BioMed Research International: Pharmacology The latest articles from Hindawi Publishing Corporation © 2015 , Hindawi Publishing Corporation . 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. Comparative Effects of Retinoic Acid or Glycolic Acid Vehiculated in Different Topical Formulations Tue, 06 Jan 2015 08:50:47 +0000 Retinoids and hydroxy acids have been widely used due to their effects in the regulation of growth and in the differentiation of epithelial cells. However, besides their similar indication, they have different mechanisms of action and thus they may have different effects on the skin; in addition, since the topical formulation efficiency depends on vehicle characteristics, the ingredients of the formulation could alter their effects. Thus the objective of this study was to compare the effects of retinoic acid (RA) and glycolic acid (GA) treatment on the hairless mouse epidermis thickness and horny layer renewal when added in gel, gel cream, or cream formulations. For this, gel, gel cream, and cream formulations (with or without 6% GA or 0.05% RA) were applied in the dorsum of hairless mice, once a day for seven days. After that, the skin was analyzed by histopathologic, morphometric, and stereologic techniques. It was observed that the effects of RA occurred independently from the vehicle, while GA had better results when added in the gel cream and cream. Retinoic acid was more effective when compared to glycolic acid, mainly in the cell renewal and the exfoliation process because it decreased the horny layer thickness. Patrícia Maria Berardo Gonçalves Maia Campos, Lorena Rigo Gaspar, Gisele Mara Silva Gonçalves, Lúcia Helena Terenciane Rodrigues Pereira, Marisa Semprini, and Ruberval Armando Lopes Copyright © 2015 Patrícia Maria Berardo Gonçalves Maia Campos et al. All rights reserved. Pharmacokinetics Interaction between Imatinib and Genistein in Rats Mon, 05 Jan 2015 14:19:00 +0000 The objective of this work was to investigate the effect of orally administered genistein on the pharmacokinetics of imatinib and N-desmethyl imatinib in rats. Twenty-five healthy male SD (Sprague-Dawley) rats were randomly divided into five groups: A group (control group), B group (multiple dose of 100 mg/kg genistein for consecutive 15 days), C group (multiple dose of 50 mg/kg genistein for consecutive 15 days), D group (a single dose of 100 mg/kg genistein), and E group (a single dose of 50 mg/kg genistein). A single dose of imatinib is administered orally 30 min after administration of genistein (100 mg/kg or 50 mg/kg). The pharmacokinetic parameters of imatinib and N-desmethyl imatinib were calculated by DAS 3.0 software. The multiple dose of 100 mg/kg or 50 mg/kg genistein significantly () decreased the and of imatinib. and the of N-desmethyl imatinib were also increased, but without any significant difference. However, the single dose of 100 mg/kg or 50 mg/kg genistein has no effect on the pharmacokinetics of imatinib and N-desmethyl imatinib. Those results indicated that multiple dose of genistein (100 mg/kg or 50 mg/kg) induces the metabolism of imatinib, while single dose of genistein has no effect. Zhe Wang, Li Wang, Meng-ming Xia, Wei Sun, Cheng-ke Huang, Xiao Cui, Guo-xin Hu, Qing-quan Lian, and Zeng-shou Wang Copyright © 2015 Zhe Wang et al. All rights reserved. Pharmacological Application of Growth Factors: Basic and Clinical Mon, 05 Jan 2015 08:04:43 +0000 Jian Xiao, Yadong Wang, Saverio Bellusci, and Xiaokun Li Copyright © 2015 Jian Xiao et al. All rights reserved. Use of Pharmacotherapies in the Treatment of Alcohol Use Disorders and Opioid Dependence in Primary Care Mon, 05 Jan 2015 07:28:13 +0000 Substance-related and addictive disorders are chronic relapsing conditions that substantially impact public health. Effective treatments for these disorders require addressing substance use/dependence comprehensively as well as other associated comorbidities. Comprehensive addressing of substance use in a medical setting involves screening for substance use, addressing substance use directly with the patient, and formulating an appropriate intervention. For alcohol dependence and opioid dependence, pharmacotherapies are available that are safe and effective when utilized in a comprehensive treatment paradigm, such as medication assisted treatment. In primary care, substance use disorders involving alcohol, illicit opioids, and prescription opioid abuse are common among patients who seek primary care services. Primary care providers report low levels of preparedness and confidence in identifying substance-related and addictive disorders and providing appropriate care and treatment. However, new models of service delivery in primary care for individuals with substance-related and addictive disorders are being developed to promote screening, care and treatment, and relapse prevention. The education and training of primary care providers utilizing approved medications for the treatment of alcohol use disorders and opioid dependence in a primary care setting would have important public health impact and reduce the burden of alcohol abuse and opioid dependence. Jinhee Lee, Thomas F. Kresina, Melinda Campopiano, Robert Lubran, and H. Westley Clark Copyright © 2015 Jinhee Lee et al. All rights reserved. Design and Delivery of a Tailored Intervention to Implement Recommendations for Multimorbid Patients Receiving Polypharmacy into Primary Care Practices Mon, 05 Jan 2015 07:26:45 +0000 Introduction. Managing polypharmacy is particularly demanding for general practitioners as coordinators of care. Recently, a German guideline for polypharmacy in primary care has been published. This paper describes the content and delivery of a tailored intervention, which aims at improving the implementation of guideline recommendations for polypharmacy into practice, considering individual barriers. Materials and Methods. Firstly, barriers for implementation and the corresponding strategies to address them have been identified. On this basis, an intervention consisting of a workshop for health care professionals and educational materials for patients has been developed. The workshop focused on knowledge, awareness, and skills. The educational materials included a tablet computer. Practice teams will elaborate individual concepts of how to implement the recommendations into their practice. The workshop has been evaluated by the participants by means of a questionnaire. Results. During the workshop 41 possible sources of medication errors and 41 strategies to improve medication management have been identified. Participants evaluated the workshop overall positively, certifying its relevancy to practice. Discussion. The concept of the workshop seemed appropriate to impart knowledge about medication management to the participants. It will have to be evaluated, if the intervention finally resulted in an improved implementation of the guideline recommendations. Cornelia Jäger, Joachim Szecsenyi, and Jost Steinhäuser Copyright © 2015 Cornelia Jäger et al. All rights reserved. Fibroblast Growth Factors Stimulate Hair Growth through β-Catenin and Shh Expression in C57BL/6 Mice Thu, 01 Jan 2015 10:04:34 +0000 Growth factors are involved in the regulation of hair morphogenesis and cycle hair growth. The present study sought to investigate the hair growth promoting activities of three approved growth factor drugs, fibroblast growth factor 10 (FGF-10), acidic fibroblast growth factor (FGF-1), and basic fibroblast growth factor (FGF-2), and the mechanism of action. We observed that FGFs promoted hair growth by inducing the anagen phase in telogenic C57BL/6 mice. Specifically, the histomorphometric analysis data indicates that topical application of FGFs induced an earlier anagen phase and prolonged the mature anagen phase, in contrast to the control group. Moreover, the immunohistochemical analysis reveals earlier induction of β-catenin and Sonic hedgehog (Shh) in hair follicles of the FGFs-treated group. These results suggest that FGFs promote hair growth by inducing the anagen phase in resting hair follicles and might be a potential hair growth-promoting agent. Wei-hong Lin, Li-Jun Xiang, Hong-Xue Shi, Jian Zhang, Li-ping Jiang, Ping-tao Cai, Zhen-Lang Lin, Bei-Bei Lin, Yan Huang, Hai-Lin Zhang, Xiao-Bing Fu, Ding-Jiong Guo, Xiao-Kun Li, Xiao-Jie Wang, and Jian Xiao Copyright © 2015 Wei-hong Lin et al. All rights reserved. Analgesic and Anti-Inflammatory Activities of Leaf Extract of Mallotus repandus (Willd.) Muell. Arg. Wed, 31 Dec 2014 15:44:54 +0000 In folk medicine Mallotus repandus (Willd.) Muell. Arg. is used to treat muscle pain, itching, fever, rheumatic arthritis, snake bite, hepatitis, and liver cirrhosis. This study aimed to evaluate the antinociceptive as well as the anti-inflammatory activities of the methanol extract of leaf. The leaves were extracted with methanol following hot extraction and tested for the presence of phytochemical constituents. Analgesic and anti-inflammatory activities were evaluated using acetic acid induced writhing test, xylene induced ear edema, cotton pellet induced granuloma, and tail immersion methods at doses of 500, 1000, and 2000 mg/kg body weight. The presence of flavonoids, saponins, and tannins was identified in the extract. The extract exhibited considerable antinociceptive and anti-inflammatory activities against four classical models of pain. In acetic acid induced writhing, xylene induced ear edema, and cotton pellet granuloma models, the extract revealed dose dependent activity. Additionally, it increased latency time in tail immersion model. It can be concluded that M. repandus possesses significant antinociceptive potential. These findings suggest that this plant can be used as a potential source of new antinociceptive and anti-inflammatory candidates. The activity of methanol extract is most likely mediated through central and peripheral inhibitory mechanisms. This study justified the traditional use of leaf part of this plant. Md. Mahadi Hasan, Nizam Uddin, Md. Rakib Hasan, A. F. M. Mahmudul Islam, Md. Monir Hossain, Akib Bin Rahman, Md. Sazzad Hossain, Ishtiaque Ahmed Chowdhury, and Md. Sohel Rana Copyright © 2014 Md. Mahadi Hasan et al. All rights reserved. Therapeutic Potential of Natural Pharmacological Agents in the Treatment of Human Diseases Sun, 28 Dec 2014 07:29:52 +0000 Kota V. Ramana, Sharad S. Singhal, and Aramati B. Reddy Copyright © 2014 Kota V. Ramana et al. All rights reserved. Novel Psychoactive Substances and Behavioral Addictions Sun, 28 Dec 2014 06:44:04 +0000 Giovanni Martinotti, Ornella Corazza, Sophia Achab, and Zsolt Demetrovics Copyright © 2014 Giovanni Martinotti et al. All rights reserved. Proteoglycans/Glycosaminoglycans: From Basic Research to Clinical Practice Sun, 21 Dec 2014 06:35:59 +0000 George Tzanakakis, Ilona Kovalszky, Paraskevi Heldin, and Dragana Nikitovic Copyright © 2014 George Tzanakakis et al. All rights reserved. Cysteine Cathepsin Activity Regulation by Glycosaminoglycans Sun, 21 Dec 2014 06:12:34 +0000 Cysteine cathepsins are a group of enzymes normally found in the endolysosomes where they are primarily involved in intracellular protein turnover but also have a critical role in MHC II-mediated antigen processing and presentation. However, in a number of pathologies cysteine cathepsins were found to be heavily upregulated and secreted into extracellular milieu, where they were found to degrade a number of extracellular proteins. A major role in modulating cathepsin activities play glycosaminoglycans, which were found not only to facilitate their autocatalytic activation including at neutral pH, but also to critically modulate their activities such as in the case of the collagenolytic activity of cathepsin K. The interaction between cathepsins and glycosaminoglycans will be discussed in more detail. Marko Novinec, Brigita Lenarčič, and Boris Turk Copyright © 2014 Marko Novinec et al. All rights reserved. Ethnopharmacological Assessment of Medicinal Plants Used against Livestock Infections by the People Living around Indus River Wed, 03 Dec 2014 08:03:50 +0000 The present study was aimed to document detailed ethnopharmacological knowledge of medicinal plants against livestock infections of an unexplored remote region of Pakistan. Semistructured questionnaires were used for data collection. Total 43 plants belonging to 26 families were found to be used in ethnoveterinary practices. Seeds (29%) were found to be the most frequent plant part used followed by leaves (22%). Ethnoveterinary recipes were mostly prepared in the form of decoction and powdering. Informant consensus factor (Fic) results revealed high consensus for gastrointestinal (0.81), mastitis (0.82), and dermatological infections (0.80). Curcuma longa ranked first with highest fidelity level (FL) value (66%) followed by Trachyspermum ammi that ranked second (58%). Preference ranking (PR) results showed that Zingiber officinale, Punica granatum, Triticum aestivum, Gossypium hirsutum, and Withania coagulans were the most preferred species for the treatment of diarrhea. Direct matrix ranking (DMR) results showed that Morus alba, Melia azedarach, Withania coagulans, Cassia fistula, Azadirachta indica, and Tamarix aphylla were the multipurpose species of the region. We invite the attention of pharmacologists and chemists for further exploration of plants having high Fic, FL, and PR values in the present study. Conservation strategies should be adopted for the protection of multipurpose plant species. Sakina Mussarat, Rahila Amber, Akash Tariq, Muhammad Adnan, Naser M. AbdElsalam, Riaz Ullah, and Roqaia Bibi Copyright © 2014 Sakina Mussarat et al. All rights reserved. Comparative Hair Restorer Efficacy of Medicinal Herb on Nude (Foxn) Mice Thu, 13 Nov 2014 05:52:28 +0000 Eclipta alba (L.) Hassk, Asiasarum sieboldii (Miq.) F. Maek (Asiasari radix), and Panax ginseng C. A. Mey (red ginseng) are traditionally acclaimed for therapeutic properties of various human ailments. Synergistic effect of each standardized plant extract was investigated for hair growth potential on nude mice, as these mutant mice genetically lack hair due to abnormal keratinization. Dried plant samples were ground and extracted by methanol. Topical application was performed on the back of nude mice daily up to completion of two hair growth generations. The hair density and length of Eclipta alba treated mice were increased significantly than control mice. Hair growth area was also distinctly visible in Eclipta alba treated mice. On the other hand, Asiasari radix and Panax ginseng treated mice developing hair loss were recognized from the abortive boundaries of hair coverage. Histomorphometric observation of nude mice skin samples revealed an increase in number of hair follicles (HFs). The presence of follicular keratinocytes was confirmed by BrdU labeling, S-phase cells in HFs. Therefore, Eclipta alba extract and/or phytochemicals strongly displayed incomparability of hair growth promotion activity than others. Thus, the standardized Eclipta alba extract can be used as an effective, alternative, and complementary treatment against hair loss. Shahnaz Begum, Mi Ra Lee, Li Juan Gu, Md. Jamil Hossain, Hyun Kyoung Kim, and Chang Keun Sung Copyright © 2014 Shahnaz Begum et al. All rights reserved. Effects of Combined Anisodamine and Neostigmine Treatment on the Inflammatory Response and Liver Regeneration of Obstructive Jaundice Rats after Hepatectomy Wed, 12 Nov 2014 06:22:39 +0000 Background. Cholestasis is associated with high rates of morbidity and mortality in patients undergoing major liver resection. This study aimed to evaluate the effects of a combined anisodamine and neostigmine (Ani+Neo) treatment on the inflammatory response and liver regeneration in rats with obstructive jaundice (OJ) after partial hepatectomy. Materials and Methods. OJ was induced in the rats by bile duct ligation. After 7 days biliary drainage and partial hepatectomy were performed. These rats were assigned to a saline group or an Ani+Neo treatment group. The expressions of inflammatory mediators, liver regeneration, and liver damage were assessed at 48 h after hepatectomy. Results. The mRNA levels of TNF-α, IL-1β, IL-6, MCP-1, and MIP-1α, in the remnant livers, and the serum levels of TNF-α and IL-1β were substantially reduced in the Ani+Neo group compared with saline group . The Ani+Neo treatment obviously promoted liver regeneration as indicated by the liver weights and Ki-67 labeling index . The serum albumin and γ-GT levels and liver neutrophil infiltration also significantly improved in the Ani+Neo group compared with the saline group. Conclusions. These results demonstrate that the combined anisodamine and neostigmine treatment is able to improve the liver regeneration in rats with OJ by substantially alleviating the inflammatory response. Chong-Hui Li, Xuan Zhang, Xin-Lan Ge, Xin Huang, Ai-Qun Zhang, and Wan-Qing Gu Copyright © 2014 Chong-Hui Li et al. All rights reserved. Antidiabetic Activity of Pterospermum acerifolium Flowers and Glucose Uptake Potential of Bioactive Fraction in L6 Muscle Cell Lines with Its HPLC Fingerprint Tue, 21 Oct 2014 08:43:33 +0000 The present study was designed to estimate the detailed antidiabetic activity of Pterospermum acerifolium (L.) Willd flowers. In vitro alpha amylase inhibition study was carried out on 50% ethanol extract of flowers (PAFEE) and its various fractions. The active ethyl acetate fraction (PAFEF) was subfractionated into three subfractions (PAFE1, PAFE2, and PAFE3) and subjected to acute toxicity studies followed by antidiabetic screening in vivo by streptozotocin-nicotinamide induced type II diabetes. Diabetic animals treated with PAFE2 (30 mg/kg) reduced the levels of fasting blood glucose, significantly () compared to that of diabetic control animals. Histological studies on drug treated groups did not show remarkable positive changes in β-cells. PAFE2 showed % glucose uptake over control and, in the presence of PI3K inhibitor wortmannin, declined to %. HPLC analysis of PAFE2 reveals the presence of quercetin and apigenin as major constituents and both are inhibiting the glycogen phosphorylase enzyme in molecular modelling studies. The study evidenced strongly that the probable glucose lowering mechanism of action of active subfraction PAFE2 is by increasing the glucose uptake in peripheral tissues and by inhibition of gluconeogenesis. Rathinavelusamy Paramaguru, Papiya Mitra Mazumder, Dinakar Sasmal, and Venkatesan Jayaprakash Copyright © 2014 Rathinavelusamy Paramaguru et al. All rights reserved. Contribution of α,β-Amyrenone to the Anti-Inflammatory and Antihypersensitivity Effects of Aleurites moluccana (L.) Willd. Sun, 19 Oct 2014 07:26:25 +0000 The aim of the study was to analyze the constituents of the dichloromethane fraction obtained from A. moluccana and also to evaluate the anti-inflammatory and antinociceptive properties of α,β-amyrenone isolated from A. moluccana in mice. The dichloromethane fraction was evaluated by gas chromatography and submitted to purification. The mixture of α,β-amyrenone was isolated and then evaluated using the carrageenan-induced paw-oedema or pleurisy and CFA-induced arthritis models in mice. Five triterpenes, α,β-amyrenone, glutinol, and α,β-amyrin were isolated from dichloromethane fraction of A. moluccana leaf extract. The mixture of α,β-amyrenone, dosed orally, was able to reduce mechanical hypersensitivity and paw-oedema induced by carrageenan, interfering with neutrophil migration. Similar results were observed in the carrageenan-induced pleurisy model. Repeated administration of the compounds was also effective in reducing the mechanical sensitization and oedema developed in the arthritis model induced by CFA. In conclusion, the results demonstrate that α,β-amyrenone interferes in both acute and chronic inflammatory processes. We can infer that these effects involve, at least in part, a reduction in the neutrophil migration. Therefore, it seems reasonable to suggest that α,β-amyrenone could represent a new therapeutic tool for the management of painful and inflammatory diseases, especially those presenting a chronic profile. Nara Lins Meira Quintão, Lilian W. Rocha, Gislaine Franciele Silva, Simone Reichert, Vanessa D. Claudino, Ruth Meri Lucinda-Silva, Angela Malheiros, Márcia Maria De Souza, Valdir Cechinel Filho, Tania M. Bellé Bresolin, Marina da Silva Machado, Theodoro Marcel Wagner, and Christiane Meyre-Silva Copyright © 2014 Nara Lins Meira Quintão et al. All rights reserved. Protective Role of 5-Lipoxigenase during Leishmania infantum Infection Is Associated with Th17 Subset Sun, 21 Sep 2014 00:00:00 +0000 Visceral leishmaniasis (VL) is a chronic and fatal disease caused by Leishmania infantum in Brazil. Leukocyte recruitment to infected tissue is a crucial event for the control of infections such as VL. Leucotriens are lipid mediators synthesized by 5-lipoxygenase (5-LO) and they display a protective role against protozoan parasites by inducing several functions in leucocytes. We determined the role of 5-LO activity in parasite control, focusing on the inflammatory immune response against Leishmania infantum infection. LTB4 is released during in vitro infection. The genetic ablation of 5-LO promoted susceptibility in highly resistant mice strains, harboring more parasites into target organs. The susceptibility was related to the failure of neutrophil migration to the infectious foci. Investigating the neutrophil failure, there was a reduction of proinflammatory cytokines involved in the related Th17 axis released into the organs. Genetic ablation of 5-LO reduced the CD4+T cells producing IL-17, without interfering in Th1 subset. L. infantum failed to activate DC from , showing reduced surface costimulatory molecule expression and proinflammatory cytokines involved in Th17 differentiation. BLT1 blockage with selective antagonist interferes with DC maturation and proinflammatory cytokines release. Thus, 5-LO activation coordinates the inflammatory immune response involved in the control of VL. Laís Amorim Sacramento, Fernando Q. Cunha, Roque Pacheco de Almeida, João Santana da Silva, and Vanessa Carregaro Copyright © 2014 Laís Amorim Sacramento et al. All rights reserved. Chondroitin Sulfate Proteoglycans in the Nervous System: Inhibitors to Repair Thu, 18 Sep 2014 00:00:00 +0000 Chondroitin sulfate proteoglycans (CSPGs) are widely expressed in the normal central nervous system, serving as guidance cues during development and modulating synaptic connections in the adult. With injury or disease, an increase in CSPG expression is commonly observed close to lesioned areas. However, these CSPG deposits form a substantial barrier to regeneration and are largely responsible for the inability to repair damage in the brain and spinal cord. This review discusses the role of CSPGs as inhibitors, the role of inflammation in stimulating CSPG expression near site of injury, and therapeutic strategies for overcoming the inhibitory effects of CSPGs and creating an environment conducive to nerve regeneration. Justin R. Siebert, Amanda Conta Steencken, and Donna J. Osterhout Copyright © 2014 Justin R. Siebert et al. All rights reserved. Biological and Molecular Effects of Small Molecule Kinase Inhibitors on Low-Passage Human Colorectal Cancer Cell Lines Wed, 17 Sep 2014 09:19:39 +0000 Low-passage cancer cell lines are versatile tools to study tumor cell biology. Here, we have employed four such cell lines, established from primary tumors of colorectal cancer (CRC) patients, to evaluate effects of the small molecule kinase inhibitors (SMI) vemurafenib, trametinib, perifosine, and regorafenib in an in vitro setting. The mutant BRAF (V600E/V600K) inhibitor vemurafenib, but also the MEK1/2 inhibitor trametinib efficiently inhibited DNA synthesis, signaling through ERK1/2 and expression of genes downstream of ERK1/2 in BRAF mutant cells only. In case of the AKT inhibitor perifosine, three cell lines showed a high or intermediate responsiveness to the drug while one cell line was resistant. The multikinase inhibitor regorafenib inhibited proliferation of all CRC lines with similar efficiency and independent of the presence or absence of KRAS, BRAF, PIK3CA, and TP53 mutations. Regorafenib action was associated with broad-range inhibitory effects at the level of gene expression but not with a general inhibition of AKT or MEK/ERK signaling. In vemurafenib-sensitive cells, the antiproliferative effect of vemurafenib was enhanced by the other SMI. Together, our results provide insights into the determinants of SMI efficiencies in CRC cells and encourage the further use of low-passage CRC cell lines as preclinical models. Falko Lange, Benjamin Franz, Claudia Maletzki, Michael Linnebacher, Maja Hühns, and Robert Jaster Copyright © 2014 Falko Lange et al. All rights reserved. The Characteristics of Thrombin in Osteoarthritic Pathogenesis and Treatment Tue, 16 Sep 2014 07:46:54 +0000 Osteoarthritis (OA) is a mechanical abnormality associated with degradation of joints. It is characterized by chronic, progressive degeneration of articular cartilage, abnormalities of bone, and synovial change. The most common symptom of OA is local inflammation resulting from exogenous stress or endogenous abnormal cytokines. Additionally, OA is associated with local and/or systemic activation of coagulation and anticoagulation pathways. Thrombin plays an important role in the stimulation of fibrin deposition and the proinflammatory processes in OA. Thrombin mediates hemostatic and inflammatory responses and guides the immune response to tissue damage. Thrombin activates intracellular signaling pathways by interacting with transmembrane domain G protein coupled receptors (GPCRs), known as protease-activated receptors (PARs). In pathogenic mechanisms, PARs have been implicated in the development of acute and chronic inflammatory responses in OA. Therefore, discovery of thrombin signaling pathways would help us to understand the mechanism of OA pathogenesis and lead us to develop therapeutic drugs in the future. Pei-Yu Chou, Chen-Ming Su, Chun-Yin Huang, and Chih-Hsin Tang Copyright © 2014 Pei-Yu Chou et al. All rights reserved. Natural Compounds and Aging: Between Autophagy and Inflammasome Sun, 14 Sep 2014 08:19:46 +0000 Aging, a natural physiological process, is characterized by a progressive loss of physiological integrity. Loss of cellular homeostasis in the aging process results from different sources, including changes in genes, cell imbalance, and dysregulation of the host-defense systems. Innate immunity dysfunctions during aging are connected with several human pathologies, including metabolic disorders and cardiovascular diseases. Recent studies have clearly indicated that the decline in autophagic capacity that accompanies aging results in the accumulation of dysfunctional mitochondria, reactive oxygen species (ROS) production, and further process dysfunction of the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome activation in the macrophages, which produce the proinflammatory cytokines. These factors impair cellular housekeeping and expose cells to higher risk in many age-related diseases, such as atherosclerosis and type 2 diabetes. In this review, we investigated the relationship between dysregulation of the inflammasome activation and perturbed autophagy with aging as well as the possible molecular mechanisms. We also summarized the natural compounds from food intake, which have potential to reduce the inflammasome activation and enhance autophagy and can further improve the age-related diseases discussed in this paper. Shih-Yi Chuang, Chih-Hung Lin, and Jia-You Fang Copyright © 2014 Shih-Yi Chuang et al. All rights reserved. Targeting Mast Cells Tryptase in Tumor Microenvironment: A Potential Antiangiogenetic Strategy Thu, 11 Sep 2014 10:27:10 +0000 Angiogenesis is a complex process finely regulated by the balance between angiogenesis stimulators and inhibitors. As a result of proangiogenic factors overexpression, it plays a crucial role in cancer development. Although initially mast cells (MCs) role has been defined in hypersensitivity reactions and in immunity, it has been discovered that MCs have a crucial interplay on the regulatory function between inflammatory and tumor cells through the release of classical proangiogenic factors (e.g., vascular endothelial growth factor) and nonclassical proangiogenic mediators granule-associated (mainly tryptase). In fact, in several animal and human malignancies, MCs density is highly correlated with tumor angiogenesis. In particular, tryptase, an agonist of the proteinase-activated receptor-2 (PAR-2), represents one of the most powerful angiogenic mediators released by human MCs after c-Kit receptor activation. This protease, acting on PAR-2 by its proteolytic activity, has angiogenic activity stimulating both human vascular endothelial and tumor cell proliferation in paracrine manner, helping tumor cell invasion and metastasis. Based on literature data it is shown that tryptase may represent a promising target in cancer treatment due to its proangiogenic activity. Here we focused on molecular mechanisms of three tryptase inhibitors (gabexate mesylate, nafamostat mesylate, and tranilast) in order to consider their prospective role in cancer therapy. Michele Ammendola, Christian Leporini, Ilaria Marech, Cosmo Damiano Gadaleta, Giovanni Scognamillo, Rosario Sacco, Giuseppe Sammarco, Giovambattista De Sarro, Emilio Russo, and Girolamo Ranieri Copyright © 2014 Michele Ammendola et al. All rights reserved. Importance of pH Homeostasis in Metabolic Health and Diseases: Crucial Role of Membrane Proton Transport Thu, 11 Sep 2014 07:22:03 +0000 Protons dissociated from organic acids in cells are partly buffered. If not, they are transported to the extracellular fluid through the plasma membrane and buffered in circulation or excreted in urine and expiration gas. Several transporters including monocarboxylate transporters and Na+/H+ exchanger play an important role in uptake and output of protons across plasma membranes in cells of metabolic tissues including skeletal muscle and the liver. They also contribute to maintenance of the physiological pH of body fluid. Therefore, impairment of these transporters causes dysfunction of cells, diseases, and a decrease in physical performance associated with abnormal pH. Additionally, it is known that fluid pH in the interstitial space of metabolic tissues is easily changed due to little pH buffering capacitance in interstitial fluids and a reduction in the interstitial fluid pH may mediate the onset of insulin resistance unlike blood containing pH buffers such as Hb (hemoglobin) and albumin. In contrast, habitual exercise and dietary intervention regulate expression/activity of transporters and maintain body fluid pH, which could partly explain the positive effect of healthy lifestyle on disease prognosis. Wataru Aoi and Yoshinori Marunaka Copyright © 2014 Wataru Aoi and Yoshinori Marunaka. All rights reserved. GHK and DNA: Resetting the Human Genome to Health Thu, 11 Sep 2014 06:59:13 +0000 During human aging there is an increase in the activity of inflammatory, cancer promoting, and tissue destructive genes plus a decrease in the activity of regenerative and reparative genes. The human blood tripeptide GHK possesses many positive effects but declines with age. It improves wound healing and tissue regeneration (skin, hair follicles, stomach and intestinal linings, and boney tissue), increases collagen and glycosaminoglycans, stimulates synthesis of decorin, increases angiogenesis, and nerve outgrowth, possesses antioxidant and anti-inflammatory effects, and increases cellular stemness and the secretion of trophic factors by mesenchymal stem cells. Recently, GHK has been found to reset genes of diseased cells from patients with cancer or COPD to a more healthy state. Cancer cells reset their programmed cell death system while COPD patients’ cells shut down tissue destructive genes and stimulate repair and remodeling activities. In this paper, we discuss GHK’s effect on genes that suppress fibrinogen synthesis, the insulin/insulin-like system, and cancer growth plus activation of genes that increase the ubiquitin-proteasome system, DNA repair, antioxidant systems, and healing by the TGF beta superfamily. A variety of methods and dosages to effectively use GHK to reset genes to a healthier state are also discussed. Loren Pickart, Jessica Michelle Vasquez-Soltero, and Anna Margolina Copyright © 2014 Loren Pickart et al. All rights reserved. The Influence of Standardized Valeriana officinalis Extract on the CYP3A1 Gene Expression by Nuclear Receptors in In Vivo Model Thu, 11 Sep 2014 06:34:10 +0000 Valeriana officinalis is one of the most popular medicinal plants commonly used as a sedative and sleep aid. It is suggested that its pharmacologically active compounds derived from the root may modulate the CYP3A4 gene expression by activation of pregnane X receptor (PXR) or constitutive androstane receptor (CAR) and lead to pharmacokinetic herb-drug interactions. The aim of the study was to determine the influence of valerian on the expression level of CYP3A1 (homologue to human CYP3A4) as well as nuclear receptors PXR, CAR, RXR, GR, and HNF-4. Male Wistar rats were given standardized valerian extract (300 mg/kg/day, p.o.) for 3 and 10 days. The expression in liver tissue was analyzed by using real-time PCR. Our result showed a decrease of CYP3A1 expression level by 35% () and 37% (), respectively. Moreover, Valeriana exhibited statistically significant reduction in RXR (approximately 28%) only after 3-day treatment. We also demonstrated a decrease in the amount HNF-4 by 22% () and 32% (), respectively. In case of CAR, the increase of expression level by 46% () was noted. These findings suggest that Valeriana officinalis extract can decrease the CYP3A4 expression and therefore may lead to interactions with synthetic drugs metabolized by this enzyme. Anna Bogacz, Przemyslaw M. Mrozikiewicz, Monika Karasiewicz, Joanna Bartkowiak-Wieczorek, Marian Majchrzycki, Przemyslaw L. Mikolajczak, Marcin Ozarowski, and Edmund Grzeskowiak Copyright © 2014 Anna Bogacz et al. All rights reserved. Neuroprotective Effects of Lipoxin A4 in Central Nervous System Pathologies Tue, 09 Sep 2014 11:09:10 +0000 Many diseases of the central nervous system are characterized and sometimes worsened by an intense inflammatory response in the affected tissue. It is now accepted that resolution of inflammation is an active process mediated by a group of mediators that can act in synchrony to switch the phenotype of cells, from a proinflammatory one to another that favors the return to homeostasis. This new genus of proresolving mediators includes resolvins, protectins, maresins, and lipoxins, the first to be discovered. In this short review we provide an overview of current knowledge into the cellular and molecular interactions of lipoxins in diseases of the central nervous system in which they appear to facilitate the resolution of inflammation, thus exerting a neuroprotective action. Alessandra Cadete Martini, Stefânia Forner, Allisson Freire Bento, and Giles Alexander Rae Copyright © 2014 Alessandra Cadete Martini et al. All rights reserved. Hyaluronan-Phosphatidylethanolamine Polymers Form Pericellular Coats on Keratinocytes and Promote Basal Keratinocyte Proliferation Tue, 09 Sep 2014 00:00:00 +0000 Aged keratinocytes have diminished proliferative capacity and hyaluronan (HA) cell coats, which are losses that contribute to atrophic skin characterized by reduced barrier and repair functions. We formulated HA-phospholipid (phosphatidylethanolamine, HA-PE) polymers that form pericellular coats around cultured dermal fibroblasts independently of CD44 or RHAMM display. We investigated the ability of these HA-PE polymers to penetrate into aged mouse skin and restore epidermal function in vivo. Topically applied Alexa647-HA-PE penetrated into the epidermis and dermis, where it associated with both keratinocytes and fibroblasts. In contrast, Alexa647-HA was largely retained in the outer cornified layer of the epidermis and quantification of fluorescence confirmed that significantly more Alexa647-HA-PE penetrated into and was retained within the epidermis than Alexa647-HA. Multiple topical applications of HA-PE to shaved mouse skin significantly stimulated basal keratinocyte proliferation and epidermal thickness compared to HA or vehicle cream alone. HA-PE had no detectable effect on keratinocyte differentiation and did not promote local or systemic inflammation. These effects of HA-PE polymers are similar to those reported for endogenous epidermal HA in youthful skin and show that topical application of HA-PE polymers can restore some of the impaired functions of aged epidermis. Caitlin J. Symonette, Aman Kaur Mann, Xiao Cherie Tan, Cornelia Tolg, Jenny Ma, Francisco Perera, Arjang Yazdani, and Eva A. Turley Copyright © 2014 Caitlin J. Symonette et al. All rights reserved. Superoxide Dismutase 1 Loss Disturbs Intracellular Redox Signaling, Resulting in Global Age-Related Pathological Changes Mon, 08 Sep 2014 05:09:05 +0000 Aging is characterized by increased oxidative stress, chronic inflammation, and organ dysfunction, which occur in a progressive and irreversible manner. Superoxide dismutase (SOD) serves as a major antioxidant and neutralizes superoxide radicals throughout the body. In vivo studies have demonstrated that copper/zinc superoxide dismutase-deficient (Sod1−/−) mice show various aging-like pathologies, accompanied by augmentation of oxidative damage in organs. We found that antioxidant treatment significantly attenuated the age-related tissue changes and oxidative damage-associated p53 upregulation in Sod1−/− mice. This review will focus on various age-related pathologies caused by the loss of Sod1 and will discuss the molecular mechanisms underlying the pathogenesis in Sod1−/− mice. Kenji Watanabe, Shuichi Shibuya, Yusuke Ozawa, Hidetoshi Nojiri, Naotaka Izuo, Koutaro Yokote, and Takahiko Shimizu Copyright © 2014 Kenji Watanabe et al. All rights reserved. Heparin and Liver Heparan Sulfate Can Rescue Hepatoma Cells from Topotecan Action Sun, 07 Sep 2014 10:53:57 +0000 Topotecan (TpT) is a major inhibitory compound of topoisomerase (topo) I that plays important roles in gene transcription and cell division. We have previously reported that heparin and heparan sulfate (HS) might be transported to the cell nucleus and they can interact with topoisomerase I. We hypothesized that heparin and HS might interfere with the action of TpT. To test this hypothesis we isolated topoisomerase I containing cell nuclear protein fractions from normal liver, liver cancer tissues, and hepatoma cell lines. The enzymatic activity of these extracts was measured in the presence of heparin, liver HS, and liver cancer HS. In addition, topo I activity, cell viability, and apoptosis of HepG2 and Hep3B cells were investigated after heparin and TpT treatments. Liver cancer HS inhibited topo I activity in vitro. Heparin treatment abrogated topo I enzyme activity in Hep3B cells, but not in HepG2 cells, where the basal activity was higher. Heparin protected the two hepatoma cell lines from TpT actions and decreased the rate of TpT induced S phase block and cell death. These results suggest that heparin and HS might interfere with the function of TpT in liver and liver cancer. József Dudás, József Bocsi, Alexandra Fullár, Kornélia Baghy, Tibor Füle, Saule Kudaibergenova, and Ilona Kovalszky Copyright © 2014 József Dudás et al. All rights reserved. Glucose, Insulin, and Oxygen Interplay in Placental Hypervascularisation in Diabetes Mellitus Tue, 02 Sep 2014 12:35:46 +0000 The placental vasculature rapidly expands during the course of pregnancy in order to sustain the growing needs of the fetus. Angiogenesis and vascular growth are stimulated and regulated by a variety of growth factors expressed in the placenta or present in the fetal circulation. Like in tumors, hypoxia is a major regulator of angiogenesis because of its ability to stimulate expression of various proangiogenic factors. Chronic fetal hypoxia is often found in pregnancies complicated by maternal diabetes as a result of fetal hyperglycaemia and hyperinsulinemia. Both are associated with altered levels of hormones, growth factors, and proinflammatory cytokines, which may act in a proangiogenic manner and, hence, affect placental angiogenesis and vascular development. Indeed, the placenta in diabetes is characterized by hypervascularisation, demonstrating high placental plasticity in response to diabetic metabolic derangements. This review describes the major regulators of placental angiogenesis and how the diabetic environment in utero alters their expression. In the light of hypervascularized diabetic placenta, the focus was placed on proangiogenic factors. Silvija Cvitic, Gernot Desoye, and Ursula Hiden Copyright © 2014 Silvija Cvitic et al. All rights reserved. Thai Massage, and Thai Herbal Compress versus Oral Ibuprofen in Symptomatic Treatment of Osteoarthritis of the Knee: A Randomized Controlled Trial Mon, 01 Sep 2014 05:56:54 +0000 The aim of this study was to verify the clinical responses to Thai massage (TM) and Thai herbal compression (THC) for treating osteoarthritis (OA) of the knee in comparison to oral ibuprofen. This study was a randomized, evaluator-blind, controlled trial. Sixty patients with OA of the knee were randomly assigned to receive either a one-hour session of TM or THC (three times weekly) or oral ibuprofen (three times daily). The duration of treatment was three weeks. The clinical assessments included visual analog scale assessing pain and stiffness, Lequesne’s functional index, time for climbing up ten steps, and physician’s and patient’s overall opinions on improvement. In a within-group comparison, each treatment modality caused a significant improvement of all variables determined for outcome assessments. In an among group comparison, all modalities provided nearly comparable clinical efficacy after a three-week symptomatic treatment of OA of the knee, in which a trend toward greatest improvement was likely to be found in THC group. In conclusion, TM and THC generally provided comparable clinical efficacy to oral ibuprofen after three weeks of treatment and could be considered as complementary and alternative treatments for OA of the knee. Natthakarn Chiranthanut, Nutthiya Hanprasertpong, and Supanimit Teekachunhatean Copyright © 2014 Natthakarn Chiranthanut et al. All rights reserved. The Nerve Growth Factor Signaling and Its Potential as Therapeutic Target for Glaucoma Sun, 31 Aug 2014 11:54:15 +0000 Neuroprotective therapies which focus on factors leading to retinal ganglion cells (RGCs) degeneration have been drawing more and more attention. The beneficial effects of nerve growth factor (NGF) on the glaucoma have been recently suggested, but its effects on eye tissue are complex and controversial in various studies. Recent clinical trials of systemically and topically administrated NGF demonstrate that NGF is effective in treating several ocular diseases, including glaucoma. NGF has two receptors named high affinity NGF tyrosine kinase receptor TrkA and low affinity receptor p75NTR. Both receptors exist in cells in retina like RGC (expressing TrkA) and glia cells (expressing p75NTR). NGF functions by binding to TrkA or p75NTR alone or both together. The binding of NGF to TrkA alone in RGC promotes RGC’s survival and proliferation through activation of TrkA and several prosurvival pathways. In contrast, the binding of NGF to p75NTR leads to apoptosis although it also promotes survival in some cases. Binding of NGF to both TrkA and p75NTR at the same time leads to survival in which p75NTR functions as a TrkA helping receptor. This review discusses the current understanding of the NGF signaling in retina and the therapeutic implications in the treatment of glaucoma. Haitao Wang, Rikang Wang, Thilini Thrimawithana, Peter J. Little, Jiangping Xu, Zhong-Ping Feng, and Wenhua Zheng Copyright © 2014 Haitao Wang et al. All rights reserved. Marked Antigiardial Activity of Yucca baccata Extracts: A Potential Natural Alternative for Treating Protozoan Infections Sun, 31 Aug 2014 07:19:48 +0000 Human Giardiosis is a public health problem in Mexico, where the national prevalence was estimated to be up to 68%. Misuse of antiprotozoal drugs may result in low effectiveness and undesirable side effects. Research on natural products is a good strategy for discovering more effective antiparasitic compounds. This study evaluated the antigiardial activity of extracts of Yucca baccata, which is native to northwestern Mexico. Forty-two gerbils (females) were weighed and orally inoculated with Giardia trophozoites. Two gerbils were selected at random to confirm infection. Forty living gerbils were randomly allocated into 5 treatment groups (8 per group). Gerbils were randomly assigned to be treated with 24.4 mg/mL, 12.2 mg/mL, and 6.1 mg/mL of extracts, metronidazole (2 mg/mL) or PBS, which were intragastrically administered once per day for 3 days. Nine gerbils died during the study course. On day 10 postinfection, gerbils were euthanized and trophozoites were quantified. Yucca extracts reduced, albeit not significantly, the trophozoite counts in the duodenum segment. Only the high-extract concentration significantly reduced the trophozoite counts in the proximal segment and it was similar to that of metronidazole. Extracts of Y. baccata may represent an effective and natural therapeutic alternative for human giardiosis. Luis Quihui-Cota, Rocio León-Trujillo, Humberto Astiazarán-García, Julián Esparza-Romero, María del Refugio Robles, Ramón E. Robles-Zepeda, Rafael Canett, and Jesús Sánchez-Escalante Copyright © 2014 Luis Quihui-Cota et al. All rights reserved. Inhibition of Peroxisome Proliferator-Activated Receptor Gamma Prevents the Melanogenesis in Murine B16/F10 Melanoma Cells Thu, 28 Aug 2014 09:40:05 +0000 The purpose of this study was to investigate if PPAR plays a role in the melanogenesis. B16/F10 cells were divided into five groups: control, melanin stimulating hormone (-MSH), -MSH+retinol, -MSH+GW9662 (PPAR antagonist), and GW9662. Cells in the control group were cultured in the Dulbecco’s modified Eagle’s medium (DMEM) for 48 hrs. To initiate the melanogenesis, cells in all -MSH groups were cultured in medium containing -MSH (10 nM) for 48 hrs. Cells were treated simultaneously with retinol (5 μM) in the -MSH+retinol group. Instead of retinol, GW9662 (10 μM) was cocultured in the -MSH+GW9662 group. Cells in the final group were cultured in the DMEM with GW9662. All the analyses were carried out 48 hours after treatments. The -MSH was able to increase cell number, melanin production, and the activity of tyrosinase, the limiting enzyme in melanogenesis. These -MSH-induced changes were prevented either by retinol or by GW9662. Further analyses of the activities of antioxidant enzymes including glutathione, catalase, and the superoxide dismutase (SOD) showed that -MSH treatment raised the activity of SOD which was dependent on PPAR level. According to our results, the -MSH-induced melanogenesis was PPAR dependent, which also modulated the expression of SOD. Jiun-Han Chen, Junn-Liang Chang, Pei-Ru Chen, Yun-Ju Chuang, Shih-Tsang Tang, Shwu-Fen Pan, Tzer-Bin Lin, Kang-Hua Chen, and Mei-Jung Chen Copyright © 2014 Jiun-Han Chen et al. All rights reserved. Extracts from Vatica diospyroides Type SS Fruit Show Low Dose Activity against MDA-MB-468 Breast Cancer Cell-Line via Apoptotic Action Thu, 28 Aug 2014 06:23:59 +0000 Very strong antiproliferative action of V. diospyroides type SS fruit extracts (IC50 range of 1.60-17.45 µg/mL) in MDA-MB-468 cell-line was observed in an MTT assay. After dosing of an extract concentration at half IC50 to cell line for 24 to 72 hours, treated cells were subjected to Annexin V-FITC/PI binding assay, followed by FACS and western blot analyses. Significant apoptotic death was observed with all extract treatments and both exposure times. Dosing with acetone extract of pericarp and cotyledon induced the highest apoptotic populations (33 and 32%, resp.), with the lowest populations of viable cells (65 and 67%, resp.). During 24 to 72 hours of dosing with methanolic extract of pericarp, the populations of viable and early apoptotic cells decreased significantly from 72.40 to 71.32% and from 12.00 to 6.36%, respectively, while the late apoptotic and nonviable cell populations continuously increased from 15.30 to 19.18% and from 0.30 to 3.14%, respectively. The expression of Bax increased within 12–48 hours of dosing, confirming apoptosis induced by time-dependent responses. The mutant p53 of MDA-MB-468 cells was expressed. Our results indicate that apoptosis and time-dependent therapeutic actions contribute to the cytotoxic effects of V. diospyroides type SS fruit on MDA-MB-468 cell. Theera Srisawat, Yaowapa Sukpondma, Siriphon Chimplee, Kanyanatt Kanokwiroon, Aman Tedasen, and Potchanapond Graidist Copyright © 2014 Theera Srisawat et al. All rights reserved. Emerging Anticancer Potentials of Goniothalamin and Its Molecular Mechanisms Thu, 28 Aug 2014 05:25:54 +0000 The treatment of most cancers is still inadequate, despite tremendous steady progress in drug discovery and effective prevention. Nature is an attractive source of new therapeutics. Several medicinal plants and their biomarkers have been widely used for the treatment of cancer with less known scientific basis of their functioning. Although a wide array of plant derived active metabolites play a role in the prevention and treatment of cancer, more extensive scientific evaluation of their mechanisms is still required. Styryl-lactones are a group of secondary metabolites ubiquitous in the genus Goniothalamus that have demonstrated to possess antiproliferative activity against cancer cells. A large body of evidence suggests that this activity is associated with the induction of apoptosis in target cells. In an effort to promote further research on the genus Goniothalamus, this review offers a broad analysis of the current knowledge on Goniothalamin (GTN) or 5, 6, dihydro-6-styryl-2-pyronone (C13H12O2), a natural occurring styryl-lactone. Therefore, it includes (i) the source of GTN and other metabolites; (ii) isolation, purification, and (iii) the molecular mechanisms of actions of GTN, especially the anticancer properties, and summarizes the role of GTN which is crucial for drug design, development, and application in future for well-being of humans. Mohamed Ali Seyed, Ibrahim Jantan, and Syed Nasir Abbas Bukhari Copyright © 2014 Mohamed Ali Seyed et al. All rights reserved. Safety of Nicergoline as an Agent for Management of Cognitive Function Disorders Thu, 28 Aug 2014 00:00:00 +0000 Nicergoline is a semisynthetic ergot derivative and has a selective alpha-1A adrenergic receptor blocking property and also other additional mechanisms of actions, both in the brain and in the periphery. It is in clinical use for over three decades in over fifty countries for conditions such as cerebral infarction, acute and chronic peripheral circulation disorders, vascular dementia, and Alzheimer’s disease and has been found to be beneficial in a variety of other conditions. However, concerns about its safety have been raised, especially after the European medicines agency’s (EMEA’s) restriction in the use of all ergot derivatives including nicergoline. But, most of the available literature and data suggest that the adverse events with nicergoline are mild and transient. Further, none of the available treatment options for cognitive disorders afford definitive resolution of symptoms. In this backdrop, we discuss the pharmacology of nicergoline with special emphasis on the safety of this compound, especially when used in patients suffering from cognitive function disorders. Bernd Saletu, Amit Garg, and Ahsan Shoeb Copyright © 2014 Bernd Saletu et al. All rights reserved. Substance Use in the Club Scene of Rome: A Pilot Study Thu, 28 Aug 2014 00:00:00 +0000 Objective. Over the last few years, a wide number of unregulated substances have been marketed on the Web and in smart and head shops; they are usually advertised as legal alternatives to commonly known drugs and are defined as “smart drugs,” “legal highs,” and “novel psychoactive substances” (NPS). Aim of our work is to describe use habits and distribution of NPS in a population of young adults in Rome club scene. Methods. A self-administered questionnaire was proposed to subjects over 18 years of age at the entrance of 5 nightclubs in Rome. Socioeconomic characteristics and substance use were investigated. Results. Preliminary results give evidence that 78% of respondents have a lifetime history of NPS use. In addition, 56% of the sample has consumed illicit drugs in the past and 39% has used psychoactive substances in the 12 hours preceding the questionnaire administration. Conclusions. A significant proportion of subjects report use of novel psychoactive substances; traditional illicit drugs consumption, particularly cocaine, appears to be very high as well in the club scene. These data highlight a serious public health challenge, since pharmacological, toxicological, and psychopathological effects linked to interactions among all these substances may be unpredictable and sometimes fatal in vulnerable individuals. Alessandro Emiliano Vento, Giovanni Martinotti, Eduardo Cinosi, Matteo Lupi, Tiziano Acciavatti, Dario Carrus, Rita Santacroce, Eleonora Chillemi, Ludovica Bonifaci, Massimo di Giannantonio, Ornella Corazza, and Fabrizio Schifano Copyright © 2014 Alessandro Emiliano Vento et al. All rights reserved. Vascular Endothelial Growth Factor Increases during Blood-Brain Barrier-Enhanced Permeability Caused by Phoneutria nigriventer Spider Venom Wed, 27 Aug 2014 08:55:09 +0000 Phoneutria nigriventer spider accidental envenomation provokes neurotoxic manifestations, which when critical, results in epileptic-like episodes. In rats, P. nigriventer venom (PNV) causes blood-brain barrier breakdown (BBBb). The PNV-induced excitotoxicity results from disturbances on Na+, K+ and Ca2+ channels and glutamate handling. The vascular endothelial growth factor (VEGF), beyond its angiogenic effect, also, interferes on synaptic physiology by affecting the same ion channels and protects neurons from excitotoxicity. However, it is unknown whether VEGF expression is altered following PNV envenomation. We found that adult and neonates rats injected with PNV showed immediate neurotoxic manifestations which paralleled with endothelial occludin, β-catenin, and laminin downregulation indicative of BBBb. In neonate rats, VEGF, VEGF mRNA, and Flt-1 receptors, glutamate decarboxylase, and calbindin-D28k increased in Purkinje neurons, while, in adult rats, the BBBb paralleled with VEGF mRNA, Flk-1, and calbindin-D28k increases and Flt-1 decreases. Statistically, the variable age had a role in such differences, which might be due to age-related unequal maturation of blood-brain barrier (BBB) and thus differential cross-signaling among components of the glial neurovascular unit. The concurrent increases in the VEGF/Flt-1/Flk-1 system in the cerebellar neuron cells and the BBBb following PNV exposure might imply a cytokine modulation of neuronal excitability consequent to homeostatic perturbations induced by ion channels-acting PNV neuropeptides. Whether such modulation represents neuroprotection needs further investigation. Monique C. P. Mendonça, Edilene S. Soares, Leila M. Stávale, Evanguedes Kalapothakis, and Maria Alice Cruz-Höfling Copyright © 2014 Monique C. P. Mendonça et al. All rights reserved. Anticancer Activity of Marine Sponge Hyrtios sp. Extract in Human Colorectal Carcinoma RKO Cells with Different p53 Status Wed, 27 Aug 2014 08:47:30 +0000 Drug development using marine bioresources is limited even though the ocean occupies about 70% of the earth and contains a large number of biological materials. From the screening test of the marine sponge extracts, we found Hyrtios sp. sponge collected from Chuuk island, Micronesia. In this study, the Hyrtios sp. extract was examined for anticancer activity against human colorectal carcinoma RKO cells that are wildtype for p53 and RKO-E6 that are p53 defective. The Hyrtios sp. extract dose-dependently inhibited viability in both cell lines. Multinucleation as an indication of mitotic catastrophe was also observed. Cytotoxicity tests gave significantly different results for RKO and RKO-E6 cells after 48 h exposure to Hyrtios sp. extract. In RKO cells treated with Hyrtios sp. extract, cell death occurred by induction of p53 and p21 proteins. In p53-defective RKO-E6 cells, Hyrtios sp. extract decreased expression of JNK protein and increased p21 protein. These results indicate that Hyrtios sp. extract induced apoptosis via different pathways depending on p53 status and could be a good natural product for developing new anticancer drugs. Hyun Kyung Lim, Woori Bae, Hyi-Seung Lee, and Joohee Jung Copyright © 2014 Hyun Kyung Lim et al. All rights reserved. Early Detection of Pathological Gambling: Betting on GPs’ Beliefs and Attitudes Wed, 27 Aug 2014 00:00:00 +0000 Pathological gambling (PG) is an addictive disorder with harm related to the high psychiatric comorbidity and increased suicidal risk. Prevalence rates in general population range from 0.2% to 2.1%. Problem gamblers are hard to attract to treatment programs for several proper reasons and for obstacles (e.g., accessibility). To address these obstacles, primary care (where the problem gambling (PrG) prevalence seems to be 6.2%) has a crucial role to play (i.e., identifying and referring patients to specialized treatment programs and treating at first line when needed and possible) in the era of online gambling offer expansion. The present work aimed to collect data on resources in the field from GPs themselves, using a 24-item online questionnaire. Swiss French-speaking participants were asked about their screening practice and knowledge. The results state that the vast majority of them are aware of the existence and the potential impact of PrG on their patients. However, PrG screening is not systematic and their knowledge of adequate treatments or referral methods is scarce. GPs being central to health screening in general, targeted advice and training on short screening tools and better knowledge of referral pathways should be promoted and continued to empower the GP’s management skills in a public health approach. Sophia Achab, Anne Chatton, Riaz Khan, Gabriel Thorens, Louise Penzenstadler, Daniele Zullino, and Yasser Khazaal Copyright © 2014 Sophia Achab et al. All rights reserved. High Guanidinium Permeability Reveals Dehydration-Dependent Ion Selectivity in the Plasmodial Surface Anion Channel Wed, 27 Aug 2014 00:00:00 +0000 Malaria parasites grow within vertebrate erythrocytes and increase host cell permeability to access nutrients from plasma. This increase is mediated by the plasmodial surface anion channel (PSAC), an unusual ion channel linked to the conserved clag gene family. Although PSAC recognizes and transports a broad range of uncharged and charged solutes, it must efficiently exclude the small Na+ ion to maintain infected cell osmotic stability. Here, we examine possible mechanisms for this remarkable solute selectivity. We identify guanidinium as an organic cation with high permeability into human erythrocytes infected with Plasmodium falciparum, but negligible uptake by uninfected cells. Transport characteristics and pharmacology indicate that this uptake is specifically mediated by PSAC. The rank order of organic and inorganic cation permeabilities suggests cation dehydration as the rate-limiting step in transport through the channel. The high guanidinium permeability of infected cells also allows rapid and stringent synchronization of parasite cultures, as required for molecular and cellular studies of this pathogen. These studies provide important insights into how nutrients and ions are transported via PSAC, an established target for antimalarial drug development. Abdullah A. B. Bokhari, Neida K. Mita-Mendoza, Alexandra Fuller, Ajay D. Pillai, and Sanjay A. Desai Copyright © 2014 Abdullah A. B. Bokhari et al. All rights reserved. Enhanced Prevalence of Plasmatic Soluble MHC Class I Chain-Related Molecule in Vascular Pregnancy Diseases Wed, 27 Aug 2014 00:00:00 +0000 The major histocompatibility complex class I related chain (MIC) is a stress-inducible protein modulating the function of immune natural killer (NK) cells, a major leukocyte subset involved in proper trophoblast invasion and spiral artery remodeling. Aim of the study was to evaluate whether upregulation of soluble MIC (sMIC) may reflect immune disorders associated to vascular pregnancy diseases (VPD). sMIC was more frequently detected in the plasma of women with a diagnostic of VPD (32%) than in normal term-matched pregnancies (1.6%, ), with highest prevalence in intrauterine fetal death (IUDF, 44%) and vascular intrauterine growth restriction (IUGR, 39%). sMIC levels were higher in preeclampsia (PE) than in IUFD () and vascular IUGR (). sMIC detection was associated with bilateral early diastolic uterine notches (), thrombocytopenia (), and high proteinuria () in PE and with the vascular etiology of IUGR (). Incubation of sMIC-positive PE plasma resulted in downregulation of NKG2D expression and NK cell-mediated IFN-γ production in vitro. Our work thus suggests that detection of sMIC molecule in maternal plasma may constitute a hallmark of altered maternal immune functions that contributes to vascular disorders that complicate pregnancy, notably by impairing NK-cell mediated production of IFN-γ, an essential cytokine favoring vascular modeling. Jean Baptiste Haumonte, Sophie Caillat-Zucman, Florence Bretelle, Marion Lambert, Luc Lyonnet, Annie Levy-Mozziconacci, Catherine Farnarier, Agostini Aubert, Leon Boubli, Laurence Camoin-Jau, Françoise Dignat George, and Pascale Paul Copyright © 2014 Jean Baptiste Haumonte et al. All rights reserved. Analgesic, Anti-Inflammatory, and Chondroprotective Activities of Cryptolepis buchanani Extract: In Vitro and In Vivo Studies Wed, 27 Aug 2014 00:00:00 +0000 Cryptolepis buchanani Roem. & Schult. is widely used in folk medicine in Southeast Asia for treating muscle tension and arthritis. This study aimed to investigate an analgesic activity of the methanol extract of C. buchanani (CBE) in acetic acid-induced writhing response in mice, and to examine its anti-inflammatory activity in ethyl phenylpropiolate- (EPP-) induced ear edema and carrageenan-induced paw edema in rats. Its effects on cartilage degradation induced by interleukin-1β (IL-1β) in porcine cartilage explant culture were also determined. This study demonstrated that CBE significantly reduced acetic acid-induced writhing response. It also inhibited edema formation in both EPP-induced ear edema and carrageenan-induced paw edema models. In cartilage explant culture, CBE significantly reduced the sulfated glycosaminoglycan and hyaluronan released into culture media while it reserved the uronic acid and collagen within the cartilage tissues. It also suppressed the matrix metalloproteinase-2 activity with no effect on cell viability. In conclusion, CBE shows analgesic, anti-inflammatory, and chondroprotective effects in this preliminary study. Therefore, CBE may be useful as an alternative treatment for osteoarthritis. Nutthiya Hanprasertpong, Supanimit Teekachunhatean, Rujirek Chaiwongsa, Siriwan Ongchai, Puongtip Kunanusorn, Chaichan Sangdee, Ampai Panthong, Samreang Bunteang, Narong Nathasaen, and Vichai Reutrakul Copyright © 2014 Nutthiya Hanprasertpong et al. All rights reserved. A Review on Plants Used for Improvement of Sexual Performance and Virility Mon, 18 Aug 2014 09:59:03 +0000 The use of plant or plant-based products to stimulate sexual desire and to enhance performance and enjoyment is almost as old as the human race itself. The present paper reviews the active, natural principles, and crude extracts of plants, which have been useful in sexual disorders, have potential for improving sexual behaviour and performance, and are helpful in spermatogenesis and reproduction. Review of refereed journals and scientific literature available in electronic databases and traditional literature available in India was extensively performed. The work reviews correlation of the evidence with traditional claims, elucidation, and evaluation of a plausible concept governing the usage of plants as aphrodisiac in total. Phytoconstituents with known structures have been classified in appropriate chemical groups and the active crude extracts have been tabulated. Data on their pharmacological activity, mechanism of action, and toxicity are reported. The present review provides an overview of the herbs and their active molecule with claims for improvement of sexual behaviour. A number of herbal drugs have been validated for their effect on sexual behavior and fertility and can therefore serve as basis for the identification of new chemical leads useful in sexual and erectile dysfunction. Nagendra Singh Chauhan, Vikas Sharma, V. K. Dixit, and Mayank Thakur Copyright © 2014 Nagendra Singh Chauhan et al. All rights reserved. Antiproliferative Activity of Hamigerone and Radicinol Isolated from Bipolaris papendorfii Tue, 12 Aug 2014 11:38:37 +0000 Secondary metabolites from fungi organisms have extensive past and present use in the treatment of many diseases and serve as compounds of interest both in their natural form and as templates for synthetic modification. Through high throughput screening (HTS) and bioassay-guided isolation, we isolated two bioactive compounds hamigerone (1) and radicinol (2). These compounds were isolated from fungus Bipolaris papendorfii, isolated from the rice fields of Dera, Himachal Pradesh, India. The structures of the compounds were established on the basis of spectroscopic data, namely, NMR (1H, 13C, mass, and UV). Both compounds were found to be antiproliferative against different cancer cells. Furthermore we have also noted that both compounds showed increase in apoptosis by favorably modulating both tumor suppressor protein (p53) and antiapoptic protein (BCL-2), and in turn increase caspase-3 expression in cancer cells. This is the first report of these compounds from fungus Bipolaris papendorfii and their anticancer activity. Periyasamy Giridharan, Shilpa A. Verekar, Akash R. Gohil, Prabhu Dutt Mishra, Amit Khanna, and Sunil Kumar Deshmukh Copyright © 2014 Periyasamy Giridharan et al. All rights reserved. Epigallocatechingallate Inhibits Migration of Human Uveal Melanoma Cells via Downregulation of Matrix Metalloproteinase-2 Activity and ERK1/2 Pathway Tue, 12 Aug 2014 09:43:46 +0000 The effects of epigallocatechingallate (EGCG) on the migration and expression of MMP-2 of uveal melanoma cells have not been reported. We studied this effect and relevant signaling pathways in a human uveal melanoma cell line (M17). MTT study found that EGCG did not affect the cell viability of M17 cells up to 100 µM. Wound-healing assay showed that EGCG significantly reduced the migration of melanoma cells in a dose-dependent manner from 20 to 100 µM. Gelatin zymography showed that secreted MMP-2 activity was dose-dependently inhibited by EGCG, whereas the MMP-2 expression at protein and mRNA levels was not affected as determined by western blot and RT-PCR analysis. EGCG significantly increased the expressions of MMP-2 endogenous inhibitors (TIMP-2 and RECK) in M17 cells. Western blot analysis of MAPK signal pathways showed that EGCG significantly decreased phosphorylated ERK1/2 levels, but not p38 and JNK levels, in melanoma cells. ERK1/2 inhibitors also reduced the migration and activity of MMP-2 in M17 cells. The present study suggested EGCG at nontoxic levels could inhibit migration of melanoma cells via downregulation of activities of secreted MMP-2 through the inhibition of the ERK1/2 phosphorylation. Therefore, EGCG may be a promising agent to be explored for the prevention of metastasis of uveal melanoma. Chi-Wu Chang, Yi-Hsien Hsieh, Wei-En Yang, Shun-Fa Yang, Yueqin Chen, and Dan-Ning Hu Copyright © 2014 Chi-Wu Chang et al. All rights reserved. Pistacia chinensis: A Potent Ameliorator of CCl4 Induced Lung and Thyroid Toxicity in Rat Model Mon, 11 Aug 2014 11:37:12 +0000 In the current study protective effect of ethanol extract of Pistacia chinensis bark (PCEB) was investigated in rats against CCl4 induced lung and thyroid injuries. PCEB dose dependently inhibited the rise of thiobarbituric acid-reactive substances, hydrogen peroxide, nitrite, and protein content and restored the levels of antioxidant enzymes, that is, catalase, peroxidase, superoxide dismutase, glutathione-S-transferase, glutathione reductase, glutathione peroxidase, γ-glutamyl transpeptidase, and quinone reductase in both lung and thyroid tissues of CCl4 treated rats. Decrease in number of leukocytes, neutrophils, and hemoglobin and T3 and T4 content as well as increase in monocytes, eosinophils, and lymphocytes count with CCl4 were restored to normal level with PCEB treatment. Histological study of CCl4 treated rats showed various lung injuries like rupture of alveolar walls and bronchioles, aggregation of fibroblasts, and disorganized Clara cells. Similarly, histology of CCl4 treated thyroid tissues displayed damaged thyroid follicles, hypertrophy, and colloidal depletion. However, PCEB exhibited protective behaviour for lungs and thyroid, with improved histological structure in a dose dependant manner. Presence of three known phenolic compounds, that is, rutin, tannin, and gallic acid, and three unknown compounds was verified in thin layer chromatographic assessment of PCEB. In conclusion, P. chinensis exhibited antioxidant activity by the presence of free radical quenching constituents. Kiran Naz, Muhammad Rashid Khan, Naseer Ali Shah, Saadia Sattar, Farah Noureen, and Madeeha Latif Awan Copyright © 2014 Kiran Naz et al. All rights reserved. Synthesis, Characterization, and In Vitro Anticancer Evaluation of Novel 2,5-Disubstituted 1,3,4-Oxadiazole Analogue Sun, 10 Aug 2014 00:00:00 +0000 In this series, we have synthesised a new 2,5-disubstituted 1,3,4-oxadiazole in search of potential therapeutics for cancer. The anticancer activities were evaluated on a panel of 60 cell lines by the National Cancer Institute according to its own screening protocol. Out of the 24 compounds, 11 were selected and evaluated via single high dose (10−5 M). In the next phase, two compounds have been selected for five-dose assay. The compounds 3-(5-benzyl-1,3,4-oxadiazol-2-yl)quinolin-2(1H)-one 18 (NSC-776965) and 3-[5-(2-phenoxymethyl-benzoimidazol-1-ylmethyl)-[1,3,4]oxadiazol-2-yl]-2-p-tolyloxy-quinoline 27 (NSC-776971) showed mean growth percentage of 66.23 and 46.61, respectively, in one-dose assay and their GI50 values ranging between 1.41–15.8 μM and 0.40–14.9 μM, respectively, in 5-dose assay. Salahuddin, Avijit Mazumder, and Mohammad Shaharyar Copyright © 2014 Salahuddin et al. All rights reserved. Caspase Mediated Synergistic Effect of Boswellia serrata Extract in Combination with Doxorubicin against Human Hepatocellular Carcinoma Thu, 07 Aug 2014 07:19:51 +0000 The study investigated the growth-inhibiting and apoptosis mediating effects of B. serrata extract as monotherapy and combination therapy with DOX against hepatocellular carcinoma cell lines. Boswellic acid rich fraction of B. serrata extract was prepared. MTT assay on HepG2 and Hep3B cells was carried out using B. serrata alone and in combination with DOX. Further, caspase-3 activity, TNF-α level, and IL-6 level were estimated. Isobolographic analysis was carried out to evaluate the effect of combination therapy. Additionally, protective effect of B. serrata extract on DOX induced hepatic toxicity was also evaluated in Wistar rats. B. serrata extract inhibited growth of HepG2 (IC50 value of  μg/mL) as well as HepG2 (IC50 value of  μg/mL). DOX inhibited growth in HepG2 and Hep3B cells with an IC50 of  μg/mL and  μg/mL. Isobolographic analysis showed combination index (CI) of DOX and B. serrata extract of to suggesting synergistic behavior against the two cell lines. B. serrata extract also caused dose dependent increase in caspase-3 activity, TNF-α level, and IL-6 level which was higher () with DOX (1 μM) and B. serrata extract (20 μg/mL) combination. B. serrata extract also protected Wistar rats against DOX induced hepatic toxicity. Mohammad Ahmed Khan, Mhaveer Singh, Masood Shah Khan, Abul Kalam Najmi, and Sayeed Ahmad Copyright © 2014 Mohammad Ahmed Khan et al. All rights reserved. HPLC-DAD Analysis, Antileishmanial, Antiproliferative, and Antibacterial Activities of Lacistema pubescens: An Amazonian Medicinal Plant Thu, 07 Aug 2014 05:59:30 +0000 Species of the genus Lacistema are traditionally used by Brazilian and Peruvian indigenous communities. The present study investigated the in vitro antileishmanial activity against several Leishmania species, cytotoxicity in murine peritoneal macrophages, antiproliferative activity against HL60 and Jurkat cells, and antibacterial activities against seven bacteria strains of the aerial parts of the methanolic crude extract and fractions of Lacistema pubescens. In addition, their chemical profile was also evaluated. Hexane fraction showed the most significant IC50 values against all promastigotes of Leishmania species tested, except for L. chagasi (IC50 = 4.2 µg/mL for L. major and IC50 = 3.5 µg/mL for L. amazonensis). This fraction also exhibited a strong activity against amastigotes of L. amazonensis (IC50 = 6.9 µg/mL). The antiproliferative activity was also observed for methanolic extract and hexane fraction with IC50 = 47.2 µg/mL and IC50 = 39.7 µg/mL for HL60, respectively. Regarding the antimicrobial activity, the overall antibacterial activity was not very significative. Phytol and sitosterol were identified in the methanolic extract. Additionally, previous studies also revealed the presence of those compounds in the hexane fraction. Among other compounds, phytol and sitosterol were probably involved in the antileishmanial and cytotoxicity activities observed in this study. Josiane Mello da Silva, Luciana Maria Ribeiro Antinarelli, Nícolas de Castro Campos Pinto, Elaine Soares Coimbra, Elaine Maria de Souza-Fagundes, Antônia Ribeiro, and Elita Scio Copyright © 2014 Josiane Mello da Silva et al. All rights reserved. Andrographolide Induces Apoptosis of C6 Glioma Cells via the ERK-p53-Caspase 7-PARP Pathway Tue, 05 Aug 2014 09:29:22 +0000 Background. Glioma is the most malignant tumor of the central nervous system. Efforts on the development of new chemotherapy are mandatory. Andrographolide (AND), a diterpenoid lactone isolated from the Andrographis paniculata, has been shown to have antitumor activities in several types of cancer cells. Whether AND can exert its antitumor activity in glioblastoma cells remains unknown. This study examined the anticancer effects of AND, both in vitro and in vivo. Methods. Cell apoptosis was assayed by flow cytometry and nuclear staining. The signaling pathway for AND was determined by western blotting. The effects of AND on tumor growth was evaluated in a mouse model. Results and Conclusion. In vitro, with application of specific inhibitors and siRNA, AND-induced apoptosis was proven through ROS-ERK-P53-caspase 7-PARP signaling pathway. In vivo, AND significantly retarded tumor growth and caused regression of well-formed tumors in vivo. Furthermore, AND did not induce apoptosis or activate ERK and p53 in primary cultured astrocyte cells, and it may serve as a potential therapeutic candidate for the treatment of glioma. Shih-Hung Yang, Seu-Mei Wang, Jhih-Pu Syu, Ying Chen, Sheng-De Wang, Yu-Sen Peng, Meng-Fai Kuo, and Hsiu-Ni Kung Copyright © 2014 Shih-Hung Yang et al. All rights reserved. In Vitro Antioxidant, Antibacterial, and Cytotoxic Activity and In Vivo Effect of Syngonium podophyllum and Eichhornia crassipes Leaf Extracts on Isoniazid Induced Oxidative Stress and Hepatic Markers Mon, 04 Aug 2014 06:46:28 +0000 The present study reports the in vitro antioxidant, antibacterial, and cytotoxic potential of Syngonium podophyllum (SP) and Eichhornia crassipes (EC) leaf aqueous extracts as well as their in vivo effect on oxidative stress and hepatic biomarkers in isoniazid induced rats. Phytochemical screening of extracts revealed the presence of flavonoids, terpenoids, reducing sugars, alkaloids, and saponins. Phenolic content in SP and EC extracts was and  mg PGE/g, respectively, while flavonoid content was and  μg QE/mg, respectively. EC extract exhibited comparatively better antioxidant activity as indicated by reducing power (0.197–0.775), DPPH radical scavenging potential (11%–96%), and metal ion chelating ability (42%–93%). Both the extracts provided 13%–65% protection against lipid peroxidation in rat tissue (liver, kidney, and brain) homogenate. SP and EC extracts exhibited 51% and 43% cytotoxicity against lung cancer (NCI-H322) cell line, respectively. Both extracts demonstrated considerable antibacterial activity against Proteus vulgaris, Salmonella typhi, and Bordetella bronchiseptica. Coadministration of E. crassipes extract with isoniazid in rats accounted for 46% decrease in malondialdehyde content and 21% increase in FRAP value of plasma. It also mitigated the isoniazid induced alterations in serum enzymes (SGOT, SGPT, and ALP), total bilirubin, creatinine, and hemoglobin contents. S. podophyllum extract was found to be hepatotoxic. Shashank Kumar, Ramesh Kumar, Astha Dwivedi, and Abhay K. Pandey Copyright © 2014 Shashank Kumar et al. All rights reserved. Hyaluronan and RHAMM in Wound Repair and the “Cancerization” of Stromal Tissues Mon, 04 Aug 2014 00:00:00 +0000 Tumors and wounds share many similarities including loss of tissue architecture, cell polarity and cell differentiation, aberrant extracellular matrix (ECM) remodeling (Ballard et al., 2006) increased inflammation, angiogenesis, and elevated cell migration and proliferation. Whereas these changes are transient in repairing wounds, tumors do not regain tissue architecture but rather their continued progression is fueled in part by loss of normal tissue structure. As a result tumors are often described as wounds that do not heal. The ECM component hyaluronan (HA) and its receptor RHAMM have both been implicated in wound repair and tumor progression. This review highlights the similarities and differences in their roles during these processes and proposes that RHAMM-regulated wound repair functions may contribute to “cancerization” of the tumor microenvironment. Cornelia Tolg, James B. McCarthy, Arjang Yazdani, and Eva A. Turley Copyright © 2014 Cornelia Tolg et al. All rights reserved. Foeniculum vulgare Mill: A Review of Its Botany, Phytochemistry, Pharmacology, Contemporary Application, and Toxicology Sun, 03 Aug 2014 06:30:10 +0000 Foeniculum vulgare Mill commonly called fennel has been used in traditional medicine for a wide range of ailments related to digestive, endocrine, reproductive, and respiratory systems. Additionally, it is also used as a galactagogue agent for lactating mothers. The review aims to gather the fragmented information available in the literature regarding morphology, ethnomedicinal applications, phytochemistry, pharmacology, and toxicology of Foeniculum vulgare. It also compiles available scientific evidence for the ethnobotanical claims and to identify gaps required to be filled by future research. Findings based on their traditional uses and scientific evaluation indicates that Foeniculum vulgare remains to be the most widely used herbal plant. It has been used for more than forty types of disorders. Phytochemical studies have shown the presence of numerous valuable compounds, such as volatile compounds, flavonoids, phenolic compounds, fatty acids, and amino acids. Compiled data indicate their efficacy in several in vitro and in vivo pharmacological properties such as antimicrobial, antiviral, anti-inflammatory, antimutagenic, antinociceptive, antipyretic, antispasmodic, antithrombotic, apoptotic, cardiovascular, chemomodulatory, antitumor, hepatoprotective, hypoglycemic, hypolipidemic, and memory enhancing property. Foeniculum vulgare has emerged as a good source of traditional medicine and it provides a noteworthy basis in pharmaceutical biology for the development/formulation of new drugs and future clinical uses. Shamkant B. Badgujar, Vainav V. Patel, and Atmaram H. Bandivdekar Copyright © 2014 Shamkant B. Badgujar et al. All rights reserved. Accumulation of Extracellular Hyaluronan by Hyaluronan Synthase 3 Promotes Tumor Growth and Modulates the Pancreatic Cancer Microenvironment Thu, 24 Jul 2014 18:42:37 +0000 Extensive accumulation of the glycosaminoglycan hyaluronan is found in pancreatic cancer. The role of hyaluronan synthases 2 and 3 (HAS2, 3) was investigated in pancreatic cancer growth and the tumor microenvironment. Overexpression of HAS3 increased hyaluronan synthesis in BxPC-3 pancreatic cancer cells. In vivo, overexpression of HAS3 led to faster growing xenograft tumors with abundant extracellular hyaluronan accumulation. Treatment with pegylated human recombinant hyaluronidase (PEGPH20) removed extracellular hyaluronan and dramatically decreased the growth rate of BxPC-3 HAS3 tumors compared to parental tumors. PEGPH20 had a weaker effect on HAS2-overexpressing tumors which grew more slowly and contained both extracellular and intracellular hyaluronan. Accumulation of hyaluronan was associated with loss of plasma membrane E-cadherin and accumulation of cytoplasmic β-catenin, suggesting disruption of adherens junctions. PEGPH20 decreased the amount of nuclear hypoxia-related proteins and induced translocation of E-cadherin and β-catenin to the plasma membrane. Translocation of E-cadherin was also seen in tumors from a transgenic mouse model of pancreatic cancer and in a human non-small cell lung cancer sample from a patient treated with PEGPH20. In conclusion, hyaluronan accumulation by HAS3 favors pancreatic cancer growth, at least in part by decreasing epithelial cell adhesion, and PEGPH20 inhibits these changes and suppresses tumor growth. Anne Kultti, Chunmei Zhao, Netai C. Singha, Susan Zimmerman, Ryan J. Osgood, Rebecca Symons, Ping Jiang, Xiaoming Li, Curtis B. Thompson, Jeffrey R. Infante, Michael A. Jacobetz, David A. Tuveson, Gregory I. Frost, H. Michael Shepard, and Zhongdong Huang Copyright © 2014 Anne Kultti et al. All rights reserved. Diagnostic and Prognostic Value of Soluble Syndecan-1 in Pleural Malignancies Thu, 24 Jul 2014 07:55:16 +0000 Background. The distinction between malignant and benign pleural effusions is a diagnostic challenge today and measuring soluble biomarkers could add to the diagnostic accuracy. Syndecan-1 is a proteoglycan involved in various cellular functions and is cleaved from the cell surface in a regulated manner. The shed fragment, which can be recovered in effusion supernatant and in serum, retains its binding capacities, but often with different functions and signalling properties than the cell-bound form. Aim. This study aimed to investigate the diagnostic and prognostic value of soluble syndecan-1 in pleural effusions and sera from patients with pleural malignancies. Study Design. Using two cohorts of patients, we assessed the diagnostic and prognostic value of soluble syndecan-1 in pleural effusions and sera, using enzyme-linked immunosorbent assays. Results. In pleural effusions, syndecan-1 distinguished malignant and benign diseases, with an odds ratio of 8.59 (95% CI 3.67 to 20.09). Furthermore, syndecan-1 in pleural effusions predicted a survival difference for patients with pleural metastatic disease and malignant mesothelioma of 11.2 and 9.2 months, respectively. However, no such effects were seen when syndecan-1 was measured in serum. Conclusion. Soluble syndecan-1 is a promising candidate biomarker for the cytopathological diagnosis and prognostication of malignant pleural effusions. Filip Mundt, Ghazal Heidari-Hamedani, Gustav Nilsonne, Muzaffer Metintas, Anders Hjerpe, and Katalin Dobra Copyright © 2014 Filip Mundt et al. All rights reserved. Synthesis, Characterization and In Vitro Anticancer Activity of C-5 Curcumin Analogues with Potential to Inhibit TNF-α-Induced NF-κB Activation Thu, 24 Jul 2014 00:00:00 +0000 In a search of new compounds active against cancer, synthesis of a series of C-5 curcumin analogues was carried out. The new compounds demonstrated good cytotoxicity against chronic myeloid leukemia (KBM5) and colon cancer (HCT116) cell lines. Further, these compounds were found to have better potential to inhibit TNF-α-induced NF-κB activation in comparison to curcumin, which show their potential to act as anti-inflammatory agents. Some compounds were found to show higher cytotoxicity against cancer cell lines in comparison to curcumin used as standard. Amit Anthwal, Bandana K. Thakur, M. S. M. Rawat, D. S. Rawat, Amit K. Tyagi, and Bharat B. Aggarwal Copyright © 2014 Amit Anthwal et al. All rights reserved. New Perspectives on Antiacne Plant Drugs: Contribution to Modern Therapeutics Thu, 24 Jul 2014 00:00:00 +0000 Acne is a common but serious skin disease, which affects approximately 80% adolescents and young adults in 11–30 age group. 42.5% of men and 50.9% of women continue to suffer from this disease into their twenties. Bacterial resistance is now at the alarming stage due to the irrational use of antibiotics. Hence, search for new lead molecule/bioactive and rational delivery of the existing drug (for better therapeutic effect) to the site of action is the need of the hour. Plants and plant-derived products have been an integral part of health care system since time immemorial. Therefore, plants that are currently used for the treatment of acne and those with a high potential are summarized in the present review. Most active plant extracts, namely, P. granatum, M. alba, A. anomala, and M. aquifolium exhibit minimum inhibitory concentration (MIC) in the range of 4–50 µg/mL against P. acnes, while aromatic oils of C. obovoides, C. natsudaidai, C. japonica, and C. nardus possess MICs 0.005–0.6 μL/mL and phytomolecules such as rhodomyrtone, pulsaquinone, hydropulsaquinone, honokiol, magnolol, xanthohumol lupulones, chebulagic acid and rhinacanthin-C show MIC in the range of 0.5–12.5 μg/mL. Novel drug delivery strategies of important plant leads in the treatment of acne have also been discussed. Priyam Sinha, Shruti Srivastava, Nidhi Mishra, and Narayan Prasad Yadav Copyright © 2014 Priyam Sinha et al. All rights reserved. Pinocembrin Protects Human Brain Microvascular Endothelial Cells against Fibrillar Amyloid- β1−40 Injury by Suppressing the MAPK/NF- κ B Inflammatory Pathways Wed, 23 Jul 2014 07:23:06 +0000 Cerebrovascular accumulation of amyloid-β (Aβ) peptides in Alzheimer’s disease (AD) may contribute to disease progression through Aβ-induced microvascular endothelial pathogenesis. Pinocembrin has been shown to have therapeutic effects in AD models. These effects correlate with preservation of microvascular function, but the effect on endothelial cells under Aβ-damaged conditions is unclear. The present study focuses on the in vitro protective effect of pinocembrin on fibrillar Aβ1−40 (fAβ1−40) injured human brain microvascular endothelial cells (hBMECs) and explores potential mechanisms. The results demonstrate that fAβ1−40-induced cytotoxicity in hBMECs can be rescued by pinocembrin treatment. Pinocembrin increases cell viability, reduces the release of LDH, and relieves nuclear condensation. The mechanisms of this reversal from Aβ may be associated with the inhibition of inflammatory response, involving inhibition of MAPK activation, downregulation of phosphor-IKK level, relief of IκBα degradation, blockage of NF-κB p65 nuclear translocation, and reduction of the release of proinflammatory cytokines. Pinocembrin does not show obvious effects on regulating the redox imbalance after exposure to fAβ1−40. Together, the suppression of MAPK and the NF-κB signaling pathways play a significant role in the anti-inflammation of pinocembrin in hBMECs subjected to fAβ1−40. This may serve as a therapeutic agent for BMEC protection in Alzheimer’s-related deficits. Rui Liu, Jin-ze Li, Jun-ke Song, Jia-lin Sun, Yong-jie Li, Si-bai Zhou, Tian-tai Zhang, and Guan-hua Du Copyright © 2014 Rui Liu et al. All rights reserved. Towards Understanding the Roles of Heparan Sulfate Proteoglycans in Alzheimer’s Disease Wed, 23 Jul 2014 07:04:48 +0000 Alzheimer’s disease (AD) is the most common form of dementia, characterized by progressive loss of memory and cognitive dysfunctions. A central pathological event of AD is accumulation and deposition of cytotoxic amyloid-β peptide (Aβ) in the brain parenchyma. Heparan sulfate proteoglycans (HSPGs) and the side chains heparan sulfate (HS) are found associated with Aβ deposits in the brains of AD patients and transgenic animal models of AD. A growing body of evidence from in vitro and in vivo studies suggests functional roles of HSPG/HS in Aβ pathogenesis. Although the question of “how and why HSPG/HS is codeposited with Aβ?” still remains, it is within reach to understand the mechanisms of the events. Recent progress by immunohistochemical examination with advanced antibodies shed light on molecular structures of HS codeposited with Aβ. Several recent reports have provided important new insights into the roles of HSPG in Aβ pathogenesis. Particularly, experiments on mouse models revealed indispensible functions of HSPG in modulating Aβ-associated neuroinflammation and clearance of Aβ from the brain. Application of molecules to interfere with the interaction between HS and Aβ peptides has demonstrated beneficial effects on AD mouse models. Elucidating the functions of HSPG/HS in Aβ deposition and toxicity is leading to further understanding of the complex pathology of AD. The progress is encouraging development of new treatments for AD by targeting HS-Aβ interactions. Gan-lin Zhang, Xiao Zhang, Xiao-min Wang, and Jin-Ping Li Copyright © 2014 Gan-lin Zhang et al. All rights reserved. -Tocotrienol Oxazine Derivative Antagonizes Mammary Tumor Cell Compensatory Response to CoCl2-Induced Hypoxia Tue, 22 Jul 2014 11:43:14 +0000 In response to low oxygen supply, cancer cells elevate production of HIF-1α, a hypoxia-inducible transcription factor that subsequently acts to stimulate blood vessel formation and promote survival. Studies were conducted to determine the role of δ-tocotrienol and a semisynthetic δ-tocotrienol oxazine derivative, compound 44, on +SA mammary tumor cell hypoxic response. Treatment with 150 µM CoCl2 induced a hypoxic response in +SA mammary tumor cells as evidenced by a large increase in HIF-1α levels, and combined treatment with compound 44 attenuated this response. CoCl2-induced hypoxia was also associated with a large increase in Akt/mTOR signaling, activation of downstream targets p70S6K and eIF-4E1, and a significant increase in VEGF production, and combined treatment with compound 44 blocked this response. Additional in vivo studies showed that intralesional treatment with compound 44 in BALB/c mice bearing +SA mammary tumors significantly decreased the levels of HIF-1α, and this effect was associated with a corresponding decrease in Akt/mTOR signaling and activation of downstream targets p70S6kinase and eIF-4E1. These findings demonstrate that treatment with the δ-tocotrienol oxazine derivative, compound 44, significantly attenuates +SA mammary tumor cell compensatory responses to hypoxia and suggests that this compound may provide benefit in the treatment of rapidly growing solid breast tumors. Suryatheja Ananthula, Parash Parajuli, Fathy A. Behery, Alaadin Y. Alayoubi, Sami Nazzal, Khalid El Sayed, and Paul W. Sylvester Copyright © 2014 Suryatheja Ananthula et al. All rights reserved. The Motile Breast Cancer Phenotype Roles of Proteoglycans/Glycosaminoglycans Tue, 22 Jul 2014 06:46:39 +0000 The consecutive stages of cancer growth and dissemination are obligatorily perpetrated through specific interactions of the tumor cells with their microenvironment. Importantly, cell-associated and tumor microenvironment glycosaminoglycans (GAGs)/proteoglycan (PG) content and distribution are markedly altered during tumor pathogenesis and progression. GAGs and PGs perform multiple functions in specific stages of the metastatic cascade due to their defined structure and ability to interact with both ligands and receptors regulating cancer pathogenesis. Thus, GAGs/PGs may modulate downstream signaling of key cellular mediators including insulin growth factor receptor (IGFR), epidermal growth factor receptor (EGFR), estrogen receptors (ERs), or Wnt members. In the present review we will focus on breast cancer motility in correlation with their GAG/PG content and critically discuss mechanisms involved. Furthermore, new approaches involving GAGs/PGs as potential prognostic/diagnostic markers or as therapeutic agents for cancer-related pathologies are being proposed. Dragana Nikitovic, Katerina Kouvidi, Kallirroi Voudouri, Aikaterini Berdiaki, Evgenia Karousou, Alberto Passi, and George N. Tzanakakis Copyright © 2014 Dragana Nikitovic et al. All rights reserved. The Nonglycemic Actions of Dipeptidyl Peptidase-4 Inhibitors Mon, 21 Jul 2014 07:51:53 +0000 A cell surface serine protease, dipeptidyl peptidase 4 (DPP-4), cleaves dipeptide from peptides containing proline or alanine in the N-terminal penultimate position. Two important incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), enhance meal-stimulated insulin secretion from pancreatic β-cells, but are inactivated by DPP-4. Diabetes and hyperglycemia increase the DPP-4 protein level and enzymatic activity in blood and tissues. In addition, multiple other functions of DPP-4 suggest that DPP-4 inhibitor, a new class of antidiabetic agents, may have pleiotropic effects. Studies have shown that DPP-4 itself is involved in the inflammatory signaling pathway, the stimulation of vascular smooth cell proliferation, and the stimulation of oxidative stress in various cells. DPP-4 inhibitor ameliorates these pathophysiologic processes and has been shown to have cardiovascular protective effects in both in vitro and in vivo experiments. However, in recent randomized clinical trials, DPP-4 inhibitor therapy in high risk patients with type 2 diabetes did not show cardiovascular protective effects. Some concerns on the actions of DPP-4 inhibitor include sympathetic activation and neuropeptide Y-mediated vascular responses. Further studies are required to fully characterize the cardiovascular effects of DPP-4 inhibitor. Na-Hyung Kim, Taeyang Yu, and Dae Ho Lee Copyright © 2014 Na-Hyung Kim et al. All rights reserved. Abarema cochliacarpos Extract Decreases the Inflammatory Process and Skeletal Muscle Injury Induced by Bothrops leucurus Venom Sun, 20 Jul 2014 12:06:45 +0000 Snakebites are a public health problem, especially in tropical countries. However, treatment with antivenom has limited effectiveness against venoms’ local effects. Here, we investigated the ability of Abarema cochliacarpos hydroethanolic extract (EAc) to protect mice against injection of Bothrops leucurus venom. Swiss mice received perimuscular venom injection and were subsequently treated orally with EAc in different doses. Treatment with EAc 100, 200, and 400 mg/kg reduced the edema induced by B. leucurus in 1%, 13%, and 39%, respectively. Although lower doses showed no antihypernociceptive effect in the Von Frey test, the higher dose significantly reduced hyperalgesia induced by the venom. Antimyotoxic activity of EAc was also observed by microscopy assessment, with treated muscles presenting preserved structures, decreased edema, and inflammatory infiltrate as compared to untreated ones. Finally, on the rotarod test, the treated mice showed better motor function, once muscle fibers were preserved and there were less edema and pain. Treated mice could stand four times more time on the rotating rod than untreated ones. Our results have shown that EAc presented relevant activities against injection of B. leucurus venom in mice, suggesting that it can be considered as an adjuvant in the treatment of envenomation. Jeison Saturnino-Oliveira, Daiana Do Carmo Santos, Adriana Gibara Guimarães, Antônio Santos Dias, Marcelo Amorim Tomaz, Marcos Monteiro-Machado, Charles Santos Estevam, Waldecy De Lucca Júnior, Durvanei Augusto Maria, Paulo A. Melo, Adriano Antunes de Souza Araújo, Márcio Roberto Viana Santos, Jackson Roberto Guedes da Silva Almeida, Rita de Cássia Meneses Oliveira, Aldeidia Pereira de Oliveira, and Lucindo José Quintans Júnior Copyright © 2014 Jeison Saturnino-Oliveira et al. All rights reserved. Obligatory Role for Endothelial Heparan Sulphate Proteoglycans and Caveolae Internalization in Catestatin-Dependent eNOS Activation Sun, 20 Jul 2014 11:38:31 +0000 The chromogranin-A peptide catestatin modulates a wide range of processes, such as cardiovascular functions, innate immunity, inflammation, and metabolism. We recently found that the cardiac antiadrenergic action of catestatin requires a PI3K-dependent NO release from endothelial cells, although the receptor involved is yet to be identified. In the present work, based on the cationic properties of catestatin, we tested the hypothesis of its interaction with membrane heparan sulphate proteoglycans, resulting in the activation of a caveolae-dependent endocytosis. Experiments were performed on bovine aortic endothelial cells. Endocytotic vesicles trafficking was quantified by confocal microscopy using a water-soluble membrane dye; catestatin colocalization with heparan sulphate proteoglycans and caveolin 1 internalization were studied by fluorimetric measurements in live cells. Modulation of the catestatin-dependent eNOS activation was assessed by immunofluorescence and immunoblot analysis. Our results demonstrate that catestatin (5 nM) colocalizes with heparan sulphate proteoglycans and induces a remarkable increase in the caveolae-dependent endocytosis and caveolin 1 internalization, which were significantly reduced by both heparinase and wortmannin. Moreover, catestatin was unable to induce Ser1179 eNOS phosphorylation after pretreatments with heparinase and methyl-β-cyclodextrin. Taken together, these results highlight the obligatory role for proteoglycans and caveolae internalization in the catestatin-dependent eNOS activation in endothelial cells. Sara Fornero, Eleonora Bassino, Roberta Ramella, Clara Gallina, Sushil K. Mahata, Bruno Tota, Renzo Levi, Giuseppe Alloatti, and Maria Pia Gallo Copyright © 2014 Sara Fornero et al. All rights reserved. Pharmacogenomics in Personalized Medicine and Drug Metabolism Thu, 17 Jul 2014 11:50:11 +0000 Wei-Chiao Chang Copyright © 2014 Wei-Chiao Chang. All rights reserved. Netrins and Their Roles in Placental Angiogenesis Thu, 17 Jul 2014 00:00:00 +0000 Netrins, a family of laminin-related proteins, were originally identified as axonal guidance molecules. Subsequently, netrins were found to modulate various biological processes including morphogenesis, tumorogenesis, adhesion, and, recently, angiogenesis. In human placenta, the most vascularized organ, the presence of netrins has also been reported. Recent studies demonstrated the involvement of netrins in the regulation of placental angiogenesis. In this review we focused on the role of netrins in human placental angiogenesis. Among all netrins examined, netrin-4 and netrin-1 have been found to be either pro- or antiangiogenic factors. These opposite effects appear to be related to the endothelial cell phenotype studied and seem also to depend on the receptor type to which netrin binds, that is, the canonical receptor member of the DCC family, the members of the UNC5 family, or the noncanonical receptor members of the integrin family or DSCAM. Mbarka Dakouane-Giudicelli, Nadia Alfaidy, and Philippe de Mazancourt Copyright © 2014 Mbarka Dakouane-Giudicelli et al. All rights reserved. Mesenchymal Stem Cell-Induced Doxorubicin Resistance in Triple Negative Breast Cancer Wed, 16 Jul 2014 15:49:42 +0000 Triple negative breast cancer (TNBC) is an aggressive histological subtype with limited treatment options and a worse clinical outcome compared with other breast cancer subtypes. Doxorubicin is considered to be one of the most effective agents in the treatment of TNBC. Unfortunately, resistance to this agent is common. In some drug-resistant cells, drug efflux is mediated by adenosine triphosphate-dependent membrane transporter termed adenosine triphosphate-binding cassette (ABC) transporter, which can drive the substrates across membranes against concentration gradient. In the tumor microenvironment, upon interaction with mesenchymal stem cells (MSCs), tumor cells exhibit altered biological functions of certain gene clusters, hence increasing stemness of tumor cells, migration ability, angiogenesis, and drug resistance. In our present study, we investigated the mechanism of TNBC drug resistance induced by adipose-derived MSCs. Upon exposure of TNBC to MSC-secreted conditioned medium (CM), noticeable drug resistance against doxorubicin with markedly increased BCRP protein expression was observed. Intracellular doxorubicin accumulation of TNBC was also decreased by MSC-secreted CM. Furthermore, we found that doxorubicin resistance of TNBC was mediated by IL-8 presented in the MSC-secreted CM. These findings may enrich the list of potential targets for overcoming drug resistance induced by MSCs in TNBC patients. Dar-Ren Chen, Dah-Yuu Lu, Hui-Yi Lin, and Wei-Lan Yeh Copyright © 2014 Dar-Ren Chen et al. All rights reserved. New Drugs on the Internet: The Case of Camfetamine Wed, 16 Jul 2014 15:48:37 +0000 Introduction. The number of new psychoactive substances (NPS) advertised for sale online is constantly increasing and it has become a phenomenon of global concern. Among NPS, Camfetamine has been rediscovered as recreational drug in 2011. Very little information is still available in the scientific literature on its nature and potential health risks. Methods. Data in scientific literature were integrated with a multilingual qualitative assessment of a range of online resources over the period of 32 months (May 2011–January 2014). Results. N-Methyl-3-phenyl-norbornan-2-amine (Camfetamine) may act as an indirect dopaminergic agonist in the central nervous system and may have mild-moderate opioid activity too. There are no current epidemiological data about recreational use of Camfetamine; our research shows that it is indeed used especially by individuals with a history of recreational polydrug misuse. It facilitates mental alertness, induces relaxation, and, unlike many other stimulants, seems not to be associated with severe physical effects. Valid causes for concern issued in our research may be Camfetamine intravenous or intramuscular administration as well as its use in conjunction with other psychoactive substances. Conclusions. It is here highlighted that more large-scale studies need to be carried out to confirm and better describe both the extent of Camfetamine misuse and possible psychotropic/adverse effects. Eduardo Cinosi, Ornella Corazza, Rita Santacroce, Matteo Lupi, Tiziano Acciavatti, Giovanni Martinotti, and Massimo di Giannantonio Copyright © 2014 Eduardo Cinosi et al. All rights reserved. Anti-Inflammatory Effect and Mechanism of the Green Fruit Extract of Solanum integrifolium Poir. Tue, 15 Jul 2014 12:04:31 +0000 The green fruit of Solanum integrifolium Poir. has been used traditionally as an anti-inflammatory and analgesic remedy in Taiwanese aboriginal medicine. The goal of this study is to evaluate the anti-inflammatory activity and mechanism of the green fruit extract of S. integrifolium. A bioactivity-guided fractionation procedure was developed to identify the active partition fraction. The methanol fraction (ME), with the highest phenolic content, exhibited the strongest inhibitory effect against LPS-mediated nitric oxide (NO) release and cytotoxicity in RAW264.7 macrophages. ME also significantly downregulated the expression of LPS-induced proinflammatory genes, such as iNOS, COX-2, IL-1β, IL-6, CCL2/MCP-1, and CCL3/MIP1α. Moreover, ME significantly upregulated HO-1 expression and stimulated the activation of extracellular-signal-regulated kinase 1/2 (ERK1/2). Pretreatment of cells with the HO-1 inhibitor zinc protoporphyrin and MEK/ERK inhibitor U0126 attenuated ME’s inhibitory activity against LPS-induced NO production. Taken together, this is the first study to demonstrate the anti-inflammatory activity of green fruit extract of S. integrifolium and its activity may be mediated by the upregulation of HO-1 expression and activation of ERK1/2 pathway. Lisu Wang, Shu-Yuan Chiou, Yi-Ting Shen, Fu-Tsun Yen, Hsiou-Yu Ding, and Ming-Jiuan Wu Copyright © 2014 Lisu Wang et al. All rights reserved. Novel Psychoactive Substances in Young Adults with and without Psychiatric Comorbidities Tue, 15 Jul 2014 08:45:49 +0000 Objective. Comorbidities between psychiatric diseases and consumption of traditional substances of abuse (alcohol, cannabis, opioids, and cocaine) are common. Nevertheless, there is no data regarding the use of novel psychoactive substances (NPS) in the psychiatric population. The purpose of this multicentre survey is to investigate the consumption of a wide variety of psychoactive substances in a young psychiatric sample and in a paired sample of healthy subjects. Methods. A questionnaire has been administered, in different Italian cities, to 206 psychiatric patients aged 18 to 26 years and to a sample of 2615 healthy subjects matched for sex, gender, and living status. Results. Alcohol consumption was more frequent in the healthy young population compared to age-matched subjects suffering from mental illness (79.5% versus 70.7%; ). Conversely, cocaine and NPS use was significantly more common in the psychiatric population (cocaine 8.7% versus 4.6%; ) (NPS 9.8% versus 3%; ). Conclusions. The use of novel psychoactive substances in a young psychiatric population appears to be a frequent phenomenon, probably still underestimated. Therefore, careful and constant monitoring and accurate evaluations of possible clinical effects related to their use are necessary. Giovanni Martinotti, Matteo Lupi, Tiziano Acciavatti, Eduardo Cinosi, Rita Santacroce, Maria Salvina Signorelli, Laura Bandini, Giulia Lisi, Diego Quattrone, Paola Ciambrone, Andrea Aguglia, Federica Pinna, Salvatore Calò, Luigi Janiri, and Massimo di Giannantonio Copyright © 2014 Giovanni Martinotti et al. All rights reserved. Sphingosine-1-Phosphate Transporters as Targets for Cancer Therapy Tue, 15 Jul 2014 08:25:31 +0000 Sphingosine-1-phosphate (S1P) is a pleiotropic lipid mediator that regulates cell survival, migration, the recruitment of immune cells, angiogenesis, and lymphangiogenesis, all of which are involved in cancer progression. S1P is generated inside cancer cells by sphingosine kinases then exported outside of the cell into the tumor microenvironment where it binds to any of five G protein coupled receptors and proceeds to regulate a variety of functions. We have recently reported on the mechanisms underlying the “inside-out” signaling of S1P, its export through the plasma membrane, and its interaction with cell surface receptors. Membrane lipids, including S1P, do not spontaneously exchange through lipid bilayers since the polar head groups do not readily go through the hydrophobic interior of the plasma membrane. Instead, specific transporter proteins exist on the membrane to exchange these lipids. This review summarizes what is known regarding S1P transport through the cell membrane via ATP-binding cassette transporters and the spinster 2 transporter and discusses the roles for these transporters in cancer and in the tumor microenvironment. Based on our research and the emerging understanding of the role of S1P signaling in cancer and in the tumor microenvironment, S1P transporters and S1P signaling hold promise as new therapeutic targets for cancer drug development. Masayuki Nagahashi, Kazuaki Takabe, Krista P. Terracina, Daiki Soma, Yuki Hirose, Takashi Kobayashi, Yasunobu Matsuda, and Toshifumi Wakai Copyright © 2014 Masayuki Nagahashi et al. All rights reserved. Molecular Mechanisms for Biliary Phospholipid and Drug Efflux Mediated by ABCB4 and Bile Salts Tue, 15 Jul 2014 06:26:19 +0000 On the canalicular membranes of hepatocytes, several ABC transporters are responsible for the secretion of bile lipids. Among them, ABCB4, also called MDR3, is essential for the secretion of phospholipids from hepatocytes into bile. The biliary phospholipids are associated with bile salts and cholesterol in mixed micelles, thereby reducing the detergent activity and cytotoxicity of bile salts and preventing cholesterol crystallization. Mutations in the ABCB4 gene result in progressive familial intrahepatic cholestasis type 3, intrahepatic cholestasis of pregnancy, low-phospholipid-associated cholelithiasis, primary biliary cirrhosis, and cholangiocarcinoma. In vivo and cell culture studies have demonstrated that the secretion of biliary phospholipids depends on both ABCB4 expression and bile salts. In the presence of bile salts, ABCB4 located in nonraft membranes mediates the efflux of phospholipids, preferentially phosphatidylcholine. Despite high homology with ABCB1, ABCB4 expression cannot confer multidrug resistance. This review summarizes our current understanding of ABCB4 functions and physiological relevance, and discusses the molecular mechanism for the ABCB4-mediated efflux of phospholipids. Shin-ya Morita and Tomohiro Terada Copyright © 2014 Shin-ya Morita and Tomohiro Terada. All rights reserved. Video Game Addiction in Gambling Disorder: Clinical, Psychopathological, and Personality Correlates Mon, 14 Jul 2014 08:54:07 +0000 Objective. We studied the prevalences of video game use (VGU) and addiction (VGA) in gambling disorder (GD) patients and compared them with subjects with non-video game use (non-VGU) in relation to their gambling behavior, psychopathology, and personality characteristics. Method. A sample of 193 GD patients (121 non-VGU, 43 VGU, and 29 VGA) consecutively admitted to our pathological gambling unit participated in the study. Assessment. Measures included the video game dependency test (VDT), symptom checklist-90-revised, and the temperament and character inventory-revised, as well as a number of other GD indices. Results. In GD, the observed prevalence of VG (use or addiction) was 37.3% (),VGU 22.3% (), and VGA 15% (). Orthogonal polynomial contrast into logistic regression showed positive linear trends for VG level and GD severity and other measures of general psychopathology. After structural equation modeling, higher VG total scores were associated with younger age, general psychopathology, and specific personality traits, but not with GD severity. Patients’ sex and age were involved in the mediational pathways between personality traits and VG impairment. Conclusions. GD patients with VG are younger and present more dysfunctional personality traits, and more general psychopathology. The presence of VG did not affect the severity of GD. Susana Jiménez-Murcia, Fernando Fernández-Aranda, Roser Granero, Mariano Chóliz, Melania La Verde, Eugenio Aguglia, Maria S. Signorelli, Gustavo M. Sá, Neus Aymamí, Mónica Gómez-Peña, Amparo del Pino-Gutiérrez, Laura Moragas, Ana B. Fagundo, Sarah Sauchelli, José A. Fernández-Formoso, and José M. Menchón Copyright © 2014 Susana Jiménez-Murcia et al. All rights reserved. Ligation Strategies for Targeting Liposomal Nanocarriers Mon, 14 Jul 2014 07:45:56 +0000 Liposomes have been exploited for pharmaceutical purposes, including diagnostic imaging and drug and gene delivery. The versatility of liposomes as drug carriers has been demonstrated by a variety of clinically approved formulations. Since liposomes were first reported, research of liposomal formulations has progressed to produce improved delivery systems. One example of this progress is stealth liposomes, so called because they are equipped with a PEGylated coating of the liposome bilayer, leading to prolonged blood circulation and improved biodistribution of the liposomal carrier. A growing research area focuses on the preparation of liposomes with the ability of targeting specific tissues. Several strategies to prepare liposomes with active targeting ligands have been developed over the last decades. Herein, several strategies for the functionalization of liposomes are concisely summarized, with emphasis on recently developed technologies for the covalent conjugation of targeting ligands to liposomes. Patricia Marqués-Gallego and Anton I. P. M. de Kroon Copyright © 2014 Patricia Marqués-Gallego and Anton I. P. M. de Kroon. All rights reserved. Erratum to “Involvement of Nrf2-Mediated Upregulation of Heme Oxygenase-1 in Mollugin-Induced Growth Inhibition and Apoptosis in Human Oral Cancer Cells” Mon, 14 Jul 2014 00:00:00 +0000 Young-Man Lee, Q-Schick Auh, Deok-Won Lee, Jun-Yeol Kim, Ha-Jin Jung, Seung-Ho Lee, and Eun-Cheol Kim Copyright © 2014 Young-Man Lee et al. All rights reserved. Collagen VI and Hyaluronan: The Common Role in Breast Cancer Mon, 14 Jul 2014 00:00:00 +0000 Collagen VI and hyaluronan are widely distributed extracellular matrix macromolecules that play a crucial role in tissue development and are highly expressed in cancers. Both hyaluronan and collagen VI are upregulated in breast cancer, generating a microenvironment that promotes tumour progression and metastasis. A growing number of studies show that these two molecules are involved in inflammation and angiogenesis by recruiting macrophages and endothelial cells, respectively. Additionally, collagen VI induces epithelial-mesenchymal transition that is correlated to increased synthesis of hyaluronan in mammary cells. Hyaluronan has also a specific role in cellular functions that depends mainly on the size of the polymer, whereas the effect of collagen VI in tumour progression may be the result of the intact molecule or the C5 peptide of α3(VI) chain, known as endotrophin. Collectively, these findings strongly support the parallel role of these molecules in tumour progression and suggest that they may be used as prognostic factors for the breast cancer treatment. Evgenia Karousou, Maria Luisa D'Angelo, Katerina Kouvidi, Davide Vigetti, Manuela Viola, Dragana Nikitovic, Giancarlo De Luca, and Alberto Passi Copyright © 2014 Evgenia Karousou et al. All rights reserved. Human Genetic Disorders and Knockout Mice Deficient in Glycosaminoglycan Sun, 13 Jul 2014 07:28:37 +0000 Glycosaminoglycans (GAGs) are constructed through the stepwise addition of respective monosaccharides by various glycosyltransferases and maturated by epimerases and sulfotransferases. The structural diversity of GAG polysaccharides, including their sulfation patterns and sequential arrangements, is essential for a wide range of biological activities such as cell signaling, cell proliferation, tissue morphogenesis, and interactions with various growth factors. Studies using knockout mice of enzymes responsible for the biosynthesis of the GAG side chains of proteoglycans have revealed their physiological functions. Furthermore, mutations in the human genes encoding glycosyltransferases, sulfotransferases, and related enzymes responsible for the biosynthesis of GAGs cause a number of genetic disorders including chondrodysplasia, spondyloepiphyseal dysplasia, and Ehlers-Danlos syndromes. This review focused on the increasing number of glycobiological studies on knockout mice and genetic diseases caused by disturbances in the biosynthetic enzymes for GAGs. Shuji Mizumoto, Shuhei Yamada, and Kazuyuki Sugahara Copyright © 2014 Shuji Mizumoto et al. All rights reserved. Therapeutic Efficacy of Vitamin E -Tocotrienol in Collagen-Induced Rat Model of Arthritis Thu, 10 Jul 2014 11:38:19 +0000 Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory disease primarily involving inflammation of the joints. Although the management of the disease has advanced significantly in the past three decades, there is still no cure for RA. The aim of this study was to determine the therapeutic efficacy of δ-tocotrienol, in the rat model of collagen-induced arthritis (CIA). Arthritis was induced by intradermal injection of collagen type II emulsified in complete Freund’s adjuvant. CIA rats were orally treated with δ-tocotrienol (10 mg/kg) or glucosamine hydrochloride (300 mg/kg) from day 25 to 50. Efficacy was assessed based on the ability to reduce paw edema, histopathological changes, suppression of collagen-specific T-cells, and a reduction in C-reactive protein (CRP) levels. It was established that δ-tocotrienol had the most significant impact in lowering paw edema when compared to glucosamine treatment. Paw edema changes correlated well with histopathological analysis where there was a significant reversal of changes in groups treated with δ-tocotrienol. The results suggest that δ-tocotrienol is efficient in amelioration of collagen-induced arthritis. Vitamin E delta-tocotrienol may be of therapeutic value against rheumatoid arthritis. Nagaraja Haleagrahara, Mirashini Swaminathan, Srikumar Chakravarthi, and Ammu Radhakrishnan Copyright © 2014 Nagaraja Haleagrahara et al. All rights reserved. Noninvasive and Quantitative Assessment of In Vivo Fetomaternal Interface Angiogenesis Using RGD-Based Fluorescence Thu, 10 Jul 2014 07:03:28 +0000 Angiogenesis is a key process for proper placental development and for the success of pregnancy. Although numerous in vitro methods have been developed for the assessment of this process, relatively few reliable in vivo methods are available to evaluate this activity throughout gestation. Here we report an in vivo technique that specifically measures placental neovascularization. The technique is based on the measurement of a fluorescent alpha beta 3 () integrin-targeting molecule called Angiolone-Alexa-Fluor 700. The integrin is highly expressed by endothelial cells during the neovascularization and by trophoblast cells during their invasion of the maternal decidua. Angiolone was injected to gravid mice at 6.5 and 11.5 days post coitus (dpc). The fluorescence was analyzed one day later at 7.5 and 12.5 dpc, respectively. We demonstrated that (i) Angiolone targets protein in the placenta with a strong specificity, (ii) this technique is quantitative as the measurement was correlated to the increase of the placental size observed with increasing gestational age, and (iii) information on the outcome is possible, as abnormal placentation could be detected early on during gestation. In conclusion, we report the validation of a new noninvasive and quantitative method to assess the placental angiogenic activity, in vivo. M. Keramidas, J. Lavaud, F. Sergent, P. Hoffmann, S. Brouillet, J.-J. Feige, J.-L. Coll, and N. Alfaidy Copyright © 2014 M. Keramidas et al. All rights reserved. Butylidenephthalide Blocks Potassium Channels and Enhances Basal Tension in Isolated Guinea-Pig Trachea Thu, 10 Jul 2014 00:00:00 +0000 Butylidenephthalide (Bdph, 30~300 μM), a constituent of Ligusticum chuanxiong Hort., significantly enhanced tension in isolated guinea-pig trachea. In this study, we investigate the mechanism(s) of Bdph-induced contraction in the tissue. Isolated trachea was bathed in 5 mL of Krebs solution containing indomethacin (3 μM), and its tension changes were isometrically recorded. Cromakalim (3 μM), an ATP-dependent K+ channel opener, significantly antagonized the Bdph-induced enhancement of baseline tension. Bdph (300 μM) also significantly antagonized cromakalim-induced relaxation. Bdph (300 μM) did not significantly influence the antagonistic effects of glibenclamide (GBC, 1 μM) and tetraethylammonium (TEA, 8 mM) against the cromakalim-induced relaxation. However, Bdph (300 μM) and 4-aminopiridine (4-AP, 5 mM), a blocker of Kv1 family of K+ channels, in combination significantly rightward shifted the log concentration-relaxation curve of cromakalim. The antagonistic effect of the combination almost equals the sum of the individual effects of Bdph and 4-AP, suggesting that the antagonistic mechanism of Bdph may be similar to that of 4-AP. All calcium channel blockers influenced neither the baseline tension nor antagonistic effect of Bdph against cromakalim. In conclusion, Bdph may be similar to 4-AP, a blocker of Kv1 family of K+ channels, to enhance the baseline tension of guinea-pig trachea. Hsin-Te Hsu, You-Lan Yang, Wan-Chen Chen, Chi-Ming Chen, and Wun-Chang Ko Copyright © 2014 Hsin-Te Hsu et al. All rights reserved. Rho/ROCK Signal Cascade Mediates Asymmetric Dimethylarginine-Induced Vascular Smooth Muscle Cells Migration and Phenotype Change Wed, 09 Jul 2014 12:37:31 +0000 Asymmetric dimethylarginine (ADMA) induces vascular smooth muscle cells (VSMCs) migration. VSMC phenotype change is a prerequisite of migration. RhoA and Rho-kinase (ROCK) mediate migration of VSMCs. We hypothesize that ADMA induces VSMC migration via the activation of Rho/ROCK signal pathway and due to VSMCs phenotype change. ADMA activates Rho/ROCK signal pathway that interpreted by the elevation of RhoA activity and phosphorylation level of a ROCK substrate. Pretreatment with ROCK inhibitor, Y27632 completely reverses the induction of ADMA on ROCK and in turn inhibits ADMA-induced VSMCs migration. When the Rho/ROCK signal pathway has been blocked by pretreatment with Y27632, the induction of ERK signal pathway by ADMA is completely abrogated. Elimination of ADMA via overexpression of dimethylarginine dimethylaminohydrolase 2 (DDAH2) and L-arginine both blocks the effects of ADMA on the activation of Rho/ROCK and extra cellular signal-regulated kinase (ERK) in VSMCs. The expression of differentiated phenotype relative proteins was reduced and the actin cytoskeleton was disassembled by ADMA, which were blocked by Y27632, further interpreting that ADMA inducing VSMCs migration via Rho/ROCK signal pathway is due to its effect on the VSMCs phenotype change. Our present study may help to provide novel insights into the therapy and prevention of atherosclerosis. Yi-ming Zhou, Xi Lan, Han-bin Guo, Yan Zhang, Li Ma, and Jian-biao Cao Copyright © 2014 Yi-ming Zhou et al. All rights reserved. Antidiabetic Effect of Sida cordata in Alloxan Induced Diabetic Rats Wed, 09 Jul 2014 11:50:43 +0000 Medicinal plants are efficient ameliorator of oxidative stress associated with diabetes mellitus. In this study, ethyl acetate fraction (SCEE) of Sida cordata was investigated for scientific validation of its folk use in diabetes. Antidiabetic effect of SCEE was confirmed by antihyperglycemic activity in normal glucose loaded and diabetic glucose loaded animals as well as normal off feed animals. Confirmation of antidiabetic activity and toxicity ameliorative role of S. cordata was investigated in a chronic multiple dose treatment study of fifteen days. A single dose of alloxan (120 mg/kg) produced a decrease in insulin level, hyperglycemia, elevated total lipids, triglycerides, and cholesterol and decreased the high-density lipoproteins. Concurrent with these changes, there was an increase in the concentration of lipid peroxidation (TBARS), H2O2, and nitrite in pancreas, liver, and testis. This oxidative stress was related to a decrease in glutathione content (GSH) and antioxidant enzymes. Administration of SCEE for 15 days after diabetes induction ameliorated hyperglycemia, restored lipid profile, blunted the increase in TBARS, H2O2, and nitrite content, and stimulated the GSH production in the organs of alloxan-treated rats. We suggested that SCEE could be used as antidiabetic component in case of diabetes mellitus. This may be related to its antioxidative properties. Naseer Ali Shah and Muhammad Rashid Khan Copyright © 2014 Naseer Ali Shah and Muhammad Rashid Khan. All rights reserved. The K–Cl Cotransporter KCC3 as an Independent Prognostic Factor in Human Esophageal Squamous Cell Carcinoma Wed, 09 Jul 2014 00:00:00 +0000 The objectives of the present study were to investigate the role of K–Cl cotransporter 3 (KCC3) in the regulation of cellular invasion and the clinicopathological significance of its expression in esophageal squamous cell carcinoma (ESCC). Immunohistochemical analysis performed on 70 primary tumor samples obtained from ESCC patients showed that KCC3 was primarily found in the cytoplasm of carcinoma cells. Although the expression of KCC3 in the main tumor (MT) was related to several clinicopathological features, such as the pT and pN categories, it had no prognostic impact. KCC3 expression scores were compared between the MT and cancer nest (CN), and the survival rate of patients with a score was lower than that of patients with a score. In addition, the survival rate of patients in whom KCC3 was expressed in the invasive front of tumor was lower than that of the patients without it. Furthermore, multivariate analysis demonstrated that the expression of KCC3 in the invasive front was one of the most important independent prognostic factors. The depletion of KCC3 using siRNAs inhibited cell migration and invasion in human ESCC cell lines. These results suggest that the expression of KCC3 in ESCC may affect cellular invasion and be related to a worse prognosis in patients with ESCC. Atsushi Shiozaki, Kenichi Takemoto, Daisuke Ichikawa, Hitoshi Fujiwara, Hirotaka Konishi, Toshiyuki Kosuga, Shuhei Komatsu, Kazuma Okamoto, Mitsuo Kishimoto, Yoshinori Marunaka, and Eigo Otsuji Copyright © 2014 Atsushi Shiozaki et al. All rights reserved. Sensitization of Cancer Cells through Reduction of Total Akt and Downregulation of Salinomycin-Induced pAkt, pGSk3β, pTSC2, and p4EBP1 by Cotreatment with MK-2206 Tue, 08 Jul 2014 12:16:08 +0000 MK-2206 is an inhibitor of Akt activation. It has been investigated as an anticancer drug in clinical trials assessing the potential of pAkt targeting therapy. The purpose of this study was to identify conditions that increase the sensitivity of cancer cells to MK-2206. We found that the treatment of cancer cells with a high concentration of salinomycin (Sal) reduced total Akt protein levels but increased activated Akt levels. When cancer cells were cotreated with MK-2206 and Sal, both pAkt and total Akt levels were reduced. Using microscopic observation, an assessment of cleaved PARP, FACS analysis of pre-G1 region, and Hoechst staining, we found that Sal increased apoptosis of MK-2206-treated cancer cells. These results suggest that cotreatment with MK-2206 and Sal sensitizes cancer cells via reduction of both pAkt and total Akt. Furthermore, cotreatment of cancer cells with Sal and MK-2206 reduced pp70S6K, pmTOR, and pPDK1 levels. In addition, Sal-induced activation of GSK3β, TSC2, and 4EBP1 was abolished by MK-2206 cotreatment. These results suggest that cotreatment using MK-2206 and Sal could be used as a therapeutic method to sensitize cancer cells through targeting of the PI3K/Akt/mTOR pathway. Our findings may contribute to the development of MK-2206-based sensitization therapies for cancer patients. Ae-Ran Choi, Ju-Hwa Kim, and Sungpil Yoon Copyright © 2014 Ae-Ran Choi et al. All rights reserved. Mallotus philippinensis Muell. Arg (Euphorbiaceae): Ethnopharmacology and Phytochemistry Review Tue, 08 Jul 2014 00:00:00 +0000 Mallotus philippinensis Muell. Arg (Euphorbiaceae) are widely distributed perennial shrub or small tree in tropical and subtropical region in outer Himalayas regions with an altitude below 1,000 m and are reported to have wide range of pharmacological activities. Mallotus philippinensis species are known to contain different natural compounds, mainly phenols, diterpenoids, steroids, flavonoids, cardenolides, triterpenoids, coumarins, isocoumarins, and many more especially phenols; that is, bergenin, mallotophilippinens, rottlerin, and isorottlerin have been isolated, identified, and reported interesting biological activities such as antimicrobial, antioxidant, antiviral, cytotoxicity, antioxidant, anti-inflammatory, immunoregulatory activity protein inhibition against cancer cell. We have selected all the pharmacological aspects and toxicological and all its biological related studies. The present review reveals that Mallotus philippinensis is a valuable source of medicinally important natural molecules and provides convincing support for its future use in modern medicine. However, the existing knowledge is very limited about Mallotus philippinensis and its different parts like steam, leaf, and fruit. Further, more detailed safety data pertaining to the acute and subacute toxicity and cardio- and immunotoxicity also needs to be generated for crude extracts or its pure isolated compounds. This review underlines the interest to continue the study of this genus of the Euphorbiaceae. Mayank Gangwar, R. K. Goel, and Gopal Nath Copyright © 2014 Mayank Gangwar et al. All rights reserved. Acetylated Hyaluronic Acid: Enhanced Bioavailability and Biological Studies Tue, 08 Jul 2014 00:00:00 +0000 Hyaluronic acid (HA), a macropolysaccharidic component of the extracellular matrix, is common to most species and it is found in many sites of the human body, including skin and soft tissue. Not only does HA play a variety of roles in physiologic and in pathologic events, but it also has been extensively employed in cosmetic and skin-care products as drug delivery agent or for several biomedical applications. The most important limitations of HA are due to its short half-life and quick degradation in vivo and its consequently poor bioavailability. In the aim to overcome these difficulties, HA is generally subjected to several chemical changes. In this paper we obtained an acetylated form of HA with increased bioavailability with respect to the HA free form. Furthermore, an improved radical scavenging and anti-inflammatory activity has been evidenced, respectively, on ABTS radical cation and murine monocyte/macrophage cell lines (J774.A1). Carmela Saturnino, Maria Stefania Sinicropi, Ortensia Ilaria Parisi, Domenico Iacopetta, Ada Popolo, Stefania Marzocco, Giuseppina Autore, Anna Caruso, Anna Rita Cappello, Pasquale Longo, and Francesco Puoci Copyright © 2014 Carmela Saturnino et al. All rights reserved. A Review on the Traditional Chinese Medicinal Herbs and Formulae with Hypolipidemic Effect Mon, 07 Jul 2014 08:02:50 +0000 Hyperlipidemia, characterized by the abnormal blood lipid profiles, is one of the dominant factors of many chronic diseases such as diabetes, obesity, and cardiovascular diseases (CVD). For the low cost, effectiveness, and fewer side effects, the popularity of using traditional Chinese medicine (TCM) to handle hyperlipidemia is increasing and its role in health care has been recognized by the public at large. Despite the importance of TCM herbs and formulations, there is no comprehensive review summarizing their scientific findings on handling hyperlipidemia. This review summarizes the recent experimental and clinical results of nine representative single Chinese herbs and seven classic TCM formulae that could improve lipid profiles so as to help understand and compare their underlying mechanisms. Most of single herbs and formulae demonstrated the improvement of hyperlipidemic conditions with multiple and diverse mechanisms of actions similar to conventional Western drugs in spite of their mild side effects. Due to increasing popularity of TCM, more extensive, well-designed preclinical and clinical trials on the potential synergistic and adverse side effects of herb-drug interactions as well as their mechanisms are warranted. Hyperlipidemic patients should be warned about the potential risks of herb-drug interactions, particularly those taking anticoagulants and antiplatelet drugs. Tung-Ting Sham, Chi-On Chan, You-Hua Wang, Jian-Mei Yang, Daniel Kam-Wah Mok, and Shun-Wan Chan Copyright © 2014 Tung-Ting Sham et al. All rights reserved. Adult Separation Anxiety and TCI-R Personality Dimensions in Patients with Anxiety, Alcohol Use, and Gambling: A Preliminary Report Thu, 03 Jul 2014 11:50:18 +0000 Background. Nowadays, adult separation anxiety disorder (ASAD) is an established diagnostic category but is little investigated in subjects with addictive behaviours. Objective. To assess the presence of ASAD among patients with addictive disorders in comparison with anxiety patients and measure the personality correlates in all these groups. Methods. 103 outpatients, meeting DSM-IV-TR criteria for anxiety disorders (38 patients), alcohol dependence (30 patients), or pathological gambling (35 patients), were assessed by the Structured Clinical Interview for Separation Anxiety Symptoms (SCI-SAS) and the Adult Separation Anxiety Checklist (ASA-27) for separation anxiety and by the Temperament and Character Inventory-Revised (TCI-R) for personality characteristics. Results. ASAD is detected in 34.2% of anxiety patients, 13.3% of alcoholics, and 11.4% of gamblers. Separation anxiety scores correlate positively with harm avoidance and negatively with self-directedness in all groups; further correlations are seen among addictive patients only, that is, self-transcendence for gamblers and cooperativeness for both alcoholics and gamblers. Conclusions. The prevalence of ASAD is lower among addictive patients than in those with anxiety disorders; correlations are found between separation anxiety and specific TCI-R dimensions, with some matching across the three diagnostic groups. Gino Pozzi, Angelo Bruschi, Andrea De Angelis, Marco Pascucci, Daniele Stavros Hatzigiakoumis, Paolo Grandinetti, Marco Di Nicola, Stefano Pini, and Luigi Janiri Copyright © 2014 Gino Pozzi et al. All rights reserved. Metabolism of Cartilage Proteoglycans in Health and Disease Thu, 03 Jul 2014 11:22:15 +0000 Cartilage proteoglycans are extracellular macromolecules with complex structure, composed of a core protein onto which a variable number of glycosaminoglycan chains are attached. Their biosynthesis at the glycosaminoglycan level involves a great number of sugar transferases well-orchestrated in Golgi apparatus. Similarly, their degradation, either extracellular or intracellular in lysosomes, involves a large number of hydrolases. A deficiency or malfunction of any of the enzymes participating in cartilage proteoglycan metabolism may lead to severe disease state. This review summarizes the findings regarding this topic. Demitrios H. Vynios Copyright © 2014 Demitrios H. Vynios. All rights reserved. 25C-NBOMe: Preliminary Data on Pharmacology, Psychoactive Effects, and Toxicity of a New Potent and Dangerous Hallucinogenic Drug Thu, 03 Jul 2014 07:37:45 +0000 Introduction. The use of novel psychoactive substances (NPSs) has rapidly increased as well as their online availability. The aim of this paper is to provide a comprehensive review of the nature and the risks associated with 25C-NBOMe, which has recently appeared in the drug market. Methods. A systematic analysis of the scientific literature and a qualitative assessment of online and media resources (e.g., e-newsgroups, chat-rooms, and e-newsletters) in 10 languages were carried out. Results. 25C-NBOMe is sold online as legal LSD or as research chemical with different designations such as “Boom,” “Pandora,” “Holland film,” or “N-bomb.” It is a partial agonist of 5-HT2A receptors. It is usually ingested orally/sublingually and, less commonly, nasally, through injection, vaginally, rectally, and smoked. Its effects include sublingual numbing, stimulation, “body high,” hallucinations, dissociation, and anxiety. 25C-NBOMe presents high risk of overdoses; acute toxicity and fatalities have been reported. Conclusions. 25C-NBOMe consumption represents an emerging phenomenon with potential harmful effects. Its use is increased by its online availability at low costs. Health and other professionals should be informed about this new trend of substance use. Francesco Saverio Bersani, Ornella Corazza, Gabriella Albano, Giuseppe Valeriani, Rita Santacroce, Flaminia Bolzan Mariotti Posocco, Eduardo Cinosi, Pierluigi Simonato, Giovanni Martinotti, Giuseppe Bersani, and Fabrizio Schifano Copyright © 2014 Francesco Saverio Bersani et al. All rights reserved. ADAMTS4 and ADAMTS5 Knockout Mice Are Protected from Versican but Not Aggrecan or Brevican Proteolysis during Spinal Cord Injury Thu, 03 Jul 2014 00:00:00 +0000 The chondroitin sulfate proteoglycans (CSPGs) aggrecan, versican, and brevican are large aggregating extracellular matrix molecules that inhibit axonal growth of the mature central nervous system (CNS). ADAMTS proteoglycanases, including ADAMTS4 and ADAMTS5, degrade CSPGs, representing potential targets for ameliorating axonal growth-inhibition by CSPG accumulation after CNS injury. We investigated the proteolysis of CSPGs in mice homozygous for Adamts4 or Adamts5 null alleles after spinal cord injury (SCI). ADAMTS-derived 50–60 kDa aggrecan and 50 kDa brevican fragments were observed in Adamts4−/−, Adamts5−/−, and wt mice but not in the sham-operated group. By contrast Adamts4−/− and Adamts5−/− mice were both protected from versican proteolysis with an ADAMTS-generated 70 kDa versican fragment predominately observed in WT mice. ADAMTS1, ADAMTS9, and ADAMTS15 were detected by Western blot in Adamts4−/− mice’ spinal cords after SCI. Immunohistochemistry showed astrocyte accumulation at the injury site. These data indicate that aggrecan and brevican proteolysis is compensated in Adamts4−/− or Adamts5−/− mice by ADAMTS proteoglycanase family members but a threshold of versican proteolysis is sensitive to the loss of a single ADAMTS proteoglycanase during SCI. We show robust ADAMTS activity after SCI and exemplify the requirement for collective proteolysis for effective CSPG clearance during SCI. Kadir Demircan, Vehap Topcu, Tomoyuki Takigawa, Sumeyya Akyol, Tomoko Yonezawa, Gulfer Ozturk, Veli Ugurcu, Rukiye Hasgul, M. Ramazan Yigitoglu, Omer Akyol, Daniel R. McCulloch, and Satoshi Hirohata Copyright © 2014 Kadir Demircan et al. All rights reserved. Drug Delivery Nanoparticles in Skin Cancers Wed, 02 Jul 2014 06:39:43 +0000 Nanotechnology involves the engineering of functional systems at nanoscale, thus being attractive for disciplines ranging from materials science to biomedicine. One of the most active research areas of the nanotechnology is nanomedicine, which applies nanotechnology to highly specific medical interventions for prevention, diagnosis, and treatment of diseases, including cancer disease. Over the past two decades, the rapid developments in nanotechnology have allowed the incorporation of multiple therapeutic, sensing, and targeting agents into nanoparticles, for detection, prevention, and treatment of cancer diseases. Nanoparticles offer many advantages as drug carrier systems since they can improve the solubility of poorly water-soluble drugs, modify pharmacokinetics, increase drug half-life by reducing immunogenicity, improve bioavailability, and diminish drug metabolism. They can also enable a tunable release of therapeutic compounds and the simultaneous delivery of two or more drugs for combination therapy. In this review, we discuss the recent advances in the use of different types of nanoparticles for systemic and topical drug delivery in the treatment of skin cancer. In particular, the progress in the treatment with nanocarriers of basal cell carcinoma, squamous cell carcinoma, and melanoma has been reported. Chiara Dianzani, Gian Paolo Zara, Giovanni Maina, Piergiorgio Pettazzoni, Stefania Pizzimenti, Federica Rossi, Casimiro Luca Gigliotti, Eric Stefano Ciamporcero, Martina Daga, and Giuseppina Barrera Copyright © 2014 Chiara Dianzani et al. All rights reserved. Efficacy of a Hypotonic Treatment for Peritoneal Dissemination from Gastric Cancer Cells: An In Vivo Evaluation Wed, 02 Jul 2014 00:00:00 +0000 The aim of the present study was to determine the efficacy of a hypotonic treatment for peritoneal dissemination from gastric cancer cells using an in vivo model. We firstly evaluated the toxicity of a peritoneal injection of distilled water (DW) (2 mL for 3 days) in mice. Macroscopic and microscopic examinations revealed that the peritoneal injection of DW did not severely damage the abdominal organs of these mice. MKN45 gastric cancer cells preincubated with NaCl buffer or DW for 20 minutes in vitro were then intraperitoneally injected into nude mice, and the development of dissemination nodules was analyzed. The total number, weight, and volume of the dissemination nodules were significantly decreased by the DW preincubation. We then determined whether the peritoneal injection of DW inhibited the establishment of peritoneal dissemination. After a peritoneal injection of MKN45 cells into nude mice, NaCl buffer or DW was injected into the abdominal cavity for 3 days. The total volume of dissemination nodules was significantly lower in DW-injected mice than in NaCl-injected mice. In conclusion, we demonstrated the safeness of a peritoneal injection of DW. Furthermore, the development of dissemination nodules from gastric cancer cells was prevented by a preincubation with or peritoneal injection of DW. Atsushi Shiozaki, Daisuke Ichikawa, Kenichi Takemoto, Yoshito Nako, Shingo Nakashima, Hiroki Shimizu, Maki Kitagawa, Toshiyuki Kosuga, Hirotaka Konishi, Shuhei Komatsu, Hitoshi Fujiwara, Kazuma Okamoto, Yoshinori Marunaka, and Eigo Otsuji Copyright © 2014 Atsushi Shiozaki et al. All rights reserved. Angiogenin Expression during Early Human Placental Development; Association with Blood Vessel Formation Tue, 01 Jul 2014 09:31:30 +0000 The placenta is a transient organ essential for fetal development. During human placental development, chorionic villi grow in coordination with a large capillary network resulting from both vasculogenesis and angiogenesis. Angiogenin is one of the most potent inducers of neovascularisation in experimental models in vivo. We and others have previously mapped angiogenin expression in the human term placenta. Here, we explored angiogenin involvement in early human placental development. We studied, angiogenin expression by in situ hybridisation and/or by RT-PCR in tissues and primary cultured trophoblastic cells and angiogenin cellular distribution by coimmunolabelling with cell markers: CD31 (PECAM-1), vascular endothelial cadherin (VE-cadherin), vascular endothelial growth factor receptor-2 (VEGF-R2), Tie-2, von Willebrand factor, CD34, erythropoeitin receptor (Epo-R), alpha-smooth muscle actin, CD45, cytokeratin 7, and Ki-67. Extravillous and villous cytotrophoblasts, isolated and differentiated in vitro, expressed and secreted angiogenin. Angiogenin was detected in villous trophoblastic layers, and structured and nascent fetal vessels. In decidua, it was expressed by glandular epithelial cells, vascular cells and macrophages. The observed pattern of angiogenin expression is compatible with a role in blood vessel formation and in cross-talk between trophoblasts and endothelial cells. In view of angiogenin properties, we suggest that angiogenin may participate in placental vasculogenesis and organogenesis. Nadine Pavlov, Jean-Louis Frendo, Jean Guibourdenche, Séverine A. Degrelle, Danièle Evain-Brion, and Josette Badet Copyright © 2014 Nadine Pavlov et al. All rights reserved. Prevalence and Correlates of Binge Drinking among Young Adults Using Alcohol: A Cross-Sectional Survey Mon, 30 Jun 2014 11:41:37 +0000 Background. Although binge drinking prevalence and correlates among young people have been extensively studied in the USA and Northern Europe, less is known for Southern Europe countries with relatively healthier drinking cultures. Objective. We aimed at analyzing prevalence and correlates of binge drinking in a representative sample of young adults in Italy. Methods. We conducted a cross-sectional survey among alcohol-consuming young adults. We carried out univariate and multivariate analyses to assess associations between recent binge drinking and candidate variables. Results. We selected 654 subjects, with 590 (mean age: 20.65 ± 1.90) meeting inclusion criteria. Prevalence for recent binge drinking was 38.0%, significantly higher for females than males. Multivariate analysis showed that high alcohol expectancies, large amount of money available during the weekend, interest for parties and discos, female gender, cannabis use, influence by peers, and electronic cigarettes smoking all were significantly associated with recent binge drinking, whereas living with parents appeared a significant protective factor. Conclusions. More than a third of young adults using alcohol are binge drinkers, and, in contrast with findings from Anglo-Saxon countries, females show higher risk as compared with males. These data suggest the increasing importance of primary and secondary prevention programmes for binge drinking. Francesco Bartoli, Daniele Carretta, Cristina Crocamo, Alessandro Schivalocchi, Giulia Brambilla, Massimo Clerici, and Giuseppe Carrà Copyright © 2014 Francesco Bartoli et al. All rights reserved. Molecular Mechanisms of Curcumin on Diabetes-Induced Endothelial Dysfunctions: Txnip, ICAM-1, and NOX2 Expressions Thu, 26 Jun 2014 10:50:10 +0000 We aim to investigate the effects of curcumin on preventing diabetes-induced vascular inflammation in association with its actions on Txnip, ICAM-1, and NOX2 enzyme expressions. Male Wistar rats were divided into four groups: control (CON), diabetic (DM; streptozotocin (STZ), i.v. 55 mg/kg BW), control-treated with curcumin (CONCUR; 300 mg/kg BW), and diabetes treated with curcumin (DMCUR; 300 mg/kg BW). 12th week after STZ injection, iris blood perfusion, leukocyte adhesion, Txnip, p47phox, and malondialdehyde (MDA) levels were determined by using laser Doppler, intravital fluorescent confocal microscopy, Western Blot analysis, and TBAR assay, respectively. The iris blood perfusion of DM and DMCUR was decreased significantly compared to CON and CONCUR . Plasma glucose and HbA1c of DM and DMCUR were increased significantly compared to CON and CONCUR . Leukocyte adhesion, ICAM-1, p47phox expression, and MDA levels in DM were increased significantly compared to CON, CONCUR, and DMCUR . Txnip expression in DM and DMCUR was significantly higher than CON and CONCUR . From Pearson’s analysis, the correlation between the plasma MDA level and the endothelial functions was significant. It suggested that curcumin could ameliorate diabetic vascular inflammation by decreasing ROS overproduction, reducing leukocyte-endothelium interaction, and inhibiting ICAM-1 and NOX2 expression. Natchaya Wongeakin, Parvapan Bhattarakosol, and Suthiluk Patumraj Copyright © 2014 Natchaya Wongeakin et al. All rights reserved. Carum copticum L.: A Herbal Medicine with Various Pharmacological Effects Wed, 25 Jun 2014 08:36:00 +0000 Carum copticum L. commonly known as “Ajwain” is cultivated in many regions of the world including Iran and India, states of Gujarat and Rajasthan. Traditionally, C. copticum has been used in the past for various therapeutic effects including bloating, fatigue, diarrhea, abdominal tumors, abdominal pain, respiratory distress, and loss of appetite. It has other health benefits such as antifungal, antioxidant, antibacterial, antiparasitic, and hypolipidemic effects. This plant contains different important components such as carbohydrates, glucosides, saponins and phenolic compounds (carvacrol), volatile oils (thymol), terpiene, paracymene and beta-pinene, protein, fat, fiber, and minerals including calcium, phosphorus, iron, and nicotinic acid (niacin). In the previous studies, several pharmacological effects were shown for C. copticum. Therefore, in this paper, the pharmacological effects of the plant were reviewed. Mohammad Hossein Boskabady, Saeed Alitaneh, and Azam Alavinezhad Copyright © 2014 Mohammad Hossein Boskabady et al. All rights reserved. Obsessive-Compulsive Aspects and Pathological Gambling in an Italian Sample Wed, 25 Jun 2014 07:32:01 +0000 Introduction. Gambling behaviour appears as repetitive and difficult to resist and seems to be aimed at neutralizing or reducing negative feelings such as anxiety and tension, confirming its similarities with the obsessive-compulsive spectrum. Aims. Estimating the prevalence of gambling behaviour in an Italian sample and assessing the effects of sociodemographic variables and the correlations between gambling behaviour and obsessive-compulsive features. Methods. A sample of 300 Italian subjects was evaluated based on gambling behaviours and obsessive-compulsive attitudes. The assessment was carried out in small centers in Italy, mainly in coffee and tobacco shops, where slot machines are located, using the South Oaks Gambling Screen (SOGS) and the MOCQ-R, a reduced form of Maudsley Obsessional-Compulsive Questionnaire. Results. A negative correlation between SOGS and MOPQ-R, with reference to the control and cleaning subscales, was evidenced in the majority of the examined subjects. Both evaluating instruments showed reliability and a good discriminative capacity. Conclusions. Our study evidenced that the sample of gamblers we analysed did not belong to the obsessive-compulsive disorders area, supporting the validity of the model proposed by DSM-5 for the classification of PG. These data confirm the importance of investing in treatments similar to those used for substance use disorders. Filippo Petruccelli, Pierluigi Diotaiuti, Valeria Verrastro, Irene Petruccelli, Maria Luisa Carenti, Domenico De Berardis, Felice Iasevoli, Alessandro Valchera, Michele Fornaro, Giovanni Martinotti, Massimo Di Giannantonio, and Luigi Janiri Copyright © 2014 Filippo Petruccelli et al. All rights reserved. Bioactivity-Guided Fractionation Identifies Amygdalin as a Potent Neurotrophic Agent from Herbal Medicine Semen Persicae Extract Tue, 24 Jun 2014 07:40:13 +0000 Herbal medicine Semen Persicae is widely used to treat blood stasis in Chinese medicine and other oriental folk medicines. Although little is known about the effects of Semen Persicae and its active compounds on neuron differentiation, our pilot study showed that Semen Persicae extract promoted neurite outgrowth in rat dopaminergic PC12 cells. In the present study, we developed a bioactivity-guided fractionation procedure for the characterization of the neurotrophic activity of Semen Persicae extract. The resultant fractions were assayed for neurite outgrowth in PC12 cells based on microscopic assessment. Through liquid-liquid extraction and reverse phase HPLC separation, a botanical glycoside amygdalin was isolated as the active compound responsible for the neurotrophic activity of Semen Persicae extract. Moreover, we found that amygdalin rapidly induced the activation of extracellular-signal-regulated kinase 1/2 (ERK1/2). A specific ERK1/2 inhibitor PD98059 attenuated the stimulatory effect of amygdalin on neurite outgrowth. Taken together, amygdalin was identified as a potent neurotrophic agent from Semen Persicae extract through a bioactivity-guided fractional procedure. The neurotrophic activity of amygdalin may be mediated by the activation of ERK1/2 pathway. Chuanbin Yang, Jia Zhao, Yuanyuan Cheng, Xuechen Li, and Jianhui Rong Copyright © 2014 Chuanbin Yang et al. All rights reserved. Inhibitory Potential of Turbinaria ornata against Key Metabolic Enzymes Linked to Diabetes Tue, 24 Jun 2014 05:42:38 +0000 One of the therapeutic approaches in treating diabetes is to reduce postprandial hyperglycemia by inhibiting major carbohydrate hydrolyzing enzymes. In the present study, crude extracts of marine seaweed, Turbinaria ornata, were tested for their antidiabetic potential using enzyme inhibitory assays (α-amylase, α-glucosidase, and dipeptidyl peptidase-IV). Among the tested extracts, methanol and acetone extracts showed significant inhibitory effects on α-amylase ( 250.9 μg/mL), α-glucosidase (535.6 μg/mL), and dipeptidyl peptidase-4 (55.2 μg/mL), respectively. Free radical scavenging activity of these extracts was analyzed using DPPH assay (65%). Extracts were tested for in vitro toxicity using DNA fragmentation assay, haemolytic assay, and MTT assay. None of the extracts showed toxicity in tested models. Furthermore, GC-MS analysis of lead extracts showed the presence of major compounds, hentriacontane, z, z-6, 28-heptatriactontadien-2-one, 8-heptadecene, and 1-heptacosanol. Our findings suggest that Turbinaria ornata can be used as a potential source for further in vivo studies in controlling hyperglycemia. P. S. Unnikrishnan, K. Suthindhiran, and M. A. Jayasri Copyright © 2014 P. S. Unnikrishnan et al. All rights reserved. Affective Dependence and Aggression: An Exploratory Study Mon, 23 Jun 2014 11:01:01 +0000 Introduction. Emotionally dependent subjects may engage in controlling, restrictive, and aggressive behaviours, which limit their partner’s autonomy. The underlying causes of such behaviours are not solely based on levels of aggression, but act as a mean of maintaining the subject’s own sense of self-worth, identity, and general functioning. Objective. The aim of the paper is to explore the correlation between affective dependency and reactive/proactive aggression and to evaluate individual differences as predisposing factors for aggressive behaviour and emotional dependency. Methods. The Spouse-Specific Dependency Scale (SSDS) and the Reactive Proactive Questionnaire (RPQ) were administered to a sample of 3375 subjects. Results. In the whole sample, a positive correlation between emotional dependency and proactive aggression was identified. Differences with regard to sex, age group, and geographical distribution were evidenced for the scores of the different scales. Conclusion. A fundamental distinction between reactive and proactive aggression was observed, anchoring proactive aggression more strictly to emotional dependency. Sociocultural and demographical variables, together with the previous structuring of attachment styles, help to determine the scope, frequency, and intensity of the demands made to the partner, as well as to feed the fears of loss, abandonment, or betrayal. Filippo Petruccelli, Pierluigi Diotaiuti, Valeria Verrastro, Irene Petruccelli, Roberta Federico, Giovanni Martinotti, Andrea Fossati, Massimo Di Giannantonio, and Luigi Janiri Copyright © 2014 Filippo Petruccelli et al. All rights reserved. Enhanced Analgesic Properties and Reduced Ulcerogenic Effect of a Mononuclear Copper(II) Complex with Fenoprofen in Comparison to the Parent Drug: Promising Insights in the Treatment of Chronic Inflammatory Diseases Thu, 19 Jun 2014 13:02:05 +0000 Analgesic and ulcerogenic properties have been studied for the copper(II) coordination complex of the nonsteroidal anti-inflammatory drug Fenoprofen and imidazole [Cu(fen)2(im)2] (Cu: copper(II) ion; fen: fenoprofenate anion from Fenoprofen, im: imidazole). A therapeutic dose of 28 mg/kg was tested for [Cu(fen)2(im)2] and 21 mg/kg was employed for Fenoprofen calcium, administered by oral gavage in female mice to compare the therapeutic properties of the new entity. The acetic acid induced writhing test was employed to study visceral pain. The percentage of inhibition in writhing and stretching was 78.9% and 46.2% for the [Cu(fen)2(im)2] and Fenoprofen calcium, respectively. This result indicates that the complex could be more effective in diminishing visceral pain. The formalin test was evaluated to study the impact of the drugs over nociceptive and inflammatory pain. The complex is a more potent analgesic on inflammatory pain than the parent drug. Ulcerogenic effects were evaluated using a model of gastric lesions induced by hypothermic-restraint stress. Fenoprofen calcium salt caused an ulcer index of about 79 mm2 while the one caused by [Cu(fen)2(im)2] was 22 mm2. The complex diminished the development of gastric mucosal ulcers in comparison to the uncomplexed drug. Possible mechanisms of action related to both therapeutic properties have been discussed. Mariela Agotegaray, Fernanda Gumilar, Mónica Boeris, Ricardo Toso, and Alejandra Minetti Copyright © 2014 Mariela Agotegaray et al. All rights reserved. Novel Drugs Development for Cardio-/Cerebrovascular Diseases Tue, 17 Jun 2014 06:53:22 +0000 Joen-Rong Sheu, Philip Aloysius Thomas, and Juei-Tang Cheng Copyright © 2014 Joen-Rong Sheu et al. All rights reserved. Amelioration of LPS-Induced Inflammation Response in Microglia by AMPK Activation Tue, 17 Jun 2014 00:00:00 +0000 Adenosine 5′-monophosphate-activated protein kinase (AMPK) is a key regulator of cellular energy homeostasis via modulating metabolism of glucose, lipid, and protein. In addition to energy modulation, AMPK has been demonstrated to associate with several important cellular events including inflammation. The results showed that ENERGI-F704 identified from bamboo shoot extract was nontoxic in concentrations up to 80 μM and dose-dependently induced phosphorylation of AMPK (Thr-172) in microglia BV2 cells. Our findings also showed that the treatment of BV2 with ENERGI-F704 ameliorated the LPS-induced elevation of IL-6 and TNF-α production. In addition, ENERGI-F704 reduced increased production of nitric oxide (NO) and prostaglandin E2 (PGE2) via downregulating the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2), respectively. Moreover, ENERGI-F704 decreased activated nuclear translocation and protein level of NF-κB. Inhibition of AMPK with compound C restored decreased NF-κB translocation by ENERGI-F704. In conclusion, ENERGI-F704 exerts inhibitory activity on LPS-induced inflammation through manipulating AMPK signaling and exhibits a potential therapeutic agent for neuroinflammatory disease. Chin-Chen Chen, Jiun-Tsai Lin, Yi-Fang Cheng, Cheng-Yi Kuo, Chun-Fang Huang, Shao-Hsuan Kao, Yao-Jen Liang, Ching-Yi Cheng, and Han-Min Chen Copyright © 2014 Chin-Chen Chen et al. All rights reserved. Biomedical Properties of a Natural Dietary Plant Metabolite, Zerumbone, in Cancer Therapy and Chemoprevention Trials Mon, 16 Jun 2014 00:00:00 +0000 Zerumbone (ZER) is a naturally occurring dietary compound, present in many natural foods consumed today. The compound derived from several plant species of the Zingiberaceae family that has been found to possess multiple biomedical properties, such as antiproliferative, antioxidant, anti-inflammatory, and anticancer activities. However, evidence of efficacy is sparse, pointing to the need for a more systematic review for assessing scientific evidence to support therapeutic claims made for ZER and to identify future research needs. This review provides an updated overview of in vitro and in vivo investigations of ZER, its cancer chemopreventive properties, and mechanisms of action. Therapeutic effects of ZER were found to be scientifically plausible and could be explained partially by in vivo and in vitro pharmacological activities. Much of the research outlined in this paper will serve as a foundation to explain ZER anticancer bioactivity, which will open the door for the development of strategies in the treatment of malignancies using ZER. Heshu Sulaiman Rahman, Abdullah Rasedee, Swee Keong Yeap, Hemn Hassan Othman, Max Stanley Chartrand, Farideh Namvar, Ahmad Bustamam Abdul, and Chee Wun How Copyright © 2014 Heshu Sulaiman Rahman et al. All rights reserved. Sexual Enhancement Products for Sale Online: Raising Awareness of the Psychoactive Effects of Yohimbine, Maca, Horny Goat Weed, and Ginkgo biloba Sun, 15 Jun 2014 09:01:56 +0000 Introduction. The use of unlicensed food and herbal supplements to enhance sexual functions is drastically increasing. This phenomenon, combined with the availability of these products over the Internet, represents a challenge from a clinical and a public health perspective. Methods. A comprehensive multilingual assessment of websites, drug fora, and other online resources was carried out between February and July 2013 with exploratory qualitative searches including 203 websites. Additional searches were conducted using the Global Public Health Intelligence Network (GPHIN). Once the active constitutes of the products were identified, a comprehensive literature search was carried out using PsycInfo and PubMed. Results. The most common sexual enhancement products available on the Internet were identified. Their active ingredients included yohimbine, maca, horny goat weed and Ginkgo biloba. These four substances were reported with the occurrence of adverse events and the induction of psychological symptoms, such as mood changes, anxiety, and hallucinations as well as addictive behaviours. Conclusions. Uncontrolled availability of sexual enhancement products that contain potentially harmful substances is a major public health concern. The possible impact on population health, particularly among subjects with psychiatric disorders, usually at risk for sexual dysfunction, may be significant. This new trend needs to be extensively studied and monitored. Ornella Corazza, Giovanni Martinotti, Rita Santacroce, Eleonora Chillemi, Massimo Di Giannantonio, Fabrizio Schifano, and Selim Cellek Copyright © 2014 Ornella Corazza et al. All rights reserved. Quercetin Significantly Inhibits the Metabolism of Caffeine, a Substrate of Cytochrome P450 1A2 Unrelated to   (−2964G>A) and (734C>A) Gene Polymorphisms Sun, 15 Jun 2014 08:11:35 +0000 Background. Quercetin is abundant in plants and human diets. Previous studies indicated that quercetin inhibited the activity of CYP1A2, and the combination of quercetin with the substrates of CYP1A2 might produce herb-drug interactions. This research aims to determine the effects of quercetin and the CYP1A2 gene polymorphisms, namely,   (−2964G>A) and (734C>A), on the metabolism of caffeine. Method. The experiment was designed into two treatment phases separated by a 2-week washout period. Six homozygous individuals for the (GG/AA) genotype and 6 heterozygous individuals for the (GA/CA) genotype were enrolled in the study. Quercetin capsules (500 mg) were given to each volunteer once daily for 13 consecutive days, and after that, each subject was coadministrated 100 mg caffeine capsules with 500 mg quercetin on the 14th day. Then a series of venous blood samples were collected for HPLC analysis. Correlation was determined between pharmacokinetics of caffeine and paraxanthine with caffeine metabolite ratio. Results. Quercetin significantly affected the pharmacokinetics of caffeine and its main metabolite paraxanthine, while no differences were found in the pharmacokinetics of caffeine and paraxanthine between GG/AA and GA/CA genotype groups. Conclusion. Quercetin significantly inhibits the caffeine metabolism, which is unrelated to (−2964G>A) and (734C>A) gene polymorphisms. Jian Xiao, Wei-Hua Huang, Jing-Bo Peng, Zhi-Rong Tan, Dong-Sheng Ou-Yang, Dong-Li Hu, Wei Zhang, and Yao Chen Copyright © 2014 Jian Xiao et al. All rights reserved. Investigation of Antiarthritic Potential of Plumeria alba L. Leaves in Acute and Chronic Models of Arthritis Sun, 15 Jun 2014 06:20:32 +0000 Aim. The present investigation was designed to evaluate antiarthritic potential of fractions of hydroalcoholic extract from leaves of P. alba. Materials and Methods. Plumeria alba L. leaves were extracted with hydroalcohol (30 : 70) to obtain hydroalcoholic extract of P. alba. This extract was further fractionated with solvents ethyl acetate and n-butanol to obtain EAPA and BPA, respectively. These fractions were tested against formaldehyde and Freund’s complete adjuvant (FCA) induced arthritis. Arthritis assessment, paw volume, body weight, motor incoordination, and nociceptive threshold were measured. On day 21, the animals were sacrificed and histopathology was done. Results. The 100 and 200 mg/kg doses of EAPA and BPA caused a significant () reduction in paw swelling in both models. Erythrocyte sedimentation rate (ESR) and spleen weight decreased significantly () in arthritic rats treated with extracts. There was significant () improvement in thymus weight in EAPA treated rats whereas significant () improvement was also seen in haemoglobin level (Hb) in diclofenac treated group. Motor incoordination and nociceptive threshold were also significantly () improved. Conclusion. The present study suggests that Plumeria alba L. has protective activity against arthritis and supports the traditional use of P. alba for rheumatism and other inflammatory diseases. Manjusha Choudhary, Vipin Kumar, Pankaj Gupta, and Surender Singh Copyright © 2014 Manjusha Choudhary et al. All rights reserved. p53 Is a Key Regulator for Osthole-Triggered Cancer Pathogenesis Thu, 12 Jun 2014 12:57:31 +0000 Osthole has been reported to have antitumor activities via the induction of apoptosis and inhibition of cancer cell growth and metastasis. However, the detailed molecular mechanisms underlying the anticancer effects of osthole in human colon cancer remain unclear. In the present study, we have assessed osthole-induced cell death in two different human colon cancer cell lines, HCT116 and SW480. Our results also showed that osthole activated proapoptotic signaling pathways in human colon cancer cells. By using cell culture insert system, osthole reduced cell motility in both human colon cancer cell lines. This study also provides evidence supporting the potential of osthole in p53 activation. Expression of p53, an apoptotic protein, was remarkably upregulated in cells treated with osthole. Importantly, the levels of phosphorylation of p53 on Ser15 (p-p53) and acetylation of p53 on Lys379 (acetyl-p53) were increased under osthole treatment. Our results also demonstrated that p53 was activated followed by generation of reactive oxygen species (ROS) and activation of c-Jun N-terminal kinase (JNK). Our study provides novel insights of p53-mediated responses under osthole treatment. Taken together, we concluded that osthole induces cancer cell death and inhibits migratory activity in a controlled manner and is a promising candidate for antitumor drug development. Ssu-Ming Huang, Cheng-Fang Tsai, Dar-Ren Chen, Min-Ying Wang, and Wei-Lan Yeh Copyright © 2014 Ssu-Ming Huang et al. All rights reserved. Targeting the Glutamatergic System to Treat Pathological Gambling: Current Evidence and Future Perspectives Thu, 12 Jun 2014 09:41:38 +0000 Pathological gambling or gambling disorder has been defined by the DSM-5 as a behavioral addiction. To date, its pathophysiology is not completely understood and there is no FDA-approved treatment for gambling disorders. Glutamate is the principal excitatory neurotransmitter in the nervous system and it has been recently involved in the pathophysiology of addictive behaviors. In this paper, we review the current literature on a class of drugs that act as modulating glutamate system in PG. A total of 19 studies have been included, according to inclusion and exclusion criteria. Clinical trial and case series using glutamatergic drugs (N-acetylcysteine, memantine, amantadine, topiramate, acamprosate, baclofen, gabapentin, pregabalin, and modafinil) will be presented to elucidate the effectiveness on gambling behaviors and on the related clinical dimensions (craving, withdrawal, and cognitive symptoms) in PG patients. The results have been discussed to gain more insight in the pathophysiology and treatment of PG. In conclusion, manipulation of glutamatergic neurotransmission appears to be promising in developing improved therapeutic agents for the treatment of gambling disorders. Further studies are required. Finally, we propose future directions and challenges in this research area. Mauro Pettorruso, Luisa De Risio, Giovanni Martinotti, Marco Di Nicola, Filippo Ruggeri, Gianluigi Conte, Massimo Di Giannantonio, and Luigi Janiri Copyright © 2014 Mauro Pettorruso et al. All rights reserved. Synthesis and Antihypertensive Screening of New Derivatives of Quinazolines Linked with Isoxazole Thu, 12 Jun 2014 08:53:44 +0000 A series of 7-substituted-3-(4-(3-(4-substitutedphenyl)-4,5-dihydroisoxazol-5-yl)phenyl)-2-substituted quinazolin-4(3H)-one (1–30) have been synthesized by the cyclization of (E)-3-(4-(3-substitutedphenyl)acrylolyl)phenyl)-2-(substitutedphenyl)-7-substituted quinazolin-4-(3H)-one with hydroxylamine hydrochloride. The synthesized compounds were examined for their in vivo antihypertensive activity using albino rats. All the titled compounds exhibited good to moderate antihypertensive activity. Compounds 7-Chloro-3-(4-(3-(4-chlorophenyl)-4,5- dihydroisoxazol-5-yl)phenyl)-2-p-tolylquinazolin-4(3H)-one (23) and 7-Chloro-3-(4-(3-(4-chlorophenyl)-4,5-dihydroisoxazol-5-yl)phenyl)-2-(4-methoxyphenyl)quinazolin-4(3H)-one (24) exhibited potent antihypertensive activity through their anticipated α1-adrenergic receptor blocking property similar to its clinically used analogue, prazosin, without affecting heart rate with prolonged duration of action when tested in adrenaline induced hypertension in anaesthetized rats. Mujeeb Ur Rahman, Ankita Rathore, Anees A. Siddiqui, Gazala Parveen, and M. Shahar Yar Copyright © 2014 Mujeeb Ur Rahman et al. All rights reserved. Effect of the Zataria multiflora on Systemic Inflammation of Experimental Animals Model of COPD Wed, 11 Jun 2014 11:46:04 +0000 The effects of Zataria multiflora (Z. multiflora) on systemic inflammation in guinea pigs model of COPD were examined. Control animals, COPD (induced by exposing animals to cigarette smoke), COPD + drinking water containing three concentrations of the extract of Z. multiflora, and COPD + dexamethasone were studied ( for each group). Serum levels of IL-8 and malondialdehyde (MDA), total blood WBC ( for all cases), and eosinophil counts () were higher and weight changes () were lower in the COPD group compared to controls. IL-8 level () and weight changes ( to ) in all treated groups with Z. multiflora and total WBC number and MDA level in treated groups with two higher concentrations of the extract and lymphocytes percentage () in the highest concentration of Z. multiflora and dexamethasone ( to ) were significantly improved compared to the COPD group. Results showed a preventive effect of hydroethanolic extract from Z. multiflora on all measured parameters in animals model of COPD which was comparable or even higher (in the highest concentration) compared to the effect of dexamethasone at the concentration used. Mohammad Hossein Boskabady and Lilla Gholami Mhtaj Copyright © 2014 Mohammad Hossein Boskabady and Lilla Gholami Mhtaj. All rights reserved. Hepatoprotective Effect of Superfine Particles of Herbal Medicine against CCl4-Induced Acute Liver Damage in Rats Mon, 09 Jun 2014 12:51:28 +0000 This study aimed to examine the hepatoprotective effects of the superfine particles of Radix Tetrastigma (SPRT) against CCl4-induced acute liver damage in rats. Animals were treated with SPRT (0.3, 0.6, and 1.2 g/kg) and showed remarkable hepatoprotection against CCl4-induced hepatotoxicity. CCl4 altered various biochemical parameters in rat liver, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), malondialdehyde (MDA), superoxide dismutase (SOD), histopathological changes, and Bax and caspase-3 expressions. SPRT significantly prevented increases in ALT and AST levels, reduced MDA level, decreased Bax and caspase-3 protein expression, enhanced SOD activity, and provided significant amelioration in the histopathological lesions. These findings suggested that SPRT has significant protective effect against acute hepatotoxicity induced by CCl4 in rats. Gang Cao, Qinglin Li, Xiaocheng Chen, Hao Cai, and Sicong Tu Copyright © 2014 Gang Cao et al. All rights reserved. Sodium Is Not Required for Chloride Efflux via Chloride/Bicarbonate Exchanger from Rat Thymic Lymphocytes Mon, 09 Jun 2014 09:11:40 +0000 Sodium-dependent Cl−/ exchanger acts as a chloride (Cl−) efflux in lymphocytes. Its functional characterization had been described when Cl− efflux was measured upon substituting extracellular sodium (Na+) by N-methyl-D-glucamine (NMDG). For Na+ and Cl− substitution, we have used D-mannitol or NMDG. Thymocytes of male Wistar rats aged 7–9 weeks were used and intracellular Cl− was measured by spectrofluorimetry using MQAE dye in bicarbonate buffers. Chloride efflux was measured in a Cl−-free buffer (Cl− substituted with isethionate acid) and in Na+ and Cl−-free buffer with D-mannitol or with NMDG. The data have shown that Cl− efflux is mediated in the absence of Na+ in a solution containing D-mannitol and is inhibited by H2DIDS. Mathematical modelling has shown that Cl− efflux mathematical model parameters (relative membrane permeability, relative rate of exchanger transition, and exchanger efficacy) were the same in control and in the medium in which Na+ had been substituted by D-mannitol. The net Cl− efflux was completely blocked in the NMDG buffer. The same blockage of Cl− efflux was caused by H2DIDS. The study results allow concluding that Na+ is not required for Cl− efflux via Cl−/ exchanger. NMDG in buffers cannot be used for substituting Na+ because NMDG inhibits the exchanger. Donatas Stakišaitis, Vaidevutis Meilus, Alfonsas Juška, Paulius Matusevičius, and Janina Didžiapetrienė Copyright © 2014 Donatas Stakišaitis et al. All rights reserved. Essential Oils and Their Constituents as Anticancer Agents: A Mechanistic View Mon, 09 Jun 2014 08:19:27 +0000 Exploring natural plant products as an option to find new chemical entities as anticancer agents is one of the fastest growing areas of research. Recently, in the last decade, essential oils (EOs) have been under study for their use in cancer therapy and the present review is an attempt to collect and document the available studies indicating EOs and their constituents as anticancer agents. This review enlists nearly 130 studies of EOs from various plant species and their constituents that have been studied so far for their anticancer potential and these studies have been classified as in vitro and in vivo studies for EOs and their constituents. This review also highlights in-depth various mechanisms of action of different EOs and their constituents reported in the treatment strategies for different types of cancer. The current review indicates that EOs and their constituents act by multiple pathways and mechanisms involving apoptosis, cell cycle arrest, antimetastatic and antiangiogenic, increased levels of reactive oxygen and nitrogen species (ROS/RNS), DNA repair modulation, and others to demonstrate their antiproliferative activity in the cancer cell. The effect of EOs and their constituents on tumour suppressor proteins (p53 and Akt), transcription factors (NF-κB and AP-1), MAPK-pathway, and detoxification enzymes like SOD, catalase, glutathione peroxidase, and glutathione reductase has also been discussed. Nandini Gautam, Anil K. Mantha, and Sunil Mittal Copyright © 2014 Nandini Gautam et al. All rights reserved.