Celastrol mitigates inflammation in sepsis by inhibiting the PKM2-dependent Warburg effect

Abstract

Background Sepsis involves life-threatening organ dysfunction and is caused by a dysregulated host response to infection. No specific therapies against sepsis have been reported. Celastrol (Cel) is a natural anti-inflammatory compound that shows potential against systemic inflammatory diseases. This study aimed to investigate the pharmacological activity and molecular mechanism of Cel in models of endotoxemia and sepsis. Methods We evaluated the anti-inflammatory efficacy of Cel against endotoxemia and sepsis in mice and macrophage cultures treated with lipopolysaccharide (LPS). We screened for potential protein targets of Cel using activity-based protein profiling (ABPP). Potential targets were validated using biophysical methods such as cellular thermal shift assays (CETSA) and surface plasmon resonance (SPR). Residues involved in Cel binding to target proteins were identified through point mutagenesis, and the functional effects of such binding were explored through gene knockdown. Results Cel protected mice from lethal endotoxemia and improved their survival with sepsis, and it significantly decreased the levels of pro-inflammatory cytokines in mice and macrophages treated with LPS (P < 0.05). Cel bound to Cys424 of pyruvate kinase M2 (PKM2), inhibiting the enzyme and thereby suppressing aerobic glycolysis (Warburg effect). Cel also bound to Cys106 in high mobility group box 1 (HMGB1) protein, reducing the secretion of inflammatory cytokine interleukin (IL)-1β. Cel bound to the Cys residues in lactate dehydrogenase A (LDHA). Conclusion Cel inhibits inflammation and the Warburg effect in sepsis via targeting PKM2 and HMGB1 protein.

Plumbagin inhibits fungal growth, HMGB1/LOX-1 pathway and inflammatory factors in A. fumigatus keratitis

“…The extracellular form of HMGB1, known as damage-associated molecular pattern (DAMP), exhibits cytokine and chemotactic activity and plays a proinflammatory role in various disease models (Kang et al, 2014 ; Tang et al, 2023 ). Numerous studies have demonstrated the effectiveness of targeting HMGB1 as an anti-inflammatory strategy, showing that inhibiting HMGB1 can significantly reduce inflammatory responses in myocarditis, sepsis, periodontitis, and other diseases by down-regulating inflammatory cytokines such as IL-1β, TNF-α, and IL-6 (Yang H. et al, 2019 ; Jiang et al, 2021 ; Luo et al, 2022 ; Yang et al, 2022 ). Previous research on Pseudomonas aeruginosa keratitis has validated the potential of targeting HMGB1 as an anti-inflammatory approach (Ekanayaka et al, 2018 ; Hazlett et al, 2021 ).…”

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“…Liver tissues were embedded in paraffin and cut into sections, and histological changes were assessed by hematoxylin-eosin staining (H&E) staining according to our previous study. 33 …”

Das Immunsystem des kritisch Kranken

“…Eben dieser Mechanismus lässt sich jedoch auch bei aktivierten Immunzellen wie beispielsweise bei proinflammatorischen Makrophagen (M1-Makrophagen) und dendritischen Zellen nachweisen, was schließlich zu steigenden Laktatkonzentrationen und damit einhergehend zunehmender Mortalität führen kann [49,50]. Ein therapeutisches Eingreifen im Sinne einer Unterdrückung dieses Mechanismus ist auch weiterhin Bestandteil aktueller Forschungen und konnte bereits erste positive Effekte erzielen [51,52,53].…”