S-nitrosothiol signaling regulates liver development and improves outcome following toxic liver injury.
S-nitrosothiol signaling regulates liver development and improves outcome following toxic liver injury.
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DOI：
10.1016/j.celrep.2013.12.007
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发表时间：
2014-01-16
期刊：
影响因子：
8.8
通讯作者：
Goessling W
中科院分区：
文献类型：
--
作者：
Cox AG;Saunders DC;Kelsey PB Jr;Conway AA;Tesmenitsky Y;Marchini JF;Brown KK;Stamler JS;Colagiovanni DB;Rosenthal GJ;Croce KJ;North TE;Goessling W
毒性肝损伤是肝衰竭和死亡的主要原因，因为该器官在大量细胞死亡中无法再生，而且几乎没有治疗选择。协调损害保护和修复的机制知之甚少。在这里，我们表明，S-亚硝基硫醇调节肝脏生长过程中的发展和损伤后在体内：在斑马鱼，NO增强肝脏形成的cGMP介导的血管活性作用无关。对乙酰氨基酚（APAP）暴露后，酶调节剂S-亚硝基谷胱甘肽还原酶（GSNOR）的抑制，通过持续激活细胞保护性Nrf2途径，最大限度地减少了毒性肝损伤，增加了细胞增殖，并提高了生存率。在GSNOR缺陷小鼠中进行的APAP损伤的临床前研究证实了脊椎动物中S-亚硝基硫醇信号传导的肝脏保护特性的保守性; GSNOR特异性抑制剂改善了肝脏组织学，并与批准的治疗N-乙酰半胱氨酸一起作用，以扩大治疗时间窗并改善结果。这些研究表明，GSNOR抑制剂将是治疗肝损伤的有益治疗候选物。
Toxic liver injury is a leading cause of liver failure and death, due to the organ’s inability to regenerate amidst massive cell death, and few therapeutic options exist. The mechanisms coordinating damage protection and repair are poorly understood. Here, we show that S-nitrosothiols regulate liver growth during development and after injury in vivo: in zebrafish, NO enhanced liver formation independent of cGMP-mediated vasoactive effects. Following acetaminophen (APAP) exposure, inhibition of the enzymatic regulator, S-nitrosoglutathione reductase (GSNOR), minimized toxic liver damage, increased cell proliferation, and improved survival through sustained activation of the cytoprotective Nrf2 pathway. Preclinical studies of APAP injury in GSNOR-deficient mice confirmed conservation of hepatoprotective properties of S-nitrosothiol signaling across vertebrates; a GSNOR-specific inhibitor improved liver histology and acted together with the approved therapy N-acetylcysteine, to expand the therapeutic time window and improve outcome. These studies demonstrate that GSNOR inhibitors will be beneficial therapeutic candidates to treat liver injury.
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影响因子：
64.5
作者：
Goessling W;North TE;Loewer S;Lord AM;Lee S;Stoick-Cooper CL;Weidinger G;Puder M;Daley GQ;Moon RT;Zon LI
通讯作者：
Zon LI
影响因子：
3.2
作者：
Kurokawa T;An J;Tsunekawa K;Shimomura Y;Kazama S;Ishikawa N;Nonami T;Sugiyama S
通讯作者：
Sugiyama S
影响因子：
4.1
作者：
Hinson, JA;Pike, SL;Mayeux, PR
通讯作者：
Mayeux, PR
影响因子：
5.3
作者：
Kobayashi, Makoto;Li, Li;Yamamoto, Masayuki
通讯作者：
Yamamoto, Masayuki
DOI：
10.1073/pnas.1113319109
发表时间：
2012-03-13
影响因子：
11.1
作者：
Beigi, Farideh;Gonzalez, Daniel R.;Hare, Joshua M.
通讯作者：
Hare, Joshua M.