European Journal of Pharmacology (v.707, #1-3)
Editorial Board (ii).
BF-30 selectively inhibits melanoma cell proliferation via cytoplasmic membrane permeabilization and DNA-binding in vitro and in B16F10-bearing mice by Hui Wang; Mengyun Ke; Yuwei Tian; Jing Wang; Bing Li; Yizhou Wang; Jie Dou; Changlin Zhou (1-10).
Cathelicidin-BF (BF-30) is a cathelicidin-like polypeptide composed of 30 amino acids and is a natural antibacterial peptide extracted from the venom of the snake Bungarus fasciatus. In our previous study, BF-30 showed broad antimicrobial activity against drug-resistant bacteria through enhancing the cytoplasmic membrane permeability. However, the anticancer activity of BF-30 has not yet been investigated. In this study, the effects of BF-30 on the proliferation of the metastatic melanoma cell line B16F10 in vitro and in vivo, as well as the mechanism were studied. Assay of cell viability, a B16F10-bearing mouse model, and histochemical examination were utilized to investigate the anti-tumor effects of BF-30. In addition, transmission electron microscope analysis, lactate dehydrogenase release assay, DNA retardation assay, Real-time PCR, Western blot, wound healing assay, and chick embryo chorioallantoic membrane assay were applied to elucidate the mechanism of BF-30 on B16F10. BF-30 inhibited B16F10 and B16 proliferation in vitro in a dose- and time-dependent manner with an IC50 of 7.3 µM and 13.9 µM, respectively. Moreover, BF-30 significantly suppressed melanoma growth in B16F10-bearing mice without body weight loss. The observed inhibition were 41.4%, 49.5% and 63.5% at the doses of 0.75, 1.5 and 3 mg/kg/day, respectively. This inhibition of metastatic melanoma cell proliferation was partially dependent on disrupting the cytoplasmic membrane, binding to genomic DNA, preventing transcription and translation of the VEGF gene. This inhibition restrained B16F10 migration and angiogenesis. These results further suggest that BF-30 may be a candidate for the treatment of malignant melanoma.
Keywords: Cathelicidin-BF; Melanoma; Permeabilization; DNA-binding; Angiogenesis;
Conserved extracellular cysteines differentially regulate the potentiation produced by Zn2+ in rat P2X4 receptors by Chao-Ying Li; Ke-Ming Xiong; Yu-Xiang Wu; Yu-Wei Liu; Lin Chen; Randall R. Stewart; Robert W. Peoples; Chu-Li Yi (11-16).
One feature of the amino acid sequence of P2X receptors identified from mammalian species, Xenopus laevis and zebrafish is the conservation of ten cysteines in the extracellular loop. Little information is available about the role of these conserved ectodomain cysteines in the function of P2X receptors. Here, we investigated the possibility that ten conserved cysteine residues in the extracellular loop of the rat P2X4 receptor may regulate zinc potentiation of the receptor using a series of individual cysteine to alanine point mutations and functional characterization of recombinant receptors expressed in Xenopus oocytes. For the C116A, C132A, C159A, C165A, C217A and C227A mutants, 10 µM zinc did not significantly affect the current activated by an EC40 concentration of ATP. By contrast, 5 µM zinc shifted the ATP concentration-response curve to the right in a parallel manner for both the C261A and C270A mutants and the magnitudes of those shifts were similar to that of the wildtype receptor. Interestingly, for the C126A and C149A mutants, 5 µM zinc potentiated ATP-activated current, but increased the maximal response to ATP by 90% and 81% respectively, without significantly changing the EC50 value of ATP. Thus, these results suggest that cysteines and disulfide bonds between cysteines are differentially involved in the potentiation of the rat P2X4 receptor by zinc.
Keywords: P2X; P2X4 receptor; Cysteine; Disulfide bond; Mutation; Zinc; Efficacy;
Inhibition of human islet amyloid polypeptide or amylin aggregation by two manganese-salen derivatives by Seifollah Bahramikia; Razieh Yazdanparast (17-25).
Aggregation of human islet amyloid polypeptide (IAPP) into pancreatic fibrillar deposits has been postulated to be one of the main contributors to impaired insulin secretion and pancreatic β-cell death in approximately 90% of type 2 diabetic patients. So, compounds that prevent cytotoxic protein/polypeptide self-assembly and amyloidogenesis are considered as novel therapeutic agents against this disease. In this study, using thioflavin-T (ThT) and Anilinonaphthalene-8-sulfonic acid (ANS) fluorescence assays, transmission electron microscopy (TEM) and docking studies, we investigated whether EUK-8 and EUK-134, two salen derivatives with proven antioxidants activities, could interfere with the conversion of synthetic human amylin to its insoluble amyloid form. Spectroscopy and electron microscopy data indicated that incubation of human amylin with either EUK-8 or EUK-134 significantly inhibited amyloid formation at two molar ratios of 1:1 and 5:1 (drugs to protein). In addition, [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] (MTT) assay showed that treatment of SK-N-MC cells with the pre-formed fibrils in the presence of compounds at drug-to-protein molar ratios of 1:1 and 5:1, dramatically increased the viability of cells compared to the only fibrils formed-treated SK-N-MC cells. Docking results also demonstrated that the aromatic rings of EUK-8 and EUK-134 interact with the hydrophobic region (23–25) of IAPP via Van der Waals interactions. Based on these results and the proven antioxidant properties of these compounds, it could be concluded that these compounds might provide a novel approach to prevent islet amyloid deposition in β-cells and provide useful information for developing other novel compounds for the treatment of type 2 diabetes.Inhibition of human Islet amyloid polypeptide (hIAPP) or amylin aggregation by two manganese-salen derivatives. Seifollah Bahramikia and Razieh Yazdanparast*. Display Omitted
Keywords: EUK-8; EUK-134; Islet amyloid polypeptide; Docking; MTT assay;
Valproic acid attenuates ischemia-reperfusion injury in the rat brain through inhibition of oxidative stress and inflammation by Satoshi Suda; Ken-ichiro Katsura; Takuya Kanamaru; Moeko Saito; Yasuo Katayama (26-31).
Valproic acid (VPA), widely used in clinical contexts for the treatment of seizures and bipolar mood disorder, has neuroprotective properties in cellular and animal models. However, the precise mechanisms underlying its neuroprotection against stroke remain unknown. In the present study, we explored the effect of VPA on experimental ischemic stroke. Male Sprague-Dawley rats were subjected to middle cerebral artery occlusion for 90 min, followed by reperfusion. The animals received a single injection of VPA (300 mg/kg) immediately, 90, or 270 min after the induction of ischemia. Vehicle-treated animals underwent the same procedure with physiological saline. Infarct volume and neurological symptoms were evaluated 24 h after reperfusion. Immunohistochemical staining for myeloperoxidase (MPO), microglia (Iba1), 4-hydroxy-2-nonenal (4-HNE), or 8-hydroxy-deoxyguanosine (8-OHdG) was performed. Ischemic boundary zone cell death was determined by TUNEL staining. VPA injected immediately or 90 min after ischemia induction significantly reduced infarct volume and improved neurological deficit compared with vehicle (P<0.05). VPA was ineffective when given 270 min after ischemia induction. VPA significantly reduced TUNEL-positive cells, MPO-positive cells, Iba1-positive cells, 4-HNE-positive cells, and 8-OHdG-positive cells compared with vehicle in the ischemic boundary zone (P<0.05). The therapeutic time window for single injection of VPA is between 0 and 90 min in this model. Our results demonstrate that single injection of VPA may have anti-inflammatory as well as antioxidative effects, leading to reduced cell death in ischemia-reperfusion injury.
Keywords: Valproic acid; Focal ischemia; Neuroprotection; Oxidative stress; Inflammation;
Relevance of the cyclophosphamide-induced cystitis model for pharmacological studies targeting inflammation and pain of the bladder by Céline Augé; Gérald Chene; Marc Dubourdeau; Denis Desoubzdanne; Bruno Corman; Stefano Palea; Philippe Lluel; Nathalie Vergnolle; Anne-Marie Coelho (32-40).
This work aimed at establishing the relevance of using the in vivo model of cyclophosphamide (CYP)-induced bladder inflammation in rats for in vivo pharmacological studies. Specifically, we measured visceral nociception, identified key inflammatory mediators and evaluated the effects of relevant pharmacological treatments. Cystitis was induced in female rats by a single CYP injection. Sensitivity of the lower abdomen to von Frey mechanical stimulation was determined as a nociceptive parameter. Bladders were assessed for weight, wall thickness and macroscopic damage. Inflammatory mediators were quantified in bladders and urines. The effects of aspirin, ibuprofen and morphine were investigated on all these parameters. A single CYP injection increased nociceptive scores and decreased nociceptive threshold in response to mechanical stimuli between 1 and 4 h post-administration. Increased bladder weight and wall thickness were associated with edema and hemorrhage. Bladder levels of IL-1β, IL-6, MCP-1 and VCAM, and urinary levels of PGE2 were increased. In contrast, a decrease in the urinary metabolites, indoxyl sulfate and pantothenic acid, was observed. Aspirin, ibuprofen and morphine decreased CYP-induced referred visceral pain. Aspirin and ibuprofen also reversed the increased wall thickness, macroscopic damage and levels of IL-1β, IL-6 and PGE2, and the decreased panthotenic acid levels. In contrast, morphine increased wall thickness, edema, hemorrhage, and bladder IL-6 and MCP-1 levels. This work presents a new and reliable method to evaluate visceral sensitivity in rats, and new relevant biomarkers identified in the bladder and urine to measure inflammation and pain parameters for in vivo pharmacological studies.
Keywords: Cystitis; Cyclophosphamide; Inflammation; Visceral pain; Urinary biomarker; Rat;
The role of NOP receptors in psychomotor stimulation and locomotor sensitization induced by cocaine and amphetamine in mice by Paul Marquez; Abdul Hamid; Kabirullah Lutfy (41-45).
We have previously shown that orphanin FQ (also known as nociceptin; OFQ/N) attenuates the motor stimulatory effect of cocaine and blocks locomotor sensitization induced by cocaine. Furthermore, we have shown that cocaine treatment altered the level of endogenous OFQ/N, raising the possibility that endogenous OFQ/N and its receptor (NOP) may be crucial in these actions of cocaine. Accordingly, in the present study, we sought to determine the role of NOP receptors in psychomotor stimulation and locomotor sensitization induced by cocaine or amphetamine. Mice lacking the NOP receptor and their wild-type littermates were habituated to motor activity chambers for 1 h, injected with cocaine (0, 15 or 30 mg/kg) or amphetamine (0, 1 or 3 mg/kg), and motor activity was recorded for 1 h. For sensitization induced by these drugs, mice were treated with saline or the highest dose of each drug once daily for three consecutive days and tested on day 8. On this day, mice were habituated to the chambers for 1 h, then received a challenge dose of cocaine (15 mg/kg) or amphetamine (1 mg/kg), and motor activity was recorded for 1 h. Cocaine and amphetamine each induced hyperlocomotion but the extent of this response was not different between NOP receptor null mice and their controls. Sensitization developed to the motor stimulatory action of each drug, but the magnitude of cocaine-induced sensitization was only higher in null mice compared to their controls. Together, the present results suggest that the endogenous OFQ/N/NOP receptor system may modulate the development of cocaine-induced locomotor sensitization.
Keywords: Cocaine; Amphetamine; Locomotor sensitization; OFQ/N (Orphanin FQ/Nociceptin); NOP receptor; ORL1 (Opioid receptor-like) receptor; Knockout mouse;
Central and peripheral antinociceptive effects of ellagic acid in different animal models of pain by Mohammad Taghi Mansouri; Bahareh Naghizadeh; Behnam Ghorbanzadeh; Yaghoub Farbood (46-53).
The present study was conducted to evaluate the analgesic effects of p.o., i.p., or i.c.v. administration of ellagic acid (EA), and investigate the possible mechanisms underlying the systemic antinociceptive activities in different animal models of pain. Using radiant heat tail-flick test, EA (100–1000 μmol/kg, retain-->p.o.) only resulted in antinociception at 1000 μmol/kg. Also, EA (10–660 μmol/kg, i.p.) produced the antinociceptive effect in a dose-dependent manner with an ED50 of 122 μmol/kg. In addition, the i.c.v. administration of EA (0.1–2 μmol/rat) resulted in dose-dependent antinociception with an ED50 of 0.33 μmol/rat. EA induced antinociception (330 μmol/kg. i.p.) was reversed by naloxone (1 mg/kg, i.p.). Likewise, EA (1–33 μmol/kg, i.p.) produced significant dose-dependent antinociception when assessed using acetic acid-induced abdominal writhing test with an ED50 of 3.5 μmol/kg. It was also demonstrated that pre-treatment with l-arginine (100 mg/kg, i.p.), a nitric oxide (NO) precursor, and methylene blue (20 mg/kg, i.p.), a guanylate cyclase (GC) inhibitor, significantly enhanced antinociception produced by EA suggesting the involvement of l-arginine–NO–cGMP pathway. Additionally, administration of glibenclamide (10 mg/kg, i.p.), an ATP-sensitive K+ channel blocker, significantly reversed antinociceptive activity induced by EA. Moreover, EA treatment had no effect on the motor activity of rats when tested in rota-rod task. The present results indicate that the dose-related antinociceptive action of EA has both peripheral and central components which involve mediation by opioidergic system and l-arginine–NO–cGMP–ATP sensitive K+ channels pathway.
Keywords: Ellagic acid; Antinociception; Nitric oxide; Potassium channel; Opioid receptor; Tail-flick; Writhing test;
Erythropoietin protects polychlorinated biphenyl (Aroclor 1254) induced neurotoxicity in mice by Hanish J.C. Singh; Tauqeer U.B. Syeda; Rahul M. Kakalij; Valluri V.L.N. Prasad; Prakash V. Diwan (54-60).
Erythropoietin is a hematopoietic cytokine factor with various biological effects and its receptors are expressed in the central nervous system, which helps in normal brain development and exerts neuroprotection in different models of brain injury. The present study was designed to evaluate the neuroprotective role of erythropoietin in Aroclor 1254 induced oxidative stress in mice. Neurotoxicity was induced by Aroclor 1254 (10 mg/kg bw/day). Erythropoietin was administered simultaneously with Aroclor 1254 for 14 days in co-treatment groups and administered before induction of neurotoxicity for 7 days in case of pretreatment groups. To assess the behavioural parameters in observation with learning and memory, open field and Y-maze were employed. Acetylcholinesterase, glutamate, antioxidant enzymes (superoxide dismutase, glutathione peroxidase and catalase) were estimated in brain tissue and corticosterone in plasma to evaluate the intensity of oxidative signalling in brain. Triglycerides and total cholesterol were estimated in plasma. Both doses of erythropoietin (500 and 1000 IU/kg) pretreatment and co-treatment, (i) significantly increased the habituation memory and percentage alteration which are indicative of the cognitive improvement, (ii) attenuated the Aroclor 1254 induced rise in acetylcholinesterase activity, corticosterone, triglycerides and total cholesterol, (iii) increased the glutamate and antioxidant enzyme levels. These results indicate that erythropoietin protects against Aroclor 1254 induced neurotoxicity and improves the cognitive function and that this cytokine could be a promising therapeutic agent for stress induced neurodegeneration.
Keywords: Erythropoietin; Aroclor 1254; Neurotoxicity; Oxidative stress; Acetylcholinesterase; Corticosterone;
Activation of the cholinergic anti-inflammatory pathway by nicotine attenuates hepatic ischemia/reperfusion injury via heme oxygenase-1 induction by Juhyun Park; Jung-Woo Kang; Sun-Mee Lee (61-70).
Hepatic ischemia/reperfusion (I/R) elicits an excessive inflammatory response, posing a lethal threat to the host. Local inflammation may be regulated by the vagus nerve and activation of the nicotinic acetylcholine receptors may also suppress peripheral inflammation. We have previously demonstrated that heme oxygenase-1 (HO-1) protects the liver against I/R injury by modulating proinflammatory mediators. Here, we investigate the cytoprotective mechanisms of nicotine, a nicotinic acetylcholine receptor agonist, against liver injury caused by I/R. Mice were subjected to 60 min of ischemia followed by 3 h of reperfusion. Nicotine (0.1, 0.3 and 1 mg/kg) and vehicle (saline) were administered intraperitoneally 20 min prior to ischemia. Serum alanine aminotransferase activity and lipid peroxidation levels increased after reperfusion, while total glutathione content decreased. These changes were markedly attenuated by nicotine. The levels of HO activity and HO-1 protein expression increased after reperfusion, and nicotine markedly augmented these increases. Serum levels of high mobility group box 1 and tumor necrosis factor-α increased after reperfusion, and nicotine prevented these increases. The nuclear translocation of NF-E2-related factor 2 and phosphorylation of both phosphatidyl inositol 3-kinase and Akt increased; nicotine also augmented these increases. The protein expression of nuclear factor-κB increased and nicotine attenuated this increase. Methyllycaconitine, a selective α7 nicotinic acetylcholine receptor antagonist, abolished these effects of nicotine. Furthermore, zinc protoporphyrin, an HO-1 inhibitor, also reversed the observed effects of nicotine. Our findings suggest that activation of α7 nicotinic acetylcholine receptor by nicotine ameliorates I/R-induced liver injury, and that this protection is likely due to inhibition of the inflammatory response through HO-1 induction.
Keywords: α7 Nicotinic acetylcholine receptor; Heme oxygenase-1; Inflammation; Ischemia/reperfusion; Nicotine;
Comparative effects of statins on murine cardiac gene expression profiles in normal mice by Masafumi Kumazaki; Hitoshi Ando; Kentarou Ushijima; Akio Fujimura (71-77).
Recent clinical data suggest that the efficacy of statin treatment in patients with heart failure varies depending on the drugs administered. The present study was undertaken to compare murine cardiac gene expression profiles following treatment with four different statins. In normal male C57BL/6J mice, 4 weeks of treatment with or without a statin (pitavastatin, pravastatin, rosuvastatin, or atorvastatin) did not affect any biochemical parameters, including the lipid profile. However, cardiac gene expression profiling by microarray analysis revealed distinct patterns among the five groups. Several genes that might be involved in cardiac function, including Ccnd2, Klf7 and Timp3, were differentially regulated by treatment with a specific statin. In the primary cultured neonatal mouse cardiomyocytes, statin-induced changes in the expression of these genes were largely unaffected by supplementation with mevalonic acid. These data indicate that statins directly regulate cardiac gene expression in a drug-specific manner in normal mice. Additional studies are needed to determine whether these differences influence the clinical efficacy in particular patients, such as those with heart failure.
Keywords: Statin; Cardiac gene expression; Heart failure; Microarray analysis;
Up-regulation of the canonical Wnt-3A and Sonic hedgehog signaling underlies melanocortin-induced neurogenesis after cerebral ischemia by Luca Spaccapelo; Maria Galantucci; Laura Neri; Miranda Contri; Roberto Pizzala; Roberto D'Amico; Alessandra Ottani; Maurizio Sandrini; Davide Zaffe; Daniela Giuliani; Salvatore Guarini (78-86).
In experimental cerebral ischemia, melanocortin MC4 receptor agonists induce neuroprotection and neurogenesis with subsequent long-lasting functional recovery. Here we investigated the molecular mechanisms underlying melanocortin-induced neurogenesis. Gerbils were subjected to transient global cerebral ischemia, then they were treated every 12 h, and until sacrifice, with 5-bromo-2′-deoxyuridine (BrdU; to label proliferating cells), and the melanocortin analog [Nle4,d-Phe7]α-melanocyte-stimulating hormone (NDP-α-MSH) or saline. NDP-α-MSH increased hippocampus dentate gyrus (DG) expression of Wnt-3A, β-catenin, Sonic hedgehog (Shh), Zif268, interleukin-10 (IL-10) and doublecortin (DCX), as detected at days 3, 6 and 10 after the ischemic insult. Further, an elevated number of BrdU immunoreactive cells was found at days 3 and 10, and an improved histological picture with reduced neuronal loss at day 10, associated with learning and memory recovery. Pharmacological blockade of the Wnt-3A/β-catenin and Shh pathways, as well as of melanocortin MC4 receptors, prevented all effects of NDP-α-MSH. These data indicate that, in experimental brain ischemia, treatment with melanocortins acting at MC4 receptors induces neural stem/progenitor cell proliferation in the DG by promptly and effectively triggering the canonical Wnt-3A/β-catenin and Shh signaling pathways. Activation of these pathways is associated with up-regulation of the repair factor Zif268 and the neurogenesis facilitating factor IL-10, and it seems to address mainly toward a neuronal fate, as indicated by the increase in DCX positive cells.
Keywords: Cerebral ischemia; Melanocortin MC4 receptor; Neurogenesis; Molecular mechanism; Signaling pathway; Wnt-3A; Sonic hedgehog; Repair factor;
Mechanisms underlying protective effects of trimetazidine on endothelial progenitor cells biological functions against H2O2-induced injury: Involvement of antioxidation and Akt/eNOS signaling pathways by Qinqin Wu; Benling Qi; Yun Liu; Bei Cheng; Lihua Liu; Yuanyuan Li; Qian Wang (87-94).
Trimetazidine (TMZ) is a widely used drug exerting cardioprotective effects against ischemic heart disease through a number of mechanisms in conditions of oxidative stress. However, there are few data regarding the effects of TMZ on endothelial lineage, especially endothelial progenitor cells (EPCs). Thus, we sought to investigate whether TMZ could protect EPCs against oxidative stress injury induced by H2O2 (100 µM) and the preliminary mechanisms involved in vitro. The results showed that pretreatment of EPCs with TMZ (10 µM) protected the proliferation, adhesion, migration, and apoptosis of EPCs against H2O2, accompanied by an increase in superoxide dismutase (SOD) activity, a decrease in malonaldehyde (MDA) content, and increases in eNOS, Akt phosphorylation, and NO production. These TMZ-mediated beneficial effects on EPCs could be attenuated by pre-incubation with the Akt inhibitor triciribine. In conclusion, the present study demonstrates that TMZ ameliorated H2O2-induced impairment of biological functions in EPCs with the involvement of antioxidation and Akt/eNOS signaling pathway. These findings suggest that TMZ mediating preservation of EPCs may contribute to its cardioprotective effects on ischemic heart disease.
Keywords: Trimetazidine; Endothelial progenitor cells; Oxidative stress; Akt/eNOS signaling pathway; Ischemic heart disease;
Activation of a retinoic acid receptor pathway by thiazolidinediones induces production of vascular endothelial growth factor/vascular permeability factor in OP9 adipocytes by Daisuke Kotake; Noriyasu Hirasawa (95-103).
Thiazolidinediones, ligands of peroxisome proliferator-activated receptorγ (PPARγ), are used in the management of type 2 diabetes mellitus. However, they can cause edema, which often leads to a discontinuation of treatment. The mechanism by which thiazolidinediones induce edema is poorly understood. We have confirmed that troglitazone (TGZ), a thiazolidinedione, induced the differentiation of a preadipocyte cell line, OP9, into adipocytes. The differentiated OP9 cells produced vascular permeability factors and the activity was completely neutralized by an antibody against vascular endothelial growth factor (VEGF). TGZ induced the expression of VEGF but not interleukin-6 and monocyte chemoattractant protein-1. 2-chloro-5-nitrobenzanilide (GW9662) blocked both the differentiation and the production of VEGF induced by TGZ. 15-deoxy-Δ12,14-Prostaglandin J2, a natural ligand of PPARγ, and another PPARγ agonist, ginkgolic acid, also induced an increase in the expression of VEGE as well as the differentiation of OP9 cells. Indomethacin, a nonsteroidal anti-inflammatory drug (NSAID) with PPARγ activity, up-regulated VEGF expression, but acetylsalicylic acid, a NSAID without PPARγ activity, did not. Although VEGF expression was enhanced under hypoxic conditions, the expression of hypoxia inducible factor and Ets-1 was down-regulated during the TGZ-induced differentiation. On the other hand, retinoic acid enhanced the expression of VEGF despite inhibiting the TGZ-induced differentiation. Moreover, retinoic acid receptor (RAR) β expression was increased by TGZ and retinoic acid. These findings suggested that the major adipocyte-derived vascular permeability factor produced in response to TGZ was VEGF, and a RAR pathway was involved in the production.
Keywords: PPARγ; Adipocyte; Edema; Vascular permeability; VEGF; RAR;
Statin therapy is beneficial for the prevention of atrial fibrillation in patients with coronary artery disease: A meta-analysis by Xue Zhou; Jian-lin Du; Jia Yuan; Yun-qing Chen (104-111).
The ability of statins to prevent atrial fibrillation (AF) in coronary artery disease (CAD) patients is controversial. To elucidate this problem, we conducted a meta-analysis. Electronic databases were searched through October 2011 to identify relevant studies. Either a fixed- or a random-effects model was used to calculate the overall combined risk estimates. Data extraction and meta-analysis were conducted using standard methods. The meta-analysis was performed with data derived from 10 cohort studies of the effects of statins on atrial fibrillation. The endpoint used was the occurrence or new onset of AF. A total of 193,839 patients were included, and 87,741 (45.26%) patients received statin therapy. The occurrence of AF was decreased by 35% in the statin therapy group compared to the non-statin-treated group (95% confidence interval: 0.57–0.74; P<0.001) with a heterogeneity of 86.2%. Subgroup analysis and sensitivity analysis were also performed to explore the source of heterogeneity and to test the stability of the results, and the subgroup results did not materially alter the conclusion. There was no significant publication bias according to Begg's and Egger's tests (Begg, p=0.21; Egger, p=0.71). Therefore, statin therapy is beneficial for preventing atrial fibrillation in patients with coronary artery disease.
Keywords: Statins; Coronary artery disease; Atrial fibrillation; Meta-analysis;
Antidepressant-like effect of macranthol isolated from Illicium dunnianum tutch in mice by Jing Li; Di Geng; Jiao Xu; Lian-Jin Weng; Qing Liu; Li-Tao Yi (112-119).
The present study was aimed to evaluate the behavioral and biochemical effects of macranthol, a triphenyl lignan isolated from Illicium dunnianum. To this aim, mice were treated with macranthol (10, 20 and 40 mg/kg) and then subjected to the forced swimming test, tail suspension test and chronic unpredictable mild stress. It was observed that macranthol significantly reduced the immobility time in the forced swimming test and tail suspension test after acute (1-day) treatment, and reversed the reduction of sucrose preference induced by chronic unpredictable mild stress after chronic (5-week) treatment. In addition, macranthol completely ameliorated the corticosterone hypersecretion by acute swim stress or chronic unpredictable mild stress. Chronic macranthol treatment attenuated the reduction of serotonergic neurotransmission in brain regions of frontal cortex and hippocampus. Taken together, our findings suggested that macranthol produced an antidepressant-like effect, which may be mediated by serotonergic and neuroendocrine system. Moreover, the finding that only chronic but not acute treatment enhanced brain-derived neurotrophic factor (BDNF) expression suggested that macranthol did not produce a rapid antidepressant-like response and long-term treatment was required in its clinical application.Display Omitted
Keywords: Macranthol; Antidepressant; Monoamine neurotransmitter; Corticosterone; Brain-derived neurotrophic factor (BDNF);
Cilostazol ameliorates systemic insulin resistance in diabetic db/db mice by suppressing chronic inflammation in adipose tissue via modulation of both adipocyte and macrophage functions by Tsutomu Wada; Yasuhiro Onogi; Yukari Kimura; Tetsuro Nakano; Hiroki Fusanobori; Yoko Ishii; Masakiyo Sasahara; Hiroshi Tsuneki; Toshiyasu Sasaoka (120-129).
Cilostazol, an inhibitor of phosphodiesterase 3B, is widely used as an anti-platelet drug in diabetic patients. Recently, cilostazol has been shown to promote preadipocyte differentiation to mature adipocyte and affect glucose homeostasis; therefore, we examined the impact of cilostazol on impaired glucose metabolism in adipose tissues of diabetic db/db mice. Administration of cilostazol at 100–300 mg/kg/day significantly improved glucose tolerance and insulin sensitivity in a dose-dependent manner in db/db mice, whereas these effects were not observed in non-diabetic control mice. Cilostazol reduced the adipocyte size and suppressed mRNA expressions of monocyte chemoattractant protein 1, CD11c, and tumor necrosis factor α (TNFα) in the epididymal fat tissue of db/db mice. As for the cellular mechanism, cilostazol attenuated lipopolysaccharide (LPS)-induced TNFα expression by decreasing the mRNA and protein levels of Toll-like receptor 4 in Raw264.3 macrophages. Cilostazol also effectively ameliorated the TNFα-induced decrease of insulin-stimulated Akt phosphorylation and [3H]2-deoxyglucose uptake by suppressing c-Jun N terminal kinase-mediated serine phosphorylation of insulin receptor substrate 1 in 3T3-L1 adipocytes. Importantly, the improvement of impaired insulin signaling was blunted by pretreatment with KT5720, a protein kinase A inhibitor, but not with GW9662, a peroxisome proliferator-activated receptor γ. These results indicate that cilostazol suppressed TNFα production from macrophages and attenuated TNFα-induced chronic inflammation in adipose tissue, leading to the improvement of glucose intolerance and insulin resistance in obese diabetic mice. Thus, the present study reveals an additional benefit in the use of cilostazol in the treatment of patients with type 2 diabetes.
Keywords: Cilostazol; Insulin resistance; TNFα; Toll-like receptor 4;
2a, a novel curcumin analog, sensitizes cisplatin-resistant A549 cells to cisplatin by inhibiting thioredoxin reductase concomitant oxidative stress damage by Binhua Zhou; Jianing Huang; Yinglin Zuo; Baojian Li; Qiang Guo; Baicheng Cui; Weiyan Shao; Jun Du; Xianzhang Bu (130-139).
(1E,4Z,6E)-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-7-(5-methylfuran-2-yl)hepta-1,4,6-trien-3-one (2a), a novel curcumin analog, was previously synthesized in our laboratory as a potential thioredoxin reductase (TrxR) inhibitor with excellent growth inhibitory effects on several TrxR over-expressed cancer cells. In this study, our further studies show that 2a is able to inhibit the growth of cisplatin-resistant A549 (A549/CDDP) cells much more effectively in a dose-dependent manner than that of A549 cells in antiproliferative activity experiments. Moreover, 2a-pretreated A549/CDDP cells are sensitive to cisplatin treatment, which is accompanied by the inhibition of TrxR activity in A549/CDDP cells. As a consequence of targeting TrxR, 2a in turn remarkably up-regulates intracellular reactive oxygen species level, depletes glutathione (GSH), and reduces the GSH/GSSG ratio, suggesting that the intracellular redox balance is shifted to a more oxidative state. Consequently, concomitant with the cell growth inhibition of 2a, apoptosis is induced by 2a probably through increased oxidative stress in A549/CDDP cells. In conclusion, these observations demonstrated that TrxR inhibitors would be promising drugs to achieve a successful combinatory or single cancer chemotherapy.
Keywords: Curcumin analog; Thioredoxin reductase; Oxidative stress; Cisplatin-resistant A549 cells;
Discovery and pharmacological characterization of SAR707 as novel and selective small molecule inhibitor of stearoyl-CoA desaturase (SCD1) by Marc D. Voss; Gerhard Zoller; Hans Matter; Andreas W. Herling; Gabriele Biemer-Daub; Anja Pfenninger; Silke Haag-Diergarten; Stefanie Keil; Markus Kohlmann; Hans-Ludwig Schmidts (140-146).
Stearoyl-CoA desaturase (SCD1) is linked to the pathogenesis of obesity, dyslipidemia and type 2 diabetes. It is the rate-limiting enzyme in the synthesis of monounsaturated 16:1 n-7 and 18:1 n-9 fatty acyl-CoAs and catalyzes an essential part of lipogenesis. Here, we describe the identification, in vitro properties and in vivo efficacy of a novel class of heterocyclic small molecule hexahydro-pyrrolopyrrole SCD1 inhibitors. SAR707, a compound representative for the series, was optimized to high in vitro potency, selectivity and favorable overall properties in enzymatic and cellular assays. In vivo, this compound reduced serum desaturation index, decreased body weight gain and improved lipid parameters and blood glucose levels of obese Zucker diabetic fatty rats treated for 4 weeks in a chronic study. In parallel, fissures of the eye lid, alopecia and inflammation of the skin were observed from day 11 on in all animals treated with the same metabolically active dose. In summary, we described in vitro and in vivo properties of a novel, potent and selective SCD1 inhibitor that improved body weight, blood glucose and triglycerides in an animal model of obesity, type 2 diabetes and dyslipidemia. However, the favorable in vivo properties of systemic SCD1 inhibition shown in our study were accompanied by dose-dependently occurring adverse target-related effects observed in skin. Thus, systemic SCD1 inhibition by small molecules might therefore not represent a feasible approach for the treatment of chronic metabolic diseases.
Keywords: Stearoyl-CoA desaturase; SCD1; Hexahydro-pyrrolopyrrole; Inhibitor; Zucker diabetic fatty rat; Fatty acid desaturation;
Histone deacetylase inhibitor, sodium butyrate, attenuates gentamicin-induced nephrotoxicity by increasing prohibitin protein expression in rats by Xuefeng Sun; Baimin Zhang; Xin Hong; Xiuhe Zhang; Xiangbo Kong (147-154).
The major purpose in our study was to investigate the effects of sodium butyrate (NaBu) on nephrotoxicity induced by gentamicin in rats and determine further whether the protective effect is mediated by modulation of prohibitin protein expression. Gentamicin was injected intraperitoneally (100 mg/kg body weight) once daily for 8 days to induce nephrotoxicity. The effect of acute and chronic treatment of sodium butyrate on nephrotoxicity induced by gentamicin was assessed. Various doses of sodium butyrate (50, 100, 200 mg/kg, i.p.) was administered 30 min prior to the daily gentamicin injection. Histological analysis was used to evaluate the lesions in kidney after gentamicin administration. Expression of prohibitin was evaluated with immunohistochemical and western blot analysis. The present study demonstrated that gentamicin treatment for 8 consecutive days significantly increased in the levels of blood urea nitrogen, creatinine, kidney injury molecule (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) which indicated nephrotoxicity induced by gentamicin. In addition, chronic treatment with NaBu significantly attenuated gentamicin-induced nephrotoxicity by increasing activities of superoxide dismutase, catalase and reduced glutathione. Immunohistochemical studies in gentamicin-induced rats also demonstrated an increase in the levels of inducible prohibitin after treatment with sodium butyrate. Our results indicated that sodium butyrate, a histone deacetylase inhibitor, decreased gentamicin-induced nephrotoxicity by enhancing renal antioxidant enzymes activity and the expression of prohibitin protein.
Keywords: Gentamicin; Sodium butyrate; Oxidative stress; Prohibitin; Nephrotoxicity;