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1.
Oncology ; 98(9): 653-660, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32454480

RESUMO

BACKGROUND: Anthracycline is used to treat various types of cancer; however, cardiotoxicity negatively affects patient prognosis. OBJECTIVES: The aim of the present study was to investigate serial changes in levels of cardiac troponin I (TnI) and B-type natriuretic peptide (BNP) in patients treated with anthracycline-containing therapy. METHODS: 91 consecutive cancer patients planned for anthracycline treatment were enrolled and followed up for 12 months. All patients underwent echocardiography and blood sampling at baseline, 3, 6, and 12 months. RESULTS: The patients were divided into two groups based on their TnI level during the follow-up period: the elevated TnI group (TnI ≥0.03 ng/mL; n = 37) and the normal TnI group (n = 54). In the elevated TnI group, the TnI levels increased at 3 and 6 months, but they returned to within normal range at 12 months after anthracycline administration. Unlike TnI, the BNP levels began to increase after 6 months, and remained increased at 12 months. The occurrence of cancer therapeutics-related cardiac dysfunction was higher in the elevated TnI group than in the normal TnI group. When we set the cut-off value of TnI at 0.029 ng/mL, sensitivity and specificity to predict an elevated BNP level of more than 100 pg/mL were 90 and 63%, respectively. Multivariate logistic regression analysis revealed that elevated TnI was an independent predictor of elevated BNP levels. CONCLUSION: Elevated TnI was an independent predictor for the development of BNP increase. The different characteristics of TnI and BNP should be considered when managing patients treated with anthracycline-containing therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Cardiotoxicidade/sangue , Peptídeo Natriurético Encefálico/sangue , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Troponina I/sangue , Antraciclinas/administração & dosagem , Antraciclinas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cardiotoxicidade/diagnóstico por imagem , Cardiotoxicidade/etiologia , Ecocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes
2.
Hum Exp Toxicol ; 39(5): 696-711, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31928237

RESUMO

Lithium is one of the most powerful and commonly used medications for the treatment of various psychiatric diseases, especially bipolar disorder. However, it has a narrow therapeutic index with toxic effects on various organs. There are several case reports of lithium-induced arrhythmia and ischemia. The current work aimed to study the toxic effects of lithium on the heart of adult albino rats and its molecular mechanisms and the ameliorating effect of N-acetyl cysteine (NAC). Sixty adult male Wistar albino rats were classified into four groups; control, NAC-treated received NAC 500 mg/kg/week dissolved in 1 ml 0.9% sodium chloride intraperitoneal, lithium-treated received 52.5 mg/kg/day of lithium carbonate dissolved in 1 ml 0.9% sodium chloride orally by gavage, and lithium-and-NAC-treated (group IV) received lithium and NAC in the previous doses. After 12 weeks, the rats of group III showed a significant accumulation of ascites and a decrease in the mean arterial blood pressure and electrocardiographic (ECG) findings of ischemia and arrhythmia. In addition, there was an elevation in cardiac biomarkers creatine kinase MB (CK-MB), cardiac troponin I (cTnI), and several histological lesions with a significant increase in the area % of Van Gieson, endothelial nitric oxide synthase (eNOS), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) immunoreaction. There was significant upregulation of microRNA-1, microRNA-21 (miRNA-21), and microRNA-29 (miRNA-29). MiRNA-21 was strongly positively correlated to the area % of 8-OHdG, while miRNA-29 was strongly positively correlated to the area % of Van Gieson staining. NAC significantly improved the cardiotoxic effects of lithium. Being a nontoxic and safe antioxidant, NAC can be used to ameliorate lithium-induced cardiac injury.


Assuntos
Acetilcisteína/uso terapêutico , Antimaníacos/toxicidade , Antioxidantes/uso terapêutico , Cardiotônicos/uso terapêutico , Cardiotoxicidade/etiologia , Carbonato de Lítio/toxicidade , Acetilcisteína/farmacologia , Animais , Antioxidantes/farmacologia , Cardiotônicos/farmacologia , Cardiotoxicidade/sangue , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/genética , Creatina Quinase Forma MB/sangue , Masculino , MicroRNAs , Miocárdio/patologia , Ratos Wistar , Troponina I/sangue
3.
J Ethnopharmacol ; 247: 112223, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31553926

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Arecae semen has been used as vermifuge and digestant in traditional Chinese medicine (TCM) for more than one thousand years. However, the toxicity effect of areca semen and its underlying mechanism are still unclear. THE AIM OF THE STUDY: This study was aimed to investigate the toxicity of arecae semen and to explore its mechanisms by serum metabolomics. MATERIALS AND METHODS: The male Wistar rats were divided into the control group and treated group (n = 6 in each group), which were given by gavage with distill water or arecae semen aqueous extract (ASAE) once a day for 30 days, respectively. Serum samples were collected from all the rats after treatment of 7-day, 14-day and 30-day for metabolomics analysis. Moreover, biochemistry analysis and histopathological examination were performed at the end of study. RESULTS: The phenomenon of diarrhea, less physical activity, tremors and body curl up were observed in the treated group. Additionally, the body weights of treated rats were significantly decreased compared with control rats from the 8th day after oral administration. Except the level of creatinekinase (CK) in the treated group significantly increased compared with the control group, there were no differences on biochemistry parameters and histopathological test in the two groups. Combined with the methods of principal component analysis (PCA), orthogonal projection to latent structure-discrimination analysis (OPLS-DA) and available databases, the treated and control rats were clearly distinguished from each other and 19 metabolites were identified as the potential biomarkers in the arecae semen treated rats. The identified biomarkers indicated that there were perturbations of the phospholipid metabolism, amino acid metabolism and fat acid metabolism in the treated group. CONCLUSIONS: This indicated that arecae semen possessed certain cardiotoxicity and inhibited the normal growth in Wistar male rats. In addition, the metabolomics approach is a useful tool to study the toxicity in TCM.


Assuntos
Areca/química , Cardiotoxicidade/etiologia , Medicamentos de Ervas Chinesas/toxicidade , Crescimento e Desenvolvimento/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Administração Oral , Aminoácidos/metabolismo , Animais , Anti-Helmínticos/administração & dosagem , Anti-Helmínticos/isolamento & purificação , Anti-Helmínticos/toxicidade , Biomarcadores/sangue , Biomarcadores/metabolismo , Cardiotoxicidade/sangue , Cardiotoxicidade/diagnóstico , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/isolamento & purificação , Fármacos Gastrointestinais/administração & dosagem , Fármacos Gastrointestinais/isolamento & purificação , Fármacos Gastrointestinais/toxicidade , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Metabolômica , Ratos , Ratos Wistar , Sementes/química , Testes de Toxicidade , Água/química
4.
Sci Transl Med ; 11(520)2019 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-31776291

RESUMO

Limb-girdle muscular dystrophy type 2A (LGMD2A or LGMDR1) is a neuromuscular disorder caused by mutations in the calpain 3 gene (CAPN3). Previous experiments using adeno-associated viral (AAV) vector-mediated calpain 3 gene transfer in mice indicated cardiac toxicity associated with the ectopic expression of the calpain 3 transgene. Here, we performed a preliminary dose study in a severe double-knockout mouse model deficient in calpain 3 and dysferlin. We evaluated safety and biodistribution of AAV9-desmin-hCAPN3 vector administration to nonhuman primates (NHPs) with a dose of 3 × 1013 viral genomes/kg. Vector administration did not lead to observable adverse effects or to detectable toxicity in NHP. Of note, the transgene expression did not produce any abnormal changes in cardiac morphology or function of injected animals while reaching therapeutic expression in skeletal muscle. Additional investigation on the underlying causes of cardiac toxicity observed after gene transfer in mice and the role of titin in this phenomenon suggest species-specific titin splicing. Mice have a reduced capacity for buffering calpain 3 activity compared to NHPs and humans. Our studies highlight a complex interplay between calpain 3 and titin binding sites and demonstrate an effective and safe profile for systemic calpain 3 vector delivery in NHP, providing critical support for the clinical potential of calpain 3 gene therapy in humans.


Assuntos
Calpaína/genética , Calpaína/uso terapêutico , Cardiotoxicidade/etiologia , Conectina/genética , Terapia Genética/efeitos adversos , Proteínas Musculares/genética , Proteínas Musculares/uso terapêutico , Distrofia Muscular do Cíngulo dos Membros/genética , Distrofia Muscular do Cíngulo dos Membros/terapia , Processamento de RNA/genética , Animais , Sítios de Ligação , Biomarcadores/sangue , Cardiotoxicidade/sangue , Conectina/química , Dependovirus/genética , Disferlina/deficiência , Disferlina/metabolismo , Estabilidade Enzimática , Regulação da Expressão Gênica , Camundongos Knockout , MicroRNAs/genética , MicroRNAs/metabolismo , Músculo Esquelético/metabolismo , Distrofia Muscular do Cíngulo dos Membros/sangue , Distrofia Muscular do Cíngulo dos Membros/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Primatas , Domínios Proteicos , Proteólise , Especificidade da Espécie , Distribuição Tecidual , Transgenes
5.
Med Ultrason ; 21(4): 449-455, 2019 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-31765454

RESUMO

AIM: The chemotherapy protocol for acute lymphoblastic leukemia (ALL) uses low doses of anthracyclines (AC), generally associated with subclinical cardiotoxicity. The aim of our study was to evaluate the serum biomarkers and echocardiography parameters in children with ALL treated with AC in order to determine the most useful element for early detection of cardiotoxicity. MATERIAL AND METHODS: In this prospective study, troponin I (TnI) and heart-type fatty acid binding protein (HFABP) were assessed five times during the first year after the onset of ALL. Serial Tissue Doppler Imaging and conventional cardiac echography were performed by two pediatric cardiologists (intraclass correlation coefficient over 0.85 for all measurements) in three periods during the study protocol. RESULTS: We evaluated 48 children with ALL. TnI increased during therapy, without returning to baseline values one year after diagnosis. HFABP did not show significant changes during the study protocol. Left ventricle outflow tract time-velocity integral and peak systolic septal mitral annulus velocity decreased during chemotherapy and returned to baseline levels at one year after diagnosis, while peak systolic tricuspid annulus velocity and excursion, maintained a descending tendency. Early filling transmitral flow velocity and E/A ratio were also transiently influenced by chemotherapy. CONCLUSIONS: The study showed signs of transient cardiotoxicity in the left ventricle and diastolic parameters after chemotherapy, compared to right ventricle parameters which maintained low values even one year after diagnosis. TnI proved to be directly proportional to chemotherapy doses but HFABP was not useful in this setting.


Assuntos
Antraciclinas/efeitos adversos , Cardiotoxicidade/sangue , Cardiotoxicidade/etiologia , Proteína 3 Ligante de Ácido Graxo/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Troponina I/sangue , Antraciclinas/uso terapêutico , Biomarcadores/sangue , Cardiotoxicidade/diagnóstico por imagem , Criança , Pré-Escolar , Diagnóstico Precoce , Ecocardiografia , Feminino , Humanos , Lactente , Masculino , Estudos Prospectivos
6.
J Pak Med Assoc ; 69(Suppl 3)(8): S103-S107, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31603888

RESUMO

Objective: To evaluate the cardio-protective effect of Ginkgo Biloba (GB) on doxorubicin induced-cardiotoxicity. Methods: The experimental study was conducted at the College of Medicine, Mustansiriya University, Baghdad, Iraq, from January to March, 2016, and comprised thirty Wistar Sprague male rats aged 3-4 months and weighing 200-400 g. The rats were divided into three equal groups (n=10); Group І (control): rats were treated with distilled water, Group ІІ (doxorubicin): rats were treated with distilled water and doxorubicin 20 mg/kg, and Group ІІІ (GB): rats were treated with GB and doxorubicin 20mg/kg. Serum malondialdehyde (MDA), glutathione reductase (GSH), lipid peroxidise (LPO), tumour necrosis factor-alpha (TNF-α), cardiac troponin (cTnI), brain natriuretic peptide (BNP) and caspase-3 (Cas-3) were measured using enzyme-linked immunosorbent assay kits. SPSS 20 was used to compare the effect GB with doxorubicin on the biomarkers of doxorubicin induced-cardiotoxicity. Results: Doxorubicin led to cardiotoxicity through elevation of cTnI, BNP, Cas-3 and LPO compared with controls (p<0.01).Also, MDA and TNF-α were elevated while; GSH was decreased significantly (p<0.01) compared with controls. Co-administration of GB with doxorubicin led to significant reduction in cTnI, Cas-3 sera levels with elevation in GSH serum level significantly (p<0.05). The effect of GB on BNP, LPO, MDA and TNF-α was insignificant (p>0.05) compared with the doxorubicin. Conclusions: GB has significant cardio-protective effect through attenuation of oxidative stress during doxorubicin induced-cardiotoxicity in rats.


Assuntos
Antioxidantes/uso terapêutico , Cardiotoxicidade/tratamento farmacológico , Doxorrubicina/toxicidade , Ginkgo biloba , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/uso terapêutico , Animais , Antioxidantes/farmacologia , Biomarcadores/sangue , Cardiotoxicidade/sangue , Masculino , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Extratos Vegetais/farmacologia , Ratos , Ratos Wistar
7.
Biomed Pharmacother ; 116: 108964, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31102935

RESUMO

AIM: Doxorubicin (DOX) is an effective chemotherapeutic drug. However, its clinical application may be hampered by dose-dependent cardiotoxicity. Alcohol metabolite and doxorubicinol (DOXol) were the most prominent components in DOX-induced cardiotoxicity. It is necessary to elucidate the level of DOXol in heart in vivo and whether DOXol could cause toxicity at such a concentration. METHODS: The pharmacokinetics and heart distribution of DOX and its second metabolite DOXol were determined in rats. Based on this concentration level in vivo, H9C2 cell was used to examine the cardiotoxicity of DOX and DOXol. Real-time cell viability was determined using the xCelligence system and the membrane-permeable of DOX, and DOXol was also assessed by determining the intracellular and extracellular concentrations. RESULTS: Our data showed that DOX level was higher than DOXol level in heart tissue. DOX had a high level in intracellular H9C2 cell and was the primary cytotoxic agent. DOXol had a significantly low level in heart tissue and less cytotoxicity than that of DOX in H9C2. DOXol in heart could not diffuse from plasma but only form in the heart. DOXol could not enter cell as easy as DOX. The less cardiotoxicity of DOXol might be caused by the less intracellular concentration.


Assuntos
Cardiotoxicidade/metabolismo , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacocinética , Metaboloma , Animais , Cardiotoxicidade/sangue , Cardiotoxicidade/patologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Doxorrubicina/sangue , Concentração Inibidora 50 , Masculino , Ratos Sprague-Dawley
8.
PLoS One ; 14(4): e0214984, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30947243

RESUMO

Type 2 diabetes (T2D) is characterised by ß-cell damage and hyperglycaemia. The lipophilic drug, probucol, has shown significant ß-cell protective and potential antidiabetic effects, which were enhanced by hydrophilic bile acid incorporation using taurocholic acid and chenodeoxycholic acid. However, probucol has severe cardiotoxicity and a variable absorption profile, which limit its potential applications in T2D. Accordingly, this study aimed to design multiple formulations to optimise probucol oral delivery in T2D and test their effects on probucol absorption and accumulation in the heart. Adult male mice were given a high fat diet (HFD), and a week later, injected with a single dose of alloxan to accelerate T2D development, and once diabetes confirmed, divided into three groups (six to seven mice each). The groups were gavaged a daily dose of probucol powder, probucol microcapsules, or probucol-bile acid microcapsules for three months, and euthanized; and blood, tissues, and feces collected for blood glucose and probucol concentration analyses. Probucol concentrations in plasma were similar among all the groups. Groups given probucol microcapsules and probucol-bile acid microcapsules showed significant reduction in probucol accumulation in the heart compared with the group given probucol powder (p<0.05). Probucol microencapsulation with or without bile acids reduced its accumulation in heart tissues, without changing plasma concentrations, which may be beneficial in reducing its cardiotoxicity and optimise its potential applications in T2D.


Assuntos
Diabetes Mellitus Tipo 2 , Probucol , Administração Oral , Animais , Cápsulas , Cardiotoxicidade/sangue , Cardiotoxicidade/prevenção & controle , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Gorduras na Dieta/efeitos adversos , Gorduras na Dieta/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Miocárdio/metabolismo , Probucol/farmacocinética , Probucol/farmacologia
9.
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
10.
Hum Exp Toxicol ; 38(1): 45-55, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29774748

RESUMO

Trazodone (TRZ) is an antidepressant drug commonly used in the treatment of depression, anxiety, and insomnia. Although some studies demonstrated the adverse effects of TRZ related to cardiovascular system, the conflicting results were observed in these studies. Therefore, we aimed to investigate the cardiac adverse effects of TRZ in rats at repeated doses in our study. In accordance with this purpose, TRZ was administered orally to rats at 5, 10, and 20 mg/kg doses for 28 days. Electrocardiogram records, serum aspartate aminotransferase (AST), lactate dehydrogenase, creatine kinase-myoglobin band, cardiac troponin-T (cTn-T) levels, DNA damage in cardiomyocytes, and histologic view of heart tissues were evaluated. In addition, glutathione (GSH) and malondialdehyde (MDA) levels were measured to determine the oxidative status of cardiac tissue after TRZ administration. Heart rate was decreased, PR interval was prolonged, and QRS and T amplitudes were decreased in 20 mg/kg TRZ-administered group compared to the control group. Serum AST and cTn-T levels were significantly increased in 10 and 20 mg/kg TRZ-administered rats with respect to control rats. DNA damage was significantly increased in these groups. Additionally, degenerative histopathologic findings were observed in TRZ-administered groups. Although there was no difference in MDA levels between groups, GSH levels were significantly decreased in 10 and 20 mg/kg TRZ-administered groups compared to the control group. Our results have shown that TRZ induced cardiotoxicity in rats dose-dependently. It is assumed that oxidative stress related to GSH depletion may be accompanied by these adverse effects.


Assuntos
Antidepressivos de Segunda Geração/toxicidade , Cardiotoxicidade , Trazodona/toxicidade , Administração Oral , Animais , Aspartato Aminotransferases/sangue , Cardiotoxicidade/sangue , Cardiotoxicidade/patologia , Cardiotoxicidade/fisiopatologia , Dano ao DNA , Relação Dose-Resposta a Droga , Glutationa/metabolismo , Coração/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Troponina T/sangue
11.
Biomed Pharmacother ; 110: 1-8, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30453253

RESUMO

BACKGROUND: Doxorubicin (DOX) is a chemotherapeutic drug limited in its usefulness by an adverse side effect, cardiotoxicity. The mechanisms leading to this detrimental occurrence are not completely clear, and lately many authors focused their attention on the possible role of microRNAs (miRNAs), small regulators of cardiovascular functions, in this phenomenon. Notably, these molecules recently emerged also as potential circulating biomarkers of several cardiac diseases. Thus, the aim of this study was the simultaneous investigation of circulating and cardiac tissue miRNAs expression upon DOX treatment in vivo. METHODS: Twenty C57BL/6 female mice were administered with 24 mg/Kg cumulative dose of DOX or saline (CTRL) for 2 weeks. Echocardiography was performed at baseline and at the end of treatment (T1). Plasma and heart samples were collected at T1, separating atria from left (LV) and right (RV) ventricles, and miRNAs expression was tested by RT-qPCR-based arrays. All putatively DOX-regulated candidates were then validated by single assays in vivo and then evaluated also in murine immortalized cardiomyocytes (HL-1) treated with 1 µM DOX for 24 h. In the end, bioinformatics target prediction was performed for all DOX-miRNAs. RESULTS: Cardiotoxicity onset was diagnosed upon impairment of six cardiac functional parameters in DOX-treated mice at T1. Samples collection, followed by screening and validation steps, identified eleven miRNAs dysregulated by the drug in plasma, while seven resulted as altered in separate heart chambers. Interestingly, miR-34a-5p and miR-451a showed a dysregulation in both plasma and tissue samples of DOX-administered animals, whereas five additional miRNAs presented chamber specific modulation. Of note, in vitro experiments showed a very modest overlap with in vivo results. Bioinformatics prediction analysis performed on miR-34a-5p and miR-451a identified several putative targets presenting no significant association with cardiotoxicity. Anyhow, the same analyses, conducted by combining all miRNAs regulated by DOX in each heart chamber, evidenced a possible dysregulation of the adherens junctions gene network, known to be involved in the onset and progression of dilated cardiomyopathy, an established detrimental side effect of the drug. CONCLUSIONS: This is the first work investigating miRNAs regulation by DOX both in plasma and heart districts of treated animals. Our results indicate a strong association of miR-34a-5p and miR-451a to DOX-induced cardiotoxicity. In addition, the observed altered expression of diverse miRNAs in separated cardiac chambers hints at a specific response to the drug, implying the existence of different players and pathways leading to dysfunction onset.


Assuntos
Antibióticos Antineoplásicos/toxicidade , Cardiotoxinas/toxicidade , Doxorrubicina/toxicidade , MicroRNAs/biossíntese , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Animais , Biomarcadores/sangue , Biomarcadores/metabolismo , Cardiotoxicidade/sangue , Cardiotoxicidade/patologia , Células Cultivadas , Feminino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Miócitos Cardíacos/patologia
12.
Toxicol Appl Pharmacol ; 363: 164-173, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30517846

RESUMO

Cardiotoxicity is a serious adverse effect of doxorubicin (DOX) treatment in cancer patients. Currently, there is a lack of sensitive biomarkers to predict the risk of DOX-induced cardiotoxicity. Using SOMAmer-based proteomic technology, 1129 proteins were profiled to identify potential early biomarkers of cardiotoxicity in plasma from male B6C3F1 mice given a weekly intravenous dose of 3 mg/kg DOX or saline (SAL) for 2, 3, 4, 6, or 8 weeks (6, 9, 12, 18, or 24 mg/kg cumulative DOX doses, respectively). Also, a group of mice received the cardio-protectant, dexrazoxane (DXZ; 60 mg/kg; intraperitoneal) 30 min before a weekly DOX or SAL dose. Proteomic analysis in plasma collected a week after the last dose showed a significant ≥1.2-fold change in level of 18 proteins in DOX-treated mice compared to SAL-treated counterparts during 8-week exposure. Of these, neurogenic locus notch homolog protein 1 (NOTCH1), von Willebrand factor (vWF), mitochondrial glutamate carrier 2, Wnt inhibitory factor 1, legumain, and mannan-binding lectin serine protease 1 were increased in plasma at 6 mg/kg cumulative DOX dose, prior to the release of myocardial injury marker, cardiac troponin I at 12 mg/kg and higher cumulative doses. These six proteins also remained significantly elevated following myocardial injury or pathology at 24 mg/kg. Pretreatment of mice with DXZ significantly attenuated DOX-induced elevated levels of only NOTCH1 and vWF with mitigation of cardiotoxicity. This suggests NOTCH1 and vWF as candidate early biomarkers of DOX cardiotoxicity, which may help in addressing a clinically important question of identifying cancer patients at risk for cardiotoxicity.


Assuntos
Antibióticos Antineoplásicos/toxicidade , Cardiotoxicidade/sangue , Doxorrubicina/toxicidade , Administração Intravenosa , Animais , Biomarcadores/sangue , Cardiotoxicidade/etiologia , Cardiotoxicidade/prevenção & controle , Dexrazoxano/administração & dosagem , Doxorrubicina/administração & dosagem , Coração/efeitos dos fármacos , Masculino , Camundongos , Miocárdio/patologia , Substâncias Protetoras/administração & dosagem , Proteoma/análise , Proteoma/efeitos dos fármacos , Proteômica , Receptor Notch1/sangue , Medição de Risco/métodos , Fator de von Willebrand/análise
13.
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
14.
Int J Mol Sci ; 19(11)2018 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-30405071

RESUMO

To investigate the toxicity of water and ethanol "Fuzi" (FZ) extracts and to explore the toxicity mechanism in rats. Water and ethanol extracts were prepared. Three groups of rats received the water extract, ethanol extract, or water by oral gavage for seven days. Pathological section staining of heart tissue. Colorimetric analysis was used to determine serum lactate dehydrogenase. The metabolic expression of small molecules in rats was measured by a metabolomics method. Western blotting was used to detect the expression of phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), mammalian target of rapamycin (mTOR), transforming growth factor-ß1 (TGF-ß1), and caspase-3. Immunohistochemistry was used to detect the expression of CTnI, mTOR, and TGF-ß1. The water and ethanol FZ extracts exert cardiotoxic effects via activating the PI3K/Akt/mTOR signaling pathway to induce cardiomyocyte apoptosis.


Assuntos
Cardiotoxicidade/metabolismo , Metabolômica , Extratos Vegetais/toxicidade , Animais , Apoptose , Cardiotoxicidade/sangue , Cardiotoxicidade/patologia , Caspase 3/metabolismo , Etanol , Masculino , Metaboloma , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Troponina I/metabolismo , Água
15.
Medicine (Baltimore) ; 97(38): e12447, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30235730

RESUMO

The current study was to evaluate soluble ST-2 level and left ventricular ejection fraction (LVEF) in patients with breast cancer receiving doxorubicin or trastuzumab treatment for 6 months and determine whether soluble ST-2 level can be used to predictive left ventricular function impairment.Patients who were diagnosed as having breast cancer receiving doxorubicin or trastuzumab or combined therapy were enrolled. Demographic data, prior medical history and related medical therapy, and site and stage of breast cancer information were collected from electronic health record. Fasting blood was used to detect soluble ST-2 and brain natriuretic peptide (BNP) levels before and after 6 months doxorubicin or trastuzumab therapy. Echocardiography was performed before and after 6 months of doxorubicin or trastuzumab therapy.Participants were divided into 3 groups based on tertiary soluble ST-2 level. Compared with 1st tertiary group, patients in the 3rd tertiary group had higher proportion receiving combined therapy (14.3% vs 4.7%, P < .05). Baseline soluble ST-2 level was similar across groups. After 6 months' therapy, soluble ST-2 level was significantly higher in the 3rd tertiary group. Pearson correlation analysis showed that soluble ST-2 level was positively correlated with left ventricular volume and E/e' ratio while negatively correlated with LVEF. Doxorubicin, trastuzumab, combined therapy, soluble ST-2 level, and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker treatment were all independently associated with LVEF change.In breast cancer patients receiving doxorubicin or trastuzumab therapy, soluble ST-2 level can be used to predict cardiac function and structure changes.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Cardiotoxicidade/sangue , Ventrículos do Coração/efeitos dos fármacos , Peptídeo Natriurético Encefálico/sangue , Valor Preditivo dos Testes , Disfunção Ventricular Esquerda/induzido quimicamente , Função Ventricular Esquerda/efeitos dos fármacos , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/sangue , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Cardiotoxicidade/metabolismo , Cardiotoxicidade/fisiopatologia , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Ecocardiografia/métodos , Feminino , Ventrículos do Coração/metabolismo , Ventrículos do Coração/fisiopatologia , Humanos , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/metabolismo , Volume Sistólico/efeitos dos fármacos , Trastuzumab/administração & dosagem , Trastuzumab/efeitos adversos , Trastuzumab/uso terapêutico , Disfunção Ventricular Esquerda/tratamento farmacológico , Disfunção Ventricular Esquerda/fisiopatologia
16.
J Pharmacol Toxicol Methods ; 94(Pt 2): 54-63, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30195582

RESUMO

The isolated rat heart (Langendorff) assay combined with NMR spectroscopy and histology were used to elucidate functional, metabolic, and histological signs of cardiotoxicity resulting from acute exposure to clinically relevant concentrations of doxorubicin and its metabolite dox-ol. Doxorubicin blood concentrations and pharmacokinetic parameters were assessed following a clinically relevant dose of 2 mg/kg in order to select concentrations for isolated heart perfusions. Isolated rat hearts were exposed to 1 or 10 µM of doxorubicin or 0.3 µM dox-ol for at least 60 min using the Langendorff perfusion method. Effects on heart function were monitored using ECGs, left ventricular contraction parameters, and microscopic histology. Cardiac energetics (PCr, ATP, and Pi) were evaluated before, during, and after exposure to doxorubicin/dox-ol in perfused hearts using NMR spectroscopy. Cardiac effects were evident following clinically relevant concentrations of doxorubicin and dox-ol in isolated rat hearts demonstrated by altered heart function, energetic reserve, and microscopic lesions. A cardiac stress test utilizing isoproterenol resulted in enhanced functional response and reductions in PCr in doxorubicin versus vehicle treated hearts indicating possible alterations in the isoproterenol mediated pathway. Dox-ol treated hearts were similar to control with regard to function, but exhibited histologic findings. The use of combined Langendorff/NMR/histology methodologies allowed for comparison of multiple indices of cardiac function at one time in which cardiac effects were evident in multiple parameters. SHORT ABSTRACT: The isolated rat heart assay combined with NMR spectroscopy and histology was used to elucidate functional, metabolic, and histological signs of cardiotoxicity resulting from acute exposure to clinically relevant concentrations of doxorubicin and its metabolite dox-ol. Heart function was altered and microscopic signs of toxicity were evident with dox and dox-ol exposures. The use of combined Langendorff/NMR/histology assays allowed for comparison of multiple indices of cardiac function at one time in which cardiac effects were evident in multiple parameters.


Assuntos
Doxorrubicina/farmacocinética , Doxorrubicina/toxicidade , Coração/efeitos dos fármacos , Coração/fisiologia , Animais , Cardiotoxicidade/sangue , Cardiotoxicidade/metabolismo , Cardiotoxicidade/patologia , Doxorrubicina/análogos & derivados , Doxorrubicina/sangue , Frequência Cardíaca/efeitos dos fármacos , Ventrículos do Coração/patologia , Preparação de Coração Isolado , Espectroscopia de Ressonância Magnética , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , Perfusão , Ratos , Ratos Sprague-Dawley , Testes de Toxicidade/métodos , Testes de Toxicidade/normas
17.
Mol Med Rep ; 18(3): 3229-3241, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30066944

RESUMO

Cordyceps sinensis (CS) is a prominent medicinal herb in traditional Chinese medicine, and fermented CS is frequently used as a substitute for natural CS. Doxorubicin (DOX), an antitumor drug used in chemotherapy, is limited by its poor cardiotoxicity. The aim of the present study was to evaluate the protective effect of fermented CS against DOX­induced cardiotoxicity and the potential underlying mechanisms. Male Sprague­Dawley rats (180­200 g) were randomly assigned to seven different treatment groups: Normal control, DOX control, DOX+captopril (0.05 g/kg), 0.75, 1.5 and 3 g/kg DOX+CS, and the CS (1.5 g/kg) control. Histopathological changes, cardiac energy metabolism, cyclic adenosine monophosphate (cAMP) signaling and the associated mRNA expression of AMP­activated protein kinase (AMPK) were then evaluated. Fermented CS decreased the left ventricular weight index, heart weight index and mortality; however, it increased diastolic blood pressure and mean arterial pressure. In addition, it shortened the duration of the QRS complex and Sα­T segment, decreased serum creatine kinase (CK) and aspartate aminotransferase activity, inhibited histopathological changes and reduced brain natriuretic peptide content. Treatment with fermented CS also increased the activities of superoxide dismutase and glutathione peroxidase, reduced malondialdehyde content, increased the mitochondrial activities of Na+K+­adenosine 5'­triphosphate (ATP) ase, Ca2+Mg2+­ATPase and CK, and increased the creatine phosphate/ATP ratio and AMP/ATP ratio. Furthermore, it decreased the ATP/adenosine 5'­diphosphate (ADP) ratio, upregulated AMPKα2 expression, reduced the activity of serum phosphodiesterases (PDEs) and increased myocardial cAMP content. The results of the present study demonstrated that fermented CS attenuated DOX­induced cardiotoxicity by inhibiting myocardial hypertrophy and myocardial damage, ameliorating systolic function and the antioxidant enzyme system, improving cardiac energy metabolism, depressing the activities of PDEs, and by upregulating the cAMP and AMPK signaling pathways. Thus, fermented CS may be a candidate for the prevention of DOX­induced cardiotoxicity, cardiac energy impairment and against a number of cardiac diseases.


Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Cardiotônicos/uso terapêutico , Cardiotoxicidade/tratamento farmacológico , Cordyceps , Doxorrubicina/efeitos adversos , Fermentação , Coração/efeitos dos fármacos , Animais , Produtos Biológicos/metabolismo , Produtos Biológicos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Cardiotônicos/metabolismo , Cardiotoxicidade/sangue , Cardiotoxicidade/fisiopatologia , Cordyceps/metabolismo , Coração/fisiopatologia , Masculino , Medicina Tradicional Chinesa , Miocárdio/patologia , Distribuição Aleatória , Ratos Sprague-Dawley
18.
Int J Nanomedicine ; 13: 4549-4561, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30127606

RESUMO

Background: Dose-dependent irreversible cardiac toxicity of doxorubicin (DOX) becomes a major obstacle for the clinical use. Nowadays much attention is being paid to combination therapy with DOX and antioxidant agents, which would improve the clinical efficacy by protecting from cardiotoxicity along with the maintained performance as an antitumor drug. With the assistance of nanoscience and polymer engineering, herein a complex polymeric micellar system was developed for co-loading DOX and a premium natural antioxidant curcumin (CUR), and we investigated whether this new formulation for DOX delivery could achieve such a goal. Methods: The dually loaded micelles co-encapsulating DOX and CUR (CPMDC) were prepared through thin-film rehydration by using the amphiphilic diblock copolymer monomethoxy poly(ethylene glycol) (mPEG)-poly(ε-caprolactone) (PCL)-N-t-butoxycarbonyl-phenylalanine (BP) synthesized by end-group modification of mPEG-PCL with BP. Quantitative analysis was conducted by HPLC methods for drugs in micelles or biosamples. Molecular dynamics simulation was performed using HyperChem software to illustrate interactions among copolymer and active pharmaceutical ingredients. The safety and antitumor efficacy were evaluated by in vitro viability of H9C2 cells, and tumor growth inhibition in tumor-bearing mice respectively. The protection effects against DOX-induced cardiotoxicity were investigated according to several physiological, histopathological and biochemical markers concerning systemic and cardiac toxicity. Results: CPMDC were obtained with favorable physicochemical properties meeting the clinical demand, including uniform particle size, fairly high encapsulation efficiency and drug loadings, as well as good drug release profiles and colloidal stability. The result from molecular dynamics simulation indicated a great impact of the interactions among copolymer and small molecules on the ratiometrical co-encapsulation of both drugs. MTT assay of in vitro H9C2 cells viability demonstrated good safety of the CPMDC formulation, which also showed definite signs of decrease in xenograft tumor growth. The studies on pharmacokinetics and tissue distribution further revealed that DOX delivered by CPMDC could result in prolonged systemic circulation and increased DOX accumulation in tumor but decreased level of the toxic metabolite doxorubicinol in heart tissue compared to free DOX alone or the cocktail combination. Conclusion: The findings from present study substantiated that such a complex micellar system codelivering DOX with CUR does produce the effect of killing two birds with one stone via distinctive nanocarrier-modified drug-drug interactions.


Assuntos
Cardiotoxicidade/tratamento farmacológico , Curcumina/administração & dosagem , Curcumina/uso terapêutico , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Micelas , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/química , Cardiotoxicidade/sangue , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Curcumina/farmacocinética , Curcumina/farmacologia , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Feminino , Humanos , Camundongos Endogâmicos C57BL , Tamanho da Partícula , Poliésteres/química , Polietilenoglicóis/química , Polímeros/química , Ratos , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Georgian Med News ; (278): 87-93, 2018 May.
Artigo em Russo | MEDLINE | ID: mdl-29905551

RESUMO

This review is devoted to the urgent problem of cardiology and oncology - the cardiotoxicity of chemotherapy drugs - anthracyclines, which are considered to be one of the most cardiotoxic and cause a variety of cardiotoxic effects. The review also examines the diagnosis, treatment or preventive treatment of this pathology. The urgency of the problem is associated with the possibility of early or late manifestations of cardiotoxicity, manifestations of cardiotoxicity against the background of cross treatment, manifestations of cardiotoxicity against the background of various concomitant diseases. The review identified 9 main categories of cardiovascular complications during chemotherapeutic treatment and presents the types of cardiotoxicity caused by the use of anthracyclines. The issue of heart failure as a manifestation of anthracycline cardiotoxicity and the approaches to early diagnosis of cardiac insufficiency were examined in detail. The recommendations of the European Society of Medical Oncology (ESMO) (2012), the recommendations the European Society of Cardiology (ESC) in 2016 regarding the diagnosis and treatment of these patients are reviewed. An overview of the literature on the treatment and diagnosis of this category of patients is presented, especially with concomitant diseases. Examination of the patients, the timing of the initiation of therapy, preventive treatment, medication correction of heart failure, the doses, the combinations of chemotherapeutic drugs are issues that are recommended for the multidisciplinary team to successfully manage these patients.


Assuntos
Antraciclinas/efeitos adversos , Antineoplásicos/efeitos adversos , Cardiomiopatias/tratamento farmacológico , Cardiotônicos/uso terapêutico , Cardiotoxicidade/tratamento farmacológico , Insuficiência Cardíaca/prevenção & controle , Biomarcadores/sangue , Cardiomiopatias/sangue , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/diagnóstico , Cardiotoxicidade/sangue , Cardiotoxicidade/diagnóstico , Cardiotoxicidade/etiologia , Ecocardiografia , Venenos Elapídicos/sangue , Coração/efeitos dos fármacos , Coração/fisiopatologia , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/diagnóstico , Humanos , Ivabradina/uso terapêutico , Peptídeo Natriurético Tipo C/sangue , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Análise de Sobrevida , Trastuzumab/efeitos adversos , Trimetazidina/uso terapêutico , Troponina I/sangue
20.
Biomed Pharmacother ; 102: 1052-1063, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29710522

RESUMO

This research focuses on screening and evaluation of bioactive constituents in plants through pharmacological assays. In present study, we evaluated phytochemicals, cytotoxic activity, in vivo effect of M. monantha against CCl4 induced toxicity in cardiac and renal tissues and its aphrodisiac potential in rats. Shade dried plant was extracted with methanol. The phytochemical screening indicates the presence of flavonoids and alkaloids. Aphrodisiac study showed improved sexual desire; may be attributed to the presence of saponins that boosts the androgen level. Cytotoxicity of the plant was assessed through brine shrimp lethality assay and nearly all the fractions showed promising results. The in vivo study focused on the protective ability of extract against CCl4-induced oxidative damage in renal and cardiac tissues of rats. Serum analysis revealed that CCl4 intoxication increased the levels of bilirubin and blood urea nitrogen (BUN). Antioxidant enzyme analysis showed that catalase, peroxidase, superoxide dismutase, glutathione-S-transferase, glutathione activity and protein levels declined due to CCl4 induced renal and cardiac toxicity. Moreover, the histopathological studies of both low & high dose plant treated group's revealed glomerular hypertrophy and glomerular congestion in kidney, cardiac degeneration and vacuolization of germinal epithelium induced by CCl4 intoxication. DNA also shows damage showed the toxic nature of the plant.


Assuntos
Medicago/química , Compostos Fitoquímicos/farmacologia , Substâncias Protetoras/farmacologia , Animais , Antioxidantes/metabolismo , Afrodisíacos/farmacologia , Artemia/efeitos dos fármacos , Bilirrubina/metabolismo , Biomarcadores/sangue , Proteínas Sanguíneas/metabolismo , Nitrogênio da Ureia Sanguínea , Cardiotoxicidade/sangue , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/patologia , Morte Celular/efeitos dos fármacos , Ensaio Cometa , Creatinina/metabolismo , Glutationa/metabolismo , Peróxido de Hidrogênio/metabolismo , Rim/efeitos dos fármacos , Rim/enzimologia , Rim/patologia , Nitritos/metabolismo , Compostos Fitoquímicos/uso terapêutico , Extratos Vegetais/farmacologia , Substâncias Protetoras/uso terapêutico , Ratos Sprague-Dawley , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
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