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 protects against cerebral ischemia reperfusion injury in a SIRT3-dependent manner

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

Published: April 1, 2025

Cerebral ischemia-reperfusion (CIR) injury critically impacts stroke prognosis, yet effective therapeutic strategies remain limited. Irisin, an exercise-induced myokine, exhibits neuroprotective effects against cerebral ischemia. SIRT3, a mitochondrial deacetylase, is similarly implicated in mitigating injury. Given that irisin exerts protection via AMPK/PGC-1α pathway activation and SIRT3 acts downstream of PGC-1α , we hypothesized mediates irisin's neuroprotection CIR In vivo was modeled by inducing transient middle artery occlusion (MCAO) mice, while vitro conditions were replicated using oxygen-glucose deprivation (OGD) PC12 neuronal cultures. To elucidate the mechanistic role targeted interventions implemented: expression silenced transfection with small interfering RNA (siRNA), its enzymatic activity pharmacologically inhibited 3-TYP, selective inhibitor. Apoptotic systematically evaluated through TUNEL staining, Western blot analysis caspase-3, Bax Bcl-2. Oxidative stress parameters, including malondialdehyde (MDA) levels glutathione (GSH) content, measured colorimetric assays. Neurological function mice quantified modified Severity Score (mNSS). Our results demonstrated mitigates apoptosis oxidative dose-dependently activating signaling. At optimal dosage, effectively restored levels, reduced damage, improved neurological recovery models. Notably, significantly attenuated specific Further validation experiments revealed overexpression synergistically enhanced irisin-mediated OGD-induced injury, whereas knockout substantially diminished efficacy. data shown exerted protective at least part, activation. This study establishes irisin/SIRT3 as novel target for ischemic stroke, providing insights future interventions.

Language: Английский

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Circulatory factors in stroke protection and recovery

Brain Research, Journal Year: 2025, Volume and Issue: unknown, P. 149594 - 149594

Published: March 1, 2025

Language: Английский

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Oxidative Stress: A New Pathophysiological Pathway in Parkinson’s Disease and a Potential Target of the Brain‐Sport Crosstalk

Parkinson s Disease, Journal Year: 2025, Volume and Issue: 2025(1)

Published: Jan. 1, 2025

Oxidative stress (OS), a condition that occurs when the balance between reactive oxygen species production and antioxidant defense mechanisms is disrupted, has been implicated in pathogenesis of several neurological conditions, including neurodegenerative vascular disorders. Ferroptosis mechanism mediating OS-induced damage, with growing evidence specific involvement both Parkinson's disease (PD) ischemic stroke. Regular physical activity may have an effect by increasing nonenzymatic enzymatic antioxidants. Among biological mediators activity, irisin act as agent capable inducing systemic changes crossing brain-blood barrier. This review aims to describe main role OS pathophysiology PD, highlighting putative emphasizing potential targeting possible shared preventive symptomatic treatment approach.

Language: Английский

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Short- and long-term effects of concurrent aerobic and resistance training on circulating irisin levels in overweight or obese individuals: a systematic review and meta-analysis of randomized controlled trials

PeerJ, Journal Year: 2024, Volume and Issue: 12, P. e17958 - e17958

Published: Sept. 19, 2024

Concurrent training (CT) is emerging as a practical and effective approach to enhance body composition, cardiovascular function, muscle mass, thereby elevating overall individual health. This study aims systematically investigate the effects of short- long-term concurrent aerobic resistance on circulating irisin levels in overweight or obese individuals.

Language: Английский

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Exercise, exerkines and exercise mimetic drugs: Molecular mechanisms and therapeutics

Life Sciences, Journal Year: 2024, Volume and Issue: 359, P. 123225 - 123225

Published: Nov. 9, 2024

Language: Английский

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