The concomitant use of ceftriaxone and proton pump inhibitors (PPIs) is common in hospital practice. However, it is unclear whether individual PPIs differ in their effects on QT interval prolongation, ventricular arrhythmia, or cardiac arrest, collectively termed as QVC events. We conducted a two-stage, real-world study. First, we screened the United States Food and Drug Administration Adverse Event Reporting System (FAERS) and the Canada Vigilance Adverse Reaction (CVAR) database with standard disproportionality measures (reporting odds ratio and proportional reporting ratio) and six drug-drug interaction (DDI) algorithms to identify combination signals that exceeded component signals. Second, we validated signal-positive combinations in the Medical Information Mart for Intensive Care IV (MIMIC-IV) intensive care unit (ICU) electronic health record (EHR) cohort by assembling adult inpatients with overlapping ceftriaxone-PPI exposures. The primary outcome was 28-day QVC events. Multivariable Cox proportional hazards models were the main analysis and complemented by propensity score matching, inverse probability of treatment weighting, and Fine-Gray competing-risk models. To address external generalisability, an additional validation was performed using ECG-ViEW II, an Asian electrocardiogram-linked real-world database. The combination of ceftriaxone and lansoprazole was significantly associated with QVC events, revealing notable DDIs (e.g., in FAERS, Ω025 = 0.54). To validate these findings, a cohort of 5,594 patients receiving ceftriaxone combined with PPIs from the MIMIC-IV database was analyzed using Cox proportional hazards models. The analyses corroborated the initial findings (lansoprazole vs. other PPIs, multivariate HR = 1.30; 95
Polystyrene (PS) is a pervasive plastic whose threat to human health is growing, yet its cardiotoxicity, particularly under clinically relevant exposure scenarios, remains poorly understood. This study addresses this critical gap by modeling intravenous exposure to nanopolystyrene, simulating clinical situations where plastic-derived medical devices directly contact blood. We established an in vitro model using human AC16 cardiomyocytes and an in vivo model via tail vein injection in Balb/c mice to compare the effects of amino-modified (PS-NH₂), carboxyl-modified (PS-COOH), and unmodified (PS-Bare) polystyrene nanoparticles. Our findings demonstrate that PS-NH₂, in contrast to PS-COOH and PS-Bare, induces significant cardiotoxicity. This toxicity was initiated by a substantial increase in reactive oxygen species (ROS), which subsequently suppressed the PI3K/AKT/mTOR signaling axis. This inhibition led to the excessive activation of autophagy and the induction of apoptosis in cardiomyocytes. In vivo, PS-NH₂ exposure caused severe pathological changes in mouse hearts, confirming its potent cardiotoxicity, characterized by inflammation, an impaired oxidative-antioxidant balance, and adverse cardiac remodeling. Notably, these detrimental effects were substantially reversed by the ROS scavenger N-acetylcysteine (NAC) or ginsenoside Rb1. In conclusion, our study reveals that Polystyrene positively charged amino-modified during degradation is the key to its cardiotoxicity, operating through a ROS-driven PI3K/AKT/mTOR pathway. These findings underscore the potential risks associated with specific surface modifications of nanoplastics and provide crucial insights for developing therapeutic strategies against plastic-induced cardiac injury.
Cardiometabolic diseases, including cardiovascular disease, type 2 diabetes mellitus (T2DM), obesity-related metabolic dysfunction, and hypertension, remain major causes of global morbidity and mortality. Beyond traditional risk factors, environmental exposure to toxic metals is increasingly recognized as a contributor to vascular and metabolic injury. Lead, cadmium, arsenic, and mercury are persistent toxicants that may accumulate in human tissues and interfere with essential trace-element homeostasis. This narrative review examines how toxic metal exposure disrupts the biological balance of iron, zinc, copper, and selenium, thereby weakening mitochondrial function, antioxidant defense, endothelial regulation, and metabolic stability. A central focus is ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation and failure of protective systems such as the selenium–GPX4–glutathione axis. Toxic metal–essential trace-element imbalance may create a pro-ferroptotic environment that promotes endothelial dysfunction, nitric oxide impairment, vascular stiffness, atherosclerotic plaque instability, myocardial ischemic vulnerability, insulin resistance, β-cell dysfunction, and cardiometabolic clustering. This review reframes heavy metal-associated cardiometabolic disease as a consequence of toxic metal–essential trace-element dyshomeostasis rather than direct toxicity alone. Clinically, this framework supports targeted exposure history, careful interpretation of metal and trace-element biomarkers, correction of documented deficiencies, and avoidance of indiscriminate supplementation. Future studies integrating exposomics, metallomics, ferroptosis biomarkers, and longitudinal cardiometabolic outcomes are needed to clarify causality and guide prevention. Toxic metal–essential trace-element imbalance, ferroptosis, and cardiometabolic injury. The graphical abstract summarizes the central concept of the review. Environmental exposure to lead, cadmium, arsenic, and mercury may disrupt the protective network of essential trace elements, including iron, zinc, copper, and selenium. This imbalance may increase redox-active iron availability, promote reactive oxygen species and lipid peroxide accumulation, weaken the GPX4–glutathione axis, and produce membrane and organelle dysfunction, thereby creating a pro-ferroptotic cellular environment. Ferroptosis may then contribute to cardiometabolic injury through endothelial dysfunction, atherosclerosis and plaque instability, myocardial vulnerability, β-cell stress and impaired insulin secretion, insulin resistance, metabolic dysregulation, obesity-related metabolic dysfunction, non-alcoholic fatty liver disease, hypertension, and broader cardiometabolic clustering. Clinically, the framework supports exposure history, biomarker assessment, correction of documented deficiencies, avoidance of indiscriminate supplementation, targeted prevention, and longitudinal monitoring in high-risk populations. Created using CanvaPro
Heart failure (HF) affects over 64 million people worldwide, with five-year mortality rates rivaling solid-organ malignancies. Despite advances in neurohormonal therapy, many patients continue to progress, suggesting additional pathophysiological drivers. Metallomic dysregulation—imbalance among essential trace elements combined with non-essential metal accumulation—engages pathways central to HF pathobiology, including oxidative stress, mitochondrial dysfunction, impaired calcium handling, and pro-fibrotic cascades. We conducted a systematic review compliant with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement, searching PubMed/MEDLINE, Embase, Scopus, and Web of Science. Eligible studies enrolled adults who were assessed for at least one metal and reported a cardiac outcome. Risk of bias was evaluated using the Cochrane risk-of-bias tool for randomized trials (RoB 2) and the Newcastle–Ottawa Scale. Twenty-nine studies met the inclusion criteria—encompassing over 90,000 participants. Iron deficiency affected approximately 30–58
Exposure to fine airborne particulate matter (PM2.5) is associated with cardiovascular disease and increased atherogenesis. While some prior studies provided mechanistic insights linking exposure to lesion progression, instability, and rupture, a complete definition of cellular events contributing to early vascular inflammation is lacking. Here we show that C57BL/6J mice exposed to concentrated ambient PM2.5 (CAP), as opposed to control mice inhaling filtered air, displayed endothelial activation, as evidenced by the increased number of leukocytes rolling on, and adhering to, the intact vasculature in vivo. As CAP exposure also induced the senescence of peripheral blood mononuclear cells (MNCs) and endothelial progenitor cells (EPCs), we further assessed the role of this outcome in PM2.5-induced vascular dysfunction. We observed that treatment with the senolytics Dasatinib and Quercetin (DQ), which eliminate senescent cells, was effective in reversing the CAP-induced senescence of both of MNCs and EPCs as demonstrated by reductions in β-galactosidase activity and the expression of genes characteristic of the senescence activated secretory phenotype (SASP). Furthermore, we found that DQ treatment was effective in reversing CAP-induced defects in in vitro EPC function (tube forming capacity) and limited in vivo endothelial activation as well. These results provide strong evidence for a role of PM2.5 in the early stages of atherogenesis by inducing endothelial activation leading to leukocyte recruitment. Our results further suggest that senolytic treatment may be efficacious in combatting adverse cardiovascular outcomes in those chronically exposed to high levels of PM2.5.
Despite advances in therapy, arterial, venous, and pulmonary vascular diseases remain leading causes of morbidity and mortality. Persistent endothelial dysfunction, inflammation, oxidative stress, and maladaptive vascular remodeling continue to drive disease progression and residual risk. CRISPR/Cas9 technology offers a unique opportunity to modify the molecular pathways underlying vascular pathophysiology directly. The PRISMA 2020 guidelines guided the systematic review. The databases PubMed/MEDLINE, Embase, Web of Science, Cochrane Library, ClinicalTrials.gov, and Google Scholar were searched from their inception until September 2025 for experimental and/or clinical studies evaluating the application of CRISPR/Cas9 on vascular disease. Included were in vitro studies, animal model studies, and early-phase human studies aimed at targeting the endothelial cell regulatory pathways, inflammatory pathways, metabolic remodeling processes, and hereditary causes of vasculopathy. Seventeen studies met the inclusion criteria. CRISPR technologies targeting PCSK9, NOS3, HIF1A, NLRP3, METTL4, BMPR2, and ACTA2 were identified to enhance repair mechanisms in endothelial cells, regulate inflammation, modulate lipid metabolism, and remodel the vascular system. The human studies demonstrated sustained gene silencing effects following a single dose of CRISPR-induced in vivo editing. The use of CRISPR technology to edit cell genomes offers potential to alter disease progression in vascular medicine, with a growing body of translational evidence supporting the feasibility and durability of the approach. CRISPR-Based Genome Editing in Vascular Disease: From Molecular Targets to Clinical Translation. This graphical abstract illustrates the therapeutic landscape of CRISPR-based genome editing in vascular disease. Key molecular targets are grouped according to their primary roles in vascular pathology, including endothelial dysfunction (NOS3, HIF1A, NRF2, ICAM1), inflammation (NLRP3, METTL4), lipid metabolism and atherosclerosis (PCSK9, LDLR, TTR), vascular remodeling (ACTA2, SOX17, MYO9B, STXBP5), and pulmonary vascular disease (BMPR2). CRISPR/Cas9-mediated genome editing of these targets modulates critical biological pathways, resulting in enhanced nitric oxide production, improved endothelial function and angiogenesis, reduced oxidative stress and inflammatory signaling, decreased lipid accumulation and plaque formation, restoration of vascular smooth muscle cell contractility, and normalization of pulmonary vascular signaling. Collectively, these molecular effects translate into improved vascular repair, enhanced blood flow, attenuation of atherosclerosis, reduced vascular remodeling, and overall improvement in vascular health. The lower panel highlights the translational progression of CRISPR technology from preclinical cellular and animal models to early human studies, including NTLA-2001 and VERVE-101, underscoring the emerging potential of precision genome editing as a disease-modifying strategy for vascular disorders. Abbreviations: NO, nitric oxide; ROS, reactive oxygen species; LDLR, low-density lipoprotein receptor; LDL-C, low-density lipoprotein cholesterol; VSMC, vascular smooth muscle cell; PAH, pulmonary arterial hypertension.
Mobocertinib, a tyrosine kinase inhibitor approved for EGFR exon 20 insertion-mutated non-small cell lung cancer, induces cardiotoxicity manifesting as QT prolongation. Salidroside, a bioactive compound from Rhodiola rosea, exhibits cardioprotective properties. We investigated electrophysiological mechanisms underlying mobocertinib cardiotoxicity and salidroside's protective efficacy using Langendorff-perfused rat hearts and neonatal rat cardiomyocytes (NRCMs). Hearts were treated with escalating mobocertinib concentrations (214, 428, 856 nM) with or without salidroside (20 μM) pretreatment; cardiac parameters including heart rate, PR, JT, QTc intervals and conduction were mapped via high-resolution multichannel electrophysiology. NRCMs underwent chronic mobocertinib exposure with/without salidroside, followed by transcriptomic sequencing, qRT-PCR, and western blot validation. Mobocertinib concentration-dependently prolonged PR, JT, QTc intervals, increased conduction time/heterogeneity, reduced heart rate/velocity, and JT/QTc prolongation persisted after washout. Salidroside pretreatment markedly attenuated these abnormalities. In NRCMs, mobocertinib prolonged field potential duration and impaired conduction; salidroside normalized parameters. Transcriptomic analysis identified enrichment in calcium signaling, aldosterone synthesis, cGMP-PKG, and adrenergic pathways. Notably, Atp2b2 was upregulated in mobocertinib group but downregulated in salidroside combination group, whereas Agtr1b showed opposite pattern. Thus, salidroside mitigates mobocertinib-induced electrophysiological toxicity by modulating Atp2b2/Agtr1b-related signaling networks, providing a novel cardioprotective strategy against mobocertinib-associated cardiotoxicity.
The TKI-targeted agent lapatinib has been applied in clinical oncology for the management of multiple malignancies. Nonetheless, its therapeutic benefit is restricted by cardiotoxic effects that endanger patient survival, and the underlying molecular basis remains unclear. The GSE146096 dataset containing transcriptomic profiles of lapatinib-exposed human cardiomyocytes was analyzed to identify ferroptosis-related differentially expressed genes (DEGs). Protein expression of selected targets was subsequently confirmed by Western Blot. Reactive oxygen species (ROS) accumulation, Fe²⁺ levels, and mitochondrial membrane potential in AC16 cells exposed to lapatinib were examined using confocal microscopy. A microplate reader was employed to quantify alterations in malondialdehyde (MDA) and glutathione (GSH) levels in cardiomyocytes. Eight ferroptosis-associated genes were identified in lapatinib-treated cardiomyocytes, including the canonical regulator GPX4. siRNA interference and Western Blot analyses demonstrated marked induction of ATF4 expression and significant suppression of GPX4 expression following lapatinib exposure in AC16 cells. CCK-8 assays indicated dose-dependent cytotoxicity. Confocal microscopy and transmission electron microscopy (TEM) revealed altered mitochondrial morphology accompanied by a reduction in mitochondrial membrane potential. Intracellular MDA levels increased substantially, whereas GSH levels declined, indicating lipid peroxidation and subsequent ferroptosis. Treatment with the ferroptosis inhibitor Ferrostatin-1 (Fer-1) or silencing of ATF4 expression effectively attenuated lapatinib-induced cytotoxicity. Lapatinib enhances ATF4 expression in cardiomyocytes, suppresses GPX4, triggers lipid peroxidation, induces ferroptosis, and thereby contributes to cardiotoxicity.
Tenascin-X (Tnxb) is a large extracellular matrix protein that has been associated with atherosclerosis. The objective of this study was to investigate the effect of Tnxb and its contribution to recovery after myocardial ischemia/reperfusion (I/R) injury. Tnxb expression was reduced in ECs of mice with ligation of the left anterior descending. Conditional Tnxb overexpression using adeno-associated viruses promoted Akt phosphorylation and mitigated myocardial injury and cardiac dysfunction in mice with myocardial I/R. Furthermore, overexpression of Tnxb alleviated apoptosis and enhanced angiogenesis in vivo and in vitro. Krueppel-like factor 4 (Klf4) recruited SWItch/sucrose nonfermentable (SWI/SNF) to the distal enhancer of Tnxb to transcriptionally activate Tnxb, thereby promoting Akt phosphorylation. The mitigating effect of Klf4 overexpression on I/R-induced endothelial apoptosis and angiogenic dysfunction was dependent on Tnxb activation, since Tnxb knockdown reversed the effects of Klf4 overexpression on myocardial I/R injury. In summary, we show that Klf4 recruits SWI/SNF to the distal enhancer of Tnxb to transcriptionally activate Tnxb, which promotes Akt phosphorylation and alleviates myocardial I/R-induced endothelial apoptosis and angiogenic dysfunction. Lastly, Tnxb was identified as a potential therapeutic target in EC injuries induced by myocardial I/R. The image(s) herein have been obtained from Servier Medical Art ( https://smart.servier.com ), which is licensed under CC BY 4.0 ( https://creativecommons.org/licenses/by/4.0/ ).
Septic cardiomyopathy (SCM) is a severe complication of sepsis, characterized by high mortality. The activation of mitophagy in cardiomyocytes is crucial for alleviating SCM. The N7-methylguanosine (m7G) modification mediated by methyltransferase 1 (METTL1) is known to negatively regulate mitophagy. This study investigated the mechanism of METTL1 in the mitophagy of cardiomyocytes in SCM. Human cardiomyocytes (HCMs) were stimulated with lipopolysaccharide (LPS) to establish the SCM model. C57BL/6 mice underwent cecal ligation and puncture (CLP) surgery to create a septic model. Mitophagy was assessed utilizing the mt-Keima assay, while mitochondrial membrane potential was measured with the JC-1 assay. MitoSOX Red assay was employed to evaluate levels of mitochondrial reactive oxygen species (ROS). The interaction between METTL1 and upstream transcription factor 2 (USF2), as well as between USF2 and PTEN-induced putative kinase protein 1 (PINK1), was confirmed through RNA immunoprecipitation (RIP) and RNA pull-down or dual luciferase reporter gene and chromatin immunoprecipitation (ChIP) assays. The silenced METTL1 mitigated LPS-triggered myocardial damage in vitro. The inhibition of mitophagy nullified the protective effects conferred by METTL1 silencing in LPS-induced HCMs. Consistently, METTL1 silencing ameliorated myocardial injury induced by sepsis in a mouse model. METTL1 enhanced the expression of USF2 in an m7G-dependent manner. USF2, in turn, inactivated the PINK1/Parkin signaling pathway by repressing PINK1 transcription. The repression of USF2 negated the protective effects of METTL1 silencing on myocardial damage and mitophagy. METTL1 aggravated myocardial injury by inhibiting PINK1/Parkin-mediated mitophagy through the upregulation of USF2 in a m7G-dependent manner in SCM models, thereby identifying METTL1 as a potential therapeutic target for SCM. Research mechanism diagram of METTL1 knockdown alleviating SCM via regulating USF2/PINK1/Parkin-mediated mitophagy
Micro- and nanoplastics (MNPs) have emerged from a diffuse environmental concern to a plausible cardiovascular exposure with potential clinical relevance. The current evidence base is heterogeneous: human observational and tissue-detection studies have identified MNPs in blood, thrombi, atherosclerotic plaques, arterial tissue, and cardiac surgical specimens, whereas cell, organoid, and animal studies provide mechanistic plausibility for vascular inflammation, thrombosis, myocardial injury, remodeling, and electrophysiological disturbance. Key clinical signals now include polyethylene detection in 58.4
Doxorubicin (DOX)–induced cardiac injury remains a major limitation of chemotherapy and is closely linked to mitochondrial dysfunction, oxidative stress, and dysregulated mitophagy. Sirtuin 5 (SIRT5), a mitochondrial deacylation-related protein, has been implicated in mitochondrial homeostasis; however, its role in DOX-induced acute cardiaotoxicity is not fully understood. Here, we investigated whether SIRT5 mitigates acute DOX-induced cardiac injury by regulating prohibitin 2 (PHB2) succinylation and mitochondrial quality control. An acute DOX-induced cardiac-damaged mouse model was established (15 mg/kg for one single dose, i.p.) in male C57BL/6 mice, serum lactate dehydrogenase (LDH), cardiac troponin T (cTnT), and cardiac creatine kinase isoenzyme MB (CK-MB) were elevated, accompanied by reduced cardiac SIRT5 expression. In primary cardiomyocytes, DOX (4 µM, 24 h) downregulated SIRT5 and induced excessive ROS production and apoptosis together with altered mitophagy-related signaling. SIRT5 overexpression attenuated DOX-triggered ROS accumulation and apoptosis and reversed these mitophagy-associated alterations. Mechanistically, PHB2 succinylation was increased upon DOX exposure, whereas SIRT5 overexpression reduced PHB2 succinylation detected by PHB2 immunoprecipitation followed by pan–succinyl-lysine immunoblotting. In addition, SIRT5 showed colocalization and interaction with PHB2. Collectively, our findings suggest that SIRT5 attenuates acute DOX-induced cardiotoxicity, potentially through modulating PHB2 succinylation and the mitophagic response, highlighting the SIRT5–PHB2 axis as a candidate target for alleviating early-onset of DOX-induced cardiac injury. The proposed protective mechanism by SIRT5 on DOX-induced cardiotoxicity.
Quasi-ultrafine particles (qUFPs; particulate matter < 0.49 μm; PM0.49) exposure is a key environmental contributor to cardiovascular disease, but its epigenetic impact on human cardiac fibroblasts (HCFs) remains unclear. Dysregulated DNMT activity and aberrant DNA methylation have been implicated in fibroblast activation and cardiac remodelling; however, the clinical utility of the DNMT inhibitor 5-Azacytidine (5-Aza) remains limited by chemical instability and toxicity, motivating nanoparticle (NP)-based delivery to improve stability and sustain therapeutic exposure. PM0.49 was collected from Chiang Dao district, Chiang Mai Province, Thailand. HCFs were exposed to PM0.49 (low and high concentrations), with or without pre-treatment using free 5-Aza or 5-Aza-loaded hyaluronic acid nanoparticles (5-Aza-NP). Epigenetic and pro-fibrotic gene markers were quantified using RT‑qPCR, and cell viability was assessed by MTT assay. Additionally, transcriptomic analysis using bulk RNA sequencing was performed to evaluate the effects of PM0.49 on HCFs and their modulation by 5-Aza-NP treatment. HCFs exposed to high concentrations of PM0.49 exhibited dysregulation of DNA methylation machinery, characterised by increased expression of DNMT1 and DNMT3A/B. Markers associated with fibroblast activation and pathogenic activation, including COL1A1 and α-SMA, were significantly induced following PM0.49 exposure, whereas these alterations were attenuated following 5-Aza treatment. NP-based delivery of 5-Aza attenuated PM0.49-induced HCF activation with reduced cytotoxicity under chronic exposure conditions. Bulk RNA sequencing identified transcriptomic alterations associated with PM0.49 exposure that were partially modulated by 5-Aza-NP treatment, with selected findings validated by RT-qPCR. Exposure to a smoke haze-period PM0.49 preparation from a biomass burning-affected rural site in Chiang Mai, Thailand, induced pathogenic HCF activation with molecular findings consistent with dysregulation of DNA methylation machinery. 5-Aza-NP attenuated PM0.49-induced fibroblast activation and modulated associated transcriptomic alterations, suggesting a potential epigenetic-based therapeutic strategy against PM0.49-induced cardiac fibroblast dysfunction. These findings warrant further validation across diverse PM compositions and sampling conditions.
The impact of metals on atherosclerotic cardiovascular disease (ASCVD) risk in workers occupationally exposed to welding fume remains unclear. We aimed to assess the associations between welding-related metals and 10-year ASCVD risk, and the mediating role of biological aging. Metals including chromium, manganese, nickel, lead, copper (Cu), and iron were detected and biological aging indices, including Klemera-Doubal method biological age (KDM-BA) and Phenotypic Age (PhenoAge), were calculated among 419 male welders in Wuhan, China. The participants had an average age of 42.77 years, of whom 93 (22.2
Doxorubicin (DOX)-induced cardiotoxicity remains a major limitation of cancer therapy. Incretin-based therapies are established cardiometabolic agents with pleiotropic cardiovascular effects; however, their potential role in mitigating DOX-related cardiac injury has not been systematically synthesized. We conducted a PRISMA 2020-compliant systematic review to evaluate the effects of incretin-based therapies on DOX-induced cardiotoxicity, with a focus on functional, structural, biomarker, and mechanistic outcomes. PubMed/MEDLINE, Embase, Web of Science, and Scopus were searched through 20 October 2025. Eligible studies included in vivo rodent models of DOX cardiotoxicity and any clinical studies directly evaluating incretin-based therapy during DOX exposure; in vitro studies, non-DOX models, combination-treatment studies, studies not focused on cardiotoxicity, gene therapy-based interventions, and reviews/editorials were excluded. Risk of bias and certainty of evidence were assessed using the SYRCLE tool and GRADE adapted for preclinical research. Thirteen rodent studies were included, and no eligible human study was identified. Investigated agents included liraglutide (n = 4), exenatide/exendin-4 (n = 4), semaglutide (n = 2), and tirzepatide (n = 3). In chronic cumulative-dose DOX models, incretin-based therapies were generally associated with preservation of left ventricular systolic function, with between-study improvements of approximately 7–20 percentage points in left ventricular ejection fraction, along with reductions in injury biomarkers. These effects were accompanied by attenuation of oxidative stress, inflammation, apoptosis, and, in some studies, ferroptosis. In contrast, findings were less consistent in acute single-dose models. Co-treatment during DOX exposure showed the most reproducible protective signal, whereas isolated pretreatment with liraglutide or tirzepatide and post-treatment with exenatide did not show a clear additional benefit. The evidence base is limited by exclusive reliance on small heterogeneous animal studies, predominantly male models, variable dosing/timing protocols, and low-to-very-low certainty of evidence. Overall, incretin-based therapies show biologically plausible cardioprotective effects in preclinical DOX cardiotoxicity, but these findings should be regarded as hypothesis-generating until confirmed in carefully designed clinical studies.
The unique physicochemical properties of nanoparticles (NPs) have facilitated the development of targeted therapies for cardiovascular diseases (CVDs). According to World Health Organization estimates, CVDs are the predominant contributors to global mortality, accounting for approximately 17.9 million deaths annually. Conventional treatments, including pharmacological interventions and surgical procedures, face significant barriers such as systemic toxicity due to non-targeted delivery, incomplete efficacy, and high financial burdens. Nanoscale innovations address these limitations through mechanisms such as targeted drug delivery and controlled release. Despite these advancements, concerns regarding NPs-induced cardiotoxicity remain unresolved. As nanomedicine advances rapidly, understanding NP functions within the cardiovascular system is essential for optimizing therapeutic outcomes in parallel to minimize unintended risks. Metal-based NPs, including gold, silver, and iron oxide, have demonstrated promising applications in cardiovascular imaging, regenerative therapy, and drug delivery; however, emerging evidence indicates their potential to induce oxidative stress, inflammatory responses, and endothelial dysfunction, contributing to atherosclerosis, myocardial injury, and arrhythmias. Inhaled and intravenously administered NPs exhibit dose-dependent toxicities that influence mitochondrial function and calcium homeostasis within cardiomyocytes. This review comprehensively analyzes in vitro and in vivo studies and notable clinical trials such as the NANOM-FIM trial. Furthermore, we discuss the role of specific antioxidants in cardioprotection and mitigating NPs-induced cardiotoxicity.
Doxorubicin-induced cardiotoxicity is a major limitation in cancer therapy. Physical exercise has been proposed as a non-pharmacological strategy capable of mitigating these effects through cardiovascular adaptations. This study evaluated whether low-intensity aerobic training attenuates cardiac dysfunction induced by doxorubicin. Twenty-five adult male Wistar rats (450 and 500 g) were allocated and divided into four groups: Control (C), Doxorubicin (D), Doxorubicin and Trained (DT), and Trained (T). The D and DT groups received weekly intraperitoneal injections of doxorubicin over a four-week period, totaling a cumulative dose of 8 mg/kg. The DT and T groups underwent low-intensity aerobic training for 25 weeks, three times a week, with sessions lasting 10 to 20 min at 50 and 60 Doxorubicin-induced cardiotoxicity increases myocardial fibrosis and promotes cardiac remodeling compatible with cardiac dysfunction. In this study, low-intensity aerobic exercise appeared to attenuate collagen accumulation and partially preserve functional parameters in Wistar rats exposed to doxorubicin. Echocardiographic and histological analyses revealed preserved systolic function and reduced deposition of type I and III collagen in animals that received doxorubicin and underwent training. These findings suggest that low-intensity aerobic training may act as a protective strategy, by mitigating myocardial remodeling and contributing to better tolerance to doxorubicin-induced injury.
Reprogramming of glycolytic metabolism plays a critical role in the pathogenesis of myocardial ischemia-reperfusion injury (MIRI). Although transient glycolysis activation may alleviate energy deficits, excessive glycolytic flux can worsen myocardial damage. This study aimed to identify specific biomarkers and therapeutic targets by investigating glycolysis-related genes in MIRI. We analyzed differentially expressed genes (DEGs) from GEO datasets GSE61592 and GSE160516 and constructed co-expression modules using weighted gene co-expression network analysis (WGCNA). By intersecting DEGs, WGCNA modules, and glycolysis-related genes, we identified glycolysis-related DEGs (GR-DEGs). Machine learning (support vector machine–recursive feature elimination and Random Forest) was applied to GR-DEGs; LOX emerged as the top intersecting feature (log2FC = 3. 67, adjusted P = 1. 44 × 10⁻⁵, validation set AUC = 0. 97). Diagnostic value was assessed using gene set enrichment analysis (GSEA), decision curve analysis (DCA), and nomogram modeling. Immune infiltration was evaluated using CIBERSORT. Experimental validation was conducted in a rat MIRI model and H9c2 hypoxia-reoxygenation (H/R) cells. GR-DEGs were enriched in pathways including ribose phosphate metabolism, collagen binding, and apoptosis. Machine learning identified LOX as a hub gene, significantly upregulated in both models. Functional analysis suggested LOX expression was significantly associated with extracellular matrix (ECM) receptor interaction pathways, with its upregulation coinciding with myocardial injury progression. LOX expression correlated positively with CD8⁺ T cells and activated memory CD4⁺ T cells, indicating its potential association with metabolic and immune microenvironment remodeling in MIRI. Our findings suggest that LOX may serve as a key candidate gene associated with MIRI pathogenesis in preclinical models, with a potential value for preclinical research exploration.
The association between serum zinc (SZn) concentration in adolescence-early adulthood and the risk of elevated carotid intima-media thickness (CIMT) in adulthood was investigated. A total of 519 participants (12–29 years) from the Tehran Lipid and Glucose Study with complete baseline data (2009–2011), including SZn concentrations, were recruited and followed through 2015–2018. CIMT was measured using high-resolution B-mode ultrasonography, and high-CIMT was defined as values above the sex-specific 90th percentile (i.e., 0.65 mm for men, 0.70 mm for women). Binary logistic regression models were used to estimate odds ratio (ORs) and 95
