期刊
REDOX BIOLOGY
卷 20, 期 -, 页码 157-166出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.redox.2018.09.019
关键词
gamma-glutamylcysteine; Sepsis; Glutathione; N-acetyl-L-eysteine; Glutathione synthetase
资金
- National Natural Science Foundation of China [31571166, 81602733, 81711703]
Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection and characterized by redox imbalance and severe oxidative stress. Glutathione (GSH) serves several vital functions, including scavenging free radicals and maintaining intracellular redox balance. Extracellular GSH is unable to be taken into the majority of human cells, and the GSH prodrug N-acetyl-L-cysteine (NAC) does not exhibit promising clinical effects. gamma-glutamylcysteine (gamma-GC), an intermediate dipeptide of the GSH-synthesis pathway and harboring anti-inflammatory properties, represents a relatively unexplored option for sepsis treatment. The anti-inflammatory efficiency of gamma-GC and the associated molecular mechanism need to be explored. In vivo investigation showed that gamma-GC reduced sepsis lethality and attenuated systemic inflammatory responses in mice, as well as inhibited lipopolysaccharide (LPS)-stimulated production of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), high-mobility group box 1 (HMGB1), and nitric oxide (NO) and the expression of inducible NO synthase and cyclooxygenase 2 in RAW264.7 cells. Moreover, both in vivo and in vitro experiments demonstrated that gamma-GC exhibited better therapeutic effects against inflammation compared with N-acetyl-L-cysteine (NAC) and GSH. Mechanistically, gamma-GC suppressed LPS-induced reactive oxygen species accumulation and GSH depletion. Inflammatory stimuli, such as LPS treatment, upregulated the expression of glutathione synthetase via activating nuclear factor-erythroid 2-related factor (Nrf2) and nuclear factor kappa B (NF-kappa B) pathways, thereby promoting synthesis of GSH from gamma-GC. These findings suggested that gamma-GC might represent a potential therapeutic agent for sepsis treatment.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据