Oxidative Medicine and Cellular Longevity最新文献

Background and purpose: Liver fibrosis poses a major global health burden, contributing substantially to morbidity and mortality worldwide. This study aims to assess the potential novel mechanisms behind the anti-fibrotic effects of sotagliflozin (Sota) in thioacetamide (TAA)-induced liver fibrosis in rats.

Experimental approach: To induce liver fibrosis in rats, 100 mg/kg of TAA was injected intraperitoneally triweekly for 6 weeks. Treated groups were orally administered sotagliflozin (10 and 20 mg/kg) for 4 weeks, concurrent with TAA injections.

Key results: Alongside the histological alterations, the elevation of liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST), lipid profiles total cholesterol (TC) and triglycerides (TAG), cytokines tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), apoptotic markers (caspase-3 and Bcl2 associated X protein [Bax] BAX), phosphatidylinositol 3-kinase (PI3K), phosphorylated protein kinase B (p-AKT), and the lipid peroxidation marker malondialdehyde (MDA) indicated liver dysfunction induced by TAA. Furthermore, indicators of liver fibrosis encompassed reduced levels of albumin, antioxidants; glutathione (GSH), superoxide dismutase (SOD), heme oxygenase-1 (HO-1), and nuclear factor erythroid 2-related factor 2 (Nrf2), antiapoptotic protein B-cell lymphoma-2 (BCL2), sirtuin-1 (SIRT1) expression, and histopathological alterations.

Conclusion and implications: This study demonstrated that daily oral treatment with sotagliflozin markedly upregulated antioxidant markers such as SIRT1 and Nrf2, attenuated TNF-α, and reduced apoptotic and fibrogenic markers, thereby protecting against TAA-induced liver fibrosis. This may have occurred through the augmentation of SIRT1/Nrf2 expression, the inhibition of PI3K/AKT, resulting in the suppression of apoptosis and inflammation.

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Oxidative stress, driven by an imbalance between oxidants and antioxidants, disrupts redox homeostasis and contributes to the development of chronic diseases, including cancer, diabetes, neurodegenerative disorders, and aging. The NRF2-KEAP1 pathway is a pivotal cellular defense mechanism against oxidative stress, regulating the transcription of cytoprotective genes. Pharmacological NRF2 activation has emerged as a promising strategy to mitigate oxidative stress-related pathologies; however, challenges regarding target specificity, pharmacodynamics, efficacy, and safety remain unresolved. Isoeugenol, a phenylpropanoid found in essential oils, has traditionally been recognized as a skin allergen but is now gaining attention for its potential as an NRF2 activator. Emerging evidence suggests that isoeugenol exerts antioxidant, anti-inflammatory, and neuroprotective effects and modulates metabolic disorders such as diabetes mellitus. Despite its therapeutic potential, the direct correlation between isoeugenol's effects and NRF2 activation remains underexplored. Existing studies indicate that isoeugenol may activate NRF2 through multiple mechanisms, including covalent modification of KEAP1 cysteine residues, increased AKT activation and GSK3β inactivation, and glutathione depletion leading to reactive oxygen species (ROS) generation. Understanding these activation pathways is critical for leveraging isoeugenol as a therapeutic agent. This review provides a comprehensive analysis of isoeugenol's role in modulating NRF2 activity and its implications for treating oxidative stress-driven diseases. By integrating current findings, this review highlights new insights into the therapeutic potential of isoeugenol in translational medicine. We propose future research directions to optimize its application in clinical settings, paving the way for more targeted and effective NRF2-based interventions in chronic disease management.

Increased levels of glutathione (GSH) and related antioxidant processes are thought to predict breast tumor aggressiveness and therapy response. In our 2012 review of 21 studies, we found that most patient breast tumors exhibited increased GSH levels compared to peritumoral tissue. However, there was no clear relationship between GSH levels and histological grade, clinical stage, or patient outcome. For this update, database searches found 59 studies that reported the levels of any of 10 metabolites, including GSH, cysteine (Cys), ascorbate (Asc), and taurine (Tau), in breast tumor tissues. The increase in the number of studies profiling tumor metabolites is mainly due to the use of an array of relatively new metabolomics technologies. However, many of these metabolomics methods are not designed to prevent sample oxidation during tissue procurement and processing. Despite this, these recent studies confirm that the levels of most of the antioxidants or related metabolites are increased in patient breast tumor tissues compared to normal tissues. In addition, poor patient outcomes are often associated with tumor tissues with higher GSH and lower Tau levels. GSH levels also increase with histological grade. There are no clear trends in the relationship between any of the antioxidant levels and tumor stage or genetically defined subtypes. Clearer trends may emerge with more uniform tissue sampling, preparation, and assay procedures. In addition, the increased use of spatial metabolomics methods may help to clarify the relationship between antioxidant levels and clinical markers.

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