Anti-rheumatoid arthritis effects in adjuvant-induced arthritis in rats and molecular docking studies of Polygonum orientale L. extracts
Gou, K.-J.; Zeng, R.; Ren, X.-D.; Dou, Q.-L.; Yang, Q.-B.; Dong, Y.; Qu, Y.
Immunology Letters 201: 59-69
ISSN/ISBN: 1879-0542 PMID: 30471320 DOI: 10.1016/j.imlet.2018.11.009
Polygonum orientale L. (family: Polygonaceae), named Hongcao in China, has effects of dispelling wind and dampness, promoting blood circulation, and relieving pain. Our group has already studied and confirmed that POEa and POEe (ethyl acetate and ethyl ether extract of P. orientale, respectively) had anti-inflammatory and analgesic effects in early research, which was mainly relevant to the existence of flavonoids. According to the clinical application of P. orientale in traditional Chinese medicine, it has long been used for rheumatic arthralgia and rheumatoid arthritis. Therefore, our group further explored whether flavonoids of P. orientale have anti-rheumatoid arthritis effect and how does they play this role. Dried small pieces of the stems and leaves of P. orientale were decocted with water and partitioned successively to obtain POEa and POEe, respectively. The anti-rheumatoid arthritis effect of P. orientale was studied by using a Freund's complete adjuvant (FCA)-induced arthritis (AIA) in a rat model. The levels of PGE2, TNF-α, and IL-1β in serum of AIA rats were detected by enzyme linked immunosorbent assay (ELISA) to explore its mechanisms. In addition, we computationally studied the relationships between the 15 chemical components of POEa and POEe, and the currently focused 9 target proteins of rheumatoid arthritis by molecular docking. Pharmacological experiments showed that POEa and POEe significantly ameliorate symptoms of rheumatoid arthritis via reducing paw swelling volume, arthritis score, and thymus and spleen indices, as well as increasing body weight in AIA rats. Simultaneously, the concentrations of PGE2, TNF-α, and IL-1β were significantly decreased by POEa and POEe. Histopathology revealed noticeable reduction in bone and cartilage, synovial hyperplasia, inflammatory cell infiltration, cartilage surface erosion, and joint degeneration by POEa and POEe treatment. In addition, the molecular docking studies showed that docking scores of 14 chemical compositions (including 12 flavonoids and 2 phenolic acids) of POEa and POEe with anti-rheumatoid arthritis protein targets were better than the complexed ligands of the anti-rheumatoid arthritis protein targets. Among them, six flavonoids in POEa and POEe had more docking protein targets (n ≥ 3). Five anti-rheumatoid arthritis targets including high-temperature requirement A1 protease (HtrA1), janus kinase 1 (JAK1), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (i-NOS), and prostaglandin E2 (PGE2) had better docking score compared with the complexed ligands. Moreover, most of the chemical components in POEa and POEe showed strong interaction with HtrA1. The flavonoids of P. orientale have anti-rheumatoid arthritis effect. In addition, the molecular docking results indicate that quercetin, catechol, orientin, and other six flavonoids may be closely related to HtrA1, JAK1, COX-2, i-NOS, and PGE2 protein target receptors. It suggests that these chemical compositions form strong protein-ligand complexes with these protein targets, especially HtrA1 to exert anti-rheumatoid arthritis. Further experimental studies show that mechanisms of anti-rheumatoid arthritis effects may also be relevant to inhibit the levels of PGE2, TNF-α, and IL-1β in serum. Therefore, our group can further explore the possible active ingredients and mechanisms of the anti-rheumatoid arthritis effects of flavonoids, and focus on the inhibition of the expression of inflammatory factors and the TGF-β1/Smad signaling pathway associated with HtrA1 protein target receptors, which can provide a direction and powerful reference for the action mechanism and drug research of anti-rheumatoid arthritis of flavonoids in P. orientale.