Herbal compound cepharanthine attenuates inflammatory arthritis by blocking macrophage M1 polarization.

OBJECTIVE: Cepharanthine (CEP) is a drug candidate for tumor, viral infection, and some inflammatory diseases, but its effect on rheumatoid arthritis (RA) and the underlying mechanism are incompletely understood. METHODS: CEP was administered intraperitoneally to a collagen-induced arthritis (CIA) model. Joints went radiological and histological examination and serum cytokines were examined with cytometry-based analysis. M1 macrophages were induced from THP-1 cells or mouse bone marrow-derived macrophages with LPS and IFN-γ. Bulk RNA-seq was performed on macrophage undergoing M1-polarizatioin. Western blotting was applied to determine pathways involved in monocyte chemotaxis and polarization. Glycolysis metabolites were measured by chemiluminescence while glycolytic enzymes were examined by quantitative PCR. RESULTS: We found CEP significantly ameliorated synovial inflammation and joint destruction of CIA mice. It downregulated TNF-α levels in serum and in joints. The number of M1 macrophages were reduced in CEP-treated mice. In vitro, CEP inhibited monocyte chemotaxis to MCP-1 by downregulating CCR2 and reducing ERK1/2 signaling. Additionally, CEP suppressed M1 polarization of macrophages induced by LPS and IFN-γ. Genes involved in IFN-γ signaling, IL-6-JAK/STAT3 signaling, glycolysis, and oxidative phosphorylation process were downregulated by CEP. Several enzymes critically involved in glycolytic metabolism were suppressed by CEP, which resulted in reduced citrate in M1-polarizing macrophages. The inhibitory effect of CEP on macrophage polarization might be attributed to the blockage of TLRs-MyD88/IRAK4-IRF5 signaling pathway together with suppression of overactivated glycolytic metabolism in M1-polarizing macrophages. CONCLUSION: CEP attenuated joint inflammation by suppressing monocyte chemotaxis and proinflammatory differentiation. It has the potential to be developed into a complementary or alternative therapy for RA.

Vitamins A and D fail to protect against tuberculosis-drug-induced liver injury: A post hoc analysis of a previous randomized controlled trial.

OBJECTIVES: Vitamins A and D provided protection from xenobiotic-induced liver injury in previous animal studies. We conducted a post hoc analysis of our previous randomized controlled trial to investigate the effects of vitamin A and D supplementation on tuberculosis-drug-induced liver injury. METHODS: The trial was conducted in a hospital in Qingdao, China, from October 2012 to March, 2015. The control group received only tuberculosis treatment. The vitamin A, vitamin D, and vitamins A & D groups received, respectively, additional supplementation of 2000 IU/d vitamin A, 400 IU/d vitamin D, and a combination of 2000 IU/d vitamin A and 400 IU/d vitamin D. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, γ-glutamyltransferase, and cholinesterase were monitored throughout the treatment. Liver injury was defined as ALT or AST three times higher than the upper limit of normal, which was defined for AST, ALT, alkaline phosphatase, γ-glutamyltransferase, and cholinesterase, respectively, as 40 U/L, 40 U/L, 150 U/L, 40 U/L, and 10 500 U/L. RESULTS: Among the 753 participants, 11% exhibited liver injury. No significant effect of vitamin A or D supplementation was observed on the incidence of liver injury or on elevated liver indices including ALT, AST, alkaline phosphatase, γ-glutamyltransferase, and cholinesterase. The interaction between vitamin A and D supplementation was not significant. CONCLUSIONS: Vitamin A and D supplementation did not protect against tuberculosis-drug-induced liver injury. Future work should evaluate the effects of higher dosages of vitamins A and D and the effects of different genotypes for vitamin A and D metabolic enzymes or receptors.