| Rheumatoid arthritis is chronic systemic autoimmune disease which characterized by joint synovitis.Early performance is joint pain,chronic synovial inflammation,synovium hyperplasia,then,pannus formation,pannus invasion against joint margins and subchondral bone,leading to different degrees of bone loss,resulting in articular cartilage,bone and joint capsule damage.This will cause joint deformity and loss of joint function.In addition,RA inflammation may also affect the body through regulating bone remodeling,consequently induce systemic bone loss and osteoporosis,which bring great harm to the people’s production and life.Current treatment methods of RA mainly includes:general treatment,immune purification,surgical treatment and drug treatment.Current drug treatments have a lot of side effects,although they are effective,combined with the etiology and pathogenesis of RA has not clear yet,to find a suitable and effective treatment for RA is imminent.The natural herbs in the treatment process can improve the body resistance,improve the general condition and relieve the side effects of other drugs caused.Although further study of their compositions should be confirmed,herbs had draw tremendous concentration in recent years.Diterpenes draw more and more attention because of its antibacterial,anti-inflammatory,antioxidant,neuroprotective and anti-cancer effects.Among them,carnosol(CS)which isolated from sage(salvia carnosa)for the first time has a strong anti-inflammatory and anti-oxidation.Also,its effects on prostate cancer,breast cancer,skin cancer,leukemia and colon cancer were reported in the literature.The reports also identified that CS can relieve a number of signaling pathways which relates in inflammation and cancer,such as NF-κB(nuclear factor kappa B),PI3K/AKT,estrogen and androgen receptors.Carnosic acid(CA)not only have the same carbon skeleton with CS,which is its oxidative degradation products,but also have many similarities in terms of biological activity and effects.Therefore,we proposed that if CS and CA had a moderating effect over arthritis and which signaling pathway regulated this moderating effect.To this end,we established a type II collagen-induced arthritis(CIA)rat model,analyzed the incidence of the experimental group,confirmed that CS and CA had the regulation effect on arthritis.The main contents and results of the experiment:Part I:In vitro experimentsCultured synovial fibroblasts(fibroblast-like synovial cells,FLS).The toxicity of CS and CA was detected by MTS assay;the influences on cell migration were detected by cell wound assay;the intracellular cytokines were detected in FLSs stimulated by TNF-a.Results:CS and CA(0μM、0.5μM、1.0μM、2.5μM、5.0μM、10μM、20μM)had no inhibition of cell proliferation;and had inhibition capacity on fibroblast-like synovial cells(FLS)stimulated by TNF-a when their concentration is 5μM and 10μM;both drugs could down-regulate inflammatory factors,osteoclasts related gene RANKL,and rheumatoid arthritis marker MMP-3.Part Ⅱ:In vivo experimentsSelected 160g-180g female Wistar rats to induce arthritis model to build rheumatoid arthritis model by CIA methods.Experiment was divided into four groups:① control group(Control):do not induce RA,intraperitoneal injection of saline solution;② negative control group(CIA + Vehicle):induction of RA,intraperitoneal injection of 10%DMSO;③ experimental group one(CIA + CS):induction of RA,intraperitoneal injection of CS(5mg/kg);④ experimental group two(CIA + CA):induction of RA,intraperitoneal injection of CA(5mg/kg).Early onset(i.e.,hind paw score of 1-2 points)began drug treatment,intraperitoneal injection of saline,10%DMSO,CS or CA,injected once a day every other day.The total treatment time was 14 days.After treatment,rats were sacrificed by euthanasia.The differences between the experimental and control groups in terms of the degree of swelling,the expression of inflammatory cytokines,joint destruction and so on were compared to identify carnosol and camosic acid effects on rheumatoid arthritis.Results:After treatments of CS or CA,both in the degree of swelling and the expression of inflammatory cytokines had significant differences.Conclusion:Both in vivo and in vitro experiments,CS and CA were harmless to normal synovial cells.The inhibition of abnormal synovial cell migration,the suppression of inflammatory factors and the inhibition of cartilage erosion and bone absorption in rats,suggesting CS and CA could act as a new research direction of rheumatoid arthritis,and provide new ideas and methods for the treatment and prognosis of rheumatoid arthritis. |
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