Inhibition of LPS-Induced Inflammatory Response in RAW264.7 Cells and Amelioration of Adjuvant Arthritis in Rats by Cimifugin Derivatives
MA Jiaxin, ZHAO Yan, HAN Mei, HONG Aotian, HAN Jiahong, CAI Enbo*, YANG Limin*
The purpose of this paper was to explore the design and synthesis of a series of cimifugin derivatives, and to screen out the derivatives with better activity, so as to further study the mechanism of action of their anti-rheumatoid arthritis. The anti-inflammatory effects of cimifugin derivatives on LPS (lipopolysaccharide)- induced RAW 264.7 cells were screened, and CFA (complete Frances adjuvant)-induced rat adjuvant arthritis model was constructed, and the body weight, ankle swelling, arthritis index, organ index and related inflammatory factors were measured, and the compounds were molecularly docked with the core targets. The pathological changes of ankle synovium were observed by HE (hematoxylin-eosin) staining. The results showed that a total of 21 cimifugin derivatives were obtained, all of which were identified as new compounds, and at the concentration of 6.25 μmol/L~50 μmol/L, these compounds more than 85% on the viability of RAW 264.7 cells, and the IC50 value of NO inhibition rate of 5 compounds was better than that of cimifugin and dexamethasone (Dex IC50 was 13.10 μmol/L). Compared with the blank group, the rats in the model group showed highly significant decrease in body weight (P<0.001), significant increase in toe swelling (P<0.01), significant increase in serum inflammatory factor levels (P<0.05) and significant increase in organ indices (P<0.05). Compared with the model group, the body weight of rats in the high dose group of compound 15 was significantly increased (P<0.01); toe swelling was significantly decreased (P<0.01); serum inflammatory factor level was significantly decreased (P<0.05); and organ index was significantly decreased (P<0.01) among which the high-dose compound 15 group had better efficacy and was better than methotrexate. Compared with the model group, compound 15 high dose group joint synovial disease and inflammatory cell infiltration significantly improved. In addition, the expression levels of p-p38/p38 were significantly reduced (P<0.01), p-ERK/ERK were highly significantly reduced (P<0.001) and Cleaved Caspase-3 were significantly reduced (P<0.01) in the synovial tissues of the ankle joints of the rats in this group. Compound 15 has good affinity with key targets. The study concluded that compound 15 can treat adjuvant arthritis induced by CFA (complete Frances adjuvant) in rats. The mechanism may be related to the regulation of MAPK signaling pathways.
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