磷脂酸肌醇-3-激酶/蛋白激酶B信号通路在肺部疾病中的作用研究进展

磷脂酸肌醇-3-激酶(PI3K)/蛋白激酶B(Akt)信号通路是细胞内与增殖、分化和凋亡相关的信号通路，是机体自我保护的重要通路。PI3K被激活后会使其下游分子Akt磷酸化，进而抑制细胞凋亡、调控细胞生存及增殖。PI3K/Akt信号通路在众多肺系疾病，如急性肺损伤、肺炎、哮喘、肺纤维化、肺癌等的发展进程中起着重要作用。该文对PI3K/Akt信号通路在肺系疾病进展中的作用机制进行了综述。     

瘦素对肝星状细胞活化的调控及其在肝纤维化进展中的作用

摘要：瘦素是一种主要由白色脂肪组织产生的激素,与肝星状细胞活化有着密切联系。瘦素与其功能性受体结合后可以通过JAK2/STAT3、PI3K/Akt、MAPK等信号通路及相关分子对肝星状细胞的活化产生影响;而肝星状细胞活化是肝纤维化发生发展的关键环节。该文就瘦素与肝星状细胞活化的相关信号通路及分子在肝纤维化发生发展中的作用进行综述,为肝纤维化的治疗提供依据。     

天然产物通过抑制PI3K信号通路抗肝纤维化的研究进展

肝纤维化是慢性肝损伤的一种内在反应,其特征是细胞外基质(extracellular matrix, ECM)的合成、降解和沉积失衡,会导致肝细胞受损和肝脏正常结构被破坏。而肝星状细胞(hepatic stellate cells, HSCs)的异常激活被认为是驱动肝纤维化的关键因素。在肝损伤的过程中,HSCs能够活化并向肌成纤维细胞转化进而产生过量的ECM。炎症和氧化应激在HSCs的激活中发挥重要作用,而HSCs凋亡则有利于肝纤维化的消退。抑制磷脂酰肌醇-3-激酶(phosphatidylinositol-3-kinase, PI3K)信号通路可降低炎症反应、氧化应激,诱导HSCs凋亡,从而改善肝纤维化。来源于植物的天然产物,包括黄酮类和萜类可以抑制PI3K信号通路,对肝纤维化的发生发展起到抑制作用。该文旨在综述PI3K信号通路在肝纤维化中的作用,总结近年来黄酮类化合物和萜类化合物通过抑制PI3K信号通路抗肝纤维化作用的证据,为进一步开发能有效防治肝纤维化的药物提供参考。     

PI3K/Akt通路在糖尿病心肌病中的研究进展

糖尿病心肌病(diabetic cardiomyopathy,DCM)是由糖尿病引发心肌结构和功能的改变一类原发性心肌病变,区别于冠状动脉粥样硬化、高血压以及病毒等因素引起的继发性心肌病。磷酯酰肌醇3激酶(phosphatidylinositol-3 kinase,PI3K)/Akt作为人体重要的信号传导通路,参与机体正常生长繁殖、调节新陈代谢等功能。PI3K/Akt信号通路的调控因子包括沉默信息调节因子1、同源性磷酸酶-张力蛋白、糖原合成酶激酶3β、雷帕霉素靶蛋白等。DCM发病过程中,PI3K/Akt信号通路的作用包括调节血糖水平、调节脂质代谢、保护内皮细胞、减轻炎症反应、改善心功能并抵抗纤维化、调节心肌细胞凋亡等。PI3K-Akt信号通路抑制剂的研发为PI3K-Akt通路靶向治疗提供了可能性。该文综述了PI3K/Akt通路在DCM中的研究进展。     

中草药黄酮类化合物治疗肝纤维化分子信号通路的研究进展

目的:为中草药黄酮类化合物治疗肝纤维化的进一步研究提供参考。方法:以"中草药""黄酮类化合物""肝纤维化""信号通路""Chinese herbal medicine""Flavonoids""Hepatic fibrosis""Signaling pathway"等为关键词,在中国知网、万方数据、维普网、PubMed、Medline等数据库中组合查询2002年1月-2018年8月发表的相关文献,对中草药黄酮类化合物治疗肝纤维化分子信号通路[如转化生长因子β(TGF-β)/Smad、Wnt/β-联蛋白(β-catenin)、Toll样受体4/核因子κB(TLR4/NF-κB)、Janus激酶/信号转导子和转录激活因子(JAK/STAT)、磷酯酰肌醇-3-激酶/蛋白激酶B(PI3K/Akt)等]的相关研究进行论述。结果与结论:共检索到相关文献169篇,其中有效文献47篇。肝纤维化是肝星状细胞活化导致细胞外基质大量沉积的结果,肝纤维化的发生和发展过程受多个分子信号转导通路的调控。柚皮素、槲皮素、荔枝核总黄酮、白杨素、葛根素等黄酮类化合物能干预与肝纤维化发生密切相关的TGF-β/Smad、Wnt/β-catenin、TLR4/NF-κB、JAK/STAT和PI3K/Akt信号通路。该类化合物治疗肝纤维化具有多靶点、多通路、多环节的特点,同一化合物可影响多个信号通路。今后应对黄酮类化合物对分子信号通路介导肝纤维化的作用机制进行研究。     

miRNA 与胆道闭锁肝纤维化

胆道闭锁(BA)是婴儿期引起梗阻性黄疸的主要病因之一, 以肝内外胆管进行性炎症和纤维性梗阻为主要特征, 导致胆汁淤积和肝纤维化及肝硬化。肝纤维化中最重要的是肝星状细胞(HSC)的活化, 这一过程受到多种机制的调节, 其中 miRNA 家族成员可通过调控靶基因的表达, 进而作用于多种信号通路促进 HSC 的活化, 在细胞外基质(ECM)的合成和降解中发挥调节作用。大量文献表明 PI3K/Akt 信号通路与肝纤维化的发生、 发展密切相关, 参与了活化 HSC 增殖、 凋亡的调控, miRNA 通过各种靶基因激活 PI3K/Akt 信号通路, 进而激活 HSC, 促进肝纤维化的发展。本文就胆道闭锁肝纤维化相关的 miRNA综述如下。     

PI3K/Akt信号通路在肿瘤发展和治疗中的作用

目前发现有多条信号网络通路参与调控肿瘤生成、增殖、凋亡等分子机制,PI3K/Akt是其中比较重要的一条信号传导途径,该通路与肿瘤的发生发展密切相关。该文就PI3K/Akt信号通路的结构组成与调控肿瘤机制进行阐述,并介绍了其在临床中的应用与前景。     

P13K/Akt信号转导通路的研究进展

PI3K/Akt信号传导通路在恶性肿瘤的发生、发展、治疗及转归中发挥着重要作用,PI3K作为联系胞外信号与细胞应答效应的桥梁分子,在一系列上游或旁路信号分子的影响下,作用于下游的信号分子对细胞的凋亡起非常重要的调节作用.在许多研究中已经证实PI3K和Akt的抗凋亡时,Akt的表达水平增高并通过保护细胞免受凋亡而促进癌细胞的生长.现就PI3K/Akt信号通路的组成与功能、调节以及其抗恶性肿瘤细胞凋亡作用机理等方面的研究进展作一综述.     

CD44单抗A3D8对NB4细胞IL-3Rα及其下游信号通路的调节

目的探讨CD44单抗A3D8对急性早幼粒细胞白血病细胞株NB4细胞IL-3Rα及其下游PI3K/Akt信号通路的调节。方法以NB4细胞为研究对象,以同型抗体IgG1为阴性对照,以A3D8为实验组,A3D8诱导NB4细胞分化凋亡过程中,real-time RT-PCR方法检测IL-3Rα基因转录水平,运用Western blot法检测IL-3Rα及下游PI3K/Akt信号通路中重要信号分子,随后将PI3K/Akt信号通路抑制剂LY294002与A3D8联合,观察二者联合对NB4细胞PI3K/Akt信号通路的影响。结果 A3D8诱导NB4细胞分化凋亡过程,可明显下调NB4细胞中IL-3RαmRNA和蛋白表达水平,抑制PI3K/Akt信号通路;LY294002可增强A3D8对NB4细胞增殖和凋亡的抑制作用,并可进一步抑制PI3K/Akt信号通路。结论 A3D8可抑制NB4细胞IL-3Rα的转录水平和蛋白表达水平,并抑制其下游PI3K/Akt信号通路。     

牛蒡子苷元通过抑制PI3-K/Akt信号通路诱导肝癌细胞凋亡

目的 探讨天然木脂素类化合物牛蒡子苷元对肝癌细胞生长的抑制作用及其可能机制。方法 采用不同浓度的牛蒡子苷元处理HepG2 和Hep3B 细胞,通过MTT 法检测细胞增殖情况,流式细胞术检测细胞凋亡及细胞周期,免疫印迹检测细胞中caspase-9 和caspase-3 的活化情况以及抗凋亡蛋白的表达。进一步通过转染Akt 质粒以及使用PI3K 抑制剂,探讨牛蒡子苷元对肝癌细胞PI3K/Akt 信号通路的影响。结果 牛蒡子苷元能以浓度依赖性方式显著抑制肝癌细胞增殖并促进其凋亡,同时抑制肝癌细胞中PI3K/Akt 信号通路活化,降低抗凋亡蛋白Bcl-xL、Mcl-1 和survivin 的表达,抑制mTOR 和S6K 的磷酸化;细胞过表达Akt 活化蛋白后可抑制牛蒡子苷元的上述效应,而PI3K 抑制剂联合作用可增强上述效应。结论 牛蒡子苷元可通过抑制PI3K/Akt 信号通路下调抗凋亡蛋白的表达进而促进肝癌细胞凋亡。     

Targeting the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin module for acute myelogenous leukemia therapy: from bench to bedside

The phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B, PKB)/mammalian Target Of Rapamycin (mTOR) signaling pathway plays a critical role in many cellular functions which are elicited by extracellular stimuli. However, constitutively active PI3K/Akt/mTOR signaling has also been firmly established as a major determinant for cell growth, proliferation, and survival in an wide array of human cancers. Thus, blocking the PI3K/AKT/mTOR signal transduction network could be an effective new strategy for targeted anticancer therapy. Pharmacological inhibitors of this signaling cascade are powerful antineoplastic agents in vitro and in xenografted models of tumors, and some of them are now being tested in clinical trials. Recent studies showed that PI3K/Akt/mTOR axis is frequently activated in acute myelogenous leukemia (AML) patient blasts and strongly contributes to proliferation, survival, and drug-resistance of these cells. Both the disease-free survival and overall survival are significantly shorter in AML cases with PI3K/Akt/mTOR upregulation. Therefore, this signal transduction cascade may represent a target for innovative therapeutic treatments of AML patients. In this review, we discuss the possible mechanisms of activation of this pathway in AML cells and the downstream molecular targets of the PI3K/Akt/mTOR signaling network which are important for blocking apoptosis, enhancing proliferation, and promoting drug-resistance of leukemic cells. We also highlight several pharmacological inhibitors which have been used to block this pathway for targeted therapy of AML. These small molecules induce apoptosis or sensitize AML cells to existing drugs, and might be used in the future for improving the outcome of this hematological disorder.     

选择性PI3K抑制剂的研究进展

磷脂酰肌醇3-激酶（PI3K）是细胞内重要的信号转导分子,在细胞存活、增殖和分化过程中起重要调节作用。PI3K是PI3K/AKT/mT0R信号转导通路中的关键节点蛋白,调控着重要的生命活动。现已证实磷脂酰肌醇3-激酶（PI3Ks）是潜力巨大的药物治疗靶点,特别是PI3Kα现己成为抗肿瘤治疗的重要靶点之一。目前己有多种针对PI3Ks的抑制剂进入临床研究。然而现有抑制剂的化学类型不多且选择性不高、临床应用受局限。因此积极研究和开发结构新颖的PI3K选择性抑制剂对于疾病的靶向治疗具有重要意义。本文将对选择性PI3K抑制剂在抗肿瘤方面的研究进展作一综述。     

抑制PI3K信号通路的抗肿瘤天然药物研究进展

磷脂酰肌醇3-激酶(PI3K)信号通路是正常细胞生理代谢的重要信号转导途径,也是肿瘤细胞发生和发展的关键信号通路。人类肿瘤基因组学研究表明,PI3K信号通路可将癌基因和多种受体与许多细胞功能联系在一起,该通路也是肿瘤中最常被激活的通路,抑制该信号通路,可抑制肿瘤的生长与转移。概述了PI3K及其信号通路与肿瘤发生、发展和转移的关系以及PI3K信号通路的主要抑制途径,综述近年来抗肿瘤天然药物抑制PI3K信号通路的研究进展。     

PI3K/Akt信号通路活化在曲妥珠单抗耐药机制意义的研究

目的探讨磷脂酰肌醇-3-激酶/丝苏氨酸蛋白激酶(PI3K/Akt)信号转导通路激活是曲妥珠单抗耐药的重要靶点之一,为乳腺癌曲妥珠单抗耐药的靶向治疗提供理论基础。方法对人乳腺癌细胞株BT474连续处理建立了耐曲妥珠单抗的耐药亚株BT-HerR,FISH法对耐药细胞株BT-HerR做Her-2表型分析,MTT法检测曲妥珠单抗对BT474和BT-HerR细胞的体外增殖抑制情况,流式细胞仪检测曲妥珠单抗干预后细胞的凋亡变化,PI3K/Akt抑制剂LY294002干预细胞后Western blot检测p-Akt表达。结果耐药细胞株BT-HerR Her-2基因表达为强阳性;曲妥珠单抗干预细胞72 h后,细胞的体外增殖受到抑制且随着浓度的升高而增强;经曲妥珠单抗处理后比较BT474与BT-HerR细胞凋亡率,差异具有显著性(P<0.01);曲妥珠单抗仅能抑制BT474的Akt蛋白磷酸化,LY294002则能同时抑制BT474的BT-HerR Akt蛋白磷酸化。结论曲妥珠单抗耐药细胞Akt蛋白磷酸化活化,PI3K/Akt抑制剂LY294002能明显抑制曲妥珠单抗耐药细胞Akt蛋白磷酸化,PI3K/Akt信号转导通路与曲妥珠单抗耐药存在明确相关性。     

气道重塑与磷脂酰肌醇3激酶/蛋白激酶B信号通路在支气管哮喘发病机制中的研究进展

支气管哮喘是一种以可逆性气流受限为特征的气道慢性炎症性疾病。在支气管哮喘众多发病机制中,气道重塑与磷脂酰肌醇 3激酶/蛋白激酶B(PI3K/PKB)通路联系紧密。气道重塑与支气管气道平滑肌细胞的增殖和凋亡密切相关。PI3K/PKB信号通路作为细胞内一条重要的信号传导通路,起到抑制细胞凋亡、促进细胞周期的进展,介导细胞增殖等作用,因而可以结合气道重塑与PI3K/PKB通路对支气管哮喘的发病和治疗进行探讨和研究。该研究现对支气管哮喘、气道重塑、PI3K/PKB通路的研究进展进行了综述,以期为支气管哮喘的治疗提供借鉴。     

ROS-dependent inhibition of the PI3K/Akt/mTOR signaling is required for Oroxylin A to exert anti-inflammatory activity in liver fibrosis

More and more evidence showed that autophagy is an inflammation-related defense mechanism against a variety of diseases including liver fibrosis. However, the essential mechanisms remain poorly understood. In this study, we sought to elucidate the impact of Oroxylin A on autophagy and further to identify the potential mechanism of its anti-inflammatory activity. We found that Oroxylin A played a critical role in controlling inflammation in murine liver fibrosis. Moreover, Oroxylin A could inhibit the secretion of pro-inflammatory cytokines in activated hepatic stellate cell (HSCs). We previously reported that Oroxylin A can induce autophagy to alleviate the pathological changes of liver fibrosis and the activation of HSC. Here we further revealed that the inhibition of the PI3K/Akt/mTOR signaling was required for Oroxylin A to induce autophagy activation, which may be the underlying mechanism of the anti-inflammatory activity of Oroxylin A. Interestingly, mTOR overexpression completely impaired the Oroxylin A-mediated autophagy activation, and in turn, damaged the anti-inflammatory activity. Importantly, Oroxylin A inhibited PI3K/Akt/mTOR signaling by scavenging reactive oxygen species (ROS). ROS accumulation by buthionine sulfoximine (BSO) could abrogate the Oroxylin A-mediated ROS elimination, the inhibition of PI3K/Akt/mTOR signaling, and anti-inflammatory activities. Overall, our results provided reliable evidence for the molecular mechanism of Oroxylin A-mediated anti-fibrosis activity, and also identified a new target for drug therapy of liver fibrosis.     

Targeting the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling network in cancer stem cells

Cancer stem cells (CSCs) comprise a subset of hierarchically organized, rare cancer cells with the ability to initiate cancer in xenografts of genetically modified murine models. CSCs are thought to be responsible for tumor onset, self-renewal/maintenance, mutation accumulation, and metastasis. The existence of CSCs could explain the high frequency of neoplasia relapse and resistance to all of currently available therapies, including chemotherapy. The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway is a key regulator of physiological cell processes which include proliferation, differentiation, apoptosis, motility, metabolism, and autophagy. Nevertheless, aberrantly upregulated PI3K/Akt/mTOR signaling characterizes many types of cancers where it negatively influences prognosis. Several lines of evidence indicate that this signaling system plays a key role also in CSC biology. Of note, CSCs are more sensitive to pathway inhibition with small molecules when compared to healthy stem cells. This observation provides the proof-of-principle that functional differences in signaling transduction pathways between CSCs and healthy stem cells can be identified. Here, we review the evidence which links the signals deriving from the PI3K/Akt/mTOR network with CSC biology, both in hematological and solid tumors. We then highlight how therapeutic targeting of PI3K/Akt/mTOR signaling with small molecule inhibitors could improve cancer patient outcome, by eliminating CSCs.     

国家“重大新药创制”科技重大专项重点关注靶点分析解读——PI3K-Akt-mTOR通路

由磷脂酰肌醇3-激酶（PI3K）、丝氨酸/苏氨酸蛋白激酶（Akt）和哺乳动物雷帕霉素靶蛋白（mTOR）组成的PI3K-Akt-mTOR通路是细胞内非常重要的信号转导途径,该通路的紊乱会引起一系列的疾病,包括癌症、神经病变、自身免疫性疾病和血液淋巴系统疾病。近年来,PI3K-Akt-mTOR通路作为药物靶点备受关注。结合汤森路透数据库资源——Thomson Reuters Integrity和Cortellis for Competitive Intelligence,对PI3K-Akt-mTOR通路的机制、相关药物研究进展、适应证、研发公司、交易、专利、文献等情报进行了数据层面的分析。     

Inhibition of PI3K/Akt signaling: an emerging paradigm for targeted cancer therapy

The phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B, PKB) signaling pathway plays a critical role in cell growth and survival. Dysregulation of this pathway has been found in a variety of cancer cells. Recently, constitutively active PI3K/Akt signaling has been firmly established as a major determinant for cell growth and survival in an array of cancers. Blocking the constitutively active PI3K/AKT signaling pathway provides a new strategy for targeted cancer therapy. Thus, inhibitors of this signaling pathway would be potential anticancer agents, particularly for cancer cells whose survival and growth are dominated by constitutively active PI3K/Akt signaling. This review describes the current understanding of small molecule drugs targeting this pathway both in vitro and in vivo. Inhibitors and functions of the upstream and downstream molecular targets of the PI3K/Akt pathway are discussed in the context of using the inhibitors to block this pathway for targeted cancer therapy. Special emphasis is placed on the following targets: receptor tyrosine kinases, PI3K, Akt, and the mammalian target of rapamycin. While the molecular therapeutic strategy holds great promise for the treatment of a variety of cancers, few small molecule inhibitors with potential high therapeutic indexes are available. Thus, new inhibitors with high selectivity, bioavailability, and potency are greatly needed. Novel approaches toward the development of PI3K/Akt pathway inhibitors as anticancer therapeutics are discussed in detail, with emphasis on chemical genetics-based and structure-based drug design.