FNDC5/irisin mitigates the cardiotoxic impacts of cancer chemotherapeutics by modulating ROS-dependent and -independent mechanisms

Redox Biology, Journal Year: 2025, Volume and Issue: 80, P. 103527 - 103527

Published: Feb. 4, 2025

Cardiotoxicity remains a major limiting factor in the clinical implementation of anthracycline chemotherapy. Though etiology doxorubicin-dependent heart damage has yet to be fully elucidated, ability doxorubicin DNA and trigger oxidative stress have been heavily implicated pathogenesis chemotherapy-associated cardiomyopathy. Here, we demonstrate that fibronectin type III domain-containing protein 5 (FNDC5), precursor for myokine irisin, is depleted hearts human cancer patients or mice exposed chemotherapeutics. In cardiomyocytes, restoration FNDC5 expression was sufficient mitigate reactive oxygen species (ROS) accumulation apoptosis following exposure, effects dependent on irisin encoding domain as well signaling via putative integrin receptor. Intriguingly, identified two parallel cascades impacted by cardiomyocytes: ROS-driven intrinsic mitochondrial pathway ROS-independent Ataxia Telangiectasia Rad3-Related Protein (ATR)/Checkpoint Kinase 1 (Chk1) pathway. fact, forms co-precipitable complex with Chk1 alluding possible intracellular actions this canonically membrane-associated protein. Whereas overexpression murine cardioprotective, introduction FNDC5-targeted shRNA into myocardium Bax up-regulation, ATR/Chk1 activation, stress, cardiac fibrosis, loss ventricular function, compromised animal survival. The detrimental impact depletion function could mitigated treatment inhibitor identifying hyperactivity causative disease. our data point potential utility FNDC5/irisin-targeted agents chemotherapy-induced cardiotoxicity, also found significant down regulation aged attenuated cardioprotective impacts exposure. Together underscore importance FNDC5/irisin maintenance health over lifespan.

Language: Английский

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Irisin Alleviates Impaired Mitochondrial Fusion via Enhancing PKA/SIRT3/mTOR Pathway in Hepatic Steatosis

Journal of Gastroenterology and Hepatology, Journal Year: 2025, Volume and Issue: unknown

Published: April 2, 2025

Hepatic steatosis, a hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD), arises from disrupted lipid homeostasis. Mitochondrial dysfunction, particularly imbalances in mitochondrial fusion and fission, plays crucial role MASLD progression. Irisin, an exercise-induced myokine, is involved metabolism, though its precise mechanisms action remain unclear. An irisin-Fc protein was prophylactically administered to mice with high-fat diet (HFD)-induced for 12 weeks. Liver tissues were analyzed using oil red O staining hepatic serum profiling evaluate irisin's therapeutic efficacy. Expression levels proteins fatty acid metabolism dynamics assessed. In palmitate (PA)-treated HepG2 cells, morphology analyzed, uptake determined through colocalization fluorescently labeled PA mitochondria. PKA activity SIRT3 expression validated agonist/inhibitor overexpression or knockdown via plasmid transfection siRNA. Irisin significantly reduced accumulation HFD-induced mouse models PA-treated cells. These effects associated enhanced fusion, indicated by increased mitofusin 2 optic atrophy type 1 excessive evidenced decreased activation dynamin-related 1. changes mediated partly PKA/SIRT3/mTOR pathway activation, which facilitated β-oxidation while inhibiting lipogenesis. Our results demonstrate the protective irisin alleviating steatosis regulating dynamics. findings provide valuable evidence antisteatogenic potential management.

Language: Английский

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The molecular determinants regulating redox signaling in diabetic endothelial cells

Frontiers in Pharmacology, Journal Year: 2025, Volume and Issue: 16

Published: April 1, 2025

Oxidation and reduction are vital for keeping life through several prime mechanisms, including respiration, metabolism, other energy supplies. Mitochondria considered the cell’s powerhouse use nutrients to produce redox potential generate ATP H 2 O process of oxidative phosphorylation by operating electron transfer proton pumping. Simultaneously, mitochondria also oxygen free radicals, called superoxide (O − ), non-enzymatically, which interacts with moieties reactive species (ROS), such as hydrogen peroxide (H peroxynitrite (ONOO−), hydroxyl radical (OH ). These modify nucleic acids, proteins, carbohydrates ultimately cause damage organs. The nutrient-sensing kinases, AMPK mTOR, function a key regulator cellular ROS levels, loss or aberrant activation mTOR signaling causes production compromises oxidant status, resulting in various injuries. increased not only directly damages DNA, lipids but alters pathways, MAPK PI3K, accumulation HIF-1α nucleus, NFkB-mediated transcription pro-inflammatory cytokines. factors mesenchymal renal endothelial cells. Here, we discuss biology that underlies pathophysiology diabetic

Language: Английский

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Irisin levels in type 2 diabetes mellitus with and without non-alcoholic fatty liver disease: a case-control study

Prospects in Pharmaceutical Sciences, Journal Year: 2024, Volume and Issue: 22(3), P. 210 - 218

Published: Sept. 26, 2024

Background: Fatty liver disease, particularly non-alcoholic fatty disease (NAFLD), affects around 25% of adults globally and up to 40% in developed countries. Often coexisting with type 2 diabetes mellitus (T2DM), NAFLD is linked insulin resistance metabolic syndrome. Irisin, a myokine induced by exercise, shows promise enhancing sensitivity, reducing hepatic steatosis, improving health. Despite its potential, further research needed fully understand irisin's mechanisms clinical implications T2DM. Objectives: This study investigates the irisin levels T2DM patients without compares them healthy controls. Methods: A case-control has been conducted involving 90 controls, aged 30-55 years, recruited from SCB Medical College, Cuttack, between September 2021 August 2022. Participants were screened for using Hepatosis Steatosis Index (HSI) divided into four groups: NAFLD, controls NAFLD. Serum measured ELISA. Anthropometric data, physical activity, various biochemical parameters assessed analyzed. Results: The significantly lower compared (p = 0.001). Among patients, those had than though not statistically significant 0.299). Significant correlations observed sensitivity markers such as HOMA-IR QUICKI across different groups. Conclusion: Lower highlight potential role pathogenesis disorders. Further elucidate therapeutic

Language: Английский

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