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Melittin ameliorates inflammation in mouse acute liver failure via inhibition of PKM2-mediated Warburg effect.

التفاصيل البيبلوغرافية
العنوان: Melittin ameliorates inflammation in mouse acute liver failure via inhibition of PKM2-mediated Warburg effect.
المؤلفون: Fan XG; Viral hepatitis of Hunan Key Laboratory and Department of Infectious Disease, Xiangya Hospital, Central South University, Changsha, 410008, China., Pei SY; Viral hepatitis of Hunan Key Laboratory and Department of Infectious Disease, Xiangya Hospital, Central South University, Changsha, 410008, China., Zhou D; Institute of Integrative Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China., Zhou PC; Viral hepatitis of Hunan Key Laboratory and Department of Infectious Disease, Xiangya Hospital, Central South University, Changsha, 410008, China., Huang Y; Viral hepatitis of Hunan Key Laboratory and Department of Infectious Disease, Xiangya Hospital, Central South University, Changsha, 410008, China., Hu XW; Viral hepatitis of Hunan Key Laboratory and Department of Infectious Disease, Xiangya Hospital, Central South University, Changsha, 410008, China., Li T; Institute of Integrative Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China., Wang Y; Viral hepatitis of Hunan Key Laboratory and Department of Infectious Disease, Xiangya Hospital, Central South University, Changsha, 410008, China.; Institute of Integrative Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China., Huang ZB; Viral hepatitis of Hunan Key Laboratory and Department of Infectious Disease, Xiangya Hospital, Central South University, Changsha, 410008, China., Li N; Viral hepatitis of Hunan Key Laboratory and Department of Infectious Disease, Xiangya Hospital, Central South University, Changsha, 410008, China. liningxy@csu.edu.cn.; Department of Blood Transfusion, Xiangya Hospital, Central South University, Changsha, 410008, China. liningxy@csu.edu.cn.
المصدر: Acta pharmacologica Sinica [Acta Pharmacol Sin] 2021 Aug; Vol. 42 (8), pp. 1256-1266. Date of Electronic Publication: 2020 Sep 16.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Nature Publishing Group Country of Publication: United States NLM ID: 100956087 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1745-7254 (Electronic) Linking ISSN: 16714083 NLM ISO Abbreviation: Acta Pharmacol Sin Subsets: MEDLINE
أسماء مطبوعة: Publication: 2009- : New York : Nature Publishing Group
Original Publication: Beijing, China : Science Press, c2000-
مواضيع طبية MeSH: Anti-Inflammatory Agents/*therapeutic use , Antioxidants/*therapeutic use , Glycolysis/*drug effects , Liver Failure, Acute/*drug therapy , Melitten/*therapeutic use , Pyruvate Kinase/*metabolism, Animals ; Anti-Inflammatory Agents/metabolism ; Anti-Inflammatory Agents/toxicity ; Antioxidants/metabolism ; Antioxidants/toxicity ; Galactosamine ; Inflammation/drug therapy ; Inflammation/etiology ; Lipopolysaccharides ; Liver Failure, Acute/chemically induced ; Liver Failure, Acute/complications ; Male ; Melitten/metabolism ; Melitten/toxicity ; Mice ; Mice, Inbred C57BL ; Molecular Docking Simulation ; Protein Binding ; RAW 264.7 Cells
مستخلص: Acute liver failure (ALF) is a fatal clinical syndrome with no special drug. Recent evidence shows that modulation of macrophage to inhibit inflammation may be a promising strategy for ALF treatment. In this study we investigated the potential therapeutic effects of melittin, a major peptide component of bee venom both in mice model of ALF and in LPS-stimulated macrophages in vitro, and elucidated the underlying mechanisms. ALF was induced in mice by intraperitoneal injection of D-galactosamine/LPS. Then the mice were treated with melittin (2, 4, and 8 mg/kg, ip). We showed that melittin treatment markedly improved mortality, attenuated severe symptoms and signs, and alleviated hepatic inflammation in D-galactosamine/LPS-induced ALF mice with the optimal dose being 4 mg/kg. In addition, melittin within the effective doses did not cause significant in vivo toxicity. In LPS-stimulated RAW264.7 macrophages, melittin (0.7 μM) exerted anti-oxidation and anti-inflammation effects. We showed that LPS stimulation promoted aerobic glycolysis of macrophages through increasing glycolytic rate, upregulated the levels of Warburg effect-related enzymes and metabolites including lactate, LDHA, LDH, and GLUT-1, and activated Akt/mTOR/PKM2/HIF-1α signaling. Melittin treatment suppressed M2 isoform of pyruvate kinase (PKM2), thus disrupted the Warburg effect to alleviate inflammation. Molecular docking analysis confirmed that melittin targeted PKM2. In LPS-stimulated RAW264.7 macrophages, knockdown of PKM2 caused similar anti-inflammation effects as melittin did. In D-galactosamine/LPS-induced ALF mice, melittin treatment markedly decreased the expression levels of PKM2 and HIF-1α in liver. This work demonstrates that melittin inhibits macrophage activation-mediated inflammation via inhibition of aerobic glycolysis by targeting PKM2, which highlights a novel strategy of using melittin for ALF treatment.
(© 2020. CPS and SIMM.)
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فهرسة مساهمة: Keywords: Akt/mTOR/PKM2/HIF-1α signaling.; M2-type pyruvate kinase; Warburg effect; acute liver failure; glycolysis; inflammation; melittin
المشرفين على المادة: 0 (Anti-Inflammatory Agents)
0 (Antioxidants)
0 (Lipopolysaccharides)
20449-79-0 (Melitten)
7535-00-4 (Galactosamine)
EC 2.7.1.40 (Pkm protein, mouse)
EC 2.7.1.40 (Pyruvate Kinase)
تواريخ الأحداث: Date Created: 20200917 Date Completed: 20211101 Latest Revision: 20220802
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC8285470
DOI: 10.1038/s41401-020-00516-0
PMID: 32939034
قاعدة البيانات: MEDLINE
الوصف
تدمد:1745-7254
DOI:10.1038/s41401-020-00516-0