Opsonization Inveigles Macrophages Engulfing Carrier-Free Bilirubin/JPH203 Nanoparticles to Suppress Inflammation for Osteoarthritis Therapy.

Osteoarthritis (OA) is a chronic inflammatory disease characterized by cartilage destruction, synovitis, and osteophyte formation. Disease-modifying treatments for OA are currently lacking. Because inflammation mediated by an imbalance of M1/M2 macrophages in the synovial cavities contributes to OA progression, regulating the M1 to M2 polarization of macrophages can be a potential therapeutic strategy. Basing on the inherent immune mechanism and pathological environment of OA, an immunoglobulin G-conjugated bilirubin/JPH203 self-assembled nanoparticle (IgG/BRJ) is developed, and its therapeutic potential for OA is evaluated. After intra-articular administration, IgG conjugation facilitates the recognition and engulfment of nanoparticles by the M1 macrophages. The internalized nanoparticles disassemble in response to the increased oxidative stress, and the released bilirubin (BR) and JPH203 scavenge reactive oxygen species (ROS), inhibit the nuclear factor kappa-B pathway, and suppress the activated mammalian target of rapamycin pathway, result in the repolarization of macrophages and enhance M2/M1 ratios. Suppression of the inflammatory environment by IgG/BRJ promotes cartilage protection and repair in an OA rat model, thereby improving therapeutic outcomes. This strategy of opsonization involving M1 macrophages to engulf carrier-free BR/JPH203 nanoparticles to suppress inflammation for OA therapy holds great potential for OA intervention and treatment.

Pharmacodynamic Evaluation of the Gexia Zhuyu Decoction in the Treatment of NAFLD and the Molecular Mechanism Underlying the TRPM4 Pathway Regulation.

Nonalcoholic fatty liver disease (NAFLD) is a clinicopathological syndrome of abnormal lipid deposition in the liver mediated by nonalcohol intake. The Gexia Zhuyu decoction, a classic traditional Chinese medicine compound, is widely used in the clinical treatment of NAFLD. However, its specific efficacy and underlying mechanisms have not been elucidated yet. This study aimed to quantitatively evaluate the efficacy of the Gexia Zhuyu decoction using pharmacodynamics and to explore its molecular mechanisms in conjunction with proteomics. High-fat diets and methionine choline-deficient diets were used to induce various NAFLD progression stages in mouse models. The effects of oral Gexia Zhuyu decoction administration on NAFLD were evaluated by measuring the serum and liver indicators of the treated mice before and after drug intervention and by comparing the changes in liver tissue. Liver TRPM4 mRNA and protein levels were measured using reverse transcription-polymerase chain reaction and Western blotting, respectively. Experimental data showed that serum ALT, AST, and liver triglyceride (TG) levels in each disease stage group of drug intervention mice decreased, and high-density lipoprotein (HDL) and superoxide dismutase (SOD) levels increased. Liver TG levels decreased after drug intervention in the liver fibrosis mice, but serum TG levels increased. Furthermore, cellular fatty changes, inflammatory changes, and fibrous tissue proliferation were all relieved. The TRPM4 protein and mRNA levels in the liver tissue were decreased, and the microRNA (miRNA)-24 expression was increased. The Gexia Zhuyu decoction has a clear therapeutic effect at each stage of NAFLD. It likely acts by altering miRNA-24 expression and regulating the target TRPM4 protein pathway to achieve NAFLD treatment.