Loss of TRIM21 alleviates cardiotoxicity by suppressing ferroptosis induced by the chemotherapeutic agent doxorubicin

EBioMedicine, Journal Year: 2021, Volume and Issue: 69, P. 103456 - 103456

Published: July 1, 2021

Doxorubicin, an anthracycline chemotherapeutic agent, is widely used in the treatment of many cancers. However, doxorubicin posts a great risk adverse cardiovascular events, which are thought to be caused by oxidative stress. We recently reported that ubiquitin E3 ligase TRIM21 interacts and ubiquitylates p62 negatively regulates p62-Keap1-Nrf2 antioxidant pathway. Therefore, we sought determine role cardiotoxicity induced damage.Using knockout mice, examined effects on two damage models: model Left Anterior Descending (LAD) model. also explored underlying mechanism RNA-sequencing heart tissues, treating mouse embryonic fibroblasts (MEFs), immortalized rat cardiomyocyte line H9c2, human AC16 with doxorubicin.TRIM21 mice protected from failure fatality both LAD models. Hearts doxorubicin-treated wild-type exhibit deformed mitochondria elevated level lipid peroxidation reminiscent ferroptosis, alleviated hearts. Mechanistically, TRIM21-deficient tissues cultured MEFs H9c2 cells display enhanced sequestration Keap1 doxorubicin-induced ferroptosis. Reconstitution but not ligase-dead binding-deficient mutants impedes protection cell death.Our study demonstrates ablation protects illustrates new function suggests as therapeutic target for reducing chemotherapy-related cardiotoxicity.NIH (CA129536; DK108989): data collection, analysis. Shanghai Pujiang Program (19PJ1401900): collection. National Natural Science Foundation (31971161): Department Veteran Affairs (BX004083): Tianjin Technology Plan Project (17ZXMFSY00020):

Language: Английский

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Drug-induced oxidative stress in cancer treatments: Angel or devil?

Redox Biology, Journal Year: 2023, Volume and Issue: 63, P. 102754 - 102754

Published: May 18, 2023

Oxidative stress (OS), defined as redox imbalance in favor of oxidant burden, is one the most significant biological events cancer progression. Cancer cells generally represent a higher level, which suggests dual therapeutic strategy by regulating status (i.e., pro-oxidant therapy and/or antioxidant therapy). Indeed, exhibits great anti-cancer capability, attributing to accumulation within cells, whereas restore homeostasis has been claimed fail several clinical practices. Targeting vulnerability pro-oxidants capable generating excessive reactive oxygen species (ROS) surfaced an important strategy. However, multiple adverse effects caused indiscriminate attacks uncontrolled drug-induced OS on normal tissues and drug-tolerant capacity some certain greatly limit their further applications. Herein, we review representative oxidative drugs summarize side organs, emphasizing that seeking balance between damage value exploiting next-generation OS-based chemotherapeutics.

Language: Английский

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Coronary blood flow in heart failure: cause, consequence and bystander

Basic Research in Cardiology, Journal Year: 2022, Volume and Issue: 117(1)

Published: Jan. 13, 2022

Heart failure is a clinical syndrome where cardiac output not sufficient to sustain adequate perfusion and normal bodily functions, initially during exercise in more severe forms also at rest. The two most frequent are heart of ischemic origin non-ischemic origin. In origin, reduced coronary blood flow causal contractile dysfunction, this true for stunned hibernating myocardium, microembolization, myocardial infarction post-infarct remodeling, possibly the takotsubo syndrome. form dilated cardiomyopathy, caused by genetic mutations, myocarditis, toxic agents or sustained tachyarrhythmias, alterations result from contribute dysfunction. Hypertrophic cardiomyopathy mutations but can increased pressure volume overload (hypertension, valve disease). with preserved ejection fraction characterized pronounced microvascular contribution which however clear. present review characterizes causes consequences its different manifestations. Apart any potentially accompanying atherosclerosis, all entities share common features impaired flow, extent: enhanced extravascular compression, nitric oxide-mediated, endothelium-dependent vasodilation vasoconstriction mediators neurohumoral activation. Impaired contributes progression thus valid target established novel treatment regimens.

Language: Английский

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Cardiovascular disease and cancer: shared risk factors and mechanisms

Nature Reviews Cardiology, Journal Year: 2024, Volume and Issue: 21(9), P. 617 - 631

Published: April 10, 2024

Language: Английский

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Targeting epigenetic and posttranslational modifications regulating ferroptosis for the treatment of diseases

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Dec. 10, 2023

Abstract Ferroptosis, a unique modality of cell death with mechanistic and morphological differences from other modes, plays pivotal role in regulating tumorigenesis offers new opportunity for modulating anticancer drug resistance. Aberrant epigenetic modifications posttranslational (PTMs) promote resistance, cancer progression, metastasis. Accumulating studies indicate that can transcriptionally translationally determine vulnerability to ferroptosis functions as driver nervous system diseases (NSDs), cardiovascular (CVDs), liver diseases, lung kidney diseases. In this review, we first summarize the core molecular mechanisms ferroptosis. Then, roles processes, including histone PTMs, DNA methylation, noncoding RNA regulation such phosphorylation, ubiquitination, SUMOylation, acetylation, ADP-ribosylation, are concisely discussed. The PTMs genesis cancers, NSD, CVDs, well application PTM modulators therapy these then discussed detail. Elucidating mediated by will facilitate development promising combination therapeutic regimens containing or PTM-targeting agents inducers be used overcome chemotherapeutic resistance could prevent addition, highlight potential approaches chemoresistance halt

Language: Английский

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WGX50 mitigates doxorubicin-induced cardiotoxicity through inhibition of mitochondrial ROS and ferroptosis

Journal of Translational Medicine, Journal Year: 2023, Volume and Issue: 21(1)

Published: Nov. 17, 2023

Abstract Background Doxorubicin (DOX)-induced cardiotoxicity (DIC) is a major impediment to its clinical application. It indispensable explore alternative treatment molecules or drugs for mitigating DIC. WGX50, an organic extract derived from Zanthoxylum bungeanum Maxim, has anti-inflammatory and antioxidant biological activity, however, function mechanism in DIC remain unclear. Methods We established DOX-induced models both vitro vivo. Echocardiography histological analyses were used determine the severity of cardiac injury mice. The myocardial damage markers cTnT, CK-MB, ANP, BNP, ferroptosis associated indicators Fe 2+ , MDA, GPX4 measured using ELISA, RT-qPCR, western blot assays. morphology mitochondria was investigated with transmission electron microscope. levels mitochondrial membrane potential, ROS, lipid ROS detected JC-1, MitoSOX™, C11-BODIPY 581/591 probes. Results Our findings demonstrate that WGX50 protects via restraining ferroptosis. In vivo, effectively relieves doxorubicin-induced dysfunction, injury, fibrosis, damage, redox imbalance. vitro, preserves by reducing level potential increasing ATP production. Furthermore, reduces iron accumulation increases expression, regulates metabolism inhibit Conclusion Taken together, pathway, which provides novel insights as promising drug candidate cardioprotection. Graphic abstract

Language: Английский

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Association of Anthracycline With Heart Failure in Patients Treated for Breast Cancer or Lymphoma, 1985-2010

JAMA Network Open, Journal Year: 2023, Volume and Issue: 6(2), P. e2254669 - e2254669

Published: Feb. 3, 2023

Importance Anthracyclines increase the risk for congestive heart failure (CHF); however, long-term cumulative incidence and factors CHF after anthracycline therapy are not well defined in population-based studies. Objective To compare of patients with breast cancer or lymphoma treated compared healthy controls from same community. Design, Setting, Participants This retrospective case-control study included data Rochester Epidemiology Project. residents Olmsted County, Minnesota, diagnosed January 1985 through December 2010 matched age, sex, comorbidities controls, a final ratio 1 case to 1.5 controls. Statistical analysis was performed between July 2017 February 2022. Exposures Cancer treatment factors. Main Outcomes Measures The main outcome new-onset CHF, as by modified Framingham criteria. Cox proportional hazards regression used estimate hazard ratios (HRs) participants vs adjusted diabetes, hypertension, hyperlipidemia, coronary artery disease, obesity, smoking history. Results A total 2196 individuals were included, 812 1384 without cancer. mean (SD) age 52.62 (14.56) years 1704 (78%) female. Median (IQR) follow-up 8.6 (5.2-13.4) group 12.5 (8.7-17.5) control group. Overall, had higher cohort even adjusting status (HR, 2.86 [95% CI, 1.90-4.32]; P < .001). After variables, greater receiving 3.25 2.11-5.00]; .001) attenuated lost statistical significance anthracyclines 1.78 0.83-3.81]; = .14). Higher comparator observed at year (1.81% 0.09%), 5 (2.91% 0.79%), 10 (5.36% 1.74%), 15 (7.42% 3.18%), 20 (10.75% 4.98%) ( There no significant differences dose less than 180 mg/m 2 those 250 0.54 0.19-1.51]) more 1.23 0.52-2.91]). At diagnosis, an independent factor associated (HR per years, 2.77 1.99-3.86]; Conclusions Relevance In this study, increased early during follow-up, persisted over time. 2-fold that

Language: Английский

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Advances in nanoparticles-based approaches in cancer theranostics

OpenNano, Journal Year: 2023, Volume and Issue: 12, P. 100152 - 100152

Published: April 12, 2023

In recent years, the incidence and mortality rate of cancer is raising worldwide. Traditional approaches for patient management including surgery, chemotherapy, radiotherapy, targeted therapies provide unsatisfactory results are often associated with adverse reactions. Over last few decades, nanotechnology has been a rapidly emerging area theragnostic in clinical research. It plays vital role as bridge between science technology miscellaneous nanoparticles (NPs) nanomedicine. general, NPs range sizes 1–100 nm thought to be acceptable medications. may enhance consistency solubility therapeutic drugs obtain site-specific targeting, controlled release, safe healthy organs. have benefit pathophysiological properties, enhanced permeability retention (EPR) effects, an advantage targeting. Furthermore, theranostic established having incorporated diagnostics therapy single system that might more personalized treatment optimal doses monitoring distribution, response by using imaging tools. this review, we discussed classes nanoparticles, targeting approaches, implications theranostics examples.

Language: Английский

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Cardiotoxic effects of common and emerging drugs: role of cannabinoid receptors

Clinical Science, Journal Year: 2024, Volume and Issue: 138(6), P. 413 - 434

Published: March 1, 2024

Drug-induced cardiotoxicity has become one of the most common and detrimental health concerns, which causes significant loss to public drug resources. Cannabinoid receptors (CBRs) have recently achieved great attention for their vital roles in regulation heart disease, with mounting evidence linking CBRs pathogenesis progression drug-induced cardiotoxicity. This review aims summarize fundamental characteristics two well-documented (CB1R CB2R) from aspects molecular structure, signaling functions cardiovascular physiology pathophysiology. Moreover, we describe CB1R CB2R occurrence induced by drugs such as antipsychotics, anti-cancer drugs, marijuana, some emerging synthetic cannabinoids. We highlight 'yin-yang' relationship between propose future perspectives CBR-based translational medicine toward curation clinical monitoring.

Language: Английский

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Coexisting atrial fibrillation and cancer: time trends and associations with mortality in a nationwide Dutch study

European Heart Journal, Journal Year: 2024, Volume and Issue: 45(25), P. 2201 - 2213

Published: April 15, 2024

Abstract Background and Aims Coexisting atrial fibrillation (AF) cancer challenge the management of both. The aim study is to comprehensively provide epidemiology coexisting AF cancer. Methods Using Dutch nationwide statistics, individuals with incident (n = 320 139) or 472 745) were identified during period 2015–19. inhabitants without a history 135) 741) matched as control cohorts by demographic characteristics. Prevalence cancer/AF at baseline, 1-year risk diagnosis, their time trends determined. association diagnosis all-cause mortality among those AF/cancer was estimated using time-dependent Cox regression. Results rate prevalence in cohort 12.6% (increasing from 11.9% 13.2%) compared 5.6% controls; 2.5% (stable over years) 1.8% controls [adjusted hazard ratio (aHR) 1.52, 95% confidence interval (CI) 1.46–1.58], which similar type. 7.5% 6.9% 8.2%) 4.3% 2.8% 1.2% (aHR 2.78, CI 2.69–2.87), but cancers oesophagus, lung, stomach, myeloma, lymphoma associated higher hazards than other types. Both diagnosed after 7.77, 7.45–8.11) 2.55, 2.47–2.63) mortality, strength varied Conclusions Atrial bidirectionally increasingly coexisting, negatively survival.

Language: Английский

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