BioMed Research International: Pharmacology The latest articles from Hindawi © 2017 , Hindawi Limited . All rights reserved. Quercetin Attenuates Vascular Calcification through Suppressed Oxidative Stress in Adenine-Induced Chronic Renal Failure Rats Sun, 11 Jun 2017 07:10:59 +0000 Background. This study investigated whether quercetin could alleviate vascular calcification in experimental chronic renal failure rats induced by adenine. Methods. 32 adult male Wistar rats were randomly divided into 4 groups fed normal diet, normal diet with quercetin supplementation (25 mg/kg·BW/d), 0.75% adenine diet, or adenine diet with quercetin supplementation. All rats were sacrificed after 6 weeks of intervention. Serum renal functions biomarkers and oxidative stress biomarkers were measured and status of vascular calcification in aorta was assessed. Furthermore, the induced nitric oxide synthase (iNOS)/p38 mitogen activated protein kinase (p38MAPK) pathway was determined to explore the potential mechanism. Results. Adenine successfully induced renal failure and vascular calcification in rat model. Quercetin supplementation reversed unfavorable changes of phosphorous, uric acid (UA) and creatinine levels, malonaldehyde (MDA) content, and superoxide dismutase (SOD) activity in serum and the increases of calcium and alkaline phosphatase (ALP) activity in the aorta () and attenuated calcification and calcium accumulation in the medial layer of vasculature in histopathology. Western blot analysis showed that iNOS/p38MAPK pathway was normalized by the quercetin supplementation. Conclusions. Quercetin exerted a protective effect on vascular calcification in adenine-induced chronic renal failure rats, possibly through the modulation of oxidative stress and iNOs/p38MAPK pathway. Xue-ying Chang, Lei Cui, Xing-zhi Wang, Lei Zhang, Dan Zhu, Xiao-rong Zhou, and Li-rong Hao Copyright © 2017 Xue-ying Chang et al. All rights reserved. Oral Candida in Patients with Fixed Orthodontic Appliance: In Vitro Combination Therapy Thu, 08 Jun 2017 00:00:00 +0000 Background. Fixed orthodontic appliance (FOA) increases the cariogenic microorganisms of mouth including candida. The aim was to evaluate the pharmacodynamic effects of some antibacterial drugs in combination with most applicable antifungal agents on candida isolated from patients with FOA. Methods. Three antifungal agents (amphotericin B (AMB), ketoconazole (KET), and itraconazole (ITZ)) and three antibacterial drugs (ciprofloxacin (CIP), doxycycline (DOX), and metronidazole (MET)) with serial concentrations have been used and microdilution broth method has been done for single and combination therapy, then fungal growth was assessed spectrophotometrically, and the combinations were evaluated by bliss independent analysis. Results. According to bliss independent interaction, the synergistic interactions depended on values that showed the best for CIP was with AMB () followed with KET () and lastly ITR () at CIP = 150 mg/L. DOX was optimal with KET () followed with AMB () and the lowest with ITR () at DOX = 75 mg/L. MET is the best with AMB () and then with ITR () and finally KET () at MET 200 mg/L. Moreover, usage of higher concentrations of antibacterial agents revealed inhibitory effects. Conclusion. This study uncovers the optimum antibiotic combination therapy against cariogenic candida with FOA by usage of low therapeutic concentrations. Wisam Alhamadi, Rafal J. Al-Saigh, Nebras N. Al-Dabagh, and Hussam W. Al-Humadi Copyright © 2017 Wisam Alhamadi et al. All rights reserved. In Vitro Anticancer Effect of Gedunin on Human Teratocarcinomal (NTERA-2) Cancer Stem-Like Cells Wed, 07 Jun 2017 00:00:00 +0000 Gedunin is one of the major compounds found in the neem tree (Azadirachta indica). In the present study, antiproliferative potential of gedunin was evaluated in human embryonal carcinoma cells (NTERA-2, a cancer stem cell model) and peripheral blood mononuclear cells (PBMCs), using Sulforhodamine (SRB) and WST-1 assays, respectively. The effects of gedunin on expression of heat shock protein 90 (HSP90), its cochaperone Cdc37, and HSP client proteins (AKT, ErbB2, and HSF1) were evaluated by real-time PCR. Effects of gedunin on apoptosis were evaluated by (a) apoptosis associated morphological changes, (b) caspase 3/7 expression, (c) DNA fragmentation, (d) TUNEL assay, and (e) real-time PCR of apoptosis related genes (Bax, p53, and survivin). Gedunin showed a promising antiproliferative effect in NTERA-2 cells with IC50 values of 14.59, 8.49, and 6.55 μg/mL at 24, 48, and 72 h after incubations, respectively, while exerting a minimal effect on PBMCs. Expression of HSP90, its client proteins, and survivin was inhibited and Bax and p53 were upregulated by gedunin. Apoptosis related morphological changes, DNA fragmentation, and increased caspase 3/7 activities confirmed the proapoptotic effects of gedunin. Collectively, results indicate that gedunin may be a good drug lead for treatment of chemo and radiotherapy resistant cancer stem cells. Luxmiga Tharmarajah, Sameera Ranganath Samarakoon, Meran Keshawa Ediriweera, Poorna Piyathilaka, Kamani Hemamamla Tennekoon, Kanishka Sithira Senathilake, Umapriyatharshini Rajagopalan, Prasanna Bandula Galhena, and Ira Thabrew Copyright © 2017 Luxmiga Tharmarajah et al. All rights reserved. Anxiolytics, Sedatives, and Hypnotics Prescribed by Dentists in Brazil in 2010 Tue, 30 May 2017 07:57:29 +0000 Objective. To describe dental prescriptions for anxiolytics, sedatives, and hypnotics for Brazilian outpatients in 2010. Methods. A cross-sectional study was conducted using data on the use of anxiolytics, sedatives, and hypnotics from the Brazilian Health Surveillance Agency, Brazil, 2010. For each prescription, prescribed drugs and the prescribed amount were identified. Prescribed medications were classified according to Anatomical Therapeutic Chemical code. We calculated the number of Defined Daily Doses (DDD) for anxiolytics, sedatives, and hypnotics by code, their mean DDD, and DDD per inhabitant per year. Results. There were 16,436 prescriptions dispensed, including anxiolytics, sedatives, and hypnotics. These prescriptions corresponded to 3,555,780.50 mg, distributed as 2,286,200.50 mg (64.30%) of anxiolytics and 1,269,580.00 mg (35.70%) of sedatives and hypnotics. This amount allowed treating approximately 474,106 individuals (number of DDD). The anxiolytics most frequently dispensed were bromazepam (25.30%), alprazolam (19.19%), and diazepam (15.60%). Sedatives and hypnotics mostly prescribed were zolpidem (9.55%), midazolam (6.99%), and flunitrazepam (2.14%). The per capita rates (100,000 inhabitants) of anxiolytics and sedatives/hypnotics were 6.83 and 1.78, respectively. Conclusions. Benzodiazepines and derivatives were the most frequently prescribed drugs. There was a low rate of dental prescriptions for anxiolytics, sedatives, and hypnotics, although excessive doses were concentrated in the same prescription. Patrícia Azevedo Lino, Maria Auxiliadora Parreiras Martins, Maria Elisa de Souza e Silva, and Mauro Henrique Nogueira Guimarães de Abreu Copyright © 2017 Patrícia Azevedo Lino et al. All rights reserved. Effects of (1E,4E)-2-Methyl-1,5-bis(4-nitrophenyl)penta-1,4-dien-3-one on Trypanosoma cruzi and Its Combinational Effect with Benznidazole, Ketoconazole, or Fluconazole Tue, 23 May 2017 00:00:00 +0000 This study reports the activity induced by (1E,4E)-2-methyl-1,5-bis(4-nitrophenyl)penta-1,4-dien-3-one (A3K2A3) against Trypanosoma cruzi. This compound showed trypanocidal activity against the multiplicative epimastigote and amastigote forms of this protozoan, with IC50 values of and  μM, respectively, and EC50 value of  μM against trypomastigotes. The combination of A3K2A3 with benznidazole or ketoconazole demonstrated strong synergism, increasing effectiveness against trypomastigotes or epimastigotes of T. cruzi. In addition, the drug combination of A3K2A3 with benznidazole or ketoconazole on LLCMK2 cells demonstrated an antagonist effect, which resulted in greater protection of the cells from drug damage. The combination of the compound with fluconazole was not effective. Transmission and scanning electron micrographs showed changes on parasites, mainly in the cytoplasmatic membrane, nucleus, mitochondrion, and Golgi complex, and a large increase in the number of autophagosome-like structures and lipid-storage bodies, accompanied by volume reduction and rounding of the parasite. A3K2A3 might be a promising compound against T. cruzi. Francieli Peron, Danielle Lazarin-Bidóia, Zia Ud Din, Edson Rodrigues-Filho, Tânia Ueda-Nakamura, Sueli de Oliveira Silva, and Celso Vataru Nakamura Copyright © 2017 Francieli Peron et al. All rights reserved. Effects of Streptococcus sanguinis Bacteriocin on Deformation, Adhesion Ability, and Young’s Modulus of Candida albicans Mon, 22 May 2017 00:00:00 +0000 In order to study the thallus changes on microscopic morphology and mechanical properties of Candida albicans antagonized by Streptococcus sanguinis bacteriocin, the adhesion ability and Young’s modulus of thalli and hypha of Candida albicans were measured by the relative measurement method using atomic force microscope’s (AFM) tapping model. The results showed that the average adhesion ability and Young’s modulus of thalli were  nN and  Mpa, respectively; the average adhesion ability and Young’s modulus of hypha were  nN and  Mpa, respectively. After being antagonized by Streptococcus sanguinis bacteriocin, the adhesion ability was decreased along with the increasing of deformation in reaction region and Young’s modulus followed the same changes. It could be concluded that the adhesion ability of hypha was greater than thalli, Young’s modulus of hypha was less than thalli, and adhesion ability and Young’s modulus of Candida albicans were decreased significantly after being antagonized by Streptococcus sanguinis bacteriocin. Shengli Ma, Wenyu Ge, Yifan Yan, Xu Huang, Li Ma, Chunmei Li, Shuyang Yu, and Chunxiao Chen Copyright © 2017 Shengli Ma et al. All rights reserved. Opioid Addiction: Social Problems Associated and Implications of Both Current and Possible Future Treatments, including Polymeric Therapeutics for Giving Up the Habit of Opioid Consumption Thu, 18 May 2017 00:00:00 +0000 Background. Detoxification programmes seek to implement the most secure and compassionate ways of withdrawing from opiates so that the inevitable withdrawal symptoms and other complications are minimized. Once detoxification has been achieved, the next stage is to enable the patient to overcome his or her drug addiction by ensuring consumption is permanently and completely abandoned, only after which can the subject be regarded as fully recovered. Methods. A systematic search on the common databases of relevant papers published until 2016 inclusive. Results and Conclusion. Our study of the available oral treatments for opioid dependence has revealed that no current treatment can actually claim to be fully effective. These treatments require daily oral administration and, consequently, regular visits to dispensaries, which in most cases results in a lack of patient compliance, which causes fluctuations in drug plasma levels. We then reviewed alternative treatments in the available scientific literature on polymeric sustained release formulations. Research has been done not only on release systems for detoxification but also on release systems for giving up the habit of taking opioids. These efforts have obtained the recent authorization of polymeric systems for use in patients that could help them to reduce their craving for drugs. M. Cristina Benéitez and M. Esther Gil-Alegre Copyright © 2017 M. Cristina Benéitez and M. Esther Gil-Alegre. All rights reserved. Radix Bupleuri: A Review of Traditional Uses, Botany, Phytochemistry, Pharmacology, and Toxicology Tue, 16 May 2017 00:00:00 +0000 Radix Bupleuri (Chaihu) has been used as a traditional medicine for more than 2000 years in China, Japan, Korea, and other Asian countries. Phytochemical studies demonstrated that this plant contains essential oils, triterpenoid saponins, polyacetylenes, flavonoids, lignans, fatty acids, and sterols. Crude extracts and pure compounds isolated from Radix Bupleuri exhibited various biological activities, such as anti-inflammatory, anticancer, antipyretic, antimicrobial, antiviral, hepatoprotective, neuroprotective, and immunomodulatory effects. However, Radix Bupleuri could also lead to hepatotoxicity, particularly in high doses and with long-term use. Pharmacokinetic studies have demonstrated that the major bioactive compounds (saikosaponins a, b2, c, and d) were absorbed rapidly in rats after oral administration of the extract of Radix Bupleuri. This review aims to comprehensively summarize the traditional uses, botany, phytochemistry, pharmacology, toxicology, and pharmacokinetics of Radix Bupleuri reported to date with an emphasis on its biological properties and mechanisms of action. Fude Yang, Xiaoxv Dong, Xingbin Yin, Wenping Wang, Longtai You, and Jian Ni Copyright © 2017 Fude Yang et al. All rights reserved. Tempol, a Superoxide Dismutase Mimetic Agent, Inhibits Superoxide Anion-Induced Inflammatory Pain in Mice Sun, 14 May 2017 07:35:20 +0000 The present study evaluated the anti-inflammatory and analgesic effects of the superoxide dismutase mimetic agent tempol in superoxide anion-induced pain and inflammation. Mice were treated intraperitoneally with tempol (10–100 mg/kg) 40 min before the intraplantar injection of a superoxide anion donor, potassium superoxide (KO2, 30 μg). Mechanical hyperalgesia and thermal hyperalgesia, paw edema, and mRNA expression of peripheral and spinal cord mediators involved in inflammatory pain, TNFα, IL-1β, IL-10, COX-2, preproET-1, , Nrf2, GFAP, and Iba-1, were evaluated. Peripheral and spinal cord reductions of antioxidant defenses and superoxide anion were also assessed. Tempol reduced KO2-induced mechanical hyperalgesia and thermal hyperalgesia and paw edema. The increased mRNA expression of the evaluated mediators and oxidative stress in the paw skin and spinal cord and increased mRNA expression of glial markers in the spinal cord induced by KO2 were successfully inhibited by tempol. KO2-induced reduction in Nrf2 mRNA expression in paw skin and spinal cord was also reverted by tempol. Corroborating the effect of tempol in the KO2 model, tempol also inhibited carrageenan and CFA inflammatory hyperalgesia. The present study demonstrates that tempol inhibits superoxide anion-induced molecular and behavioral alterations, indicating that tempol deserves further preclinical studies as a promising analgesic and anti-inflammatory molecule for the treatment of inflammatory pain. Catia C. F. Bernardy, Ana C. Zarpelon, Felipe A. Pinho-Ribeiro, Cássia Calixto-Campos, Thacyana T. Carvalho, Victor Fattori, Sergio M. Borghi, Rubia Casagrande, and Waldiceu A. Verri Jr. Copyright © 2017 Catia C. F. Bernardy et al. All rights reserved. Lurasidone in the Treatment of Bipolar Depression: Systematic Review of Systematic Reviews Tue, 09 May 2017 07:01:48 +0000 Introduction. A burgeoning number of systematic reviews considering lurasidone in the treatment of bipolar depression have occurred since its Food and Drug Administration extended approval in 2013. While a paucity of available quantitative evidence still precludes preliminary meta-analysis on the matter, the present quality assessment of systematic review of systematic reviews, nonetheless, aims at highlighting current essential information on the topic. Methods. Both published and unpublished systematic reviews about lurasidone mono- or adjunctive therapy in the treatment of bipolar depression were searched by two independent authors inquiring PubMed/Cochrane/Embase/Scopus from inception until October 2016. Results. Twelve included systematic reviews were of moderate-to-high quality and consistent in covering the handful of RCTs available to date, suggesting the promising efficacy, safety, and tolerability profile of lurasidone. Concordance on the drug profile seems to be corroborated by a steadily increasing number of convergent qualitative reports on the matter. Limitations. Publication, sponsorship, language, citation, and measurement biases. Conclusions. Despite being preliminary in nature, this overview stipulates the effectiveness of lurasidone in the acute treatment of Type I bipolar depression overall. As outlined by most of the reviewed evidence, recommendations for future research should include further controlled trials of extended duration. Michele Fornaro, Domenico De Berardis, Giampaolo Perna, Marco Solmi, Nicola Veronese, Laura Orsolini, Elisabetta Filomena Buonaguro, Felice Iasevoli, Cristiano André Köhler, André Ferrer Carvalho, and Andrea de Bartolomeis Copyright © 2017 Michele Fornaro et al. All rights reserved. The Effects of Formaldehyde on Cytochrome P450 Isoform Activity in Rats Sun, 07 May 2017 00:00:00 +0000 Formaldehyde (FA) is an occupational and indoor pollutant. Long-term exposure to FA can irritate the respiratory mucosa, with potential carcinogenic effects on the airways. The effects of acute FA poisoning on the activities of CYP450 isoforms CYP1A2, CYP2C11, CYP2E1, and CYP3A2 were assessed by determining changes in the pharmacokinetic parameters of the probe drugs phenacetin, tolbutamide, chlorzoxazone, and testosterone, respectively. Rats were randomly divided into three groups: control, low FA dose (exposure to 110 ppm for 2 h for 3 days), and high FA dose (exposure to 220 ppm for 2 h for 3 days). A mixture of the four probe drugs was injected into rats and blood samples were taken at a series of time points. Plasma concentrations of the probe drugs were measured by HPLC. The pharmacokinetic parameters , , and of tolbutamide, chlorzoxazone, and testosterone increased significantly in the high dose versus control group (), whereas the CL of chlorzoxazone and testosterone decreased significantly (). However, , , and of phenacetin decreased significantly (), whereas the CL of phenacetin increased significantly () compared to controls. Thus, acute FA poisoning suppressed the activities of CYP2C11, CYP2E1, and CYP3A2 and induced the activity of CYP1A2 in rats. And the change of CYP450 activity caused by acute FA poisoning may be associated with FA potential carcinogenic effects on the airways. Min Xu, Huaqiao Tang, Qian Rong, Yuanli Zhang, Yinglun Li, Ling Zhao, Gang Ye, Fei Shi, and Cheng Lv Copyright © 2017 Min Xu et al. All rights reserved. Integrated Stress Response as a Therapeutic Target for CNS Injuries Thu, 27 Apr 2017 08:54:50 +0000 Central nervous system (CNS) injuries, caused by cerebrovascular pathologies or mechanical contusions (e.g., traumatic brain injury, TBI) comprise a diverse group of disorders that share the activation of the integrated stress response (ISR). This pathway is an innate protective mechanism, with encouraging potential as therapeutic target for CNS injury repair. In this review, we will focus on the progress in understanding the role of the ISR and we will discuss the effects of various small molecules that target the ISR on different animal models of CNS injury. Lorenzo Romero-Ramírez, Manuel Nieto-Sampedro, and M. Asunción Barreda-Manso Copyright © 2017 Lorenzo Romero-Ramírez et al. All rights reserved. Glycyrrhizin Protects Rats from Sepsis by Blocking HMGB1 Signaling Tue, 18 Apr 2017 09:17:34 +0000 Background. HMGB1 acts as an important inflammatory mediator and is a potential therapeutic target for sepsis. Glycyrrhizin (GL), a natural triterpene glycoside derived from licorice, has been demonstrated to inhibit HMGB1 activity. The aim of this study is to explore how GL affects the HMGB1 signaling in sepsis. Methods. We used a CLP model of sepsis and in vitro LPS or HMGB1-treated NR8383 cells to examine the effects of GL on expression of HMGB1 and proinflammatory cytokines. Furthermore, we explored the effect of GL on interactions between HMGB1 and RAGE or TLR4 and the activations of NF-κB and MAPKs. Results. GL significantly decreased mortality and reduced serum levels of HMGB1 in vivo. GL also attenuated the release and expression of HMGB1 and proinflammatory cytokines. Direct stimulation by HMGB1 elevated the release of proinflammatory cytokines faster than LPS did and it was also inhibited by GL. Furthermore, GL blocked the interaction of HMGB1 with RAGE and TLR4 and suppressed the downstream MAPKs/NF-κB signaling pathway. Conclusion. GL may protect rats against sepsis by blocking the interaction of HMGB1 with cell surface receptors and HMGB1-mediated inflammatory responses. Feng Zhao, Yong Fang, Shuixiang Deng, Xiantao Li, Yun Zhou, Ye Gong, Hechen Zhu, and Wei Wang Copyright © 2017 Feng Zhao et al. All rights reserved. Pharmacokinetic and Pharmacodynamic Evaluation of Marbofloxacin in Pig against Korean Local Isolates of Actinobacillus pleuropneumoniae Thu, 06 Apr 2017 00:00:00 +0000 The pharmacokinetics of marbofloxacin in pigs after intravenous (i.v.), intramuscular (i.m.), and peroral (p.o.) administration and pharmacokinetic/pharmacodynamic indices of this drug against Korean local isolates of Actinobacillus pleuropneumoniae were determined in this study. Marbofloxacin (2.50 mg/kg of body weight) was administered, and blood samples were collected with designated time intervals. Plasma-extracted marbofloxacin was injected into the LC-MS/MS system. The in vitro and ex vivo antibacterial activities of marbofloxacin were evaluated against 20 isolates of A. pleuropneumoniae. The mean peak plasma concentrations () after i.v., i.m., and p.o administration were , , and  µg/mL at , , and  h, respectively. The area under the plasma concentration-time curves (AUC0–24) and elimination half-lives were , , and  h·μg/mL and , , and  h, for i.v., i.m., and p.o. administration, correspondingly. The AUC0–24/MICs of marbofloxacin after i.v., i.m., and p.o. administration were , , and  h, respectively. The /MIC values were , , and , and T>MICs were , , and  h, after i.v., i.m., and p.o. administration, respectively. Thus, marbofloxacin dosage of 2.50 mg/kg of body weight by i.v., i.m., and p.o. administration with 24 h dosing interval will provide effective treatment for the infection of pig by A. pleuropneumonia. Md. Akil Hossain, Hae-chul Park, Kyunghun Jeong, Yang ho Jang, Dae Gyun Kim, JeongWoo Kang, and Kwang-jick Lee Copyright © 2017 Md. Akil Hossain et al. All rights reserved. Antifatigue Effects of Antrodia cinnamomea Cultured Mycelium via Modulation of Oxidative Stress Signaling in a Mouse Model Thu, 23 Mar 2017 07:39:38 +0000 Antrodia cinnamomea, a folk medicinal mushroom, has numerous biological effects. In this study, we aim to assess whether the antifatigue effects of A. cinnamomea mycelia (AC) and its underlying mechanisms are related to oxidative stress signaling using behavioral mouse models and biochemical indices detection. Mice were orally treated with AC at doses of 0.1, 0.3, and 0.9 g/kg for three weeks. AC had no effect on the spontaneous activities of mice indicating its safety on central nervous system. Furthermore, results obtained from weight-loaded forced swimming test, rotary rod test, and exhausted running test confirmed that AC significantly enhanced exercise tolerance of mice. Biochemical indices levels showed that these effects were closely correlated with inhibiting the depletion of glycogen and adenosine triphosphate stores, regulating oxidative stress-related parameters (superoxide dismutase, glutathione peroxidase, reactive oxygen species, and malondialdehyde) in serum, skeletal muscle, and liver of mice. Moreover, the effects of AC may be related with its regulation on the activations of AMP-activated protein kinase, protein kinase B, and mammalian target of rapamycin in liver and skeletal muscle of mice. Altogether, our data suggest that the antifatigue properties of AC may be one such modulation mechanism via oxidative stress-related signaling in mice. Yange Liu, Lanzhou Li, Shengshu An, Yuanzhu Zhang, Shiwei Feng, Lu Zhao, Lirong Teng, and Di Wang Copyright © 2017 Yange Liu et al. All rights reserved. Integrating Transcriptomics, Proteomics, and Metabolomics Profiling with System Pharmacology for the Delineation of Long-Term Therapeutic Mechanisms of Bufei Jianpi Formula in Treating COPD Thu, 23 Mar 2017 06:54:28 +0000 In previous work, we identified 145 active compounds from Bufei Jianpi formula (BJF) by system pharmacology and found that BJF showed short-term effect on chronic obstructive pulmonary disease (COPD) rats. Here, we applied the transcriptomic, proteomic, and metabolomics approaches to illustrate the long-term anti-COPD action and its system mechanism of BJF. BJF has obvious anti-COPD effect through decreasing inflammatory cytokines level, preventing protease-antiprotease imbalance and collagen deposition on week 32 by continuous oral administration to rats from weeks 9 to 20. Subsequently, applying the transcriptomic, proteomic, and metabolomics techniques, we detected a number of regulated genes, proteins, and metabolites, mainly related to antioxidant activity, focal adhesion, or lipid metabolism, in lung tissues of COPD and BJF-treated rats. Afterwards, we integrated system pharmacology target, transcript, protein, and metabolite data sets and found that many genes, proteins, and metabolites in rats BJF-treated group and the target proteins of BJF were mainly attributed to lipid metabolism, inflammatory response, oxidative stress, and focal adhesion. Taken together, BJF displays long-term anti-COPD effect probably by system regulation of the lipid metabolism, inflammatory response pathways oxidative stress, and focal adhesion. Peng Zhao, Jiansheng Li, Ya Li, Yange Tian, Liping Yang, and Suyun Li Copyright © 2017 Peng Zhao et al. All rights reserved. Effects of FMO3 Polymorphisms on Pharmacokinetics of Sulindac in Chinese Healthy Male Volunteers Sun, 26 Feb 2017 07:46:32 +0000 Sulindac is a nonsteroidal anti-inflammatory drug, which is clinically used for the ailments of various inflammations. This study investigated the allele frequencies of FMO3 E158K and E308G and evaluated the influences of these two genetic polymorphisms on the pharmacokinetics of sulindac and its metabolites in Chinese healthy male volunteers. Eight FMO3 wild-type (FMO3 HHDD) subjects and seven FMO3 homozygotes E158K and E308G mutant (FMO3 hhdd) subjects were recruited from 247 healthy male volunteers genotyped by PCR-RFLP method. The plasma concentrations of sulindac, sulindac sulfide, and sulindac sulfone were determined by UPLC, while the pharmacokinetic parameters of the two different FMO3 genotypes were compared with each other. The frequencies of FMO3 E158K and E308G were 20.3% and 20.1%, respectively, which were in line with Hardy-Weinberg equilibrium ( = 0.977, = 0.944). The mean values of , , and of sulindac were significantly higher in FMO3 hhdd group than those of FMO3 HHDD group (), while the pharmacokinetic parameters except of sulindac sulfide and sulindac sulfone showed no statistical difference between the two groups. The two FMO3 mutants were in close linkage disequilibrium and might play an important role in the pharmacokinetics of sulindac in Chinese healthy male volunteers. Yong-Jun Tang, Kai Hu, Wei-Hua Huang, Chong-Zhi Wang, Zhi Liu, Yao Chen, Dong-Sheng Ouyang, Zhi-Rong Tan, Hong-Hao Zhou, and Chun-Su Yuan Copyright © 2017 Yong-Jun Tang et al. All rights reserved. Inhibitory Activities of Stauntonia hexaphylla Leaf Constituents on Rat Lens Aldose Reductase and Formation of Advanced Glycation End Products and Antioxidant Thu, 23 Feb 2017 09:54:09 +0000 Stauntonia hexaphylla (Thunb.) Decne. (Lardizabalaceae) leaves (SHL) have been used traditionally as analgesics, sedatives, diuretics, and so on, in China. To date, no data have been reported on the inhibitory effect of SHL and its constituents on rat lens aldose reductase (RLAR) and advanced glycation end products (AGEs). Therefore, the inhibitory effect of compounds isolated from SHL extract on RLAR and AGEs was investigated to evaluate potential treatments of diabetic complications. The ethyl acetate (EtOAC) fraction of SHL extract showed strong inhibitory activity on RLAR and AGEs; therefore, EtOAc fraction (3.0 g) was subjected to Sephadex LH-20 column chromatography, for further fractionation, with 100% MeOH solvent system to investigate its effect on RLAR and AGEs. Phytochemical investigation of SHL led to the isolation of seven compounds. Among the isolated compounds, chlorogenic acid, calceolarioside B, luteolin-3′-O-β-D-glucopyranoside, quercetin-3-O-β-D-glucopyranoside, and luteolin-7-O-β-D-glucopyranoside exhibited significant inhibitory activity against RLAR with IC50 in the range of 7.34–23.99 μM. In addition, 3-(3,4-dihydroxyphenyl) propionic acid, neochlorogenic acid, and luteolin-3′-O-β-D-glucopyranoside exhibited the most potent inhibitory activity against formation of AGEs, with an IC50 value of 115.07–184.06 μM, compared to the positive control aminoguanidine (820.44 μM). Based on these findings, SHL dietary supplements could be considered for the prevention and/or treatment of diabetes complication. Seung Hwan Hwang, Shin Hwa Kwon, Set Byeol Kim, and Soon Sung Lim Copyright © 2017 Seung Hwan Hwang et al. All rights reserved. Angiotensin-(1-7) Downregulates Diabetes-Induced cGMP Phosphodiesterase Activation in Rat Corpus Cavernosum Sun, 19 Feb 2017 08:01:46 +0000 Molecular mechanisms of the beneficial effects of angiotensin-(1-7), Ang-(1-7), in diabetes-related complications, including erectile dysfunction, remain unclear. We examined the effect of diabetes and/or Ang-(1-7) treatment on vascular reactivity and cyclic guanosine monophosphate (cGMP) phosphodiesterase (PDE) in corpus cavernosum. Male Wistar rats were grouped as (1) control, (2) diabetic (streptozotocin, STZ, treated), (3) control + Ang-(1-7), and (4) diabetic + Ang-(1-7). Following 3 weeks of Ang-(1-7) treatment subsequent to induction of diabetes, rats were sacrificed. Penile cavernosal tissue was isolated to measure vascular reactivity, PDE gene expression and activity, and levels of p38MAP kinase, nitrites, and cGMP. Carbachol-induced vasorelaxant response after preincubation of corpus cavernosum with PE was significantly attenuated in diabetic rats, and Ang-(1-7) markedly corrected the diabetes-induced impairment. Gene expression and activity of PDE and p38MAP kinase were significantly increased in cavernosal tissue of diabetic rats, and Ang-(1-7) markedly attenuated STZ-induced effects. Ang-(1-7) significantly increased the levels of nitrite and cGMP in cavernosal tissue of control and diabetic rats. Cavernosal tissue of diabetic rats had significantly reduced cGMP levels and Ang-(1-7) markedly prevented the STZ-induced cGMP depletion. This study demonstrates that attenuation of diabetes-induced PDE activity might be one of the key mechanisms in the beneficial effects of Ang-(1-7). Gursev S. Dhaunsi, Mariam Yousif, Batoul Makki, Saghir Akhtar, and Ibrahim F. Benter Copyright © 2017 Gursev S. Dhaunsi et al. All rights reserved. JianPi JieDu Recipe Inhibits Epithelial-to-Mesenchymal Transition in Colorectal Cancer through TGF-β/Smad Mediated Snail/E-Cadherin Expression Thu, 16 Feb 2017 13:13:55 +0000 JPJD was an ideal alternative traditional Chinese medicine compound in the prevention and treatment of CRC, but its underlying mechanisms has not been fully elucidated. In this study, we demonstrated in vitro that TGF-β-induced EMT promoted the invasion and metastasis of CRC cells, reduced the expression of E-cadherin, and elevated the expression of Vimentin. However, JPJD could inhibit the invasive and migratory ability of TGF-β-stimulated CRC cells in a concentration-dependent manner through increasing the expression of E-cadherin and repressing the expression of Vimentin, as well as the inhibition of TGF-β/Smad signaling pathway. Meanwhile, JPJD reduced the transcriptional activities of EMT-associated factors Snail and E-cadherin during the initiation of TGF-β-induced EMT. In vivo, the results demonstrated that JPJD can significantly inhibit the liver and lung metastasis of orthotopic CRC tumor in nude mice, as well as significantly prolonging the survival time of tumor-bearing in a dose-dependent manner. Additionally, JPJD can upregulate the expression of E-cadherin and Smad2/3 in the cytoplasm and downregulate the expression of Vimentin, p-Smad2/3, and Snail in the orthotopic CRC tumor tissues. In conclusions, our new findings provided evidence that JPJD could inhibit TGF-β-induced EMT in CRC through TGF-β/Smad mediated Snail/E-cadherin expression. Xuan Liu, Qing Ji, Wanli Deng, Ni Chai, Yuanyuan Feng, Lihong Zhou, Hua Sui, Chunpu Li, Xiaoting Sun, and Qi Li Copyright © 2017 Xuan Liu et al. All rights reserved. Parathyroid Hormone (1-34) Might Not Improve Early Bone Healing after Sinus Augmentation in Healthy Rabbits Thu, 09 Feb 2017 09:50:43 +0000 Purpose. This study evaluated the effect of administering intermittent parathyroid hormone [PTH (1-34), henceforth PTH] on the early-stage bone healing of maxillary sinus augmentation in healthy rabbits. Materials and Methods. Bovine bone mineral was grafted on the sinuses of 20 female New Zealand white rabbits. The animals were randomly divided into two groups, PTH () or saline (), in which either PTH or saline was injected subcutaneously 5 days a week for 2 weeks. Half of the animals in each group were killed at 2 weeks postoperatively and the other half were killed at 4 weeks postoperatively. The dosage of PTH was 10 μg/kg/day. Radiographic and histomorphometric analyses were performed. Result. The new bone area (NBA) did not differ significantly between the PTH and saline groups. The NBA in the PTH group in the total augmented area and in the demarcated window, center, and Schneiderian membrane regions increased significantly from 2 to 4 weeks. The number of osteoclasts decreased significantly from 2 to 4 weeks in both groups, with no difference between the two groups. Conclusion. Intermittent PTH might not stimulate new bone formation in healthy rabbits during the first 4 weeks of healing. Jisun Huh, Ui-Won Jung, Kyeong-Mee Park, Hyun Sil Kim, Kee-Deog Kim, and Wonse Park Copyright © 2017 Jisun Huh et al. All rights reserved. Resveratrol Increases Serum BDNF Concentrations and Reduces Vascular Smooth Muscle Cells Contractility via a NOS-3-Independent Mechanism Sun, 05 Feb 2017 10:42:20 +0000 Resveratrol is a polyphenol that presents both antineuroinflammatory properties and the ability to interact with NOS-3, what contributes to vasorelaxation. Brain-derived neurotrophic factor (BNDF), a molecule associated with neuroprotection in many neurodegenerative disorders, is considered as an important element of maintaining stable cerebral blood flow. Vascular smooth muscle cells (VSMCs) are considered to be an important element in the pathogenesis of neurodegeneration and a potential preventative target by agents which reduce the contractility of the vessels. Our main objectives were to define the relationship between serum and long-term oral resveratrol administration in the rat model, as well as to assess the effect of resveratrol on phenylephrine- (PHE-) induced contraction of vascular smooth muscle cells (VSMCs). Moreover, we attempt to define the dependence of contraction mechanisms on endothelial NO synthase. Experiments were performed on Wistar rats () pretreated with resveratrol (4 weeks; 10 mg/kg p.o.) or placebo. Serum BDNF levels were quantified after 2 and 4 weeks of treatment with ELISA. Contraction force was measured on isolated and perfused tail arteries as the increase of perfusion pressure with a constant flow. Values of serum BNDF in week 0 were  ng/mL (treated) and  ng/mL (control) ( = ns). After 2 weeks of treatment, BDNF in the treatment group was higher than in controls,  ng/mL and  ng/mL, respectively. () Following 4 weeks of treatment, BDNF values were higher in the resveratrol group compared to control  ng/mL and  ng/mL, respectively (). EC50 values obtained for PHE in resveratrol pretreated arteries were significantly higher than controls ( × 10−7 M/L versus × 10−8 M/L, ). These results show a significant increase in BDNF concentration in the resveratrol pretreated group. The reactivity of resistant arteries was significantly reduced for resveratrol pretreated vessels and this effect was partially NOS-3 independent. Michał Wiciński, Bartosz Malinowski, Mateusz M. Węclewicz, Elżbieta Grześk, and Grzegorz Grześk Copyright © 2017 Michał Wiciński et al. All rights reserved. Electrospun Nanofibers Loaded with Quercetin Promote the Recovery of Focal Entrapment Neuropathy in a Rat Model of Streptozotocin-Induced Diabetes Mon, 30 Jan 2017 00:00:00 +0000 In this study, quercetin-loaded zein-based nanofibers were developed using electrospinning technique. The therapeutic effect of these quercetin-loaded nanofibers on neuropathy in streptozotocin- (STZ-) induced diabetes in rats was assessed. Diabetic condition was induced in male Wistar rats by STZ, after which a crush injury of the right sciatic nerve was performed to induce mononeuropathy. Functional recovery was assessed using walking track analysis, measurements of foot withdrawal reflex, nerve conduction velocity, and morphological analysis. The oxidative stress status and the ratio of phosphorylated extracellular recognition kinase (pERK)/extracellular recognition kinase (ERK) expression in the nerve lesion were also assessed in order to elucidate the potential mechanisms involved. Results showed that quercetin-loaded zein-based nanofibers slightly enhanced functional recovery from neuropathy in STZ-diabetic rats. The potential mechanism might partially involve improvements in oxidative stress status and the ratio of pERK/ERK expression in the nerve lesion. Chonlathip Thipkaew, Jintanaporn Wattanathorn, and Supaporn Muchimapura Copyright © 2017 Chonlathip Thipkaew et al. All rights reserved. Tang-Luo-Ning Improves Mitochondrial Antioxidase Activity in Dorsal Root Ganglia of Diabetic Rats: A Proteomics Study Wed, 04 Jan 2017 00:00:00 +0000 Tang-luo-ning (TLN) is a traditional Chinese herbal recipe for treating diabetic peripheral neuropathy (DPN). In this study, we investigated mitochondrial protein profiles in a diabetic rat model and explored the potential protective effect of TLN. Diabetic rats were established by injection of streptozocin (STZ) and divided into model, alpha lipoic acid (ALA), and TLN groups. Mitochondrial proteins were isolated from dorsal root ganglia and proteomic analysis was used to quantify the differentially expressed proteins. Tang-luo-ning mitigated STZ-induced diabetic symptoms and blood glucose level, including response time to cold or hot stimulation and nerve conductive velocity. As compared to the normal, there were 388 differentially expressed proteins in the TLN group, 445 in ALA group, and 451 in model group. As compared to the model group, there were 275 differential proteins in TLN group and 251 in ALA group. As compared to model group, mitochondrial complex III was significantly decreased, while glutathione peroxidase and peroxidase were increased in TLN group. When compared with ALA group, the mitochondrial complex III was increased, and mitochondrial complex IV was decreased in TLN group. Together, TLN should have a strong antioxidative activity, which appears to be modulated through regulation of respiratory complexes and antioxidases. Taojing Zhang, Yanbin Gao, Yanbin Gong, Hui Zhou, Peifeng Xie, Song Guan, and Wenming Yi Copyright © 2017 Taojing Zhang et al. All rights reserved. Natural Therapies for Cardiovascular Diseases Wed, 21 Dec 2016 06:42:39 +0000 Xiaochen Yang, Guoyan Yang, Giuseppe Caminiti, and Francesca Borrelli Copyright © 2016 Xiaochen Yang et al. All rights reserved. A Naphthalenic Derivative ND-1 Inhibits Thrombus Formation by Interfering the Binding of Fibrinogen to Integrin αIIbβ3 Tue, 20 Dec 2016 09:53:24 +0000 Integrin αIIbβ3 plays a crucial role in the process of platelet aggregation. Three integrin αIIbβ3 antagonists (abciximab, eptifibatide, and tirofiban) have been approved by FDA for clinical use. Unfortunately, they all showed severe side effects such as thrombocytopenia and bleeding risk. Thus, researches on the development of more effective and safer antiplatelet agents are needed. In this manuscript we reported a novel naphthalenic derivative compound ND-1 with potent antithrombotic effect and lower bleeding risk. ND-1 inhibited ADP-, collagen-, thrombin-, and U46619-induced platelet aggregation with IC50 values of 1.29, 14.46, 12.84, and 40.24 μM, respectively. Mechanism studies indicated that ND-1 inhibited the binding of fibrinogen to integrin αIIbβ3 in a dose-dependent manner with an IC50 value of 3.12 μM. ND-1 inhibited P-selectin expression induced by ADP, collagen, thrombin, and U46619 on the surface of platelets. Additionally, this compound reduced platelets spreading to the immobilized fibrinogen. In vivo, ND-1 potently decreased thrombus formation in an arteriovenous shunt thrombosis model in rats and slightly prolonged bleeding time in a tail cutting model in mice. Taken together, our results reveal that ND-1 is a novel antagonist of αIIbβ3 with strong antithrombotic effect and lower bleeding risk. Xue Ding, Tong-dan Liu, Zhou-ling Xie, Qi Zhao, Yuan Cao, Xiao-dong Liu, Cai-hui Wang, Rwibasira Rudinga Gamariel, Xin Ming, Zhi-yu Li, and Yi Kong Copyright © 2016 Xue Ding et al. All rights reserved. Ethnobotanical Research at the Kutukú Scientific Station, Morona-Santiago, Ecuador Thu, 15 Dec 2016 11:49:38 +0000 This work features the results of an ethnobotanical study on the uses of medicinal plants by the inhabitants of the region near to the Kutukú Scientific Station of Universidad Politécnica Salesiana, located in the Morona-Santiago province, southeast of Ecuador. In the surroundings of the station, one ethnic group, the Shuar, has been identified. The survey hereafter reports a total of 131 plant species, with 73 different therapeutic uses. Jose Luis Ballesteros, Francesco Bracco, Marco Cerna, Paola Vita Finzi, and Giovanni Vidari Copyright © 2016 Jose Luis Ballesteros et al. All rights reserved. Effects of Raloxifene on the Proliferation and Apoptosis of Human Aortic Valve Interstitial Cells Wed, 23 Nov 2016 13:32:06 +0000 We aimed to explore the effects of raloxifene (RAL) on the proliferation and apoptosis of human aortic valve interstitial cells (AVICs). Different concentrations of RAL were used to act on AVICs. MTS kit is used to test the effects of different concentrations of RAL on the proliferation of AVICs. Cell cycle and apoptosis test used flow cytometry after seven-day treatment. The relative expression levels of caspase-3 and caspase-8 are tested with RT-qPCR and Western blot. The results of MTS testing revealed that the absorbance value (OD value) of the cells in the concentration groups of 10 and 100 nmol/L RAL at a wavelength of 490 nm at five, seven, and nine days significantly decreased compared with that in the control group. Meanwhile, the results of flow cytometry of the cells collected after seven days showed that the ratio of the S stage and the cell apoptosis rate of AVICs can be significantly reduced by RAL in the concentration groups of 10 and 100 nmol/L. The mRNA and protein expressions of caspase-3 and caspase-8 were significantly decreased compared with those in the control group. This study laid the foundation for further treatment of aortic valve disease by using RAL. Zhimin Fu, Bin Luo, Mingpeng Li, Bin Peng, and Zheng Wang Copyright © 2016 Zhimin Fu et al. All rights reserved. Cornel Iridoid Glycoside Improves Locomotor Impairment and Decreases Spinal Cord Damage in Rats Sun, 20 Nov 2016 08:27:56 +0000 Purpose. This study was to investigate the effects of cornel iridoid glycoside (CIG) on spinal cord injury (SCI) in rats. Methods. The thoracic cord (at T9) of rats was injured by clip compression for 30 sec. Locomotor function was assessed using the Basso, Beattie, and Bresnahan (BBB) rating scale. Neuroanatomic stereological parameters as well as Nogo-A, p75 neurotrophin receptor (p75NTR), and ROCKII expression were measured by histological processing, immunohistochemistry, and stereological analyses. The axons passing through the lesion site were detected by BDA tracing. Results. Intragastric administration of CIG (60 and 180 mg/kg) improved the locomotor impairment at 10, 17, 24, and 31 days post-injury (dpi) compared with untreated SCI model rats. CIG treatment decreased the volume of the lesion epicenter (LEp) and increased the volume of spared tissue and the number of surviving neurons in the injured spinal cord at 31 dpi. CIG promoted the growth of BDA-positive axons and their passage through the lesion site and decreased the expression of Nogo-A, p75NTR, and ROCKII both in and around the LEp. Conclusion. CIG improved the locomotor impairment, decreased tissue damage, and downregulated the myelin-associated inhibition signaling pathway in SCI rats. The results suggest that CIG may be beneficial for SCI therapy. Wen-jing Tang, Deng-lei Ma, Cui-cui Yang, Li Zhang, Ya-li Li, Lan Zhang, and Lin Li Copyright © 2016 Wen-jing Tang et al. All rights reserved. Rationale for the Successful Management of EDTA Chelation Therapy in Human Burden by Toxic Metals Tue, 08 Nov 2016 14:17:18 +0000 Exposure to environmental and occupational toxicants is responsible for adverse effects on human health. Chelation therapy is the only procedure able to remove toxic metals from human organs and tissue, aiming to treat damage related to acute and/or chronic intoxication. The present review focuses on the most recent evidence of the successful use of the chelating agent ethylenediaminetetraacetic acid (EDTA). Assessment of toxic-metal presence in humans, as well as the rationale of EDTA therapy in cardiovascular and neurodegenerative diseases, is reported. Maria Elena Ferrero Copyright © 2016 Maria Elena Ferrero. All rights reserved. Tropisetron Protects Against Acetaminophen-Induced Liver Injury via Suppressing Hepatic Oxidative Stress and Modulating the Activation of JNK/ERK MAPK Pathways Mon, 07 Nov 2016 11:51:46 +0000 Objectives. To investigate the protective effects of tropisetron on acetaminophen- (APAP-) induced liver injury in a mice model. Methods. C57BL/6 male mice were given tropisetron (0.3 to 10 mg/kg) 30 minutes before a hepatotoxic dose of acetaminophen (300 mg/kg) intraperitoneally. Twenty hours after APAP intoxication, sera alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, hepatic myeloperoxidase (MPO), malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) activities, and liver histopathological changes were examined. The MAP kinases were also detected by western blotting. Results. Our results showed that tropisetron pretreatment significantly attenuated the acute elevations of the liver enzyme ALT level, hepatic MPO activity, and hepatocytes necrosis in a dose-dependent manner (0.3–10 mg/kg) in APAP-induced hepatotoxicity mice. Tropisetron (1 and 3 mg/kg) suppressed APAP-induced hepatic lipid peroxidation expression and alleviated GSH and SOD depletion. Administration of tropisetron also attenuated the phosphorylation of c-Jun-NH2-terminal protein kinase (JNK) and extracellular signal-regulated kinase (ERK) caused by APAP. Conclusion. Our data demonstrated that tropisetron’s hepatoprotective effect was in part correlated with the antioxidant, which were mediated via JNK and ERK pathways on acetaminophen-induced liver injury in mice. Fu-Chao Liu, Hung-Chen Lee, Chia-Chih Liao, Allen H. Li, and Huang-Ping Yu Copyright © 2016 Fu-Chao Liu et al. All rights reserved. MediterrAsian Diet Products That Could Raise HDL-Cholesterol: A Systematic Review Tue, 01 Nov 2016 09:02:51 +0000 Background. High HDL-cholesterol (HDL-C) values are negatively correlated with cardiovascular diseases. This review analyses the effect of the supplementation with various Mediterranean diet products (artichoke, bergamot, and olive oil) and Asian diet products (red yeast rice) on the HDL-C value in dyslipidemic subjects. Methods. A systematic review has been done involving all the English written studies published from the 1st of January 1958 to the 31st of March 2016. Results. The results of this systematic review indicate that the dietary supplementation with red yeast rice, bergamot, artichoke, and virgin olive oil has promising effects on the increase of HDL-C serum levels. The artichoke leaf extract and virgin olive oil appear to be particularly interesting, while bergamot extract needs further research and the effect of red yeast rice seems to be limited to patients with previous myocardial infarction. Conclusions. Various MediterrAsian diet products or natural extracts may represent a potential intervention treatment to raise HDL-C in dyslipidemic subjects. Mariangela Rondanelli, Attilio Giacosa, Paolo Morazzoni, Davide Guido, Mario Grassi, Gabriella Morandi, Chiara Bologna, Antonella Riva, Pietro Allegrini, and Simone Perna Copyright © 2016 Mariangela Rondanelli et al. All rights reserved. Alendronate Can Improve Bone Alterations in Experimental Diabetes by Preventing Antiosteogenic, Antichondrogenic, and Proadipocytic Effects of AGEs on Bone Marrow Progenitor Cells Thu, 20 Oct 2016 10:03:11 +0000 Bisphosphonates such as alendronate are antiosteoporotic drugs that inhibit the activity of bone-resorbing osteoclasts and secondarily promote osteoblastic function. Diabetes increases bone-matrix-associated advanced glycation end products (AGEs) that impair bone marrow progenitor cell (BMPC) osteogenic potential and decrease bone quality. Here we investigated the in vitro effect of alendronate and/or AGEs on the osteoblastogenic, adipogenic, and chondrogenic potential of BMPC isolated from nondiabetic untreated rats. We also evaluated the in vivo effect of alendronate (administered orally to rats with insulin-deficient Diabetes) on long-bone microarchitecture and BMPC multilineage potential. In vitro, the osteogenesis (Runx2, alkaline phosphatase, type 1 collagen, and mineralization) and chondrogenesis (glycosaminoglycan production) of BMPC were both decreased by AGEs, while coincubation with alendronate prevented these effects. The adipogenesis of BMPC (PPARγ, intracellular triglycerides, and lipase) was increased by AGEs, and this was prevented by coincubation with alendronate. In vivo, experimental Diabetes (a) decreased femoral trabecular bone area, osteocyte density, and osteoclastic TRAP activity; (b) increased bone marrow adiposity; and (c) deregulated BMPC phenotypic potential (increasing adipogenesis and decreasing osteogenesis and chondrogenesis). Orally administered alendronate prevented all these Diabetes-induced effects on bone. Thus, alendronate could improve bone alterations in diabetic rats by preventing the antiosteogenic, antichondrogenic, and proadipocytic effects of AGEs on BMPC. Sara Rocío Chuguransky, Ana María Cortizo, and Antonio Desmond McCarthy Copyright © 2016 Sara Rocío Chuguransky et al. All rights reserved. Synergistic Effects of Danshen (Salvia Miltiorrhiza Radix et Rhizoma) and Sanqi (Notoginseng Radix et Rhizoma) Combination in Inhibiting Inflammation Mediators in RAW264.7 Cells Tue, 18 Oct 2016 11:16:25 +0000 Aims. This study aims to investigate the possible synergistic interactions of the Danshen-Sanqi combination on vascular disease via their anti-inflammatory activities. Methods. Nine combination ratios of Danshen-Sanqi extracts were screened in the RAW264.7 cell line and their anti-inflammatory effects were examined in lipopolysaccharide- (LPS-) induced nitric oxide (NO), tumor necrosis factor (TNF), and monocyte chemoattractant protein-1 (MCP-1) generation pathways. The interaction between Danshen and Sanqi on each target was analysed using combination index (CI) and isobologram models. Additionally, the anti-inflammatory activities of key bioactive compounds from Danshen and Sanqi were tested using the same models. The compounds from each herb that exerted the most potent activity were combined to evaluate their possible synergistic/antagonistic interactions. Results. Danshen-Sanqi 8 : 2 was found to be the optimal ratio and exerted a synergistic effect in inhibiting NO, TNF, and MCP-1 when the concentrations were higher than 1.24, 1.89, and 2.17 mg/mL, respectively. Although dihydrotanshinone I (DT) and ginsenoside Rd (Rd) from Danshen and Sanqi, respectively, exhibited the greatest individual bioactivity in the assays, antagonistic effects were observed for the DT-Rd combination 7 : 3. Conclusion. This study provided scientific evidence to support the traditional use of the Danshen-Sanqi combination for vascular disease through their synergistic interactions on anti-inflammatory pathways. Xian Zhou, Valentina Razmovski-Naumovski, Dennis Chang, Chunguang Li, Antony Kam, Mitchell Low, Alan Bensoussan, and Kelvin Chan Copyright © 2016 Xian Zhou et al. All rights reserved. Molecular Role of EGFR-MAPK Pathway in Patchouli Alcohol-Induced Apoptosis and Cell Cycle Arrest on A549 Cells In Vitro and In Vivo Mon, 17 Oct 2016 09:16:23 +0000 Nowadays, chemotherapy is still the main effective treatment for cancer. Herb prescriptions containing Pogostemon cablin Benth (also known as “Guang-Huo-Xiang”) have been widely used in Chinese medicine today. In our research, we found that patchouli alcohol, a compound isolated from the oil of Pogostemon cablin Benth, exerted antitumor ability against human lung cancer A549 cells ability both in vitro and in vivo. MTT assay was used to assess cell viability. Hoechst 33342 staining and TUNEL cover glass staining provided the visual evidence of apoptosis. Caspase activity measurement showed that patchouli alcohol activated caspase 9 and caspase 3 of mitochondria-mediated apoptosis. Consistently, patchouli alcohol inhibited the xenograft tumor in vivo. Further investigation of the underlying molecular mechanism showed that MAPK and EGFR pathway might contribute to the antitumor effect of patchouli alcohol. Our study proved that patchouli alcohol might be able to serve as a novel antitumor compound in the clinical treatment of lung cancer. XinGang Lu, Liu Yang, ChengHua Lu, ZhenYu Xu, HongFu Qiu, JiaJia Wu, JingWen Wang, JiaFeng Tong, Yin Zhu, and Jie Shen Copyright © 2016 XinGang Lu et al. All rights reserved. First Report of Eurycoma longifolia Jack Root Extract Causing Relaxation of Aortic Rings in Rats Sun, 09 Oct 2016 10:04:09 +0000 Although Eurycoma longifolia has been studied for erectile function, the blood pressure- (BP-) lowering effect has yet to be verified. Hence, this study aims at investigating the BP-lowering properties of the plant with a view to develop an antihypertensive agent that could also preserve erectile function. Ethanolic root extract was partitioned by hexane, dichloromethane (DCM), ethyl acetate, butanol, and water. The DCM fraction, found to be potent in relaxing phenylephrine- (PE-) precontracted rat aortic rings, was further purified by column chromatography. Subfraction DCM-II, being the most active in relaxing aortae, was studied for effects on the renin-angiotensin and kallikrein-kinin systems in aortic rings. The effect of DCM-II on angiotensin-converting enzyme (ACE) activity was also evaluated in vitro. Results showed that DCM-II reduced () the contractions evoked by angiotensin I and angiotensin II (Ang II). In PE-precontracted rings treated with DCM-II, the Ang II-induced contraction was attenuated () while bradykinin- (BK-) induced relaxation enhanced (). In vitro, DCM-II inhibited () the activity of ACE. These data demonstrate that the vasodilatory effect of DCM-II appears to be mediated via inhibition of Ang II type 1 receptor and ACE as well as enhancement of Ang II type 2 receptor activation and BK activity. Bae Huey Tee, See Ziau Hoe, Swee Hung Cheah, and Sau Kuen Lam Copyright © 2016 Bae Huey Tee et al. All rights reserved. Discovery of Potential Inhibitors of Aldosterone Synthase from Chinese Herbs Using Pharmacophore Modeling, Molecular Docking, and Molecular Dynamics Simulation Studies Mon, 03 Oct 2016 13:58:08 +0000 Aldosterone synthase (CYP11B2) is a key enzyme for the biosynthesis of aldosterone, which plays a significant role for the regulation of blood pressure. Excess aldosterone can cause the dysregulation of the renin-angiotensin-aldosterone system (RAAS) and lead to hypertension. Therefore, research and development of CYP11B2 inhibitor are regarded as a novel approach for the treatment of hypertension. In this study, the pharmacophore models of CYP11B2 inhibitors were generated and the optimal model was used to identify potential CYP11B2 inhibitors from the Traditional Chinese Medicine Database (TCMD, Version 2009). The hits were further refined by molecular docking and the interactions between compounds and CYP11B2 were analyzed. Compounds with high Fitvalue, high docking score, and expected interactions with key residues were selected as potential CYP11B2 inhibitors. Two most promising compounds, ethyl caffeate and labiatenic acid, with high Fitvalue and docking score were reserved for molecular dynamics (MD) study. All of them have stability of ligand binding which suggested that they might perform the inhibitory effect on CYP11B2. This study provided candidates for novel drug-like CYP11B2 inhibitors by molecular simulation methods for the hypertension treatment. Ganggang Luo, Fang Lu, Liansheng Qiao, Xi Chen, Gongyu Li, and Yanling Zhang Copyright © 2016 Ganggang Luo et al. All rights reserved. Phytochemical Screening and Antinociceptive and Antidiarrheal Activities of Hydromethanol and Petroleum Benzene Extract of Microcos paniculata Barks Thu, 29 Sep 2016 14:09:47 +0000 Introduction. Microcos paniculata is traditionally used for treating diarrhea, wounds, cold, fever, hepatitis, dyspepsia, and heat stroke. Objective. To investigate the qualitative phytochemical constituents of hydromethanol (HMPB) and petroleum benzene extract of Microcos paniculata barks (PBMPB) and to evaluate their antinociceptive and antidiarrheal activities. Methods. Phytochemical constituents and antinociceptive and antidiarrheal activities were determined and evaluated by different tests such as Molisch’s, Fehling’s, Mayer’s, Wagner’s, Dragendorff’s, frothing, FeCl3, alkali, Pew’s, and Salkowski’s test, general test of glycosides, Baljet and NH4OH test, formalin-induced paw licking, acetic acid-induced writhing, tail immersion, and hot plate tests, and castor oil and MgSO4 induced diarrheal tests. Results. These extracts revealed the presence of saponins, flavonoids, and triterpenoids and significantly (, versus control) reduced paw licking and abdominal writhing of mice. At 30 min after their administration, PBMPB revealed significant increase in latency (, versus control) in tail immersion test. In hot plate test, HMPB and PBMPB 200 mg/kg showed significant increase in response latency (, versus control) at 30 min after their administration. Moreover, both extracts significantly (, versus control) inhibited percentage of diarrhea in antidiarrheal models. Conclusion. Study results indicate that M. paniculata may provide a source of plant compounds with antinociceptive and antidiarrheal activities. Rafath Ara Moushome, Mst. Irin Akter, and Md. Abdullah Aziz Copyright © 2016 Rafath Ara Moushome et al. All rights reserved. Effect of Oral Coadministration of Ascorbic Acid with Ling Zhi Preparation on Pharmacokinetics of Ganoderic Acid A in Healthy Male Subjects: A Randomized Crossover Study Sun, 25 Sep 2016 14:24:02 +0000 The objective of this randomized, open-label, single-dose, two-phase crossover study was to determine the effect of ascorbic acid on pharmacokinetics of ganoderic acid A, an important biologically active triterpenoid compound with anticancer activities, following oral administration of water extract of fruiting bodies of Ling Zhi in 12 healthy male subjects. Each subject was randomized to receive either one of the two regimens: (1) a single dose of 3,000 mg of the Ling Zhi preparation or (2) a single dose of 3,000 mg of the Ling Zhi preparation in combination with 2,500 mg of ascorbic acid. After a washout period of at least two weeks, subjects were switched to receive the alternate regimen. Blood samples were collected in each phase immediately before dosing and at specific time points for 8 hours after dosing. Plasma ganoderic acid A concentrations were quantified using liquid chromatography-mass spectrometry (LC-MS). The pharmacokinetic parameters analyzed were maximal plasma concentration (), time to reach peak concentration (), area under the plasma concentration-time curve (), and half-life (). An oral coadministration of ascorbic acid with Ling Zhi preparation did not significantly alter the pharmacokinetic parameters of ganoderic acid A in healthy male subjects. Patcharanee Tawasri, Chadarat Ampasavate, Somsak Tharatha, Natthakarn Chiranthanut, and Supanimit Teekachunhatean Copyright © 2016 Patcharanee Tawasri et al. All rights reserved. Antihyperalgesic Effect of Hesperidin Improves with Diosmin in Experimental Neuropathic Pain Thu, 08 Sep 2016 13:18:19 +0000 Neuropathic pain is caused by a primary lesion, dysfunction, or transitory perturbation in the peripheral or central nervous system. In this study, we investigated the hesperidin antihyperalgesic effects alone or combined with diosmin in a model of neuropathic pain to corroborate a possible synergistic antinociceptive activity. Mechanical and thermal hyperalgesia were assessed in the aesthesiometer and plantar tests, respectively, after chronic constriction injury (CCI) model in rats receiving hesperidin (HS, 5 doses from 10 to 1000 mg/kg) alone or combined with diosmin (DS, 10 and 100 mg/kg) in comparison to gabapentin (31.6 mg/kg). UHPLC-MS analysis of cerebral samples was used to recognize the central concentrations of these flavonoids. Participation of different receptors was also investigated in the presence of haloperidol, bicuculline, and naloxone antagonists. Acute hesperidin administration significantly decreased mechanical and thermal hyperalgesia in CCI rats. Antihyperalgesic response of hesperidin, improved by a combination with diosmin (DS10/HS100) in both stimuli, was blockaded by haloperidol, bicuculline, and naloxone, but not WAY100635, antagonists. Both flavonoids were detected in brain samples. In conclusion, hesperidin alone and combined with diosmin produces antihyperalgesic response in the CCI model in rats. Antihyperalgesic effect of DS10/HS100 combination involves central activity partially modulated by D2, , and opioids, but not by 5-, receptors. Azucena I. Carballo-Villalobos, María-Eva González-Trujano, Francisco Pellicer, and Francisco J. López-Muñoz Copyright © 2016 Azucena I. Carballo-Villalobos et al. All rights reserved. rLj-RGD3, a Novel Three-RGD-Motif-Containing Recombinant Protein from Lampetra japonica, Protects PC12 Cells from Injury Induced by Oxygen-Glucose Deprivation and Reperfusion Mon, 05 Sep 2016 06:26:53 +0000 rLj-RGD3 is a 14.5 kDa recombinant protein with 3 RGD (Arg-Gly-Asp) motifs from the salivary gland secretions of Lampetra japonica, which is a histidine-rich and arginine-rich protein. Previous reports indicated that rLj-RGD3 has typical functions of RGD-toxin protein, such as platelet aggregation suppression tumour metastasis and angiogenesis inhibition. Because histidine and arginine have cerebral ischemia-reperfusion and neuroprotective functions, we investigated whether rLj-RGD3 has such activities and studied the mechanism. The effects of rLj-RGD3 on neuroprotection and antiapoptosis were determined. The expression level of focal adhesion kinase (FAK), p-FAK, Caspase-3, and Bcl-2 after oxygen-glucose deprivation and reperfusion (OGD-R) was examined. The viability of PC12 cells incubated with rLj-RGD3 at high concentrations (16 μmol/L) increased significantly due to its ability to protect the cells from apoptosis after OGD-R-induced injury. Furthermore, rLj-RGD3 attenuated the damage due to OGD-R. Most of the PC12 cells were apoptotic after OGD-R. In contrast, the number of apoptotic PC12 cells was significantly decreased in the group treated with a high-dose of rLj-RGD3. In addition, rLj-RGD3 activated FAK and p-FAK protein. rLj-RGD3 inhibited Caspase-3 and upregulated Bcl-2 protein expression in PC12 cells after OGD-R. The study provides the first evidence for neuroprotective effects of rLj-RGD3 in ischemic injury that may be partly mediated through inhibition of Caspase-3 and upregulation of Bcl-2, FAK, and p-FAK protein expression. Li Lv, Qian Lu, Fangyu Shao, Weiping Li, Qin Zhou, Jihong Wang, and Qingwei Li Copyright © 2016 Li Lv et al. All rights reserved. Prosexual Effect of Chrysactinia mexicana A. Gray (Asteraceae), False Damiana, in a Model of Male Sexual Behavior Tue, 30 Aug 2016 16:33:47 +0000 Chrysactinia mexicana A. Gray (Asteraceae) and Turnera diffusa Willd (Turneraceae) are employed in traditional medicine as aphrodisiacs; however, there is no scientific evidence supporting the prosexual properties of C. mexicana. The aim of this study was to determine whether an aqueous extract of C. mexicana (Cm) stimulates rat male sexual behavior in the sexual exhaustion paradigm. Sexually exhausted (SExh) male rats were treated with Cm (80, 160, and 320 mg/kg), an aqueous extract of T. diffusa (Td), or yohimbine. The sexual exhaustion state in the control group was characterized by a low percentage of males exhibiting mounts, intromissions, and ejaculations and no males demonstrating mating behavior after ejaculation. Cm (320 mg/kg), Td, or yohimbine significantly increased the proportion of SExh rats that ejaculated and resumed copulation after ejaculation. In males that exhibited reversal of sexual exhaustion, Cm (320 mg/kg) improved sexual performance by reducing the number of intromissions and shrinking ejaculation latency. The effects of treatments on sexual behavior were not related with alterations in general locomotion. In conclusion, the prosexual effects of Cm, as well as those of Td, are established at a central level, which supports the traditional use of C. mexicana for stimulating sexual activity. R. Estrada-Reyes, O. A. Ferreyra-Cruz, G. Jiménez-Rubio, O. T. Hernández-Hernández, and L. Martínez-Mota Copyright © 2016 R. Estrada-Reyes et al. All rights reserved. Effect of Diabetes Mellitus on Tuberculosis Treatment Outcome and Adverse Reactions in Patients Receiving Directly Observed Treatment Strategy in India: A Prospective Study Wed, 24 Aug 2016 09:15:46 +0000 Despite successful implementation of directly observed treatment, short course (DOTS) in India, the growing number of diabetes mellitus (DM) patients appears to be a cause in the increasing tuberculosis (TB) incidence, affecting their management. In this regard, a prospective study was conducted on DOTS patients in three primary health care centers in urban slum region of South Delhi, India, to evaluate the effect of DM on sputum conversion, treatment outcome, and adverse drug reactions (ADR) due to anti-TB treatment. Eligible TB patients underwent blood glucose screening at treatment initiation. Disease presentation, clinical outcome, and ADRs were compared between patients of TB with and without DM. Out of 316 patients, the prevalence of DM was found to be 15.8%, in which 19.4% and 9.6% were PTB and EPTB patients, respectively. DM patients have observed higher sputum positivity (OR 1.247 95% CI; 0.539–2.886) at the end of 2-month treatment and poor outcome (OR 1.176 95% CI; 0.310–4.457) at the completion of treatment compared with non DM patients. Presence of DM was significantly associated (OR 3.578 95% CI; 1.114–11.494, ) with the development of ADRs. DM influences the treatment outcome of PTB patients in our setting and also on the ADR incidence. Ali Nasir Siddiqui, Khalid Umer Khayyam, and Manju Sharma Copyright © 2016 Ali Nasir Siddiqui et al. All rights reserved. In Vitro and In Vivo Anti-Helicobacter Activities of Eryngium foetidum (Apiaceae), Bidens pilosa (Asteraceae), and Galinsoga ciliata (Asteraceae) against Helicobacter pylori Thu, 18 Aug 2016 06:20:32 +0000 This study was performed to evaluate the antimicrobial activities of extracts of Bidens pilosa, Galinsoga ciliata, and Eryngium foetidum against 6 clinical strains of Helicobacter pylori in vitro and in vivo. Broth microdilution method was used in vitro. In vivo, Swiss mice were inoculated with H. pylori and divided into 5 groups; the control group received the vehicle and the four others received 125, 250, and 500 mg/kg of methanol extract of Eryngium foetidum and ciprofloxacin (500 mg/kg) for 7 days, respectively. Helicobacter pylori colonization and number of colonies in gastric biopsies culture were assessed on days 1 and 7 after treatment. The lowest MIC value (64 μg/mL) and the best spectrum of bactericidal effect (MBC/MIC = 1) were obtained with the methanol extract of Eryngium foetidum. The number of H. pylori infected animals was 17% (plant-extract) and 0% (ciprofloxacin) compared to 100% for the infected untreated group. Plant-extract ( CFU) and ciprofloxacin ( CFU) significantly reduced bacterial load in gastric mucosa compared to untreated, inoculated mice ( CFU). Conclusion. The present data provided evidence that methanol extract of Eryngium foetidum could be a rich source of metabolites with antimicrobial activity to fight Helicobacter pylori infections. Laure brigitte Kouitcheu Mabeku, Bertrand Eyoum Bille, and Eveline Nguepi Copyright © 2016 Laure brigitte Kouitcheu Mabeku et al. All rights reserved. The Modulatory Effect of Ischemia and Reperfusion on Arginine Vasopressin-Induced Arterial Reactions Wed, 03 Aug 2016 14:03:41 +0000 Aim of the Study. The purpose of this study was to investigate the impact of ischemia and reperfusion on the resistance of arteries to AVP (arginine vasopressin), with a particular emphasis on the role of smooth muscle cells in the action of vasopressin receptors and the role of the cGMP-associated signalling pathway. Materials and Methods. Experiment was performed on the perfunded tail arteries from male Wistar rats. The constriction triggered by AVP after 30 minutes of ischemia and 30 and 90 minutes of reperfusion was analysed. Analogous experiments were also carried out in the presence of 8Br-cGMP. Results. Ischemia reduces and reperfusion increases in a time-dependent manner the arterial reaction to AVP. The presence of 8Br-cGMP causes a significant decrease of arterial reactivity under study conditions. Conclusions. Ischemia and reperfusion modulate arterial contraction triggered by AVP. The effect of 8Br-cGMP on reactions, induced by AVP after ischemia and reperfusion, indicates that signalling pathway associated with nitric oxide (NO) and cGMP regulates the tension of the vascular smooth muscle cells. Katarzyna Szadujkis-Szadurska, Bartosz Malinowski, Małgorzata Piotrowska, Grzegorz Grześk, Michał Wiciński, and Marta Gajdus Copyright © 2016 Katarzyna Szadujkis-Szadurska et al. All rights reserved. The Role of RhoJ in Endothelial Cell Biology and Tumor Pathology Sun, 31 Jul 2016 06:29:42 +0000 Background. RhoJ, an endothelially expressed member of Cdc42 (cell division cycle 42) subfamily of Rho GTPase, plays an important role in endocytic pathway, adipocyte differentiation, endothelial motility, tube formation, and focal adhesion. RhoJ is a selective and effective therapeutic target in tumor tissues or retinopathy. Methods. A systematic review was related to “small Rho GTPase” or “RhoJ” with “endothelial motility, tube formation and focal adhesion” and “tumor therapy”. This led to many cross-references involving RhoJ and these data have been incorporated into the following study. Results. We have grouped the role of RhoJ according to three main effects: RhoJ regulates endocytic pathway and adipocyte differentiation in early studies, and RhoJ shows an important role in endothelial cell biology; furthermore, RhoJ blockade serves as a target in tumor vasculature and enhances the effects of anticancer drug. Conclusions. More research is necessary to understand the role of RhoJ in many aspects, on the basis of current knowledge of the role of RhoJ blockade in tumor vessels, there are opportunities for the therapy of tumor, and RhoJ is expressed outside tumour vasculature and is involved in wound healing. Taking advantage of the opportunities could result in a development in tumor therapy. Ting-Ting Shi, Gang Li, and Hong-Tao Xiao Copyright © 2016 Ting-Ting Shi et al. All rights reserved. Luteolin Prevents H2O2-Induced Apoptosis in H9C2 Cells through Modulating Akt-P53/Mdm2 Signaling Pathway Mon, 25 Jul 2016 09:53:07 +0000 Introduction. Luteolin, a falconoid compound in many Chinese herbs and formula, plays important roles in cardiovascular diseases. The underlying mechanism of luteolin remains to be further elaborated. Methods. A model of hydrogen peroxide- (H2O2-) induced H9C2 cells apoptosis was established. Cell viabilities were examined with an MTT assay. ,-Dichlorofluorescin diacetate (DCFH-DA) and flow cytometry were used to detect ROS level and apoptosis rate, respectively. The expressions of signaling proteins related to apoptosis were analyzed by western blot and mRNA levels were detected by real-time polymerase chain reaction (PCR). Quercetin was applied as positive drug. Results. Incubation with various concentrations of H2O2 (0, 50, 100, and 200 μM) for 1 h caused dose-dependent loss of cell viability and 100 μM H2O2 reduced the cell viability to approximately 50%. Treatments with luteolin and quercetin protected cells from H2O2-induced cytotoxicity and reduced cellular ROS level and apoptosis rate. Moreover, luteolin could downregulate the expressions of Bax, caspase-8, cleaved-caspase-3, and p53 in apoptotic signaling pathway. Further study showed that the expressions of Akt, Bcl-2, and Mdm2 were upregulated by luteolin. Conclusion. Luteolin protects H9C2 cells from H2O2-induced apoptosis. The protective and antiapoptotic effects of luteolin could be mediated by regulating the Akt-P53/Mdm2 apoptotic pathway. Hong Chang, Chun Li, Kuiyuan Huo, Qiyan Wang, Linghui Lu, Qian Zhang, Yong Wang, and Wei Wang Copyright © 2016 Hong Chang et al. All rights reserved. Effects of the Aqueous Extract of Eremomastax speciosa (Acanthaceae) on Sexual Behavior in Normal Male Rats Wed, 20 Jul 2016 05:58:19 +0000 Objective. We studied prosexual effects of Eremomastax speciosa aqueous extract in male adult rats. Materials and Methods. 100 and 500 mg/kg of extract were administered orally (days 0, 1, 4, 7, 14, and 28 (posttreatment)). The sexual behavior of rats receiving a single dose (500 mg/kg) was also evaluated after pretreatment with Lω-NAME (10 mg/kg), haloperidol (1 mg/kg), or atropine (5 mg/kg). Controls received distilled water or testosterone enanthate (20 mg/kg/day/3 days (s.c.) before the test). Results. The extract (days 1–14) had no significant effect on mount, intromission, and ejaculation frequencies but on day 28 (14 days after treatment), it increased frequency of mounts and intromissions at 500 mg/kg. Mount, intromission, and ejaculation latencies reduced and postejaculatory intervals decreased but the effect did not persist 2 weeks after treatment. Extract prosex effects were greatly reduced by atropine and completely abolished by haloperidol, while Lω-NAME increased mount latency and potentiated extract effect on intromission and ejaculation latencies. Conclusion. In summary, E. speciosa extract can have positive effects on male sexual motivation and performance when administered for two weeks at the dose of 500 mg/kg. The effects (dopaminergic and/or cholinergic dependent) tend to appear during the posttreatment period. B. Nchegang, C. Mezui, F. Longo, Z. E. Nkwengoua, A. P. Amang, and P. V. Tan Copyright © 2016 B. Nchegang et al. All rights reserved. Quantitative In Vitro and In Vivo Evaluation of Intestinal and Blood-Brain Barrier Transport Kinetics of the Plant N-Alkylamide Pellitorine Mon, 04 Jul 2016 12:25:04 +0000 Objective. To evaluate the gut mucosa and blood-brain barrier (BBB) pharmacokinetic permeability properties of the plant N-alkylamide pellitorine. Methods. Pure pellitorine and an Anacyclus pyrethrum extract were used to investigate the permeation of pellitorine through (1) a Caco-2 cell monolayer, (2) the rat gut after oral administration, and (3) the BBB in mice after intravenous and intracerebroventricular administration. A validated bioanalytical UPLC-MS2 method was used to quantify pellitorine. Results. Pellitorine was able to cross the Caco-2 cell monolayer from the apical-to-basolateral and from the basolateral-to-apical side with apparent permeability coefficients between and  cm/h and between and  cm/h, respectively. In rats, a serum elimination rate constant of 0.3 h−1 was obtained. Intravenous injection of pellitorine in mice resulted in a rapid and high permeation of pellitorine through the BBB with a unidirectional influx rate constant of 153 μL/(g·min). In particular, 97% of pellitorine reached the brain tissue, while only 3% remained in the brain capillaries. An efflux transfer constant of 0.05 min−1 was obtained. Conclusion. Pellitorine shows a good gut permeation and rapidly permeates the BBB once in the blood, indicating a possible role in the treatment of central nervous system diseases. Lieselotte Veryser, Nathalie Bracke, Evelien Wynendaele, Tanmayee Joshi, Pratima Tatke, Lien Taevernier, and Bart De Spiegeleer Copyright © 2016 Lieselotte Veryser et al. All rights reserved. Phytochemical, Antimicrobial, and Toxicological Evaluation of Traditional Herbs Used to Treat Sore Throat Sun, 26 Jun 2016 11:28:35 +0000 The in vitro antibacterial activities of 29 traditional medicinal plants used in respiratory ailments were assessed on multidrug resistant Gram-positive and Gram-negative bacteria isolated from the sore throat patients and two reference strains. The methanolic, n-hexane, and aqueous extracts were screened by the agar well diffusion assay. Bioactive fractions of effective extracts were identified on TLC coupled with bioautography, while their toxicity was determined using haemolytic assay against human erythrocytes. Qualitative and quantitative phytochemical analysis of effective extracts was also performed. Methanolic extract of 18 plants showed antimicrobial activity against test strains. Adhatoda vasica (ZI = 17–21 mm, MIC: 7.12–62.5 μg/mL), Althaea officinalis (ZI = 16–20 mm, MIC: 15.62–31.25 μg/mL), Cordia latifolia (ZI = 16–20 mm, MIC: 12.62–62.5 μg/mL), Origanum vulgare (ZI = 20–22 mm, MIC: 3–15.62 μg/mL), Thymus vulgaris (ZI = 21–25 mm, MIC: 7.81–31.25 μg/mL), and Ziziphus jujuba (ZI = 14–20 mm, MIC: 7.81–31.25 μg/mL) showed significant antibacterial activity. Alkaloid fractions of Adhatoda vasica, Cordia latifolia, and Origanum vulgare and flavonoid fraction of the Althaea officinalis, Origanum vulgare, Thymus Vulgaris, and Ziziphus jujuba exhibited antimicrobial activity. Effective plant extracts show 0.93–0.7% erythrocyte haemolysis. The results obtained from this study provide a scientific rationale for the traditional use of these herbs and laid the basis for future studies to explore novel antimicrobial compounds. Arifa Mehreen, Muzzamil Waheed, Iram Liaqat, and Najma Arshad Copyright © 2016 Arifa Mehreen et al. All rights reserved. Effects of Total Alkaloids of Sophora alopecuroides on Biofilm Formation in Staphylococcus epidermidis Sun, 19 Jun 2016 09:20:30 +0000 Staphylococcus epidermidis (S. epidermidis) is an opportunistic pathogen with low pathogenicity and a cause of the repeated outbreak of bovine mastitis in veterinary clinical settings. In this report, a biofilm model of S. epidermidis was generated and the minimal inhibitory concentration (MIC) and sub-MIC (SMIC) on bacterial cultures were assessed for the following agents: total alkaloids of Sophora alopecuroides (TASA), ciprofloxacin (CIP), and erythromycin (ERY). The formation and characteristic parameters of biofilm were analyzed in terms of XTT assay, silver staining, and confocal laser scanning microscope (CLSM). Results showed that a sub-MIC of TASA could inhibit 50% biofilm of bacterial activity, while 250-fold MIC of CIP and ERY MICs only inhibited 50% and 47% of biofilm formation, respectively. All three agents could inhibit the biofilm formation at an early stage, but TASA showed a better inhibitory effect on the late stage of biofilm thickening. A morphological analysis using CLSM further confirmed the destruction of biofilm by these agents. These results thus suggest that TASA has an inhibitory effect on biofilm formation of clinic S. epidermidis, which may be a potential agent warranted for further study on the treatment prevention of infection related to S. epidermidis in veterinary clinic. Xue Li, Cuiping Guan, Yulong He, Yujiong Wang, Xiaoming Liu, and Xuezhang Zhou Copyright © 2016 Xue Li et al. All rights reserved. Cardiovascular Actions and Therapeutic Potential of Tetramethylpyrazine (Active Component Isolated from Rhizoma Chuanxiong): Roles and Mechanisms Mon, 23 May 2016 06:27:35 +0000 Tetramethylpyrazine (TMP), a pharmacologically active component isolated from the rhizome of the Chinese herb Rhizoma Chuanxiong (Chuanxiong), has been clinically used in China and Southeast Asian countries for the prevention and treatment of cardiovascular diseases (CVDs) for about fifty years. The pharmacological effects of TMP on the cardiovascular system have attracted great interest. Emerging experimental studies and clinical trials have demonstrated that TMP prevents atherosclerosis as well as ischemia-reperfusion injury. The cardioprotective effects of TMP are mainly related to its antioxidant, anti-inflammatory, or calcium-homeostasis effects. This review focuses on the roles and mechanisms of action of TMP in the cardiovascular system and provides a novel perspective on TMP’s clinical use. Ming Guo, Yue Liu, and Dazhuo Shi Copyright © 2016 Ming Guo et al. All rights reserved. Amlodipine Ameliorates Ischemia-Induced Neovascularization in Diabetic Rats through Endothelial Progenitor Cell Mobilization Sun, 08 May 2016 14:33:43 +0000 Objectives. We investigated whether amlodipine could improve angiogenic responses in a diabetic rat model of acute myocardial infarction (AMI) through improving bone marrow endothelial progenitor cell (EPC) mobilization, in the same way as angiotensin converting enzyme inhibitors. Methods. After induction of AMI by coronary artery ligation, diabetic rats were randomly assigned to receive perindopril (2 mgkg−1 day−1), amlodipine (2.5 mgkg−1 day−1), or vehicle by gavage ( per group). Circulating EPC counts before ligation and on days 1, 3, 5, 7, 14, and 28 after AMI were measured in each group. Microvessel density, cardiac function, and cardiac remodeling were assessed 4 weeks after treatment. The signaling pathway related to EPC mobilization was also measured. Results. Circulating EPC count in amlodipine- and perindopril-treated rats peaked at day 7, to an obvious higher level than the control group peak which was reached earlier (at day 5). Rats treated with amlodipine showed improved postischemia neovascularization and cardiac function, together with reduced cardiac remodeling, decreased interstitial fibrosis, and cardiomyocyte apoptosis. Amlodipine treatment also increased cardiac SDF-1/CXCR4 expression and gave rise to activation of VEGF/Akt/eNOS signaling in bone marrow. Conclusions. Amlodipine promotes neovascularization by improving EPC mobilization from bone marrow in diabetic rats after AMI, and activation of VEGF/Akt/eNOS signaling may in part contribute to this. Jiayin Sun, Jun Xie, Lina Kang, Albert Ferro, Li Dong, and Biao Xu Copyright © 2016 Jiayin Sun et al. All rights reserved. Psoralen and Isopsoralen Ameliorate Sex Hormone Deficiency-Induced Osteoporosis in Female and Male Mice Sat, 30 Apr 2016 11:20:18 +0000 Osteoporosis is a systemic skeletal disease, which is characterized by a systemic destruction of bone mass and microarchitecture. With life standard improved, the treatment of osteoporosis attracted more attention. The aim of this study is to verify the osteoprotective effect of psoralen and isopsoralen in females and males. Female and male mice were divided into 7 groups in this study: control group (sham-operation), model group (by ovariectomy or orchidectomy), positive control group (females given estradiol valerate; males given alendronate sodium), psoralen groups (10 mg/kg and 20 mg/kg), and isopsoralen groups (10 mg/kg and 20 mg/kg). After administration of psoralen and isopsoralen for 8 weeks, osteoporosis was ameliorated with increasing bone strength and improving trabecular bone microstructure as indicated by CT scan and pathology. Serum alkaline phosphatase (ALP), tartrate resistant acid phosphatase (TRACP), osteocalcin (OC), and C-terminal cross-linking telopeptides of type I collagen (CTX-1) were examined. Decreased TRACP and increased ALP/TRACP suggested restoring from bone destruction. These results suggest that psoralen and isopsoralen may be used as good natural compounds for the treatment of osteoporosis in males, as well as females. Xiaomei Yuan, Yanan Bi, Zeman Yan, Weiling Pu, Yuhong Li, and Kun Zhou Copyright © 2016 Xiaomei Yuan et al. All rights reserved. An Interoperability Platform Enabling Reuse of Electronic Health Records for Signal Verification Studies Thu, 31 Mar 2016 17:59:48 +0000 Depending mostly on voluntarily sent spontaneous reports, pharmacovigilance studies are hampered by low quantity and quality of patient data. Our objective is to improve postmarket safety studies by enabling safety analysts to seamlessly access a wide range of EHR sources for collecting deidentified medical data sets of selected patient populations and tracing the reported incidents back to original EHRs. We have developed an ontological framework where EHR sources and target clinical research systems can continue using their own local data models, interfaces, and terminology systems, while structural interoperability and Semantic Interoperability are handled through rule-based reasoning on formal representations of different models and terminology systems maintained in the SALUS Semantic Resource Set. SALUS Common Information Model at the core of this set acts as the common mediator. We demonstrate the capabilities of our framework through one of the SALUS safety analysis tools, namely, the Case Series Characterization Tool, which have been deployed on top of regional EHR Data Warehouse of the Lombardy Region containing about 1 billion records from 16 million patients and validated by several pharmacovigilance researchers with real-life cases. The results confirm significant improvements in signal detection and evaluation compared to traditional methods with the missing background information. Mustafa Yuksel, Suat Gonul, Gokce Banu Laleci Erturkmen, Ali Anil Sinaci, Paolo Invernizzi, Sara Facchinetti, Andrea Migliavacca, Tomas Bergvall, Kristof Depraetere, and Jos De Roo Copyright © 2016 Mustafa Yuksel et al. All rights reserved. The Compound of Mangiferin-Berberine Salt Has Potent Activities in Modulating Lipid and Glucose Metabolisms in HepG2 Cells Wed, 30 Mar 2016 14:25:57 +0000 The mangiferin-berberine (MB) salt was synthesized by ionic bonding of mangiferin (M) and berberine (B) at an equal molecular ratio. This study aimed to investigate the activities of MB salt in modulating lipid and glucose metabolisms in HepG2 cells. After 24 h treatment of the studying compounds, cellular AMP-activated protein kinase α (AMPKα)/acetyl-CoA carboxylase (ACC) protein levels and carnitine palmitoyltransferase (CPT) 1 activities, intracellular lipid contents, mRNA expression levels of target genes, glucose consumption, and glucose production amounts were determined. Compound C (CC) was used in the blocking experiments. Our results showed that MB salt increased p-AMPKα (Thr172)/p-ACC (Ser79) levels and CPT1 activity and suppressed oleic acid- (OA-) induced lipid accumulation and upregulation of lipogenic genes potently in HepG2 cells. The above activities of MB salt were AMPK dependent and were superior to those of M or B when administered at an equal molar concentration. MB salt enhanced basal and insulin-stimulated glucose consumption and suppressed gluconeogenesis more potently than M or B alone. The inhibiting activity of MB salt on cellular gluconeogenesis was AMPK dependent. Our results may support MB salt as a new kind of agent for the development of novel lipid or glucose-lowering drugs in the future. Can Wang, Jian-Dong Jiang, Wei Wu, and Wei-Jia Kong Copyright © 2016 Can Wang et al. All rights reserved. Anticonvulsant and Toxicological Evaluation of Parafluorinated/Chlorinated Derivatives of 3-Hydroxy-3-ethyl-3-phenylpropionamide Wed, 24 Feb 2016 13:45:16 +0000 Although the anticonvulsant activity of 3-hydroxy-3-ethyl-3-phenylproionamide (HEPP) is well-known, its use is limited by the pharmacotoxicological profile. We herein tested its fluorinated and chlorinated derivatives (F-HEPP and Cl-HEPP) with two seizure models, maximal electroshock seizures (MES), and intraperitoneal pentylenetetrazole (PTZ) administration. Neurotoxicity was examined via the rotarod test. With in silico methods, binding was probed on possible protein targets— receptors and the sodium channel Nav1.2. The median effective doses (ED50) of HEPP, F-HEPP, and Cl-HEPP in the MES seizure model were 129.6, 87.1, and 62.0 mg/kg, respectively, and 66.4, 43.5, and in the PTZ seizure model 43.5 mg/kg. The HEPP-induced neurotoxic effect, which occurred at twice the ED50 against MES (), did not occur with F-HEPP or Cl-HEPP. Docking studies revealed that all tested ligands bound to receptors on a site near to the benzodiazepine binding site. However, on the sodium channel open pore Nav1.2, R-HEPP had interactions similar to those reported for phenytoin, while its enantiomer and the ligands F-HEPP and Cl-HEPP reached a site that could disrupt the passage of sodium. Our results show that, as anticonvulsant agents, parahalogen substituted compounds have an advantageous pharmacotoxicological profile compared to their precursor. Osvaldo Garrido-Acosta, Sergio E. Meza-Toledo, Liliana Anguiano-Robledo, Marvin A. Soriano-Ursúa, José Correa-Basurto, Asghar Davood, and Germán Chamorro-Cevallos Copyright © 2016 Osvaldo Garrido-Acosta et al. All rights reserved. Characterization and Functions of Protease-Activated Receptor 2 in Obesity, Diabetes, and Metabolic Syndrome: A Systematic Review Tue, 23 Feb 2016 14:24:21 +0000 Proteinase-activated receptor 2 (PAR2) is a cell surface receptor activated by serine proteinases or specific synthetic compounds. Interest in PAR2 as a pharmaceutical target for various diseases is increasing. Here we asked two questions relevant to endothelial dysfunction and diabetes: How is PAR2 function affected in blood vessels? What role does PAR2 have in promoting obesity, diabetes, and/or metabolic syndrome, specifically via the endothelium and adipose tissues? We conducted a systematic review of the published literature in PubMed and Scopus (July 2015; search terms: par2, par-2, f2lr1, adipose, obesity, diabetes, and metabolic syndrome). Seven studies focused on PAR2 and vascular function. The obesity, diabetes, or metabolic syndrome animal models differed amongst studies, but each reported that PAR2-mediated vasodilator actions were preserved in the face of endothelial dysfunction. The remaining studies focused on nonvascular functions and provided evidence supporting the concept that PAR2 activation promoted obesity. Key studies showed that PAR2 activation regulated cellular metabolism, and PAR2 antagonists inhibited adipose gain and metabolic dysfunction in rats. We conclude that PAR2 antagonists for treatment of obesity indeed show early promise as a therapeutic strategy; however, endothelial-specific PAR2 functions, which may offset mechanisms that produce vascular dysfunction in diabetes, warrant additional study. Satomi Kagota, Kana Maruyama, and John J. McGuire Copyright © 2016 Satomi Kagota et al. All rights reserved. Antiobesity and Antidiabetes Effects of a Cudrania tricuspidata Hydrophilic Extract Presenting PTP1B Inhibitory Potential Thu, 18 Feb 2016 11:28:46 +0000 Diabetes and obesity represent the major health problems and the most age-related metabolic diseases. Protein-tyrosine phosphatase 1B (PTP1B) has emerged as an important regulator of insulin signal transduction and is regarded as a pharmaceutical target for metabolic disorders. To find novel natural materials presenting therapeutic activities against diabetes and obesity, we screened various herb extracts using a chip screening allowing the determination of PTP1B inhibitory effects of the tested compounds using insulin receptor (IR) as the substrate. Cudrania tricuspidata leaves (CTe) had a strong inhibitory effect on PTP1B activity and substantially inhibited fat accumulation in 3T3-L1 cells. CTe was orally administrated to diet-induced obesity (DIO) mice once daily for 3 weeks after which changes in glucose, insulin metabolism, and fat accumulation were examined. Hepatic enzyme markers (aspartate aminotransferase, AST, and alanine aminotransferase, ALT) and total fat mass and triglyceride levels decreased in CTe-treated mice, whereas body weight and total cholesterol concentration slightly decreased. CTe increased the phosphorylation of IRS-1 and Akt in liver tissue. Furthermore, CTe treatment significantly lowered blood glucose levels and improved insulin secretion in DIO mice. Our results strongly suggest that CTe may represent a promising therapeutic substance against diabetes and obesity. Dae Hoon Kim, Sooung Lee, Youn Wook Chung, Byeong Mo Kim, Hanseul Kim, Kunhong Kim, and Kyung Mi Yang Copyright © 2016 Dae Hoon Kim et al. All rights reserved. Pharmacology: The Pharmacodynamics of Nutrients and Nutrient Interactions in Biological Functions Tue, 22 Dec 2015 13:12:46 +0000 M. Hasan Mohajeri, Gunter P. Eckert, James R. Pauly, and Christopher M. Butt Copyright © 2015 M. Hasan Mohajeri et al. All rights reserved. Phytochemicals in Cancer Prevention and Therapy Sun, 13 Dec 2015 10:47:36 +0000 Poyil Pratheeshkumar, Young-Ok Son, Preethi Korangath, Kanjoormana Aryan Manu, and Kodappully Sivaraman Siveen Copyright © 2015 Poyil Pratheeshkumar et al. All rights reserved. Update on Medicinal Plants with Potency on Mycobacterium ulcerans Tue, 08 Dec 2015 14:21:00 +0000 Mycobacterium ulcerans disease has been a serious threat for people living in rural remote areas. Due to poverty or availability of traditional medicine these populations rely on herbal remedies. Currently, data on the anti-Mycobacterium ulcerans activity of plants, so far considered community-based knowledge, have been scientifically confirmed, concomitantly with some medicinal plants used to treat infectious diseases in general. Products derived from plants usually responsible for the biological properties may potentially control Mycobacterium ulcerans disease; numerous studies have aimed to describe the chemical composition of these plant antimicrobials. Thus, the present work provides the first compilation of medicinal plants that demonstrated inhibitory potential on Mycobacterium ulcerans. This work shows that the natural products represent potential alternatives to standard therapies for use as curative medicine for Mycobacterium ulcerans disease. Patrick Valere Tsouh Fokou, Alexander Kwadwo Nyarko, Regina Appiah-Opong, Lauve Rachel Tchokouaha Yamthe, Mark Ofosuhene, and Fabrice Fekam Boyom Copyright © 2015 Patrick Valere Tsouh Fokou et al. All rights reserved. Impact of Clinical Pharmacy Services on KAP and QOL in Cancer Patients: A Single-Center Experience Mon, 30 Nov 2015 15:19:55 +0000 This study was to evaluate the efficacy of pharmaceutical intervention (PI) on chemotherapy knowledge-attitude-practice (KAP) and quality of life (QOL) in cancer patients. A prospective, randomized, controlled study was carried out at Oncology Ward in a tertiary hospital affiliated to Southern Medical University, China. Eligible patient was randomly assigned to pharmaceutical intervention (PI) group or control group. Each patient in PI group was given information booklets and was given 30 min face-to-face medication education and psychological counseling by clinical pharmacists, 2 sessions per week for 2 months. Patients in control group only received conventional treatment. All participants were asked to complete a structured Chemotherapy KAP Questionnaire and QOL Questionnaire at pre- and poststudy time. A total of 149 cancer patients (77 in PI group and 72 in control group) completed the study. The baseline scores of KAP and QOL in 2 groups were similar. At the end of study, only knowledge score was significantly increased; meanwhile no difference existed for attitude, practice, and QOL scores in control group; both KAP scores and QOL score were significantly increased in PI group. As for the between-group comparison, both KAP scores and QOL score in PI group were significantly higher than those in control group. In conclusion, pharmaceutical intervention has a positive role in increasing chemotherapy-related knowledge, improving patients’ positive emotions, dealing with chemotherapy adverse reactions, and improving the quality of life of patients. Yan Wang, Huimin Wu, and Feng Xu Copyright © 2015 Yan Wang et al. All rights reserved. Hypoglycemic and Antidiabetic Effect of Pleurotus sajor-caju Aqueous Extract in Normal and Streptozotocin-Induced Diabetic Rats Mon, 23 Nov 2015 16:02:41 +0000 Introduction. Pleurotus sajor-caju (PSC) is an edible oyster mushroom featuring high nutritional values and pharmacological properties. Objective. To investigate the hypoglycemic and antidiabetic effects of single and repeated oral administration of PSC aqueous extract in normal and diabetic rats. Materials and Methods. A single dose of 500, 750, or 1000 mg/kg of the PSC extract was given to experimental rats to determine the effects on blood glucose (BG) and oral glucose tolerance test (OGTT). The effective dose (750 mg/kg) of PSC extract was repeatedly administrated daily for 21 days in diabetic rats to examine its antidiabetic effects in terms of BG control, body weight, urine sugar, HbA1c, and several serum profiles. Results. The dose of 750 mg/kg showed the most significant BG reduction (23.5%) in normal rats 6 hours after administration in BG study (). In OGTT study, the same dose produced a maximum BG fall of 41.3% in normal rats and 36.5% in diabetic rats 3 hours after glucose administration. In 21-day study, treated diabetic rats showed significant improvement in terms of fasting BG, body weight, and urine sugar as compared to control diabetic rats. Conclusion. The study evidenced scientifically the beneficial use of PSC as an alternative medicine in diabetes management. Sze Han Ng, Mohd Shazwan Mohd Zain, Fatariah Zakaria, Wan Rosli Wan Ishak, and Wan Amir Nizam Wan Ahmad Copyright © 2015 Sze Han Ng et al. All rights reserved. Effects of Shared Electronic Health Record Systems on Drug-Drug Interaction and Duplication Warning Detection Sun, 22 Nov 2015 12:18:25 +0000 Shared electronic health records (EHRs) systems can offer a complete medication overview of the prescriptions of different health care providers. We use health claims data of more than 1 million Austrians in 2006 and 2007 with 27 million prescriptions to estimate the effect of shared EHR systems on drug-drug interaction (DDI) and duplication warnings detection and prevention. The Austria Codex and the ATC/DDD information were used as a knowledge base to detect possible DDIs. DDIs are categorized as severe, moderate, and minor interactions. In comparison to the current situation where only DDIs between drugs issued by a single health care provider can be checked, the number of warnings increases significantly if all drugs of a patient are checked: severe DDI warnings would be detected for 20% more persons, and the number of severe DDI warnings and duplication warnings would increase by 17%. We show that not only do shared EHR systems help to detect more patients with warnings but DDIs are also detected more frequently. Patient safety can be increased using shared EHR systems. Christoph Rinner, Wilfried Grossmann, Simone Katja Sauter, Michael Wolzt, and Walter Gall Copyright © 2015 Christoph Rinner et al. All rights reserved. Overcoming Multidrug Resistance in Cancer Stem Cells Mon, 16 Nov 2015 11:47:59 +0000 The principle mechanism of protection of stem cells is through the expression of ATP-binding cassette (ABC) transporters. These transporters serve as the guardians of the stem cell population in the body. Unfortunately these very same ABC efflux pumps afford protection to cancer stem cells in tumors, shielding them from the adverse effects of chemotherapy. A number of strategies to circumvent the function of these transporters in cancer stem cells are currently under investigation. These strategies include the development of competitive and allosteric modulators, nanoparticle mediated delivery of inhibitors, targeted transcriptional regulation of ABC transporters, miRNA mediated inhibition, and targeting of signaling pathways that modulate ABC transporters. The role of ABC transporters in cancer stem cells will be explored in this paper and strategies aimed at overcoming drug resistance caused by these particular transporters will also be discussed. Karobi Moitra Copyright © 2015 Karobi Moitra. All rights reserved. Black Rice Anthocyanins Suppress Metastasis of Breast Cancer Cells by Targeting RAS/RAF/MAPK Pathway Mon, 16 Nov 2015 06:40:06 +0000 Overexpression of human epidermal growth factor receptor 2 (HER2) drives the biology of 30% of breast cancer cases. As a transducer of HER2 signaling, RAS/RAF/MAPK pathway plays a pivotal role in the development of breast cancer. In this study, we examined the molecular mechanisms underlying the chemopreventive effects of black rice anthocyanins (BRACs) extract and identified their molecular targets in HER2+ breast cancer cells. Treatment of MDA-MB-453 cells (HER2+) with BRACs inhibited cell migration and invasion, suppressed the activation of mitogen-activated protein kinase kinase kinase (RAF), mitogen-activated protein kinase kinase (MEK), and c-Jun N-terminal kinase (JNK), and downregulated the secretion of matrix metalloproteinase 2 (MMP2) and MMP9. BRACs also weakened the interactions of HER2 with RAF, MEK, and JNK proteins, respectively, and decreased the mRNA expression of raf, mek, and jnk. Further, we found combined treatment with BRACs and RAF, MEK, or JNK inhibitors could enhance the antimetastatic activity, compared with that of each treatment. Transient transfection with small interfering RNAs (siRNAs) specific for raf, mek, and jnk inhibited their mRNA expression in MDA-MB-453 cells. Moreover, cotreatment with BRACs and siRNA induces a more remarkable inhibitory effect than that by either substance alone. In summary, our study suggested that BRACs suppress metastasis in breast cancer cells by targeting the RAS/RAF/MAPK pathway. Xiang-Yan Chen, Jie Zhou, Li-Ping Luo, Bin Han, Fei Li, Jing-Yao Chen, Yan-Feng Zhu, Wei Chen, and Xiao-Ping Yu Copyright © 2015 Xiang-Yan Chen et al. All rights reserved. Protective Effect of Enalapril against Methionine-Enriched Diet-Induced Hypertension: Role of Endoplasmic Reticulum and Oxidative Stress Thu, 12 Nov 2015 06:22:52 +0000 In the present study, we investigated the effect of methionine-enriched diet (MED) on blood pressure in rats and examined the protective effect of enalapril, a widely used angiotensin converting enzyme inhibitors (ACEi) class antihypertensive drug. The results showed that MED induced significant increase of SBP and Ang II-induced contractile response in aortae of rats. MED significantly increased plasma levels of homocysteine (Hcy) and ACE. In addition, MED increased the phosphorylation of protein kinase R-like endoplasmic reticulum kinase (PERK) and eukaryotic initiation factor 2 (eIF2α) and expression of activating transcription factor 3 (ATF3) and ATF6 in aortae of rats, indicating the occurrence of endoplasmic reticulum (ER) stress. Moreover, MED resulted in oxidative stress as evidenced by significant increase of TBARS level and decrease of superoxide dismutase and catalase activities. Administration of enalapril could effectively inhibit these pathological changes induced by MED in rats. These results demonstrated that ACE-mediated ER stress and oxidative stress played an important role in high Hcy-induced hypertension and MED may exert a positive loop between the activation of ACE and accumulation of Hcy, aggravating the pathological condition of hypertension. The data provide novel insights into the mechanism of high Hcy-associated hypertension and the therapeutic efficiency of enalapril. Yanfen Zhou, Lianyou Zhao, Zhimin Zhang, and Xuanhao Lu Copyright © 2015 Yanfen Zhou et al. All rights reserved. Following “the Roots” of Kratom (Mitragyna speciosa): The Evolution of an Enhancer from a Traditional Use to Increase Work and Productivity in Southeast Asia to a Recreational Psychoactive Drug in Western Countries Tue, 10 Nov 2015 14:05:50 +0000 The use of substances to enhance human abilities is a constant and cross-cultural feature in the evolution of humanity. Although much has changed over time, the availability on the Internet, often supported by misleading marketing strategies, has made their use even more likely and risky. This paper will explore the case of Mitragyna speciosa Korth. (kratom), a tropical tree used traditionally to combat fatigue and improve work productivity among farm populations in Southeast Asia, which has recently become popular as novel psychoactive substance in Western countries. Specifically, it (i) reviews the state of the art on kratom pharmacology and identification; (ii) provides a comprehensive overview of kratom use cross-culturally; (iii) explores the subjective experiences of users; (iv) identifies potential risks and side-effects related to its consumption. Finally, it concludes that the use of kratom is not negligible, especially for self-medication, and more clinical, pharmacological, and socioanthropological studies as well as a better international collaboration are needed to tackle this marginally explored phenomenon. Eduardo Cinosi, Giovanni Martinotti, Pierluigi Simonato, Darshan Singh, Zsolt Demetrovics, Andres Roman-Urrestarazu, Francesco Saverio Bersani, Balasingam Vicknasingam, Giulia Piazzon, Jih-Heng Li, Wen-Jing Yu, Máté Kapitány-Fövény, Judit Farkas, Massimo Di Giannantonio, and Ornella Corazza Copyright © 2015 Eduardo Cinosi et al. All rights reserved. Mechanistic Studies on the Use of Polygonum multiflorum for the Treatment of Hair Graying Tue, 10 Nov 2015 13:51:08 +0000 Polygonum multiflorum is a traditional Chinese medicine with a long history in hair growth promotion and hair blackening. The purpose of the study was to examine the effect and the mechanism of Polygonum multiflorum in hair blackening. C57BL/6 mice hair fade was induced with H2O2 and used in this research. Hair pigmentogenesis promotion activities of Polygonum Multiflorum Radix (PMR, raw crude drug), Polygonum Multiflorum Radix Preparata (PMRP, processed crude drug), and their major chemical constituent TSG were investigated. The regulation effects of several cytokines and enzymes such as POMC, α-MSH, MC1R, ASIP, MITF, TYR, TRP-1, and TRP-2 were investigated. PMR group gave out the most outstanding black hair among all groups with the highest contents of total melanin, α-MSH, MC1R, and TYR. Promotion of hair pigmentogenesis was slightly decreased after processing in the PMRP group. TSG as the major constituent of PMR showed weaker hair color regulation effects than both PMR and PMRP. PMR, but not PMRP, should be used to blacken hair. The α-MSH, MC1R, and TYR were the major targets in the medicinal use of PMR in hair graying. Chemical constituents other than TSG may contribute to the hair color regulation activity of PMR. Ming-Nuan Han, Jian-Mei Lu, Guang-Yuan Zhang, Jie Yu, and Rong-Hua Zhao Copyright © 2015 Ming-Nuan Han et al. All rights reserved. Vitamin E Supplementation Delays Cellular Senescence In Vitro Tue, 03 Nov 2015 07:51:07 +0000 Vitamin E is an important antioxidant that protects cells from oxidative stress-induced damage, which is an important contributor to the progression of ageing. Ageing can be studied in vitro using primary cells reaching a state of irreversible growth arrest called senescence after a limited number of cellular divisions. Generally, the most utilized biomarker of senescence is represented by the expression of the senescence associated β-galactosidase (SA-β-gal). We aimed here to study the possible effects of vitamin E supplementation in two different human primary cell types (HUVECs and fibroblasts) during the progression of cellular senescence. Utilizing an unbiased automated system, based on the detection of the SA-β-gal, we quantified cellular senescence in vitro and showed that vitamin E supplementation reduced the numbers of senescent cells during progression of ageing. Acute vitamin E supplementation did not affect cellular proliferation, whereas it was decreased after chronic treatment. Mechanistically, we show that vitamin E supplementation acts through downregulation of the expression of the cycline dependent kinase inhibitor P21. The data obtained from this study support the antiageing properties of vitamin E and identify possible mechanisms of action that warrant further investigation. Giorgio La Fata, Nicole Seifert, Peter Weber, and M. Hasan Mohajeri Copyright © 2015 Giorgio La Fata et al. All rights reserved. Intake of Meals Containing High Levels of Carbohydrates or High Levels of Unsaturated Fatty Acids Induces Postprandial Dysmetabolism in Young Overweight/Obese Men Mon, 02 Nov 2015 06:51:41 +0000 Postprandial metabolic response depends on the meals’ components and can be different in normal weight and obese people. However, there are some discrepancies between various reports. The aim of this study was to determine the metabolic response after intake of standardised meals with various fat and carbohydrate contents and to determine the differences among normal weight and overweight/obese individuals. The study group comprised 46 healthy men. The participants were divided into two groups and study was carried out using a crossover method. Group I received high- and normal-carbohydrate meals, whereas group II received high-carbohydrate and high-fat meals. Glucose, insulin, triglyceride, and free fatty acids levels were measured at fasting state and at 30, 60, 120, 180, and 240 minutes after meal intake. Despite the lack of differences in glucose levels, insulin levels were higher among overweight/obese individuals after each meal. TG and FFA levels were higher after normal-carbohydrate and high-fat meals. Moreover, in overweight/obese young men after high-fat meal intake postprandial hypertriglyceridemia was observed, even if meals contained predominantly unsaturated fatty acids, and fasting triglycerides levels were in normal range. The conducted study showed that postprandial metabolic response depends not only on the meal macronutrient content but also on the current body mass index (BMI). Edyta Adamska, Lucyna Ostrowska, Joanna Gościk, Magdalena Waszczeniuk, Adam Krętowski, and Maria Górska Copyright © 2015 Edyta Adamska et al. All rights reserved. Coevolution between Cancer Activities and Food Structure of Human Being from Southwest China Sun, 01 Nov 2015 09:35:54 +0000 Yunnan and Tibet are the lowest cancer mortality and the largest producer for anticancer crops (brown rice, barley, buckwheat, tea, walnut, mushrooms, and so forth). Shanghai and Jiangsu province in China have the highest mortality of cancers, which are associated with the sharp decline of barley. Yawen Zeng, Juan Du, Xiaoying Pu, Jiazhen Yang, Tao Yang, Shuming Yang, and Xiaomeng Yang Copyright © 2015 Yawen Zeng et al. All rights reserved. Influence of Sorghum Kafirin on Serum Lipid Profile and Antioxidant Activity in Hyperlipidemic Rats (In Vitro and In Vivo Studies) Mon, 26 Oct 2015 12:51:28 +0000 The aim of this study was to compare in vitro the antioxidant potential of sorghum kafirin and sorghum flour and their influence on lipids and antioxidant capacity in rats. The antioxidant activity in sorghum kafirin extract measured by the DPPH and TEAC methods was increased 30 and 65 times, respectively, compared to that of its counterpart, sorghum flour. According to electrophoresis assay, the kafirins tert-butanol extract showed a high proportion of α-kafirin monomers, and its amino acid composition revealed higher hydrophobic amino acid content such as alanine, isoleucine, leucine, tyrosine and phenylalanine than sorghum flour extract. Diets supplemented with sorghum kafirin extract have improved lipid metabolism and increased the serum antioxidant potential (67%) especially in rats fed with added cholesterol. The bioactive peptides generated from kafirin in vivo hydrolysis appear to be associated with the positive effect on serum lipids and antioxidant activity. According to these results, sorghum kafirin extract at the levels used in this study apparently could be used for prevention of atherosclerosis and other chronic diseases. Raquel A. Ortíz Cruz, José L. Cárdenas López, Gustavo A. González Aguilar, Humberto Astiazarán García, Shela Gorinstein, Rafael Canett Romero, and Maribel Robles Sánchez Copyright © 2015 Raquel A. Ortíz Cruz et al. All rights reserved. Corrigendum to “Sensitization of Cancer Cells through Reduction of Total Akt and Downregulation of Salinomycin-Induced pAkt, pGSk3β, pTSC2, and p4EBP1 by Cotreatment with MK-2206” Wed, 21 Oct 2015 11:22:20 +0000 Ae-Ran Choi, Ju-Hwa Kim, and Sungpil Yoon Copyright © 2015 Ae-Ran Choi et al. All rights reserved. Systematic Review of the Use of Phytochemicals for Management of Pain in Cancer Therapy Tue, 20 Oct 2015 13:11:07 +0000 Pain in cancer therapy is a common condition and there is a need for new options in therapeutic management. While phytochemicals have been proposed as one pain management solution, knowledge of their utility is limited. The objective of this study was to perform a systematic review of the biomedical literature for the use of phytochemicals for management of cancer therapy pain in human subjects. Of an initial database search of 1,603 abstracts, 32 full-text articles were eligible for further assessment. Only 7 of these articles met all inclusion criteria for this systematic review. The average relative risk of phytochemical versus control was 1.03 [95% CI 0.59 to 2.06]. In other words (although not statistically significant), patients treated with phytochemicals were slightly more likely than patients treated with control to obtain successful management of pain in cancer therapy. We identified a lack of quality research literature on this subject and thus were unable to demonstrate a clear therapeutic benefit for either general or specific use of phytochemicals in the management of cancer pain. This lack of data is especially apparent for psychotropic phytochemicals, such as the Cannabis plant (marijuana). Additional implications of our findings are also explored. Andrew M. Harrison, Fabrice Heritier, Bennett G. Childs, J. Michael Bostwick, and Mikhail A. Dziadzko Copyright © 2015 Andrew M. Harrison et al. All rights reserved. Medications and Nutritional Supplements in Athletes during the 2000, 2004, 2008, and 2012 FIFA Futsal World Cups Tue, 20 Oct 2015 11:23:05 +0000 Objective. To examine the use of medications and nutritional supplements among top-level male futsal players during international tournaments. Materials and Methods. This retrospective survey of the four consecutive 2000 to 2012 FIFA (Fédération Internationale de Football Association) Futsal World Cup tournaments analyzes data about the use of medications and nutritional supplements by each player prior to every match. A total of 5264 reports on 1064 futsal players were collected from the 188 matches played. Results. A total of 4237 medications and 8494 nutritional supplements (0.8 and 1.6 per player per match, resp.) were prescribed, and 64% of the players used at least one type of medication over the four tournaments. The most frequently prescribed medication was nonsteroidal anti-inflammatory drugs (NSAIDs) (41.1%), whereby 45.7% of all players consumed at least one NSAID during the tournament and 27.4% did so prior to every match. Conclusions. The intake of medications, particularly of NSAIDs, is frequently high among top-level futsal players and follows a similar pattern to that found in FIFA Football World Cups. Campaigns should be instituted to understand this prescription practice by team physicians involving professional football players, with the aim to decrease its use and to prevent athletes from potential short- and long-term risks. André Pedrinelli, Leandro Ejnisman, Lorenzo Fagotti, Jiri Dvorak, and Philippe M. Tscholl Copyright © 2015 André Pedrinelli et al. All rights reserved. Antiproliferative and Antiestrogenic Activities of Bonediol an Alkyl Catechol from Bonellia macrocarpa Sun, 18 Oct 2015 14:43:46 +0000 The purpose of this study was to investigate antiproliferative activity of bonediol, an alkyl catechol isolated from the Mayan medicinal plant Bonellia macrocarpa. Bonediol was assessed for growth inhibition of androgen-sensitive (LNCaP), androgen-insensitive (PC-3), and metastatic androgen-insensitive (PC-3M) human prostate tumor cells; toxicity on normal cell line (HEK 293) was also evaluated. Hedgehog pathway was evaluated and competitive 3H-estradiol ligand binding assay was performed. Additionally, antioxidant activity on Nrf2-ARE pathway was evaluated. Bonediol induced a growth inhibition on prostate cancer cell lines (IC50 from 8.5 to 20.6 µM). Interestingly, bonediol binds to both estrogen receptors (ERα (2.5 µM) and ERβ (2.1 µM)) and displaces the native ligand E2 (17β-estradiol). No significant activity was found in the Hedgehog pathway. Additionally, activity of bonediol on Nrf2-ARE pathway suggested that bonediol could induce oxidative stress and activation of detoxification enzymes at 1 µM (3.8-fold). We propose that the compound bonediol may serve as a potential chemopreventive treatment with therapeutic potential against prostate cancer. Rosa Moo-Puc, Edgar Caamal-Fuentes, Sergio R. Peraza-Sánchez, Anna Slusarz, Glenn Jackson, Sara K. Drenkhahn, and Dennis B. Lubahn Copyright © 2015 Rosa Moo-Puc et al. All rights reserved. PLK-1 Targeted Inhibitors and Their Potential against Tumorigenesis Sun, 18 Oct 2015 12:52:24 +0000 Mitotic kinases are the key components of the cell cycle machinery and play vital roles in cell cycle progression. PLK-1 (Polo-like kinase-1) is a crucial mitotic protein kinase that plays an essential role in both the onset of G2/M transition and cytokinesis. The overexpression of PLK-1 is strongly correlated with a wide spectrum of human cancers and poor prognosis. The (si)RNA-mediated depletion of PLK-1 arrests tumor growth and triggers apoptosis in cancer cells without affecting normal cells. Therefore, PLK-1 has been selected as an attractive anticancer therapeutic drug target. Some small molecules have been discovered to target the catalytic and noncatalytic domains of PLK-1. These domains regulate the catalytic activation and subcellular localization of PLK-1. However, while PLK-1 inhibitors block tumor growth, they have been shown to cause severe adverse complications, such as toxicity, neutropenia, and bone marrow suppression during clinical trials, due to a lack of selectivity and specificity within the human kinome. To minimize these toxicities, inhibitors should be tested against all protein kinases in vivo and in vitro to enhance selectivity and specificity against targets. Here, we discuss the potency and selectivity of PLK-1-targeted inhibitors and their molecular interactions with PLK-1 domains. Shiv Kumar and Jaebong Kim Copyright © 2015 Shiv Kumar and Jaebong Kim. All rights reserved. Curcumin Enhanced Busulfan-Induced Apoptosis through Downregulating the Expression of Survivin in Leukemia Stem-Like KG1a Cells Sun, 18 Oct 2015 12:17:55 +0000 Leukemia relapse and nonrecurrence mortality (NRM) due to leukemia stem cells (LSCs) represent major problems following hematopoietic stem cell transplantation (HSCT). To eliminate LSCs, the sensitivity of LSCs to chemotherapeutic agents used in conditioning regimens should be enhanced. Curcumin (CUR) has received considerable attention as a result of its anticancer activity in leukemia and solid tumors. In this study, we investigated the cytotoxic effects and underlying mechanisms in leukemia stem-like KG1a cells exposed to busulfan (BUS) and CUR, either alone or in combination. KG1a cells exhibiting BUS-resistance demonstrated by MTT and annexin V/propidium iodide (PI) assays, compared with HL-60 cells. CUR induced cell growth inhibition and apoptosis in KG1a cells. Apoptosis of KG1a cells was significantly enhanced by treatment with CUR+BUS, compared with either agent alone. CUR synergistically enhanced the cytotoxic effect of BUS. Seven apoptosis-related proteins were modulated in CUR- and CUR+BUS-treated cells analyzed by proteins array analysis. Importantly, the antiapoptosis protein survivin was significantly downregulated, especially in combination group. Suppression of survivin with specific inhibitor YM155 significantly increased the susceptibility of KG1a cells to BUS. These results demonstrated that CUR could increase the sensitivity of leukemia stem-like KG1a cells to BUS by downregulating the expression of survivin. Guangyang Weng, Yingjian Zeng, Jingya Huang, Jiaxin Fan, and Kunyuan Guo Copyright © 2015 Guangyang Weng et al. All rights reserved. Effect and Mechanism of Total Flavonoids Extracted from Cotinus coggygria against Glioblastoma Cancer In Vitro and In Vivo Sun, 18 Oct 2015 12:17:52 +0000 Flavonoids, a major constituent of Cotinus coggygria (CC), have been reported to possess diverse biological activities, including antigenotoxic and hepatoprotective effects; however, few studies have investigated the biological activity of the total flavonoids of Cotinus coggygria, especially in terms of its cytotoxicity in cancer cells. In the present study, the Cotinus coggygria flavonoids (CCF) were extracted from Cotinus coggygria and characterized by HPLC. These results indicated that CCF extracts could inhibit cell proliferation, with IC50 values of 128.49 µg/mL (U87), 107.62 µg/mL (U251), and 93.57 µg/mL (DBTRG-05MG). The current investigation also revealed that CCF induced apoptosis in highly malignant glioblastoma cells, a process that apparently involved the inhibition of Akt coupled with ERK protein expression. This finding suggests that the PI3K/Akt-ERK signaling pathway is regulated by CCF and leads to the inhibition of the glioblastoma cancer cells. Furthermore, a significant antitumor effect of CCF was observed in xenograft animal models of glioblastoma multiforme in vivo. Taken together, these data suggest that CCF is the active component in the Cotinus coggygria plant that offers potential therapeutic modality in the abrogation of cancer cell proliferation, including the induction of apoptosis. Gang Wang, JunJie Wang, Li Du, and Fei Li Copyright © 2015 Gang Wang et al. All rights reserved. Antiproliferative Activity of T. welwitschii Extract on Jurkat T Cells In Vitro Sun, 18 Oct 2015 12:17:22 +0000 Triumfetta welwitschii is a plant used traditionally for the treatment of fever and diarrhoea. Previous work has shown that T. welwitschii has antibacterial activity. The purpose of this study was to investigate T. welwitschii extract for anticancer activity against Jurkat T cells. The Jurkat T cell line is used to study acute T cell leukaemia. An antiproliferation assay, determination of induction of apoptosis, the determination of the effect of the combination of the extract and GSH, and effects of the extract on DNA leakage were conducted. T. welwitschii was found to decrease cell viability in a dose- and time-dependent manner. T. welwitschii caused apoptosis in the Jurkat T cells as shown by DNA fragmentation. When T. welwitschii was combined with reduced GSH, it was found that the growth of the Jurkat T cells was significantly reduced compared to untreated cells after 72 h of treatment. This was unexpected, as cancer cells have elevated levels of GSH compared to normal cells. The results of this study show that T. welwitschii is a potential source of compounds that may serve as leads for anticancer compounds. Batanai Moyo and Stanley Mukanganyama Copyright © 2015 Batanai Moyo and Stanley Mukanganyama. All rights reserved. The Ethanolic Extract of Taiwanofungus camphoratus (Antrodia camphorata) Induces Cell Cycle Arrest and Enhances Cytotoxicity of Cisplatin and Doxorubicin on Human Hepatocellular Carcinoma Cells Sun, 18 Oct 2015 12:16:47 +0000 Taiwanofungus camphoratus (synonym Antrodia camphorata) is a widely used medicinal fungus in the folk medicine of Taiwan with several pharmacological features such as anti-inflammatory, liver protection, antihypertensive, and antioxidative activities. The ethanolic extract of T. camphoratus (TCEE) which contains abundant bioactive compounds including triterpenoids and polysaccharides also has antitumor effects in various human cancer cell lines. The aims of this study are to clarify the antitumor effects of TCEE on human hepatocellular carcinoma cells and also evaluate the combination drug effects with conventional chemotherapy agents, cisplatin and doxorubicin. In the present study, the TCEE treatment induced cell cycle arrest and suppressed cell growth on both Hep3B and HepJ5 cells. Expression of cell cycle inhibitors, P21 and P27, and activation of apoptosis executer enzyme, caspase-3, were also induced by TCEE. In combination with the chemotherapy agents, TCEE treatment further enhanced the tumor suppression efficiency of cisplatin and doxorubicin. These results together suggested that TCEE is a potential ingredient for developing an integrated chemotherapy for human liver cancer. Liang-Tzung Lin, Chen-Jei Tai, Ching-Hua Su, Fang-Mo Chang, Chen-Yen Choong, Chien-Kai Wang, and Cheng-Jeng Tai Copyright © 2015 Liang-Tzung Lin et al. All rights reserved. Garcinia dulcis Fruit Extract Induced Cytotoxicity and Apoptosis in HepG2 Liver Cancer Cell Line Sun, 18 Oct 2015 12:07:46 +0000 Garcinia dulcis or locally known in Malaysia as “mundu” belongs to the family of Clusiaceae. The study was conducted to investigate the anticancer potential of different parts of G. dulcis fruit extracts and their possible mechanism of action in HepG2 liver cancer cell line. MTT assay showed that the peel, flesh, and seed extracts of G. dulcis induced cytotoxicity in HepG2 cell line with IC50 values of 46.33 ± 4.51, 38.33 ± 3.51, and 7.5 ± 2.52 µg/mL, respectively. The flesh extract of G. dulcis induced cell cycle arrest at sub-G1 (apoptosis) phase in a time-dependent manner. Staining with Annexin V-FITC and propidium iodide showed that 41.2% of the cell population underwent apoptosis after 72 hours of exposure of the HepG2 cell line to G. dulcis flesh extract. Caspase-3 has been shown to be activated which finally leads to the death of HepG2 cell (apoptosis). GC-MS analysis showed that the highest percentage of compound identified in the extract of G. dulcis flesh was hydroxymethylfurfural and 3-methyl-2,5-furandione, together with xanthones and flavonoids (based on literature), could synergistically contribute to the observed effects. This finding suggested that the flesh extract of G. dulcis has its own potential as cancer chemotherapeutic agent against liver cancer cell. Mohd Fadzelly Abu Bakar, Nor Ezani Ahmad, Monica Suleiman, Asmah Rahmat, and Azizul Isha Copyright © 2015 Mohd Fadzelly Abu Bakar et al. All rights reserved. HPTLC Analysis of Bioactivity Guided Anticancer Enriched Fraction of Hydroalcoholic Extract of Picrorhiza kurroa Sun, 18 Oct 2015 11:50:35 +0000 Objective. Hydroalcoholic extract of Picrorhiza kurroa and its fractions were subjected to in vitro screening for cytotoxicity; further best active fraction (BAF) obtained was tested against Ehrlich ascites carcinoma (EAC) model in Balb/c mice after its quality control analysis. Methods. Cytotoxicities of all the fractions and mother extract of P. kurroa were determined, using MTT assay on breast cancer (MCF-7, MDA-MB 231) and cervical cancer (HeLa, SiHa) cell lines. Metabolic fingerprinting was developed using HPTLC with quantification of biomarkers (cucurbitacins B and E; betulinic acid; picrosides 1 and 2; and apocynin) in BAF. The EAC tumor-bearing mice were used for in vivo anticancer activity after oral administration (50 mg Kg−1) for 10 days. Results. Cytotoxicity assay of mother extract and its fractions over breast cancer and cervix cancer cell lines showed that dichloromethane (DCM) fraction was most cytotoxic (IC50 36.0–51.0 µg mL−1 at 72 h). Oral administration of DCM fraction showed significant reduction in tumor regression parameters, viable tumor cell count and restoration of hematological parameters may be due to presence of cucurbitacins B and E; betulinic acid; picrosides 1 and 2; and apocynin, as compared to the untreated mice of the control group. Conclusion. The DCM fraction of P. kurroa displayed potent anticancer activity and can be further explored for the development of a potential candidate for cancer therapy. Md. Nasar Mallick, Mhaveer Singh, Rabea Parveen, Washim Khan, Sayeed Ahmad, Mohammad Zeeshan Najm, and Syed Akhtar Husain Copyright © 2015 Md. Nasar Mallick et al. All rights reserved. Improving Performance of Clinical Research: Development and Interest of Electronic Health Records Mon, 12 Oct 2015 12:43:58 +0000 Ariel Beresniak, Andreas Schmidt, Danielle Dupont, Mats Sundgren, Dipak Kalra, and Georges J. E. De Moor Copyright © 2015 Ariel Beresniak et al. All rights reserved. Acute Effects of the Novel Psychoactive Drug 2C-B on Emotions Mon, 12 Oct 2015 11:55:01 +0000 Background. 2C-B (Nexus) is one of the most widespread novel psychoactive substances. There is limited information about its pharmacological properties, and few studies in humans concern its acute and chronic effects. 2C-B has been classified as a stimulant, hallucinogen, entactogen, and/or empathogen. Objectives. To evaluate the emotional, subjective, and cardiovascular effects of 2C-B. Methods. Twenty healthy recreational 2C-B users (12 women) self-administered a 20 mg dose of 2C-B. Evaluations included emotional (IAPS, FERT, and speech), subjective (visual analog scales, ARCI, VESSPA, HRS, and POMS questionnaires), and cardiovascular effects (blood pressure and heart rate). Results. Positive subjective effects predominated with a reduction of anger under the influence of 2C-B. It did, however, increase reactivity to negative emotional stimuli and decrease the ability to recognize expressions of happiness. Augmented emotionality in speech could be appreciated by others. 2C-B induced euphoria and well-being, changes in perceptions, and slight hallucinogenic states. Mild sympathetic actions were observed. Conclusions. The specific profile that 2C-B exerts on emotions suggests its classification as an entactogen with psychedelic properties. Débora González, Marta Torrens, and Magí Farré Copyright © 2015 Débora González et al. All rights reserved. Postmarketing Safety Study Tool: A Web Based, Dynamic, and Interoperable System for Postmarketing Drug Surveillance Studies Mon, 12 Oct 2015 10:02:48 +0000 Postmarketing drug surveillance is a crucial aspect of the clinical research activities in pharmacovigilance and pharmacoepidemiology. Successful utilization of available Electronic Health Record (EHR) data can complement and strengthen postmarketing safety studies. In terms of the secondary use of EHRs, access and analysis of patient data across different domains are a critical factor; we address this data interoperability problem between EHR systems and clinical research systems in this paper. We demonstrate that this problem can be solved in an upper level with the use of common data elements in a standardized fashion so that clinical researchers can work with different EHR systems independently of the underlying information model. Postmarketing Safety Study Tool lets the clinical researchers extract data from different EHR systems by designing data collection set schemas through common data elements. The tool interacts with a semantic metadata registry through IHE data element exchange profile. Postmarketing Safety Study Tool and its supporting components have been implemented and deployed on the central data warehouse of the Lombardy region, Italy, which contains anonymized records of about 16 million patients with over 10-year longitudinal data on average. Clinical researchers in Roche validate the tool with real life use cases. A. Anil Sinaci, Gokce B. Laleci Erturkmen, Suat Gonul, Mustafa Yuksel, Paolo Invernizzi, Bharat Thakrar, Anil Pacaci, H. Alper Cinar, and Nihan Kesim Cicekli Copyright © 2015 A. Anil Sinaci et al. All rights reserved. Analysis of Requirements for the Medication Profile to Be Used in Clinical Research: Protocol Feasibility Studies and Patient Recruitment Sun, 11 Oct 2015 14:08:15 +0000 A “Medication Profile,” the information about the medicines a person is using and has used, is a core part of many electronic health record systems and summaries. However, there is little objective research into the data elements that the profile should contain to support the uses it must serve. With the increasing emphasis on secondary uses of electronic health information, as well as supporting the requirements to support direct to patient care, the Medication Profile should also support the requirements from clinical research. However, there is little, if any, description of these available. This paper describes an analysis of a set of study eligibility criteria that was undertaken to investigate which medication-related data elements would be required to support two clinical research use cases: the parameters to query a patient’s Medication Profile to assess their suitability for entry into a trial (patient recruitment) and the parameters to query a set of Medication Profiles in a data warehouse to assess whether the eligibility criteria as described would yield a reasonable cohort of patients as potential subjects (protocol feasibility). These medication-related data elements then become information requirements that a Medication Profile should ideally meet, in order to be able to support these two uses in the clinical research domain. Julie M. James, Dipak Kalra, and Jane Portlock Copyright © 2015 Julie M. James et al. All rights reserved. Using Electronic Health Records to Support Clinical Trials: A Report on Stakeholder Engagement for EHR4CR Sun, 11 Oct 2015 13:42:38 +0000 Background. The conduct of clinical trials is increasingly challenging due to greater complexity and governance requirements as well as difficulties with recruitment and retention. Electronic Health Records for Clinical Research (EHR4CR) aims at improving the conduct of trials by using existing routinely collected data, but little is known about stakeholder views on data availability, information governance, and acceptable working practices. Methods. Senior figures in healthcare organisations across Europe were provided with a description of the project and structured interviews were subsequently conducted to elicit their views. Results. 37 structured interviewees in Germany, UK, Switzerland, and France indicated strong support for the proposed EHR4CR platform. All interviewees reported that using the platform for assessing feasibility would enhance the conduct of clinical trials and the majority also felt it would reduce workloads. Interviewees felt the platform could enhance trial recruitment and adverse event reporting but also felt it could raise either ethical or information governance concerns in their country. Conclusions. There was clear support for EHR4CR and a belief that it could reduce workloads and improve the conduct and quality of trials. However data security, privacy, and information governance issues would need to be carefully managed in the development of the platform. Colin McCowan, Elizabeth Thomson, Cezary A. Szmigielski, Dipak Kalra, Frank M. Sullivan, Hans-Ulrich Prokosch, Martin Dugas, and Ian Ford Copyright © 2015 Colin McCowan et al. All rights reserved. Antidepressant-Like Effect of the Leaves of Pseudospondias microcarpa in Mice: Evidence for the Involvement of the Serotoninergic System, NMDA Receptor Complex, and Nitric Oxide Pathway Sun, 11 Oct 2015 12:42:31 +0000 Depression continues to be a major global health problem. Although antidepressants are used for its treatment, efficacy is often inconsistent. Thus, the search for alternative therapeutic medicines for its treatment is still important. In this study, the antidepressant-like effect of Pseudospondias microcarpa extract (30–300 mg kg−1, p.o.) was investigated in two predictive models of depression—forced swimming test and tail suspension test in mice. Additionally, the mechanism(s) of action involved were assessed. Acute treatment with the extract dose dependently reduced immobility of mice in both models. The antidepressant-like effect of the extract (100 mg kg−1, p.o.) was blocked by -chlorophenylalanine and cyproheptadine but not prazosin, propranolol, or yohimbine. Concomitant administration of D-cycloserine and the extract potentiated the anti-immobility effect. In contrast, D-serine, a full agonist of glycine/NMDA receptors, abolished the effects. Anti-immobility effects of PME were prevented by pretreatment of mice with L-arginine (750 mg kg−1, i.p.) and sildenafil (5 mg kg−1, i.p.). On the contrary, pretreatment of mice with L-NAME (30 mg kg−1, i.p.) or methylene blue (10 mg kg−1, i.p.) potentiated its effects. The extract produces an antidepressant-like effect in the FST and TST that is dependent on the serotoninergic system, NMDA receptor complex, and the nitric oxide pathway. Donatus Wewura Adongo, Kennedy Kwami Edem Kukuia, Priscilla Kolibea Mante, Elvis Ofori Ameyaw, and Eric Woode Copyright © 2015 Donatus Wewura Adongo et al. All rights reserved. Translational Medicine and Patient Safety in Europe: TRANSFoRm—Architecture for the Learning Health System in Europe Sun, 11 Oct 2015 11:42:49 +0000 The Learning Health System (LHS) describes linking routine healthcare systems directly with both research translation and knowledge translation as an extension of the evidence-based medicine paradigm, taking advantage of the ubiquitous use of electronic health record (EHR) systems. TRANSFoRm is an EU FP7 project that seeks to develop an infrastructure for the LHS in European primary care. Methods. The project is based on three clinical use cases, a genotype-phenotype study in diabetes, a randomised controlled trial with gastroesophageal reflux disease, and a diagnostic decision support system for chest pain, abdominal pain, and shortness of breath. Results. Four models were developed (clinical research, clinical data, provenance, and diagnosis) that form the basis of the projects approach to interoperability. These models are maintained as ontologies with binding of terms to define precise data elements. CDISC ODM and SDM standards are extended using an archetype approach to enable a two-level model of individual data elements, representing both research content and clinical content. Separate configurations of the TRANSFoRm tools serve each use case. Conclusions. The project has been successful in using ontologies and archetypes to develop a highly flexible solution to the problem of heterogeneity of data sources presented by the LHS. Brendan C. Delaney, Vasa Curcin, Anna Andreasson, Theodoros N. Arvanitis, Hilde Bastiaens, Derek Corrigan, Jean-Francois Ethier, Olga Kostopoulou, Wolfgang Kuchinke, Mark McGilchrist, Paul van Royen, and Peter Wagner Copyright © 2015 Brendan C. Delaney et al. All rights reserved. Effects of Dietary Supplementation of Oregano Essential Oil to Sows on Oxidative Stress Status, Lactation Feed Intake of Sows, and Piglet Performance Sun, 11 Oct 2015 10:16:54 +0000 Fifty-four multiparous large white sows were used to determine the effects of supplementing oregano essential oil (OEO) to the gestation and lactation diets on oxidative stress status, lactation feed intake, and their piglet performance. Two groups were fed diets with (OEO; ) or without (Control; ) supplemental 15 mg/kg OEO during gestation and lactation. The serum levels of reactive oxygen species (ROS) (), 8-hydroxy-deoxyguanosine (8-OHdG) (), and thiobarbituric acid reactive substances (TBARS) () were higher during gestation (days 90 and 109) and lactation (days 1 and 3) than in early gestation (day 10). Compared with the control group, the OEO diet significantly reduced sows’ serum concentrations of 8-OHdG () and TBARS () on day 1 of lactation. The OEO diet increased the sows’ counts of faecal lactobacillus () while reducing Escherichia coli () and Enterococcus (). In the third week of lactation the treatment tended to increase sow’s feed intake (), which resulted in higher average daily gain () of piglets. Our results demonstrated that there is an increased systemic oxidative stress during late gestation and early lactation of sows. The OEO supplementation to sows’ diet improved performance of their piglets, which may be attributed to the reduced oxidative stress. Chengquan Tan, Hongkui Wei, Haiqing Sun, Jiangtao Ao, Guang Long, Siwen Jiang, and Jian Peng Copyright © 2015 Chengquan Tan et al. All rights reserved. User Satisfaction Evaluation of the EHR4CR Query Builder: A Multisite Patient Count Cohort System Sun, 11 Oct 2015 08:06:06 +0000 The Electronic Health Records for Clinical Research (EHR4CR) project aims to develop services and technology for the leverage reuse of Electronic Health Records with the purpose of improving the efficiency of clinical research processes. A pilot program was implemented to generate evidence of the value of using the EHR4CR platform. The user acceptance of the platform is a key success factor in driving the adoption of the EHR4CR platform; thus, it was decided to evaluate the user satisfaction. In this paper, we present the results of a user satisfaction evaluation for the EHR4CR multisite patient count cohort system. This study examined the ability of testers ( and from 5 countries) to perform three main tasks (around 20 minutes per task), after a 30-minute period of self-training. The System Usability Scale score obtained was 55.83 (SD: 15.37), indicating a moderate user satisfaction. The responses to an additional satisfaction questionnaire were positive about the design of the interface and the required procedure to design a query. Nevertheless, the most complex of the three tasks proposed in this test was rated as difficult, indicating a need to improve the system regarding complicated queries. Iñaki Soto-Rey, Aurèle N’Dja, James Cunningham, Axel Newe, Benjamin Trinczek, Caroline Lafitte, Brita Sedlmayr, and Fleur Fritz Copyright © 2015 Iñaki Soto-Rey et al. All rights reserved. Contribution of Electronic Medical Records to the Management of Rare Diseases Sun, 11 Oct 2015 07:58:54 +0000 Purpose. Electronic health record systems provide great opportunity to study most diseases. Objective of this study was to determine whether electronic medical records (EMR) in ophthalmology contribute to management of rare eye diseases, isolated or in syndromes. Study was designed to identify and collect patients’ data with ophthalmology-specific EMR. Methods. Ophthalmology-specific EMR software (Softalmo software Corilus) was used to acquire ophthalmological ocular consultation data from patients with five rare eye diseases. The rare eye diseases and data were selected and collected regarding expertise of eye center. Results. A total of 135,206 outpatient consultations were performed between 2011 and 2014 in our medical center specialized in rare eye diseases. The search software identified 29 congenital aniridia, 6 Axenfeld/Rieger syndrome, 11 BEPS, 3 Nanophthalmos, and 3 Rubinstein-Taybi syndrome. Discussion. EMR provides advantages for medical care. The use of ophthalmology-specific EMR is reliable and can contribute to a comprehensive ocular visual phenotype useful for clinical research. Conclusion. Routinely EMR acquired with specific software dedicated to ophthalmology provides sufficient detail for rare diseases. These software-collected data appear useful for creating patient cohorts and recording ocular examination, avoiding the time-consuming analysis of paper records and investigation, in a University Hospital linked to a National Reference Rare Center Disease. Dominique Bremond-Gignac, Elisabeth Lewandowski, and Henri Copin Copyright © 2015 Dominique Bremond-Gignac et al. All rights reserved. Anti-Inflammatory and Anticancer Activities of Taiwanese Purple-Fleshed Sweet Potatoes (Ipomoea batatas L. Lam) Extracts Mon, 05 Oct 2015 14:11:02 +0000 Purple-fleshed sweet potato (PFSP) (Ipomoea batatas L. Lam) has been known to possess high amount of anthocyanins which contribute to its antioxidant activity. However, a few reports are available concerning its anti-inflammatory and anticancer properties. In this study, PFSP “Tainung 73,” which is locally grown in Taiwan, was steamed and extracted using acidified ethanol pH 3.5 under 80°C. Two kinds of crude anthocyanins extracts were obtained, namely, SP (Steamed, Peeled) and SNP (Steamed, No Peeled). Then, anti-inflammatory and anticancer activities of these extracts were investigated. Cell viability assay (MTT) showed that SP and SNP extracts were not toxic to RAW 264.7 cells. They even exhibited anti-inflammatory activities by suppressing the production of NO and proinflammatory cytokines, such as NF-κβ, TNF-α, and IL-6, in LPS-induced macrophage cells. Anticancer activities of these extracts were displayed through their ability to inhibit the growth of cancer cell lines, such as MCF-7 (breast cancer), SNU-1 (gastric cancer), and WiDr (colon adenocarcinoma), in concentration- and time-dependent manner. Further studies also revealed that SP extracts could induce apoptosis in MCF-7 and SNU-1 cancer cells through extrinsic and intrinsic pathway. In the future, PSFP extracts may have potential to be applied in nutraceutical, pharmaceutical, and food industries. Marcelia Sugata, Chien-Yih Lin, and Yang-Chia Shih Copyright © 2015 Marcelia Sugata et al. All rights reserved. Efficacy and Safety of Ashwagandha (Withania somnifera) Root Extract in Improving Sexual Function in Women: A Pilot Study Sun, 04 Oct 2015 13:01:32 +0000 Background. Many women experience sexual dysfunction where there are orgasm disorders and sexual difficulties. Ashwagandha (Withania somnifera) is a herb known to improve the body’s physical and psychological condition. Objective. The purpose of the study was to determine the efficacy and safety of a high-concentration ashwagandha root extract (HCARE) supplementation for improving sexual function in healthy females. Methods. In this pilot study, 50 study subjects were randomized to either (i) HCARE-treated group or (ii) placebo- (starch-) treated group. The subjects consumed either HCARE or placebo capsules of 300mg twice daily for 8 weeks. Sexual function was assessed using two psychometric scales, the Female Sexual Function Index (FSFI) Questionnaire and the Female Sexual Distress Scale (FSDS), and by the number of total and successful sexual encounters. Results. The analysis indicates that treatment with HCARE leads to significantly higher improvement, relative to placebo, in the FSFI Total score (), FSFI domain score for “arousal” (), “lubrication” (), “orgasm” (), and “satisfaction” (), and also FSDS score () and the number of successful sexual encounters () at the end of the treatment. Conclusions. This study demonstrated that oral administration of HCARE may improve sexual function in healthy women. The present study is registered in the Clinical Trial Registry, Government of India, with a number CTRI/2015/07/006045. Swati Dongre, Deepak Langade, and Sauvik Bhattacharyya Copyright © 2015 Swati Dongre et al. All rights reserved. Synergistic Inhibitory Effects of Cetuximab and Cisplatin on Human Colon Cancer Cell Growth via Inhibition of the ERK-Dependent EGF Receptor Signaling Pathway Mon, 28 Sep 2015 06:37:14 +0000 The purpose of this study was to evaluate the anticancer efficacy of cetuximab combined with cisplatin (combination treatment) on colon cancer growth, as well as its underlying action mechanism. Combination treatment synergistically potentiated the effect of cetuximab on cell growth inhibition and apoptosis induction in HCT116 and SW480 cells. Combination treatment further suppressed the expression of the activated form of epidermal growth factor receptor (EGFR) and MAP kinase (p-ERK and p-p38) and also significantly inhibited the activity of activator protein-1 (AP-1) and nuclear factor kappa B (NF-κB). Additionally, the expression of cyclooxygenase-2 (COX-2) and interleukin-8 (IL-8) mRNA was significantly reduced by the combination treatment as compared to the expression seen for treatment with cetuximab or cisplatin alone. We found that the synergistic inhibitory effects of cetuximab and cisplatin on AP-1 and NF-κB activation, as well as on cell viability, were reversed by pretreatment with an ERK inhibitor. Results demonstrate that combined treatment with cetuximab and cisplatin exerts synergistic anticancer effects on colon cancer cells and also suggest that the ERK pathway plays a critical role in these effects via the suppression of the EGFR signaling pathway, along with the inhibition of COX-2, IL-8, and AP-1 and NF-κB. Dong Ju Son, Ji Eun Hong, Jung Ok Ban, Ju Ho Park, Hye Lim Lee, Sun Mi Gu, Jae Yeon Hwang, Myung Hee Jung, Dong Won Lee, Sang-Bae Han, and Jin Tae Hong Copyright © 2015 Dong Ju Son et al. All rights reserved. Adverse Psychiatric Effects Associated with Herbal Weight-Loss Products Thu, 17 Sep 2015 07:03:37 +0000 Obesity and overeating are among the most prevalent health concerns worldwide and individuals are increasingly using performance and image-enhancing drugs (PIEDs) as an easy and fast way to control their weight. Among these, herbal weight-loss products (HWLPs) often attract users due to their health claims, assumed safety, easy availability, affordable price, extensive marketing, and the perceived lack of need for professional oversight. Reports suggest that certain HWLPs may lead to onset or exacerbation of psychiatric disturbances. Here we review the available evidence on psychiatric adverse effects of HWLPs due to their intrinsic toxicity and potential for interaction with psychiatric medications. F. Saverio Bersani, Marialuce Coviello, Claudio Imperatori, Marta Francesconi, Christina M. Hough, Giuseppe Valeriani, Gianfranco De Stefano, Flaminia Bolzan Mariotti Posocco, Rita Santacroce, Amedeo Minichino, and Ornella Corazza Copyright © 2015 F. Saverio Bersani et al. All rights reserved. Chemotherapy-Induced Nausea and Vomiting Sun, 06 Sep 2015 13:51:29 +0000 Bernardo Leon Rapoport, Alexander Molasiotis, Haralambos Raftopoulos, and Fausto Roila Copyright © 2015 Bernardo Leon Rapoport et al. All rights reserved. Prevention of Nausea and Vomiting in Patients Undergoing Oral Anticancer Therapies for Solid Tumors Thu, 03 Sep 2015 13:17:02 +0000 Chemotherapy-induced nausea and vomiting (CINV) is still a common and debilitating side effect despite recent advances in its prevention and treatment. The intrinsic emetogenicity of chemotherapy agents allowed grouping into four risk groups (high, moderate, low, and minimal risk of emetogenicity). The prevention of acute and delayed CINV for intravenous agents and one day regimens is well studied, although, there are few data about management of CINV induced by oral cytotoxic agents and targeted therapies, usually administered in extended regimens of daily oral use. Until now treatment of nausea and vomiting caused by oral antineoplastic agents remains largely empirical. The level of evidence of prophylactic antiemetics recommended for these agents is low. There are differences in the classification of emetogenic potential of oral antineoplastic agents between the international guidelines and different recommendations for prophylactic antiemetic regimens. Herein we review the evidence for antiemetic regimens for the most used oral antineoplastic agents for solid tumors and propose antiemetic regimens for high to moderate risk and low to minimal risk of emetogenicity. Ana Lúcia Costa, Catarina Abreu, Teresa Raquel Pacheco, Daniela Macedo, Ana Rita Sousa, Catarina Pulido, António Quintela, and Luís Costa Copyright © 2015 Ana Lúcia Costa et al. All rights reserved. A Randomized, Double-Blind Pilot Study of Dose Comparison of Ramosetron to Prevent Chemotherapy-Induced Nausea and Vomiting Thu, 03 Sep 2015 12:00:13 +0000 Purpose. This study was conducted to determine the optimal dose titration of ramosetron to prevent the Rhodes Index of Nausea, Vomiting, and Retching (RINVR). Methods. Patients treated with folic acid, 5-fluorouracil, and oxaliplatin were randomized into three groups (0.3 mg, 0.45 mg, and 0.6 mg ramosetron before chemotherapy). The pharmacokinetics and pharmacodynamics using RINVR were evaluated. Results. Seventeen, 15, and 18 patients received ramosetron at doses of 0.3 mg, 0.45 mg, and 0.6 mg, respectively. (h), (ng/mL), and (ng·h/mL) were associated with dose escalation significantly, showing a reverse correlation with the RINVR during chemotherapy. Acute CINV was observed in four patients (22.2%), two patients (14.3%), and one (5.6%) patient and a delayed CINV on day 7 was found in eight (47%), three (21.4%), and five (27.8%) patients in each group. The complete response rate was increased with dose escalation (35.3%, 50.0%, and 72.2% in each group) and also showed the tendency for decreasing moderate-to-severe CINV. Conclusions. This study shows a trend regarding the dose-response relationship for ramosetron to prevent CINV, including delayed emesis. It suggested that dose escalation should be considered in patients with CINV in a subsequent cycle of chemotherapy, and an individual approach using RINVR could be useful to monitor CINV. Ka-Rham Kim, Gaeun Kang, Myung-Seo Ki, Hyun-Jeong Shim, Jun-Eul Hwang, Woo-Kyun Bae, Ik-Joo Chung, Jong-Keun Kim, Seongwook Jeong, and Sang-Hee Cho Copyright © 2015 Ka-Rham Kim et al. All rights reserved. Management of Chemotherapy Induced Nausea and Vomiting in Patients on Multiday Cisplatin Based Combination Chemotherapy Thu, 03 Sep 2015 11:30:24 +0000 Introduction of cisplatin based chemotherapy has revolutionized the treatment of germ cell tumors. A common side effect of multiday cisplatin chemotherapy is severe nausea and vomiting. Considerable progress has been made in the control of these side effects since the introduction of cisplatin based chemotherapy in the 1970s. Germ cell tumor which is a model for a curable neoplasm has also turned into an excellent testing ground to develop effective strategies to prevent chemotherapy induced nausea and vomiting (CINV) in multiday cisplatin based regimens. The use of combination of a 5-hydroxytryptamine (HT)3 receptor antagonist, a neurokinin-1 (NK1) antagonist, and dexamethasone has greatly improved our ability to prevent and control acute and delayed CINV. Mechanism and pattern of CINV with multiday chemotherapy may differ from those in single day chemotherapy and therefore efficacy of antiemetic drugs as observed in single day chemotherapy may not be applicable. There are only few randomized clinical trials with special emphasis on multiday chemotherapy. Further studies are essential to determine the efficacy, optimal dose, and duration of the newer agents and combinations in multiday cisplatin based chemotherapy. Praveen Ranganath, Lawrence Einhorn, and Costantine Albany Copyright © 2015 Praveen Ranganath et al. All rights reserved. A Review of NEPA, a Novel Fixed Antiemetic Combination with the Potential for Enhancing Guideline Adherence and Improving Control of Chemotherapy-Induced Nausea and Vomiting Thu, 03 Sep 2015 11:28:00 +0000 Combination antiemetic regimens targeting multiple molecular pathways associated with emesis have become the standard of care for prevention of chemotherapy-induced nausea and vomiting (CINV) related to highly and moderately emetogenic chemotherapies. Antiemetic consensus guidelines from several professional societies are widely available and updated regularly as new data emerges. Unfortunately, despite substantial research supporting the notion that guideline conformity improves CINV control, adherence to antiemetic guidelines is unsatisfactory. While studies are needed to identify specific barriers to guideline use and explore measures to enhance adherence, a novel approach has been taken to improve clinician adherence and patient compliance, with the development of a new combination antiemetic. NEPA is an oral fixed combination of a new highly selective NK1 receptor antagonist (RA), netupitant, and the pharmacologically and clinically distinct 5-HT3 RA, palonosetron. This convenient antiemetic combination offers guideline-consistent prophylaxis by targeting two critical pathways associated with CINV in a single oral dose administered only once per cycle. This paper will review and discuss the NEPA data in the context of how this first combination antiemetic may overcome some of the barriers interfering with adherence to antiemetic guidelines, enhance patient compliance, and offer a possible advance in the prevention of CINV for patients. Paul J. Hesketh, Matti Aapro, Karin Jordan, Lee Schwartzberg, Snezana Bosnjak, and Hope Rugo Copyright © 2015 Paul J. Hesketh et al. All rights reserved. Efficacy of Olanzapine Combined Therapy for Patients Receiving Highly Emetogenic Chemotherapy Resistant to Standard Antiemetic Therapy Thu, 03 Sep 2015 11:23:53 +0000 Objective. Olanzapine is proved to be effective for chemotherapy induced nausea and vomiting (CINV). But its efficacy in combination with standard antiemetic therapy is unknown. The purpose of this study is to prove the preventive effect of olanzapine for the prevention of CINV caused by highly emetogenic chemotherapy when used with standard antiemetic therapy. Method. Gynecologic cancer patients receiving cisplatin-based chemotherapy who had grade 2 or 3 nausea in overall phase (0–120 h after chemotherapy) despite standard therapy were assigned to this study. From the next cycles to cycles in which patients developed grade 2 or 3 nausea, they received olanzapine with standard therapy. 5 mg oral olanzapine was administered for 7 days from the day before chemotherapy. The effectiveness of preventive administration of olanzapine was evaluated retrospectively. The primary endpoint was nausea control rate (grade 0 or 1) with olanzapine. Results. Fifty patients were evaluable. The nausea control rate with olanzapine was improved from 58% to 98% in acute phase (0–24 h after chemotherapy) and 2% to 94% in delayed phase (24–120 h after chemotherapy). In overall phase, the nausea control rate improved from 0% to 92%, and it was statistically significant (). Conclusion. Preventive use of olanzapine combined with standard antiemetic therapy showed improvement in control of refractory nausea. Masakazu Abe, Yuka Kasamatsu, Nobuhiro Kado, Shiho Kuji, Aki Tanaka, Nobutaka Takahashi, Munetaka Takekuma, and Yasuyuki Hirashima Copyright © 2015 Masakazu Abe et al. All rights reserved. Prophylactic Management of Radiation-Induced Nausea and Vomiting Thu, 03 Sep 2015 10:56:17 +0000 The incidence of nausea and vomiting after radiotherapy is often underestimated by physicians, though some 50–80% of patients may experience these symptoms. The occurrence of radiotherapy-induced nausea and vomiting (RINV) will depend on radiotherapy-related factors, such as the site of irradiation, the dosing, fractionation, irradiated volume, and radiotherapy techniques. Patients should receive antiemetic prophylaxis as suggested by the international antiemetic guidelines based upon a risk assessment, taking especially into account the affected anatomic region and the planned radiotherapy regimen. In this field the international guidelines from the Multinational Association of Supportive Care in Cancer (MASCC)/European Society of Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO) guidelines as well as the National Comprehensive Cancer Network (NCCN) are widely endorsed. The emetogenicity of radiotherapy regimens and recommendations for the appropriate use of antiemetics including 5-hydroxytryptamine (5-HT3) receptor antagonists, steroids, and other antiemetics will be reviewed in regard to the applied radiotherapy or radiochemotherapy regimen. Petra Feyer, Franziska Jahn, and Karin Jordan Copyright © 2015 Petra Feyer et al. All rights reserved. Treatment of Breakthrough and Refractory Chemotherapy-Induced Nausea and Vomiting Thu, 03 Sep 2015 09:47:26 +0000 Despite significant progress in the prevention of chemotherapy-induced nausea and vomiting (CINV) with the introduction of new antiemetic agents, 30–50% of patients receiving moderately or highly emetogenic chemotherapy (MEC or HEC) and guideline directed prophylactic antiemetics develop breakthrough CINV. International guidelines recommend the treatment of breakthrough CINV with an agent from a drug class that was not used in the prophylactic antiemetic regimen and recommend using the breakthrough medication continuously rather than using it on an as needed basis. There have been very few studies on the treatment of breakthrough CINV. A recent double-blind, randomized, phase III study suggested that olanzapine may be an effective agent for the treatment of breakthrough CINV. Refractory CINV occurs when patients develop CINV during subsequent cycles of chemotherapy when antiemetic prophylaxis has not been successful in controlling CINV in earlier cycles. Patients who develop refractory CINV should be considered for a change in their prophylactic antiemetic regimen. If significant anxiety exists, a benzodiazepine may be added to the prophylactic regimen. If a refractory patient is receiving HEC, olanzapine may be added to the prophylactic regimen. If the patient is receiving MEC, olanzapine or an NK-1 receptor antagonist may be added to the prophylactic regimen. Rudolph M. Navari Copyright © 2015 Rudolph M. Navari. All rights reserved. Biological and Pharmacological Aspects of the NK1-Receptor Thu, 03 Sep 2015 09:20:44 +0000 The neurokinin 1 receptor (NK-1R) is the main receptor for the tachykinin family of peptides. Substance P (SP) is the major mammalian ligand and the one with the highest affinity. SP is associated with multiple processes: hematopoiesis, wound healing, microvasculature permeability, neurogenic inflammation, leukocyte trafficking, and cell survival. It is also considered a mitogen, and it has been associated with tumorigenesis and metastasis. Tachykinins and their receptors are widely expressed in various human systems such as the nervous, cardiovascular, genitourinary, and immune system. Particularly, NK-1R is found in the nervous system and in peripheral tissues and are involved in cellular responses such as pain transmission, endocrine and paracrine secretion, vasodilation, and modulation of cell proliferation. It also acts as a neuromodulator contributing to brain homeostasis and to sensory neuronal transmission associated with depression, stress, anxiety, and emesis. NK-1R and SP are present in brain regions involved in the vomiting reflex (the nucleus tractus solitarius and the area postrema). This anatomical localization has led to the successful clinical development of antagonists against NK-1R in the treatment of chemotherapy-induced nausea and vomiting (CINV). The first of these antagonists, aprepitant (oral administration) and fosaprepitant (intravenous administration), are prescribed for high and moderate emesis. Susana Garcia-Recio and Pedro Gascón Copyright © 2015 Susana Garcia-Recio and Pedro Gascón. All rights reserved. The Assessment of Oral Microflora Exposed to 3% Ethanolic Extract of Brazilian Green Propolis Preparation Used for Hygiene Maintenance following Minor Oral Surgeries Wed, 26 Aug 2015 14:23:41 +0000 The aim of this study was to investigate the influence of a topically administered hygienic preparation containing a 3% ethanolic extract of Brazilian green propolis (EEP-B) on oral microflora spectrum changes in a group of patients who underwent common oral surgery procedures. Two gel samples were compared: the tested gel containing an active ingredient, that is, a 3% EEP-B (gel GA), and a placebo as the negative control (gel GC). The collection of microbiological material included 14 patients requiring surgical extraction of wisdom molars and short endosseous implant installation. Clinical examinations were carried out as follow-up, that is, baseline and after 5-6 weeks’ time. During the first and subsequent assessment, swabs were taken from the mucosal surface. The number of microorganism species was found to have increased following the application of GC gel over the period of 5-6 weeks. This mainly affected Gram-positive rods and bacilli as well as Gram-negative rods. Application of the GA gel enriched with 3% EEP-B caused a profound reduction in the amount of Neisseria spp. and Bifidobacterium spp. strains. Elimination of seven species of microorganisms was observed: Streptococcus acidominimus, Streptococcus oralis, Staphylococcus epidermidis, Veillonella parvula, Bifidobacterium breve, Bifidobacterium longum, and Lactobacillus acidophilus. Tadeusz Morawiec, Anna Mertas, Robert D. Wojtyczka, Iwona Niedzielska, Arkadiusz Dziedzic, Anna Bubiłek-Bogacz, Jakub Sender, Jacek Wróbel, Marta Tanasiewicz, Piotr Wesołowski, and Wojciech Król Copyright © 2015 Tadeusz Morawiec et al. All rights reserved. Antimicrobial Effects and Resistant Regulation of Magnolol and Honokiol on Methicillin-Resistant Staphylococcus aureus Wed, 19 Aug 2015 13:39:19 +0000 The antimicrobial killing activity toward methicillin-resistant Staphylococcus aureus (MRSA) has been a serious emerging global issue. In a continuing search for compounds with antibacterial activity against several microorganisms including S. aureus and MRSA, an n-hexane extract of Magnolia officinalis was found to contain magnolol. This compound exhibited potent activity against S. aureus, standard methicillin-susceptible S. aureus (MSSA), and MRSA as well as clinical MRSA isolates. When combined with oxacillin, the antibacterial activities of magnolol and honokiol against the MRSA strain were increased compared to single treatment without antibiotics at 10 µg/mL and 25 µg/mL, respectively. These activities of magnolol and honokiol were dose dependent. Also, magnolol showed synergistic effects with oxacillin against 13 clinical isolates of MRSA. It was determined that magnolol and honokiol had a synergistic effect with oxacillin against MRSA strain. Furthermore, the magnolol inhibited the expression of the resistant genes, mecA, mecI, femA, and femB, in mRNA. We concluded that the antibacterial activity of magnolol against MRSA strain is more related to the mecI’s pathway and components of the cell wall than mecR1. Therefore, the results obtained in this study suggest that the combination of magnolol and antibiotics could lead to the development of new combination antibiotics against MRSA infection. Su Young Kim, Ju Kim, Seung-Il Jeong, Kwang Yeop Jahng, and Kang-Yeol Yu Copyright © 2015 Su Young Kim et al. All rights reserved. Evaluation of Antileishmanial Activity of Albaha Medicinal Plants against Leishmania amazonensis Wed, 19 Aug 2015 09:33:37 +0000 Sixteen methanolic extracts obtained from thirteen plant species, selected either from ethnobotanical or chemotaxonomical data, were screened for their antileishmanial activity against Leishmania amazonensis. The cytotoxic activity against normal peritoneal macrophages from normal BALB/c mice was also determined. Eight extracts had IC50 values ranging from <12.5 to 37.8 µg/mL against promastigotes. Achillea biebersteinii flower, Euphorbia helioscopia, and Solanum incanum leaf extracts showed antileishmanial activities with IC50 between <12.5–26.9 µg/mL and acceptable selectivity indices of 8–5. The other leishmanicidal plant extracts, with IC50 ranging from 18.0 to 29.5 µg/mL, exhibited low selectivity indices. Saeed S. Al-Sokari, Nasser A. Awadh Ali, Lianet Monzote, and Mohamed A. Al-Fatimi Copyright © 2015 Saeed S. Al-Sokari et al. All rights reserved. Evaluation of Antioxidant and Antibacterial Potentials of Nigella sativa L. Suspension Cultures under Elicitation Wed, 12 Aug 2015 08:39:57 +0000 Nigella sativa L. (family Ranunculaceae) is an annual herb of immense medicinal properties because of its major active components (i.e., thymoquinone (TQ), thymohydroquinone (THQ), and thymol (THY)). Plant tissue culture techniques like elicitation, Agrobacterium mediated transformation, hairy root culture, and so on, are applied for substantial metabolite production. This study enumerates the antibacterial and antioxidant potentials of N. sativa epicotyl suspension cultures under biotic and abiotic elicitation along with concentration optimization of the elicitors for enhanced TQ and THY production. Cultures under different concentrations of pectin and manganese chloride (MnCl2) elicitation (i.e., 5 mg/L, 10 mg/L, and 15 mg/L) showed that the control, MnCl2 10 mg/L, and pectin 15 mg/L suspension extracts greatly inhibited the growth of E. coli, S. typhimurium, and S. aureus (MIC against E. coli, i.e., , , and , resp.). Elicitation decreased SOD enzyme activity whereas CAT enzyme activity increased remarkably under MnCl2 elicitation. MnCl2 10 mg/L and pectin 15 mg/L elicitation enhanced the DPPH radical inhibition ability, but ferric scavenging activity was comparable to the control. TQ and THY were quantified by LC-MS/MS in the cultures with high bioactive properties revealing maximum content under MnCl2 10 mg/L elicitation. Therefore, MnCl2 elicitation can be undertaken on large scale for sustainable metabolite production. Hera Chaudhry, Nida Fatima, and Iffat Zareen Ahmad Copyright © 2015 Hera Chaudhry et al. All rights reserved. Therapeutic Strategies against Inflammation-Related Diseases: Molecular Mechanisms and Clinical Applications Tue, 04 Aug 2015 13:34:37 +0000 Wen-Bin Wu and Wei-Chien Huang Copyright © 2015 Wen-Bin Wu and Wei-Chien Huang. All rights reserved. Huangqin-Tang Ameliorates TNBS-Induced Colitis by Regulating Effector and Regulatory CD4+ T Cells Tue, 04 Aug 2015 11:25:18 +0000 Huangqin-Tang decoction (HQT) is a classic traditional Chinese herbal formulation that is widely used to ameliorate the symptoms of gastrointestinal disorders, including inflammatory bowel disease (IBD). This study was designed to investigate the therapeutic potential and immunological regulatory activity of HQT in experimental colitis in rats. Using an animal model of colitis by intrarectally administering 2,4,6-trinitrobenzenesulfonic acid (TNBS), we found that administration of HQT significantly inhibited the severity of TNBS-induced colitis in a dose-dependent manner. In addition, treatment with HQT produced better results than that with mesalazine, as shown by improvedweight loss bleeding and diarrhoea scores, colon length, and intestinal inflammation. As for potential immunological regulation of HQT action, the percentages of Th1 and Th17 cells were reduced, but those Th2 and Treg cells were enhanced in LPMCs after HQT treatment. Additionally, HQT lowered the levels of Th1/Th17-associated cytokines but increased production of Th2/Treg-associated cytokines in the colon and MLNs. Furthermore, we observed a remarkable suppression of the Th1/Th17-associated transcription factors T-bet and ROR-γt. However, expression levels of the Th2/Treg-associated transcription factors GATA-3 and Foxp3 were enhanced during treatment with HQT. Our results suggest that HQT has the therapeutic potential to ameliorate TNBS-induced colitis symptoms. This protective effect is possibly mediated by its effects on CD4+ T cells subsets. Ying Zou, Wen-Yang Li, Zheng Wan, Bing Zhao, Zhi-Wei He, Zhu-Guo Wu, Guo-Liang Huang, Jian Wang, Bin-Bin Li, Yang-Jia Lu, Cong-Cong Ding, Hong-Gang Chi, and Xue-Bao Zheng Copyright © 2015 Ying Zou et al. All rights reserved. Prognosis Relevance of Serum Cytokines in Pancreatic Cancer Tue, 04 Aug 2015 11:24:52 +0000 The overall survival of patients with pancreatic ductal adenocarcinoma is extremely low. Although gemcitabine is the standard used chemotherapy for this disease, clinical outcomes do not reflect significant improvements, not even when combined with adjuvant treatments. There is an urgent need for prognosis markers to be found. The aim of this study was to analyze the potential value of serum cytokines to find a profile that can predict the clinical outcome in patients with pancreatic cancer and to establish a practical prognosis index that significantly predicts patients’ outcomes. We have conducted an extensive analysis of serum prognosis biomarkers using an antibody array comprising 507 human cytokines. Overall survival was estimated using the Kaplan-Meier method. Univariate and multivariate Cox’s proportional hazard models were used to analyze prognosis factors. To determine the extent that survival could be predicted based on this index, we used the leave-one-out cross-validation model. The multivariate model showed a better performance and it could represent a novel panel of serum cytokines that correlates to poor prognosis in pancreatic cancer. B7-1/CD80, EG-VEGF/PK1, IL-29, NRG1-beta1/HRG1-beta1, and PD-ECGF expressions portend a poor prognosis for patients with pancreatic cancer and these cytokines could represent novel therapeutic targets for this disease. Carolina Torres, Ana Linares, Maria José Alejandre, Rogelio J. Palomino-Morales, Octavio Caba, Jose Prados, Antonia Aránega, Juan R. Delgado, Antonio Irigoyen, Joaquina Martínez-Galán, Francisco M. Ortuño, Ignacio Rojas, and Sonia Perales Copyright © 2015 Carolina Torres et al. All rights reserved. Flax Fiber Hydrophobic Extract Inhibits Human Skin Cells Inflammation and Causes Remodeling of Extracellular Matrix and Wound Closure Activation Tue, 04 Aug 2015 11:23:40 +0000 Inflammation is the basis of many diseases, with chronic wounds amongst them, limiting cell proliferation and tissue regeneration. Our previous preclinical study of flax fiber applied as a wound dressing and analysis of its components impact on the fibroblast transcriptome suggested flax fiber hydrophobic extract use as an anti-inflammatory and wound healing preparation. The extract contains cannabidiol (CBD), phytosterols, and unsaturated fatty acids, showing great promise in wound healing. In in vitro proliferation and wound closure tests the extract activated cell migration and proliferation. The activity of matrix metalloproteinases in skin cells was increased, suggesting activation of extracellular components remodeling. The expression of cytokines was diminished by the extract in a cannabidiol-dependent manner, but β-sitosterol can act synergistically with CBD in inflammation inhibition. Extracellular matrix related genes were also analyzed, considering their importance in further stages of wound healing. The extract activated skin cell matrix remodeling, but the changes were only partially cannabidiol- and β-sitosterol-dependent. The possible role of fatty acids also present in the extract is suggested. The study shows the hydrophobic flax fiber components as wound healing activators, with anti-inflammatory cannabidiol acting in synergy with sterols, and migration and proliferation promoting agents, some of which still require experimental identification. Monika Styrczewska, Anna Kostyn, Anna Kulma, Grazyna Majkowska-Skrobek, Daria Augustyniak, Anna Prescha, Tadeusz Czuj, and Jan Szopa Copyright © 2015 Monika Styrczewska et al. All rights reserved. Interleukin-27 Protects Cardiomyocyte-Like H9c2 Cells against Metabolic Syndrome: Role of STAT3 Signaling Mon, 03 Aug 2015 13:01:52 +0000 The present results demonstrated that high glucose (G), salt (S), and cholesterol C (either alone or in combination), as mimicking extracellular changes in metabolic syndrome, damage cardiomyocyte-like H9c2 cells and reduce their viability in a time-dependent manner. However, the effects were greatest when cells were exposed to all three agents (GSC). The mRNA of glycoprotein (gp) 130 and WSX-1, both components of the interleukin (IL)-27 receptor, were present in H9c2 cells. Although mRNA expression was not affected by exogenous treatment with IL-27, the expression of gp130 mRNA (but not that of WSX-1 mRNA) was attenuated by GSC. Treatment of IL-27 to H9c2 cells increased activation of signal transducer and activator of transcription 3 (STAT3) and protected cells from GSC-induced cytochrome c release and cell damage. The protective effects of IL-27 were abrogated by the STAT3 inhibitor, stattic. The results of the present study clearly demonstrate that the STAT3 pathway triggered by anti-inflammatory IL-27 plays a role in protecting cardiomyocytes against GSC-mediated damage. Wei-Lian Phan, Yu-Tzu Huang, and Ming-Chieh Ma Copyright © 2015 Wei-Lian Phan et al. All rights reserved. Cardamonin Regulates miR-21 Expression and Suppresses Angiogenesis Induced by Vascular Endothelial Growth Factor Tue, 21 Jul 2015 13:15:03 +0000 Cardamonin has promising potential in cancer prevention and therapy by interacting with proteins and modifying the expressions and activities, including factors of cell survival, proliferation, and angiogenesis. In our precious study, we have demonstrated that cardamonin suppressed vascular endothelial growth factor- (VEGF-) induced angiogenesis as evaluated in the mouse aortic ring assay. It is also known that microRNAs (miRNAs) play important roles in angiogenesis. Herein, we hypothesized whether antiangiogenesis effect of cardamonin in human umbilical vein endothelial cells (HUVECs) triggered by VEGF was associated with miRNAs. We found that cardamonin reduced the miR-21 expression induced by VEGF in HUVECs. Treatment with miR-21 mimics abolished the effects of cardamonin on VEGF-induced cell proliferation, migration, and angiogenesis in HUVECs. However, treatment with miR-21 inhibitors presented the opposite effects, indicating the vital role of miR-21 in this process. Our study provides a new insight of the preliminary mechanism of anti-VEGF-induced angiogenesis by cardamonin in HUVECs. Fu-Sheng Jiang, Sha-Sha Tian, Jin-Jian Lu, Xing-Hong Ding, Chao-Dong Qian, Bin Ding, Zhi-Shan Ding, and Bo Jin Copyright © 2015 Fu-Sheng Jiang et al. All rights reserved. Antibiofilm Activity of Chilean Propolis on Streptococcus mutans Is Influenced by the Year of Collection Sun, 12 Jul 2015 12:41:39 +0000 The chemical composition of propolis varies according to factors that could have an influence on its biological properties. Polyphenols from propolis have demonstrated an inhibitory effect on Streptococcus mutans growth. However, it is not known if different years of propolis collection may affect its activity. We aimed to elucidate if the year of collection of propolis influences its activity on Streptococcus mutans. Polyphenol-rich extracts were prepared from propolis collected in three different years, characterized by LC-MS and quantified the content of total polyphenols and flavonoids groups. Finally, was evaluated the antibacterial effect on Streptococcus mutans and the biofilm formation. Qualitative differences were observed in total polyphenols, flavones, and flavonols and the chemical composition between the extracts, affecting the strength of inhibition of biofilm formation but not the antimicrobial assays. In conclusion, chemical composition of propolis depends on the year of collection and influences the strength of the inhibition of biofilm formation. Jorge Jesús Veloz, Nicolás Saavedra, Alexis Lillo, Marysol Alvear, Leticia Barrientos, and Luis A. Salazar Copyright © 2015 Jorge Jesús Veloz et al. All rights reserved. Artemisia princeps Inhibits Biofilm Formation and Virulence-Factor Expression of Antibiotic-Resistant Bacteria Sun, 12 Jul 2015 12:40:29 +0000 In this study, we used ethanol extract of A. princeps and investigated its antibacterial effects against MRSA. Ethanol extract of A. princeps significantly inhibited MRSA growth and organic acid production during glucose metabolism at concentrations greater than 1 mg/mL (P < 0.05). MRSA biofilm formation was observed using scanning electron microscopy (SEM) and safranin staining. A. princeps extract was found to inhibit MRSA biofilm formation at concentrations higher than 2 mg/mL significantly (P < 0.05). Bactericidal effects of the A. princeps were observed using confocal laser microscopy, which showed that A. princeps was bactericidal in a dose-dependent manner. Using real-time PCR, expression of mecA, an antibiotic-resistance gene of MRSA, was observed, along with that of sea, agrA, and sarA. A. princeps significantly inhibited mecA, sea, agrA, and sarA, mRNA expression at the concentrations greater than 1 mg/mL (P < 0.05). The phytochemical analysis of A. princeps showed a relatively high content of organic acids and glycosides. The results of this study suggest that the ethanol extract of A. princeps may inhibit proliferation, acid production, biofilm formation, and virulence gene expressions of MRSA, which may be related to organic acids and glycosides, the major components in the extract. Na-Young Choi, Sun-Young Kang, and Kang-Ju Kim Copyright © 2015 Na-Young Choi et al. All rights reserved. Evaluation of Synergetic Anticancer Activity of Berberine and Curcumin on Different Models of A549, Hep-G2, MCF-7, Jurkat, and K562 Cell Lines Mon, 29 Jun 2015 06:56:57 +0000 Ayurvedic system of medicine is using Berberis aristata and Curcuma longa herbs to treat different diseases including cancer. The study was performed to evaluate the synergetic anticancer activity of Berberine and Curcumin by estimating the inhibition of the cell proliferation by cytotoxicity assay using MTT method on specified human cell lines (A549, Hep-G2, MCF-7, Jurkat, and K562). All the cells were harvested from the culture and seeded in the 96-well assay plates at seeding density of 2.0 × 104 cells/well and were incubated for 24 hours. Test items Berberine with Curcumin (1 : 1), Curcumin 95% pure, and Berberine 95% pure were exposed at the concentrations of 1.25, 0.001, and 0.5 mg/mL, respectively, and incubated for a period of 48 hours followed by dispensing MTT solution (5 mg/mL). The cells were incubated at 37 ± 1°C for 4 hours followed by addition of DMSO for dissolving the formazan crystals and absorbance was read at 570 nm. Separate wells were prepared for positive control, controls (only medium with cells), and blank (only medium). The results had proven the synergetic anticancer activity of Berberine with Curcumin inducing cell death greater percentage of >77% when compared to pure curcumin with <54% and pure Berberine with <45% on average on all cell line models. Acharya Balakrishna and M. Hemanth Kumar Copyright © 2015 Acharya Balakrishna and M. Hemanth Kumar. All rights reserved. Chemical, Bioactive, and Antioxidant Potential of Twenty Wild Culinary Mushroom Species Thu, 25 Jun 2015 11:23:56 +0000 The chemical, bioactive, and antioxidant potential of twenty wild culinary mushroom species being consumed by the people of northern Himalayan regions has been evaluated for the first time in the present study. Nutrients analyzed include protein, crude fat, fibres, carbohydrates, and monosaccharides. Besides, preliminary study on the detection of toxic compounds was done on these species. Bioactive compounds evaluated are fatty acids, amino acids, tocopherol content, carotenoids (β-carotene, lycopene), flavonoids, ascorbic acid, and anthocyanidins. Fruitbodies extract of all the species was tested for different types of antioxidant assays. Although differences were observed in the net values of individual species all the species were found to be rich in protein, and carbohydrates and low in fat. Glucose was found to be the major monosaccharide. Predominance of UFA (65–70%) over SFA (30–35%) was observed in all the species with considerable amounts of other bioactive compounds. All the species showed higher effectiveness for antioxidant capacities. S. K. Sharma and N. Gautam Copyright © 2015 S. K. Sharma and N. Gautam. All rights reserved. Accelerated Recovery of Endothelium Function after Stent Implantation with the Use of a Novel Systemic Nanoparticle Curcumin Mon, 08 Jun 2015 13:01:45 +0000 Curcumin was reported to exhibit a wide range of pharmacological effects including antioxidant, anti-inflammatory, and antiproliferative activities and significantly prevent smooth muscle cells migration. In the present study, a novel kind of curcumin loaded nanoparticles (Cur-NP) has been prepared and characterized with the aim of inhibiting inflammation formation and accelerating the healing process of the stented arteries. Cur-NP was administrated intravenously after stent implantation twice a week and detailed tissue responses were evaluated. The results demonstrated that intravenous administration of Cur-NP after stent implantation accelerated endothelial cells restoration and endothelium function recovery and may potentially be an effective therapeutic alternative to reduce adverse events for currently available drug eluting stents. Qi Lu, Fang Ye, Xiangjun Yang, Qingqing Gu, Peng Wang, Jianhua Zhu, Li Shen, and Feirong Gong Copyright © 2015 Qi Lu et al. All rights reserved. Effects of the Chinese Herbal Formulation (Liu Wei Di Huang Wan) on the Pharmacokinetics of Isoflavones in Postmenopausal Women Thu, 04 Jun 2015 07:49:34 +0000 A combination of soy isoflavones and Liu Wei Di Huang Wan (LWDHW) is potentially effective for postmenopausal women with intolerable vasomotor episodes who are not suitable candidates for hormonal therapy. The objective of this open-label, three-phase, crossover study was to determine the influence of both single and multiple oral doses of LWDHW on isoflavone pharmacokinetics in healthy postmenopausal women. Eleven subjects were assigned to receive the following regimens in a fixed sequence with washout periods of at least one week: Phase A, a single oral dose of soy milk; Phase B, a single oral dose of soy milk coadministered with LWDHW; and Phase C, multiple oral doses of LWDHW for 14 days followed by a single oral dose of soy milk. Blood samples were collected and mixed with β-glucuronidase/sulfatase to hydrolyze isoflavone conjugates to their respective aglycones (i.e., daidzein and genistein) and were determined using high performance liquid chromatography. The pharmacokinetic parameters analyzed were maximal plasma concentration , time to reach peak concentration , area under the plasma concentration-time curve (AUC), and half-life (). The results found no statistically significant differences in pharmacokinetic parameters of daidzein and genistein among the three regimens. Wirin Limopasmanee, Sunee Chansakaow, Noppamas Rojanasthien, Maleeya Manorot, Chaichan Sangdee, and Supanimit Teekachunhatean Copyright © 2015 Wirin Limopasmanee et al. All rights reserved. Tramadol and Tramadol+Caffeine Synergism in the Rat Formalin Test Are Mediated by Central Opioid and Serotonergic Mechanisms Thu, 04 Jun 2015 07:16:37 +0000 Different analgesic combinations with caffeine have shown this drug to be capable of increasing the analgesic effect. Many combinations with nonsteroidal anti-inflammatory drugs (NSAIDs) have been carried out, but, in regard to opioids, only combinations with morphine and tramadol have been reported. The antinociceptive synergism mechanism of these combinations is not well understood. The purpose of the present study was to determine the participation of spinal and supraspinal opioidergic and serotonergic systems in the synergic effect of the tramadol+caffeine combination in the rat formalin test. At the supraspinal level, the opioid antagonist, naloxone, completely reversed the effect of the drug combination, whereas ketanserin, a 5-HT2 receptor antagonist, inhibited the effect by 60%; however, ondansetron, a 5-HT3 receptor antagonist, did not alter the combination effect. When the antagonists were intrathecally administered, there was a significant reduction in all tramadol-caffeine combination effects. With respect to tramadol alone, there was significant participation of the opioid system at the supraspinal level, whereas it was the serotonergic system that participated at the spinal level by means of the two receptors studied. In conclusion, the tramadol+caffeine combination synergically activated the opioid and serotonergic systems at the supraspinal level, as well as at the spinal level, to produce the antinociception. Norma Carrillo-Munguía, Ma. Eva González-Trujano, Miguel Huerta, Xochitl Trujillo, and M. Irene Díaz-Reval Copyright © 2015 Norma Carrillo-Munguía et al. All rights reserved. Antiedematogenic Evaluation of Copaifera langsdorffii Leaves Hydroethanolic Extract and Its Major Compounds Thu, 21 May 2015 14:33:38 +0000 Inflammatory disorders affect many people worldwide, and medicinal plants are used to ameliorate these health problems. This paper reports the antiedematogenic and analgesic evaluation of Copaifera langsdorffii Desf. leaves hydroethanolic extract (Cop) and two of its isolated compounds: quercetin-3-O-α-L-rhamnopyranosyl (quercitrin) and kaempferol-3-O-α-L-rhamnopyranosyl (afzelin). For that, the following experimental protocols were undertaken locomotor performance, writhing induced by acetic acid, antinociceptivity induced by formalin, hot plate latency, paw oedema induced by carrageenan and dextran, and cell migration induced by lipopolysaccharide (LPS), as well as the measurement of nitric oxide (NO), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and interleukin 10 (IL-10) in macrophages. Neither the extract nor the isolated compounds displayed analgesic activity. The obtained results showed that C. langsdorffii extract possesses antiedematogenic properties acting on peripheral sites, whereas quercitrin and afzelin are not involved. Moreover, these properties are not associated with cell migration inhibition, TNF-α, IL-6, or IL-10 regulation. Ricardo Andrade Furtado, Cristiane Teixeira Vilhena Bernardes, Mauro Nogueira da Silva, Karina Furlani Zoccal, Lúcia Helena Faccioli, and Jairo Kenupp Bastos Copyright © 2015 Ricardo Andrade Furtado et al. All rights reserved. Signal Transduction Inhibitors as Promising Anticancer Agents Thu, 21 May 2015 07:15:36 +0000 Raj Kumar, Cedric Dos Santos, Tarunveer Singh Ahluwalia, and Sandeep Singh Copyright © 2015 Raj Kumar et al. All rights reserved. Anticancer Properties of Natural Products Wed, 20 May 2015 13:37:37 +0000 István Zupkó, Walter Jaeger, Zeki Topcu, and Chin-Chung Wu Copyright © 2015 István Zupkó et al. All rights reserved. Interaction of Panax quinquefolius Saponin and Dual Antiplatelets on Vascular Endothelial Function in Rats with Acute Myocardial Infarction Tue, 19 May 2015 09:55:02 +0000 The objective of this study is to investigate the interaction of Panax quinquefolius saponin (PQS) and dual antiplatelets (aspirin and clopidogrel) on antiplatelet activity and vascular endothelial function in rats with acute myocardial infarction (AMI). Forty-eight male SD rats were randomly designed into sham group, model group, dual antiplatelet group, and PQS plus dual antiplatelet group. AMI rats were induced by ligation of left anterior descending coronary artery (LAD) and dual antiplatelet agents and additional PQS to dual antiplatelets were intragastrically administered for 28 days, respectively. The ventricular cavity area and cardiac transverse area ratio in PQS + dual antiplatelet group showed a decreased tendency. PAgT(%) decreased significantly in both dual antiplatelet group and PQS + dual antiplatelet group. TXB2 concentration significantly decreased in dual antiplatelet and PQS + dual antiplatelet groups, whereas 6-keto-PGF1α concentration significantly increased in PQS + dual antiplatelet group. Rats in PQS + dual antiplatelet group demonstrated a significant decrease in plasma ET-1 concentration and an increase in serum NO concentration compared with dual antiplatelet group. The combination therapy of PQS and dual antiplatelets showed some beneficial effects on vascular endothelial function and ventricular remodeling in rats with AMI. Baojun Wang, Yue Liu, Qinghua Shang, Qingxiang Zhang, Lei Zhang, Jiangang Liu, and Dazhuo Shi Copyright © 2015 Baojun Wang et al. All rights reserved. Roles of ER and GPR30 in Proliferative Response of Human Bladder Cancer Cell to Estrogen Mon, 18 May 2015 11:03:45 +0000 Bladder cancer belongs to one of the most common cancers and is a leading cause of deaths in our society. Urothelial carcinoma of the bladder (UCB) is the main type of this cancer, and the estrogen receptors in UCB remain to be studied. Our experiment aimed to investigate the possible biological effect of 17β-estradiol on human bladder-derived T24 carcinoma cells and to indicate its related mechanisms. T24 cells were treated with various doses of 17β-estradiol, and cell proliferation was detected using MTT assays. 17β-estradiol promoted T24 cell proliferation independent of ERβ/GPR30-regulated EGFR-MAPK pathway, while it inhibited cell growth via GPR30. Furthermore, the expression levels of downstream genes (c-FOS, BCL-2, and CYCLIN D1) were increased by 17β-estradiol and this effect was independently associated with activity of the EGFR-MAPK pathway. The two estrogen receptors might be potential therapeutic targets for the treatment of bladder cancer. Weiren Huang, Yuanbin Chen, Yuchen Liu, Qiaoxia Zhang, Zhou Yu, Lisha Mou, Hanwei Wu, Li Zhao, Ting Long, Danian Qin, and Yaoting Gui Copyright © 2015 Weiren Huang et al. All rights reserved. Screening Active Compounds from Garcinia Species Native to China Reveals Novel Compounds Targeting the STAT/JAK Signaling Pathway Mon, 18 May 2015 07:48:54 +0000 Natural compounds from medicinal plants are important resources for drug development. In a panel of human tumor cells, we screened a library of the natural products from Garcinia species which have anticancer potential to identify new potential therapeutic leads and discovered that caged xanthones were highly effective at suppressing multiple cancer cell lines. Their anticancer activities mainly depended on apoptosis pathways. For compounds in sensitive cancer line, their mechanisms of mode of action were evaluated. 33-Hydroxyepigambogic acid and 35-hydroxyepigambogic acid exhibited about 1 μM IC50 values against JAK2/JAK3 kinases and less than 1 μM IC50 values against NCI-H1650 cell which autocrined IL-6. Thus these two compounds provided a new antitumor molecular scaffold. Our report describes 33-hydroxyepigambogic acid and 35-hydroxyepigambogic acid that inhibited NCI-H1650 cell growth by suppressing constitutive STAT3 activation via direct inhibition of JAK kinase activity. Linfeng Xu, Yuanzhi Lao, Yanhui Zhao, Jian Qin, Wenwei Fu, Yingjia Zhang, and Hongxi Xu Copyright © 2015 Linfeng Xu et al. All rights reserved. Hepatocellular Carcinoma Growth Is Inhibited by Euphorbia helioscopia L. Extract in Nude Mice Xenografts Mon, 18 May 2015 07:07:09 +0000 Euphorbia helioscopia L. is a traditional Chinese medicine; recently research found that its ethyl acetate extract (EAE) plays an important role on tumor cell proliferation, apoptosis, invasion, and metastasis in vitro. But the effect of EAE for tumor cells in vivo has not been reported. To explore the inhibitory effect of EAE and molecular mechanism on hepatocellular carcinoma (HCC) SMMC-7721 cells in vivo, we utilized the nude mouse xenograft model of HCC. Treated with EAE (50, 100, and 200 μg/mL), the volume of xenograft was measured during the entire process of EAE treatment. In EAE treatment group, the volume of xenograft was significantly reduced compared with the control group () and the protein expressions of CyclinD1, bcl-2, and MMP-9 were reduced, while those of bax, caspase-3, and nm23-H1 were increased. A significant change trend with increasing EAE concentrations has presented, compared with controls. Moreover, the ultrastructural morphology of xenografts showed significant changes, including nuclear pyknosis and chromatin condensation, We found that EAE could effectively inhibit tumor growth, induce apoptosis, and inhibit tumor invasion and metastasis in vivo; it is suggested that EAE is a potential candidate for as a new anticancer agent. Junsheng Cheng, Wei Han, Zheyuan Wang, Yuan Shao, Yingzhen Wang, Yawu Zhang, Zhongxin Li, Xiaodong Xu, and Youcheng Zhang Copyright © 2015 Junsheng Cheng et al. All rights reserved. Heteronemin, a Spongean Sesterterpene, Induces Cell Apoptosis and Autophagy in Human Renal Carcinoma Cells Mon, 18 May 2015 06:44:18 +0000 Heteronemin is a bioactive marine sesterterpene isolated from the sponge Hyrtios sp. Previous reports have shown that heteronemin possesses anticancer activity. Here, heteronemin displayed cytotoxic effects against three human cancer cell lines (A549, ACHN, and A498) and exhibited potent activity in A498 human renal carcinoma cells, with an IC50 value of 1.57 μM by MTT assay and a GI50 value of 0.77 μM by SRB assay. Heteronemin initiates apoptotic cell death by downregulating Bcl-2 and Bcl-xL and upregulating Bax, leading to the disruption of the mitochondrial membrane potential and the release of cytochrome from the mitochondria. These effects were associated with the activation of caspase-3/caspase-8/caspase-9, followed by PARP cleavage. Furthermore, heteronemin inhibited the phosphorylation of AKT signaling pathway and ERK and activated p38 and JNK. The specific inhibition of the p38 pathway by SB203580 or p38 siRNA treatment reversed the heteronemin-induced cytotoxicity and apoptotic signaling. Heteronemin also induced autophagy in A498 cells, and treatment with chloroquine (autophagy inhibitor) or SP600125 (JNK inhibitor) inhibited autophagy and increased heteronemin-induced cytotoxicity and apoptotic signaling. Taken together, this study proposes a novel treatment paradigm in which the combination of heteronemin and autophagy inhibitors leads to enhanced RCC cell apoptosis. Szu-Ying Wu, Ping-Jyun Sung, Ya-Ling Chang, Shiow-Lin Pan, and Che-Ming Teng Copyright © 2015 Szu-Ying Wu et al. All rights reserved. Vitamin K1 Exerts Antiproliferative Effects and Induces Apoptosis in Three Differently Graded Human Colon Cancer Cell Lines Sun, 17 May 2015 14:13:11 +0000 Vitamin K1 has been demonstrated as having anticancer potentiality mainly in liver cancer cells. Beyond the reported mechanisms of cancer inhibition (cell cycle arrest and induction of apoptosis), a possible control by vitamin K1 on molecules affecting cell growth could be hypothesized. In the literature, few (if any) data are available on its antitumor effects on colon cancer cells. Therefore, the aims of the study were to investigate in three differently graded human colon cancer cell lines (Caco-2, HT-29, and SW480) the effects of increasing concentrations of vitamin K1 (from 10 μM to 200 μM) administered up to 72 h on (1) cell proliferation, (2) apoptosis with the possible involvement of the MAPK pathway, and (3) polyamine biosynthesis. Vitamin K1 treatment caused a significant antiproliferative effect and induced apoptosis in all the cell lines, with the involvement of the MAPK pathway. A concomitant and significant decrease in the polyamine biosynthesis occurred. This is the first study demonstrating a significant polyamine decrease in addition to the antiproliferative and proapoptotic effects following vitamin K1 administration to colon cancer cell lines. Therapeutically, combinations of vitamin K1 with polyamine inhibitors and/or analogues may represent a suitable option for chemoprevention and/or treatment in future strategies for colorectal cancer management. Antonella Orlando, Michele Linsalata, Valeria Tutino, Benedetta D'Attoma, Maria Notarnicola, and Francesco Russo Copyright © 2015 Antonella Orlando et al. All rights reserved. Ecdysteroids Sensitize MDR and Non-MDR Cancer Cell Lines to Doxorubicin, Paclitaxel, and Vincristine but Tend to Protect Them from Cisplatin Sun, 17 May 2015 13:37:42 +0000 Ecdysteroids, analogs of the insect molting hormone, are known for their various mild, nonhormonal bioactivities in mammals. Previously, we reported that less-polar ecdysteroids can modulate the doxorubicin resistance of a multidrug resistant (MDR) mouse lymphoma cell line expressing the human ABCB1 transporter. Here, we describe the ability of 20-hydroxyecdysone (1) and its mono- (2) and diacetonide (3) derivatives to sensitize various MDR and non-MDR cancer cell lines towards doxorubicin, paclitaxel, vincristine, or cisplatin. Drug IC50 values with or without ecdysteroid were determined by MTT assay. Compound 3 significantly sensitized all cell lines to each chemotherapeutic except for cisplatin, whose activity was decreased. In order to overcome solubility and stability issues for the future in vivo administration of compound 3, liposomal formulations were developed. By means of their combination index values obtained via checkerboard microplate method, a formulation showed superior activity to that of compound 3 alone. Because ecdysteroids act also on non-ABCB1 expressing (sensitive) cell lines, our results demonstrate that they do not or not exclusively exert their adjuvant anticancer activity as ABCB1 inhibitors, but other mechanisms must be involved, and they opened the way towards their in vivo bioactivity testing against various cancer xenografts. Ana Martins, Péter Sipos, Katalin Dér, József Csábi, Walter Miklos, Walter Berger, Attila Zalatnai, Leonard Amaral, Joseph Molnár, Piroska Szabó-Révész, and Attila Hunyadi Copyright © 2015 Ana Martins et al. All rights reserved. Curcumin and Its Analogue Induce Apoptosis in Leukemia Cells and Have Additive Effects with Bortezomib in Cellular and Xenograft Models Sun, 17 May 2015 13:17:40 +0000 Combination therapy of bortezomib with other chemotherapeutics is an emerging treatment strategy. Since both curcumin and bortezomib inhibit NF-κB, we tested the effects of their combination on leukemia cells. To improve potency, a novel Mannich-type curcumin derivative, C-150, was synthesized. Curcumin and its analogue showed potent antiproliferative and apoptotic effects on the human leukemia cell line, HL60, with different potency but similar additive properties with bortezomib. Additive antiproliferative effects were correlated well with LPS-induced NF-κB inhibition results. Gene expression data on cell cycle and apoptosis related genes, obtained by high-throughput QPCR, showed that curcumin and its analogue act through similar signaling pathways. In correlation with in vitro results similar additive effect could be obsereved in SCID mice inoculated systemically with HL60 cells. C-150 in a liposomal formulation given intravenously in combination with bortezomib was more efficient than either of the drugs alone. As our novel curcumin analogue exerted anticancer effects in leukemic cells at submicromolar concentration in vitro and at 3 mg/kg dose in vivo, which was potentiated by bortezomib, it holds a great promise as a future therapeutic agent in the treatment of leukemia alone or in combination. L. I. Nagy, L. Z. Fehér, G. J. Szebeni, M. Gyuris, P. Sipos, R. Alföldi, B. Ózsvári, L. Hackler Jr., A. Balázs, P. Batár, I. Kanizsai, and L. G. Puskás Copyright © 2015 L. I. Nagy et al. All rights reserved. Antiproliferative Activity of Flavonoids from Croton sphaerogynus Baill. (Euphorbiaceae) Sun, 17 May 2015 12:58:06 +0000 Croton sphaerogynus is a shrub from the Atlantic Rain Forest in southeastern Brazil. A lyophilized crude EtOH extract from leaves of C. sphaerogynus, obtained by maceration at room temperature (seven days), was suspended in methanol and partitioned with hexane. The purified MeOH phase was fractionated over Sephadex LH-20 yielding five fractions (F1–F5) containing flavonoids, as characterized by HPLC-DAD and HPLC-MS analyses. The antiproliferative activity of the crude EtOH extract, MeOH and hexane phases, and fractions F1–F5 was evaluated on in vitro cell lines NCI-H460 (nonsmall cell lung), MCF-7 (breast cancer), and U251 (glioma). The MeOH phase showed activity (mean log GI50 0.54) higher than the hexane phase and EtOH extract (mean log GI50 1.13 and 1.19, resp.). F1 exhibited activity against NCI-H460 (nonsmall cell lung) (GI50 1.2 μg/mL), which could be accounted for the presence of flavonoids and/or diterpenes. F4 showed moderate activity (mean log GI50 1.05), while F5 showed weak activity (mean log GI50 1.36). It is suggested that the antiproliferative activity of the crude EtOH extract and MeOH phase is accounted for a synergistic combination of flavonoids and diterpenes. Kátia Pereira dos Santos, Lucimar B. Motta, Deborah Y. A. C. Santos, Maria L. F. Salatino, Antonio Salatino, Marcelo J. Pena Ferreira, João Henrique G. Lago, Ana Lúcia T. G. Ruiz, João E. de Carvalho, and Cláudia M. Furlan Copyright © 2015 Kátia Pereira dos Santos et al. All rights reserved. Cosuppression of Sprouty and Sprouty-Related Negative Regulators of FGF Signalling in Prostate Cancer: A Working Hypothesis Sun, 17 May 2015 12:55:38 +0000 Deregulation of FGF receptor tyrosine kinase (RTK) signalling is common in prostate cancer. Normally, to moderate RTK signalling, induction of Sprouty (SPRY) and Sprouty-related (SPRED) antagonists occurs. Whilst decreased SPRY and SPRED has been described in some cancers, their role in prostate cancer is poorly understood. Therefore, we hypothesise that due to the need for tight regulation of RTK signalling, SPRY and SPRED negative regulators provide a degree of redundancy which ensures that a suppression of one or more family member does not lead to disease. Contrary to this, our analyses of prostates from 24-week-old Spry1- or Spry2-deficientmice, either hemizygous (+/−) or homozygous (−/−) for the null allele, revealed a significantly greater incidence of PIN compared to wild-type littermates. We further investigated redundancy of negative regulators in the clinical setting in a preliminary analysis of Gene Expression Omnibus and Oncomine human prostate cancer datasets. Consistent with our hypothesis, in two datasets analysed a significant cosuppression of SPRYs and SPREDs is evident. These findings demonstrate the importance of negative regulators of receptor tyrosine signalling, such as Spry, in the clinical setting, and highlight their importance for future pharmacopeia. Stephen J. Assinder, Daniella Beniamen, and Frank J. Lovicu Copyright © 2015 Stephen J. Assinder et al. All rights reserved. Deguelin Induces Apoptosis by Targeting Both EGFR-Akt and IGF1R-Akt Pathways in Head and Neck Squamous Cell Cancer Cell Lines Sun, 17 May 2015 12:52:35 +0000 Deguelin, a rotenoid compound from the African plant Mundulea sericea (Leguminosae), has been shown to possess antitumor activities but the exact role for the growth factor receptor mediated signaling pathway in head and neck squamous cell carcinoma (HNSCC) is currently still unclear. In the present study, we investigated the effect of deguelin on epidermal growth factor receptor (EGFR) and insulin-like growth factor-1 receptor (IGF1R) pathways in HNSCC cell lines. Flowcytometric analysis revealed accumulation of annexin V positivity in deguelin-treated cells, showing that deguelin induced apoptosis. The deguelin-induced apoptosis was accompanied by the reduction of constitutive phosphorylated levels of IGF1R, Akt, and extracellular signal-regulated kinase1/2 (ERK1/2). LY294002-mediated inhibition of phosphatidylinositol-3 kinase, which is an upstream effector for Akt activation, increased cleavage of poly(ADP-ribosyl) polymerase (PARP) but ERK inhibition by U0126 did not. Deguelin inhibited both IGF-1- and EGF-induced Akt activation. These results showed that deguelin possessed antitumor effect by targeting Akt in dual axis such as EGFR and IGF1R signaling pathways and suggested that it provides an applicable therapeutic strategy for HNSCC patients. Yuh Baba, Masato Fujii, Toyonobu Maeda, Atsuko Suzuki, Satoshi Yuzawa, and Yasumasa Kato Copyright © 2015 Yuh Baba et al. All rights reserved. Progesterone and Src Family Inhibitor PP1 Synergistically Inhibit Cell Migration and Invasion of Human Basal Phenotype Breast Cancer Cells Sun, 17 May 2015 12:43:04 +0000 Basal phenotype breast cancer is one of the most aggressive breast cancers that frequently metastasize to brain. The role of sex hormones and their receptors in development of this disease is largely unclear. We demonstrated that mPRα was expressed at a moderate level in a brain metastatic BPBC cell line MB231Br, which was derived from the parent mPRα undetectable MB231 cells. It functioned as an essential mediator for progesterone induced inhibitory effects on cell migration of MB231Br and, when coincubated with PP1, synergistically enhanced the progesterone’s inhibitory effect on cell migration and invasion in vitro. Progesterone and PP1 cotreatment induced a cascade of molecular signaling events, such as dephosphorylation of FAK, downregulation of MMP9, VEGF, and KCNMA1 expressions. Our in vitro study demonstrated that mPRα was expressed and functioned as an essential mediator for progesterone induced inhibitory effects on cell migration and invasion in BPBC cells. This inhibitory effect was enhanced by PP1 via FAK dephosphorylation, MMP9, VEGF, and KCNMA1 downregulation mechanisms. Our study provides a new clue toward the development of novel promising agents and pathways for inhibiting nuclear hormonal receptor-negative and endocrine-resistant breast cancers. Mingxuan Xie, Li Zhou, Xi Chen, Lindsey O. Gainey, Jian Xiao, Mark S. Nanes, Anji Hou, Shaojin You, and Qiong Chen Copyright © 2015 Mingxuan Xie et al. All rights reserved. Organotypic Culture of Breast Tumor Explants as a Multicellular System for the Screening of Natural Compounds with Antineoplastic Potential Sun, 17 May 2015 12:29:32 +0000 Breast cancer is the leading cause of death in women worldwide. The search for novel compounds with antitumor activity, with less adverse effects and higher efficacy, and the development of methods to evaluate their toxicity is an area of ​​intense research. In this study we implemented the preparation and culture of breast tumor explants, which were obtained from precision-cut breast tumor slices. In order to validate the model we are proposing to screen antineoplastic effect of natural compounds, we selected caffeic acid, ursolic acid, and rosmarinic acid. Using the Krumdieck tissue slicer, precision-cut tissue slices were prepared from breast cancer samples; from these slices, 4 mm explants were obtained and incubated with the selected compounds. Viability was assessed by Alamar Blue assay, LDH release, and histopathological criteria. Results showed that the viability of the explants cultured in the presence of paclitaxel (positive control) decreased significantly (); however, tumor samples responded differently to each compound. When the explants were coincubated with paclitaxel and compounds, a synergic effect was observed. This study shows that ex vivo culture of breast cancer explants offers a suitable alternative model for evaluating natural or synthetic compounds with antitumor properties within the complex microenvironment of the tumor. Irma Edith Carranza-Torres, Nancy Elena Guzmán-Delgado, Consuelo Coronado-Martínez, José Inocente Bañuelos-García, Ezequiel Viveros-Valdez, Javier Morán-Martínez, and Pilar Carranza-Rosales Copyright © 2015 Irma Edith Carranza-Torres et al. All rights reserved. Antioxidant and Proapoptotic Activities of Sclerocarya birrea [(A. Rich.) Hochst.] Methanolic Root Extract on the Hepatocellular Carcinoma Cell Line HepG2 Sun, 17 May 2015 12:28:18 +0000 The main goal of this study was to characterize the in vitro antioxidant activity and the apoptotic potential of S. birrea methanolic root extract (MRE). Among four tested extracts, obtained with different solvents, MRE showed the highest content of polyphenols, flavonoids, and tannins together with antioxidant activities tested with superoxide, nitric oxide, ABTS, and beta-carotene bleaching assays. Moreover, the cytotoxic effect of MRE was evaluated on the hepatocarcinoma cell line HepG2. In these cells, MRE treatment induced apoptosis and generated reactive oxygen species (ROS) in dose-dependent manner. The cytotoxic effect promoted by MRE was prevented by pretreatment of HepG2 cells with N-acetyl-L-cysteine (NAC), suggesting that oxidative stress was pivotal in MRE-mediated cell death. Moreover, we showed that the MRE treatment induced the mitochondrial membrane depolarization and the cytochrome c release from mitochondria into the cytosol. It suggests that the apoptosis occurred in a mitochondrial-dependent pathway. Interestingly, MRE showed a sensibly lower cytotoxicity, associated with a low increase of ROS, in normal human dermal fibroblasts compared to HepG2 cells. It is suggested that the methanolic root extract of S. Birrea is able to selectively increase intracellular ROS levels in cancer cells, promoting cell death. Maria Francesca Armentano, Faustino Bisaccia, Rocchina Miglionico, Daniela Russo, Nicoletta Nolfi, Monica Carmosino, Paula B. Andrade, Patrícia Valentão, Moussoukhoye Sissokho Diop, and Luigi Milella Copyright © 2015 Maria Francesca Armentano et al. All rights reserved. Protein Drugs Related to Allergic Reaction Mon, 11 May 2015 07:43:16 +0000 Ji-Fu Wei, Tian-Rui Xu, Ming-Can Yu, Xing-Ding Zhou, Zuo-Tao Zhao, and Yang Jin Copyright © 2015 Ji-Fu Wei et al. All rights reserved. Evaluation of Aqueous Leaf Extract of Cardiospermum halicacabum (L.) on Fertility of Male Rats Thu, 07 May 2015 06:35:01 +0000 Treatment with 100 mg/kg and 200 mg/kg body weight of aqueous leaf extract (ALE) of Cardiospermum halicacabum for 30 days produced a significant dose dependent increase in the sperm counts and sperm motility in both caput and cauda regions. Further, significant increase in serum testosterone level was evident at all applied doses. However, no significant changes in the weight of sex organs were observed. Aqueous leaf extract also increased the number of females impregnated, number of implantations, and number of viable fetuses while decreasing the total number of resorption sites in the pregnant females. However, the total cholesterol level in the serum remained unchanged and there were no records on renotoxicity; nevertheless ALE exhibited a hepatoprotective effect. It was concluded that aqueous leaf extract of Cardiospermum halicacabum enhanced sperm concentration, motility, and testosterone, leading to positive results in fertility. L. Dinithi. C. Peiris, M. A. T. Dhanushka, and T. A. H. D. G. Jayathilake Copyright © 2015 L. Dinithi. C. Peiris et al. All rights reserved. Adverse Events of Monoclonal Antibodies Used for Cancer Therapy Tue, 05 May 2015 07:33:23 +0000 In 1997, the first monoclonal antibody (MoAb), the chimeric anti-CD20 molecule rituximab, was approved by the US Food and Drug administration for use in cancer patients. Since then, the panel of MoAbs that are approved by international regulatory agencies for the treatment of hematopoietic and solid malignancies has continued to expand, currently encompassing a stunning amount of 20 distinct molecules for 11 targets. We provide a brief scientific background on the use of MoAbs in cancer therapy, review all types of monoclonal antibodies-related adverse events (e.g., allergy, immune-related adverse events, cardiovascular adverse events, and pulmonary adverse events), and discuss the mechanism and treatment of adverse events. Mei Guan, Yan-Ping Zhou, Jin-Lu Sun, and Shu-Chang Chen Copyright © 2015 Mei Guan et al. All rights reserved. Clinical Characteristics of Inpatients with Anaphylaxis in China Mon, 04 May 2015 13:48:13 +0000 Objective. To analyze the clinical characteristics of inpatients with anaphylaxis and the factors that influenced those characteristics. Methods. Using the patient records from 1990 to 2013 from three highly ranked Chinese hospitals, we retrospectively analyzed the characteristics of 108 inpatients with anaphylaxis (not anaphylaxis admitted). Results. The mean patient age was years old and male-to-female ratio was 1 : 1.3. The number of patients with anaphylaxis increased gradually, and cases diagnosed after 2005 accounted for 68.5% of the 108 total cases. The most common trigger was medications. The most common clinical manifestations included cutaneous, nervous, respiratory, circulatory, and digestive signs and symptoms. Male patients were more likely to experience loss of consciousness. Multisystem involvement was more likely to develop in patients with low BP, whereas it was uncommon in those with anaphylaxis induced by antibiotics or anesthetics. Epinephrine was used as the first-line treatment for 56 cases. Conclusions. Inpatient with anaphylaxis was more common in female patients and the number increased gradually during the study period. The most common trigger was medications. Patients with low BP were prone to having multisystem involvement, whereas the cases of anaphylaxis induced by antibiotics and anesthetics were less likely to involve multiple organ systems. Rui Tang, Han-Yi Xu, Ju Cao, Shi Chen, Jin-Lu Sun, Hong Hu, Hai-Chao Li, Ying Diao, and Zhi Li Copyright © 2015 Rui Tang et al. All rights reserved. Diversity of House Dust Mite Species in Xishuangbanna Dai, a Tropical Rainforest Region in Southwest China Mon, 04 May 2015 12:56:20 +0000 Purpose. To survey the species diversity of home dust mites (HDM) in Xishuangbanna, a tropical rainforest region in Southwest China. Methods. From August 2010 to January 2011, mite-allergic patients and healthy controls were invited to participate. Dust samples from the patients’ homes were collected, and mites in the samples were isolated. Permanent slides were prepared for morphologically based species determination. Results. In total, 6316 mite specimens of morphologically identifiable species were found in 233 dust samples taken from 41 homes. The result shows that the mite family of Pyroglyphidae occupied the highest percentage of the total amount of mites collected, followed by Cheyletidae family. The most common adult Pyroglyphidae mites were Dermatophagoides (D.) farinae, D. pteronyssinus, and D. siboney. The most common mites found from other families were Blomia tropicalis, Tyrophagus putrescentiae, and Aleuroglyphus ovatus. Four main allergenic dust mite species D. farinae, D. pteronyssinus, D. siboney, and Blomia tropicalis were found to be coinhabiting in 6/41 homes. Conclusion. The HDM population in homes in Xishuangbanna, a tropical rainforest region in Southwest China, has its own characteristics. It has rich dust mite species and the dust mite densities do not show significant variation across seasons. Jing-Miao Yu, Qing-Hua Luo, Jin-Lu Sun, Cun-Lian Shi, Jia Yin, Yu-Ling Zhou, Rui Tang, Hui Zhang, Zhang Yu, and Meng Chen Copyright © 2015 Jing-Miao Yu et al. All rights reserved. Effects of Streptococcus sanguinis Bacteriocin on Cell Surface Hydrophobicity, Membrane Permeability, and Ultrastructure of Candida Thallus Wed, 29 Apr 2015 11:24:06 +0000 Candida albicans (C.a) and Candida tropicalis (C.t) were treated with Streptococcus sanguinis bacteriocin (S.s bacteriocin), respectively; the bacteriostatic dynamics of S.s bacteriocin, their effects on cell surface hydrophobicity, leakage of inorganic phosphorus and macromolecular substance, cytosolic calcium concentration, and ultrastructure changes of Candida thallus were detected and analyzed. The results showed that inhibitory effect of S.s bacteriocin on C.a and C.t reached peak level at 24 h, the cell-surface hydrophobicity decreased significantly (P < 0.05) after S.s bacteriocin treatment, and there was leakage of cytoplasmic inorganic phosphorus and macromolecular substance from C.a and C.t; cytosolic calcium concentration decreased greatly. After 24 h treatment by S.s bacteriocin, depressive deformity and defect could be found in the cell surface of C.a and C.t; the thallus displayed irregular forms: C.a was shrunken, there was unclear margins abutting upon cell wall and cell membrane, nucleus disappeared, and cytoplasm was inhomogeneous; likewise, C.t was first plasmolysis, and then the cytoplasm was shrunk, the ultrastructure of cell wall and cell membrane was continuously damaged, and the nucleus was karyolysis. It was illustrated that S.s bacteriocin had similar antifungal effect on C.a and C.t; their cell surface hydrophobicity, membrane permeability, and ultrastructure were changed significantly on exposure to S.s bacteriocin. Shengli Ma, Yingnan Zhao, Xue Xia, Xue Dong, Wenyu Ge, and Hui Li Copyright © 2015 Shengli Ma et al. All rights reserved. Efficacy of Sublingual Immunotherapy with Dermatophagoides farinae Extract in Monosensitized and Polysensitized Patients with Allergic Rhinitis: Clinical Observation and Analysis Mon, 27 Apr 2015 11:54:57 +0000 Aim. To investigate differences in the efficacy of sublingual immunotherapy with Dermatophagoides farinae drops in monosensitized and polysensitized allergic rhinitis patients. Methods. The patients enrolled in the study were treated for more than one year by sublingual immunotherapy (SLIT) using Dermatophagoides farinae drops and were divided into a monosensitized group () and a polysensitized group (). Total nasal symptom scores of patients before and after SLIT were analyzed to evaluate the curative effect. The phylogenetic tree of dust mite allergens as well as other allergens that were tested by skin prick test was constructed to help the analysis. Results. There was no significant difference in the efficacy of SLIT between dust mite monosensitized and polysensitized patients. Conclusions. Both dust mite monosensitized and polysensitized patients could be cured by SLIT using Dermatophagoides farinae drops. This study provides a reference for the selection of allergens to be used in immunotherapy for polysensitized AR patients. Chen-Xia Xu, Miao-Lian Zhang, Bi-Zhou Li, Ying He, Ze-Hong Zou, Qiu-Rong Wu, Ai-Lin Tao, He Lai, and Jin-Lu Sun Copyright © 2015 Chen-Xia Xu et al. All rights reserved. Analysis of Anaphylactic Shock Caused by 17 Types of Traditional Chinese Medicine Injections Used to Treat Cardiovascular and Cerebrovascular Diseases Mon, 27 Apr 2015 11:48:43 +0000 Several reports describing anaphylactic shock following treatment of cardiovascular and cerebrovascular diseases with Chinese herbal injections were described. Our analysis of these reports showed that anaphylactic shock caused by traditional Chinese medicine (TCM) injections for the treatment of cardiovascular and cerebrovascular diseases is common but also sometimes fatal. Therefore, we proposed the following four suggestions for improving the clinical safety of delivering Chinese herbal injections and reducing the occurrence of allergic shock. First, patients with cardiovascular and cerebrovascular diseases are at high risk, so they should only be given TCM injections after a doctor’s diagnosis and approval. Second, people in allergic groups can suffer anaphylactic shock, so vigilance is important in the treatment of all age groups, although even more caution should be exercised when treating children or elderly people. In fact, TCM injections may not be appropriate for those age groups, so that they should be carefully considered before treatment. Third, no significant gender differences have been noted in patients with anaphylactic shock, so all patients should be carefully monitored, irrespective of gender. Fourth, the timeframe in which different drugs cause anaphylactic shock varies; thus, patients should be observed as long as possible. Yu-Jiao Guo, De-Wang Wang, Ling Meng, and Yong-Qing Wang Copyright © 2015 Yu-Jiao Guo et al. All rights reserved. Artemisia Allergy Research in China Mon, 27 Apr 2015 11:46:55 +0000 Artemisia is the most important outdoor allergen throughout China. It can cause allergic rhinitis, asthma, or both of them. Since it was verified as an allergenic pollen in 1960, it was identified two times in the Chinese National Pollen Survey (1984, 2009). The first oral immunotherapy double-blinded trial for Artemisia pollen asthma research was conducted in China in 1989 and published in 1990. 40 years since that study, there have been many published research reports on Chinese Artemisia allergy. This review summarizes the information regarding the discovery of Artemisia as an allergenic pollen, pollen account, epidemiology, allergen components, immunological changes in hay fever patients, natural course from rhinitis to asthma, diagnosis, and immunotherapies in China. Rui Tang, Jin-Lu Sun, Jia Yin, and Zhi Li Copyright © 2015 Rui Tang et al. All rights reserved. {2-[1-(3-Methoxycarbonylmethyl-1H-indol-2-yl)-1-methyl-ethyl]-1H-indol-3-yl}-acetic Acid Methyl Ester Inhibited Hepatocellular Carcinoma Growth in Bel-7402 Cells and Its Resistant Variants by Activation of NOX4 and SIRT3 Wed, 15 Apr 2015 11:18:05 +0000 2-[1-(3-Methoxycarbonylmethyl-1H-indol-2-yl)-1-methyl-ethyl]-1H-indol-3-yl-acetic acid methyl ester (MIAM) is a novel indole compound, which possessed high efficacy against many cancers xenografted in mice without obvious toxicity. In this study, we aimed to investigate the effects of MIAM on human hepatocellular carcinoma (HCC) Bel-7402 cells and its resistant variants Bel-7402/5FU. MIAM inhibited the growth of HCC more potent in Bel-7402/5FU cells than its parent cells. MIAM increased cellular reactive oxygen species (ROS) levels, induced cell apoptosis, and arrested cell cycle in G0/G1 phase. MIAM might exert its action on Bel-7402/5FU cells through activation of NADPH oxidase 4 (NOX4)/p22, Sirtuin3 (SIRT3)/SOD2, and SIRT3/p53/p21 pathways. MIAM might inhibit HCC growth through the modulation of SIRT3. When SIRT3 was silenced, the inhibitory effect of MIAM on Bel-7402/5FU was lowered, showing the characteristic of resistance against MIAM, whereas Bel-7402/5FU cells with high expression of SIRT3 by SIRT3 adenovirus infection demonstrated the high sensitivity to MIAM. These results suggested that MIAM might exert its action against Bel-7402/5FU growth through upregulation of SIRT3. We suggested that MIAM might be a promising candidate compound which could develop as a potent anticancer agent targeting NOX4 and SIRT3 activation. Ye Li, Wenjing Wang, Xiaoxue Xu, Shiyue Sun, Xiaoyu Xu, and Xian-jun Qu Copyright © 2015 Ye Li et al. All rights reserved. African Flora Has the Potential to Fight Multidrug Resistance of Cancer Wed, 15 Apr 2015 07:47:01 +0000 Background. Continuous efforts from scientists of diverse fields are necessary not only to better understand the mechanism by which multidrug-resistant (MDR) cancer cells occur, but also to boost the discovery of new cytotoxic compounds to fight MDR phenotypes. Objectives. The present review reports on the contribution of African flora in the discovery of potential cytotoxic phytochemicals against MDR cancer cells. Methodology. Scientific databases such as PubMed, ScienceDirect, Scopus, Google Scholar, and Web of Knowledge were used to retrieve publications related to African plants, isolated compounds, and drug resistant cancer cells. The data were analyzed to highlight cytotoxicity and the modes of actions of extracts and compounds of the most prominent African plants. Also, thresholds and cutoff points for the cytotoxicity and modes of action of phytochemicals have been provided. Results. Most published data related to the antiproliferative potential of African medicinal plants were from Cameroon, Egypt, Nigeria, or Madagascar. The cytotoxicity of phenolic compounds isolated in African plants was generally much better documented than that of terpenoids and alkaloids. Conclusion. African flora represents an enormous resource for novel cytotoxic compounds. To unravel the full potential, efforts should be strengthened throughout the continent, to meet the challenge of a successful fight against MDR cancers. Victor Kuete and Thomas Efferth Copyright © 2015 Victor Kuete and Thomas Efferth. All rights reserved. A Novel Animal Model of Impaired Glucose Tolerance Induced by the Interaction of Vitamin E Deficiency and 60Co Radiation Tue, 14 Apr 2015 11:34:30 +0000 Impaired glucose tolerance (IGT), known as the prediabetes stage, is usually induced by habits of life or environmental factors. Established IGT animal models are mostly conducted with chemical compounds such as streptozocin or genetic modification. However, the occasion of exposure to these factors in daily life is seldom. The objective of this study was to establish a new animal model of IGT induced by VE deficiency in diet and exposure to radiation. SD rats were treated individually or in combination of these two factors. In the combination group, the calculated insulin sensitivity index decreased; then HOMA-β value increased. Oxidative damage and IGT were observed. Insulin secretion level in perfusate from pancreas response to glucose was characterized by a rapid but reduced first phase and an obviously defective second phase upon pancreas perfusion. Histopathological images demonstrated the pathological changes. Western blotting analysis showed that the insulin signaling pathway was downregulated. The interaction of VE deficiency in diet and exposure to radiation could break the equilibrium of oxidation and antioxidation and result in IGT. More importantly, a new IGT model was successfully established which may be conducive to further research into development of drugs against human IGT. Yue Guan, Yan Cheng, Ying Yin, Jialin Duan, Guo Wei, Yan Weng, Chao Guo, Yanrong Zhu, Yanhua Wang, Miaomiao Xi, and Aidong Wen Copyright © 2015 Yue Guan et al. All rights reserved. Chitosan Prevents Gentamicin-Induced Nephrotoxicity via a Carbonyl Stress-Dependent Pathway Sun, 12 Apr 2015 12:44:25 +0000 Aminoglycosides are widely used to treat infections; however, their applications are limited by nephrotoxicity. With the increase of antibiotic resistance, the use of aminoglycosides is inevitable. Low-molecular-weight chitosan (LMWC) has shown renal protective effects in dialysis patients. However, no study has evaluated LMWC for preventing aminoglycoside-induced nephrotoxicity or determined the mechanisms underlying the renal protective effects. In this study, LMWC (165 or 825 mg/kg/day) or metformin (100 mg/kg/day) was orally administered for 13 days to rats with nephropathy induced by gentamicin (GM), a kind of aminoglycoside (150 mg/kg/day i.p. for 6 days). Both LMCW doses improved renal function. Serum creatinine levels improved in rats treated with 165 and 825 mg/kg/day LMWC (from 2.14 ± 0.74 mg/dL to 1.26 ± 0.46 mg/dL and 0.69 ± 0.12 mg/dL, resp., P < 0.05). Blood urea nitrogen levels were also improved in these rats (from 73.73 ± 21.13 mg/dL to 58.70 ± 22.71 mg/dL and 28.82 ± 3.84 mg/dL, resp., P < 0.05). Additionally, renal tissue morphology improved after LMWC treatment, and accumulation of renal methylglyoxal, a damage factor associated with carbonyl stress, was reversed. These results show that LMWC prevents GM-induced renal toxicity via a carbonyl stress-dependent pathway. Chu-Kung Chou, Yi-Chieh Li, Shih-Ming Chen, Yi-Min Shih, and Jen-Ai Lee Copyright © 2015 Chu-Kung Chou et al. All rights reserved. Membrane Transport: Ionic Environments, Signal Transduction, and Development of Therapeutic Targets Sun, 12 Apr 2015 08:37:47 +0000 Akio Tomoda, Yoshinori Marunaka, Douglas C. Eaton, and Anuwat Dinudom Copyright © 2015 Akio Tomoda et al. All rights reserved. Preventive Effect of Liothyronine on Electroconvulsive Therapy-Induced Memory Deficit in Patients with Major Depressive Disorder: A Double-Blind Controlled Clinical Trial Mon, 06 Apr 2015 11:50:38 +0000 Introduction and Objective. Despite the effectiveness of electroconvulsive therapy (ECT) in treating major depressive disorder (MDD), its cognitive side effects make it less popular. This study investigated the impact of liothyronine on ECT-induced memory deficit in patients with MDD. Methodology. This is a double-blind clinical trial, in which 60 patients with MDD who were referred for ECT were selected. The diagnosis was based on the criteria of DSM-IV-TR. Patients were divided randomly into two groups to receive either liothyronine (50 mcg every morning) or placebo. After the assessment with Wechsler Memory Scale-Revised (WMS-R) before first session of ECT, posttests were repeated again, two months after the completion of ECT. Findings. By controlling the pretest scores, the mean scores of the experimental group were higher than the control group in delayed recall, verbal memory, visual memory, general memory, and attention/concentration scales (). Conclusion. Liothyronine may prevent ECT-induced memory impairment in patients with MDD. This study has been registered in IRCT under IRCT201401122660N2. Arash Mohagheghi, Asghar Arfaie, Shahrokh Amiri, Masoud Nouri, Salman Abdi, and Salman Safikhanlou Copyright © 2015 Arash Mohagheghi et al. All rights reserved. Corrigendum to “Semiphysiological versus Empirical Modelling of the Population Pharmacokinetics of Free and Total Cefazolin during Pregnancy” Mon, 30 Mar 2015 08:49:38 +0000 J. G. Coen van Hasselt, Karel Allegaert, Kristel van Calsteren, Jos H. Beijnen, Jan H. M. Schellens, and Alwin D. R. Huitema Copyright © 2015 J. G. Coen van Hasselt et al. All rights reserved. Natural Bioactives in Cancer Treatment and Prevention Thu, 26 Mar 2015 09:01:46 +0000 Yih-Shou Hsieh, Shun-Fa Yang, Gautam Sethi, and Dan-Ning Hu Copyright © 2015 Yih-Shou Hsieh et al. All rights reserved. The Role of Lipids Mediators in Inflammation and Resolution Tue, 24 Mar 2015 12:08:30 +0000 Alexandre de Paula Rogerio, Carlos Artério Sorgi, Ruxana Sadikot, and Troy Carlo Copyright © 2015 Alexandre de Paula Rogerio et al. All rights reserved. Vitamin A, Cancer Treatment and Prevention: The New Role of Cellular Retinol Binding Proteins Tue, 24 Mar 2015 09:16:37 +0000 Retinol and vitamin A derivatives influence cell differentiation, proliferation, and apoptosis and play an important physiologic role in a wide range of biological processes. Retinol is obtained from foods of animal origin. Retinol derivatives are fundamental for vision, while retinoic acid is essential for skin and bone growth. Intracellular retinoid bioavailability is regulated by the presence of specific cytoplasmic retinol and retinoic acid binding proteins (CRBPs and CRABPs). CRBP-1, the most diffuse CRBP isoform, is a small 15 KDa cytosolic protein widely expressed and evolutionarily conserved in many tissues. CRBP-1 acts as chaperone and regulates the uptake, subsequent esterification, and bioavailability of retinol. CRBP-1 plays a major role in wound healing and arterial tissue remodelling processes. In the last years, the role of CRBP-1-related retinoid signalling during cancer progression became object of several studies. CRBP-1 downregulation associates with a more malignant phenotype in breast, ovarian, and nasopharyngeal cancers. Reexpression of CRBP-1 increased retinol sensitivity and reduced viability of ovarian cancer cells in vitro. Further studies are needed to explore new therapeutic strategies aimed at restoring CRBP-1-mediated intracellular retinol trafficking and the meaning of CRBP-1 expression in cancer patients’ screening for a more personalized and efficacy retinoid therapy. Elena Doldo, Gaetana Costanza, Sara Agostinelli, Chiara Tarquini, Amedeo Ferlosio, Gaetano Arcuri, Daniela Passeri, Maria Giovanna Scioli, and Augusto Orlandi Copyright © 2015 Elena Doldo et al. All rights reserved. Comprehensive Review on Betulin as a Potent Anticancer Agent Thu, 19 Mar 2015 12:46:47 +0000 Numerous plant-derived substances, and their derivatives, are effective antitumour and chemopreventive agents. Yet, there are also a plethora of tumour types that do not respond, or become resistant, to these natural substances. This requires the discovery of new active compounds. Betulin (BE) is a pentacyclic triterpene and secondary metabolite of plants abundantly found in the outer bark of the birch tree Betulaceae sp. BE displays a broad spectrum of biological and pharmacological properties, among which the anticancer and chemopreventive activity attract most of the attention. In this vein, BE and its natural and synthetic derivatives act specifically on cancer cells with low cytotoxicity towards normal cells. Although the antineoplastic mechanism of action of BE is not well understood yet, several interesting aspects of BE’s interactions are coming to light. This review will summarize the anticancer and chemopreventive potential of BE in vitro and in vivo by carefully dissecting and comparing the doses and tumour lines used in previous studies, as well as focusing on mechanisms underlying its activity at cellular and molecular level, and discuss future prospects. Sylwia Katarzyna Król, Michał Kiełbus, Adolfo Rivero-Müller, and Andrzej Stepulak Copyright © 2015 Sylwia Katarzyna Król et al. All rights reserved. Inactivation of Src-to-Ezrin Pathway: A Possible Mechanism in the Ouabain-Mediated Inhibition of A549 Cell Migration Thu, 19 Mar 2015 12:44:54 +0000 Ouabain, a cardiac glycoside found in plants, is primarily used in the treatment of congestive heart failure and arrhythmia because of its ability to inhibit Na+/K+-ATPase pump. Recently ouabain has been shown to exert anticancer effects but the underlying mechanism is not clear. Here, we explored the molecular mechanism by which ouabain exerts anticancer effects in human lung adenocarcinoma. Employing proteomic techniques, we found 7 proteins downregulated by ouabain in A549 including p-ezrin, a protein associated with pulmonary cancer metastasis in a dose-dependent manner. In addition, when the relative phosphorylation levels of 39 intracellular proteins were compared between control and ouabain-treated A549 cells, p-Src (Y416) was also found to be downregulated by ouabain. Furthermore, western blot revealed the ouabain-mediated downregulation of p-FAK (Y925), p-paxillin (Y118), p130CAS, and Na+/K+-ATPase subunits that have been shown to be involved in the migration of cancer cells. The inhibitory effect of ouabain and Src inhibitor PP2 on the migration of A549 cells was confirmed by Boyden chamber assay. Anticancer effects of ouabain in A549 cells appear to be related to its ability to regulate and inactivate Src-to-ezrin signaling, and proteins involved in focal adhesion such as Src, FAK, and p130CAS axis are proposed here. Hye Kyoung Shin, Byung Jun Ryu, Sik-Won Choi, Seong Hwan Kim, and Kyunglim Lee Copyright © 2015 Hye Kyoung Shin et al. All rights reserved. Thyroid Hormone and P-Glycoprotein in Tumor Cells Thu, 19 Mar 2015 12:38:45 +0000 P-glycoprotein (P-gp; multidrug resistance pump 1, MDR1; ABCB1) is a plasma membrane efflux pump that when activated in cancer cells exports chemotherapeutic agents. Transcription of the P-gp gene (MDR1) and activity of the P-gp protein are known to be affected by thyroid hormone. A cell surface receptor for thyroid hormone on integrin v3 also binds tetraiodothyroacetic acid (tetrac), a derivative of L-thyroxine (T4) that blocks nongenomic actions of T4 and of 3,5,3′-triiodo-L-thyronine (T3) at v3. Covalently bound to a nanoparticle, tetrac as nanotetrac acts at the integrin to increase intracellular residence time of chemotherapeutic agents such as doxorubicin and etoposide that are substrates of P-gp. This action chemosensitizes cancer cells. In this review, we examine possible molecular mechanisms for the inhibitory effect of nanotetrac on P-gp activity. Mechanisms for consideration include cancer cell acidification via action of tetrac/nanotetrac on the Na+/H+ exchanger (NHE1) and hormone analogue effects on calmodulin-dependent processes and on interactions of P-gp with epidermal growth factor (EGF) and osteopontin (OPN), apparently via v3. Intracellular acidification and decreased H+ efflux induced by tetrac/nanotetrac via NHE1 is the most attractive explanation for the actions on P-gp and consequent increase in cancer cell retention of chemotherapeutic agent-ligands of MDR1 protein. Paul J. Davis, Sandra Incerpi, Hung-Yun Lin, Heng-Yuan Tang, Thangirala Sudha, and Shaker A. Mousa Copyright © 2015 Paul J. Davis et al. All rights reserved. Lipid Mediators Are Critical in Resolving Inflammation: A Review of the Emerging Roles of Eicosanoids in Diabetes Mellitus Thu, 19 Mar 2015 12:17:21 +0000 The biosynthesis pathway of eicosanoids derived from arachidonic acid, such as prostaglandins and leukotrienes, relates to the pathophysiology of diabetes mellitus (DM). A better understanding of how lipid mediators modulate the inflammatory process may help recognize key factors underlying the progression of diabetes complications. Our review presents recent knowledge about eicosanoid synthesis and signaling in DM-related complications, and discusses eicosanoid-related target therapeutics. Fernando H. G. Tessaro, Thais S. Ayala, and Joilson O. Martins Copyright © 2015 Fernando H. G. Tessaro et al. All rights reserved. New Insights into Glomerular Parietal Epithelial Cell Activation and Its Signaling Pathways in Glomerular Diseases Thu, 19 Mar 2015 11:41:17 +0000 The glomerular parietal epithelial cells (PECs) have aroused an increasing attention recently. The proliferation of PECs is the main feature of crescentic glomerulonephritis; besides that, in the past decade, PEC activation has been identified in several types of noninflammatory glomerulonephropathies, such as focal segmental glomerulosclerosis, diabetic glomerulopathy, and membranous nephropathy. The pathogenesis of PEC activation is poorly understood; however, a few studies delicately elucidate the potential mechanisms and signaling pathways implicated in these processes. In this review we will focus on the latest observations and concepts about PEC activation in glomerular diseases and the newest identified signaling pathways in PEC activation. Hua Su, Shan Chen, Fang-Fang He, Yu-Mei Wang, Philip Bondzie, and Chun Zhang Copyright © 2015 Hua Su et al. All rights reserved. Ouabain-Induced Cytoplasmic Vesicles and Their Role in Cell Volume Maintenance Thu, 19 Mar 2015 11:29:27 +0000 Cellular swelling is controlled by an active mechanism of cell volume regulation driven by a Na+/K+-dependent ATPase and by aquaporins which translocate water along the osmotic gradient. Na+/K+-pump may be blocked by ouabain, a digitalic derivative, by inhibition of ATP, or by drastic ion alterations of extracellular fluid. However, it has been observed that some tissues are still able to control their volume despite the presence of ouabain, suggesting the existence of other mechanisms of cell volume control. In 1977, by correlating electron microscopy observation with ion and water composition of liver slices incubated in different metabolic conditions in the presence or absence of ouabain, we observed that hepatocytes were able to control their volume extruding water and recovering ion composition in the presence of ouabain. In particular, hepatocytes were able to sequester ions and water in intracellular vesicles and then secrete them at the bile canaliculus pole. We named this “vesicular mechanism of cell volume control.” Afterward, this mechanism has been confirmed by us and other laboratories in several mammalian tissues. This review summarizes evidences regarding this mechanism, problems that are still pending, and questions that need to be answered. Finally, we shortly review the importance of cell volume control in some human pathological conditions. M. A. Russo, E. Morgante, A. Russo, G. D. van Rossum, and M. Tafani Copyright © 2015 M. A. Russo et al. All rights reserved. Involvement of the Gut Chemosensory System in the Regulation of Colonic Anion Secretion Thu, 19 Mar 2015 11:08:05 +0000 The primary function of the gastrointestinal (GI) tract is the extraction of nutrients from the diet. Therefore, the GI tract must possess an efficient surveillance system that continuously monitors the luminal content for beneficial or harmful compounds. Recent studies have shown that specialized cells in the intestinal lining can sense changes in this content. These changes directly influence fundamental GI processes such as secretion, motility, and local blood flow via hormonal and/or neuronal pathways. Until recently, most studies examining the control of ion transport in the colon have focused on neural and hormonal regulation. However, study of the regulation of gut function by the gut chemosensory system has become increasingly important, as failure of this system causes dysfunctions in host homeostasis, as well as functional GI disorders. Furthermore, regulation of ion transport in the colon is critical for host defense and for electrolytes balance. This review discusses the role of the gut chemosensory system in epithelial transport, with a particular emphasis on the colon. A. Kuwahara Copyright © 2015 A. Kuwahara. All rights reserved. Physiological Impact of Abnormal Lipoxin A4 Production on Cystic Fibrosis Airway Epithelium and Therapeutic Potential Thu, 19 Mar 2015 10:27:47 +0000 Lipoxin A4 has been described as a major signal for the resolution of inflammation and is abnormally produced in the lungs of patients with cystic fibrosis (CF). In CF, the loss of chloride transport caused by the mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) Cl− channel gene results in dehydration, mucus plugging, and reduction of the airway surface liquid layer (ASL) height which favour chronic lung infection and neutrophil based inflammation leading to progressive lung destruction and early death of people with CF. This review highlights the unique ability of LXA4 to restore airway surface hydration, to stimulate airway epithelial repair, and to antagonise the proinflammatory program of the CF airway, circumventing some of the most difficult aspects of CF pathophysiology. The report points out novel aspects of the cellular mechanism involved in the physiological response to LXA4, including release of ATP from airway epithelial cell via pannexin channel and subsequent activation of and P2Y11 purinoreceptor. Therefore, inadequate endogenous LXA4 biosynthesis reported in CF exacerbates the ion transport abnormality and defective mucociliary clearance, in addition to impairing the resolution of inflammation, thus amplifying the vicious circle of airway dehydration, chronic infection, and inflammation. Gerard Higgins, Fiona Ringholz, Paul Buchanan, Paul McNally, and Valérie Urbach Copyright © 2015 Gerard Higgins et al. All rights reserved. Placing Ion Channels into a Signaling Network of T Cells: From Maturing Thymocytes to Healthy T Lymphocytes or Leukemic T Lymphoblasts Thu, 19 Mar 2015 10:08:20 +0000 T leukemogenesis is a multistep process, where the genetic errors during T cell maturation cause the healthy progenitor to convert into the leukemic precursor that lost its ability to differentiate but possesses high potential for proliferation, self-renewal, and migration. A new misdirecting “leukemogenic” signaling network appears, composed by three types of participants which are encoded by (1) genes implicated in determined stages of T cell development but deregulated by translocations or mutations, (2) genes which normally do not participate in T cell development but are upregulated, and (3) nondifferentially expressed genes which become highly interconnected with genes expressed differentially. It appears that each of three groups may contain genes coding ion channels. In T cells, ion channels are implicated in regulation of cell cycle progression, differentiation, activation, migration, and cell death. In the present review we are going to reveal a relationship between different genetic defects, which drive the T cell neoplasias, with calcium signaling and ion channels. We suggest that changes in regulation of various ion channels in different types of the T leukemias may provide the intracellular ion microenvironment favorable to maintain self-renewal capacity, arrest differentiation, induce proliferation, and enhance motility. Oxana Dobrovinskaya, Iván Delgado-Enciso, Laura Johanna Quintero-Castro, Carlos Best-Aguilera, Rocío Monserrat Rojas-Sotelo, and Igor Pottosin Copyright © 2015 Oxana Dobrovinskaya et al. All rights reserved. Blood Brain Barrier: A Challenge for Effectual Therapy of Brain Tumors Thu, 19 Mar 2015 10:08:12 +0000 Brain tumors are one of the most formidable diseases of mankind. They have only a fair to poor prognosis and high relapse rate. One of the major causes of extreme difficulty in brain tumor treatment is the presence of blood brain barrier (BBB). BBB comprises different molecular components and transport systems, which in turn create efflux machinery or hindrance for the entry of several drugs in brain. Thus, along with the conventional techniques, successful modification of drug delivery and novel therapeutic strategies are needed to overcome this obstacle for treatment of brain tumors. In this review, we have elucidated some critical insights into the composition and function of BBB and along with it we have discussed the effective methods for delivery of drugs to the brain and therapeutic strategies overcoming the barrier. Arijit Bhowmik, Rajni Khan, and Mrinal Kanti Ghosh Copyright © 2015 Arijit Bhowmik et al. All rights reserved. Multifaceted Roles of Cysteinyl Leukotrienes in Eliciting Eosinophil Granule Protein Secretion Thu, 19 Mar 2015 08:08:14 +0000 Cysteinyl leukotrienes (cysLTs) are cell membrane-impermeant lipid mediators that play major roles in the pathogenesis of eosinophilic inflammation and are recognized to act via at least 2 receptors, namely, cysLT1 receptor (cysLT1R) and cysLT2 receptor (cysLT2R). Eosinophils, which are granulocytes classically associated with host defense against parasitic helminthes and allergic conditions, are distinguished from leukocytes by their dominant population of cytoplasmic crystalloid (also termed secretory, specific, or secondary) granules that contain robust stores of diverse preformed proteins. Human eosinophils are the main source of cysLTs and are recognized to express both cysLTs receptors (cysLTRs) on their surface, at the plasma membrane. More recently, we identified the expression of cysLTRs in eosinophil granule membranes and demonstrated that cysLTs, acting via their granule membrane-expressed receptors, elicit secretion from cell-free human eosinophil granules. Herein, we review the multifaceted roles of cysLTs in eliciting eosinophil granule protein secretion. We discuss the intracrine and autocrine/paracrine secretory responses evoked by cysLTs in eosinophils and in cell-free extracellular eosinophil crystalloid granules. We also discuss the importance of this finding in eosinophil immunobiology and speculate on its potential role(s) in eosinophilic diseases. Renata Baptista-dos-Reis, Valdirene S. Muniz, and Josiane S. Neves Copyright © 2015 Renata Baptista-dos-Reis et al. All rights reserved. Exposure to Allergen Causes Changes in NTS Neural Activities after Intratracheal Capsaicin Application, in Endocannabinoid Levels and in the Glia Morphology of NTS Thu, 19 Mar 2015 08:00:10 +0000 Allergen exposure may induce changes in the brainstem secondary neurons, with neural sensitization of the nucleus solitary tract (NTS), which in turn can be considered one of the causes of the airway hyperresponsiveness, a characteristic feature of asthma. We evaluated neurofunctional, morphological, and biochemical changes in the NTS of naive or sensitized rats. To evaluate the cell firing activity of NTS, in vivo electrophysiological experiments were performed before and after capsaicin challenge in sensitized or naive rats. Immunohistochemical studies, endocannabinoid, and palmitoylethanolamide quantification in the NTS were also performed. This study provides evidence that allergen sensitization in the NTS induced: (1) increase in the neural firing response to intratracheal capsaicin application, (2) increase of endocannabinoid anandamide and palmitoylethanolamide, a reduction of 2-arachidonoylglycerol levels in the NTS, (3) glial cell activation, and (4) prevention by a Group III metabotropic glutamate receptor activation of neural firing response to intratracheal application of capsaicin in both naïve and sensitized rats. Therefore, normalization of ovalbumin-induced NTS neural sensitization could open up the prospect of new treatments based on the recovery of specific brain nuclei function and for extensive studies on acute or long-term efficacy of selective mGlu ligand, in models of bronchial hyperreactivity. Giuseppe Spaziano, Livio Luongo, Francesca Guida, Stefania Petrosino, Maria Matteis, Enza Palazzo, Nikol Sullo, Vito de Novellis, Vincenzo Di Marzo, Francesco Rossi, Sabatino Maione, and Bruno D’Agostino Copyright © 2015 Giuseppe Spaziano et al. All rights reserved. Aging: Mitigation and Intervention Strategies Tue, 10 Mar 2015 07:50:49 +0000 Chi-Feng Hung, Jorge Azofeifa-Navas, Huanran Tan, Chih-Chi Andrew Hu, and Nicole Clarke Copyright © 2015 Chi-Feng Hung et al. All rights reserved. Wu-Tou Decoction Inhibits Chronic Inflammatory Pain in Mice: Participation of TRPV1 and TRPA1 Ion Channels Mon, 09 Mar 2015 09:09:56 +0000 Wu-tou decoction (WTD) is a classic traditional Chinese medicine formula and has been used effectively to treat joint diseases clinically. Previous reports indicated that WTD possesses anti-inflammatory activity; however, its actions on pain have not been clarified. Here, we investigated the antinociceptive activity of WTD in CFA-induced mice, and its possible mechanism of the action associated with transient receptor potential (TRP) ion channels was also explored. Our results showed that 1.58, 3.15, and 6.30 g/kg WTD significantly attenuated mechanical, cold, and heat hypersensitivities. Moreover, WTD effectively inhibited spontaneous nociceptive responses to intraplantar injections of capsaicin and cinnamaldehyde, respectively. WTD also effectively suppressed jumping and wet-dog-shake behaviors to intraperitoneal injection of icilin. Additionally, WTD significantly reduced protein expression of TRPV1 and TRPA1 in dorsal root ganglia and skins of injured paw. Collectively, our data demonstrate firstly that WTD exerts antinociceptive activity in inflammatory conditions by attenuating mechanical, cold, and heat hypersensitivities. This antinociceptive effect may result in part from inhibiting the activities of TRPV1, TRPA1, and TRPM8, and the suppression of TRPV1 and TRPA1 protein by WTD was also highly effective. These findings suggest that WTD might be an attractive and suitable therapeutic agent for the management of chronic inflammatory pain. Chao Wang, Chunfang Liu, Hongye Wan, Danhua Wang, Danni Sun, Tengfei Xu, Yue Yang, Yakun Qu, Ying Xu, Xianghong Jing, Junling Liu, Shuping Chen, Zhiqiang Liu, and Na Lin Copyright © 2015 Chao Wang et al. All rights reserved. Inhibition of Osteoclast Activation by Phloretin through Disturbing αvβ3 Integrin-c-Src Pathway Thu, 05 Mar 2015 11:07:50 +0000 This study was to explore the sequential signaling of disorganization of the actin cytoskeletal architecture by phloretin. RAW 264.7 macrophages were incubated with 1–20 M phloretin for 5 days in the presence of RANKL. C57BL/6 mice were ovariectomized (OVX) and orally treated with 10 mg/kg phloretin once a day for 8 weeks. Phloretin allayed RANKL stimulated formation of actin podosomes with the concomitant retardation of the vinculin activation. Oral administration of phloretin suppressed the induction of femoral gelsolin and vinculin in OVX mice. The RANK-RANKL interaction resulted in the αv3 integrin induction, which was demoted by phloretin. The RANKL induction of actin rings and vacuolar-type H+-ATPase entailed Pyk2 phosphorylation and c-Src and c-Cbl induction, all of which were blunted by phloretin. Similar inhibition was also observed in phloretin-exposed OVX mouse femoral bone tissues with decreased trabecular collagen formation. Phloretin suppressed the paxillin induction in RANKL-activated osteoclasts and in OVX epiphyseal bone tissues. Also, phloretin attenuated the Syk phosphorylation and phospholipase C induction by RANKL in osteoclasts. These results suggest that phloretin was an inhibitor of actin podosomes and sealing zone, disrupting αv3 integrin-c-Src-Pyk2/Syk signaling pathway for the regulation of actin cytoskeletal organization in osteoclasts. Eun-Jung Lee, Jung-Lye Kim, Ju-Hyun Gong, Sin-Hye Park, and Young-Hee Kang Copyright © 2015 Eun-Jung Lee et al. All rights reserved. A Low-Dose Combination of Fluvastatin and Valsartan: A New “Drug” and a New Approach for Decreasing the Arterial Age Tue, 03 Mar 2015 13:47:31 +0000 We have developed a new “drug” and approach that appear to be effective in reducing arterial age. This “drug” represents a low, subtherapeutic dose of statin and sartan and particularly their low-dose combination. The improvement of arterial wall characteristics, also reflecting in a decrease of arterial age, was achieved after a short period of treatment (one month) with the above-mentioned drugs. In addition, we have also implemented a new, innovative therapeutic approach, consisting of intermittent (cyclic) treatment—alternating short “treatment” periods and much longer “rest” periods (when the beneficial effects are still present but gradually decline). This new “drug” and approach both merit further investigation in order to confirm their antiaging efficacy. Miodrag Janić, Mojca Lunder, and Mišo Šabovič Copyright © 2015 Miodrag Janić et al. All rights reserved. Topical Anti-Inflammatory Effects of Isorhamnetin Glycosides Isolated from Opuntia ficus-indica Mon, 02 Mar 2015 11:17:15 +0000 Opuntia ficus-indica (OFI) has been widely used in Mexico as a food and for the treatment of different health disorders such as inflammation and skin aging. Its biological properties have been attributed to different phytochemicals such as the isorhamnetin glycosides which are the most abundant flavonoids. Moreover, these compounds are considered a chemotaxonomic characteristic of OFI species. The aim of this study was to evaluate the effect of OFI extract and its isorhamnetin glycosides on different inflammatory markers in vitro and in vivo. OFI extract was obtained by alkaline hydrolysis of OFI cladodes powder and pure compounds were obtained by preparative chromatography. Nitric oxide (NO), cyclooxygenase-2 (COX-2), tumor necrosis factor- (TNF-) α, and interleukin- (IL-) 6 production were measured. NO production was tested in lipopolysaccharide-stimulated RAW 264.7 cells while in vivo studies were carried on croton oil-induced ear edema model. OFI extract and diglycoside isorhamnetin-glucosyl-rhamnoside (IGR) at 125 ng/mL suppressed the NO production in vitro (% and %, resp.) without affecting cell viability. Likewise, IGR inhibited the ear edema (%) equating the indomethacin effects (%). Both IGR and OFI extract significantly inhibited the COX-2, TNF-α, and IL-6 production. IGR seems to be a suitable natural compound for development of new anti-inflammatory ingredient. Marilena Antunes-Ricardo, Janet A. Gutiérrez-Uribe, Carlos Martínez-Vitela, and Sergio O. Serna-Saldívar Copyright © 2015 Marilena Antunes-Ricardo et al. All rights reserved. Prokinetic Activity of Prunus persica (L.) Batsch Flowers Extract and Its Possible Mechanism of Action in Rats Mon, 02 Mar 2015 06:22:40 +0000 The peach tree, Prunus persica (L.) Batsch, is widely cultivated in China, and its flowers have been used for centuries in traditional Chinese medicine to treat gut motility disorders. But few studies have explored the pharmacological effect of Prunus persica (L.) Batsch flowers on gastrointestinal motility. In this study, the activities of different extracts from Prunus persica (L.) Batsch flowers on the smooth muscle contractions were evaluated using isolated colon model, and the ethyl acetate extract (EAE) showed the strongest effects in vitro. EAE (10−8–10−5 g/mL) caused a concentration-dependent stimulatory effect in rat colonic tissue. Additionally, ketotifen (100 µM), cimetidine (10 µM), and pyrilamine (1 µM) produced a significant inhibition of contractions caused by EAE. Furthermore, immunofluorescence and toluidine blue staining revealed increased numbers of mast cells in the EAE group, and EAE increased histamine release from the colonic tissues. These data indicate that EAE has significant prokinetic activity and acts by a mechanism that mainly involves mast cell degranulation. Our study provides a pharmacological basis for the use of an extract of Prunus persica (L.) Batsch flowers in the treatment of gut motility disorders. Wei Han, Jing Dong Xu, Feng Xian Wei, Yong Dong Zheng, Jian Zhong Ma, Xiao Dong Xu, Zhen Gang Wei, Wen Wang, and You Cheng Zhang Copyright © 2015 Wei Han et al. 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.