Abstract
Alcoholic liver disease (ALD) is the most frequent liver disease worldwide, resulting in severe harm to personal health and posing a serious burden to public health. Based on the reported antioxidant and anti-inflammatory capacities of scutellarin (SCU), this study investigated its protective role in male BALB/c mice with acute alcoholic liver injury after oral administration (10, 25, and 50 mg/kg). The results indicated that SCU could lessen serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and improve the histopathological changes in acute alcoholic liver; it reduced alcohol-induced malondialdehyde (MDA) content and increased glutathione peroxidase (GSH-Px), catalase (CAT), and superoxide dismutase (SOD) activity. Furthermore, SCU decreased tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-Iβ messenger RNA (mRNA) expression levels, weakened inducible nitric oxide synthase (iNOS) activity, and inhibited nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome activation. Mechanistically, SCU suppressed cytochrome P450 family 2 subfamily E member 1 (CYP2E1) upregulation triggered by alcohol, increased the expression of oxidative stress-related nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) pathways, and suppressed the inflammation-related degradation of inhibitor of nuclear factor-κB (NF-κB)-α (IκBα) as well as activation of NF-κB by mediating the protein kinase B (AKT) and p38 mitogen-activated protein kinase (MAPK) pathways. These findings demonstrate that SCU protects against acute alcoholic liver injury via inhibiting oxidative stress by regulating the Nrf2/HO-1 pathway and suppressing inflammation by regulating the AKT, p38 MAPK/NF-κB pathways.
摘要
肝病(ALD)是世界上最常见的肝脏疾病, 严重危害个人健康, 对公共卫生造成严重负担. 基于灯盏花乙素(SCU)抗氧化和抗炎能力的报道, 本研究探究了SCU(10、 25和50 mg/kg, 口服给药)对急性酒精性肝损伤BALB/c小鼠的保护作用. 结果表明: SCU可降低血清谷丙转氨酶(ALT)和天冬氨酸转氨酶(AST)水平, 改善急性酒精性肝组织病理改变; 降低酒精诱导的丙二醛(MDA)含量, 提高谷胱甘肽过氧化物酶(GSH-Px)、 过氧化氢酶(CAT)和超氧化物歧化酶(SOD)活性. 此外, SCU会降低肿瘤坏死因子-α(TNF-α)、 白细胞介素6(IL-6)和IL-1β的mRNA表达水平, 削弱诱导型一氧化氮合酶(iNOS)活性和抑制NOD样受体蛋白3(NLRP3)炎症小体激活. 从机制方面而言, SCU可抑制酒精诱导的CYP450代谢酶家族中的CYP2E1上调, 增加氧化应激相关的核因子E2相关因子2(Nrf2)和血红素加氧酶-1(HO-1)通路的表达, 通过介导蛋白激酶B(AKT)和p38 MAPK通路抑制炎症相关核因子-κB抑制蛋白α因子(IκBα)的降解以及核因子-κB因子(NF-κB)的激活. 这些结果表明, SCU通过调控Nrf2/HO-1通路抑制氧化应激, 通过调控AKT、p38 MAPK/NF-κB通路抑制炎症反应, 从而保护急性酒精性肝损伤.
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Acknowledgments
This work was supported by the Basic Science (Natural Science) Research Project of Higher Education of Jiangsu Province (Nos. 21KJB230001 and 21KJB350019), the Open Foundation of Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening (No. HY202101), the Postdoctoral Science Foundation of Lianyungang (No. LYG20220013), and the Priority Academic Program Development of Jiangsu Higher Education Institutions of China.
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Xiao ZHANG, Zhicheng DONG, Hui FAN, and Guili YU performed the experimental research and data analysis. Xiao ZHANG, Nana HE, and Xueqing LI wrote and edited the manuscript. Qiankun YANG and Enzhuang PAN performed the establishment of animal models. Panpan ZHAO, Mian FU, and Jingquan DONG contributed to the study design, data analysis, writing and editing of the manuscript. All authors have read and approved the final manuscript, and therefore, have full access to all the data in the study and take responsibility for the integrity and security of the data.
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Xiao ZHANG, Zhicheng DONG, Hui FAN, Qiankun YANG, Guili YU, Enzhuang PAN, Nana HE, Xueqing LI, Panpan ZHAO, Mian FU, and Jingquan DONG declare that they have no conflicts of interest.
All institutional and national guidelines for the care and use of laboratory animals were followed. The study was approved by the Jiangsu Ocean University Animal Ethics Committee (No. 2020220671), China.
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Zhang, X., Dong, Z., Fan, H. et al. Scutellarin prevents acute alcohol-induced liver injury via inhibiting oxidative stress by regulating the Nrf2/HO-1 pathway and inhibiting inflammation by regulating the AKT, p38 MAPK/NF-κB pathways. J. Zhejiang Univ. Sci. B 24, 617–631 (2023). https://doi.org/10.1631/jzus.B2200612
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DOI: https://doi.org/10.1631/jzus.B2200612