Antidiabetic thiazolidinediones induce ductal differentiation but not apoptosis in pancreatic cancer cells

AIM: Thiazolidinediones (TZD) are a new class of oral antidiabetic drugs that have been shown to inhibit growth of same epithelial cancer cells. Although TZD were found to be ligands for peroxisome proliferator-activated receptor γ (PPARγ), the mechanism by which TZD exert their anticancer effect is presently unclear. In this study, we analyzed the mechanism by which TZD inhibit growth of human pancreatic carcinoma cell lines in order to evaluate the potential therapeutic use of these drugs in pancreatic adenocarcinoma. METHODS: The effects of TZD in pancreatic cancer cells were assessed in anchorage-independent growth assay. Expression of PPARy was measured by reverse-transcription polymerase chain reaction and confirmed by Western blot analysis. PPARy activity was evaluated by transient reporter gene assay. Flow cytometry and DMA fragmentation,assay were used to determine the effect of TZD on cell cycle progression and apoptosis respectively. The effect of TZD on ductal differentiation markers was performed by Western blot. RESULTS: Exposure to TZD inhibited colony formation in a PPARγ-dependent manner. Growth inhibition was linked to G1 phase cell cycle arrest through induction of the ductal differentiation program without any increase of the apoptotic rate. CONCLUSION: TZD treatment in pancreatic cancer cells has potent inhibitory effects on growth by a PPAR-dependent induction of pacreatic ductal differentiation.

Design,synthesis and in vitro evaluation of a series thiazolidinediones analogs as PPAR modulators

A series of thiazolidinediones analogs, as PPAR modulators, were designed, synthesized and evaluated in vitro.

Oral bisphosphonates improve the bone mineral density in men with diabetes with or without thiazolidinediones

Objective: Osteoporosis and type 2 diabetes mellitus (DM) two of the most common chronic conditions and represent major public health burdens. Epidemiological and observational studies indicate that thiazolidinedione (TZD) therapy with rosiglitazone and pioglitazone is associated with an increased risk of fractures and decreased bone mineral density (BMD). To our knowledge, no data are available to evaluate bisphosphonate therapy in thiazolidinedione-treated patients. The aim of this study was to investigate the benefit of bisphosphonates to improve changes in BMD in subjects with DM associated with TZDs. Methods: In a cross-sectional observational study using a retrospective review of electronic medical records, the changes in BMD in subjects with type 2 DM. The study subjects were divided into four groups. First group with DM receiving both TZDs and BPs;second group neither;third group receiving only TZDs and the fourth only BPs. The comparison of annual percent changes in BMD between the groups were carried out. Results: Decreased BMD noted in subjects with DM on TZDs. Bisphosphonates improved BMD in subjects with DM on TZDs. BMD improved in subjects with DM in those not receiving TZDs also. Conclusion: We conclude that concomitant treatment with bisphosphonates improves BMD in subjects with diabetes and on TZDs.

Indirect comparison of efficacy and safety of chiglitazar and thiazolidinedione in patients with type 2 diabetes:A meta-analysis

BACKGROUND Chiglitazar is an emerging pan-agonist of all peroxisome proliferator activated receptors(PPAR)-α,δandγ,and has therapeutic potential for type 2 diabetes(T2D).However,to date,no clinical studies or meta-analyses have compared the efficacy and safety of chiglitazar and traditional PPAR-γagonist thiazolidinediones(TZDs).A meta-analysis concerning this topic is therefore required.AIM To compare the efficacy and safety of chiglitazar and TZD in patients with T2D.METHODS PubMed,Medline,Embase,the Cochrane Central Register of Controlled Trials,Reference Citation Analysis and Clinicaltrial.gov websites were searched from August 1994 to March 2022.Randomized controlled trials(RCTs)of chiglitazar or TZD vs placebo in patients with T2D were included.Indirect comparisons and sensitivity analyses were implemented to evaluate multiple efficacy and safety endpoints of interest.RESULTS We included 93 RCTs that compared TZD with placebo and one that compared chiglitazar with placebo.For efficacy endpoints,the augmented dose of chiglitazar resulted in greater reductions in hemoglobin(Hb)A1c[weighted mean difference(WMD)=-0.15%,95%confidence interval(CI):-0.27 to-0.04%],triglycerides(WMD=-0.17 mmol/L,95%CI:-0.24 to-0.11 mmol/L)and alanine aminotransferase(WMD=-5.25 U/L,95%CI:-8.50 to-1.99 U/L),and a greater increase in homeostasis model assessment-β(HOMA-β)(WMD=17.75,95%CI:10.73-24.77)when compared with TZD treatment.For safety endpoints,the risks of hypoglycemia,edema,bone fractures,upper respiratory tract infection,urinary tract infection,and weight gain were all comparable between the augmented dose of chiglitazar and TZD.In patients with baseline HbA1c≥8.5%,body mass index≥30 kg/m^(2)or diabetes duration<10 years,the HbA1c reduction and HOMA-βincrease were more conspicuous for the augmented dose of chiglitazar compared with TZD.CONCLUSION Augmented dose of chiglitazar,a pan-activator of PPARs,may serve as an antidiabetic agent with preferable glycemic and lipid control,betterβ-cell function preserving capacity,and does not increase the risk of safety concerns when compared with TZD.

ZnO Nanobelts: An Efficient Catalyst for Synthesis of 5-Arylidine-2,4-Thiazolidinediones and 5-Arylidine-Rhodanines

A facile preparation of ZnO nanobelts by chemical precipitation technique and its utility as catalyst in Knoevenagel condensation of 2,4-thiazolidinedione/rhodanine has been described. X-ray diffraction and transmission electron microscopy techniques revealed the formation ZnO nanobelts. Scanning electron microscopic observations indicate that the lengths of nanobelts are ranging from a few hundreds of micrometers to a few millimeters. Its use for the condensation of aldehydes and active methylene compounds under solvent free reaction condition at 90℃ afforded the corresponding products in excellent yields in minute time.

痰热清注射液治疗慢性阻塞性肺病急性加重期作用机制探讨

目的:研究痰热清注射液治疗慢性阻塞性肺病急性加重期作用机制。方法:在线查询TCMSP数据库、既往文献获取黄芩、熊胆粉、山羊角、金银花、连翘等中药的主要活性成分,利用swisstargetprediction数据库获取其活性成分对应靶点;利用GeneCards、OMMI、Drug Bank等数据库获取慢性阻塞性肺病急性加重期靶点。利用Venny平台在线获取药物与疾病靶点交集,通过DAVID数据库对相交靶点进行基因本体分析和通路富集分析,使用STRING数据库构建蛋白相互作用网络,借助Cytoscapr软件行可视化处理并筛选主要活性成分、关键靶点。最后通过AutoDock vina软件将核心靶点与核心成分进行分子对接验证,并利用pymol可视化处理。结果:痰热清注射液中含主要活性成分90个,对应靶点557个;连翘、黄芩、金银花为痰热清注射液的关键作用药物;baicalein、Norwogonin、5,7,4’-Trihydroxy-8-methoxyflavone、5,2’,6’-Trihydroxy-7,8-dimethoxyflavone、(2R)-7-hydroxy-5-methoxy-2-phenylchroman-4-one、Panicolin、Skullcapflavone II、Moslosooflavone、5,7,2,5-tetrahydroxy-8,6-dimethoxyflavone、quercetin等为核心活性成分;STAT3、HSP90AA1、ESR1、SRC、EP300、AKT1、JUN、PIK3R1、RELA等靶点为蛋白互作网络中的核心靶点。结论:痰热清注射液治疗主要通过黄酮类物质调节细胞炎症反应、细胞增殖、凋亡等对慢性阻塞性肺病急性加重期发挥潜在作用。

基于网络药理学及分子对接探讨二至丸治疗早发性卵巢功能不全的作用机制

目的基于网络药理学方法探讨二至丸治疗早发性卵巢功能不全(POI)的可能分子作用机制。方法使用网络药理学平台(TCMSP)采集二至丸的有效成分和相关的基因;通过基因组注释数据平台(GeneCards)、人类孟德尔遗传数据库(OMIM)数据库获取POI疾病靶点;用蛋白互作网络数据库(STRING)构建蛋白质相互作用网络(PPI),通过CytoHubba筛选核心靶点。使用生物学信息注释数据库(DAVID)平台进行富集分析,采用Cytoscape 3.10.0软件进行拓扑学分析,利用AutoDockTools进行分子对接。结果二至丸内最主要的有效成分为槲皮素、木犀草素、山柰酚、刺槐素等,其中的AKT1、TP53等是关键靶点,包含的通路主要为PI3K-Akt信号通路、流体剪切应力和动脉粥样硬化信号通路等。分子对接验证大部分靶点与成分能进行有效结合。结论揭示二至丸能够经多种成分、靶点及多条信号通路对POI发挥协同治疗作用。

Acknowledgments to reviewers of World Journal of Gastrointestinal Pharmacology and Therapeutics

Many reviewers have contributed their expertise and time to the peer review, a critical process to ensure the quality of World Journal of Gastrointestinal

Acknowledgments to reviewers of World Journal of Gastrointestinal Pharmacology and Therapeutics

We acknowledge our sincere thanks to our reviewers. Many reviewers have contributed their expertise and time to the peer review, a critical process to ensure the quality of our World Series Journals. Both the editors of the journals and authors of the manuscripts submitted to the journals are grateful to the following reviewers

Acknowledgments to reviewers of World Journal of Gastrointestinal Pharmacology and Therapeutics

Many reviewers have contributed their expertise and time to the peer review,a critical process to ensure the quality of World Journal of Gastrointestinal

Acknowledgments to reviewers of World Journal of Gastrointestinal Pharmacology and Therapeutics

We acknowledge our sincere thanks to our reviewers.Many reviewers have contributed their expertise and time to the peer review,a critical process to ensure the quality of our World Series Journals.Both the editors of the journals and authors of the manuscripts submitted to the journals are grateful to the following reviewers for reviewing the articles(either published or rejected) over the past period of time.

Acknowledgments to reviewers of World Journal of Gastrointestinal Pharmacology and Therapeutics

Many reviewers have contributed their expertise and time to the peer review, a critical process to ensure the quality of World Journal of Gastrointestinal Pharmacology and Therapeutics. The editors

Acknowledgments to reviewers of World Journal of Gastrointestinal Pharmacology and Therapeutics

Many reviewers have contributed their expertise and time to the peer review,a critical process to ensure the quality of World Journal of Gastrointestinal Pharmacology and Therapeutics.The editors and authors of the articles submitted to the journal are grateful to the

Role of renal proximal tubule transport in thiazolidinedioneinduced volume expansion

Thiazolidinediones （TZDs）, pharmacological activa-tors of peroxisome-proliferator-activated receptors γ （PPARγ）, significantly improve insulin resistance and lower plasma glucose concentrations. However, the use of TZDs is associated with plasma volume expansion, the mechanism of which has been a matter of contro-versy. Originally, PPARγ-mediated enhanced transcrip-tion of the epithelial Na channel （ENaC） γ subunit was thought to play a central role in TZD-induced volume expansion. However, later studies suggested that the activation of ENaC alone could not explain TZD-induced volume expansion. We have recently shown that TZDs rapidly stimulate sodium-coupled bicarbonate absorp-tion from renal proximal tubule （PT） in vitro and in vivo. TZD-induced transport stimulation was dependent on PPARγ/Src/EGFR/ERK, and observed in rat, rabbit and human. However, this stimulation was not observed in mouse PTs where Src/EGFR is constitutively activated. Analysis in mouse embryonic fbroblast cells confrmed the existence of PPARγ/Src-dependent non-genomic signaling, which requires the ligand binding ability but not the transcriptional activity of PPARγ. The TZD-in-duced enhancement of association between PPARγ and Src supports an obligatory role for Src in this signal-ing. These results support the view that TZD-induced volume expansion is multifactorial. In addition to the PPARγ-dependent enhanced expression of the sodium transport system（s） in distal nephrons, the PPARγ-dependent non-genomic stimulation of renal proximal transport may be also involved in TZD-induced volume expansion.

HPLC法同时测定保健食品中9种降糖药物的含量

目的:建立同时测定保健食品中磺酰脲类、非磺酰脲类、噻唑脘二酮类等9种降糖药物含量的高效液相色谱方法。方法:迪马Diamonsil C18色谱柱(4.6 mm×250 mm,5μm),流动相为0.1%冰醋酸-0.01mol/L乙酸铵水溶液-乙腈(53:47),柱温为35℃,进样量为10μL,流速为1.0 mL·min^(-1),检测波长为210 nm。结果:9种化学降糖药完全分离,检出限为0.03~0.4μg·mL-1;9种药物具有宽的线性范围和良好的线性关系(r≥0.9998);在辅助降糖类保健食品中的加样回收率大于95%,RSD为0.77%~2.03%。结论:该方法准确、简便、可操作性强,适用于筛查降糖类保健食品中磺酰脲类、非磺酰脲类、噻唑脘二酮类等9种降糖药物的非法添加。

953例口服降糖药不良反应/事件报告分析

目的探讨口服降糖药品不良反应/事件(ADR/ADE)发生的一般规律和特点,为临床合理用药提供依据。方法采用回顾性研究方法,收集2012年1月1日至2022年12月31日武汉市ADR/ADE自发呈报系统数据库中10种口服降糖药ADR/ADE报告,采用描述性方法对报告信息、患者人口学特征、用药情况和累及系统-器官分布及临床表现等进行分析。结果共纳入口服降糖药ADR/ADE报告953例,涉及1405例次,数量呈逐年上升趋势,程度以“一般”为主(88.67%),“严重”占11.33%;以胃肠系统损害、皮肤及其附件损害和代谢与营养障碍最为多见,频次排序前3位的药物类别为α-糖苷酶抑制剂、噻唑烷二酮类和双胍联合噻唑烷二酮复方制剂。不同类别药物所致ADR/ADE的累及系统-器官和临床表现各具特点,钠-葡萄糖共转运蛋白2抑制剂以尿路损害和生殖器瘙痒为主,二肽基肽酶Ⅳ抑制剂以皮肤及皮肤附件疾病损害为主,格列奈类所致低血糖居多,其他类别最常见胃肠道不适,基本与药品说明书相符。结论口服降糖药的ADR/ADE涉及系统广泛,且呈逐年增多趋势,特别需关注新型口服降糖药,通过多方位药学服务,提升患者自我管理能力,加强ADR/ADE风险防范意识,及时识别并处理ADR/ADE,保障患者用药安全。

《医宗金鉴·正骨心法要旨》中治疗伤科瘀肿疼痛方剂的用药规律分析

目的:分析《医宗金鉴·正骨心法要旨》中治疗伤科瘀肿疼痛方剂的用药规律。方法:收集《医宗金鉴·正骨心法要旨》中治疗伤科瘀肿疼痛的方剂,对组方中药物的出现频次及药性、药味、归经、功效进行统计,分析用药规律。结果:共收集到《医宗金鉴·正骨心法要旨》中治疗瘀肿疼痛的内服、外用方剂57首,涉及中药179味。出现频次≥5的药物有35味,当归出现频次最多。药性出现频次较高的为温、寒、平,药味出现频次较高的为辛、苦、甘,归经主要归肝经、脾经、心经,药物功效主要为补虚、活血、清热。关联药物数最多的药物是当归,规则支持度最高的药物组合为川芎-当归;增益最高的药物组合为生姜-人参、甘草。核心药物组合有4组,分别为人参-生姜-大枣-茯苓-白术、柴胡-栀子-半夏-黄芩、当归-川芎-熟地黄-白芍、血竭-木香-酒。结论:《医宗金鉴·正骨心法要旨》中治疗伤科瘀肿疼痛的方剂多采用性温、味辛、归肝经的药物,核心药物组合以健脾益气、疏肝清火、补血活血、活血止痛药物为主,用药规律符合其专从血论、气血并重、消补并用的治伤思想。

槲皮素与芦丁对离体大鼠主动脉环的舒张作用及机制

目的:比较研究槲皮素与芦丁对离体大鼠胸主动脉环的作用及其可能的途径。方法:采用累积加药法,检测槲皮素和芦丁对去氧肾上腺素(pheny lephrine,PE)预收缩的胸主动脉环张力的影响。结果:槲皮素对离体大鼠内皮完整和去内皮的胸主动脉环均有浓度依赖性的舒张作用,而芦丁对PE预收缩血管的舒张作用是内皮依赖性的。槲皮素和芦丁对内皮完整的胸主动脉环的最大舒张反应分别为(77.20±6.11)%和(44.28±7.48)%,但两者对内皮完整的胸主动脉环最大舒张的半数有效浓度无明显差异。用一氧化氮合酶抑制剂L-NAM E(0.1 mm o l/L)预处理后,可阻断芦丁诱导的舒张血管作用,但不能阻断槲皮素引起的舒张血管作用;用鸟苷酸环化酶抑制剂亚甲蓝(10μm o l/L)预处理后,两者的血管舒张作用均被阻断。用环氧合酶抑制剂吲哚美辛(10μm o l/L)预处理后可减弱槲皮素诱导的舒张血管作用,但不能阻断芦丁引起的舒张血管作用。结论:槲皮素的舒血管作用强于芦丁,槲皮素可能是通过鸟苷酸环化酶和环氧合酶途径产生非内皮依赖性的血管舒张作用,而芦丁可能是通过NO-鸟苷酸环化酶途径产生内皮依赖性的血管舒张作用。

慢性癫痫对大鼠空间记忆再生能力的影响

目的 :探讨慢性癫痫对大鼠空间记忆再生能力的影响 ,检测组胺前体物质组氨酸和胆碱酯酶抑制剂TAK- 14 7对癫痫诱发记忆障碍的作用。方法 :大鼠在放射状八臂 (四臂放食物 )迷宫训练成功后 ,隔日腹腔注射亚惊厥剂量 ( 35 mg/ kg)的戊四唑 ,直至完全点燃。完全点燃后在同一迷宫中测记忆的再现过程。结果 :完全点燃后第1d至第 18d,大鼠在放射状迷宫中的错误次数较对照组明显上升 ,且维持在一相对平衡的状态 ,31d后与对照组一致。TAK- 14 7剂量依赖性地改善了癫痫诱发的空间记忆再现障碍 ,包括参考记忆和工作记忆。组氨酸剂量依赖性地改善参考记忆 ,不影响工作记忆。结论 :戊四唑点燃癫痫可导致大鼠空间记忆再生能力下降 。

黄芪舒张血管平滑肌的作用及机制

目的 :探讨黄芪对血管平滑肌的舒张作用及其机制。方法 :采用大鼠离体胸主动脉环灌流模型。在去除血管环内皮后 ,观察累积浓度黄芪对基础状态 (基础组 )、苯肾上腺素 (PE)预收缩 (苯肾上腺素组 )、氯化钾预收缩(氯化钾组 )的血管环的作用和黄芪对经无钙液 (无钙液组 )、无钙液加肝素 (肝素组 )、普萘洛尔 (普萘洛尔组 )预处理后的血管环的作用。结果 :在血管内皮被去除后 ,黄芪对基础状态或氯化钾预收缩的血管环无影响 ;当黄芪浓度累积达 (10 -1、3× 10 -1、10 0 、3× 10 0 ) g/L时 ,对 PE(3× 10 -7mol/L)预收缩的血管环产生剂量依赖性舒张作用 (P<0 .0 5 )。经无钙液预处理后 ,黄芪 (3× 10 0 g/L )对血管环的舒张作用未被阻断 ;但经无钙液加肝素预处理后 ,该作用被显著抑制 (P<0 .0 1) ;而普萘洛尔预处理不影响黄芪对 PE预收缩血管环的舒张作用。结论 :黄芪对去除内皮的血管具有舒张作用。其机制可能与阻断血管平滑肌细胞内质网上的三磷酸肌醇敏感的钙离子通道 ,抑制内钙的释放有关。