Apocynin alleviates thioacetamide-induced acute liver injury: Role of NOX1/NOX4/NF-κB/NLRP3 pathways

IF 3.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Cytokine Pub Date : 2024-09-04 DOI:10.1016/j.cyto.2024.156747
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Abstract

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 explore its 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 and catalase 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 and TNF-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.

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Apocynin 可减轻硫代乙酰胺诱导的急性肝损伤:NOX1/NOX4/NF-κB/NLRP3通路的作用
肝脏具有独特的再生能力,但如果治疗不当,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的核心过程。NOX 同工酶是产生 ROS、激活 NF-κB 和 NLRP3 的重要酶类,抑制 NOX 同工酶对缓解急性肝损伤(ALI)至关重要。在本研究中,我们使用了一种天然的强效 NOX 抑制剂阿朴西宁,探讨其通过调节关键的氧化和炎症通路对硫代乙酰胺(TAA)诱导的 ALI 的潜在保护作用。给大鼠注射一次 TAA(500 毫克/千克/i.p.),并在 TAA 挑战前用阿朴昔宁(10 毫克/千克/i.p.)治疗两次。收集血清和肝组织进行生化、mRNA 表达、Western 印迹分析和组织病理学评估。转氨酶、谷丙转氨酶(ALP)、谷草转氨酶(GGT)和胆红素水平的降低证明阿朴昔宁的预处理改善了肝功能障碍。阿朴昔宁降低了 NOX1 和 NOX4 的 mRNA 表达,进而缓解了氧化应激,表现为 MDA 和 NOx 水平降低,GSH 水平、过氧化氢酶和 SOD 活性升高。此外,阿朴昔宁还能明显降低 MPO 基因的表达。我们还发现,阿朴西宁通过激活 IκBα、抑制 IKKα、IKKβ、NF-κBp65 和 p-NF-κBp65、IL-6 和 TNF-α 改善了炎症反应。此外,阿朴昔宁还能促进抗炎药物 IL-10 的基因表达,降低肝脏 NLRP3、Caspase-1 和 IL-1β 的水平。这些结果表明,阿朴西宁对 ALI 的保护作用与抑制 NOX1 和 NOX4 以及调节氧化和炎症途径有关。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cytokine
Cytokine 医学-免疫学
CiteScore
7.60
自引率
2.60%
发文量
262
审稿时长
48 days
期刊介绍: The journal Cytokine has an open access mirror journal Cytokine: X, sharing the same aims and scope, editorial team, submission system and rigorous peer review. * Devoted exclusively to the study of the molecular biology, genetics, biochemistry, immunology, genome-wide association studies, pathobiology, diagnostic and clinical applications of all known interleukins, hematopoietic factors, growth factors, cytotoxins, interferons, new cytokines, and chemokines, Cytokine provides comprehensive coverage of cytokines and their mechanisms of actions, 12 times a year by publishing original high quality refereed scientific papers from prominent investigators in both the academic and industrial sectors. We will publish 3 major types of manuscripts: 1) Original manuscripts describing research results. 2) Basic and clinical reviews describing cytokine actions and regulation. 3) Short commentaries/perspectives on recently published aspects of cytokines, pathogenesis and clinical results.
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