BioMed Research International: Pharmacology The latest articles from Hindawi Publishing Corporation © 2015 , Hindawi Publishing Corporation . All rights reserved. Effect of Supplemental Lutein and Zeaxanthin on Serum, Macular Pigmentation, and Visual Performance in Patients with Early Age-Related Macular Degeneration Sun, 01 Mar 2015 13:03:52 +0000 Purpose. To compare the 2-year effect of multiple doses of lutein/zeaxanthin on serum, macular pigmentation, and visual performance on patients with early age-related macular degeneration (AMD). Methods. In this randomized, double-blinded, and placebo-controlled trial, 112 early AMD patients randomly received either 10 mg lutein, 20 mg lutein, a combination of lutein (10 mg) and zeaxanthin (10 mg), or placebo daily for 2 years. Serum concentration of lutein/zeaxanthin, macular pigment optical density (MPOD), visual functions including best-spectacle corrected visual acuity (BCVA), contrast sensitivity (CS), flash recovery time (FRT), and vision-related quality of life (VFQ25) was quantified. Results. Serum lutein concentration and MPOD significantly increased in all the active treatment groups. Supplementation with 20 mg lutein was the most effective in increasing MPOD and CS at 3 cycles/degree for the first 48 weeks. However, they both significantly increased to the same peak value following supplementation with either 10 mg or 20 mg lutein during the intervention. No statistical changes of BCVA or FRT were observed during the trial. Conclusions. Long-term lutein supplementation could increase serum lutein concentration, MPOD, and visual sensitivities of early AMD patients. 10 mg lutein daily might be an advisable long-term dosage for early AMD treatment. Yang-Mu Huang, Hong-Liang Dou, Fei-Fei Huang, Xian-Rong Xu, Zhi-Yong Zou, and Xiao-Ming Lin Copyright © 2015 Yang-Mu Huang et al. All rights reserved. Curcumin Mitigates Accelerated Aging after Irradiation in Drosophila by Reducing Oxidative Stress Sun, 01 Mar 2015 12:51:21 +0000 Curcumin, belonging to a class of natural phenol compounds, has been extensively studied due to its antioxidative, anticancer, anti-inflammatory, and antineurodegenerative effects. Recently, it has been shown to exert dual activities after irradiation, radioprotection, and radiosensitization. Here, we investigated the protective effect of curcumin against radiation damage using D. melanogaster. Pretreatment with curcumin (100 M) recovered the shortened lifespan caused by irradiation and increased eclosion rate. Flies subjected to high-dose irradiation showed a mutant phenotype of outstretched wings, whereas curcumin pretreatment reduced incidence of the mutant phenotype. Protein carbonylation and formation of H2Ax foci both increased following high-dose irradiation most likely due to generation of reactive oxygen species. Curcumin pretreatment reduced the amount of protein carbonylation as well as formation of H2Ax foci. Therefore, we suggest that curcumin acts as an oxidative stress reducer as well as an effective protective agent against radiation damage. Ki Moon Seong, Mira Yu, Kyu-Sun Lee, Sunhoo Park, Young Woo Jin, and Kyung-Jin Min Copyright © 2015 Ki Moon Seong et al. All rights reserved. The Differential Effects of a Selective Kappa-Opioid Receptor Agonist, U50488, in Guinea Pig Heart Tissues Sun, 01 Mar 2015 11:29:11 +0000 The differential effects of a selective kappa- (κ-) opioid receptor agonist, U50488, were elucidated by monitoring the contraction of isolated guinea pig atrial and ventricular muscles. In electrically driven left atria, U50488 in nanomolar concentration range decreased the contractile force. Norbinaltorphimine (norBNI), a selective κ-receptor antagonist, and pertussis toxin (PTX) abolished the negative inotropic effect of U50488. In contrast, the inhibitory effect was not affected by the pretreatment of atropine or propranolol. Even though U50488 exerted a negative inotropic effect in the left atrium, it did not affect the contractile force of the right atrium and ventricles paced at 2 Hz. Similarly, the beating rate of the spontaneously beating right atrium was also unaffected by U50488. These results indicate that the activation of κ-opioid receptors can only produce negative inotropic effect in left atria via activation of PTX-sensitive G protein in guinea pigs. The absence of negative inotropic effects in right atria and ventricles suggests that there may be a greater distribution of functional κ-opioid receptors in guinea pig left atria than in right atria and ventricles, and the distribution of the receptors may be species-specific. Chi-Feng Hung, Hsin-Ju Li, Hsun-Hao Chang, Gon-Ann Lee, and Ming Jai Su Copyright © 2015 Chi-Feng Hung et al. All rights reserved. Temozolomide and Radiotherapy versus Radiotherapy Alone in High Grade Gliomas: A Very Long Term Comparative Study and Literature Review Sun, 01 Mar 2015 09:55:03 +0000 Temozolomide (TMZ) is the first line drug in the care of high grade gliomas. The combined treatment of TMZ plus radiotherapy is more effective in the care of brain gliomas then radiotherapy alone. Aim of this report is a survival comparison, on a long time (>10 years) span, of glioma patients treated with radiotherapy alone and with radiotherapy + TMZ. Materials and Methods. In this report we retrospectively reviewed the outcome of 128 consecutive pts with diagnosis of high grade gliomas referred to our institutions from April 1994 to November 2001. The first 64 pts were treated with RT alone and the other 64 with a combination of RT and adjuvant or concomitant TMZ. Results. Grade 3 (G3) haematological toxicity was recorded in 6 (9%) of 64 pts treated with RT and TMZ. No G4 haematological toxicity was observed. Age, histology, and administration of TMZ were statistically significant prognostic factors associated with 2 years overall survival (OS). PFS was for GBM 9 months, for AA 11. Conclusions. The combination of RT and TMZ improves long term survival in glioma patients. Our results confirm the superiority of the combination on a long time basis. Salvatore Parisi, Pietro Corsa, Arcangela Raguso, Antonio Perrone, Sabrina Cossa, Tindara Munafò, Gerardo Sanpaolo, Elisa Donno, Maria Antonietta Clemente, Michele Piombino, Federico Parisi, and Guido Valle Copyright © 2015 Salvatore Parisi et al. All rights reserved. Vitamin Supplementation as Possible Prophylactic Treatment against Migraine with Aura and Menstrual Migraine Sat, 28 Feb 2015 11:04:48 +0000 Migraine is the most common form of headache disorder globally. The etiology of migraine is multifactorial, with genetic components and environmental interactions considered to be the main causal factors. Some researchers postulate that deficits in mitochondrial energy reserves can cause migraine or an increase in homocysteine levels can lead to migraine attacks; therefore, vitamins could play a vital role in migraine prevention. For instance, riboflavin influences mitochondrial dysfunction and prevents migraine. Genes such as flavoenzyme 5,10-methylenetetrahydrofolate reductase (MTHFR), especially the C677T variant, have been associated with elevated plasma levels of homocysteine and migraine with aura. Homocysteine catalyzation requires the presence of vitamins B6, B12, and folic acid, which can decrease the severity of migraine with aura, making these vitamins potentially useful prophylactic agents for treating migraine with aura. Menstrual migraine, on the other hand, is associated with increased prostaglandin (PG) levels in the endometrium, indicating a role for vitamin E, which is an anti-PG. Vitamin C can also be used as a scavenger of reactive oxygen species for treating neurogenic inflammation in migraine patients. This paper reviews possible therapies based on vitamin supplementation for migraine prophylaxis, focusing on migraine with aura and menstrual migraine. Munvar Miya Shaik and Siew Hua Gan Copyright © 2015 Munvar Miya Shaik and Siew Hua Gan. All rights reserved. Lutein Has a Protective Effect on Hepatotoxicity Induced by Arsenic via Nrf2 Signaling Thu, 26 Feb 2015 06:00:34 +0000 Arsenic produces liver disease through the oxidative stress. While lutein can alleviate cytotoxic and oxidative injury, nuclear factor erythroid 2-related factor 2 (Nrf2) pathway plays a critical role in defending oxidative species. However, the mechanisms by which lutein protects the liver against the effect of arsenic are not known. Therefore, this study aims to investigate the mechanisms involved in the action of lutein using mice model in which hepatotoxicity was induced by arsenic. We found that mice treatment with lutein could reverse changes in morphological and liver indexes and result in a significant improvement in hepatic function comparing with arsenic trioxide group. Lutein treatment improved the activities of antioxidant enzymes and attenuated increasing of ROS and MDA induced by arsenic trioxide. Lutein could increase the mRNA and protein expression of Nrf2 signaling related genes (Nrf2, Nqo1, Ho-1, and Gst). These findings provide additional evidence that lutein may be useful for reducing reproductive injury associated with oxidative stress by the activation of Nrf2 signaling. Our findings suggest a possible mechanism of antioxidant lutein in preventing the hepatotoxicity, which implicate that a dietary lutein may be a potential treatment for liver diseases, especially for arsenicosis therapy. Shugang Li, Yusong Ding, Qiang Niu, Shangzhi Xu, Lijuan Pang, Rulin Ma, Mingxia Jing, Gangling Feng, Jing Xia Tang, Qian Zhang, Xiaomei Ma, Yizhong Yan, Jingyu Zhang, Meng Wei, Hai Xia Wang, Feng Li, and Shuxia Guo Copyright © 2015 Shugang Li et al. All rights reserved. Direct Effects of (−)-Epicatechin and Procyanidin B2 on the Respiration of Rat Heart Mitochondria Tue, 24 Feb 2015 15:36:10 +0000 Flavonol (−)-epicatechin and its derived dimer procyanidin B2, present in high amounts in cocoa products, have been shown to exert beneficial effects on the heart and cardiovascular system; however, their mechanism of action has not been fully elucidated. We studied effects of (−)-epicatechin and procyanidin B2 on the oxidative phosphorylation of isolated rat heart mitochondria. (−)-Epicatechin and procyanidin B2 had stimulating effect (up to 30% compared to control) on substrate-driven (State 2) mitochondrial respiration. Their effect was dependent on the respiratory substrates used. (−)-Epicatechin at higher concentrations (from 0.27 µg/mL) significantly decreased (up to 15%) substrate- and ADP-driven (State 3) mitochondrial respiration in case of pyruvate and malate oxidation only. Procyanidin B2 (0.7–17.9 ng/mL) inhibited State 3 respiration rate up to 19%, the most profound effect being expressed with succinate as the substrate. (−)-Epicatechin at concentrations of 0.23 µg/mL and 0.46 µg/mL prevented loss of the cytochrome from mitochondria when substrate was succinate, supporting the evidence of membrane stabilizing properties of this flavonol. Thus, both (−)-epicatechin and procyanidin B2 directly influenced mitochondrial functions and the observed effects could help to explain cardiometabolic risk reduction ascribed to the consumption of modest amounts of cocoa products. Dalia M. Kopustinskiene, Arunas Savickas, David Vetchý, Ruta Masteikova, Arturas Kasauskas, and Jurga Bernatoniene Copyright © 2015 Dalia M. Kopustinskiene et al. All rights reserved. Resveratrol Prevents Cardiovascular Complications in the SHR/STZ Rat by Reductions in Oxidative Stress and Inflammation Mon, 23 Feb 2015 11:33:41 +0000 The cardioprotective effects of resveratrol are well established in animal models of metabolic disease but are yet to be investigated in a combined model of hypertension and diabetes. This study investigated the ability of resveratrol’s antioxidant and anti-inflammatory effects to prevent cardiovascular complications in the spontaneously hypertensive streptozotocin-induced diabetic rat. Diabetes was induced in eight-week-old male spontaneously hypertensive rats via a single intravenous injection of streptozotocin. Following this, resveratrol was administered orally for an eight-week period until the animals were sixteen weeks of age. Upon completion of the treatment regime assessments of oxidative stress, lipid peroxidation, inflammation, and cardiovascular function were made. Resveratrol administration to hypertensive-diabetic animals did not impact upon blood glucose or haemodynamics but significantly reduced oxidative stress, lipid peroxidation, and inflammatory cytokines. Reductions in systemic levels of oxidative stress and inflammation conferred improvements in vascular reactivity and left ventricular pump function and electrophysiology. This study demonstrates that resveratrol administration to hypertensive diabetic animals can elicit cardioprotective properties via antioxidant and anti-inflammatory effects. The observed preservation of cardiovascular function was independent of changes in blood glucose concentration and haemodynamics, suggesting that oxidative stress and inflammation are key components within the pathological cascade associated with hypertension and diabetes. Rebecca K. Vella, Candice Pullen, Fiona R. Coulson, and Andrew S. Fenning Copyright © 2015 Rebecca K. Vella et al. All rights reserved. Encapsulation of Curcumin in Diblock Copolymer Micelles for Cancer Therapy Sun, 22 Feb 2015 11:29:30 +0000 Application of nanoparticles has recently promising results for water insoluble agents like curcumin. In this study, we synthesized polymeric nanoparticle-curcumin (PNPC) and then showed its efficiency, drug loading, stability, and safety. Therapeutic effects of PNPC were also assessed on two cell lines and in an animal model of breast cancer. PNPC remarkably suppressed mammary and hepatocellular carcinoma cells proliferation (). Under the dosing procedure, PNPC was safe at 31.25 mg/kg and lower doses. Higher doses demonstrated minimal hepatocellular and renal toxicity in paraclinical and histopathological examinations. Tumor take rate in PNPC-treated group was 37.5% compared with 87.5% in control (). Average tumor size and weight were significantly lower in PNPC group than control (). PNPC increased proapoptotic Bax protein expression (). Antiapoptotic Bcl-2 protein expression, however, was lower in PNPC-treated animals than the control ones (). In addition, proliferative and angiogenic parameters were statistically decreased in PNPC-treated animals (). These results highlight the suppressing role for PNPC in in vitro and in vivo tumor growth models. Our findings provide credible evidence for superior biocompatibility of the polymeric nanocarrier in pharmacological arena together with an excellent tumor-suppressing response. Ali Mohammad Alizadeh, Majid Sadeghizadeh, Farhood Najafi, Sussan K. Ardestani, Vahid Erfani-Moghadam, Mahmood Khaniki, Arezou Rezaei, Mina Zamani, Saeed Khodayari, Hamid Khodayari, and Mohammad Ali Mohagheghi Copyright © 2015 Ali Mohammad Alizadeh et al. All rights reserved. Lespedeza davurica (Lax.) Schindl. Extract Protects against Cytokine-Induced β-Cell Damage and Streptozotocin-Induced Diabetes Sun, 22 Feb 2015 11:04:30 +0000 Lespedeza has been used for the management of diabetes in folklore medicine. The purpose of this study is to investigate the protective effects of the methanol extract of Lespedeza davurica (LD) on cytokine-induced β-cell damage and streptozotocin- (STZ-) induced diabetes. RINm5F cells were treated with interleukin- (IL-) 1β and interferon- (IFN-) γ to induce pancreatic β-cell damage. The exposure of LD extract significantly decreased cell death, nitric oxide (NO) production, nitric oxide synthase (iNOS) expression, and nucleus factor-kappa B (NF-κB) p65 activation. Antidiabetic effects of LD extract were observed by oral glucose tolerance test (OGTT) in normal rats and by checking the biochemical, physiological, and histopathological parameters in STZ-induced diabetic rats. In OGTT, glucose clearance levels improved by oral treatment of LD extract. The water intake, urine volume, blood glucose, and serum TG, TC, TBARS, and DPP-IV levels were significantly decreased, and liver glycogen content was significantly increased by treatment of LD extract (250 mg/kg BW) in STZ-induced diabetic rats. Also, insulin immunoreactivity of the pancreases was increased in LD extract administrated rats compared with diabetic control rats. These results indicate that LD extract may protect pancreatic β-cell damage and regulate the blood glucose in STZ-induced diabetic rats. Bhesh Raj Sharma and Dong Young Rhyu Copyright © 2015 Bhesh Raj Sharma and Dong Young Rhyu. All rights reserved. Tetramethylpyrazine Enhances Vascularization and Prevents Osteonecrosis in Steroid-Treated Rats Wed, 11 Feb 2015 12:29:11 +0000 Steroid-induced osteonecrosis of the femoral head (steroid-induced ONFH) is an avascular necrosis disease of bone. Tetramethylpyrazine (TMP), with significant vascular protective properties, has been widely used for the treatments of ischemic neural disorders and cardiovascular diseases. However, its role in the treatment of steroid-induced ONFH has not been evaluated. In this study, our results showed that TMP significantly decreased the ratio of empty lacuna, adipose tissue area, and adipocyte perimeter in steroid-induced ONFH rats histopathologically. TMP also reduced the levels of serum lipid dramatically by haematological examination. According to the micro-CT quantification, TMP could improve the microstructure of the trabecular bone and increases bone mineral density in steroid-induced ONFH rats. Moreover, TMP significantly increased the vessel volume, vessel surface, percentage of vessel volume, and vessel thickness of the femoral heads by micro-CT. Interestingly, the downregulation of VEGF and FLK1 proteins in the sera and necrotic femoral heads could be reversed by TMP treatment, and this was true for their mRNA expressions in femoral heads. In conclusion, these findings suggest for the first time that TMP may prevent steroid-induced ONFH and also enhance femoral head vascularization by inhibiting the effect of steroid on VEGF/FLK1 signal pathway. Yini Jiang, Chunfang Liu, Weiheng Chen, Hui Wang, Chao Wang, and Na Lin Copyright © 2015 Yini Jiang et al. All rights reserved. The Gastrointestinal Irritation of Polygala Saponins and Its Potential Mechanism In Vitro and In Vivo Sun, 01 Feb 2015 09:59:42 +0000 Processing alters the pharmacological activity and reduces the gastrointestinal toxicity of the polygalae. To investigate the effect of processing, different glycosyl substituent products were tested. Hypnotic and subhypnotic doses of pentobarbital-induced sleep tests on mice were used to evaluate the sedative activity of polygala saponins with different glycosyl substituents; isolated gut motility experiment was employed to study excitatory effects of different polygala saponins; the gastrointestinal irritation effects of different polygala saponins were compared by measuring the levels of gastric PGE2 and intestinal TNF-α on mice. When compared with control, Onjisaponin B (OJB) and tenuifolin (TEN), but not senegenin (SNG), significantly increased the number of sleeping mice and prolonged the sleeping time (); 80, 40, and 20 mg/L of OJB and 80 mg/L of TEN, but not SNG, obviously changed the amplitude and frequency of isolated jejunum (); all the three compounds significantly decreased the level of gastric PGE2 but had no obvious influences on the reduction of intestinal TNF-α level. For sedative and hypnotic effects, OJB > TEN > SNG; for the protection form gastrointestinal irritation and damages, OJB > TEN > SNG. Therefore, in processing Polygala, glycosyl breaking may be related to the decline of pharmacological activity and gastrointestinal toxicity of polygala saponins. Li Wen, Nan Xia, PeiPei Tang, Yi Hong, ZiZhen Wang, YaJie Liu, YanJu Liu, JianJun Liu, and XiangQiong Li Copyright © 2015 Li Wen et al. All rights reserved. Normal and Pathological Placental Angiogenesis Sat, 31 Jan 2015 10:49:14 +0000 Nathalie Bardin, Padma Murthi, and Nadia Alfaidy Copyright © 2015 Nathalie Bardin et al. All rights reserved. Circulating MicroRNAs as Clinical Biomarkers in the Predictions of Pregnancy Complications Thu, 29 Jan 2015 08:03:39 +0000 Predicting pregnancy complications is a major topic for clinicians and biologists for maternal and fetal monitoring. Noninvasive biomarkers in maternal blood such as circulating microRNAs (miRNAs) are promising molecules to predict pregnancy disorders. miRNAs are noncoding short RNAs that regulate mRNA expression by repressing the translation or cleaving the transcript. miRNAs are released to the extracellular systemic circulation via exosomes. The discovery of plasma- or serum-derived miRNAs and of free-circulating exosomes that contain miRNAs provides useful information about the physiological or pathophysiological roles of the miRNAs. Specific placental miRNAs are present in maternal plasma in different ways depending on whether the pregnancy is normal or pathological or if there is no pregnancy. This paper focuses on placental miRNAs and extracellular miRNAs to the placenta whose misregulation could lead to pregnancy complications. Marthe Tsochandaridis, Laurent Nasca, Caroline Toga, and Annie Levy-Mozziconacci Copyright © 2015 Marthe Tsochandaridis et al. All rights reserved. Angiogenesis in the Placenta: The Role of Reactive Oxygen Species Signaling Thu, 29 Jan 2015 07:04:05 +0000 Proper placental development and function are central to the health of both the mother and the fetus during pregnancy. A critical component of healthy placental function is the proper development of its vascular network. Poor vascularization of the placenta can lead to fetal growth restriction, preeclampsia, and in some cases fetal death. Therefore, understanding the mechanisms by which uterine stressors influence the development of the placental vasculature and contribute to placental dysfunction is of central importance to ensuring a healthy pregnancy. In this review we discuss how oxidative stress observed in maternal smoking, maternal obesity, and preeclampsia has been associated with aberrant angiogenesis and placental dysfunction resulting in adverse pregnancy outcomes. We also highlight that oxidative stress can influence the expression of a number of transcription factors important in mediating angiogenesis. Therefore, understanding how oxidative stress affects redox-sensitive transcription factors within the placenta may elucidate potential therapeutic targets for correcting abnormal placental angiogenesis and function. Robyn D. Pereira, Nicole E. De Long, Ruijun C. Wang, Fereshteh T. Yazdi, Alison C. Holloway, and Sandeep Raha Copyright © 2015 Robyn D. Pereira et al. All rights reserved. CCAAT/Enhancer Binding Protein β in relation to ER Stress, Inflammation, and Metabolic Disturbances Wed, 28 Jan 2015 06:46:07 +0000 The prevalence of the metabolic syndrome and underlying metabolic disturbances increase rapidly in developed countries. Various molecular targets are currently under investigation to unravel the molecular mechanisms that cause these disturbances. This is done in attempt to counter or prevent the negative health consequences of the metabolic disturbances. Here, we reviewed the current knowledge on the role of C/EBP-β in these metabolic disturbances. C/EBP-β deletion in mice resulted in downregulation of hepatic lipogenic genes and increased expression of β-oxidation genes in brown adipose tissue. Furthermore, C/EBP-β is important in the differentiation and maturation of adipocytes and is increased during ER stress and proinflammatory conditions. So far, studies were only conducted in animals and in cell systems. The results found that C/EBP-β is an important transcription factor within the metabolic disturbances of the metabolic system. Therefore, it is interesting to examine the potential role of C/EBP-β at molecular and physiological level in humans. Sophie E. van der Krieken, Herman E. Popeijus, Ronald P. Mensink, and Jogchum Plat Copyright © 2015 Sophie E. van der Krieken et al. All rights reserved. Lunasin Inhibits Cell Proliferation via Apoptosis and Reduces the Production of Proinflammatory Cytokines in Cultured Rheumatoid Arthritis Synovial Fibroblasts Tue, 27 Jan 2015 11:27:33 +0000 Lunasin, a peptide with 43 amino acid residues and initially isolated and identified in soybean cotyledon, has gained extensive attention due to its anti-inflammatory and anticancer properties. However, its treatment efficacy on rheumatoid arthritis (RA) and corresponding mechanisms have not been reported. Herein, the synovial fibroblasts harvested and isolated from patients with RA were treated with lunasin at various concentrations to examine the proliferation, apoptosis status, and corresponding cell cycle of cultured RA synovial fibroblasts. Meanwhile, the underlying mechanisms of lunasin for RA treatment are explored through Western blot, real-time PCR, ELISA, and luciferase reporter assays. Lunasin significantly inhibited the proliferation and induced the apoptosis of cultured RA synovial fibroblasts. In addition, lunasin reduced the production of interleukin-6 (IL-6), IL-8, and matrix metalloproteinase-3 (MMP-3) and suppressed the activation of NF-κB in cultured RA synovial fibroblasts but did not reveal obvious modulation on the secretion and gene expression of MMP-1. Therefore, lunasin will have promising potential as a novel nutritional supplement or drug candidate for RA due to its potency of suppressing synovial cell proliferation and decreasing the production of proinflammatory cytokines and MMPs in synovial cells. Shaohui Jia, Shufang Zhang, Hong Yuan, and Ning Chen Copyright © 2015 Shaohui Jia et al. All rights reserved. Portulaca oleracea L.: A Review of Phytochemistry and Pharmacological Effects Mon, 26 Jan 2015 08:17:01 +0000 Portulaca oleracea L., belonging to the Portulacaceae family, is commonly known as purslane in English and Ma-Chi-Xian in Chinese. It is a warm-climate, herbaceous succulent annual plant with a cosmopolitan distribution. It is eaten extensively as a potherb and added in soups and salads around the Mediterranean and tropical Asian countries and has been used as a folk medicine in many countries. Diverse compounds have been isolated from Portulaca oleracea, such as flavonoids, alkaloids, polysaccharides, fatty acids, terpenoids, sterols, proteins vitamins and minerals. Portulaca oleracea possesses a wide spectrum of pharmacological properties such as neuroprotective, antimicrobial, antidiabetic, antioxidant, anti-inflammatory, antiulcerogenic, and anticancer activities. However, few molecular mechanisms of action are known. This review provides a summary of phytochemistry and pharmacological effects of this plant. Yan-Xi Zhou, Hai-Liang Xin, Khalid Rahman, Su-Juan Wang, Cheng Peng, and Hong Zhang Copyright © 2015 Yan-Xi Zhou et al. All rights reserved. Natural Compounds Regulate Glycolysis in Hypoxic Tumor Microenvironment Thu, 22 Jan 2015 13:17:06 +0000 In the early twentieth century, Otto Heinrich Warburg described an elevated rate of glycolysis occurring in cancer cells, even in the presence of atmospheric oxygen (the Warburg effect). Recently it became a therapeutically interesting strategy and is considered as an emerging hallmark of cancer. Hypoxia inducible factor-1 (HIF-1) is one of the key transcription factors that play major roles in tumor glycolysis and could directly trigger Warburg effect. Thus, how to inhibit HIF-1-depended Warburg effect to assist the cancer therapy is becoming a hot issue in cancer research. In fact, HIF-1 upregulates the glucose transporters (GLUT) and induces the expression of glycolytic enzymes, such as hexokinase, pyruvate kinase, and lactate dehydrogenase. So small molecules of natural origin used as GLUT, hexokinase, or pyruvate kinase isoform M2 inhibitors could represent a major challenge in the field of cancer treatment. These compounds aim to suppress tumor hypoxia induced glycolysis process to suppress the cell energy metabolism or enhance the susceptibility of tumor cells to radio- and chemotherapy. In this review, we highlight the role of natural compounds in regulating tumor glycolysis, with a main focus on the glycolysis under hypoxic tumor microenvironment. Jian-Li Gao and Ying-Ge Chen Copyright © 2015 Jian-Li Gao and Ying-Ge Chen. All rights reserved. The Combined Inhibitory Effect of the Adenosine A1 and Cannabinoid CB1 Receptors on cAMP Accumulation in the Hippocampus Is Additive and Independent of A1 Receptor Desensitization Sun, 18 Jan 2015 09:37:54 +0000 Adenosine A1 and cannabinoid CB1 receptors are highly expressed in hippocampus where they trigger similar transduction pathways. We investigated how the combined acute activation of A1 and CB1 receptors modulates cAMP accumulation in rat hippocampal slices. The CB1 agonist WIN55212-2 (0.3–30 M) decreased forskolin-stimulated cAMP accumulation with an EC50 of 6.6 ± 2.7 M and an of 31% ± 2%, whereas for the A1 agonist, N6-cyclopentyladenosine (CPA, 10–150 nM), an EC50 of 35 ± 19 nM, and an of 29% ± 5 were obtained. The combined inhibitory effect of WIN55212-2 (30 M) and CPA (100 nM) on cAMP accumulation was 41% ± 6% (), which did not differ () from the sum of the individual effects of each agonist (43% ± 8%) but was different () from the effects of CPA or WIN55212-2 alone. Preincubation with CPA (100 nM) for 95 min caused desensitization of adenosine A1 activity, which did not modify the effect of WIN55212-2 (30 M) on cAMP accumulation. In conclusion, the combined effect of CB1 and A1 receptors on cAMP formation is additive and CB1 receptor activity is not affected by short-term A1 receptor desensitization. André Serpa, Sara Correia, Joaquim A. Ribeiro, Ana M. Sebastião, and José F. Cascalheira Copyright © 2015 André Serpa et al. All rights reserved. Thymoquinone-Loaded Nanostructured Lipid Carrier Exhibited Cytotoxicity towards Breast Cancer Cell Lines (MDA-MB-231 and MCF-7) and Cervical Cancer Cell Lines (HeLa and SiHa) Tue, 06 Jan 2015 09:15:59 +0000 Thymoquinone (TQ) has been shown to exhibit antitumor properties. Thymoquinone-loaded nanostructured lipid carrier (TQ-NLC) was developed to improve the bioavailability and cytotoxicity of TQ. This study was conducted to determine the cytotoxic effects of TQ-NLC on breast cancer (MDA-MB-231 and MCF-7) and cervical cancer cell lines (HeLa and SiHa). TQ-NLC was prepared by applying the hot high pressure homogenization technique. The mean particle size of TQ-NLC was 35.66 ± 0.1235 nm with a narrow polydispersity index (PDI) lower than 0.25. The zeta potential of TQ-NLC was greater than −30 mV. Polysorbate 80 helps to increase the stability of TQ-NLC. Differential scanning calorimetry showed that TQ-NLC has a melting point of 56.73°C, which is lower than that of the bulk material. The encapsulation efficiency of TQ in TQ-NLC was 97.63 ± 0.1798% as determined by HPLC analysis. TQ-NLC exhibited antiproliferative activity towards all the cell lines in a dose-dependent manner which was most cytotoxic towards MDA-MB-231 cells. Cell shrinkage was noted following treatment of MDA-MB-231 cells with TQ-NLC with an increase of apoptotic cell population (). TQ-NLC also induced cell cycle arrest. TQ-NLC was most cytotoxic towards MDA-MB-231 cells. It induced apoptosis and cell cycle arrest in the cells. Wei Keat Ng, Latifah Saiful Yazan, Li Hua Yap, Wan Abd Ghani Wan Nor Hafiza, Chee Wun How, and Rasedee Abdullah Copyright © 2015 Wei Keat Ng et al. All rights reserved. Comparative Effects of Retinoic Acid or Glycolic Acid Vehiculated in Different Topical Formulations Tue, 06 Jan 2015 08:50:47 +0000 Retinoids and hydroxy acids have been widely used due to their effects in the regulation of growth and in the differentiation of epithelial cells. However, besides their similar indication, they have different mechanisms of action and thus they may have different effects on the skin; in addition, since the topical formulation efficiency depends on vehicle characteristics, the ingredients of the formulation could alter their effects. Thus the objective of this study was to compare the effects of retinoic acid (RA) and glycolic acid (GA) treatment on the hairless mouse epidermis thickness and horny layer renewal when added in gel, gel cream, or cream formulations. For this, gel, gel cream, and cream formulations (with or without 6% GA or 0.05% RA) were applied in the dorsum of hairless mice, once a day for seven days. After that, the skin was analyzed by histopathologic, morphometric, and stereologic techniques. It was observed that the effects of RA occurred independently from the vehicle, while GA had better results when added in the gel cream and cream. Retinoic acid was more effective when compared to glycolic acid, mainly in the cell renewal and the exfoliation process because it decreased the horny layer thickness. Patrícia Maria Berardo Gonçalves Maia Campos, Lorena Rigo Gaspar, Gisele Mara Silva Gonçalves, Lúcia Helena Terenciane Rodrigues Pereira, Marisa Semprini, and Ruberval Armando Lopes Copyright © 2015 Patrícia Maria Berardo Gonçalves Maia Campos et al. All rights reserved. Pharmacokinetics Interaction between Imatinib and Genistein in Rats Mon, 05 Jan 2015 14:19:00 +0000 The objective of this work was to investigate the effect of orally administered genistein on the pharmacokinetics of imatinib and N-desmethyl imatinib in rats. Twenty-five healthy male SD (Sprague-Dawley) rats were randomly divided into five groups: A group (control group), B group (multiple dose of 100 mg/kg genistein for consecutive 15 days), C group (multiple dose of 50 mg/kg genistein for consecutive 15 days), D group (a single dose of 100 mg/kg genistein), and E group (a single dose of 50 mg/kg genistein). A single dose of imatinib is administered orally 30 min after administration of genistein (100 mg/kg or 50 mg/kg). The pharmacokinetic parameters of imatinib and N-desmethyl imatinib were calculated by DAS 3.0 software. The multiple dose of 100 mg/kg or 50 mg/kg genistein significantly () decreased the and of imatinib. and the of N-desmethyl imatinib were also increased, but without any significant difference. However, the single dose of 100 mg/kg or 50 mg/kg genistein has no effect on the pharmacokinetics of imatinib and N-desmethyl imatinib. Those results indicated that multiple dose of genistein (100 mg/kg or 50 mg/kg) induces the metabolism of imatinib, while single dose of genistein has no effect. Zhe Wang, Li Wang, Meng-ming Xia, Wei Sun, Cheng-ke Huang, Xiao Cui, Guo-xin Hu, Qing-quan Lian, and Zeng-shou Wang Copyright © 2015 Zhe Wang et al. All rights reserved. Pharmacological Application of Growth Factors: Basic and Clinical Mon, 05 Jan 2015 08:04:43 +0000 Jian Xiao, Yadong Wang, Saverio Bellusci, and Xiaokun Li Copyright © 2015 Jian Xiao et al. All rights reserved. Use of Pharmacotherapies in the Treatment of Alcohol Use Disorders and Opioid Dependence in Primary Care Mon, 05 Jan 2015 07:28:13 +0000 Substance-related and addictive disorders are chronic relapsing conditions that substantially impact public health. Effective treatments for these disorders require addressing substance use/dependence comprehensively as well as other associated comorbidities. Comprehensive addressing of substance use in a medical setting involves screening for substance use, addressing substance use directly with the patient, and formulating an appropriate intervention. For alcohol dependence and opioid dependence, pharmacotherapies are available that are safe and effective when utilized in a comprehensive treatment paradigm, such as medication assisted treatment. In primary care, substance use disorders involving alcohol, illicit opioids, and prescription opioid abuse are common among patients who seek primary care services. Primary care providers report low levels of preparedness and confidence in identifying substance-related and addictive disorders and providing appropriate care and treatment. However, new models of service delivery in primary care for individuals with substance-related and addictive disorders are being developed to promote screening, care and treatment, and relapse prevention. The education and training of primary care providers utilizing approved medications for the treatment of alcohol use disorders and opioid dependence in a primary care setting would have important public health impact and reduce the burden of alcohol abuse and opioid dependence. Jinhee Lee, Thomas F. Kresina, Melinda Campopiano, Robert Lubran, and H. Westley Clark Copyright © 2015 Jinhee Lee et al. All rights reserved. Design and Delivery of a Tailored Intervention to Implement Recommendations for Multimorbid Patients Receiving Polypharmacy into Primary Care Practices Mon, 05 Jan 2015 07:26:45 +0000 Introduction. Managing polypharmacy is particularly demanding for general practitioners as coordinators of care. Recently, a German guideline for polypharmacy in primary care has been published. This paper describes the content and delivery of a tailored intervention, which aims at improving the implementation of guideline recommendations for polypharmacy into practice, considering individual barriers. Materials and Methods. Firstly, barriers for implementation and the corresponding strategies to address them have been identified. On this basis, an intervention consisting of a workshop for health care professionals and educational materials for patients has been developed. The workshop focused on knowledge, awareness, and skills. The educational materials included a tablet computer. Practice teams will elaborate individual concepts of how to implement the recommendations into their practice. The workshop has been evaluated by the participants by means of a questionnaire. Results. During the workshop 41 possible sources of medication errors and 41 strategies to improve medication management have been identified. Participants evaluated the workshop overall positively, certifying its relevancy to practice. Discussion. The concept of the workshop seemed appropriate to impart knowledge about medication management to the participants. It will have to be evaluated, if the intervention finally resulted in an improved implementation of the guideline recommendations. Cornelia Jäger, Joachim Szecsenyi, and Jost Steinhäuser Copyright © 2015 Cornelia Jäger et al. All rights reserved. Fibroblast Growth Factors Stimulate Hair Growth through β-Catenin and Shh Expression in C57BL/6 Mice Thu, 01 Jan 2015 10:04:34 +0000 Growth factors are involved in the regulation of hair morphogenesis and cycle hair growth. The present study sought to investigate the hair growth promoting activities of three approved growth factor drugs, fibroblast growth factor 10 (FGF-10), acidic fibroblast growth factor (FGF-1), and basic fibroblast growth factor (FGF-2), and the mechanism of action. We observed that FGFs promoted hair growth by inducing the anagen phase in telogenic C57BL/6 mice. Specifically, the histomorphometric analysis data indicates that topical application of FGFs induced an earlier anagen phase and prolonged the mature anagen phase, in contrast to the control group. Moreover, the immunohistochemical analysis reveals earlier induction of β-catenin and Sonic hedgehog (Shh) in hair follicles of the FGFs-treated group. These results suggest that FGFs promote hair growth by inducing the anagen phase in resting hair follicles and might be a potential hair growth-promoting agent. Wei-hong Lin, Li-Jun Xiang, Hong-Xue Shi, Jian Zhang, Li-ping Jiang, Ping-tao Cai, Zhen-Lang Lin, Bei-Bei Lin, Yan Huang, Hai-Lin Zhang, Xiao-Bing Fu, Ding-Jiong Guo, Xiao-Kun Li, Xiao-Jie Wang, and Jian Xiao Copyright © 2015 Wei-hong Lin et al. All rights reserved. Analgesic and Anti-Inflammatory Activities of Leaf Extract of Mallotus repandus (Willd.) Muell. Arg. Wed, 31 Dec 2014 15:44:54 +0000 In folk medicine Mallotus repandus (Willd.) Muell. Arg. is used to treat muscle pain, itching, fever, rheumatic arthritis, snake bite, hepatitis, and liver cirrhosis. This study aimed to evaluate the antinociceptive as well as the anti-inflammatory activities of the methanol extract of leaf. The leaves were extracted with methanol following hot extraction and tested for the presence of phytochemical constituents. Analgesic and anti-inflammatory activities were evaluated using acetic acid induced writhing test, xylene induced ear edema, cotton pellet induced granuloma, and tail immersion methods at doses of 500, 1000, and 2000 mg/kg body weight. The presence of flavonoids, saponins, and tannins was identified in the extract. The extract exhibited considerable antinociceptive and anti-inflammatory activities against four classical models of pain. In acetic acid induced writhing, xylene induced ear edema, and cotton pellet granuloma models, the extract revealed dose dependent activity. Additionally, it increased latency time in tail immersion model. It can be concluded that M. repandus possesses significant antinociceptive potential. These findings suggest that this plant can be used as a potential source of new antinociceptive and anti-inflammatory candidates. The activity of methanol extract is most likely mediated through central and peripheral inhibitory mechanisms. This study justified the traditional use of leaf part of this plant. Md. Mahadi Hasan, Nizam Uddin, Md. Rakib Hasan, A. F. M. Mahmudul Islam, Md. Monir Hossain, Akib Bin Rahman, Md. Sazzad Hossain, Ishtiaque Ahmed Chowdhury, and Md. Sohel Rana Copyright © 2014 Md. Mahadi Hasan et al. All rights reserved. Therapeutic Potential of Natural Pharmacological Agents in the Treatment of Human Diseases Sun, 28 Dec 2014 07:29:52 +0000 Kota V. Ramana, Sharad S. Singhal, and Aramati B. Reddy Copyright © 2014 Kota V. Ramana et al. All rights reserved. Novel Psychoactive Substances and Behavioral Addictions Sun, 28 Dec 2014 06:44:04 +0000 Giovanni Martinotti, Ornella Corazza, Sophia Achab, and Zsolt Demetrovics Copyright © 2014 Giovanni Martinotti et al. All rights reserved. Proteoglycans/Glycosaminoglycans: From Basic Research to Clinical Practice Sun, 21 Dec 2014 06:35:59 +0000 George Tzanakakis, Ilona Kovalszky, Paraskevi Heldin, and Dragana Nikitovic Copyright © 2014 George Tzanakakis et al. All rights reserved. Cysteine Cathepsin Activity Regulation by Glycosaminoglycans Sun, 21 Dec 2014 06:12:34 +0000 Cysteine cathepsins are a group of enzymes normally found in the endolysosomes where they are primarily involved in intracellular protein turnover but also have a critical role in MHC II-mediated antigen processing and presentation. However, in a number of pathologies cysteine cathepsins were found to be heavily upregulated and secreted into extracellular milieu, where they were found to degrade a number of extracellular proteins. A major role in modulating cathepsin activities play glycosaminoglycans, which were found not only to facilitate their autocatalytic activation including at neutral pH, but also to critically modulate their activities such as in the case of the collagenolytic activity of cathepsin K. The interaction between cathepsins and glycosaminoglycans will be discussed in more detail. Marko Novinec, Brigita Lenarčič, and Boris Turk Copyright © 2014 Marko Novinec et al. All rights reserved. Ethnopharmacological Assessment of Medicinal Plants Used against Livestock Infections by the People Living around Indus River Wed, 03 Dec 2014 08:03:50 +0000 The present study was aimed to document detailed ethnopharmacological knowledge of medicinal plants against livestock infections of an unexplored remote region of Pakistan. Semistructured questionnaires were used for data collection. Total 43 plants belonging to 26 families were found to be used in ethnoveterinary practices. Seeds (29%) were found to be the most frequent plant part used followed by leaves (22%). Ethnoveterinary recipes were mostly prepared in the form of decoction and powdering. Informant consensus factor (Fic) results revealed high consensus for gastrointestinal (0.81), mastitis (0.82), and dermatological infections (0.80). Curcuma longa ranked first with highest fidelity level (FL) value (66%) followed by Trachyspermum ammi that ranked second (58%). Preference ranking (PR) results showed that Zingiber officinale, Punica granatum, Triticum aestivum, Gossypium hirsutum, and Withania coagulans were the most preferred species for the treatment of diarrhea. Direct matrix ranking (DMR) results showed that Morus alba, Melia azedarach, Withania coagulans, Cassia fistula, Azadirachta indica, and Tamarix aphylla were the multipurpose species of the region. We invite the attention of pharmacologists and chemists for further exploration of plants having high Fic, FL, and PR values in the present study. Conservation strategies should be adopted for the protection of multipurpose plant species. Sakina Mussarat, Rahila Amber, Akash Tariq, Muhammad Adnan, Naser M. AbdElsalam, Riaz Ullah, and Roqaia Bibi Copyright © 2014 Sakina Mussarat et al. All rights reserved. Comparative Hair Restorer Efficacy of Medicinal Herb on Nude (Foxn) Mice Thu, 13 Nov 2014 05:52:28 +0000 Eclipta alba (L.) Hassk, Asiasarum sieboldii (Miq.) F. Maek (Asiasari radix), and Panax ginseng C. A. Mey (red ginseng) are traditionally acclaimed for therapeutic properties of various human ailments. Synergistic effect of each standardized plant extract was investigated for hair growth potential on nude mice, as these mutant mice genetically lack hair due to abnormal keratinization. Dried plant samples were ground and extracted by methanol. Topical application was performed on the back of nude mice daily up to completion of two hair growth generations. The hair density and length of Eclipta alba treated mice were increased significantly than control mice. Hair growth area was also distinctly visible in Eclipta alba treated mice. On the other hand, Asiasari radix and Panax ginseng treated mice developing hair loss were recognized from the abortive boundaries of hair coverage. Histomorphometric observation of nude mice skin samples revealed an increase in number of hair follicles (HFs). The presence of follicular keratinocytes was confirmed by BrdU labeling, S-phase cells in HFs. Therefore, Eclipta alba extract and/or phytochemicals strongly displayed incomparability of hair growth promotion activity than others. Thus, the standardized Eclipta alba extract can be used as an effective, alternative, and complementary treatment against hair loss. Shahnaz Begum, Mi Ra Lee, Li Juan Gu, Md. Jamil Hossain, Hyun Kyoung Kim, and Chang Keun Sung Copyright © 2014 Shahnaz Begum et al. All rights reserved. Effects of Combined Anisodamine and Neostigmine Treatment on the Inflammatory Response and Liver Regeneration of Obstructive Jaundice Rats after Hepatectomy Wed, 12 Nov 2014 06:22:39 +0000 Background. Cholestasis is associated with high rates of morbidity and mortality in patients undergoing major liver resection. This study aimed to evaluate the effects of a combined anisodamine and neostigmine (Ani+Neo) treatment on the inflammatory response and liver regeneration in rats with obstructive jaundice (OJ) after partial hepatectomy. Materials and Methods. OJ was induced in the rats by bile duct ligation. After 7 days biliary drainage and partial hepatectomy were performed. These rats were assigned to a saline group or an Ani+Neo treatment group. The expressions of inflammatory mediators, liver regeneration, and liver damage were assessed at 48 h after hepatectomy. Results. The mRNA levels of TNF-α, IL-1β, IL-6, MCP-1, and MIP-1α, in the remnant livers, and the serum levels of TNF-α and IL-1β were substantially reduced in the Ani+Neo group compared with saline group . The Ani+Neo treatment obviously promoted liver regeneration as indicated by the liver weights and Ki-67 labeling index . The serum albumin and γ-GT levels and liver neutrophil infiltration also significantly improved in the Ani+Neo group compared with the saline group. Conclusions. These results demonstrate that the combined anisodamine and neostigmine treatment is able to improve the liver regeneration in rats with OJ by substantially alleviating the inflammatory response. Chong-Hui Li, Xuan Zhang, Xin-Lan Ge, Xin Huang, Ai-Qun Zhang, and Wan-Qing Gu Copyright © 2014 Chong-Hui Li et al. All rights reserved. Antidiabetic Activity of Pterospermum acerifolium Flowers and Glucose Uptake Potential of Bioactive Fraction in L6 Muscle Cell Lines with Its HPLC Fingerprint Tue, 21 Oct 2014 08:43:33 +0000 The present study was designed to estimate the detailed antidiabetic activity of Pterospermum acerifolium (L.) Willd flowers. In vitro alpha amylase inhibition study was carried out on 50% ethanol extract of flowers (PAFEE) and its various fractions. The active ethyl acetate fraction (PAFEF) was subfractionated into three subfractions (PAFE1, PAFE2, and PAFE3) and subjected to acute toxicity studies followed by antidiabetic screening in vivo by streptozotocin-nicotinamide induced type II diabetes. Diabetic animals treated with PAFE2 (30 mg/kg) reduced the levels of fasting blood glucose, significantly () compared to that of diabetic control animals. Histological studies on drug treated groups did not show remarkable positive changes in β-cells. PAFE2 showed % glucose uptake over control and, in the presence of PI3K inhibitor wortmannin, declined to %. HPLC analysis of PAFE2 reveals the presence of quercetin and apigenin as major constituents and both are inhibiting the glycogen phosphorylase enzyme in molecular modelling studies. The study evidenced strongly that the probable glucose lowering mechanism of action of active subfraction PAFE2 is by increasing the glucose uptake in peripheral tissues and by inhibition of gluconeogenesis. Rathinavelusamy Paramaguru, Papiya Mitra Mazumder, Dinakar Sasmal, and Venkatesan Jayaprakash Copyright © 2014 Rathinavelusamy Paramaguru et al. All rights reserved. Contribution of α,β-Amyrenone to the Anti-Inflammatory and Antihypersensitivity Effects of Aleurites moluccana (L.) Willd. Sun, 19 Oct 2014 07:26:25 +0000 The aim of the study was to analyze the constituents of the dichloromethane fraction obtained from A. moluccana and also to evaluate the anti-inflammatory and antinociceptive properties of α,β-amyrenone isolated from A. moluccana in mice. The dichloromethane fraction was evaluated by gas chromatography and submitted to purification. The mixture of α,β-amyrenone was isolated and then evaluated using the carrageenan-induced paw-oedema or pleurisy and CFA-induced arthritis models in mice. Five triterpenes, α,β-amyrenone, glutinol, and α,β-amyrin were isolated from dichloromethane fraction of A. moluccana leaf extract. The mixture of α,β-amyrenone, dosed orally, was able to reduce mechanical hypersensitivity and paw-oedema induced by carrageenan, interfering with neutrophil migration. Similar results were observed in the carrageenan-induced pleurisy model. Repeated administration of the compounds was also effective in reducing the mechanical sensitization and oedema developed in the arthritis model induced by CFA. In conclusion, the results demonstrate that α,β-amyrenone interferes in both acute and chronic inflammatory processes. We can infer that these effects involve, at least in part, a reduction in the neutrophil migration. Therefore, it seems reasonable to suggest that α,β-amyrenone could represent a new therapeutic tool for the management of painful and inflammatory diseases, especially those presenting a chronic profile. Nara Lins Meira Quintão, Lilian W. Rocha, Gislaine Franciele Silva, Simone Reichert, Vanessa D. Claudino, Ruth Meri Lucinda-Silva, Angela Malheiros, Márcia Maria De Souza, Valdir Cechinel Filho, Tania M. Bellé Bresolin, Marina da Silva Machado, Theodoro Marcel Wagner, and Christiane Meyre-Silva Copyright © 2014 Nara Lins Meira Quintão et al. All rights reserved. Protective Role of 5-Lipoxigenase during Leishmania infantum Infection Is Associated with Th17 Subset Sun, 21 Sep 2014 00:00:00 +0000 Visceral leishmaniasis (VL) is a chronic and fatal disease caused by Leishmania infantum in Brazil. Leukocyte recruitment to infected tissue is a crucial event for the control of infections such as VL. Leucotriens are lipid mediators synthesized by 5-lipoxygenase (5-LO) and they display a protective role against protozoan parasites by inducing several functions in leucocytes. We determined the role of 5-LO activity in parasite control, focusing on the inflammatory immune response against Leishmania infantum infection. LTB4 is released during in vitro infection. The genetic ablation of 5-LO promoted susceptibility in highly resistant mice strains, harboring more parasites into target organs. The susceptibility was related to the failure of neutrophil migration to the infectious foci. Investigating the neutrophil failure, there was a reduction of proinflammatory cytokines involved in the related Th17 axis released into the organs. Genetic ablation of 5-LO reduced the CD4+T cells producing IL-17, without interfering in Th1 subset. L. infantum failed to activate DC from , showing reduced surface costimulatory molecule expression and proinflammatory cytokines involved in Th17 differentiation. BLT1 blockage with selective antagonist interferes with DC maturation and proinflammatory cytokines release. Thus, 5-LO activation coordinates the inflammatory immune response involved in the control of VL. Laís Amorim Sacramento, Fernando Q. Cunha, Roque Pacheco de Almeida, João Santana da Silva, and Vanessa Carregaro Copyright © 2014 Laís Amorim Sacramento et al. All rights reserved. Chondroitin Sulfate Proteoglycans in the Nervous System: Inhibitors to Repair Thu, 18 Sep 2014 00:00:00 +0000 Chondroitin sulfate proteoglycans (CSPGs) are widely expressed in the normal central nervous system, serving as guidance cues during development and modulating synaptic connections in the adult. With injury or disease, an increase in CSPG expression is commonly observed close to lesioned areas. However, these CSPG deposits form a substantial barrier to regeneration and are largely responsible for the inability to repair damage in the brain and spinal cord. This review discusses the role of CSPGs as inhibitors, the role of inflammation in stimulating CSPG expression near site of injury, and therapeutic strategies for overcoming the inhibitory effects of CSPGs and creating an environment conducive to nerve regeneration. Justin R. Siebert, Amanda Conta Steencken, and Donna J. Osterhout Copyright © 2014 Justin R. Siebert et al. All rights reserved. Biological and Molecular Effects of Small Molecule Kinase Inhibitors on Low-Passage Human Colorectal Cancer Cell Lines Wed, 17 Sep 2014 09:19:39 +0000 Low-passage cancer cell lines are versatile tools to study tumor cell biology. Here, we have employed four such cell lines, established from primary tumors of colorectal cancer (CRC) patients, to evaluate effects of the small molecule kinase inhibitors (SMI) vemurafenib, trametinib, perifosine, and regorafenib in an in vitro setting. The mutant BRAF (V600E/V600K) inhibitor vemurafenib, but also the MEK1/2 inhibitor trametinib efficiently inhibited DNA synthesis, signaling through ERK1/2 and expression of genes downstream of ERK1/2 in BRAF mutant cells only. In case of the AKT inhibitor perifosine, three cell lines showed a high or intermediate responsiveness to the drug while one cell line was resistant. The multikinase inhibitor regorafenib inhibited proliferation of all CRC lines with similar efficiency and independent of the presence or absence of KRAS, BRAF, PIK3CA, and TP53 mutations. Regorafenib action was associated with broad-range inhibitory effects at the level of gene expression but not with a general inhibition of AKT or MEK/ERK signaling. In vemurafenib-sensitive cells, the antiproliferative effect of vemurafenib was enhanced by the other SMI. Together, our results provide insights into the determinants of SMI efficiencies in CRC cells and encourage the further use of low-passage CRC cell lines as preclinical models. Falko Lange, Benjamin Franz, Claudia Maletzki, Michael Linnebacher, Maja Hühns, and Robert Jaster Copyright © 2014 Falko Lange et al. All rights reserved. The Characteristics of Thrombin in Osteoarthritic Pathogenesis and Treatment Tue, 16 Sep 2014 07:46:54 +0000 Osteoarthritis (OA) is a mechanical abnormality associated with degradation of joints. It is characterized by chronic, progressive degeneration of articular cartilage, abnormalities of bone, and synovial change. The most common symptom of OA is local inflammation resulting from exogenous stress or endogenous abnormal cytokines. Additionally, OA is associated with local and/or systemic activation of coagulation and anticoagulation pathways. Thrombin plays an important role in the stimulation of fibrin deposition and the proinflammatory processes in OA. Thrombin mediates hemostatic and inflammatory responses and guides the immune response to tissue damage. Thrombin activates intracellular signaling pathways by interacting with transmembrane domain G protein coupled receptors (GPCRs), known as protease-activated receptors (PARs). In pathogenic mechanisms, PARs have been implicated in the development of acute and chronic inflammatory responses in OA. Therefore, discovery of thrombin signaling pathways would help us to understand the mechanism of OA pathogenesis and lead us to develop therapeutic drugs in the future. Pei-Yu Chou, Chen-Ming Su, Chun-Yin Huang, and Chih-Hsin Tang Copyright © 2014 Pei-Yu Chou et al. All rights reserved. Natural Compounds and Aging: Between Autophagy and Inflammasome Sun, 14 Sep 2014 08:19:46 +0000 Aging, a natural physiological process, is characterized by a progressive loss of physiological integrity. Loss of cellular homeostasis in the aging process results from different sources, including changes in genes, cell imbalance, and dysregulation of the host-defense systems. Innate immunity dysfunctions during aging are connected with several human pathologies, including metabolic disorders and cardiovascular diseases. Recent studies have clearly indicated that the decline in autophagic capacity that accompanies aging results in the accumulation of dysfunctional mitochondria, reactive oxygen species (ROS) production, and further process dysfunction of the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome activation in the macrophages, which produce the proinflammatory cytokines. These factors impair cellular housekeeping and expose cells to higher risk in many age-related diseases, such as atherosclerosis and type 2 diabetes. In this review, we investigated the relationship between dysregulation of the inflammasome activation and perturbed autophagy with aging as well as the possible molecular mechanisms. We also summarized the natural compounds from food intake, which have potential to reduce the inflammasome activation and enhance autophagy and can further improve the age-related diseases discussed in this paper. Shih-Yi Chuang, Chih-Hung Lin, and Jia-You Fang Copyright © 2014 Shih-Yi Chuang et al. All rights reserved. Targeting Mast Cells Tryptase in Tumor Microenvironment: A Potential Antiangiogenetic Strategy Thu, 11 Sep 2014 10:27:10 +0000 Angiogenesis is a complex process finely regulated by the balance between angiogenesis stimulators and inhibitors. As a result of proangiogenic factors overexpression, it plays a crucial role in cancer development. Although initially mast cells (MCs) role has been defined in hypersensitivity reactions and in immunity, it has been discovered that MCs have a crucial interplay on the regulatory function between inflammatory and tumor cells through the release of classical proangiogenic factors (e.g., vascular endothelial growth factor) and nonclassical proangiogenic mediators granule-associated (mainly tryptase). In fact, in several animal and human malignancies, MCs density is highly correlated with tumor angiogenesis. In particular, tryptase, an agonist of the proteinase-activated receptor-2 (PAR-2), represents one of the most powerful angiogenic mediators released by human MCs after c-Kit receptor activation. This protease, acting on PAR-2 by its proteolytic activity, has angiogenic activity stimulating both human vascular endothelial and tumor cell proliferation in paracrine manner, helping tumor cell invasion and metastasis. Based on literature data it is shown that tryptase may represent a promising target in cancer treatment due to its proangiogenic activity. Here we focused on molecular mechanisms of three tryptase inhibitors (gabexate mesylate, nafamostat mesylate, and tranilast) in order to consider their prospective role in cancer therapy. Michele Ammendola, Christian Leporini, Ilaria Marech, Cosmo Damiano Gadaleta, Giovanni Scognamillo, Rosario Sacco, Giuseppe Sammarco, Giovambattista De Sarro, Emilio Russo, and Girolamo Ranieri Copyright © 2014 Michele Ammendola et al. All rights reserved. Importance of pH Homeostasis in Metabolic Health and Diseases: Crucial Role of Membrane Proton Transport Thu, 11 Sep 2014 07:22:03 +0000 Protons dissociated from organic acids in cells are partly buffered. If not, they are transported to the extracellular fluid through the plasma membrane and buffered in circulation or excreted in urine and expiration gas. Several transporters including monocarboxylate transporters and Na+/H+ exchanger play an important role in uptake and output of protons across plasma membranes in cells of metabolic tissues including skeletal muscle and the liver. They also contribute to maintenance of the physiological pH of body fluid. Therefore, impairment of these transporters causes dysfunction of cells, diseases, and a decrease in physical performance associated with abnormal pH. Additionally, it is known that fluid pH in the interstitial space of metabolic tissues is easily changed due to little pH buffering capacitance in interstitial fluids and a reduction in the interstitial fluid pH may mediate the onset of insulin resistance unlike blood containing pH buffers such as Hb (hemoglobin) and albumin. In contrast, habitual exercise and dietary intervention regulate expression/activity of transporters and maintain body fluid pH, which could partly explain the positive effect of healthy lifestyle on disease prognosis. Wataru Aoi and Yoshinori Marunaka Copyright © 2014 Wataru Aoi and Yoshinori Marunaka. All rights reserved. GHK and DNA: Resetting the Human Genome to Health Thu, 11 Sep 2014 06:59:13 +0000 During human aging there is an increase in the activity of inflammatory, cancer promoting, and tissue destructive genes plus a decrease in the activity of regenerative and reparative genes. The human blood tripeptide GHK possesses many positive effects but declines with age. It improves wound healing and tissue regeneration (skin, hair follicles, stomach and intestinal linings, and boney tissue), increases collagen and glycosaminoglycans, stimulates synthesis of decorin, increases angiogenesis, and nerve outgrowth, possesses antioxidant and anti-inflammatory effects, and increases cellular stemness and the secretion of trophic factors by mesenchymal stem cells. Recently, GHK has been found to reset genes of diseased cells from patients with cancer or COPD to a more healthy state. Cancer cells reset their programmed cell death system while COPD patients’ cells shut down tissue destructive genes and stimulate repair and remodeling activities. In this paper, we discuss GHK’s effect on genes that suppress fibrinogen synthesis, the insulin/insulin-like system, and cancer growth plus activation of genes that increase the ubiquitin-proteasome system, DNA repair, antioxidant systems, and healing by the TGF beta superfamily. A variety of methods and dosages to effectively use GHK to reset genes to a healthier state are also discussed. Loren Pickart, Jessica Michelle Vasquez-Soltero, and Anna Margolina Copyright © 2014 Loren Pickart et al. All rights reserved. The Influence of Standardized Valeriana officinalis Extract on the CYP3A1 Gene Expression by Nuclear Receptors in In Vivo Model Thu, 11 Sep 2014 06:34:10 +0000 Valeriana officinalis is one of the most popular medicinal plants commonly used as a sedative and sleep aid. It is suggested that its pharmacologically active compounds derived from the root may modulate the CYP3A4 gene expression by activation of pregnane X receptor (PXR) or constitutive androstane receptor (CAR) and lead to pharmacokinetic herb-drug interactions. The aim of the study was to determine the influence of valerian on the expression level of CYP3A1 (homologue to human CYP3A4) as well as nuclear receptors PXR, CAR, RXR, GR, and HNF-4. Male Wistar rats were given standardized valerian extract (300 mg/kg/day, p.o.) for 3 and 10 days. The expression in liver tissue was analyzed by using real-time PCR. Our result showed a decrease of CYP3A1 expression level by 35% () and 37% (), respectively. Moreover, Valeriana exhibited statistically significant reduction in RXR (approximately 28%) only after 3-day treatment. We also demonstrated a decrease in the amount HNF-4 by 22% () and 32% (), respectively. In case of CAR, the increase of expression level by 46% () was noted. These findings suggest that Valeriana officinalis extract can decrease the CYP3A4 expression and therefore may lead to interactions with synthetic drugs metabolized by this enzyme. Anna Bogacz, Przemyslaw M. Mrozikiewicz, Monika Karasiewicz, Joanna Bartkowiak-Wieczorek, Marian Majchrzycki, Przemyslaw L. Mikolajczak, Marcin Ozarowski, and Edmund Grzeskowiak Copyright © 2014 Anna Bogacz et al. All rights reserved. Neuroprotective Effects of Lipoxin A4 in Central Nervous System Pathologies Tue, 09 Sep 2014 11:09:10 +0000 Many diseases of the central nervous system are characterized and sometimes worsened by an intense inflammatory response in the affected tissue. It is now accepted that resolution of inflammation is an active process mediated by a group of mediators that can act in synchrony to switch the phenotype of cells, from a proinflammatory one to another that favors the return to homeostasis. This new genus of proresolving mediators includes resolvins, protectins, maresins, and lipoxins, the first to be discovered. In this short review we provide an overview of current knowledge into the cellular and molecular interactions of lipoxins in diseases of the central nervous system in which they appear to facilitate the resolution of inflammation, thus exerting a neuroprotective action. Alessandra Cadete Martini, Stefânia Forner, Allisson Freire Bento, and Giles Alexander Rae Copyright © 2014 Alessandra Cadete Martini et al. All rights reserved. Hyaluronan-Phosphatidylethanolamine Polymers Form Pericellular Coats on Keratinocytes and Promote Basal Keratinocyte Proliferation Tue, 09 Sep 2014 00:00:00 +0000 Aged keratinocytes have diminished proliferative capacity and hyaluronan (HA) cell coats, which are losses that contribute to atrophic skin characterized by reduced barrier and repair functions. We formulated HA-phospholipid (phosphatidylethanolamine, HA-PE) polymers that form pericellular coats around cultured dermal fibroblasts independently of CD44 or RHAMM display. We investigated the ability of these HA-PE polymers to penetrate into aged mouse skin and restore epidermal function in vivo. Topically applied Alexa647-HA-PE penetrated into the epidermis and dermis, where it associated with both keratinocytes and fibroblasts. In contrast, Alexa647-HA was largely retained in the outer cornified layer of the epidermis and quantification of fluorescence confirmed that significantly more Alexa647-HA-PE penetrated into and was retained within the epidermis than Alexa647-HA. Multiple topical applications of HA-PE to shaved mouse skin significantly stimulated basal keratinocyte proliferation and epidermal thickness compared to HA or vehicle cream alone. HA-PE had no detectable effect on keratinocyte differentiation and did not promote local or systemic inflammation. These effects of HA-PE polymers are similar to those reported for endogenous epidermal HA in youthful skin and show that topical application of HA-PE polymers can restore some of the impaired functions of aged epidermis. Caitlin J. Symonette, Aman Kaur Mann, Xiao Cherie Tan, Cornelia Tolg, Jenny Ma, Francisco Perera, Arjang Yazdani, and Eva A. Turley Copyright © 2014 Caitlin J. Symonette et al. All rights reserved. Superoxide Dismutase 1 Loss Disturbs Intracellular Redox Signaling, Resulting in Global Age-Related Pathological Changes Mon, 08 Sep 2014 05:09:05 +0000 Aging is characterized by increased oxidative stress, chronic inflammation, and organ dysfunction, which occur in a progressive and irreversible manner. Superoxide dismutase (SOD) serves as a major antioxidant and neutralizes superoxide radicals throughout the body. In vivo studies have demonstrated that copper/zinc superoxide dismutase-deficient (Sod1−/−) mice show various aging-like pathologies, accompanied by augmentation of oxidative damage in organs. We found that antioxidant treatment significantly attenuated the age-related tissue changes and oxidative damage-associated p53 upregulation in Sod1−/− mice. This review will focus on various age-related pathologies caused by the loss of Sod1 and will discuss the molecular mechanisms underlying the pathogenesis in Sod1−/− mice. Kenji Watanabe, Shuichi Shibuya, Yusuke Ozawa, Hidetoshi Nojiri, Naotaka Izuo, Koutaro Yokote, and Takahiko Shimizu Copyright © 2014 Kenji Watanabe et al. All rights reserved. Heparin and Liver Heparan Sulfate Can Rescue Hepatoma Cells from Topotecan Action Sun, 07 Sep 2014 10:53:57 +0000 Topotecan (TpT) is a major inhibitory compound of topoisomerase (topo) I that plays important roles in gene transcription and cell division. We have previously reported that heparin and heparan sulfate (HS) might be transported to the cell nucleus and they can interact with topoisomerase I. We hypothesized that heparin and HS might interfere with the action of TpT. To test this hypothesis we isolated topoisomerase I containing cell nuclear protein fractions from normal liver, liver cancer tissues, and hepatoma cell lines. The enzymatic activity of these extracts was measured in the presence of heparin, liver HS, and liver cancer HS. In addition, topo I activity, cell viability, and apoptosis of HepG2 and Hep3B cells were investigated after heparin and TpT treatments. Liver cancer HS inhibited topo I activity in vitro. Heparin treatment abrogated topo I enzyme activity in Hep3B cells, but not in HepG2 cells, where the basal activity was higher. Heparin protected the two hepatoma cell lines from TpT actions and decreased the rate of TpT induced S phase block and cell death. These results suggest that heparin and HS might interfere with the function of TpT in liver and liver cancer. József Dudás, József Bocsi, Alexandra Fullár, Kornélia Baghy, Tibor Füle, Saule Kudaibergenova, and Ilona Kovalszky Copyright © 2014 József Dudás et al. All rights reserved. Glucose, Insulin, and Oxygen Interplay in Placental Hypervascularisation in Diabetes Mellitus Tue, 02 Sep 2014 12:35:46 +0000 The placental vasculature rapidly expands during the course of pregnancy in order to sustain the growing needs of the fetus. Angiogenesis and vascular growth are stimulated and regulated by a variety of growth factors expressed in the placenta or present in the fetal circulation. Like in tumors, hypoxia is a major regulator of angiogenesis because of its ability to stimulate expression of various proangiogenic factors. Chronic fetal hypoxia is often found in pregnancies complicated by maternal diabetes as a result of fetal hyperglycaemia and hyperinsulinemia. Both are associated with altered levels of hormones, growth factors, and proinflammatory cytokines, which may act in a proangiogenic manner and, hence, affect placental angiogenesis and vascular development. Indeed, the placenta in diabetes is characterized by hypervascularisation, demonstrating high placental plasticity in response to diabetic metabolic derangements. This review describes the major regulators of placental angiogenesis and how the diabetic environment in utero alters their expression. In the light of hypervascularized diabetic placenta, the focus was placed on proangiogenic factors. Silvija Cvitic, Gernot Desoye, and Ursula Hiden Copyright © 2014 Silvija Cvitic et al. All rights reserved. Thai Massage, and Thai Herbal Compress versus Oral Ibuprofen in Symptomatic Treatment of Osteoarthritis of the Knee: A Randomized Controlled Trial Mon, 01 Sep 2014 05:56:54 +0000 The aim of this study was to verify the clinical responses to Thai massage (TM) and Thai herbal compression (THC) for treating osteoarthritis (OA) of the knee in comparison to oral ibuprofen. This study was a randomized, evaluator-blind, controlled trial. Sixty patients with OA of the knee were randomly assigned to receive either a one-hour session of TM or THC (three times weekly) or oral ibuprofen (three times daily). The duration of treatment was three weeks. The clinical assessments included visual analog scale assessing pain and stiffness, Lequesne’s functional index, time for climbing up ten steps, and physician’s and patient’s overall opinions on improvement. In a within-group comparison, each treatment modality caused a significant improvement of all variables determined for outcome assessments. In an among group comparison, all modalities provided nearly comparable clinical efficacy after a three-week symptomatic treatment of OA of the knee, in which a trend toward greatest improvement was likely to be found in THC group. In conclusion, TM and THC generally provided comparable clinical efficacy to oral ibuprofen after three weeks of treatment and could be considered as complementary and alternative treatments for OA of the knee. Natthakarn Chiranthanut, Nutthiya Hanprasertpong, and Supanimit Teekachunhatean Copyright © 2014 Natthakarn Chiranthanut et al. All rights reserved. The Nerve Growth Factor Signaling and Its Potential as Therapeutic Target for Glaucoma Sun, 31 Aug 2014 11:54:15 +0000 Neuroprotective therapies which focus on factors leading to retinal ganglion cells (RGCs) degeneration have been drawing more and more attention. The beneficial effects of nerve growth factor (NGF) on the glaucoma have been recently suggested, but its effects on eye tissue are complex and controversial in various studies. Recent clinical trials of systemically and topically administrated NGF demonstrate that NGF is effective in treating several ocular diseases, including glaucoma. NGF has two receptors named high affinity NGF tyrosine kinase receptor TrkA and low affinity receptor p75NTR. Both receptors exist in cells in retina like RGC (expressing TrkA) and glia cells (expressing p75NTR). NGF functions by binding to TrkA or p75NTR alone or both together. The binding of NGF to TrkA alone in RGC promotes RGC’s survival and proliferation through activation of TrkA and several prosurvival pathways. In contrast, the binding of NGF to p75NTR leads to apoptosis although it also promotes survival in some cases. Binding of NGF to both TrkA and p75NTR at the same time leads to survival in which p75NTR functions as a TrkA helping receptor. This review discusses the current understanding of the NGF signaling in retina and the therapeutic implications in the treatment of glaucoma. Haitao Wang, Rikang Wang, Thilini Thrimawithana, Peter J. Little, Jiangping Xu, Zhong-Ping Feng, and Wenhua Zheng Copyright © 2014 Haitao Wang et al. All rights reserved. Marked Antigiardial Activity of Yucca baccata Extracts: A Potential Natural Alternative for Treating Protozoan Infections Sun, 31 Aug 2014 07:19:48 +0000 Human Giardiosis is a public health problem in Mexico, where the national prevalence was estimated to be up to 68%. Misuse of antiprotozoal drugs may result in low effectiveness and undesirable side effects. Research on natural products is a good strategy for discovering more effective antiparasitic compounds. This study evaluated the antigiardial activity of extracts of Yucca baccata, which is native to northwestern Mexico. Forty-two gerbils (females) were weighed and orally inoculated with Giardia trophozoites. Two gerbils were selected at random to confirm infection. Forty living gerbils were randomly allocated into 5 treatment groups (8 per group). Gerbils were randomly assigned to be treated with 24.4 mg/mL, 12.2 mg/mL, and 6.1 mg/mL of extracts, metronidazole (2 mg/mL) or PBS, which were intragastrically administered once per day for 3 days. Nine gerbils died during the study course. On day 10 postinfection, gerbils were euthanized and trophozoites were quantified. Yucca extracts reduced, albeit not significantly, the trophozoite counts in the duodenum segment. Only the high-extract concentration significantly reduced the trophozoite counts in the proximal segment and it was similar to that of metronidazole. Extracts of Y. baccata may represent an effective and natural therapeutic alternative for human giardiosis. Luis Quihui-Cota, Rocio León-Trujillo, Humberto Astiazarán-García, Julián Esparza-Romero, María del Refugio Robles, Ramón E. Robles-Zepeda, Rafael Canett, and Jesús Sánchez-Escalante Copyright © 2014 Luis Quihui-Cota et al. All rights reserved. Inhibition of Peroxisome Proliferator-Activated Receptor Gamma Prevents the Melanogenesis in Murine B16/F10 Melanoma Cells Thu, 28 Aug 2014 09:40:05 +0000 The purpose of this study was to investigate if PPAR plays a role in the melanogenesis. B16/F10 cells were divided into five groups: control, melanin stimulating hormone (-MSH), -MSH+retinol, -MSH+GW9662 (PPAR antagonist), and GW9662. Cells in the control group were cultured in the Dulbecco’s modified Eagle’s medium (DMEM) for 48 hrs. To initiate the melanogenesis, cells in all -MSH groups were cultured in medium containing -MSH (10 nM) for 48 hrs. Cells were treated simultaneously with retinol (5 μM) in the -MSH+retinol group. Instead of retinol, GW9662 (10 μM) was cocultured in the -MSH+GW9662 group. Cells in the final group were cultured in the DMEM with GW9662. All the analyses were carried out 48 hours after treatments. The -MSH was able to increase cell number, melanin production, and the activity of tyrosinase, the limiting enzyme in melanogenesis. These -MSH-induced changes were prevented either by retinol or by GW9662. Further analyses of the activities of antioxidant enzymes including glutathione, catalase, and the superoxide dismutase (SOD) showed that -MSH treatment raised the activity of SOD which was dependent on PPAR level. According to our results, the -MSH-induced melanogenesis was PPAR dependent, which also modulated the expression of SOD. Jiun-Han Chen, Junn-Liang Chang, Pei-Ru Chen, Yun-Ju Chuang, Shih-Tsang Tang, Shwu-Fen Pan, Tzer-Bin Lin, Kang-Hua Chen, and Mei-Jung Chen Copyright © 2014 Jiun-Han Chen et al. All rights reserved. Extracts from Vatica diospyroides Type SS Fruit Show Low Dose Activity against MDA-MB-468 Breast Cancer Cell-Line via Apoptotic Action Thu, 28 Aug 2014 06:23:59 +0000 Very strong antiproliferative action of V. diospyroides type SS fruit extracts (IC50 range of 1.60-17.45 µg/mL) in MDA-MB-468 cell-line was observed in an MTT assay. After dosing of an extract concentration at half IC50 to cell line for 24 to 72 hours, treated cells were subjected to Annexin V-FITC/PI binding assay, followed by FACS and western blot analyses. Significant apoptotic death was observed with all extract treatments and both exposure times. Dosing with acetone extract of pericarp and cotyledon induced the highest apoptotic populations (33 and 32%, resp.), with the lowest populations of viable cells (65 and 67%, resp.). During 24 to 72 hours of dosing with methanolic extract of pericarp, the populations of viable and early apoptotic cells decreased significantly from 72.40 to 71.32% and from 12.00 to 6.36%, respectively, while the late apoptotic and nonviable cell populations continuously increased from 15.30 to 19.18% and from 0.30 to 3.14%, respectively. The expression of Bax increased within 12–48 hours of dosing, confirming apoptosis induced by time-dependent responses. The mutant p53 of MDA-MB-468 cells was expressed. Our results indicate that apoptosis and time-dependent therapeutic actions contribute to the cytotoxic effects of V. diospyroides type SS fruit on MDA-MB-468 cell. Theera Srisawat, Yaowapa Sukpondma, Siriphon Chimplee, Kanyanatt Kanokwiroon, Aman Tedasen, and Potchanapond Graidist Copyright © 2014 Theera Srisawat et al. All rights reserved. Emerging Anticancer Potentials of Goniothalamin and Its Molecular Mechanisms Thu, 28 Aug 2014 05:25:54 +0000 The treatment of most cancers is still inadequate, despite tremendous steady progress in drug discovery and effective prevention. Nature is an attractive source of new therapeutics. Several medicinal plants and their biomarkers have been widely used for the treatment of cancer with less known scientific basis of their functioning. Although a wide array of plant derived active metabolites play a role in the prevention and treatment of cancer, more extensive scientific evaluation of their mechanisms is still required. Styryl-lactones are a group of secondary metabolites ubiquitous in the genus Goniothalamus that have demonstrated to possess antiproliferative activity against cancer cells. A large body of evidence suggests that this activity is associated with the induction of apoptosis in target cells. In an effort to promote further research on the genus Goniothalamus, this review offers a broad analysis of the current knowledge on Goniothalamin (GTN) or 5, 6, dihydro-6-styryl-2-pyronone (C13H12O2), a natural occurring styryl-lactone. Therefore, it includes (i) the source of GTN and other metabolites; (ii) isolation, purification, and (iii) the molecular mechanisms of actions of GTN, especially the anticancer properties, and summarizes the role of GTN which is crucial for drug design, development, and application in future for well-being of humans. Mohamed Ali Seyed, Ibrahim Jantan, and Syed Nasir Abbas Bukhari Copyright © 2014 Mohamed Ali Seyed et al. All rights reserved. Substance Use in the Club Scene of Rome: A Pilot Study Thu, 28 Aug 2014 00:00:00 +0000 Objective. Over the last few years, a wide number of unregulated substances have been marketed on the Web and in smart and head shops; they are usually advertised as legal alternatives to commonly known drugs and are defined as “smart drugs,” “legal highs,” and “novel psychoactive substances” (NPS). Aim of our work is to describe use habits and distribution of NPS in a population of young adults in Rome club scene. Methods. A self-administered questionnaire was proposed to subjects over 18 years of age at the entrance of 5 nightclubs in Rome. Socioeconomic characteristics and substance use were investigated. Results. Preliminary results give evidence that 78% of respondents have a lifetime history of NPS use. In addition, 56% of the sample has consumed illicit drugs in the past and 39% has used psychoactive substances in the 12 hours preceding the questionnaire administration. Conclusions. A significant proportion of subjects report use of novel psychoactive substances; traditional illicit drugs consumption, particularly cocaine, appears to be very high as well in the club scene. These data highlight a serious public health challenge, since pharmacological, toxicological, and psychopathological effects linked to interactions among all these substances may be unpredictable and sometimes fatal in vulnerable individuals. Alessandro Emiliano Vento, Giovanni Martinotti, Eduardo Cinosi, Matteo Lupi, Tiziano Acciavatti, Dario Carrus, Rita Santacroce, Eleonora Chillemi, Ludovica Bonifaci, Massimo di Giannantonio, Ornella Corazza, and Fabrizio Schifano Copyright © 2014 Alessandro Emiliano Vento et al. All rights reserved. Safety of Nicergoline as an Agent for Management of Cognitive Function Disorders Thu, 28 Aug 2014 00:00:00 +0000 Nicergoline is a semisynthetic ergot derivative and has a selective alpha-1A adrenergic receptor blocking property and also other additional mechanisms of actions, both in the brain and in the periphery. It is in clinical use for over three decades in over fifty countries for conditions such as cerebral infarction, acute and chronic peripheral circulation disorders, vascular dementia, and Alzheimer’s disease and has been found to be beneficial in a variety of other conditions. However, concerns about its safety have been raised, especially after the European medicines agency’s (EMEA’s) restriction in the use of all ergot derivatives including nicergoline. But, most of the available literature and data suggest that the adverse events with nicergoline are mild and transient. Further, none of the available treatment options for cognitive disorders afford definitive resolution of symptoms. In this backdrop, we discuss the pharmacology of nicergoline with special emphasis on the safety of this compound, especially when used in patients suffering from cognitive function disorders. Bernd Saletu, Amit Garg, and Ahsan Shoeb Copyright © 2014 Bernd Saletu et al. All rights reserved. Vascular Endothelial Growth Factor Increases during Blood-Brain Barrier-Enhanced Permeability Caused by Phoneutria nigriventer Spider Venom Wed, 27 Aug 2014 08:55:09 +0000 Phoneutria nigriventer spider accidental envenomation provokes neurotoxic manifestations, which when critical, results in epileptic-like episodes. In rats, P. nigriventer venom (PNV) causes blood-brain barrier breakdown (BBBb). The PNV-induced excitotoxicity results from disturbances on Na+, K+ and Ca2+ channels and glutamate handling. The vascular endothelial growth factor (VEGF), beyond its angiogenic effect, also, interferes on synaptic physiology by affecting the same ion channels and protects neurons from excitotoxicity. However, it is unknown whether VEGF expression is altered following PNV envenomation. We found that adult and neonates rats injected with PNV showed immediate neurotoxic manifestations which paralleled with endothelial occludin, β-catenin, and laminin downregulation indicative of BBBb. In neonate rats, VEGF, VEGF mRNA, and Flt-1 receptors, glutamate decarboxylase, and calbindin-D28k increased in Purkinje neurons, while, in adult rats, the BBBb paralleled with VEGF mRNA, Flk-1, and calbindin-D28k increases and Flt-1 decreases. Statistically, the variable age had a role in such differences, which might be due to age-related unequal maturation of blood-brain barrier (BBB) and thus differential cross-signaling among components of the glial neurovascular unit. The concurrent increases in the VEGF/Flt-1/Flk-1 system in the cerebellar neuron cells and the BBBb following PNV exposure might imply a cytokine modulation of neuronal excitability consequent to homeostatic perturbations induced by ion channels-acting PNV neuropeptides. Whether such modulation represents neuroprotection needs further investigation. Monique C. P. Mendonça, Edilene S. Soares, Leila M. Stávale, Evanguedes Kalapothakis, and Maria Alice Cruz-Höfling Copyright © 2014 Monique C. P. Mendonça et al. All rights reserved. Anticancer Activity of Marine Sponge Hyrtios sp. Extract in Human Colorectal Carcinoma RKO Cells with Different p53 Status Wed, 27 Aug 2014 08:47:30 +0000 Drug development using marine bioresources is limited even though the ocean occupies about 70% of the earth and contains a large number of biological materials. From the screening test of the marine sponge extracts, we found Hyrtios sp. sponge collected from Chuuk island, Micronesia. In this study, the Hyrtios sp. extract was examined for anticancer activity against human colorectal carcinoma RKO cells that are wildtype for p53 and RKO-E6 that are p53 defective. The Hyrtios sp. extract dose-dependently inhibited viability in both cell lines. Multinucleation as an indication of mitotic catastrophe was also observed. Cytotoxicity tests gave significantly different results for RKO and RKO-E6 cells after 48 h exposure to Hyrtios sp. extract. In RKO cells treated with Hyrtios sp. extract, cell death occurred by induction of p53 and p21 proteins. In p53-defective RKO-E6 cells, Hyrtios sp. extract decreased expression of JNK protein and increased p21 protein. These results indicate that Hyrtios sp. extract induced apoptosis via different pathways depending on p53 status and could be a good natural product for developing new anticancer drugs. Hyun Kyung Lim, Woori Bae, Hyi-Seung Lee, and Joohee Jung Copyright © 2014 Hyun Kyung Lim et al. All rights reserved. Early Detection of Pathological Gambling: Betting on GPs’ Beliefs and Attitudes Wed, 27 Aug 2014 00:00:00 +0000 Pathological gambling (PG) is an addictive disorder with harm related to the high psychiatric comorbidity and increased suicidal risk. Prevalence rates in general population range from 0.2% to 2.1%. Problem gamblers are hard to attract to treatment programs for several proper reasons and for obstacles (e.g., accessibility). To address these obstacles, primary care (where the problem gambling (PrG) prevalence seems to be 6.2%) has a crucial role to play (i.e., identifying and referring patients to specialized treatment programs and treating at first line when needed and possible) in the era of online gambling offer expansion. The present work aimed to collect data on resources in the field from GPs themselves, using a 24-item online questionnaire. Swiss French-speaking participants were asked about their screening practice and knowledge. The results state that the vast majority of them are aware of the existence and the potential impact of PrG on their patients. However, PrG screening is not systematic and their knowledge of adequate treatments or referral methods is scarce. GPs being central to health screening in general, targeted advice and training on short screening tools and better knowledge of referral pathways should be promoted and continued to empower the GP’s management skills in a public health approach. Sophia Achab, Anne Chatton, Riaz Khan, Gabriel Thorens, Louise Penzenstadler, Daniele Zullino, and Yasser Khazaal Copyright © 2014 Sophia Achab et al. All rights reserved. Enhanced Prevalence of Plasmatic Soluble MHC Class I Chain-Related Molecule in Vascular Pregnancy Diseases Wed, 27 Aug 2014 00:00:00 +0000 The major histocompatibility complex class I related chain (MIC) is a stress-inducible protein modulating the function of immune natural killer (NK) cells, a major leukocyte subset involved in proper trophoblast invasion and spiral artery remodeling. Aim of the study was to evaluate whether upregulation of soluble MIC (sMIC) may reflect immune disorders associated to vascular pregnancy diseases (VPD). sMIC was more frequently detected in the plasma of women with a diagnostic of VPD (32%) than in normal term-matched pregnancies (1.6%, ), with highest prevalence in intrauterine fetal death (IUDF, 44%) and vascular intrauterine growth restriction (IUGR, 39%). sMIC levels were higher in preeclampsia (PE) than in IUFD () and vascular IUGR (). sMIC detection was associated with bilateral early diastolic uterine notches (), thrombocytopenia (), and high proteinuria () in PE and with the vascular etiology of IUGR (). Incubation of sMIC-positive PE plasma resulted in downregulation of NKG2D expression and NK cell-mediated IFN-γ production in vitro. Our work thus suggests that detection of sMIC molecule in maternal plasma may constitute a hallmark of altered maternal immune functions that contributes to vascular disorders that complicate pregnancy, notably by impairing NK-cell mediated production of IFN-γ, an essential cytokine favoring vascular modeling. Jean Baptiste Haumonte, Sophie Caillat-Zucman, Florence Bretelle, Marion Lambert, Luc Lyonnet, Annie Levy-Mozziconacci, Catherine Farnarier, Agostini Aubert, Leon Boubli, Laurence Camoin-Jau, Françoise Dignat George, and Pascale Paul Copyright © 2014 Jean Baptiste Haumonte et al. All rights reserved. High Guanidinium Permeability Reveals Dehydration-Dependent Ion Selectivity in the Plasmodial Surface Anion Channel Wed, 27 Aug 2014 00:00:00 +0000 Malaria parasites grow within vertebrate erythrocytes and increase host cell permeability to access nutrients from plasma. This increase is mediated by the plasmodial surface anion channel (PSAC), an unusual ion channel linked to the conserved clag gene family. Although PSAC recognizes and transports a broad range of uncharged and charged solutes, it must efficiently exclude the small Na+ ion to maintain infected cell osmotic stability. Here, we examine possible mechanisms for this remarkable solute selectivity. We identify guanidinium as an organic cation with high permeability into human erythrocytes infected with Plasmodium falciparum, but negligible uptake by uninfected cells. Transport characteristics and pharmacology indicate that this uptake is specifically mediated by PSAC. The rank order of organic and inorganic cation permeabilities suggests cation dehydration as the rate-limiting step in transport through the channel. The high guanidinium permeability of infected cells also allows rapid and stringent synchronization of parasite cultures, as required for molecular and cellular studies of this pathogen. These studies provide important insights into how nutrients and ions are transported via PSAC, an established target for antimalarial drug development. Abdullah A. B. Bokhari, Neida K. Mita-Mendoza, Alexandra Fuller, Ajay D. Pillai, and Sanjay A. Desai Copyright © 2014 Abdullah A. B. Bokhari et al. All rights reserved. Analgesic, Anti-Inflammatory, and Chondroprotective Activities of Cryptolepis buchanani Extract: In Vitro and In Vivo Studies Wed, 27 Aug 2014 00:00:00 +0000 Cryptolepis buchanani Roem. & Schult. is widely used in folk medicine in Southeast Asia for treating muscle tension and arthritis. This study aimed to investigate an analgesic activity of the methanol extract of C. buchanani (CBE) in acetic acid-induced writhing response in mice, and to examine its anti-inflammatory activity in ethyl phenylpropiolate- (EPP-) induced ear edema and carrageenan-induced paw edema in rats. Its effects on cartilage degradation induced by interleukin-1β (IL-1β) in porcine cartilage explant culture were also determined. This study demonstrated that CBE significantly reduced acetic acid-induced writhing response. It also inhibited edema formation in both EPP-induced ear edema and carrageenan-induced paw edema models. In cartilage explant culture, CBE significantly reduced the sulfated glycosaminoglycan and hyaluronan released into culture media while it reserved the uronic acid and collagen within the cartilage tissues. It also suppressed the matrix metalloproteinase-2 activity with no effect on cell viability. In conclusion, CBE shows analgesic, anti-inflammatory, and chondroprotective effects in this preliminary study. Therefore, CBE may be useful as an alternative treatment for osteoarthritis. Nutthiya Hanprasertpong, Supanimit Teekachunhatean, Rujirek Chaiwongsa, Siriwan Ongchai, Puongtip Kunanusorn, Chaichan Sangdee, Ampai Panthong, Samreang Bunteang, Narong Nathasaen, and Vichai Reutrakul Copyright © 2014 Nutthiya Hanprasertpong et al. All rights reserved. A Review on Plants Used for Improvement of Sexual Performance and Virility Mon, 18 Aug 2014 09:59:03 +0000 The use of plant or plant-based products to stimulate sexual desire and to enhance performance and enjoyment is almost as old as the human race itself. The present paper reviews the active, natural principles, and crude extracts of plants, which have been useful in sexual disorders, have potential for improving sexual behaviour and performance, and are helpful in spermatogenesis and reproduction. Review of refereed journals and scientific literature available in electronic databases and traditional literature available in India was extensively performed. The work reviews correlation of the evidence with traditional claims, elucidation, and evaluation of a plausible concept governing the usage of plants as aphrodisiac in total. Phytoconstituents with known structures have been classified in appropriate chemical groups and the active crude extracts have been tabulated. Data on their pharmacological activity, mechanism of action, and toxicity are reported. The present review provides an overview of the herbs and their active molecule with claims for improvement of sexual behaviour. A number of herbal drugs have been validated for their effect on sexual behavior and fertility and can therefore serve as basis for the identification of new chemical leads useful in sexual and erectile dysfunction. Nagendra Singh Chauhan, Vikas Sharma, V. K. Dixit, and Mayank Thakur Copyright © 2014 Nagendra Singh Chauhan et al. All rights reserved. Antiproliferative Activity of Hamigerone and Radicinol Isolated from Bipolaris papendorfii Tue, 12 Aug 2014 11:38:37 +0000 Secondary metabolites from fungi organisms have extensive past and present use in the treatment of many diseases and serve as compounds of interest both in their natural form and as templates for synthetic modification. Through high throughput screening (HTS) and bioassay-guided isolation, we isolated two bioactive compounds hamigerone (1) and radicinol (2). These compounds were isolated from fungus Bipolaris papendorfii, isolated from the rice fields of Dera, Himachal Pradesh, India. The structures of the compounds were established on the basis of spectroscopic data, namely, NMR (1H, 13C, mass, and UV). Both compounds were found to be antiproliferative against different cancer cells. Furthermore we have also noted that both compounds showed increase in apoptosis by favorably modulating both tumor suppressor protein (p53) and antiapoptic protein (BCL-2), and in turn increase caspase-3 expression in cancer cells. This is the first report of these compounds from fungus Bipolaris papendorfii and their anticancer activity. Periyasamy Giridharan, Shilpa A. Verekar, Akash R. Gohil, Prabhu Dutt Mishra, Amit Khanna, and Sunil Kumar Deshmukh Copyright © 2014 Periyasamy Giridharan et al. All rights reserved. Epigallocatechingallate Inhibits Migration of Human Uveal Melanoma Cells via Downregulation of Matrix Metalloproteinase-2 Activity and ERK1/2 Pathway Tue, 12 Aug 2014 09:43:46 +0000 The effects of epigallocatechingallate (EGCG) on the migration and expression of MMP-2 of uveal melanoma cells have not been reported. We studied this effect and relevant signaling pathways in a human uveal melanoma cell line (M17). MTT study found that EGCG did not affect the cell viability of M17 cells up to 100 µM. Wound-healing assay showed that EGCG significantly reduced the migration of melanoma cells in a dose-dependent manner from 20 to 100 µM. Gelatin zymography showed that secreted MMP-2 activity was dose-dependently inhibited by EGCG, whereas the MMP-2 expression at protein and mRNA levels was not affected as determined by western blot and RT-PCR analysis. EGCG significantly increased the expressions of MMP-2 endogenous inhibitors (TIMP-2 and RECK) in M17 cells. Western blot analysis of MAPK signal pathways showed that EGCG significantly decreased phosphorylated ERK1/2 levels, but not p38 and JNK levels, in melanoma cells. ERK1/2 inhibitors also reduced the migration and activity of MMP-2 in M17 cells. The present study suggested EGCG at nontoxic levels could inhibit migration of melanoma cells via downregulation of activities of secreted MMP-2 through the inhibition of the ERK1/2 phosphorylation. Therefore, EGCG may be a promising agent to be explored for the prevention of metastasis of uveal melanoma. Chi-Wu Chang, Yi-Hsien Hsieh, Wei-En Yang, Shun-Fa Yang, Yueqin Chen, and Dan-Ning Hu Copyright © 2014 Chi-Wu Chang et al. All rights reserved. Pistacia chinensis: A Potent Ameliorator of CCl4 Induced Lung and Thyroid Toxicity in Rat Model Mon, 11 Aug 2014 11:37:12 +0000 In the current study protective effect of ethanol extract of Pistacia chinensis bark (PCEB) was investigated in rats against CCl4 induced lung and thyroid injuries. PCEB dose dependently inhibited the rise of thiobarbituric acid-reactive substances, hydrogen peroxide, nitrite, and protein content and restored the levels of antioxidant enzymes, that is, catalase, peroxidase, superoxide dismutase, glutathione-S-transferase, glutathione reductase, glutathione peroxidase, γ-glutamyl transpeptidase, and quinone reductase in both lung and thyroid tissues of CCl4 treated rats. Decrease in number of leukocytes, neutrophils, and hemoglobin and T3 and T4 content as well as increase in monocytes, eosinophils, and lymphocytes count with CCl4 were restored to normal level with PCEB treatment. Histological study of CCl4 treated rats showed various lung injuries like rupture of alveolar walls and bronchioles, aggregation of fibroblasts, and disorganized Clara cells. Similarly, histology of CCl4 treated thyroid tissues displayed damaged thyroid follicles, hypertrophy, and colloidal depletion. However, PCEB exhibited protective behaviour for lungs and thyroid, with improved histological structure in a dose dependant manner. Presence of three known phenolic compounds, that is, rutin, tannin, and gallic acid, and three unknown compounds was verified in thin layer chromatographic assessment of PCEB. In conclusion, P. chinensis exhibited antioxidant activity by the presence of free radical quenching constituents. Kiran Naz, Muhammad Rashid Khan, Naseer Ali Shah, Saadia Sattar, Farah Noureen, and Madeeha Latif Awan Copyright © 2014 Kiran Naz et al. All rights reserved. Synthesis, Characterization, and In Vitro Anticancer Evaluation of Novel 2,5-Disubstituted 1,3,4-Oxadiazole Analogue Sun, 10 Aug 2014 00:00:00 +0000 In this series, we have synthesised a new 2,5-disubstituted 1,3,4-oxadiazole in search of potential therapeutics for cancer. The anticancer activities were evaluated on a panel of 60 cell lines by the National Cancer Institute according to its own screening protocol. Out of the 24 compounds, 11 were selected and evaluated via single high dose (10−5 M). In the next phase, two compounds have been selected for five-dose assay. The compounds 3-(5-benzyl-1,3,4-oxadiazol-2-yl)quinolin-2(1H)-one 18 (NSC-776965) and 3-[5-(2-phenoxymethyl-benzoimidazol-1-ylmethyl)-[1,3,4]oxadiazol-2-yl]-2-p-tolyloxy-quinoline 27 (NSC-776971) showed mean growth percentage of 66.23 and 46.61, respectively, in one-dose assay and their GI50 values ranging between 1.41–15.8 μM and 0.40–14.9 μM, respectively, in 5-dose assay. Salahuddin, Avijit Mazumder, and Mohammad Shaharyar Copyright © 2014 Salahuddin et al. All rights reserved. Caspase Mediated Synergistic Effect of Boswellia serrata Extract in Combination with Doxorubicin against Human Hepatocellular Carcinoma Thu, 07 Aug 2014 07:19:51 +0000 The study investigated the growth-inhibiting and apoptosis mediating effects of B. serrata extract as monotherapy and combination therapy with DOX against hepatocellular carcinoma cell lines. Boswellic acid rich fraction of B. serrata extract was prepared. MTT assay on HepG2 and Hep3B cells was carried out using B. serrata alone and in combination with DOX. Further, caspase-3 activity, TNF-α level, and IL-6 level were estimated. Isobolographic analysis was carried out to evaluate the effect of combination therapy. Additionally, protective effect of B. serrata extract on DOX induced hepatic toxicity was also evaluated in Wistar rats. B. serrata extract inhibited growth of HepG2 (IC50 value of  μg/mL) as well as HepG2 (IC50 value of  μg/mL). DOX inhibited growth in HepG2 and Hep3B cells with an IC50 of  μg/mL and  μg/mL. Isobolographic analysis showed combination index (CI) of DOX and B. serrata extract of to suggesting synergistic behavior against the two cell lines. B. serrata extract also caused dose dependent increase in caspase-3 activity, TNF-α level, and IL-6 level which was higher () with DOX (1 μM) and B. serrata extract (20 μg/mL) combination. B. serrata extract also protected Wistar rats against DOX induced hepatic toxicity. Mohammad Ahmed Khan, Mhaveer Singh, Masood Shah Khan, Abul Kalam Najmi, and Sayeed Ahmad Copyright © 2014 Mohammad Ahmed Khan et al. All rights reserved. HPLC-DAD Analysis, Antileishmanial, Antiproliferative, and Antibacterial Activities of Lacistema pubescens: An Amazonian Medicinal Plant Thu, 07 Aug 2014 05:59:30 +0000 Species of the genus Lacistema are traditionally used by Brazilian and Peruvian indigenous communities. The present study investigated the in vitro antileishmanial activity against several Leishmania species, cytotoxicity in murine peritoneal macrophages, antiproliferative activity against HL60 and Jurkat cells, and antibacterial activities against seven bacteria strains of the aerial parts of the methanolic crude extract and fractions of Lacistema pubescens. In addition, their chemical profile was also evaluated. Hexane fraction showed the most significant IC50 values against all promastigotes of Leishmania species tested, except for L. chagasi (IC50 = 4.2 µg/mL for L. major and IC50 = 3.5 µg/mL for L. amazonensis). This fraction also exhibited a strong activity against amastigotes of L. amazonensis (IC50 = 6.9 µg/mL). The antiproliferative activity was also observed for methanolic extract and hexane fraction with IC50 = 47.2 µg/mL and IC50 = 39.7 µg/mL for HL60, respectively. Regarding the antimicrobial activity, the overall antibacterial activity was not very significative. Phytol and sitosterol were identified in the methanolic extract. Additionally, previous studies also revealed the presence of those compounds in the hexane fraction. Among other compounds, phytol and sitosterol were probably involved in the antileishmanial and cytotoxicity activities observed in this study. Josiane Mello da Silva, Luciana Maria Ribeiro Antinarelli, Nícolas de Castro Campos Pinto, Elaine Soares Coimbra, Elaine Maria de Souza-Fagundes, Antônia Ribeiro, and Elita Scio Copyright © 2014 Josiane Mello da Silva et al. All rights reserved. Andrographolide Induces Apoptosis of C6 Glioma Cells via the ERK-p53-Caspase 7-PARP Pathway Tue, 05 Aug 2014 09:29:22 +0000 Background. Glioma is the most malignant tumor of the central nervous system. Efforts on the development of new chemotherapy are mandatory. Andrographolide (AND), a diterpenoid lactone isolated from the Andrographis paniculata, has been shown to have antitumor activities in several types of cancer cells. Whether AND can exert its antitumor activity in glioblastoma cells remains unknown. This study examined the anticancer effects of AND, both in vitro and in vivo. Methods. Cell apoptosis was assayed by flow cytometry and nuclear staining. The signaling pathway for AND was determined by western blotting. The effects of AND on tumor growth was evaluated in a mouse model. Results and Conclusion. In vitro, with application of specific inhibitors and siRNA, AND-induced apoptosis was proven through ROS-ERK-P53-caspase 7-PARP signaling pathway. In vivo, AND significantly retarded tumor growth and caused regression of well-formed tumors in vivo. Furthermore, AND did not induce apoptosis or activate ERK and p53 in primary cultured astrocyte cells, and it may serve as a potential therapeutic candidate for the treatment of glioma. Shih-Hung Yang, Seu-Mei Wang, Jhih-Pu Syu, Ying Chen, Sheng-De Wang, Yu-Sen Peng, Meng-Fai Kuo, and Hsiu-Ni Kung Copyright © 2014 Shih-Hung Yang et al. All rights reserved. In Vitro Antioxidant, Antibacterial, and Cytotoxic Activity and In Vivo Effect of Syngonium podophyllum and Eichhornia crassipes Leaf Extracts on Isoniazid Induced Oxidative Stress and Hepatic Markers Mon, 04 Aug 2014 06:46:28 +0000 The present study reports the in vitro antioxidant, antibacterial, and cytotoxic potential of Syngonium podophyllum (SP) and Eichhornia crassipes (EC) leaf aqueous extracts as well as their in vivo effect on oxidative stress and hepatic biomarkers in isoniazid induced rats. Phytochemical screening of extracts revealed the presence of flavonoids, terpenoids, reducing sugars, alkaloids, and saponins. Phenolic content in SP and EC extracts was and  mg PGE/g, respectively, while flavonoid content was and  μg QE/mg, respectively. EC extract exhibited comparatively better antioxidant activity as indicated by reducing power (0.197–0.775), DPPH radical scavenging potential (11%–96%), and metal ion chelating ability (42%–93%). Both the extracts provided 13%–65% protection against lipid peroxidation in rat tissue (liver, kidney, and brain) homogenate. SP and EC extracts exhibited 51% and 43% cytotoxicity against lung cancer (NCI-H322) cell line, respectively. Both extracts demonstrated considerable antibacterial activity against Proteus vulgaris, Salmonella typhi, and Bordetella bronchiseptica. Coadministration of E. crassipes extract with isoniazid in rats accounted for 46% decrease in malondialdehyde content and 21% increase in FRAP value of plasma. It also mitigated the isoniazid induced alterations in serum enzymes (SGOT, SGPT, and ALP), total bilirubin, creatinine, and hemoglobin contents. S. podophyllum extract was found to be hepatotoxic. Shashank Kumar, Ramesh Kumar, Astha Dwivedi, and Abhay K. Pandey Copyright © 2014 Shashank Kumar et al. All rights reserved. Hyaluronan and RHAMM in Wound Repair and the “Cancerization” of Stromal Tissues Mon, 04 Aug 2014 00:00:00 +0000 Tumors and wounds share many similarities including loss of tissue architecture, cell polarity and cell differentiation, aberrant extracellular matrix (ECM) remodeling (Ballard et al., 2006) increased inflammation, angiogenesis, and elevated cell migration and proliferation. Whereas these changes are transient in repairing wounds, tumors do not regain tissue architecture but rather their continued progression is fueled in part by loss of normal tissue structure. As a result tumors are often described as wounds that do not heal. The ECM component hyaluronan (HA) and its receptor RHAMM have both been implicated in wound repair and tumor progression. This review highlights the similarities and differences in their roles during these processes and proposes that RHAMM-regulated wound repair functions may contribute to “cancerization” of the tumor microenvironment. Cornelia Tolg, James B. McCarthy, Arjang Yazdani, and Eva A. Turley Copyright © 2014 Cornelia Tolg et al. All rights reserved. Foeniculum vulgare Mill: A Review of Its Botany, Phytochemistry, Pharmacology, Contemporary Application, and Toxicology Sun, 03 Aug 2014 06:30:10 +0000 Foeniculum vulgare Mill commonly called fennel has been used in traditional medicine for a wide range of ailments related to digestive, endocrine, reproductive, and respiratory systems. Additionally, it is also used as a galactagogue agent for lactating mothers. The review aims to gather the fragmented information available in the literature regarding morphology, ethnomedicinal applications, phytochemistry, pharmacology, and toxicology of Foeniculum vulgare. It also compiles available scientific evidence for the ethnobotanical claims and to identify gaps required to be filled by future research. Findings based on their traditional uses and scientific evaluation indicates that Foeniculum vulgare remains to be the most widely used herbal plant. It has been used for more than forty types of disorders. Phytochemical studies have shown the presence of numerous valuable compounds, such as volatile compounds, flavonoids, phenolic compounds, fatty acids, and amino acids. Compiled data indicate their efficacy in several in vitro and in vivo pharmacological properties such as antimicrobial, antiviral, anti-inflammatory, antimutagenic, antinociceptive, antipyretic, antispasmodic, antithrombotic, apoptotic, cardiovascular, chemomodulatory, antitumor, hepatoprotective, hypoglycemic, hypolipidemic, and memory enhancing property. Foeniculum vulgare has emerged as a good source of traditional medicine and it provides a noteworthy basis in pharmaceutical biology for the development/formulation of new drugs and future clinical uses. Shamkant B. Badgujar, Vainav V. Patel, and Atmaram H. Bandivdekar Copyright © 2014 Shamkant B. Badgujar et al. 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. 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. 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. 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.