| Rheumatoid arthritis (RA) is a chronic systemic inflammatory disorder that is characterized by synovial hyperplasia, neoangiogenesis, and progressive destruction of cartilage and bone. Although there are a few ant-rheumatic drugs showing on treating RA, their side effects and toxicity call for new and more effective natural drugs. Total flavonoids from Litsea coreana Levl. (TFLC) are the effective fraction of Litsea coreana Levl., a traditional Chinese medicine. TFLC were the effective component and had therapy effect on RA. Our preliminary study demonstrate that TFLC without toxicity has a significant anti-arthritic effect on AA rats which could be associated with its anti-inflammatory and immunomodulatory properties. but the expression and mechanism of TFLC in RA is still not well-known and need further studying.Although the pathogenesis of RA is not completely understood, autoantibody and immune complex production, sustained chronic production of inflammatory mediators, and networks of cytokine production have all been shown to play a role. Because several inflammatory genes(TNF-α,IL-1,IL-10,iNOS,COX-2) that mediate these processes are regulated by nuclear factor-κB (NF-κB), we hypothesized that the activity of TFLC is mediated through modulation of NF-κB activation. In this study, collagen-induced arthritis (CIA) in rats which well represents RA is chosen, based on abstracting and purification of collagen type II. We use the peritoneal macrophages (PMφ) as the researching platform, and this investigation was carried out to find effects on inflammatory cytokines in vitro effect. we have focused on TFLC and tested its effects on the translocation activation of NF-κB from activated macrophages, using as models the murine macrophages. It can help us to have a deep view in the molecular mechanism of the curing effect of TFLC, we can get the basement for the research of the new medicine. The study contains three sections:1. Induce collagen-induced arthritis in ratsCollagen-induced arthritis in rats (CIA) was induced with this product, and the animal model was successful by determing body weight, paw swelling, polyarthritis index and histopathology examination. The result show that TFLC(50,100,200 mg·kg-1 ) singnificantly inhibited the paw swelling and increased body weight of CIA rats. The pathological damage of knee joint was reversed by TFLC.2. Investigate the effect of total flavonids of Litsea coreana Leve. (TFLC) on cytokines production and immunity of peritoneal macrophage (PMΦ) from collagen-induced arthritis (CIA)TFLC was incubated with PMΦfrom CIA rats in vitro to study the effects and mechanism of it on the immune function of CIA rats. TFLC(0.05,0.5,5μg·ml-1)markedly reduced IL-1 and IL-2 in CIA rats. Meanwhile, TFLC singnificantly reduced TNF-αand NO level , and inhibited the expression of TNF-α,IL-1,iNOS and COX-2 mRNA in PMΦ. The result show that TFLC has marked therapeutic effect on CIA rats, which is related to reducing the phagocytosis and inhibiting the secretion and expression of cytokines.3. investigate the influence of TFLC on LPS induced NF-κB activation and IκBαexpression in peritoneal macrophage (PMΦ) from collagen-induced arthritis (CIA)The inhibitory effects of TFLC on inflammatory gene (IκBαand NF-κB/p65) expression were measured by western blotting. The expression and activation of nucleus p65 protein in PMΦin LPS group was obviously higher then other 4 groups, but changers in the IκBαexpression between LPS group and other 4 groups was of controversy. TFLC was observed to reduce the level of nuclear factor-kB (NF-κB) activity and inhibited the degradation of an inhibitory protein called inhibitorκB (IκB). Therefore, it was suggested that TFLC inhibited the expression of LPS-induced inflammatory genes by suppressing NF-κB activation at the transcriptional level. Together, these results suggest a new mechanism for the anti-inflammatory effects of TFLC in rheumatoid arthritis (RA) and the potential of drugs, which interfere with intracellular NF-κB transport mechanisms, as novel agents to treat RA.
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