气道重塑与PI3K/PKB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。本文综述了支气管哮喘、气道重塑、PI3K/PKB通路的研究进展。     

PI3K/Akt信号通路调控哮喘气道黏液高分泌的研究现状

哮喘是气道炎症性疾病,气道黏膜炎症微环境促使杯状细胞化生而引起黏液高分泌,富含炎症介质的黏液滞留在气道进一步加重气道炎症、诱发高反应性并促使气道重塑;重症哮喘黏液栓阻塞气道引起窒息、甚至猝死。磷酯酰激醇3-激酶(PI3K)/丝氨酸苏氨酸蛋白激酶(Akt)信号通路与下游靶点或细胞相互作用而参与哮喘气道黏液高分泌。本文在阐述PI3K/Akt信号通路与哮喘气道黏液高分泌的基础上,重点综述PI3K/Akt信号通路通过调控炎症细胞、核因子-κB(NF-κB)、Toll样受体(TLRs)以及丝裂原活化蛋白激酶(MAPKs)而参与哮喘气道黏液高分泌的研究现状,为哮喘气道黏液高分泌的实验研究与新药开发提供理论依据。     

磷酸肌醇-3激酶/蛋白激酶B信号转导通路对消化系统的影响

磷酸肌醇-3激酶( phosphatidylinositol 3 kinase,PI3K)是生长因子超家族信号传导过程中的重要分子,可调节多种细胞功能,并在炎症、肿瘤和心血管疾病的发病机制中起重要作用.PI3K及其下游分子蛋白激酶B(AKT,PKB)所组成的信号通路参与增殖、凋亡等多种细胞功能的调节.近年PI3K/AKT信号通路在慢性炎症和肠道免疫中的研究日益增多[1-2],现将PI3 K/AKT信号通路在消化系统疾病发病机制中研究的新进展作一综述.     

PI3K/Akt信号通路与肝纤维化

PI3K/Akt信号通路为细胞内重要信号传导通路之一,在促进细胞增殖、抑制凋亡的过程中发挥重要作用。PI3K/Akt信号通路与肝纤维化的发生、发展密切相关。通过干预PI3K/Akt信号通路,研究肝纤维化的发病机制和药物治疗是有意义的途径。该文就PI3K/Akt信号通路的构成、转导途径及其在肝纤维化中的作用作一综述。     

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。     

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.     

甘精胰岛素抗胰岛β细胞脂性凋亡的信号转导通路

目的研究甘精胰岛素(glargine)是否通过胰岛素特有的信号途径(磷脂酰肌醇3激酶—蛋白激酶B通路,PI3K-PKB/Akt)激活核因子κB(NF-κB),揭示其完整的抗胰岛β细胞凋亡途径,寻找保护β细胞药物靶点。方法Western blot检测glargine和普通胰岛素(RI)抗β细胞脂性凋亡时PKB/Akt活性的变化,以及PI3K抑制剂wortmmanin对NF-κB活性的影响;流式细胞仪测定wortmmanin对glargine和RI抗凋亡作用的影响。结果Glargine或者RI增加PKB/Akt活性,PI3K抑制剂wortmmanin可阻断它们的抗凋亡作用,从而证实glargine和RI的抗凋亡作用通过PI3K-PKB/Akt途径;wortmmanin可阻断glargine和RI诱导的NF-κB激活,证明它们抗脂性凋亡时PI3K-PKB/Akt通路处于NF-κB的上游。结论glargine和RI激活PI3K-PKB/Akt通路导致NF-κB途径激活,从而发挥抗凋亡作用。     

上皮间质转化与哮喘气道重塑的研究进展

支气管哮喘是一类以气道重塑为病理基础的呼吸道疾病,反复的炎性浸润与组织损伤修复可导致气道重塑,目前有关气道重塑形成的机制尚不全面。研究表明,上皮间质转化在气道重塑的发生和发展过程中发挥重要作用。气道上皮可通过分泌多种因子及信号通路诱发间质转化,进而导致哮喘气道重塑。该文对上皮间质转化与哮喘气道重塑之间的研究进行综述,为临床后续哮喘治疗和研究提供参考。     

中医药调控PI3K/AKT信号通路防治慢性心力衰竭研究状况

慢性心力衰竭(CHF)是各种心血管疾病的终末期表现,是各种心脏结构或功能疾病所造成的心室充盈和(或)射血分数受损的一组综合征。该病的发病机制复杂多样,大多与细胞凋亡的活性增强有关。磷酸肌醇-3激酶/蛋白激酶B(PI3K/AKT)信号通路参与CHF的发生、发展和病理形成。相关研究表明,PI3K/AKT通路是中药治疗CHF的关键靶通路。本文对近年来中药调控PI3K/AKT通路干预CHF的机制和作用进行分析和总结,发现中药提取物、中成药及中药复方均可改善CHF的心肌细胞损伤,其作用机制与细胞凋亡、炎症因子、氧化应激和心室重构密切相关。同时创造性地总结了PI3K/AKT通路在防治CHF中存在的对立性争议,并分析了产生争议原因,以期为CHF的治疗和新药研发提供新思路。     

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。     

Emodin ameliorates ovalbumin-induced airway remodeling in mice by suppressing airway smooth muscle cells proliferation

Increased number of airway smooth muscle cells (ASMCs) is a characteristic of airway remodeling in asthma. In this study we investigated whether emodin alleviated airway remodeling in a murine asthma model and reduced the proliferation of ASMCs in vitro. We provided in vivo evidence suggesting that intraperitoneal injection of emodin (20 mg/kg) 1 h prior to OVA challenge apparently alleviated the thickness of airway smooth muscle, the mass of alpha-smooth muscle actin (α-SMA), collagen deposition, epithelial damage, goblet cell hyperplasia, airway inflammation and airway hyperresponsiveness (AHR) in lung tissue. Meanwhile, we found that emodin suppressed the activation of the Akt pathway in lung tissue of allergic mouse models. Additionally, we found that emodin inhibited cellular proliferation and Akt activation in a dose-dependent manner in vitro. Furthermore, LY294002, an inhibitor for PI3K, abrogated serum-induced phosphorylation of Akt, and decreased the proliferation of ASMCs. These findings indicated that emodin alleviated ASMCs proliferation by inhibiting PI3K/Akt pathway in vivo and in vitro, which may provide a potential therapeutic option for airway smooth muscle remodeling in asthma.     

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) reduces vascular endothelial growth factor expression in allergen-induced airway inflammation

Vascular endothelial growth factor (VEGF) plays a pivotal role in the pathogenesis of bronchial asthma. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) has been implicated in regulating cell survival signaling through the phosphoinositide 3-kinase (PI3K)/Akt pathway. The key role of PI3K in VEGF-mediated signal transduction is established. However, the effects of PTEN on VEGF-mediated signaling in asthma are unknown. This study aimed to determine the effect of PI3K inhibitors and PTEN on VEGF expression in allergen-induced airway inflammation. We have used a female C57BL/6 mouse model for asthma to determine the role of PTEN in allergen-induced airway inflammation, specifically in the expression of VEGF. Allergen-induced airway inflammation leads to increased activity of PI3K in lung tissue. These mice develop the following typical pathophysiological features of asthma in the lungs: increased numbers of inflammatory cells of the airways; airway hyper-responsiveness; increased expression of interleukin (IL)-4, IL-5, IL-13, intercellular adhesion molecule 1, vascular cell adhesion molecule 1, regulated on activation normal T cell expressed and secreted (RANTES), and eotaxin; increased vascular permeability; and increased levels of VEGF. Administration of PI3K inhibitors or adenoviruses carrying PTEN cDNA reduced the symptoms of asthma and decreased the increased levels of plasma extravasation and VEGF in allergen-induced asthmatic lungs. These results indicate that PTEN reduces VEGF expression in allergen-induced airway inflammation.     

Anti-cancer alkyl-lysophospholipids inhibit the phosphatidylinositol 3-kinase-Akt/PKB survival pathway

Synthetic alkyl-lysophospholipids (ALPs) represent a new class of anti-tumor agents that target cell membranes and induce apoptosis. However, the exact mechanisms by which ALPs exert these effects remain unclear. Here, we investigated in the epithelial carcinoma cell lines A431 and HeLa the effect of three clinically relevant ALPs [Et-18-OCH3 (Edelfosine), HePC (Miltefosine) and D-21266 (Perifosine)] on the phosphatidylinositol 3-kinase (PI3K)-Akt/PKB survival pathway. We found that growth factor-induced Akt/PKB activation in these cells is dependent on PI3K and that all three ALPs inhibited this pathway in a dose-dependent manner. We further showed that inhibition of the PI3K-Akt/PKB pathway by wortmannin or ALPs is associated with activation of the pro-apoptotic SAPK/JNK pathway. Inhibition of the PI3K-Akt/PKB survival pathway represents a novel mode of action of ALPs that may significantly contribute to the induction of apoptosis.     

Molecular mechanisms of deguelin-induced apoptosis in transformed human bronchial epithelial cells

Increasing evidence has demonstrated that the phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway plays an important role in cell proliferation, apoptosis, angiogenesis, adhesion, invasion, and migration, functions that are critical to cancer cell survival and metastasis. Increased expression of activated Akt has been observed in the early stages of tobacco-induced lung carcinogenesis. Moreover, blocking the PI3K/Akt pathway specifically inhibits the proliferation of non-small cell lung cancer (NSCLC) cells, indicating that the PI3K/Akt pathway is a potential target for chemoprevention and therapy in lung cancer. The aim of this work is to study the lung cancer chemopreventive potential of PI3K/Akt inhibitors using an in vitro lung carcinogenesis model. We found that genetic or pharmacologic approaches targeting the PI3K/Akt pathway inhibited the proliferation of premalignant and malignant human bronchial epithelial (HBE) cells. After screening several natural products to identify a potential lung cancer chemopreventive agent, we have found that deguelin, a rotenoid isolated from Mundulea sericea (Leguminosae), specifically inhibits the growth of transformed HBE and NSCLC cells by inducing cell-cycle arrest in the G2/M phase and apoptosis, with no detectable toxic effects on normal HBE cells, most likely due to the agent's ability to inhibit PI3K/Akt-mediated signaling pathways. The specific sensitivity of premalignant and malignant HBE and NSCLC cells to deguelin suggests that this drug could be clinically useful for chemoprevention in early-stage lung carcinogenesis and for therapy in confirmed lung cancer.     

Overexpressed Hsp70 alleviated formaldehyde‐induced apoptosis partly via PI3K/Akt signaling pathway in human bronchial epithelial cells

Formaldehyde (FA) is a ubiquitous environmental pollutant, which can induce apoptosis in lung cell and is related to the pathogenesis of asthma, pneumonia, and chronic obstructive pulmonary disease. Heat shock protein 70 (Hsp70) is an ATP‐dependent molecular chaperone and exhibits an anti‐apoptosis ability in a variety of cells. Previous studies reported that the expression of Hsp70 was induced when organisms were exposed to FA. Whether Hsp70 plays a role in the FA‐induced apoptosis and the involved cell signaling pathway remain largely unknown. In this study, human bronchial epithelial cells with overexpressed Hsp70 and the control were exposed to different concentrations of FA (0, 40, 80, and 160 μmol/L) for 24 hours. Apoptosis and the expression levels of PI3K, Akt, p‐Akt, MEK, p‐MEK, and GLI2 were detected by Annexin‐APC/7AAD double‐labeled flow cytometry and western blot. The results showed that overexpression of Hsp70 decreased the apoptosis induced by FA and alleviated the decline of PI3k and p‐Akt significantly. Inhibitor (LY 294002, a specific inhibitor of PI3K‐Akt) test result indicated that PI3K‐Akt signaling pathway was involved in the inhibition of FA‐induced apoptosis by Hsp70 overexpression and also active in the maintenance of GLI2 level. However, it also suggested that other signaling pathways activated by overexpressed Hsp70 participated in this process, which was needed to be elucidated in further research.     

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.     

5-Aza-2′-deoxycytidine inhibited PDGF-induced rat airway smooth muscle cell phenotypic switching

Airway smooth muscle (ASM) cell phenotypic switching played an important role in airway remodeling in asthma. In vitro platelet-derived growth factor (PDGF) induced ASM cell phenotypic switching from a mature to pro-remodeling phenotype, but the mechanism remained incompletely understood. This study was to explore the effect of DNA methyltransferase inhibitor 5-Aza-2′-deoxycytidine (Aza-CdR) on PDGF-induced rat ASM cell phenotypic switching and biological behaviors. Rat airway smooth muscle (RASM) cells were obtained by primary explant techniques. Western blot, 3-dimensional gel contraction, transwell and wound healing assay, and MTT were applied to detect cell phenotypic switching, contractility, migration and proliferation, respectively. Cytoskeleton rearrangement was observed by immunofluorescence. Results showed Aza-CdR inhibited PDGF-induced down-regulation of contractile markers in RASM cells and increased cell contractility. Aza-CdR inhibited PDGF-induced RASM cell migration by abrogating cell morphology change and cytoskeletal reorganization and attenuated the effect of PDGF on proliferating cell nuclear antigen expression and cell cycle progression, ultimately cell proliferation. PDGF-induced DNA methyltransferase 1 (DNMT1) expression was mediated by activation of PI3K/Akt and ERK signaling in RASM cells. Selective depletion of DNMT1 protein by Aza-CdR inhibited PDGF-induced RASM cell phenotypic switching, revealing DNMT1-mediated DNA methylation was implicated in asthmatic ASM remodeling. We proposed for the first time that DNMT1 played a key role in PDGF-induced RASM cell phenotypic switching and Aza-CdR is promising in intervening ASM remodeling in asthma. Although study of abnormal DNA methylation in PDGF-stimulated ASM cells is in its infancy, this work contributes to providing new insights into the mechanism of ASM remodeling and may be helpful for developing effective treatments for airway remodeling in asthma.