Adenosine 5'-monophosphate prevents sepsis-associated muscle wasting by activating AMPK and suppressing IL-1β inflammatory cytokines

ATF4-histone 2-hydroxyisobutyrylation feedback loop drives sepsis-induced inflammation.

BACKGROUND AND PURPOSE The role and mechanisms of lysine 2-hydroxyisobutyrylation (Khib) in the acute inflammatory phase of sepsis remain unclear. We investigated the function and underlying mechanisms of histone H4 lysine 5 2-hydroxyisobutyrylation (H4K5-hib) in sepsis-induced inflammation in vivo and in vitro. EXPERIMENTAL APPROACH Acute sepsis was induced by caecal ligation and puncture (CLP) in mice, and inflammatory responses were modelled in lipopolysaccharide (LPS)-stimulated macrophages. CUT&Tag-seq was used to identify genomic targets associated with H4K5-hib and activating transcription factor 4 (ATF4). Immunofluorescence, Western blotting, qPCR, dual-luciferase assays, and ELISA were performed to investigate the underlying mechanisms. KEY RESULTS H4K5-hib levels were increased in macrophages during the acute inflammatory phase of sepsis. LPS stimulation enhanced H4K5-hib enrichment at the ATF4 promoter, thereby promoting ATF4 transcription. Inhibition of EP300-mediated 2-hydroxyisobutyrylation or mutation of H4K5 abolished ATF4 activation. Increased H4K5-hib activated the ATF4/NLRP3 signalling axis, promoting inflammasome assembly and amplifying inflammatory responses. ATF4 directly bound to the EP300 promoter and enhanced its transcription, forming a positive feedback loop that further increased H4K5-hib levels. In CLP-induced sepsis, pharmacological inhibition of EP300 or ATF4 reduced H4K5-hib levels and suppressed NLRP3 inflammasome activation. CONCLUSION AND IMPLICATIONS These findings reveal a previously unrecognized epigenetic mechanism underlying sepsis-induced inflammation and identify the EP300/ATF4/H4K5-hib positive feedback loop as a potential therapeutic target for sepsis.

AMPK–Nrf2–mediated cardioprotection by luteolin in a murine model of endotoxic myocardial damage

Multi-organ failure brought on by the body's aberrant reaction to microbial invasion is the hallmark of polymicrobial sepsis, a potentially fatal condition. The study aimed to elucidate the putative cardioprotective action of luteolin against endotoxic heart injury induced by experimental sepsis in mice. Experimental animals were divided in to four groups, each contain 6 mice. Cecal Ligation and Puncture, Sham, DMSO & luteolin-treated groups 50mg/kg IP, 1hour before Cecal Ligation and Puncture, after that animals were sacrificed 24 hours after Cecal Ligation and Puncture. Markers evaluated include, IL-1β, TNFα, TNF αr1, HO-1 F2-ISOPROSTANEMPO, CASPASE-11 & troponin by ELISA technique, histopathological study & PCR for gene expression of AMPK-Nrf2 was done. IL-1β, TNFα, TNFαr1, HO-1, MPO, CASPASE-11, F2-isoprostane, tissue mRNA expression of AMPK-Nrf22 genes were significantly altered in the luteolin-treated group compared to the CLP group (p<0.05). We conclude that Luteolin contains anti-inflammatory and anti-oxidative properties; we conclude that it has cardioprotective benefits. Additionally, luteolin demonstrated a cardioprotective impact by influencing the AMPK-Nrf2 genes' tissue mRNA expression.

Prophylactic polydatin protects against sepsis-induced muscle atrophy by suppressing endoplasmic reticulum stress via SIRT3 upregulation in a mouse CLP model.

Sepsis-induced muscle atrophy is closely related to the poor prognosis of patients and poses a clinical challenge due to the lack of effective therapies. Polydatin (PD) is a natural phenolic compound possessing great anti-inflammatory property, but its potential effect on sepsis-induced muscle atrophy has not been clarified. In this study, a mouse sepsis model established by cecal ligation and puncture (CLP) using male C57BL/6J mice (8 weeks old) and an in vitro model of LPS-stimulated C2C12 myotubes were employed to investigate the effect of PD against sepsis-induced muscle atrophy. The underlying molecular mechanisms were further explored by integrating transcriptomic analysis, network pharmacology, and experimental validation. The results demonstrated that PD intervention markedly reduced protein degradation mediated by the ubiquitin-proteasome system and attenuated sepsis-induced muscle atrophy. Mechanistically, transcriptomic analysis suggested that its effect was associated with the modulation of endoplasmic reticulum (ER) stress, while network pharmacology identified sirtuin 3 (SIRT3) as the potential molecular target. Further experiments indicated that PD upregulated SIRT3 expression and suppressed the activation of ER stress in vivo and in vitro. Notably, the protective effects of PD were counteracted by inhibition of SIRT3 via specific inhibitor and siRNA, suggesting its important role in mitigating ER stress and muscle atrophy. Collectively, PD effectively alleviates sepsis-induced muscle atrophy, which might be achieved by suppressing ER stress via the upregulation of SIRT3, highlighting its potential as a protective strategy against this clinical condition.

Dexmedetomidine attenuates sepsis-associated NET formation and Th17 polarization through α2-adrenergic receptor-associated regulation of hepatic HPD.

FGF21 attenuates sepsis-induced myocardial injury via AMPK-mediated mitochondrial biogenesis.

Sepsis is a life-threatening infection that often leads to myocardial injury. Here we explored the role of fibroblast growth factor 21 (FGF21) in sepsis-induced myocardial injury and its underlying mechanism. A mouse model of sepsis-associated myocardial injury was established by cecal ligation and puncture (CLP). Serum FGF21 levels were upregulated in CLP mice (sham: ∼300 pg/mL; CLP: ∼420 pg/mL). CLP led to myocardial injury, inflammation, and apoptosis. Cardiac-specific overexpression of FGF21 via AAV9-cTnT improved 5-day survival rate from ∼20% (CLP) to ∼60% (CLP + OE-FGF21), reduced histological damage, suppressed apoptosis, and upregulated p-AMPK/AMPK and PGC-1α. In LPS-treated H9C2 cells, FGF21 overexpression reversed the LPS-induced decline in mitochondrial function. The AMPK agonist AICAR mimicked, while the AMPK antagonist Compound C partially reversed, the protective effects of FGF21. In conclusion, FGF21 overexpression alleviates sepsis-associated myocardial injury by restoring mitochondrial function via AMPK/PGC-1α pathway.

β-Hydroxybutyrate induces microglial M2 polarization by inhibiting the NF-κB/NLRP3 pathway to ameliorate cerebral ischemia–reperfusion injury

Elevated endogenous BHB under obese conditions exerts neuroprotective effects against CIRI, and exogenous BHB can mimic this effect.