Search Results (1,267)

Background: Doxorubicin-induced cardiotoxicity (DIC) is a major limitation of anthracycline chemotherapy and is characterized by oxidative stress, apoptosis, and myocardial remodeling. Dysregulation of AMP-activated protein kinase (AMPK) and its downstream effector sirtuin-1 (SIRT1) has been implicated in the molecular pathogenesis of DIC. Vardenafil (Var), a selective phosphodiesterase-5 inhibitor, has shown cardiovascular benefits; however, its impact on AMPK/SIRT1 signaling during DIC remains unclear. Methods: DIC was induced in rats by cumulative doxorubicin administration. Cardiac function, serum injury biomarkers, oxidative stress indices, histopathological alterations, apoptosis, fibrosis, and molecular markers associated with the AMPK/SIRT1 pathway were evaluated. In addition, molecular docking was performed to assess the potential interaction of Var with AMPK. Results: Var significantly improved cardiac function and reduced serum levels of lactate dehydrogenase, creatine kinase, and blood urea nitrogen. Treatment attenuated myocardial oxidative stress, restored glutathione content, reduced lipid peroxidation, and alleviated histopathological damage. Furthermore, Var suppressed caspase-3 and TGF-β1 expression while enhancing HO-1 levels. Var treatment was associated with restoration of cardiac phosphorylated AMPK (p-AMPK) expression and increased SIRT1, Nrf2, and PPARγ levels in doxorubicin-treated rats, consistent with modulation of an AMPK/SIRT1-associated cytoprotective network. Molecular docking demonstrated favorable interactions between Var and AMPK, providing supportive in silico evidence for the observed molecular findings. Conclusions: These findings demonstrate that Var attenuates doxorubicin-induced cardiotoxicity, and its cardioprotective effects are associated with restoration of the p-AMPK/SIRT1/Nrf2/PPARγ signaling pathway, together with reductions in oxidative stress, apoptosis, and fibrosis. Collectively, these findings suggest that Var attenuates early Dox-induced cardiac injury, potentially through modulation of the AMPK/SIRT1 signaling pathway, warranting further validation in long-term and dose–response studies. Full article

The clinical use of doxorubicin (DOX), an effective chemotherapeutic drug for breast cancer, is limited by off-target nephrotoxicity, which is exacerbated in elderly patients. While excessive mitochondrial fission is known to contribute to DOX-induced cardiotoxicity, its role in DOX-induced nephrotoxicity, particularly in the context of renal aging, remains unclear. To explore this and investigate the therapeutic potential of the mitochondrial fission inhibitor Mdivi-1, female Wistar rats with D-galactose-induced accelerated renal aging were allocated into four groups: vehicle, DOX, DOX+Mdivi-1 co-treatment, and DOX+Mdivi-1 post-treatment. DOX administration resulted in significant renal dysfunction, oxidative stress, inflammation, and histopathological damage. Mitochondrial dysfunction along with the increased expression of fission protein, decreased fusion proteins, and activation of apoptotic markers and PINK1 expression were also evident. Remarkably, both co-treatment and post-treatment with Mdivi-1 comparably and significantly attenuated DOX-induced renal damage. This study suggests that Mdivi-1 mitigates DOX-induced nephrotoxicity in the aged kidney by modulating mitochondrial dynamics, suppressing oxidative stress and inflammation, and inhibiting apoptosis. These findings highlight mitochondrial fission as a promising therapeutic target for the treatment of doxorubicin toxicity and provide further support for the possible use of Mdivi-1 as a therapeutic strategy to protect the kidneys of elderly breast cancer patients undergoing chemotherapy. Full article

Breast cancer (BC) is the most incidental cancer in women. Patients’ living conditions and survival rates have significantly improved with the success of two first-line endocrine therapies of selective estrogen-receptor modulators (SERMs from 1977) and aromatase inhibitors (AIs from 1995). Unfortunately, both therapies have produced significant resistance. AI resistance reaches 50% in metastatic estrogen-dependent BC cases, leading oncologists to seek a substitute for current therapies. We target the reductive 17β-hydroxysteroid dehydrogenase type 7 (17β-HSD7), which stimulates the synthesis of the active estrogen estradiol (E2) and reduces the potent androgen dihydrotestosterone (DHT) simultaneously, triggering negative feedback on 17β-HSD7 expression. INH7(464), an improved 17β-HSD7 inhibitor, efficiently blocks estrogen conversion at an IC₅₀ of 92 ± 8 nM. INH7(464) inhibited cell proliferation by decreasing E2 levels and restoring DHT, successively arresting the cell cycle in G0/G1 phase. In vivo, INH7(464) reduced tumor size by 49% on Day 22 in BC xenografts with T47D. INH7(464) reduced E2 levels in mouse blood circulation and xenograft tumor tissue. There is no demonstrated cytotoxicity or cardiotoxicity of INH7(464) on cellular levels and mouse models under the experimental conditions. 17β-HSD7 is a potential target for estrogen-dependent BC therapy, while INH7(464) is promising for a preclinical lead compound (PCT/CA2022/050966). Full article

Doxorubicin-induced cardiotoxicity is an important concern in veterinary oncology, and early detection of myocardial injury remains clinically challenging. This exploratory pilot study described changes in cardiac fatty acid-binding protein (h-FABP), cardiac troponin I (cTnI), NT-proBNP, conventional echocardiographic variables, and 24-h Holter-derived heart rate variability parameters in dogs with hemangiosarcoma treated with doxorubicin. Fourteen dogs were prospectively evaluated before treatment initiation and one week after the third doxorubicin dose, corresponding to a cumulative dose of 90 mg/m². The study did not include a control group, a predefined cardiotoxicity endpoint, or diagnostic-performance analysis. Plasma biomarkers, echocardiographic parameters, ventricular arrhythmic events, and Holter-derived time- and frequency-domain heart rate variability variables were compared between both time points. Cardiac troponin I increased significantly after three doxorubicin doses, from a median of 0.05 ng/mL to 0.15 ng/mL (p = 0.002). In contrast, h-FABP did not change significantly, with median values of 2.43 ng/mL at baseline and 2.62 ng/mL after treatment (p = 0.27). NT-proBNP also showed no significant change (p = 0.87). Among echocardiographic variables, E-point septal separation, fractional shortening, ejection fraction, LA/Ao, and LVDd index did not change significantly. Ventricular arrhythmic events were infrequent and were described descriptively, whereas Holter-derived HRV variables did not show statistically significant differences between time points. In this exploratory cohort, cTnI increased after three doxorubicin doses, whereas h-FABP and NT-proBNP did not change significantly at the evaluated time point. Because h-FABP was measured one week after treatment, its potential short-term post-infusion release cannot be assessed. Larger studies with serial early sampling, predefined cardiotoxicity endpoints, appropriate control groups, and adjusted statistical analyses are required. Full article

Anthracycline cardiotoxicity involves early oxidative–inflammatory injury to the myocardium and vasculature. Repurposing anti-inflammatory agents may offer pragmatic cardioprotection. The purpose of this study is to evaluate whether sulfasalazine (SSZ) mitigates doxorubicin (DOX)-induced myocardial and aortic injury in rats. Twenty-eight male Wistar albino rats were randomized to: Control (vehicle, n = 8), DOX (20 mg/kg i.p., single dose; n = 10), and SSZ + DOX (SSZ 300 mg/kg i.p. once daily for 3 days, then DOX 20 mg/kg i.p.; n = 10). At 24 h post-DOX, ECG and invasive blood pressure (BP) were recorded. The heart and thoracic aorta were harvested for histopathology and oxidative stress assays (MDA, SOD, GSH, CAT; composite indices where applicable). Compared with SSZ + DOX, the DOX group exhibited higher BP and greater arrhythmic burden. In the aorta, DOX elevated MDA and reduced SOD, GSH, and CAT versus the control, whereas SSZ + DOX shifted these toward control values. In the myocardium, DOX decreased SOD and increased oxidative index; SSZ + DOX attenuated histological injury (edema, hemorrhage, cardiomyocyte degeneration) and restored aortic intima–media thickness toward control. Heart rate was lower in SSZ + DOX than other groups. Short-course SSZ pretreatment alleviated early DOX-induced oxidative stress and structural damage in myocardial and aortic tissues, with concurrent improvement in hemodynamic and ECG profiles. These data support further dose–timing optimization and longer-term functional studies to define SSZ’s translational potential as an adjunct cardioprotective strategy during anthracycline exposure. Full article

Semaglutide, a recombinant DNA-derived long-acting GLP-1 receptor agonist, has emerged as a key player for patients with or without T2DM and obesity. It exerts pleiotropic effects by modulating glycemic regulation and energy homeostasis. Mechanistically, it stimulates glucose-dependent insulin secretion and suppresses glucagon while enhancing satiety through POMC/NPY modulation in the arcuate nucleus and delaying gastric emptying. Beyond its metabolic utility, semaglutide is cardioprotective, leveraging the PI3K/Akt and eNOS pathways to improve vasodilation, reduce reactive oxygen species (ROS), and stabilize atherosclerotic plaques by inhibiting pro-inflammatory cytokines like TNF-α. While it improves cardiac output via PKA-mediated inotropy, potential cardiotoxicity, including resting tachycardia and autonomic-driven arrhythmias, requires clinical vigilance, particularly regarding electrolyte imbalances in heart failure patients. Ultimately, its robust vasculoprotective profile reinforces its potential as a cornerstone in cardiovascular pharmacotherapy. Further research is needed to better understand the effects of semaglutide on cardiac function and pathologies as it advances as a cardiac drug. This review discusses multiple molecular targets of semaglutide on the heart. Full article

Background: Breast cancer patients are exposed to cardiovascular complications related to both pre-existing cardiovascular risk factors and cardiotoxic cancer therapies. Heart failure with preserved ejection fraction (HFpEF) is an emerging and often under-recognized condition in this population, potentially present before treatment initiation and further influenced by oncologic therapies. This study aimed to characterize baseline HFpEF probability and its longitudinal evolution using validated scoring systems in a real-world cardio-oncology cohort. Methods: We retrospectively evaluated 145 women with breast cancer undergoing baseline cardio-oncology assessment before initiation of potentially cardiotoxic therapies. HFpEF probability was estimated using three validated algorithms (H₂FPEF, ABA, and HFA-PEFF). A subgroup of 89 patients underwent exploratory reassessment after 12 ± 3 months to investigate longitudinal changes in HFpEF probability according to treatment. Results: At baseline, HFpEF probability varied substantially according to the scoring system applied, with 14.8–41.5% of patients classified as having intermediate-to-high probability. Agreement among the three algorithms was limited, particularly between HFA-PEFF and H₂FPEF/ABA scores. Exploratory longitudinal analyses showed no significant changes in HFpEF probability categories during follow-up. Conclusions: HFpEF probability assessment in breast cancer patients showed substantial baseline heterogeneity across validated scoring systems, with clinically relevant differences in risk classification and limited inter-score agreement. These findings provide novel insights into an underexplored cardio-oncology phenotype and suggest that currently available HFpEF scoring systems may not be directly interchangeable in this clinical setting. Prospective studies including provocative testing are needed to determine the clinical relevance of HFpEF probability scores in breast cancer patients. Full article

Purpose: The aim of this study was to test the hypothesis that Tenascin-C (TNC) levels increase following thoracic radiotherapy (RT), and that elevated serum TNC levels are associated with corresponding increases in myocardial TNC expression in histopathological specimens, supporting its role as a potential biomarker of radiation-induced cardiotoxicity. Methods: Blood and cardiac tissue samples from rats 8 weeks after thoracic radiotherapy were analyzed to evaluate changes in serum TNC levels and myocardial TNC expression, and their association with radiation exposure. Male Wistar rats were randomized to a single 12-Gy dose of mediastinal irradiation or sham irradiation. Serum TNC levels were assessed with rat ELISA kits. Myocardial TNC expression was assessed using immunohistochemistry, and staining intensity was semi-quantitatively graded by blinded observers. Results: Serum Tenascin-C (TNC) levels were elevated in RT only group compared to control (p < 0.001), paralleled by a marked increase in myocardial TNC expression (p < 0.001). A consistent concordance between circulating and tissue-level TNC was observed, supporting its potential as a biomarker of radiation-induced cardiac injury. Conclusions: Significant associations were observed between radiation exposure and both serum Tenascin-C levels and myocardial Tenascin-C expression, demonstrating a concordance between circulating and tissue findings and supporting Tenascin-C as a promising biomarker of radiation-induced cardiotoxicity. Full article

Introduction: Sevoflurane may exert cytotoxic effects in some cell types, but its impact on human cardiomyocytes and the potential protective role of remifentanil remain unclear. This study aimed to investigate whether remifentanil mitigates sevoflurane-induced apoptotic damage in human cardiomyocytes, with an exploratory focus on TRPA1 calcium channels. Materials and Methods: Human cardiomyocyte cells were exposed to sevoflurane (5.1% for 6 h) and/or remifentanil (2.5 µM for 30 min), with or without the TRPA1 antagonist AP18. Apoptosis, intracellular reactive oxygen species (ROS), mitochondrial depolarisation, caspase-3 and -9 activities, and cytosolic calcium levels were measured. Results: Sevoflurane exposure was associated with increased apoptosis, ROS production, mitochondrial depolarisation, caspase-3 and -9 activities, and intracellular calcium levels compared with the control group. Remifentanil pretreatment appeared to reduce these sevoflurane-related changes. In several parameters, the addition of AP18 partially reversed the effects of remifentanil, suggesting that TRPA1 channels may contribute to these effects. However, findings were not entirely consistent across all measured variables. Conclusions: Remifentanil effectively mitigates sevoflurane-induced apoptotic damage in human cardiomyocytes, likely by modulating oxidative stress and preserving mitochondrial function. The partial reversal by AP18 suggests that TRPA1 channels may contribute to these protective effects, though additional mechanisms are likely involved. Further mechanistic and translational studies are warranted to elucidate the precise signalling pathways and clinical relevance of these observations. Full article

Anthracycline agents, principally doxorubicin and daunorubicin, are widely used in oncology yet carry a narrow therapeutic index and pronounced interindividual pharmacokinetic variability that exposes patients simultaneously to the risk of subtherapeutic dosing and cumulative cardiotoxicity. Conventional therapeutic drug monitoring (TDM) based on periodic venous sampling and offline high-performance liquid chromatography cannot resolve the sub-minute concentration dynamics that determine organ-specific drug exposure. Electrochemical aptamer-based (EAB) sensors couple nucleic-acid aptamers, self-assembled monolayers, and methylene blue redox reporters on gold microelectrodes to convert binding-induced conformational changes into real-time, reagent-free electrochemical signals. Recent advances in this field fall into five areas: signal interrogation strategies, from kinetic differential measurement to calibration-free Fourier-transform impedance spectroscopy (FFT-EIS); interface engineering including nanostructured electrodes and AI-guided aptamer design; in vivo multi-compartment pharmacokinetic monitoring and closed-loop feedback drug delivery; the mechanisms of in vivo signal drift alongside antifouling countermeasures spanning hydrogel barriers, zwitterionic brushes, and xenonucleic acid backbone substitution; and FDA premarket pathways and clinical translation, including Premarket Approval requirements and the emerging Real-Time Clinical Trial (RTCT) framework. In live rodents, dual-compartment monitoring has resolved a reproducible 30–60 min plasma-to-ISF lag for doxorubicin at 12 s temporal resolution; calibration-free FFT-EIS interrogation achieves inter-animal coefficients of variation below 12% without individual pre-calibration; and xenonucleic acid backbone substitution has extended continuous in vivo operation to seven consecutive days. Unlike prior EAB reviews that survey general molecular targets or benchtop aptasensors, this review uniquely integrates anthracycline-specific in vivo pharmacokinetics, multi-compartment plasma–ISF monitoring, calibration-free interrogation, XNA-enabled long-term stability, and FDA/RTCT regulatory translation into a single clinical roadmap. Three gaps still separate rodent proof-of-concept work from chemotherapy patients: clinical-context validation, tumor microenvironment calibration, and anthracycline-specific XNA aptamer design. Full article

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

Background/Objectives: The clinical application of the potent antitumor alkaloid camptothecin is severely limited by its high systemic toxicity, poor solubility, and rapid inactivation. This study aimed to design, synthesize, and evaluate a novel series of camptothecin–lipid conjugates where natural steroids and triterpenoids serve as lipophilic carriers to enhance cellular penetration and mitigate cardiotoxicity. Herein, we implemented an endogenous targeting strategy by conjugating camptothecin with natural steroids and triterpenoids, which serve as biomimetic lipophilic vectors to achieve tumor-selective intracellular delivery. Methods: Eleven novel camptothecin-based hybrids linked via succinic acid or ethylene glycol spacers were synthesized and characterized. Their in vitro cytotoxicity was evaluated against eight cancer cell lines of varied embryologic origin (Jurkat, HCT 116, A549, HL60, K562, HeLa, HEK293, and Fibroblasts). Cell cycle distribution, apoptosis induction, and topoisomerase I inhibitory activity were assessed using flow cytometry and enzyme assays. In silico pharmacokinetic profiling, including P-glycoprotein interaction and cardiotoxicity mitigation, was substantiated via ADME algorithms. Results: Among the series, compounds 12 (cholestanol conjugate) and 26 (betulin derivative) emerged as the primary lead candidates based on an optimal composite of submicromolar cytotoxicity, exceptional tumor selectivity indices (up to 7.0 for 12), and active topoisomerase I inhibition. Compounds 11–14 generally shared prominent S-phase cell cycle arrest, while the lead hybrids 12 and 26 successfully combined high apoptotic triggering with favorable in silico ADME safety profiling, including eliminated cardiotoxicity for the structural analogs. Conclusions: The integration of steroidal and triterpenoid pharmacophores via strategic spacers provides a reliable foundation for developing targeted, low-toxicity camptothecin–lipid conjugates with optimized safety profiles for cancer therapy. Full article

Cancer therapy-related cardiac dysfunction (CTRCD) is a significant complication of anthracycline-based regimens and anti-HER2 agents. Global longitudinal strain (GLS) detects subclinical dysfunction before ejection fraction decline and is recommended by the 2022 ESC guidelines for surveillance. Sacubitril/valsartan, an angiotensin receptor–neprilysin inhibitor, has shown cardioprotective potential in recent trials. Following PRISMA 2020 guidelines, we searched PubMed, EMBASE, and Cochrane CENTRAL through February 2026. Three RCTs met eligibility criteria (n= 350; PROSPERO: CRD420261383124): Hsu 2025 (n = 100, 12 months), PRADA II 2025 (n = 138, 18 months), and SARAH 2025 (n = 112, 6 months). Random-effects meta-analysis used REML with Hartung–Knapp–Sidik–Jonkman adjustment. The pooled mean difference in final GLS significantly favored sacubitril/valsartan (MD −0.95%; 95% CI −1.40 to −0.50; p = 0.012; I² = 0%). Final LVEF showed a consistent trend (MD +1.53%; 95% CI −0.47 to 3.52; p = 0.082; I² = 0%). Hypotension was numerically more frequent with sacubitril/valsartan (OR 5.10; 95% CI 0.52–49.50; p = 0.091). Sacubitril/valsartan initiated during anthracycline therapy was associated with significant GLS preservation. However, GLS is a surrogate imaging marker and hard clinical events were rare or absent, so the modest effect magnitude and limited number of trials warrant cautious interpretation; the clinical benefit remains uncertain and requires confirmation in adequately powered trials with hard clinical endpoints. Full article