PMID- 30326393 OWN - NLM STAT- MEDLINE DCOM- 20190401 LR - 20190401 IS - 2213-2317 (Electronic) IS - 2213-2317 (Linking) VI - 20 DP - 2019 Jan TI - gamma-glutamylcysteine exhibits anti-inflammatory effects by increasing cellular glutathione level. PG - 157-166 LID - S2213-2317(18)30836-X [pii] LID - 10.1016/j.redox.2018.09.019 [doi] AB - 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-1beta (IL-1beta), 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-kappaB) pathways, thereby promoting synthesis of GSH from gamma-GC. These findings suggested that gamma-GC might represent a potential therapeutic agent for sepsis treatment. CI - Copyright (c) 2018 The Authors. Published by Elsevier B.V. All rights reserved. FAU - Yang, Yang AU - Yang Y AD - State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, Jiangsu, China; Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, Jiangsu, China; Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, Jiangsu, China. FAU - Li, Ling AU - Li L AD - State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, Jiangsu, China. FAU - Hang, Qiyun AU - Hang Q AD - State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, Jiangsu, China. FAU - Fang, Yuan AU - Fang Y AD - Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, Jiangsu, China; Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, Jiangsu, China. FAU - Dong, Xiaoliang AU - Dong X AD - State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, Jiangsu, China. FAU - Cao, Peng AU - Cao P AD - Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, Jiangsu, China; Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, Jiangsu, China. Electronic address: caopeng@jsatcm.com. FAU - Yin, Zhimin AU - Yin Z AD - Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing 210046, Jiangsu, China. Electronic address: yinzhimin@njnu.edu.cn. FAU - Luo, Lan AU - Luo L AD - State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, Jiangsu, China. Electronic address: lanluo@nju.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180926 PL - Netherlands TA - Redox Biol JT - Redox biology JID - 101605639 RN - 0 (Anti-Inflammatory Agents) RN - 0 (Dipeptides) RN - 0 (Lipopolysaccharides) RN - 0 (NF-E2-Related Factor 2) RN - 0 (NF-kappa B) RN - 0 (Nfe2l2 protein, mouse) RN - 0 (Reactive Oxygen Species) RN - GAN16C9B8O (Glutathione) RN - M984VJS48P (gamma-glutamylcysteine) SB - IM MH - Animals MH - Anti-Inflammatory Agents/*pharmacology MH - Dipeptides/*pharmacology MH - Disease Models, Animal MH - Glutathione/*metabolism MH - Inflammation/etiology/metabolism/mortality/pathology MH - Intracellular Space/drug effects/metabolism MH - Lipopolysaccharides/adverse effects MH - Male MH - Mice MH - Models, Biological MH - NF-E2-Related Factor 2/metabolism MH - NF-kappa B/metabolism MH - Oxidative Stress/drug effects MH - RAW 264.7 Cells MH - Reactive Oxygen Species/metabolism MH - Sepsis/etiology/metabolism/mortality/pathology PMC - PMC6197438 OTO - NOTNLM OT - Glutathione OT - Glutathione synthetase OT - N-acetyl-L-cysteine OT - Sepsis OT - gamma-glutamylcysteine EDAT- 2018/10/17 06:00 MHDA- 2019/04/02 06:00 PMCR- 2018/09/26 CRDT- 2018/10/17 06:00 PHST- 2018/09/10 00:00 [received] PHST- 2018/09/25 00:00 [accepted] PHST- 2018/10/17 06:00 [pubmed] PHST- 2019/04/02 06:00 [medline] PHST- 2018/10/17 06:00 [entrez] PHST- 2018/09/26 00:00 [pmc-release] AID - S2213-2317(18)30836-X [pii] AID - 10.1016/j.redox.2018.09.019 [doi] PST - ppublish SO - Redox Biol. 2019 Jan;20:157-166. doi: 10.1016/j.redox.2018.09.019. Epub 2018 Sep 26.