Qin Tingting, Wang Mingliang, Zhang Ting, Wang Yingyu, Zhang Yunyun, Hasnat Muhammad, Zhuang Zirui, Ding Yongfang, Peng Yunru
Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
Department of Pharmacology and Toxicology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China.
Front Pharmacol. 2021 Oct 26;12:775730. doi: 10.3389/fphar.2021.775730. eCollection 2021.
Fibrosis is a worldwide public health problem, which typically results from chronic diseases and often leads to organ malfunction. Chronic inflammation has been suggested to be the major trigger for fibrogenesis, yet mechanisms by which inflammatory signals drive fibrogenesis have not been fully elucidated. Total C-21 steroidal glycosides (TCSG) from are the main active components of the root of Royle ex Wight, which exert hepatoprotective and anti-inflammation properties. In this study, we established a mouse model with the coexistence of hepatic and renal fibrosis and aimed to investigate the effects of TCSG from on fibrosis and explored the potential mechanisms. The results of biochemical and pathological examinations showed that TCSG from improved liver and kidney function and alleviated hepatic and renal fibrosis by reducing collagen and extracellular matrix deposition in bile duct ligation and unilateral ureteral occlusion (BDL&UUO) mice. According to network pharmacology analysis, the mechanisms underlying the effects of TCSG from on hepatic and renal fibrosis were associated with inflammatory response pathways, including "Signaling by interleukins", "MAP kinase activation", "MyD88 cascade initiated on plasma membrane", and "Interleukin-1 family signaling". Regression analysis and western blot results revealed that IL-1β/MyD88 inflammation signaling played an essential role in the anti-fibrotic effects of TCSG from . Further data displayed that TCSG from affected inflammatory response and extracellular matrix deposition via suppressing the activation of p38 MAPK/JNK and NF-κB p65 signaling cascades both in the liver and kidney of BDL&UUO mice. Thus, our findings suggest TCSG from as a natural regimen against hepatic and renal fibrosis and provide direct evidence that IL-1β/MyD88 signaling crucially contributes to hepatic and renal fibrosis and modulates liver-kidney crosstalk by maintaining tight control over inflammatory responses.
纤维化是一个全球性的公共卫生问题，通常由慢性疾病引起，且常常导致器官功能障碍。慢性炎症被认为是纤维化形成的主要触发因素，然而炎症信号驱动纤维化形成的机制尚未完全阐明。来自[植物名称未给出]的总C-21甾体糖苷（TCSG）是[植物名称未给出] Royle ex Wight根的主要活性成分，具有肝脏保护和抗炎特性。在本研究中，我们建立了肝纤维化和肾纤维化共存的小鼠模型，旨在研究来自[植物名称未给出]的TCSG对纤维化的影响并探索其潜在机制。生化和病理检查结果表明，来自[植物名称未给出]的TCSG通过减少胆管结扎和单侧输尿管梗阻（BDL&UUO）小鼠的胶原蛋白和细胞外基质沉积，改善了肝脏和肾脏功能，减轻了肝纤维化和肾纤维化。根据网络药理学分析，来自[植物名称未给出]的TCSG对肝纤维化和肾纤维化作用的潜在机制与炎症反应途径有关，包括“白细胞介素信号传导”、“MAP激酶激活”、“质膜上启动的MyD88级联反应”和“白细胞介素-1家族信号传导”。回归分析和蛋白质印迹结果显示，IL-1β/MyD88炎症信号在来自[植物名称未给出]的TCSG的抗纤维化作用中起重要作用。进一步的数据显示，来自[植物名称未给出]的TCSG通过抑制BDL&UUO小鼠肝脏和肾脏中p38 MAPK/JNK和NF-κB p65信号级联反应的激活，影响炎症反应和细胞外基质沉积。因此，我们的研究结果表明，来自[植物名称未给出]的TCSG可作为一种抗肝纤维化和肾纤维化的天然疗法，并提供了直接证据，证明IL-1β/MyD88信号传导对肝纤维化和肾纤维化至关重要，并通过对炎症反应的严格控制来调节肝肾相互作用。
