PI3K/AKT/mTOR信号通路参与脊髓损伤后神经元自噬的研究进展

PI3K/AKT/mTOR信号通路是脊髓损伤后的一条经典的自噬途径,脊髓损伤后导致的神经元细胞凋亡、轴 突脱髓鞘和炎症反应等受 PI3K/AKT/mTOR 信号通路的调控,并和神经元自噬相关。介绍脊髓损伤后 PI3K/AKT/ mTOR信号通路在神经元自噬过程中的主要作用,为进一步研究脊髓损伤提供参考。     

PI3K/AKT/mTOR介导自噬在卵巢癌治疗中的研究进展

卵巢癌是妇科常见恶性肿瘤,死亡率居女性生殖系统恶性肿瘤的首位,确诊多属晚期,手术辅以化疗仍是目前的主要治疗手段.但化疗存在严重的不良反应,预后欠佳.卵巢癌发生、发展中磷脂酰肌醇3-激酶(PI3K)/蛋白激酶B(AKT)/哺乳动物西罗莫司靶蛋白(mTOR)信号通路异常激活,抑制PI3K/AKT/mTOR信号通路可提高自噬...     

雷公藤红素通过PI3K/AKT/mTOR信号通路对胃癌MFC细胞增殖和凋亡的影响

目的研究雷公藤红素对胃癌MFC细胞内PI3K/AKT/mTOR信号通路的影响及其对胃癌MFC细胞增殖的抑制和促凋亡作用机制。方法分别设置对照组和雷公藤红素低、中、高剂量(5、10、20 mmol/L)组,采用MTT法检测雷公藤红素对胃癌MFC细胞增殖的影响;采用流式细胞技术检测雷公藤红素对胃癌MFC细胞周期的影响及MFC细胞凋亡的情况;Western blotting检测雷公藤红素对胃癌MFC细胞内凋亡相关蛋白Bax、Bcl-2和PI3K、AKT和mTOR蛋白表达的影响;实时定量PCR检测雷公藤红素对胃癌MFC细胞内PI3K、AKT和mTORm RNA表达的影响。结果与对照组比较,雷公藤红素能够呈剂量相关性地显著抑制胃癌MFC细胞的增殖(P0.05);与对照组比较,雷公藤红素能够呈剂量相关性地显著引起MFC细胞G2/M期阻滞(P0.05);与对照组比较,雷公藤红素能够呈剂量相关性地显著促进MFC细胞的凋亡(P0.05);与对照组比较,雷公藤红素能够呈剂量相关性地显著抑制MFC细胞内抗凋亡蛋白Bcl-2蛋白和PI3K、AKT、mTOR蛋白的表达(P0.05),显著促进MFC细胞内促凋亡蛋白Bax的表达(P0.05);与对照组比较,雷公藤红素能够呈剂量相关性地显著抑制MFC细胞内PI3K、AKT和mTORm RNA的表达(P0.05)。结论雷公藤红素能够抑制胃癌MFC细胞的增殖并促进胃癌MFC细胞凋亡,其作用机制可能是通过抑制胃癌MFC细胞内PI3K/AKT/mTOR信号通路中PI3K、AKT、mTOR等蛋白的表达而抑制胃癌MFC细胞的增殖,进而促进胃癌MFC细胞内促凋亡蛋白Bax的表达,同时抑制抗凋亡蛋白Bcl-2的表达,从而促进胃癌MFC细胞凋亡。     

PI3K/Akt/mTOR信号通路与结直肠恶性肿瘤

结直肠癌(colorectal cancer,CRC)是世界大多数地区最常见的恶性肿瘤之一。它的发展是一个多步骤过程,以改变正常细胞的分子信号为启动点,促进细胞发展,最终产生一种表型改变的恶性转化细胞。已有报道指出磷脂酰肌醇3-激酶/蛋白激酶B/哺乳动物雷帕霉素靶蛋白[phosphatidylinositol-3-kinase(PI3K)/protein kinase B(Akt)/the mammalian target of Rapamycin(mTOR),PI3K/Akt/mTOR]信号通路与结直肠恶性肿瘤产生有紧密的联系。也有报道证明约60%~70%的结直肠癌患者存在Akt信号的活化及PTEN的表达受损,进而说明PI3K/Akt/mTOR信号通路抑制药可以作为恶性肿瘤治疗的潜在靶点。近年来,PI3K/Akt/mTOR信号通路受到越来越多的关注,在不同的实验模型中利用针对这条通路的天然及合成药物来降低恶性肿瘤负荷。将近年来PI3K/Akt/mTOR信号通路在结直肠恶性肿瘤中的研究做一综述,并就今后结直肠恶性肿瘤中该通路可能的研究方向进行展望。     

PI3K/Akt/mTOR信号传导通路与前列腺癌关系的研究进展

前列腺癌是威胁中老年男性健康的常见肿瘤,成为男性癌症死因的第二位。 PI3K/Akt/mTOR信号通路能够通过维持细胞生存、抑制细胞凋亡、促进细胞周期运行及血管生成等促进前列腺癌病程发展。本文综合国内外文献,阐述PI3K/Akt/mTOR信号通路在前列腺癌发生发展中的作用以及和通路相关的药物治疗进展。     

高糖激活PI3K/AKT/mTORC1通路诱导人肾小管上皮细胞骨桥蛋白的表达

目的探讨高糖刺激上调人肾小管上皮细胞株(HK-2)骨桥蛋白(OPN)表达的分子机制。方法利用高糖(25mmol·L-1)刺激HK-2细胞,并应用特异性抑制剂、siRNA抑制PI3K和(或)mTOR活性,应用Real-time PCR检测OPN mRNA表达;Western blot检测OPN、p-AKT、p-S6、Raptor和Rictor蛋白表达。结果高糖刺激呈时间依赖性上调HK-2细胞OPN表达,其中,OPN mRNA在刺激48h后达高峰;OPN蛋白表达在72h达到最高。此外,高糖刺激激活PI3K/AKT/mTORC1信号通路。利用PI3K特异性抑制剂LY294002、mTORC1特异性抑制剂rapamycin抑制PI3K/AKT/mTOR通路后,HK-2细胞的OPN表达明显降低。进一步,siRNA敲低Raptor降低HK-2细胞中OPN蛋白的表达,而敲低Rictor对OPN蛋白表达无影响。结论高糖通过激活PI3K/AKT/mTORC1通路上调HK-2细胞OPN的表达。     

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/mTOR信号通路与肿瘤

在近年来的肿瘤治疗中,靶向生物治疗逐渐成为研究的热点。该文就磷脂酰肌醇3-激酶/蛋白激酶B/哺乳动物雷帕霉素靶蛋白[phosphatidylinositol-3-kinase(PI3K)/protein kinase B(Akt)/the mammalian target of Rapamycin(mTOR),PI3K/Akt/mTOR]信号通路予以综述,重点包括PI3K/Akt/mTOR信号转导在肿瘤机制中作用以及肿瘤治疗过程中耐药性方面的关系等。     

PI3K/AKT/mTOR信号通路参与自身免疫性

自身免疫性疾病（autoimmune disease，AD）是机体因自身抗原免疫耐受障碍而对自身抗原产生免疫反应，从而引起机体组织损伤的一类疾病。近年研究发现，磷脂酰肌醇-3-激酶/蛋白激酶B/雷帕霉素靶蛋白（phosphatidylin ositol 3-kinase/protein kinase B/mechanistic target of rapamycin kinase，PI3K/AKT/mTOR）信号通路与AD发病密切相关，其主要参与免疫细胞增殖分化、炎性细胞因子分泌、自噬及氧化应激等过程。本文重点概述PI3K/AKT/mTOR信号通路参与AD发病机理的研究进展。     

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。     

Total saponins isolated from Radix et Rhizoma Leonticis suppresses tumor cells growth by regulation of PI3K/Akt/mTOR and p38 MAPK pathways

Both PI3K/AKT/mTOR and mitogen activated protein kinase (MAPK) signaling cascades played an important role in tumorigenesis, a more complete understanding of these signaling pathways allowed the development of new therapeutic strategies. Total saponins isolated from Radix et Rhizoma Leonticis (RLTS) was recognized with anticancer properties. In a murine hepatocellular carcinoma H22 cell-bearing mouse model, RLTS exhibited significant inhibitory effect on tumor growth. Here, we investigated the role of RLTS on the PI3K/AKT/mTOR signaling pathway and MAPK pathways in liver and lung cancer cells. Results obtained showed RLTS inhibited cell proliferation and induced cell apoptosis in vitro, which attributed to the inhibition on the activation of PI3K/AKT/mTOR cascade and its related signaling molecules, such as activated VEGFR and NF-κB, and activation of p38 MAPK in tumor cells. Additional, RLTS inhibited cell migration and downregulated proteins that mediated metastasis including CXCR4, MMP2 and MMP9. Overall, these findings suggested that RLTS interfered with multiple signaling cascades involved in tumorigenesis and had potential in cancer therapy.     

Dual inhibitors of PI3K/mTOR or mTOR-selective inhibitors: which way shall we go?

The phosphatidylinositol-3-kinase (PI3K)/AKT/mTOR signaling pathway is a central regulator in cell proliferation, growth, and angiogenesis. Inhibition of this pathway therefore is a major strategy for cancer chemotherapy. In order to induce the maximal therapeutic outcome in cancer treatment, vertical inhibition of the PI3K/AKT/mTOR pathway or horizontal inhibition of PI3K/AKT/mTOR and other kinases has been reported. In this review, we discuss the drug design and clinical development of dual inhibitors of PI3K and mTOR as well as the mTOR-selective inhibitors, classified based on the mechanism of action and the chemical structures. Structural determinants for increasing selectivity toward PI3Kα or mTOR are revealed from the structure-activity relationship of the reported inhibitors. Current clinical development in combination therapy of inhibitors involving in the PI3K/AKT/mTOR pathway is also discussed.     

Targeting the PI3K/AKT/mTOR signaling network in acute myelogenous leukemia

Background: The PI3K/Akt/mammalian target of rapamycin (mTOR) signaling pathway plays a central role in cell growth, proliferation and survival not only under physiological conditions but also in a variety of tumor cells. Therefore, the PI3K/Akt/mTOR axis may be a critical target for cancer therapy. Objective: This review discusses how PI3K/Akt/mTOR signaling network is constitutively active in acute myelogenous leukemia (AML), where it strongly influences proliferation, survival and drug-resistance of leukemic cells, and how effective targeting of this pathway with pharmacological inhibitors, used alone or in combination with existing drugs, may result in suppression of leukemic cell growth, including leukemic stem cells. Methods: We searched the literature for articles dealing with activation of this pathway in AML and highlighting the efficacy of small molecules directed against the PI3K/Akt/mTOR signaling cascade. Conclusions: The limit of acceptable toxicity for standard chemotherapy has been reached in AML. Therefore, new therapeutic strategies are needed. Targeting the PI3K/Akt/mTOR signaling network with small molecule inhibitors, alone or in combinations with other drugs, may result in less toxic and more efficacious treatment of AML patients. Efforts to exploit selective inhibitors of the PI3K/Akt/mTOR pathway that show effectiveness and safety in the clinical setting are currently underway.     

PI3K/AKT/mTOR信号通路抑制剂在宫颈癌治疗中的研究进展

宫颈癌是女性常见恶性肿瘤之一。针对局部晚期及复发转移的宫颈癌患者尚未有令人满意的治疗手段,因此探索和发展更有效的治疗方案具有重要的意义。PI3K/AKT/m TOR信号通路在人类子宫颈癌细胞的增殖、分化和凋亡中具有重要的调节作用,有希望成为开发宫颈癌治疗药物的新型靶标。综述了近年来PI3K/AKT/m TOR信号通路的单一及双重靶点抑制剂针对宫颈癌的临床前及临床研究情况,包括PI3K抑制剂(wortmannin、LY294002、吲哚-3-甲醇)、AKT抑制剂(SC-66、MK-2206、木黄酮、冬凌草甲素和雷公藤)、m TOR抑制剂(替西罗莫司和依维莫司)及双重靶点抑制剂(GSK2126458、BEZ235、BGT226、PF04691502、GDC-0980和PKI-587)等。     

Sinomenine ester derivative inhibits glioblastoma by inducing mitochondria-dependent apoptosis and autophagy by PI3K/AKT/mTOR and AMPK/mTOR pathway

Glioblastoma multiforme (GBM) in the central nervous system is the most lethal advanced glioma and currently there is no effective treatment for it. Studies of sinomenine, an alkaloid from the Chinese medicinal plant, Sinomenium acutum, showed that it had inhibitory effects on several kinds of cancer. Here, we synthesized a sinomenine derivative, sino-wcj-33 (SW33), tested it for antitumor activity on GBM and explored the underlying mechanism. SW33 significantly inhibited proliferation and colony formation of GBM and reduced migration and invasion of U87 and U251 cells. It also arrested the cell cycle at G2/M phase and induced mitochondria-dependent apoptosis. Differential gene enrichment analysis and pathway validation showed that SW33 exerted anti-GBM effects by regulating PI3K/AKT and AMPK signaling pathways and significantly suppressed tumorigenicity with no obvious adverse effects on the body. SW33 also induced autophagy through the PI3K/AKT/mTOR and AMPK/mTOR pathways. Thus, SW33 appears to be a promising drug for treating GBM effectively and safely.     

PI3K/AKT/mTOR信号通路抑制剂在卵巢癌治疗中的研究进展

卵巢癌是女性生殖系统最致命的恶性肿瘤。目前,针对卵巢癌的规范治疗方案是肿瘤细胞减灭术辅以紫杉醇/铂类联合化疗,然而大多数晚期卵巢癌患者最终因对化疗药物耐药而复发。PI3K/AKT/m TOR信号通路作为一条重要的原癌基因通路,在卵巢癌中激活并在卵巢癌的增殖、侵袭、细胞周期进程、血管形成及耐药中发挥着重要的作用,抑制该通路是卵巢癌的一个潜在治疗方法。对PI3K/AKT/m TOR信号通路抑制剂在卵巢癌治疗中的研究进展进行综述。