Iridin Prevented Against Lipopolysaccharide-Induced Inflammatory Responses of Macrophages via Inactivation of PKM2-Mediated Glycolytic Pathways

Zhen-Hua Ying,1 Hui-Min Li,1 Wen-Ying Yu,2 Chen-Huan Yu2– 4 1Zhejiang Provincial People’s Hospital, Hangzhou Medical College, Hangzhou, 310006, People’s Republic of China; 2Zhejiang Key Laboratory of Experimental Animal and Safety Evaluation, Hangzhou Medical College, H...

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Autores principales:	Ying ZH, Li HM, Yu WY, Yu CH
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2021
Materias:	isoflavone glycolysis warburg effect pkm2 jak/stats nf-κb Pathology RB1-214 Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/03a78c09c4f847ad90f912aa3e0f2b29
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spelling	oai:doaj.org-article:03a78c09c4f847ad90f912aa3e0f2b292021-12-02T12:14:54ZIridin Prevented Against Lipopolysaccharide-Induced Inflammatory Responses of Macrophages via Inactivation of PKM2-Mediated Glycolytic Pathways1178-7031https://doaj.org/article/03a78c09c4f847ad90f912aa3e0f2b292021-02-01T00:00:00Zhttps://www.dovepress.com/iridin-prevented-against-lipopolysaccharide-induced-inflammatory-respo-peer-reviewed-article-JIRhttps://doaj.org/toc/1178-7031Zhen-Hua Ying,1 Hui-Min Li,1 Wen-Ying Yu,2 Chen-Huan Yu2– 4 1Zhejiang Provincial People’s Hospital, Hangzhou Medical College, Hangzhou, 310006, People’s Republic of China; 2Zhejiang Key Laboratory of Experimental Animal and Safety Evaluation, Hangzhou Medical College, Hangzhou, 310013, People’s Republic of China; 3Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Hangzhou, 310018, People’s Republic of China; 4Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, 310022, People’s Republic of ChinaCorrespondence: Chen-Huan YuInstitute of Cancer and Basic Medicine, Chinese Academy of Sciences, Hangzhou, 310018, People’s Republic of ChinaEmail yuchenhuan2002@163.comPurpose: Abnormal glycolysis of immune cells contributed to the development of inflammatory response. Inhibition of this Warburg phenotype could be a promising strategy for preventing various inflammatory diseases. Iridin (IRD) is a natural isoflavone, and exerts anticancer, antioxidant, and anti-inflammatory effects. However, the underlying mechanism of IRD on acute inflammation remains unknown. In this study, the protective effects of IRD against lipopolysaccharide (LPS)-induced inflammation were investigated in murine macrophage RAW264.7 cells and in mice.Methods: The inhibition of IRD on NO production in culture medium was detected by Griess assay while the levels of TNF-α, IL-1β, and MCP-1 were detected by ELISA assay. The effects of IRD on OCR and ECAR levels in LPS-treated macrophages were monitored by using Seahorse Analyzer. The apoptosis rate as well as the release of ROS and NO of RAW264.7 cells were analyzed by flow cytometric assay. The protective effects of IRD were investigated on LPS-induced inflammation in mice. The expressions of PKM2 and its downstream (p-JAK1, p-STAT1, p-STAT3, p-p65, iNOS, and COX2) in cells and in lung tissues were detected by Western blotting analysis.Results: IRD treatment at the concentrations of 12.5– 50 μM significantly inhibited the productions of TNF-α, IL-1β, MCP-1, and ROS, and suppressed the levels of glucose uptake and lactic acid in LPS-treated RAW264.7 cells. Oral administration with IRD (20– 80 mg/kg) inhibited LPS-induced acute lung injury as well as inflammatory cytokine production in mice. Moreover, IRD targeted pyruvate kinase isozyme type M2 (PKM2) and suppressed its downstream p-JAK1, p-STAT1, p-STAT3, p-p65, iNOS, and COX2, which could be abolished by PKM2 agonist DASA-58 and antioxidant N-acetyl-L-cysteine, but partly be reversed by NF-κB activator CUT129 and JAK1 activator RO8191.Conclusion: IRD alleviated LPS-induced inflammation through suppressing PKM2-mediated pathways, and could be a potential candidate for the prevention of inflammatory diseases.Keywords: isoflavone, glycolysis, Warburg effect, PKM2, JAK/STATs, NF-κBYing ZHLi HMYu WYYu CHDove Medical Pressarticleisoflavoneglycolysiswarburg effectpkm2jak/statsnf-κbPathologyRB1-214Therapeutics. PharmacologyRM1-950ENJournal of Inflammation Research, Vol Volume 14, Pp 341-354 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	isoflavone glycolysis warburg effect pkm2 jak/stats nf-κb Pathology RB1-214 Therapeutics. Pharmacology RM1-950
spellingShingle	isoflavone glycolysis warburg effect pkm2 jak/stats nf-κb Pathology RB1-214 Therapeutics. Pharmacology RM1-950 Ying ZH Li HM Yu WY Yu CH Iridin Prevented Against Lipopolysaccharide-Induced Inflammatory Responses of Macrophages via Inactivation of PKM2-Mediated Glycolytic Pathways
description	Zhen-Hua Ying,1 Hui-Min Li,1 Wen-Ying Yu,2 Chen-Huan Yu2– 4 1Zhejiang Provincial People’s Hospital, Hangzhou Medical College, Hangzhou, 310006, People’s Republic of China; 2Zhejiang Key Laboratory of Experimental Animal and Safety Evaluation, Hangzhou Medical College, Hangzhou, 310013, People’s Republic of China; 3Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Hangzhou, 310018, People’s Republic of China; 4Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, 310022, People’s Republic of ChinaCorrespondence: Chen-Huan YuInstitute of Cancer and Basic Medicine, Chinese Academy of Sciences, Hangzhou, 310018, People’s Republic of ChinaEmail yuchenhuan2002@163.comPurpose: Abnormal glycolysis of immune cells contributed to the development of inflammatory response. Inhibition of this Warburg phenotype could be a promising strategy for preventing various inflammatory diseases. Iridin (IRD) is a natural isoflavone, and exerts anticancer, antioxidant, and anti-inflammatory effects. However, the underlying mechanism of IRD on acute inflammation remains unknown. In this study, the protective effects of IRD against lipopolysaccharide (LPS)-induced inflammation were investigated in murine macrophage RAW264.7 cells and in mice.Methods: The inhibition of IRD on NO production in culture medium was detected by Griess assay while the levels of TNF-α, IL-1β, and MCP-1 were detected by ELISA assay. The effects of IRD on OCR and ECAR levels in LPS-treated macrophages were monitored by using Seahorse Analyzer. The apoptosis rate as well as the release of ROS and NO of RAW264.7 cells were analyzed by flow cytometric assay. The protective effects of IRD were investigated on LPS-induced inflammation in mice. The expressions of PKM2 and its downstream (p-JAK1, p-STAT1, p-STAT3, p-p65, iNOS, and COX2) in cells and in lung tissues were detected by Western blotting analysis.Results: IRD treatment at the concentrations of 12.5– 50 μM significantly inhibited the productions of TNF-α, IL-1β, MCP-1, and ROS, and suppressed the levels of glucose uptake and lactic acid in LPS-treated RAW264.7 cells. Oral administration with IRD (20– 80 mg/kg) inhibited LPS-induced acute lung injury as well as inflammatory cytokine production in mice. Moreover, IRD targeted pyruvate kinase isozyme type M2 (PKM2) and suppressed its downstream p-JAK1, p-STAT1, p-STAT3, p-p65, iNOS, and COX2, which could be abolished by PKM2 agonist DASA-58 and antioxidant N-acetyl-L-cysteine, but partly be reversed by NF-κB activator CUT129 and JAK1 activator RO8191.Conclusion: IRD alleviated LPS-induced inflammation through suppressing PKM2-mediated pathways, and could be a potential candidate for the prevention of inflammatory diseases.Keywords: isoflavone, glycolysis, Warburg effect, PKM2, JAK/STATs, NF-κB
format	article
author	Ying ZH Li HM Yu WY Yu CH
author_facet	Ying ZH Li HM Yu WY Yu CH
author_sort	Ying ZH
title	Iridin Prevented Against Lipopolysaccharide-Induced Inflammatory Responses of Macrophages via Inactivation of PKM2-Mediated Glycolytic Pathways
title_short	Iridin Prevented Against Lipopolysaccharide-Induced Inflammatory Responses of Macrophages via Inactivation of PKM2-Mediated Glycolytic Pathways
title_full	Iridin Prevented Against Lipopolysaccharide-Induced Inflammatory Responses of Macrophages via Inactivation of PKM2-Mediated Glycolytic Pathways
title_fullStr	Iridin Prevented Against Lipopolysaccharide-Induced Inflammatory Responses of Macrophages via Inactivation of PKM2-Mediated Glycolytic Pathways
title_full_unstemmed	Iridin Prevented Against Lipopolysaccharide-Induced Inflammatory Responses of Macrophages via Inactivation of PKM2-Mediated Glycolytic Pathways
title_sort	iridin prevented against lipopolysaccharide-induced inflammatory responses of macrophages via inactivation of pkm2-mediated glycolytic pathways
publisher	Dove Medical Press
publishDate	2021
url	https://doaj.org/article/03a78c09c4f847ad90f912aa3e0f2b29
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Iridin Prevented Against Lipopolysaccharide-Induced Inflammatory Responses of Macrophages via Inactivation of PKM2-Mediated Glycolytic Pathways

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