Search Results (3)

Background and Aim: Biliary atresia is a rare, progressive disease that affects the bile ducts in newborns. Persistent bile duct obstruction induces various pathological conditions, including jaundice, inflammation, and liver fibrosis; however, the exact pathogenesis of biliary atresia is not yet fully understood. Nuclear factor-κB (NF-κB) is widely acknowledged as a key regulator in the pathogenesis of hepatitis and liver fibrosis, and extensive research has been conducted to develop strategies to effectively inhibit its activity to mitigate liver damage. Exosome-based therapeutic platforms offer targeted NF-κB inhibition with low immunogenicity and enhanced liver-specific delivery. This study aimed to evaluate the therapeutic efficacy of Exo-SrIκB in treating cholestatic liver fibrosis using experimental animal models. Methods: Exo-SrIκB (an exosome-based therapy containing the super-repressor IκB protein) using EXPLOR technology (Exosome engineering for Protein Loading via Optically Reversible protein-protein interactions) to encapsulate the super repressor IκB (SrIκB) within exosomes. The therapeutic efficacy of Exo-SrIκB was assessed in minipig and mouse models with experimentally induced cholestatic liver disease. Results: Administration of Exo-SrIκB significantly attenuated liver fibrosis progression in both animal models by inhibiting NF-κB nuclear translocation and reducing the expression of fibrotic markers. Treated animals exhibited reduced collagen deposition, lower α-SMA levels, and improved hepatic function compared to untreated controls. Conclusion: Exo-SrIκB effectively suppressed NF-κB signaling and alleviated liver fibrosis in experimental cholestatic liver disease models, suggesting that exosome-based therapeutics may offer a targeted and biocompatible application to managing liver fibrosis and other chronic liver diseases. Full article

Activation of Kupffer cells (KCs) by gut-derived lipopolysaccharide (LPS) instigates nuclear factor-κB (NF-κB)-mediated inflammatory responses in alcohol-associated liver diseases (ALD). Here, we utilized a novel optogenetically engineered exosome technology called ‘exosomes for protein loading via optically reversible protein–protein interactions (EXPLOR)’ to efficiently deliver the super-repressor IκB-loaded exosomes (Exo-srIκB) to the liver and examined its therapeutic potential in acute-on-chronic alcohol-associated liver injury. We detected enhanced uptake of DiI-labeled Exo-srIκB by LPS-treated inflammatory KCs, which suppressed LPS-induced inflammatory gene expression levels. In animal experiments, a single intravenous injection of Exo-srIκB prior to alcohol binge drinking significantly attenuated alcohol-associated hepatic steatosis and infiltration of neutrophils and macrophages but not a liver injury. Notably, three consecutive days of Exo-srIκB injection remarkably reduced alcohol-associated liver injury, steatosis, apoptosis of hepatocytes, fibrosis-related gene expression levels in hepatic stellate cells, infiltration of neutrophils and macrophages, and inflammatory gene expression levels in hepatocytes and KCs. In particular, the above effects occurred with inhibition of nuclear translocation of NF-κB in liver tissues, and these beneficial effects of Exo-srIκB on ALD were shown regardless of doses. Our results suggest an exosome-based modulation of NF-κB activity in KCs by Exo-srIκB as a novel and efficient therapeutic approach in ALD. Full article

Complex regional pain syndrome (CRPS) is a condition associated with neuropathic pain that causes significant impairment of daily activities and functioning. Nuclear factor kappa B (NFκB) is thought to play an important role in the mechanism of CRPS. Recently, exosomes loaded with super-repressor inhibitory kappa B (Exo-srIκB, IκB; inhibitor of NFκB) have been shown to have potential anti-inflammatory effects in various inflammatory disease models. We investigated the therapeutic effect of Exo-srIκB on a rodent model with chronic post-ischemia pain (CPIP), a representative animal model of Type I CRPS. After intraperitoneal injection of a vehicle, Exo-srIκB, and pregabalin, the paw withdrawal threshold (PWT) was evaluated up to 48 h. Administration of Exo-srIκB increased PWT compared to the vehicle and pregabalin, and the relative densities of p-IκB and IκB showed significant changes compared to the vehicle 24 h after Exo-srIκB injection. The levels of several cytokines and chemokines were reduced by the administration of Exo-srIκB in mice with CPIP. In conclusion, our results showed more specifically the role of NFκB in the pathogenesis of CRPS and provided a theoretical background for novel treatment options for CRPS. Full article