Calcineurin (CN), a unique protein phosphatase, plays an important role in immune regulation. In this study we used CN as a target enzyme to investigate the immunosuppressive properties of a series of natural compounds from Garcinia mangostana L., and discovered an active compound, isogarcinol. Enzymatic assays showed that isogarcinol inhibited CN in a dose-dependent manner. At concentrations resulting in relatively low cytotoxicity isogarcinol significantly inhibited proliferation of murine spleen T-lymphocytes induced by concanavalin A (ConA) and the mixed lymphocyte reaction (MLR). In addition, it performed much better in acute toxicity tests and via oral administration in mice than cyclosporin A (CsA), with few adverse reactions and low toxicity in experimental animals. Oral administration of isogarcinol in mice resulted in a dose-dependent decrease in delayed type hypersensitivity (DTH) and prolonged graft survival in allogeneic skin transplantation. These findings suggest that isogarcinol could serve as a new oral immunomodulatory drug for preventing transplant rejection, and for long-term medication in autoimmune diseases.
Isogarcinol is a natural compound that we extracted from Garcinia mangostana L., and we were the first to report that it is a new immunosuppressant. In the present study, we investigated the immune regulation and anti-inflammatory effects of isogarcinol on collagen-induced arthritis (CIA) and explored its potential mechanism in the treatment of rheumatoid arthritis. The oral administration of isogarcinol significantly reduced clinical scores, alleviated cartilage and bone erosion, and reduced the levels of serum inflammatory cytokines in CIA mice. Isogarcinol inhibited xylene-induced mouse ear edema in vivo. In vitro, isogarcinol decreased iNOS and COX-2 mRNA expression and NO content by inhibiting NF-κB expression. Furthermore, isogarcinol decreased the activity of NFAT and inhibited IL-2 expression. The mechanism of action of isogarcinol is associated with down-regulation of both autoimmune and inflammatory reactions.
Glycyrol is a natural compound extracted from Glycyrrhiza uralensis, first reported by us to be a new immunosuppressant. Here, we demonstrate its beneficial effect in collagen-induced arthritis (CIA) in mice, a model for rheumatoid arthritis (RA) in man, and we document the underlying mechanisms. Peroral administration of glycyrol significantly reduced clinical scores, alleviated cartilage and bone erosion and reduced levels of serum inflammatory cytokines. Glycyrol also decreased delayed-type hypersensitivity, improved carbon clearance and reduced acetic acid-induced capillary permeability. Furthermore, glycyrol decreased NF-κB and NFAT transcriptional activities and inhibited IL-2 expression. The therapeutic effect of glycyrol was associated with down-regulation of both autoimmune and inflammatory reactions. In addition, we demonstrated that glycyrol has minimal acute toxicity in mice. Therefore, we propose that glycyrol may hold promise for future treatment of RA.
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