腺苷酸活化蛋白激酶激活剂的研究进展

腺苷酸活化蛋白激酶(AMPK)在真核细胞的能量感受与调节中起关键作用,被AMP等其他因素激活后具有加速分解代谢、降低合成代谢的功能,从而稳定人体糖代谢与脂代谢。AMPK激活剂在2型糖尿病等代谢异常的动物模型中体现出较好的治疗效果。对近年来AMPK激活剂的研究进展进行综述,期望对该类药物的研发提供参考。     

以葡萄糖激酶为靶点的抗糖尿病新药研究

葡萄糖激酶是糖代谢途径中的关键酶,它的异常会导致机体糖代谢紊乱而引起糖尿病等相关疾病。近年来,人们逐渐意识到以葡萄糖激酶为靶点来研究糖尿病具有极其广阔的前景。该文对葡萄糖激酶抗糖尿病的机制及其激活剂的研究现状进行了综述,提出阐明葡萄糖激酶靶点的研究及其激活剂的寻找是未来研究的方向。     

蛋白激酶AMPK高效制备及活性检测方法的建立

目的 建立高效的腺苷酸依赖的蛋白激酶（AMPK）的制备方法,并建立1种基于酶联免疫吸附（ELISA）法的AMPK的激酶活性检测方法以用于药物筛选。方法 利用大肠杆菌表达系统,将AMPK的α、β和γ 3个亚基与钙调素依赖性蛋白激酶β(CAMKK β)共表达,重组AMPK被CAMKK β磷酸化修饰并激活,进而纯化得到具有激酶活性的重组AMPK蛋白复合体。根据AMPK底物乙酰辅酶A羧化酶（ACC）的磷酸化修饰位点（Ser79）设计合成生物素标记的多肽（SAMS）作为AMPK激酶的底物。在ATP存在的情况下AMPK对生物素标记的SAMS多肽进行磷酸化修饰,反应产物转移到链霉亲和素包被的酶标板中,SAMS多肽通过链霉亲和素结合到酶标板。以能够识别SAMS磷酸化修饰的抗体作为一抗进行ELISA检测,SAMS的磷酸化修饰水平反应AMPK的激酶活性。结果 利用大肠杆菌表达系统成功得到有激酶活性的AMPK蛋白复合体,建立了ELISA检测AMPK的激酶活性方法。通过对AMPK激活剂A-769662检测,证明该方法可以用于AMPK激活剂/抑制剂的筛选。结论 通过构建大肠杆菌共表达系统,成功获得了AMPK激酶...     

溶栓药物研究进展

从两个方面综述了溶栓药物的研究进展 ,包括组织纤溶酶原激活剂的突变体 (rPA、Monteplase、TNK tPA、nPA、K1K2 Pu嵌合体 )以及一些其它来源的纤溶酶原激活剂比如尿激酶原、葡激酶、吸血蝙蝠唾液纤溶酶原激活剂、蚓激酶、纳豆激酶和蛇毒纤溶酶原激活剂等     

治疗2型糖尿病药物葡萄糖激酶激活剂的研究进展

葡萄糖激酶是己糖激酶家族成员,在细胞内司职葡萄糖磷酸化生成6-磷酸葡萄糖,对体内葡萄糖稳态起关键性作用。肝脏中,在葡萄糖激酶作用下葡萄糖磷酸化以促进糖原合成;而在β细胞中,其刺激诱导胰岛素释放。葡萄糖激酶激活剂可增加该酶对葡萄糖的敏感性及胰岛素分泌和肝脏糖原的合成,减少肝脏葡萄糖输出。在2型糖尿病动物模型中,一些小分子葡萄糖激酶激活剂已证实是有效的降糖剂,有的已经进入临床试验。     

葡萄糖激酶激活剂治疗2型糖尿病有效性和安全性的Meta分析

目的 系统评价葡萄糖激酶激活剂治疗2型糖尿病的有效性和安全性。方法 检索PubMed、Cochrane Library、Web of Science、Embase、中国知网等数据库，时间为建库至2022年3月。纳入葡萄糖激酶激活剂与安慰剂（或其他口服降糖药）对照治疗2型糖尿病的随机对照试验，提取资料并用RevMan 5.4软件进行Meta分析。结果 纳入9项研究，2 150名患者。降糖效果方面，与对照组相比，葡萄糖激酶激活剂能显著降低糖尿病患者糖化血红蛋白[MD=-0.40,95%CI(-0.53,-0.26),P<0.000 01]、空腹血糖[MD=-0.53,95%CI(-0.85,-0.20),P=0.001]和餐后2 h血糖[MD=-2.28,95%CI(-2.68,-1.88),P<0.000 01]。安全性方面，总体上葡萄糖激酶激活剂的低血糖发生率要高于对照组[RR=1.55,95%CI(1.20,2.01),P=0.000 8]；根据葡萄糖激酶激活剂激活的脏器进行亚组分析，胰腺肝脏双激活剂组[RR=1.44,95%CI(1.11,1.89),P=0.007]和...     

溶栓药物研究新进展

本文综述了临床研究开发的几种溶栓药物新进展。包括组织型纤溶酶原激活剂的突变体（mon-teplase,reteplase,teneceplase,lanoteplase)、嵌合体（K1K2Pu)、尿激酶原、葡激酶和吸血蝙蝠唾液纤溶酶原激活剂等。     

一种潜在的溶血栓药物——纳豆激酶

纳豆中提取出纳豆激酶（Ｎattokinase,简称ＮＫ）具有溶栓作用还兼具促进体内组织纤溶酶型激活剂（tＰＡ）合成的功效。ＮＫ是一个分子量小的单链肽,可利用枯草杆菌进行液体发酵生产,因此有望成为新一代的口服溶血栓药物。     

瑞舒伐他汀对内皮细胞中组织因子途径抑制物表达的影响

目的探讨瑞舒伐他汀对组织因子途径抑制物(TF-PI)表达的调节作用及机制。方法培养人脐静脉内皮细胞(HUVECs),给予多种剂量的瑞舒伐他汀和(或)肿瘤坏死因子-α(TNF-α)、磷酸腺苷激活的蛋白激酶(AMPK)抑制剂与激活剂处理细胞,利用实时定量PCR、Western blot技术检测内皮细胞中TFPI表达的变化。结果 TNF-α下调内皮细胞中TFPI的的表达水平,而这一作用被瑞舒伐他汀所阻断。而且,瑞舒伐他汀呈时间及剂量依赖性上调TFPI的mRNA与蛋白水平。AMPK抑制剂———Compoud C则可逆转瑞舒伐他汀对TFPI表达的上调作用,而AMPK激动剂———Aicar则具有与瑞舒伐他汀相似的上调TFPI的作用。结论瑞舒伐他汀通过激活AMPK途径上调血管内皮细胞中TFPI的表达。     

肠粘消对术后肠粘连大鼠纤溶系统的影响

目的 探讨肠粘消对术后肠粘连大鼠组织型纤维酶原激活剂抑制剂、组织型纤维酶原激活剂的影响.方法 采用发色底物法测定大鼠组织型纤维酶原激活剂抑制剂、组织型纤维酶原激活剂的活性.结果 肠粘消能升高术后肠粘连大鼠血中组织型纤维酶原激活剂的活性,而对组织型纤维酶原激活剂抑制剂的活性无影响.结论 肠粘消可能通过升高术后肠粘连大鼠血中组织型纤维酶原激活剂的活性溶解纤维蛋白元,起到预防术后肠粘连的发生.     

Development of Novel Alkene Oxindole Derivatives As Orally Efficacious AMP-Activated Protein Kinase Activators

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Discovery of Pyridones As Oral AMPK Direct Activators

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Direct AMP-activated protein kinase activators: a review of evidence from the patent literature

Introduction: AMP-activated protein kinase (AMPK), a heterotrimeric protein complex with serine/threonine kinase activity has a central role in controlling cellular energy expenditure. Small molecule-based activation of AMPK represents an attractive therapeutic proposition because of AMPK's ability to regulate several anabolic and catabolic pathways that are critical to the development of metabolic disorders and cancer.

Areas covered: A comprehensive review of published patents that disclose direct AMPK activators is provided: 26 patents comprising 10 chemical classes, and supporting in vitro and in vivo data are discussed.

Expert opinion: AMPK activation holds promise as a possible pharmacological intervention in several disease states. The development of direct, highly specific AMPK activators is necessary to fully realize the opportunities linked to AMPK activation and appreciate the risks associated with it.     

AMPK activator C24 inhibits hepatic lipogenesis and ameliorates dyslipidemia in HFHC diet-induced animal models

Dyslipidemia is a chronic metabolic disease characterized by elevated levels of lipids in plasma.Recently,various studies demonstrate that the increased activity of adenosine 5′-monophosphate-activated protein kinase(AMPK)causes health benefits in energy regulation.Thus,great efforts have been made to develop AMPK activators as a metabolic syndrome treatment.In the present study,we investigated the effects of the AMPK activator C24 on dyslipidemia and the potential mechanisms.We showed that C24(5-40μM)dose-dependently increased the phosphorylation of AMPKαand acetyl-CoA carboxylase(ACC),and inhibited lipogenesis in HepG2 cells.Using compound C,an AMPK inhibitor,or hepatocytes isolated from liver tissue-specific AMPK knockout AMPKα1α2fl/fl;Alb-cre mice(AMPK LKO),we demonstrated that the lipogenesis inhibition of C24 was dependent on hepatic AMPK activation.In rabbits with high-fat and high-cholesterol diet-induced dyslipidemia,administration of C24(20,40,and 60 mg·kg^?1·d^?1,ig,for 4 weeks)dose-dependently decreased the content of TG,total cholesterol(TC),and low-density lipoprotein cholesterol(LDL-C)in plasma and played a role in protecting against hepatic dysfunction by decreasing lipid accumulation.A lipid-lowering effect was also observed in high-fat and high-cholesterol diet-fed hamsters.In conclusion,our results demonstrate that the small molecular AMPK activator C24 alleviates hyperlipidemia and represents a promising compound for the development of a lipid-lowering drug.     

腺苷酸活化蛋白激酶促胰岛β细胞凋亡机制的研究进展

腺苷酸活化蛋白激酶(AMPK)是调节细胞能量代谢的关键酶。近几年深入研究发现其具有促胰岛β细胞凋亡的作用,研究发现其可通过线粒体凋亡途径、内质网应激凋亡途径及哺乳动物雷帕霉素靶蛋白(mTOR)通路等诱导细胞凋亡,本文就AMPK促进胰岛β细胞凋亡的作用及可能的机制作一简要综述。     

Diabetic cardiovascular disease--AMP-activated protein kinase (AMPK) as a therapeutic target

Cardiovascular complications are the leading cause of death and morbidity in patients with diabetes; accounting for around 7 out of 10 of all causes of death in this population. Returning patients to normoglycaemia alone has been shown to have little effect on cardiovascular end points, therefore new therapies and strategies are required in order to reduce the incidence and improve outcomes of cardiovascular disease in diabetic individuals. The metabolic enzyme AMP-activated protein kinase (AMPK) has emerged in recent years as an attractive potential therapeutic target for diabetic vascular disease, and studies have shown improved endothelial and smooth muscle cell function following AMPK activation. Additionally, improved lipid profiles, reduced hypertrophic cardiomyocyte growth and protection from cardiac ischaemia-reperfusion injury have also been observed as beneficial outcomes of AMPK therapy. In this review we will discuss in detail the potential downstream targets of AMPK activation in the cardiovascular system. We will also provide an overview of long-known and newly discovered direct and indirect AMPK activators, as well as novel synthesised AMPK-activating compounds, which will highlight the potential for further exploiting AMPK in a therapeutic context for cardiovascular disease in diabetes.     

AMP-activated protein kinase and the control of smooth muscle cell hyperproliferation in vascular disease

Smooth muscle cell (SMC) accumulation within the arterial intima contributes to the formation of atherosclerotic lesions. Emerging data indicate that the adenosine monophosphate-activated protein kinase (AMPK) is a potent inhibitor of SMC proliferation. The anti-proliferative action of AMPK is mediated through multiple mechanisms, including the regulation of cyclin dependent kinase inhibitors expression p21(Cip1) and p27(kip1) and the inhibition of the mammalian target of rapamycin complex 1 (mTORC1). A favorable effect of AMPK activation on intima hyperplasia has been demonstrated in in vivo experimental models by using the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), or by studying the AMPKα(-/-) mice. Starting from these evidences, a number of atheroprotective drugs with antiproliferative properties have been shown to induce AMPK phosphorylation. Among them, the Ca(2+) channel blocker nifedipine was demonstrated to act through AMPK, independent of its calcium channel blocking activity. In the present review I summarize current knowledge on the basic biological function of AMPK in relationship to vascular SMC proliferation; the evidence for the role of AMPK in in vivo intima hyperplasia; and the drugs for which a pharmacological activity on AMPK has been shown.     

AMP-activated protein kinase modulators: a patent review (2006 - 2010)

INTRODUCTION: AMPK is a key player in the regulation of energy balance at both the cellular and whole-body levels, placing it at the center stage in studies of metabolic disorders. Recently, AMPK has also been identified as a potential target for either therapy or prevention of some types of cancer. Thus, identification of AMPK modulators for possible use as novel therapeutic drugs, both for treatment of metabolic disorders and cancer, will have a high commercial potential. AREAS COVERED: This review covers the structures and activities of AMPK modulators described in the patent literature since 2006. The patents reviewed include those for direct and/or indirect activators of AMPK, and novel pharmaceutical compounds with potential for use in the prevention and/or treatment of metabolic disorders, and cancer targeting AMPK. EXPERT OPINION: Targeting of AMPK appears to be an attractive strategy in the treatment of metabolic disorders. However, some detrimental effects of AMPK have also been reported, including a possible tumor-promoting effect in some settings and a heart disease-causing effect. Moreover, activation of AMPK in the hypothalamus may cause undesired consequences, such as an increase in feeding and body weight gain. These effects, therefore, must be carefully assessed for the development of therapeutic drugs targeting AMPK.     

Mitochondrial inhibitor as a new class of insulin sensitizer

Insulin resistance is a major risk factor for type 2 diabetes. AMP-activated protein kinase (AMPK) is a drug target in the improvement of insulin sensitivity. Several insulin-sensitizing medicines are able to activate AMPK through inhibition of mitochondrial functions. These drugs, such as metformin and STZ, inhibit ATP synthesis in mitochondria to raise AMP/ATP ratio in the process of AMPK activation. However, chemicals that activate AMPK directly or by activating its upstream kinases have not been approved for treatment of type 2 diabetes in humans. In an early study, we reported that berberine inhibited oxygen consumption in mitochondria, and increased AMP/ATP ratio in cells. The observation suggests an indirect mechanism for AMPK activation by berberine. Berberine stimulates glycolysis for ATP production that offsets the cell toxicity after mitochondria inhibition. The study suggests that mitochondrial inhibition is an approach for AMPK activation. In this review article, literature is critically reviewed to interpret the role of mitochondria function in the mechanism of insulin resistance, which supports that mitochondria inhibitors represent a new class of AMPK activator. The inhibitors are promising candidates for insulin sensitizers. This review provides a guideline in search for small molecule AMPK activators in the drug discovery for type 2 diabetes.