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標題: 4’,5,7-三羥基黃酮對幽門螺旋桿菌感染胃腺癌細胞發炎之抑制
In vitro anti-inflammatory effect of 4',5,7-Trihydroxyflavone in the Helicobacter pylori-infected gastric adenocarcinoma cells
作者: 黃凱民
Huang, Kai-ming
Contributors: 李敏雄;吳登強;蘇南維
Min-Hsiung Lee;Deng-Chyang Wu;Nan-Wei Su
王苑春
Yuan-Chuen Wang
中興大學
關鍵字: 4',5,7-Trihydroxyflavone;anti-inflammation;Helicobacter pylori;gastric adenocarcinoma cells;immune reaction
4’,5,7-Trihydroxyflavone;抗發炎;幽門螺旋桿菌;胃腺癌細胞;免疫反應
日期: 2012
Issue Date: 2012-09-04 14:45:55 (UTC+8)
Publisher: 食品暨應用生物科技學系所
摘要: 幽門螺旋桿菌於1994被世界衛生組織 (WHO) 列為第一級致癌因子。感染Cag A+幽門螺旋桿菌會造成胃上皮細胞嚴重的發炎,繼而演生成萎縮性胃炎,以致於胃癌及胃腺癌。4’,5,7- trihydroxyflavone為類黃酮化合物,富含於天然蔬果中,尤其是芹菜、香菜及九層塔等,具有抗發炎、抗癌及抗氧化等生理活性。本研究探討活體外 4’,5,7- trihydroxyflavone 對幽門螺旋桿菌感染MKN45胃腺癌細胞之發炎相關因子包括COX-2、IL-6、IL-8、ICAM-1及ROS及其他因子如MUC-2之影響,並提出 4’,5,7- trihydroxyflavone 作用相關之機轉。
研究結果顯示,於20 μg/mL 之作用劑量下,MKN45胃腺癌細胞及幽門螺旋桿菌之存活率分別為 80 %及53 %。在幽門螺旋桿菌感染宿主細胞之NF-κB 途徑中,4’,5,7- trihydroxyflavone 顯著的增加IκBα之表現,於20 μg/mL處理劑量之蛋白質表現為控制組之218%;4’,5,7- trihydroxyflavone亦顯著降低發炎相關因子如 COX-2、IL-6、IL-8、ICAM-1及ROS之表現,10 μg/mL之處理劑量下,IL-8及ICAM-1之生成量分別為控制組之 77 %及69 %;2.5 μg/mL 之處理劑量下,過氧化氫及超氧陰離子之生成量分別為控制組之 40 %及72 %。此外,10 μg/mL 之4’,5,7- trihydroxyflavone亦顯著地增加MUC-2之mRNA及蛋白質表現 (分別為控制組之133 %及184 %)。
在幽門螺旋桿菌感染 MKN45 胃腺癌細胞之模式系統中,4’,5,7- trihydroxyflavone之作用包括:(1) 抑制 NF-κB 路徑之啟動,因此抑制了其下游發炎相關因子如 COX-2、 ICAM-1、IL-8 及 IL-6 等之表現;(2) 消除由 IL-8 刺激嗜中性白血球以及菌體脂多醣誘發產生之高量活性氧物質;(3) 增加黏液素 (mucin) 之產生,以保護宿主細胞避免受到幽門螺旋桿菌之攻擊,以及保護胃黏膜層。本研究結果顯示,4’,5,7- trihydroxyflavone 對幽門螺旋桿菌造成宿主細胞發炎之現象具有高度且多方面的抑制作用,具有開發成為防治胃癌藥物之高度潛力。
Helicobacter pylori has been classified as a group I carcinogen by WHO in 1994. Cag A+ H. pylori infection results in serious gastric epithelial cell inflammation, atrophic gastritis, and then progresses to gastric cancer. 4’,5,7- trihydroxyflavone, one of flavonoids, abounds in fruits and vegetables, especially in basil, cilantro, and parsley. As reported, 4’,5,7-trihydroxyflavone exhibited anti-inflammatory, anti-cancer, and anti-oxidative activities. In this study, we investigated in vitro effect of 4’,5,7- trihydroxyflavone on the H. pylori-induced inflammation, in which the inflammatory factor expressions including COX-2、IL-6、IL-8、ICAM-1 and ROS and other factors such as MUC-2 were examined. The relevant mechanisms of 4’,5,7- trihydroxyflavone are proposed.
In the results, viabilities for MKN45 cells and H. pylori were 88 and 53%, respectively, at 20 μg/mL treatment. H. pylori stimulation initiated the NF-κB pathway, in which the IκBα expression significantly increased at 20 μg/mL of treatment dose (218% of that of the control). 4’,5,7- trihydroxyflavone significantly decreased the inflammatory factor (i.e. COX-2、IL-6、IL-8、ICAM-1 and ROS) expressions, for which, IL-8 and ICAM-1 levels were 77 and 69 %, respectively, of that of the controls at 10 μg/mL treatment as well as 40 and 72% of that of the controls, respectively, for the hydrogen peroxide and superoxide anion production at 2.5 μg/mL treatment. Additionally, 10 μg/mL of 4’,5,7- trihydroxyflavone significantly increased both MUC-2 mRNA and protein expressions (133 and 184% of that of the controls).
In the H. pylori-infected MKN45 gastric adenocarcinoma cell model system, 4’,5,7- trihydroxyflavone showed a critical role in (1) the inhibition of NF-κB activation, thus down-regulating the downstream inflammatory factors such as COX-2, ICAM-1, IL-8 and IL-6; (2) scavenging the high amounts of hydrogen peroxide and superoxide anions induced by neutrophil and H. pylori lipopolysaccharide; (3) the promotion of mucin secretion to protect the host cells against H. pylori attachment. The results suggest that 4’,5,7-trihydroxyflavone may has the high potential applications in the drug discovery on gastric cancer therapy.
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