The role of myocardial energy metabolism perturbations in diabetic cardiomyopathy: from the perspective of novel protein post-translational modifications

Clinical Epigenetics, Journal Year: 2025, Volume and Issue: 17(1)

Published: Jan. 26, 2025

Diabetic cardiomyopathy (DbCM), a significant chronic complication of diabetes, manifests as myocardial hypertrophy, fibrosis, and other pathological alterations that substantially impact cardiac function elevate the risk cardiovascular diseases patient mortality. Myocardial energy metabolism disturbances in DbCM, encompassing glucose, fatty acid, ketone body lactate metabolism, are crucial factors contribute to progression DbCM. In recent years, novel protein post-translational modifications (PTMs) such lactylation, β-hydroxybutyrylation, succinylation have been demonstrated be intimately associated with process, conjunction acetylation, they participate regulation activity gene expression cardiomyocytes. This review examines epigenetic pathogenesis primarily focusing on perturbations PTMs them. It provides detailed analysis mechanisms these DbCM enhance understanding pathophysiology establish theoretical foundation for development new treatment strategies

Language: Английский

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Lactate transporter MCT4 regulates the hub genes for lipid metabolism and inflammation to attenuate intracellular lipid accumulation in non-alcoholic fatty liver disease (NAFLD)

Genes & Diseases, Journal Year: 2025, Volume and Issue: 12(4), P. 101554 - 101554

Published: Feb. 15, 2025

Non-alcoholic fatty liver disease (NAFLD) patients have multiple metabolic disturbances, with markedly elevated levels of lactate. Lactate accumulations play pleiotropic roles in progression through rearrangements and epigenetic modifications. Monocarboxylate transporter 4 (MCT4) is highly expressed hepatocytes responsible for transporting intracellular lactate out the cell. To explore whether MCT4 played any role NAFLD development, we overexpressed silenced performed a comprehensive vitro vivo analysis. Our results revealed that overexpression down-regulated genes lipid synthesis while up-regulating involved catabolism. Conversely, silencing expression or inhibiting led to accumulation glucose metabolites, resulting hepatic steatosis. In mouse model NAFLD, found exogenous significantly reduced metabolism alleviated hepatocellular Mechanistically, steatosis by regulating group hub such as Arg2, Olr1, Cd74, Mmp8, Irf7, Spp1, Apoe, which turn impacted pathways inflammatory response, PPAR, HIF-1, TNF, IL-17, PI3K-AKT, Wnt, JAK-STAT. Collectively, our strongly suggest may an important inflammation thus serve potential therapeutic target NAFLD.

Language: Английский

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New Types of Post-Translational Modification of Proteins in Cardiovascular Diseases

Journal of Cardiovascular Translational Research, Journal Year: 2025, Volume and Issue: unknown

Published: March 3, 2025

Post-translational modifications (PTMs), which are covalent alterations of proteins after their synthesis, critical for proper function and the maintenance cellular physiology. The significance PTMs in context cardiovascular diseases (CVDs) has been increasingly recognized due to potential influence protein stability, activity, localization, thereby affecting progression CVDs. identification understanding CVDs at molecular level vital discovery new biomarkers targets clinical interventions. This article provides a comprehensive overview role mechanisms types PTMs, such as acetylation, crotonylation, succinylation, S-nitrosylation, malonylation, S-palmitonylation, β-hydroxybutyrylation lactylation, CVDs, highlighting importance advancing diagnostic therapeutic approaches

Language: Английский

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L- and D-Lactate: unveiling their hidden functions in disease and health

Cell Communication and Signaling, Journal Year: 2025, Volume and Issue: 23(1)

Published: March 12, 2025

Lactate, once considered a mere byproduct of anaerobic metabolism, is now recognized as critical signaling molecule with diverse roles in physiology and pathology. There are two stereoisomers lactate: L- D-lactate. Recent studies have shown that disruptions these lactate distinct effects on health disease. L-lactate central to glycolysis energy transfer through the Cori cycle but also acts dominant lactylation isomer induced by glycolysis, influencing metabolism cell survival. Although less studied, D-lactate linked metabolic disorders plays role mitochondrial dysfunction oxidative stress. This review focuses both examines their biosynthesis, transport, expanding physiological pathological processes, particularly functions cancer, immune regulation, inflammation, neurodegeneration other diseases. Finally, we assess therapeutic prospects targeting highlighting emerging strategies for intervention clinical settings. Our synthesizes current understanding D-lactate, offering insights into potential targets innovation.

Language: Английский

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The role of lactate metabolism and lactylation in pulmonary arterial hypertension

Respiratory Research, Journal Year: 2025, Volume and Issue: 26(1)

Published: March 12, 2025

Pulmonary arterial hypertension (PAH) is a complex and progressive disease characterized by elevated pulmonary artery pressure vascular remodeling. Recent studies have underscored the pivotal role of metabolic dysregulation epigenetic modifications in pathogenesis PAH. Lactate, byproduct glycolysis, now recognized as key molecule that links cellular metabolism with activity regulation. findings indicate that, addition to altered glycolytic dysregulated. Lactate homeostasis lactylation—a novel modification—also play significant development This review synthesizes current knowledge regarding relationship between PAH, particular focus on cumulative effects lactate cells. Furthermore, lactylation, an emerging modification, discussed context By elucidating interplay lactylation this aims provide insights into potential therapeutic targets. Understanding these pathways may lead innovative strategies for managing PAH improving patient outcomes. Future research should underlying mechanisms through which influences pathophysiology thereby aiding targeted interventions.

Language: Английский

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Oxidative stress and inflammation mediate the adverse effects of cadmium exposure on all-cause and cause-specific mortality in patients with diabetes and prediabetes

Cardiovascular Diabetology, Journal Year: 2025, Volume and Issue: 24(1)

Published: March 29, 2025

The effect of cadmium exposure on mortality risk among individuals with diabetes and prediabetes remains unclear, particularly regarding potential mediation by oxidative stress inflammation. This study aimed to investigate the associations blood levels all-cause, cardiovascular disease (CVD), cancer mediating effects inflammation biomarkers in patients prediabetes. In this prospective cohort study, we analyzed 17,687 adults from National Health Nutrition Examination Survey (NHANES, 1999-2018). Nine related (gamma-glutamyl transferase [GGT], uric acid [UA], high-density lipoprotein [HDL], UA HDL ratio [UHR]) (neutrophil-lymphocyte [NLR], monocyte-lymphocyte [MLR], neutrophil-monocyte-lymphocyte [NMLR], systemic response index [SIRI], immune-inflammation [SII]) were systematically assessed. Kaplan-Meier survival analysis, Cox proportional hazards models, restricted cubic splines (RCS) applied evaluate association risk. Generalized linear models used assess biomarkers, while regression RCS evaluated their mortality. Causal analysis identified biological pathways mediated Stratified sensitivity analyses further employed confirm robustness results. During 161,047.75 person-years follow-up, 3562 deaths occurred, including 1214 CVD 680 cancer. Higher associated increased risks all-cause (fully adjusted hazard [HR]: 2.17; 95% confidence interval [CI] 1.69-2.79, comparing highest vs. lowest quartile), (HR 2.06; CI 1.41-3.02), 2.38; 1.47-3.85), without evidence nonlinear relationship. Mediation indicated that UA, NLR, MLR, NMLR, SIRI partially mortality, although proportions relatively modest (ranging 1.4 4.8%). Additionally, GGT a small fraction Cadmium increases CVD, Oxidative appear mediate adverse effect. These findings emphasize urgent need for targeted interventions reduce cadmium-related risks. What is currently known about topic? linked are critical development complications. key research question? Does increase prediabetes? Are involved these effects? new? cause-specific associations. How might influence clinical practice? Monitor cadmium, stress,

Language: Английский

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Intersection of Cardio‐Oncology: An Overview of Radiation‐Induced Heart Disease in the Context of Tumors

Journal of the American Heart Association, Journal Year: 2025, Volume and Issue: unknown

Published: May 13, 2025

Radiation‐induced heart disease (RIHD) is a prevalent cardiovascular complication of radiation therapy, with coronary being the most common manifestation. Clinical presentations RIHD vary and may include conduction abnormalities, ischemic disease, cardiomyopathy, failure, valvular damage. Even low doses significantly increase risk often associated severe stenosis detected via angiography. damage to cardiac endothelium triggers inflammatory responses oxidative stress, which contribute progression atherosclerosis. This study explores how activates multiple signaling pathways through generation reactive oxygen species, resulting in vascular endothelial damage, cellular senescence, responses, DNA It further examines impact on integrity tight junction proteins, leading increased permeability infiltration by cells. From clinical perspective, we emphasize challenges posed coexistence tumors many patients RIHD, as complicate microenvironment have mutually reinforcing interactions radiation‐induced We also discuss various therapeutic strategies, including novel approaches targeting senescence immune focus potential use navitoclax IL‐6 (interleukin‐6) inhibitors prevent irreversible cardiomyocyte fibrosis ongoing In conclusion, multifaceted involving complex biological processes pathways. Early intervention targeted therapies are crucial for improving patient outcomes. Future research should prioritize uncovering molecular mechanisms developing more effective strategies.

Language: Английский

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H3K18 Lactylation-Mediated CHI3L1 Expression Exacerbates Diabetic Arterial Calcification

Published: Jan. 1, 2024

Metabolic changes are an important characteristic of vascular complications in diabetes. The accumulation lactate the microenvironment can promote VSMC calcification diabetes, although specific mechanism remains to be fully elucidated. Lactate participates lactylation as a substrate and plays role many diseases. In this study, we explored characteristics diabetic arterial underlying molecular mechanism. We found that high-glucose calcified VSMC, overall level was significantly increased. Mass spectrometry analysis revealed significant upregulation H3 histone lactylation. After site-specific point-mutation (lysine-to-arginine) at K18 simulate delactylation modification, reduced. Through combination H3K18la ChIP-seq, RNA-seq, ChIP-qPCR experiments, confirmed upregulate CHI3L1. generated CHI3L1 knockdown VSMCs constructed mouse model by knockout whole gene. alleviated osteogenic phenotype transformation calcification. RNA-seq downstream signaling showed activates IL-13-IL-13Ra2-JAK1-STAT3 pathway. Targeted inhibition IL-13Ra2 reduced conclude environment, site undergoes modification VSMCs, upregulating CHI3L1, which turn regulates pathway, ultimately exacerbating Our study elucidates epigenetic promotes diabetes.Funding: This work supported Changzhou Municipal Health Commission (CQ20210122), Project Medical Center Nanjing University (CZKYCMCB202209), China Postdoctoral Science Foundation (2023M730372).Declaration Interest: All authors declared they have no conflict interest.Ethical Approval: vivo experiments were approved Animal Care Research Committee (China). animal procedures performed accordance with Guidelines Experiments from Ethics, National Department (1998).

Language: Английский

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