Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
Cytokine. 2024 Nov;183:156747. doi: 10.1016/j.cyto.2024.156747. Epub 2024 Sep 4.
The liver has a distinctive capacity to regenerate, yet severe acute injury can be life-threatening if not treated appropriately. Inflammation and oxidative stress are central processes implicated in the pathophysiology of acute livery injury. NOX isoforms are important enzymes for ROS generation, NF-κB and NLRP3 activation, its inhibition could be vital in alleviating acute liver injury (ALI). Here in our study, we used apocynin, a natural occurring potent NOX inhibitor, to exploreits potential protective effect against thioacetamide (TAA)-induced ALI through modulating crucial oxidative and inflammatory pathways. Rats were injected once with TAA (500 mg/kg/i.p) and treated with apocynin (10 mg/kg/i.p) twice before TAA challenge. Sera and hepatic tissues were collected for biochemical, mRNA expression, western blot analysis and histopathological assessments. Pretreatment with apocynin improved liver dysfunction evidenced by decreased levels of aminotransferases, ALP, GGT and bilirubin. Apocynin reduced mRNA expression of NOX1 and NOX4 which in turn alleviated oxidative stress, as shown by reduction in MDA and NOx levels, and elevation in GSH levels andcatalase and SOD activities. Moreover, apocynin significantly reduced MPO gene expression. We also demonstrate that apocynin ameliorated inflammation through activating IκBα and suppressing IKKα, IKKβ, NF-κBp65 and p-NF-κBp65, IL-6 andTNF-α. Additionally, apocynin potentiated the gene expression of anti-inflammatory IL-10 and reduced levels of hepatic NLRP3, Caspase-1 and IL-1β. These results suggest that apocynin protects against ALI in association with the inhibition of NOX1 and NOX4 and regulating oxidative and inflammatory pathways.
肝脏具有独特的再生能力，但如果不进行适当治疗，严重的急性损伤可能会危及生命。炎症和氧化应激是急性肝损伤病理生理学中的核心过程。NOX 同工酶是 ROS 产生、NF-κB 和 NLRP3 激活的重要酶，其抑制可能对缓解急性肝损伤（ALI）至关重要。在本研究中，我们使用了一种天然存在的强效 NOX 抑制剂——apocynin，通过调节关键的氧化和炎症途径，来探索其对硫代乙酰胺（TAA）诱导的 ALI 的潜在保护作用。大鼠一次性注射 TAA（500mg/kg/i.p），在 TAA 攻击前两次用 apocynin（10mg/kg/i.p）处理。收集血清和肝组织进行生化、mRNA 表达、western blot 分析和组织病理学评估。apocynin 预处理可改善肝功能，表现为转氨酶、碱性磷酸酶、γ-谷氨酰转移酶和胆红素水平降低。apocynin 降低了 NOX1 和 NOX4 的 mRNA 表达，从而减轻了氧化应激，表现为 MDA 和 NOx 水平降低，GSH 水平和过氧化氢酶、超氧化物歧化酶活性升高。此外，apocynin 显著降低了 MPO 基因表达。我们还证明，apocynin 通过激活 IκBα 和抑制 IKKα、IKKβ、NF-κBp65 和 p-NF-κBp65、IL-6 和 TNF-α，改善了炎症。此外，apocynin 增强了抗炎性 IL-10 的基因表达，并降低了肝 NLRP3、Caspase-1 和 IL-1β 的水平。这些结果表明，apocynin 可通过抑制 NOX1 和 NOX4 以及调节氧化和炎症途径来预防 ALI。
