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1.
J Physiol Pharmacol ; 67(1): 121-8, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27010901

RESUMO

Prolactin-releasing peptide (PrRP) is an anorexigenic neuropeptide expressed in the brain where it regulates food intake and energy expenditure. The C-terminal Arg-Phe-NH2 of PrRP is crucial for its biological activity. In our previous study, we showed that PrRP analogs myristoylated or palmitoylated at the N- terminus seem to cross the blood-brain barrier and lower food intake following peripheral administration. In this study, myristoylated and palmitoylated PrRP31 analogs with a modified C-terminal Phe were designed and tested. Lipidized analogs containing Phe(31) replaced by aromatic non-coded amino acids or tyrosine revealed high binding affinity to rat pituitary RC-4B/C cells with endogenous PrRP and neuropeptide FF 2 receptors and to CHO-K1 cells overexpressing either PrRP or neuropeptide FF 2 receptors. The analogs also showed strong agonistic properties at the GPR10 receptor using the beta-lactamase reporter gene assay. Moreover, lipidized PrRP analogs, especially those that were palmitoylated, demonstrated strong and long-lasting anorexigenic effects in fasted mice after subcutaneous administration. The most efficient PrRP31 analogs with PheCl2(31), either palmitoylated or myristoylated at the N-terminus, are promising candidates for the study of food disorders, possibly for anti-obesity treatment. Despite the therapeutic potential in targeting central GPR10, the endogenous ligand PrRP cannot cross the blood-brain barrier. Understanding biological activity and transport of novel structural analogs of PrRP with a potential central anorexigenic effect is of key therapeutic significance.


Assuntos
Neuropeptídeos/farmacologia , Hormônio Liberador de Prolactina/análogos & derivados , Hormônio Liberador de Prolactina/farmacologia , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Células CHO , Linhagem Celular , Cricetulus , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Lipídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuropeptídeos/metabolismo , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Hormônio Liberador de Prolactina/metabolismo , Ratos , Receptores de Neuropeptídeos/metabolismo
2.
Nutr Diabetes ; 5: e183, 2015 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-26524638

RESUMO

BACKGROUND: Omentin-1 is an anti-inflammatory adipokine produced preferentially by visceral adipose tissue. Plasma levels of omentin-1 are decreased in obesity and other insulin-resistant states. Insulin resistance contributes to the changes of cholesterol synthesis and absorption as well. The aim of this study was to characterise omentin-1 plasma levels in obese patients with diabetes mellitus type 1 during weight reduction, and to elucidate the relationship between cholesterol metabolism and omentin-1. METHODS: Plasma levels of omentin-1 were measured in obese type 1 diabetics (n=14, body mass index >30 kg m(-2), age 29-62 years) by enzyme-linked immunosorbent assay (BioVendor). Gas chromatography with flame ionisation detector (Fisons Plc.,) was used to measure squalene and non-cholesterol sterols-markers of cholesterol synthesis and absorption (phase I). Measurements were repeated after 1 month (phase II; 1 week of fasting in the hospital setting and 3 weeks on a diet containing 150 g saccharides per day) and after 1 year (phase III) on a diet with 225 g saccharides per day. RESULTS: Omentin-1 plasma levels were stable during phases I and II, but significantly increased (P<0.001) during phase III. Omentin-1 plasma dynamics were significantly associated with plasma levels of high-density lipoprotein (P=0.005) and triacylglycerols (P=0.01), as well as with lathosterol (P=0.03). CONCLUSION: Omentin-1 plasma levels significantly increased during the weight reduction programme. Omentin-1 plasma dynamics suggest a close relationship with cholesterol metabolism.

3.
Int J Obes (Lond) ; 39(6): 986-93, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25771926

RESUMO

OBJECTIVES: Obesity is a frequent metabolic disorder but an effective therapy is still scarce. Anorexigenic neuropeptides produced and acting in the brain have the potential to decrease food intake and ameliorate obesity but are ineffective after peripheral application. We have designed lipidized analogs of prolactin-releasing peptide (PrRP), which is involved in energy balance regulation as demonstrated by obesity phenotypes of both PrRP- and PrRP-receptor-knockout mice. RESULTS: Lipidized PrRP analogs showed binding affinity and signaling in PrRP receptor-expressing cells similar to natural PrRP. Moreover, these analogs showed high binding affinity also to anorexigenic neuropeptide FF-2 receptor. Peripheral administration of myristoylated and palmitoylated PrRP analogs to fasted mice induced strong and long-lasting anorexigenic effects and neuronal activation in the brain areas involved in food intake regulation. Two-week-long subcutaneous administration of palmitoylated PrRP31 and myristoylated PrRP20 lowered food intake, body weight and improved metabolic parameters, and attenuated lipogenesis in mice with diet-induced obesity. CONCLUSIONS: Our data suggest that the lipidization of PrRP enhances stability and mediates its effect in central nervous system. Strong anorexigenic and body-weight-reducing effects make lipidized PrRP an attractive candidate for anti-obesity treatment.


Assuntos
Fármacos Antiobesidade/farmacologia , Lipídeos/química , Obesidade/prevenção & controle , Hormônio Liberador de Prolactina/farmacologia , Animais , Regulação do Apetite , Ingestão de Alimentos , Metabolismo Energético , Meia-Vida , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hormônio Liberador de Prolactina/análogos & derivados , Transdução de Sinais
4.
Physiol Res ; 64(2): 221-8, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25317681

RESUMO

The aim of this study was to explore the changes in the adipokines leptin and adiponectin in obese patients with type 1 diabetes mellitus (T1DM) who underwent seven days of fasting and 21 days of low-calorie diet (LCD). The plasma leptin and adiponectin concentrations were measured in 14 obese patients with T1DM at baseline, immediately after 7 days of fasting, and after 21 days of LCD. 13 non-obese patients with T1DM were studied only after an overnight fasting. Bioimpedance technique was used for determination of body composition. Obese T1DM patients lost 6.0 kg (6.0; 6.8) (median, 25 %; 75 %) and decreased their fat tissue after fasting and LCD. Plasma leptin in obese T1DM was significantly higher than in non-obese T1DM patients: 9.10 (5.06; 25.89) vs. 1.71 (1.12; 7.08) microg . l(-1) and transiently decreased immediately after fasting: 3.45 microg . l(-1) (1.47; 7.00), (P<0.05). Adiponectin/leptin ratio in obese T1DM was significantly lower than in non-obese T1DM patients: 0.67 (0.57; 1.49) vs. 3.50 (2.46; 6.30) . 10(3) and transiently increased immediately after fasting: 2.22 (1.26; 3.24) . 10(3), (P<0.05). We conclude that obese patients with T1DM are characterized by hyperleptinemia that is reduced by prolonged fasting, but only slightly affected by low calorie diet.


Assuntos
Adiponectina/sangue , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/complicações , Leptina/sangue , Obesidade/sangue , Obesidade/etiologia , Redução de Peso , Tecido Adiposo/patologia , Adulto , Composição Corporal , Restrição Calórica , Diabetes Mellitus Tipo 1/dietoterapia , Jejum , Ácidos Graxos não Esterificados/sangue , Feminino , Glucose/metabolismo , Técnica Clamp de Glucose , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
5.
Physiol Res ; 62(3): 267-76, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23489182

RESUMO

Obesity in T1DM patients is associated with the components of metabolic syndrome. The influence of controlled fasting and low calorie diet (LCD) on insulin sensitivity and glucose metabolism was studied in 14 obese patients with type 1 diabetes mellitus (T1DM) (42.6+/-9.4 years, BMI 32.4+/-2.1 kg m(-2)). Insulin sensitivity in obese T1DM patients was measured using a hyperinsulinemic-euglycemic clamp before fasting, immediately after 7 days of fasting, and after 21 days of LCD. Glucose oxidation and non-oxidative glucose disposal were measured before and during the clamp by indirect calorimetry. In the control group of 13 of non-obese T1DM patients (36.9+/-13.9 years, BMI 22.6+/-2.1 kg m(-2)), only one hyperinsulinemic-euglycemic clamp was performed. Obese T1DM patients lost 6.1+/-1.1 kg after fasting and maintained reduction in body weight after 21 days of LCD. Fasting transiently reduced insulin-mediated glucose disposal in the clamp (from 9.69+/-1.48 to 6.78+/-1.21 mg min(-1) kg(-1), P<0.001). This was caused by reduced glucose oxidation after the fasting period (from 2.81+/-0.52 to 0.88+/-0.98 mg min(-1) kg(-1), P<0.001). We conclude that one week of fasting transiently decreased insulin-mediated glucose disposal in T1DM patients. This was caused by reduced glucose oxidation.


Assuntos
Glicemia/metabolismo , Restrição Calórica/métodos , Diabetes Mellitus Tipo 1/metabolismo , Jejum/metabolismo , Resistência à Insulina , Insulina/sangue , Obesidade/metabolismo , Adulto , Diabetes Mellitus Tipo 1/complicações , Feminino , Humanos , Masculino , Obesidade/complicações
6.
Vnitr Lek ; 57(11): 970-4, 2011 Nov.
Artigo em Tcheco | MEDLINE | ID: mdl-22165706

RESUMO

Current model of metabolic and nutritional disorders management utilizes modern techniques that promote some of the nutritional techniques to pharmacoteherapy. This approach is demonstrated on an example of multiple organ failure and systemic inflammatory reaction managed with pharmacologically active nutritional substrates, such as arginine, glutamine, taurine, threonine and cysteine. Treatment of sarcopenia in older age is also discussed. Personalized nourishment as a component part of a wider term personalized medicine represents a new approach that requires recognition of individual differences in human genome and its expression. However, this approach also requires a change of attitude towards laboratory diagnostics and clinical practice, with patients and clinical prediction as the focal point. From this perspective, there is a need to replace current traditional laboratory tests with a new system that utilizes molecular biology and bioinformatics.


Assuntos
Suplementos Nutricionais , Necessidades Nutricionais , Medicina de Precisão , Humanos , Insuficiência de Múltiplos Órgãos/terapia , Sarcopenia/terapia
7.
Vnitr Lek ; 57(5): 441-50, 2011 May.
Artigo em Tcheco | MEDLINE | ID: mdl-21695924

RESUMO

OBJECTIVE: The aim of the study was to elucidate the role and importance of hypocholesterolemia in clinically serious conditions. It was a monocentric, prospective clinical study. MATERIAL AND METHODS: Two groups of patients were recruited to the study--one group were patients with coronary heart disease (CHD), who underwent miniinvasive cardiosurgical operation without extracorporeal circulatio (n = 17) and one group of patients, who sustain polytrauma (n = 19). Thirty six patients were recruited into the study. We performed the determination of sterols (total cholesterol, HDL-cholesterol, LDL-cholesterol, triacylglycerols), and their precursors (beta-sitosterol, campesterol, lathosterol, skvalen), interleukin IL-6 and cortisol in the blood serum. The short version of ACTH stimulation test was performed. The oxidative burst of granulocytes was evaluated. The blood samples were taken on the day of admission, the first, the fourth and the eighth post-operative and post-traumatic day. RESULTS: There was a significant decline of total cholesterol (TC) and LDL-cholesterol level with full recovery during observed period. There was a decline of cholesterol synthesis (lathosterol and lathosterol/cholesterol ratio) together with a decline of total cholesterol. There was a significantly negative correlation between IL-6 level and total cholesterol. Despite no confirmation of disturbance of adrenal function, there was a significantly positive correlation between lathosterol/cholesterol ratio (a de novo cholesterol synthesis marker) and cortisol level after the ACTH stimulation test. There was a significant breakdown of bactericidal function of granulocytes along with a decline of cholesterol level. CONCLUSION: There was decline of endogenous cholesterol synthesis in clinically serious conditions. The cholesterol synthesis rate is negatively influenced by IL-6 level. The rate of endogenous cholesterol synthesis positively correlated with cortisol production by the adrenals and with bactericidal function of granulocytes.


Assuntos
Colesterol/biossíntese , Doença das Coronárias/cirurgia , Traumatismo Múltiplo/metabolismo , Estresse Fisiológico , Adulto , Idoso , Colesterol/sangue , Doença das Coronárias/metabolismo , Feminino , Humanos , Hidrocortisona/metabolismo , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade
8.
Physiol Res ; 58 Suppl 1: S13-S17, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19857031

RESUMO

Various reactive oxygen species (ROS) may be produced from normal biochemical, essential metabolic processes or from external sources as exposure to a variety of agents presented in the environment. Lipids, proteins, carbohydrates and DNA are all capable of reacting with ROS and can be implicated in etiology of various human disorders (rheumatoid arthritis, reperfusion injury, atherosclerosis, lung diseases etc.). In the organism damage by ROS is counteracted with natural antioxidants (glutathione peroxidases, superoxide dismutases, catalase, glutathione, ubiquinol, uric acid, and essential minerals) and nutritional antioxidants from diet (i.e. vitamins E, C, carotenoids). Possible mechanisms of nutritional depletion and side effects of high intake are in the article described.


Assuntos
Antioxidantes/uso terapêutico , Suplementos Nutricionais , Vitaminas/uso terapêutico , Antioxidantes/efeitos adversos , Cálcio/metabolismo , Dano ao DNA , Suplementos Nutricionais/efeitos adversos , Homeostase , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Carbonilação Proteica/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Vitaminas/efeitos adversos
9.
Vnitr Lek ; 55(4): 412-5, 2009 Apr.
Artigo em Tcheco | MEDLINE | ID: mdl-19449760

RESUMO

Functional food and nutritional supplements balance the difference between the natural nutritional requirement of man, as a slowly changing genotype, and the nutrition of today's man. This type of specifically treated food enables the nutrition of both the healthy population, where functional food eliminates certain risks and have a preventative effect (fibre, microelements), and the nutrition of the ill, which is based on the therapeutical and regulatory effect of nutrients (organ-specific nutrition).


Assuntos
Diabetes Mellitus/dietoterapia , Suplementos Nutricionais , Alimentos Formulados , Humanos , Necessidades Nutricionais
10.
Pharmazie ; 63(11): 819-22, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19069243

RESUMO

OBJECTIVE: There is evidence to suppose that cholesterol-lowering drugs such as statins might confer protection against dementia, probably via modulation of cholesterol synthesis in the brain. The aim of the present study was to investigate possible influence of two lipophilic statins (simvastatin and atorvastatin) on cholesterol synthesis in selected parts of rat central nervous system (CNS). METHODS: Three groups of rats were orally treated with simvastatin (10 mg/kg b.wt.), atorvastatin (10 mg/kg b.wt.) or vehicle (aqua) for 9 days. At the end of experiment, brains (for basal ganglia, frontal cortex and hippocampus) and spinal cord were isolated and cholesterol synthesis was determined using the incorporation of deuterium from deuterated water. ANOVA with Fisher's LSD Multiple-Comparison Test and Kruskal-Wallis test were applied for statistical evaluation. P < 0.05 was considered statistically significant. RESULTS: Significant reductions of cholesterol synthesis rate were detected in both experimental groups (vs. controls) in all studied localisations. Both drugs elicited comparable effects on cholesterol synthesis rate irrespective of the examined tissue. CONCLUSIONS: This study brings additional evidence of the role of statins in the CNS cholesterol synthesis. The finding that both statins were able to lower braincholesterol synthesis without altering plasma cholesterol supports the idea of their local action inthe brain. For comparison of the effects of statins in the spinal cord and selected parts of brain, the deuterium technique was utilised for the first time.


Assuntos
Anticolesterolemiantes/farmacologia , Química Encefálica/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Colesterol/biossíntese , Ácidos Heptanoicos/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Pirróis/farmacologia , Sinvastatina/farmacologia , Animais , Atorvastatina , Biomarcadores , Sistema Nervoso Central/efeitos dos fármacos , Colesterol/sangue , Cinética , Masculino , Ratos , Ratos Wistar
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