Wen Huang

Acute pancreatitis (AP) is a common and potentially fatal inflammatory disorder lacking effective targeted therapies. Mitochondrial dysfunction, marked by ATP depletion and excessive ROS production, lies at the heart of disease initiation and progression. This study presents a hierarchically targeted nanotherapeutic, Cu-CDs/Kyna@RM (RMCK), in which copper-doped, mitochondria-targeting carbon dots (Cu-CDs) are grafted with kynurenic acid (Kyna) and encapsulated within red blood cell-macrophage hybrid membranes. Upon systemic administration, RMCK homes to inflamed pancreatic tissue, where it sequentially releases Cu-CDs to target mitochondria, scavenge ROS, liberate Kyna, and restore mitochondrial function. It markedly improves survival, lowers serum amylase/lipase, attenuates pancreatic edema and necrosis, and prevents secondary lung injury, outperforming free Kyna therapy. In vitro, RMCK significantly reduces sodium taurocholate (STC)-induced acinar cell injury, measured by decreased cell necrosis and LDH release. Mechanistic studies including transcriptomics, immunohistochemistry, and functional assays reveal that RMCK amplifies GPR35-NF-κB inhibition to curb cytokine storms, prevents mtDNA-driven inflammasome activation, and alleviates hypoxia to downregulate HIF-1α and upregulate PPARγ for restored fatty acid oxidation. By integrating organ- and organelle-level targeting with ROS scavenging and mitochondrial energy remodeling, RMCK delivers synergistic, precision therapy for AP and offers a versatile platform for other inflammatory diseases characterized by mitochondrial dysfunction.

Introduction: Carnitine palmitoyltransferase 1A (CPT1A) is crucial for mitochondrial function, and its dysfunction has been linked to the development of several diseases. However, the role of CPT1A in severe acute pancreatitis (SAP) and its underlying mechanisms remain unclear. Mitochondrial damage-mediated pyroptosis has been identified as a critical factor in pancreatic acinar cell death during SAP. this study aimed to evaluate the protective role of CPT1A in SAP and investigate its association with pancreatic acinar cell pyroptosis.Methods: SAP models were established in male C57BL/6 mice by retrograde injection of 3% sodium taurocholate (STC) into the pancreatic duct and in primary acinar cells treated with 5 mM STC. Changes in Cpt1a mRNA and protein expression were assessed. Pancreatic pyroptosis was evaluated via activation of NLRP3 inflammasome-related proteins. Cpt1a was knocked down (siRNA) or inhibited (etomoxir) in cells. Cell viability was measured using Hoechst/PI staining, western blotting, and LDH release assays. The effects of CPT1A activators (C75, L-carnitine(LC)) on mitochondrial function (ΔΨm, mtROS, ox-mtDNA release) were examined in acinar cells.Results: In STC-induced SAP models (in vivo and in vitro), CPT1A expression was downregulated. Activating CPT1A with C75 or LC protected mitochondrial function (preserving ΔΨm, reducing mtROS, inhibiting ox-mtDNA release), thereby suppressing pyroptosis. LC treatment alleviated SAP in mice by inhibiting the NLRP3/GSDMD/Caspase-1 pathway and reducing acinar cell pyroptosis.Discussion: These findings reveal a novel protective mechanism of CPT1A in SAP. Enhancing CPT1A activity preserves mitochondrial functions and suppresses NLRP3/GSDMD-mediated pancreatic acinar cell pyroptosis, highlighting CPT1A as a potential therapeutic target.

Background: Isatidis Folium, a botanical drug widely used in traditional medicine, is known for its anti-inflammatory properties, including heat-clearing, detoxifying, and blood-cooling effects. Although its potential in sepsis treatment has been suggested, the bioactive metabolites and underlying mechanisms remain poorly understood.Methods: Network pharmacology and molecular docking were employed to identify the therapeutic effects and mechanisms of Indirubin, the major bioactive metabolite of Isatidis Folium, in sepsis treatment. In vivo, a cecal ligation and puncture (CLP)-induced mouse sepsis model was used to evaluate the protective effects of Indirubin through histopathological analysis, ELISA, and biochemical assays. In vitro, RAW264.7 cells were stimulated with LPS and treated with varying concentrations of Indirubin. The anti-inflammatory effects of Indirubin were assessed using ELISA, apoptosis assays, and Western blotting.Results: Network pharmacology analysis identified Indirubin as the major bioactive metabolite of Isatidis Folium and EGFR and SRC as its key molecular targets. Experimental validation demonstrated that Indirubin significantly improved survival rates, alleviated tissue injury, and suppressed inflammatory responses in sepsis models. Mechanistically, Indirubin inhibited LPS-induced activation of the EGFR/SRC/PI3K and NF-κB/MAPK pathways in macrophages, significantly reducing cell death and inflammation in RAW264.7 cells.Conclusion: Indirubin, the primary bioactive metabolite of Isatidis Folium, exerts protective effects against sepsis by targeting the EGFR/SRC/PI3K and NF-κB/MAPK signaling pathways in macrophages. These findings provide a mechanistic basis for the development of Indirubin as a multi-target therapeutic agent for sepsis treatment.

Cardiovascular diseases (CVDs) and their severe complications have posed immense challenges to global healthcare systems. A significant obstacle in this field lies in the development of innovative targets, mechanisms, and drugs to mitigate the side effects associated with current antiplatelet therapies. Through screening relevant CVD targets in the Gene Card database, we found that AhR appears to be linked to CVDs. Computer-aided drug screening and molecular docking techniques identified famciclovir as a potential AhR inhibitor. Further experiments demonstrated that famciclovir suppresses AhR expression and platelet activation in thrombin-stimulated platelets, significantly reducing mitochondrial damage and oxidative stress. Notably, oral administration of famciclovir significantly inhibits thrombin-induced platelet aggregation without affecting coagulation factors or thrombolysis systems. Moreover, famciclovir mitigates FeCl₃-induced carotid arterial thrombosis and cerebral thrombosis induced by middle cerebral artery occlusion. Our study suggests that inhibiting AhR expression with famciclovir effectively reduces platelet activation and thrombosis, offering promise as a potential therapeutic strategy for improving CVDs.