Journal
REDOX BIOLOGY
Volume 20, Issue -, Pages 157-166Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.redox.2018.09.019
Keywords
gamma-glutamylcysteine; Sepsis; Glutathione; N-acetyl-L-eysteine; Glutathione synthetase
Categories
Funding
- National Natural Science Foundation of China [31571166, 81602733, 81711703]
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available