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1.
Nat Commun ; 11(1): 4809, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32968055

RESUMO

Kinase inhibitors (KIs) represent an important class of anti-cancer drugs. Although cardiotoxicity is a serious adverse event associated with several KIs, the reasons remain poorly understood, and its prediction remains challenging. We obtain transcriptional profiles of human heart-derived primary cardiomyocyte like cell lines treated with a panel of 26 FDA-approved KIs and classify their effects on subcellular pathways and processes. Individual cardiotoxicity patient reports for these KIs, obtained from the FDA Adverse Event Reporting System, are used to compute relative risk scores. These are then combined with the cell line-derived transcriptomic datasets through elastic net regression analysis to identify a gene signature that can predict risk of cardiotoxicity. We also identify relationships between cardiotoxicity risk and structural/binding profiles of individual KIs. We conclude that acute transcriptomic changes in cell-based assays combined with drug substructures are predictive of KI-induced cardiotoxicity risk, and that they can be informative for future drug discovery.


Assuntos
Cardiotoxicidade/genética , Cardiotoxicidade/metabolismo , Perfilação da Expressão Gênica/métodos , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Transcriptoma , Antineoplásicos/farmacologia , Cardiotoxicidade/tratamento farmacológico , Linhagem Celular , Relação Dose-Resposta a Droga , Aprovação de Drogas , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Análise de Regressão , Medição de Risco , Fatores de Risco , Alinhamento de Sequência , Estados Unidos , United States Food and Drug Administration
2.
Ecotoxicol Environ Saf ; 204: 111040, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32798748

RESUMO

Tebuconazole (TEB) is a common triazole fungicide that is widely used throughout the world in agriculture applications. We previously reported that TEB induces cardiac toxicity in rats. The aim of this study was to investigate the underlying mechanism of the toxicity induced by TEB in cardiac cells. TEB induced dose-dependent cell death in H9c2 cardiomyoblasts and in adult rat ventricular myocytes (ARVM). The comet assay and western blot analysis showed a concentration-dependent increase in DNA damage and in p53 and p21 protein levels 24 h after TEB treatment. Our findings also showed that TEB triggered the mitochondrial pathway of apoptosis as evidenced by a loss of mitochondrial transmembrane potential (ΔΨm), an increase in Bax/Bcl-2 ratio, an activation of caspase-9 and caspase-3, a cleavage of poly (ADP-ribose) polymerase (PARP) and an increase in the proportion of cells in the sub-G1 phase. In addition, TEB promoted ROS production in cardiac cells and consequently increased the amounts of MDA, the end product of lipid peroxidation. Treatment of cardiomyocytes with the ROS scavenger N-acetylcysteine reduced TEB-induced DNA damage and activation of the mitochondrial pathway of apoptosis. These results indicate that the genotoxic and cytotoxic effects of TEB are mediated through a ROS-dependent pathway in cardiac cells.


Assuntos
Apoptose , Cardiotoxicidade/metabolismo , Dano ao DNA , Fungicidas Industriais/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Triazóis/toxicidade , Animais , Cardiotoxicidade/etiologia , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/fisiologia , Ratos , Ratos Wistar
3.
Ecotoxicol Environ Saf ; 202: 110922, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32800257

RESUMO

Fluorene-9-bisphenol (BHPF) is a substitute for bisphenol A (BPA), which is widely used to manufacture plastic products. Previous studies indicate that BHPF has an anti-estrogenic effect and induces cytotoxicity in mice oocytes. However, the effects of acute BHPF exposure on the aquatic organism obtain little attention. In this study, a series of BHPF concentrations (1 µM, 2 µM, 5 µM, 10 µM, 20 µM) was used to exposed zebrafish embryos from 2 h post-fertilization (hpf). The results showed the LC50 at 96hpf was 2.88 µM (1.01 mg/L). Acute exposure induced malformation in morphology, and retarded epiboly rate at 10hpf, increased apoptosis. Moreover, acute BHPF exposure led cardiotoxicity, by impeding cardiac looping, decreasing cardiac contractility (reducing the stroke volume and cardiac output, decreasing fractional shortening of ventricle). Besides that, BHPF exposure altered the expression of cardiac transcriptional regulators and development related genes. In conclusion, acute BHPF exposure induced developmental abnormality, retarded cardiac morphogenesis and injured the cardiac contractility. This study indicated BHPF would be an unneglected threat for the safety of aquatic organisms.


Assuntos
Compostos Benzidrílicos/toxicidade , Fenóis/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Cardiotoxicidade/metabolismo , Embrião não Mamífero/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Fluorenos/toxicidade , Camundongos , Oócitos/crescimento & desenvolvimento , Plásticos , Testes de Toxicidade Aguda , Poluentes Químicos da Água/metabolismo , Peixe-Zebra
4.
Toxicol Appl Pharmacol ; 398: 115029, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32376357

RESUMO

Resveratrol (RSV), a natural polyphenolic compound commonly found in food, has antioxidant and aryl hydrocarbon receptor (AHR) antagonist effects. We have recently demonstrated that AHR mediated reactive oxygen species (ROS) generation contributes to the cardiac developmental toxicity of ambient fine particle matter (PM2.5). Thus, we hypothesized that RSV protects against the cardiac developmental toxicity of PM2.5 by inhibiting ROS generation and AHR activity. To test this concept, we exposed zebrafish embryos to extractable organic matter (EOM) from PM2.5 in the presence or absence of RSV. We found that RSV significantly counteracted EOM-induced cardiac malformations in zebrafish embryos. The EOM-induced ROS production, DNA damage and apoptosis in the heart of zebrafish embryos were also counteracted by RSV supplementation. Furthermore, RSV attenuated EOM-induced changes in the expression of genes involved in cardiac development (nkx2.5, sox9b, axin2), oxidative stress (nrf2a, nrf2b, gstp1, gstp2, sod1, sod2, cat) and apoptosis (p53, bax). However, RSV did not suppress EOM-induced AHR activity. In conclusion, our data indicates that RSV protects against the PM2.5-induced heart malformations by inhibiting oxidative stress rather than through AHR antagonism.


Assuntos
Embrião não Mamífero/efeitos dos fármacos , Cardiopatias Congênitas/induzido quimicamente , Cardiopatias Congênitas/tratamento farmacológico , Material Particulado/efeitos adversos , Substâncias Protetoras/farmacologia , Resveratrol/farmacologia , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/metabolismo , Embrião não Mamífero/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Coração/efeitos dos fármacos , Cardiopatias Congênitas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Peixe-Zebra , Proteínas de Peixe-Zebra/metabolismo
5.
Nat Biomed Eng ; 4(4): 446-462, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32284552

RESUMO

Environmental factors are the largest contributors to cardiovascular disease. Here we show that cardiac organoids that incorporate an oxygen-diffusion gradient and that are stimulated with the neurotransmitter noradrenaline model the structure of the human heart after myocardial infarction (by mimicking the infarcted, border and remote zones), and recapitulate hallmarks of myocardial infarction (in particular, pathological metabolic shifts, fibrosis and calcium handling) at the transcriptomic, structural and functional levels. We also show that the organoids can model hypoxia-enhanced doxorubicin cardiotoxicity. Human organoids that model diseases with non-genetic pathological factors could help with drug screening and development.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Coração/efeitos dos fármacos , Modelos Cardiovasculares , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Organoides/efeitos dos fármacos , Cardiotoxicidade/metabolismo , Cardiotoxicidade/patologia , Desenvolvimento de Medicamentos , Humanos , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/genética , Organoides/metabolismo , Organoides/patologia , Oxigênio/metabolismo
6.
J Mol Cell Cardiol ; 140: 56-67, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32135167

RESUMO

AIMS: Doxorubicin (DOX) is a broad-spectrum anticancer drug with considerable cardiotoxicity. DOX can induce myocardial apoptosis by modulating multiple signalling pathways. A better understanding of the underlying mechanism of DOX's cardiotoxicity will improve its clinical application and help avoid heart failure in patients. METHODS AND RESULTS: Models of DOX cardiotoxicity in cultured cardiomyocytes and mice were used. Cell death was determined by TUNEL and caspase 3/7 activity assay. Quaking (QKI) expression was detected by immunoblotting; microRNA-31-5p and circular RNA (circRNA) levels were determined by qRT-PCR. Luciferase reporter assays were performed to validate the miR-31-5p target. We found that DOX treatment upregulated miR-31-5p expression both in cultured cardiomyocytes and in mouse heart tissue. Silencing of miR-31-5p significantly alleviated the myocardial apoptosis induced by DOX treatment both in vivo and in vitro. Further analysis indicated QKI as a direct target of miR-31-5p, which has been reported to influence circRNA expression in a series of cell types. We found that circPan3 was specifically downregulated in cardiomyocytes upon DOX treatment. We further confirmed that the downregulation of circPan3 was due to the silencing of QKI by miR-31-5p. CONCLUSIONS: Our data reveal links among miR-31-5p, QKI and circPan3 in the apoptotic programme of cardiomyocytes. MiR-31-5p acted as a negative regulator of circPan3 by directly suppressing QKI, which may be a potential therapeutic target and strategy for DOX-induced cardiotoxicity.


Assuntos
Cardiotoxicidade/metabolismo , Doxorrubicina/farmacologia , MicroRNAs/metabolismo , RNA Circular/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Antagomirs/administração & dosagem , Apoptose/efeitos dos fármacos , Apoptose/genética , Proteínas de Transporte/genética , Linhagem Celular , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Interferência de RNA , Ratos , Transfecção
7.
Oxid Med Cell Longev ; 2020: 3579143, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32190171

RESUMO

There is a distinct increase in the risk of heart disease in people exposed to ionizing radiation (IR). Radiation-induced heart disease (RIHD) is one of the adverse side effects when people are exposed to ionizing radiation. IR may come from various forms, such as diagnostic imaging, radiotherapy for cancer treatment, nuclear disasters, and accidents. However, RIHD was mainly observed after radiotherapy for chest malignant tumors, especially left breast cancer. Radiation therapy (RT) has become one of the main ways to treat all kinds of cancer, which is used to reduce the recurrence of cancer and improve the survival rate of patients. The potential cause of radiation-induced cardiotoxicity is unclear, but it may be relevant to oxidative stress. Oxidative stress, an accumulation of reactive oxygen species (ROS), disrupts intracellular homeostasis through chemical modification and damages proteins, lipids, and DNA; therefore, it results in a series of related pathophysiological changes. The purpose of this review was to summarise the studies of oxidative stress in radiotherapy-induced cardiotoxicity and provide prevention and treatment methods to reduce cardiac damage.


Assuntos
Cardiotoxicidade/patologia , Estresse Oxidativo/efeitos da radiação , Radiação , Animais , Antioxidantes/farmacologia , Cardiotoxicidade/metabolismo , Humanos , Oxirredução/efeitos dos fármacos , Oxirredução/efeitos da radiação , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
8.
Food Chem Toxicol ; 137: 111134, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32006631

RESUMO

Tebuconazole is an effective systemic fungicide that belongs to the triazoles family. It has been widely used in both agricultural and medical sectors for the control of fungal diseases. Although TEB poses serious threats to mammals health, studies regarding its cardiotoxicity are very limited. Thus, we aimed to evaluate the effects of TEB on some biochemical parameters, the induction of apoptosis and DNA damage in the heart tissue. Male Wistar rats were treated with TEB at varied oral doses for 28 consecutive days. This study demonstrates that TEB decreased cardiac acetylcholinesterase, increased serum marker enzymes such as creatinine phosphokinase (CPK) and lactate dehydrogenase (LDH), and altered the lipid profile by increasing serum levels of total cholesterol (T-CHOL), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and reduced high-density lipoprotein cholesterol (HDL-C) levels. Furthermore, TEB increased levels of p53 and Bax/Bcl2 ratio, released the cytochrome c into the cytosol and activated caspase-9 and caspase-3. Besides, our results showed that TEB induced genotoxic effects. TEB induced DNA fragmentation and increased the frequency of micronucleated bone marrow cells. Moreover, TEB treatment developed fibrosis in the myocardium. Our results suggest that TEB exposure may affect myocardial cells normal functioning and triggers apoptosis.


Assuntos
Cardiotoxicidade/etiologia , Fungicidas Industriais/toxicidade , Triazóis/toxicidade , Animais , Apoptose/efeitos dos fármacos , Cardiotoxicidade/genética , Cardiotoxicidade/metabolismo , Cardiotoxicidade/fisiopatologia , LDL-Colesterol/metabolismo , Citocromos c/metabolismo , Fragmentação do DNA/efeitos dos fármacos , Humanos , Masculino , Ratos , Ratos Wistar , Triglicerídeos/metabolismo
9.
Sci Rep ; 10(1): 3426, 2020 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-32099011

RESUMO

The study was conducted to evaluate the cardio-protective activity of combination (COMB) of syringic acid (SA) and resveratrol (RV) against isoproterenol (ISO) induced cardio-toxicity in rats. Rats were pre-treated orally with SA (50 mg/kg), RV (50 mg/kg) and combination of SA (25 mg/kg) and RV (25 mg/kg) along with positive control gallic acid (50 mg/kg) for 30 days. The effects of ISO on cardiac markers, lipid profile and lipid peroxidation marker, anti-oxidant enzymes and m-RNA expression of nuclear factor-kappa B (NF-kB) and tumor necrosis factor-α (TNF-α) were observed along with histopathological observations of simple and transmission electron microscopes (TEM). Serum creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH) and alkaline phosphatase were significantly increased while cardiac tissue CK-MB, LDH, superoxide dismutase and catalase were significantly decreased in ISO administered rats, which also exhibited a significant increase in total cholesterol, triglycerides, low density lipoprotein cholesterol, very low density lipoprotein cholesterol and thiobarbutyric acid reactive substances and significant decrease in high density lipoprotein cholesterol in serum and heart. The m-RNA levels of inflammatory markers NF-kB and TNF-α were significantly increased in ISO treated rats. COMB Pre-treatment significantly reversed the ISO actions. Histopathological studies of simple and TEM were also co-related with the above biochemical parameters. Docking studies with NF-kB were also performed. Evidence has shown for the first time in this approach that COMB pre-treatment ameliorated ISO induced cardio-toxicity in rats and revealed cardio-protection.


Assuntos
Cardiotônicos/farmacologia , Cardiotoxicidade , Ácido Gálico/análogos & derivados , Isoproterenol/efeitos adversos , NF-kappa B/metabolismo , Resveratrol/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Animais , Cardiotoxicidade/metabolismo , Cardiotoxicidade/prevenção & controle , Ácido Gálico/farmacologia , Isoproterenol/farmacologia , Masculino , Ratos , Ratos Wistar
10.
Mol Cell Biochem ; 466(1-2): 139-148, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32016695

RESUMO

Pirarubicin (THP), an anthracycline drug, is widely used as a basic therapeutic agent for the treatment of carcinoma and lymphatic malignant tumor. However, it exerts irreversible cardiotoxicity in varying degrees. At present, dexrazoxane (DZR) is the only cardioprotective agent used to treat anthracycline drug-induced cardiotoxicity, but it may reduce the anticancer effect of anthracycline drugs, causing severe granulocytopenia and other adverse reactions. Therefore, it is necessary to discover more effective and less toxic drugs for the treatment of THP-induced cardiotoxicity. The present study aimed to investigate the effects and possible mechanisms of rutin (RUT) against THP-induced cardiomyocyte injury. An in vitro cardiomyocyte injury model of THP-treated murine immortalized cardiomyocytes (HL-1) was used in this study. The results showed that RUT markedly increased the viability of HL-1 cells through protection against THP-induced cardiomyocyte injury. Furthermore, RUT significantly inhibited myocardial oxidative insult by adjusting the levels of intracellular reactive oxygen species (ROS). Our data also indicated that RUT activated JunD signaling pathways, thereby affecting the expression levels of some apoptotic proteins by decreasing miR-125b-1-3p expression level. In addition, intracellular ROS level significantly increased in HL-1 cells treated with THP after miR-125b-1-3p mimic transfection, whereas the expression of JunD was downregulated and that of some apoptotic proteins was upregulated. However, this effect was markedly reversed by RUT. Therefore, we inferred that the protective effect of RUT on THP cardiotoxicity was achieved through regulation of the JunD gene by miR-125b-1-3p. This experiment revealed the protective effect of RUT on THP-induced cardiotoxicity at the non-coding RNA level and provided a theoretical foundation for the application of RUT as a protective agent against THP cardiotoxicity.


Assuntos
Cardiotoxicidade , Doxorrubicina/análogos & derivados , MicroRNAs/metabolismo , Miócitos Cardíacos , Proteínas Proto-Oncogênicas c-jun/metabolismo , Rutina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Cardiotoxicidade/metabolismo , Cardiotoxicidade/patologia , Cardiotoxicidade/prevenção & controle , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacologia , Camundongos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia
11.
Mediators Inflamm ; 2020: 8641026, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32104151

RESUMO

Methotrexate (MTX) is a commonly used chemotherapeutic agent. Oxidative stress and inflammation have been proved in the development of MTX toxicity. Paeonol is a natural phenolic compound with various pharmacological activities including antioxidant and anti-inflammatory properties. The aim of the present study was to evaluate the protective effect of paeonol against MTX-induced cardiac toxicity in rats and to evaluate the various mechanisms that underlie this effect. Paeonol (100 mg/kg) was administered orally for 10 days. MTX cardiac toxicity was induced at the end of the fifth day of the experiment, with or without paeonol pretreatment. MTX-induced cardiac damage is evidenced by a distortion in the normal cardiac histological structure, with significant oxidative and nitrosative stress shown as a significant increase in NADPH oxidase-2, malondialdehyde, and nitric oxide levels along with a decrease in reduced glutathione concentration and superoxide dismutase activity compared to the control group. MTX-induced inflammatory effects are evidenced by the increased cardiac toll-like receptor 4 (TLR4) mRNA expression and protein level as well as increased cardiac tumor necrosis factor- (TNF-) α and interleukin- (IL-) 6 levels along with increased nuclear factor- (NF-) κB/p65 immunostaining. MTX increased apoptosis as shown by the upregulation of cardiac caspase 3 immunostaining. Paeonol was able to correct the oxidative and nitrosative stress as well as the inflammatory and apoptotic parameters and restore the normal histological structure compared to MTX alone. In conclusion, paeonol has a protective effect against MTX-induced cardiac toxicity through inhibiting oxidative and nitrosative stress and suppressing the TLR4/NF-κB/TNF-α/IL-6 inflammatory pathway, as well as causing an associated reduction in the proapoptotic marker, caspase 3.


Assuntos
Acetofenonas/uso terapêutico , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/metabolismo , Metotrexato/toxicidade , NF-kappa B/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Caspase 3/metabolismo , Imuno-Histoquímica , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo
12.
Circ Res ; 126(8): 947-964, 2020 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-32091972

RESUMO

RATIONALE: Drug-induced proarrhythmia is so tightly associated with prolongation of the QT interval that QT prolongation is an accepted surrogate marker for arrhythmia. But QT interval is too sensitive a marker and not selective, resulting in many useful drugs eliminated in drug discovery. OBJECTIVE: To predict the impact of a drug from the drug chemistry on the cardiac rhythm. METHODS AND RESULTS: In a new linkage, we connected atomistic scale information to protein, cell, and tissue scales by predicting drug-binding affinities and rates from simulation of ion channel and drug structure interactions and then used these values to model drug effects on the hERG channel. Model components were integrated into predictive models at the cell and tissue scales to expose fundamental arrhythmia vulnerability mechanisms and complex interactions underlying emergent behaviors. Human clinical data were used for model framework validation and showed excellent agreement, demonstrating feasibility of a new approach for cardiotoxicity prediction. CONCLUSIONS: We present a multiscale model framework to predict electrotoxicity in the heart from the atom to the rhythm. Novel mechanistic insights emerged at all scales of the system, from the specific nature of proarrhythmic drug interaction with the hERG channel, to the fundamental cellular and tissue-level arrhythmia mechanisms. Applications of machine learning indicate necessary and sufficient parameters that predict arrhythmia vulnerability. We expect that the model framework may be expanded to make an impact in drug discovery, drug safety screening for a variety of compounds and targets, and in a variety of regulatory processes.


Assuntos
Antiarrítmicos/química , Arritmias Cardíacas/tratamento farmacológico , Cardiotoxinas/química , Simulação por Computador , Descoberta de Drogas/métodos , Canal de Potássio ERG1/química , Antiarrítmicos/metabolismo , Antiarrítmicos/uso terapêutico , Arritmias Cardíacas/metabolismo , Cardiotoxicidade/metabolismo , Cardiotoxicidade/prevenção & controle , Cardiotoxinas/efeitos adversos , Cardiotoxinas/metabolismo , Descoberta de Drogas/tendências , Canal de Potássio ERG1/metabolismo , Feminino , Humanos , Síndrome do QT Longo/tratamento farmacológico , Síndrome do QT Longo/metabolismo , Aprendizado de Máquina , Masculino , Moxifloxacina/química , Moxifloxacina/metabolismo , Moxifloxacina/uso terapêutico , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Fenetilaminas/química , Fenetilaminas/metabolismo , Fenetilaminas/uso terapêutico , Estrutura Secundária de Proteína , Sulfonamidas/química , Sulfonamidas/metabolismo , Sulfonamidas/uso terapêutico , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/metabolismo , Inibidores da Topoisomerase II/uso terapêutico
13.
Int J Nanomedicine ; 15: 1101-1115, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32110010

RESUMO

Background: The clinical use of doxorubicin (DOX) is severely limited due to its cardiotoxicity. Thus, there is a need for prophylactic and treatment strategies against DOX-induced cardiotoxicity. Purpose: The purpose of this study was to develop a liquiritigenin-loaded submicron emulsion (Lq-SE) with enhanced oral bioavailability and to explore its efficacy against DOX-induced cardiotoxicity. Methods: Lq-SE was prepared using high-pressure homogenization and characterized using several analytical techniques. The formulation was optimized by central composite design response surface methodology (CCD-RSM). In vivo pharmacokinetic studies, biochemical analyses, reactive oxygen species (ROS) assays, histopathologic assays, and Western blot analyses were performed. Results: Each Lq-SE droplet had a mean particle size of 221.7 ± 5.80 nm, a polydispersity index (PDI) of 0.106 ± 0.068 and a zeta potential of -28.23 ± 0.42 mV. The area under the curve (AUC) of Lq-SE was 595% higher than that of liquiritigenin (Lq). Lq-SE decreased the release of serum cardiac enzymes and ameliorated histopathological changes in the hearts of DOX-challenged mice. Lq-SE significantly reduced oxidative stress by adjusting the levels of ROS, increasing the activity of antioxidative enzymes and inhibiting the protein expression of NOX4 and NOX2. Furthermore, Lq-SE significantly improved the inflammatory response through the mitogen-activated protein kinase (MAPK)/nuclear factor-κB (NF-κB) signalling pathway and induced cardiomyocyte apoptosis. Conclusion: Lq-SE could be used as an effective cardioprotective agent against DOX in chemotherapy to enable better treatment outcomes.


Assuntos
Cardiotoxicidade/prevenção & controle , Doxorrubicina/efeitos adversos , Emulsões/química , Flavanonas/farmacologia , Administração Oral , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Disponibilidade Biológica , Cardiotônicos/farmacologia , Cardiotoxicidade/metabolismo , Emulsões/administração & dosagem , Feminino , Flavanonas/administração & dosagem , Flavanonas/farmacocinética , Coração/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Nus , Miocárdio/metabolismo , Miocárdio/patologia , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
14.
Molecules ; 25(4)2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32075047

RESUMO

Advances in cancer treatment have led to significant improvements in long-term survival in many types of cancer, but heart dysfunction and heart failure, associated with cancer treatment, have also increased. Anthracyclines are the main cause of this type of cardiotoxicity. In this study, we describe a combined experimental and cell morphology analysis approach for the high-throughput measurement and analysis of a cardiomyocyte cell profile, using partial least square linear discriminant analysis (PLS-LDA) as the pattern recognition algorithm. When screening a small-scale natural compound library, rosmarinic acid (RosA), as a candidate drug, showed the same cardioprotective effect as the positive control. We investigated the protective mechanism of RosA on a human cardiomyocyte cell line (AC16) and human induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs). We showed that RosA pretreatment suppressed doxorubicin (Dox)-induced cell apoptosis and decreased the activity of caspase-9. RosA promotes the expression of Heme oxygenase-1 (HO-1) and reduces the production of reactive oxygen species (Ros), which is induced by Dox. Meanwhile, it can also promote the expression of cardiac-development-related protein, including histone deacetylase 1 (HDAC1), GATA binding protein 4 (GATA4) and troponin I3, cardiac type (CTnI). Collectively, our data support the notion that RosA is a protective agent in hiPSC-CMs and has the potential for therapeutic use in the treatment of cancer therapy-related cardiac dysfunction and heart failure.


Assuntos
Cardiotoxicidade/metabolismo , Cinamatos/metabolismo , Depsídeos/metabolismo , Doxorrubicina/efeitos adversos , Miócitos Cardíacos/efeitos dos fármacos , Antibióticos Antineoplásicos/efeitos adversos , Antibióticos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Cardiotoxicidade/etiologia , Cardiotoxicidade/patologia , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Doxorrubicina/farmacologia , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Neoplasias/complicações , Neoplasias/tratamento farmacológico
15.
Oxid Med Cell Longev ; 2020: 3690123, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32064022

RESUMO

Thioridazine (THIO) is a phenothiazine derivative that is mainly used for the treatment of psychotic disorders. However, cardiac arrhythmias especially QT interval prolongation associated with the application of this compound have received serious attention after its introduction into clinical practice, and the mechanisms underlying the cardiotoxicity induced by THIO have not been well defined. The present study was aimed at exploring the long-term effects of THIO on the hERG and L-type calcium channels, both of which are relevant to the development of QT prolongation. The hERG current (I hERG) and the calcium current (I Ca-L) were measured by patch clamp techniques. Protein levels were analyzed by Western blot, and channel-chaperone interactions were determined by coimmunoprecipitation. Reactive oxygen species (ROS) were determined by flow cytometry and laser scanning confocal microscopy. Our results demonstrated that THIO induced hERG channel deficiency but did not alter channel kinetics. THIO promoted ROS production and stimulated endoplasmic reticulum (ER) stress and the related proteins. The ROS scavenger N-acetyl cysteine (NAC) significantly attenuated hERG reduction induced by THIO and abolished the upregulation of ER stress marker proteins. Meanwhile, THIO increased the degradation of hERG channels via disrupting hERG-Hsp70 interactions. The disordered hERG proteins were degraded in proteasomes after ubiquitin modification. On the other hand, THIO increased I Ca-L density and intracellular Ca2+ ([Ca2+]i) in neonatal rat ventricular cardiomyocytes (NRVMs). The specific CaMKII inhibitor KN-93 attenuated the intracellular Ca2+ overload, indicating that ROS-mediated CaMKII activation promoted calcium channel activation induced by THIO. Optical mapping analysis demonstrated the slowing effects of THIO on cardiac repolarization in mouse hearts. THIO significantly prolonged APD50 and APD90 and increased the incidence of early afterdepolarizations (EADs). In human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), THIO also resulted in APD prolongation. In conclusion, dysfunction of hERG channel proteins and activation of L-type calcium channels via ROS production might be the ionic mechanisms for QT prolongation induced by THIO.


Assuntos
Potenciais de Ação/efeitos dos fármacos , Canais de Cálcio Tipo L/metabolismo , Cardiotoxicidade/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Canais de Potássio Éter-A-Go-Go/metabolismo , Tioridazina/toxicidade , Potenciais de Ação/fisiologia , Animais , Benzilaminas/farmacologia , Cálcio/metabolismo , Canais de Cálcio Tipo L/fisiologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Estresse do Retículo Endoplasmático/genética , Canais de Potássio Éter-A-Go-Go/fisiologia , Células HEK293 , Proteínas de Choque Térmico HSP70/metabolismo , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Masculino , Camundongos , Miócitos Cardíacos/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Sulfonamidas/farmacologia , Ubiquitinação
16.
Biomed Pharmacother ; 123: 109751, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31958751

RESUMO

Doxorubicin (DOX), a wide-spectrum chemotherapeutic agent, is recognized to have cardiotoxic side effects when it is applied in hematological diseases and solid tumor management. However, the mechanisms behind the DOX-induced anomaly of vascular homeostasis remain mostly elusive. qRT-PCR and immumohistochemical staining indicated cardiac increase of miR-526b-3p, and decrease of CD31 and CD34 in DOX-treated mice. The regulatory function of miR-526b-3p on cardiac function and cardiac microvessel density was detected via the transfection of miR-526b-3p mimics or inhibitor into Human Umbilical Vein Endothelial Cells (HUVECs) and the administration of rAAV in mice. HUVECs proliferation, apoptosis, tube formation, and migration were inspected by EdU, flow cytometry, tube formation and transwell assays. MiR-526b-3p was anti-proliferative but apoptosis-initiating in HUVECs, and aggravated cardiac abnormalities caused by DOX. Mechanically, the relationship between miR-526b-3p and VEGFA was disclosed by qRT-PCR. VEGFA and STAT3 interaction was confirmed by ChIP and luciferase reporter assay. MiR-526b-3p targeted STAT3 to reduce VEGFA transcription. We designed rescue assays and presented that the negative effects of miR-526b-3p on cardiac dysfunction and HUVECs were rescued by VEGFA reintroduction in DOX-affected mice. Overall, miR-526b-3p accelerated doxorubicin-induced cardiotoxicity through modulating STAT3/VEGFA, highlighting that targeting miR-526b-3p as a potential method to protect against DOX-induced cardiac dysfunction.


Assuntos
Cardiotoxicidade/metabolismo , Doxorrubicina/farmacologia , MicroRNAs/metabolismo , Fator de Transcrição STAT3/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Antígenos CD34/metabolismo , Cardiotoxicidade/genética , Linhagem Celular , Movimento Celular , Proliferação de Células , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Molécula-1 de Adesão Celular Endotelial a Plaquetas
17.
Cancer Chemother Pharmacol ; 85(3): 563-571, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31915967

RESUMO

PURPOSE: It has been supposed that cardiac toxicity of doxorubicin is due to its production of free radicals and inflammatory cytokines. Dapsone, an antibiotic drug which is the principal in a multidrug regimen for the treatment of leprosy, is a sulfone with anti-inflammatory and antioxidant immunosuppressive properties. Therefore, we designed this study to investigate the possible effects of dapsone on doxorubicin-induced cardiotoxicity. METHODS: Male rats were administrated doxorubicin (2.5 mg/kg) and dapsone (1, 3, 10 mg/kg) intraperitoneally six times in 2 weeks. Then electrocardiographic (ECG) parameters (QRS complexes, RR and QT intervals) alternation, papillary muscle contraction and excitation, and histopathological changes were assessed. Also, the heart tissue levels of malondialdehyde (MDA) as oxidant factor and superoxide dismutase (SOD) as antioxidant enzyme, tumor necrosis factor-alpha (TNF-α) and serum level of CK-MB were analyzed. RESULTS: Administration of dapsone with doxorubicin significantly reversed alterations induced by doxorubicin in serum levels of CK-MB, ECG parameters, papillary muscle contractility and excitation. Furthermore, the measurement of MDA, SOD and TNF-α tissue level indicated that dapsone significantly reduced oxidative stress and inflammation. These findings were consistent with histopathological analysis. CONCLUSION: Dapsone exerts cardioprotective effects on doxorubicin-induced cardiotoxicity through its anti-inflammatory and antioxidant mechanism.


Assuntos
Cardiotoxicidade/tratamento farmacológico , Dapsona/farmacologia , Doxorrubicina/efeitos adversos , Coração/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Cardiotoxicidade/metabolismo , Citocinas/metabolismo , Inflamação/induzido quimicamente , Inflamação/metabolismo , Masculino , Malondialdeído/metabolismo , Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo
18.
Int J Radiat Biol ; 96(3): 349-359, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31976800

RESUMO

Purpose: Ionizing radiation is a risk factor to the whole organism, including the heart. Cardiac damage is considered to be a late effect of radiation exposure. While the acute cardiotoxicity of high doses is well characterized, the knowledge about nature and magnitude of the cardiac risk following lower doses exposure is incomplete. It has been shown that the cardiotoxic effects of radiation are source-, dose- and time-dependent. This paper provides an overview on these dependencies with regard to the molecular responses at the cellular and tissue levels. Main focus is put on the Nuclear Magnetic Resonance (NMR)-based and Mass Spectrometry (MS)-based metabolomic approaches in search of toxicity markers of relatively small doses of radiation.Conclusions: Available literature indicates that radiation exposure affects metabolites associated with: energy production, degradation of proteins and cell membranes, expression of proteins and stress response. Such effects are common for both animal and human studies. However, the specific metabolic response depends on several factors, including the examined organ. Radiation metabolomics can be used to explain the mechanisms of development of radiation-induced heart disease and to find an organ-specific biomarker of radiation exposure. The main aim of this review was to collect the information on the human cardiotoxicity biomarkers. In addition it also summarizes results of the studies on the metabolic responses to ionizing radiation for other organs, as well as the comparative data concerning animal studies.


Assuntos
Biomarcadores/análise , Cardiotoxicidade/diagnóstico , Cardiotoxicidade/metabolismo , Coração/efeitos da radiação , Metabolômica/métodos , Radiobiologia/tendências , Animais , Doenças Cardiovasculares/etiologia , Fibroblastos/metabolismo , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Camundongos , Mitocôndrias/metabolismo , Estresse Oxidativo , Lesões por Radiação , Proteção Radiológica , Radiação Ionizante , Fatores de Risco
19.
Int J Mol Sci ; 21(2)2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31963461

RESUMO

As many novel cancer therapies continue to emerge, the field of Cardio-Oncology (or onco-cardiology) has become crucial to prevent, monitor and treat cancer therapy-related cardiovascular toxicity. Furthermore, given the narrow therapeutic window of most cancer therapies, drug-drug interactions are prevalent in the cancer population. Consequently, there is an increased risk of affecting drug efficacy or predisposing individual patients to adverse side effects. Here we review the role of cytochrome P450 (CYP450) enzymes in the field of Cardio-Oncology. We highlight the importance of cardiac medications in preventive Cardio-Oncology for high-risk patients or in the management of cardiotoxicities during or following cancer treatment. Common interactions between Oncology and Cardiology drugs are catalogued, emphasizing the impact of differential metabolism of each substrate drug on unpredictable drug bioavailability and consequent inter-individual variability in treatment response or development of cardiovascular toxicity. This inter-individual variability in bioavailability and subsequent response can be further enhanced by genomic variants in CYP450, or by modifications of CYP450 gene, RNA or protein expression or function in various 'omics' related to precision medicine. Thus, we advocate for an individualized approach to each patient by a multidisciplinary team with clinical pharmacists evaluating a treatment plan tailored to a practice of precision Cardio-Oncology. This review may increase awareness of these key concepts in the rapidly evolving field of Cardio-Oncology.


Assuntos
Antineoplásicos/efeitos adversos , Cardiotoxicidade/tratamento farmacológico , Doenças Cardiovasculares/tratamento farmacológico , Sistema Enzimático do Citocromo P-450/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Neoplasias/tratamento farmacológico , Preparações Farmacêuticas/metabolismo , Cardiotoxicidade/etiologia , Cardiotoxicidade/metabolismo , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Interações Medicamentosas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/metabolismo , Humanos , Neoplasias/genética , Neoplasias/patologia , Preparações Farmacêuticas/administração & dosagem , Farmacogenética , Medicina de Precisão
20.
Clin Exp Hypertens ; 42(5): 381-392, 2020 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31630586

RESUMO

Background: Doxorubicin (DOX) is a potential chemotherapeutic agent but its use is restricted due to cardiotoxicity. Edaravone is a potent-free radical scavenging agent used in cerebral ischaemia. Benidipine is a triple calcium channel blocker.Objective: We investigated the potential cardioprotective effects of edaravone and benidipine alone and their combination against DOX-induced cardiotoxicity. Cardiotoxicity was induced by administering six equal injections of DOX (2.5 mg/kg) on alternative days for 2 weeks.Result: DOX-treated group showed significant increase level of lipid peroxide and decrease in antioxidant status along with mitochondrial enzymatic activity. Cardiotoxity effect of DOX illustrated by significantly increased the cardiac biomarkers such as Cardiac troponin-I, Brain natriuretic peptide, Creatine kinase-MB in serum. Significant increased activation of TNF-α, Caspase-3 activity and myocardial infarct size in DOX-treated group. Histopathological evaluation also confirmed the DOX-induced cardiotoxicity. Pretreated with edaravone and benidipine was significantly attenuated level of thiobarbituric acid reactive substance, endogenous enzymes, mitochondrial enzyme activities and cardiac biomarkers. Furthermore, pretreated group showed decreased activation of TNF-α, Caspase-3 activity along with reduction in the myocardial infarct size. Histopathological evaluation also strengthened the above results.Conclusion: Taken together these results suggest that the pretreated with edaravone and benidipine have potential protective effect against DOX-induced cardiotoxicity.


Assuntos
Cardiotoxicidade , Di-Hidropiridinas/farmacologia , Doxorrubicina/toxicidade , Edaravone/farmacologia , Mitocôndrias , Miocárdio/metabolismo , Animais , Antibióticos Antineoplásicos/toxicidade , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Biomarcadores/sangue , Cardiotoxicidade/etiologia , Cardiotoxicidade/metabolismo , Cardiotoxicidade/prevenção & controle , Hipertensão/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Ratos , Resultado do Tratamento
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