线粒体蛋白VDAC1或可作为IBD的治疗靶点
创作:一只赵崽儿呀 审核:aluba 07月07日
  • CD患者、UC患者与DSS诱导结肠炎小鼠的结肠VDAC1表达增加,VDAC1调控代谢、脂质转运、细胞凋亡和炎症小体激活;
  • VDAC1互作分子VBIT-12可抑制DSS诱导的结肠细胞的VDAC1过表达、VDAC1寡聚化和细胞凋亡,并可缓解DSS诱导的小鼠结肠炎症状;
  • VBIT-12通过抑制炎症细胞浸润、细胞凋亡、线粒体DNA释放及caspase-1与NRLP3炎症小体的激活以缓解炎症;
  • VBIT-12抑制DSS诱导的ATP门控P2X7-Ca2+/K+通道和ER-IP3R-Ca2+通道及线粒体抗病毒蛋白的增加。
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近期研究表明,线粒体功能障碍可能驱动IBD——包括溃疡性结肠炎(UC)及克罗恩病(CD)。电压依赖性阴离子通道1(VDAC1)是一种线粒体蛋白。Molecular Therapy上发表的一项最新研究,发现UC患者、CD患者及DSS诱导的结肠炎小鼠模型的结肠VDAC1表达上调,而VBIT-12(近期鉴定出的VDAC1互作分子)可抑制结肠细胞的凋亡、VDAC1过表达及寡聚化,并减少炎症细胞浸润、线粒体DNA释放及NLRP3炎性小体活化,从而缓解DSS诱导的小鼠结肠炎。该研究结果提示,靶向VDAC1或是IBD的潜在治疗策略。
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Molecular Therapy [IF:11.454]

The role of the mitochondrial protein VDAC1 in inflammatory bowel disease: a potential therapeutic target

线粒体蛋白VDAC1在IBD中的作用:潜在的治疗靶点

10.1016/j.ymthe.2021.06.024

07-01, Article

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Recent studies have implicated mitochondrial dysfunction as a trigger of inflammatory bowel diseases, including Crohn's disease (CD) and ulcerative colitis (UC). We have investigated the role of the mitochondria gate-keeper protein, the voltage-dependent-anion channel 1 (VDAC1) in gastrointestinal inflammation and tested the effects of the newly developed VDAC1-interacting molecules, VBIT-4 and VBIT-12, on UC induced by dextran-sulfate-sodium (DSS) or trinitrobenzene sulphonic acid (TNBS) in mice. VDAC1, which controls metabolism, lipids transport, apoptosis, and inflammasome activation, is overexpressed in the colon of CD and UC patients and DSS-treated mice. VBIT-12 treatment of cultured colon cells inhibited the DSS-induced VDAC1 overexpression, oligomerization, and apoptosis. In the DSS-treated mice, VBIT-12 suppressed weight loss, diarrhea, rectal bleeding, pro-inflammatory cytokine production, crypt and epithelial cell damage, and focal inflammation. VBIT-12 also inhibited the infiltration of inflammatory cells, apoptosis, mtDNA release, and activation of caspase-1 and NRLP3 inflammasome to reduce the inflammatory response. The levels of the ATP-gated P2X7-Ca2+/K+ channel and ER-IP3R-Ca2+ channel, and of the mitochondrial anti-viral protein (MAVS), mediating NLRP3 inflammasome assembly and activation, were highly increased in DSS-treated mice, but not when VBIT-12 treated. We conclude that UC may be promoted by VDAC1-overexpression and may therefore be amenable to treatment with novel VDAC1-interacting molecules. This VDAC1-based strategy exploits a completely new target for UC treatment, and opens a new avenue for treating other inflammatory/autoimmune diseases.

First Authors:
Ankit Verma,Srinivas Pittala

Correspondence Authors:
Varda Shoshan-Barmatz

All Authors:
Ankit Verma,Srinivas Pittala,Belal Alhozeel,Anna Shteinfer-Kuzmine,Ehud Ohana,Rajeev Gupta,Jay H Chung,Varda Shoshan-Barmatz

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