Therapeutic effects of sphingosine kinase inhibitor N,N-dimethylsphingosine (DMS) in experimental chronic Chagas disease cardiomyopathy

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2017-08-16T16:44:20Z No. of bitstreams: 1 Vasconcelos JF Therapeutic effects....pdf: 5296745 bytes, checksum: 1f932cf358f4ef9b9c7ab2a388430048 (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2017-08-16T17:37:48Z (GMT) No. of bitstreams: 1 Vasconcelos JF Therapeutic effects....pdf: 5296745 bytes, checksum: 1f932cf358f4ef9b9c7ab2a388430048 (MD5)Made available in DSpace on 2017-08-16T17:37:49Z (GMT). No. of bitstreams: 1 Vasconcelos JF Therapeutic effects....pdf: 5296745 bytes, checksum: 1f932cf358f4ef9b9c7ab2a388430048 (MD5) Previous issue date: 2017National Council for Scientific and Technological Development (CNPq) and Bahia Research Foundation (FAPESB).Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Hospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, Brasil / Universidade Salvador. Escola de Ciências da Saúde. Salvador, BA, BrasilFundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Hospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, BrasilHospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, BrasilHospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, BrasilHospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, BrasilHospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, Brasil / Universidade Federal de Bahia. Instituto de Ciências da Saúde. Departamento de Bioquímica e Biofísica. Salvador, BA, BrasilUniversidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Centro de Ciências da Saúde. Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, BrasilHospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, BrasilFundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Hospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, BrasilFundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Hospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, BrasilChagas disease cardiomyopathy is a parasite-driven inflammatory disease to which there are no effective treatments. Here we evaluated the therapeutic potential of N,N-dimethylsphingosine(DMS), which blocks the production of sphingosine-1-phosphate(S1P), a mediator of cellular events during inflammatory responses, in a model of chronic Chagas disease cardiomyopathy. DMS-treated, Trypanosoma cruzi-infected mice had a marked reduction of cardiac inflammation, fibrosis and galectin-3 expression when compared to controls. Serum concentrations of galectin-3, IFNγ and TNFα, as well as cardiac gene expression of inflammatory mediators were reduced after DMS treatment. The gene expression of M1 marker, iNOS, was decreased, while the M2 marker, arginase1, was increased. DMS-treated mice showed an improvement in exercise capacity. Moreover, DMS caused a reduction in parasite load in vivo. DMS inhibited the activation of lymphocytes, and reduced cytokines and NO production in activated macrophage cultures in vitro, while increasing IL-1β production. Analysis by qRT-PCR array showed that DMS treatment modulated inflammasome activation induced by T. cruzi on macrophages. Altogether, our results demonstrate that DMS, through anti-parasitic and immunomodulatory actions, can be beneficial in the treatment of chronic phase of T. cruzi infection and suggest that S1P-activated processes as possible therapeutic targets for the treatment of Chagas disease cardiomyopathy

Administration of granulocyte-colony stimulating factor accompanied with a balanced diet improves cardiac function alterations induced by high fat diet in mice.

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2016-03-23T16:29:20Z No. of bitstreams: 1 Daltro PS Administration.pdf: 1867804 bytes, checksum: fcda37c5e209578598c6bc17baa39bdb (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2016-03-23T16:47:24Z (GMT) No. of bitstreams: 1 Daltro PS Administration.pdf: 1867804 bytes, checksum: fcda37c5e209578598c6bc17baa39bdb (MD5)Made available in DSpace on 2016-03-23T16:47:24Z (GMT). No. of bitstreams: 1 Daltro PS Administration.pdf: 1867804 bytes, checksum: fcda37c5e209578598c6bc17baa39bdb (MD5) Previous issue date: 2015Hospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilHospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilHospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilHospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilHospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, BrasilHospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilHospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilBackground/Objectives: High fat diet (HFD) is a major contributor to the development of obesity and cardiovascular diseases due to the induction of cardiac structural and hemodynamic abnormalities. We used a model of diabetic cardiomyopathy in C57Bl/6 mice fed with a HFD to investigate the effects of granulocyte-colony stimulating factor (G-CSF), a cytokine known for its beneficial effects in the heart, on cardiac anatomical and functional abnormalities associated with obesity and type 2 diabetes. Methods: Groups of C57Bl/6 mice were fed with standard diet (n = 8) or HFD (n = 16). After 36 weeks, HFD animals were divided into a group treated with G-CSF + standard diet (n = 8) and a vehicle control group + standard diet (n = 8). Cardiac structure and function were assessed by electrocardiography, echocardiography and treadmill tests, in addition to the evaluation of body weight, fasting glicemia, insulin and glucose tolerance at different time points. Histological analyses were performed in the heart tissue. Results: HFD consumption induced metabolic alterations characteristic of type 2 diabetes and obesity, as well as cardiac fibrosis and reduced exercise capacity. Upon returning to a standard diet, obese mice body weight returned to non-obese levels. G-CSF administration accelerated the reduction in of body weight in obese mice. Additionally, G-CSF treatment reduced insulin levels, diminished heart fibrosis, increased exercise capacity and reversed cardiac alterations, including bradycardia, elevated QRS amplitude, augmented P amplitude, increased septal wall thickness, left ventricular posterior thickening and cardiac output reduction. Conclusion: Our results indicate that G-CSF administration caused beneficial effects on obesity-associated cardiac impairment