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膝痹宁Ⅱ方调控SETDB2/H3K9me3信号轴缓解寒湿痹阻型KOA大鼠冷刺激疼痛敏感性的机制
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| 篇名： | 膝痹宁Ⅱ方调控SETDB2/H3K9me3信号轴缓解寒湿痹阻型KOA大鼠冷刺激疼痛敏感性的机制 |
| TITLE： | Mechanism of Xibining Ⅱ in alleviating cold stimulus pain sensitivity in rats with cold-damp obstruction-type KOA by regulating SETDB2/H3K9me3 signaling axis |
| 摘要： | 目的 基于SET域分叉组蛋白赖氨酸甲基转移酶2（SETDB2）/组蛋白H3第9位赖氨酸三甲基化修饰（H3K9me3）信号轴研究膝痹宁Ⅱ方缓解寒湿痹阻型膝骨关节炎（KOA）大鼠冷刺激疼痛敏感性的作用机制。方法将50只大鼠随机分为对照组（灌胃并髓鞘内注射等体积生理盐水），模型组（灌胃并髓鞘内注射等体积生理盐水），膝痹宁Ⅱ方低、高剂量组（4、8g/kg膝痹宁Ⅱ方药液，灌胃）和膝痹宁Ⅱ方高剂量+小干扰RNA（siRNA）组（灌胃8g/kg膝痹宁Ⅱ方药液+髓鞘内注射SETDB2的siRNA，0.2mmol/L，20μL/只），每组10只。除对照组外，其余各组大鼠均构建寒湿痹阻型KOA模型；造模14d后开始给药，持续28d。末次给药后，检测大鼠冷刺激疼痛敏感性行为学变化，观察膝关节软骨组织病理形态学变化，检测血清中炎症因子[肿瘤坏死因子α（TNF-α）、白细胞介素1β（IL-1β）]、疼痛介质[降钙素基因相关肽（CGRP）、神经生长因子（NGF）]含量以及背根神经节（DRG）组织中SETDB2/H3K9me3信号轴和炎症因子、疼痛介质相关蛋白及mRNA的表达。结果给药28d后，与模型组比较，膝痹宁Ⅱ方低、高剂量组大鼠的冷刺激缩足潜伏期均显著延长（P＜0.05），丙酮低温实验阳性次数均显著减少（P＜0.05），膝关节组织的Mankin评分、国际骨关节炎研究学会评分以及血清中炎症因子、疼痛介质含量和DRG组织中炎症因子、疼痛介质的表达均显著降低（P＜0.05），DRG组织中SETDB2、H3K9me3蛋白表达均显著上调（P＜0.05）；髓鞘内注射SETDB2的siRNA后，高剂量膝痹宁Ⅱ方的上述作用均被显著逆转（P＜0.05）。结论膝痹宁Ⅱ方可能通过激活SETDB2/H3K9me3信号轴减轻炎症与疼痛反应，进而改善寒湿痹阻型KOA大鼠的冷刺激疼痛敏感性。 |
| ABSTRACT： | OBJECTIVE To investigate the mechanism by which the traditional Chinese medicine formula Xibining Ⅱ modulates cold-stimulus pain sensitivity in rats with cold-damp obstruction-type knee osteoarthritis （KOA） based on the SET domain bifurcated histone lysine methyltransferase 2 （SETDB2）/histone H3 lysine 9 trimethylation （H3K9me3） signaling axis. METHODS Fifty SD rats were randomly divided into control group （intragastric administration and intrathecal injection of equal volumes of normal saline）， model group （intragastric administration and intrathecal injection of equal volumes of normal saline）， Xibining Ⅱ low- and high-dose groups （4， 8 g/kg Xibining Ⅱ， intragastric administration）， and high-dose of Xibining Ⅱ+small interfering RNA （siRNA） group （8 g/kg of Xibining Ⅱ via intragastric administration and intrathecal injection of SETDB2 siRNA at 0.2 mmol/L， 20 μL per rat）， with 10 rats in each group. Except for the control group， cold-damp obstruction-type KOA model was induced in other groups. Drug administration commenced 14 days post-modeling and continued for 28 days. Following the final administration， the following were assessed： behavioral changes in cold-stimulation pain sensitivity， histopathological changes in the articular cartilage of the knee joint， the contents of inflammatory factors [tumor necrosis factor-α （TNF-α）， interleukin-1β （IL-1β）] and pain mediators [calcitonin gene-related peptide （CGRP）， nerve growth factor （NGF）]， as well as the expressions of SETDB2/H3K9me3 signaling axis，inflammatory factors and pain mediators related proteins and mRNAs in dorsal root ganglion （DRG） tissue. RESULTS After 28 days of drug administration， compared with the model group， Xibining Ⅱ low- and high-dose groups exhibited significantly prolonged cold-stimulus paw withdrawal latency （P＜0.05）； the number of positive responses in the acetone low-temperature test was significantly reduced （P＜0.05）； Mankin score and the Osteoarthritis Research Society International score for knee joint tissue， as well as the levels of inflammatory factors and pain mediators in the serum and their expression in DRG tissue were all significantly decreased （P＜0.05）； the protein expressions of SETDB2 and H3K9me3 in DRG tissue were significantly increased （P＜0.05）. Intrathecal injection of SETDB2 siRNA reversed the above effects of high-dose of Xibining Ⅱ （P＜0.05）. CONCLUSIONS Xibining Ⅱ may alleviate inflammatory and pain responses by activating the SETDB2/H3K9me3 signaling axis， ultimately improving cold-stimulus pain sensitivity in rats with cold-damp obstruction-type KOA. |
| 期刊： | 2026年第37卷第03期 |
| 作者： | 胡恩睿；魏义保；刘德仁；奥布力艾散·麦麦提吐逊；王培民；廖太阳 |
| AUTHORS： | HU Enrui，WEI Yibao，LIU Deren，Aobuliaisan·Maimaitituxun，WANG Peimin，LIAO Taiyang |
| 关键字： | 膝痹宁Ⅱ方；膝骨关节炎；寒湿痹阻型；疼痛敏感性；SETDB2/H3K9me3信号轴 |
| KEYWORDS： | Xibining Ⅱ； knee osteoarthritis； cold-damp obstruction-type； pain sensitivity； SETDB2/H3K9me3 signaling axis |
| 阅读数： | 3 次 |
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