Lu Xiaohui, Wu Kefei, Jiang Simin, Li Yi, Wang Yating, Li Hongyu, Li Guanglan, Liu Qinghua, Zhou Yi, Chen Wei, Mao Haiping
Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
NHC Key Laboratory of Clinical Nephrology, Guangdong Provincial Key Laboratory of Nephrology, Sun Yat-sen University, Guangzhou, China.
Front Pharmacol. 2023 May 17;14:1153503. doi: 10.3389/fphar.2023.1153503. eCollection 2023.
Baicalein (5,6,7-trihydroxyflavone) is a traditional Chinese medicine with multiple pharmacological and biological activities including anti-inflammatory and anti-fibrotic effects. However, whether baicalein has a therapeutic impact on peritoneal fibrosis has not been reported yet. In the present study, network pharmacology and molecular docking approaches were performed to evaluate the role and the potential mechanisms of baicalein in attenuating peritoneal dialysis-associated peritoneal fibrosis. The results were validated in both animal models and the cultured human mesothelial cell line. Nine intersection genes among baicalein targets and the human peritoneum RNA-seq dataset including four encapsulating peritoneal sclerosis samples and four controls were predicted by network analysis. Among them, MMP2, BAX, ADORA3, HIF1A, PIM1, CA12, and ALOX5 exhibited higher expression in the peritoneum with encapsulating peritoneal sclerosis compared with those in the control, which might be crucial targets of baicalein against peritoneal fibrosis. Furthermore, KEGG and GO enrichment analyses suggested that baicalein played an anti-peritoneal fibrosis role through the regulating cell proliferation, inflammatory response, and AGE-RAGE signaling pathway. Moreover, molecular docking analysis revealed a strong potential binding between baicalein and MMP2, which was consistent with the predictive results. Importantly, using a mouse model of peritoneal fibrosis by intraperitoneally injecting 4.25% glucose dialysate, we found that baicalein treatment significantly attenuated peritoneal fibrosis, as evident by decreased collagen deposition, protein expression of -SMA and fibronectin, and peritoneal thickness, at least, by reducing the expression of MMP2, suggesting that baicalein may have therapeutic potential in suppressing peritoneal dialysis-related fibrosis.
黄芩素（5,6,7 - 三羟基黄酮）是一种具有多种药理和生物学活性的传统中药，包括抗炎和抗纤维化作用。然而，黄芩素对腹膜纤维化是否具有治疗作用尚未见报道。在本研究中，采用网络药理学和分子对接方法来评估黄芩素在减轻腹膜透析相关腹膜纤维化中的作用及潜在机制。在动物模型和培养的人腹膜间皮细胞系中对结果进行了验证。通过网络分析预测了黄芩素靶点与人腹膜RNA测序数据集（包括四个包裹性腹膜硬化样本和四个对照）之间的9个交集基因。其中，与对照组相比，MMP2、BAX、ADORA3、HIF1A、PIM1、CA12和ALOX5在包裹性腹膜硬化的腹膜中表达较高，这可能是黄芩素抗腹膜纤维化的关键靶点。此外，KEGG和GO富集分析表明，黄芩素通过调节细胞增殖、炎症反应和AGE - RAGE信号通路发挥抗腹膜纤维化作用。而且，分子对接分析显示黄芩素与MMP2之间具有很强的潜在结合力，这与预测结果一致。重要的是，通过腹腔注射4.25%葡萄糖透析液建立小鼠腹膜纤维化模型，我们发现黄芩素治疗可显著减轻腹膜纤维化，表现为胶原沉积减少、α - SMA和纤连蛋白的蛋白表达降低以及腹膜厚度减小，至少是通过降低MMP2的表达实现的，这表明黄芩素在抑制腹膜透析相关纤维化方面可能具有治疗潜力。
