Abstract：
The study aims to investigate the effects and potential mechanism of raw and processed Aconitum pendulum Busch on rheumatoid arthritis(RA) and analyze their toxicity attenuating and efficacy retaining effects. The bovine type Ⅱ collagen-induced arthritis(CIA) rat model was established. The weight, cardiac index, immune organ index, and arthritis index of the rats were recorded and calculated after administration. ELISA was used to measure the expressions of creatine kinase(CK), cardiac troponin T(cTnT), and multiple factors. The pathological morphological changes in heart tissue and ankle joint tissue were observed by hematoxylin-eosin staining. Connexin 43(Cx43) expression in the hearts of CIA rats was detected via immunohistochemical method. The levels of endogenous metabolites in the serum of CIA rats were detected by UPLC-Q-TOF-MS. Potential biomarkers were screened, and related metabolic pathways were analyzed. The results showed that raw A. pendulum could induce local myocardial fiber degeneration and necrosis, increase the cardiac index, decrease the average positive area of Cx43 expression significantly, and increase the expressions of CK and cTnT in cardiac tissue of rats. Meanwhile, raw A. pendulum could decrease the immune organ index, interleukin-6(IL-6), and other inflammatory cytokine contents in the serum and improve the damaged synovium and joint surface of CIA rats, with toxicity and efficacy coexisting. The Zanba stir-fired A. pendulum could reduce the index of arthritis, immune organ index, and content of IL-6 and inflammatory cytokines in serum and improve damaged synovium and joint surface of CIA rats with no obvious cardiac toxicity, showing significant toxicity attenuating and efficacy retaining effects. A total of 19 potential biomarkers of raw A. pendulum and Zanba stir-fired A. pendulum against RA were screened by serum metabolomics, including glycerophospholipid metabolism, glycine, serine, and threonine metabolism, arginine and proline metabolism, and steroid hormone synthesis. In conclusion, Xizang medicine A. pendulum is preventive and curative for RA. Raw A. pendulum has certain cardiotoxicity, and Zanba stir-fired A. pendulum has significant toxicity attenuating and efficacy retaining effects. The anti-RA mechanism may be related to the regulation of glycerophospholipid and amino acid metabolism.
摘要：
本研究旨在探讨生乌头摆布希对类风湿关节炎（RA）的疗效和潜在机制，并分析其毒性减弱和疗效保留作用。建立牛Ⅱ型胶原诱导关节炎(CIA)大鼠模型。重量,心脏指数,免疫器官指数,给药后记录并计算大鼠的关节炎指数。ELISA法检测肌酸激酶(CK)的表达,心肌肌钙蛋白T(cTnT),和多种因素。苏木精-伊红染色观察心脏组织和踝关节组织的病理形态学变化。采用免疫组织化学方法检测Cx43在CIA大鼠心脏中的表达。UPLC-Q-TOF-MS检测CIA大鼠血清中内源性代谢产物的水平。筛选了潜在的生物标志物，并对相关代谢通路进行分析。结果表明，生A.摆可以引起局部心肌纤维变性和坏死，增加心脏指数,Cx43表达的平均阳性面积显着降低，并增加大鼠心脏组织中CK和cTnT的表达。同时,生A.摆可降低免疫器官指数，白细胞介素-6（IL-6），和其他炎性细胞因子在血清中的含量，改善CIA大鼠滑膜和关节表面的损伤，毒性和功效并存。Zanba搅拌的A.摆锤可以降低关节炎的指数，免疫器官指数,和血清中IL-6和炎性细胞因子的含量，改善CIA大鼠滑膜和关节表面的损伤，无明显的心脏毒性，表现出显著的毒性减弱和功效保留作用。通过血清代谢组学筛选了19种针对RA的原始A.punlium和Zanba搅拌A.punlium的潜在生物标志物，包括甘油磷脂代谢，甘氨酸,丝氨酸,苏氨酸代谢，精氨酸和脯氨酸代谢，和类固醇激素合成。总之,西藏医学A.钟摆对RA具有预防和治疗作用。生A.摆有一定的心脏毒性，和zanba搅拌点火A.pumplium具有显着的毒性减弱和功效保留作用。抗RA的作用机制可能与调节甘油磷脂和氨基酸代谢有关。
