Flavaglines Ameliorate Experimental Colitis and Protect Against Intestinal Epithelial Cell Apoptosis and Mitochondrial Dysfunction.
Flavaglines Ameliorate Experimental Colitis and Protect Against Intestinal Epithelial Cell Apoptosis and Mitochondrial Dysfunction.
复制标题
DOI：
10.1097/mib.0000000000000592
复制
发表时间：
2016-01
影响因子：
4.9
通讯作者：
Theiss AL
中科院分区：
文献类型：
--
作者：
Han J;Zhao Q;Basmadjian C;Désaubry L;Theiss AL
黄连素是一类天然化合物，对神经元和心肌细胞具有抗炎和细胞保护作用。黄伐他林以抑制素为配体，这是调节线粒体功能、细胞生存和转录的支架蛋白。这项研究测试了黄素类药物促进肠上皮细胞动态平衡和预防实验性结肠炎的治疗潜力，在实验性结肠炎模型中，炎症是由上皮溃疡驱动的。观察两种细胞株在单独和联合应用促炎症细胞因子肿瘤坏死因子α和干扰素γ时的存活率和细胞内环境的变化。在葡聚糖硫酸钠诱导的结肠炎模型中，野生型小鼠每天1次，连续4d，腹腔注射Fl3 0.1 mg/kg或赋形剂，观察Fl3的体内抗炎作用。Fl3和Fl37可增加基础Caco 2-BBE和IEC-6细胞存活率，减少细胞凋亡率，降低上皮单层通透性。Fl3和Fl37可抑制肿瘤坏死因子α和干扰素γ诱导的核因子kappaB和cox2的表达、细胞凋亡和通透性增加。Fl3和Fl37通过保护呼吸链复合体I的活性和抑制蛋白的表达，对肿瘤坏死因子α诱导的线粒体超氧化物歧化具有保护作用。P38-MAPK的激活对于Fl3和Fl37在肿瘤坏死因子α处理过程中对屏障通透性和线粒体衍生的活性氧产生的保护作用是必不可少的。在葡聚糖硫酸钠结肠炎期间注射FL3的小鼠表现出结肠抑制素表达增加和p38-MAPK激活，屏障功能保留，炎症较少。这些结果表明，黄烷素具有治疗结肠炎的潜力，并保护肠上皮细胞存活、线粒体功能和屏障完整性。
Flavaglines are a family of natural compounds shown to have anti-inflammatory and cytoprotective effects in neurons and cardiomyocytes. Flavaglines target prohibitins as ligands, which are scaffold proteins that regulate mitochondrial function, cell survival, and transcription. This study tested the therapeutic potential of flavaglines to promote intestinal epithelial cell homeostasis and to protect against a model of experimental colitis in which inflammation is driven by epithelial ulceration. Survival and homeostasis of Caco2-BBE and IEC-6 intestinal epithelial cell lines were measured during treatment with the flavaglines FL3 or FL37 alone and in combination with the proinflammatory cytokines tumor necrosis factor (TNF) α and interferon γ. Wild-type mice were intraperitoneally injected with 0.1 mg/kg FL3 or vehicle once daily for 4 days during dextran sodium sulfate–induced colitis to test the in vivo anti-inflammatory effect of FL3. FL3 and FL37 increased basal Caco2-BBE and IEC-6 cell viability, decreased apoptosis, and decreased epithelial monolayer permeability. FL3 and FL37 inhibited TNFα- and interferon γ–induced nuclear factor kappa B and Cox2 expression, apoptosis, and increased permeability in Caco2-BBE cells. FL3 and FL37 protected against TNFα-induced mitochondrial superoxide generation by preserving respiratory chain complex I activity and prohibitin expression. p38-MAPK activation was essential for the protective effect of FL3 and FL37 on barrier permeability and mitochondrial-derived reactive oxygen species production during TNFα treatment. Mice administered FL3 during dextran sodium sulfate colitis exhibited increased colonic prohibitin expression and p38-MAPK activation, preserved barrier function, and less inflammation. These results suggest that flavaglines exhibit therapeutic potential against colitis and preserve intestinal epithelial cell survival, mitochondrial function, and barrier integrity.