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1.
PLoS One ; 11(8): e0160870, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27513579

RESUMO

BACKGROUND AND PURPOSE: Treatment with triglyceride emulsions of docosahexaenoic acid (tri-DHA) protected neonatal mice against hypoxia-ischemia (HI) brain injury. The mechanism of this neuroprotection remains unclear. We hypothesized that administration of tri-DHA enriches HI-brains with DHA/DHA metabolites. This reduces Ca2+-induced mitochondrial membrane permeabilization and attenuates brain injury. METHODS: 10-day-old C57BL/6J mice following HI-brain injury received tri-DHA, tri-EPA or vehicle. At 4-5 hours of reperfusion, mitochondrial fatty acid composition and Ca2+ buffering capacity were analyzed. At 24 hours and at 8-9 weeks of recovery, oxidative injury, neurofunctional and neuropathological outcomes were evaluated. In vitro, hyperoxia-induced mitochondrial generation of reactive oxygen species (ROS) and Ca2+ buffering capacity were measured in the presence or absence of DHA or EPA. RESULTS: Only post-treatment with tri-DHA reduced oxidative damage and improved short- and long-term neurological outcomes. This was associated with increased content of DHA in brain mitochondria and DHA-derived bioactive metabolites in cerebral tissue. After tri-DHA administration HI mitochondria were resistant to Ca2+-induced membrane permeabilization. In vitro, hyperoxia increased mitochondrial ROS production and reduced Ca2+ buffering capacity; DHA, but not EPA, significantly attenuated these effects of hyperoxia. CONCLUSIONS: Post-treatment with tri-DHA resulted in significant accumulation of DHA and DHA derived bioactive metabolites in the HI-brain. This was associated with improved mitochondrial tolerance to Ca2+-induced permeabilization, reduced oxidative brain injury and permanent neuroprotection. Interaction of DHA with mitochondria alters ROS release and improves Ca2+ buffering capacity. This may account for neuroprotective action of post-HI administration of tri-DHA.


Assuntos
Ácidos Docosa-Hexaenoicos/uso terapêutico , Ácido Eicosapentaenoico/uso terapêutico , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Animais , Cálcio/metabolismo , Ácidos Docosa-Hexaenoicos/metabolismo , Emulsões , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
2.
Scand Cardiovasc J ; 48(6): 343-8, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25130063

RESUMO

OBJECTIVES: Ghrelin is an anabolic hormone that is elevated in heart failure (HF), with resistance to its anabolic effects. This resolves after heart transplantation (HTx). Ghrelin exists in acylated and des-acyl forms, with the acylated form being primarily responsible for endocrine actions. We tested the hypothesis that ghrelin derangements in HF are due to inadequate acylation and that this resolves post transplantation. DESIGN: Plasma levels of des-acyl and acylated ghrelin and acylated/total ratios were assessed in HF (n = 20), post-HTx (n = 35), and healthy controls (n = 4), and correlated with each other and with clinical parameters. RESULTS: Median (interquartile range) of des-acyl ghrelin level, was 167 (121-195) pg/ml in HF versus 149 (130-223) pg/ml in post-HTx, p = NS. Acylated ghrelin level was 76 (51-99) pg/ml versus 13 (0-30) pg/ml, p < 0.001. Acylated/total ratios were 0.33 (0.20-0.47) versus 0.08 (0-0.13), p < 0.001. The correlation between acylated and total ghrelin levels was greater in HF than that in HTx. Acyl ghrelin correlated inversely with body mass index in HF, but not in HTx. CONCLUSION: Acylated ghrelin and the acylated/total ratio were dramatically higher in HF compared with those in HTx. Acylation rather than secretion of ghrelin is upregulated in HF and the resistance to ghrelin's anabolic and appetite-stimulating effects is not at the level of acylation, but downstream at the ghrelin-receptor level.


Assuntos
Grelina , Insuficiência Cardíaca , Transplante de Coração/métodos , Acilação , Idoso , Índice de Massa Corporal , Feminino , Grelina/sangue , Grelina/metabolismo , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Regulação para Cima
3.
PLoS One ; 8(2): e56233, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23437099

RESUMO

We questioned if acute administration of n-3 fatty acids (FA) carried in n-3 rich triglyceride (TG) emulsions provides neuroprotection in neonatal mice subjected to hypoxic-ischemic (H/I) brain injury. We examined specificity of FA, optimal doses, and therapeutic windows for neuroprotection after H/I. H/I insult was induced in C57BL/6J 10-day-old mice by right carotid artery ligation followed by exposure to 8% O(2) for 15 minutes at 37°C. Intraperitoneal injection with n-3-rich TG emulsions, n-6 rich TG emulsions or saline for control was administered at different time points before and/or after H/I. In separate experiments, dose responses were determined with TG containing only docosahexaenoic acid (Tri-DHA) or eicosapentaenoic acid (Tri-EPA) with a range of 0.1-0.375 g n-3 TG/kg, administered immediately after H/I insult. Infarct volume and cerebral blood flow (CBF) were measured. Treatment with n-3 TG emulsions both before- and after- H/I significantly reduced total infarct volume by a mean of 43% when administered 90 min prior to H/I and by 47% when administered immediately after H/I. In post-H/I experiments Tri-DHA, but not Tri-EPA exhibited neuroprotective effects with both low and high doses (p<0.05). Moreover, delayed post-H/I treatment with Tri-DHA significantly decreased total infarct volume by a mean of 51% when administered at 0 hr, by 46% at 1 hr, and by 51% at 2 hr after H/I insult. No protective effect occurred with Tri-DHA injection at 4 hr after H/I. There were no n-3 TG related differences in CBF. A significant reduction in brain tissue death was maintained after Tri-DHA injection at 8 wk after the initial brain injury. Thus, n-3 TG, specifically containing DHA, is protective against H/I induced brain infarction when administered up to 2 hr after H/I injury. Acute administration of TG-rich DHA may prove effective for treatment of stroke in humans.


Assuntos
Ácidos Graxos Ômega-3/uso terapêutico , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Triglicerídeos/uso terapêutico , Animais , Animais Recém-Nascidos , Tempo de Sangramento , Glicemia/metabolismo , Encéfalo/irrigação sanguínea , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/fisiopatologia , Infarto Encefálico/tratamento farmacológico , Infarto Encefálico/patologia , Infarto Encefálico/fisiopatologia , Circulação Cerebrovascular/efeitos dos fármacos , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácidos Docosa-Hexaenoicos/farmacologia , Ácidos Docosa-Hexaenoicos/uso terapêutico , Ácido Eicosapentaenoico/administração & dosagem , Ácido Eicosapentaenoico/farmacologia , Ácido Eicosapentaenoico/uso terapêutico , Emulsões , Ácidos Graxos Ômega-3/administração & dosagem , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Ômega-6/administração & dosagem , Ácidos Graxos Ômega-6/farmacologia , Ácidos Graxos Ômega-6/uso terapêutico , Hipóxia-Isquemia Encefálica/patologia , Hipóxia-Isquemia Encefálica/fisiopatologia , Injeções Intraperitoneais , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Fatores de Tempo , Triglicerídeos/sangue , Triglicerídeos/farmacologia
4.
Curr Opin Clin Nutr Metab Care ; 14(2): 158-67, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21178607

RESUMO

PURPOSE OF REVIEW: With important effects on neuronal lipid composition, neurochemical signaling and cerebrovascular pathobiology, docosahexaenoic acid (DHA), a n-3 polyunsaturated fatty acid, may emerge as a neuroprotective agent against cerebrovascular disease. This paper examines pathways for DHA accretion in brain and evidence for possible roles of DHA in prophylactic and therapeutic approaches for cerebrovascular disease. RECENT FINDINGS: DHA is a major n-3 fatty acid in the mammalian central nervous system and enhances synaptic activities in neuronal cells. DHA can be obtained through diet or to a limited extent via conversion from its precursor, α-linolenic acid (α-LNA). DHA attenuates brain necrosis after hypoxic ischemic injury, principally by modulating membrane biophysical properties and maintaining integrity in functions between presynaptic and postsynaptic areas, resulting in better stabilizing intracellular ion balance in hypoxic-ischemic insult. Additionally, DHA alleviates brain apoptosis, by inducing antiapoptotic activities such as decreasing responses to reactive oxygen species, upregulating antiapoptotic protein expression, downregulating apoptotic protein expression, and maintaining mitochondrial integrity and function. SUMMARY: DHA in brain relates to a number of efficient delivery and accretion pathways. In animal models DHA renders neuroprotection after hypoxic-ischemic injury by regulating multiple molecular pathways and gene expression.


Assuntos
Encéfalo/metabolismo , Ácidos Docosa-Hexaenoicos/metabolismo , Hipóxia-Isquemia Encefálica/metabolismo , Fármacos Neuroprotetores/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácidos Graxos Ômega-3/administração & dosagem , Ácidos Graxos Ômega-3/metabolismo , Humanos , Hipóxia-Isquemia Encefálica/patologia , Hipóxia-Isquemia Encefálica/prevenção & controle , Fármacos Neuroprotetores/administração & dosagem
6.
Eur J Heart Fail ; 11(8): 789-94, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19556330

RESUMO

AIMS: Severe heart failure (HF) is often associated with cachexia that reverses post-heart transplantation (HTx) with frequent development of obesity. Ghrelin is a novel appetite-stimulating hormone. The aim was to determine the role of ghrelin in regulating appetite, food intake, and body composition in HF and post-HTx. METHODS AND RESULTS: We measured serial ghrelin, hunger sensation, caloric intake, and body composition in 12 HF patients awaiting HTx, 12 patients 12.7 +/- 8.6 months post-HTx, and 7 controls. Seven of 12 HF patients were followed for longitudinal analysis post-HTx. Body mass index was 23.1 +/- 3.1 in HF and 31.5 +/- 5.5 post-HTx (P < 0.001). Heart transplantation patients had gained 18.0 +/- 7.7 kg since HTx. Ghrelin area under the curve between controlled meals (control: 186 +/- 39; HF: 264 +/- 71; HTx: 194 +/- 47 ng min/mL, P < 0.007) was higher in HF, but test meal caloric intake (control: 1185 +/- 650; HF: 391 +/- 103; HTx: 831 +/- 309 kcal, P < 0.008) was lower in HF. The longitudinal analysis confirmed these findings. CONCLUSION: Heart failure may be associated with resistance to the appetite-stimulating effects of ghrelin, which may contribute to cachexia. Heart transplantation may be associated with resolution of ghrelin resistance, which may contribute to weight gain. These findings are preliminary and should be confirmed in larger trials.


Assuntos
Resistência a Medicamentos , Grelina , Insuficiência Cardíaca/cirurgia , Transplante de Coração , Receptores de Grelina/efeitos dos fármacos , Adulto , Análise de Variância , Apoptose , Área Sob a Curva , Caquexia , Estudos de Casos e Controles , Estudos Transversais , Ingestão de Energia , Feminino , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade , Projetos Piloto , Índice de Gravidade de Doença , Estatística como Assunto , Fatores de Tempo , Aumento de Peso
7.
Eur J Heart Fail ; 11(5): 525-8, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19380328

RESUMO

AIMS: Severe heart failure (HF) is associated with cachexia; this is often reversed post cardiac transplantation (HTx) with frequent development of obesity. Growth hormone (GH) resistance is common in HF and may contribute to cachexia. Whether GH resistance resolves post HTx is unknown. We aimed to confirm that HF is associated with GH resistance and to test the hypothesis that GH resistance resolves post HTx. METHODS AND RESULTS: We measured GH, insulin-like growth factor-1 (IGF-1), and body composition in 10 HF patients awaiting HTx, in 18 patients 11 +/- 8 months post HTx, and seven controls. Body mass index was 23.5 +/- 3.2 in HF patients and 29.3 +/- 5.7 post HTx. HTx patients had gained 14 +/- 8 kg since HTx. GH was elevated in HF (control: 0.21 +/- 0.25; HF: 1.13 +/- 1.19; HTx: 0.11 +/- 0.13 ng/mL; P < 0.007), while IGF-1 was higher in HTx (control: 114 +/- 57; HF: 94 +/- 52; HTx: 190 +/- 106 ng/mL; P < 0.02). HTx had higher total body and abdominal fat %. CONCLUSION: GH resistance is present in severe HF and resolves post HTx. These findings should be confirmed through larger trials.


Assuntos
Hormônio do Crescimento/sangue , Insuficiência Cardíaca/sangue , Transplante de Coração , Adulto , Composição Corporal/fisiologia , Progressão da Doença , Feminino , Seguimentos , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/cirurgia , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Prognóstico , Radioimunoensaio , Índice de Gravidade de Doença , Fatores de Tempo
8.
J Heart Lung Transplant ; 25(1): 36-41, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16399528

RESUMO

BACKGROUND: Substantial weight gain frequently occurs after cardiac transplant (CT) and increases the risk of secondary disease. It is unclear, however, if weight gain after CT is related to glucocorticoid immunosuppressive therapy. METHODS: A retrospective chart review was performed on the first 200 patients undergoing CT and the first 200 patients undergoing renal transplant (RT) at Columbia Presbyterian Medical Center, starting in January 2000. Patients who survived 1 year and had their weight recorded at transplant were included in the study. Rejection episodes and prednisone treatment was recorded for CT patients. Regression analysis was used to determine predictors of weight gain. RESULTS: A total of 158 CT patients and 128 RT patients were included in the data analysis. The weight of CT patients at time of transplant was (mean +/- SD) 76.3 +/- 14.6 kg and increased by 10.3 +/- 10.6 kg (p < 0.05) by 1-year post-transplant. Pre-transplant weight of the RT patients was 74.1 +/- 20.1 kg; by 1-year post-RT, weight increased by 3.5 +/- 8.6 kg (p < 0.05). The weight gain in CT patients was significantly greater than in the RT patients (p < 0.001). Post-transplant weight change in multiple regression models was related to age, gender (male) and transplant type (cardiac), but not to prednisone dose or pre-transplant weight. CONCLUSIONS: CT results in substantial post-surgical weight gain, which is greater than that observed for RT. Overweight and obesity development was not related to prednisone dose alone. This observation may have important clinical and research implications.


Assuntos
Transplante de Coração , Complicações Pós-Operatórias , Aumento de Peso , Adulto , Fatores Etários , Idoso , Feminino , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais
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