目的 观察雷公藤Tripterygium wilfordii煨制前后对胶原诱导型关节炎（collagen-induced arthritis，CIA）模型大鼠的影响，并基于代谢组学与琥珀酸/血管内皮生长因子（vascular endothelial growth factor，VEGF）炎症信号通路共同探索雷公藤煨制的增效机制。方法 采用大鼠尾根部皮内注射牛II型胶原乳剂复制CIA大鼠模型，分别给予醋酸地塞米松、雷公藤生品总提取物、雷公藤煨制品总提取物治疗20 d。通过大鼠足肿胀度、关节炎评分、血清中白细胞介素-1β（interleukin-1β，IL-1β）水平、滑膜病理组织切片评估药效；采用代谢组学技术对各组间的代谢差异进行表征；检测滑膜中琥珀酸脱氢酶（succinate dehydrogenase，SDH）活力以及琥珀酸和富马酸的含量；采用免疫组化法检测滑膜组织VEGFA、血小板-内皮细胞黏附分子（platelet endothelial cell adhesion molecule-1，CD31）表达。结果 与模型组比较，雷公藤生品总提取物组和煨制品总提取物组大鼠足肿胀度和关节炎评分显著降低（P<0.05），血清中IL-1β水平显著降低（P<0.05），滑膜组织病理改变明显减轻，滑膜中琥珀酸含量显著降低（P<0.05），SDH活力无明显改变，滑膜组织VEGFA和CD31表达均显著下调（P<0.05）。与生品总提取物组比较，煨制品总提取物组SDH活力无明显改变，其余各项指标明显更向对照组接近（P<0.05）。代谢组学结果表明，从模型组中共筛选出15个差异代谢物，经煨制总提取物治疗后，6个差异代谢物较模型组明显回调（P<0.05），且与生品总提取物组相比明显更接近对照组（P<0.05）。这些代谢物的变化涉及了缬氨酸、亮氨酸和异亮氨酸生物合成、色氨酸代谢、能量代谢、花生四烯酸代谢。结论 煨制可显著提高雷公藤对CIA模型大鼠的治疗效果，其增效作用机制可能与调控缬氨酸、亮氨酸和异亮氨酸生物合成，色氨酸代谢，能量代谢，花生四烯酸代谢途径有关。雷公藤可通过调节琥珀酸/VEGF信号通路改善类风湿关节炎，煨制可增强雷公藤对该信号通路的调控从而发挥增效作用。

Objective To explore the enhancing efficacy mechanism of roasted Tripterygium wilfordii (TW) based on metabolomics and succinate/vascular endothelial growth factor (VEGF) signal pathway by observing the effect of TW before and after roasting on collagen-induced arthritis (CIA) model rats. Methods CIA model rats were induced by hypodermic injecting with bovine type II collagen emulsion into the tails of rats and then treated with dexamethasone acetate, total extract of TW and total extract of roasted TW for 20 d. The curative effect was assessed by paw swelling, arthritis scores, serum levels of interleukin-1β (IL-1β) and pathological sections of synovial tissue. The differences in metabolic expression profiles among groups were characterized based on metabolomics. Succinate dehydrogenase (SDH) viability as well as succinate and fumarate content in synovial tissue were detected. The expressions of VEGFA and platelet endothelial cell adhesion molecule-1 (CD31) in synovial tissue was measured by immunohistochemistry. Results Compared with model group, paw swelling and arthritis scores in total extract and roasted total extract groups were significantly decreased (P< 0.05), interleukin-1β level in serum was significantly decreased (P< 0.05), synovial histopathological changes were ameliorated, content of succinate in synovium was significantly decreased (P< 0.05), SDH activity was not significantly changed, expressions of VEGFA and CD31 in synovium were significantly decreased (P< 0.05). Compared with total extract group, SDH activity in roasted total extract group had no obvious change, and the other indexes were obviously closer to the control group (P < 0.05). The metabolomics results showed that a total of 15 differential metabolites were screened from the model group. Among them, six differential metabolites were significantly callback compared to the model group after treatment with roasted total extract. Moreover, the levels of these six metabolites in roasted total extract group were significantly closer to the levels in control group than in total extract group (P< 0.05). The results indicated that these metabolite changes involved valine, leucine and isoleucine biosynthesis, tryptophan metabolism, energy metabolism and arachidonic acid metabolism.Conclusion Roasting is able to improve the therapeutic effect of TW on CIA model rats. The enhancing efficacy mechanism may be related to the regulation of valine, leucine and isoleucine biosynthesis, tryptophan metabolism, energy metabolism and arachidonic acid metabolic pathways. TW modulates the succinate/VEGF inflammatory signal pathway to improve rheumatoid arthritis. Roasting enhances the anti-rheumatoid arthritis effect of TW by regulating succinate/VEGF signal pathway.

R285.5

国家自然科学基金资助项目（81860686）；江西省主要学科学术和技术带头人资助项目（20182BCB22004）；江西中医药大学校级科技创新团队发展计划（CXTD22007）