背景:毛冬青钩。etArn(IP),传统上以其促进血液循环的特性而闻名,肿胀和疼痛缓解,热量清除,和排毒,已用于治疗血栓闭塞性脉管炎(TAO)。尽管它的传统应用,IP对TAO发挥治疗作用的具体机制尚不清楚.
目的:本研究旨在揭示IP对TAO的治疗作用的潜在机制,采用网络药理学和代谢组学方法。
方法:在本研究中,通过股动脉注射月桂酸钠建立大鼠TAO模型,随后口服IP给药7天。测量血浆凝固参数以评估IP的治疗效果。对股动脉和腓肠肌的潜在影响进行了组织病理学评估。网络药理学用于预测TAO的相关靶标和模型途径。超高效液相色谱-四极杆飞行时间质谱(UPLC-QTOF-MS/MS)用于大鼠血浆的代谢谱分析。免疫组织化学(IHC)用于验证IP促进TAO血液循环的机制。
结果:研究表明,IP改善了TAO的血液生化功能,在血管保护和维持正常血管和腓肠肌形态方面发挥了重要作用。网络药理学表明,IP化合物在调节脂质和动脉粥样硬化中起治疗作用。代谢组学分析显示,涉及鞘脂代谢和类固醇生物合成的途径被明显破坏。联合分析显示溶血磷脂酰胆碱和IP组分之间有很强的相关性,包括三萜类和环烯醚萜类成分,通过调节鞘脂代谢支持IP的治疗作用。此外,SPHK1/S1PR1,TNF-α的表达水平降低,IL-1β,在IP治疗组中观察到IL-6,表明IP主要通过调节SPHK1/S1PR1信号通路对脉管系统发挥保护作用。
结论:在这项研究中,我们发现IP通过调节鞘脂途径的稳态紊乱保护血管免受损伤并治疗TAO.这些发现表明IP通过调节鞘脂代谢和SPHK1/S1PR1信号通路促进血管系统,降低炎症因子水平,为其治疗潜力提供新的见解。
BACKGROUND: Ilex pubescens Hook. et Arn (IP), traditionally known for its properties of promoting blood circulation, swelling and pain relief, heat clearing, and detoxification, has been used in the treatment of thromboangiitis obliterans (TAO). Despite its traditional applications, the specific mechanisms by which IP exerts its therapeutic effects on TAO remain unclear.
OBJECTIVE: This study aims to uncover the underlying mechanisms in the therapeutic effects of IP on TAO, employing network pharmacology and metabolomic approaches.
METHODS: In this study, a rat TAO model was established by injecting sodium laurate through the femoral artery, followed by the oral administration of IP for 7 days. Plasma coagulation parameters were measured to assess the therapeutic effects of IP. The potential influence on the femoral artery and gastrocnemius muscle was histopathologically evaluated. Network pharmacology was employed to predict relevant targets and model pathways for TAO. Ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS/MS) was used for the metabolic profile analysis of rat plasma. Immunohistochemistry (IHC) was used to verify the mechanisms by which IP promotes blood circulation in TAO.
RESULTS: The study revealed that IP improved blood biochemical function in TAO and played a significant role in vascular protection and maintaining normal blood vessels and gastrocnemius morphologies. Network pharmacology showed that IP compounds play a therapeutic role in modulating lipids and atherosclerosis. Metabolomic analysis revealed that the pathways involved in sphingolipid metabolism and steroid biosynthesis were significantly disrupted. The joint analysis showed a strong correlation between lysophosphatidylcholine and IP components, including triterpenoid and iridoid components, which support the curative action of IP through the modulation of sphingolipid metabolism. Furthermore, decreased expression levels of SPHK1/S1PR1, TNF-α, IL-1β, and IL-6 were observed in the IP-treated group, suggesting that IP exerts a protective effect on the vasculature primarily by regulating of the SPHK1/S1PR1 signaling pathway.
CONCLUSIONS: In this study, we found that IP protects the vasculature against injury and treats TAO by regulating the steady-state disturbance of the sphingolipid pathway. These findings suggest that IP promotes vasculature by modulating sphingolipid metabolism and SPHK1/S1PR1 signaling pathway and reduce levels of inflammatory factors, offering new insights into its therapeutic potential.