Tirzepatide prevents neurodegeneration through multiple molecular pathways

Journal of Translational Medicine, Journal Year: 2024, Volume and Issue: 22(1)

Published: Jan. 29, 2024

Abstract Background Several evidence demonstrated that glucagon-like peptide 1 receptor agonists (GLP1-RAs) reduce the risk of dementia in type 2 diabetes patients by improving memory, learning, and overcoming cognitive impairment. In this study, we elucidated molecular processes underlying protective effect Tirzepatide (TIR), a dual glucose-dependent insulinotropic polypeptide agonist (GIP-RA)/ GLP-1RA, against learning memory disorders. Methods We investigated effects TIR on markers neuronal growth (CREB BDNF), apoptosis (BAX/Bcl2 ratio) differentiation (pAkt, MAP2, GAP43, AGBL4), insulin resistance (GLUT1, GLUT4, GLUT3 SORBS1) neuroblastoma cell line (SHSY5Y) exposed to normal high glucose concentration. The potential role DNA methylation genes involved neuroprotection epigenetic modulators (miRNA 34a), 212), 29c) was also investigated. proliferation detected measuring Ki-67 through flow cytometry. data were analysed SPSS IBM Version 23 or GraphPad Prism 7.0 software expressed as means ± SEM. Differences between mean values considered significant at p-value < 0.05. used for drawing figures. Results For first time, it highlighted: (a) activation pAkt/CREB/BDNF pathway downstream signaling cascade; (b) efficacy neuroprotection; (c) counteracting hyperglycemia resistance-related level. Conclusions can ameliorate glucose-induced neurodegeneration overcome resistance. Thus, study provides new insight into diabetes-related neuropathy. Graphical

Language: Английский

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Lipotoxicity as a therapeutic target in obesity and diabetic cardiomyopathy

Journal of Pharmacy & Pharmaceutical Sciences, Journal Year: 2024, Volume and Issue: 27

Published: April 19, 2024

Unhealthy sources of fats, ultra-processed foods with added sugars, and a sedentary lifestyle make humans more susceptible to developing overweight obesity. While lipids constitute an integral component the organism, excessive abnormal lipid accumulation that exceeds storage capacity droplets disrupts intracellular composition fatty acids results in release deleterious species, thereby giving rise pathological state termed lipotoxicity. This condition induces endoplasmic reticulum stress, mitochondrial dysfunction, inflammatory responses, cell death. Recent advances omics technologies analytical methodologies clinical research have provided novel insights into mechanisms lipotoxicity, including gut dysbiosis, epigenetic epitranscriptomic modifications, dysfunction droplets, post-translational altered membrane composition. In this review, we discuss recent knowledge on underlying development lipotoxicity lipotoxic cardiometabolic disease obesity, particular focus diabetic cardiomyopathy.

Language: Английский

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Unlocking the power of empagliflozin: Rescuing inflammation in hyperglycaemia‐ exposed human cardiomyocytes through comprehensive multi‐level analysis

European Journal of Heart Failure, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 14, 2025

Aims Hyperglycaemic conditions increase cardiac stress, a common phenomenon associated with inflammation, aging, and metabolic imbalance. Sodium–glucose cotransporter 2 inhibitors, class of anti‐diabetic drugs, showed to improve cardiovascular functions although their mechanism action has not yet been fully established. This study investigated the effects empagliflozin on cardiomyocytes following high glucose exposure, specifically focusing inflammatory responses. Methods results A three‐part strategy was formulated: (i) meta‐analysis selected randomized clinical trials carried out assess anti‐inflammatory in diabetic patients; (ii) impact human cardiomyocyte AC16 cells exposed normal (5 mM) (33 concentrations for 7 days explored by evaluating gene expression protein levels pivotal markers endoplasmic reticulum damage, calcium modulation; (iii) silico data from bioinformatic analyses were exploited construct an interaction map delineating potential tissue. Empagliflozin reversed high‐glucose mediated alterations at transcriptional level, decreasing inflammatory, metabolic, aging signatures. Specifically, vitro experiments cardiomyocytes, meta‐analyses biomarkers peripheral blood samples, sequencing pathological heart tissues, all support that exerts both systemically directly tissue, cardiomyocytes. Conclusion Our provides insights based robust mechanistic optimizing failure management highlights intricate interplay between diabetes, health.

Language: Английский

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Empagliflozin protects against heart failure with preserved ejection fraction partly by inhibiting the senescence-associated STAT1–STING axis

Cardiovascular Diabetology, Journal Year: 2024, Volume and Issue: 23(1)

Published: July 23, 2024

Abstract Heart failure with preserved ejection fraction (HFpEF) is a mortal clinical syndrome without effective therapies. Empagliflozin (EMPA) improves cardiovascular outcomes in HFpEF patients, but the underlying mechanism remains elusive. Here, mice were fed high-fat diet (HFD) supplemented L-NAME for 12 weeks and subsequently intraperitoneally injected EMPA another 4 weeks. A 4D-DIA proteomic assay was performed to detect protein changes failing hearts. We identified 310 differentially expressed proteins (DEPs) (ctrl vs. group) 173 DEPs (HFpEF group). The regulation of immune system processes enriched all groups interferon response genes (STAT1, Ifit1, Ifi35 Ifi47) upregulated downregulated after administration. In addition, treatment suppressed increase levels aging markers (p16 p21) Further bioinformatics analysis verified STAT1 as hub transcription factor during pathological mice. next treated H9C2 cells IFN-γ, primary agonist phosphorylation, investigate whether plays beneficial role by blocking activation. Our results showed that IFN-γ caused cardiomyocyte senescence activation, which inhibited Notably, inhibition significantly reduced cellular possibly regulating STING expression. findings revealed mitigates cardiac inflammation inhibiting STAT1–STING axis may act pivotal pathogenesis HFpEF, especially under inflammatory conditions. Graphical abstract schematic figure depicts model (this drawn using FigDraw software).

Language: Английский

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Critical Appraisal of Pharmaceutical Therapy in Diabetic Cardiomyopathy—Challenges and Prospectives

Pharmaceuticals, Journal Year: 2025, Volume and Issue: 18(1), P. 134 - 134

Published: Jan. 20, 2025

Diabetes mellitus (DM) is a multifaceted disorder with pandemic spread and remarkable burden of cardiovascular mortality morbidity. Diabetic cardiomyopathy (DBCM) has been increasingly recognized as the development cardiac dysfunction, which accompanied by heart failure (HF) symptoms in absence obvious reasons like ischemic disease, hypertension, or valvulopathies. Several pathophysiological mechanisms have proposed, including metabolic disorders (e.g., glycation products), oxidative stress, low-grade inflammation, mitochondrial etc., should guide new therapeutic strategies. Up to now, HF treatment not differed between patients without diabetes, limits expected benefits despite high risk former group. However, DBCM may require different management, prioritize anti-diabetic medications testing other novel therapies. This review aims appraise challenges prospectives individualized pharmaceutical therapy for DBCM.

Language: Английский

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Algorithms and tools for data-driven omics integration to achieve multilayer biological insights: a narrative review

Journal of Translational Medicine, Journal Year: 2025, Volume and Issue: 23(1)

Published: April 10, 2025

Systems biology is a holistic approach to biological sciences that combines experimental and computational strategies, aimed at integrating information from different scales of processes unravel pathophysiological mechanisms behaviours. In this scenario, high-throughput technologies have been playing major role in providing huge amounts omics data, whose integration would offer unprecedented possibilities gaining insights on diseases identifying potential biomarkers. the present review, we focus strategies applied literature integrate genomics, transcriptomics, proteomics, metabolomics year range 2018-2024. Integration approaches were divided into three main categories: statistical-based approaches, multivariate methods, machine learning/artificial intelligence techniques. Among them, statistical (mainly based correlation) ones with slightly higher prevalence, followed by learning Integrating multiple layers has shown great uncovering molecular mechanisms, putative biomarkers, aid classification, most time resulting better performances when compared single analyses. However, significant challenges remain. The nature platforms introduces issues such as variable data quality, missing values, collinearity, dimensionality. These further increase combining datasets, complexity heterogeneity integration. We report found cope these challenges, but some open still remain should be addressed disclose full

Language: Английский

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Exploring shared therapeutic targets in diabetic cardiomyopathy and diabetic foot ulcers through bioinformatics analysis

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Jan. 2, 2024

Abstract Advanced diabetic cardiomyopathy (DCM) patients are often accompanied by severe peripheral artery disease. For with DCM combined foot ulcer (DFU), there currently no good therapeutic targets and drugs. Here, we investigated the underlying network of molecular actions associated occurrence these two complications. The datasets were downloaded from Gene Expression Omnibus (GEO) database. We performed enrichment protein–protein interaction analyses, screened for hub genes. Construct transcription factors (TFs) microRNAs regulatory networks validated Finally, drug prediction docking verification performed. identified 299 common differentially expressed genes (DEGs), many which involved in inflammation lipid metabolism. 6 DEGs as (PPARG, JUN, SLC2A1, CD4, SCARB1 SERPINE1). These immune response. 31 TFs 2 key miRNAs closely related to Interestingly, our study suggested that fenofibrate, a lipid-lowering medication, holds promise potential treatment DFU due its stable binding revealed involves target DFU. Understanding is pivotal advancing comprehension multifaceted complications diabetes facilitating development future interventions.

Language: Английский

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The redox-active defensive Selenoprotein T as a novel stress sensor protein playing a key role in the pathophysiology of heart failure

Journal of Translational Medicine, Journal Year: 2024, Volume and Issue: 22(1)

Published: April 20, 2024

Abstract Maladaptive cardiac hypertrophy contributes to the development of heart failure (HF). The oxidoreductase Selenoprotein T (SELENOT) emerged as a key regulator during rat cardiogenesis and acute protection. However, its action in chronic settings dysfunction is not understood. Here, we investigated role SELENOT pathophysiology HF: (i) by designing small peptide (PSELT), recapitulating activity via redox site, assessed beneficial preclinical model HF [aged spontaneously hypertensive (SHHF) rats] against isoproterenol (ISO)-induced ventricular H9c2 adult human AC16 cardiomyocytes; (ii) evaluating intra-cardiomyocyte production secretion under hypertrophied stimulation. Results showed that PSELT attenuated systemic inflammation, lipopolysaccharide (LPS)-induced macrophage M1 polarization, myocardial injury, severe ultrastructural alterations, while counteracting mediators fibrosis, aging, DNA damage restoring desmin downregulation upregulation failing hearts. In hemodynamic assessment, improved contractile impairment at baseline following ischemia/reperfusion reduced infarct size normal At cellular level, counteracted ISO-mediated alterations through motif, mitigating ISO-triggered intracellular secretion, phenomenon presumably reflects extent cell damage. Altogether, these results indicate could represent novel sensor cardiomyocytes potential PSELT-based new therapeutic approach HF. Graphical

Language: Английский

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Dapagliflozin for Atrial Fibrillation

Cardiovascular Drugs and Therapy, Journal Year: 2024, Volume and Issue: 38(1), P. 1 - 3

Published: Feb. 1, 2024

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Editorial: Transcriptional regulation in cardiovascular diseases

Frontiers in Cardiovascular Medicine, Journal Year: 2024, Volume and Issue: 11

Published: Jan. 17, 2024

Cardiovascular diseases are the most dangerous diseases, which can cause dysfunction of human circulatory system, and eventually lead to an increased risk sudden cardiac death. Crea, (2023, Padro et al., (2023). Emerging evidence revealed that transcriptional mis-regulation induced abnormal gene expression is one major causes multiple cardiovascular diseases. Disse The anti-inflammatory pro-inflammatory properties macrophages make research model multidisciplinary interaction a prospective promising form suitable for development mechanism research.Using principles technologies bioinformatics process genes, In summary, this topic aims provide new discoveries insights on regulation (such as myocardial infarction, heart failure, hypertrophy, etc.), in anticipation therapeutic targets or strategies treatment above series topics also highlights importance linkage between molecular biology experiments analysis techniques

Language: Английский

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