Diabetic cardiomyopathy: Early diagnostic biomarkers, pathogenetic mechanisms, and therapeutic interventions

Cell Death Discovery, Год журнала: 2023, Номер 9(1)

Опубликована: Июль 21, 2023

Abstract Diabetic cardiomyopathy (DCM) mainly refers to myocardial metabolic dysfunction caused by high glucose, and hyperglycemia is an independent risk factor for cardiac function in the absence of coronary atherosclerosis hypertension. DCM, which a severe complication diabetes, has become leading cause heart failure diabetic patients. The initial symptoms are inconspicuous, patients gradually exhibit left ventricular eventually develop total failure, brings great challenge early diagnosis DCM. To date, underlying pathological mechanisms DCM complicated have not been fully elucidated. Although there therapeutic strategies available treatment focused on controlling blood glucose lipids, lack effective drugs targeting injury. Thus, large percentage with inevitably failure. Given neglected symptoms, intricate cellular molecular mechanisms, drugs, it necessary explore diagnostic biomarkers, further understand signaling pathways involved pathogenesis summarize current strategies, new targeted interventions.

Язык: Английский

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

Phytotherapy Research, Год журнала: 2024, Номер 38(5), С. 2496 - 2517

Опубликована: Март 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.

Язык: Английский

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New insights into the role of mitochondrial metabolic dysregulation and immune infiltration in septic cardiomyopathy by integrated bioinformatics analysis and experimental validation

Cellular & Molecular Biology Letters, Год журнала: 2024, Номер 29(1)

Опубликована: Янв. 30, 2024

Abstract Background Septic cardiomyopathy (SCM), a common cardiovascular comorbidity of sepsis, has emerged among the leading causes death in patients with sepsis. SCM’s pathogenesis is strongly affected by mitochondrial metabolic dysregulation and immune infiltration disorder. However, specific mechanisms their intricate interactions SCM remain unclear. This study employed bioinformatics analysis drug discovery approaches to identify regulatory molecules, distinct functions, underlying metabolism microenvironment, along potential interventional strategies SCM. Methods GSE79962, GSE171546, GSE167363 datasets were obtained from Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) module identified using Limma Weighted Correlation Network Analysis (WGCNA), followed functional enrichment analysis. Machine learning algorithms, including support vector machine–recursive feature elimination (SVM–RFE), least absolute shrinkage selection operator (LASSO) regression, random forest, used screen mitochondria-related hub for early diagnosis Subsequently, nomogram was developed based on six genes. The immunological landscape evaluated single-sample gene set (ssGSEA). We also explored expression pattern distribution mitochondria/inflammation-related pathways UMAP plots single-cell dataset. Potential drugs Drug Signatures Database (DSigDB). In vivo vitro experiments performed validate pathogenetic mechanism therapeutic efficacy candidate drugs. Results Six DEGs [MitoDEGs; translocase inner membrane domain-containing 1 (TIMMDC1), ribosomal protein S31 (MRPS31), F-box only 7 (FBXO7), phosphatidylglycerophosphate synthase (PGS1), LYR motif containing (LYRM7), chaperone BCS1 (BCS1L)] identified. diagnostic model demonstrated high reliability validity both training validation sets. microenvironment differed between control groups. Spearman correlation revealed that MitoDEGs significantly associated cells. Upregulated showed remarkably naive/memory B cell, CD14 + monocyte, plasma cell subgroup, evidenced plot. varied across subgroups individuals. Metformin predicted be most promising highest combined score. Its restoring function suppressing inflammatory responses been validated. Conclusions presents comprehensive SCM, providing novel direction medical intervention

Язык: Английский

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Zishen Tongyang Huoxue decoction (TYHX) alleviates sinoatrial node cell ischemia/reperfusion injury by directing mitochondrial quality control via the VDAC1–β-tubulin signaling axis

Journal of Ethnopharmacology, Год журнала: 2023, Номер 320, С. 117371 - 117371

Опубликована: Ноя. 18, 2023

Язык: Английский

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Ginsenoside Rb1 ameliorates heart failure through DUSP-1-TMBIM-6-mediated mitochondrial quality control and gut flora interactions

Phytomedicine, Год журнала: 2024, Номер 132, С. 155880 - 155880

Опубликована: Июль 20, 2024

Язык: Английский

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Nuclear receptor subfamily 4 group A member 1 promotes myocardial ischemia/reperfusion injury through inducing mitochondrial fission factor-mediated mitochondrial fragmentation and inhibiting FUN14 domain containing 1-depedent mitophagy

International Journal of Biological Sciences, Год журнала: 2024, Номер 20(11), С. 4458 - 4475

Опубликована: Янв. 1, 2024

This study investigated the mechanism by which NR4A1 regulates mitochondrial fission factor (Mff)-related and FUN14 domain 1 (FUNDC1)-mediated mitophagy following cardiac ischemia-reperfusion injury(I/R). Our findings showed that damage regulation was positively correlated with pathological pan-apoptosis of myocardial cell mitochondria. Compared wild-type mice (WT), NR4A1-knockout exhibited resistance to injury fission, characterized activation. Results increased expression level, activating mediated Mff restoring phenotype FUNDC1. The inactivation FUNDC1 phosphorylation could not mediate normalization in a timely manner, leading an excessive stress response unfolded proteins imbalance homeostasis. process disrupted quality control network, accumulation damaged mitochondria activation pan-apoptotic programs. data indicate is novel critical target I/R exertsand negative regulatory effects Mff-mediated mito-fission inhibiting FUNDC1-mediated mitophagy. Targeting crosstalk balance between NR4A1-Mff-FUNDC1 potential approach for treating I/R.

Язык: Английский

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Zishenhuoxue decoction-induced myocardial protection against ischemic injury through TMBIM6-VDAC1-mediated regulation of calcium homeostasis and mitochondrial quality surveillance

Phytomedicine, Год журнала: 2023, Номер 132, С. 155331 - 155331

Опубликована: Дек. 31, 2023

Язык: Английский

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The role of mitochondrial quality surveillance in skin aging: Focus on mitochondrial dynamics, biogenesis and mitophagy

Ageing Research Reviews, Год журнала: 2023, Номер 87, С. 101917 - 101917

Опубликована: Март 25, 2023

Язык: Английский

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Mitochondrial disorder and treatment of ischemic cardiomyopathy: Potential and advantages of Chinese herbal medicine

Biomedicine & Pharmacotherapy, Год журнала: 2023, Номер 159, С. 114171 - 114171

Опубликована: Янв. 13, 2023

Mitochondrial dysfunction is the main cause of damage to pathological mechanism ischemic cardiomyopathy. In addition, mitochondrial can also affect homeostasis cardiomyocytes or endothelial cell dysfunction, leading a vicious cycle oxidative stress. And an important basis for cardiomyopathy and reperfusion injury after myocardial infarction end-stage coronary heart disease. Therefore, mitochondria be used as therapeutic targets against ischemia injury, regulation morphology, function structure key way targeting quality control mechanisms. includes mechanisms such mitophagy, dynamics (mitochondrial fusion/fission), biosynthesis, unfolded protein responses. Among them, increase fragmentation caused by fission initial factor. The protective fusion strengthen interaction synthesis paired promote biosynthesis. hypoxia, formation fragments, fragmented lead damaged DNA production, which biosynthesis insufficient ATP ROS. Burst growth loss membrane potential. This eventually leads accumulation mitochondria. Then, under leadership complete degradation process through transport morphologically structurally lysosomes degradation. But once increases, may activate pathway cardiomyocyte death. Although laboratory studies have found that variety mitochondrial-targeted drugs reduce protect cardiomyocytes, there are still few successfully passed clinical trials. this review, we describe role MQS in ischemia/hypoxia-induced physiopathology elucidate relevant further explained advantages natural products improving protecting cells from perspective pharmacological mechanism, its related Potential targeted therapies improve ischemia/hypoxia discussed, aiming accelerate development cardioprotective dysfunction.

Язык: Английский

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Bmal1 downregulation leads to diabetic cardiomyopathy by promoting Bcl2/IP3R-mediated mitochondrial Ca2+ overload

Redox Biology, Год журнала: 2023, Номер 64, С. 102788 - 102788

Опубликована: Июнь 20, 2023

Brain and muscle arnt-like protein 1 (Bmal1) is a crucial transcription factor, regulating circadian rhythm involved in multiple heart diseases. However, it unknown whether Bmal1 promotes diabetic cardiomyopathy (DCM) pathogenesis. The objective of this investigation was to ascertain the vital role progression DCM. Mice with T2D H9c2 cardiomyoblasts exposed high glucose palmitic acid (HGHP) were used. Cardiomyocyte-specific knockout mouse (CKB) also generated, cardiac overexpressed type 2 diabetes (T2D) mice using an adeno-associated virus. gene recombinant adenovirus used either knockdown or overexpress cardiomyoblasts. expression significantly altered hearts. downregulation CKB accelerated hypertrophy diastolic dysfunction, while overexpression ameliorated these pathological changes DCM mice. Furthermore, had significant mitochondrial ultrastructural defects, reactive oxygen species accumulation, apoptosis, which could be alleviated by overexpressing Bmal1. In cardiomyoblasts, genetic HGHP markedly decreased binding Bcl2 IP3R, thus increasing Ca2+ release mitochondria through mitochondria-associated endoplasmic reticulum membranes. Importantly, chromatin immunoprecipitation revealed bind directly promoter region. augmented Bmal1/Bcl2 binding, enhancing inhibition on IP3R activity, alleviating overload subsequent cell apoptosis. These results show that development Bcl2/IP3R-mediated overload. Therapy targeting clock can treat

Язык: Английский

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