Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 49
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
BMC Cancer ; 19(1): 1086, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31718601

RESUMO

BACKGROUND: It has been shown that bcl2, bcl-XL and mcl-1 protein levels are high in chronic lymphocytic leukemia cells, and resultantly, apoptosis does not occur chronic lymphocytic leukemia cells. Apelin and apela (ELABELA/ELA/Toddler) are two peptide ligands for a class A G-protein coupled receptor called apelin receptor. Studies have shown that ELA inhibits apoptosis by inhibiting apoptotic proteins and activating anti-apoptotic proteins. Proteins and genes involved in apoptosis are valuable for targeted cancer therapy. We hypothesized that serum levels may be increased in patients with chronic lymphocytic leukemia based on the antiapoptotic effect of ELA. We compared serum ELABELA levels of healthy volunteers and patients with chronic lymphocytic leukemia. We aimed to draw attention to a new molecule worthy of research in targeted cancer treatment. METHODS: Forty two untreated CLL patients and 41 healthy volunteers were included in the study. Serum ELA levels were measured by using enzyme-linked immunosorbent assay kits (Dhanghai Sunred Biological Technology co. Ltd), automated ELISA reader (Thermo Scientific, FINLAND) and computer program (Scanlt for Multiscan F.C.2.5.1) in accordance with the manufacturer's instructions. Statistical analysis was done by Statistical Package for Social Sciences for Windows 20 (IBM SPSS Inc., Chicago, IL) ve MedCalc programs. ELA and variables related to CLL were correlated with Spearman correlation anlysis test. ROC analysis and Youden index method were used to determine a cut off point for ELA. All p-values were 2-sided with statistical significance at 0.05 alpha levels. RESULTS: In our study, we found that serum ELA levels were significantly higher in patients with CLL. CONCLUSIONS: This study highlights that ELA targeting may be a potential therapeutic option for treating CLL.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/metabolismo , Hormônios Peptídicos/antagonistas & inibidores , Idoso , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Biomarcadores Tumorais/metabolismo , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Razão de Chances , Hormônios Peptídicos/metabolismo , Estudos Prospectivos , Curva ROC , Fatores de Risco
2.
Trends Pharmacol Sci ; 40(10): 725-734, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31500846

RESUMO

The urotensinergic system, comprised of a G protein-coupled receptor (UT) and two endogenous ligands named urotensin II (UII) and urotensin II-related peptide (URP), has garnered significant attention due to its involvement in the initiation and/or the evolution of various diseases. Accordingly, multiple studies using animal models have demonstrated that UT antagonists may have utility as potential therapeutic agents for treating atherosclerosis, pulmonary arterial hypertension, heart failure, and cancer. Unfortunately, clinical investigations of UT antagonist candidates showed limited efficacy in humans. This system, which has yet to be effectively targeted, therefore remains to be therapeutically exploited. Here, we discuss various hypotheses that could explain the in vivo failure of UT antagonists.


Assuntos
Hormônios Peptídicos/agonistas , Hormônios Peptídicos/antagonistas & inibidores , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Urotensinas/agonistas , Urotensinas/antagonistas & inibidores , Animais , Sistemas de Liberação de Medicamentos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/agonistas , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Ligantes , Hormônios Peptídicos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais/efeitos dos fármacos , Urotensinas/metabolismo
3.
J Biol Chem ; 293(41): 15840-15854, 2018 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-30139742

RESUMO

The cardioprotective vasodilator peptide adrenomedullin 2/intermedin (AM2/IMD) and the related adrenomedullin (AM) and calcitonin gene-related peptide (CGRP) signal through three heterodimeric receptors comprising the calcitonin receptor-like class B G protein-coupled receptor (CLR) and a variable receptor activity-modifying protein (RAMP1, -2, or -3) that determines ligand selectivity. The CGRP receptor (RAMP1:CLR) favors CGRP binding, whereas the AM1 (RAMP2:CLR) and AM2 (RAMP3:CLR) receptors favor AM binding. How AM2/IMD binds the receptors and how RAMPs modulate its binding is unknown. Here, we show that AM2/IMD binds the three purified RAMP-CLR extracellular domain (ECD) complexes with a selectivity profile that is distinct from those of CGRP and AM. AM2/IMD bound all three ECD complexes but preferred the CGRP and AM2 receptor complexes. A 2.05 Å resolution crystal structure of an AM2/IMD antagonist fragment-bound RAMP1-CLR ECD complex revealed that AM2/IMD binds the complex through a unique triple ß-turn conformation that was confirmed by peptide and receptor mutagenesis. Comparisons of the receptor-bound conformations of AM2/IMD, AM, and a high-affinity CGRP analog revealed differences that may have implications for biased signaling. Guided by the structure, enhanced-affinity AM2/IMD antagonist variants were developed, including one that discriminates the AM1 and AM2 receptors with ∼40-fold difference in affinities and one stabilized by an intramolecular disulfide bond. These results reveal differences in how the three peptides engage the receptors, inform development of AM2/IMD-based pharmacological tools and therapeutics, and provide insights into RAMP modulation of receptor pharmacology.


Assuntos
Adrenomedulina/metabolismo , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Proteína Semelhante a Receptor de Calcitonina/metabolismo , Hormônios Peptídicos/metabolismo , Proteínas Modificadoras da Atividade de Receptores/metabolismo , Receptores de Adrenomedulina/metabolismo , Adrenomedulina/isolamento & purificação , Peptídeo Relacionado com Gene de Calcitonina/isolamento & purificação , Proteína Semelhante a Receptor de Calcitonina/isolamento & purificação , Desenho de Fármacos , Células HEK293 , Humanos , Ligantes , Mutagênese Sítio-Dirigida , Hormônios Peptídicos/antagonistas & inibidores , Hormônios Peptídicos/genética , Hormônios Peptídicos/isolamento & purificação , Ligação Proteica , Conformação Proteica , Engenharia de Proteínas , Proteína 1 Modificadora da Atividade de Receptores/isolamento & purificação , Proteína 1 Modificadora da Atividade de Receptores/metabolismo , Proteína 2 Modificadora da Atividade de Receptores/isolamento & purificação , Proteína 2 Modificadora da Atividade de Receptores/metabolismo , Proteína 3 Modificadora da Atividade de Receptores/isolamento & purificação , Proteína 3 Modificadora da Atividade de Receptores/metabolismo , Proteínas Modificadoras da Atividade de Receptores/isolamento & purificação , Receptores de Adrenomedulina/isolamento & purificação
4.
Physiol Res ; 67(Suppl 1): S69-S81, 2018 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-29947529

RESUMO

The heavy impact of obesity on the development and progression of cardiovascular disease has sparked sustained efforts to uncover the mechanisms linking excess adiposity to vascular dysfunction. Impaired vasodilator reactivity has been recognized as an early hemodynamic abnormality in obese patients, but also increased vasoconstrictor tone importantly contributes to their vascular damage. In particular, upregulation of the endothelin (ET)-1 system, consistently reported in these patients, might accelerate atherosclerosis and its complication, given the pro-inflammatory and mitogenic properties of ET-1. In recent years, a number of gut hormones, in addition to their role as modulators of food intake, energy balance, glucose and lipid metabolism, and insulin secretion and action, have demonstrated favorable vascular actions. They increase the bioavailability of vasodilator mediators like nitric oxide, but they have also been shown to inhibit the ET-1 system. These features make gut hormones promising tools for targeting both the metabolic and cardiovascular complications of obesity, a view supported by recent large-scale clinical trials indicating that novel drugs for type 2 diabetes with cardiovascular potential may translate into clinically significant advantages. Therefore, there is real hope that better understanding of the properties of gut-derived substances might provide more effective therapies for the obesity-related cardiometabolic syndrome.


Assuntos
Endotelina-1/metabolismo , Hormônios Gastrointestinais/metabolismo , Obesidade/metabolismo , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/administração & dosagem , Vasoconstritores/metabolismo , Fármacos Antiobesidade/administração & dosagem , Fármacos Antiobesidade/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Endotelina-1/agonistas , Endotelina-1/antagonistas & inibidores , Hormônios Gastrointestinais/antagonistas & inibidores , Humanos , Resistência à Insulina/fisiologia , Obesidade/tratamento farmacológico , Hormônios Peptídicos/antagonistas & inibidores , Hormônios Peptídicos/metabolismo , Vasoconstrição/fisiologia
5.
J Med Chem ; 60(23): 9838-9859, 2017 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-29131958

RESUMO

Benzotriazepin-2-ones were designed to mimic the suggested bioactive γ-turn conformation of the Bip-Lys-Tyr tripeptide in Urocontrin ([Bip4]URP), which modulates the urotensin II receptor (UT) and differentiates the effects of the endogenous ligands urotensin II (UII) and urotensin II-related peptide (URP). Twenty-six benzotriazepin-2-ones were synthesized by acylation of anthranilate-derived amino ketones with an aza-glycine equivalent, chemoselective nitrogen functionalization, and ring closure. Several mimics exhibited selective modulatory effects on hUII- and URP-associated vasoconstriction in an ex vivo rat aortic ring bioassay. The C5 p-hydroxyphenethenyl benzotriazepin-2-one 20g decreased hUII potency and efficacy without changing URP induced vasoconstriction. Its saturated phenethyl counterpart 23g decreased URP potency without influencing hUII-mediated contraction. To our knowledge, 20g and 23g represent the first achiral molecules that modulate selectively hUII and URP biological activities. Effectively synthesized, benzotriaepin-2-one turn mimics offer the potential to differentiate the respective roles, signaling pathways, and phenotypic outcomes of hUII and URP in the UT system.


Assuntos
Benzazepinas/química , Benzazepinas/farmacologia , Desenho de Fármacos , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/metabolismo , Vasoconstrição/efeitos dos fármacos , Animais , Aorta/efeitos dos fármacos , Aorta/fisiologia , Benzazepinas/síntese química , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Hormônios Peptídicos/antagonistas & inibidores , Hormônios Peptídicos/metabolismo , Ratos , Ratos Sprague-Dawley
6.
J Diabetes Complications ; 31(2): 304-310, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27776915

RESUMO

BACKGROUND: Glucose derived metabolism generates reactive metabolites affecting the neuronal system and lifespan in C. elegans. Here, the role of the insulin homologue ins-7 and its downstream effectors in the generation of high glucose induced neuronal damage and shortening of lifespan was studied. RESULTS: In C. elegans high glucose conditions induced the expression of the insulin homologue ins-7. Abrogating ins-7 under high glucose conditions in non-neuronal cells decreased reactive oxygen species (ROS)-formation and accumulation of methylglyoxal derived advanced glycation endproducts (AGEs), prevented structural neuronal damage and normalised head motility and lifespan. The restoration of lifespan by decreased ins-7 expression was dependent on the concerted action of sod-3 and glod-4 coding for the homologues of iron-manganese superoxide dismutase and glyoxalase 1, respectively. CONCLUSIONS: Under high glucose conditions mitochondria-mediated oxidative stress and glycation are downstream targets of ins-7. This impairs the neuronal system and longevity via a non-neuronal/neuronal crosstalk by affecting sod-3 and glod-4, thus giving further insight into the pathophysiology of diabetic complications.


Assuntos
Proteínas de Caenorhabditis elegans/antagonistas & inibidores , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Glucose/intoxicação , Lactoilglutationa Liase/metabolismo , Estresse Oxidativo , Hormônios Peptídicos/antagonistas & inibidores , Superóxido Dismutase/metabolismo , Animais , Comportamento Animal , Caenorhabditis elegans/enzimologia , Caenorhabditis elegans/crescimento & desenvolvimento , Proteínas de Caenorhabditis elegans/agonistas , Proteínas de Caenorhabditis elegans/genética , Retroalimentação Fisiológica , Técnicas de Silenciamento de Genes , Técnicas de Inativação de Genes , Produtos Finais de Glicação Avançada/metabolismo , Lactoilglutationa Liase/antagonistas & inibidores , Lactoilglutationa Liase/genética , Longevidade , Mutação , Neuroproteção , Concentração Osmolar , Hormônios Peptídicos/agonistas , Hormônios Peptídicos/genética , Hormônios Peptídicos/metabolismo , Interferência de RNA , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/antagonistas & inibidores , Superóxido Dismutase/genética , Análise de Sobrevida
7.
Pharmacol Rep ; 68(6): 1326-1331, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27710862

RESUMO

BACKGROUND: Spexin (SPX) is a recently discovered neuropeptide that exhibits a large spectrum of central and peripheral regulatory activity, especially when considered as a potent anorexigenic factor. It has already been proven that antidepressants, including selective serotonin reuptake inhibitors (SSRI), can modulate peptidergic signaling in various brain structures. Despite these findings, there is so far no information regarding the influence of treatment with the SSRI antidepressant escitalopram on brain SPX expression. METHODS: In this current study we measured SPX mRNA and protein expression in the selected brain structures (hypothalamus, hippocampus and striatum) of rats chronically treated with a 10mg/kg dose of escitalopram using quantitative Real-Time PCR and immunohistochemistry. RESULTS: Strikingly, long-term (4 week) drug treatment led to the downregulation of SPX expression in the rat hypothalamus. This supports the hypothesis that SPX may be involved in the hypothalamic serotonin-dependent actions of SSRI antidepressants and possibly also in the central mechanism of body mass increase. Conversely, SPX expression increased in the hippocampus and striatum. CONCLUSIONS: This is the first report of the effects of a neuropsychiatric medication on SPX expression in animal brain. Our findings shed a new light on the pharmacology of antidepressants and may contribute to a better understanding of the alternative mechanisms responsible for antidepressant action.


Assuntos
Citalopram/farmacologia , Corpo Estriado/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Hormônios Peptídicos/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Animais , Corpo Estriado/metabolismo , Regulação da Expressão Gênica , Hipocampo/metabolismo , Hipotálamo/metabolismo , Masculino , Hormônios Peptídicos/antagonistas & inibidores , Hormônios Peptídicos/genética , Ratos , Ratos Sprague-Dawley
8.
Pharmacol Rev ; 67(1): 214-58, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25535277

RESUMO

Urotensin II (UII) is a cyclic neuropeptide that was first isolated from the urophysis of teleost fish on the basis of its ability to contract the hindgut. Subsequently, UII was characterized in tetrapods including humans. Phylogenetic studies and synteny analysis indicate that UII and its paralogous peptide urotensin II-related peptide (URP) belong to the somatostatin/cortistatin superfamily. In mammals, the UII and URP genes are primarily expressed in cholinergic neurons of the brainstem and spinal cord. UII and URP mRNAs are also present in various organs notably in the cardiovascular, renal, and endocrine systems. UII and URP activate a common G protein-coupled receptor, called UT, that exhibits relatively high sequence identity with somatostatin, opioid, and galanin receptors. The UT gene is widely expressed in the central nervous system (CNS) and in peripheral tissues including the retina, heart, vascular bed, lung, kidney, adrenal medulla, and skeletal muscle. Structure-activity relationship studies and NMR conformational analysis have led to the rational design of a number of peptidic and nonpeptidic UT agonists and antagonists. Consistent with the wide distribution of UT, UII has now been shown to exert a large array of biologic activities, in particular in the CNS, the cardiovascular system, and the kidney. Here, we review the current knowledge concerning the pleiotropic actions of UII and discusses the possible use of antagonists for future therapeutic applications.


Assuntos
Hormônios Peptídicos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Urotensinas/metabolismo , Sequência de Aminoácidos , Animais , Antagonistas de Hormônios/farmacologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Ligantes , Dados de Sequência Molecular , Hormônios Peptídicos/antagonistas & inibidores , Hormônios Peptídicos/química , Hormônios Peptídicos/genética , Conformação Proteica , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/genética , Transdução de Sinais , Relação Estrutura-Atividade , Urotensinas/antagonistas & inibidores , Urotensinas/química , Urotensinas/genética
9.
J Cell Physiol ; 229(6): 762-71, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24151046

RESUMO

Gastrokine 1 (GKN1) plays an important role in maintaining gastric mucosa integrity. Here, we investigated whether gastrokine 2 (GKN2) contributes to the homeostasis of gastric epithelial cells by regulating GKN1 activity. We analyzed cell viability, proliferation, and death in AGS cells transfected with GKN1, GKN2, GKN1 plus GKN2 using MTT, BrdU incorporation, and apoptosis assays, respectively. In addition, the expression levels of the cell cycle- and apoptosis-related proteins, miR-185, DNMT1, and EZH2 were determined. We also compared the expression of GKN1, GKN2, and CagA in 50 non-neoplastic gastric mucosae and measured GKN2 expression in 169 gastric cancers by immunohistochemistry. GKN2 inhibited anti-proliferative and pro-apoptotic activities, miR-185 induction, and anti-epigenetic modifications of GKN1. There was a positive correlation between GKN1 and GKN2 expression (P = 0.0074), and the expression of GKN1, but not GKN2, was significantly lower in Helicobacter pylori CagA-positive gastric mucosa (P = 0.0013). Interestingly, ectopic GKN1 expression in AGS cells increased GKN2 mRNA and protein expression in a time-dependent manner (P = 0.01). Loss of GKN2 expression was detected in 126 (74.6%) of 169 gastric cancers by immunohistochemical staining and was closely associated with GKN1 expression and differentiation of gastric cancer cells (P = 0.0002 and P = 0.0114, respectively). Overall, our data demonstrate that in the presence of GKN2, GKN1 loses its ability to decrease cell proliferation, induce apoptosis, and inhibit epigenetic alterations in gastric cancer cells. Thus, we conclude that GKN2 may contribute to the homeostasis of gastric epithelial cells by inhibiting GKN1 activity.


Assuntos
Proteínas de Transporte/metabolismo , Mucosa Gástrica/fisiologia , Regulação da Expressão Gênica/fisiologia , Homeostase/fisiologia , Hormônios Peptídicos/metabolismo , Antígenos de Bactérias/genética , Antígenos de Bactérias/metabolismo , Apoptose/fisiologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Proteínas de Transporte/genética , Linhagem Celular Tumoral , Proliferação de Células , Helicobacter pylori/metabolismo , Humanos , Proteínas I-kappa B/genética , Proteínas I-kappa B/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Hormônios Peptídicos/antagonistas & inibidores , Hormônios Peptídicos/genética
10.
Br J Pharmacol ; 168(4): 807-21, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22994258

RESUMO

BACKGROUND AND PURPOSE: Recent evidence suggested that urotensin II (UII) and its paralog peptide UII-related peptide (URP) might exert common but also divergent physiological actions. Unfortunately, none of the existing antagonists were designed to discriminate specific UII- or URP-associated actions, and our understanding, on how these two endogenous peptides can trigger different, but also common responses, is limited. EXPERIMENTAL APPROACH: Ex vivo rat and monkey aortic ring contraction as well as dissociation kinetics studies using transfected CHO cells expressing the human urotensin (UT) receptors were used in this study. KEY RESULTS: Ex vivo rat and monkey aortic ring contraction studies revealed the propensity of [Pep(4)]URP to decrease the maximal response of human UII (hUII) without any significant change in potency, whereas no effect was noticeable on the URP-induced vasoconstriction. Dissociation experiments demonstrated the ability of [Pep(4)]URP to increase the dissociation rate of hUII, but not URP. Surprisingly, URP, an equipotent UII paralog, was also able to accelerate the dissociation rate of membrane-bound (125)I-hUII, whereas hUII had no noticeable effect on URP dissociation kinetics. Further experiments suggested that an interaction between the glutamic residue at position 1 of hUII and the UT receptor seems to be critical to induce conformational changes associated with agonistic activation. Finally, we demonstrated that the N-terminal domain of the rat UII isoform was able to act as a specific antagonist of the URP-associated actions. CONCLUSION: Such compounds, that is [Pep(4)]URP and rUII(1-7), should prove to be useful as new pharmacological tools to decipher the specific role of UII and URP in vitro but also in vivo.


Assuntos
Aorta Torácica/efeitos dos fármacos , Hormônios Peptídicos/antagonistas & inibidores , Hormônios Peptídicos/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Urotensinas/antagonistas & inibidores , Animais , Células CHO , Cricetinae , Cricetulus , Humanos , Técnicas In Vitro , Peptídeos e Proteínas de Sinalização Intracelular , Macaca fascicularis , Masculino , Hormônios Peptídicos/química , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas G/genética , Transfecção , Urotensinas/farmacologia , Vasoconstrição/efeitos dos fármacos
11.
Alcohol ; 45(7): 621-30, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21840158

RESUMO

Neurons in the central amygdala (CeA) co-express dynorphin and corticotropin-releasing hormone (CRH). Moreover, the activity of both the CRH and dynorphin systems in CeA is altered by alcohol treatments, effects suggesting interactions between the CRH and dynorphin systems. Thus, the objectives of the present study were to investigate the effects of (1) activating CRH receptors (CRHRs) by microinjection of CRH in CeA and (2) blocking CRHRs by local microinjections of CRHR antagonists in the CeA on the alcohol-induced changes in the extracellular concentrations of dynorphin A1-8 with in vivo microdialysis experiments. Microdialysis probes with a microinjection port were implanted in the CeA of alcohol-naïve Sprague-Dawley rats. Microinjections of CRH or antalarmin, a CRH receptor type 1 (CRHR1) antagonist, or anti-sauvagine-30, a CRH receptor type 2 (CRHR2) antagonist, at the level of CeA were followed by an intraperitoneal injection of either saline or 2.8 g ethanol/kg body weight. The content of dynorphin A1-8 was determined in dialyzate samples obtained prior to and following the various treatments using a specific radioimmunoassay. Activation of CRHRs in CeA induced an increase in the extracellular concentrations of dynorphin A1-8. Moreover, acute alcohol administration increased the extracellular concentrations of dynorphin A1-8 in CeA, an effect that was attenuated by blocking CRHR2 with anti-sauvagine-30 microinjection but not blocking CRHR1 with antalarmin microinjection. Therefore, the findings suggest an interaction between the CRH and dynorphin A1-8 systems at the level of CeA in response to acute alcohol exposure.


Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Dinorfinas/metabolismo , Fragmentos de Peptídeos/metabolismo , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Proteínas de Anfíbios/antagonistas & inibidores , Animais , Hormônio Liberador da Corticotropina/farmacologia , Etanol/farmacologia , Masculino , Microdiálise , Microinjeções , Hormônios Peptídicos/antagonistas & inibidores , Pirimidinas/farmacologia , Pirróis/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Hormônio Liberador da Corticotropina/fisiologia
12.
Peptides ; 32(9): 1893-901, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21839129

RESUMO

Neuronostatin, a recently discovered endogenous bioactive peptide, was encoded by pro-mRNA of somatostatin that contributes to modulation of nociception. However, nociceptive effect of neuronostatin is still not fully known. The aim of this study was to evaluate effect of neuronostatin on nociception and elucidate its possible mechanism of action. Intracerebroventricular (i.c.v.) administration of neuronostatin (0.3, 3, 6, 12nmol/mouse) produced a dose- and time-related antinociceptive effect in the tail immersion assay in mice, an acute pain model. The antinociceptive effect of neuronostatin was significantly antagonized by naloxone, and was strongly inhibited by co-injection with ß-funaltrexamine or nor-binaltorphimine, but not by naltrindole. Also, melanocortin 3/4 receptor antagonist, SHU9119, completely blocked the effect of neuronostatin. These data indicated the involvement of both µ- and κ-opioid receptors and central melanocortin system in the analgesic response induced by neuronostatin. In addition, neuronostatin (6nmol, i.c.v.) increased c-Fos protein expression in the periaqueductal gray (PAG) and the nucleus raphe magnus (NRM) that have a pivotal role in regulating descending pain pathways. Taken together, this study is the first to reveal that neuronostatin produces antinociceptive effect via opioid and central melanocortin systems, which is associated with an increase in neuronal activity the PAG and NRM.


Assuntos
Nociceptividade/efeitos dos fármacos , Hormônios Peptídicos/administração & dosagem , Hormônios Peptídicos/farmacologia , Dor Aguda/tratamento farmacológico , Analgésicos/administração & dosagem , Analgésicos/farmacologia , Animais , Relação Dose-Resposta a Droga , Imuno-Histoquímica , Infusões Intraventriculares , Masculino , Hormônios Estimuladores de Melanócitos/farmacologia , Camundongos , Modelos Animais , Naloxona/farmacologia , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Antagonistas de Entorpecentes , Hormônios Peptídicos/antagonistas & inibidores , Hormônios Peptídicos/síntese química , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Receptor Tipo 3 de Melanocortina/antagonistas & inibidores , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores
13.
Peptides ; 31(9): 1711-4, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20600426

RESUMO

Neuronostatin, a recently discovered peptide derived from the somatostatin preprohormone, significantly inhibited both food and water intake when administered centrally in adult male rats. Because neuronostatin is highly produced in the hypothalamus, an area of the brain through which important feeding circuits, including the central melanocortin system, communicate, we sought to determine if the anorexigenic and antidipsogenic effects of neuronostatin would be reversed by pretreatment with the melanocortin 3/4 receptor antagonist, SHU9119. SHU9119 pretreatment reversed the effect of neuronostatin on both food and water intake. We have shown recently that the central oxytocin system is a potential downstream mediator of the anorexignic action of alpha-MSH. We therefore tested whether the effects of neuronostatin also were dependent upon central oxytocin receptors. Neuronostatin-induced anorexia was not reversed by pretreatment with the oxytocin receptor antagonist, OVT, suggesting that neuronostatin acts through a unique subset of POMC neurons that do not signal via central oxytocin receptors.


Assuntos
Regulação do Apetite/fisiologia , Ingestão de Líquidos/fisiologia , Melanocortinas/metabolismo , Fragmentos de Peptídeos/fisiologia , Hormônios Peptídicos/fisiologia , Somatostatina/fisiologia , Animais , Anorexia/induzido quimicamente , Regulação do Apetite/efeitos dos fármacos , Ingestão de Líquidos/efeitos dos fármacos , Antagonistas de Hormônios/farmacologia , Injeções Intraventriculares , Masculino , Melanocortinas/antagonistas & inibidores , Hormônios Estimuladores de Melanócitos/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ocitocina/administração & dosagem , Ocitocina/análogos & derivados , Ocitocina/antagonistas & inibidores , Ocitocina/metabolismo , Ocitocina/farmacologia , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/antagonistas & inibidores , Hormônios Peptídicos/administração & dosagem , Hormônios Peptídicos/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Receptor Tipo 3 de Melanocortina/antagonistas & inibidores , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Receptores de Ocitocina/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Somatostatina/administração & dosagem , Somatostatina/antagonistas & inibidores , Fatores de Tempo
14.
Addict Biol ; 12(1): 17-21, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17407493

RESUMO

The appetite-regulating hormones leptin and ghrelin are altered in alcoholism and influence the hypothalamic-pituitary-adrenal system. We investigated whether acute ethanol ingestion and stress exposure affect ghrelin secretion. Nine healthy male volunteers were exposed to a standardized laboratory stressor involving public speaking on 2 days. On the first day they ingested 0.6 g/kg ethanol and on the second a placebo drink 50 minutes before the stressor. Plasma ghrelin, cortisol, glucose, and insulin were measured at baseline and in eight subsequent samples obtained up to 120 minutes after drinking (75 minutes after stress onset). The stress test induced a transient and significant rise in cortisol, which was not altered by prior alcohol administration. No significant change of ghrelin, insulin or glucose levels was observed after the stressor. Ghrelin declined significantly within 15 minutes after alcohol drinking, fell to a minimum of 66% of baseline at 75 minutes and remained at that level until the last sample at 120 minutes. No significant ghrelin changes were observed during placebo experiments. Insulin and glucose were not significantly influenced by stress or by alcohol. We conclude that alcohol drinking acutely attenuates circulating ghrelin levels. This effect is more pronounced than would be expected from the calories ingested with alcohol, as compared with a prior report where liquid meals of different caloric content were administered. We could not observe a stress effect on ghrelin, which does not support a role for ghrelin in stress-induced anorexia.


Assuntos
Intoxicação Alcoólica/fisiopatologia , Etanol/farmacologia , Hormônios Peptídicos/antagonistas & inibidores , Estresse Psicológico/complicações , Adulto , Apetite/fisiologia , Nível de Alerta/efeitos dos fármacos , Nível de Alerta/fisiologia , Glicemia/metabolismo , Ingestão de Energia/fisiologia , Grelina , Humanos , Hidrocortisona/sangue , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/fisiopatologia , Insulina/sangue , Masculino , Hormônios Peptídicos/sangue , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/fisiopatologia , Valores de Referência , Estresse Psicológico/fisiopatologia
15.
Scand J Gastroenterol ; 42(4): 447-53, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17454854

RESUMO

OBJECTIVE: Ghrelin is an orexigenic peptide with remarkable prokinetic effects. However, its mechanisms in regulating feeding and gastrointestinal migrating myoelectrical complex (MMC) are not fully understood. The aim of this study was to examine the effects of ghrelin on feeding regulation and duodenal motility in rats. MATERIAL AND METHODS: Feeding regulation was investigated at different times after intravenous injection of ghrelin and its receptor antagonist (D-Lys3)GHRP-6 in fasted rats. Rats were supplied with a pair of silver bipolar electrodes embedded in the duodenal serosa for electromyography. Ghrelin was injected intravenously into the rats during the fed state or fasted state. Some rats were pretreated with atropine, phentolamine, propranolol, L-arginine, the 5-hydroxytryptamine3 receptor antagonist ondansetron, and (D-Lys3)GHRP-6. RESULTS: Ghrelin had little effect on food intake in the first 30 min after administration, but was found to increase feeding during the subsequent hours. (D-Lys3)GHRP-6 decreased feeding and antagonized the effect of ghrelin. Ghrelin induced duodenal MMC after administration in the fed state, and shortened the duodenal MMC cycle length and the duration of phase III during fasting. The amplitude and frequency of phase III were increased without affecting the percentage of phase III in the MMC cycle. Pretreatment with atropine, L-arginine, ondansetron, and (D-Lys3)GHRP-6 inhibited the effects of ghrelin. Propranolol and phentolamine had little influence on these effects. CONCLUSIONS: Ghrelin appears to be closely related to feeding and intestinal motility. The excitatory effects of ghrelin are dependent on the cholinergic pathway, and it has a close relationship with the NOS-NO or 5-HT pathway. The ghrelin receptor is involved in its activities.


Assuntos
Ingestão de Alimentos/efeitos dos fármacos , Hormônio do Crescimento/farmacologia , Complexo Mioelétrico Migratório/efeitos dos fármacos , Hormônios Peptídicos/farmacologia , Animais , Arginina/farmacologia , Atropina/farmacologia , Duodeno/efeitos dos fármacos , Duodeno/fisiologia , Eletromiografia , Motilidade Gastrointestinal/efeitos dos fármacos , Grelina , Oligopeptídeos/farmacologia , Ondansetron/farmacologia , Hormônios Peptídicos/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores de Grelina
16.
Drug Discov Today ; 12(7-8): 276-88, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17395087

RESUMO

Ghrelin, a hormone that is produced mainly by the stomach, was identified originally as the endogenous ligand of the growth hormone secretagogue (GHS) receptor. Ghrelin might also be synthesized in other organs, where it might have autocrine or paracrine effects. GHS receptors are present in tissues other than the hypothalamus and pituitary, which indicates that ghrelin has other effects in addition to stimulating the release of growth hormone. Recently, it has been suggested that ghrelin might be involved in the pathogenesis of many diseases and be a therapeutic target in these diseases. Here, we provide an overview of the physiological effects of ghrelin and of its pathological and potential therapeutic roles.


Assuntos
Obesidade/fisiopatologia , Hormônios Peptídicos/fisiologia , Animais , Grelina , Humanos , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Hormônios Peptídicos/antagonistas & inibidores , Hormônios Peptídicos/metabolismo , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Grelina , Transdução de Sinais/efeitos dos fármacos
17.
Am J Physiol Regul Integr Comp Physiol ; 292(4): R1728-37, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17204592

RESUMO

Fasting triggers a constellation of physiological and behavioral changes, including increases in peripherally produced ghrelin and centrally produced hypothalamic neuropeptide Y (NPY). Refeeding stimulates food intake in most species; however, hamsters primarily increase foraging and food hoarding with smaller increases in food intake. Fasting-induced increases in foraging and food hoarding in Siberian hamsters are mimicked by peripheral ghrelin, central NPY, and NPY Y1 receptor agonist injections. Because fasting stimulates ghrelin and subsequently NPY synthesis/release, it may be that fasting-induced increased hoarding is mediated by NPY Y1 receptor activation. Therefore, we asked: Can an Y1 receptor antagonist block fasting- or ghrelin-induced increases in foraging, food hoarding, and food intake? This was accomplished by injecting the NPY Y1 receptor antagonist 1229U91 intracerebroventricularly in hamsters fasted, fed, or given peripheral ghrelin injections and housed in a running wheel-based food delivery foraging system coupled with simulated-burrow housing. Three foraging conditions were used: 1) no running wheel access, free food, 2) running wheel access, free food, or 3) foraging requirement (10 revolutions/pellet) for food. Fasting was a more potent stimulator of foraging and food hoarding than ghrelin. Concurrent injections of 1229U91 completely blocked fasting- and ghrelin-induced increased foraging and food intake and attenuated, but did not always completely block, fasting- and ghrelin-induced increases in food hoarding. Collectively, these data suggest that the NPY Y1 receptor is important for the effects of ghrelin- and fasting-induced increases in foraging and food intake, but other NPY receptors and/or other neurochemical systems are involved in increases in food hoarding.


Assuntos
Ingestão de Alimentos/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Hormônios Peptídicos/administração & dosagem , Receptores de Neuropeptídeo Y/fisiologia , Animais , Cricetinae , Jejum/sangue , Privação de Alimentos/fisiologia , Grelina , Injeções , Injeções Intraventriculares , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Hormônios Peptídicos/antagonistas & inibidores , Hormônios Peptídicos/sangue , Hormônios Peptídicos/farmacologia , Peptídeos Cíclicos/administração & dosagem , Peptídeos Cíclicos/farmacologia , Phodopus , Receptores de Neuropeptídeo Y/efeitos dos fármacos , Fatores de Tempo
18.
Peptides ; 27(12): 3261-8, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17097764

RESUMO

Urotensin II (UII) was first discovered in the urophyses of goby fish and later identified in mammals, while urotensin II-related peptide (URP) was recently isolated from rat brain. We studied the effects of UII on isolated heart preparations of Chinook salmon and Sprague-Dawley rats. Native rat UII caused potent and sustained, dose-dependent dilation of the coronary arteries in the rat, whereas non-native UII (human and trout UII) showed attenuated vasodilation. Rat URP dilated rat coronary arteries, with 10-fold less potency compared with rUII. In salmon, native trout UII caused sustained dilation of the coronary arteries, while rat UII and URP caused significant constriction. Nomega-nitro-(l)-arginine methyl (l-NAME) and indomethacin significantly attenuated the URP and rat UII-induced vasodilation in the rat heart. We conclude that UII is a coronary vasodilator, an action that is species form specific. We also provide the first evidence for cardiac actions of URP, possibly via mechanisms common with UII.


Assuntos
Vasos Coronários/metabolismo , Miocárdio/metabolismo , Hormônios Peptídicos/fisiologia , Salmão , Urotensinas/fisiologia , Animais , Masculino , Hormônios Peptídicos/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Urotensinas/antagonistas & inibidores
19.
Diabetes ; 55(12): 3486-93, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17130496

RESUMO

The gastric hormone ghrelin and its receptor, growth hormone secretagogue receptor (GHSR), are expressed in pancreas. Here, we report that ghrelin is released from pancreatic islets to regulate glucose-induced insulin release. Plasma concentrations of ghrelin, as well as insulin, were higher in pancreatic veins than in arteries. GHSR antagonist and immunoneutralization of endogenous ghrelin enhanced glucose-induced insulin release from perfused pancreas, whereas exogenous ghrelin suppressed it. GHSR antagonist increased plasma insulin levels in gastrectomized and normal rats to a similar extent. Ghrelin knockout mice displayed enhanced glucose-induced insulin release from isolated islets, whereas islet density, size, insulin content, and insulin mRNA levels were unaltered. Glucose tolerance tests (GTTs) in ghrelin knockout mice showed increased insulin and decreased glucose responses. Treatment with high-fat diet produced glucose intolerance in GTTs in wild-type mice. In ghrelin knockout mice, the high-fat diet-induced glucose intolerance was largely prevented, whereas insulin responses to GTTs were markedly enhanced. These findings demonstrate that ghrelin originating from pancreatic islets is a physiological regulator of glucose-induced insulin release. Antagonism of the ghrelin function can enhance insulin release to meet increased demand for insulin in high-fat diet-induced obesity and thereby normalize glycemic control, which may provide a potential therapeutic application to counteract the progression of type 2 diabetes.


Assuntos
Gorduras na Dieta , Intolerância à Glucose/prevenção & controle , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Hormônios Peptídicos/antagonistas & inibidores , Hormônios Peptídicos/metabolismo , Animais , Glicemia/metabolismo , Grelina , Insulina/sangue , Insulina/genética , Secreção de Insulina , Masculino , Camundongos , Camundongos Knockout , Hormônios Peptídicos/deficiência , Hormônios Peptídicos/genética , RNA Mensageiro/genética , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa
20.
Mol Interv ; 6(5): 249-52, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17035664

RESUMO

In the battle to treat the pandemic of obesity, one therapeutic strategy is to block endogenous signals that stimulate appetite and control body weight. One such molecule is ghrelin, a gut peptide that is the only known orexigenic hormone and is a likely contributor to mealtime hunger. The relative importance of ghrelin in long-term body-weight regulation (and thus its promise as an anti-obesity target) is uncertain, however, because genetic and pharmacologic blockade of ghrelin signaling have yielded variable results to date. Using a novel approach of vaccinating rats against their own ghrelin, Zorilla et al. report that animals with high ghrelin-specific antibody titers displayed restricted body weight, without evidence of non-specific inflammation following the vaccine. These results favor a meaningful role for ghrelin in energy homeostasis, hinting at a possible new anti-obesity approach. More broadly, the work of Zorilla et al. supports the feasibility of vaccinations directed against specific autologous targets--immunopharmacotherapy that could potentially be developed to target a wide array of medical conditions.


Assuntos
Fármacos Antiobesidade/uso terapêutico , Obesidade/prevenção & controle , Obesidade/terapia , Hormônios Peptídicos/antagonistas & inibidores , Vacinas/uso terapêutico , Animais , Peso Corporal , Grelina , Humanos , Hormônios Peptídicos/fisiologia , Ratos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...