Department of Urology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
Wuhan University Institute of Urological Disease, Wuhan 430060, China.
J Agric Food Chem. 2023 Sep 13;71(36):13284-13303. doi: 10.1021/acs.jafc.3c01880. Epub 2023 Aug 30.
Acute kidney injury and chronic renal fibrosis are intractable pathological processes to resolve, yet limited strategies are able to effectively address them. Cardamonin (CAD) is a flavonoid with talented antioxidant, anti-inflammatory capacity, and satisfactory biosafety. In our study, animal and cellular models of renal ischemia/reperfusion (I/R) and unilateral ureteral obstruction (UUO) were successfully constructed to confirm whether CAD confers protective effects and underlying mechanisms. Animal experiments demonstrated that CAD application (100 mg/kg) distinctly ameliorated tissue damage and improved renal function. Meanwhile, the continuous oral administration of CAD after UUO surgery efficiently inhibited renal fibrosis as confirmed by hematoxylin-eosin (H&E), Sirius red, and Masson staining as well as the downregulated mRNA and protein expression of collagen I, α-smooth muscle actin (α-SMA), collagen III, and fibronectin. Interestingly, in transforming growth factor β1 (TGF-β1)-stimulated and hypoxia/reoxygenation (H/R)-exposed human kidney-2 (HK-2) cells, protective effects of CAD were again authenticated. Meanwhile, we performed bioinformatics analysis and constructed the "ingredient-target-pathway-disease" network to conclude that the potential mechanisms of CAD protection may be through the regulation of oxidative stress, inflammation, apoptosis, and mitogen-activated protein kinase (MAPK) pathway. Furthermore, experimental data validated that CAD evidently decreased the reactive oxygen species (ROS) production and malondialdehyde (MDA) content while depressing the mRNA and protein expression of inflammatory markers (tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and Il-1β) and inhibiting apoptosis as evidenced by decreased levels of P53, BAX, cleaved caspase-3, and apoptotic rate in renal I/R and UUO models. In addition, the impact of CAD on restraining oxidative stress and inflammation was attributed to its ability to elevate antioxidant enzyme activities including catalase, superoxide dismutase 1 (SOD1), and superoxide dismutase 2 (SOD2) and to inhibit the inflammation-associated MARK/nuclear factor-κB (MAPK/NF-κB) signaling pathway. In conclusion, cardamonin restored the antioxidative capacity to block oxidative stress and suppressed the MAPK/NF-κB signaling pathway to alleviate inflammatory response, thus mitigating I/R-generated acute kidney injury/UUO-induced renal fibrosis in vivo and in vitro, which indicated the potential therapeutic advantage of cardamonin in attenuating acute and chronic kidney injuries.
急性肾损伤和慢性肾纤维化是难以解决的病理过程，但目前可用的治疗策略十分有限。小豆蔻明（CAD）是一种具有强大抗氧化、抗炎能力且生物安全性良好的黄酮类化合物。在本研究中，我们成功构建了肾缺血/再灌注（I/R）和单侧输尿管梗阻（UUO）的动物和细胞模型，以验证 CAD 是否具有保护作用及其潜在机制。动物实验表明，CAD 应用（100mg/kg）可明显改善组织损伤并改善肾功能。同时，UUO 手术后连续口服 CAD 可有效抑制肾纤维化，这可通过苏木精-伊红（H&E）、天狼星红和 Masson 染色以及胶原 I、α-平滑肌肌动蛋白（α-SMA）、胶原 III 和纤维连接蛋白的 mRNA 和蛋白表达下调得到证实。有趣的是，在转化生长因子β1（TGF-β1）刺激和缺氧/复氧（H/R）暴露的人肾-2（HK-2）细胞中，CAD 的保护作用再次得到验证。同时，我们进行了生物信息学分析，并构建了“成分-靶标-通路-疾病”网络，得出 CAD 保护的潜在机制可能是通过调节氧化应激、炎症、细胞凋亡和丝裂原活化蛋白激酶（MAPK）通路。此外，实验数据验证了 CAD 可明显降低活性氧（ROS）的产生和丙二醛（MDA）的含量，同时抑制肾 I/R 和 UUO 模型中炎症标志物（肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）和 Il-1β）的 mRNA 和蛋白表达，并通过降低 P53、BAX、cleaved caspase-3 和细胞凋亡率来抑制细胞凋亡。此外，CAD 抑制氧化应激和炎症的作用归因于其提高抗氧化酶活性（包括过氧化氢酶、超氧化物歧化酶 1（SOD1）和超氧化物歧化酶 2（SOD2））和抑制炎症相关的丝裂原激活蛋白激酶/核因子-κB（MAPK/NF-κB）信号通路的能力。总之，小豆蔻明恢复了抗氧化能力以阻断氧化应激，并抑制了 MAPK/NF-κB 信号通路以减轻炎症反应，从而减轻体内和体外 I/R 引起的急性肾损伤/UUO 引起的肾纤维化，这表明小豆蔻明在减轻急性和慢性肾损伤方面具有潜在的治疗优势。
