Daily Sepsis Research Analysis

Sepsis-induced cardiac injury lacks a mechanism-specific therapy, and loss of endogenous myocardial defense signaling may amplify inflammatory damage. We investigated whether recombinant neuregulin-1 (rNRG-1) protects against cecal ligation and puncture (CLP)-induced cardiac injury and whether stimulator of interferon genes (STING)-linked macrophage pyroptosis-associated signaling contributes to this response. Male mice underwent CLP or sham surgery. Myocardial NRG-1/ErbB4 signaling was assessed over time, rNRG-1 was administered intravenously at 25 μg/kg immediately before CLP, and cardiac function, injury markers, inflammatory infiltration, survival, cGAS-STING signaling, and pyroptosis-associated readouts were evaluated. AAV-mediated STING overexpression was used to test whether STING activation weakens rNRG-1-mediated protection. CLP rapidly reduced myocardial NRG-1 abundance and ErbB4 phosphorylation, while NRG-1 and ErbB4 signals were detectable in vascular, myocardial, and CD68-positive inflammatory-cell-rich compartments. rNRG-1 improved left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), reduced serum creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH), increased 14-day survival from 26.67% to 60.00%, and decreased myocardial CD68-positive macrophage accumulation and myeloperoxidase (MPO)-positive inflammatory cell infiltration. rNRG-1 also suppressed cGAS expression and the phosphorylation of STING, TBK1, IRF3, and NF-κB p65, while reducing NLRP3, cleaved caspase-1, GSDMD-N, and IL-18 levels, with fewer CD68-positive cells showing STING activation, downstream inflammatory signaling, or pyroptosis-associated markers. AAV-mediated STING overexpression worsened CLP-induced dysfunction and substantially weakened the functional, biochemical, inflammatory, and pyroptosis-associated signaling effects of rNRG-1. These findings indicate that polymicrobial sepsis is associated with reduced myocardial NRG-1/ErbB4 signaling and that rNRG-1 attenuates early septic cardiac injury in association with reduced STING-linked inflammatory and pyroptosis-associated signaling in CD68-positive, macrophage-rich myocardial regions, rather than establishing a macrophage-specific mechanism.

BACKGROUND: In this study, metabolomics and transcriptomics were applied to reveal the potential mechanisms underlying the protective effects of β-hydroxybutyrate (BHB) on sepsis-associated encephalopathy (SAE). METHODS: A mouse SAE model was established. The Barnes maze was used to evaluate cecal ligation and puncture (CLP)-induced cognitive impairment. Neuronal survival, microglial activation, and proinflammatory cytokine levels were assessed using Nissl staining, immunofluorescence staining, and RT-qPCR. Serum metabolites and cerebral genes from control, SAE, and SAE mice treated with BHB were compared. Metabolomics and transcriptomics analysis were performed. Finally, based on the integrated transcriptomic and metabolomic analyses, we identified the target signaling pathway. RESULTS: Our results demonstrated that β-hydroxybutyrate (BHB) markedly reversed CLP-induced cognitive impairment. BHB administration attenuated neuronal loss and histopathological damage in the hippocampus, accompanied by reduced production of pro-inflammatory cytokines and decreased activation of Iba-1-positive microglia in SAE mice. Metabolomic profiling revealed that SAE induced significant alterations in serum metabolic signatures, with galactose, glycerophosphocholine, taurine, and hypotaurine levels markedly decreased. BHB treatment partially restored these metabolite levels toward normal. Transcriptomic analysis identified significant enrichment of the NF-κB signaling pathway in response to BHB treatment in SAE mice. Correlation analysis further showed that NF-κB-associated inflammatory genes (including VCAM1, TNF, NFKBIA, NFKB1, IL6, IL1B, ICAM1, CXCL family members, CD40, and CCL4/5) were strongly and negatively correlated with galactose, hypotaurine, and taurine levels, whereas glycerophosphocholine exhibited weak or non-significant associations. Consistent with the multi-omics findings, protein-level validation by Western blot confirmed that BHB suppressed SAE-induced activation of the NF-κB pathway in hippocampal tissue. CONCLUSION: Overall, this study reveals that BHB exerts neuroprotective effects in SAE through integrated metabolic and transcriptional reprogramming, in which attenuation of NF-κB-mediated inflammatory signaling represents a key mechanistic link between altered serum metabolites and downstream gene expression changes.

BACKGROUND: COVID-19 has been closely associated with coagulation abnormalities. However, existing biomarkers, including D-dimer and fibrin degradation products (FDP), exhibit limited accuracy in stratifying disease severity and predicting long-term clinical outcomes. OBJECTIVES: This study aimed to use proteomic analysis to identify plasma biomarkers associated with COVID-19 severity and prognosis, and validate their predictive utility for mortality and thromboembolic complications. METHODS: Plasma proteomic profiles were analyzed across three COVID-19 severity classes. Differential expression analysis and functional analysis were performed. Clustering analysis was used to identify proteins correlated with disease severity. Candidate biomarkers were validated in an independent cohort. Predictive performance of the biomarkers for mortality, sepsis and venous thromboembolism was evaluated using bootstrap-corrected ROC analyses and multivariable regression analyses. RESULTS: Proteomic analysis revealed progressive involvement of the coagulation and complement pathway with increasing disease severity. SERPINA1 and CD59 were identified as candidate biomarkers and exhibited significantly higher plasma levels in severe cases. Bootstrap-corrected ROC analyses demonstrated strong predictive performance: SERPINA1 achieved AUCs of 0.775 and 0.924 for 30-day and 12-month mortality, and CD59 achieved AUCs of 0.720 for sepsis; the combined model further improved prediction of 12-month mortality (AUC 0.946) and sepsis (AUC 0.904), outperforming D-dimer and FDP. Multivariable regression confirmed their independent prognostic value. CONCLUSION: This exploratory study identifies SERPINA1 and CD59 as candidate prognostic biomarkers in COVID-19, highlighting the role of coagulation and complement-related pathways in disease severity and warranting further prospective validation.