Search Results (69)

Doxorubicin (DOX) remains an effective chemotherapeutic agent, but its clinical use is limited by dose-dependent cardiotoxicity. Mitochondrial dysfunction and metabolic remodeling are central features of DOX-induced cardiac injury. ATP synthase inhibitory factor-1 (IF1) is an endogenous inhibitor of the hydrolytic activity of mitochondrial ATP synthase and has emerged as an important regulator of cellular bioenergetics. Cardiac IF1 expression is increased in multiple pathological conditions; however, its role in chemotherapy-induced cardiotoxicity remains unclear. Here, we investigated the contribution of IF1 to DOX-induced cardiotoxicity using male C57BL/6J wild-type (WT) and IF1 knockout (IF1KO) mice, isolated cardiac mitochondria, cultured neonatal cardiomyocytes, and AC16 human cardiomyocytes. Cardiac function was assessed by echocardiography, mitochondrial function by high-resolution respirometry and Seahorse metabolic flux analysis, and myocardial injury by histological and ultrastructural analyses. DOX treatment markedly increased cardiac IF1 protein levels despite reduced IF1 mRNA expression. IF1 deficiency enhanced mitochondrial respiration in isolated cardiac mitochondria and cultured cardiomyocytes under both basal and DOX-stressed conditions. IF1KO mice exhibited attenuated cardiac dysfunction and improved myocardial ultrastructure following DOX treatment compared with WT mice. In AC16 cardiomyocytes exposed to DOX, overexpression of WT IF1 improved cellular metabolic activity but provided only limited preservation of mitochondrial respiratory capacity. In contrast, overexpression of the dominant-negative IF1 mutant (IF1E30A) not only improved metabolic activity but also preserved mitochondrial respiration. These findings identify IF1 as a key regulator of metabolic adaptation during DOX stress. Upregulation of functional IF1 may represent an adaptive response that promotes glycolytic ATP production during mitochondrial stress, whereas inhibition of IF1 activity preserves metabolic activity primarily through maintenance of mitochondrial function. Collectively, these findings provide new insights into the role of IF1 in DOX-induced cardiomyopathy and highlight IF1 as a potential therapeutic target in cardio-oncology. Full article

Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation, playing a critical role in the pathogenesis of various cardiomyopathies, including hypertrophic, dilated, diabetic, ischemic, doxorubicin-induced, and septic cardiomyopathy, as well as myocardial ischemia–reperfusion injury. This article provides a comprehensive narrative review of the molecular mechanisms of ferroptosis—centered on dysregulation of the GPX4/System Xc⁻ axis, iron metabolism, and lipid metabolism—and its role in cardiovascular diseases, with a specific focus on the cardioprotective effects of Traditional Chinese Medicine (TCM). Through a systematic analysis of recent literature, we highlight active components (e.g., baicalin, ginsenoside Rg3, resveratrol, tanshinone IIA), compound formulations (e.g., Qishen Granule, Zhilong Huoxue Tongyu Capsule), and electroacupuncture therapy, which exert effects via multi-target regulation of ferroptosis-related pathways such as Nrf2/HO-1/GPX4, p53/SLC7A11, and PI3K/AKT. Evidence indicates that TCM interventions effectively alleviate cardiomyocyte ferroptosis by activating the Nrf2 antioxidant pathway to upregulate GPX4/SLC7A11, modulating iron metabolism to reduce labile iron pools, and inhibiting ACSL4/ALOX15-mediated lipid peroxidation, with these effects validated in diverse cardiovascular disease models showing improved cardiac function. Targeting ferroptosis offers a novel therapeutic strategy for cardiovascular diseases, and TCM—with its synergistic multi-component, multi-target, multi-pathway advantages—holds significant potential in this context. Future research should prioritize elucidating complex network mechanisms and advancing clinical translation via high-quality studies to provide new theoretical foundations and drug candidates for cardiovascular disease management. Full article

Background: Doxorubicin (DOX) is a highly effective chemotherapy drug, but its use is limited by dose-dependent cardiotoxicity, driving the search for protective natural products. Although the herb Viscum coloratum (Kom.) Nakai is known for its cardiovascular benefits, the cardioprotective effects and mechanisms of its isolated compound, DHDK, remain unexplored. Methods: The protective effect of DHDK was first evaluated in DOX-injured H9c2 cardiomyocytes. Subsequently, an integrated network toxicology (incorporating DOX-induced toxicity targets and relevant chronic disease pathways such as aging and lipid metabolism) and pharmacology (DHDK) approach identified core targets, which were then refined through Protein–Protein Interaction (PPI) analysis and molecular docking. The underlying mechanism was investigated using lipidomics and validated through a series of in vitro assays, including CCK-8, q-PCR, biochemical tests, and flow cytometry, as well as in an in vivo rat model. Results: DHDK significantly alleviated DOX-induced cardiomyocyte toxicity. Integrated analysis identified 56 intersecting targets, with PPARG confirmed as the primary target via PPI and molecular docking. Lipidomics revealed that DHDK potently attenuated DOX-induced accumulation of pathogenic lipids (e.g., fatty acids, ceramides). Mechanistically, DHDK activated PPARG, which in turn upregulated CPT1B, a key regulator of fatty acid β-oxidation (FAO). This enhanced cell viability, ATP production, and mitochondrial membrane potential while reducing oxidative stress. These protective effects, which were abolished by the inhibition of PPARG or CPT1B, were further validated in vivo. Conclusion: This study demonstrates that DHDK exerts its cardioprotective effect by activating the PPARG-CPT1B-FAO axis, effectively correcting lipid metabolic disorders. Given that lipid dysregulation is a hallmark of various internal metabolic diseases, DHDK may also hold therapeutic potential for other heart conditions driven by metabolic disturbances, such as diabetic cardiomyopathy, highlighting its broad relevance to the field of internal diseases. Full article

Doxorubicin (DOX) is an effective drug for the treatment of solid tumors and hematological malignancies in both children and adults. The most serious side effect is doxorubicin-induced cardiotoxicity (DIC), which can lead to cardiomyopathy and irreversible and highly fatal cardiac decompensation. The precise mechanisms underlying DIC are not fully understood, and currently, no fully effective preventive or therapeutic strategies exist. Drug repositioning has emerged as a promising approach to mitigate DIC, leveraging existing safety profiles while potentially reducing the time and cost of clinical translation. In this review, we summarize current evidence on drug repurposing for DIC, with a particular focus on the antidepressant paroxetine, which shows potential cardioprotective effects beyond its established role as a selective serotonin reuptake inhibitor (SSRI). Full article

Background: Doxorubicin (Dox)-induced cardiotoxicity is the most important side effect of the drug and significantly limits its use in susceptible patients. Therefore, preventive measures are required to alleviate the Dox-induced cardiac failure. In this study, curcumin, a strong antioxidant agent, was investigated for its potential protective effect on dox-induced cardiotoxicity with its effect on Apelin expression as a mediator of cardiac function. Methods: Wistar albino rats were equally divided into four groups as Control, DOX, CUR, and CUR+DOX. Dox was administered a single dose of 20 mg/kg bw intraperitoneally while 100 mg/kg bw curcumin was given orally for 14 days before the Dox use. Results: DOX group showed a prolonged QT interval on an electrocardiogram and elevated cardiac troponin levels. In biochemical analyses, decreased Superoxide Dismutase activity and increased Malondialdehyde level and Catalase activity were detected in DOX group. Gene expression of Apelin decreased significantly while NF-κB increased in DOX group. Degenerative changes in histopathology, and increased iNOS and nitrotyrosine immunoreactivity were detected in DOX group. However, no significant changes were observed at reduced Glutathione, TNF-, and IL-1β levels. Curcumin use in Dox-given rats altered most of the disturbed parameters investigated in this study, indicating an alleviating effect on Dox-induced cardiotoxicity. Serum and heart Apelin levels and mRNA expression in heart tissue were detected to significantly increase in CUR+DOX group as compared to DOX group. Furthermore, NF-κB mRNA expression was significantly decreased in heart tissue of CUR+DOX group compared with the DOX group. Conclusions: The results suggest that Apelin acts as an important mediator in Dox cardiotoxicity and may be used as a target for treatment of certain cardiomyopathies. By regulating Apelin expression, curcumin may serve as a potential adjunct in cardioprotective approaches. Full article

Oxidative stress and mitochondrial dysfunction play a key role in the early stage of Doxorubicin (Doxo)-induced cardiotoxicity. Our study investigated the potential cardioprotective role of Simvastatin (Sim), widely known for its antioxidant properties, in an in vitro model of Doxo-induced acute cardiotoxicity. Human Cardiomyocytes (HCMs) were treated with Sim (10 µM, 4 h) and then co-exposed to Doxo (1 µM) and Sim for 20 h. Our data showed that Sim co-treatment significantly (p < 0.05) reduced both cytosolic and mitochondrial Doxo-induced reactive oxygen species overproduction. In Sim co-treated cells, significant reductions in nuclear factor erythroid 2-related factor 2 (Nrf2) gene expression (p < 0.01) and catalase (CAT), heme-oxygenase 1 (HO-1), and superoxide dismutase 2 (SOD2) levels (p < 0.05) compared to Doxo-treated cells were also demonstrated, suggesting a decreased need for compensatory antioxidant defense responses. Moreover, significant reductions in Doxo-induced mitochondrial calcium overload, mitochondrial membrane depolarization (p < 0.005), and apoptosis (p < 0.005) confirmed the protective effects of Sim co-treatment on cardiomyocytes. These data confirm that Sim could be a valuable therapeutic strategy for reducing Doxo-induced HCM damage, preventing the development of dilated cardiomyopathy and long-term heart damage, which are the main limitations of anthracycline use. Finally, real-time PCR analysis revealed that Sim co-treatment significantly reduced (p < 0.001) the Doxo-induced overexpression of MAP4K4, a mitogen-activated protein kinase kinase kinase kinase-4 (MAP4K4) involved in oxidative stress-induced cell death, thus suggesting the involvement of other molecular mechanisms in Sim-mediated cardioprotection. Full article

Background: The cardiotoxic effects of doxorubicin (DOX), a powerful chemotherapeutic drug, are widely recognized. Cuproptosis, a unique copper-dependent form of controlled cell death, may be involved in DOX-induced cardiomyopathy, according to recent findings. This study employs both in vivo and in silico procedures to investigate the protective effects of the copper chelator penicillamine (PEN) and the role of cuproptosis in DOX-related cardiotoxicity. Methods: Thirty-two adult Sprague Dawley rats were allocated into four groups (n = 8): control, DOX, DOX+PEN, and PEN. Cardiac function was assessed via echocardiography. Serum cardiac biomarkers (LDH, CK-MB, CTnI), oxidative stress markers (SOD, GPX, MDA), and expression levels of cuproptosis-related genes (FDX1, LIAS, SLC31A1, ATP7A) were evaluated. Histopathological examinations and immunohistochemical staining for FDX1, SLC31A1, and DLAT were performed. Molecular docking simulated PEN’s interaction with cuproptosis-related proteins. Network pharmacology and molecular docking studies were also conducted to identify core molecular targets and simulate PEN’s binding interactions with key cuproptosis regulators. Results: DOX administration induced significant cardiac dysfunction, oxidative stress, and upregulation of cuproptosis markers. PEN treatment mitigated these effects, improved cardiac function, reduced fibrosis, and suppressed the expression of cuproptosis-related genes and proteins. Docking results confirmed strong interactions between PEN and cuproptosis-regulatory proteins. Network pharmacology revealed 14 key overlapping targets linking PEN with cuproptosis and DOX-induced cardiotoxicity. Conclusion: This study provides experimental evidence implicating cuproptosis in DOX-induced cardiomyopathy. PEN exerts cardioprotection, potentially by targeting this pathway, offering a promising therapeutic strategy. Full article

Objectives: Chemotherapy improves survival in breast cancer patients but increases the risk of myocardial dysfunction and heart failure. Since early prediction of cardiomyopathy remains difficult, biomarkers are needed for detecting myocardial damage before heart failure develops. This study examines the association between oxidative stress biomarkers and myocardial dysfunction in a chemotherapy-induced rat model. Methods: Forty-two rats were randomized into four groups: control (n = 7), doxorubicin only (n = 7), doxorubicin plus trastuzumab (n = 7), and doxorubicin plus trastuzumab with cardioprotective intervention (n = 21). Doxorubicin and trastuzumab were administered sequentially over 28 days. Echocardiography with speckle-tracking was utilized to measure longitudinal strain (LS, −%). Reduced LS was defined by a LS with a median value less than 23% on day 28. Blood samples were collected for biomarker analysis, focusing on superoxide dismutase (SOD) and glutathione (GSH). Myocardium fibrosis was assessed using Masson’s trichrome staining. Results: Thirty-four rats survived and underwent LS analysis. All rats treated with doxorubicin and trastuzumab exhibited reduced LS, while those receiving cardioprotective intervention maintained preserved LS on day 28. The reduced LS group had significantly lower SOD and higher GSH levels compared to the preserved LS group. SOD and GSH correlated strongly with LS (SOD, r = 0.590, p = 0.001; GSH, r = −0.590, p = 0.003), and LS correlated with fibrosis area (r = −0.660, p < 0.001). SOD and GSH effectively predicted reduced LS. Conclusions: In a rat model of chemotherapy-induced cardiomyopathy, oxidative stress biomarkers correlated with myocardial dysfunction, as indicated by LS. These findings highlight the potential of biomarker monitoring to improve early detection and prevention strategies for chemotherapy-induced cardiomyopathy. Full article

Background/Objectives: Diabetic cardiomyopathy is a distinct myocardial dysfunction characterized by structural and functional changes in the heart that occur in diabetic patients independently of coronary artery disease or hypertension. It is closely associated with oxidative stress, inflammation, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress, and contributes to progressive cardiac damage. This study aimed to evaluate the cardioprotective effects of dapagliflozin (DAPA) and trimetazidine (TMZ) in a rat model of doxorubicin-induced cardiomyopathy with streptozotocin-induced diabetes, focusing on their potential mechanisms related to ER stress. Methods: A total of 48 Sprague Dawley rats aged 6–8 weeks were randomly distributed equally into six cages. The diabetes model was induced by intraperitoneal administration of streptozotocin (STZ) and rats with blood glucose levels above 250 mg/dL were considered diabetic. For those rats with diabetes, cardiotoxicity was induced by intraperitoneal injection of 5 mg/kg/week doxorubicin (DOXO) for 4 weeks. After a cumulative dose of 20 mg/kg doxorubicin, a week break was given, followed by the administration of TMZ (10 mg/kg) and/or DAPA (10 mg/kg) to the treatment groups. Results: STZ administration caused diabetes and significant degeneration in cardiomyocytes. With the addition of DOXO (STZ + DOXO), cardiomyocyte degeneration became more severe. When the study groups were histopathologically evaluated based on parameters of degenerative cardiomyocytes, vascular congestion, and edema, it was shown that both TMZ and DAPA, whether applied alone or in combination, reduced damage in heart tissue. Both TMZ and DAPA reduced cardiomyocyte damage, and their combination provided the lowest level of damage through the reduced ER stress pathway by reducing GRP 78 and CHOP positivity. Conclusions: TMZ and DAPA reduce ER stress and have protective effects against diabetic-induced cardiotoxicity. Combination therapy or TMZ was found to be more effective than DAPA in alleviating ER stress. Combination therapy appears to carry potential effects for reducing cardiac cell damage in individuals with diabetes. Full article

N6-methyladenosine (m6A) is the most prevalent internal chemical modification in eukaryotic messenger RNA (mRNA), significantly impacting its lifecycle through dynamic and reversible processes involving methyltransferase, demethylase, and binding proteins. These processes regulate mRNA stability, splicing, nuclear export, translation, and degradation. Programmed cell death (PCD), a tightly controlled process encompassing apoptosis, pyroptosis, ferroptosis, autophagy, and necroptosis, plays a crucial role in maintaining cellular homeostasis, tissue development, and function. Recently, m6A modification has emerged as a significant research area due to its role in regulating PCD and its implications in cardiovascular diseases (CVDs). In this review, we delve into the intricate relationship between various PCD types and m6A modification, emphasizing their pivotal roles in the initiation and progression of CVDs such as myocardial ischemia-reperfusion (I/R), atherosclerosis (AS), pulmonary hypertension (PH), cardiomyopathy, doxorubicin (Dox)-induced cardiotoxicity (DIC), heart failure (HF), and myocardial infarction (MI). Our findings underscore the potential of elucidating the roles of m6A and PCD in CVD to pave new pathways for prevention and treatment strategies. Full article

Doxorubicin is a highly effective anticancer agent, but its clinical use is restricted by severe side effects, including atherosclerosis and cardiomyopathy. These complications are partly attributed to doxorubicin’s ability to induce endothelial-to-mesenchymal transition (EndMT) in vascular endothelial cells, a critical process in the initiation and progression of atherosclerosis and cardiomyopathy. GV1001, a multifunctional peptide with anti-inflammatory, anti-cancer, antioxidant, and anti-Alzheimer’s properties, has demonstrated inhibition of EndMT. We investigated whether GV1001 could counteract doxorubicin-induced EndMT in endothelial cells and prevent atherosclerosis in a mouse model. The results revealed that GV1001 significantly suppressed EndMT induced by doxorubicin, likely through its protective effects on mitochondria. By mitigating mitochondrial damage, GV1001 reduced the accumulation of mitochondrial and cellular reactive oxygen species (ROS), repressed the activation of nuclear factor kappa B (NF-κB), and reduced the production of proinflammatory cytokines in endothelial cells. Additionally, GV1001 reduced systemic and vascular inflammation, lipid accumulation, and monocyte/macrophage infiltration within arterial walls in mice. In conclusion, GV1001 appears to prevent doxorubicin-induced atherosclerosis by safeguarding vascular endothelial cells from mitochondrial dysfunction, inflammation, and phenotypic changes. These findings suggest the potential of GV1001 as a therapeutic agent to mitigate the long-term cardiovascular side effects associated with doxorubicin treatment in humans. Full article

Doxorubicin (DOX) has been widely used as a cytotoxic chemotherapeutic. However, DOX has a number of side effects, such as myelotoxicity or gonadotoxicity, the most dangerous of which is cardiotoxicity. Cardiotoxicity can manifest as cardiac arrhythmias, myocarditis, and pericarditis; life-threatening late cardiotoxicity can result in heart failure months or years after the completion of chemotherapy. The development of late cardiomyopathy is not yet fully understood. The most important question is how DOX reprograms the cardiomyocyte, after which DOX is excreted from the body, initially without symptoms. However, clinically overt cardiomyopathy develops over the following months and years. Since the 1980s, DOX-induced disorders in cardiomyocytes have been thought to be related to oxidative stress and dependent on the Fe/reactive oxygen species (ROS) mechanism. That line of evidence was supported by dexrazoxane (DEX) protection, the only Food and Drug Administration (FDA)-approved drug for preventing DOX-induced cardiomyopathy, which complexes iron. Thus, the hypothesis related to Fe/ROS provides a plausible explanation for the induction of the development of late cardiomyopathy via DOX. However, in subsequent studies, DEX was used to identify another important mechanism in DOX-induced cardiomyopathy that is related to topoisomerase 2β (Top2β). Does the Top2β hypothesis explain the mechanisms of the development of DOX-dependent late heart failure? Several of these mechanisms have been identified to date, proving the involvement of Top2β in the regulation of the redox balance, including oxidative stress. Thus, the development of late cardiomyopathy can be explained based on mechanisms related to Top2β. In this review, we highlight free radical theory, iron imbalance, calcium overload, and finally, a theory based on Top2β. Full article

Diabetes mellitus (DM) is a significant risk factor for various cancers, with the impact of anti-diabetic therapies on cancer progression differing across malignancies. Among these therapies, metformin has gained attention for its potential anti-cancer effects, primarily through modulation of the AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) pathway and the induction of autophagy. Beyond metformin, other conventional anti-diabetic treatments, such as insulin, sulfonylureas (SUs), pioglitazone, and dipeptidyl peptidase-4 (DPP-4) inhibitors, have also been examined for their roles in cancer biology, though findings are often inconclusive. More recently, novel medications, like glucagon-like peptide-1 (GLP-1) receptor agonists, dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) agonists, and sodium-glucose co-transporter-2 (SGLT-2) inhibitors, have revolutionized DM management by not only improving glycemic control but also delivering substantial cardiovascular and renal benefits. Given their diverse metabolic effects, including anti-obesogenic properties, these novel agents are now under meticulous investigation for their potential influence on tumorigenesis and cancer advancement. This review aims to offer a comprehensive exploration of the evolving landscape of glucose-lowering treatments and their implications in cancer biology. It critically evaluates experimental evidence surrounding the molecular mechanisms by which these medications may modulate oncogenic signaling pathways and reshape the tumor microenvironment (TME). Furthermore, it assesses translational research and clinical trials to gauge the practical relevance of these findings in real-world settings. Finally, it explores the potential of anti-diabetic medications as adjuncts in cancer treatment, particularly in enhancing the efficacy of chemotherapy, minimizing toxicity, and addressing resistance within the framework of immunotherapy. Full article

Mutual interaction between doxorubicin (DOX) and cardiomyocytes is crucial for cardiotoxicity progression. Cardiomyocyte injury is an important pathological feature of DOX-induced cardiomyopathy, and its molecular pathogenesis is multifaceted. In addition to the direct toxic effects of DOX on cardiomyocytes, DOX-induced exosomes in the extracellular microenvironment also regulate the pathophysiological states of cardiomyocytes. However, the mechanisms by which DOX regulates exosome secretion and subsequent pathogenesis remain incompletely understood. Here, we found that DOX significantly increased exosome secretion from cardiomyocytes, and inhibiting this release could alleviate cardiomyocyte injury. DOX promoted exosome secretion by reducing cardiomyocyte silencing information regulator 1 (SIRT1) expression, exacerbating cardiotoxicity. DOX impaired lysosomal acidification in cardiomyocytes, reducing the degradation of intracellular multivesicular bodies (MVBs), resulting in an increase in MVB volume before fusing with the plasma membrane to release their contents. Mechanistically, SIRT1 loss inhibited lysosomal acidification by reducing the expression of the ATP6V1A subunit of the lysosomal vacuolar-type H+ ATPase (V-ATPase) proton pump. Overexpressing SIRT1 increased ATP6V1A expression, improved lysosomal acidification, inhibited exosome secretion, and thereby alleviated DOX-induced cardiotoxicity. Interestingly, DOX also induced mitochondrial-derived vesicle formation in cardiomyocytes, which may further increase the abundance of MVBs and promote exosome release. Collectively, this study identified SIRT1-mediated impairment of lysosomal acidification as a key mechanism underlying the increased exosome secretion from cardiomyocytes induced by DOX, providing new insights into DOX-induced cardiotoxicity pathogenesis. Full article

Doxorubicin (DOX) is a potent chemotherapeutic agent with well-documented dose-dependent cardiotoxicity. Regular exercise is recognized for its cardioprotective effects against DOX-induced cardiac inflammation, although the precise mechanisms remain incompletely understood. The activation of inflammasomes has been implicated in the pathogenesis and treatment of DOX-induced cardiotoxicity, with the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome emerging as a key mediator in cardiovascular inflammation. This study aimed to investigate the role of exercise in modulating the NLRP3 inflammasome to protect against DOX-induced cardiac inflammation. Male Sprague–Dawley rats were randomly assigned to receive a 10-day course of DOX or saline injections, with or without a preceding 10-week treadmill running regimen. Cardiovascular function and histological changes were subsequently evaluated. DOX-induced cardiotoxicity was characterized by cardiac atrophy, systolic dysfunction, and hypotension, alongside activation of the NLRP3 inflammasome. Our findings revealed that regular exercise preserved cardiac mass and hypertrophic indices and prevented DOX-induced cardiac dysfunction, although it did not fully preserve blood pressure. These results underscore the significant cardioprotective effects of exercise against DOX-induced cardiotoxicity. While regular exercise did not entirely prevent DOX-induced hypotension, our findings demonstrate that it confers protection against DOX-induced cardiotoxicity by suppressing NLRP3 inflammasome activation in the heart, underscoring its anti-inflammatory role. Further research should explore the temporal dynamics and interactions among exercise, pyroptosis, and other pathways in DOX-induced cardiotoxicity to enhance translational applications in cardiovascular medicine. Full article