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戴宗顺,张逢,林也,黄红,李鑫,彭清华,蔡雄.青藤碱配伍芍药苷协同增效抗胶原诱导性关节炎作用机制研究[J].湖南中医药大学学报,2023,43(12):2143-2149[点击复制] |
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| 青藤碱配伍芍药苷协同增效抗胶原诱导性关节炎作用机制研究 |
| 戴宗顺,张逢,林也,黄红,李鑫,彭清华,蔡雄 |
| (湖南中医药大学中医诊断学湖南省重点实验室, 湖南 长沙 410208;宁乡市人民医院中医风湿免疫科, 湖南 长沙 410600) |
| 摘要: |
| 目的 探讨青藤碱配伍芍药苷抗胶原诱导性关节炎（collagen induced arthritis，CIA）药效作用及其机制。方法 将60只雌性Wistar大鼠随机分为正常组、模型组、甲氨蝶呤组（1 mg/kg）、青藤碱组（50 mg/kg）、芍药苷组（120 mg/kg）和青藤碱（50 mg/kg）配伍芍药苷（120 mg/kg）组（青芍配伍组），每组10只。除正常组外，其余大鼠尾根部皮内多点注射牛Ⅱ型胶原/非完全弗氏佐剂乳剂建立CIA模型。正常组和模型组大鼠灌胃等体积蒸馏水，用药组灌胃相应药物，连续30 d。造模后，每3天检测大鼠后足肿胀容积、关节炎指数评分及体质量；治疗结束后，CT检测大鼠关节骨破坏情况；HE染色观察踝关节病理变化；ELISA法检测血清肿瘤坏死因子-α（tumor necrosis factor-α，TNF-α）、白细胞介素-1β（interleukin-1β，IL-1β）含量；Western blot法检测关节骨组织基质金属蛋白酶-2（matrix metalloproteinase-2，MMP-2）、基质金属蛋白酶-9（matrix metalloproteinase-9，MMP-9）和基质金属蛋白酶抑制因子-1（tissue inhibitor of metalloproteinase-1，TIMP-1）的表达水平。结果 与正常组相比，模型组大鼠足肿胀容积、关节炎指数评分明显增加（P<0.01），体质量降低（P<0.01），足趾各关节骨侵蚀严重，关节腔隙狭窄甚至消失，血清TNF-α、IL-1β及关节骨组织MMP-2、MMP-9、TIMP-1蛋白表达均增高（P<0.01）。与模型组比较，甲氨蝶呤组、青藤碱组、芍药苷组和青芍配伍组大鼠足肿胀容积及关节炎指数评分均降低（P<0.01），体质量增加（P<0.01），骨破坏程度均明显减轻，血清TNF-α、IL-1β水平及关节骨组织MMP-2、MMP-9、TIMP-1蛋白表达均降低（P<0.01）。与青藤碱组或芍药苷组比较，青芍配伍组大鼠足肿胀容积及关节炎指数评分降低（P<0.01），体质量增加（P<0.01），骨破坏程度减轻，TNF-α、IL-1β水平及关节骨组织MMP-2、MMP-9、TIMP-1蛋白表达降低（P<0.01）。结论 青藤碱配伍芍药苷对CIA具有较强的治疗作用，在一定程度上比单用青藤碱或芍药苷的抗关节炎效果明显。其机制可能与抑制TNF-α、IL-1β表达，降低关节骨组织MMP-2、MMP-9表达，同时促进TIMP-1表达有关。 |
| 关键词: 青藤碱 芍药苷 配伍用药 胶原诱导性关节炎 细胞因子 基质金属蛋白酶 |
| DOI：10.3969/j.issn.1674-070X.2023.12.001 |
| 投稿时间：2023-05-18 |
| 基金项目:国家自然科学基金面上项目（82274506，81373540）；中国博士后科学基金面上项目（2022M721128）；湖南省自然科学基金项目（2023JJ30455，2023JJ40477）；湖南省教育厅科学基金一般项目（22C0197）；长沙市自然科学基金项目（kq2208499）；湖南中医药大学校级科研基金项目（2021XJJJ007）；湖南中医药大学院校联合课题重点项目（2022XYLH158）。 |
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| Mechanism of action of sinomenine combined with paeoniflorin on collagen Ⅱ-induced arthritis |
| DAI Zongshun,ZHANG Feng,LIN Ye,HUANG Hong,LI Xin,PENG Qinghua,CAI Xiong |
| (Hunan Key Laboratory of TCM Prescription and Syndromes Translational Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China;Rheumatology and Immunology Department of TCM, People's Hospital of Ningxiang City, Changsha, Hunan 410600, China) |
| Abstract: |
| Objective To investigate the therapeutic effects and mechanism of the combination of sinomenine(SIN) and paeoniflorin(PF) on collagen-induced arthritis(CIA).Methods Sixty female Wistar rats were randomized into normal, model, methotrexate(1 mg/kg), SIN(50 mg/kg), PF(120 mg/kg), and SIN(50 mg/kg) combined with PF(120 mg/kg)(SIN combined with PF group) groups, with 10 rats in each group. Except the normal group, the CIA model was established by multi-point injection of bovine collagen type II/incomplete Freund adjuvant emulsion in the tail root skin of rats. The normal group and model group were orally administered distilled water, while the medication groups were orally administered corresponding drugs, continuously for 30 d. After modeling, the swelling volume of the hind paws, arthritis index score, and body weight of the rats were measured every 3 days. After treatment, CT scans were used to evaluate joint bone destruction in the rats, HE staining was used to observe pathological changes in the ankle joints; the serum content of tumor necrosis factor-alpha(TNF-α) and interleukin-1β(IL-1β) was measured by ELISA, and the expression levels of matrix metalloproteinase-2(MMP-2), matrix metalloproteinase-9(MMP-9), and tissue inhibitors of metalloproteinase-1(TIMP-1) in joint bone tissues were determined by Western blot.Results Compared with the normal group, the hind paw swelling volume and arthritis index score of model group was significantly higher(P<0.01), and the body weight was lower(P<0.01). The significant bone erosion in the toe joints with narrowing or even disappearance of the joint space was observed in the model group. While the levels of TNF-α and IL-1β in the serum and the protein expressions of MMP-2, MMP-9, and TIMP-1 in joint bone tissues all increased(P<0.01).Compared with model group, the swelling volume of hind paws and arthritic index score of rats in methotrexate, SIN, PF, and SIN combined with PF groups were lower(P<0.01), the body weight was higher(P<0.01), the degree of bone destruction significantly decreased, and the levels of TNF-α and IL-1β in serum and the protein expressions of MMP-2, MMP-9, and TIMP-1 in joint bone tissue decreased(P<0.01). Compared with SIN or PF group, the swelling volume of hind paws and arthritic index score of rats in SIN combined with PF group were lower(P<0.01), the body weight was higher(P<0.01), the degree of bone destruction decreased, and the levels of TNF-α and IL-1β in serum and the protein expressions of MMP-2, MMP-9, and TIMP-1 in joint bone tissue were lower(P<0.01).Conclusion SIN combined with PF has strong therapeutic effects on CIA, and the anti-arthritis effects are more obvious than SIN or PF alone to a certain extent. The mechanism may be related to inhibiting the expressions of TNF-α and IL-1β, lowering expressions of MMP-2 and MMP-9 in joint bone tissue, and promoting the expression of TIMP-1. |
| Key words: sinomenine paeoniflorin combination of medication collagen Ⅱ-induced arthritis cytokines matrix metalloproteinase |
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