双苓扶正抗癌制剂对SGC-7901细胞凋亡及其相关基因表达的影响

目的：研究双芩扶正抗癌制剂对人胃癌SGC-7901细胞凋亡及其凋亡相关基因表达的影响。方法：应用体外培养方法和流式细胞技术，检测双芩扶正抗癌制剂对人胃癌SGC-7901细胞的细胞凋亡率及其凋亡相关基因bax、bcl-2的阳性蛋白标记率。结果：双芩扶正抗癌制剂80-320μg／ml可诱导人胃癌SGC-7901细胞凋亡，同时可促进凋亡诱导基因bax和下调凋亡抑制基因bcl-2的表达。结论：双芩扶正抗癌制剂的抗肿瘤作用机制之一可能与其影响bax基因及bcl-2基因的表达而诱导癌细胞凋亡有关。

Effect of Nimesulide on proliferation and apoptosis of human hepatoma SMMC-7721 cells

AIM: Cyclooxygenase-2 (COX-2) has been suggested to be associated with carcinogenesis. We sought to investigate the effect of the selective COX-2 inhibitor, Nimesulide on proliferation and apoptosis of SMMC-7721 human hepatoma cells.METHODS: This study was carried out on the culture of hepatic carcinoma SMMC-7721 cell line. Various concentrations of Nimesulide (0, 200 micromol/L, 300 micromol/L, 400 micromol/L) were added and incubated. Cell proliferation was detected with MTT colorimetric assay, cell apoptosis by electron microscopy, flow cytometry and TUNEL.RESULTS: Nimesulide could significantly inhibit SMMC-7721 cells proliferation dose-dependent and in a dependent manner compared with that of the control group. The duration lowest inhibition rate produced by Nimesulide in SMMC-7721 cells was 19.06%, the highest inhibition rate was 58.49%. After incubation with Nimesulide for 72 h, the most highest apoptosis rate and apoptosis index of SMMC-7721 cells comparing with those of the control were 21.20%+/-1.62% vs 2.24%+/-0.26% and 21.23+/-1.78 vs 2.01+/-0.23 (P【0.05). CONCLUSION:The selective COX-2 inhibitor, Nimesulide can inhibit the proliferation of SMMC-7721 cells and increase apoptosis rate and apoptosis index of SMMC-7721 cells. The apoptosis rate and the apoptosis index are dose-dependent. Under electron microscope SMMC-7721 cells incubated with 300 micromol and 400 micromol Nimesulide show apoptotic characteristics. With the clarification of the mechanism of selective COX-2 inhibitors, These COX-2 selective inhibitors can become the choice of prevention and treatment of cancers.

Selective COX-2 inhibitor,NS-398,suppresses cellular proliferation in human hepatocellular carcinoma cell lines via cell cycle arrest

AIM: To investigate the growth inhibitory mechanism of NS-398, a selective cyclooxygenase-2 (COX-2) inhibitor, in two hepatocellular carcinoma (HCC) cell lines (HepG2 and Huh7). METHODS: HepG2 and Huh7 cells were treated with NS-398. Its effects on cell viability, cell proliferation, cell cycles, and gene expression were respectively evaluated by water-soluble tetrazolium salt (WST-1) assay, 4’-6-diamidino-2-phenylindole (DAPI) staining, flow cytometer analysis, and Western blotting, with dimethyl sulfoxide (DMSO) as positive control. RESULTS: NS-398 showed dose- and time-dependent growth-inhibitory effects on the two cell lines. Proliferating cell nuclear antigen (PCNA) expressions in HepG2 and Huh7 cells, particularly in Huh7 cells were inhibited in a time- and dose-independent manner. NS-398 caused cell cycle arrest in the G1 phase with cell accumulation in the sub-G1 phase in HepG2 and Huh7 cell lines. No evidence of apoptosis was observed in two cell lines. CONCLUSION: NS-398 reduces cell proliferation by inducing cell cycle arrest in HepG2 and Huh7 cell lines, and COX-2 inhibitors may have potent chemoprevention effects on human hepatocellular carcinoma.

Specific COX-2 inhibitor NS398 induces apoptosis in human liver cancer cell line HepG2 through BCL-2

AIM: To evaluate the effects of NS-398, a cyclooxygenase-2 (COX-2) inhibitor, on the proliferation and apoptosis of HepG2 cells. METHODS: The effects of NS-398 on the proliferation of HepG2 cells were evaluated by MTT. DNA fragmentation gel analysis was used to analyze the apoptotic cells. DNA ploidy and apoptotic cell percentage were calculated by flow cytornetry. The expression of COX-2 and Bcl-2 mRNA was identified by competitive RT-PCR. Furthermore, expression level of Bcl-2 was detected using Western blot in HepG2 after treated with NS-398. RESULTS: NS-398 inhibited cell proliferation and induced apoptosis of HepG2 cells in a concentration-dependent manner. DNA ploidy analysis showed that S phase cells were significantly decreased with increase of NS-398 concentration. The quiescent GO/G1 phase was accumulated with decrease of Bcl-2 mRNA. Whereas NS-398 had no effect on the expression of COX-2 mRNA, and no correlations were found between COX-2 mRNA and HepG2 cell proliferation and apoptosis induced by NS-398 (r=0.056 and r=0.119, respectively). Bcl-2 protein level was inhibited after treated with NS-398. CONCLUSION: NS-398 significantly inhibits the proliferation and induces apoptosis of HepG2 cells. Mechanisms involved may be accumulation of quiescent GO/G1 phase and decrease of Bcl-2 expression.

Exacerbation of inflammatory bowel disease by nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors:Fact or fiction?

The existence of a possible link between inflammatory bowel disease （IBD） and nonsteroidal anti-inflammatory drugs （NSAIDs） has been repeatedly suggested. Recently, a few studies have addressed the issue of a possible, similar effect by selective cyclooxygenase-2 inhibitors （COXIBs）. The present article reviews the available scientific evidence for this controversial subject.

Selective cyclooxygenase-2 inhibitor ameliorates cholecystokinin-octapeptide-induced acute pancreatitis in rats

AIM： To investigate the effect of selective Cyclooxygenase-2 （COX-2） inhibitor 4-[5-（4-Chloro-phenyl）-3- （trifluoromethyl）- 1H-pyrazol- 1-yl] benzenesulfonamide （SC-236）, on the cholecystokinin （CCK）-octapeptideinduced acute pancreatitis （AP） in rats. METHODS： Wistar rat weighing 240 g to 260 g were divided into three groups. （1） Normal DMSO treated group, （2） SC-236 at 4 mg/kg treated group; SC-236 systemically administered via the intravenous （i.v.） catheter, followed by 75 μg/kg CCK octapeptide subcutaneously three times, after 1, 3 and 5 h. This whole procedure was repeated for 5 d. （3） Dimethyl sulfoxide （DMSO） treated group： an identical protocol was used in this group as in the SC-236 cohort （see 2. above）. Repeated CCK octapeptide treatment resulted in a typical experimentally induced pancreatitis in the Wistar rats. RESULTS： SC-236 improved the severity of CCK- octapeptide-induced AP as measured by laboratory criteria [the pancreatic weight/body weight （p.w/ b.w） ratio, the level of serum amylase and lipase]. The SC-236 treated group showed minimal histologic evidence of pancreatitis and a significant reduction in myeloperoxidase activity. SC-236 also increased heat shock protein （HSP）-60 and HSP72 compared with the DMSO-treated group in the CCK-octapeptide-induced AP and also reduced the pancreatic levels of COX-2. Furthermore, SC-236 reduced proinflammatory cytokine synthesis and inhibited NF-KB activation compared with the DMSO-treated group in the CCK-octapeptide-induced AP. CONCLUSION： Our results suggested that COX-2 plays pivotal role in the development of AP and COX-2 inhibitors may play a beneficial role in preventing AP.

Hexahydrocurcumin enhances inhibitory effect of 5-fluorouracil on HT-29 human colon cancer cells

AIM： To investigate the ability of hexahydrocurcumin （HHC） to enhance 5-fluorouracil （5-FU） in inhibiting the growth of HT-29 cells by focusing on cyclooxygenase （COX）-2 expression.METHODS： Antiproliferative effects of HHC and 5-FU, alone and in combination, on growth of HT-29 human colon cancer cells were assessed using 5-diphenyltetrazolium bromide （MTT） reduction assay. In combinationtreatment, low doses of 5-FU were used combined with various concentrations of HHC to minimize the toxic- ity and side effects of 5-FU. The therapeutic effects of these drugs on down-regulation of COX-2 mRNA and protein expression were examined using semi-quantitative reverse transcription-polymerase chain reaction （RT-PCR） and Western blotting analysis.RESULTS： Ml-I- reduction assay indicated that HHC alone markedly decreased the viability of HT-29 human colon cancer cells compared to control. Semi-quantitative RT-PCR analysis indicated that HHC is a selective COX-2 inhibitor. This finding was supported by the ob- servation that HHC significantly down-regulates COX-2 mRNA expression compared to the control （control： 100.05% ± 0.03% vs HHC： 61.01% ± 0.35%, P 〈 0.05） but does not alter COX-1 mRNA. In combined treatment, addition of HHC to a low dose of 5-FU exerts a synergistic effect against the growth of HT-29 cells by markedly reducing cell viability to a greater degree than monotherapy. Semi-quantitative RT-PCR indicated that 5-FU at the concentration of 5 pmol/L in combina- tion with HHC at the concentration of 25 pmol/L signifi- cantly down-regulates COX-2 mRNA expression when compared with values in cells treated with 5-FU or HHC alone （HHC ＋ 5-FU： 31.93% ± 5.69%, 5-FU： 100.66% ± 4.52% vs HHC： 61.01% ±0.35%, P 〈 0.05）.CONCLUSION： HHC together with 5-FU exerts a synergistic effect and may prove chemotherapeutically useful in treating human colon cancer.

Expression of Plasminogen Activator Inhibitor-2 is Negatively Associated with Invasive Potential in Hepatocellular Carcinoma Cells

Objective To investigate the association between plasminogen activator inhibitor(PAI)-2 expression and invasive potential in hepatocellular carcinoma(HCC) cells.Methods The HCC cell lines with high,low,and non-metastatic potentials,namely MHCC97-H,MHCC97-L,and SMMC-7721 respectively,were cultured in vitro.Matrigel invasion assay and Western blot of PAI-2 protein expression were conducted.Results The number of invaded cells in MHCC97-L was significantly higher than that in SMMC-7721(P=0.005),whereas that in MHCC97-H was higher than in MHCC97-L(P=0.017) and SMMC-7721(P=0.001).Contrarily,PAI-2 protein expression was gradually reducing from SMMC-7721,MHCC97-L,to MHCC97-H(MHCC97-H vs.MHCC97-L,P<0.001;MHCC97-H vs.SMMC-7721,P=0.001;MHCC97-L vs.SMMC-7721,P=0.001).The Pearson's correlation analysis revealed a significant negative association between invaded cell number and PAI-2 expression(r= 0.892,P=0.001).Conclusion PAI-2 expression may be negatively associated with the invasive potential of HCC.

Indomethacin but not a selective cyclooxygenase-2 inhibitor inhibits esophageal adenocarcinogenesis in rats

AIM： To evaluate the effects of indomethacin [dual cyclooxygenase （COX）-I/COX-2 inhibitor] and 3-（3,4-difluorophenyl）-4-（4-（methylsulfonyl） phenyl）- 2-（5H）-furanone （MF-tricyclic） （COX-2 selective inhibi- tor） in a rat experimental model of Barrett＇s esophagus and esophageal adenocarcinoma.METHODS： A total of 112 surviving post-surgery rats were randomly divided into three groups： the control group （n = 48）, which did not receive any treatment; the indomethacin group （n = 32）, which were given 2 mg/kg per day of the COX-I/COX-2 inhibitor; and the MF-tricyclic group （n = 32）, which received 10 mg/kg per day of the selective COX-2 inhibitor. Randomly se- lected rats were killed either 8 wk or 16 wk after sur- gery. The timing of the deaths was in accordance with a previous study performed in our group. Only rats that were killed at the times designated by the protocol were included in the study. We then assessed the histology and prostaglandin E2 （PGE2） expression levels in the rat esophagi. An additional group of eight animals that did not undergo esophagojejunostomy were included in order to obtain normal esophageal tissue as a control. RESULTS： Compared to a control group with no treat- ment （vehicle-treated rats）, indomethacin treatment was associated with decreases in ulcerated esophageal mucosa （16% vs 35% and 14% vs 17%, 2 mo and 4 mo after surgery, respectively; P = 0.021）, length of intestinal metaplasia in continuity with anastomosis （2 4- 1.17 mm vs 2.29 ＋ 0.75 mm and 1.25 4- 0.42 mm vs 3.5 4- 1.54 mm, 2 mo and 4 mo after surgery, respec- tively; P = 0.007）, presence of intestinal metaplasia beyond anastomosis （20% vs 71.4% and 0% vs 60%, 2 mo and 4 mo after surgery, respectively; P = 0.009）, severity of dysplasia （0% vs 71.4% and 20% vs 85.7% high-grade dysplasia, 2 mo and 4 mo after surgery, re- spectively; P = 0.002）, and adenocarcinoma incidence （0% vs 57.1% and 0% vs 60%, 2 mo and 4 mo after surgery, respectively; P 〈 0.0001）. Treatment with the selective COX-2 inhibitor, MF-tricyclic, did not prevent development of intestinal metaplasia or adenocarci- noma. In parallel, we observed a significant decrease in PGE2 levels in indomethacin-treated rats, but not in those treated with MF-tricyclic, at both 2 mo and 4 mo. Compared to control rats that did not undergo surgery （68 ＋ 8 ng/g, P = 0.0022 Kruskal-Wallis test） there was a significant increase in PGE2 levels in the esophageal tissue of the rats that underwent surgery either 2 mo （1332 ＋ 656 ng/g） or 4 mo （1121 ＋ 1015 ng/g） after esophagojejunostomy. However, no differences were found when esophageal PGE2 levels were compared 2 mo vs 4 mo post-esophagojejunostomy. At both the 2- and 4-mo timepoints, we observed a significant decrease in PGE2 levels in indomethacin-treated rat esophagi compared to those in either the control or MF-tricyclic groups （P = 0.049 and P = 0.017, respec- tively）. No differences in PGE2 levels were found when we compared levels in rats treated with MF-tricyclic to not-treated rats. CONCLUSION： In this rat model of gastrointestinal reflux, indomethacin was associated with a decrease in the severity of esophagitis and reduced development of esophageal intestinal metaplasia and adenocarcinoma.

The inhibitory effect of selective cyclooxygenase-2 inhibitor NS-398 on the cholangiocarcinoma line (QBC939)

Objective： We studied the inhibitory effect of human cholangiocarcinoma line （QBC939） treated by selective cyclooxygenase-2 （COX-2） inhibitor NS-398 and provided the theoretical foundation for the clinical practice. Methods： Selec- tive COX-2 inhibitor NS-398 on the growth suppression was evaluated by MTT method. The apoptotic rate was quantified and cell cycle by flow cytometry （FCM）. Invasive ability was detected by Transwell. The expression of vascular endothelial growth factor （VEGF） and COX-2 in cholangiocarcinoma line was determined by enzyme-linked immunosorbent assay （ELISA）. Results： NS-398 could be time-dose dependently inhibited the growth, induced apoptosis, invasived ability, S phase was inhibited, down-regulate the expression of VEGF and COX-2 in cholangiocarcinoma line （QBC939）. Conclusion： NS398 can inhibit proliferation of cholangiocarcinoma cell line QBC939 and inhibit the invasive ability and induce its apoptosis in vitro, which may contributed to the COX-2 dependent pathway to reduce the release of VEGF.

CO_(2) Reduction on Metal-Doped SnO_(2)(110)Surface Catalysts:Manipulating the Product by Changing the Ratio of Sn:O

The electrocatalytic carbon dioxide reduction reaction(CO_(2) RR)producing HCOOH and CO is one of the most promising approaches for storing renewable electricity as chemical energy in fuels.SnO_(2) is a good catalyst for CO_(2)-to-HCOOH or CO_(2)-to-CO conversion,with different crystal planes participating the catalytic process.Among them,(110)surface SnO_(2) is very stable and easy to synthesisze.By changing the ratio of Sn:O for SnO_(2)(110),we have two typical SnO_(2) thin films:fully oxidized(stoichiometric)and partially reduced.In this work,we are concerned with different metals(Fe,Co,Ni,Cu,Ru,Rh,Pd,Ag,Os,Ir,Pt,and Au)-doped SnO_(2)(110)with different activity and selectivity for CO_(2) RR.All these changes are manipulated by adjusting the ratio of Sn:O in(110)surface.The results show that stochiometric and reduced Cu/Ag doped SnO_(2)(110)have different selectivity for CO_(2) RR.More specifically,stochiometric Cu/Ag-doped SnO_(2)(110)tends to generate CO(g).Meanwhile,the reduced surface tends to generate HCOOH(g).Moreover,we also considered the competitive hydrogen evolution reaction(HER).The catalysts SnO_(2)(110)doped by Ru,Rh,Pd,Os,Ir,and Pt have high activity for HER,and others are good catalysts for CO_(2) RR.

Protective role of metalloproteinase inhibitor(AE-941) on ulcerative colitis in rats

AIM:To evaluate the protective role of AE-941,a matrix metalloproteinase(MMP) inhibitor,on ulcerative colitis(UC) in rats.METHODS:Sprague Dawley(SD) rats were randomly divided into three groups:a control group,an AE-941 treatment group,and an UC model group.Rats were sacrificed on days 7,21,or 56 following administration of treatment by enema and the disease activity index(DAI),colonic mucosa damage index(CMDI) and colonic expression of MMP-2 and MMP-9 were assessed.RESULTS:DAI and CDMI scores in the UC model group increased significantly compared to the control group at all timepoints(P < 0.001),and also increased significantly at the 21-and 56-d timepoints compared to the AE-941-treated group(DAI:21-and 56-d = 2.09 ± 0.25,1.52 ± 0.30 vs 1.55 ± 0.28,0.59 ± 0.19,respectively,P = 0.040 and 0.007,CMDI:21-and 56-d = 3.03 ± 0.42,1.60 ± 0.35 vs 2.08 ± 0.46,0.86 ± 0.37,respectively,P = 0.040 and 0.005).Furthermore,the colonic expression of MMP-2 and MMP-9 in the UC model group increased significantly compared to the control group(P < 0.001),and also increased compared to the AE-941-treated group on the 21-and 56-d timepoints(MMP-2:21-and 56-d = 0.6048 ± 0.0522,0.4163 ± 0.0330vs 0.3983 ± 0.0218,0.1093 ± 0.0072,respectively,P = 0.010;MMP-9:21-and 56-d = 0.6873 ± 0.0472,0.4328 ± 0.0257vs 0.5179 ± 0.0305,0.2673 ± 0.0210,respectively,P = 0.010 and 0.040).CONCLUSION:Expression of MMP-2 and MMP-9 increased significantly in rats with UC.AE-941 can reduce colonic mucosal damage by downregulating the expression of MMP-2 and MMP-9.

Pathogenesis of NSAID-induced gastric damage:Importance of cyclooxygenase inhibition and gastric hypermotility

This article reviews the pathogenic mechanism of nonsteroidal anti-inflammatory drug(NSAID)-induced gastric damage,focusing on the relation between cyclooxygenase(COX) inhibition and various functional events.NSAIDs,such as indomethacin,at a dose that inhibits prostaglandin(PG) production,enhance gastric motility,resulting in an increase in mucosal permeability,neutrophil infiltration and oxyradical production,and eventually producing gastric lesions.These lesions are prevented by pretreatment with PGE 2 and antisecretory drugs,and also via an atropine-sensitive mechanism,not related to antisecretory action.Although neither rofecoxib(a selective COX-2 inhibitor) nor SC-560(a selective COX-1 inhibitor) alone damages the stomach,the combined administration of these drugs provokes gastric lesions.SC-560,but not rofecoxib,decreases prostaglandin E 2(PGE 2) production and causes gastric hypermotility and an increase in mucosal permeability.COX-2 mRNA is expressed in the stomach after administration of indomethacin and SC-560 but not rofecoxib.The up-regulation of indomethacin-induced COX-2 expression is prevented by atropine at a dose that inhibits gastric hypermotility.In addition,selective COX-2 inhibitors have deleterious influences on the stomach when COX-2 is overexpressed under various conditions,including adrenalectomy,arthritis,and Helicobacter pylori-infection.In summary,gastric hypermotility plays a primary role in the pathogenesis of NSAID-induced gastric damage,and the response,causally related with PG deficiency due to COX-1 inhibition,occurs prior to other pathogenic events such as increased mucosal permeability;and the ulcerogenic properties of NSAIDs require the inhibition of both COX-1 and COX-2,the inhibition of COX-1 upregulates COX-2 expression in association with gastric hypermotility,and PGs produced by COX-2 counteract the deleterious effect of COX-1 inhibition.

不同中药复方对慢性心衰大鼠MMP-2、TIMP-2的影响

目的研究基质金属蛋白酶2(MMP-2)及内源性基质金属蛋白酶组织抑制剂2(TIMP-2)在慢性心衰中的作用,从分子生物学角度探讨中药不同配伍对慢性心衰心室重构的影响,并进一步阐明其作用机理。方法以冠脉结扎法配合力竭式游泳、减食等方法造成大鼠慢性心衰动物模型,分成模型组、西药组、益气中药组、活血中药组、益气活血中药组、益气活血利水中药组和正常组。利用实时荧光定量PCR技术及SABC免疫组化法检测慢性心衰大鼠MMP-2、TIMP-2表达的变化情况。结果慢性心衰动物模型组大鼠心肌MMP-2表达明显升高,TIMP-2表达降低,与假手术组比较,差异有统计学意义(P<0.01);经过治疗,各用药组大鼠心肌组织MMP-2表达明显降低,TIMP-2表达升高,其中益气活血组、益气活血利水组与西药组比较,差异无统计学意义(P>0.05),且益气活血利水组疗效明显优于益气活血组(P<0.01)。结论益气活血利水中药作用于心肌组织,通过影响MMP-2、TIMP-2的表达,抑制或逆转心室重构的过程,从而达到治疗慢性心衰的目的。

妇宁膨胀栓治疗高危型人乳头瘤病毒持续感染的Meta分析及循证药物经济学研究

目的系统评价妇宁膨胀栓治疗高危型人乳头瘤病毒(HR-HPV)持续感染的临床疗效、安全性与经济性,为HR-HPV持续感染患者提供循证药学依据。方法计算机检索中英文数据库自建库至2024年6月,妇宁膨胀栓治疗HR-HPV持续感染的临床研究文献,由两位研究者根据纳入排除标准独立对文献进行筛选,然后进行数据提取。使用Cochrane手册评价纳入研究质量,运用R4.1.3软件进行Meta分析。药物经济学评价采用决策分析软件TreeAge Pro 2011进行成本-效果分析。结果共纳入8篇文献,共1281例患者,所有文献均为中文文献。Meta分析结果显示:妇宁膨胀栓治疗HR-HPV感染转阴率显著高于重组人干扰素α-2b制剂;妇宁膨胀栓治疗HR-HPV感染HPV-DNA病毒载量显著低于重组人干扰素α-2b制剂;妇宁膨胀栓治疗HR-HPV感染腰腹坠痛消失占比、阴道分泌物异常消失占比、外阴瘙痒消失占比均高于重组人干扰素α-2b制剂;妇宁膨胀栓治疗HR-HPV感染复发率显著低于重组人干扰素α-2b制剂;妇宁膨胀栓治疗HR-HPV感染不良反应发生率显著低于重组人干扰素α-2b制剂。经济学分析结果:①成本-效果分析:两组成本-效果比分别为:重组人干扰素α-2b阴道泡腾片组CER=6829.06,妇宁膨胀栓组CER=7444.94,ICER(ΔC/ΔE)=11993.40。妇宁膨胀栓降价至74.1元/枚,重组人干扰素α-2b阴道泡腾片组的成本-效果比(C/E)=6829.06。妇宁膨胀栓组的成本-效果比=6796.40;两组增量成本-效果比(ΔC/ΔE)=6555.18。②敏感性分析结果:药品价格分别向上、向下调整10%,妇宁膨胀栓组的成本-效果比最高为7237.29,最低为6355.51;重组人干扰素α-2b阴道泡腾片组的成本-效果比最高为7240.89,最低为6417.24。结论妇宁膨胀栓治疗HR-HPV持续感染疗效显著,可提高HPV转阴率,降低HPV-DNA病毒载量、复发率及不良反应发生率,降价至74.1元/枚后相较于重组人干扰素α-2b阴道泡腾片经济性更优。

Efficacy and safety of saxagliptin in patients with type 2 diabetes mellitus:a meta-analysis of randomized controlled trials

As a new oral hypoglycemic agent, saxagliptin belongs to the class of dipeptidyl peptidase-4 （DPP-4） inhibitors. However, it remains inconclusive whether saxagliptin is associated with increased risk of adverse events （AE） and efficacy as add-on treatment. Therefore, we performed an up-to-date meta-analysis to compare the efficacy and safety of saxagliptin with placebo and other oral hypoglycemic agents in adult patients with type 2 diabetes mellitus （T2DM）. Randomized clinical trials （RCTs） comparing saxagliptin with comparators were retrieved by selecting articles from Pubmed, Embase, Cochrane Library and Clinical Trials Registry Platform up to Oct. 2013. Weighted mean difference （WMD） was used to analyze the effect of hypoglycemic agents on HbAlc, weight and fasting plasma glucose （FPG）. While the patients who achieved HbAlc〈7.0% and had AE were analyzed as relative risks （RR）. A total of 18 articles from 16 RCTs and one clinic trial from the WHO International Clinical Trials Registry Platform met the included criterion. Clinically significant decrease from baseline HbAlc compared with placebo was certified for 2.5 mg/day saxagliptin （WMD = -0.45%, 95% CI, -0.48% to -0.42%） and 5 mg/d saxagliptin （WMD = -0.52%, 95% CI, -0.60% to -0.44%）. Saxagliptin as add-on therapy was superior to thiazolidinediones, up-titrated glyburide, up-titrated metformin or metformin monotherapy in achieving HbA1c〈7.0%. Treatment with saxagliptin had negligible effect on weight, and it was considered weight neutral. Saxagliptin treatment did not increase the risk of hypoglycemia （RR = 1.28, 95% CI 0.72 to 2.27, P = 0.40） and serious adverse experiences （RR = 1.25, 95% CI 0.94 to 1.66, P = 0.13）. No statistically significant differences were observed between saxagliptin and comparators in terms of the risk of infections. The present study showed that saxagliptin was effective in improving glycaemic control in T2DM with a low risk of hypoglycaemia and incidence of infections in either monotherapy or add-on treatment. This founding should be further certified by large-sample size and good-designed RCT.

Incretin-based therapies for type 2 diabetes with nonalcoholic fatty liver disease: a systematic review and meta-analysis

We conducted a systematic review and meta-analysis of randomized controlled trials（RCTs） to determine the effectiveness and safety of incretin-based therapies（IBTs） for the treatment of type 2 diabetes（T2DM） with nonalcoholic fatty liver disease（NAFLD）. Electronic databases such as the Cochrane library, EMbase, Pub Med, and three Chinese databases were searched for RCTs that compared IBTs with other treatments or placebo for T2 DM with NAFLD. Two reviewers independently assessed the risk of bias, extracted, and analyzed the data. A meta-analysis was performed using Revman 5.2. Publication bias was evaluated. Seven RCTs involving 532 patients were ultimately included. The results of meta-analysis（random-effects model） revealed that IBTs had a significant reduction in serum ALT（WMD –12.30, 95% CI –17.53~–7.06） and BMI（WMD –2.64, 95% CI –4.35~–0.94）. However, there was no significant difference in other outcomes including Hb A1 c, AST, TC, TG and HOMA-RA. IBTs were well tolerated by patients but the evidence was limited. The significant decrease in hepatic biochemical markers following treatment with IBTs, as well as improvements in BMI, suggested that IBTs may be an effective option for T2 DM with NAFLD.

Canagliflozin,an inhibitor of sodium-glucose co-transporter 2,advances in the treatment of type 2 diabetes

Canagliflozin(CANA)is a sodium-glucose co-transporter 2 inhibitor.One of the important mechanisms of CANA is the inhibitory effect on the glucose uptake in the proximal tubule of the nephron,and the other mechanism can be the reduction of inflammatory cytokine expression monocytes and macrophages.It is proved by FDA for the management of type 2 diabetes.In the present work,we summarized the publication and clinical evidence of the CANA on healthy individuals and those with related metabolic diseases,such as type 1 and 2 diabetes,obesity,or cardiovascular and kidney diseases.This drug has been reported to offer potential advantages in regulating body weight and reducing heart failure,hypoglycemia,and stroke risk in patients with type 2 diabetes.Some in vitro and animal experiments also show that this drug has good effects on cancer treatment.However,some case reports and experiments also show the side effect of CANA,such as amputation,fracture,and pancreatitis,while the mechanism is still unknown.Overall,CANA has a good effect on the management of type 2 diabetes by reducing the risk of kidney failure,cardiovascular diseases,and stroke.However,as a new drug,more clinical trials and experiments of CANA should be carried out in the future.

Design and synthesis of 2-aminobenzimidazoles as potential BACE1 inhibitors

Fragment-based drug discovery （FBDD） has been widely applied in the research of aspartyl protease inhibitors. In the present study, we reported our work on 2-aminobenzimidazole as the original fragment, which was predicted to bind with the catalytic aspartyl dyad （Asp228 and Asp32） of D-site amyloid precursor protein cleaving enzyme 1 （BACE1）. A series of novel 2-aminobenzimidazole derivatives were designed and synthesized. The results from FRET assay revealed that three out of the 12 designed 2-aminobenzimidazoles could inhibit more than 50% of the enzymatic potency of BACE1 at 10 pM. Docking study showed that 2-aminobenzimidazole could form multiple hydrogen bonds and occupy S1/$2＇ pockets well.