Capacity of extracellular globins to reduce liver fibrosis via scavenging reactive oxygen species and promoting MMP-1 secretion.
Capacity of extracellular globins to reduce liver fibrosis via scavenging reactive oxygen species and promoting MMP-1 secretion.
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DOI：
10.1016/j.redox.2022.102286
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发表时间：
2022-06
期刊：
影响因子：
11.4
通讯作者：
Kawada N
中科院分区：
文献类型：
--
作者：
Hieu VN;Thuy LTT;Hai H;Dat NQ;Hoang DV;Hanh NV;Phuong DM;Hoang TH;Sawai H;Shiro Y;Sato-Matsubara M;Oikawa D;Tokunaga F;Yoshizato K;Kawada N
肝星状细胞(HSCs)是肝纤维化的主要细胞类型，是全球医疗保健的重要负担。细胞珠蛋白是一种在造血干细胞中表达的珠蛋白家族成员，它能抑制肝星状细胞的激活，减少胶原的产生。我们研究了珠蛋白家族成员血红蛋白(Hb)、肌红蛋白(MB)和脑红蛋白(NGB)的抗纤维化特性，并与CyGB进行了比较。我们研究了培养的人肝星状细胞(HHSteCs)中的珠蛋白的生物学活性及其对四氯化碳(CCl4)诱导的小鼠肝硬变的影响。在无细胞系统中，所有的珠蛋白都表现出比谷胱甘肽更强的抗氧化能力。细胞分级显示胞外MB、NGB和CyGB的内吞作用，但没有HB；内吞的球蛋白定位于细胞内膜、胞浆和细胞骨架部分。MB、Ngb和Cygb，而不是Hb，清除了HHSteCs自发产生的或由过氧化氢或转化生长因子β1刺激产生的活性氧，并通过抑制COL1A1启动子活性而减少了胶原1A1的产生。二硫键突变体NGB对血红素和超氧化物的清除活性降低，胶原抑制能力降低。MB和NGB处理的HHSteCs的RNA测序显示，细胞外基质编码和纤维化相关基因以及HSC失活标记下调。经MB和NGB处理后，基质金属蛋白酶(MMP1)-1表达上调，MMP1基因下调部分逆转了珠蛋白对胶原蛋白分泌的影响。重要的是，给予MB、NGB和CyGB抑制了CCl4诱导的小鼠肝纤维化。这些发现揭示了MB和NGB在抑制HSCs和抑制肝纤维化发展中意想不到的作用，表明珠蛋白治疗可能是抗击纤维化肝病的一种新策略。通过内吞作用进入人肝星状细胞。清除细胞内的反应性氧化物种。抑制COL1A1启动子活性，促进基质金属蛋白酶-1分泌。抑制四氯化碳诱导的小鼠肝纤维化。肌红蛋白、脑红蛋白和细胞红蛋白，但不包括血红蛋白：
Hepatic stellate cells (HSCs) are the primary cell type in liver fibrosis, a significant global health care burden. Cytoglobin (CYGB), a globin family member expressed in HSCs, inhibits HSC activation and reduces collagen production. We studied the antifibrotic properties of globin family members hemoglobin (HB), myoglobin (MB), and neuroglobin (NGB) in comparison with CYGB. We characterized the biological activities of globins in cultured human HSCs (HHSteCs) and their effects on carbon tetrachloride (CCl4)-induced cirrhosis in mice. All globins demonstrated greater antioxidant capacity than glutathione in cell-free systems. Cellular fractionation revealed endocytosis of extracellular MB, NGB, and CYGB, but not HB; endocytosed globins localized to intracellular membranous, cytoplasmic, and cytoskeletal fractions. MB, NGB, and CYGB, but not HB, scavenged reactive oxygen species generated spontaneously or stimulated by H2O2 or transforming growth factor β1 in HHSteCs and reduced collagen 1A1 production via suppressing COL1A1 promoter activity. Disulfide bond-mutant NGB displayed decreased heme and superoxide scavenging activity and reduced collagen inhibitory capacity. RNA sequencing of MB- and NGB-treated HHSteCs revealed downregulation of extracellular matrix–encoding and fibrosis-related genes and HSC deactivation markers. Upregulation of matrix metalloproteinase (MMP)-1 was observed following MB and NGB treatment, and MMP-1 knockdown partially reversed globin-mediated effects on secreted collagen. Importantly, administration of MB, NGB, and CYGB suppressed CCl4-induced mouse liver fibrosis. These findings revealed unexpected roles for MB and NGB in deactivating HSCs and inhibiting liver fibrosis development, suggesting that globin therapy may represent a new strategy for combating fibrotic liver disease. Internalize into human hepatic stellate cells via endocytosis pathway. Scavenge intracellular reactive oxidative species. Suppress COL1A1 promoter activity and promote matrix metaloproteinase-1 secretion. Suppress carbon tetrachloride-induced mouse liver fibrosis. Myoglobin, neuroglobin, and cytoglobin, but not hemoglobin:
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影响因子：
13.5
作者：
García-Trevijano, ER;Iraburu, MJ;Rojkind, M
通讯作者：
Rojkind, M
影响因子：
5.6
作者：
Schon HT;Bartneck M;Borkham-Kamphorst E;Nattermann J;Lammers T;Tacke F;Weiskirchen R
通讯作者：
Weiskirchen R
DOI：
10.1002/hep.31752
发表时间：
2021-06
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Dat NQ;Thuy LTT;Hieu VN;Hai H;Hoang DV;Thi Thanh Hai N;Thuy TTV;Komiya T;Rombouts K;Dong MP;Hanh NV;Hoang TH;Sato-Matsubara M;Daikoku A;Kadono C;Oikawa D;Yoshizato K;Tokunaga F;Pinzani M;Kawada N
通讯作者：
Kawada N
影响因子：
4.8
作者：
Braganza, Andrea;Quesnelle, Kelly;Shiva, Sruti
通讯作者：
Shiva, Sruti
影响因子：
29.4
作者：
Jiang JX;Venugopal S;Serizawa N;Chen X;Scott F;Li Y;Adamson R;Devaraj S;Shah V;Gershwin ME;Friedman SL;Török NJ
通讯作者：
Török NJ