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1.
Stem Cells ; 42(5): 430-444, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38253331

RESUMO

It has been documented that the uterus plays a key cardio-protective role in pre-menopausal women, which is supported by uterine cell therapy, to preserve cardiac functioning post-myocardial infarction, being effective among females. However, whether such therapies would also be beneficial among males is still largely unknown. In this study, we aimed to fill in this gap in knowledge by examining the effects of transplanted uterine cells on infarcted male hearts. We identified, based on major histocompatibility complex class I (MHC-I) expression levels, 3 uterine reparative cell populations: MHC-I(neg), MHC-I(mix), and MHC-I(pos). In vitro, MHC-I(neg) cells showed higher levels of pro-angiogenic, pro-survival, and anti-inflammatory factors, compared to MHC-I(mix) and MHC-I(pos). Furthermore, when cocultured with allogeneic mixed leukocytes, MHC-I(neg) had lower cytotoxicity and leukocyte proliferation. In particular, CD8+ cytotoxic T cells significantly decreased, while CD4+CD25+ Tregs and CD4-CD8- double-negative T cells significantly increased when cocultured with MHC-I(neg), compared to MHC-I(mix) and MHC-I(pos) cocultures. In vivo, MHC-I(neg) as well as MHC-I(mix) were found under both syngeneic and allogeneic transplantation in infarcted male hearts, to significantly improve cardiac function and reduce the scar size, via promoting angiogenesis in the infarcted area. All of these findings thus support the view that males could also benefit from the cardio-protective effects observed among females, via cell therapy approaches involving the transplantation of immuno-privileged uterine reparative cells in infarcted hearts.


Assuntos
Infarto do Miocárdio , Útero , Infarto do Miocárdio/terapia , Infarto do Miocárdio/patologia , Masculino , Feminino , Animais , Útero/irrigação sanguínea , Camundongos , Camundongos Endogâmicos C57BL , Antígenos de Histocompatibilidade Classe I/metabolismo
2.
Physiol Rep ; 10(15): e15379, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35938295

RESUMO

We examined the beneficial effects of olive oil against heart failure post-myocardial infarction (PMI), induced by coronary artery ligation in rats. Animals were divided into sham and ligated groups and fed either regular chow, olive oil (10% wt/wt), or corn oil (10% wt/wt) and were followed up to 16 weeks. On the echocardiography at 3 days (PMI), in the ligated regular chow (LRC), ligated olive oil (LOO), and ligated corn oil (LCO) left ventricular ejection fraction (LVEF) decrease was 12.14%, 16.42%, and 17.53% from the baseline, respectively. However, only LOO group improved LVEF significantly at 16 weeks PMI and became comparable with all sham groups. Both scar formation and collagen deposition at 16 weeks PMI were less pronounced in the LOO group. Myocardial TNF-α level at 4 weeks of PMI increased by 176%, 11%, and 181% in the LRC, LOO, and LCO groups, respectively. Plasma TNF-α levels in LOO were significantly lower than LRC group after 4 weeks of PMI. Myocardial redox ratio (reduced glutathione/oxidized glutathione) decreased at 4 weeks PMI by 44.4%, 16.4%, and 36.9% in the LRC, LOO, and LCO groups, respectively, compared to the baseline. These changes in the redox ratio at 16 weeks PMI were further exacerbated in the LRC and LCO groups. Lipid hydroperoxides formation increased at 4 weeks PMI by 137.4%, 14.6%, and 97.1% in the LRC, LOO, and LCO groups, respectively. Since coronary artery ligation decreased left ventricular ejection fraction, increased myocardial TNF-α and oxidative stress, and since olive oil was able to inhibit these effects, it is proposed that dietary olive oil modulates cardiac remodeling and heart failure subsequent to myocardial infarction.


Assuntos
Insuficiência Cardíaca , Infarto do Miocárdio , Animais , Óleo de Milho/farmacologia , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/prevenção & controle , Infarto do Miocárdio/prevenção & controle , Miocárdio , Azeite de Oliva/farmacologia , Ratos , Ratos Sprague-Dawley , Volume Sistólico , Fator de Necrose Tumoral alfa/farmacologia , Função Ventricular Esquerda , Remodelação Ventricular
3.
Cells ; 11(14)2022 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-35883625

RESUMO

Clinical evidence suggests that the prevalence of cardiac disease is lower in premenopausal women compared to postmenopausal women and men. Although multiple factors contribute to this difference, uterine stem cells may be a major factor, as a high abundance of these cells are present in the uterus. Uterine-derived stem cells have been reported in several studies as being able to contribute to cardiac neovascularization after injury. However, our studies uniquely show the presence of an "utero-cardiac axis", in which uterine stem cells are able to home to cardiac tissue to promote tissue repair. Additionally, we raise the possibility of a triangular relationship among the bone marrow, uterus, and heart. In this review, we discuss the exchange of stem cells across different organs, focusing on the relationship that exists between the heart, uterus, and bone marrow. We present increasing evidence for the existence of an utero-cardiac axis, in which the uterus serves as a reservoir for cardiac reparative stem cells, similar to the bone marrow. These cells, in turn, are able to migrate to the heart in response to injury to promote healing.


Assuntos
Medula Óssea , Endométrio , Células da Medula Óssea , Endométrio/fisiologia , Feminino , Humanos , Masculino , Células-Tronco , Útero/fisiologia
4.
Arch Osteoporos ; 14(1): 69, 2019 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-31250192

RESUMO

The state of osteoporosis care in Latin America is not well known. The results of our scorecard indicate an urgent need to improve policy frameworks, service provision, and service uptake for osteoporosis in Brazil, Mexico, Colombia, and Argentina. The scorecard serves as an important marker to measure future progress. PURPOSE: We developed a scorecard to summarize key indicators of the burden of osteoporosis and its management in Brazil, Mexico, Colombia, and Argentina. The goal of the scorecard is to reduce the risk of osteoporotic fractures by promoting healthcare policies that will improve patient access to timely diagnosis and treatment. METHODS: We conducted a systematic review of osteoporosis. We also interviewed several key opinion leaders to gather information on government policy, access to fracture risk assessments, and access to medications. We then leveraged a peer-reviewed template, initially applied to 27 European countries, to synthesize the information into a scorecard for Latin America. We presented information according to four main categories: burden of disease, policy framework, service provision, and service uptake and used a traffic light color coding system to indicate high, intermediate, and low risk. RESULTS: The systematic review included 108 references, of which 49 were specific to Brazil. The number of osteoporotic fractures in Brazil, Mexico, Colombia, and Argentina was forecasted to increase substantially (34% to 76% in each country) from 2015 to 2030. In general, policy frameworks, service provision, and service uptake were not structured to support current patients with osteoporosis and did not account for the future increases in fracture burden. Across all four countries, there was inadequate access to programs for secondary fracture prevention and only a small minority of patients received treatment for osteoporosis. CONCLUSIONS: Osteoporosis management, including the rate of post-fracture care, is very poor in Brazil, Mexico, Colombia, and Argentina and needs to be strengthened. Improvements in the rates of care are necessary to curb the debilitating impact of osteoporotic fractures on patients and health systems.


Assuntos
Osteoporose , Fraturas por Osteoporose/prevenção & controle , Argentina , Brasil , Colômbia , Efeitos Psicossociais da Doença , Feminino , Política de Saúde , Acessibilidade aos Serviços de Saúde , Humanos , América Latina , México , Guias de Prática Clínica como Assunto
5.
J Med Econ ; 22(7): 638-644, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30835577

RESUMO

Objective: Osteoporosis is under-diagnosed and under-treated worldwide. Information on the burden of osteoporosis in Latin American countries is limited. This study aimed to estimate the economic burden of osteoporosis in adults aged 50-89 years in Brazil, Mexico, Colombia, and Argentina. Methods: Analyses were conducted using a burden of illness model. Where possible, country-specific model inputs were informed by a systematic review and expert opinion. Osteoporosis-related fracture costs were calculated for hospitalizations, testing, surgeries, prescription drugs, and patient productivity losses. Costs were expressed in 2018 USD for the annual burden, annual burden per 1,000 at risk, and projected 5-year burden. No discounting was applied. Results: Over 840,000 osteoporosis-related fractures were predicted to occur in 2018, amounting to a total annual cost of ∼1.17 billion USD. The total projected 5-year cost was ∼6.25 billion USD. Annual costs were highest in Mexico (411 million USD), followed by Argentina (360 million USD), Brazil (310 million USD), and Colombia (94 million USD). The average burden per 1,000 at risk was greatest in Argentina (32,583 USD), followed by Mexico (16,671 USD), Colombia (8,240 USD), and Brazil (6,130 USD). Conclusions: Over the next 5 years, ∼4,485,352 fractures are anticipated to occur in Brazil, Mexico, Colombia, and Argentina. To control and prevent these fractures, stakeholders must work together to close the care gap. Efforts to identify individuals at high fracture risk, initiate treatment, and improve long-term treatment persistence will be essential in minimizing the financial and patient burden of osteoporosis in Latin America.


Assuntos
Efeitos Psicossociais da Doença , Fixação Interna de Fraturas/economia , Custos de Cuidados de Saúde , Osteoporose/economia , Fraturas por Osteoporose/economia , Idoso , Idoso de 80 Anos ou mais , Argentina/epidemiologia , Brasil/epidemiologia , Colômbia , Feminino , Fixação Interna de Fraturas/métodos , Fixação Interna de Fraturas/estatística & dados numéricos , Humanos , Incidência , América Latina/epidemiologia , Masculino , México , Pessoa de Meia-Idade , Osteoporose/diagnóstico , Osteoporose/epidemiologia , Osteoporose/terapia , Fraturas por Osteoporose/diagnóstico , Fraturas por Osteoporose/epidemiologia , Fraturas por Osteoporose/terapia , Medição de Risco
6.
PLoS One ; 12(7): e0179452, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28678856

RESUMO

We previously reported that Vitamin C (Vit C) protects against doxorubicin (Dox)-induced cardiotoxicity by reducing oxidative stress, p38 mitogen-activated kinase (MAPK) and p53 activation and rescuing cell death in isolated adult cardiomyocytes. The pattern of activation and the role of oxidative stress as well as down-stream mechanisms for such protection remain elusive. Therefore the present study aims to analyze time-dependant generation of reactive oxygen species (ROS) and the activation of stress induced signalling pathways in cardiomyocytes treated with Dox and Vit C. The data provides further understanding of heart pathophysiology in response to Dox at the cellular level, and may help to optimize the timing of various therapeutic approaches. Cardiomyocytes isolated from adult Sprague-Dawley rats were exposed to Dox (10 µM), Vit C (25 µM), and Dox + Vit C for different time intervals up to 24 h. p38-JNK (SB203580) and p53 (pifithrin-α) inhibitors were used to determine the role of each respective signalling protein. Dox administration to cardiomyocytes increased the levels of ROS in a time-dependent manner that followed the activation of stress-induced proteins p53, p38 and JNK MAPKs, culminating in an increase in autophagy and apoptosis markers. Dox-induced increase in ROS was alleviated by Vit C adjuvant treatment at all time-points and this was also correlated with blunting of the activation of the studied signaling pathways leading to the prevention of apoptosis and preservation of cell viability. Protective effect of Vit C against the activation of stress induced proteins, autophagy and apoptosis was mainly attributed to its antioxidant properties even though blockage of p38, JNK and p53 by pharmacological inhibitors also suppressed Dox-induced apoptosis. ROS is defined as a key inducer of cardiomyocyte damage under Dox exposure; Vit C could effectively counteract all Dox-induced changes in cardiomyocytes and may potentially be used as an antioxidant adjuvant therapy to protect against Dox-induced cardiomyopathy.


Assuntos
Ácido Ascórbico/farmacologia , Doxorrubicina/toxicidade , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Antibióticos Antineoplásicos/toxicidade , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Biomarcadores/metabolismo , Western Blotting , Células Cultivadas , Masculino , Miócitos Cardíacos/metabolismo , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Fatores de Tempo
7.
FASEB J ; 30(9): 3069-82, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27221978

RESUMO

This study was performed to investigate how to overcome immunorejection associated with allogeneic stem cell therapy in the infarcted heart. Allogeneic bone marrow mesenchymal stem cell (MSC) differentiation increases major histocompatibility complex II (MHC II) expression, inducing transition from immunoprivileged to immunogenic phenotype. MHC II expression is regulated by the class II transactivator (CIITA). We isolated and characterized mouse and human MSCs and knocked down CIITA expression. Wild-type (WT) or CIITA-knockout (CIITA(-)) mouse MSCs were implanted into infarcted mouse myocardia, and recipient allo-antibody formation, cell survival, and cardiac function were measured. WT mouse and human MSCs that were myogenically differentiated showed increased MHC II and CIITA expression. Differentiated CIITA(-) MSCs lacked MHC II induction and showed reduced cytotoxicity in allogeneic leukocyte coculture. Differentiation of human MSCs increased MHC II expression, which resulted in cytotoxicity in allogeneic leukocyte coculture and was prevented by CIITA small interfering RNA. In contrast to WT MSCs, CIITA(-) MSCs did not initiate recipient allo-antibody formation and instead survived in the injured myocardium and significantly improved ventricular function. Decreasing CIITA expression in allogeneic MSCs abolished MHC II induction during myogenic differentiation and prevented immunorejection of these cells from the infarcted myocardium, which enhanced beneficial functional effects of MSC implantation on myocardial repair.-Huang, X.-P., Ludke, A., Dhingra, S., Guo, J., Sun, Z., Zhang, L., Weisel, R. D., Li, R.-K. Class II transactivator knockdown limits major histocompatibility complex II expression, diminishes immune rejection, and improves survival of allogeneic bone marrow stem cells in the infarcted heart.


Assuntos
Células-Tronco Mesenquimais/fisiologia , Infarto do Miocárdio/terapia , Proteínas Nucleares/metabolismo , Transativadores/metabolismo , Animais , Células da Medula Óssea , Diferenciação Celular , Feminino , Regulação da Expressão Gênica/imunologia , Regulação da Expressão Gênica/fisiologia , Rejeição de Enxerto/imunologia , Humanos , Masculino , Camundongos , Camundongos Knockout , Miocárdio , Proteínas Nucleares/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transplante de Células-Tronco , Transativadores/genética , Transplante Homólogo
8.
J Mol Cell Cardiol ; 94: 32-42, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26996757

RESUMO

BACKGROUND: Mast cells (MCs) dynamically participate in wound healing after myocardial infarction (MI) by releasing cytokines. Indeed, MC-deficient mice undergo rapid left ventricular dilation post-MI. Mesenchymal stem cells (MSCs) are recruited to the injured region following an MI and have potential for cardiac repair. In the current study, we evaluate the effect of MCs on MSC proliferation and myogenic differentiation. METHODS AND RESULTS: MCs were cultured from mouse bone marrow and MC granulate (MCG) was extracted from MCs via freeze-thaw cycles followed by filtration. α-SMA (smooth muscle actin) expression was examined as an indicator of myogenic differentiation. MSC/MC co-culture resulted in decreased MSC differentiation indicated by α-SMA suppression in MSCs. MCG also suppressed α-SMA expression and increased MSC migration and proliferation in a dose-dependent manner. Removal of MCG rescued α-SMA expression and MSC differentiation. Platelet derived growth factor (PDGF) receptor blockade using AG1296 also rescued MSC differentiation even after MCG treatment. Real-time PCR and Western blot showed that MCG exerted its effects on MSCs via downregulation of miR-145 and miR-143, downregulation of myocardin, upregulation of Klf4, and increased Erk and Elk1 phosphorylation. CONCLUSIONS: MCs promote MSC proliferation and migration by suppressing their myogenic differentiation. MCs accomplish this via activation of the PDGF pathway, downregulation of miR-145/143, and modulation of the myocardin-Klf4 axis. These data suggest a potential role for MSC/MC interaction in the infarcted heart where MCs may inhibit MSCs from differentiation and promote their proliferation whereby increased cardiac MSC accumulation promotes eventual cardiac regeneration after MCs cease activity.


Assuntos
Diferenciação Celular , Mastócitos/metabolismo , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Actinas/genética , Actinas/metabolismo , Animais , Biomarcadores , Movimento Celular , Proliferação de Células , Técnicas de Cocultura , Grânulos Citoplasmáticos/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Expressão Gênica , Imunofenotipagem , Fator 4 Semelhante a Kruppel , Masculino , Transplante de Células-Tronco Mesenquimais , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Fosforilação , Fator de Crescimento Derivado de Plaquetas/metabolismo , Regeneração , Transdução de Sinais , Proteínas Elk-1 do Domínio ets/metabolismo
9.
J Mol Cell Cardiol ; 84: 116-28, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25939780

RESUMO

Cell therapy to prevent cardiac dysfunction after myocardial infarction (MI) is less effective in aged patients because aged cells have decreased regenerative capacity. Allogeneic transplanted stem cells (SCs) from young donors are usually rejected. Maintaining transplanted SC immunoprivilege may dramatically improve regenerative outcomes. The uterus has distinct immune characteristics, and we showed that reparative uterine SCs home to the myocardium post-MI. Here, we identify immunoprivileged uterine SCs and assess their effects on cardiac regeneration after allogeneic transplantation. We found more than 20% of cells in the mouse uterus have undetectable MHC I expression by flow cytometry. Uterine MHC I((neg)) and MHC I((pos)) cells were separated by magnetic cell sorting. The MHC I((neg)) population expressed the SC markers CD34, Sca-1 and CD90, but did not express MHC II or c-kit. In vitro, MHC I((neg)) and ((pos)) SCs show colony formation and endothelial differentiation capacity. In mixed leukocyte co-culture, MHC I((neg)) cells showed reduced cell death and leukocyte proliferation compared to MHC I((pos)) cells. MHC I((neg)) and ((pos)) cells had significantly greater angiogenic capacity than mesenchymal stem cells. The benefits of intramyocardial injection of allogeneic MHC I((neg)) cells after MI were comparable to syngeneic bone marrow cell transplantation, with engraftment in cardiac tissue and limited recruitment of CD4 and CD8 cells up to 21 days post-MI. MHC I((neg)) cells preserved cardiac function, decreased infarct size and improved regeneration post-MI. This new source of immunoprivileged cells can induce neovascularization and could be used as allogeneic cell therapy for regenerative medicine.


Assuntos
Coração/fisiopatologia , Regeneração , Transplante de Células-Tronco , Células-Tronco/citologia , Células-Tronco/imunologia , Útero/citologia , Animais , Antígenos Ly/metabolismo , Sobrevivência Celular/genética , Cicatriz/complicações , Cicatriz/patologia , Técnicas de Cocultura , Matriz Extracelular/metabolismo , Feminino , Regulação da Expressão Gênica , Testes de Função Cardíaca , Antígenos de Histocompatibilidade Classe I/metabolismo , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/complicações , Infarto do Miocárdio/genética , Infarto do Miocárdio/fisiopatologia , Infarto do Miocárdio/terapia , Miocárdio/patologia , Neovascularização Fisiológica/genética , Transplante Homólogo , Cicatrização/genética
10.
PLoS One ; 9(11): e111370, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25393402

RESUMO

Canopy FGF signaling regulator 2 (CNPY2) is a FGF21-modulated protein containing a saposin B-type domain. In vitro studies have shown CNPY2 is able to enhance neurite outgrowth in neurons and stabilize the expression of low density lipoprotein receptor in macrophages and hepatocytes. However, no in vivo data are available on the normal expression of CNPY2 and information is lacking on which cell types express this protein in tissues. To address this, the present study examined CNPY2 expression at the mRNA and protein levels. Quantitative PCR and ELISA examination of mouse tissues showed that CNPY2 varies between organs, with the highest expression in the heart, lung and liver. Immunohistochemistry detected CNPY2 in a variety of cell types including skeletal, cardiac and smooth muscle myocytes, endothelial cells and epithelial cells. CNPY2 was also detectable in mouse blood and human and mouse uteri. These data demonstrate CNPY2 is widely distributed in tissues and suggest the protein has biological functions that have yet to be identified. Using these new observations we discuss possible functions of the protein.


Assuntos
Epitélio/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Animais , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Peptídeos e Proteínas de Sinalização Intracelular/genética , Fígado/metabolismo , Pulmão/metabolismo , Proteínas de Membrana/biossíntese , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , RNA Mensageiro/biossíntese
11.
Can J Cardiol ; 30(11): 1299-306, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25092405

RESUMO

Rejuvenation is one of the greatest challenges of modern science. Aging affects every tissue and organ in the body, leading to a deterioration of normal function and inhibition of repair mechanisms. Cell therapy has received much attention for its potential to regenerate organs, but in the context of cardiac repair, the initial clinical trials in aged patients did not replicate the dramatic benefits recorded in preclinical studies with young animals. The benefits of autologous cell therapy are reduced in the elderly, the largest target group for regenerative medicine. Adult stem cell functionality decreases with age which impairs tissue regeneration. In this review we discuss the age-related changes in stem cell function, with particular attention to stem cell therapy in heart disease. We also focus on possible mechanisms of adult stem cell aging and targets for rejuvenation strategies to reverse the aging process. We provide useful insights on how to apply this knowledge to advance cellular therapies for heart disease.


Assuntos
Envelhecimento , Cardiopatias/terapia , Medicina Regenerativa/métodos , Medicina Regenerativa/organização & administração , Rejuvenescimento/fisiologia , Transplante de Células-Tronco , Células-Tronco/fisiologia , Animais , Cardiopatias/patologia , Humanos
12.
Cytokine ; 61(1): 304-14, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23141143

RESUMO

Toll-like receptors (TLRs) are important in a variety of inflammatory diseases including acute cardiac disorders. TLR4 innate signaling regulates the synthesis of anti-inflammatory cytokine, interleukin-10 (IL-10) upon TLR4 agonists' re-stimulation. Anti-apoptotic action of IL-10 in cardiac dysfunction is generally accepted but its protective mechanism through TLR4 is not yet understood. We studied the effect of IL-10 in the activation of TLR4 downstream signals leading to cardiomyocytes survival. IL-10 caused a significant increase in the expression of CD14, MyD88 and TLR4. TLR4 activation led to the translocation of the interferon regulatory factor 3 (IRF3) into the nucleus. Phosphorylation of IRF3 enhanced mRNA synthesis for IL-1ß but not TNF-α and was elevated even after removal of IL-10 stimulation. Furthermore, degradation of inhibitory kappa B (IκB) kinase (Ikk) suggested that IκBß was the main activating kinase for IRF3-regulated NF-κB activation and phosphorylation of p65. Phosphorylated NF-κB p65 was translocated into the nucleus. Concomitantly, an increase in Bcl-xL activity inhibited Bax and the proteolytic activity of caspase 3 as well as a decrease in PARP cleavage. An inhibition of MyD88, modulated the above listed responses to IL-10 as there was a decrease in TLR4 and IRF3 and an increase in TNF-α mRNA. This was associated with a decrease in NF-κB p65, Bcl-xL mRNA and protein levels as well as there was an activation of Bax and PARP cleavage independent of caspase 3 activation. These data in cardiomyocytes suggest that IL-10 induced anti-apoptotic signaling involves upregulation of TLR4 through MyD88 activation.


Assuntos
Interleucina-10/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Miócitos Cardíacos/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Apoptose , Caspase 3/metabolismo , Inibidores de Caspase , Sobrevivência Celular , Células Cultivadas , Quinase I-kappa B/metabolismo , Fator Regulador 3 de Interferon/metabolismo , Interleucina-1beta/genética , Receptores de Lipopolissacarídeos/biossíntese , Masculino , Fator 88 de Diferenciação Mieloide/antagonistas & inibidores , Fosforilação , Poli(ADP-Ribose) Polimerase-1 , Poli(ADP-Ribose) Polimerases/metabolismo , Transporte Proteico , RNA Mensageiro/biossíntese , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/genética , Proteína X Associada a bcl-2/antagonistas & inibidores , Proteína bcl-X/metabolismo
13.
Can J Physiol Pharmacol ; 90(8): 1095-103, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22808939

RESUMO

This study analyzed and compared the content of isoflavones in 2 soy products, the effectiveness of isoflavones as antioxidants, in vitro, and demonstrated the antioxidant effect of a soy diet in rats with myocardial infarction (MI). Isoflavone content was analyzed in soybean hypocotyl (SH) and isolated soy protein (ISP). The quality (TAR) and quantity (TRAP) of antioxidants present in the samples was quantified. The amount of daidzin was higher in SH (9 times) and genistein in ISP (5 times). SH presented a 3-fold increase in TAR, while both products exhibited same TRAP. The rats were fed an ISP diet for 9 weeks. Animals were distributed among 6 treatment groups: (i) Sham Casein; (ii) Infarct Casein < 25%; (iii) Infarct Casein > 25%; (iv) Sham Soy; (v) Infarct Soy < 25%; and (vi) Infarct Soy > 25%. MI was induced 5 weeks after the commencement of the diets. Lipid peroxidation (LPO), antioxidant enzyme activity, and levels of nitrites/nitrates were determined in blood. Rats receiving the ISP diet demonstrated increased activity of antioxidant enzyme activity and nitrite/nitrate content. In addition, the increase in LPO seen in rats subjected to MI was significantly mitigated when the ISP diet was given. These findings suggest a nutritional approach of using a soy-based diet for the prevention of oxidative-stress-related diseases such as heart failure.


Assuntos
Antioxidantes/farmacologia , Isoflavonas/análise , Isoflavonas/farmacologia , Infarto do Miocárdio/dietoterapia , Estresse Oxidativo/efeitos dos fármacos , Proteínas de Soja/química , Proteínas de Soja/uso terapêutico , Animais , Biomarcadores/análise , Biomarcadores/metabolismo , Modelos Animais de Doenças , Genisteína/análise , Hemoglobinas/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Infarto do Miocárdio/sangue , Infarto do Miocárdio/enzimologia , Ratos , Ratos Wistar , Espécies Reativas de Nitrogênio/sangue
14.
Am J Physiol Cell Physiol ; 303(6): C645-53, 2012 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-22763122

RESUMO

Vitamin C (Vit C) has been shown to be protective against doxorubicin (Dox)-induced cardiotoxicity. However, Vit C uptake into cardiomyocytes is poorly understood. Furthermore, whether the antioxidant enzyme reserve is enhanced by Vit C is also not known. The present study investigated an influence of Dox on Vit C transporters, expression of endogenous antioxidant reserve as well as enzymes, oxidative stress, and apoptosis in isolated cardiomyocytes. Cardiomyocytes isolated from adult Sprague-Dawley rats were exposed to control (culture medium 199 alone), Dox (10 µM), Vit C (25 µM), and Vit C + Dox for 24 h. Vit C transporter expression and localization, oxidative stress, antioxidant enzymes, and apoptosis were studied. Expression and localization of sodium-dependent vitamin C transporter-2 (SVCT-2) in the sarcolemma was reduced by Dox, but Vit C supplementation was able to blunt this change. There was a decrease in the expression of antioxidant enzymes glutathione peroxidase (GPx), catalase, and Cu/Zn superoxide dismutase (SOD) due to Dox, but only GPx expression was completely prevented and Cu/Zn SOD was partially rescued by Vit C. Dox-induced decrease in antioxidant reserve and increase in oxidative stress were partially mitigated by Vit C. Dox-induced apoptosis was ameliorated by Vit C. It is suggested that cardioprotection offered by Vit C in Dox-induced cardiomyopathy may involve an upregulation of SVCT-2 transporter followed by a reduction in oxidative stress as well as blunting of cardiomyocyte injury.


Assuntos
Ácido Ascórbico/farmacologia , Regulação para Baixo/fisiologia , Doxorrubicina/toxicidade , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Transportadores de Sódio Acoplados à Vitamina C/antagonistas & inibidores , Animais , Ácido Ascórbico/metabolismo , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Doxorrubicina/antagonistas & inibidores , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Ratos , Ratos Sprague-Dawley , Transportadores de Sódio Acoplados à Vitamina C/biossíntese , Transportadores de Sódio Acoplados à Vitamina C/metabolismo
15.
Exp Physiol ; 97(6): 741-9, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22366564

RESUMO

We investigated the myocardial thioredoxin-1 and hydrogen peroxide concentrations and their association with some prosurvival and pro-apoptotic proteins, during the transition from myocardial infarction (MI) to heart failure in rats. Male Wistar rats were divided into the following six groups: three sham-operated groups and three MI groups, each at at 2, 7 and 28 days postsurgery. Cardiac function was analysed by echocardiography; the concentration of H(2)O(2) and the ratio of reduced to oxidized glutathione were measured spectrophotometrically, while the myocardial immunocontent of thioredoxin-1, angiotensin II, angiotensin II type 1 and type 2 receptors, p-JNK/JNK, p-ERK/ERK, p-Akt/Akt, p-mTOR/mTOR and p-GSK3ß/GSK3ß was evaluated by Western blot. Our results show that thioredoxin-1 appears to make an important contribution to the reduced H(2)O(2) concentration. It was associated with lower JNK expression in the early period post-MI (2 days). However, thioredoxin-1 decreased, while renin-angiotensin system markers and levels of H(2)O(2) increased, over 28 days post-MI, in parallel with some signalling proteins involved in maladaptative cardiac remodelling and ventricular dysfunction. These findings provide insight into the time course profile of endogenous antioxidant adaptation to ischaemic injury, which may be useful for the design of therapeutical strategies targeting oxidative stress post-MI.


Assuntos
Peróxido de Hidrogênio/metabolismo , Infarto do Miocárdio/metabolismo , Tiorredoxinas/metabolismo , Angiotensina II/metabolismo , Animais , Antioxidantes/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Dissulfeto de Glutationa/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Coração/fisiopatologia , Insuficiência Cardíaca/metabolismo , MAP Quinase Quinase 4/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Miocárdio/metabolismo , Estresse Oxidativo/fisiologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Sistema Renina-Angiotensina/fisiologia , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Remodelação Ventricular/fisiologia
16.
Mol Cell Biochem ; 360(1-2): 215-24, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21938406

RESUMO

Understanding the molecular basis of doxorubicin (Dox)-induced cardiomyopathy is crucial to finding cardioprotective strategies. Oxidative stress-mediated pathways are known to contribute to cardiomyocyte apoptosis due to Dox. Improving the antioxidant defenses of cardiomyocytes could be one strategy for cardiac protection. We tested the effects of vitamin C (Vit C), a potent antioxidant, on Dox-induced cardiomyocyte apoptosis. Adult rat cardiomyocytes were incubated for 24 h with Dox (0.01-10 µM), with and without different concentrations of Vit C (5-100 µM). Exposure to Dox (10 µM) resulted in a 98% increase in the production of reactive oxygen species (ROS) and creatine kinase (CK) release, 70% increase in p53 as well as ASK-1 activation, 40% increase in p38 activation, 30% increase in pro-apoptotic Bax over anti-apoptotic Bcl-xl ratio and caspase activation, and about 20% reduction in cell viability. Vit C (25 µM) was able to mitigate Dox-induced changes by decreasing ROS and CK release by 50%, reducing p53 activation by 40%. The increase in ASK-1 and p38 was also significantly mitigated, and apoptosis was reduced while cardiomyocytes viability was improved. This study shows that Dox-induced cardiomyocyte death is mediated by a direct membrane effect as well as intracytoplasmic changes promoting the cardiomyocyte apoptosis. These findings suggest a nutritional approach of using Vit C for preventing Dox-induced cardiotoxicity and better management of cancer patients.


Assuntos
Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Cardiotônicos/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/prevenção & controle , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Creatina Quinase/metabolismo , Relação Dose-Resposta a Droga , Doxorrubicina , Ativação Enzimática , MAP Quinase Quinase Quinase 5/metabolismo , Masculino , Miócitos Cardíacos/enzimologia , Miócitos Cardíacos/metabolismo , Estresse Oxidativo , Permeabilidade , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
17.
Exp Clin Cardiol ; 16(3): 70-4, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22065936

RESUMO

Trastuzumab (Trz) is a monoclonal antibody against the human epidermal growth factor receptor 2 that is found to be overexpressed in 25% to 30% of breast cancer patients. In spite of the therapeutic benefits of Trz, cardiotoxic side effects are still an issue. This effect is potentiated particularly when Trz is administered following doxorubicin (DOX) treatment. Among the various mechanisms that may account for DOX and Trz-induced cardiotoxicity, the role of oxidative stress has gained significant support. The present review discusses the evidence supporting the hypothesis that oxidative stress comes from multiple sources through an increase in the production of reactive oxygen species and/or a decrease in antioxidant defense systems. The adjuvant use of Trz can potentiate cardiomyocyte damage through a 'dual-hit' mechanism, which includes inhibition of the neuregulin-1 survival signalling pathway and angiotensin II-induced activation of NADPH oxidase, with the ability to further increase reactive oxygen species production. Preventive therapies for DOX- and Trz-induced cardiac dysfunction have eluded investigators, but may include the prophylactic use of angiotensin-converting enzyme inhibitors, beta-blockers and use of antioxidants. Thus, a better understanding of the mechanisms leading to this characteristic drug-induced cardiomyopathy, as well as potential cardioprotective strategies is required.

18.
PLoS One ; 6(9): e25009, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21949832

RESUMO

BACKGROUND: We have already reported that TNF-α increases cardiomyocyte apoptosis and IL-10 treatment prevented these effects of TNF-α. Present study investigates the role of Akt and Jak/Stat pathway in the IL-10 modulation of TNF-α induced cardiomyocyte apoptosis. METHODOLOGY/PRINCIPAL FINDINGS: Cardiomyocytes isolated from adult Sprague Dawley rats were exposed to TNF-α (10 ng/ml), IL-10 (10 ng/ml) and TNF-α+IL-10 (ratio 1) for 4 h. Exposure to TNF-α resulted in an increase in cardiomyocyte apoptosis as measured by flow cytometry and TUNEL assay. IL-10 by itself had no effect, but it prevented TNF-α induced apoptosis. IL-10 treatment increased Akt levels within cardiomyocytes and this change was associated with an increase in Jak1 and Stat3 phosphorylation. Pre-exposure of cells to Akt inhibitor prevented IL-10 induced Stat3 phosphorylation. Furthermore, in the presence of Akt or Stat3 inhibitor, IL-10 treatment was unable to block TNF-α induced cardiomyocyte apoptosis. CONCLUSION: It is suggested that IL-10 modulation of TNF-α induced cardiomyocyte apoptosis is mediated by Akt via Stat3 activation.


Assuntos
Apoptose/efeitos dos fármacos , Interleucina-10/farmacologia , Miócitos Cardíacos/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Transcrição STAT3/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Apoptose/fisiologia , Western Blotting , Caspase 3/metabolismo , Células Cultivadas , Citometria de Fluxo , Imunofluorescência , Masculino , Miócitos Cardíacos/citologia , Fosforilação , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Regulação para Cima
19.
Can J Physiol Pharmacol ; 88(3): 233-40, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20393588

RESUMO

Diabetes and its associated complications are major known health disorders. Diabetes mellitus increases the risk of cardiovascular morbidity and mortality by promoting cardiomyopathy. It appears to arise as a result of the diabetic state, at times independent of vascular or valvular pathology. It manifests initially as asymptomatic diastolic dysfunction, which progresses to symptomatic heart failure. The compliance of the heart wall is decreased and contractile function is impaired. The pathophysiology of diabetic cardiomyopathy is incompletely understood but appears to be multifactorial in origin. Several hypotheses have been proposed, including oxidative stress, inflammation, endothelial dysfunction, metabolic derangements, abnormalities in ion homeostasis, alterations in structural proteins, and interstitial fibrosis. Amongst these various mechanisms, an increase in reactive oxygen species, leading to oxidative stress, has received significant experimental support. This review focuses on the role of oxidative stress in the pathogenesis of diabetic cardiomyopathy and the potential of antioxidant therapy.


Assuntos
Cardiomiopatias/metabolismo , Diabetes Mellitus/metabolismo , Estresse Oxidativo/fisiologia , Animais , Antioxidantes/metabolismo , Cardiomiopatias/etiologia , Cardiomiopatias/patologia , Complicações do Diabetes/metabolismo , Complicações do Diabetes/patologia , Diabetes Mellitus/patologia , Produtos Finais de Glicação Avançada/metabolismo , Humanos , Espécies Reativas de Oxigênio/metabolismo
20.
J Cardiovasc Pharmacol ; 55(1): 89-95, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19904214

RESUMO

The study was designed to test whether the ingestion grape juice (GJ) could modulate monocrotaline (MCT)-induced Cor pulmonale resulting from antioxidant properties. Three-week-old male Wistar rats received GJ (10 mL/kg/day) by gavage for 6 weeks. A single injection of MCT (60 mg/kg body weight intraperitoneally) was administered at the end of the third week. Animals were divided in four groups: control, MCT, GJ, and GJ + MCT. MCT promoted a significant increase in right ventricle (36%) and lung (70%) weight to body weight ratio. There was an increase in the right systolic (38%) as well as in the end diastolic (70%) ventricular pressures. MCT caused a significant decrease in lung endothelial nitric oxide synthase (20%) but increase in lipid peroxidation (13%) and catalase (43%). MCT-induced decrease in the endothelial nitric oxide synthase and increase in the right ventricular end diastolic pressure were prevented by GJ, whereas right systolic ventricular pressure and lung weight to body weight ratio were corrected only partially. MCT-induced increase in heart and right ventricle to body weight ratios was not changed by GJ. GJ blunted MCT-induced increase in lipid peroxidation but had no effect on the changes in catalase and superoxide dismutase activities. GJ appears to offer some protection against MCT-induced Cor pulmonale and right ventricle function changes.


Assuntos
Antioxidantes/farmacologia , Bebidas , Doença Cardiopulmonar/tratamento farmacológico , Vitis/química , Animais , Peso Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Peroxidação de Lipídeos/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Monocrotalina/toxicidade , Óxido Nítrico Sintase Tipo III/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Doença Cardiopulmonar/fisiopatologia , Ratos , Ratos Wistar , Pressão Ventricular/efeitos dos fármacos
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