mangostin and Arthritis--Rheumatoid

Rheumatoid arthritis (RA) is an autoimmune disease that causes physical disability in people worldwide. Despite progress made in RA treatment in the past decade, new drugs with high efficacy but few long-term adverse effects are still needed. This study focused on evaluating the therapeutic potential of α-mangostin on established collagen-induced arthritis (CIA) in DBA/1J mice. Arthritic DBA/1J mice were orally administered with two doses of α-mangostin (10 and 40 mg/kg) daily, for 33 days. Alpha-mangostin significantly decreased the clinical score in the short term at both doses and decreased the histopathological score at the higher dose. This improvement was accompanied by a reduction on serum levels of anti-collagen IgG2a autoantibodies and of the production of LIX/CXCL5, IP-10/CXCL10, MIG/CXCL9, RANTES/CCL5, IL-6 and IL-33 in the joints of CIA mice. Alpha-mangostin also exhibited an anti-oxidant effect decreasing the NADPH oxidase activity and lipid peroxidation and preserving the levels of reduced glutathione in the arthritic joints. In vitro this xanthone demonstrated modulatory properties on LPS-activated dendritic cells, although in Th1 and Th17-polarized lymphocytes promotes a pro-apoptotic phenotype. Altogether this study illustrates the capacity of α-mangostin to ameliorate the early clinical and histological signs of established CIA by reducing the inflammatory and oxidative responses.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Arthritis, Experimental; Arthritis, Rheumatoid; Collagen; Cytokines; Dendritic Cells; Garcinia mangostana; Immunoglobulin G; Inflammation; Knee Joint; Male; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred DBA; Oxidative Stress; Th1 Cells; Th17 Cells; Xanthones

α-Mangostin (α-M) is a commonly used traditional medicine with various biological and pharmacological activities. Our study aimed to explore the effects and mechanism of α-M in regulating apoptosis of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS). α-M of 10 to 100 μM was used to treat RA-FLS for 24 hours, followed by measuring cell viability and apoptosis. The involvement of reactive oxygen species (ROS) and mitogen-activated protein kinases was detected. Treatment of α-M promoted apoptosis and reduced viability of RA-FLS in a dose-dependent manner. The mitochondrial membrane potential in RA-FLS was remarkably reduced by α-M treatment, accompanied by the cytochrome c accumulation in the cytosol and increased activities of caspase-3 and caspase-9. Moreover, we found that α-M treatment promoted ROS production and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation. The proapoptotic activity of α-M in RA-FLS was markedly reversed by the co-induction with the ERK1/2 inhibitor LY3214996 or ROS scavenger N-acetyl-l-cysteine. In conclusion, our studies found that α-M had remarkable proapoptotic activities in RA-FLS, which is regulated by the induction of ROS accumulation and ERK1/2 phosphorylation. α-M may thus have potential therapeutic effects for rheumatoid arthritis.

Topics: Acetylcysteine; Aged; Apoptosis; Arthritis, Rheumatoid; Benzamides; Caspase 3; Caspase 9; Cell Survival; Cytochromes c; Female; Humans; MAP Kinase Signaling System; Membrane Potential, Mitochondrial; Middle Aged; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Protein Kinase Inhibitors; Reactive Oxygen Species; Sulfonamides; Synoviocytes; Xanthones

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Arthritis, Experimental; Arthritis, Rheumatoid; Cell Proliferation; Cells, Cultured; Forkhead Transcription Factors; Humans; Hyperplasia; Interleukin-1beta; Male; NF-kappa B; Rats; Rats, Sprague-Dawley; Signal Transduction; Synovial Membrane; Synoviocytes; T-Lymphocytes, Regulatory; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A; Xanthones

Rheumatoid arthritis (RA) is a complicated and heterogeneous chronic disease with the characteristic of progressive joint destruction, deformity and disability. It is associated with not only genetic but also environmental factors. Many studies suggest that RA-derived fibroblast-like synoviocyte (RA-FLS) is involved in the pathogenic process of RA. The apoptosis and proliferation of RA-FLS is of great importance in the development and progression in RA. Nowadays, more and more traditional Chinese medicine (TCM) or natural products are studied in the treatment of RA.. To investigate the effects of several natural products and the apoptosisinduced effect of α-mangostin and its underlying mechanisms in RA-FLS MH7A cells.. The effects of natural products on MH7A cells were detected by MTT assay. Annexin V-FITC/PI double labeling and DAPI staining were adopted to observe the apoptosis induced by α-mangostin. The apoptosis related proteins were measured with western blotting analysis. ROS accumulation was determined by DHE staining.. Xantones, including Garcinone C, α-mangostin and γ-mangostin, significantly inhibited the MH7A cell viability. And α-mangostin induces apoptosis in MH7A cells. Further study showed that α-mangostin increased the ratio of Bax/Bcl-2 and increased the ROS generation in MH7A cells.. α-Mangostin induces the apoptosis of MH7A cells through increasing ROS accumulation and the ratio of Bax/Bcl-2, suggesting that α-mangostin should be benefit to the therapy of RA.

Topics: Apoptosis; Arthritis, Rheumatoid; Cell Line; Fibroblasts; Humans; Reactive Oxygen Species; Synovial Membrane; Xanthones