Neutrophil extracellular traps drive intestinal microvascular endothelial ferroptosis by impairing Fundc1-dependent mitophagy

Redox Biology, Год журнала: 2023, Номер 67, С. 102906 - 102906

Опубликована: Окт. 4, 2023

Microvascular endothelial damage caused by intestinal ischemia‒reperfusion (II/R) is a primary catalyst for microcirculation dysfunction and enterogenous infection. Previous studies have mainly focused on how neutrophil extracellular traps (NETs) ferroptosis cause epithelial injury, little attention has been given to NETs, from circulatory neutrophils, affect cells during II/R. This study aimed unravel the mechanisms through which NETs microvascular dysfunction. We first detected heightened local NET infiltration around microvasculature, accompanied increased cell ferroptosis, resulting in both human animal II/R models. However, administration of inhibitor ferrostatin-1 or inhibition via neutrophil-specific peptidylarginine deiminase 4 (Pad4) deficiency led positive outcomes, with reduced function recovery. Moreover, RNA-seq analysis revealed significant enrichment mitophagy- ferroptosis-related signaling pathways HUVECs incubated NETs. Mechanistically, elevated formation induced Fundc1 phosphorylation at Tyr18 cells, mitophagy inhibition, mitochondrial quality control imbalance, excessive ROS generation lipid peroxidation, Nevertheless, using activator urolithin A AAV-Fundc1 transfection could reverse this process ameliorate damage. demonstrate that NETosis result microcirculatory conclude suppressed can mitigate improving Fundc1-dependent mitophagy. Targeting be promising approach treating II/R-induced

Язык: Английский

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Mitochondrial quality control in human health and disease

Military Medical Research, Год журнала: 2024, Номер 11(1)

Опубликована: Май 29, 2024

Abstract Mitochondria, the most crucial energy-generating organelles in eukaryotic cells, play a pivotal role regulating energy metabolism. However, their significance extends beyond this, as they are also indispensable vital life processes such cell proliferation, differentiation, immune responses, and redox balance. In response to various physiological signals or external stimuli, sophisticated mitochondrial quality control (MQC) mechanism has evolved, encompassing key like biogenesis, dynamics, mitophagy, which have garnered increasing attention from researchers unveil specific molecular mechanisms. this review, we present comprehensive summary of primary mechanisms functions regulators involved major components MQC. Furthermore, critical regulated by MQC its diverse roles progression systemic diseases been described detail. We discuss agonists antagonists targeting MQC, aiming explore potential therapeutic research prospects enhancing stabilize function.

Язык: Английский

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Urolithin A Provides Cardioprotection and Mitochondrial Quality Enhancement in Rodents and Improves Human Cardiovascular Biomarkers

iScience, Год журнала: 2025, Номер 28(2), С. 111814 - 111814

Опубликована: Янв. 14, 2025

Язык: Английский

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SIRT6 Mitigates Heart Failure With Preserved Ejection Fraction in Diabetes

Circulation Research, Год журнала: 2022, Номер 131(11), С. 926 - 943

Опубликована: Окт. 24, 2022

Heart failure with preserved ejection fraction (HFpEF) is a growing health problem without effective therapies. Epidemiological studies indicate that diabetes strong risk factor for HFpEF, and about 45% of patients HFpEF are suffering from diabetes, yet the underlying mechanisms remain elusive.Using combination echocardiography, hemodynamics, RNA-sequencing, molecular biology, in vitro vivo approaches, we investigated roles SIRT6 (sirtuin 6) regulation endothelial fatty acid (FA) transport diabetes.We first observed expression was markedly diminished cardiac tissues heart diabetes. We then established an experimental mouse model induced by long-term high-fat diet feeding low-dose streptozocin challenge. also generated unique humanized transgenic model, which single copy human transgene engineered at Rosa26 locus conditionally Cre-loxP technology. found genetically restoring diabetic mice ameliorated diastolic dysfunction concurrently decreased lipid accumulation. gain- or loss-of-function showed downregulated FA uptake. Mechanistically, suppressed PPARγ through SIRT6-dependent deacetylation histone H3 lysine 9 around promoter region; reduction mediated inhibition Importantly, oral administration small molecule activator MDL-800 to mitigated accumulation dysfunction.The impairment links alteration across barrier. Genetic pharmacological strategies restored function alleviated limiting uptake improving metabolism, thus warranting further clinical evaluation.

Язык: Английский

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Urolithin A inhibits breast cancer progression via activating TFEB-mediated mitophagy in tumor macrophages

Journal of Advanced Research, Год журнала: 2024, Номер unknown

Опубликована: Апрель 1, 2024

Urolithin A (UA) is a naturally occurring compound that converted from ellagitannin-like precursors in pomegranates and nuts by intestinal flora. Previous studies have found UA exerts tumor-suppressive effects through antitumor cell proliferation promotion of memory T-cell expansion, but its role tumor-associated macrophages remains unknown. Our study aims to reveal how affects tumor cells inhibit breast cancer progression. Observe the effect treatment on progression though vivo vitro experiments. Western blot PCR assays were performed discover macrophage autophagy inflammation. Co-ip Molecular docking used explore specific molecular mechanisms. We observed could simultaneously harmful inflammatory factors, especially for InterleuKin-6 (IL-6) necrosis factor α (TNF-α), both macrophages, thereby improving microenvironment delaying Mechanistically, induced key regulator autophagy, transcription EB (TFEB), into nucleus partially mTOR-dependent manner inhibited ubiquitination degradation TFEB, which facilitated clearance damaged mitochondria via mitophagy-lysosomal pathway under supernatant stress, reduced deleterious factors release nucleic acid mitochondria. experimental suggest block recognition TFEB 1433 induce nuclear localization. Notably, demonstrated inhibitory multiple models. elucidated anti-breast perspective macrophages. Specifically, crucial downstream target

Язык: Английский

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Mitochondrial Dysfunction in Endothelial Progenitor Cells: Unraveling Insights from Vascular Endothelial Cells

Biology, Год журнала: 2024, Номер 13(2), С. 70 - 70

Опубликована: Янв. 23, 2024

Endothelial dysfunction is associated with several lifestyle-related diseases, including cardiovascular and neurodegenerative it contributes significantly to the global health burden. Recent research indicates a link between risk factors (CVRFs), excessive production of reactive oxygen species (ROS), mitochondrial impairment, endothelial dysfunction. Circulating progenitor cells (EPCs) are recruited into vessel wall maintain appropriate function, repair, angiogenesis. After attachment, EPCs differentiate mature (ECs). Like ECs, also susceptible CVRFs, metabolic chronic inflammation. Therefore, may have long-term effects on function ECs which differentiate, particularly in presence damage. However, CVRFs impaired has hardly been investigated. In this review, we aim consolidate existing knowledge development vascular endothelium, place context recent studies investigating consequences EPCs, discuss role Thus, gain comprehensive understanding mechanisms involved EPC deterioration relation address potential therapeutic interventions targeting promote function.

Язык: Английский

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Autophagy in High-Fat Diet and Streptozotocin-Induced Metabolic Cardiomyopathy: Mechanisms and Therapeutic Implications

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(4), С. 1668 - 1668

Опубликована: Фев. 15, 2025

Metabolic cardiomyopathy, encompassing diabetic and obese is an escalating global health concern, driven by the rising prevalence of metabolic disorders such as insulin resistance, type 1 2 diabetes, obesity. These conditions induce structural functional alterations in heart, including left ventricular dysfunction, fibrosis, ultimately heart failure, particularly presence coronary artery disease or hypertension. Autophagy, a critical cellular process for maintaining cardiac homeostasis, frequently disrupted cardiomyopathy. This review explores role autophagy pathogenesis high-fat diet (HFD) streptozotocin (STZ)-induced focusing on non-selective selective pathways, mitophagy, ER-phagy, ferritinophagy. Key proteins genes PINK1, Parkin, ULK1, AMPK, mTOR, ATG7, ATG5, Beclin-1, miR-34a are central to regulation Dysregulated autophagic flux impairs mitochondrial function, promotes oxidative stress, drives fibrosis heart. Additionally, processes lipophagy, regulated PNPLA8, ferritinophagy, modulated NCOA4, play pivotal roles lipid metabolism iron homeostasis. Emerging therapeutic strategies targeting autophagy, plant extracts (e.g., curcumin, dihydromyricetin), endogenous compounds sirtuin 3, LC3), lipid/glucose-lowering drugs, offer promising avenues mitigating effects Despite recent advances, precise mechanisms underlying this context remain poorly understood. A deeper understanding autophagy's regulatory networks, involving these proteins, may lead novel approaches treating

Язык: Английский

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A novel strategy for the protective effect of ginsenoside Rg1 against ovarian reserve decline by the PINK1 pathway

Pharmaceutical Biology, Год журнала: 2025, Номер 63(1), С. 68 - 81

Опубликована: Янв. 25, 2025

Context The decline in ovarian reserve is a major concern female reproductive health, often associated with oxidative stress and mitochondrial dysfunction. Although ginsenoside Rg1 known to modulate mitophagy, its effectiveness mitigating remains unclear.

Язык: Английский

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Pharmacological Effects of Urolithin A and Its Role in Muscle Health and Performance: Current Knowledge and Prospects

Nutrients, Год журнала: 2023, Номер 15(20), С. 4441 - 4441

Опубликована: Окт. 19, 2023

Urolithin A (UA) is a naturally occurring compound derived from the metabolism of gut microbiota, which has attracted considerable research attention due to its pharmacological effects and potential implications in muscle health performance. Recent studies have demonstrated that exhibits diverse biological activities, encompassing anti-inflammatory, antioxidant, anti-tumor, anti-aging properties. In terms health, accumulating evidence suggests may promote protein synthesis growth through various pathways, offering promise mitigating atrophy. Moreover, enhance performance by improving mitochondrial function regulating autophagy. Nonetheless, further comprehensive investigations are still warranted elucidate underlying mechanisms assess feasibility safety human subjects, thereby advancing applications realms

Язык: Английский

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Dysfunctional Mitochondria Clearance in Situ: Mitophagy in Obesity and Diabetes-Associated Cardiometabolic Diseases

Diabetes & Metabolism Journal, Год журнала: 2024, Номер 48(4), С. 503 - 517

Опубликована: Фев. 15, 2024

Several mitochondrial dysfunctions in obesity and diabetes include impaired membrane potential, excessive reactive oxygen species generation, reduced DNA, increased Ca2+ flux, dynamics disorders. Mitophagy, specialized autophagy, is responsible for clearing dysfunctional mitochondria physiological pathological conditions. As a paradox, inhibition activation of mitophagy have been observed diabetes-related heart disorders, with both exerting bidirectional effects. Suppressed beneficial to homeostasis, also known as benign mitophagy. On the contrary, most cases, harmful elimination thus defined detrimental In diabetes, two classical pathways appear regulate mitophagy, including PTEN-induced putative kinase 1 (PINK1)/Parkin-dependent receptors/adapters-dependent After pharmacologic interventions morphology function restored, cell viability has further improved. Herein, we summarize dysfunction alterations well underlying upstream mechanisms, order provide novel therapeutic strategies

Язык: Английский

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