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| 1 | Chemotherapy-induced intestinal inflammatory responses are mediated by exosome secretion of double-strand DNA via AIM2 inflammasome activation显示文摘化疗经常被知道导致严重的胃肠的道毒性,但是内在的机制仍然保持不清楚。这研究作为一个代表性的代理人认为广泛地应用的细胞毒素的代理人是 irinotecan (CPT-11 ) 并且证明治疗从说明混合物的限制剂量的肠的毒性的肠导致双海滨 DNA 的巨大的版本。明确地,通过 exosome 分泌物释放的 self-DNA 进入天生的有免疫力的房间的 cytosol 并且激活 AIM2 (在黑瘤 2 不在) inflammasome。这导致成熟 IL-1 和 IL-18 分泌物并且导致肠的 mucositis 和迟了发作的腹泻。有趣地,在 AIM2 缺乏的老鼠或由象镇静药那样的一个药理学禁止者,没有影响 CPT-11 的 anticancer 功效, AIM2 发信号的废除显著地减少导致药的腹泻的发生。这些调查结果提供化疗怎么触发引起肠的毒性的天生的有免疫力的回答的机械学的卓见,并且揭示维持反瘤效果,但是围绕联系不利煽动性的反应的新化疗政体。 | Lian, Qiaoshi Xu, Jun Yan, Shanshan Huang, Min Ding, Honghua Sun, Xiaoyu Bi, Aiwei Ding, Jian Sun, Bing Geng, Meiyu | 2017 | Cell Research2017，27，6： | 18 |
| 2 | SLC1A1-mediated cellular and mitochondrial influx of R-2-hydroxyglutarate in vascular endothelial cells promotes tumor angiogenesis in IDH1-mutant solid tumors显示文摘Muta nt isocitrate dehydrog en ase 1(mlDH1)drives tumorigenesis via produci ng on cometabolite R-2-hydroxyglutarate(R-2-HG)across various tumor types.However,mlDHl in hibitors appear only effective in hematological tumors.The therapeutic ben efit in solid tumors remains elusive,likely due to the complex tumor microenvironment.In this study,we discover that R-2-HG produced by IDH1-mutant tumor cells is preferentially imported into vascular endothelial cells and remodels mitochondrial respiration to promote tumor angiogenesis,conferring a therapeutic vulnerability in IDH1-mutant solid tumors.Mechanistically,SLC1 Alz a Na'-depe ndent glutamate tran sporter that is prefere ntially expressed in en dothelial cells,facilitates the in flux of R-2-HG from the tumor microenvironment into the endothelial cells as well as the intracellular trafficking of R-2-HG from cytoplasm to mitochondria.R-2-HG hijacks SLC1A1 to promote mitochondrial Na^(+)/Ca^(2+)exchange,which activates the mitochondrial respiratory chain and fuels vascular en dothelial cell migratio n in tumor an giogenesis.SLC1A1 deficiency in mice abolishes mlDHl-promoted tumor an giogenesis as well as the therapeutic benefit of mlDHl in hibitor in solid tumors.Moreover,we report that HH2301,a newly discovered mlDHl inhibitor,shows promising efficacy in treating IDH1-mutant cholangiocarcinoma in preclinical models.Together,we identify a new role of SLC1A1 as a gatekeeper of R-2-HG-mediated crosstalk between IDH1-mutant tumor cells and vascular en dothelial cells,and dem on strate the therapeutic potential of mlDHl in hibitors in treating IDH1-muta nt solid tumors via disrupting R-2-HG-promoted tumor angiogenesis. | Xiaomin Wang Ziqi Chen Jun Xu Shuai Tang Nan An Lei Jiang Yixiang Zhang Shaoying Zhang Qingli Zhang Yanyan Shen Shijie Chen Xiaojing Lan Ting Wang Linhui Zhai Siyuwei Cao Siqi Guo Yingluo Liu Aiwei Bi Yuehong Chen Xiameng Gai Yichen Duan Ying Zheng Yixian Fu Yize Li Liang Yuan Linjiang Tong Kun Mo Mingcheng Wang Shu-Hai Lin Minjia Tan Cheng Luo Yi Chen Jia Liu Qiansen Zhang Leping Li Min Huang | 2022 | Cell Research2022，32，7： | 2 |
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