2-APQC, a small-molecule activator of Sirtuin-3 (SIRT3), alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Май 15, 2024

Abstract Sirtuin 3 (SIRT3) is well known as a conserved nicotinamide adenine dinucleotide + (NAD )-dependent deacetylase located in the mitochondria that may regulate oxidative stress, catabolism and ATP production. Accumulating evidence has recently revealed SIRT3 plays its critical roles cardiac fibrosis, myocardial fibrosis even heart failure (HF), through deacetylation modifications. Accordingly, discovery of activators elucidating their underlying mechanisms HF should be urgently needed. Herein, we identified new small-molecule activator (named 2-APQC) by structure-based drug designing strategy. 2-APQC was shown to alleviate isoproterenol (ISO)-induced hypertrophy vitro vivo rat models. Importantly, knockout mice, could not relieve HF, suggesting dependent on for protective role. Mechanically, found inhibit mammalian target rapamycin (mTOR)-p70 ribosomal protein S6 kinase (p70S6K), c-jun N-terminal (JNK) transforming growth factor-β (TGF-β)/ small mother against decapentaplegic (Smad3) pathways improve ISO-induced fibrosis. Based upon RNA-seq analyses, demonstrated SIRT3-pyrroline-5-carboxylate reductase 1 (PYCR1) axis closely assoiated with HF. By activating PYCR1, enhance mitochondrial proline metabolism, inhibited reactive oxygen species (ROS)-p38 mitogen activated (p38MAPK) pathway thereby protecting mitochondrialoxidative damage. Moreover, activation facilitate AMP-activated (AMPK)-Parkin necrosis. Together, our results demonstrate targeted alleviates regulating homeostasis, which provide clue exploiting promising candidate future therapeutics.

Язык: Английский

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Se Alleviated Pb-Caused Neurotoxicity in Chickens: SPS2-GPx1-GSH-IL-2/IL-17-NO Pathway, Selenoprotein Suppression, Oxidative Stress, and Inflammatory Injury

Antioxidants, Год журнала: 2024, Номер 13(3), С. 370 - 370

Опубликована: Март 18, 2024

Lead (Pb), a heavy metal environmental pollutant, poses threat to the health of humans and birds. Inflammation is one most common pathological phenomena in case illness poisoning. However, underlying mechanisms inflammation remain unclear. The cerebellum thalamus are important parts nervous system. To date, there have been no reports Pb inducing animal cerebellums or thalami. Selenium (Se) can relieve Therefore, we aimed explore mechanism by which Se alleviates toxicity thalami chickens establishing chicken or/and treatment model. Our results demonstrated that exposure caused inflammatory damage thalami, evidenced characteristics inflammation, decrease anti-inflammatory factors (interleukin (IL)-2 interferon-γ (INF-γ)), increase pro-inflammatory (IL-4, IL-6, IL-12β, IL-17, nitric oxide (NO)). Moreover, found IL-2/IL-17–NO pathway took part Pb-caused injury. above findings were reversed supplementation dietary Se, meaning relieved via pathway. In addition, an up-regulated oxidative index malondialdehyde (MDA) two down-regulated antioxidant indices (glutathione (GSH) total capacity (TAC)) recorded after received stimulation, indicating excess oxidant/antioxidant imbalance stress, stress mediated GSH–IL-2 axis. Interestingly, inhibited four glutathione peroxidase (GPx) family members (GPx1, GPx2, GPx3, GPx4), three deiodinase (Dio) (Dio1, Dio2, Dio3), fifteen other selenoproteins (selenophosphate synthetase 2 (SPS2), selenoprotein (Sel)H, SelI, SelK, SelM, SelO, SelP1, SelPb, SelS, SelT, SelU, (Sep)n1, Sepw1, Sepx1, Sep15), suggesting reduced resulted involving SPS2–GPx1–GSH supplementation, as expected, changes mentioned above, improved mitigated chickens. For first time, discovered SPS2–GPx1–GSH–IL-2/IL-17–NO involved complex conclusion, this study Pb-induced This offers novel insights into pollutant-caused poisoning provides theoretical basis for detoxification effect against toxic pollutants.

Язык: Английский

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Glabridin Ameliorates Alcohol-Caused Liver Damage by Reducing Oxidative Stress and Inflammation via p38 MAPK/Nrf2/NF-κB Pathway

Nutrients, Год журнала: 2023, Номер 15(9), С. 2157 - 2157

Опубликована: Апрель 30, 2023

Licorice is a traditional and versatile herbal medicine food. Glabridin (Gla) kind of isoflavone extracted from the licorice root, which has anti-obesity, anti-atherosclerotic, antioxidative effects. Alcoholic liver disease (ALD) widespread induced by chronic alcohol consumption. However, studies demonstrating effect Gla on ALD are rare. The research explored positive in C57BL/6J mice fed Lieber–DeCarli ethanol diet HepG2 cells treated with ethanol. alleviated ethanol-induced injury, including reducing vacuolation lipid accumulation. serum levels inflammatory cytokines were decreased Gla-treated mice. reactive oxygen species apoptosis attenuated antioxidant enzyme activity restored treatment. In vitro, reduced cytotoxicity, nuclear factor kappa B (NF-κB) translocation, enhanced (erythroid-derived 2)-like 2 (Nrf2) translocation. Anisomycin (an agonist p38 MAPK) eliminated role ethanol-caused oxidative stress inflammation. On whole, can alleviate alcoholic damage via MAPK/Nrf2/NF-κB pathway may be used as novel health product or drug to potentially ALD.

Язык: Английский

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SIRT3/6: an amazing challenge and opportunity in the fight against fibrosis and aging

Cellular and Molecular Life Sciences, Год журнала: 2024, Номер 81(1)

Опубликована: Янв. 31, 2024

Abstract Fibrosis is a typical aging-related pathological process involving almost all organs, including the heart, kidney, liver, lung, and skin. Fibrogenesis highly orchestrated defined by sequences of cellular response molecular signals mechanisms underlying disease. In pathophysiologic conditions associated with organ fibrosis, variety injurious stimuli such as metabolic disorders, epigenetic changes, aging may induce progression fibrosis. Sirtuins protein kind deacetylase which can regulate cell metabolism participate in physiological functions. this review, we outline our current understanding common principles fibrogenic functional role SIRT3/6 addition, novel protective strategies have been identified directly or indirectly according to these mechanisms. Here, highlight biological function focus on well their inhibitors activators preventative therapeutic interventions for tissue Graphical abstract

Язык: Английский

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Roles of SIRT3 in cardiovascular and neurodegenerative diseases

Ageing Research Reviews, Год журнала: 2025, Номер unknown, С. 102654 - 102654

Опубликована: Янв. 1, 2025

Язык: Английский

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Daucosterol Alleviates Alcohol−Induced Hepatic Injury and Inflammation through P38/NF−κB/NLRP3 Inflammasome Pathway

Nutrients, Год журнала: 2023, Номер 15(1), С. 223 - 223

Опубликована: Янв. 1, 2023

Alcoholic liver disease (ALD) is caused by chronic excessive alcohol consumption, which leads to inflammation, oxidative stress, lipid accumulation, fibrosis/cirrhosis, and even cancer. However, there are currently no effective drugs for ALD. Herein, we report that a natural phytosterol Daucosterol (DAU) can effectively protect against injury alcohol, plays anti-inflammatory antioxidative roles in many inflammatory diseases. Our results demonstrate DAU ameliorates inflammation induced through p38/nuclear factor kappa B (NF-κB)/NOD-like receptor protein-3 (NLRP3) inflammasome pathway. Briefly, decreases NF-κB nuclear translocation inhibits NLRP3 activation decreasing p38 phosphorylation. At the same time, also protects hepatic stress accumulation. In conclusion, our research provides new clue about protective effects of naturally active substances on

Язык: Английский

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Inhibiting mir-34a-5p regulates doxorubicin-induced autophagy disorder and alleviates myocardial pyroptosis by targeting Sirt3-AMPK pathway

Biomedicine & Pharmacotherapy, Год журнала: 2023, Номер 168, С. 115654 - 115654

Опубликована: Окт. 6, 2023

Doxorubicin (DOX) is a commonly used chemotherapy drug widely applied in various cancers such as breast cancer, leukemia, and sarcomas. However, its usage limited by cardiotoxicity. Additionally, the cardiac toxicity of DOX accumulates with dose duration, making it imperative to identify therapeutic targets for DOX-induced cardiomyopathy (DIC). It has been reported that miRNAs are involved progression DIC. Mir-34a-5p identified an early diagnostic marker While studies have shown involvement mir-34a-5p DIC apoptosis, not validated animal models, nor potential improvement inhibiting confirmed. Autophagy pyroptosis key factors development can serve treatment. In this study, we found was upregulated heart after treatment inhibition mir-34-5p reduced autophagy We also inhibited regulating reducing mitochondrial reactive oxygen species. Moreover, Sirtuin3 (Sirt3) target gene using double-luciferase reporter assay. overexpression Sirt3 alleviating autophagy. Our research findings suggest beneficial role This provides prospects treating

Язык: Английский

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SIRT3 regulates mitochondrial function: A promising star target for cardiovascular disease therapy

Biomedicine & Pharmacotherapy, Год журнала: 2023, Номер 170, С. 116004 - 116004

Опубликована: Дек. 11, 2023

Dysregulation of mitochondrial homeostasis is common to all types cardiovascular diseases. SIRT3 regulates apoptosis and autophagy, material energy metabolism, oxidative stress, inflammation, fibrosis. As an important mediator node in the network mechanisms, essential many activities. This review explains how tricarboxylic acid cycle treat A novel description impact lifestyle factors on expression from angles nutrition, exercise, temperature provided.

Язык: Английский

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The mechanism and therapeutic strategies in Doxorubicin induced cardiotoxicity: Role of programmed cell death

Cell Stress and Chaperones, Год журнала: 2024, Номер unknown

Опубликована: Сен. 1, 2024

Язык: Английский

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A Putative Adverse Outcome Pathway Linking Diesel Engine Exhaust with Increased Risks of Metabolism-Related Diseases: A Metabolomics-Based Molecular Epidemiology Study

Environmental Technology & Innovation, Год журнала: 2025, Номер 38, С. 104116 - 104116

Опубликована: Фев. 27, 2025

Язык: Английский

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