水飛薊素藉由調控PI-3 kinase/Akt/mTOR路徑抑制由缺氧引起之血管內皮增生因子之分泌來達到老年黃斑部病變之預防治療

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题名:	水飛薊素藉由調控PI-3 kinase/Akt/mTOR路徑抑制由缺氧引起之血管內皮增生因子之分泌來達到老年黃斑部病變之預防治療 Silibinin inhibits VEGF secretion and age-related macular degeneration in a hypoxia-dependent manner through the PI-3kinase/Akt/mTOR pathway
作者:	林承輝 Lin, Cheng-Hui
关键词:	水飛薊素;老年性黃斑部病變;血管新生作用;缺氧狀態;缺氧性誘導因子;silibinin;AMD;angiogenesis;hypoxia;HIF-1α
日期:	2013-07-11
上传时间:	2018-11-20 09:45:25 (UTC+8)
摘要:	老年性黃斑部病變(age-related macular degeneration, AMD)中，由缺氧環境導致之新生血管作用扮演著十分重要的作用。根據統計，AMD已成為65歲以上之老年人眼睛疾病中主要致盲原因，而治療AMD藥物種類有限，不僅高成本而且也具有副作用，因此開發治療AMD之藥物也成為老年醫學中重要之一環。AMD可分為乾式AMD與濕式AMD，前者成因為代謝性廢棄物堆積在視網膜底部，後者則是因為不正常之血管新生造成。在有關AMD文獻中，很少有相關動物疾病模式或有效治療AMD之方法。因此，我們利用類黃酮(flavonoids)化合物水飛薊素(silibinin)進行由缺氧環境與VEGF誘導所產生類似黃斑部病變動物模式之研究。我們將視網膜色素上皮細胞(RPE cells)暴露在缺氧環境中，並利用西方墨點法來探討RPE細胞中相關蛋白分子表現，結果發現缺氧性誘導因子(HIF-1α)蛋白在低氧濃度下會大量累積。除此之外，我們認為缺氧狀態下HIF-1α蛋白之累積是藉由PI3K/Akt/mTOR路徑活化所造成。在動物實驗中，我們將挪威棕鼠曝露於全身性低氧環境中並利用玻璃體內注射方式注射人工合成VEGF蛋白至挪威棕鼠右眼中，建立了類似濕式AMD動物疾病模式，並且每日口服silibinin 500 mg/kg餵食，與控制組相比發現silibinin的確能減緩由低氧濃度與投與VEGF所產生類似濕式AMD之病徵。綜合以上無論是在體外和體內，silibinin能作為一種預防與治療濕式AMD之候選藥物。 Hypoxia-mediated neovascularization plays an important role in age-related macular degeneration (AMD). There are few animal models or effective treatments for AMD. Here, we investigated the effects of the flavonoid silibinin on hypoxia- and VEGF-induced angiogenesis in a rat AMD model. Retinal pigmented epithelial (RPE) cells were subjected to hypoxia in vitro and the effects of silibinin on activation of key hypoxia-induced pathways were examined by elucidating the hypoxia-inducible factor-1 alpha (HIF-1α) protein level by Western blot. A rat model of AMD was developed by intravitreal injection of VEGF in Brown Norway rats, with or without concomitant exposure of animals to hypoxia. Animals were treated with oral silibinin starting at day 7 post-VEGF injection and AMD changes were followed by fluorescein angiography on days 14 and 28 post-injection. Silibinin pretreatment of RPE cells increased proline hydroxylase-2 expression, inhibited HIF-1α subunit accumulation, and inhibited VEGF secretion. Silibinin-induced HIF-1α and VEGF down-regulation required suppression of hypoxia-induced phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway. In the rat model of AMD, silibinin administration prevented VEGF- and VEGF plus hypoxia-induced retinal oedema and neovascularization. The effects of silibinin, both in vitro and in vivo, support its potential as a therapeutic for the prevention of neovascular AMD.
描述:	博士指導教授-鄭幼文委員-顧記華委員-何昭德委員-王惠珀委員-李美賢委員-黃聰龍委員-蕭哲志
数据类型:	thesis
显示于类别:	[藥學系] 博碩士論文

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