Quercetin inhibits necroptosis in cardiomyocytes after ischemia–reperfusion via DNA‐PKcs‐SIRT5‐orchestrated mitochondrial quality control

Phytotherapy Research, Journal Year: 2024, Volume and Issue: 38(5), P. 2496 - 2517

Published: March 6, 2024

Abstract We investigated the mechanism by which quercetin preserves mitochondrial quality control (MQC) in cardiomyocytes subjected to ischemia–reperfusion stress. An enzyme‐linked immunosorbent assay was employed vivo experiments assess myocardial injury markers, measure transcript levels of SIRT5/DNAPK‐cs/MLKL during various time intervals ischemia–reperfusion, and observe structural changes using transmission electron microscopy. In vitro investigations, adenovirus transfection establish a gene‐modified model DNA‐PKcs, primary were obtained from mouse with modified SIRT5 gene. Reverse transcription polymerase chain reaction, laser confocal microscopy, immunofluorescence localization, JC‐1 fluorescence assay, Seahorse energy analysis, other assays applied corroborate regulatory influence on MQC network after ischemia–reperfusion. demonstrated that caused structure myocardium. It seen had beneficial effect tissue, providing protection. As process continued, DNA‐PKcs/SIRT5/MLKL transcripts also found change. investigations revealed mitigated cardiomyocyte oxidative stress through regulated mitophagy kinetics sustain optimal metabolism levels. Quercetin, desuccinylation, modulated stability together they “mitophagy‐unfolded protein response.” This preserved integrity membrane genome, dynamics, metabolism. Quercetin may operate synergistically oversee regulation unfolded response DNA‐PKcs‐SIRT5 interaction.

Language: Английский

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SGLT2 inhibitors: from glucose-lowering to cardiovascular benefits

Cardiovascular Research, Journal Year: 2024, Volume and Issue: 120(5), P. 443 - 460

Published: March 8, 2024

Abstract An increasing number of individuals are at high risk type 2 diabetes (T2D) and its cardiovascular complications, including heart failure (HF), chronic kidney disease (CKD), eventually premature death. The sodium-glucose co-transporter-2 (SGLT2) protein sits in the proximal tubule human nephrons to regulate glucose reabsorption inhibition by gliflozins represents cornerstone contemporary T2D HF management. Herein, we aim provide an updated overview pleiotropy gliflozins, mechanistic insights delineate related (CV) benefits. By discussing evidence obtained preclinical models landmark randomized controlled trials, move from bench bedside across broad spectrum cardio- cerebrovascular diseases. With trials confirming a reduction major adverse CV events (MACE; composite endpoint death, non-fatal myocardial infarction, stroke), SGLT2 inhibitors strongly mitigate for hospitalization diabetics non-diabetics alike while conferring renoprotection specific patient populations. Along four pathophysiological axes (i.e. systemic, vascular, cardiac, renal levels), into key mechanisms that may underlie their beneficial effects, gliflozins’ role modulation inflammation, oxidative stress, cellular energy metabolism, housekeeping mechanisms. We also discuss how this drug class controls hyperglycaemia, ketogenesis, natriuresis, hyperuricaemia, collectively contributing pleiotropic effects. Finally, evolving data setting diseases arrhythmias presented potential implications future research clinical practice comprehensively reviewed.

Language: Английский

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Sodium-glucose cotransporter-2 inhibitors and their potential role in dementia onset and cognitive function in patients with diabetes mellitus: a systematic review and meta-analysis

Frontiers in Neuroendocrinology, Journal Year: 2024, Volume and Issue: 73, P. 101131 - 101131

Published: Feb. 16, 2024

This systematic review and meta-analysis aimed to determine the association between use of sodium-glucose cotransporter 2 (SGLT-2) inhibitors dementia onset as well cognitive function in patients with diabetes mellitus. We comprehensively searched MEDLINE, Embase, CENTRAL databases select relevant studies published up August 2023. The SGLT-2 significantly lowers risk compared SGLT-2i non-users (Hazard ratio: 0.68, 95 % CI: 0.50-0.92). Furthermore, our findings indicated a positive effect inhibitor on score improvement, demonstrated by standardized mean difference 0.88 (95 0.32-1.44), particularly among populations mild impairment or dementia. indicate potential role reducing These underscore need for well-controlled large clinical trials future research this field.

Language: Английский

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Endothelial Protection by Sodium-Glucose Cotransporter 2 Inhibitors: A Literature Review of In Vitro and In Vivo Studies

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(13), P. 7274 - 7274

Published: July 2, 2024

Endothelial dysfunction often precedes the development of cardiovascular diseases, including heart failure. The cardioprotective benefits sodium-glucose cotransporter 2 inhibitors (SGLT2is) could be explained by their favorable impact on endothelium. In this review, we summarize current knowledge direct in vitro effects SGLT2is endothelial cells, as well systematic observations preclinical models. Four putative mechanisms are explored: oxidative stress, nitric oxide (NO)-mediated pathways, inflammation, and cell survival proliferation. Both vivo studies suggest that share a class effect attenuating reactive oxygen species (ROS) enhancing NO bioavailability increasing synthase activity reducing scavenging ROS. Moreover, significantly suppress inflammation preventing expression adhesion receptors pro-inflammatory chemokines vivo, indicating another for protection. However, have not consistently shown regulation molecule SGLT2is. While improve under death-inducing stimuli, angiogenesis remains uncertain. Further experimental required to accurately determine interplay among these various complications, failure acute myocardial infarction.

Language: Английский

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Different types of cell death in diabetic endothelial dysfunction

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 168, P. 115802 - 115802

Published: Oct. 31, 2023

Diabetes mellitus is a metabolic disease caused by disorders of insulin secretion and utilization. Long-term hyperglycemia, resistance, glucose lipid metabolism cause vascular endothelial cell damage. Endothelial dysfunction key feature diabetic complications such as nephropathy, retinopathy, neuropathy, atherosclerosis. Importantly, death thought to be factor contributing injury. Morphologically, can divided into three forms: type I apoptosis, II autophagy, III necrosis. According the difference in function, accidental (ACD) regulated (RCD). RCD controlled process involving numerous proteins precise signaling cascades. Multiple subroutines covered may involved dysfunction, including necroptosis, pyroptosis, entosis, ferroptosis, ferroautophagy, parthanatos, netotic death, lysosome-dependent alkaliptosis, oxeiptosis, cuproptosis, PANoptosis. This article briefly reviews mechanism significance associated with which will help deepen understanding provide new therapeutic ideas.

Language: Английский

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Sirtuin-3 activates the mitochondrial unfolded protein response and reduces cerebral ischemia/reperfusion injury

International Journal of Biological Sciences, Journal Year: 2023, Volume and Issue: 19(13), P. 4327 - 4339

Published: Jan. 1, 2023

Sirtuin-3 (Sirt3) deacetylates several mitochondrial proteins implicated into cerebral ischemia/reperfusion (I/R) injury. The unfolded protein response (UPRmt) favors proteostasis during various stressors. Here, we used Sirt3 transgenic mice and a transient middle artery occlusion model to evaluate the molecular basis of on UPRmt brain post-ischemic dysfunction. present study illustrated that abundance was suppressed in after ischemic abnormalities. Overexpression vivo infarction size attenuated neuroinflammation I/R overexpression restored neural viability by reducing ROS synthesis, maintaining potential improving adenosine triphosphate synthesis. protected neuronal mitochondria against malfunction via eliciting forkhead box O3 (Foxo3)/sphingosine kinase 1 (Sphk1) pathway. Inhibiting either or Foxo3/Sphk1 pathway relieved favorable influence function behavior. In contrast, Sphk1 sufficient reduce size, attenuate neuroinflammation, sustain prevent abnormalities post-ischemia Thus, protects homeostasis, Sirt3/Foxo3/Sphk1 is promosing therapeutic candidate for stroke.

Language: Английский

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Role and molecular mechanisms of SGLT2 inhibitors in pathological cardiac remodeling (Review)

Molecular Medicine Reports, Journal Year: 2024, Volume and Issue: 29(5)

Published: March 11, 2024

Cardiovascular diseases are caused by pathological cardiac remodeling, which involves fibrosis, inflammation and cell dysfunction. This includes autophagy, apoptosis, oxidative stress, mitochondrial dysfunction, changes in energy metabolism, angiogenesis dysregulation of signaling pathways. These heart structure and/or function ultimately result failure. In an effort to prevent this, multiple cardiovascular outcome trials have demonstrated the benefits sodium‑glucose cotransporter type 2 inhibitors (SGLT2is), hypoglycemic drugs initially designed treat diabetes mellitus. SGLT2is include empagliflozin dapagliflozin, listed as guideline 2021 European Guidelines for Heart Failure 2022 American Association/American College Cardiology/Heart Society America Management. recent years, studies using animal models explored mechanisms remodeling. article reviews role remodeling induced different etiologies provide a further evaluation underlying inhibition SGLT2is, well development novel drug targets.

Language: Английский

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Vascular endothelial cell injury: causes, molecular mechanisms, and treatments

MedComm, Journal Year: 2025, Volume and Issue: 6(2)

Published: Jan. 16, 2025

Vascular endothelial cells form a single layer of flat that line the inner surface blood vessels, extending from large vessels to microvasculature various organs. These are crucial metabolic and endocrine components body, playing vital roles in maintaining circulatory stability, regulating vascular tone, preventing coagulation thrombosis. Endothelial cell injury is regarded as pivotal initiating factor pathogenesis diseases, triggered by multiple factors, including infection, inflammation, hemodynamic changes, which significantly compromise integrity function. This review examines causes, underlying molecular mechanisms, potential therapeutic approaches for injury, focusing specifically on damage cardiac ischemia/reperfusion (I/R) sepsis, diabetes. It delves into intricate signaling pathways involved emphasizing oxidative stress, mitochondrial dysfunction, inflammatory mediators, barrier damage. Current treatment strategies-ranging pharmacological interventions regenerative lifestyle modifications-face ongoing challenges limitations. Overall, this highlights importance understanding within context diseases necessity innovative methods improve patient outcomes.

Language: Английский

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Impact of sodium-glucose cotransporter-2 inhibitors on pulmonary vascular cell function and arterial remodeling

World Journal of Cardiology, Journal Year: 2025, Volume and Issue: 17(1)

Published: Jan. 21, 2025

Sodium-glucose cotransporter-2 (SGLT-2) inhibitors represent a cutting-edge class of oral antidiabetic therapeutics that operate through selective inhibition glucose reabsorption in proximal renal tubules, consequently augmenting urinary excretion and attenuating blood levels. Extensive clinical investigations have demonstrated their profound cardiovascular efficacy. Parallel basic science research has elucidated the mechanistic pathways which diverse SGLT-2 beneficially modulate pulmonary vascular cells arterial remodeling. Specifically, these exhibit promising potential enhancing endothelial cell function, suppressing smooth muscle proliferation migration, reversing remodeling, maintaining hemodynamic equilibrium. This comprehensive review synthesizes current literature to delineate mechanisms by enhance function reverse thereby offering novel therapeutic perspectives for diseases.

Language: Английский

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Dapagliflozin improves myocardial flow reserve in patients with type 2 diabetes: the DAPAHEART Trial: a preliminary report

Cardiovascular Diabetology, Journal Year: 2022, Volume and Issue: 21(1)

Published: Sept. 3, 2022

Abstract Objective Cardiovascular (CV) outcome trials have shown that in patients with type 2 diabetes (T2D), treatment sodium-glucose cotransporter-2 inhibitors (SGLT-2i) reduces CV mortality and hospital admission rates for heart failure (HF). However, the mechanisms behind these benefits are not fully understood. This study was performed to investigate effects of SGLT-2i dapagliflozin on myocardial perfusion glucose metabolism T2D stable coronary artery disease (coronary stenosis ≥ 30% < 80%), or without previous percutaneous intervention (> 6 months) but no HF. Methods a single-center, prospective, randomized, double-blind, controlled clinical trial including 16 randomized (10 mg daily) placebo. The primary detect changes uptake (MGU) from baseline 4 weeks after initiation by [(18)F]2-deoxy-2-fluoro-D-glucose (FDG) PET/CT during hyperinsulinemic euglycemic clamp. main secondary assess whether hypothetical MGU were associated blood flow (MBF) reserve (MFR) measured 13 N-ammonia PET/CT. registered at eudract.ema.europa.eu (EudraCT No. 2016-003614-27) ClinicalTrials.gov (NCT 03313752). Results (n = 8) placebo 8). groups well-matched characteristics (age, duration, HbA1c, renal function). There significant change clamp group (2.22 ± 0.59 vs 1.92 0.42 μmol/100 g/min, p 0.41) compared (2.00 0.55 1.60 0.45 0.5). Dapagliflozin significantly improved MFR (2.56 0.26 3.59 0.35 0.006 2.34 0.21 2.38 0.24 0.81; int 0.001) reduction resting MBF corrected cardiac workload (p 0.005; 0.045). A trend toward an increase stress also detected 0.054). Conclusions SGLT-2 inhibition increases patients. We provide new insight into benefits, as our data show more resistant detrimental obstructive atherosclerosis due increased MFR, probably caused improvement microvascular dysfunction. Trial registration EudraCT 2016-003614-27; Identifier: NCT03313752

Language: Английский

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