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γ-glutamylcysteine exhibits anti-inflammatory effects by increasing cellular glutathione level
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. Extrace...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197438/ https://www.ncbi.nlm.nih.gov/pubmed/30326393 http://dx.doi.org/10.1016/j.redox.2018.09.019 |
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author | Yang, Yang Li, Ling Hang, Qiyun Fang, Yuan Dong, Xiaoliang Cao, Peng Yin, Zhimin Luo, Lan |
author_facet | Yang, Yang Li, Ling Hang, Qiyun Fang, Yuan Dong, Xiaoliang Cao, Peng Yin, Zhimin Luo, Lan |
author_sort | Yang, Yang |
collection | PubMed |
description | 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. γ-glutamylcysteine (γ-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 γ-GC and the associated molecular mechanism need to be explored. In vivo investigation showed that γ-GC reduced sepsis lethality and attenuated systemic inflammatory responses in mice, as well as inhibited lipopolysaccharide (LPS)-stimulated production of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), 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 γ-GC exhibited better therapeutic effects against inflammation compared with N-acetyl-L-cysteine (NAC) and GSH. Mechanistically, γ-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-κB) pathways, thereby promoting synthesis of GSH from γ-GC. These findings suggested that γ-GC might represent a potential therapeutic agent for sepsis treatment. |
format | Online Article Text |
id | pubmed-6197438 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-61974382018-10-24 γ-glutamylcysteine exhibits anti-inflammatory effects by increasing cellular glutathione level Yang, Yang Li, Ling Hang, Qiyun Fang, Yuan Dong, Xiaoliang Cao, Peng Yin, Zhimin Luo, Lan Redox Biol Research Paper 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. γ-glutamylcysteine (γ-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 γ-GC and the associated molecular mechanism need to be explored. In vivo investigation showed that γ-GC reduced sepsis lethality and attenuated systemic inflammatory responses in mice, as well as inhibited lipopolysaccharide (LPS)-stimulated production of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), 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 γ-GC exhibited better therapeutic effects against inflammation compared with N-acetyl-L-cysteine (NAC) and GSH. Mechanistically, γ-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-κB) pathways, thereby promoting synthesis of GSH from γ-GC. These findings suggested that γ-GC might represent a potential therapeutic agent for sepsis treatment. Elsevier 2018-09-26 /pmc/articles/PMC6197438/ /pubmed/30326393 http://dx.doi.org/10.1016/j.redox.2018.09.019 Text en © 2018 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Research Paper Yang, Yang Li, Ling Hang, Qiyun Fang, Yuan Dong, Xiaoliang Cao, Peng Yin, Zhimin Luo, Lan γ-glutamylcysteine exhibits anti-inflammatory effects by increasing cellular glutathione level |
title | γ-glutamylcysteine exhibits anti-inflammatory effects by increasing cellular glutathione level |
title_full | γ-glutamylcysteine exhibits anti-inflammatory effects by increasing cellular glutathione level |
title_fullStr | γ-glutamylcysteine exhibits anti-inflammatory effects by increasing cellular glutathione level |
title_full_unstemmed | γ-glutamylcysteine exhibits anti-inflammatory effects by increasing cellular glutathione level |
title_short | γ-glutamylcysteine exhibits anti-inflammatory effects by increasing cellular glutathione level |
title_sort | γ-glutamylcysteine exhibits anti-inflammatory effects by increasing cellular glutathione level |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197438/ https://www.ncbi.nlm.nih.gov/pubmed/30326393 http://dx.doi.org/10.1016/j.redox.2018.09.019 |
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