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1.
BMC Complement Altern Med ; 19(1): 317, 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31744501

RESUMO

BACKGROUND: Doxorubicin (DOX) is a chemotherapy drug for malignant tumors. The clinical application of DOX is limited due to its dosage relative cardiotoxicity. Oxidative damage and cardiac inflammation appear to be involved in DOX-related cardiotoxicity. Shenmai injection (SMI), which mainly consists of Panax ginsengC.A.Mey.and Ophiopogon japonicus (Thunb.) Ker Gawl, is widely used for the treatment of atherosclerotic coronary heart disease and viral myocarditis in China. In this study, we investigated the protective effect of Shenmai injection on doxorubicin-induced acute cardiac injury via the regulation of inflammatory mediators. METHODS: Male ICR mice were randomly divided into seven groups: control, DOX (10 mg/kg), SMI (5 g/kg), DOX with pretreatment with SMI (0.5 g/kg, 1.5 g/kg or 5 g/kg) and DOX with post-treatment with SMI (5 g/kg). Forty-eight hours after the last DOX administration, all mice were anesthetized for ultrasound echocardiography. Then, serum was collected for biochemical and inflammatory cytokine detection, and heart tissue was collected for histological and Western blot detection. RESULTS: A cumulative dose of DOX (10 mg/kg) induced acute cardiotoxicity in mice manifested by altered echocardiographic outcome, and increased tumor necrosis factor, interleukin 6 (IL-6), monocyte chemotactic protein 1, interferon-γ, and serum AST and LDH levels, as well as cardiac cytoplasmic vacuolation and myofibrillar disarrangement. DOX also caused the increase in the expression of IKK-α and iNOS and produced a large amount of NO, resulting in the accumulation of nitrotyrosine in the heart tissue. Pretreatment with SMI elicited a dose-dependent cardioprotective effect in DOX-dosed mice as evidenced by the normalization of serum inflammatory mediators, as well as improve dcardiac function and myofibril disarrangement. CONCLUSIONS: SMI could recover inflammatory cytokine levels and suppress the expression of IKK-α and iNOS in vivo, which was increased by DOX. Overall, there was evidence that SMI could ameliorate DOX-induced cardiotoxicity by inhibiting inflammation and recovering heart dysfunction.


Assuntos
Antineoplásicos/toxicidade , Cardiotoxicidade/prevenção & controle , Doxorrubicina/toxicidade , Medicamentos de Ervas Chinesas/administração & dosagem , Mediadores da Inflamação/metabolismo , Animais , Cardiotoxicidade/etiologia , Cardiotoxicidade/genética , Cardiotoxicidade/metabolismo , Coração/efeitos dos fármacos , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Ophiopogon/química , Panax/química , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
3.
Biomed Res Int ; 2019: 1528278, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31355248

RESUMO

Oxidative stress and cardiomyocytes apoptosis were closely involved in the pathological process of doxorubicin- (Dox-) induced cardiac injury. MicroRNA-451 (miR-451) was mainly expressed in cardiomyocytes. However, the role of miR-451 in Dox-induced cardiac injury remained unclear. Our study aimed to investigate the effect of miR-451 on Dox-induced cardiotoxicity in mice. We established a Dox-induced cardiotoxicity model in the mice and manipulated miR-451 expression in the heart using a miR-451 inhibitor, which was injected every other day beginning at one day before Dox injection. Oxidative stress and apoptosis in the hearts were evaluated. miR-451 levels were significantly increased in Dox-treated mice or cardiomyocytes. miR-451 inhibition attenuated Dox-induced whole-body wasting and heart atrophy, reduced cardiac injury, restored cardiac function, and improved cardiomyocyte contractile function. Moreover, miR-451 inhibition reduced oxidative stress and cardiomyocytes apoptosis in vivo and in vitro. miR-451 inhibition increased the expression of calcium binding protein 39 (Cab39) and activated adenosine monophosphate activated protein kinase (AMPK) signaling pathway. A specific inhibitor of AMPK abolished the protection provided by miR-451 inhibition against cell injury in vitro. In conclusion, miR-451 inhibition protected against Dox-induced cardiotoxicity via activation of AMPK signaling pathway.


Assuntos
Cardiotoxicidade/genética , Traumatismos Cardíacos/genética , MicroRNAs/genética , Estresse Oxidativo/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Cardiotoxicidade/patologia , Modelos Animais de Doenças , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacologia , Traumatismos Cardíacos/induzido quimicamente , Traumatismos Cardíacos/patologia , Humanos , Camundongos , MicroRNAs/antagonistas & inibidores , Miócitos Cardíacos/efeitos dos fármacos , Proteínas Quinases/genética , Transdução de Sinais/efeitos dos fármacos
4.
Environ Toxicol Pharmacol ; 70: 103198, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31154273

RESUMO

Cadmium (Cd) is a highly toxic heavy metal with several harmful effects including cardiotoxicity. For the first time, we aimed to evaluate the possible cardioprotective effect of carvedilol (CAR) in Cd induced cardiotoxicity and study the mechanisms involved in such protection including endothelial nitric oxide synthase (eNOS) and HO1/Nrf2 pathway. CAR (1,10 mg/kg/d) was administered orally for 4 weeks with Cd induced cardiac injury (3 mg/kg/d) orally for 4 weeks. We measured cardiac enzymes, mean arterial pressure changes, heme oxygenase-1 (HO1) and total antioxidant capacity (TAC). Moreover; cardiac tissue malondialdehyde (MDA), tumor necrosis factor alpha (TNFα), western blotting of caspase3 and eNOS levels and histopathology were evaluated. Immunoexpression of eNOS in cardiac tissue, gene expression changes of HO1, and nuclear factor erythroid 2-related factor 2 (Nrf2) using real time polymerase chain reactions (rtPCR) were detected. Our results showed that CAR could significantly decrease Cd induced cardiotoxicity.


Assuntos
Cádmio/toxicidade , Cardiotônicos/farmacologia , Cardiotoxicidade/metabolismo , Carvedilol/farmacologia , Animais , Cardiotônicos/uso terapêutico , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/genética , Carvedilol/uso terapêutico , Heme Oxigenase (Desciclizante)/genética , Masculino , Malondialdeído/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Fator 2 Relacionado a NF-E2/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos
5.
Hum Exp Toxicol ; 38(9): 1111-1124, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31179749

RESUMO

Cardiotoxicity is one of the most significant reasons of attrition in drug development. The present study assessed the sensitivity of various endpoints for early monitoring of drug-induced cardiotoxicity using human embryonic stem cell-derived cardiac cells, including precursors as well as mature cardiomyocytes, by correlating changes in cardiac biomarker expression. Directed differentiation was induced and cardiac progenitor cell (CPC) population were treated with cardiotoxic drugs, namely, doxorubicin (Dox) and paclitaxel (Pac), and with noncardiotoxic drug, namely penicillin G. To assess cardiac-specific toxicity, the changes in the expression of key markers of cardiac lineage, such as Nkx2.5, Tbx5, α-myosin heavy chain α-MHC, and cardiac troponin T, were studied using quantitative real-time polymerase chain reaction (qRT-PCR) and flow cytometry (FC). The half-maximal inhibition in the expression of these cardiac markers was analyzed from the dose-response curves. We also assessed the half-maximal inhibition (IC50) in cardiac cells using propidium iodide dye (IC50 PI) and by measuring disruption in the mitochondrial membrane potential (IC50 MMP). We observed that the most sensitive marker was α-MHC in the case of both Dox and Pac, and the order of sensitivity of the various prediction assays was MMP > protein expression by FC > gene expression by qRT-PCR > cell viability by PI staining. The results could enrich the screening of drug-induced cardiotoxicity in vitro and propose disruption in MMP along with downregulation of α-MHC protein as a potential biomarker of predicting cardiotoxicity earlier during drug safety evaluation.


Assuntos
Cardiotoxicidade/fisiopatologia , Doxorrubicina/toxicidade , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Paclitaxel/toxicidade , Biomarcadores/metabolismo , Cardiotoxicidade/genética , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Proteína Homeobox Nkx-2.5/genética , Humanos , Miócitos Cardíacos/fisiologia , Cadeias Pesadas de Miosina/genética , Penicilina G/farmacologia , Proteínas com Domínio T/genética
6.
J Agric Food Chem ; 67(17): 5033-5042, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30964671

RESUMO

Many studies have shown that fluorosis due to long-term fluoride intake has damaging effects on the heart. However, the mechanisms underlying cardiac fluorosis have not been illuminated in detail. We performed high-throughput transcriptome sequencing (RNA-Seq) on rat cardiac tissue to explore the molecular effects of NaF exposure. In total, 372 and 254 differentially expressed genes (DEGs) were identified between a group given 30 mg/L NaF and control and between a group given 90 mg/L NaF and control, respectively. The transcript levels of most of these genes were significantly down-regulated and many were distributed in the Toll-like receptor signaling pathway. Transcriptome analysis revealed that herpes simplex infection, ECM-receptor interaction, influenza A, cytokine-cytokine receptor interaction, apoptosis, and Toll-like receptor signaling pathway were significantly affected. IL-6 and IL-10 may play a crucial role in the cardiac damage caused by NaF as external stimuli according to protein-protein interaction (PPI) network analysis. The results of qRT-PCR and Western blotting showed a marked decreased mRNA and protein levels of IL-1, IL-6, and IL-10 in the low concentration fluoride (LF) and high concentration fluoride (HF) groups, which was in agreement with RNA-Seq results. This is the first study to investigate NaF-induced cardiotoxicity at a transcriptome level.


Assuntos
Cardiotoxicidade/etiologia , Cardiotoxicidade/metabolismo , Fluoretos/toxicidade , Receptores Toll-Like/metabolismo , Animais , Cardiotoxicidade/genética , Perfilação da Expressão Gênica , Humanos , Interleucina-1/genética , Interleucina-1/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Ligação Proteica/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Receptores Toll-Like/genética
7.
J Cancer Res Clin Oncol ; 145(6): 1635-1643, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30923943

RESUMO

PURPOSE: Radiation-induced cardiac toxicity (RICT) is an increasingly well-appreciated source of morbidity and mortality in patients receiving thoracic radiotherapy (RT). Currently available methods to predict RICT are suboptimal. We investigated circulating microRNAs (c-miRNAs) as potential biomarkers of RICT in patients undergoing definitive RT for non-small-cell lung cancer (NSCLC). METHODS: Data from 63 patients treated on institutional trials were analyzed. Prognostic models of grade 3 or greater (G3 +) RICT based on pre-treatment c-miRNA levels ('c-miRNA'), mean heart dose (MHD) and pre-existing cardiac disease (PCD) ('clinical'), and a combination of these ('c-miRNA + clinical') were developed. Elastic net Cox regression and full cross validation were used for variable selection, model building, and model evaluation. Concordance statistic (c-index) and integrated Brier score (IBS) were used to evaluate model performance. RESULTS: MHD, PCD, and serum levels of 14 c-miRNA species were identified as jointly prognostic for G3 + RICT. The 'c-miRNA and 'clinical' models yielded similar cross-validated c-indices (0.70 and 0.72, respectively) and IBSs (0.26 and 0.28, respectively). However, prognostication was not improved by combining c-miRNA and clinical factors (c-index 0.70, IBS 0.28). The 'c-miRNA' and 'clinical' models were able to significantly stratify patients into high- and low-risk groups of developing G3 + RICT. Chi-square testing demonstrated a marginally significantly higher prevalence of PCD in patients with high- compared to low-risk c-miRNA profile (p = 0.09), suggesting an association between some c-miRNAs and PCD. CONCLUSIONS: We identified a pre-treatment c-miRNA signature prognostic for G3 + RICT. With further development, pre- and mid-treatment c-miRNA profiling could contribute to patient-specific dose selection and treatment adaptation.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/radioterapia , Cardiotoxicidade/sangue , Cardiotoxicidade/etiologia , MicroRNA Circulante/sangue , Neoplasias Pulmonares/radioterapia , Lesões por Radiação/sangue , Lesões por Radiação/etiologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/genética , Cardiotoxicidade/genética , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Feminino , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Masculino , MicroRNAs/sangue , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Lesões por Radiação/genética
8.
Biomed Pharmacother ; 111: 1467-1477, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30841462

RESUMO

Tripterygium wilfordii Hook. F. is a plant used in traditional Chinese medicine to treat rheumatoid arthritis, lupus erythematosus, and psoriasis in China. However, its main active substance, triptolide, has toxic effects on the heart, liver, and kidneys, which limit its clinical application. Therefore, determining the mechanism of cardiotoxicity in triptolide and identifying effective early-warning biomarkers is beneficial for preventing irreversible myocardial injury. We observed changes in microRNAs and aryl hydrocarbon receptor (AhR) as potential biomarkers in triptolide-induced acute cardiotoxicity by using techniques such as polymerase chain reaction (PCR) assay. The results revealed that triptolide increased the heart/body ratio and caused myocardial fiber breakage, cardiomyocyte hypertrophy, increased cell gaps, and nuclear dissolution in treated male rats. Real-time PCR array detection revealed a more than 2-fold increase in the expression of 108 microRNA genes in the hearts of the male rats; this not only regulated the signaling pathways of ErbB, FOXO, AMPK, Hippo, HIF-1α, mTOR, and PI3K-Akt but also participated in biological processes such as cell adhesion, cell cycling, action potential, locomotory behavior, apoptosis, and DNA binding. Moreover, triptolide reduced the circulatory and cardiac levels of AhR protein as a target of these microRNAs and the messenger RNA expression of its downstream gene CYP1 A1. However, decreases in myocardial lactate dehydrogenase, creatine kinase MB, catalase, and glutathione peroxidase activity and an increase in circulating cardiac troponin I were observed only in male rats. Moreover, plasma microRNAs exhibited dynamic change. These results revealed that circulating microRNAs and AhR protein are potentially early-warning biomarkers for triptolide-induced cardiotoxicity.


Assuntos
Biomarcadores/metabolismo , Cardiotoxicidade/genética , Diterpenos/farmacologia , MicroRNAs/genética , Miócitos Cardíacos/efeitos dos fármacos , Fenantrenos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Cardiotoxicidade/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Compostos de Epóxi/farmacologia , Feminino , Masculino , Medicina Tradicional Chinesa/métodos , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Tripterygium/química
9.
Circ Heart Fail ; 12(3): e005234, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30871347

RESUMO

Background Anthracycline chemotherapeutics, such as doxorubicin, are used widely in the treatment of numerous malignancies. The primary dose-limiting adverse effect of anthracyclines is cardiotoxicity that often presents as heart failure due to dilated cardiomyopathy years after anthracycline exposure. Recent data from animal studies indicate that anthracyclines cause cardiac atrophy. The timing of onset and underlying mechanisms are not well defined, and the relevance of these findings to human disease is unclear. Methods and Results Wild-type mice were sacrificed 1 week after intraperitoneal administration of doxorubicin (1-25 mg/kg), revealing a dose-dependent decrease in cardiac mass ( R2=0.64; P<0.0001) and a significant decrease in cardiomyocyte cross-sectional area (336±29 versus 188±14 µm2; P<0.0001). Myocardial tissue analysis identified a dose-dependent upregulation of the ubiquitin ligase, MuRF1 (muscle ring finger-1; R2=0.91; P=0.003) and a molecular profile of muscle atrophy. To investigate the determinants of doxorubicin-induced cardiac atrophy, we administered doxorubicin 20 mg/kg to mice lacking MuRF1 (MuRF1-/-) and wild-type littermates. MuRF1-/- mice were protected from cardiac atrophy and exhibited no reduction in contractile function. To explore the clinical relevance of these findings, we analyzed cardiac magnetic resonance imaging data from 70 patients in the DETECT-1 cohort and found that anthracycline exposure was associated with decreased cardiac mass evident within 1 month and persisting to 6 months after initiation. Conclusions Doxorubicin causes a subacute decrease in cardiac mass in both mice and humans. In mice, doxorubicin-induced cardiac atrophy is dependent on MuRF1. These findings suggest that therapies directed at preventing or reversing cardiac atrophy might preserve the cardiac function of cancer patients receiving anthracyclines.


Assuntos
Antineoplásicos/efeitos adversos , Doxorrubicina/efeitos adversos , Insuficiência Cardíaca/induzido quimicamente , Coração/efeitos dos fármacos , Proteínas Musculares/genética , Atrofia Muscular/induzido quimicamente , Proteínas com Motivo Tripartido/genética , Ubiquitina-Proteína Ligases/genética , Animais , Antineoplásicos/administração & dosagem , Cardiotoxicidade/diagnóstico por imagem , Cardiotoxicidade/etiologia , Cardiotoxicidade/genética , Cardiotoxicidade/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Ecocardiografia , Expressão Gênica , Coração/diagnóstico por imagem , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Humanos , Injeções Intraperitoneais , Imagem por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Musculares/metabolismo , Atrofia Muscular/diagnóstico por imagem , Atrofia Muscular/genética , Atrofia Muscular/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Regulação para Cima
10.
Environ Toxicol ; 34(3): 319-329, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30496632

RESUMO

Bisphenol A (BPA), an estrogenic compound, is used in manufacture of polycarbonate plastics and epoxy resins. Curcumin, the active ingredient of turmeric, is a potent protective compound against cardiac diseases. In this study the protective effect of nanomicelle curcumin on BPA-induced subchronic cardiotoxicity in rats was evaluated. Rats were divided into 6 groups including control, nanomicelle curcumin (50 mg/kg, gavage), BPA (50 mg/kg, gavage), nanomicelle curcumin (10, 25, and 50 mg/kg) plus BPA. The treatments were continued for 4 weeks. Results revealed that BPA significantly induced histophatological injuries including focal lymphatic inflammation, nuclear degenerative changes and cytoplasmic vacuolation, increased body weight, systolic and diastolic blood pressures, malondialdehyde and Creatine phosphokinase-MB level and decreased glutathione content in comparison with control group. In addition, in electrocardiographic graph, RR, QT, and PQ intervals were increased by BPA. Western blot analysis showed that BPA up-regulated phosphorylated p38 (p38-mitogen-activated protein kinase) and JNK (c-jun NH2 terminal kinases), while down-regulated phosphorylated AKT (Protein Kinase B) and ERK1/2 (extracellular signal-regulated protein kinases 1 and 2). However, nanomicelle curcumin (50 mg/kg) significantly improved these toxic effects of BPA in rat heart tissue. The results provide evidence that nanomicelle curcumin showed preventive effects on subchronic exposure to BPA induced toxicity in the heart tissue in rats.


Assuntos
Compostos Benzidrílicos/toxicidade , Cardiotoxicidade/prevenção & controle , Curcumina/administração & dosagem , Fenóis/toxicidade , Substâncias Protetoras/administração & dosagem , Animais , Cardiotoxicidade/etiologia , Cardiotoxicidade/genética , Cardiotoxicidade/metabolismo , Regulação para Baixo/efeitos dos fármacos , Glutationa/metabolismo , Coração/efeitos dos fármacos , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , Malondialdeído/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosforilação/efeitos dos fármacos , Ratos , Ratos Wistar
11.
Hum Exp Toxicol ; 38(2): 255-266, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30303030

RESUMO

Periostin is an extracellular matrix protein from the fasciclin family that guides cellular trafficking and extracellular matrix organization. Periostin stimulates mature cardiomyocytes to reenter the cell cycle. The molecular mechanism behind such stimulation remains to be explored. A DNA microarray technology constituting 30,429 gene-level probe sets was utilized to investigate effects of recombinant murine periostin peptide on the gene expression pattern in a rat model of isoproterenol (ISO)-induced myocardial injury. The experiment was performed on 84 adult male Sprague-Dawley rats in four groups ( n = 21): (1) control group, (2) only periostin applied group, (3) ISO cardiotoxicity group, and (4) ISO + periostin group. The experiment was continued for 28 days, and rats were killed on days 1, 7, and 28 ( n = 7). Microarray analyses revealed that periostin significantly altered the expression of at least ±2-fold of 2474 genes in the ISO + periostin group compared to the ISO cardiotoxicity group of which 521 genes altered out of 30,429 gene-level probe sets. Ingenuity pathway analysis indicated that multiple pathway networks were affected by periostin, with predominant changes occurring in the expression of genes involved in oxidative phosphorylation, oxidative stress, fatty acid metabolism, and TNF-α NF-κB signaling pathways. These findings indicate that periostin alters gene expression profile in the ISO-induced myocardial injury and modulates local myocardial inflammation, possibly mitigating inflammation through TNF-α NF-κB signaling pathway along with a decreased Casp7 activity and apoptotic cell death.


Assuntos
Cardiotoxicidade/genética , Moléculas de Adesão Celular/farmacologia , Isoproterenol/toxicidade , Transcriptoma/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Masculino , Ratos Sprague-Dawley
12.
Yonsei Med J ; 60(1): 30-37, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30554488

RESUMO

PURPOSE: The present study aimed to investigate correlations between uridine glucuronosyltransferase 2B7 (UGT2B7) -161 single nucleotide polymorphism C to T (C>T) and the occurrence of cardiotoxicity in Chinese breast cancer (BC) patients undergoing epirubicin/cyclophosphamide-docetaxel (EC-D) adjuvant chemotherapy. MATERIALS AND METHODS: 427 BC patients who had underwent surgery were consecutively enrolled in this prospective cohort study. All patients were scheduled to receive EC-D adjuvant chemotherapy regimen, and they were divided into UGT2B7 -161 CC (n=141), UGT2B7 -161 CT (n=196), and UGT2B7 -161 TT (n=90) groups according to their genotypes. Polymerase chain reaction was performed for determination of UGT2B7 -161 genotypes. Cardiotoxicity was defined as an absolute decline in left ventricular ejection fraction (LVEF) of at least 10% points from baseline to a value less than 53%, heart failure, acute coronary artery syndrome, or fatal arrhythmia. RESULTS: LVEF values were lower at cycle (C) 4, C8, 3 months after chemotherapy (M3), M6, M9, and M12 compared to C0 (all p<0.001), in BC patients undergoing EC-D adjuvant chemotherapy. Cardiotoxicity was recorded for 4.2% of the overall population and was lowest in the UGT2B7 -161 TT group (1.1%), compared to UGT2B7 -161 CT (3.1%) and UGT2B7 -161 CC (7.8%) group (p=0.026). Multivariate logistic regression revealed that UGT2B7 -161 T allele could independently predict a low occurrence of cardiotoxicity in BC patients undergoing EC-D adjuvant chemotherapy (p=0.004). CONCLUSION: A UGT2B7 -161 T allele serves as a potential biomarker for predicting a low occurrence of cardiotoxicity in BC patients undergoing EC-D adjuvant chemotherapy.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Cardiotoxicidade/genética , Ciclofosfamida/efeitos adversos , Docetaxel/efeitos adversos , Epirubicina/efeitos adversos , Glucuronosiltransferase/genética , Polimorfismo de Nucleotídeo Único/genética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cardiotoxicidade/fisiopatologia , Quimioterapia Adjuvante , Ciclofosfamida/uso terapêutico , Docetaxel/uso terapêutico , Epirubicina/uso terapêutico , Feminino , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Análise Multivariada , Estudos Prospectivos , Volume Sistólico
13.
Biosci Biotechnol Biochem ; 83(4): 653-658, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30558506

RESUMO

Doxorubicin (Dox) is an anthracycline antibiotic that has been used to treat different cancers. Dox-induced cardiotoxicity is common in clinical practice, while its mechanism is unknown. It has been proved that lncRNA FOXC2-AS1 may promote doxorubicin resistance and WNT1-inducible signaling pathway protein-1 (WISP1) blocks doxorubicin-induced cardiomyocyte death. Our study aimed to investigate the involvement of lncRNA FOXC2-AS1 and WISP1 in doxorubicin-induced cardiotoxicity and to explore their interactions. In our study we observed that FOXC2-AS1 and WISP1 mRNA were downregulated in heart tissues of mice with Dox-induced cardiotoxicity. FOXC2-AS1 and WISP1 mRNA expression were positively correlated in mice with Dox-induced cardiotoxicity but not in healthy mice. Overexpression of FOXC2-AS1 promoted to viability of mice cardiomyocytes under Dox treatment and also increased the expression level of WISP1. In contrast, WISP1 overexpression showed no significant effect on FOXC2-AS1. We therefore conclude that lncRNA FOXC2-AS1 may upregulate WISP1 to protect cardiomyocytes from doxorubicin-induced cardiotoxicity.


Assuntos
Antibióticos Antineoplásicos/toxicidade , Proteínas de Sinalização Intercelular CCN/genética , Cardiotoxicidade/genética , Doxorrubicina/toxicidade , Fatores de Transcrição Forkhead/genética , Proteínas Proto-Oncogênicas/genética , RNA Longo não Codificante/genética , Animais , Pressão Sanguínea , Proteínas de Sinalização Intercelular CCN/metabolismo , Cardiotoxicidade/etiologia , Cardiotoxicidade/metabolismo , Cardiotoxicidade/fisiopatologia , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica , Coração/efeitos dos fármacos , Coração/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Plasmídeos/genética , Plasmídeos/metabolismo , Cultura Primária de Células , Proteínas Proto-Oncogênicas/metabolismo , RNA Longo não Codificante/metabolismo , Transdução de Sinais , Transfecção
14.
J Pediatr Hematol Oncol ; 41(2): e94-e96, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30045149

RESUMO

Current treatment of high-grade osteosarcoma consists of preoperative chemotherapy, typically using some combination of doxorubicin, cisplatin, ifosfamide, and/or high-dose methotrexate followed by surgical resection. In this report, we present a case of a 21-year-old woman with high-grade osteosarcoma of the chest wall who received 5 times the planned dose of doxorubin and 4 times the planned dose of ifosfamide. She survived this chemotherapy overdose after administration of dimethyl sulfoxide and phenobarbital. Despite the administration of 5 times the proposed dose of doxorubicin, the patient survived without cardiotoxicity, and later delivered a normal baby. Although there are many studies evaluating treatment for chemotherapy regimen-related toxicity, sparse data exist with respect to chemotherapy overdose and the appropriate course of action. This case further confirms the lower cardiotoxicity of continuous intravenous infusion of doxorubicin and provides support for the use of dimethyl sulfoxide in the prevention of toxicity in chemotherapy overdose.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Cardiotoxicidade/prevenção & controle , Dimetil Sulfóxido/administração & dosagem , Osteossarcoma , Proteínas Supressoras de Tumor/genética , Ubiquitina-Proteína Ligases/genética , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Cardiotoxicidade/genética , Cardiotoxicidade/patologia , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Humanos , Ifosfamida/administração & dosagem , Ifosfamida/efeitos adversos , Osteossarcoma/tratamento farmacológico , Osteossarcoma/genética , Osteossarcoma/patologia , Fenobarbital/administração & dosagem , Fenobarbital/efeitos adversos
15.
Environ Toxicol ; 34(3): 271-282, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30520268

RESUMO

The risk of pesticides on the human health and environment has drawn increasing attention. Today, new tools are developed to reduce pesticide adverse effects. This study aimed to evaluate the toxicity induced by, thiamethoxam (TMX), and the cytoprotective effect of a novel polysaccharide, named fenugreek seed water polysaccharide (FWEP) in vitro using H9c2 cardiomyoblastes and in vivo using Wistar rat model. Animals were assigned into four groups per eight rats each: group 1 served as a control group, group 2 received TMX, group 3, and group 4 received both FWEP and TMX tested at two doses (100 and 200 mg/kg, respectively). Regarding the in vitro study, our results demonstrated that TMX induced a decrease in H9c2 cell viability up to 70% with the highest concentration. In vivo, TMX injection induced marked heart damage noted by a significant increase in plasma lactate dehydrogenase, creatine phosphokinase, troponin-T, aspartate amino transferase activities, cholesterol, and triglyceride levels. Concomitant alterations in cardiac antioxidant defense system revealed depletion in the levels of glutathione and non-protein thiol and an increase in the activity of superoxide dismutase, catalase, and glutathione peroxidase. Similarly, a significant increase in heart lipid, malondialdehyde, advanced oxidation protein product and in protein carbonyls levels was also noted. In addition, heart tissues histo-architecture displayed major presence of apoptosis and necrosis as confirmed by DNA degradation. However, supplementation with FWEP alleviated heart oxidative damage and genotoxicity. In this manner, ABTS radical-scavenging activity, linoleic acid oxidation tests and heart genomic and DNA nicking assay had proved FWEP strong antioxidant potential. In conclusion, FWEP provided significant protection against TMX-induced heart injury, and could be a useful and efficient agent against cardiotoxicity and atherosclerosis.


Assuntos
Cardiotoxicidade/tratamento farmacológico , Dano ao DNA/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Polissacarídeos/administração & dosagem , Trigonella/química , Animais , Antioxidantes/metabolismo , Cardiotoxicidade/etiologia , Cardiotoxicidade/genética , Cardiotoxicidade/metabolismo , Catalase/metabolismo , Colesterol/metabolismo , Feminino , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Humanos , Masculino , Malondialdeído/metabolismo , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Sementes/química , Superóxido Dismutase/metabolismo , Tiametoxam/efeitos adversos , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
16.
Cancer Biomark ; 23(4): 473-484, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30452398

RESUMO

OBJECTIVE: This study aimed to evaluate predictive value of 14 pro-angiogenic miRNAs for cardiotoxicity induced by epirubicin/cyclophosphamide follow by docetaxel (EC-D) in breast cancer (BC) patients. METHODS: Three hundred and sixty-three BC patients receiving EC-D neoadjuvant chemotherapy were consecutively enrolled in this prospective cohort study. Peripheral blood sample was obtained from each patient, and plasma was separated. The expressions of 14 pro-angiogenic miRNAs, cardiac troponin I (cTnI) and N-terminal pro brain natriuretic peptide (NT-proBNP) were evaluated. Left ventricular ejection fraction (LVEF) level at C0, the end of 4 cycles of EC chemotherapy (C4), the end of 4 cycles of docetaxel treatment (C8), 3rd months (M3), 6th months (M6), 9th months (M9) and 12th months (M12) after surgery were assessed. RESULTS: LVEF decreased at C4, C8, M3, M6, M9 and M12 compared with C0, and the total cardiotoxicity incidence was 5.2%. Additionally, the levels of let-7f, miR-17-5p, miR-20a, miR-126, miR-210 and miR-378 were reduced in cardiotoxicity patients. Multivariate logistic regression revealed that miR-17-5p and miR-20a were independently predictive factors for less cardiotoxicity. Receiver operating characteristics (ROC) curve displayed a satisfactory predictive value for lower cardiotoxicity risk with area under curve (AUC) of 0.842 of the combination of the miR-17-5p and miR-20a expressions. In addition, let-7f,miR-126, miR-210 and miR-378 levels negatively correlated with cTnI expression, and let-7f and miR-130a expressions reversely correlated with NT-proBNP level.CONLUSIONS: miR-17-5p and miR-20a could be served as biomarkers for lower cardiotoxicity induced by EC-D neoadjuvant chemotherapy in BC patients.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Ácidos Nucleicos Livres/sangue , MicroRNAs/sangue , Adulto , Idoso , Biomarcadores Tumorais/sangue , Neoplasias da Mama/sangue , Neoplasias da Mama/complicações , Cardiotoxicidade/sangue , Cardiotoxicidade/genética , Ciclofosfamida/efeitos adversos , Docetaxel/efeitos adversos , Epirubicina/efeitos adversos , Feminino , Humanos , Pessoa de Meia-Idade , Troponina I/sangue
18.
Surg Oncol ; 27(3): 526-538, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30217315

RESUMO

The long-time paradoxical situation of non-coding RNAs (ncRNAs) has been terminated for they emerge as executive at full spectrum of gene expression and translation. More recently, it has been demonstrated that some ncRNAs apparently are associated with chemotherapy, causing cardiotoxicity, which taint long-term recovery of patients in growing body of evidence. The current review focused on up-to-date knowledge on regulation change and molecular signaling of ncRNAs, at mean time evaluate their potentials as diagnostic biomarkers or therapeutic targets to monitor and protect cardio function.


Assuntos
Antineoplásicos/efeitos adversos , Cardiotoxicidade/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias/tratamento farmacológico , RNA não Traduzido/genética , Animais , Humanos
19.
Free Radic Biol Med ; 129: 59-72, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30172748

RESUMO

Doxorubicin (DOX) is a highly effective anticancer anthracycline drug, but its side effects at the level of the heart has limited its widespread clinical application. Melatonin is a documented potent antioxidant, nontoxic and cardioprotective agent, and it is involved in maintaining mitochondrial homeostasis and function. The present study established acute DOX-induced cardiotoxicity models in both H9c2 cells incubated with 1 µM DOX and C57BL/6 mice treated with DOX (20 mg/kg cumulative dose). Melatonin markedly alleviated the DOX-induced acute cardiac dysfunction and myocardial injury. Both in vivo and in vitro studies verified that melatonin inhibited DOX-induced mitochondrial dysfunction and morphological disorders, apoptosis, and oxidative stress via the activation of AMPK and upregulation of PGC1α with its downstream signaling (NRF1, TFAM and UCP2). These effects were reversed by the use of AMPK siRNA or PGC1α siRNA in H9c2 cells, and were also negated by the cotreatment with AMPK inhibitor Compound C in vivo. Moreover, PGC1α knockdown was without effect on the AMPK phosphorylation induced by melatonin in the DOX treated H9c2 cells. Therefore, AMPK/PGC1α pathway activation may represent a new mechanism for melatonin exerted protection against acute DOX cardiotoxicity through preservation of mitochondrial homeostasis and alleviation of oxidative stress and apoptosis.


Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Cardiomiopatias/prevenção & controle , Cardiotônicos/farmacologia , Cardiotoxicidade/prevenção & controle , Doxorrubicina/antagonistas & inibidores , Melatonina/farmacologia , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Apoptose/efeitos dos fármacos , Cardiomiopatias/etiologia , Cardiomiopatias/genética , Cardiomiopatias/patologia , Cardiotoxicidade/etiologia , Cardiotoxicidade/genética , Cardiotoxicidade/patologia , Linhagem Celular , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Doxorrubicina/efeitos adversos , Regulação da Expressão Gênica , Proteínas de Grupo de Alta Mobilidade/genética , Proteínas de Grupo de Alta Mobilidade/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Fator 1 Nuclear Respiratório/genética , Fator 1 Nuclear Respiratório/metabolismo , Oxazinas/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/antagonistas & inibidores , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Fosforilação/efeitos dos fármacos , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos , Transdução de Sinais , Proteína Desacopladora 2/genética , Proteína Desacopladora 2/metabolismo
20.
Drug Discov Today Technol ; 28: 13-21, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30205876

RESUMO

Cardiovascular diseases (CVDs) are leading causes of death worldwide, and drug-induced cardiotoxicity is among the most common cause of drug withdrawal from the market. Improved models of cardiac tissue are needed to study the mechanisms of CVDs and drug-induced cardiotoxicity. Human pluripotent stem cell-derived cardiomyocytes (hPSC-CM) have provided a major advance to our ability to study these conditions. Combined with efficient genome editing technologies, such as CRISPR/Cas9, we now have the ability to study with greater resolution the genetic causes and underlying mechanisms of inherited and drug-induced cardiotoxicity, and to investigate new treatments. Here, we review recent advances in the use of hPSC-CMs and CRISPR/Cas9-mediated genome editing to study cardiotoxicity and model CVD.


Assuntos
Sistemas CRISPR-Cas , Cardiotoxicidade/genética , Doenças Cardiovasculares/genética , Edição de Genes , Células-Tronco/fisiologia , Animais , Cardiotoxicidade/terapia , Doenças Cardiovasculares/terapia , Diferenciação Celular/genética , Genoma Humano , Humanos , Miócitos Cardíacos/citologia , Miócitos Cardíacos/fisiologia , Células-Tronco/citologia
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