多囊卵巢综合征(Polycystic ovary syndrome,PCOS)是一组生殖内分泌代谢紊乱的综合征,临床以稀发排卵、高雄激素体征、胰岛素抵抗为主要特征,其中育龄期发病率高,对女性生育力造成严重不良影响。PCOS的发生发展涉及多种信号通路,腺苷酸...多囊卵巢综合征(Polycystic ovary syndrome,PCOS)是一组生殖内分泌代谢紊乱的综合征,临床以稀发排卵、高雄激素体征、胰岛素抵抗为主要特征,其中育龄期发病率高,对女性生育力造成严重不良影响。PCOS的发生发展涉及多种信号通路,腺苷酸活化蛋白激酶(AMP-activated protein kinase,AMPK)及哺乳动物雷帕霉素靶蛋白(Mammalian target of rapamycin,mTOR)作为细胞能量感受器是其中两个关键靶点。二者在PCOS各个发病部位包括下丘脑-垂体-卵巢轴、子宫内膜、脂肪与骨骼肌中发挥重要的调节作用,通过影响细胞自噬、氧化应激、炎症、线粒体功能、葡萄糖摄取等,促进卵泡的发育和成熟,改善胰岛素抵抗。近年来,中医药因其成分多样、靶点众多等优势广泛应用于临床,研究人员已对PCOS的发病以及中药治疗及改善PCOS的机制进行了大量研究,结果提示AMPK与mTOR相关通路在其中发挥关键作用。通过总结中药干预AMPK与mTOR及其相关通路治疗PCOS的研究结果,为临床治疗及基础研究提供参考。展开更多
Hepatocellular carcinoma(HCC) is one of the leading causes of cancer-related death worldwide. It is associated with a poor prognosis and has limited treatment options. Sorafenib, a multi-targeted kinase inhibitor, is ...Hepatocellular carcinoma(HCC) is one of the leading causes of cancer-related death worldwide. It is associated with a poor prognosis and has limited treatment options. Sorafenib, a multi-targeted kinase inhibitor, is the only available systemic agent for treatment of HCC that improves overall survival for patients with advanced stage disease; unfortunately, an effective second-line agent for the treatment of progressive or sorafenib-resistant HCC has yet to be identified. This review focuses on components of the mammalian target of rapamycin(mTOR) pathway, its role in HCC pathogenesis, and dual mTOR inhibition as a therapeutic option with potential efficacy in advanced HCC. There are several important upstream and downstream signals in the mTOR pathway, and alternative tumor-promoting pathways are known to exist beyond mTORC1 inhibition in HCC. This review analyzes the relationships of the upstream and downstream regulators of mTORC1 and mTORC2 signaling; it also provides a comprehensive global picture of the interaction between mTORC1 and mTORC2 which demonstrates the pre-clinical relevance of the mTOR pathway in HCC pathogenesis and progression. Finally, it provides scientific rationale for dual mTORC1 and mTORC2 inhibition in the treatment of HCC. Clinical trials utilizing mTORC1 inhibitors and dual mTOR inhibitors in HCC are discussed as well. The mTOR pathway is comprised of two main components, mTORC1 and mTORC2; each has a unique role in the pathogenesis and progression of HCC. In phase Ⅲ studies, mTORC1 inhibitors demonstrate anti-tumor ac-tivity in advanced HCC, but dual mTOR(mTORC1 and mTORC2) inhibition has greater therapeutic potential in HCC treatment which warrants further clinical investigation.展开更多
目的:探讨肿瘤微环境中神经元对胶质瘤细胞迁移能力的影响。方法:分离培养胚胎18 d(E18)大鼠神经元,利用表达靶向神经连接蛋白3(NLGN3)分子shRNA的重组慢病毒(Lv-NLGN3-shRNA)感染神经元,real time RT-PCR和酶联免疫吸附试验(ELISA)检测...目的:探讨肿瘤微环境中神经元对胶质瘤细胞迁移能力的影响。方法:分离培养胚胎18 d(E18)大鼠神经元,利用表达靶向神经连接蛋白3(NLGN3)分子shRNA的重组慢病毒(Lv-NLGN3-shRNA)感染神经元,real time RT-PCR和酶联免疫吸附试验(ELISA)检测NLGN3的表达,收集神经元培养上清与胶质瘤细胞系U251细胞共培养,Transwell实验检测U251细胞迁移能力,Western Blot方法检测U251细胞中哺乳动物雷帕霉素靶蛋白(mTOR)和基质金属蛋白酶-9(MMP-9)的表达。结果:Lv-NLGN3-shRNA重组慢病毒感染能够降低大鼠原代神经元中NLGN3 mRNA和蛋白的的表达,神经元培养上清与U251细胞共培养可以增加后者的迁移能力并上调mTOR和MMP-9的表达。然而,NLGN3表达被Lv-NLGN3-shRNA抑制后,培养上清对U251细胞促迁移能力下降,同时mTOR和MMP-9表达降低。结论:大鼠原代神经元可以通过NLGN3/mTOR/MMP-9信号通路增强U251细胞的迁移能力,这一途径可能是胶质瘤细胞转移的机制之一。展开更多
文摘多囊卵巢综合征(Polycystic ovary syndrome,PCOS)是一组生殖内分泌代谢紊乱的综合征,临床以稀发排卵、高雄激素体征、胰岛素抵抗为主要特征,其中育龄期发病率高,对女性生育力造成严重不良影响。PCOS的发生发展涉及多种信号通路,腺苷酸活化蛋白激酶(AMP-activated protein kinase,AMPK)及哺乳动物雷帕霉素靶蛋白(Mammalian target of rapamycin,mTOR)作为细胞能量感受器是其中两个关键靶点。二者在PCOS各个发病部位包括下丘脑-垂体-卵巢轴、子宫内膜、脂肪与骨骼肌中发挥重要的调节作用,通过影响细胞自噬、氧化应激、炎症、线粒体功能、葡萄糖摄取等,促进卵泡的发育和成熟,改善胰岛素抵抗。近年来,中医药因其成分多样、靶点众多等优势广泛应用于临床,研究人员已对PCOS的发病以及中药治疗及改善PCOS的机制进行了大量研究,结果提示AMPK与mTOR相关通路在其中发挥关键作用。通过总结中药干预AMPK与mTOR及其相关通路治疗PCOS的研究结果,为临床治疗及基础研究提供参考。
文摘Hepatocellular carcinoma(HCC) is one of the leading causes of cancer-related death worldwide. It is associated with a poor prognosis and has limited treatment options. Sorafenib, a multi-targeted kinase inhibitor, is the only available systemic agent for treatment of HCC that improves overall survival for patients with advanced stage disease; unfortunately, an effective second-line agent for the treatment of progressive or sorafenib-resistant HCC has yet to be identified. This review focuses on components of the mammalian target of rapamycin(mTOR) pathway, its role in HCC pathogenesis, and dual mTOR inhibition as a therapeutic option with potential efficacy in advanced HCC. There are several important upstream and downstream signals in the mTOR pathway, and alternative tumor-promoting pathways are known to exist beyond mTORC1 inhibition in HCC. This review analyzes the relationships of the upstream and downstream regulators of mTORC1 and mTORC2 signaling; it also provides a comprehensive global picture of the interaction between mTORC1 and mTORC2 which demonstrates the pre-clinical relevance of the mTOR pathway in HCC pathogenesis and progression. Finally, it provides scientific rationale for dual mTORC1 and mTORC2 inhibition in the treatment of HCC. Clinical trials utilizing mTORC1 inhibitors and dual mTOR inhibitors in HCC are discussed as well. The mTOR pathway is comprised of two main components, mTORC1 and mTORC2; each has a unique role in the pathogenesis and progression of HCC. In phase Ⅲ studies, mTORC1 inhibitors demonstrate anti-tumor ac-tivity in advanced HCC, but dual mTOR(mTORC1 and mTORC2) inhibition has greater therapeutic potential in HCC treatment which warrants further clinical investigation.
