从Wnt/β-catenin串扰轴探究湿热痹颗粒治疗痛风性关节炎湿热证的作用机制  

Investigation on the pharmacological mechanisms of Shirebi granules in treating gouty arthritis with damp-heat syndrome based on crosstalk of Wnt/β-catenin signaling

作　　者：李欣[1] 毛霞[1] 马旺明 江红 付璐 向小梅 陈文佳 李玮婕 王萍 张彦琼 许海玉[1] LI Xin;MAO Xia;MA Wang-ming;JIANG Hong;FU Lu;XIANG Xiao-mei;CHEN Wen-jia;LI Wei-jie;WANG Ping;ZHANG Yan-qiong;XU Hai-yu(Institute of Chinese Materia Medica,China Academy of Chinese Medical Sciences,Beijing 100700,China)

机构地区：[1]中国中医科学院中药研究所,北京100700

出　　处：《药学学报》2023年第8期2424-2433,共10页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金青年科学基金项目(82204711);中央本级重大增减支项目(2060302);青年岐黄学者培养项目(国中医药人教函[2022]256号).

摘　　要：痛风性关节炎是一类由自身免疫异常引起的代谢性风湿病,目前临床中用于治疗此类疾病的一线西药易引起不良反应,从中医药中寻求治疗药物成为研究热点。中医临床将痛风性关节炎归为湿热痹证,对症治疗的湿热痹颗粒疗效确切,但作用机制尚不清晰。本研究旨在探究湿热痹颗粒治疗痛风性关节炎湿热证的作用机制。首先,建立“湿热痹方剂候选靶标−痛风性关节炎湿热证相关基因”的相互作用网络,通过计算网络节点拓扑特征值,筛选湿热痹颗粒治疗痛风性关节炎湿热证的关键候选靶标,并对关键候选靶标进行功能挖掘,发现湿热痹颗粒候选靶标可通过调节Wnt/β-catenin串扰轴,减轻炎症反应和干预脂质代谢生物过程,从而发挥其缓解痛风性关节炎湿热证的作用。进一步基于病证结合大鼠模型的实验验证表明,湿热痹颗粒可显著改善痛风性关节炎湿热证大鼠的关节炎严重程度,降低关节炎症与步态评分、肿胀指数,升高机械痛阈值(P<0.05),降低痛风性关节炎湿热证大鼠血清炎症因子IL-1β、IL-6、TNF-α的含量(P<0.01);还能显著降低痛风性关节炎湿热证大鼠关节局部温度,提高热痛阈值,增加饮水量(P<0.01),抑制脂肪酸氧化相关酶含量的异常变化(P<0.01);Western blot机制层面的验证结果显示,湿热痹颗粒可升高痛风性关节炎湿热证大鼠Wnt、β-catenin蛋白表达水平(P<0.01),降低p65、p-p65、PPARγ蛋白表达(P<0.01),即湿热痹颗粒可能通过调节Wnt/β-catenin串扰轴矫正“炎症−免疫”失衡和脂质代谢紊乱,发挥缓解疾病严重度的作用。本研究为中药病−证−方复杂关联机制的解析提供方法学参考,为中成药优势品种的临床合理用药及痛风性关节炎的新药研发奠定了良好基础。本研究获得中国中医科学院医学实验中心实验动物伦理委员会批准(批准号:ERCCACMS11-2302-08)。Gouty arthritis is a type of metabolic rheumatic disease caused by autoimmune abnormalities.Currently,the use of Western medicine in the clinical treatment of gouty arthritis has been associated with a high risk of adverse reactions.Therefore,there is a growing interest in exploring therapeutic drugs from traditional Chinese medicine as a potential alternative.According to the theory of traditional Chinese medicine,gouty arthritis has been classified as damp-heat arthralgia syndrome.Shirebi granules has been found to have good clinical efficacy in treating gouty arthritis.However,its underlying pharmacological mechanisms remain unclear.To address this problem,the study first established the interaction network of candidate targets for Shirebi granules,which is used to treat damp-heat syndrome of gouty arthritis.Then,the key candidate targets of Shirebi granules for treating gouty arthritis with damp-heat syndrome were screened by calculating the topological features of the network nodes.Then,the functional mining of the key candidate targets revealed that the candidate targets of Shirebi granules may intervene in the biological process of inflammatory response and lipid metabolism through the crosstalk of Wnt/β-catenin signaling.To verify the effectiveness of Shirebi granules in treating gouty arthritis with damp-heat syndrome,a rat model was established.The results demonstrated that the granules significantly improved the severity of arthritis in rats with this condition,reduced joint inflammation,gait score,swelling index,increased mechanical pain threshold(P<0.05),and reduced the content of serum inflammatory factors IL-1β,IL-6,and TNF-αin gouty arthritis rats with damp-heat syndrome(P<0.01)gouty.It was also found that Shirebi granules effectively alleviated the symptoms of dampness heat syndrome such as local joint fever and dry mouth by reducing the temperature of the joints in acute gouty arthritis with damp-heat syndrome(AD)rats,increasing the threshold of heat pain,increasing water intake(P<0.01),and i

关 键 词：湿热痹颗粒 痛风性关节炎 湿热证 “免疫−炎症”失衡 脂质代谢 

分 类 号：R966[医药卫生—药理学]