RESUMO
The present study characterizes the oral pharmacokinetics of D-Pinitol, a natural insulin mimetic inositol, in human healthy volunteers (14 males and 11 females). D-Pinitol absorption was studied in (a) subjects receiving a single oral dose of 15 mg/kg (n = 10), or (b) 5 mg/kg pure D-Pinitol (n = 6), and (c) subjects receiving D-Pinitol as part of carbohydrate-containing carob pods-derived syrup with a 3.2% D-Pinitol (Dose of 1600 mg/subject, n = 9). The volunteers received a randomly assigned single dose of either D-Pinitol or carob pod-derived syrup. Blood samples were collected at 0, 15, 30, 45, 60, 90, 120, 180, 240, 360 and 1440 min after intake. Plasma concentration of D-Pinitol was measured and pharmacokinetic parameters obtained. The data indicate that when given alone, the oral absorption of D-Pinitol is dose-dependent and of extended duration, with a Tmax reached after almost 4 h, and a half-life greater than 5 h. When the source of D-Pinitol was a carob pods-derived syrup, Cmax was reduced to 40% of the expected based on the data of D-Pinitol alone, suggesting a reduced absorption probably because of competition with monosaccharide transport. In this group, Tmax was reached before that of D-Pinitol alone, but the estimated half-life remained the same. In the D-Pinitol groups, plasma concentrations of glucose, insulin, glucagon, ghrelin, free fatty acids, and pituitary hormones were additionally measured. A dose of 15 mg/kg of D-Pinitol did not affect glucose levels in healthy volunteers, but reduced insulin and increased glucagon and ghrelin concentrations. D-Pinitol did not increase other hormones known to enhance plasma glucose, such as cortisol or GH, which were surprisingly reduced after the ingestion of this inositol. Other pituitary hormones (gonadotropins, prolactin, and thyroid-stimulating hormone) were not affected after D-Pinitol ingestion. In a conclusion, D-Pinitol is absorbed through the oral route, having an extended half-life and displaying the pharmacological profile of an endocrine pancreas protector, a pharmacological activity of potential interest for the treatment or prevention of insulin resistance-associated conditions.
Assuntos
Fabaceae , Jejum , Glicemia , Ácidos Graxos não Esterificados , Feminino , Grelina , Glucagon , Glucose , Voluntários Saudáveis , Humanos , Hidrocortisona , Inositol/análogos & derivados , Insulina , Masculino , Prolactina , TireotropinaRESUMO
Background: Myeloperoxidase (MPO) and advanced oxidation protein products, or AOPP (a type of MPO-derived chlorinated adducts), have been implicated in Parkinson´s disease (PD). Human MPO also show sex-based differences in PD. The objective was to study the relationship of MPO and AOPP in the cerebrospinal fluid (CSF) with motor features of idiopathic PD in male and female patients. Methods: MPO concentration and activity and AOPP content were measured in the CSF and serum in 34 patients and 30 controls. CSF leukocytes and the integrity of the blood-brain barrier were evaluated. Correlations of MPO and AOPP with clinical variables were examined. Results: The blood-brain barrier was intact and CSF leukocyte count was normal in all patients. CSF MPO concentration and activity were similar in the cohort of patients and controls, but CSF MPO content was significantly higher in male patients than in PD women (p = 0.0084). CSF MPO concentration correlated with disease duration in male and female patients (p < 0.01). CSF MPO concentration was significantly higher in men with disease duration ≥12 years versus the remainder of the male subjects (p < 0.01). Changes in CSF MPO in women were not significant. Serum MPO concentration and activity were significantly higher in all PD patients relative to controls (p < 0.0001). CSF MPO was not correlated with serum MPO. Serum AOPP were detected in all patients, but CSF AOPP was undetectable in 53% of patients. AOPP were not quantifiable in controls. Conclusions: CSF MPO is not a good biomarker for PD because mean CSF MPO concentration and activity are not different between the cohort of patients and controls. CSF MPO concentration positively correlated with disease duration in men and women, but CSF MPO is significantly enhanced only in male patients with disease duration longer than 12 years. It can be hypothesized that the MPO-related immune response in early-stage PD might be weak in all patients, but then the MPO-related immune response is progressively enhanced in men, not women. Since the blood-brain barrier is intact, and CSF MPO is not correlated with serum MPO, CSF myeloperoxidase would reflect MPO content in brain cells, not blood-derived cells. Finally, serum AOPP was detected in all patients, but not controls, which is consistent with the occurrence of chlorinative stress in blood serum in PD. The study of CSF AOPP as biomarker could not be assessed because the ELISA assay was hampered by its detection limit in the CSF.
RESUMO
BACKGROUND: Stressful episodes and high alcohol consumption during adolescence are considered major risk factors for the development of psychiatric disorders in adulthood. Identification of mechanisms underlying these early events, which enhanced vulnerability to mental illness, is essential for both their prevention and treatment. METHODS: Male Wistar rats were used to investigate the long-term effects of early restraint stress and intermittent alcohol exposure (intragastric administration of 3 g/kg ethanol; 4 days/week for 4 weeks during adolescence) on anxiety-like behavior and the expression of signaling systems associated with emotional behaviors [e.g., corticosterone, fatty acid-derived molecules and endocannabinoid enzymes, glutamate receptor subunits, corticotropin releasing hormone receptors (CRHR1 and CRHR2) and neuropeptide Y receptors (NPY1R and NPYR2)] in the blood and amygdala. RESULTS: Overall, both stress and alcohol exposure during adolescence induced anxiogenic-like behaviors, increased plasma levels of corticosterone and increases in the amygdalar expression of the cannabinoid CB2 receptor and certain subunits of glutamate receptors (i.e., mGluR1, mGluR5 and NMDAR1) in young adult rats. In addition, there were specific main effects of alcohol exposure on the expression of the cannabinoid CB1 receptor, monoacylglycerol lipase (MAGL) and NPY2R in the amygdala, and significant increases were observed in rats exposed to alcohol. Interestingly, there were significant interaction effects between restraint stress and alcohol exposure on the expression of plasma 2-arachidonoyl glycerol (2-AG), and both CRHR1,2 and NPY1R in the amygdala. Thus, the restraint stress was associated with increased 2-AG levels, which was not observed in rats exposed to alcohol. The alcohol exposure was associated with an increased expression of CRHR1,2 but the restraint stress prevented these increases (stress alcohol rats). In contrast, NPY1R was only increased in rats exposed to stress and alcohol. Finally, we did not observe any potentiation of the behavioral and molecular effects by the combination of stress and alcohol, which is concordant with an overall ceiling effect on some of the variables. CONCLUSION: Separate and combined early stress and alcohol induced a common anxious phenotype with increased corticosterone in adulthood. However, there were differences in the amygdalar expression of signaling systems involved in maladaptive changes in emotional behavior. Therefore, our results suggest the existence of partially different mechanisms for stress and alcohol exposures.
Assuntos
Alcoolismo , Ansiedade/etiologia , Endocanabinoides , Ácido Glutâmico , Fenótipo , Transdução de Sinais/efeitos dos fármacos , Estresse Fisiológico , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Masculino , Transtornos Mentais/prevenção & controle , Ratos , Ratos Wistar , Receptores de Glutamato Metabotrópico/efeitos dos fármacosRESUMO
Obesity is currently a major epidemic in the developed world. However, we lack a wide range of effective pharmacological treatments and therapies against obesity, and those approved are not devoid of adverse effects. Dietary components such as palmitoleic acid have been proposed to improve metabolic disbalance in obesity, although the mechanisms involved are not well understood. Both palmitoleic acid (POA) and oleic acid (OA) can be transformed in N-acylethanolamines (NAEs), mediating the effects of dietary POA and OA. To test this hypothesis, here, we study the effects on food intake and body weight gain of palmitoleylethanolamide (POEA) and the OA-derived NAE analogue, oleoylethanolamide (OEA), in Sprague-Dawley rats with a hypercaloric cafeteria diet (HFD). Plasma biochemical metabolites, inflammatory mediators, and lipogenesis-associated liver protein expression were also measured. The results indicate that POEA is able to improve health status in diet-induced obesity, decreasing weight, liver steatosis, inflammation, and dyslipemia. The action of POEA was found to be almost identical to that of OEA, which is an activator of the nuclear peroxisome proliferator receptor alpha (PPARα), and it is structurally related to POEA. These results suggest that the dietary administration of either POA or POEA might be considered as nutritional intervention as complementary treatment for complicated obesity in humans.
Assuntos
Ácidos Graxos Monoinsaturados/farmacologia , Ácidos Graxos Monoinsaturados/uso terapêutico , Obesidade/tratamento farmacológico , Ácidos Oleicos/farmacologia , Ácidos Oleicos/uso terapêutico , Animais , Peso Corporal , Citocinas , Dieta , Endocanabinoides , Etanolaminas , Ácidos Graxos , Fígado Gorduroso/metabolismo , Humanos , Resistência à Insulina , Lipogênese , Fígado/metabolismo , Masculino , Ácido Oleico/uso terapêutico , Ratos , Ratos Sprague-DawleyRESUMO
Learning experiences are potent modulators of adult hippocampal neurogenesis (AHN). However, the vast majority of findings on the learning-induced regulation of AHN derive from aversively-motivated tasks, mainly the water maze paradigm, in which stress is a confounding factor that affects the AHN outcome. Currently, little is known regarding the effect of appetitively-motivated training on AHN. Hence we studied how spatial learning to find food rewards in a hole-board maze modulates AHN (cell proliferation and immature neurons) and AHN-related hippocampal neuroplasticity markers (BDNF, IGF-II and CREB phosphorylation) in mice. The 'Trained' mice were tested for both spatial reference and working memory and compared to 'Pseudotrained' mice (exposed to different baited holes in each session, thus avoiding the reference memory component of the task) and 'Control' mice (exposed to the maze without rewards). In contrast to Pseudotrained and Control mice, the number of proliferating hippocampal cells were reduced in Trained mice, but they notably increased their population of immature neurons assessed by immunohistochemistry. This evidence shows that hole-board spatial reference learning diminishes cell proliferation in favor of enhancing young neurons' survival. Interestingly, the enhanced AHN in the Trained mice (specifically in the suprapyramidal blade) positively correlated with their reference memory performance, but not with their working memory. Furthermore, the Trained animals increased the hippocampal protein expression of all the neuroplasticity markers analyzed by western blot. Results show that the appetitively-motivated hole-board task is a useful paradigm to potentiate and/or investigate AHN and hippocampal plasticity minimizing aversive variables such as fear or stress.
Assuntos
Comportamento Apetitivo/fisiologia , Hipocampo/fisiologia , Memória de Curto Prazo/fisiologia , Neurogênese , Neurônios/fisiologia , Aprendizagem Espacial/fisiologia , Animais , Masculino , Camundongos Endogâmicos C57BL , Motivação/fisiologia , Plasticidade Neuronal , RecompensaRESUMO
High-fat diet-induced obesity (DIO) is associated with fatty liver and elevated IL-6 circulating levels. IL-6 administration in rodents has yielded contradictory results regarding its effects on steatosis progression. In some models of fatty liver disease, high doses of human IL-6 ameliorate the liver steatosis, whereas restoration of IL-6 in DIO IL-6-/- mice up-regulates hepatic lipogenic enzymes and aggravates steatosis. We further examined the effects of chronic low doses of murine IL-6 on hepatic lipid metabolism in WT mice in DIO. IL-6 was delivered twice daily in C57BL/6J DIO mice for 15 days. The status and expression of IL-6-signalling mediators and targets were investigated in relation to the steatosis and lipid content in blood and in liver. IL-6 administration in DIO mice markedly raised circulating levels of lipids, glucose and leptin, elevated fat liver content and aggravated steatosis. Under IL-6 treatment there was hepatic Stat3 activation and increased gene expression of Socs3 and Tnf-alpha whereas the gene expression of endogenous IL-6, IL-6-receptor, Stat3, Cpt1 and the enzymes involved in lipogenesis was suppressed. These data further implicate IL-6 in fatty liver disease modulation in the context of DIO, and indicate that continuous stimulation with IL-6 attenuates the IL-6-receptor response, which is associated with high serum levels of leptin, glucose and lipids, the lowering levels of lipogenic and Cpt1 hepatic enzymes and with increased Tnf-alpha hepatic expression, a scenario evoking that observed in IL-6-/- mice exposed to DIO and in obese Zucker rats.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/patologia , Interleucina-6/administração & dosagem , Interleucina-6/efeitos adversos , Leptina/sangue , Fígado/metabolismo , Animais , Glicemia/metabolismo , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Receptor gp130 de Citocina/metabolismo , Regulação para Baixo/efeitos dos fármacos , Ácidos Graxos/metabolismo , Fígado Gorduroso/sangue , Fígado Gorduroso/genética , Interleucina-6/farmacologia , Fígado/enzimologia , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Obesos , Modelos Biológicos , PPAR alfa/metabolismo , Ratos Zucker , Receptores para Leptina/metabolismo , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
Interleukin-6 (IL-6) has emerged as an important mediator of fatty acid metabolism with paradoxical effects in the liver. Administration of IL-6 has been reported to confer protection against steatosis, but plasma and tissue IL-6 concentrations are elevated in chronic liver diseases, including fatty liver diseases associated with obesity and alcoholic ingestion. In this study, we further investigated the role of IL-6 on steatosis induced through a high-fat diet (HFD) in wild-type (WT) and IL-6-deficient (IL-6(-/-)) mice. Additionally, HFD-fed IL-6(-/-) mice were also chronically treated with recombinant IL-6 (rIL-6). Obesity in WT mice fed a HFD associated with elevated serum IL-6 levels, fatty liver, upregulation of carnitine palmitoyltransferase 1 (CPT1) and signal transducer and activator of transcription-3 (STAT3), increased AMP kinase phosphorylation (p-AMPK), and downregulation of the hepatic lipogenic enzymes fatty acid synthase (FAS) and stearoyl-CoA desaturase 1 (SCD1). The HFD-fed IL-6(-/-) mice showed severe steatosis, no changes in CPT1 levels or AMPK activity, no increase in STAT3 amounts, inactivated STAT3, and marked downregulation of the expression of acetyl-CoA carboxylase (ACCα/ß), FAS and SCD1. The IL-6 chronic replacement in HFD-fed IL-6 -/-: mice restored hepatic STAT3 and AMPK activation but also increased the expression of the lipogenic enzymes ACCα/ß, FAS and SCD1. Furthermore, rIL-6 administration was associated with aggravated steatosis and elevated fat content in the liver. We conclude that, in the context of HFD-induced obesity, the administration of rIL-6 might contribute to the aggravation of fatty liver disease through increasing lipogenesis.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Interleucina-6/administração & dosagem , Interleucina-6/deficiência , Lipogênese/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/etiologia , Proteínas Quinases Ativadas por AMP/metabolismo , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Animais , Carnitina O-Palmitoiltransferase/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Ácido Graxo Sintase Tipo I/genética , Ácido Graxo Sintase Tipo I/metabolismo , Células Hep G2 , Humanos , Interleucina-6/genética , Lipogênese/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Fosforilação , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/genética , Fator de Transcrição STAT3/metabolismo , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/metabolismoRESUMO
De novo lipogenesis and hypercaloric diets are thought to contribute to increased fat mass, particularly in abdominal fat depots. CB1 is highly expressed in adipose tissue, and CB1-mediated signalling is associated with stimulation of lipogenesis and diet-induced obesity, though its contribution to increasing fat deposition in adipose tissue is controversial. Lipogenesis is regulated by transcription factors such as liver X receptor (LXR), sterol-response element binding protein (SREBP) and carbohydrate-responsive-element-binding protein (ChREBP). We evaluated the role of CB1 in the gene expression of these factors and their target genes in relation to lipogenesis in the perirenal adipose tissue (PrAT) of rats fed a high-carbohydrate diet (HCHD) or a high-fat diet (HFD). Both obesity models showed an up-regulated gene expression of CB1 and Lxrα in this adipose pad. The Srebf-1 and ChREBP gene expressions were down-regulated in HFD but not in HCHD. The expression of their target genes encoding for lipogenic enzymes showed a decrease in diet-induced obesity and was particularly dramatic in HFD. In HCHD, CB1 blockade by AM251 reduced the Srebf-1 and ChREBP expression and totally abrogated the remnant gene expression of their target lipogenic enzymes. The phosphorylated form of the extracellular signal-regulated kinase (ERK-p), which participates in the CB1-mediated signalling pathway, was markedly present in the PrAT of obese rats. ERK-p was drastically repressed by AM251 indicating that CB1 is actually functional in PrAT of obese animals, though its activation loses the ability to stimulate lipogenesis in PrAT of obese rats. Even so, the remnant expression levels of lipogenic transcription factors found in HCHD-fed rats are still dependent on CB1 activity. Hence, in HCHD-induced obesity, CB1 blockade may help to further potentiate the reduction of lipogenesis in PrAT by means of inducing down-regulation of the ChREBP and Srebf-1 gene expression, and consequently in the expression of lipogenic enzymes.