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1.
Mol Med Rep ; 24(4)2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34328199

RESUMO

Myocardial fibrosis is a pathological process characterized by excessive accumulation of extracellular matrix in myocardial interstitial spaces. Myocardial fibrosis is a fundamental process in ventricular remodeling and a primary contributor to the progression of heart failure. Liquiritigenin (LQ) is a flavanone compound with anti­oxidative, anti­carcinogenic, anti­inflammatory and estrogenic properties. The present study aimed to investigate the regulatory potential of LQ treatment in a mouse model of isoprenaline (ISO)­induced cardiac fibrosis and in cultured H9C2 cardiomyocytes stimulated with angiotensin II (Ang II). The treatment of ISO­induced mice with LQ significantly decreased the levels of cardiac injury­related proteins in the serum and ECM accumulation in mouse heart tissues. LQ treatment also effectively alleviated cardiac dysfunction in ISO­treated mice. Further analyses revealed that LQ inhibited ISO­induced collagen formation and activation of the transforming growth factor­ß1 (TGF­ß1)/Smad2 and protein kinase B (AKT)/extracellular signal­regulated kinase (ERK) signaling pathways. As a major pathological event in myocardial fibrosis, the apoptosis of cardiomyocytes has been considered a key mechanism contributing to impaired left ventricle performance. The pretreatment of rat cardiomyocytes with LQ significantly reduced the apoptosis of H9C2 cells, and inhibited Ang II­induced activation of the TGF­ß1/Smad2 and AKT/ERK pathways. In conclusion, the present study revealed that LQ ameliorated ISO­induced myocardial fibrosis in mice and inhibited the apoptosis of cardiomyocytes in vitro by inhibiting the TGF­ß1/Smad2 and AKT/ERK signaling pathways. These results suggested the anti­fibrotic and cardioprotective potential of LQ in fibrosis, thus supporting the use of LQ for the management of cardiomyocyte injury and myocardial fibrosis in patients with cardiac diseases.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fibrose/tratamento farmacológico , Flavanonas/farmacologia , Cardiopatias/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína Smad2/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Angiotensina II/toxicidade , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Fibrose/induzido quimicamente , Flavanonas/uso terapêutico , Cardiopatias/induzido quimicamente , Cardiopatias/patologia , Testes de Função Cardíaca/efeitos dos fármacos , Isoproterenol/toxicidade , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Ratos , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/antagonistas & inibidores , Fator de Crescimento Transformador beta1/antagonistas & inibidores
2.
Biomed Pharmacother ; 138: 111531, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34311530

RESUMO

Heart failure (HF) is the advanced heart disease with high morbidity and mortality. Compound DanShen Dripping Pill (CDDP) is a widely used Traditional Chinese Medicine for cardiovascular disease treatment. Herein, we investigated if CDDP can protect mice against doxorubicin (DOX) or isoprenaline (ISO)-induced HF. After 3 days feeding of normal chow containing CDDP, mice were started DOX or ISO treatment for 4 weeks or 18 days. At the end of treatment, mice were conducted electrocardiogram and echocardiographic test. Blood and heart samples were determined biochemical parameters, myocardial structure and expression of the related molecules. CDDP normalized DOX/ISO-induced heart weight changes, HF parameters and fibrogenesis. The DOX/ISO-impaired left ventricular ejection fraction and fractional shortening were restored by CDDP. Mechanistically, CDDP blocked DOX/ISO-inhibited expression of antioxidant enzymes and DOX/ISO-induced expression of pro-fibrotic molecules, inflammation and cell apoptosis. Additional DOX/ISO-impaired targets in cardiac function but protected by CDDP were identified by RNAseq, qRT-PCR and Western blot. In addition, CDDP protected cardiomyocytes against oxygen-glucose deprivation-induced injuries. Taken together, our study shows that CDDP can protect against myocardial injuries in different models, suggesting its potential application for HF treatment.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Cardiopatias/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Cardiotoxicidade , Linhagem Celular , Modelos Animais de Doenças , Doxorrubicina , Fibrose , Cardiopatias/induzido quimicamente , Cardiopatias/metabolismo , Cardiopatias/patologia , Mediadores da Inflamação/metabolismo , Isoproterenol , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Volume Sistólico/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos
3.
J Toxicol Sci ; 46(5): 199-207, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33952797

RESUMO

Cardiovascular complications have been well documented as the downside to conventional cancer chemotherapy. As a notable side effect of cisplatin (CDDP), cardiotoxicity represents a major obstacle to the successful treatment of cancer. It has been reported that Salvianolic acid B (SalB) possesses cardioprotective quality. However, the effect of SalB on cardiac damage caused by conventional cancer chemotherapy remains unclear. In this study, we clarified the protective effect of SalB on cisplatin-induced heart injury. Furthermore, in H9c2 cells, SalB dramatically reduced cisplatin-induced apoptosis and oxidative stress by modulating the nuclear factor erythroid-2-related factor 2 (Nrf2) signaling pathway. In conclusion, SalB had great potential in mitigating cisplatin-induced cardiac injury. Furthermore, more attention should be placed on natural active compounds containing SalB with antioxidant effects for the treatment of cardiomyopathy.


Assuntos
Antineoplásicos , Antioxidantes/uso terapêutico , Benzofuranos/uso terapêutico , Cisplatino , Cardiopatias/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Antioxidantes/farmacologia , Benzofuranos/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Creatina Quinase Forma MB/sangue , Coração/efeitos dos fármacos , Coração/fisiopatologia , Cardiopatias/induzido quimicamente , Cardiopatias/metabolismo , Cardiopatias/patologia , Heme Oxigenase-1/genética , L-Lactato Desidrogenase/sangue , Masculino , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Miocárdio/patologia , NAD(P)H Desidrogenase (Quinona)/genética , Estresse Oxidativo/efeitos dos fármacos , Ratos , Transdução de Sinais/efeitos dos fármacos , Volume Sistólico/efeitos dos fármacos
4.
Curr Cardiol Rep ; 23(6): 65, 2021 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-33961140

RESUMO

PURPOSE OF REVIEW: In this review, we summarize the major known cardiac toxicities of common chemotherapeutic agents and the role of nuclear cardiac imaging for the surveillance and assessment of cancer therapeutics-related cardiac dysfunction in routine clinical practice. RECENT FINDINGS: Cardiotoxicity from chemotherapy causes a significant mortality and limits potentially life-saving treatment in cancer patients. Close monitoring of cardiac function during chemotherapy is an accepted method for reducing these adverse effects especially in patients with cancer therapeutics-related cardiac dysfunction. Nuclear imaging is a sensitive, specific, and highly reproducible modality for assessment of cardiac function. Nuclear imaging techniques including equilibrium radio nucleotide angiography, myocardial perfusion imaging, and novel experimental molecular imaging are the various objective tools available in addition to conventional echocardiography and cardiac magnetic resonance imaging in the surveillance, assessment, and follow-up of cancer therapeutics-related cardiac dysfunction.


Assuntos
Antineoplásicos , Cardiopatias , Neoplasias , Antineoplásicos/efeitos adversos , Cardiotoxicidade/diagnóstico por imagem , Cardiotoxicidade/etiologia , Ecocardiografia , Cardiopatias/induzido quimicamente , Cardiopatias/diagnóstico por imagem , Humanos , Neoplasias/tratamento farmacológico
5.
J Endocrinol ; 249(3): 209-222, 2021 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-33847279

RESUMO

Currently, there are no conventional treatments for stress-induced cardiomyopathy (SCM, also known as Takotsubo syndrome), and the existing therapies are not effective. The recently discovered G protein-coupled estrogen receptor (GPER) executes the rapid effects of estrogen (E2). In this study, we investigated the effects and mechanism of GPER on epinephrine (Epi)-induced cardiac stress. SCM was developed with a high dose of Epi in adult rats and human-induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs). (1) GPER activation with agonist G1/E2 prevented an increase in left ventricular internal diameter at end-systole, the decrease both in ejection fraction and cardiomyocyte shortening amplitude elicited by Epi. (2) G1/E2 mitigated heart injury induced by Epi, as revealed by reduced plasma brain natriuretic peptide and lactate dehydrogenase release into culture supernatant. (3) G1/E2 prevented the raised phosphorylation and internalization of ß2-adrenergic receptors (ß2AR). (4) Blocking Gαi abolished the cardiomyocyte contractile inhibition by Epi. G1/E2 downregulated Gαi activity of cardiomyocytes and further upregulated cAMP concentration in culture supernatant treated with Epi. (5) G1/E2 rescued decreased Ca2+ amplitude and Ca2+ channel current (ICa-L) in rat cardiomyocytes. Notably, the above effects of E2 were blocked by the GPER antagonist, G15. In hiPSC-CM (which expressed GPER, ß1AR and ß2ARs), knockdown of GPER by siRNA abolished E2 effects on increasing ICa-L and action potential duration in the stress state. In conclusion, GPER played a protective role against SCM. Mechanistically, this effect was mediated by balancing the coupling of ß2AR to the Gαs and Gαi signaling pathways.


Assuntos
Epinefrina/farmacologia , Estradiol/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Animais , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Cardiopatias/induzido quimicamente , Humanos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Interferência de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos beta 1/genética , Receptores Adrenérgicos beta 1/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/genética , Estresse Fisiológico/efeitos dos fármacos
6.
Clin Pediatr (Phila) ; 60(6-7): 279-289, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33896217

RESUMO

The use of electronic vapor products (EVPs) has increased dramatically in the past decade. The objectives of our study were to examine the frequency of EVP use; to identify demographic characteristics, risk-taking behaviors, and beliefs about vaping; and to determine symptoms associated with EVPs among adolescents. A questionnaire addressing these objectives was administered to a convenience sample of subjects aged 12 to 23 years. Among 494 completed questionnaires, 80% of responders were considered experimenters/nonusers (never tried or tried one time) and 20% were considered frequent users (at least once a month). We identified demographic features and risk-taking behaviors associated with EVP use. In the previous 6 months, frequent users were more likely to report headache, cough, sleep disturbances, dehydration, weakness, racing heart, chest pain, and tremors. Our findings provide evidence to support efforts to decrease EVP use through screening, education, and preventative strategies.


Assuntos
Desidratação/induzido quimicamente , Cardiopatias/induzido quimicamente , Debilidade Muscular/induzido quimicamente , Nicotina/efeitos adversos , Transtornos do Sono-Vigília/induzido quimicamente , Tremor/induzido quimicamente , Vaping/efeitos adversos , Adolescente , Adulto , Criança , Estudos Transversais , Feminino , Humanos , Masculino , Estudos Prospectivos , Fatores de Risco , Inquéritos e Questionários , Vaping/patologia , Adulto Jovem
7.
Free Radic Biol Med ; 169: 410-415, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33930514

RESUMO

Redox abnormalities are at the crossroad of cardiovascular diseases, cancer and cardiotoxicity from anticancer treatments. Indeed, disturbances of the redox equilibrium are common drivers of these conditions. Not only is an increase in oxidative stress a fundamental mechanism of action of anthracyclines (which have historically been the most studied anticancer treatments) but also this is at the basis of the toxic cardiovascular effects of antineoplastic targeted drugs and radiotherapy. Here we examine the oxidative mechanisms involved in the different cardiotoxicities induced by the main redox-based antineoplastic treatments, and discuss novel approaches for the treatment of such toxicities.


Assuntos
Antineoplásicos , Cardiopatias , Neoplasias , Antraciclinas/efeitos adversos , Antineoplásicos/efeitos adversos , Cardiotoxicidade , Cardiopatias/induzido quimicamente , Humanos , Neoplasias/tratamento farmacológico , Estresse Oxidativo
8.
Sci Total Environ ; 782: 146866, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-33848856

RESUMO

Ambient PM2.5 has been proved to be an independent risk factor for cardiovascular diseases; however, little information is available on the age-dependent effects of PM2.5 on the cardiovascular system and the underlying mechanisms following chronic exposure. In this study, multi-aged mice were exposed to PM2.5 via the newly developed real-ambient PM2.5 exposure system to investigate age-related effects on the heart after long-term exposure. First, the chemical and physical properties of PM2.5 used in the exposure system were analyzed. The heart rate of conscious mice was recorded, and results showed that exposure of aged mice to PM2.5 for 26 weeks significantly increased heart rate. Histological analysis and ELISA assays indicated that aged mice were more sensitive to PM2.5 exposure in terms of inducing cardiac oxidative stress and inflammation. Furthermore, untargeted metabolomics revealed that taurine was involved with the PM2.5-induced cardiac dysfunction. The reduced taurine concentration in the heart was examined by LC-MS and imaging mass spectrometry; it may be due to the increased p53 expression level, ROS and inflammatory cytokines. These results emphasize the age-dependent effects of PM2.5 on the cardiovascular system and suggest that taurine may be the novel cardiac effect target for PM2.5-induced heart dysfunction in the aged.


Assuntos
Poluentes Atmosféricos , Cardiopatias , Poluentes Atmosféricos/análise , Poluentes Atmosféricos/toxicidade , Animais , Coração , Cardiopatias/induzido quimicamente , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Material Particulado/análise , Material Particulado/toxicidade , Taurina
9.
Am J Hematol ; 96(6): E193-E196, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33661527
10.
BMJ Case Rep ; 14(3)2021 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-33762277

RESUMO

Hydroxychloroquine has been widely prescribed to treat patients with COVID-19 pneumonia. A 73-year-0ld woman with COVID-19 pneumonia was treated with dexamethasone and hydroxychloroquine. Her home medications, citalopram and donepezil, were continued. The ECG prior to starting hydroxychloroquine showed normal sinus rhythm with prolonged corrected QT (QTc) of 497 ms, due to citalopram and donepezil therapy. Repeat ECG on days 3 and 4 of hydroxychloroquine therapy showed significantly prolonged QTc of 557 ms and 538 ms, respectively, despite normal serum electrolytes. All QT-prolonging medications including hydroxychloroquine were discontinued on day 4; however, she suffered a transient torsades de pointes lasting for about 15 s, which resolved before any intervention. QTc improved to 477 ms, after discontinuation of QT-prolonging medications. The patient had QTc prolongation and torsades de pointes due to therapy with multiple QT-prolonging medications. Medicine reconciliation and careful monitoring of QTc may help prevent cardiac complications in patients with COVID-19 treated with hydroxychloroquine.


Assuntos
COVID-19/tratamento farmacológico , Dexametasona/efeitos adversos , Hidroxicloroquina/efeitos adversos , Torsades de Pointes/induzido quimicamente , Idoso , Anti-Infecciosos/efeitos adversos , Anti-Infecciosos/uso terapêutico , Citalopram/efeitos adversos , Citalopram/uso terapêutico , Dexametasona/uso terapêutico , Donepezila/efeitos adversos , Donepezila/uso terapêutico , Quimioterapia Combinada , Eletrocardiografia/métodos , Feminino , Cardiopatias/induzido quimicamente , Cardiopatias/prevenção & controle , Humanos , Hidroxicloroquina/uso terapêutico , Síndrome do QT Longo/induzido quimicamente , SARS-CoV-2
11.
Life Sci ; 274: 119299, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33675899

RESUMO

AIMS: Cardiac fibrosis is a pathological hallmark of progressive heart diseases currently lacking effective treatment. Nicotinamide mononucleotide (NMN), a member of the vitamin B3 family, is a defined biosynthetic precursor of nicotinamide adenine dinucleotide (NAD+). Its beneficial effects on cardiac diseases are known, but its effects on cardiac fibrosis and the underlying mechanism remain unclear. We aimed to elucidate the protective effect of NMN against cardiac fibrosis and its underlying mechanisms of action. MATERIALS AND METHODS: Cardiac fibrosis was induced by isoproterenol (ISO) in mice. NMN was administered by intraperitoneal injection. In vitro, cardiac fibroblasts (CFs) were stimulated by transforming growth factor-beta (TGF-ß) with or without NMN and sirtinol, a SIRT1 inhibitor. Levels of cardiac fibrosis, NAD+/SIRT1 alteration, oxidative stress, and Smad3 acetylation were evaluated by real-time polymerase chain reaction, western blots, immunohistochemistry staining, immunoprecipitation, and assay kits. KEY FINDINGS: ISO treatment induced cardiac dysfunction, fibrosis, and hypertrophy in vivo, whereas NMN alleviated these changes. Additionally, NMN suppressed CFs activation stimulated by TGF-ß in vitro. Mechanistically, NMN restored the NAD+/SIRT1 axis and inhibited the oxidative stress and Smad3 acetylation induced by ISO or TGF-ß. However, the protective effects of NMN were partly antagonized by sirtinol in vitro. SIGNIFICANCE: NMN could attenuate cardiac fibrosis in vivo and fibroblast activation in vitro by suppressing oxidative stress and Smad3 acetylation in a NAD+/SIRT1-dependent manner.


Assuntos
Fibrose/tratamento farmacológico , Cardiopatias/tratamento farmacológico , Isoproterenol/toxicidade , Mononucleotídeo de Nicotinamida/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Proteína Smad3/metabolismo , Acetilação , Animais , Cardiotônicos/toxicidade , Fibrose/induzido quimicamente , Fibrose/metabolismo , Fibrose/patologia , Cardiopatias/induzido quimicamente , Cardiopatias/metabolismo , Cardiopatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-Dawley , Proteína Smad3/química
12.
Life Sci ; 275: 119414, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33774032

RESUMO

Astragaloside IV (AS-IV), the major active constituent purified from Astragalus membranaceus, was previously reported to have protective effects against cardiac dysfunction. However, the underlying mechanism remains unknown. In the present study, we investigated the protective effect of AS-IV on lipopolysaccharide (LPS)-induced cardiac dysfunction and explored the potential mechanism by focusing on miRNA-1 (miR-1) at the animal and cellular levels. A series of methods were used, including echocardiography, flow cytometry, ELISA, immunofluorescence, transmission electron microscopy, RT-PCR, and western blotting. The results showed that both AS-IV and the miR-1 inhibitor improved cardiac dysfunction, reduced heart injury, inhibited apoptosis and autophagy, and regulated the expression of calcium- and mitochondrial energy metabolism-related proteins in the heart tissue of rats treated with LPS. Importantly, AS-IV downregulated the expression of miR-1 mRNA in heart tissue. All effects of AS-IV were at least partly abolished by miR-1 mimics. In the in vitro study, both AS-IV and the miR-1 inhibitor inhibited apoptosis and autophagy and regulated the expression of calcium- and mitochondrial energy metabolism-related proteins in heart cells treated with LPS. Similarly, AS-IV downregulated the expression of miR-1 mRNA in heart cells. All effects of AS-IV on cells were at least partly abolished by miR-1 mimics. Furthermore, miR-1 mimics exhibited effects similar to LPS both in animal and cellular studies. Taken together, these results suggest that AS-IV protects against LPS-induced cardiac dysfunction by inhibiting calcium-mediated apoptosis and autophagy by targeting miR-1, highlighting a new mechanism for the therapeutic effect of AS-IV on cardiac dysfunction.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Cardiotônicos/farmacologia , Cardiopatias/prevenção & controle , Lipopolissacarídeos/efeitos adversos , MicroRNAs/metabolismo , Saponinas/farmacologia , Triterpenos/farmacologia , Animais , Ecocardiografia , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Imunofluorescência , Coração/efeitos dos fármacos , Cardiopatias/induzido quimicamente , Masculino , Microscopia Eletrônica de Transmissão , Miocárdio/metabolismo , Miocárdio/ultraestrutura , Ratos , Ratos Sprague-Dawley
14.
Eur J Pharmacol ; 900: 174013, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-33766620

RESUMO

RATIONALE: Higenamine (HG), is one of the main active components in many widely used Chinese herbs, and a common ingredient of health products in Europe and North America. Several groups, including our own, have previously shown the beneficial effects of HG against cardiomyocyte death during acute ischemic damage. However, the effect of HG on chronic cardiac remodeling, such as cardiac fibrosis, remains unknown. OBJECTIVE: Herein, we aim to investigate the role of HG in cardiac fibrosis in vivo as well as its cellular and molecular mechanisms. METHODS AND RESULTS: Chronic pressure overload with transverse aortic constriction (TAC) significantly increased cardiac hypertrophy, fibrosis, and cardiac dysfunction in mice, which were significantly attenuated by HG. Consistently, cardiac fibrosis induced by the chronic infusion of isoproterenol (ISO), was also significantly reduced by HG. Interestingly, our results showed that HG had no effect on adult mouse CM hypertrophy in vitro. However, HG suppressed the activation of cardiac fibroblasts (CFs) in vitro. Furthermore, TGF-ß1-induced expression of ACTA2, a marker of fibroblast activation, was significantly suppressed by HG. Concomitantly, HG inhibited TGF-ß1-induced phosphorylation of Smad2/3 in CFs. HG also reduced the expression of extracellular matrix molecules such as collagen I and collagen III. To our surprise, the inhibitory effect of HG on CFs activation was independent of the activation of the beta2 adrenergic receptor (ß2-AR) that is known to mediate the effect of HG on antagonizing CMs apoptosis. CONCLUSION: Our findings suggest that HG ameliorates pathological cardiac fibrosis and dysfunction at least partially by suppressing TGF-ß1/Smad signaling and CFs activation.


Assuntos
Alcaloides/farmacologia , Fibrinolíticos/farmacologia , Fibroblastos/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/antagonistas & inibidores , Tetra-Hidroisoquinolinas/farmacologia , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Actinas/antagonistas & inibidores , Agonistas Adrenérgicos beta , Animais , Aorta/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Cardiomegalia/induzido quimicamente , Cardiomegalia/prevenção & controle , Fibrose/prevenção & controle , Cardiopatias/induzido quimicamente , Cardiopatias/prevenção & controle , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico , Isoproterenol , Camundongos , Ratos , Ratos Sprague-Dawley
15.
Mayo Clin Proc ; 96(4): 964-974, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33518408

RESUMO

OBJECTIVE: To investigate the impact of epilepsy on secondary cardiac morbidities and sudden death in patients with epilepsy. PATIENTS AND METHODS: The present cohort study evaluated data obtained from a subset of adult patients listed in the Taiwan National Health Insurance Research Database with an International Classification of Diseases, Ninth Revision, diagnosis code of epilepsy from January 1, 1997, to December 31, 2013; the date of epilepsy diagnosis or antiepilepsy drug prescription was defined as the index date. Patients with cardiac disease prior to the index date were excluded, and the remaining patients were categorized into epilepsy and nonepilepsy groups. Frequency matching was performed to balance the covariates across groups for the comparison of outcomes. The development of myocardial infarction (MI) and arrhythmia and/or the occurrence of sudden death were the outcomes for evaluation. A Cox proportional hazards regression model and competing risk analysis were used to compare the risks of cardiac morbidities and sudden death between groups. RESULTS: The final analysis included a total of 5411 patients with epilepsy and 21,644 participants without epilepsy. The epilepsy group had significantly higher risks for development of MI (hazard ratio [HR], 1.71; 95% CI, 1.62 to 1.81; P<.001) and arrhythmia (HR, 2.11; 95% CI, 1.97 to 2.25; P<.001) and the occurrence of sudden death (HR, 1.83; 95% CI, 1.53 to 2.18; P<.001) compared with the nonepilepsy group. CONCLUSION: Our results indicate that the risks for development of MI and arrhythmia and the occurrence of sudden death were higher in patients with epilepsy. These findings support the hypothesis that epilepsy may lead to secondary cardiac dysfunction and increases the risk of sudden death.


Assuntos
Anticonvulsivantes/efeitos adversos , Morte Súbita Cardíaca/epidemiologia , Epilepsia/complicações , Epilepsia/tratamento farmacológico , Cardiopatias/induzido quimicamente , Cardiopatias/epidemiologia , Cardiopatias/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticonvulsivantes/uso terapêutico , Estudos de Coortes , Morte Súbita Cardíaca/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Taiwan/epidemiologia , Estados Unidos/epidemiologia , Adulto Jovem
16.
Eur J Pharmacol ; 898: 173955, 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33617823

RESUMO

The use of doxorubicin (DOX) as an antineoplastic drug is compromised by its cardiotoxicity risk. Although several mechanisms have been proposed for DOX-induced cardiac dysfunction, there is still increased interest in assessing its effects. Likewise, it is important to find protocols that can prevent or minimize the side effects of DOX without hindering its antitumor activity. Thus, this study was designed to investigate the molecular mechanisms underlying DOX cardiotoxicity, with a special focus on cardiac energy metabolism and the ability of Alda-1 (ALDH2 agonist) to prevent DOX-induced cardiac alterations. We explored the effects of DOX on the histological morphology of the myocardium, on lipid profile, and on the expression of genes related to fatty acid metabolism, in the presence and absence of Alda-1 (8 mg/kg body weight; b.wt.). Two DOX treatment protocols were used: a single dose of DOX (4 mg/kg b.wt.); four doses of DOX (4 mg/kg b.wt.), one dose/week, for 4 weeks. Treatment with DOX caused a progressive injury in the cardiac tissue and an increase in the blood total cholesterol, high-density lipoproteins, very low-density lipoproteins and triglyceride, as well as an up-regulation of FABP4 (DOX and DOX + Alda-1 groups) and Slc27a2 (in DOX-treated animals). Alda-1 administration promoted reduction in the severity of the histopathological injuries (after single dose of DOX) and Slc27a2 overexpression was restored. In conclusion, the study revealed novel insights regarding the development of DOX-mediated cardiomyopathy, indicating a relationship between DOX exposure and FABP4 and Slc27a2 overexpression, and confirmed the cardioprotective effect of Alda-1.


Assuntos
Benzamidas/farmacologia , Benzodioxóis/farmacologia , Doxorrubicina , Metabolismo Energético/efeitos dos fármacos , Cardiopatias/prevenção & controle , Metabolismo dos Lipídeos/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Transcriptoma , Aldeído-Desidrogenase Mitocondrial/genética , Aldeído-Desidrogenase Mitocondrial/metabolismo , Animais , Cardiotoxicidade , Coenzima A Ligases/genética , Coenzima A Ligases/metabolismo , Modelos Animais de Doenças , Metabolismo Energético/genética , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Perfilação da Expressão Gênica , Cardiopatias/induzido quimicamente , Cardiopatias/genética , Cardiopatias/metabolismo , Metabolismo dos Lipídeos/genética , Lipídeos/sangue , Masculino , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos Wistar
17.
Oxid Med Cell Longev ; 2021: 6406318, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33505582

RESUMO

This study was undertaken to evaluate the therapeutic potential effect of pentoxifylline (PTX) against arsenic trioxide (ATO)-induced cardiac oxidative damage in mice. Thirty-six male albino mice were divided into six groups and treated intraperitoneally with normal saline (group 1), ATO (5 mg/kg; group 2), PTX (100 mg/kg; group 3), and different doses of PTX (25, 50, and 100 mg/kg; groups 4, 5, and 6, respectively) with ATO. After four weeks, the blood sample was collected for biochemical experiments. In addition, cardiac tissue was removed for assessment of oxidative stress markers and histopathological changes (such as hemorrhage, necrosis, infiltration of inflammatory cells, and myocardial degeneration). The findings showed that ATO caused a significant raise in serum biochemical markers such as lactate dehydrogenase (LDH), creatine phosphokinase (CPK) and troponin-I (cTnI), glucose, total cholesterol (TC), and triglyceride (TG) levels. In addition to histopathological changes in cardiac tissue, ATO led to the significant increase in cardiac lipid peroxidation (LPO) and nitric oxide (NO); remarkable decrease in the activity of cardiac antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx); and the depletion of the total antioxidant capacity (TAC) and total thiol groups (TTGs). PTX was able to reduce the increased levels of serum cardiac markers (LDH, CPK, cTnI, TC, and TG), cardiac LPO, and improve antioxidant markers (TAC, TTGs, CAT, SOD, and GPx) alongside histopathologic changes. However, no significant changes were observed in elevated serum glucose and cardiac NO levels. In conclusion, the current study showed the potential therapeutic effect of PTX in the prevention of ATO-induced cardiotoxicity via reversing the oxidative stress.


Assuntos
Antioxidantes/farmacologia , Trióxido de Arsênio/toxicidade , Cardiotoxicidade/prevenção & controle , Cardiopatias/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Pentoxifilina/farmacologia , Animais , Antineoplásicos/toxicidade , Cardiotoxicidade/etiologia , Cardiotoxicidade/metabolismo , Cardiotoxicidade/patologia , Cardiopatias/induzido quimicamente , Cardiopatias/metabolismo , Cardiopatias/patologia , Peroxidação de Lipídeos , Masculino , Malondialdeído/metabolismo , Camundongos , Necrose , Óxido Nítrico/metabolismo , Vasodilatadores/farmacologia
18.
Food Chem Toxicol ; 149: 111979, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33450301

RESUMO

Consumption of energy drinks has been associated with adverse cardiovascular effects; however, little is known about the ingredients that may contribute to these effects. We therefore characterized the chemical profiles and in vitro effects of energy drinks and their ingredients on human induced pluripotent stem cell (iPSC)-derived cardiomyocytes, and identified the putative active ingredients using a multivariate prediction model. Energy drinks from 17 widely-available over-the-counter brands were evaluated in this study. The concentrations of six common ingredients (caffeine, taurine, riboflavin, pantothenic acid, adenine, and L-methionine) were quantified by coupling liquid chromatography with a triple quadrupole mass spectrometer for the acquisition of LC-MS/MS spectra. In addition, untargeted analyses for each beverage were performed with a platform combining LC, ion mobility spectrometry and mass spectrometry (LC-IMS-MS) measurements. Approximately 300 features were observed across samples in the untargeted studies, and of these ~100 were identified. In vitro effects of energy drinks and some of their ingredients were then tested in iPSC-derived cardiomyocytes. Data on the beat rate (positive and negative chronotropy), ion channel function (QT prolongation), and cytotoxicity were collected in a dilution series. We found that some of the energy drinks elicited adverse effects on the cardiomyocytes with the most common being an increase in the beat rate, while QT prolongation was also observed at the lowest concentrations. Finally, concentration addition modeling using quantitative data from the 6 common ingredients and multivariate prediction modeling was used to determine potential ingredients responsible for the adverse effects on the cardiomyocytes. These analyses suggested theophylline, adenine, and azelate as possibly contributing to the in vitro effects of energy drinks on QT prolongation in cardiomyocytes.


Assuntos
Bebidas Energéticas/análise , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Cálcio/metabolismo , Diferenciação Celular , Sobrevivência Celular/efeitos dos fármacos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Cardiopatias/induzido quimicamente , Humanos , Medição de Risco
19.
Int J Hematol ; 113(3): 422-429, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33389656

RESUMO

The second-generation proteasome inhibitor carfilzomib produces superior outcomes in relapsed or refractory multiple myeloma (MM). We conducted a single-arm trial of twice-weekly carfilzomib (27 mg/m2)-dexamethasone (Kd27) for relapsed and refractory MM in China. Kd27 was administered in 28-day cycles to 123 patients previously treated with ≥ 2 other regimens, including treatment with bortezomib and an immunomodulatory drug, and refractory to their most recent therapy. Overall response rate (ORR) was the primary endpoint; progression-free survival (PFS) and overall survival (OS) were key secondary endpoints. Primary analysis was conducted when all patients received ≥ 6 cycles of Kd27 or discontinued Kd27. Median age was 60 years; median number of prior regimens was 4; 74% were refractory to proteasome inhibitors and immunomodulatory drugs. ORR was 35.8% (95% CI 27.3-44.9), median PFS was 5.6 (95% CI 4.6-6.5) months, and median OS was 16.6 (95% CI 12.2-NE) months. Grade ≥ 3 adverse events (AEs) occurred in 76.4% of patients. Grade ≥ 3 AEs of interest included hypertension (13.8%), acute renal failure (3.3%), cardiac failure (0.8%), ischemic heart disease (0.0%), and peripheral neuropathy (0.0%); 5.7% of patients discontinued carfilzomib due to AEs. Carfilzomib-dexamethasone produced a clinically meaningful response without new safety findings in Chinese patients with previously treated MM.Trial registration: NCT03029234.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Terapia de Salvação , Injúria Renal Aguda/induzido quimicamente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , China , Terapia Combinada , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Resistencia a Medicamentos Antineoplásicos , Feminino , Cardiopatias/induzido quimicamente , Transplante de Células-Tronco Hematopoéticas , Humanos , Hipertensão/induzido quimicamente , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/terapia , Oligopeptídeos/administração & dosagem , Oligopeptídeos/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Intervalo Livre de Progressão , Recidiva
20.
J Food Sci ; 86(2): 546-562, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33438268

RESUMO

Previous research has shown that the extracts from the Ganoderma lucidum spore (GS) have potentially cardioprotective effects, but there is still abundant room for development in determining its mechanism. In this study, the rat model of cardiac dysfunction was established by intraperitoneal injection of trimethylamine-N-oxide (TMAO), and the extracts of GS (oil, lipophilic components, and polysaccharides) were given intragastrically at a dose of 50 mg/kg/day to screen the pharmacological active components of GS. After 50 days of treatments, we found that the extraction from GS reduced the levels of total cholesterol, triglyceride, and low-density lipoprotein; increased the levels of high-density lipoprotein; and reduced the levels of serum TMAO when compared to the model group (P < 0.05); especially the GS polysaccharides (DT) and GS lipophilic components (XF) exhibited decreases in serum TMAO compared to TMAO-induced control. The results of 16S rRNA sequencing showed that GS could change the gut microbiota, increasing the abundance of Firmicutes and Proteobacteria in the DT-treated group and XF-treated group, while reducing the abundance of Actinobacteria and Tenericutes. Quantitative proteomics analysis showed that GS extracts (DT and XF) could regulate the expression of some related proteins, such as Ucp1 (XF-TMAO/M-TMAO ratio is 2.76), Mpz (8.52), Fasn (2.39), Nefl (1.85), Mtnd5 (0.83), Mtnd2 (0.36), S100a8 (0.69), S100a9 (0.70), and Bdh1 (0.72). The results showed that XF can maintain the metabolic balance and function of the heart by regulating the expression of some proteins related to cardiovascular disease, and DT can reduce the risk of cardiovascular diseases by targeting gut microbiota.


Assuntos
Cardiopatias/induzido quimicamente , Cardiopatias/prevenção & controle , Metilaminas/toxicidade , Reishi/química , Animais , Bactérias/classificação , Bactérias/efeitos dos fármacos , Bactérias/genética , Microbioma Gastrointestinal/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Óxidos/farmacologia , RNA Ribossômico 16S/genética , Ratos , Esporos
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