Manool调节Keap1/Nrf2/ARE通路对CCl - 4诱导的小鼠肝毒性的保护作用

IF 0.9 Q4 GENETICS & HEREDITY

Gene Reports Pub Date : 2025-09-12 DOI:10.1016/j.genrep.2025.102341

Hafiza Adeena Saleem Khan , Imtiaz Mustafa , Nimra Aziz , Khalil Ahmad , Syed Ali Raza Shah , Jaweria Nisar , Mirza Muhammad Suleman

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引用次数: 0

摘要

肝脏疾病是一个主要的健康问题，氧化应激是肝细胞损伤的关键因素。甘露醇是一种来自鼠尾草的二萜，据报道具有抗氧化活性，但其保护肝脏的作用仍未得到充分研究。目的探讨甘露醇对ccl4诱导小鼠肝毒性的保护作用，重点探讨其对Keap1/Nrf2/ARE通路的保护作用。方法40只白化病小鼠（每组10只）分为阴性对照组（NC，健康小鼠）、阳性对照组（PC，未处理CCl4诱导小鼠）、标准对照组（SC，水飞蓟素诱导CCl4小鼠，剂量为100 mg/kg体重）和两个治疗组（Mn-1和Mn-2，剂量分别为1和2 mg/kg体重的CCl4诱导小鼠）。治疗21天。检测血清肝功能指标、氧化应激指标、凋亡蛋白（Bcl-2、Bax、Caspase-3、Caspase-9）、炎症介质（NF-κB、TNF-α、IL-1β、IL-6、COX-2）和基因表达（Keap1、Nrf2、HO-1、NQO1）。组织病理学检查证实肝保护。结果manool恢复ALT、AST和蛋白谱呈剂量依赖性。它增加了营业税和商品及服务税，同时降低了服务价格。基因表达分析显示Keap1下调，Nrf2、HO-1、NQO1上调。manol还能降低促凋亡（Bax、Caspase-3、Caspase-9）和炎症标志物（NF-κB、TNF-α、IL-1β、IL-6、COX-2），增强抗凋亡Bcl-2。组织学分析证实ccl4引起的肝损伤减弱。结论甘醇通过调节氧化应激、细胞凋亡、炎症及Keap1/Nrf2/ARE通路发挥肝保护作用。这些发现支持其作为氧化性肝损伤的天然候选物的潜力，尽管进一步的机制和转化研究是必要的。

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Manool modulates Keap1/Nrf2/ARE pathway to protect against CCl₄-induced hepatotoxicity in mice

Background

Liver diseases are a major health concern, with oxidative stress being a key contributor to hepatocellular injury. Manool, a diterpene from Salvia species, has reported antioxidant activity, but its hepatoprotective role remains underexplored.

Objective

To evaluate the protective effects of Manool against CCl4-induced hepatotoxicity in mice, focusing on the Keap1/Nrf2/ARE pathway.

Methods

Forty albino mice (n = 10 per group) were divided into negative control (NC; healthy mice), positive control (PC; CCl4 induced mice without treatment), standard control (SC; CCl4 induced mice treated with silymarin at dose 100 mg/kg body weight), and two treatment groups (Mn-1 and Mn-2; CCl4 induced mice treated with manool at dose of 1 and 2 mg/kg body weight respectively). Treatments were administered for 21 days. Serum liver function markers, oxidative stress indices, apoptotic proteins (Bcl-2, Bax, Caspase-3, Caspase-9), inflammatory mediators (NF-κB, TNF-α, IL-1β, IL-6, COX-2), and gene expression (Keap1, Nrf2, HO-1, NQO1) were assessed. Histopathological examination was performed to confirm liver protection.

Results

Manool restored ALT, AST, and protein profiles in a dose-dependent manner. It increased TAC and GST, while reducing TOS. Gene expression analysis showed downregulation of Keap1 and upregulation of Nrf2, HO-1, and NQO1. Manool also reduced pro-apoptotic (Bax, Caspase-3, Caspase-9) and inflammatory markers (NF-κB, TNF-α, IL-1β, IL-6, COX-2), while enhancing anti-apoptotic Bcl-2. Histological analysis confirmed attenuation of CCl₄-induced hepatic damage.

Conclusion

Manool exerts hepatoprotective effects by modulating oxidative stress, apoptosis, inflammation, and the Keap1/Nrf2/ARE pathway. These findings support its potential as a natural candidate for managing oxidative liver injury, though further mechanistic and translational studies are warranted.

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来源期刊

Gene Reports Biochemistry, Genetics and Molecular Biology-Genetics

CiteScore

3.30

自引率

7.70%

发文量

246

审稿时长

49 days

期刊介绍： Gene Reports publishes papers that focus on the regulation, expression, function and evolution of genes in all biological contexts, including all prokaryotic and eukaryotic organisms, as well as viruses. Gene Reports strives to be a very diverse journal and topics in all fields will be considered for publication. Although not limited to the following, some general topics include: DNA Organization, Replication & Evolution -Focus on genomic DNA (chromosomal organization, comparative genomics, DNA replication, DNA repair, mobile DNA, mitochondrial DNA, chloroplast DNA). Expression & Function - Focus on functional RNAs (microRNAs, tRNAs, rRNAs, mRNA splicing, alternative polyadenylation) Regulation - Focus on processes that mediate gene-read out (epigenetics, chromatin, histone code, transcription, translation, protein degradation). Cell Signaling - Focus on mechanisms that control information flow into the nucleus to control gene expression (kinase and phosphatase pathways controlled by extra-cellular ligands, Wnt, Notch, TGFbeta/BMPs, FGFs, IGFs etc.) Profiling of gene expression and genetic variation - Focus on high throughput approaches (e.g., DeepSeq, ChIP-Seq, Affymetrix microarrays, proteomics) that define gene regulatory circuitry, molecular pathways and protein/protein networks. Genetics - Focus on development in model organisms (e.g., mouse, frog, fruit fly, worm), human genetic variation, population genetics, as well as agricultural and veterinary genetics. Molecular Pathology & Regenerative Medicine - Focus on the deregulation of molecular processes in human diseases and mechanisms supporting regeneration of tissues through pluripotent or multipotent stem cells.