the scope, frequency, and intensity of the demands made to the partner, as well as to feed the fears of loss, abandonment, or betrayal. Filippo Petruccelli, Pierluigi Diotaiuti, Valeria Verrastro, Irene Petruccelli, Roberta Federico, Giovanni Martinotti, Andrea Fossati, Massimo Di Giannantonio, and Luigi Janiri Copyright © 2014 Filippo Petruccelli et al. All rights reserved. Enhanced Analgesic Properties and Reduced Ulcerogenic Effect of a Mononuclear Copper(II) Complex with Fenoprofen in Comparison to the Parent Drug: Promising Insights in the Treatment of Chronic Inflammatory Diseases Thu, 19 Jun 2014 13:02:05 +0000 Analgesic and ulcerogenic properties have been studied for the copper(II) coordination complex of the nonsteroidal anti-inflammatory drug Fenoprofen and imidazole [Cu(fen)2(im)2] (Cu: copper(II) ion; fen: fenoprofenate anion from Fenoprofen, im: imidazole). A therapeutic dose of 28 mg/kg was tested for [Cu(fen)2(im)2] and 21 mg/kg was employed for Fenoprofen calcium, administered by oral gavage in female mice to compare the therapeutic properties of the new entity. The acetic acid induced writhing test was employed to study visceral pain. The percentage of inhibition in writhing and stretching was 78.9% and 46.2% for the [Cu(fen)2(im)2] and Fenoprofen calcium, respectively. This result indicates that the complex could be more effective in diminishing visceral pain. The formalin test was evaluated to study the impact of the drugs over nociceptive and inflammatory pain. The complex is a more potent analgesic on inflammatory pain than the parent drug. Ulcerogenic effects were evaluated using a model of gastric lesions induced by hypothermic-restraint stress. Fenoprofen calcium salt caused an ulcer index of about 79 mm2 while the one caused by [Cu(fen)2(im)2] was 22 mm2. The complex diminished the development of gastric mucosal ulcers in comparison to the uncomplexed drug. Possible mechanisms of action related to both therapeutic properties have been discussed. Mariela Agotegaray, Fernanda Gumilar, Mónica Boeris, Ricardo Toso, and Alejandra Minetti Copyright © 2014 Mariela Agotegaray et al. All rights reserved. Novel Drugs Development for Cardio-/Cerebrovascular Diseases Tue, 17 Jun 2014 06:53:22 +0000 Joen-Rong Sheu, Philip Aloysius Thomas, and Juei-Tang Cheng Copyright © 2014 Joen-Rong Sheu et al. All rights reserved. Amelioration of LPS-Induced Inflammation Response in Microglia by AMPK Activation Tue, 17 Jun 2014 00:00:00 +0000 Adenosine 5′-monophosphate-activated protein kinase (AMPK) is a key regulator of cellular energy homeostasis via modulating metabolism of glucose, lipid, and protein. In addition to energy modulation, AMPK has been demonstrated to associate with several important cellular events including inflammation. The results showed that ENERGI-F704 identified from bamboo shoot extract was nontoxic in concentrations up to 80 μM and dose-dependently induced phosphorylation of AMPK (Thr-172) in microglia BV2 cells. Our findings also showed that the treatment of BV2 with ENERGI-F704 ameliorated the LPS-induced elevation of IL-6 and TNF-α production. In addition, ENERGI-F704 reduced increased production of nitric oxide (NO) and prostaglandin E2 (PGE2) via downregulating the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2), respectively. Moreover, ENERGI-F704 decreased activated nuclear translocation and protein level of NF-κB. Inhibition of AMPK with compound C restored decreased NF-κB translocation by ENERGI-F704. In conclusion, ENERGI-F704 exerts inhibitory activity on LPS-induced inflammation through manipulating AMPK signaling and exhibits a potential therapeutic agent for neuroinflammatory disease. Chin-Chen Chen, Jiun-Tsai Lin, Yi-Fang Cheng, Cheng-Yi Kuo, Chun-Fang Huang, Shao-Hsuan Kao, Yao-Jen Liang, Ching-Yi Cheng, and Han-Min Chen Copyright © 2014 Chin-Chen Chen et al. All rights reserved. Biomedical Properties of a Natural Dietary Plant Metabolite, Zerumbone, in Cancer Therapy and Chemoprevention Trials Mon, 16 Jun 2014 00:00:00 +0000 Zerumbone (ZER) is a naturally occurring dietary compound, present in many natural foods consumed today. The compound derived from several plant species of the Zingiberaceae family that has been found to possess multiple biomedical properties, such as antiproliferative, antioxidant, anti-inflammatory, and anticancer activities. However, evidence of efficacy is sparse, pointing to the need for a more systematic review for assessing scientific evidence to support therapeutic claims made for ZER and to identify future research needs. This review provides an updated overview of in vitro and in vivo investigations of ZER, its cancer chemopreventive properties, and mechanisms of action. Therapeutic effects of ZER were found to be scientifically plausible and could be explained partially by in vivo and in vitro pharmacological activities. Much of the research outlined in this paper will serve as a foundation to explain ZER anticancer bioactivity, which will open the door for the development of strategies in the treatment of malignancies using ZER. Heshu Sulaiman Rahman, Abdullah Rasedee, Swee Keong Yeap, Hemn Hassan Othman, Max Stanley Chartrand, Farideh Namvar, Ahmad Bustamam Abdul, and Chee Wun How Copyright © 2014 Heshu Sulaiman Rahman et al. All rights reserved. Sexual Enhancement Products for Sale Online: Raising Awareness of the Psychoactive Effects of Yohimbine, Maca, Horny Goat Weed, and Ginkgo biloba Sun, 15 Jun 2014 09:01:56 +0000 Introduction. The use of unlicensed food and herbal supplements to enhance sexual functions is drastically increasing. This phenomenon, combined with the availability of these products over the Internet, represents a challenge from a clinical and a public health perspective. Methods. A comprehensive multilingual assessment of websites, drug fora, and other online resources was carried out between February and July 2013 with exploratory qualitative searches including 203 websites. Additional searches were conducted using the Global Public Health Intelligence Network (GPHIN). Once the active constitutes of the products were identified, a comprehensive literature search was carried out using PsycInfo and PubMed. Results. The most common sexual enhancement products available on the Internet were identified. Their active ingredients included yohimbine, maca, horny goat weed and Ginkgo biloba. These four substances were reported with the occurrence of adverse events and the induction of psychological symptoms, such as mood changes, anxiety, and hallucinations as well as addictive behaviours. Conclusions. Uncontrolled availability of sexual enhancement products that contain potentially harmful substances is a major public health concern. The possible impact on population health, particularly among subjects with psychiatric disorders, usually at risk for sexual dysfunction, may be significant. This new trend needs to be extensively studied and monitored. Ornella Corazza, Giovanni Martinotti, Rita Santacroce, Eleonora Chillemi, Massimo Di Giannantonio, Fabrizio Schifano, and Selim Cellek Copyright © 2014 Ornella Corazza et al. All rights reserved. Quercetin Significantly Inhibits the Metabolism of Caffeine, a Substrate of Cytochrome P450 1A2 Unrelated to   (−2964G>A) and (734C>A) Gene Polymorphisms Sun, 15 Jun 2014 08:11:35 +0000 Background. Quercetin is abundant in plants and human diets. Previous studies indicated that quercetin inhibited the activity of CYP1A2, and the combination of quercetin with the substrates of CYP1A2 might produce herb-drug interactions. This research aims to determine the effects of quercetin and the CYP1A2 gene polymorphisms, namely,   (−2964G>A) and (734C>A), on the metabolism of caffeine. Method. The experiment was designed into two treatment phases separated by a 2-week washout period. Six homozygous individuals for the (GG/AA) genotype and 6 heterozygous individuals for the (GA/CA) genotype were enrolled in the study. Quercetin capsules (500 mg) were given to each volunteer once daily for 13 consecutive days, and after that, each subject was coadministrated 100 mg caffeine capsules with 500 mg quercetin on the 14th day. Then a series of venous blood samples were collected for HPLC analysis. Correlation was determined between pharmacokinetics of caffeine and paraxanthine with caffeine metabolite ratio. Results. Quercetin significantly affected the pharmacokinetics of caffeine and its main metabolite paraxanthine, while no differences were found in the pharmacokinetics of caffeine and paraxanthine between GG/AA and GA/CA genotype groups. Conclusion. Quercetin significantly inhibits the caffeine metabolism, which is unrelated to (−2964G>A) and (734C>A) gene polymorphisms. Jian Xiao, Wei-Hua Huang, Jing-Bo Peng, Zhi-Rong Tan, Dong-Sheng Ou-Yang, Dong-Li Hu, Wei Zhang, and Yao Chen Copyright © 2014 Jian Xiao et al. All rights reserved. Investigation of Antiarthritic Potential of Plumeria alba L. Leaves in Acute and Chronic Models of Arthritis Sun, 15 Jun 2014 06:20:32 +0000 Aim. The present investigation was designed to evaluate antiarthritic potential of fractions of hydroalcoholic extract from leaves of P. alba. Materials and Methods. Plumeria alba L. leaves were extracted with hydroalcohol (30 : 70) to obtain hydroalcoholic extract of P. alba. This extract was further fractionated with solvents ethyl acetate and n-butanol to obtain EAPA and BPA, respectively. These fractions were tested against formaldehyde and Freund’s complete adjuvant (FCA) induced arthritis. Arthritis assessment, paw volume, body weight, motor incoordination, and nociceptive threshold were measured. On day 21, the animals were sacrificed and histopathology was done. Results. The 100 and 200 mg/kg doses of EAPA and BPA caused a significant () reduction in paw swelling in both models. Erythrocyte sedimentation rate (ESR) and spleen weight decreased significantly () in arthritic rats treated with extracts. There was significant () improvement in thymus weight in EAPA treated rats whereas significant () improvement was also seen in haemoglobin level (Hb) in diclofenac treated group. Motor incoordination and nociceptive threshold were also significantly () improved. Conclusion. The present study suggests that Plumeria alba L. has protective activity against arthritis and supports the traditional use of P. alba for rheumatism and other inflammatory diseases. Manjusha Choudhary, Vipin Kumar, Pankaj Gupta, and Surender Singh Copyright © 2014 Manjusha Choudhary et al. All rights reserved. p53 Is a Key Regulator for Osthole-Triggered Cancer Pathogenesis Thu, 12 Jun 2014 12:57:31 +0000 Osthole has been reported to have antitumor activities via the induction of apoptosis and inhibition of cancer cell growth and metastasis. However, the detailed molecular mechanisms underlying the anticancer effects of osthole in human colon cancer remain unclear. In the present study, we have assessed osthole-induced cell death in two different human colon cancer cell lines, HCT116 and SW480. Our results also showed that osthole activated proapoptotic signaling pathways in human colon cancer cells. By using cell culture insert system, osthole reduced cell motility in both human colon cancer cell lines. This study also provides evidence supporting the potential of osthole in p53 activation. Expression of p53, an apoptotic protein, was remarkably upregulated in cells treated with osthole. Importantly, the levels of phosphorylation of p53 on Ser15 (p-p53) and acetylation of p53 on Lys379 (acetyl-p53) were increased under osthole treatment. Our results also demonstrated that p53 was activated followed by generation of reactive oxygen species (ROS) and activation of c-Jun N-terminal kinase (JNK). Our study provides novel insights of p53-mediated responses under osthole treatment. Taken together, we concluded that osthole induces cancer cell death and inhibits migratory activity in a controlled manner and is a promising candidate for antitumor drug development. Ssu-Ming Huang, Cheng-Fang Tsai, Dar-Ren Chen, Min-Ying Wang, and Wei-Lan Yeh Copyright © 2014 Ssu-Ming Huang et al. All rights reserved. Targeting the Glutamatergic System to Treat Pathological Gambling: Current Evidence and Future Perspectives Thu, 12 Jun 2014 09:41:38 +0000 Pathological gambling or gambling disorder has been defined by the DSM-5 as a behavioral addiction. To date, its pathophysiology is not completely understood and there is no FDA-approved treatment for gambling disorders. Glutamate is the principal excitatory neurotransmitter in the nervous system and it has been recently involved in the pathophysiology of addictive behaviors. In this paper, we review the current literature on a class of drugs that act as modulating glutamate system in PG. A total of 19 studies have been included, according to inclusion and exclusion criteria. Clinical trial and case series using glutamatergic drugs (N-acetylcysteine, memantine, amantadine, topiramate, acamprosate, baclofen, gabapentin, pregabalin, and modafinil) will be presented to elucidate the effectiveness on gambling behaviors and on the related clinical dimensions (craving, withdrawal, and cognitive symptoms) in PG patients. The results have been discussed to gain more insight in the pathophysiology and treatment of PG. In conclusion, manipulation of glutamatergic neurotransmission appears to be promising in developing improved therapeutic agents for the treatment of gambling disorders. Further studies are required. Finally, we propose future directions and challenges in this research area. Mauro Pettorruso, Luisa De Risio, Giovanni Martinotti, Marco Di Nicola, Filippo Ruggeri, Gianluigi Conte, Massimo Di Giannantonio, and Luigi Janiri Copyright © 2014 Mauro Pettorruso et al. All rights reserved. Synthesis and Antihypertensive Screening of New Derivatives of Quinazolines Linked with Isoxazole Thu, 12 Jun 2014 08:53:44 +0000 A series of 7-substituted-3-(4-(3-(4-substitutedphenyl)-4,5-dihydroisoxazol-5-yl)phenyl)-2-substituted quinazolin-4(3H)-one (1–30) have been synthesized by the cyclization of (E)-3-(4-(3-substitutedphenyl)acrylolyl)phenyl)-2-(substitutedphenyl)-7-substituted quinazolin-4-(3H)-one with hydroxylamine hydrochloride. The synthesized compounds were examined for their in vivo antihypertensive activity using albino rats. All the titled compounds exhibited good to moderate antihypertensive activity. Compounds 7-Chloro-3-(4-(3-(4-chlorophenyl)-4,5- dihydroisoxazol-5-yl)phenyl)-2-p-tolylquinazolin-4(3H)-one (23) and 7-Chloro-3-(4-(3-(4-chlorophenyl)-4,5-dihydroisoxazol-5-yl)phenyl)-2-(4-methoxyphenyl)quinazolin-4(3H)-one (24) exhibited potent antihypertensive activity through their anticipated α1-adrenergic receptor blocking property similar to its clinically used analogue, prazosin, without affecting heart rate with prolonged duration of action when tested in adrenaline induced hypertension in anaesthetized rats. Mujeeb Ur Rahman, Ankita Rathore, Anees A. Siddiqui, Gazala Parveen, and M. Shahar Yar Copyright © 2014 Mujeeb Ur Rahman et al. All rights reserved. Effect of the Zataria multiflora on Systemic Inflammation of Experimental Animals Model of COPD Wed, 11 Jun 2014 11:46:04 +0000 The effects of Zataria multiflora (Z. multiflora) on systemic inflammation in guinea pigs model of COPD were examined. Control animals, COPD (induced by exposing animals to cigarette smoke), COPD + drinking water containing three concentrations of the extract of Z. multiflora, and COPD + dexamethasone were studied ( for each group). Serum levels of IL-8 and malondialdehyde (MDA), total blood WBC ( for all cases), and eosinophil counts () were higher and weight changes () were lower in the COPD group compared to controls. IL-8 level () and weight changes ( to ) in all treated groups with Z. multiflora and total WBC number and MDA level in treated groups with two higher concentrations of the extract and lymphocytes percentage () in the highest concentration of Z. multiflora and dexamethasone ( to ) were significantly improved compared to the COPD group. Results showed a preventive effect of hydroethanolic extract from Z. multiflora on all measured parameters in animals model of COPD which was comparable or even higher (in the highest concentration) compared to the effect of dexamethasone at the concentration used. Mohammad Hossein Boskabady and Lilla Gholami Mhtaj Copyright © 2014 Mohammad Hossein Boskabady and Lilla Gholami Mhtaj. All rights reserved. Hepatoprotective Effect of Superfine Particles of Herbal Medicine against CCl4-Induced Acute Liver Damage in Rats Mon, 09 Jun 2014 12:51:28 +0000 This study aimed to examine the hepatoprotective effects of the superfine particles of Radix Tetrastigma (SPRT) against CCl4-induced acute liver damage in rats. Animals were treated with SPRT (0.3, 0.6, and 1.2 g/kg) and showed remarkable hepatoprotection against CCl4-induced hepatotoxicity. CCl4 altered various biochemical parameters in rat liver, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), malondialdehyde (MDA), superoxide dismutase (SOD), histopathological changes, and Bax and caspase-3 expressions. SPRT significantly prevented increases in ALT and AST levels, reduced MDA level, decreased Bax and caspase-3 protein expression, enhanced SOD activity, and provided significant amelioration in the histopathological lesions. These findings suggested that SPRT has significant protective effect against acute hepatotoxicity induced by CCl4 in rats. Gang Cao, Qinglin Li, Xiaocheng Chen, Hao Cai, and Sicong Tu Copyright © 2014 Gang Cao et al. All rights reserved. Sodium Is Not Required for Chloride Efflux via Chloride/Bicarbonate Exchanger from Rat Thymic Lymphocytes Mon, 09 Jun 2014 09:11:40 +0000 Sodium-dependent Cl−/ exchanger acts as a chloride (Cl−) efflux in lymphocytes. Its functional characterization had been described when Cl− efflux was measured upon substituting extracellular sodium (Na+) by N-methyl-D-glucamine (NMDG). For Na+ and Cl− substitution, we have used D-mannitol or NMDG. Thymocytes of male Wistar rats aged 7–9 weeks were used and intracellular Cl− was measured by spectrofluorimetry using MQAE dye in bicarbonate buffers. Chloride efflux was measured in a Cl−-free buffer (Cl− substituted with isethionate acid) and in Na+ and Cl−-free buffer with D-mannitol or with NMDG. The data have shown that Cl− efflux is mediated in the absence of Na+ in a solution containing D-mannitol and is inhibited by H2DIDS. Mathematical modelling has shown that Cl− efflux mathematical model parameters (relative membrane permeability, relative rate of exchanger transition, and exchanger efficacy) were the same in control and in the medium in which Na+ had been substituted by D-mannitol. The net Cl− efflux was completely blocked in the NMDG buffer. The same blockage of Cl− efflux was caused by H2DIDS. The study results allow concluding that Na+ is not required for Cl− efflux via Cl−/ exchanger. NMDG in buffers cannot be used for substituting Na+ because NMDG inhibits the exchanger. Donatas Stakišaitis, Vaidevutis Meilus, Alfonsas Juška, Paulius Matusevičius, and Janina Didžiapetrienė Copyright © 2014 Donatas Stakišaitis et al. All rights reserved. Essential Oils and Their Constituents as Anticancer Agents: A Mechanistic View Mon, 09 Jun 2014 08:19:27 +0000 Exploring natural plant products as an option to find new chemical entities as anticancer agents is one of the fastest growing areas of research. Recently, in the last decade, essential oils (EOs) have been under study for their use in cancer therapy and the present review is an attempt to collect and document the available studies indicating EOs and their constituents as anticancer agents. This review enlists nearly 130 studies of EOs from various plant species and their constituents that have been studied so far for their anticancer potential and these studies have been classified as in vitro and in vivo studies for EOs and their constituents. This review also highlights in-depth various mechanisms of action of different EOs and their constituents reported in the treatment strategies for different types of cancer. The current review indicates that EOs and their constituents act by multiple pathways and mechanisms involving apoptosis, cell cycle arrest, antimetastatic and antiangiogenic, increased levels of reactive oxygen and nitrogen species (ROS/RNS), DNA repair modulation, and others to demonstrate their antiproliferative activity in the cancer cell. The effect of EOs and their constituents on tumour suppressor proteins (p53 and Akt), transcription factors (NF-κB and AP-1), MAPK-pathway, and detoxification enzymes like SOD, catalase, glutathione peroxidase, and glutathione reductase has also been discussed. Nandini Gautam, Anil K. Mantha, and Sunil Mittal Copyright © 2014 Nandini Gautam et al. All rights reserved. Efficacy of Annona squamosa L in the Synthesis of Glycosaminoglycans and Collagen during Wound Repair in Streptozotocin Induced Diabetic Rats Mon, 09 Jun 2014 06:08:34 +0000 The aim of this work was to find out the effects of Annona squamosa on the formation of glycosaminoglycans and collagen during wound healing in normal and diabetic rats. Diabetes induced rats were segregated into 4 groups, each containing six animals. Groups I and III served as the normal and diabetic control while groups II and IV served as normal and diabetic treated. The animals were treated with 200 μL of Annona squamosa extract topically. The granulation tissues formed were removed on the 8th day and the amount of glycosaminoglycans (GAGs) and collagen formed was evaluated by sequential extraction and SDSPAGE, respectively. Histological evaluation was also carried out using Masson's trichrome stain. In vitro wound healing efficacy of A. squamosa in human dermal fibroblast culture (HDF) was also carried out. The fibroblasts treated with varying concentrations of A. squamosa were examined for proliferation and closure of the wound area and photographed. A. squamosa increased cellular proliferation in HDF culture. The granulation tissues of treated wounds showed increased levels of glycosaminoglycans and collagen which were also confirmed by histopathology. The results strongly substantiate the beneficial effects of A. squamosa on the formation of glycosaminoglycans and collagen during wound healing. Thangavel Ponrasu and Lonchin Suguna Copyright © 2014 Thangavel Ponrasu and Lonchin Suguna. All rights reserved. Pleurodesis Induction in Rats by Copaiba (Copaifera multijuga Hayne) Oil Mon, 09 Jun 2014 00:00:00 +0000 This study aims to assess and compare copaiba oleoresin of Copaifera multijuga and 0.5% silver nitrate for the induction of pleurodesis in an experimental model. Ninety-six male Wistar rats were divided into three groups: control (0.9% saline solution), copaiba (copaiba oil), and silver nitrate (0.5% silver nitrate). The substances were injected into the right pleural cavity and the alterations were observed macroscopically and microscopically at 24, 48, 72, and 504 h. The value of macroscopic alterations grade and acute inflammatory reaction grade means was higher in the 24 h copaiba group in relation to silver nitrate. Fibrosis and neovascularization means in the visceral pleura were higher in 504 h copaiba group in relation to the silver nitrate group. The grade of the alveolar edema mean was higher in the silver nitrate group in relation to the copaiba group, in which this alteration was not observed. The presence of bronchopneumonia was higher in the 24 h silver nitrate group () in relation to the copaiba group (). In conclusion, both groups promoted pleurodesis, with better results in copaiba group and the silver nitrate group presented greater aggression to the pulmonary parenchyma. Fernando Luiz Westphal, Mauro Canzian, Fabio Alessandro Pieri, Alfredo Coimbra Reichl, Paulo Manuel Pêgo-Fernandes, Luis Carlos Lima, and Valdir F. Veiga-Junior Copyright © 2014 Fernando Luiz Westphal et al. All rights reserved. Iminoflavones Combat 1,2-Dimethyl Hydrazine-Induced Aberrant Crypt Foci Development in Colon Cancer Thu, 05 Jun 2014 13:26:22 +0000 The aim of the present study was to evaluate the antitumor potential of iminoflavones in in vitro and in vivo anticancer models. Preliminary screening in various cancer cell lines revealed four potential iminoflavones out of which IMF-8 was taken based on its activity against colon cancer cells. This was further confirmed by observing the nuclear changes in the cells by AO/EB and Hoechst 33342 staining studies. In vivo activity was assessed by dimethyl hydrazine-(DMH-) induced colon cancer model in rats. Animals were administered DMH (20 mg/kg, b.w. for 10 weeks and 30 mg/kg b.w., i.p. for 10 weeks) and were supplemented with (IMF-8) iminoflavone-8 (200 mg/kg, p.o. for 14 days). Results showed that DMH induced 100% aberrant crypt foci (ACF) and polyps which were significantly reduced in the IMF-8 treated group. IMF-8 significantly increased the catalase and GSH levels whereas it reduced the TNF-α and IL-6 levels markedly which suggests the antioxidative and anti-inflammatory actions of flavonoids present in IMF-8. The histopathological images of the IMF-8 treated colon showed no signs of mucosal crypt abscess. These findings suggest that the semi-synthetic iminoflavones, IMF-8, effectively inhibit DMH-induced ACFs and colonic crypts by alleviating the oxidative stress and suppressing the inflammation. V. Ganga Prasad, Shishir Kawade, B. S. Jayashree, Neetinkumar D. Reddy, Albi Francis, Pawan G. Nayak, Anoop Kishore, K. Nandakumar, C. Mallikarjuna Rao, and Rekha R. Shenoy Copyright © 2014 V. Ganga Prasad et al. All rights reserved. Nanotechnology-Applied Curcumin for Different Diseases Therapy Thu, 05 Jun 2014 08:44:13 +0000 Curcumin is a lipophilic molecule with an active ingredient in the herbal remedy and dietary spice turmeric. It is used by different folks for treatment of many diseases. Recent studies have discussed poor bioavailability of curcumin because of poor absorption, rapid metabolism, and rapid systemic elimination. Nanotechnology is an emerging field that is potentially changing the way we can treat diseases through drug delivery with curcumin. The recent investigations established several approaches to improve the bioavailability, to increase the plasma concentration, and to enhance the cellular permeability processes of curcumin. Several types of nanoparticles have been found to be suitable for the encapsulation or loading of curcumin to improve its therapeutic effects in different diseases. Nanoparticles such as liposomes, polymeric nanoparticles, micelles, nanogels, niosomes, cyclodextrins, dendrimers, silvers, and solid lipids are emerging as one of the useful alternatives that have been shown to deliver therapeutic concentrations of curcumin. This review shows that curcumin’s therapeutic effects may increase to some extent in the presence of nanotechnology. The presented board of evidence focuses on the valuable special effects of curcumin on different diseases and candidates it for future clinical studies in the realm of these diseases. Negar Ghalandarlaki, Ali Mohammad Alizadeh, and Soheil Ashkani-Esfahani Copyright © 2014 Negar Ghalandarlaki et al. All rights reserved. Diazepam Potentiates the Antidiabetic, Antistress and Anxiolytic Activities of Metformin in Type-2 Diabetes Mellitus with Cooccurring Stress in Experimental Animals Wed, 04 Jun 2014 11:51:26 +0000 Psychological stress is considered as one of the limiting factors in the management of type-2 diabetes mellitus (T2DM). Therefore, the basic objective of the present study was to evaluate the antidiabetic effect of metformin, diazepam, and their combination in cooccurring T2DM and stress condition (DMS). T2DM was induced in the male rats by administering streptozotocin (45 mg/kg, i.p.) and nicotinamide (110 mg/kg, i.p.) with time lag of 15 min. Rats were subjected to two sessions of cold restraint stress paradigm for one hour on the sixth and seventh day after streptozotocin injection. Administration of metformin (25 mg/kg, p.o.) and diazepam (1 mg/kg, p.o.) in combination from the seventh to thirteenth day after streptozotocin injection showed better improvement in glucose tolerance and insulin sensitivity compared to monotherapy of either drug. In addition, the combination significantly attenuated DMS-induced hyperglycemia, hypertriglyceridaemia, hypercorticosteronemia, anxiety-like behavior, and insulin resistance through modulating insulin signaling pathway in the liver compared to monotherapy. Further, improvement of mitochondrial function, integrity, and oxidative stress in hippocampus, hypothalamus, prefrontal cortex, striatum, amygdala, and nucleus accumbens was observed with the combination. Therefore, metformin in combination with diazepam may be a better therapeutic option in the management of T2DM with cooccurring stress condition. Debapriya Garabadu and Sairam Krishnamurthy Copyright © 2014 Debapriya Garabadu and Sairam Krishnamurthy. All rights reserved. Carvedilol Ameliorates Early Diabetic Nephropathy in Streptozotocin-Induced Diabetic Rats Wed, 04 Jun 2014 07:35:53 +0000 Diabetic nephropathy results in end-stage renal disease. On the other hand, carvedilol has been reported to have various pharmacological properties. The aim of this study therefore is to evaluate the possible protective effect of carvedilol on streptozotocin-induced early diabetic nephropathy and various mechanisms underlie this effect in rats. Single i.p. injection of streptozotocin (65 mg/kg) was administered to induce early diabetic nephropathy in Wistar rats. Oral administration of carvedilol at a dose level of 1 and 10 mg/kg daily for 4 weeks resulted in nephroprotective effect as evident by significant decrease in serum creatinine level, urinary albumin/creatinine ratio, and kidney index as well as renal levels of malondialdehyde, nitric oxide, tumor necrosis factor-α, and cyclooxygenase-2 with a concurrent increase in creatinine clearance and renal reduced glutathione level compared to diabetic untreated rats. The protective effect of carvedilol was confirmed by renal histopathological examination. The electron microscopic examination indicated that carvedilol could effectively ameliorate glomerular basement membrane thickening and podocyte injury. In conclusion, carvedilol protects rats against streptozotocin-induced early diabetic nephropathy possibly, in part, through its antioxidant as well as anti-inflammatory activities, and ameliorating podocyte injury. Mohamed A. Morsy, Salwa A. Ibrahim, Entesar F. Amin, Maha Y. Kamel, Soha A. Abdelwahab, and Magdy K. Hassan Copyright © 2014 Mohamed A. Morsy et al. All rights reserved. Synthesis, Characterization, and Preclinical Evaluation of New Thiazolidin-4-ones Substituted with p-Chlorophenoxy Acetic Acid and Clofibric Acid against Insulin Resistance and Metabolic Disorder Tue, 03 Jun 2014 09:05:47 +0000 We synthesized twenty thiazolidin-4-one derivatives, which were then characterized by standard chromatographic and spectroscopic methods. From the in vitro glucose uptake assay, two compounds behaved as insulin sensitizers, where they enhanced glucose uptake in isolated rat diaphragm. In high-carbohydrate diet-induced insulin resistant mice, these two thiazolidin-4-ones attenuated hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia, and glucose intolerance. They raised the plasma leptin but did not reverse the diabetes-induced hypoadiponectinemia. Additionally, compound 3a reduced adiposity. The test compounds were also able to reverse the disturbed liver antioxidant milieu. To conclude, these two novel thiazolidin-4-ones modulated multiple mechanisms involved in metabolic disorders, reversing insulin resistance and thus preventing the development of type-2 diabetes. Vasantharaju S. Gowdra, Jayesh Mudgal, Punit Bansal, Pawan G. Nayak, Seethappa A. Manohara Reddy, Gautham G. Shenoy, Manna Valiathan, Mallikarjuna R. Chamallamudi, and Gopalan K. Nampurath Copyright © 2014 Vasantharaju S. Gowdra et al. All rights reserved. In Silico Molecular Docking and In Vitro Antidiabetic Studies of Dihydropyrimido[4,5-a]acridin-2-amines Mon, 02 Jun 2014 09:09:38 +0000 An in vitro antidiabetic activity on α-amylase and α–glucosidase activity of novel 10-chloro-4-(2-chlorophenyl)-12-phenyl-5,6-dihydropyrimido[4,5-a]acridin-2-amines (3a–3f) were evaluated. Structures of the synthesized molecules were studied by FT-IR, 1H NMR, 13C NMR, EI-MS, and single crystal X-ray structural analysis data. An in silico molecular docking was performed on synthesized molecules (3a–3f). Overall studies indicate that compound 3e is a promising compound leading to the development of selective inhibition of α-amylase and α-glucosidase. A. Bharathi, Selvaraj Mohana Roopan, C. S. Vasavi, Punnagai Munusami, G. A. Gayathri, and M. Gayathri Copyright © 2014 A. Bharathi et al. All rights reserved. Effect of Alocasia indica Tuber Extract on Reducing Hepatotoxicity and Liver Apoptosis in Alcohol Intoxicated Rats Thu, 29 May 2014 12:09:05 +0000 The possible protective role of ethanolic extract of A. indica tuber (EEAIT) in hepatotoxicity and apoptosis of liver caused by alcohol in rats was investigated. Treatment of rats with alcohol (3 g ethanol per kg body weight per day for 15 days intraperitoneally) produced marked elevation of liver biomarkers such as serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), -glutamyl transpeptidase (-GT), and total bilirubin levels which were reduced by EEAIT in a dose-dependent manner. Furthermore, EEAIT improved antioxidant status (MDA, NO, and GSH) and preserved hepatic cell architecture. Simultaneous supplementation with EEAIT significantly restored hepatic catalase (CAT) and superoxide dismutase (SOD) activity levels towards normal. The studies with biochemical markers were strongly supported by the histopathological evaluation of the liver tissue. EEAIT also attenuated apoptosis and necrosis features of liver cell found in immunohistochemical evaluation. HPLC analysis of the extract showed the presence of three major peaks of which peak 2 (RT: 33.33 min) contains the highest area (%) and UV spectrum analysis identified it as flavonoids. It is therefore suggested that EEAIT can provide a definite protective effect against chronic hepatic injury caused by alcohol in rats, which may mainly be associated with its antioxidative effect. Swagata Pal, Ankita Bhattacharjee, Sandip Mukherjee, Koushik Bhattacharya, Soumya Mukherjee, and Suman Khowala Copyright © 2014 Swagata Pal et al. All rights reserved. Purification and Characterization of BmooAi: A New Toxin from Bothrops moojeni Snake Venom That Inhibits Platelet Aggregation Thu, 29 May 2014 07:35:20 +0000 In this paper, we describe the purification/characterization of BmooAi, a new toxin from Bothrops moojeni that inhibits platelet aggregation. The purification of BmooAi was carried out through three chromatographic steps (ion-exchange on a DEAE-Sephacel column, molecular exclusion on a Sephadex G-75 column, and reverse-phase HPLC chromatography on a C2/C18 column). BmooAi was homogeneous by SDS-PAGE and shown to be a single-chain protein of 15,000 Da. BmooAi was analysed by MALDI-TOF Spectrometry and revealed two major components with molecular masses 7824.4 and 7409.2 as well as a trace of protein with a molecular mass of 15,237.4 Da. Sequencing of BmooAi by Edman degradation showed two amino acid sequences: IRDFDPLTNAPENTA and ETEEGAEEGTQ, which revealed no homology to any known toxin from snake venom. BmooAi showed a rather specific inhibitory effect on platelet aggregation induced by collagen, adenosine diphosphate, or epinephrine in human platelet-rich plasma in a dose-dependent manner, whereas it had little or no effect on platelet aggregation induced by ristocetin. The effect on platelet aggregation induced by BmooAi remained active even when heated to 100°C. BmooAi could be of medical interest as a new tool for the development of novel therapeutic agents for the prevention and treatment of thrombotic disorders. Mayara Ribeiro de Queiroz, Carla Cristine N. Mamede, Nadia Cristina G. de Morais, Kelly Cortes Fonseca, Bruna Barbosa de Sousa, Thaís M. Migliorini, Déborah Fernanda C. Pereira, Leonilda Stanziola, Leonardo A. Calderon, Rodrigo Simões-Silva, Andreimar Martins Soares, and Fábio de Oliveira Copyright © 2014 Mayara Ribeiro de Queiroz et al. All rights reserved. Roles of Renal Proximal Tubule Transport in Acid/Base Balance and Blood Pressure Regulation Wed, 28 May 2014 10:36:54 +0000 Sodium-coupled bicarbonate absorption from renal proximal tubules (PTs) plays a pivotal role in the maintenance of systemic acid/base balance. Indeed, mutations in the Na+-HC cotransporter NBCe1, which mediates a majority of bicarbonate exit from PTs, cause severe proximal renal tubular acidosis associated with ocular and other extrarenal abnormalities. Sodium transport in PTs also plays an important role in the regulation of blood pressure. For example, PT transport stimulation by insulin may be involved in the pathogenesis of hypertension associated with insulin resistance. Type 1 angiotensin (Ang) II receptors in PT are critical for blood pressure homeostasis. Paradoxically, the effects of Ang II on PT transport are known to be biphasic. Unlike in other species, however, Ang II is recently shown to dose-dependently stimulate human PT transport via nitric oxide/cGMP/ERK pathway, which may represent a novel therapeutic target in human hypertension. In this paper, we will review the physiological and pathophysiological roles of PT transport. Motonobu Nakamura, Ayumi Shirai, Osamu Yamazaki, Nobuhiko Satoh, Masashi Suzuki, Shoko Horita, Hideomi Yamada, and George Seki Copyright © 2014 Motonobu Nakamura et al. All rights reserved. Antioxidant Potential, DNA Protection, and HPLC-DAD Analysis of Neglected Medicinal Jurinea dolomiaea Roots Wed, 28 May 2014 06:44:01 +0000 Jurinea dolomiaea Boiss., family Compositae, is a medicinally important plant of alpine region. Its tuberous roots are used in various ailments in folk medicine. This study was undertaken to estimate total phenolic (TPC) and total flavonoid contents (TFC) and to determine anti-free radical potential by diverse in vitro antioxidant assays. Crude methanol extract (JDME) was fractionated into n-hexane (JDHE), chloroform (JDCE), ethyl acetate (JDEE), n-butanol (JDBE), and aqueous (JDAE) fractions. The results indicated that JDEE and JDCE constituted the highest amount of TFC ( mg rutin equivalent/g sample) and TPC ( mg gallic acid equivalent/g sample), respectively. Significant correlation of TFC with IC50 values was recorded for •OH (), H2O2 (), and ABTS () assay. It could be made clear that JDEE was the most potent in antioxidant activity as compared to others, with generally lower IC50 values for DPPH ( μg/mL), ABTS ( μg/mL), H2O2 ( μg/mL), •OH ( μg/mL), ( μg/mL), and antilipid peroxidation ( μg/mL). HPLC chromatogram of JDEE revealed the presence of catechin, caffeic acid, and rutin. The results indicated the antioxidant activities of J. dolomiaea roots and merit further investigations for their use in oxidative stress related disorders. Naseer Ali Shah, Muhammad Rashid Khan, Kiran Naz, and Mubarak Ali Khan Copyright © 2014 Naseer Ali Shah et al. All rights reserved. Antiartherosclerotic Effects of Plant Flavonoids Tue, 27 May 2014 10:58:35 +0000 Atherosclerosis is the process of hardening and narrowing the arteries. Atherosclerosis is generally associated with cardiovascular diseases such as strokes, heart attacks, and peripheral vascular diseases. Since the usage of the synthetic drug, statins, leads to various side effects, the plants flavonoids with antiartherosclerotic activity gained much attention and were proven to reduce the risk of atherosclerosis in vitro and in vivo based on different animal models. The flavonoids compounds also exhibit lipid lowering effects and anti-inflammatory and antiatherogenic properties. The future development of flavonoids-based drugs is believed to provide significant effects on atherosclerosis and its related diseases. This paper discusses the antiatherosclerotic effects of selected plant flavonoids such as quercetin, kaempferol, myricetin, rutin, naringenin, catechin, fisetin, and gossypetin. Shamala Salvamani, Baskaran Gunasekaran, Noor Azmi Shaharuddin, Siti Aqlima Ahmad, and Mohd Yunus Shukor Copyright © 2014 Shamala Salvamani et al. All rights reserved. Individual Differences in Gambling Proneness among Rats and Common Marmosets: An Automated Choice Task Tue, 27 May 2014 07:03:19 +0000 Interest is rising for animal modeling of pathological gambling. Using the operant probabilistic-delivery task (PDT), gambling proneness can be evaluated in laboratory animals. Drawing a comparison with rats, this study evaluated the common marmoset (Callithrix jacchus) using a PDT. By nose- or hand-poking, subjects learnt to prefer a large (LLL, 5-6 pellets) over a small (SS, 1-2 pellets) reward and, subsequently, the probability of occurrence of large-reward delivery was decreased progressively to very low levels (from 100% to 17% and 14%). As probability decreased, subjects showed a great versus little shift in preference from LLL to SS reinforcer. Hence, two distinct subpopulations (“non-gambler” versus “gambler”) were differentiated within each species. A proof of the model validity comes from marmosets’ reaction to reward-delivery omission. Namely, depending on individual temperament (“gambler” versus “non-gambler”), they showed either persistence (i.e., inadequate pokes towards LLL) or restlessness (i.e., inadequate pokes towards SS), respectively. In conclusion, the marmoset could be a suitable model for preclinical gambling studies. Implementation of the PDT to species other than rats may be relevant for determining its external validity/generalizability and improving its face/construct validity. Francesca Zoratto, Emma Sinclair, Arianna Manciocco, Augusto Vitale, Giovanni Laviola, and Walter Adriani Copyright © 2014 Francesca Zoratto et al. All rights reserved. Biochemical and Neurotransmitters Changes Associated with Tramadol in Streptozotocin-Induced Diabetes in Rats Mon, 26 May 2014 11:06:31 +0000 The incidence of diabetes is increasing worldwide. Chronic neuropathic pain occurs in approximately 25% of diabetic patients. Tramadol, an atypical analgesic with a unique dual mechanism of action, is used in the management of painful diabetic neuropathy. It acts on monoamine transporters to inhibit the reuptake of norepinephrine (NE), serotonin (5-HT), and dopamine (DA). The purpose of this study was to evaluate the effects of diabetes on the brain neurotransmitter alterations induced by tramadol in rats, and to study the hepatic and renal toxicities of the drug. Eighty Sprague-Dawley rats were divided randomly into two sets: the normal set and the diabetic set. Diabetes was induced in rats. Tramadol was administered orally once daily for 28 days. The levels of DA, NE, and 5-HT in cerebral cortex, thalamus/hypothalamus, midbrain, and brainstem were evaluated in rats. In addition, the renal toxicity and histopathological effects of the drug were assessed. The induction of diabetes altered neurotransmitter levels. Oral administration of tramadol significantly decreased the neurotransmitter levels. Diabetes significantly altered the effects of tramadol in all brain regions. Tramadol affected function and histology of the liver and kidney. The clinical effects of tramadol in diabetic patients should be stressed. Essam Ezzeldin, Wafaa A. H. Souror, Toqa El-Nahhas, Abdel Nasser M. M. Soudi, and Abdelaaty A. Shahat Copyright © 2014 Essam Ezzeldin et al. All rights reserved. Synthesis and Anticancer Activity of N-Aryl-5-substituted-1,3,4-oxadiazol-2-amine Analogues Mon, 26 May 2014 06:43:33 +0000 In continuance of our search for anticancer agents, we report herein the synthesis and anticancer activity of some novel oxadiazole analogues. The compounds were screened for anticancer activity as per National Cancer Institute (NCI US) protocol on leukemia, melanoma, lung, colon, CNS, ovarian, renal, prostate, and breast cancers cell lines. N-(2,4-Dimethylphenyl)-5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-amine (4s) showed maximum activity with mean growth percent (GP) of 62.61 and was found to be the most sensitive on MDA-MB-435 (melanoma), K-562 (leukemia), T-47D (breast cancer), and HCT-15 (colon cancer) cell lines with GP of 15.43, 18.22, 34.27, and 39.77, respectively. Maximum GP was observed on MDA-MB-435 (melanoma) cell line () by compound N-(2,4-dimethylphenyl)-5-(4-hydroxyphenyl)-1,3,4-oxadiazol-2-amine (4u). Mohamed Jawed Ahsan, Jyotika Sharma, Monika Singh, Surender Singh Jadav, and Sabina Yasmin Copyright © 2014 Mohamed Jawed Ahsan et al. All rights reserved. Antiphospholipid Antibodies in Women Undergoing In Vitro Fertilization Treatment: Clinical Value of IgA Anti-β2glycoprotein I Antibodies Determination Sun, 25 May 2014 12:42:50 +0000 Implantation failure could be related to antiphospholipid antibodies (aPL). We retrospectively analyzed the usefulness of aPL determination in women undergoing IVF. Conventional aPL of the antiphospholipid syndrome, lupus anticoagulant (LA), anticardiolipin antibodies (aCL), anti-β2glycoprotein I (aβ2GPI) antibodies, and IgG and IgM isotypes as well as IgA isotype were analyzed in women presenting with at least two implantation failures after in vitro fertilization (IVF). In a population of 40 IVF patients, a total prevalence of 20% (8/40) of aPL was found, significantly different from that of the control population (100 healthy blood donors, ). Among the panels of aPL tested, aβ2GPI IgA antibodies were the most prevalent (62.5% 5/8), significantly higher in IVF patients (12.5%, 5/40) than in controls (1%, 1/100) (). No difference according to the numbers of IVF attempts and success of embryo implantation was found between aPL positive and negative IVF patients. In contrast, no accomplished pregnancy with full-term live birth was observed in aPL positive IVF patients. Altogether our data led us to propose aPL assessment, in particular aβ2GPI IgA antibodies, in support of IVF treated women. In a perspective way, an early aPL detection could be the basis for defining novel therapeutic strategy. Odile Paulmyer-Lacroix, Laura Despierres, Blandine Courbiere, and Nathalie Bardin Copyright © 2014 Odile Paulmyer-Lacroix et al. All rights reserved. Bioassay-Guided Isolation and Antioxidant Evaluation of Flavonoid Compound from Aerial Parts of Lippia nodiflora L. Sun, 25 May 2014 07:09:22 +0000 The present study was designed to identify the DPPH (2, 2-diphenyl-1-picrylhydrazyl) free-radical scavenging constituents from methanol extract of L. nodiflora using bioassay-guided fractionation. The ethyl acetate fraction (EAF) revealed a strong antioxidant activity, compared to other fractions through in vitro DPPH radical-scavenging assay. The repeated fractionation of active EAF by silica gel column chromatography yielded a compound with strong antioxidant potential. The isolated bioactive compound was determined as 2-(3, 4-dimethoxyphenyl)-5-hydroxy-7-methoxy-4H-chromen-4-one (5-hydroxy-3′, 4′, 7-trimethoxyflavone), by comparing spectral data (UV, IR, 1H NMR, 13C NMR, and MS) with literature reports. The isolated compound demonstrated an excellent antioxidant activity through all antioxidant assays and also significantly inhibited lipid peroxidation at a concentration of 50 μg/mL. The results obtained suggested that extracts from L. nodiflora or its derived phytocompound can be used potentially as a bioactive source of natural antioxidants by contributing beneficial health effects. A. Sudha and P. Srinivasan Copyright © 2014 A. Sudha and P. Srinivasan. All rights reserved. Research of Electrosurgical Ablation with Antiadhesive Functionalization on Thermal and Histopathological Effects of Brain Tissues In Vivo Thu, 22 May 2014 09:10:12 +0000 Thermal injury and tissue sticking are two major concerns in the electrosurgery. In the present study, the effect of lateral thermal injury caused by different electrosurgical electrodes on wound healing was investigated. An electrosurgical unit equipped with untreated (SS) and titanium oxide layer-coated (TiO2-coated) stainless steel needle-type electrodes was used to create lesions on the rat brain tissue. TiO2 layers were produced by radiofrequency plasma and magnetron sputtering in the form of amorphous (TO-SS-1), anatase (TO-SS-2), and rutile (TO-SS-3) phase. Animals were sacrificed for evaluations at 0, 2, 7, and 28 days postoperatively. TO-SS-3 electrodes generated lower levels of sticking tissue, and the thermographs showed that the recorded highest temperature in brain tissue from the TO-SS-3 electrode was significantly lower than in the SS electrode. The total injury area of brain tissue caused by TO-SS-1 and TO-SS-3 electrodes was significantly lower than that caused by SS electrodes at each time point. The results of the present study reveal that the plating of electrodes with a TiO2 film with rutile phases is an efficient method for improving the performance of electrosurgical units and should benefit wound healing. Wen-Tien Hsiao, Chun-Ming Kung, Jan-Show Chu, Keng-Liang Ou, and Pei-Wen Peng Copyright © 2014 Wen-Tien Hsiao et al. All rights reserved. Antidiabetic Activity of Artemisia amygdalina Decne in Streptozotocin Induced Diabetic Rats Wed, 21 May 2014 11:07:22 +0000 Artemisia species have been extensively used for the management of diabetes in folklore medicine. The current study was designed to investigate the antidiabetic and antihyperlipidemic effects of Artemisia amygdalina. Petroleum ether, ethyl acetate, methanol, and hydroethanolic extracts of Artemisia amygdalina were tested for their antidiabetic potentials in diabetic rats. The effect of extracts was observed by checking the biochemical, physiological, and histopathological parameters in diabetic rats. The hydroethanolic and methanolic extracts each at doses of 250 and 500 mg/kg b. w significantly reduced glucose levels in diabetic rats. The other biochemical parameters like cholesterol, triglycerides, low density lipoproteins (LDL), serum creatinine, serum glutamate pyruvate transaminase (SGPT), serum glutamate oxaloacetate transaminase (SGOT), and alkaline phosphatise (ALP), were found to be reduced by the hydroethanolic and methanolic extracts. The extracts also showed reduction in the feed and water consumption of diabetic rats when compared with the diabetic control. The histopathological results of treated groups showed the regenerative/protective effect on β-cells of pancreas in diabetic rats. The current study revealed the antidiabetic potential of Artemisia amygdalina being effective in hyperglycemia and that it can effectively protect against other metabolic aberrations caused by diabetes in rats, which seems to validate its therapeutic traditional use. Khalid Ghazanfar, Bashir A. Ganai, Seema Akbar, Khan Mubashir, Showkat Ahmad Dar, Mohammad Younis Dar, and Mudasir A. Tantry Copyright © 2014 Khalid Ghazanfar et al. All rights reserved. NGF Accelerates Cutaneous Wound Healing by Promoting the Migration of Dermal Fibroblasts via the PI3K/Akt-Rac1-JNK and ERK Pathways Wed, 21 May 2014 09:33:56 +0000 As a well-known neurotrophic factor, nerve growth factor (NGF) has also been extensively recognized for its acceleration of healing in cutaneous wounds in both animal models and randomized clinical trials. However, the underlying mechanisms accounting for the therapeutic effect of NGF on skin wounds are not fully understood. NGF treatment significantly accelerated the rate of wound healing by promoting wound reepithelialization, the formation of granulation tissue, and collagen production. To explore the possible mechanisms of this process, the expression levels of CD68, VEGF, PCNA, and TGF-1 in wounds were detected by immunohistochemical staining. The levels of these proteins were all significantly raised in NGF-treated wounds compared to untreated controls. NGF also significantly promoted the migration, but not the proliferation, of dermal fibroblasts. NGF induced a remarkable increase in the activity of PI3K/Akt, JNK, ERK, and Rac1, and blockade with their specific inhibitors significantly impaired the NGF-induced migration. In conclusion, NGF significantly accelerated the healing of skin excisional wounds in rats and the fibroblast migration induced by NGF may contribute to this healing process. The activation of PI3K/Akt, Rac1, JNK, and ERK were all involved in the regulation of NGF-induced fibroblast migration. Ji-Cai Chen, Bei-Bei Lin, Hou-Wen Hu, Cai Lin, Wen-Yang Jin, Fa-Biao Zhang, Yan-An Zhu, Cai-Jiao Lu, Xiao-Jie Wei, and Rui-Jie Chen Copyright © 2014 Ji-Cai Chen et al. All rights reserved. In Vitro Antioxidant, Antiproliferative, and Phytochemical Study in Different Extracts of Nyctanthes arbortristis Flowers Tue, 20 May 2014 09:28:25 +0000 Nyctanthes arbortristis L. (Oleaceae) is widely used in the Indian system of traditional medicine and is reported to have various biological activities. The present study was intended to evaluate the antioxidant and antiproliferative activities of flower extracts of Nyctanthes arbortristis. The shade dried flowers were extracted with 95% ethanol under sonication and the antioxidant activities were investigated using in vitro assays along with the determination of phytochemical constituents (total polyphenol and total flavonoid). Arborside C and β-monogentiobioside ester of α-Crocetin were identified in crude active extracts through LCMS/MS analysis. The antiproliferative activity was carried out by MTT assay by employing different human cancer cell lines. The lowest IC50 value of 24.56 ± 6.63 μg/mL was observed against Colo 205 cell line. The extract exhibited significant antioxidant and antiproliferative properties and the observed biological activities in this study provide scientific validation of ethnomedicinal use of this plant. Manjulatha Khanapur, Ravi K. Avadhanula, and Oruganti H. Setty Copyright © 2014 Manjulatha Khanapur et al. All rights reserved. A Quantitative Ethnopharmacological Documentation of Natural Pharmacological Agents Used by Pediatric Patients in Mauritius Mon, 19 May 2014 00:00:00 +0000 The pediatric population constitutes the most vulnerable patients due to a dearth of approved drugs. Consequently, there is a pressing need to probe novel natural pharmacological agents in an endeavour to develop new drugs to address pediatric illnesses. To date, no studies have explored the use of natural therapies for pediatric health care in Mauritius. Parents () from different regions of the island were interviewed. Quantitative indexes such as fidelity level (FL), informant consensus factor (), and use-value (UV) were calculated. Thirty-two plants were reported to be used by pediatric patients. Gastrointestinal disorders () encompassing regurgitation, infantile colic, and stomach aches were the most common ailments managed with herbs. Matricaria chamomilla used for infantile colic and its pharmacological properties has previously been documented for pediatric patients. Product from A. mellifera (UV = 0.75) was the most utilized zootherapy for managing cough. Most plants and animal products reported in this study have bioactive constituents supported by existing scientific literature but their use for the pediatric population is scant. The present ethnopharmacological study has opened new perspectives for further research into their pharmacology, which can subsequently support and facilitate timely pediatric medicinal product development. M. Fawzi Mahomoodally and D. Priyamka Sreekeesoon Copyright © 2014 M. Fawzi Mahomoodally and D. Priyamka Sreekeesoon. All rights reserved. Health-Related Quality of Life and Preferred Health-Seeking Institutions among Rural Elderly Individuals with and without Chronic Conditions: A Population-Based Study in Guangdong Province, China Sun, 18 May 2014 09:02:11 +0000 The aim of this study was to examine health-related quality of life (HRQL) as measured by SF-36 and to identify these factors and the preferred health-seeking institutions of 12,800 persons aged 60 and older with and without chronic conditions in rural areas of Guangdong Province by multistage stratified cluster sampling method. HRQL among rural elderly subjects with chronic conditions was lower than that of elderly subjects with no chronic conditions. Multiple linear regression showed that marital status, living with children, cardiovascular disease, osteoporosis, cataract disease, and mental disease were the main affecting factors of HRQL. The main preferred health-seeking institutions selected by the rural elderly were community/town health service institutions, district hospitals, or secondary hospitals. Our findings indicate that the elderly in rural areas of Guangdong Province have a poor HRQL and incorrect health-seeking pathway. The healthcare policymakers should emphasize the need of developing effective and targeted community services strategies to improve the elderly individuals’ HRQL in rural areas of China. Zhiheng Zhou, Caixia Wang, Huajie Yang, Xiang Wang, Chanjiao Zheng, and Jiaji Wang Copyright © 2014 Zhiheng Zhou et al. All rights reserved. Holoptelea integrifolia (Roxb.) Planch: A Review of Its Ethnobotany, Pharmacology, and Phytochemistry Sun, 18 May 2014 00:00:00 +0000 Holoptelea integrifolia (Ulmaceae) is a versatile medicinal plant used in various indigenous systems of medicine for curing routine healthcare maladies. It is traditionally used in the treatment and prevention of several ailments like leprosy, inflammation, rickets, leucoderma, scabies, rheumatism, ringworm, eczema, malaria, intestinal cancer, and chronic wounds. In vitro and in vivo pharmacological investigations on crude extracts and isolated compounds showed antibacterial, antifungal, analgesic, antioxidant, anti-inflammatory, anthelmintic, antidiabetic, antidiarrhoeal, adaptogenic, anticancer, wound healing, hepatoprotective, larvicidal, antiemetic, CNS depressant, and hypolipidemic activities. Phytochemical analysis showed the presence of terpenoids, sterols, saponins, tannins, proteins, carbohydrates, alkaloids, phenols, flavonoids, glycosides, and quinines. Numerous compounds including Holoptelin-A, Holoptelin-B, friedlin, epifriedlin, β-amyrin, stigmasterol, β-sitosterol, 1, 4-napthalenedione, betulin, betulinic acid, hexacosanol, and octacosanol have been identified and isolated from the plant species. The results of several studies indicated that H. integrifolia may be used as an effective therapeutic remedy in the prevention and treatment of various ailments. However, further studies on chemical constituents and their mechanisms in exhibiting certain biological activities are needed. In addition, study on the toxicity of the crude extracts and the compounds isolated from this plant should be assessed to ensure their eligibility to be used as source of modern medicines. Showkat Ahmad Ganie and Surender Singh Yadav Copyright © 2014 Showkat Ahmad Ganie and Surender Singh Yadav. All rights reserved. Pharmacological Treatments in Gambling Disorder: A Qualitative Review Sun, 18 May 2014 00:00:00 +0000 Gambling disorder (GD) is a psychiatric condition associated with both social and family costs; DSM-5 currently includes GD among addictive disorders. Despite the high burden of this condition, to date there are no treatment guidelines approved by Food and Drug Administration (FDA). Purpose of this paper is to offer a qualitative overview about the different pharmacologic agents used for the treatment of GD. Our analysis, conducted on a final selection of 75 scientific papers, demonstrates that a variety of pharmaceutical classes have been utilised, with different results. Published data, although limited by brief duration of the studies and small number of enrolled subjects, shows mixed evidence for serotonergic antidepressants, opioid antagonists, and mood stabilizers. Other compounds, such as glutamatergic agents and psychostimulants, deserve further studies. Matteo Lupi, Giovanni Martinotti, Tiziano Acciavatti, Mauro Pettorruso, Marcella Brunetti, Rita Santacroce, Eduardo Cinosi, Giuseppe Di Iorio, Marco Di Nicola, and Massimo Di Giannantonio Copyright © 2014 Matteo Lupi et al. All rights reserved. The Multiple Roles of EG-VEGF/PROK1 in Normal and Pathological Placental Angiogenesis Thu, 15 May 2014 15:46:11 +0000 Placentation is associated with several steps of vascular adaptations throughout pregnancy. These vascular changes occur both on the maternal and fetal sides, consisting of maternal uterine spiral arteries remodeling and placental vasculogenesis and angiogenesis, respectively. Placental angiogenesis is a pivotal process for efficient fetomaternal exchanges and placental development. This process is finely controlled throughout pregnancy, and it involves ubiquitous and pregnancy-specific angiogenic factors. In the last decade, endocrine gland derived vascular endothelial growth factor (EG-VEGF), also called prokineticin 1 (PROK1), has emerged as specific placental angiogenic factor that controls many aspects of normal and pathological placental angiogenesis such as recurrent pregnancy loss (RPL), gestational trophoblastic diseases (GTD), fetal growth restriction (FGR), and preeclampsia (PE). This review recapitulates EG-VEGF mediated-angiogenesis within the placenta and at the fetomaternal interface and proposes that its deregulation might contribute to the pathogenesis of several placental diseases including FGR and PE. More importantly this paper argues for EG-VEGF clinical relevance as a potential biomarker of the onset of pregnancy pathologies and discusses its potential usefulness for future therapeutic directions. Nadia Alfaidy, Pascale Hoffmann, Houssine Boufettal, Naima Samouh, Touria Aboussaouira, Mohamed Benharouga, Jean-Jacques Feige, and Sophie Brouillet Copyright © 2014 Nadia Alfaidy et al. All rights reserved. Antiproliferative and Apoptotic Effects of Sesbania grandiflora Leaves in Human Cancer Cells Thu, 15 May 2014 00:00:00 +0000 Natural phytochemicals and their derivatives are good drug candidates for anticancer therapeutic approaches against multiple targets. We report here the initial findings from our studies on the anticancer properties of the leaves of the medicinal plant Sesbania grandiflora. In the current study, five different solvent fractions from the leaves of S. grandiflora were tested on cancer cell lines such as MCF-7, HepG2, Hep-2, HCT-15, and A549. The methanolic fraction of S. grandiflora was found to exert potent antiproliferative effects especially in the human lung cancer cell line, A549. Caspase 3 was activated in the methanolic fraction treated A549 cells thereby leading to cell death by apoptosis. DAPI staining, DNA laddering, and decrease in mitochondrial membrane potential further confirmed the apoptotic mode of cell death. The high levels of ROS intermediates as evidenced by DCF-DA staining could have played a role in the apoptotic induction. Decrease in levels of cyclin D1 and decrease in the activation of NFkB were observed in A549 cells on treatment with methanolic fraction, giving a hint on the possible mechanism of action. These results prove that the medicinal plant S. grandiflora can be explored further for promising candidate molecules to combat cancer, especially lung cancer. Sankar Pajaniradje, Kumaravel Mohankumar, Ramya Pamidimukkala, Srividya Subramanian, and Rukkumani Rajagopalan Copyright © 2014 Sankar Pajaniradje et al. All rights reserved. Phytochemical, Therapeutic, and Ethnopharmacological Overview for a Traditionally Important Herb: Boerhavia diffusa Linn. Wed, 14 May 2014 10:48:18 +0000 Boerhavia diffusa (BD) is a plant of rasayana category as per ayurvedic claims. It is reported to possess antiaging, disease prevention, and life strengthening activities which hold enormous influence in disease burden and affordability/availability of healthcare in the world. Objective. This paper has been compiled to comment on the studies reported for BD to highlight its chemical and therapeutic potential along with its ethnopharmacological considerations. Methods. In the present paper, a detailed account of chemical constituents and pharmacological activities has been presented. All the findings were correlated with modern pharmacological activities to appraise the value of BD. Results. Chemical analysis of BD gives a wide variety of chemical constituents, namely, rotenoids, flavonoids, xanthones, purine nucleoside, lignans, and steroids. Various ethnopharmacological reports emphasize its role in disorders of reproductive system, gastrointestinal system, respiratory system, urinary system, hepatic system/jaundice, cardiovascular system, and cancer. Conclusions. The studies on the therapeutic activities of BD range from studies on crude extracts to isolated compounds; however some of the studies require sophistication and validated results. BD is a plant of enormous importance in the purview of its chemical and therapeutic properties. Shikha Mishra, Vidhu Aeri, Praveen Kumar Gaur, and Sanjay M. Jachak Copyright © 2014 Shikha Mishra et al. All rights reserved. Glycyrrhizic Acid in the Treatment of Liver Diseases: Literature Review Tue, 13 May 2014 13:40:49 +0000 Glycyrrhizic acid (GA) is a triterpene glycoside found in the roots of licorice plants (Glycyrrhiza glabra). GA is the most important active ingredient in the licorice root, and possesses a wide range of pharmacological and biological activities. GA coupled with glycyrrhetinic acid and 18-beta-glycyrrhetic acid was developed in China or Japan as an anti-inflammatory, antiviral, and antiallergic drug for liver disease. This review summarizes the current biological activities of GA and its medical applications in liver diseases. The pharmacological actions of GA include inhibition of hepatic apoptosis and necrosis; anti-inflammatory and immune regulatory actions; antiviral effects; and antitumor effects. This paper will be a useful reference for physicians and biologists researching GA and will open the door to novel agents in drug discovery and development from Chinese herbs. With additional research, GA may be more widely used in the treatment of liver diseases or other conditions. Jian-yuan Li, Hong-yan Cao, Ping Liu, Gen-hong Cheng, and Ming-yu Sun Copyright © 2014 Jian-yuan Li et al. All rights reserved. Neuropathologic Implication of Peripheral Neuregulin-1 and EGF Signals in Dopaminergic Dysfunction and Behavioral Deficits Relevant to Schizophrenia: Their Target Cells and Time Window Tue, 13 May 2014 11:33:36 +0000 Neuregulin-1 and epidermal growth factor (EGF) are implicated in the pathogenesis of schizophrenia. To test the developmental hypothesis for schizophrenia, we administered these factors to rodent pups, juveniles, and adults and characterized neurobiological and behavioral consequences. These factors were also provided from their transgenes or infused into the adult brain. Here we summarize previous results from these experiments and discuss those from neuropathological aspects. In the neonatal stage but not the juvenile and adult stages, subcutaneously injected factors penetrated the blood-brain barrier and acted on brain neurons, which later resulted in persistent behavioral and dopaminergic impairments associated with schizophrenia. Neonatally EGF-treated animals exhibited persistent hyperdopaminergic abnormalities in the nigro-pallido-striatal system while neuregulin-1 treatment resulted in dopaminergic deficits in the corticolimbic dopamine system. Effects on GABAergic and glutamatergic systems were transient or limited. Even in the adult stage, intracerebral administration and transgenic expression of these factors produced similar but not identical behavioral impairments, although the effects of intracerebral administration were reversible. These findings suggest that dopaminergic development is highly vulnerable to circulating ErbB ligands in the pre- and perinatal stages. Once maldevelopment of the dopaminergic system is established during early development, dopamine-associating behavioral deficits become irreversible and manifest at postpubertal stages. Hiroyuki Nawa, Hidekazu Sotoyama, Yuriko Iwakura, Nobuyuki Takei, and Hisaaki Namba Copyright © 2014 Hiroyuki Nawa et al. All rights reserved. Apoptosis Induction by Polygonum minus Is Related to Antioxidant Capacity, Alterations in Expression of Apoptotic-Related Genes, and S-Phase Cell Cycle Arrest in HepG2 Cell Line Tue, 13 May 2014 08:15:48 +0000 Polygonum minus (Polygonaceae) is a medicinal herb distributed throughout eastern Asia. The present study investigated antiproliferative effect of P. minus and its possible mechanisms. Four extracts (petroleum ether, methanol, ethyl acetate, and water) were prepared by cold maceration. Extracts were subjected to phytochemical screening, antioxidant, and antiproliferative assays; the most bioactive was fractionated using vacuum liquid chromatography into seven fractions (F1–F7). Antioxidant activity was measured via total phenolic content (TPC), 2,2-diphenyl-1-picrylhydrazyl (DPPH), and ferric reducing antioxidant power (FRAP) assays. Antiproliferative activity was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Most active fraction was tested for apoptosis induction and cell cycle arrest in HepG2 cells using flow cytometry and confocal microscopy. Apoptotic-related gene expression was studied by RT-PCR. Ethyl acetate extract was bioactive in initial assays. Its fraction, F7, exhibited highest antioxidant capacity (TPC;  mg GAE/g extract, DPPH; :  μg/mL, FRAP;  μmol Fe (II)/mg extract) and selective antiproliferative effect (:  μg/mL). F7 induced apoptosis in concentration- and time-dependent manner and caused cell cycle arrest at S-phase. Upregulation of proapoptotic genes (Bax, p53, and caspase-3) and downregulation of antiapoptotic gene, Bcl-2, were observed. In conclusion, F7 was antiproliferative to HepG2 cells by inducing apoptosis, cell cycle arrest, and via antioxidative effects. Mohd Alfazari Mohd Ghazali, Ghanya Al-Naqeb, Kesavanarayanan Krishnan Selvarajan, Mizaton Hazizul Hasan, and Aishah Adam Copyright © 2014 Mohd Alfazari Mohd Ghazali et al. All rights reserved. Propolis Varnish: Antimicrobial Properties against Cariogenic Bacteria, Cytotoxicity, and Sustained-Release Profile Tue, 13 May 2014 07:43:17 +0000 Varnishes are preparations that differ in the polymeric matrix and therapeutical agents. In dentistry they are used to prevent caries. In this study we developed a propolis varnish, considering propolis properties against cariogenic bacteria. To a chitosan polymeric base (CHV) was added ethanolic propolis extract in different concentrations: PV1 (5%), PV2 (10%), and PV3 (15%). Antimicrobial activity was carried out against Streptococcus mutans (SM), Streptococcus sanguinis (SG), Streptococcus salivarius (SS), and Lactobacillus casei (LC) through agar diffusion method. The three propolis concentrations incorporated were effective in inhibiting the growth of all microorganisms, but without significant difference between the zones of inhibition observed. Cytotoxicity assay was done by MTT method. Data were analyzed by one-way ANOVA and Bonferroni test. None of the varnishes were cytotoxic, keeping 80% of viable cells, while CHV allowed cellular proliferation (120%). Sustained-release test was carried out by applying 40 μL of each varnish in the buccal surface of bovine teeth and kept in an ethanol/water solution removed in regular times. According to the “independent model approach,” the release profiles were distinct from each varnish and the most prolonged was PV3 (8 weeks). Varnish formulations had satisfactory antimicrobial activity against cariogenic bacteria and have a low cytotoxicity (<50%). Mariana P. De Luca, Juçara R. Franca, Filipe Augusto F. F. Macedo, Liliana Grenho, Maria Esperanza Cortes, André Augusto G. Faraco, Allyson N. Moreira, and Vagner R. Santos Copyright © 2014 Mariana P. De Luca et al. All rights reserved. Pycnogenol Ameliorates Depression-Like Behavior in Repeated Corticosterone-Induced Depression Mice Model Tue, 13 May 2014 00:00:00 +0000 Oxidative stress is considered to be a mechanism of major depression. Pycnogenol (PYC) is a natural plant extract from the bark of Pinus pinaster Aiton and has potent antioxidant activities. We studied the ameliorative effect of PYC on depression-like behavior in chronic corticosterone- (CORT-) treated mice for 20 days. After the end of the CORT treatment period, PYC (0.2 mg/mL) was orally administered in normal drinking water. Depression-like behavior was investigated by the forced swimming test. Immobility time was significantly longer by CORT exposure. When the CORT-treated mice were supplemented with PYC, immobility time was significantly shortened. Our results indicate that orally administered PYC may serve to reduce CORT-induced stress by radical scavenging activity. Lin Mei, Miyako Mochizuki, and Noboru Hasegawa Copyright © 2014 Lin Mei et al. All rights reserved. Gastric Antiulcerogenic and Hypokinetic Activities of Terminalia fagifolia Mart. & Zucc. (Combretaceae) Mon, 12 May 2014 10:19:02 +0000 The acute toxicity, the antioxidant activity, and the pharmacological activity on the gastrointestinal tract of rodents of the ethanolic extract (TFEE) from the bark of Terminalia fagifolia Mart. & Zucc. (Combretaceae) and of its aqueous (TFAqF), hydroalcoholic (TFHAF), and hexanic (TFHEXF) partition fractions have been evaluated. TFEE presented low acute toxicity, antioxidant, and antiulcerogenic activity against ethanol-induced ulcers, which was partially blocked by pretreatment with L-NAME and indomethacin. It reduced the total acidity and raised the pH of gastric secretion. Additionally, TFEE delayed gastric emptying and slightly inhibited the small intestinal transit and also presented a weakly antidiarrheal activity. The antiulcerogenic and antioxidant activity were also detected in TFAqF and TFHAF but not in TFHEXF. The antisecretory and gastroprotective activity of TFEE partially involve the nitric oxide and prostaglandin participation. Nevertheless, TFEE, TFAqF, and TFHAF drastically reduced the mucus layer adhered to the gastric wall of rats treated with ethanol or indomethacin. Complementary studies are required in order to clarify the paradox of the presence of a gastroprotector activity in this plant that, at the same time, reduces the mucus layer adhered to the gastric wall. Paulo Humberto M. Nunes, Maria do Carmo C. Martins, Rita de Cássia M. Oliveira, Mariana H. Chaves, Elcilene A. Sousa, José Roberto S. A. Leite, Leiz Maria Véras, and Fernanda Regina C. Almeida Copyright © 2014 Paulo Humberto M. Nunes et al. All rights reserved. Can Melatonin Help Us in Radiation Oncology Treatments? Sun, 11 May 2014 12:47:59 +0000 Nowadays, radiotherapy has become an integral part of the treatment regimen in various malignancies for curative or palliative purposes. Ionizing radiation interacts with biological systems to produce free radicals, which attack various cellular components. Radioprotectors act as prophylactic agents that are administered to shield normal cells and tissues from the harmful effects of radiation. Melatonin has been shown to be both a direct free radical scavenger and an indirect antioxidant by stimulating antioxidant enzymes and suppressing prooxidative enzymes activity. In addition to its antioxidant property, there have also been reports implicating antiapoptotic function for melatonin in normal cells. Furthermore, through its antitumor and radiosensitizing properties, treatment with melatonin may prevent tumor progression. Therefore, addition of melatonin to radiation therapy could lower the damage inflicted to the normal tissue, leading to a more efficient tumor control by use of higher doses of irradiation during radiotherapy. Thus, it seems that, in the future, melatonin may improve the therapeutic gain in radiation oncology treatments. Ehsan Mihandoost, Alireza Shirazi, Seied Rabie Mahdavi, and Akbar Aliasgharzadeh Copyright © 2014 Ehsan Mihandoost et al. All rights reserved. ATF4- and CHOP-Dependent Induction of FGF21 through Endoplasmic Reticulum Stress Sun, 11 May 2014 11:39:49 +0000 Fibroblast growth factor 21 (FGF21) is an important endogenous regulator involved in the regulation of glucose and lipid metabolism. FGF21 expression is strongly induced in animal and human subjects with metabolic diseases, but little is known about the molecular mechanism. Endoplasmic reticulum (ER) stress plays an essential role in metabolic homeostasis and is observed in numerous pathological processes, including type 2 diabetes, overweight, nonalcoholic fatty liver disease (NAFLD). In this study, we investigate the correlation between the expression of FGF21 and ER stress. We demonstrated that TG-induced ER stress directly regulated the expression and secretion of FGF21 in a dose- and time-dependent manner. FGF21 is the target gene for activating transcription factor 4 (ATF4) and CCAAT enhancer binding protein homologous protein (CHOP). Suppression of CHOP impaired the transcriptional activation of FGF21 by TG-induced ER stress in CHOP−/− mouse primary hepatocytes (MPH), and overexpression of ATF4 and CHOP resulted in FGF21 promoter activation to initiate the transcriptional programme. In mRNA stability assay, we indicated that ER stress increased the half-life of mRNA of FGF21 significantly. In conclusion, FGF21 expression is regulated by ER stress via ATF- and CHOP-dependent transcriptional mechanism and posttranscriptional mechanism, respectively. Xiao-shan Wan, Xiang-hong Lu, Ye-cheng Xiao, Yuan Lin, Hong Zhu, Ting Ding, Ying Yang, Yan Huang, Yi Zhang, Yan-Long Liu, Zhu-mei Xu, Jian Xiao, and Xiao-kun Li Copyright © 2014 Xiao-shan Wan et al. All rights reserved. Nucleobase-Based Barbiturates: Their Protective Effect against DNA Damage Induced by Bleomycin-Iron, Antioxidant, and Lymphocyte Transformation Assay Thu, 08 May 2014 14:12:54 +0000 A number of nucleobase-based barbiturates have been synthesized by combination of nucleic acid bases and heterocyclic amines and barbituric acid derivatives through green and efficient multicomponent route and one pot reaction. This approach was accomplished efficiently using aqueous medium to give the corresponding products in high yield. The newly synthesized compounds were characterized by spectral analysis (FT-IR, 1H NMR, 13C NMR, HMBC, and UV spectroscopy) and elemental analysis. Representative of all synthesized compounds was tested and evaluated for antioxidant, bleomycin-dependent DNA damage, and Lymphocyte Transformation studies. Compounds TBC > TBA > TBG showed highest lymphocyte transformation assay, TBC > TBA > BG showed inhibitory antioxidant activity using ABTS methods, and TBC > BPA > BAMT > TBA > 1, 3-TBA manifested the best protective effect against DNA damage induced by bleomycin. Bhaveshkumar D. Dhorajiya, Bharatkumar Z. Dholakiya, Ahmed S. Ibrahim, and Farid A. Badria Copyright © 2014 Bhaveshkumar D. Dhorajiya et al. All rights reserved. Evaluating the Cancer Therapeutic Potential of Cardiac Glycosides Thu, 08 May 2014 00:00:00 +0000 Cardiac glycosides, also known as cardiotonic steroids, are a group of natural products that share a steroid-like structure with an unsaturated lactone ring and the ability to induce cardiotonic effects mediated by a selective inhibition of the Na+/K+-ATPase. Cardiac glycosides have been used for many years in the treatment of cardiac congestion and some types of cardiac arrhythmias. Recent data suggest that cardiac glycosides may also be useful in the treatment of cancer. These compounds typically inhibit cancer cell proliferation at nanomolar concentrations, and recent high-throughput screenings of drug libraries have therefore identified cardiac glycosides as potent inhibitors of cancer cell growth. Cardiac glycosides can also block tumor growth in rodent models, which further supports the idea that they have potential for cancer therapy. Evidence also suggests, however, that cardiac glycosides may not inhibit cancer cell proliferation selectively and the potent inhibition of tumor growth induced by cardiac glycosides in mice xenografted with human cancer cells is probably an experimental artifact caused by their ability to selectively kill human cells versus rodent cells. This paper reviews such evidence and discusses experimental approaches that could be used to reveal the cancer therapeutic potential of cardiac glycosides in preclinical studies. José Manuel Calderón-Montaño, Estefanía Burgos-Morón, Manuel Luis Orta, Dolores Maldonado-Navas, Irene García-Domínguez, and Miguel López-Lázaro Copyright © 2014 José Manuel Calderón-Montaño et al. All rights reserved. Synergistic Effect and Antiquorum Sensing Activity of Nymphaea tetragona (Water Lily) Extract Thu, 08 May 2014 00:00:00 +0000 Salmonellosis is a common and widely distributed food borne disease where Salmonella typhimurium is one of the most important etiologic agents. The purpose of this study was to investigate the antimicrobial activity of Nymphaea tetragona alone and in combination with antibiotics against S. typhimurium. It also aimed to assess the plant for quorum sensing inhibition (QSI) activity and to identify the bioactive compounds. The antibacterial activities of the extract were assessed using broth microdilution method. Disk agar diffusion method was employed to determine the QSI and bioactive compounds were identified by GC-MS analysis. Ethyl acetate fraction of N. tetragona extract (EFNTE) demonstrated good antimicrobial activity (MIC 781 μg/mL) against 4 strains out of 5. FIC index ranged from 0.375 to 1.031 between EFNTE/tylosin and 0.515 to 1.250 between EFNTE/streptomycin against S. typhimurium. Among all extracts, EFNTE and butanol fraction more significantly inhibited pigment production of C. violaceum. Polyphenols were identified as major compound of EFNTE and butanol fraction. These results indicate that combination among N. tetragona extract and antibiotics could be useful to combat drug-resistance Salmonella infections and polyphenols are promising new components from N. tetragona that warrant further investigation as a candidate anti-Salmonella agent and quorum sensing inhibitor. Md. Akil Hossain, Ji-Yong Park, Jin-Yoon Kim, Joo-Won Suh, and Seung-Chun Park Copyright © 2014 Md. Akil Hossain et al. All rights reserved. Cytotoxic Effect of Icaritin and Its Mechanisms in Inducing Apoptosis in Human Burkitt Lymphoma Cell Line Wed, 07 May 2014 09:52:40 +0000 Icaritin (ICT), a hydrolytic product of icariin from Epimedium genus, exhibits antitumor activities in several human solid-tumor and myeloid leukemia cells with extensive influence on various cell signal molecules, such as MAPKs being involved in cell proliferation and Bcl-2 participating in cell apoptosis. However, the effect of icaritin on Burkitt Lymphoma has not been elucidated. In the present study, we first screened the potential effect of icaritin on Burkitt lymphoma Raji and P3HR-1 cell lines and found that icaritin showed cytotoxicity in both cell lines. We further found that icaritin could significantly inhibit Raji cells proliferation with S-phase arrest of cell cycle and induced cell apoptosis accompanied by activation of caspase-8 and caspase-9 and cleavage of PARP. We also observed that icaritin was able to decrease Bcl-2 levels, thus shifting the Bcl-2/Bax ratio, and it could obviously reduce c-Myc, a specific molecular target in Burkitt lymphoma. Our findings demonstrated that icaritin showed cytotoxicity, inhibited cell growth, caused S arrest, and induced apoptosis in Burkitt lymphoma cells and provided a rationale for the further evaluation of icaritin for Burkitt lymphoma therapy. Zi-Jian Li, Can Yao, Su-Fang Liu, Long Chen, Ya-Ming Xi, Wen Zhang, and Guang-Sen Zhang Copyright © 2014 Zi-Jian Li et al. All rights reserved. In Vitro Screening for β-Hydroxy-β-methylglutaryl-CoA Reductase Inhibitory and Antioxidant Activity of Sequentially Extracted Fractions of Ficus palmata Forsk Tue, 06 May 2014 12:55:36 +0000 Hypercholesterolemia-induced oxidative stress has been strongly implicated in the pathogenesis of atherosclerosis, which is one of the major causes of mortality worldwide. The current work, for the first time, accounts the antioxidant, genoprotective, antilipoperoxidative, and HMG-CoA reductase (EC inhibitory properties of traditional medicinal plant, Ficus palmata Forsk. Our result showed that among sequentially extracted fractions of Ficus palmata Forsk, FPBA (F. palmata bark aqueous extract) and FPLM (F. palmata leaves methanolic extract) extracts have higher phenolic content and also exhibited significantly more radical scavenging (DPPH and Superoxide) and antioxidant (FRAP) capacity. Moreover, FPBA extract also exhibited significantly higher inhibition of lipid peroxidation assay. Additionally, results showed almost complete and partial protection of oxidatively damaged DNA by these plant extracts when compared to mannitol. Furthermore, our results showed that FPBA extract ( µg/mL) exhibited noteworthy inhibition of HMG-CoA reductase activity as compared to other extracts, which might suggest its role as cardioprotective agent. In conclusion, results showed that FPBA extract not only possess significant antioxidant and genoprotective property but also is able to attenuate the enzymatic activity of HMG-CoA reductase, which might suggest its role in combating various oxidative stress-related diseases, including atherosclerosis. Danish Iqbal, M. Salman Khan, Amir Khan, Mohd. Sajid Khan, Saheem Ahmad, Ashwani K. Srivastava, and Paramdeep Bagga Copyright © 2014 Danish Iqbal et al. All rights reserved. Iron (FeII) Chelation, Ferric Reducing Antioxidant Power, and Immune Modulating Potential of Arisaema jacquemontii (Himalayan Cobra Lily) Tue, 06 May 2014 12:42:23 +0000 This study explored the antioxidant and immunomodulatory potential of ethnomedicinally valuable species, namely, Arisaema jacquemontii of north-western Himalayan region. The tubers, leaves, and fruits of this plant were subjected to extraction using different solvents. In vitro antioxidant studies were performed in terms of chelation power on ferrous ions and FRAP assay. The crude methanol extract of leaves was found to harbour better chelating capacity (58% at 100 μg/mL) and reducing power (FRAP value  μMFe3+/g dry wt.) than all the other extracts. The crude methanol extract was thus further partitioned with solvents to yield five fractions. Antioxidant study of fractions suggested that the methanol fraction possessed significant chelation capacity (49.7% at 100 μg/mL) and reducing power with FRAP value of 1435.4 μM/g dry wt. The fractions were also studied for immune modulating potential where it was observed that hexane fraction had significant suppressive effect on mitogen induced T-cell and B-cell proliferation and remarkable stimulating effect on humoral response by 141% and on DTH response by 168% in immune suppressed mice as compared to the controls. Therefore, it can be concluded that A. jacquemontii leaves hold considerable antioxidant and immunomodulating potential and they can be explored further for the identification of their chemical composition for a better understanding of their biological activities. Rasleen Sudan, Madhulika Bhagat, Sahil Gupta, Jasvinder Singh, and Anupurna Koul Copyright © 2014 Rasleen Sudan et al. All rights reserved. Computational Analysis of mRNA Expression Profiles Identifies the ITG Family and PIK3R3 as Crucial Genes for Regulating Triple Negative Breast Cancer Cell Migration Tue, 06 May 2014 11:28:10 +0000 Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer that does not express estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (Her2/neu). TNBC has worse clinical outcomes than other breast cancer subtypes. However, the key molecules and mechanisms of TNBC migration remain unclear. In this study, we compared two normalized microarray datasets from GEO database between Asian (GSE33926) and non-Asian populations (GSE46581) to determine the molecules and common pathways in TNBC migration. We demonstrated that 16 genes in non-Asian samples and 9 genes in Asian samples are related to TNBC migration. In addition, our analytic results showed that 4 genes, PIK3R3, ITGB1, ITGAL, and ITGA6, were involved in the regulation of actin cytoskeleton. Our results indicated potential genes that link to TNBC migration. This study may help identify novel therapeutic targets for drug development in cancer therapy. Sukhontip Klahan, Mei-Shin Wu, Edward Hsi, Chi-Cheng Huang, Ming-Feng Hou, and Wei-Chiao Chang Copyright © 2014 Sukhontip Klahan et al. All rights reserved. Phyllanthus wightianus Müll. Arg.: A Potential Source for Natural Antimicrobial Agents Mon, 05 May 2014 00:00:00 +0000 Phyllanthus wightianus belongs to Euphorbiaceae family having ethnobotanical importance. The present study deals with validating the antimicrobial potential of solvent leaf extracts of P. wightianus. 11 human bacterial pathogens (Bacillus subtilis, Streptococcus pneumoniae, Staphylococcus epidermidis, Proteus vulgaris, Pseudomonas aeruginosa, Klebsiella pneumoniae, Salmonella typhimurium, Escherichia coli, Shigella flexneri, Proteus vulgaris, and Serratia marcescens) and 4 fungal pathogens (Candida albicans, Cryptococcus neoformans, Mucor racemosus, and Aspergillus niger) were also challenged with solvent leaf extracts usingagar well and disc diffusion methods. Further, identification of the active component present in the bioactive extract was done using GC-MS analysis. Results show that all extracts exhibited broad spectrum (6–29 mm) of antibacterial activity on most of the tested organisms. The results highlight the fact that the well in agar method was more effective than disc diffusion method. Significant antimicrobial activity was detected in methanol extract against S. pneumoniae (29 mm) with MIC and MBC values of 15.62 μg/mL. GC-MS analysis revealed that 29 bioactive constituents were present in methanolic extract of P. wightianus, of which 9,12-octadecaenioic acid (peak area 22.82%; RT-23.97) and N-hexadecanoic acid (peak area 21.55% RT-21.796) are the major compounds. The findings of this study show that P. wightianus extracts may be used as an anti-infective agent in folklore medicine. D. Natarajan, R. Srinivasan, and M. S. Shivakumar Copyright © 2014 D. Natarajan et al. All rights reserved. Antidepressant-Like Effect of Ilex paraguariensis in Rats Sun, 04 May 2014 16:36:57 +0000 In this study, we investigated the possible antidepressant-like effect of I. paraguariensis in rats. Rats were treated for four weeks with an aqueous extract of I. paraguariensis in drinking water, following the traditional preparation of this beverage. After the period of treatment, behavioral (elevated plus-maze, open field test, and forced swimming test) and biochemical parameters (lipid peroxidation assay, thiol content, vitamin C levels, and monoamine oxidase activity) were evaluated. Animals were also analyzed on forced swimming test after 24 hours of I. paraguariensis intake. An additional group was injected with selegiline 24 hours and 30 minutes before forced swimming test as positive control. HPLC analysis revealed the profile of I. paraguariensis extract. I. paraguariensis reduced the immobility time on forced swimming test without significant changes in locomotor activity in the open field test. Any anxiolytic/anxiogenic effect of I. paraguariensis was observed in rats through the elevated plus-maze test. The antidepressant-like effect of I. paraguariensis was not accompanied by inhibitory effect on monoamine oxidase activity. There were no significant alterations on lipid peroxidation, thiol content, and vitamin C levels among the groups. In conclusion, aqueous extract of I. paraguariensis decreases the time of immobility in rats suggesting an antidepressant-like effect. Elizete De Moraes Reis, Francisco Waldomiro Schreiner Neto, Vitória Berg Cattani, Luis Ricardo Peroza, Alcindo Busanello, Caroline Queiroz Leal, Aline Augusti Boligon, Tássia Fontana Lehmen, Milena Libardoni, Margareth Linde Athayde, and Roselei Fachinetto Copyright © 2014 Elizete De Moraes Reis et al. All rights reserved. Exploring Population Pharmacokinetic Modeling with Resampling Visualization Sun, 04 May 2014 08:08:58 +0000 Background. In the last decade, population pharmacokinetic (PopPK) modeling has spread its influence in the whole process of drug research and development. While targeting the construction of the dose-concentration of a drug based on a population of patients, it shows great flexibility in dealing with sparse samplings and unbalanced designs. The resampling approach has been considered an important statistical tool to assist in PopPK model validation by measuring the uncertainty of parameter estimates and evaluating the influence of individuals. Methods. The current work describes a graphical diagnostic approach for PopPK models by visualizing resampling statistics, such as case deletion and bootstrap. To examine resampling statistics, we adapted visual methods from multivariate analysis, parallel coordinate plots, and multidimensional scaling. Results. Multiple models were fitted, the information of parameter estimates and diagnostics were extracted, and the results were visualized. With careful scaling, the dependencies between different statistics are revealed. Using typical examples, the approach proved to have great capacity to identify influential outliers from the statistical perspective, which deserves special attention in a dosing regimen. Discussion. By combining static graphics with interactive graphics, we are able to explore the multidimensional data from an integrated and systematic perspective. Complementary to current approaches, our proposed method provides a new way for PopPK modeling analysis. Fenghua Zuo, Jun Li, and Xiaoyong Sun Copyright © 2014 Fenghua Zuo et al. All rights reserved. Cecropia pachystachya: A Species with Expressive In Vivo Topical Anti-Inflammatory and In Vitro Antioxidant Effects Wed, 30 Apr 2014 09:20:37 +0000 Cecropia pachystachya is a species traditionally used in Brazil to treat inflammation. This work aims to evaluate the topical anti-inflammatory and antioxidant activities of the methanolic extract of C. pachystachya (CPM) and to perform its chemical fingerprint by HPLC-DAD. The topical anti-inflammatory activity was evaluated using the mouse models of acute ear inflammation induced by croton oil, arachidonic acid, capsaicin, EPP, phenol, and chronic inflammation induced by multiple application of croton oil. The in vitro antioxidant effect of CPM was investigated using DPPH, reducing power, β-carotene bleaching, and TBARS assays. HPLC analysis was performed to quantify the antioxidant phenolics orientin, isoorientin, and chlorogenic acid previously identified in CPM. CPM exhibited significant anti-inflammatory effect in the acute models, in some cases comparable to the reference drugs. Histopathological analysis showed a moderate chronic skin anti-inflammatory effect with decrease in vasodilation, edema, cell infiltration, and epidermal hyperproliferation. It also showed strong in vitro antioxidant activity. The contents of orientin, isoorientin, and chlorogenic acid were 66.5 ± 1.8, 118.8 ± 0.7, and 5.4 ± 0.2 µg/mg extract, respectively. The topical anti-inflammatory activity of CPM could be based on its antioxidant properties, although other effects are probably involved, including COX inhibition and other mechanisms. Natália Ramos Pacheco, Nícolas de Castro Campos Pinto, Josiane Mello da Silva, Renata de Freitas Mendes, Juliana de Carvalho da Costa, Danielle Maria de Oliveira Aragão, Maria Christina Marques Nogueira Castañon, and Elita Scio Copyright © 2014 Natália Ramos Pacheco et al. All rights reserved. Phytochemical Screening, Physicochemical Properties, Acute Toxicity Testing and Screening of Hypoglycaemic Activity of Extracts of Eremurus himalaicus Baker in Normoglycaemic Wistar Strain Albino Rats Tue, 29 Apr 2014 12:05:23 +0000 In the present study EtOAc, MeOH, and aqueous extracts of Eremurus himalaicus were evaluated for hypoglycaemic effect in normal rats using both oral glucose tolerance test and 14-day oral administration study. Phytochemical and physicochemical screening was also done. In oral glucose tolerance test the aqueous and MeOH extracts of Eremurus himalaicus at a dose level of 500 mg/kg body weight prior to glucose load resulted in a significant fall in blood glucose level within 150 min. of glucose administration. The aqueous extract at a dose level of 250 mg/kg body weight and 500 mg/kg body weight also showed good hypoglycaemic response (P < 0.001); this was followed by MeOH extract at a dose level of 500 mg/kg body weight (P < 0.05), while MeOH extract at dose level of 250 mg/kg body weight and ethyl acetate extract at dose level of 250 mg/kg body weight and 500 mg/kg body weight exhibited insignificant effect. Phytochemical screening of extracts revealed the presence of alkaloids, terpenoids, phenolics, tannins, saponins, cardiac glycosides, and flavonoids. The results indicate that aqueous extract possess significant hypoglycaemic activity in normoglycaemic rats which may be attributed to the above-mentioned chemical constituents. Ahlam Mushtaq, Seema Akbar, Mohammad A. Zargar, Adil F. Wali, Akhtar H. Malik, Mohammad Y. Dar, Rabia Hamid, and Bashir A. Ganai Copyright © 2014 Ahlam Mushtaq et al. All rights reserved. Fenugreek Seed Extract Inhibit Fat Accumulation and Ameliorates Dyslipidemia in High Fat Diet-Induced Obese Rats Tue, 29 Apr 2014 11:58:01 +0000 This study investigated the inhibitory effect of aqueous extract of Trigonella foenum-graecum seeds (AqE-TFG) on fat accumulation and dyslipidemia in high fat diet- (HFD-) induced obese rats. Female Wistar rats were fed with HFD ad libitum, and the rats on HFD were treated orally with AqE-TFG or orlistat ((HFD for 28 days + AqE-TFG (0.5 and 1.0 g/kg) or orlistat (10 mg/kg) from day 8 to 28), respectively. Treatment with AqE-TFG produced significant reduction in body weight gain, body mass index (BMI), white adipose tissue (WAT) weights, blood glucose, serum insulin, lipids, leptin, lipase, and apolipoprotein-B levels and elevation in adiponectin levels. AqE-TFG improved serum aspartate amino transferase (AST), alanine amino transferase (ALT), and lactate dehydrogenase (LDH) levels. AqE-TFG treatment reduced the hepatic and cardiac thiobarbituric acid reactive substances (TBARS) and elevated the antioxidant enzyme (glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT)) levels. In addition, liver and uterine WAT lipogenic enzyme (fatty acid synthetase (FAS) and glucose-6-phosphate dehydrogenase (G6PD)) activities were restored towards normal levels. These findings demonstrated the preventive effect of AqE-TFG on fat accumulation and dyslipidemia, due to inhibition of impaired lipid digestion and absorption, in addition to improvement in glucose and lipid metabolism, enhancement of insulin sensitivity, increased antioxidant defense, and downregulation of lipogenic enzymes. Parveen Kumar, Uma Bhandari, and Shrirang Jamadagni Copyright © 2014 Parveen Kumar et al. All rights reserved. Hyperammonemia Associated with Valproic Acid Concentrations Tue, 29 Apr 2014 10:08:32 +0000 Valproic acid, a branched short-chain fatty acid, has numerous action mechanisms which turn it into a broad spectrum anticonvulsant drug and make its use possible in some other pathologies such as bipolar disorder. It is extensively metabolized in liver, representing β-oxidation in the mitochondria one of its main metabolic route (40%). Carnitine is responsible for its entry into the mitochondria as any other fatty acid. Long-term high-dose VPA therapy or acute VPA overdose induces carnitine depletion, resulting in high levels of ammonia in blood. As a high correlation between salivary valproic acid levels and plasma ultrafiltrate levels was found in humans, saliva becomes a promising monitoring fluid in order to study valproic acid pharmacokinetics and its toxic effect. Extended-release (twice daily) formulations of valproic acid or carnitine supplementation are the proposed two therapeutic strategies in order to reverse hyperammonemia. Marta Vázquez, Pietro Fagiolino, Cecilia Maldonado, Ismael Olmos, Manuel Ibarra, Silvana Alvariza, Natalia Guevara, Laura Magallanes, and Ivette Olano Copyright © 2014 Marta Vázquez et al. All rights reserved. Amarogentin, a Secoiridoid Glycoside, Abrogates Platelet Activation through PLCγ2-PKC and MAPK Pathways Tue, 29 Apr 2014 08:15:04 +0000 Amarogentin, an active principle of Gentiana lutea, possess antitumorigenic, antidiabetic, and antioxidative properties. Activation of platelets is associated with intravascular thrombosis and cardiovascular diseases. The present study examined the effects of amarogentin on platelet activation. Amarogentin treatment (15~60 μM) inhibited platelet aggregation induced by collagen, but not thrombin, arachidonic acid, and U46619. Amarogentin inhibited collagen-induced phosphorylation of phospholipase C (PLC)γ2, protein kinase C (PKC), and mitogen-activated protein kinases (MAPKs). It also inhibits in vivo thrombus formation in mice. In addition, neither the guanylate cyclase inhibitor ODQ nor the adenylate cyclase inhibitor SQ22536 affected the amarogentin-mediated inhibition of platelet aggregation, which suggests that amarogentin does not regulate the levels of cyclic AMP and cyclic GMP. In conclusion, amarogentin prevents platelet activation through the inhibition of PLCγ2-PKC cascade and MAPK pathway. Our findings suggest that amarogentin may offer therapeutic potential for preventing or treating thromboembolic disorders. Ting-Lin Yen, Wan-Jung Lu, Li-Ming Lien, Philip Aloysius Thomas, Tzu-Yin Lee, Hou-Chang Chiu, Joen-Rong Sheu, and Kuan-Hung Lin Copyright © 2014 Ting-Lin Yen et al. All rights reserved. Evaluation of Anticonvulsant, Sedative, Anxiolytic, and Phytochemical Profile of the Methanol Extract from the Aerial Parts of Swertia corymbosa (Griseb.) Wight ex C.B. Clarke Sun, 27 Apr 2014 08:57:15 +0000 The objective of the present study was to evaluate the anxiolytic, antidepressant, and anticonvulsant activity of the methanolic extract of Swertia corymbosa (SCMeOH). After acute toxicity test, oral treatment with SCMeOH at doses of 125, 250, and 500 mg/kg behavioral models of open field, elevated-plus-maze, actophotometer, rotarod, pentylenetetrazole, isoniazid, and maximal electroshock induced seizure models were utilized. In open field test, SCMeOH (125, 250, and 500 mg/kg) (, ) increased the number of rearings. However, the number of central motor and ambulation (, ) were reduced. Likewise, the number of entries and the time spent in open arm were increased while the number of locomotion was decreased () in elevated-plus-maze and actophotometer test, respectively. SCMeOH (125–500 mg/kg) protected the mice against the pentylenetetrazole and isoniazid induced convulsions; it causes significant ( and ) dose dependent increase in latency of convulsion. Treatment with SCMeOH reduced the duration of the tonic hind limb extension induced by electroshock. Two major compounds such as gentiopicroside and swertianin were analyzed by HPLC system. G. Mahendran, G. Thamotharan, S. Sengottuvelu, and V. Narmatha Bai Copyright © 2014 G. Mahendran et al. All rights reserved. Role of Dried Fruits of Carissa carandas as Anti-Inflammatory Agents and the Analysis of Phytochemical Constituents by GC-MS Sun, 27 Apr 2014 06:35:31 +0000 Inflammation plays an important role in various diseases with high prevalence within populations such as rheumatoid arthritis, ulcer, atherosclerosis, and asthma. Many drugs are available in the market for inflammatory diseases. They exhibit several unwanted side effects to humans. Therefore, alternative treatments with safer compounds are needed. Carissa carandas plant is used in traditional medicinal system for its various diseases curing property. In the present study, we examined the anti-inflammatory effects of dried fruit methanol extract on carrageenan-induced hind paw edema in rats. C. carandas was defatted with petroleum ether, followed by methanol extraction. The methanol extracts of the dried fruits of Carissa carandas were given orally to the experimental rats caused significant activity () when compared with the control group. The maximum inhibition of paw edema was found to be in Group V, that is, 76.12% with inhibition of paw volume in a dose-dependent manner. The anti-inflammatory activity of the methanol extract of the dried fruits shows that the presence of potential constituents present in this extract may provide assistance in the drug discovery process. The phytochemical compounds of the extract were screened by GC-MS analysis and it was found that 11 compounds are present in methanol extract of dried fruits of Carissa carandas. N. Anupama, G. Madhumitha, and K. S. Rajesh Copyright © 2014 N. Anupama et al. All rights reserved. In Vitro Antiplasmodial Activities and Synergistic Combinations of Differential Solvent Extracts of the Polyherbal Product, Nefang Sun, 27 Apr 2014 00:00:00 +0000 Nefang, a polyherbal product composed of Mangifera indica (bark and leaf), Psidium guajava, Carica papaya, Cymbopogon citratus, Citrus sinensis, and Ocimum gratissimum (leaves), is a potential therapy against P. falciparum malaria. In vitro antiplasmodial activities of its constituent solvent extracts were analyzed on CQ-sensitive (3D7) and multidrug resistant (Dd2) P. falciparum strains. The interactions involving the differential solvent extracts were further analyzed using a variable potency ratio drug combination approach. Effective concentration 50 (EC50) values were determined by nonlinear regression curve-fitting of the dose-response data and used in calculating the fractional inhibitory concentration 50 (FIC50) and combination indices (CI) for each pair. The derived EC50 values (3D7/Dd2, μg/mL) are Nefang-96.96/55.08, MiB-65.33/34.58, MiL-82.56/40.04, Pg-47.02/25.79, Cp-1188/317.5, Cc-723.3/141, Cs-184.4/105.1, and Og-778.5/118.9. Synergism was obtained with MiB/Pg (CI = 0.351), MiL/Pg (0.358), MiB/Cs (0.366), MiL/Cs (0.482), Pg/Cs (0.483), and Cs/Og (0.414) when analyzed at equipotency ratios. Cytotoxicity testing of Nefang and the solvent extracts on two human cell lines (Hep G2 and U2OS) revealed no significant toxicity relative to their antiplasmodial activities (SI > 20). Taken together, our data confirm the antimalarial activities of Nefang and its constituent plant extracts and identified extract pairs with promising synergistic interactions for exploitation towards a rational phytotherapeutic and evidence-based antimalarial drug discovery. Protus Arrey Tarkang, Kathrin Diehl Franzoi, Sukjun Lee, Eunyoung Lee, Diego Vivarelli, Lucio Freitas-Junior, Michel Liuzzi, Tsabang Nolé, Lawrence S. Ayong, Gabriel A. Agbor, Faith A. Okalebo, and Anastasia N. Guantai Copyright © 2014 Protus Arrey Tarkang et al. All rights reserved. In Vitro Larvicidal and Antioxidant Activity of Dihydrophenanthroline-3-carbonitriles Thu, 24 Apr 2014 14:12:05 +0000 Many naturally occurring and synthetic compounds containing dihydrocyanopyridine and cyanopyran moiety show pharmacological properties. The aim of this study is to investigate the larvicidal and antioxidant potential of dihydrophenanthroline-3-carbonitrile derivatives 4a–f. A novel series of 2-amino-10-chloro-4,12-diphenyl-1,4,5,6-tetrahydrobenzo[j][1,7]phenanthroline-3-carbonitrile derivatives were synthesized by reacting different substituted acridine chalcones through Michel addition. The compounds were synthesized in excellent yields and the structures were corroborated on the basis of FT-IR, 1H NMR, 13C NMR, and ESI Mass analysis data. All the synthesized compounds were evaluated for larvicidal activity against Aedes aegypti and Culex quinquefasciatus larvae. Furthermore, the antioxidant activity was studied by the 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay method. From the antioxidant assay, the compound 4c was reported with profound antioxidant potential. A. Bharathi, Selvaraj Mohana Roopan, Abdul Abdul Rahuman, and Govindasamy Rajakumar Copyright © 2014 A. Bharathi et al. All rights reserved. Amelioration of Paracetamol-Induced Hepatotoxicity in Rat by the Administration of Methanol Extract of Muntingia calabura L. Leaves Thu, 24 Apr 2014 09:43:43 +0000 Muntingia calabura L. is a tropical plant species that belongs to the Elaeocarpaceae family. The present study is aimed at determining the hepatoprotective activity of methanol extract of M. calabura leaves (MEMC) using two models of liver injury in rats. Rats were divided into five groups and received 10% DMSO (negative control), 50 mg/kg N-acetylcysteine (NAC; positive control), or MEMC (50, 250, and 500 mg/kg) orally once daily for 7 days and on the 8th day were subjected to the hepatotoxic induction using paracetamol (PCM). The blood and liver tissues were collected and subjected to biochemical and microscopical analysis. The extract was also subjected to antioxidant study using the 2,2-diphenyl-1-picrylhydrazyl-(DPPH) and superoxide anion-radical scavenging assays. At the same time, oxygen radical antioxidant capacity (ORAC) and total phenolic content were also determined. From the histological observation, lymphocyte infiltration and marked necrosis were observed in PCM-treated groups (negative control), whereas maintenance of hepatic structure was observed in group pretreated with N-acetylcysteine and MEMC. Hepatotoxic rats pretreated with NAC or MEMC exhibited significant decrease in ALT and AST enzymes level. Moreover, the extract also exhibited good antioxidant activity. In conclusion, MEMC exerts potential hepatoprotective activity that could be partly attributed to its antioxidant activity and, thus warrants further investigations. N. D. Mahmood, S. S. Mamat, F. H. Kamisan, F. Yahya, M. F. F. Kamarolzaman, N. Nasir, N. Mohtarrudin, S. F. Md. Tohid, and Z. A. Zakaria Copyright © 2014 N. D. Mahmood et al. All rights reserved. Evaluation of Anti-Candida Activity of Vitis vinifera L. Seed Extracts Obtained from Wine and Table Cultivars Wed, 23 Apr 2014 14:44:43 +0000 For the first time, grape seed extracts (GSEs), obtained from wine and table cultivars of Vitis vinifera L., cultured in experimental fields of Lazio and Puglia regions of Italy and grown in different agronomic conditions, have been tested on 43 Candida species strains. We demonstrated a significant correlation between the content of the flavan-3-ols in GSEs extracts, with a polymerization degree ≥4, and anti-Candida activity. Moreover, we demonstrated that GSEs, obtained from plants cultured with reduced irrigation, showed a content of polymeric flavan-3-ols 250 mg/g with geometric mean MIC values between 5.7 and 20.2 mg/L against Candida albicans reference strains. GSE, showing 573 mg/g of polymeric flavan-3-ols, has been tested in an experimental murine model of vaginal candidiasis by using noninvasive in vivo imaging technique. The results pointed out a significant inhibition of Candida albicans load 5 days after challenge. These findings indicate that GSEs with high content of polymeric flavan-3-ols can be used in mucosal infection as vaginal candidiasis. Giovanna Simonetti, Anna Rita Santamaria, Felicia Diodata D'Auria, Nadia Mulinacci, Marzia Innocenti, Francesca Cecchini, Eva Pericolini, Elena Gabrielli, Simona Panella, Donato Antonacci, Anna Teresa Palamara, Anna Vecchiarelli, and Gabriella Pasqua Copyright © 2014 Giovanna Simonetti et al. All rights reserved. The Influence of BMX Gene Polymorphisms on Clinical Symptoms after Mild Traumatic Brain Injury Tue, 22 Apr 2014 09:36:10 +0000 Mild traumatic brain injury (mTBI) is one of the most common neurological disorders. Most patients diagnosed with mTBI could fully recover, but 15% of patients suffer from persistent symptoms. In recent studies, genetic factors were found to be associated with recovery and clinical outcomes after TBI. In addition, results from our previous research have demonstrated that the bone marrow tyrosine kinase gene in chromosome X (BMX), a member of the Tec family of kinases, is highly expressed in rats with TBI. Therefore, our aim in this study was to identify the association between genetic polymorphisms of BMX and clinical symptoms following mTBI. Four tagging single nucleotide polymorphisms (tSNPs) of BMX with minimum allele frequency (MAF) >1% were selected from the HapMap Han Chinese database. Among these polymorphisms, rs16979956 was found to be associated with the Beck anxiety inventory (BAI) and dizziness handicap inventory (DHI) scores within the first week after head injury. Additionally, another SNP, rs35697037, showed a significant correlation with dizziness symptoms. These findings suggested that polymorphisms of the BMX gene could be a potential predictor of clinical symptoms following mTBI. Yu-Jia Wang, Yu-Wen Hsu, Che-Mai Chang, Chung-Che Wu, Ju-Chi Ou, Yan-Rou Tsai, Wen-Ta Chiu, Wei-Chiao Chang, Yung-Hsiao Chiang, and Kai-Yun Chen Copyright © 2014 Yu-Jia Wang et al. All rights reserved. Topical Application of Cleome viscosa Increases the Expression of Basic Fibroblast Growth Factor and Type III Collagen in Rat Cutaneous Wound Tue, 22 Apr 2014 00:00:00 +0000 Cleome viscosa L. (Cleomaceae) is an important traditional medicine of the Indian-Ayurvedic and Chinese-medicine system documented for rheumatic arthritis, hypertension, malaria, neurasthenia, and wound healing. The plant is also known as Asian spider flower and is distributed throughout the greater part of India. The present study explored the wound healing property of C. viscosa methanol extract (CvME) and its related mechanism using Wistar rat cutaneous excision wound model. Wound contraction rate, hydroxyproline quantification, and histopathological examination of wound granulation tissue were performed. The healing potential was comparatively assessed with a reference gentamicin sulfate hydrogel (0.01% w/w). Western blot for COL3A1, bFGF, and Smad-2, Smad-3, Smad-4, and Smad-7 was performed with 7-day postoperative granulation tissue. Results revealed that the topical application of CvME (2.5% w/w) significantly accelerated the wound contraction rate (95.14%, 24 postoperative days), increased the hydroxyproline content (3.947 mg/100 mg tissue), and improved histopathology of wound tissue as compared to control groups. Western blot analysis revealed that CvME significantly upregulated the expression of COL3A1 and bFGF and increased the Smad-mediated collagen production in granulation tissue. These findings suggest that C. viscosa promoted the wound repair process by attenuating the Smad-mediated collagen production in wound granulation tissue. Aadesh Upadhyay, Pronobesh Chattopadhyay, Danswrang Goyary, Papiya M. Mazumder, and Vijay Veer Copyright © 2014 Aadesh Upadhyay et al. All rights reserved. Effect of Dietary Intake of Avocado Oil and Olive Oil on Biochemical Markers of Liver Function in Sucrose-Fed Rats Thu, 17 Apr 2014 13:32:31 +0000 Metabolic changes, along with cardiovascular and hepatic factors, are associated with the development of diseases such as diabetes, dyslipidemia, and obesity. We evaluated the effect of avocado oil supplementation (centrifuged and solvent extracted), compared with olive oil, upon the hepatic function in sucrose-fed rats. Twenty-five rats were divided into five groups: control (basal diet), a sucrose-fed group (basal diet plus 30% sucrose solution), and three other groups (S-OO, S-AOC, and S-AOS, indicating basal diet plus 30% sucrose solution plus olive oil OO, avocado oil extracted by centrifugation AOC or using solvent AOS, resp.). Glucose, total cholesterol, triglycerides, total protein, albumin, globulin, direct bilirubin, glutamic pyruvic transaminase, glutamic oxaloacetic transaminase, alkaline phosphatase, cholinesterase, and α-amylase concentrations were determined and avocado oil effect on them was studied. In some cases the induced metabolic alteration significantly affected total protein and bilirubin levels and also had a highly significant effect on α-amylase levels. AOC and AOS exhibited effects similar to those of olive oil, according to the nonsignificant difference in fatty acid profile observed by other authors. Avocado oil consumption could be beneficial in the control of altered metabolic profile illnesses as it presents effects on hepatic function biochemical markers similar to olive oil. Octavio Carvajal-Zarrabal, Cirilo Nolasco-Hipolito, Ma. Guadalupe Aguilar-Uscanga, Guadalupe Melo Santiesteban, Patricia M. Hayward-Jones, and Dulce Ma. Barradas-Dermitz Copyright © 2014 Octavio Carvajal-Zarrabal et al. All rights reserved. Association between Risk Factors for Vascular Dementia and Adiponectin Thu, 17 Apr 2014 12:22:25 +0000 Vascular dementia is caused by various factors, including increased age, diabetes, hypertension, atherosclerosis, and stroke. Adiponectin is an adipokine secreted by adipose tissue. Adiponectin is widely known as a regulating factor related to cardiovascular disease and diabetes. Adiponectin plasma levels decrease with age. Decreased adiponectin increases the risk of cardiovascular disease and diabetes. Adiponectin improves hypertension and atherosclerosis by acting as a vasodilator and antiatherogenic factor. Moreover, adiponectin is involved in cognitive dysfunction via modulation of insulin signal transduction in the brain. Case-control studies demonstrate the association between low adiponectin and increased risk of stroke, hypertension, and diabetes. This review summarizes the recent findings on the association between risk factors for vascular dementia and adiponectin. To emphasize this relationship, we will discuss the importance of research regarding the role of adiponectin in vascular dementia. Juhyun Song, Won Taek Lee, Kyung Ah Park, and Jong Eun Lee Copyright © 2014 Juhyun Song et al. All rights reserved. Effect of Curcumin on Lifespan, Activity Pattern, Oxidative Stress, and Apoptosis in the Brains of Transgenic Drosophila Model of Parkinson’s Disease Thu, 17 Apr 2014 10:19:53 +0000 Background. A time dependent loss of dopaminergic neurons and the formation of intracellular aggregates of alpha synuclein have been reported in PD model flies. Methods. The progeny (PD flies) expressing human alpha synuclein was exposed to 25, 50, and 100 µM of curcumin mixed in the diet for 24 days. The effect of curcumin was studied on lifespan, activity pattern, oxidative stress, and apoptosis in the brains of PD model flies. The activity of PD model flies was monitored by using Drosophila activity monitors (DAMs). For the estimation of oxidative stress, lipid peroxidation and protein carbonyl content were estimated in the flies brains of each treated groups. The cell death in Drosophila brain was analyzed by isolating brains in Ringer’s solution placing them in 70% ethanol and stained in acridine orange to calculate the gray scale values. Results. The exposure of flies to 25, 50, and 100 µM of curcumin showed a dose dependent significant delay in the loss of activity pattern, reduction in the oxidative stress and apoptosis, and increase in the life span of PD model flies. Conclusion. Curcumin is potent in reducing PD symptoms. Yasir Hasan Siddique, Falaq Naz, and Smita Jyoti Copyright © 2014 Yasir Hasan Siddique et al. All rights reserved. In Search of the Active Metabolites of an Anticancer Piperazinedione, TW01003, in Rats Thu, 17 Apr 2014 10:05:12 +0000 TW01003, a piperazinedione derivative designed as an antimitotic agent, exhibited potent anticancer and antiangiogenesis activities in mice. However, oral administration of this compound in rats led to poor systemic bioavailability which suggested that in vivo efficacy might come from its metabolites. This report describes the identification of TW01003 metabolites in pig and Wistar rats. Following intravenous administration of TW01003, pig urine samples were subjected to sulfatase and glucuronidase treatment to monitor the biotransformation products. Rats were given TW01003 both intravenously and orally, and blood samples were collected and then analyzed by HPLC to quantitatively determine the metabolic transformation of TW01003 to its metabolite. A sulfate conjugate, TW01003 sulfate, was identified as the major metabolite for TW01003 after intravenous injection in both pig and rats. However, in rats, the glucuronide conjugate became major metabolite 30 min after TW01003 oral dosing. Pharmacokinetic analysis after intravenous administration of TW01003 indicated that TW01003 sulfate had a systemic bioavailability 2.5 times higher, volume of distribution three times higher, residence time seven times longer, and clearance rate 2.3 times lower compared to TW01003. Our results indicate that the potent anticancer and antiangiogenesis activities of TW01003 might not come from TW01003 per se but from its metabolites TW01003 sulfate. Chun-Li Wang, Ching-Kuei Chen, Yao-Horng Wang, and Yu-Wen Cheng Copyright © 2014 Chun-Li Wang et al. All rights reserved. Anticancer Drug-Incorporated Layered Double Hydroxide Nanohybrids and Their Enhanced Anticancer Therapeutic Efficacy in Combination Cancer Treatment Thu, 17 Apr 2014 09:42:54 +0000 Objective. Layered double hydroxide (LDH) nanoparticles have been studied as cellular delivery carriers for anionic anticancer agents. As MTX and 5-FU are clinically utilized anticancer drugs in combination therapy, we aimed to enhance the therapeutic performance with the help of LDH nanoparticles. Method. Anticancer drugs, MTX and 5-FU, and their combination, were incorporated into LDH by reconstruction method. Simply, LDHs were thermally pretreated at 400°C, and then reacted with drug solution to simultaneously form drug-incorporated LDH. Thus prepared MTX/LDH (ML), 5-FU/LDH (FL), and (MTX + 5-FU)/LDH (MFL) nanohybrids were characterized by X-ray diffractometer, scanning electron microscopy, infrared spectroscopy, thermal analysis, zeta potential measurement, dynamic light scattering, and so forth. The nanohybrids were administrated to the human cervical adenocarcinoma, HeLa cells, in concentration-dependent manner, comparing with drug itself to verify the enhanced therapeutic efficacy. Conclusion. All the nanohybrids successfully accommodated intended drug molecules in their house-of-card-like structures during reconstruction reaction. It was found that the anticancer efficacy of MFL nanohybrid was higher than other nanohybrids, free drugs, or their mixtures, which means the multidrug-incorporated LDH nanohybrids could be potential drug delivery carriers for efficient cancer treatment via combination therapy. Tae-Hyun Kim, Gyeong Jin Lee, Joo-Hee Kang, Hyoung-Jun Kim, Tae-il Kim, and Jae-Min Oh Copyright © 2014 Tae-Hyun Kim et al. All rights reserved. Antitumor and Antiangiogenic Activities of Curcumin in Cervical Cancer Xenografts in Nude Mice Wed, 16 Apr 2014 12:17:24 +0000 To evaluate the effects of curcumin (CUR) on tumor progression and angiogenesis in cervical cancer- (CaSki-) implanted nude mice and on the angiogenic biomarkers: vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2), and epidermal growth factor receptor (EGFR). CaSki cells were subcutaneously injected in nude mice to establish subcutaneous tumors. One month after injection, mice were orally administered vehicle or 500, 1,000, and 1,500 mg/kg of CUR daily × 30 consecutive days. Tumor volume was measured every 3-4 days. At the end of the study, tumor microvasculature was observed under confocal microscope, and immunohistochemical analyses were performed to detect CD31, VEGF, COX-2, and EGFR. CUR at the doses of 1,000 and 1,500 mg/kg showed significant tumor growth retardation (21.03% and 35.57%) versus CaSki + vehicle group. The microvascular density (MVD) in CaSki + vehicle group was significantly increased versus Control + vehicle group and significantly reduced by CUR (1,000 and 1,500 mg/kg). VEGF, COX-2, and EGFR expressions were upregulated in CaSki + vehicle group and attenuated significantly by CUR (1,000 and 1,500 mg/kg). In conclusion, high dose CUR inhibited tumor growth and angiogenesis in CaSki-implanted mice probably mediated by the downregulation of VEGF, COX-2 and EGFR. CUR may have a role in treating human cervical cancer and should be explored further. Pornphrom Yoysungnoen-Chintana, Parvapan Bhattarakosol, and Suthiluk Patumraj Copyright © 2014 Pornphrom Yoysungnoen-Chintana et al. All rights reserved. Activity Exerted by a Testosterone Derivative on Myocardial Injury Using an Ischemia/Reperfusion Model Wed, 16 Apr 2014 08:38:10 +0000 Some reports indicate that several steroid derivatives have activity at cardiovascular level; nevertheless, there is scarce information about the activity exerted by the testosterone derivatives on cardiac injury caused by ischemia/reperfusion (I/R). Analyzing these data, in this study, a new testosterone derivative was synthetized with the objective of evaluating its effect on myocardial injury using an ischemia/reperfusion model. In addition, perfusion pressure and coronary resistance were evaluated in isolated rat hearts using the Langendorff technique. Additionally, molecular mechanism involved in the activity exerted by the testosterone derivative on perfusion pressure and coronary resistance was evaluated by measuring left ventricular pressure in the absence or presence of the following compounds: flutamide, prazosin, metoprolol, nifedipine, indomethacin, and PINANE TXA2. The results showed that the testosterone derivative significantly increases the perfusion pressure and coronary resistance in isolated heart. Other data indicate that the testosterone derivative increases left ventricular pressure in a dose-dependent manner (0.001–100 nM); however, this phenomenon was significantly inhibited by indomethacin and PINANE-TXA2   at a dose of 1 nM. In conclusion, these data suggest that testosterone derivative induces changes in the left ventricular pressure levels through thromboxane receptor activation. Figueroa-Valverde Lauro, Díaz-Cedillo Francisco, García-Cervera Elodia, Pool-Gómez Eduardo, López-Ramos Maria, Rosas-Nexticapa Marcela, Hau-Heredia Lenin, Sarabia-Alcocer Betty, and Velázquez-Sarabia Betty Monica Copyright © 2014 Figueroa-Valverde Lauro et al. All rights reserved. Perinatal Pharmacology Sun, 13 Apr 2014 08:43:54 +0000 Karel Allegaert, Vassilios Fanos, Johannes N. van den Anker, and Stephanie Laër Copyright © 2014 Karel Allegaert et al. All rights reserved. Effect of Toona microcarpa Harms Leaf Extract on the Coagulation System Thu, 10 Apr 2014 17:48:23 +0000 Toona microcarpa Harms is a tonic, antiperiodic, antirheumatic, and antithrombotic agent in China and India and an astringent and tonic for treating diarrhea, dysentery, and other intestinal infections in Indonesia. In this study, we prepared ethyl-acetate extract from the air-dried leaves of Toona microcarpa Harms and investigated the anticoagulant activities in vitro by performing activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT) assays. Antiplatelet aggregation activity of the extract was examined using adenosine diphosphate (ADP), collagen, and thrombin as agonists, and the inhibitions of factor Xa and thrombin were also investigated. Bleeding and clotting times in mice were used to determine its anticoagulant activities in vivo. It is found that Toona microcarpa Harms leaf extract (TMHE) prolonged APTT, PT, and TT clotting times in a dose-dependent manner and significantly inhibited platelet aggregation induced by thrombin, but not ADP or collagen. Clotting time and bleeding time assays showed that TMHE significantly prolonged clotting and bleeding times in vivo. In addition, at the concentration of 1 mg/mL, TMHE inhibited human thrombin activity by 73.98 ± 2.78%. This is the first report to demonstrate that THME exhibits potent anticoagulant effects, possibly via inhibition of thrombin activity. Hao Chen, Min Jin, Yi-Fen Wang, Yong-Qing Wang, Ling Meng, Rong Li, Jia-Ping Wang, Li Gao, Yi Kong, and Ji-Fu Wei Copyright © 2014 Hao Chen et al. All rights reserved. The Antihyperglycemic Effects of Rhizoma Coptidis and Mechanism of Actions: A Review of Systematic Reviews and Pharmacological Research Thu, 10 Apr 2014 14:08:01 +0000 Rhizoma Coptidis (Huang Lian in Chinese pinyin) is among the most widely used traditional Chinese herbal medicines and has a profound history of more than 2000 years of being used as a therapeutic herb. The antidiabetic effects of Rhizoma Coptidis have been extensively investigated in animal experiments and clinical trials and its efficacy as a promising antihyperglycemic agent has been widely discussed. In the meantime, findings from modern pharmacological studies have contributed the majority of its bioactivities to berberine, the isoquinoline alkaloids component of the herb, and a number of experiments testing the antidiabetic effects of berberine have been initiated. Therefore, we conducted a review of the current evidence profile of the antihyperglycemic effects of Rhizoma Coptidis as well as its main component berberine and the possible mechanism of actions, in order to summarize research evidence in this area and identify future research directions. Hui Wang, Wei Mu, Hongcai Shang, Jia Lin, and Xiang Lei Copyright © 2014 Hui Wang et al. All rights reserved. Distinct Action of Flavonoids, Myricetin and Quercetin, on Epithelial Cl− Secretion: Useful Tools as Regulators of Cl− Secretion Thu, 10 Apr 2014 14:06:28 +0000 Epithelial Cl− secretion plays important roles in water secretion preventing bacterial/viral infection and regulation of body fluid. We previously suggested that quercetin would be a useful compound for maintaining epithelial Cl− secretion at a moderate level irrespective of cAMP-induced stimulation. However, we need a compound that stimulates epithelial Cl− secretion even under cAMP-stimulated conditions, since in some cases epithelial Cl− secretion is not large enough even under cAMP-stimulated conditions. We demonstrated that quercetin and myricetin, flavonoids, stimulated epithelial Cl− secretion under basal conditions in epithelial A6 cells. We used forskolin, which activates adenylyl cyclase increasing cytosolic cAMP concentrations, to study the effects of quercetin and myricetin on cAMP-stimulated epithelial Cl− secretion. In the presence of forskolin, quercetin diminished epithelial Cl− secretion to a level similar to that with quercetin alone without forskolin. Conversely, myricetin further stimulated epithelial Cl− secretion even under forskolin-stimulated conditions. This suggests that the action of myricetin is via a cAMP-independent pathway. Therefore, myricetin may be a potentially useful compound to increase epithelial Cl− secretion under cAMP-stimulated conditions. In conclusion, myricetin would be a useful compound for prevention from bacterial/viral infection even under conditions that the amount of water secretion driven by cAMP-stimulated epithelial Cl− secretion is insufficient. Hongxin Sun, Naomi Niisato, Kyosuke Nishio, Kirk L. Hamilton, and Yoshinori Marunaka Copyright © 2014 Hongxin Sun et al. All rights reserved. Pomegranate Fruit as a Rich Source of Biologically Active Compounds Thu, 10 Apr 2014 11:04:42 +0000 Pomegranate is a widely used plant having medicinal properties. In this review, we have mainly focused on the already published data from our laboratory pertaining to the effect of methanol extract of pericarp of pomegranate (PME) and have compared it with other relevant literatures on Punica. Earlier, we had shown its antiproliferative effect using human breast (MCF-7, MDA MB-231), and endometrial (HEC-1A), cervical (SiHa, HeLa), and ovarian (SKOV3) cancer cell lines, and normal breast fibroblasts (MCF-10A) at concentration of 20–320 μg/mL. The expressions of selected estrogen responsive genes (PR, pS2, and C-Myc) were downregulated by PME. Unlike estradiol, PME did not increase the uterine weight and proliferation in bilaterally ovariectomized Swiss-Albino mice models and its cardioprotective effects were comparable to that of 17β-estradiol. We had further assessed the protective role of PME on skeletal system, using MC3T3-E1 cells. The results indicated that PME (80 μg/mL) significantly increased ALP (Alkaline Phosphatase) activity, supporting its suggested role in modulating osteoblastic cell differentiation. The antiosteoporotic potential of PME was also evaluated in ovariectomized (OVX) rodent model. The results from our studies and from various other studies support the fact that pomegranate fruit is indeed a source of biologically active compounds. Sreeja Sreekumar, Hima Sithul, Parvathy Muraleedharan, Juberiya Mohammed Azeez, and Sreeja Sreeharshan Copyright © 2014 Sreeja Sreekumar et al. All rights reserved. -Mangostin Suppresses the Viability and Epithelial-Mesenchymal Transition of Pancreatic Cancer Cells by Downregulating the PI3K/Akt Pathway Thu, 10 Apr 2014 00:00:00 +0000 α-Mangostin, a natural product isolated from the pericarp of the mangosteen fruit, has been shown to inhibit the growth of tumor cells in various types of cancers. However, the underlying molecular mechanisms are largely unclear. Here, we report that α-mangostin suppressed the viability and epithelial-mesenchymal transition (EMT) of pancreatic cancer cells through inhibition of the PI3K/Akt pathway. Treatment of pancreatic cancer BxPc-3 and Panc-1 cells with α-mangostin resulted in loss of cell viability, accompanied by enhanced cell apoptosis, cell cycle arrest at G1 phase, and decrease of cyclin-D1. Moreover, Transwell and Matrigel invasion assays showed that α-mangostin significantly reduced the migration and invasion of pancreatic cancer cells. Consistent with these results, α-mangostin decreased the expression of MMP-2, MMP-9, N-cadherin, and vimentin and increased the expression of E-cadherin. Furthermore, we found that α-mangostin suppressed the activity of the PI3K/Akt pathway in pancreatic cancer cells as demonstrated by the reduction of the Akt phosphorylation by α-mangostin. Finally, α-mangostin significantly inhibited the growth of BxPc-3 tumor mouse xenografts. Our results suggest that α-mangostin may be potentially used as a novel adjuvant therapy or complementary alternative medicine for the management of pancreatic cancers. Qinhong Xu, Jiguang Ma, Jianjun Lei, Wanxing Duan, Liang Sheng, Xin Chen, Ang Hu, Zheng Wang, Zheng Wu, Erxi Wu, Qingyong Ma, and Xuqi Li Copyright © 2014 Qinhong Xu et al. All rights reserved. Potential Therapeutic Effects of Neurotrophins for Acute and Chronic Neurological Diseases Wed, 09 Apr 2014 13:48:10 +0000 The neurotrophins (NTs) nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), NT-3, and NT-4/5 are proteins that regulate cell proliferation, differentiation, and survival in both the developing and mature central nervous system (CNS) by binding to two receptor classes, Trk receptors and p75 NTR. Motivated by the broad growth- and survival-promoting effects of these proteins, numerous studies have attempted to use exogenous NTs to prevent the death of cells that are associated with neurological disease or promote the regeneration of severed axons caused by mechanical injury. Indeed, such neurotrophic effects have been repeatedly demonstrated in animal models of stroke, nerve injury, and neurodegenerative disease. However, limitations, including the short biological half-lives and poor blood-brain permeability of these proteins, prevent routine application from treating human disease. In this report, we reviewed evidence for the neuroprotective efficacy of NTs in animal models, highlighting outstanding technical challenges and discussing more recent attempts to harness the neuroprotective capacity of endogenous NTs using small molecule inducers and cell transplantation. Junying Cai, Fuzhou Hua, Linhui Yuan, Wei Tang, Jun Lu, Shuchun Yu, Xifeng Wang, and Yanhui Hu Copyright © 2014 Junying Cai et al. All rights reserved. Medicinal Practice of Bioactive Compounds (Natural/Synthetic): An Insight into Gastrointestinal Disorders Mon, 07 Apr 2014 06:50:01 +0000 Mahmood Ameen Abdulla, Ibrahim Banat, and Patrick Naughton Copyright © 2014 Mahmood Ameen Abdulla et al. All rights reserved. Characterization of Imidazoline Receptors in Blood Vessels for the Development of Antihypertensive Agents Thu, 03 Apr 2014 13:35:47 +0000 It has been indicated that activation of peripheral imidazoline I2-receptor (I-2R) may reduce the blood pressure in spontaneously hypertensive rats (SHRs). Also, guanidinium derivatives show the ability to activate imidazoline receptors. Thus, it is of special interest to characterize the I-2R using guanidinium derivatives in blood vessels for development of antihypertensive agent(s). Six guanidinium derivatives including agmatine, amiloride, aminoguanidine, allantoin, canavanine, and metformin were applied in this study. Western blot analysis was used for detecting the expression of imidazoline receptor in tissues of Wistar rats. The isometric tension of aortic rings isolated from male rats was also estimated. The expression of imidazoline receptor on rat aorta was identified. However, guanidinium derivatives for detection of aortic relaxation were not observed except agmatine and amiloride which induced a marked relaxation in isolated aortic rings precontracted with phenylephrine or KCl. Both relaxations induced by agmatine and amiloride were attenuated by glibenclamide at concentration enough to block ATP-sensitive potassium () channels. Meanwhile, only agmatine-induced relaxation was abolished by BU224, a selective antagonist of imidazoline I2-receptors. Taken together, we suggest that agmatine can induce vascular relaxation through activation of peripheral imidazoline I2-receptor to open channels. Thus, agmatine-like compound has the potential to develop as a new therapeutic agent for hypertension in the future. Mei-Fen Chen, Jo-Ting Tsai, Li-Jen Chen, Tung-Pi Wu, Jia-Jang Yang, Li-Te Yin, Yu-lin Yang, Tai-An Chiang, Han-Lin Lu, and Ming-Chang Wu Copyright © 2014 Mei-Fen Chen et al. All rights reserved. Montanoa frutescens and Montanoa grandiflora Extracts Reduce Anxiety-Like Behavior during the Metestrus-Diestrus Phase of the Ovarian Cycle in Wistar Rats Tue, 01 Apr 2014 11:38:42 +0000 In previous studies, the anxiolytic-like effects of Montanoa tomentosa and Montanoa frutescens were reported in male rats, but the potential anxiolytic-like effects of Montanoa plants during the different phases of the ovarian cycle in rats remain to be explored. The anxiolytic-like effects of the aqueous crude extracts of M. frutescens (25 and 50 mg/kg) and M. grandiflora (25 and 50 mg/kg) in the elevated plus maze were investigated in Wistar rats during the estrous cycle and compared with 2 mg/kg diazepam as a reference anxiolytic drug. To investigate any motor effect (i.e., hyperactivity, no changes, or hypoactivity) associated with the treatments, the rats were evaluated in the open field test. The M. frutescens (25 and 50 mg/kg) and M. grandiflora (50 mg/kg) extracts exerted anxiolytic-like effects during the metestrus-diestrus phase, similar to diazepam, without disrupting spontaneous motor activity. No significant effects of the extracts were detected in either behavioral test during the proestrus-estrus phase, whereas diazepam produced motor hypoactivity in the open field test. These results indicate that the M. frutescens and M. grandiflora extracts possess anxiolytic-like effects that depend on the ovarian cycle phase, supporting the Mexican ancient medicinal use of these plants to ameliorate anxiety disorders. Juan Francisco Rodríguez-Landa, Julio Vicente-Serna, Luis Alfredo Rodríguez-Blanco, María de Jesús Rovirosa-Hernández, Francisco García-Orduña, and Miguel Carro-Juárez Copyright © 2014 Juan Francisco Rodríguez-Landa et al. All rights reserved. Preliminary In Vitro and In Vivo Evaluation of Antidiabetic Activity of Ducrosia anethifolia Boiss. and Its Linear Furanocoumarins Mon, 31 Mar 2014 06:49:39 +0000 Aim. Ducrosia anethifolia is used as flavoring additive. There have been little detailed phytochemical reports on this genus and the antidiabetic activity of this plant is not yet evaluated. Method. Structure of compounds was deduced by spectroscopic analyses. Preliminary in vitro evaluation of the antidiabetic activity of crude extract and its furanocoumarins was carried out (α-amylase, α-glucosidase, and β-galactosidase). The in vivo activity was investigated by measuring some oxidative stress markers. Biomarkers of liver injury and kidney were also determined. Results. Eight linear furanocoumarins, psoralen, 5-methoxypsoralen, 8-methoxypsoralen, imperatorin, isooxypeucedanin, pabulenol, oxypeucedanin methanolate, oxypeucedanin hydrate, and 3-O-glucopyranosyl-β-sitosterol, were isolated. All compounds were reported for the first time from the genus Ducrosia except pabulenol. The blood glucose level, liver function enzymes, total protein, lipid, and cholesterol levels were significantly normalized by extract treatment. The antioxidant markers, glucolytic, and gluconeogenic enzymes were significantly ameliorated and the elevated level of kidney biomarkers in the diabetic groups was restored. The compounds showed inhibitory activity in a concentration dependant manner. Imperatorin and 5-methoxypsoralen showed the most potent inhibiting power. Conclusion. D. anethifolia extract showed hypoglycemic, hypolipidemic, and antioxidant effect as well as ameliorating kidney function. This extract and some linear furanocoumarins exhibited carbohydrate metabolizing enzymes inhibitory effect. Nagwa M. M. Shalaby, Howaida I. Abd-Alla, Hanan F. Aly, Marzougah A. Albalawy, Kamel H. Shaker, and Jalloul Bouajila Copyright © 2014 Nagwa M. M. Shalaby et al. All rights reserved. Preparation of Naringenin/β-Cyclodextrin Complex and Its More Potent Alleviative Effect on Choroidal Neovascularization in Rats Thu, 27 Mar 2014 08:50:11 +0000 Choroidal neovascularization (CNV) is characterized by abnormal blood vessels growing from the choroid. Current remedies for CNV have not shown favorable therapeutic efficacy. It is urgent to identify and develop more safe and potent anti-CNV agents via multiple technologies. We previously showed that the natural product naringenin attenuated CNV. However, naringenin has poor water solubility and low bioavailability. Here, we prepared the β-cyclodextrin (β-CD) complex of naringenin and characterized it using infrared spectra and X-ray diffraction analyses. Determination of content and solubility in the complex showed that naringenin accounted for 20.53% in the complex and its solubility was increased by more than 10-fold. Using a laser-induced CNV model in rats we demonstrated that naringenin/β-CD complex more significantly reduced CNV area than naringenin alone in rats. Furthermore, naringenin and its β-CD complex significantly inhibited the mRNA and protein expression of VEGF, COX-2, PI3K, p38MAPK, MMP-2, and MMP-9 in retina and choroid tissues. Naringenin/β-CD complex showed more significant inhibitory effect on VEGF and COX-2 expression than naringenin. These results collectively indicated that naringenin/β-CD complex could be a promising therapeutic option for CNV and that the beneficial effects could be linked to the anti-inflammatory properties of naringenin. Xin-rong Xu, Hai-tao Yu, Li Hang, Yan Shao, Shu-hua Ding, and Xue-wen Yang Copyright © 2014 Xin-rong Xu et al. All rights reserved. Anti-Proliferative Effect and Phytochemical Analysis of Cymbopogon citratus Extract Thu, 27 Mar 2014 00:00:00 +0000 The antiproliferative and antioxidant potential of Cymbopogon citratus (Lemon grass) extracts were investigated. The extracts were isolated by solvent maceration method and thereafter subjected to antiproliferative activity test on five different cancer cells: human colon carcinoma (HCT-116), breast carcinoma (MCF-7 and MDA-MB 231), ovarian carcinoma (SKOV-3 and COAV), and a normal liver cell line (WRL 68). The cell viability was determined using MTT assay. The DPPH radical scavenging assay revealed a concentration dependent trend. A maximum percentage inhibition of 45% and an IC50 of 278?µg/mL were observed when aqueous extract was evaluated. In contrast, 48.3% and IC50 of 258.9?µg/mL were observed when 50% ethanolic extract was evaluated. Both extracts at concentration of 50 to 800?µg/mL showed appreciative metal chelating activity with IC50 value of ?µg/mL to ?µg/mL. Depending on extraction solvent content, extract obtained from 50% ethanolic solvent proved to be more potent on breast cancer MCF-7 cell line (IC50 = 68?µg/mL). On the other hand, 90% ethanolic extract showed a moderate potency on the ovarian cancer (COAV) and MCF-7 cells having an IC50 of 104.6?µg/mL each. These results suggested antiproliferative efficacy of C. citratus ethanolic extract against human cancer cell lines. Mohammed F. Halabi and Bassem Y. Sheikh Copyright © 2014 Mohammed F. Halabi and Bassem Y. Sheikh. All rights reserved. Multidrug Resistance 1 Gene Variants, Pesticide Exposure, and Increased Risk of DNA Damage Wed, 26 Mar 2014 17:18:35 +0000 The P-glycoprotein, encoded by the multidrug resistance (MDR)1 gene, extrudes fat-soluble compounds to the extracellular environment. However, the DNA damage of pesticides in subjects with genetic variation in MDR1 has not been investigated. In this study, the comet assay was applied to examine the extent of DNA damage in the peripheral blood of 195 fruit growers who had been exposed to pesticides and 141 unexposed controls. The MDR1 polymorphisms were identified. Questionnaires were administered to obtain demographic data and occupational history. Results showed subjects experiencing high (2.14 m/cell, ) or low pesticide exposure (2.18 m/cell, ) had a significantly greater DNA tail moment than controls (1.28 m/cell). Compared to the MDR1 T-129C (rs3213619) TC/CC carriers, the TT carriers had increased DNA tail moment in controls (1.30 versus 1.12 m/cell, ). Similar results were observed in the high and low pesticide-exposed groups. Combined analysis revealed that pesticide-exposed fruit growers with MDR1 -129 TT genotype had the greatest DNA damage in the subjects with the combinations of pesticide exposure and MDR1 -129 genotypes. In conclusion, pesticide exposed individuals with susceptible MDR1 -129 genotypes may experience increased risk of DNA damage. Chun-Chieh Chen, Chun-Huang Huang, Man-Tzu Marcie Wu, Chia-Hsuan Chou, Chia-Chen Huang, Tzu-Yen Tseng, Fang-Yu Chang, Ying-Ti Li, Chun-Cheng Tsai, Tsung-Shing Wang, and Ruey-Hong Wong Copyright © 2014 Chun-Chieh Chen et al. All rights reserved. Alleviation of Plasma Homocysteine Level by Phytoestrogen -Zearalanol Might Be Related to the Reduction of Cystathionine -Synthase Nitration Mon, 24 Mar 2014 16:24:06 +0000 Hyperhomocysteinemia is strongly associated with cardiovascular diseases. Previous studies have shown that phytoestrogen -zearalanol can protect cardiovascular system from hyperhomocysteinemia and ameliorate the level of plasma total homocysteine; however, the underlying mechanisms remain to be clarified. The aim of this research is to investigate the possible molecular mechanisms involved in ameliorating the level of plasma homocysteine by -zearalanol. By the successfully established diet-induced hyperhomocysteinemia rat models, we found that, after -zearalanol treatment, the activity of cystathionine -synthase, the key enzyme in homocysteine metabolism, was significantly elevated and level of nitrative stress in liver was significantly reduced. In correlation with this, results also showed a decreased nitration level of cystathionine -synthase in liver. Together data implied that alleviation of plasma homocysteine level by phytoestrogen -zearalanol might be related to the reduction of cystathionine -synthase nitration. Hui Zhang, Qi Sun, Teng Liu, Lu Ma, Panpan Zhen, Ke Wang, Lingqiao Lu, Xin Liu, Xin Zhang, Dandan Song, Xiaoyun Zuo, Huirong Liu, and Wen Wang Copyright © 2014 Hui Zhang et al. All rights reserved. Recombinant Keratinocyte Growth Factor 1 in Tobacco Potentially Promotes Wound Healing in Diabetic Rats Mon, 24 Mar 2014 13:53:15 +0000 Keratinocyte growth factor 1 (KGF1) is a growth factor that promotes epidermal cell proliferation, migration, differentiation, and wound repair. It is expressed at low levels in a form of inclusion body in E. coli. In order to increase its expression and activity, we produced tobacco plants expressing KGF1 via Agrobacterium-mediated transformation using a potato virus X (PVX)-based vector (pgR107). The vector contained the sequence encoding the KGF1 gene fused with a green florescence protein. The recombinant plasmid was introduced into leaf cells of Nicotiana benthamiana (a wild Australian tobacco) via Agrobacterium-mediated agroinfiltration. As determined by fluorescence and Western blot of leaf extracts, the KGF1 gene was correctly translated into the tobacco plants. The recombinant KGF1 was purified from plant tissues by heparin affinity chromatography, and cell proliferation in NIH/3T3 cells was stimulated by the purified KGF1. The purified KGF1 was also applied to the wounds of type-II diabetic rats. KGF1 had accumulated to levels as high as 530 μg/g fresh weight in the leaves of agroinfected plants. We show that plant-derived KGF1 can promote the proliferation of NIH/3T3 cells and have significant effects on the type-II diabetic rat. The present findings indicated that KGF1 from tobacco maintains its biological activity, implying prospective industrial production in a plant bioreactor. Zhi-Guo Feng, Shi-Feng Pang, Ding-Jiong Guo, Yue-Tao Yang, Bin Liu, Ji-Wei Wang, Ke-Qin Zheng, and Yi Lin Copyright © 2014 Zhi-Guo Feng et al. All rights reserved. Cerebrovascular and Neuroprotective Effects of Adamantane Derivative Thu, 20 Mar 2014 07:32:33 +0000 Objectives. The influence of 5-hydroxyadamantane-2-on was studied on the rats’ brain blood flow and on morphological state of brain tissue under the condition of brain ischemia. The interaction of the substance with NMDA receptors was also studied. Methods. Study has been implemented using the methods of local blood flow registration by laser flowmeter, [3H]-MK-801binding, and morphological examination of the brain tissue. We used the models of global transient ischemia of the brain, occlusion of middle cerebral artery, and hypergravity ischemia of the brain. Results. Unlike memantine, antagonist of glutamatergic receptors, the 5-hydroxyadamantane-2-on does not block NMDA receptors but enhances the cerebral blood flow of rats with brain ischemia. This effect is eliminated by bicuculline. Under conditions of permanent occlusion of middle cerebral artery, 5-hydroxyadamantane-2-on has recovered compensatory regeneration in neural cells, axons, and glial cells, and the number of microcirculatory vessels was increased. 5-Hydroxyadamantane-2-on was increasing the survival rate of animals with hypergravity ischemia. Conclusions. 5-Hydroxyadamantane-2-on, an adamantane derivative, which is not NMDA receptors antagonist, demonstrates significant cerebrovascular and neuroprotective activity in conditions of brain ischemia. Presumably, the GABA-ergic system of brain vessels is involved in mechanisms of cerebrovascular and neuroprotective activity of 5-hydroxyadamantane-2-on. Ruben S. Mirzoyan, Tamara S. Gan’shina, Denis V. Maslennikov, Georgy I. Kovalev, Ivan A. Zimin, Boris M. Pyatin, Nina I. Avdyunina, Anna M. Kukhtarova, Nelly G. Khostikyan, Vahe S. Meliksetyan, Cristina B. Alikhanyan, and Narine R. Mirzoyan Copyright © 2014 Ruben S. Mirzoyan et al. All rights reserved. Cardiac Electrophysiological Alterations in Heart/Muscle-Specific Manganese-Superoxide Dismutase-Deficient Mice: Prevention by a Dietary Antioxidant Polyphenol Wed, 19 Mar 2014 12:35:43 +0000 Cardiac electrophysiological alterations induced by chronic exposure to reactive oxygen species and protective effects of dietary antioxidant have not been thoroughly examined. We recorded surface electrocardiograms (ECG) and evaluated cellular electrophysiological abnormalities in enzymatically-dissociated left ventricular (LV) myocytes in heart/muscle-specific manganese-superoxide dismutase-deficient (H/M-Sod2−/−) mice, which exhibit dilated cardiomyopathy due to increased oxidative stress. We also investigated the influences of intake of apple polyphenols (AP) containing mainly procyanidins with potent antioxidant activity. The QRS and QT intervals of ECG recorded in H/M-Sod2−/− mice were prolonged. The effective refractory period in the LV myocardium of H/M-Sod2−/− mice was prolonged, and susceptibility to ventricular tachycardia or fibrillation induced by rapid ventricular pacing was increased. Action potential duration in H/M-Sod2−/− LV myocytes was prolonged, and automaticity was enhanced. The density of the inwardly rectifier K+ current () was decreased in the LV cells of H/M-Sod2−/− mice. The AP intake partially improved these electrophysiological alterations and extended the lifespan in H/M-Sod2−/− mice. Thus, chronic exposure of the heart to oxidative stress produces a variety of electrophysiological abnormalities, increased susceptibility to ventricular arrhythmias, and action potential changes associated with the reduced density of . Dietary intake of antioxidant nutrients may prevent oxidative stress-induced electrophysiological disturbances. Tadahiro Sunagawa, Takahiko Shimizu, Akio Matsumoto, Motoyuki Tagashira, Tomomasa Kanda, Takuji Shirasawa, and Haruaki Nakaya Copyright © 2014 Tadahiro Sunagawa et al. All rights reserved. Study of Effect of Salvianolic Acid B on Motor Function Recovery in Rats with Spinal Cord Injury Tue, 18 Mar 2014 11:55:46 +0000 In this study effect of salvianolic acid B was observed on motor function recovery of rats with spinal cord injury. 50 rats were selected and after inducing SCI their recovery under controlled conditions was studied using Sal B and PBS (as control). Both compounds were introduced intraperitoneally in respective groups of traumatic rats at the same time intervals for 28 days. It was observed that Sal B introduced at 5  mg/kg/day resulted in better motor function recovery. BBB score was recorded which increased significantly along with the reduction in cavity area observed by bright field microscopy of tissues, that is, from 1 to 10 and from  mm2 to  mm2, in Sal B treated group, respectively, compared to PBS group. Statistical analysis was carried out using SPSS software (SPSS, Chicago, IL, USA), values were expressed as mean ± SEM, and value <0.01 was considered significant. Effect of Sal B on expression of NF-kB p65 and IkBα was studied and OD values of densitometry of western blots were taken. MPO activity was also studied. It was observed that treatment of Sal B significantly reduced the expression of both compounds in Sal B treated group as compared to control group after 28 days of treatment. Chong Xun, Yang Hu, Ming Lu, Shouyu Wang, and Decheng Lv Copyright © 2014 Chong Xun et al. All rights reserved. Perinatal Hypoxia-Ischemia Reduces α7 Nicotinic Receptor Expression and Selective α7 Nicotinic Receptor Stimulation Suppresses Inflammation and Promotes Microglial Mox Phenotype Mon, 17 Mar 2014 16:19:23 +0000 Inflammation plays a central role in neonatal brain injury. During brain inflammation the resident macrophages of the brain, the microglia cells, are rapidly activated. In the periphery, α7 nicotinic acetylcholine receptors (α7R) present on macrophages can regulate inflammation by suppressing cytokine release. In the current study we investigated α7R expression in neonatal mice after hypoxia-ischemia (HI). We further examined possible anti-inflammatory role of α7R stimulation in vitro and microglia polarization after α7R agonist treatment. Real-time PCR analysis showed a 33% reduction in α7R expression 72 h after HI. Stimulation of primary microglial cells with LPS in combination with increasing doses of the selective α7R agonist AR-R 17779 significantly attenuated TNFα release and increased α7R transcript in microglial cells. Gene expression of M1 markers CD86 and iNOS, as well as M2 marker CD206 was not influenced by LPS and/or α7R agonist treatment. Further, Mox markers heme oxygenase (Hmox1) and sulforedoxin-1 (Srx1) were significantly increased, suggesting a polarization towards the Mox phenotype after α7R stimulation. Thus, our data suggest a role for the α7R also in the neonatal brain and support the anti-inflammatory role of α7R in microglia, suggesting that α7R stimulation could enhance the polarization towards a reparative Mox phenotype. Sansan Hua, C. Joakim Ek, Carina Mallard, and Maria E. Johansson Copyright © 2014 Sansan Hua et al. All rights reserved. Genetic Polymorphisms of ORAI1 and Chronic Kidney Disease in Taiwanese Population Mon, 17 Mar 2014 11:55:32 +0000 Taiwan has very high incidence and prevalence of chronic kidney disease (CKD), which easily progresses to end-stage renal disease (ESRD). The association between inflammation and CKD has been explored in several studies. ORAI1 functions as a pore-forming subunit of the store-operated calcium channels which are involved in the regulation of immune system. Hence, we conducted a case-control study to determine whether the genetic polymorphisms of ORAI1 gene is a susceptibility factor to CKD and its clinical features in a Taiwanese population. Five hundred seventy-nine CKD patients from a hospital-based CKD care program were included in the study. Five tagging single nucleotide polymorphisms (tSNPs) of ORAI1 were selected from the genotyping data of the Han Chinese population from the HapMap project. Among these polymorphisms, rs12313273 was found to be significantly associated with elevated serum calcium levels, which has been linked to increased risk of death in CKD patients. To have a better management of serum calcium, we suggest that ORAI1 polymorphisms might be used as a potential biomarker for initiating non-calcium-based phosphate binder in CKD patients in the future. Daw-Yang Hwang, Shu-Chen Chien, Yu-Wen Hsu, Chih-Chin Kao, Shih-Ying Cheng, Hui-Chen Lu, Mai-Szu Wu, and Jer-Ming Chang Copyright © 2014 Daw-Yang Hwang et al. All rights reserved. Association of Single Nucleotide Polymorphisms in Estrogen Receptor Alpha Gene with Susceptibility to Knee Osteoarthritis: A Case-Control Study in a Chinese Han Population Mon, 17 Mar 2014 09:41:05 +0000 Osteoarthritis (OA) is the most prevalent form of arthritis and its multifactorial nature has been increasingly recognized. Genetic factors play an important role in OA etiology and estrogen receptor alpha (ESR1) gene polymorphisms may be involved. This study tried to explore whether the ESR1 gene single nucleotide polymorphisms (SNPs) were associated with primary knee OA in the Chinese Han population. Two SNPs, rs2234693 and rs9340799, were genotyped in 469 cases and 522 controls. Rs2234693 was associated with knee OA in the dominant genetic model (TT + TC versus CC) and a higher T allele frequency existed among females. The combined genotype (TT + TC) and T allele were related with mild knee OA only. For rs9340799, A allele was associated with knee OA in all subjects and females . Statistical differences were detected in the dominant genetic model (AA + AG versus GG) among females . The combined genotype (AA + AG) and A allele were merely correlated with mild knee OA. ESR1 gene is considerably associated with knee OA etiology in the Chinese Han population. Xiaoyu Dai, Chao Wang, Jin Dai, Dongquan Shi, Zhihong Xu, Dongyang Chen, Huajian Teng, and Qing Jiang Copyright © 2014 Xiaoyu Dai et al. All rights reserved. Merit of Ginseng in the Treatment of Heart Failure in Type 1-Like Diabetic Rats Mon, 17 Mar 2014 08:27:24 +0000 The present study investigated the merit of ginseng in the improvement of heart failure in diabetic rats and the role of peroxisome proliferator-activated receptors δ (PPARδ). We used streptozotocin-induced diabetic rat (STZ-rat) to screen the effects of ginseng on cardiac performance and PPARδ expression. Changes of body weight, water intake, and food intake were compared in three groups of age-matched rats; the normal control (Wistar rats) received vehicle, STZ-rats received vehicle and ginseng-treated STZ-rats. We also determined cardiac performances in addition to blood glucose level in these animals. The protein levels of PPARδ in hearts were identified using Western blotting analysis. In STZ-rats, cardiac performances were decreased but the food intake, water intake, and blood glucose were higher than the vehicle-treated control. After a 7-day treatment of ginseng in STZ-rats, cardiac output was markedly enhanced without changes in diabetic parameters. This treatment with ginseng also increased the PPARδ expression in hearts of STZ-rats. The related signal of cardiac contractility, troponin I phosphorylation, was also raised. Ginseng-induced increasing of cardiac output was reversed by the cotreatment with PPARδ antagonist GSK0660. Thus, we suggest that ginseng could improve heart failure through the increased PPARδ expression in STZ-rats. Cheng-Chia Tsai, Paul Chan, Li-Jen Chen, Chen Kuei Chang, Zhongmin Liu, and Jia-Wei Lin Copyright © 2014 Cheng-Chia Tsai et al. All rights reserved. Rosiglitazone Regulates Anti-Inflammation and Growth Inhibition via PTEN Thu, 13 Mar 2014 14:32:04 +0000 Peroxisome proliferator-activated receptor gamma (PPAR) agonist has anti-inflammatory and anticancer properties. However, the mechanisms by which PPAR agonist rosiglitazone interferes with inflammation and cancer via phosphatase and tensin homolog-(PTEN)-dependent pathway remain unclear. We found that lower doses (<25?µM) of rosiglitazone significantly inhibited lipopolysaccharide-(LPS)-induced nitric oxide (NO) release (via inducible nitric oxide synthase, iNOS), prostaglandin E2 (PGE2) production (via cyclooxygenase-2, COX-2), and activation of Akt in RAW 264.7 murine macrophages. However, rosiglitazone did not inhibit the production of reactive oxygen species (ROS). In PTEN knockdown (shPTEN) cells exposed to LPS, rosiglitazone did not inhibit NO release, PGE2 production, and activation of Akt. These cells had elevated basal levels of iNOS, COX-2, and ROS. However, higher doses (25–100?µM) of rosiglitazone, without LPS stimulation, did not block NO release and PGE2 productions, but they inhibited p38 MAPK phosphorylation and blocked ROS generation in shPTEN cells. In addition, rosiglitazone caused G1 arrest and reduced the number of cells in S?+?G2/M phase, leading to growth inhibition. These results indicate that the anti-inflammatory property of rosiglitazone is related to regulation of PTEN independent of inhibition on ROS production. However, rosiglitazone affected the dependence of PTEN-deficient cell growth on ROS. Chiou-Feng Lin, Kung-Chia Young, Chyi-Huey Bai, Bu-Chin Yu, Ching-Ting Ma, Yu-Chieh Chien, Chiu-Ling Chiang, Chao-Sheng Liao, Hsin-Wen Lai, and Chiung-Wen Tsao Copyright © 2014 Chiou-Feng Lin et al. All rights reserved. Antihypertensive Action of Allantoin in Animals Wed, 12 Mar 2014 16:41:45 +0000 The agonists of imidazoline I-1 receptors (I-1R) are widely used to lower blood pressure. It has been indicated that guanidinium derivatives show an ability to activate imidazoline receptors. Also, allantoin has a chemical stricture similar to guanidinium derivatives. Thus, it is of special interest to characterize the effect of allantoin on I-1R. In conscious male spontaneous hypertensive rats (SHRs), mean blood pressure (MBP) was recorded using the tail-cuff method. Furthermore, the hemodynamic analyses in catheterized rats were applied to measure the actions of allantoin in vivo. Allantoin decreased blood pressures in SHRs at 30 minutes, as the most effective time. Also, this antihypertensive action was shown in a dose-dependent manner from SHRs treated with allantoin. Moreover, in anesthetized rats, allantoin inhibited cardiac contractility and heart rate as showing in hemodynamic max significantly. Also, the peripheral blood flow was markedly increased by allantoin. Both actions were diminished by efaroxan at the dose sufficient to block I-1R. Thus, we suggest that allantoin, as I-1R agonist, has the potential to develop as a new therapeutic agent for hypertension in the future. Mei-Fen Chen, Jo-Ting Tsai, Li-Jen Chen, Tung-Pi Wu, Jia-Jang Yang, Li-Te Yin, Yu-lin Yang, Tai-An Chiang, Han-Lin Lu, and Ming-Chang Wu Copyright © 2014 Mei-Fen Chen et al. All rights reserved. Digging Up the Human Genome: Current Progress in Deciphering Adverse Drug Reactions Mon, 10 Mar 2014 09:14:57 +0000 Adverse drug reactions (ADRs) are a major clinical problem. In addition to their clinical impact on human health, there is an enormous cost associated with ADRs in health care and pharmaceutical industry. Increasing studies revealed that genetic variants can determine the susceptibility of individuals to ADRs. The development of modern genomic technologies has led to a tremendous advancement of improving the drug safety and efficacy and minimizing the ADRs. This review will discuss the pharmacogenomic techniques used to unveil the determinants of ADRs and summarize the current progresses concerning the identification of biomarkers for ADRs, with a focus on genetic variants for genes encoding drug-metabolizing enzymes, drug-transporter proteins, and human leukocyte antigen (HLA). The knowledge gained from these cutting-edge findings will form the basis for better prediction and management for ADRs, ultimately making the medicine personalized. Shih-Chi Su, Wen-Hung Chung, and Shuen-Iu Hung Copyright © 2014 Shih-Chi Su et al. All rights reserved. Characterization of Musclin as a New Target for Treatment of Hypertension Sun, 09 Mar 2014 12:40:04 +0000 Musclin is a novel skeletal muscle-derived factor found in the signal sequence trap of mouse skeletal muscle cDNAs. Recently, it has been demonstrated that musclin is involved in the pathogenesis of spontaneously hypertensive rats (SHRs). However, it is known as a genetic hypertension model. In the present study, we aim to investigate the role of musclin in another animal model of hypertension and characterize the direct effect of musclin on vascular contraction. The results show that expression of musclin was increased in arterial tissues isolated from DOCA-salt induced hypertensive rats or the normal rats received repeated vasoconstriction with phenylephrine. Additionally, direct incubation with phenylephrine did not modify the expression of musclin in the in vitro studies. Also, the direct effect of musclin on the increase of intracellular calcium was observed in a concentration-dependent manner. These results provide the evidence to support that musclin is involved in hypertension. Thus, musclin is suitable to be considered as a novel target for treatment of hypertension. Jia-Wei Lin, Cheng-Chia Tsai, Li-Jen Chen, Ho-Shan Niu, Chen Kuei Chang, and Chiang-Shan Niu Copyright © 2014 Jia-Wei Lin et al. All rights reserved. Folic Acid Supplementation and Preterm Birth: Results from Observational Studies Mon, 03 Mar 2014 12:13:32 +0000 Introduction. Folic acid (FA) supplementation is recommended worldwide in the periconceptional period for the prevention of neural tube defects. Due to its involvement in a number of cellular processes, its role in other pregnancy outcomes such as miscarriage, recurrent miscarriage, low birth weight, preterm birth (PTB), preeclampsia, abruptio placentae, and stillbirth has been investigated. PTB is a leading cause of perinatal mortality and morbidity; therefore its association with FA supplementation is of major interest. The analysis of a small number of randomized clinical trials (RCTs) has not found a beneficial role of FA in reducing the rate of PTBs. Aim of the Study. The aim of this review was to examine the results from recent observational studies about the effect of FA supplementation on PTB. Materials and Methods. We carried out a search on Medline and by manual search of the observational studies from 2009 onwards that analyzed the rate of PTB in patients who received supplementation with FA before and/or throughout pregnancy. Results. The results from recent observational studies suggest a slight reduction of PTBs that is not consistent with the results from RCTs. Further research is needed to better understand the role of FA supplementation before and during pregnancy in PTB. Elena Mantovani, Francesca Filippini, Renata Bortolus, and Massimo Franchi Copyright © 2014 Elena Mantovani et al. All rights reserved. Brazilin Ameliorates High Glucose-Induced Vascular Inflammation via Inhibiting ROS and CAMs Production in Human Umbilical Vein Endothelial Cells Sun, 02 Mar 2014 00:00:00 +0000 Vascular inflammatory process has been suggested to play a key role in the initiation and progression of atherosclerosis, a major complication of diabetes mellitus. Recent studies have shown that brazilin exhibits antihepatotoxic, antiplatelet, cancer preventive, or anti-inflammatory properties. Thus, we investigated whether brazilin suppresses vascular inflammatory process induced by high glucose (HG) in cultured human umbilical vein endothelial cells (HUVEC). HG induced nitrite production, lipid peroxidation, and intracellular reactive oxygen species formation in HUVEC cells, which was reversed by brazilin. Western blot analysis revealed that brazilin markedly inhibited HG-induced phosphorylation of endothelial nitric oxide synthase. Besides, we investigated the effects of brazilin on the MAPK signal transduction pathway because MAPK families are associated with vascular inflammation under stress. Brazilin blocked HG-induced phosphorylation of extracellular signal-regulated kinase and transcription factor NF-κB. Furthermore, brazilin concentration-dependently attenuated cell adhesion molecules (ICAM-1 and VCAM-1) expression induced by various concentrations of HG in HUVEC. Taken together, the present data suggested that brazilin could suppress high glucose-induced vascular inflammatory process, which may be closely related with the inhibition of oxidative stress, CAMs expression, and NF-κB activation in HUVEC. Our findings may highlight a new therapeutic intervention for the prevention of vascular diseases. Thanasekaran Jayakumar, Chao-Chien Chang, Shoei-Loong Lin, Yung-Kai Huang, Chien-Ming Hu, Antoinet Ramola Elizebeth, Shih-Chang Lin, and Cheuk-sing Choy Copyright © 2014 Thanasekaran Jayakumar et al. All rights reserved. Improved Candidate Drug Mining for Alzheimer’s Disease Thu, 27 Feb 2014 16:34:29 +0000 Alzheimer's disease (AD) is the main cause of dementia for older people. Although several antidementia drugs such as donepezil, rivastigmine, galantamine, and memantine have been developed, the effectiveness of AD drug therapy is still far from satisfactory. Recently, the single nucleotide polymorphisms (SNPs) have been chosen as one of the personalized medicine markers. Many pharmacogenomics databases have been developed to provide comprehensive information by associating SNPs with drug responses, disease incidence, and genes that are critical in choosing personalized therapy. However, we found that some information from different sets of pharmacogenomics databases is not sufficient and this may limit the potential functions for pharmacogenomics. To address this problem, we used approximate string matching method and data mining approach to improve the searching of pharmacogenomics database. After computation, we can successfully identify more genes linked to AD and AD-related drugs than previous online searching. These improvements may help to improve the pharmacogenomics of AD for personalized medicine. Yu-Huei Cheng, Li-Yeh Chuang, Hsueh-Wei Chang, and Cheng-Hong Yang Copyright © 2014 Yu-Huei Cheng et al. All rights reserved. Effects of Various Antiepileptics Used to Alleviate Neuropathic Pain on Compound Action Potential in Frog Sciatic Nerves: Comparison with Those of Local Anesthetics Mon, 24 Feb 2014 12:27:22 +0000 Antiepileptics used for treating neuropathic pain have various actions including voltage-gated Na+ and Ca2+ channels, glutamate-receptor inhibition, and -receptor activation, while local anesthetics are also used to alleviate the pain. It has not been fully examined yet how nerve conduction inhibitions by local anesthetics differ in extent from those by antiepileptics. Fast-conducting compound action potentials (CAPs) were recorded from frog sciatic nerve fibers by using the air-gap method. Antiepileptics (lamotrigine and carbamazepine) concentration dependently reduced the peak amplitude of the CAP ( and 0.50 mM, resp.). Carbamazepine analog oxcarbazepine exhibited an inhibition smaller than that of carbamazepine. Antiepileptic phenytoin (0.1 mM) reduced CAP amplitude by 15%. On the other hand, other antiepileptics (gabapentin, sodium valproate, and topiramate) at 10 mM had no effect on CAPs. The CAPs were inhibited by local anesthetic levobupivacaine ( mM). These results indicate that there is a difference in the extent of nerve conduction inhibition among antiepileptics and that some antiepileptics inhibit nerve conduction with an efficacy similar to that of levobupivacaine or to those of other local anesthetics (lidocaine, ropivacaine, and cocaine) as reported previously. This may serve to know a contribution of nerve conduction inhibition in the antinociception by antiepileptics. Yuhei Uemura, Tsugumi Fujita, Sena Ohtsubo, Naomi Hirakawa, Yoshiro Sakaguchi, and Eiichi Kumamoto Copyright © 2014 Yuhei Uemura et al. All rights reserved. TAZ Is Highly Expressed in Gastric Signet Ring Cell Carcinoma Mon, 24 Feb 2014 12:15:23 +0000 Transcriptional coactivator with PDZ-binding motif (TAZ) is known to bind to a variety of transcription factors to control cell differentiation and organ development. We examined TAZ protein levels in 146 stage II–IV gastric cancer using immunohistochemistry (IHC), while TAZ mRNA was confirmed by quantitative reverse-transcription polymerase chain reaction (QRT-PCR) in 84 samples with enough tissue. TAZ protein expression was positive in 113 out of 146 (77.4%) gastric cancer samples. In parallel, TAZ mRNA expression was successfully detected in 81 of the 84 (96.4%) samples. Protein levels of TAZ were positively correlated with its mRNA levels (). High expression of TAZ protein was observed with higher percentage in gastric cancer samples with histology of signet ring cell carcinoma (SRCC) than adenocarcinoma (85.7% versus 60.2%, ). Similarly, TAZ mRNA level was higher in SRCC than in adenocarcinoma (). When correlated with survival, the median overall survival (OS) is 14 months (95% CI: 12.2–15.8 months) in all patients. There was no significant association between survival and other clinical characteristics or TAZ expression levels. Our results show that TAZ is highly expressed in SRCC. TAZ might be considered as a target for the treatment of gastric SRCC in future. Guofeng Yue, Xia Sun, Ana Gimenez-Capitan, Jie Shen, Lixia Yu, Cristina Teixido, Wenxian Guan, Rafael Rosell, Baorui Liu, and Jia Wei Copyright © 2014 Guofeng Yue et al. All rights reserved. Histone Deacetylase Inhibitor Impairs Plasminogen Activator Inhibitor-1 Expression via Inhibiting TNF-α-Activated MAPK/AP-1 Signaling Cascade Sun, 23 Feb 2014 13:37:08 +0000 Tumor necrosis factor-(TNF-)- upregulates plasminogen activator inhibitor-(PAI-) 1 expression in pleural mesothelial cells (PMCs), contributing to fibrin deposition and pleural fibrosis. Histone deacetylases (HDACs) have been found implicated in fibrogenesis. However, the roles of TNF- or HDAC in the regulation of PAI-1 expression have not been well investigated. We aimed to examine the effects and mechanisms of HDAC inhibition on TNF--induced PAI-1 expression in human PMCs. MeT-5A human PMCs were treated with TNF- in the presence or absence of the m-carboxycinnamic acid bishydroxamide (CBHA), an HDAC class II inhibitor, and the HDAC activity, PAI-1 protein expression, mRNA, and activated signalings were analyzed. CBHA abrogated TNF--induced HDAC activity, PAI-1 protein and, mRNA expression in MeT-5A cells. Moreover, CBHA significantly enhanced mitogen-activated protein kinase phosphatase-(MKP-) 5/MKP-1 expression and inhibited p38/JNK activations, ATF2/c-Jun translocation, and PAI-1 promoter activity. Altogether, our data suggest that HDAC inhibition may abrogate TNF--activated MAPK/AP-1 signaling and PAI-1 expression in human PMCs. Given the antifibrotic effect through PAI-1 abrogation, CBHA may be utilized as a novel agent in the treatment of fibrotic diseases. Wei-Lin Chen, Joen-Rong Sheu, Che-Jen Hsiao, Shih-Hsin Hsiao, Chi-Li Chung, and George Hsiao Copyright © 2014 Wei-Lin Chen et al. All rights reserved. Effects of SCH-23390 in Combination with a Low Dose of 17β-Estradiol on Anxiety-Like Behavior in Ovariectomized Rats Sun, 23 Feb 2014 11:28:47 +0000 The aim of this study was to explore effects on anxiety-like behavior of D1 dopamine receptor agonist, SKF-38393, and of D1 dopamine receptor antagonist, SCH-23390, given alone or in combination with a low dose of 17β-estradiol (17β-E2) to ovariectomized (OVX) rats. Two weeks after surgery, OVX rats began 14 days of treatment with the vehicle, a low dose of 17β-E2 (5.0 μg/rat, s.c.), SKF-38393 (0.1 mg/kg, i.p.), SCH-23390 (0.1 mg/kg, i.p.), SKF-38393 plus 17β-E2, or SCH-23390 plus 17β-E2. The animals were tested in the black and white model (BWM) and the open field test (OFT). SCH-23390 (0.1 mg/kg, i.p.) alone or in a combination with a low dose of 17β-E2 (5.0 μg/rat, s.c.) resulted in anxiolytic-like effect in OVX rats in the BWM. Repeated treatment with SCH-23390 and 17β-E2 profoundly increased anxiolytic-like effect of single substances exerted per se. Coadministration of SCH-23390 with 17β-E2 increased frequency of rearing and grooming in OVX rats in OFT. SKF-38393 (0.1 mg/kg, i.p.) treatment failed to alter anxiety-like behavior in OVX rats in the BWM. The results of the present study suggest that 17β-E2 and SCH-23390 interact to exert anxiolytic-like action and that each of these drugs can potentiate effects of each other. Julia Fedotova Copyright © 2014 Julia Fedotova. All rights reserved. The Effects of Gene Polymorphisms in Interleukin-4 and Interleukin-6 on the Susceptibility of Rheumatoid Arthritis in a Chinese Population Sun, 23 Feb 2014 07:05:13 +0000 Background. Interleukin-4 (IL-4) and interleukin-6 (IL-6) have been reported to associate with pathogenesis of rheumatoid arthritis (RA); however, the role of IL-4 and IL-6 genetic polymorphisms in RA remains unknown. Method. A total of 752 unrelated Chinese patients with RA and 798 healthy Chinese volunteers with no family histories of any autoimmune diseases were recruited. The promoter IL-4-590 C/T and IL-6-174 G/C polymorphisms were genotyped. Result. The genotype distributions and allele frequencies of IL-4-590 C/T and IL-6-174 G/C polymorphisms in RA patients were significantly different from healthy volunteers. Statistically significant differences were observed in genotypes for IL-4-590 and IL-6-174. The frequencies of both the T allele on the IL-4-590 and the C on the IL-6-174 were significantly increased in RA patients. Conclusion. The IL-4-590 and IL-6-174 promoter polymorphisms may be associated with increased risk of RA and could be used as genetic marker for assessing the susceptibility and severity of RA in Chinese. Xiang Li, Wei Chai, Ming Ni, Meng Xu, Zijian Lian, Lewis Shi, Yang Bai, and Yan Wang Copyright © 2014 Xiang Li et al. All rights reserved. Mechanisms of Ascorbyl Radical Formation in Human Platelet-Rich Plasma Mon, 17 Feb 2014 13:24:56 +0000 Recently, many clinical reports have suggested that the ascorbyl free radical () can be treated as a noninvasive, reliable, real-time marker of oxidative stress, but its generation mechanisms in human blood have rarely been discussed. In this study, we used upstream substances, enzyme inhibitors, and free radical scavengers to delineate the mechanisms of formation in human platelet-rich plasma (PRP). Our results show that the doublet signal was detected in PRP samples by using electron spin resonance, and the hyperfine splitting of the doublet signal was gauss and -factor = 2.00627, which was determined to be the . We observed that the inhibitors of NADPH oxidase (NOX), cyclooxygenase (COX), lipoxygenase (LOX), cytochrome P450 (CYP450), mitochondria complex III, and nitric oxide synthase (NOS), but not xanthine oxidase, diminished the intensity of the signal dose dependently. All enzyme inhibitors showed no obvious antioxidant activity during a Fenton reaction assay. In summary, the obtained data suggest that formation is associated with NOX, COX, LOX, CYP450, eNOS, and mitochondria in human PRP. Kou-Gi Shyu, Chao-Chien Chang, Yu-Chieh Yeh, Joen-Rong Sheu, and Duen-Suey Chou Copyright © 2014 Kou-Gi Shyu et al. All rights reserved. Rosiglitazone Increases Cerebral Klotho Expression to Reverse Baroreflex in Type 1-Like Diabetic Rats Thu, 13 Feb 2014 10:01:56 +0000 Reduced baroreflex sensitivity (BRS) is widely observed in diabetic human and animals. Rosiglitazone is one of the clinically used thiazolidinediones (TZD) known as PPARγ agonist. Additionally, the klotho protein produced from choroid plexus in the central nervous system is regulated by PPARγ. In an attempt to develop the new therapeutic strategy, we treated streptozotocin-induced diabetic rats (STZ) with rosiglitazone (STZ + TZD) orally at 10 mg/kg for 7 days. Also, STZ rats were subjected to intracerebroventricular (ICV) infusion of recombinant klotho at a dose of 3 μg/2.5 μL via syringe pump (8 μg/hr) daily for 7 days. The BRS and heart rate variability were then estimated under challenge with a depressor dose of sodium nitroprusside (50 μg/kg) or a pressor dose of phenylephrine (8 μg/kg) through an intravenous injection. Lower expression of klotho in medulla oblongata of diabetic rats was identified. Cerebral infusion of recombinant klotho or oral administration of rosiglitazone reversed BRS in diabetic rats. In conclusion, recovery of the decreased klotho in brain induced by rosiglitazone may restore the impaired BRS in diabetic rats. Thus, rosiglitazone is useful to reverse the reduced BRS through increasing cerebral klotho in diabetic disorders. Li-Jen Chen, Meng-Fu Cheng, Po-Ming Ku, and Jia-Wei Lin Copyright © 2014 Li-Jen Chen et al. All rights reserved. Phytochemical Prospection and Modulation of Antibiotic Activity In Vitro by Lippia origanoides H.B.K. in Methicillin Resistant Staphylococcus aureus Mon, 10 Feb 2014 14:13:46 +0000 The Lippia origanoides H.B.K. ethanol extract (LOEE) and hexane (LOHEX), dichloromethane (LODCM), and ethyl acetate (LOEA) fractions were tested for their antimicrobial activity alone or in combination with antibiotics against a methicillin resistant Staphylococcus aureus (MRSA) strain. The natural products did not show antimicrobial activity against multidrug resistant strain at the clinically significant concentrations tested. However, a modulatory effect in the antibacterial activity of the neomycin and amikacin was verified when LOEE, LOHEX and LODCM were added to the growth medium at subinhibitory concentrations. A similar modulation was found when the natural products were changed for chlorpromazine, an inhibitor of bacterial efflux pumps, suggesting the involvement of resistance mediated by efflux system in the MRSA tested. The fractions LOHEX and LODCM showed a modulatory activity bigger than their majority compounds (carvacrol, thymol, and naringenin), indicating that this activity is not due to their majority compounds only, but it is probably due to a synergism between their chemical components. These results indicate that L. origanoides H.B.K. can be a source of phytochemicals able to modify the phenotype of resistance to aminoglycosides in MRSA. Humberto Medeiros Barreto, Filipe Cerqueira Fontinele, Aldeídia Pereira de Oliveira, Daniel Dias Rufino Arcanjo, Bernadete Helena Cavalcanti dos Santos, Aislan Pereira Lira de Abreu, Henrique Douglas Melo Coutinho, Romezio Alves Carvalho da Silva, Taciana Oliveira de Sousa, Maria das Graças Freire de Medeiros, Antonia Maria das Graças Lopes Citó, and José Arimateia Dantas Lopes Copyright © 2014 Humberto Medeiros Barreto et al. All rights reserved. Low Dose of Valproate Improves Motor Function after Traumatic Brain Injury Thu, 06 Feb 2014 12:10:51 +0000 Background. Traumatic brain injuries (TBIs) are a major health care problem worldwide. Approximately 1.5 million new TBI cases occur annually in the United States, with mortality rates ranging between 35% and 40% in severe patients. Despite the incidence of these injuries and their substantial socioeconomic implications, no specific pharmacological intervention is available for clinical use. Several studies have indicated that 300 mg/kg or 400 mg/kg of valproate (VPA) exhibits neuroprotective effects in animal models. However, humans cannot tolerate high doses of VPA. This study aims to investigate whether 30 mg/kg of VPA administered to rats affects TBIs. Methods. We used a rat model to test the effects of 30 mg/kg of VPA on TBIs. Molecular identifications for histone acetylation and phosphorylation of cAMP response element-binding protein (CREB) and phosphorylated extracellular signal regulated kinase (ERK) were performed. Results. The results indicated that treating adult rats with VPA after TBIs significantly decreased the contusion volume and recovery of contusion-related skilled forelimb reaching deficits. Applying VPA also increased histone acetylation, p-ERK, and p-CREB expression in the brain. Furthermore, applying VPA reduced inflammation, glial fibrillary acidic protein activation, and apoptosis. Conclusion. This study found that 30 mg/kg of VPA assists in treating TBIs in rat models. Yu-Ting Tai, Wen-Yuan Lee, Fei-Peng Lee, Tien-Jen Lin, Chia-Lin Shih, Jia-Yi Wang, Wen-Ta Chiu, and Kuo-Sheng Hung Copyright © 2014 Yu-Ting Tai et al. All rights reserved. Ginseng Is Useful to Enhance Cardiac Contractility in Animals Tue, 04 Feb 2014 14:00:36 +0000 Ginseng has been shown to be effective on cardiac dysfunction. Recent evidence has highlighted the mediation of peroxisome proliferator-activated receptors (PPARs) in cardiac function. Thus, we are interested to investigate the role of PPARδ in ginseng-induced modification of cardiac contractility. The isolated hearts in Langendorff apparatus and hemodynamic analysis in catheterized rats were applied to measure the actions of ginseng ex vivo and in vivo. In normal rats, ginseng enhanced cardiac contractility and hemodynamic significantly. Both actions were diminished by GSK0660 at a dose enough to block PPARδ. However, ginseng failed to modify heart rate at the same dose, although it did produce a mild increase in blood pressure. Data of intracellular calcium level and Western blotting analysis showed that both the PPARδ expression and troponin I phosphorylation were raised by ginseng in neonatal rat cardiomyocyte. Thus, we suggest that ginseng could enhance cardiac contractility through increased PPARδ expression in cardiac cells. Jia-Wei Lin, Yih-Giun Cherng, Li-Jen Chen, Ho-Shan Niu, Chen Kuei Chang, and Chiang-Shan Niu Copyright © 2014 Jia-Wei Lin et al. All rights reserved. A Replication Study for the Association of rs726252 in PAPPA2 with Developmental Dysplasia of the Hip in Chinese Han Population Mon, 03 Feb 2014 16:16:27 +0000 Developmental dysplasia of the hip (DDH) is a common developmental hip disorder, which ranges from mild acetabulum malformation to irreducible hip dislocation. A previous study suggested a significant association of pregnancy-associated plasma protein-A2 (PAPPA2) with DDH susceptibility in Chinese Han population. But with the consideration of the sample size, the association was still debatable. To confirm the association of the reported single nucleotide polymorphism (SNP) in PAPPA2, rs726252 with DDH, we conducted a case-control study in a larger number of subjects. We genotyped rs726252 in 697 DDH subjects and 707 control subjects by TaqMan assay. The association between this SNP and DDH was evaluated statistically. No significant difference was found in any comparison of genotype distribution nor allele frequency between cases and controls. Our replication study indicated that the association between rs726252 and DDH in Chinese Han population was debatable. The association between PAPPA2 and DDH should be evaluated by additional studies. Dongquan Shi, Wei Sun, Xingquan Xu, Zheng Hao, Jin Dai, Zhihong Xu, Dongyang Chen, Huajian Teng, and Qing Jiang Copyright © 2014 Dongquan Shi et al. All rights reserved. Semiphysiological versus Empirical Modelling of the Population Pharmacokinetics of Free and Total Cefazolin during Pregnancy Mon, 03 Feb 2014 11:10:06 +0000 This work describes a first population pharmacokinetic (PK) model for free and total cefazolin during pregnancy, which can be used for dose regimen optimization. Secondly, analysis of PK studies in pregnant patients is challenging due to study design limitations. We therefore developed a semiphysiological modeling approach, which leveraged gestation-induced changes in creatinine clearance (CrCL) into a population PK model. This model was then compared to the conventional empirical covariate model. First, a base two-compartmental PK model with a linear protein binding was developed. The empirical covariate model for gestational changes consisted of a linear relationship between CL and gestational age. The semiphysiological model was based on the base population PK model and a separately developed mixed-effect model for gestation-induced change in CrCL. Estimates for baseline clearance (CL) were 0.119 L/min (RSE 58%) and 0.142 L/min (RSE 44%) for the empirical and semiphysiological models, respectively. Both models described the available PK data comparably well. However, as the semiphysiological model was based on prior knowledge of gestation-induced changes in renal function, this model may have improved predictive performance. This work demonstrates how a hybrid semiphysiological population PK approach may be of relevance in order to derive more informative inferences. J. G. Coen van Hasselt, Karel Allegaert, Kristel van Calsteren, Jos H. Beijnen, Jan H. M. Schellens, and Alwin D. R. Huitema Copyright © 2014 J. G. Coen van Hasselt et al. All rights reserved. Effects of Momordica charantia L. on the Blood Rheological Properties in Diabetic Patients Mon, 03 Feb 2014 07:14:58 +0000 An evaluation of the rheological properties and the effects of Momordica. charantia L. (M. charantia) nanoparticles and polyethylene glycol (PEG) microspheres adsorbed with M. charantia nanoparticles on the blood of hyperglycemic patients is presented. Blood samples were collected according to glycemic status: normoglycemic and hyperglycemic . General and hematological characteristics were determined. Blood rheological parameters were determined at room temperature and under a temperature scan. We determined the effects on whole blood viscosity of treatment with an extract of M. charantia, PEG, or PEG microspheres adsorbed with plant extract. The viscosity of the blood of hyperglycemic patients is greater than that of normoglycemic patients. Nanoparticles of M. charantia extracts lowered blood viscosity at equivalent rates in normo- and hyperglycemic individuals. PEG microspheres did not reduce blood viscosity in hyperglycemic individuals. However, PEG microspheres adsorbed with nanofraction extracts of M. charantia reduced blood viscosity. These data suggest that the effects of diabetes on the viscosity of the blood should be considered. The use of a nanoparticles extract of M. charantia and its adsorption on PEG microspheres may represent an alternative for the control and treatment of blood disorders in diabetic patients. Eduardo Luzía França, Elton Brito Ribeiro, Edson Fredulin Scherer, Déborah Giovanna Cantarini, Rafael Souza Pessôa, Fernando Luzía França, and Adenilda Cristina Honorio-França Copyright © 2014 Eduardo Luzía França et al. All rights reserved. Growth Inhibition by Bupivacaine Is Associated with Inactivation of Ribosomal Protein S6 Kinase 1 Wed, 29 Jan 2014 11:08:31 +0000 Bupivacaine is an amide type long acting local anesthetic used for epidural anesthesia and nerve blockade in patients. Use of bupivacaine is associated with severe cytotoxicity and apoptosis along with inhibition of cell growth and proliferation. Although inhibition of Erk, Akt, and AMPK seemingly appears to mediate some of the bupivacaine effects, potential downstream targets that mediate its effect remain unknown. S6 kinase 1 is a common downstream effector of several growth regulatory pathways involved in cell growth and proliferation known to be affected by bupivacaine. We have accordingly attempted to relate the growth inhibitory effects of bupivacaine with the status of S6K1 activity and we present evidence that decrease in cell growth and proliferation by bupivacaine is mediated through inactivation of S6 kinase 1 in a concentration and time dependent manner. We also show that ectopic expression of constitutively active S6 kinase 1 imparts substantial protection from bupivacaine induced cytotoxicity. Inactivation of S6K1 though associated with loss of putative mTOR mediated phosphorylation did not correspond with loss of similar phosphorylations in 4EBP1 indicating that S6K1 inhibition was not mediated through inactivation of mTORC1 signaling pathway or its down regulation. Mushtaq Ahmad Beigh, Mehvish Showkat, Basharat Bashir, Asma Bashir, Mahboob ul Hussain, and Khurshid Iqbal Andrabi Copyright © 2014 Mushtaq Ahmad Beigh et al. All rights reserved. Modulation of c-Fos and BDNF Protein Expression in Pentylenetetrazole-Kindled Mice following the Treatment with Novel Antiepileptic Compound HHL-6 Wed, 29 Jan 2014 06:44:29 +0000 Brain-derived neurotrophic factor (BDNF) and c-Fos are shown to promote epileptogenesis and are taken as a marker of neuronal activity. The present study investigated the expression of BDNF and c-Fos in mice brain with pentylenetetrazol- (PTZ-) induced generalized seizure and evaluated the effect of novel tryptamine derivative HHL-6 on the expression of these two markers. The subconvulsive dose of PTZ (50 mg/kg) was administered on alternate days in the experimental groups until the seizure scores 4-5 developed in the PTZ-control group. At the end of each experiment, animals were sacrificed, brain samples were collected and cryosectioned, and immunohistochemical analysis of BDNF and c-Fos protein was performed. Data obtained from two sections per mouse ( animals/group) is presented as means ± S.E.M. The test compound HHL-6 demonstrated a potent anticonvulsant activity in the PTZ-induced seizure in mice. Significant reduction in the BDNF () and c-Fos () protein expression was observed in the HHL-6 treated group. Based on these results we suggest that one of the possible mechanisms of HHL-6 to inhibit epileptogenesis might be due to its controlling effect on the cellular and molecular expression of the factors that contribute to the development of epileptogenic plasticity in the CNS. Saima Mahmood Malhi, Huma Jawed, Farina Hanif, Nadeem Ashraf, Farhat Zubair, Bina S. Siddiqui, Sabira Begum, Nurul Kabir, and Shabana Usman Simjee Copyright © 2014 Saima Mahmood Malhi et al. All rights reserved. P-Cresyl Sulfate Is a Valuable Predictor of Clinical Outcomes in Pre-ESRD Patients Wed, 29 Jan 2014 00:00:00 +0000 Background/Aims. Previous studies have reported p-cresyl sulfate (PCS) was related to endothelial dysfunction and adverse clinical effect. We investigate the adverse effects of PCS on clinical outcomes in a chronic kidney disease (CKD) cohort study. Methods. 72 predialysis patients were enrolled from a single medical center. Serum biochemistry data and PCS were measured. The clinical outcomes including cardiovascular event, all-cause mortality, and dialysis event were recorded during a 3-year follow-up. Results. After adjusting other independent variables, multivariate Cox regression analysis showed age (HR: 1.12, ), cardiovascular disease history (HR: 6.28, ), and PCS (HR: 1.12, ) were independently associated with cardiovascular event; age (HR: 0.91, ), serum albumin (HR: 0.03, ), and PCS level (HR: 1.17, ) reached significant correlation with dialysis event. Kaplan-Meier analysis revealed that patients with higher serum p-cresyl sulfate (>6 mg/L) were significantly associated with cardiovascular and dialysis event (log rank , log rank , resp.). Conclusion. Our study shows serum PCS could be a valuable marker in predicting cardiovascular event and renal function progression in CKD patients without dialysis. Cheng-Jui Lin, Chi-Feng Pan, Chih-Kuang Chuang, Fang-Ju Sun, Duen-Jen Wang, Han-Hsiang Chen, Hsuan-Liang Liu, and Chih-Jen Wu Copyright © 2014 Cheng-Jui Lin et al. All rights reserved. Human Pharmacokinetics of High Dose Oral Curcumin and Its Effect on Heme Oxygenase-1 Expression in Healthy Male Subjects Wed, 29 Jan 2014 00:00:00 +0000 Purpose. Heme oxygenase-1 (HO-1) has been proposed to exert pharmacological benefits by its antioxidative and anti-inflammatory effects. HO-1 expression may be affected by the GT length polymorphism in the promoter region of the HO-1 gene. We investigated the inducibility of HO-1 by orally administered curcumin in healthy male subjects and its correlation with the GT length polymorphism. Methods. In an open label uncontrolled phase-1 pilot study, ten male subjects received 12 g of oral curcumin. To investigate the effects of the GT length polymorphism on the inducibility of HO-1, five subjects with homozygous short and five with homozygous long GT genotypes were studied. Plasma concentrations of curcumin, bilirubin, HO-1 mRNA, and protein expression in peripheral blood mononuclear cells (PBMCs) were analyzed over 48 hours. Results. At a detection limit of 1 µg/mL curcumin could not be detected in plasma of any subject. Compared to baseline, HO-1 mRNA and protein levels were not induced in PBMCs at any time point up to 48 hours. There was no correlation between any of the parameters and GT length polymorphism. Conclusions. Oral curcumin administration has low bioavailability and does not induce HO-1 on mRNA or protein level in PBMCs. Uros Klickovic, Daniel Doberer, Ghazaleh Gouya, Stefan Aschauer, Stefan Weisshaar, Angela Storka, Martin Bilban, and Michael Wolzt Copyright © 2014 Uros Klickovic et al. All rights reserved. Potential Activity of 3-(2-Chlorophenyl)-1-phenyl-propenonein Accelerating Wound Healing in Rats Wed, 22 Jan 2014 08:17:29 +0000 Wound healing involves inflammation followed by granular tissue development and scar formation. In this study, synthetic chalcone 3-(2-Chlorophenyl)-1-phenyl-propenone (CPPP) was investigated for a potential role in enhancing wound healing and closure. Twenty-four male rats were divided randomly into 4 groups: carboxymethyl cellulose (CMC) (0.2 mL), Intrasite gel, and CPPP (25 or 50 mg/mL). Gross morphology, wounds treatment with the CPPP, and Intrasite gel accelerate the rate of wound healing compared to CMC group. Ten days after surgery, the animals were sacrificed. Histological assessment revealed that the wounds treated with CPPP showed that wound closure site contained little amount of scar and the granulation tissue contained more collagen and less inflammatory cells than wound treated with CMC. This finding was confirmed with Masson’s trichrome staining. The antioxidant defence enzymes catalase (CAT) and superoxide dismutase (SOD) were significantly increased in the wound homogenates treated with CPPP () compared to CMC treated group. However, in the CPPP treatment group, lipid peroxidation (MDA) was significantly decreased (), suggesting that the CPPP also has an important role in protection against lipid peroxidation-induced skin injury after ten days of treatment with CPPP, which is similar to the values of cytokines TGF-β and TNF-α in tissue homogenate. Finally the administration of CPPP at a dosage of 25 and 50 mg/kg was suitable for the stimulation of wound healing. Summaya M. Dhiyaaldeen, Mohammed A. Alshawsh, Suzy M. Salama, Nahla S. I. Alwajeeh, Rami Al Batran, Salmah Ismail, and Mahmood Ameen Abdulla Copyright © 2014 Summaya M. Dhiyaaldeen et al. All rights reserved. Preventive Effect of Zea mays L. (Purple Waxy Corn) on Experimental Diabetic Cataract Thu, 16 Jan 2014 11:35:51 +0000 Recently, substances possessing antioxidant can prevent cataractogenesis of diabetic cataract. Therefore, this study was carried out to determine the anticataract effect of Zea mays L. (purple waxy corn), a flavonoids rich plant, in experimental diabetic cataract. Enucleated rat lenses were incubated in artificial aqueous humor containing 55 mM glucose with various concentrations of Zea mays L. (purple waxy corn) ranging between 2, 10, and 50 mg/mL at room temperature for 72 h. At the end of the incubation period, the evaluation of lens opacification, MDA level, and the activities of SOD, CAT, GPx, and AR in lens were performed. The results showed that both medium and high doses of extract decreased lens opacity together with the decreased MDA level. In addition, medium dose of extract increased GPx activity while the high dose decreased AR activity. No other significant changes were observed. The purple waxy corn seeds extract is the potential candidate to protect against diabetic cataract. The mechanism of action may occur via the decreased oxidative stress and the suppression of AR. However, further research in vivo is still essential. Paphaphat Thiraphatthanavong, Jintanaporn Wattanathorn, Supaporn Muchimapura, Wipawee Thukham-mee, Panakaporn Wannanon, Terdthai Tong-un, Bhalang Suriharn, and Kamol Lertrat Copyright © 2014 Paphaphat Thiraphatthanavong et al. All rights reserved. Serotonin Reuptake Inhibitors in Pregnancy: Can Genes Help Us in Predicting Neonatal Adverse Outcome? Sun, 12 Jan 2014 00:00:00 +0000 Lots has been written on use of SSRI during pregnancy and possible short and long term negative outcomes on neonates. the literature so far has described a various field of peripartum illness related to SSRI exposure during foetal life, such as increased incidence of low birth weight, respiratory distress, persistent pulmonary hypertension, poor feeding, and neurobehavioural disease. We know that different degrees of outcomes are possible, and not all the newborns exposed to SSRIs during pregnancy definitely will develop a negative outcome. So far, still little is known about the possible etiologic mechanism that could not only explain the adverse neonatal effects but also the degree of clinical involvement and presentation in the early period after birth. Pharmacogenetics and moreover pharmacogenomics, the study of specific genetic variations and their effect on drug response, are not widespread. This review describes possible relationship between SSRIs pharmacogenetics and different neonatal outcomes and summarizes the current pharmacogenetic inquiries in relation to maternal-foetal environment. Valentina Giudici, Laura Pogliani, Dario Cattaneo, Dario Dilillo, and Gian Vincenzo Zuccotti Copyright © 2014 Valentina Giudici et al. All rights reserved. Phytochemical and Pharmacological Properties of Gymnema sylvestre: An Important Medicinal Plant Mon, 06 Jan 2014 13:38:25 +0000 Gymnema sylvestre (Asclepiadaceae), popularly known as “gurmar” for its distinct property as sugar destroyer, is a reputed herb in the Ayurvedic system of medicine. The phytoconstituents responsible for sweet suppression activity includes triterpene saponins known as gymnemic acids, gymnemasaponins, and a polypeptide, gurmarin. The herb exhibits a broad range of therapeutic effects as an effective natural remedy for diabetes, besides being used for arthritis, diuretic, anemia, osteoporosis, hypercholesterolemia, cardiopathy, asthma, constipation, microbial infections, indigestion, and anti-inflammatory. G. sylvestre has good prospects in the treatment of diabetes as it shows positive effects on blood sugar homeostasis, controls sugar cravings, and promotes regeneration of pancreas. The herbal extract is used in dietary supplements since it reduces body weight, blood cholesterol, and triglyceride levels and holds great prospects in dietary as well as pharmacological applications. This review explores the transition of a traditional therapeutic to a modern contemporary medication with an overview of phytochemistry and pharmacological activities of the herb and its phytoconstituents. Pragya Tiwari, B. N. Mishra, and Neelam S. Sangwan Copyright © 2014 Pragya Tiwari et al. All rights reserved. In Vitro Wound Healing Potential and Identification of Bioactive Compounds from Moringa oleifera Lam Tue, 31 Dec 2013 10:54:57 +0000 Moringa oleifera Lam. (M. oleifera) from the monogeneric family Moringaceae is found in tropical and subtropical countries. The present study was aimed at exploring the in vitro wound healing potential of M. oleifera and identification of active compounds that may be responsible for its wound healing action. The study included cell viability, proliferation, and wound scratch test assays. Different solvent crude extracts were screened, and the most active crude extract was further subjected to differential bioguided fractionation. Fractions were also screened and most active aqueous fraction was finally obtained for further investigation. HPLC and LC-MS/MS analysis were used for identification and confirmation of bioactive compounds. The results of our study demonstrated that aqueous fraction of M. oleifera significantly enhanced proliferation and viability as well as migration of human dermal fibroblast (HDF) cells compared to the untreated control and other fractions. The HPLC and LC-MS/MS studies revealed kaempferol and quercetin compounds in the crude methanolic extract and a major bioactive compound Vicenin-2 was identified in the bioactive aqueous fraction which was confirmed with standard Vicenin-2 using HPLC and UV spectroscopic methods. These findings suggest that bioactive fraction of M. oleifera containing Vicenin-2 compound may enhance faster wound healing in vitro. Abubakar Amali Muhammad, Nur Aimi Syarina Pauzi, Palanisamy Arulselvan, Faridah Abas, and Sharida Fakurazi Copyright © 2013 Abubakar Amali Muhammad et al. All rights reserved. Multiclass Prediction with Partial Least Square Regression for Gene Expression Data: Applications in Breast Cancer Intrinsic Taxonomy Mon, 30 Dec 2013 18:09:40 +0000 Multiclass prediction remains an obstacle for high-throughput data analysis such as microarray gene expression profiles. Despite recent advancements in machine learning and bioinformatics, most classification tools were limited to the applications of binary responses. Our aim was to apply partial least square (PLS) regression for breast cancer intrinsic taxonomy, of which five distinct molecular subtypes were identified. The PAM50 signature genes were used as predictive variables in PLS analysis, and the latent gene component scores were used in binary logistic regression for each molecular subtype. The 139 prototypical arrays for PAM50 development were used as training dataset, and three independent microarray studies with Han Chinese origin were used for independent validation (). The agreement between PAM50 centroid-based single sample prediction (SSP) and PLS-regression was excellent (weighted Kappa: 0.988) within the training samples, but deteriorated substantially in independent samples, which could attribute to much more unclassified samples by PLS-regression. If these unclassified samples were removed, the agreement between PAM50 SSP and PLS-regression improved enormously (weighted Kappa: 0.829 as opposed to 0.541 when unclassified samples were analyzed). Our study ascertained the feasibility of PLS-regression in multi-class prediction, and distinct clinical presentations and prognostic discrepancies were observed across breast cancer molecular subtypes. Chi-Cheng Huang, Shih-Hsin Tu, Ching-Shui Huang, Heng-Hui Lien, Liang-Chuan Lai, and Eric Y. Chuang Copyright © 2013 Chi-Cheng Huang et al. All rights reserved. Pharmacological Intervention of Nicotine Dependence Sun, 29 Dec 2013 08:25:20 +0000 Nicotine dependence is a major cause of mortality and morbidity all over the world. Various medications have been tried to treat nicotine dependence including nicotine replacement therapy, bupropion, and varenicline. A newer venture to nicotine dependence treatment is a nicotine vaccine which is yet to get footsteps in common practice. The present review assimilates various pharmacotherapeutic measures to address nicotine dependence. However, it is to be noted that psychological interventions, when combined with pharmacotherapy, offer the greatest benefits to the patients. Raka Jain, Pradipta Majumder, and Tina Gupta Copyright © 2013 Raka Jain et al. All rights reserved. Antiatherosclerotic Potential of Clopidogrel: Antioxidant and Anti-Inflammatory Approaches Thu, 26 Dec 2013 12:53:05 +0000 Background. Atherosclerosis is characterized by endothelial dysfunction, vascular inflammation, and the buildup of lipids, cholesterol, calcium, and cellular debris within the intima of the walls of large and medium size arteries. Objective. To evaluate the effect of clopidogrel on atherosclerosis progression. Materials and Methods. A total of 28 local domestic rabbits were assigned to four groups: normal control, atherogenic control, vehicle control, and clopidogrel treated. Serum triglycerides, total cholesterol, HDL-C, plasma high sensitive C-reactive protein (hsCRP), plasma malondialdehyde (MDA), and plasma reduced glutathione (GSH) were measured at the end of the experiment. Immunohistochemical of aortic atherosclerotic changes were also performed. Results. There was no statistically significant difference between atherogenic control group and vehicle group. Levels of lipid profile, atherogenic index, hsCRP, and MDA are increased while GSH levels were decreased in animals on atherogenic diet. Immunohistochemical analysis showed that aortic expressions of VCAM-1, MCP-1, TNF-α, and IL-17A were significantly increased in atherogenic control group. Histopathologic finding showed that animals on atherogenic diet have significant atherosclerotic lesion. Compared to atherogenic control group clopidogrel do not have significant effect on lipid profile. Clopidogrel significantly reduces hsCRP and MDA levels and increases GSH level. Furthermore, clopidogrel treatment significantly reduced aortic expressions parameters and the histopathologic examination of the aortic arch showed a significant reduction of atherosclerotic lesion. Conclusions. This study outlines how clopidogrel reduces lipid peroxidation, systemic inflammation, and aortic expression of inflammatory markers and hence reduces the progression of atherosclerosis. Najah R. Hadi, Bassim I. Mohammad, Ihsan M. Ajeena, and Hussam H. Sahib Copyright © 2013 Najah R. Hadi et al. All rights reserved. Effect of Complexation with Arabinogalactan on Pharmacokinetics of “Guest” Drugs in Rats: For Example, Warfarin Thu, 26 Dec 2013 10:19:09 +0000 A pharmacokinetic study of the warfarin (WF) : arabinogalactan (AG) complex with the 1 : 10 mass ratio after its intragastric introduction to Wistar rats at a dose of 5 mg/kg (WF dose in the complex was 0.5 mg/kg) once a day for three days was conducted. It was found that , , and AUC of WF in the complex form were lower than after the introduction of blank WF at the same dose, but its elimination (Cl, MRT) was much faster. Significant accumulation () and an abrupt increase in plasma concentration after the third introduction were observed for blank WF, whereas the complex showed a much more moderate increase in concentration at this point. However, despite obvious differences in pharmacokinetic parameters, the efficacies of both agents were virtually identical; the complex differed from blank WF by only 15%. This value is rather insignificant and does not impair its anticoagulant activity. Thus, we can conclude that introduction of the WF : AG complex is safe in terms of reduction of the bleeding risk and accumulation. Mikhail V. Khvostov, Alexander A. Chernonosov, Tatjana G. Tolstikova, Marat F. Kasakin, Olga S. Fedorova, and Alexander V. Dushkin Copyright © 2013 Mikhail V. Khvostov et al. All rights reserved. Effects of Tamarindus indica Fruit Pulp Extract on Abundance of HepG2 Cell Lysate Proteins and Their Possible Consequential Impact on Metabolism and Inflammation Wed, 25 Dec 2013 10:11:17 +0000 The fruit pulp extract of Tamarindus indica has been reported for its antioxidant and hypolipidemic properties. In this study, the methanol extract of T. indica fruit pulp was investigated for its effects on the abundance of HepG2 cell lysate proteins. Cell lysate was extracted from HepG2 cells grown in the absence and presence of the methanol extract of T. indica fruit pulp. Approximately 2500 spots were resolved using two-dimensional gel electrophoresis and the abundance of 20 cellular proteins was found to be significantly reduced. Among the proteins of reduced abundance, fourteen, including six proteins involved in metabolism (including ethanolamine phosphate cytidylyltransferase), four mitochondrial proteins (including prohibitin and respiratory chain proteins), and four proteins involved in translation and splicing, were positively identified by mass spectrometry and database search. The identified HepG2 altered abundance proteins, when taken together and analyzed by Ingenuity Pathways Analysis (IPA) software, are suggestive of the effects of T. indica fruit pulp extract on metabolism and inflammation, which are modulated by LXR/RXR. In conclusion, the methanol fruit pulp extract of T. indica was shown to cause reduced abundance of HepG2 mitochondrial, metabolic, and regulatory proteins involved in oxidative phosphorylation, protein synthesis, and cellular metabolism. Ursula R. W. Chong, Puteri S. Abdul-Rahman, Azlina Abdul-Aziz, Onn H. Hashim, and Sarni Mat-Junit Copyright © 2013 Ursula R. W. Chong et al. All rights reserved. Modes of Inhibition of α-Amylase and α-Glucosidase by Aqueous Extract of Morinda lucida Benth Leaf Tue, 24 Dec 2013 09:19:38 +0000 Diabetes mellitus is a metabolic disorder of glucose metabolism. The management of blood glucose level is the hallmark in the treatment of this disease. This may be achieved through the use of oral hypoglycemic drugs such as biguanides, insulin secretagogues, and α-glucosidase inhibitors. The purpose of the present study was to investigate the inhibitory effect of Morinda lucida leaf extracts on the activities of α-amylase and α-glucosidase. This was performed using α-amylase from Aspergillus oryzae and α-glucosidase from Saccharomyces cerevisiae. Aqueous extract of Morinda lucida gave the highest percentage yield (9.99%) of the plant out of the three extracts (compared to acetone and ethanolic extracts) and possesses the highest inhibitory activity against α-amylase (IC50 value of 2.30 mg/mL) and α-glucosidase (IC50 value of 2.00 mg/mL). Kinetic analysis revealed that the aqueous extract of this plant leaf inhibited the α-amylase competitively but displayed mixed noncompetitive mode of inhibition towards α-glucosidase. It can be concluded that aqueous extract of Morinda lucida exhibited the best inhibitory activity on the two enzymes studied and the presence of phytochemicals like flavonoids, saponins, and tannins may have contributed greatly to the inhibitory activity of the plant extract. M. I. Kazeem, J. O. Adamson, and I. A. Ogunwande Copyright © 2013 M. I. Kazeem et al. All rights reserved. DPYD, TYMS, TYMP, TK1, and TK2 Genetic Expressions as Response Markers in Locally Advanced Rectal Cancer Patients Treated with Fluoropyrimidine-Based Chemoradiotherapy Mon, 23 Dec 2013 16:36:41 +0000 This study is to investigate multiple chemotherapeutic agent- and radiation-related genetic biomarkers in locally advanced rectal cancer (LARC) patients following fluoropyrimidine-based concurrent chemoradiotherapy (CCRT) for response prediction. We initially selected 6 fluoropyrimidine metabolism-related genes (DPYD, ORPT, TYMS, TYMP, TK1, and TK2) and 3 radiotherapy response-related genes (GLUT1, HIF-1α, and HIF-2α) as targets for gene expression identification in 60 LARC cancer specimens. Subsequently, a high-sensitivity weighted enzymatic chip array was designed and constructed to predict responses following CCRT. After CCRT, 39 of 60 (65%) LARC patients were classified as responders (pathological tumor regression grade ). Using a panel of multiple genetic biomarkers (chip), including DPYD, TYMS, TYMP, TK1, and TK2, at a cutoff value for 3 positive genes, a sensitivity of 89.7% and a specificity of 81% were obtained (AUC: 0.915; 95% CI: 0.840–0.991). Negative chip results were significantly correlated to poor CCRT responses (TRG 0-1) (, hazard ratio: 22.704, 95% CI: 3.055–235.448 in multivariate analysis). Disease-free survival analysis showed significantly better survival rate in patients with positive chip results (). We suggest that a chip including DPYD, TYMS, TYMP, TK1, and TK2 genes is a potential tool to predict response in LARC following fluoropyrimidine-based CCRT. Ming-Yii Huang, Chan-Han Wu, Chun-Ming Huang, Fu-Yen Chung, Ching-Wen Huang, Hsiang-Lin Tsai, Chin-Fan Chen, Shiu-Ru Lin, and Jaw-Yuan Wang Copyright © 2013 Ming-Yii Huang et al. All rights reserved. In Vitro and In Vivo Antimalarial Evaluations of Myrtle Extract, a Plant Traditionally Used for Treatment of Parasitic Disorders Mon, 23 Dec 2013 15:26:58 +0000 Based on the collected ethnobotanical data from the Traditional Medicine and Materia Medica Research Center (TMRC), Iran, Myrtus communis L. (myrtle) was selected for the assessment of in vitro and in vivo antimalarial and cytotoxic activities. Methanolic extract of myrtle was prepared from the aerial parts and assessed for antiplasmodial activity, using the parasite lactate dehydrogenase (pLDH) assay against chloroquine-resistant (K1) and chloroquine-sensitive (3D7) strains of Plasmodium falciparum. The 4-day suppressive test was employed to determine the parasitemia suppression of the myrtle extract against P. berghei  in vivo. The IC50 values of myrtle extract were 35.44 µg/ml against K1 and 0.87 µg/ml against 3D7. Myrtle extract showed a significant suppression of parasitaemia (84.8 ± 1.1% at 10 mg/kg/day) in mice infected with P. berghei after 4 days of treatment. Cytotoxic activity was carried out against mammalian cell lines using methyl thiazol tetrazolium (MTT) assay. No cytotoxic effect on mammalian cell lines up to 100 µg/mL was shown. The results support the traditional use of myrtle in malaria. Phytochemical investigation and understanding the mechanism of action would be in our upcoming project. Farzaneh Naghibi, Somayeh Esmaeili, Noor Rain Abdullah, Mehdi Nateghpour, Mahdieh Taghvai, Siamak Kamkar, and Mahmoud Mosaddegh Copyright © 2013 Farzaneh Naghibi et al. All rights reserved. Sedation of Newborn Infants for the INSURE Procedure, Are We Sure? Mon, 23 Dec 2013 10:49:47 +0000 Background. Neonatal intubation is a stressful procedure that requires premedication to improve intubation conditions and reduce stress and adverse physiological responses. Premedication used during the INSURE (INtubation, SURfactant therapy, Extubation) procedure should have a very short duration of action with restoration of spontaneous breathing within a few minutes. Aims. To determine the best sedative for intubation during the INSURE procedure by systematic review of the literature. Methods. We reviewed all relevant studies reporting on premedication, distress, and time to restoration of spontaneous breathing during the INSURE procedure. Results. This review included 12 studies: two relatively small studies explicitly evaluated the effect of premedication (propofol and remifentanil) during the INSURE procedure, both showing good intubation conditions and an average extubation time of about 20 minutes. Ten studies reporting on fentanyl or morphine provided insufficient information about these items. Conclusions. Too little is known in the literature to draw a solid conclusion on which premedication could be best used during the INSURE procedure. Both remifentanil and propofol are suitable candidates but dose-finding studies to detect effective nontoxic doses in newborns with different gestational ages are necessary. Ellen H. M. de Kort, Irwin K. M. Reiss, and Sinno H. P. Simons Copyright © 2013 Ellen H. M. de Kort et al. All rights reserved. Impact of Pregnancy on Zonisamide Pharmacokinetics in Rabbits Wed, 18 Dec 2013 09:26:32 +0000 Pregnancy is associated with various physiological changes which may lead to significant alterations in the pharmacokinetics of many drugs. The present study was aimed to investigate the potential effects of pregnancy on the pharmacokinetic profile of zonisamide (ZNM) in the rabbit. Seven female rabbits were used in this study. The pregnant and nonpregnant rabbits received ZNM orally at a dose of 10 mg/kg and blood samples were collected from the animals just before receiving the drug and then serially for up to 24 h. The plasma samples were analyzed using tandem mass spectrometric method. Following a single oral dose of ZNM to the rabbits, the mean values of ZNM plasma concentrations at different times were consistently low in pregnant compared to nonpregnant rabbits. The mean values of ZNM’s and were significantly () decreased, whereas the CL/F exhibited substantial increase () in pregnant compared to nonpregnant rabbits. , , , MRT, and Vd/F showed no significant differences between the two groups. The present study demonstrates that pregnancy decreased ZNM plasma concentrations in rabbits and that the decrease could be due to decreased extent of gastrointestinal absorption, induced hepatic metabolism, or enhanced renal elimination of the drug. Kamal M. Matar Copyright © 2013 Kamal M. Matar. All rights reserved. Moving toward Personalized Medicine in the Methadone Maintenance Treatment Program: A Pilot Study on the Evaluation of Treatment Responses in Taiwan Mon, 16 Dec 2013 14:54:50 +0000 This pilot study simultaneously evaluated the effects of various factors, including genetic variations of CYP2B6, CYP2C19, and ABCB1, demographic characteristics, disease states, methadone-drug interactions (MDIs), and poly-substance use, on the treatment responses among non-HIV patients in the methadone maintenance treatment program (MMTP) in Taiwan. A total of 178 patients were recruited from two major hospitals that provided MMTP services in southern Taiwan, and information regarding concomitant medications and diseases was acquired from the National Health Insurance (NHI) program. The results demonstrated that the methadone maintenance dose, CYP2B6 785G allele, and ABCB1 2677T allele have positive effects on the methadone plasma concentration. In contrast, patients with HCV coinfection, alcohol problems, and psychiatric diseases may have a negative response to treatment. Thus, a comprehensive evaluation of treatment responses in the MMTP should include not only genetic polymorphisms in methadone metabolism and transporter proteins, but also concomitant diseases, MDIs, and poly-substance use. The results also suggest that personalized medicine may be indispensable for a better outcome of the MMTP. Hsin-Ya Lee, Jih-Heng Li, Yuh-Ling Sheu, Hsin-Pei Tang, Wei-Chiao Chang, Tze-Chun Tang, Yi-Chun Yeh, Shing-Yaw Wang, and Ray-H. Liu Copyright © 2013 Hsin-Ya Lee et al. All rights reserved. In Vivo Evaluation of Ethanolic Extract of Zingiber officinale Rhizomes for Its Protective Effect against Liver Cirrhosis Thu, 12 Dec 2013 14:40:21 +0000 Zingiber officinale is a traditional medicine against various disorders including liver diseases.The aim of this study was to assess the hepatoprotective activity of the ethanolic extract of rhizomes of Z. officinale (ERZO) against thioacetamide-induced hepatotoxicity in rats. Five groups of male Sprague Dawley have been used. In group 1 rats received intraperitoneal (i.p.) injection of normal saline while groups 2–5 received thioacetamide (TAA, 200 mg/kg; i.p.) for induction of liver cirrhosis, thrice weekly for eight weeks. Group 3 received 50 mg/kg of silymarin. The rats in groups 4 and 5 received 250 and 500 mg/kg of ERZO (dissolved in 10% Tween), respectively. Hepatic damage was assessed grossly and microscopically for all of the groups. Results confirmed the induction of liver cirrhosis in group 2 whilst administration of silymarin or ERZO significantly reduced the impact of thioacetamide toxicity. These groups decreased fibrosis of the liver tissues. Immunohistochemistry assessment against proliferating cell nuclear antigen did not show remarkable proliferation in the ERZO-treated rats when compared with group 2. Moreover, factions of the ERZO extract were tested on Hep-G2 cells and showed antiproliferative activity (IC50 38–60 μg/mL). This study showed hepatoprotective effect of ERZO. Daleya Abdulaziz Bardi, Mohammed Farouq Halabi, Nor Azizan Abdullah, Elham Rouhollahi, Maryam Hajrezaie, and Mahmood Ameen Abdulla Copyright © 2013 Daleya Abdulaziz Bardi et al. All rights reserved. Off-Label Use of Ondansetron in Pregnancy in Western Australia Thu, 12 Dec 2013 10:55:18 +0000 Aims. Nausea and vomiting of pregnancy is the most common medical condition in pregnancy. There is an increasing trend to prescribe ondansetron although its safety for use in pregnancy has not been established. Methods. Exposed pregnancies were all births in Western Australia, 2002–2005, where the mother was dispensed ondansetron under the Australian Pharmaceutical Benefits Scheme, compared with all other births during the same period. Outcomes investigated include maternal and child characteristics, birth defects, pregnancy, and delivery characteristics. Results. There were 96,968 births from 2002 to 2005. Ondansetron was dispensed to 251 pregnant women during this period. The women dispensed ondansetron were more likely to be privately insured (OR: 5.8; 95% CI: 4.3–7.9), to be Caucasian (3.3; 1.9–5.7), not to smoke during their pregnancy (2.9; 1.8–4.7), to have a multiple birth (2.7; 1.5–5.0), and to have used fertility treatment (1.8; 1.0–3.4). There was a small but not significantly increased risk of a major birth defect with first trimester exposure (1.2; 0.6–2.2). Conclusions. Our study did not detect any adverse outcomes from the use of ondansetron in pregnancy but could not conclude that ondansetron is safe to use in pregnancy. Lyn Colvin, Andrew W. Gill, Linda Slack-Smith, Fiona J. Stanley, and Carol Bower Copyright © 2013 Lyn Colvin et al. All rights reserved. Antibacterial, Antioxidant, and Anticholinesterase Activities of Plant Seed Extracts from Brazilian Semiarid Region Tue, 10 Dec 2013 15:20:32 +0000 The antimicrobial, antioxidant, and anticholinesterase activities of ethanolic seed extracts of twenty-one plant species from Brazilian semiarid region were investigated. The extracts were tested for antimicrobial activity against six bacteria strains and three yeasts. Six extracts presented activity against the Gram (−) organism Salmonella choleraesuis and the Gram (+) organisms Staphylococcus aureus and Bacillus subtilis. The MIC values ranged from 4.96 to 37.32 mg/mL. The Triplaris gardneriana extract presented activity against the three species, with MIC values 18.8, 13.76, and 11.15 mg/mL, respectively. Five extracts presented antioxidant activity, with EC50 values ranging from 69.73 μg/mL (T. gardneriana) to 487.51 μg/mL (Licania rigida). For the anticholinesterase activity, eleven extracts were capable of inhibiting the enzyme activity. From those, T. gardneriana, Parkia platycephala and Connarus detersus presented the best activities, with inhibition values of 76.7, 71.5, and 91.9%, respectively. The extracts that presented antimicrobial activity were tested for hemolytic assay against human A, B, and O blood types and rabbit blood. From those, only the Myracrodruon urundeuva extract presented activity (about 20% of hemolysis at the lowest tested concentration, 1.9 µg/mL). Infrared spectroscopy of six representative extracts attested the presence of tannins, polyphenols, and flavonoids, which was confirmed by a qualitative phytochemical assay. Davi Felipe Farias, Terezinha Maria Souza, Martônio Ponte Viana, Bruno Marques Soares, Arcelina Pacheco Cunha, Ilka Maria Vasconcelos, Nágila Maria Pontes Silva Ricardo, Paulo Michel Pinheiro Ferreira, Vânia Maria Maciel Melo, and Ana Fontenele Urano Carvalho Copyright © 2013 Davi Felipe Farias et al. All rights reserved. Merit of Anisodamine Combined with Opioid -Receptor Activation in the Protection against Myocardial Injury during Cardiopulmonary Bypass Tue, 10 Dec 2013 10:29:52 +0000 Myocardial ischemia/reperfusion (MIR) injury easily occurrs during cardiopulmonary bypass surgery in elderly patients. In an attempt to develop an effective strategy, we employed a pig model of MIR injury to investigate the maximum rate of change of left ventricular pressure, left ventricular enddiastolic pressure, and left intraventricular pressure. Coronary sinus cardiac troponin T (TnT) and adenosine-triphosphate (ATP) content in myocardium were measured. The ultrastructures for MIR injury were visualized by transmission electron microscopy (TEM). The role of -opioid receptor activation using D-Ala2, D-Leu5-enkephalin (DADLE) in both early (D1) and late (D2) phases of cardioprotection was identified. Also, the merit of cardioprotection by DADLE in combination with anisodamine, the muscarinic receptor antagonist (D+M), was evaluated. Glibenclamide was employed at the dose sufficient to block ATP-sensitive potassium channels. Significant higher cardiac indicators, reduced TnT and increased ATP contents, were observed in D1, D2, and D+M groups compared with the control group. DADLE induced protection was better in later phase of ischemia that was attenuated by glibenclamide. DADLE after the ischemia showed no benefit, but combined treatment with anisodamine showed a marked postischemic cardioprotection. Thus, anisodamine is helpful in combination with DADLE for postischemic cardioprotection. Xuan Hong, Huimin Fan, Rong Lu, Paul Chan, and Zhongmin Liu Copyright © 2013 Xuan Hong et al. All rights reserved. Combination of Telmisartan with Cisplatin Controls Oral Cancer Cachexia in Rats Thu, 05 Dec 2013 15:59:28 +0000 The objective of the present investigation was to study the effect of combination of telmisartan with cisplatin in oral cancer cachexia induced by applying 0.5% 4-nitroquinoline-1-oxide (4-NQO) in propylene glycol to tongue, thrice a week for 8 weeks. From 8th to 22nd week, cisplatin (0.23 mg/kg, i.v.) was administered once in three weeks and telmisartan (5 mg/kg/day, p.o.) was administered daily. 4-NQO produced significant decrease in food intake, body weight, hyperglycemia, dyslipidemia, hypertension, and bradycardia, worsened hemodyanamics, increased cachexia markers like insulin, C-reactive protein, and interleukin-6, and increased tumor markers like lactate dehydrogenase and γ-glutamyl transferase.Treatment with combination of telmisartan with cisplatin produced significant increase in food intake and body weight and controlled hyperglycaemia and dyslipidemia, preserved hemodynamic function, and decreased the cachexia markers while cisplatin alone did not produce any increase in food intake and body weight. Further, the combination of telmisartan with cisplatin significantly reduced tumor marker levels. Combination of telmisartan with cisplatin prevented 4-NQO induced oxidative stress, hyperplasia and hyperkeratosis, premalignant dysplasia, and invasive squamous cell carcinoma in the tongue. Our data suggests that combination of telmisartan with cisplatin treatment is beneficial in controlling cancer cachexia. Telmisartan can be used as an add-on therapy with cisplatin or other traditional chemotherapeutic agents. Bhoomika M. Patel and Deepak Damle Copyright © 2013 Bhoomika M. Patel and Deepak Damle. All rights reserved. Antituberculosis: Synthesis and Antimycobacterial Activity of Novel Benzimidazole Derivatives Thu, 05 Dec 2013 08:45:44 +0000 A total of seven novel benzimidazoles were synthesized by a 4-step reaction starting from 4-fluoro-3-nitrobenzoic acid under relatively mild reaction conditions. The synthesized compounds were screened for their antimycobacterial activity against M. tuberculosis H37Rv (MTB-H37Rv) and INH-resistant M. tuberculosis (INHR-MTB) strains using agar dilution method. Three of them displayed good activity with MIC of less than 0.2 μM. Compound ethyl 1-(2-(4-(4-(ethoxycarbonyl)-2-aminophenyl)piperazin-1-yl)ethyl)-2-(4-(5-(4-fluorophenyl)pyridin-3-ylphenyl-1H-benzo[d]imidazole-5-carboxylate (5g) was found to be the most active with MIC of 0.112 μM against MTB-H37Rv and 6.12 μM against INHR-MTB, respectively. Yeong Keng Yoon, Mohamed Ashraf Ali, Tan Soo Choon, Rusli Ismail, Ang Chee Wei, Raju Suresh Kumar, Hasnah Osman, and Farzana Beevi Copyright © 2013 Yeong Keng Yoon et al. All rights reserved. Low-Cytotoxic Synthetic Bromorutaecarpine Exhibits Anti-Inflammation and Activation of Transient Receptor Potential Vanilloid Type 1 Activities Thu, 28 Nov 2013 17:46:04 +0000 Rutaecarpine (RUT), the major bioactive ingredient isolated from the Chinese herb Evodia rutaecarpa, possesses a wide spectrum of biological activities, including anti-inflammation and preventing cardiovascular diseases. However, its high cytotoxicity hampers pharmaceutical development. We designed and synthesized a derivative of RUT, bromo-dimethoxyrutaecarpine (Br-RUT), which showed no cytotoxicity at 20 μM. Br-RUT suppressed nitric oxide (NO) production and tumor necrosis factor-α release in concentration-dependent (0~20 μM) manners in lipopolysaccharide (LPS)-treated RAW 264.7 macrophages; protein levels of inducible NO synthase (iNOS) and cyclooxygenase-2 induced by LPS were downregulated. Br-RUT inhibited cell migration and invasion of ovarian carcinoma A2780 cells with 0~48 h of treatment. Furthermore, Br-RUT enhanced the expression of transient receptor potential vanilloid type 1 and activated endothelial NOS in human aortic endothelial cells. These results suggest that the synthetic Br-RUT possesses very low cytotoxicity but retains its activities against inflammation and vasodilation that could be beneficial for cardiovascular disease therapeutics. Chi-Ming Lee, Jiun-An Gu, Tin-Gan Rau, Che-Hsiung Yang, Wei-Chi Yang, Shih-Hao Huang, Feng-Yen Lin, Chun-Mao Lin, and Sheng-Tung Huang Copyright © 2013 Chi-Ming Lee et al. All rights reserved. The Effect of Apigenin on Pharmacokinetics of Imatinib and Its Metabolite N-Desmethyl Imatinib in Rats Thu, 28 Nov 2013 15:41:04 +0000 The purpose of this study was to determine the effect of apigenin on the pharmacokinetics of imatinib and N-desmethyl imatinib in rats. Healthy male SD rats were randomly divided into four groups: A group (the control group), B group (the long-term administration of 165 mg/kg apigenin for 15 days), C group (a single dose of 165 mg/kg apigenin), and D group (a single dose of 252 mg/kg apigenin). The serum concentrations of imatinib and N-desmethyl imatinib were measured by HPLC, and pharmacokinetic parameters were calculated using DAS 3.0 software. The parameters of , , , , and for imatinib in group B were different from those in group A (). Besides, and in groups C and D differed distinctly from those in group A as well. The parameters of and for N-desmethyl imatinib in group C were significantly lower than those in group A (); however, compared with groups B and D, the magnitude of effect was modest. Those results indicated that apigenin in the short-term study inhibited the metabolism of imatinib and its metabolite N-desmethyl imatinib, while in the long-term study the metabolism could be accelerated. Xian-yun Liu, Tao Xu, Wan-shu Li, Jun Luo, Pei-wu Geng, Li Wang, Meng-ming Xia, Meng-chun Chen, Lei Yu, and Guo-xin Hu Copyright © 2013 Xian-yun Liu et al. All rights reserved.