Interaction between dual specificity phosphatase-1 and cullin-1 attenuates alcohol-related liver disease by restoring p62-mediated mitophagy

International Journal of Biological Sciences, Год журнала: 2023, Номер 19(6), С. 1831 - 1845

Опубликована: Янв. 1, 2023

Besides abstinence, no effective treatment exists for alcohol-related liver disease (ALD), a dreaded consequence of alcohol abuse. In this study, we assessed the roles on ALD dual specificity phosphatase-1 (DUSP1), an hepatoprotective enzyme, and Cullin-1 (CUL1), member E3 ubiquitin ligase complex that exerts also transcriptional suppression mitochondrial genes. Alcohol downregulated hepatic DUSP1 expression in wild-type mice. Notably, transgenic (Dusp1Tg ) mice showed resistance to alcohol-mediated dysfunction, as evidenced by decreased AST/ALT activity, improved metabolism, suppressed fibrosis, inflammation, oxidative stress. Functional experiments demonstrated overexpression prevents damage hepatocytes through restoring mitophagy. Accordingly, pharmacological blockade mitophagy abolished actions DUSP1. Molecular assays binds cytosolic CUL1 its translocation nucleus. Importantly, silencing restored transcription p62 Parkin, resulting activation, sustained integrity hepatocyte function upon These results indicate downregulation interrupts DUSP1/CUL1 interaction, leading nuclear inhibition via repression Parkin. Thus, targeting DUSP1/CUL1/p62 axis will be key approach restore well alleviate symptoms ALD.

Язык: Английский

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Matrine attenuating cardiomyocyte apoptosis in doxorubicin-induced cardiotoxicity through improved mitochondrial membrane potential and activation of mitochondrial respiratory chain Complex I pathway

Biomedicine & Pharmacotherapy, Год журнала: 2024, Номер 173, С. 116464 - 116464

Опубликована: Март 18, 2024

The study aimed to demonstrate that matrine can reduce apoptosis in H9c2 cells induced by the cardiotoxic anticancer drug doxorubicin (DOX).The researchers pretreated with different concentrations of before exposing them DOX and cultured for 24 h. They assessed cell survival rates using counting kit-8 MTT assay. Hoechst 33258 dye kits were used determine apoptosis, while laser confocal JC-1 method was applied test mitochondrial membrane potential (MMP). Complex I activities detected following manufacturer's protocol. results indicated pretreatment significantly increased rate injured DOX. Additionally, reduced through improvement MMP activity I, which damaged

Язык: Английский

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Deciphering mitochondrial dysfunction: Pathophysiological mechanisms in vascular cognitive impairment

Biomedicine & Pharmacotherapy, Год журнала: 2024, Номер 174, С. 116428 - 116428

Опубликована: Апрель 9, 2024

Vascular cognitive impairment (VCI) encompasses a range of deficits arising from vascular pathology. The pathophysiological mechanisms underlying VCI remain incompletely understood; however, chronic cerebral hypoperfusion (CCH) is widely acknowledged as principal pathological contributor. Mitochondria, crucial for cellular energy production and intracellular signaling, can lead to numerous neurological impairments when dysfunctional. Recent evidence indicates that mitochondrial dysfunction—marked by oxidative stress, disturbed calcium homeostasis, compromised mitophagy, anomalies in dynamics—plays pivotal role pathogenesis. This review offers detailed examination the latest insights into dysfunction within context, focusing on both origins consequences health. It aims lay robust scientific groundwork guiding development refinement mitochondrial-targeted interventions VCI.

Язык: Английский

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Canagliflozin Mitigates Diabetic Cardiomyopathy through Enhanced PINK1-Parkin Mitophagy

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(13), С. 7008 - 7008

Опубликована: Июнь 26, 2024

Diabetic cardiomyopathy (DCM) is a major determinant of mortality in diabetic populations, and the potential strategies are insufficient. Canagliflozin has emerged as cardioprotective agent diabetes, yet its underlying molecular mechanisms remain unclear. We employed high-glucose challenge (60 mM for 48 h) vitro to rat cardiomyocytes (H9C2), with or without canagliflozin treatment (20 µM). In vivo, male C57BL/6J mice were subjected streptozotocin high-fat diet induce followed by administration (10, 30 mg·kg−1·d−1) 12 weeks. Proteomics echocardiography used assess heart. Histopathological alterations assessed use Oil Red O Masson’s trichrome staining. Additionally, mitochondrial morphology mitophagy analyzed through biochemical imaging techniques. A proteomic analysis highlighted autophagy-related proteins after canagliflozin. conditions impaired respiration ATP production, alongside decreasing related expression PINK1-Parkin pathway. High-glucose also reduced PGC-1α-TFAM signaling, which responsible biogenesis. significantly alleviated cardiac dysfunction improved function both vivo. Specifically, suppressed oxidative stress, enhancing levels sustaining respiratory capacity. It activated PINK1-Parkin-dependent via increased phosphorylation adenosine monophosphate-activated protein kinase (AMPK). Notably, PINK1 knockdown negated beneficial effects on integrity, underscoring critical role mediating these protective effects. fosters function, highlighting an effective DCM.

Язык: Английский

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ZLN005, a PGC-1α agonist, delays photoreceptor degeneration by enhancing mitochondrial biogenesis in a murine model of retinitis pigmentosa

Neuropharmacology, Год журнала: 2025, Номер 269, С. 110361 - 110361

Опубликована: Фев. 12, 2025

Retinitis pigmentosa (RP) is a hereditary neurodegenerative disease characterized by the degeneration of photoreceptors caused mutations in various genes. Increasing evidence suggests that mitochondrial biogenesis plays critical role many diseases. This study investigated rd1 mice, widely recognized model RP. Male C57BL/6 mice and age-matched were used for vivo experiments, while H2O2 was employed on 661w cells to establish an vitro model. Our findings revealed regulatory PGC-1α/NRF-1/TFAM pathway significantly downregulated mice. Treatment with ZLN005, PGC-1α agonist, markedly improved visual function alleviated thinning retinal outer nuclear layer. Additionally, ZLN005 enhanced restored photoreceptors. Further analysis confirmed rescued photoreceptor promoting through pathway. In summary, our results highlight progression offers potential strategy delay RP maintaining could be combined existing therapies improving treatment outcomes synergistic pathways.

Язык: Английский

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