Daily Sepsis Research Analysis

Peroxiredoxin 6 (PRDX6) is widely acknowledged as a suppressor of ferroptosis, and recent studies have demonstrated that inhibition of macrophage ferroptosis can alleviate sepsis-associated acute lung injury (SA-ALI). Nonetheless, the specific involvement of PRDX6 in regulating macrophage ferroptosis during SA-ALI remains unexplored. This study aims to elucidate the mechanistic role of PRDX6 in modulating macrophage ferroptosis within the context of SA-ALI. Mouse alveolar macrophages (MH-S cells) were infected with either a PRDX6 overexpression lentivirus or a ZC3H13 knockdown lentivirus prior to lipopolysaccharide (LPS) treatment. In vivo, mice were treated with the same lentiviral constructs and subjected to a SA-ALI model via cecal ligation and puncture (CLP). This study demonstrates that PRDX6 overexpression or ZC3H13 knockdown significantly attenuated LPS-induced ferroptosis in alveolar macrophages and alleviated lung injury in CLP-induced SA-ALI mouse models. However, simultaneous knockdown of both ZC3H13 and PRDX6 abolished the protective effect conferred by ZC3H13 silencing, indicating that PRDX6 mediates the anti-ferroptotic role of ZC3H13 inhibition. Mechanistically, PRDX6 suppresses p53 expression, thereby upregulating SLC7A11 and inhibiting ferroptosis. Additionally, ZC3H13 promotes the m6A modification of PRDX6 mRNA, which facilitates its degradation in a YTHDF2-dependent manner, ultimately leading to reduced PRDX6 expression. Overall, these findings demonstrate that the methyltransferase ZC3H13 modulates PRDX6 expression by elevating the m6A methylation level of PRDX6 mRNA in a YTHDF2-dependent manner, thereby influencing the p53/SLC7A11 axis and promoting ferroptosis in alveolar macrophages, ultimately contributing to the progression of SA-ALI.

Skeletal muscle inflammation associated with sepsis has been identified as a critical pathological process contributing to metabolic dysfunction and poor clinical outcomes. Voltage-gated sodium channels (VGSCs) have been implicated in immune modulation; however, their specific roles in skeletal muscle inflammation remain poorly understood. In this study, the VGSC subtype Nav1.5 was investigated as a potential regulator of inflammation, and the therapeutic efficacy of a novel recombinant scorpion peptide, DKK678, was evaluated. An in vitro model using lipopolysaccharide (LPS)-stimulated C2C12 cells and an in vivo cecal ligation and puncture (CLP) model in septic mice were established. In both models, Nav1.5 expression was significantly upregulated in response to inflammatory stimuli, while Nav1.4 expression remained unchanged. The nuclear factor kappa B (NF-κB) signaling pathway was found to be activated, contributing to increased expression of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), adhesion molecules (VCAM-1), and gap junction proteins (Cx43). Suppression of VGSC activity using lidocaine resulted in the inhibition of NF-κB phosphorylation and downregulation of inflammatory markers, while the expression of interleukin-10 (IL-10) and interleukin-4 (IL-4) were restored. Tetrodotoxin (TTX) treatment did not replicate these effects, suggesting Nav1.5-specific involvement. DKK678 was developed through bioinformatic design and molecular docking simulations, which predicted a stronger binding affinity and structural stability with Nav1.5 compared to Nav1.4. These predictions were validated through functional experiments. In vitro, DKK678 treatment dose-dependently inhibited LPS-induced NF-κB pathway activation and reversed abnormal expression of VCAM-1 and Cx43. In vivo, DKK678 significantly ameliorated CLP-induced skeletal muscle damage, suppressed inflammatory cytokine production, and improved tissue histopathology. Furthermore, the structural integrity of immune organs such as the thymus and spleen was preserved in DKK678-treated septic mice, with partial restoration of lymphocyte populations and organ indices. Notably, Nav1.5 expression was downregulated by DKK678, while Nav1.4 expression remained unaffected. These results demonstrate that Nav1.5 serves as a critical inflammatory modulator in skeletal muscle and immune tissues. Its upregulation was shown to drive NF-κB pathway activation and inflammatory cytokine production. By targeting Nav1.5, DKK678 was able to exert dual protective effects on both skeletal muscle and immune organs under septic conditions. The therapeutic potential of DKK678 was found to be comparable to that of dexamethasone (DEX) at high doses, without altering Nav1.4 expression. In conclusion, the present study provides new mechanistic insight into the role of Nav1.5 in skeletal muscle inflammation and identifies DKK678 as a promising peptide therapeutic that targets Nav1.5 to suppress NF-κB-mediated inflammatory injury. These findings suggest that Nav1.5 inhibition represents a viable strategy for the treatment of sepsis-associated myositis and related inflammatory disorders.

BACKGROUND: Sodium-glucose cotransport-2 inhibitors (SGLT2i) have established benefits in diabetes mellitus, heart failure, and chronic kidney disease, but their physiological effects during critical illness remain unclear. We explored whether dapagliflozin affected urinary output, fluid balance, and other physiological parameters in critically ill patients with acute organ dysfunction. METHODS: This secondary analysis of the DEFENDER trial included 401 critically ill patients with acute organ dysfunction randomized to receive dapagliflozin 10 mg daily or standard care. We analyzed urinary output, fluid balance, electrolytes, acid-base status, glycemia, and vasopressor requirements over the first five days using Bayesian models. RESULTS: Dapagliflozin progressively increased urinary output (day 5: + 157 mL/day, 95% CrI -90 to 386, probability 90%) and decreased fluid balance (day 5: -290 mL/day, 95% CrI -564 to -27, probability 98%). Furosemide use was lower in the dapagliflozin group (overall -3%, 95% CrI -7% to 1%, probability 90%). Dapagliflozin had minimal effects on creatinine and electrolytes but was associated with progressive small decreases in pH (day 5: -0.02, probability 96%). Maximum glucose levels were consistently lower with dapagliflozin (-9 mg/dL overall, probability 83%). Norepinephrine requirements showed a time-dependent increase in the dapagliflozin group, with the expected dose difference reaching 0.034 mcg/kg/min by day 5 (probability 94%), and heterogeneity analysis revealed larger effects in patients with sepsis or on mechanical ventilation. CONCLUSION: This exploratory analysis suggests dapagliflozin may enhance diuresis and reduce loop diuretic requirements in critically ill patients, potentially at the cost of increased vasopressor needs. Glucose levels were likely slightly lower with dapagliflozin. Given the study's limitations and heterogeneous treatment effects, these findings should be considered hypothesis-generating pending confirmation in prospective trials.