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1.
Folia Biol (Praha) ; 67(2): 49-61, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34624937

RESUMO

This study investigated the impact of exogenous replacement therapy with acylated ghrelin (AG) post sleeve gastrectomy (SG) on the memory function in rats. In addition, we investigated the possible underlying mechanisms, including the effects on markers of oxidative stress, tau phosphorylation, and apoptosis. Adult male Wistar rats were divided into four groups (N = 18/group) as follows: sham (control), SG, SG+AG (100 µM), and SG+AG+LY294002 (0.25 µg/100 g). We continued all treatments daily for four weeks post-surgery. SG impaired the spatial, retention, and recognition memories as tested by the Morris water maze test, passive avoidance test, and novel object recognition test, respectively. Also, it enhanced the levels of reactive oxygen species and lipid peroxides, reduced glutathione and protein levels of Bcl-2, and increased the levels of Bax and cleaved caspase-3 in the hippocampus. In addition, SG reduced the hippocampal levels of acetylcholine and brain-derived neurotrophic factor. Concomitantly, it inhibited the hippocampal activity of Akt and increased the activity of glycogen synthase kinase 3ß and tau protein phosphorylation. Exogenous administration of acylated ghrelin to rats that had undergone SG prevented memory deficits. Also, it prevented the alteration in the above-mentioned biochemical parameters, an effect that was abolished by co-administration of LY294002 (phosphoinositide 3-kinase inhibitor). In conclusion, AG replacement therapy after SG in rats protects them against memory deficits and hippocampal damage by suppressing tau protein phosphorylation, mediated by activating PI3K/Aktinduced inhibition of glycogen synthase kinase 3ß.


Assuntos
Grelina , Proteínas tau , Animais , Apoptose , Gastrectomia , Grelina/metabolismo , Grelina/farmacologia , Hipocampo/metabolismo , Masculino , Estresse Oxidativo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Proteínas tau/metabolismo
2.
Int J Mol Sci ; 22(16)2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34445772

RESUMO

In this review we described the interactions between ghrelin and the growth hormone (GH)-insulin-like growth factor 1 (IGF-1) axis in children and adults with growth hormone deficiency (GHD). A possible involvement of these interactions in the pathogenesis of unexplained cases of GHD was suggested. Current research provides more and more details to the knowledge on the circadian rhythm of ghrelin. We gathered reports on the decreasing effect of Helicobacter pylori-related chronic gastritis on the number of ghrelin immunopositive cells and the consequent decrease in ghrelin serum concentration. The gastrointestinal tract microflora modification of the ghrelin action, by the mechanism of molecular mimicry, was also stressed. Moreover, the mutual relationships between ghrelin and the TSH-FT4/FT3 axis in growth and metabolic processes are described. It is to be recalled that FT4 and FT3 exert a permissive impact on IGF-1 action and, in turn, GH, in reaction mediated by IGF-1, enhances the monodeiodination of FT4 to FT3. Finally, we discussed the latest attempts to use the GH secretagogue receptor (GHS-R) analogues for possible diagnostic and therapeutic purposes.


Assuntos
Grelina/metabolismo , Hormônio do Crescimento/deficiência , Hormônio do Crescimento/metabolismo , Animais , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Receptores de Grelina/metabolismo
3.
Int J Mol Sci ; 22(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34445634

RESUMO

Cannabinoids have been reported as orexigenic, i.e., as promoting food intake that, among others, is controlled by the so-called "hunger" hormone, ghrelin. The aim of this paper was to look for functional and/or molecular interactions between ghrelin GHSR1a and cannabinoid CB2 receptors at the central nervous system (CNS) level. In a heterologous system we identified CB2-GHSR1a receptor complexes with a particular heteromer print consisting of impairment of CB2 receptor/Gi-mediated signaling. The blockade was due to allosteric interactions within the heteromeric complex as it was reverted by antagonists of the GHSR1a receptor. Cannabinoids acting on the CB2 receptor did not affect cytosolic increases of calcium ions induced by ghrelin acting on the GHSR1a receptor. In situ proximity ligation imaging assays confirmed the expression of CB2-GHSR1a receptor complexes in both heterologous cells and primary striatal neurons. We tested heteromer expression in neurons from offspring of high-fat-diet mouse mothers as they have more risk to be obese. Interestingly, there was a marked upregulation of those complexes in striatal neurons from siblings of pregnant female mice under a high-fat diet.


Assuntos
Corpo Estriado/patologia , Dieta Hiperlipídica/efeitos adversos , Grelina/metabolismo , Neurônios/patologia , Obesidade/patologia , Receptor CB2 de Canabinoide/metabolismo , Receptores de Grelina/metabolismo , Animais , Canabinoides/farmacologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Feminino , Grelina/genética , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Obesidade/etiologia , Obesidade/metabolismo , Receptor CB2 de Canabinoide/genética , Receptores de Grelina/genética , Transdução de Sinais , Regulação para Cima
4.
Nutrients ; 13(8)2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34444945

RESUMO

Anorexia nervosa (AN) is a severe eating disorder where caloric restriction, excessive physical activity and metabolic alterations lead to life-threatening situations. Despite weight restoration after treatment, a significant part of patients experience relapses. In this translational study, we combined clinical and preclinical approaches. We describe preliminary data about the effect of weight gain on the symptomatology of patients suffering from acute AN (n = 225) and partially recovered (n = 41). We measured more precisely physical activity with continuous cardiac monitoring in a sub-group (n = 68). Using a mouse model, we investigated whether a long-term food restriction followed by nutritional recovery associated or not with physical activity may differentially impact peripheral and central homeostatic regulation. We assessed the plasma concentration of acyl ghrelin, desacyl ghrelin and leptin and the mRNA expression of hypothalamic neuropeptides and their receptors. Our data show an effect of undernutrition history on the level of physical activity in AN. The preclinical model supports an important role of physical activity in the recovery process and points out the leptin system as one factor that can drive a reliable restoration of metabolic variables through the hypothalamic regulation of neuropeptides involved in feeding behavior.


Assuntos
Anorexia Nervosa/metabolismo , Anorexia Nervosa/reabilitação , Exercício Físico , Adolescente , Adulto , Animais , Anorexia Nervosa/sangue , Índice de Massa Corporal , Peso Corporal , Comportamento Alimentar , Feminino , Grelina/análogos & derivados , Grelina/sangue , Grelina/metabolismo , Frequência Cardíaca , Humanos , Hipotálamo/metabolismo , Leptina/sangue , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Neuropeptídeos/metabolismo , RNA Mensageiro/metabolismo , Recidiva , Ganho de Peso , Adulto Jovem
5.
Nat Commun ; 12(1): 5064, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417468

RESUMO

Ghrelin, also called "the hunger hormone", is a gastric peptide hormone that regulates food intake, body weight, as well as taste sensation, reward, cognition, learning and memory. One unique feature of ghrelin is its acylation, primarily with an octanoic acid, which is essential for its binding and activation of the ghrelin receptor, a G protein-coupled receptor. The multifaceted roles of ghrelin make ghrelin receptor a highly attractive drug target for growth retardation, obesity, and metabolic disorders. Here we present two cryo-electron microscopy structures of Gq-coupled ghrelin receptor bound to ghrelin and a synthetic agonist, GHRP-6. Analysis of these two structures reveals a unique binding pocket for the octanoyl group, which guides the correct positioning of the peptide to initiate the receptor activation. Together with mutational and functional data, our structures define the rules for recognition of the acylated peptide hormone and activation of ghrelin receptor, and provide structural templates to facilitate drug design targeting ghrelin receptor.


Assuntos
Oligopeptídeos/química , Receptores de Grelina/química , Sequência de Aminoácidos , Animais , Sítios de Ligação , Linhagem Celular , Microscopia Crioeletrônica , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/química , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Grelina/metabolismo , Células HEK293 , Humanos , Modelos Moleculares , Oligopeptídeos/metabolismo , Ligação Proteica , Receptores de Grelina/metabolismo , Receptores de Grelina/ultraestrutura
7.
Nutrients ; 13(7)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206176

RESUMO

Energy restriction is a first therapy in the treatment of obesity, but the underlying biological mechanisms have not been completely clarified. We analyzed the effects of restriction of high-fat diet (HFD) on weight loss, circulating gut hormone levels and expression of hypothalamic neuropeptides. Ten-week-old male Wistar rats (n = 40) were randomly distributed into four groups: two fed ad libitum a normal diet (ND) (N group) or a HFD (H group) and two subjected to a 25% caloric restriction of ND (NR group) or HFD (HR group) for 9 weeks. A 25% restriction of HFD over 9 weeks leads to a 36% weight loss with regard to the group fed HFD ad libitum accompanied by normal values in adiposity index and food efficiency ratio (FER). This restriction also carried the normalization of NPY, AgRP and POMC hypothalamic mRNA expression, without changes in CART. Caloric restriction did not succeed in improving glucose homeostasis but reduced HFD-induced hyperinsulinemia. In conclusion, 25% restriction of HFD reduced adiposity and improved metabolism in experimental obesity, without changes in glycemia. Restriction of the HFD triggered the normalization of hypothalamic NPY, AgRP and POMC expression, as well as ghrelin and leptin levels.


Assuntos
Restrição Calórica/métodos , Dieta com Restrição de Gorduras/métodos , Doenças Metabólicas/prevenção & controle , Neuropeptídeos/metabolismo , Obesidade/dietoterapia , Adiposidade/fisiologia , Proteína Relacionada com Agouti/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Gorduras na Dieta/administração & dosagem , Modelos Animais de Doenças , Ingestão de Alimentos/fisiologia , Grelina/metabolismo , Hipotálamo/metabolismo , Leptina/metabolismo , Masculino , Doenças Metabólicas/etiologia , Neuropeptídeo Y/metabolismo , Obesidade/complicações , Pró-Opiomelanocortina/metabolismo , Ratos , Ratos Wistar , Perda de Peso/fisiologia
8.
Artigo em Inglês | MEDLINE | ID: mdl-34119636

RESUMO

Ferulic acid (FA) is a phenolic acid found within the plant cell wall that has physiological benefits as an antioxidant. Although metabolic benefits of FA supplementation are described, lacking are reports of effects on appetite regulation. Thus, our objective was to determine if FA affects food or water intake, using chicks as a model. At 4 days post-hatch, broiler chicks were intraperitoneally injected with 0 (vehicle), 12.5, 25, or 50 mg/kg of FA. Chicks treated with 50 mg/kg of FA consumed 70% less food than controls at 30 min post-injection, and the effect dissipated thereafter. Water intake was not affected at any time. In a behavior analysis, FA-treated chicks defecated fewer times than vehicle-injected chicks, while other behaviors were not affected. There was an increase in c-Fos immunoreactivity within the hypothalamic arcuate nucleus (ARC) of FA-treated chicks, and no differences were detected in other nuclei. mRNA abundance was measured in the whole hypothalamus and the ARC. There was decreased hypothalamic galanin, ghrelin, melanocortin receptor 3, and pro-opiomelanocortin (POMC) mRNA in FA-treated chicks. Within the ARC, there was an increase in c-Fos mRNA and a decrease in POMC mRNA in response to FA. It is likely that the mechanism responsible for mediating FA's transient effects on food intake originates within the ARC, possibly involving POMC. A greater understanding of the short-term, mild appetite-suppressive effects of FA may have applications to treating eating disorders and modulating food intake in animal models of obesity.


Assuntos
Galinhas/metabolismo , Ácidos Cumáricos/química , Compostos Fitoquímicos/química , Animais , Animais Recém-Nascidos , Anorexia/induzido quimicamente , Apoptose , Apetite , Regulação do Apetite , Núcleo Arqueado do Hipotálamo/metabolismo , Comportamento Animal , Ácidos Cumáricos/farmacologia , Modelos Animais de Doenças , Ingestão de Líquidos/efeitos dos fármacos , Galanina/metabolismo , Grelina/metabolismo , Hipotálamo/metabolismo , Pró-Opiomelanocortina/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Receptor Tipo 3 de Melanocortina/metabolismo , Transdução de Sinais
9.
Comput Math Methods Med ; 2021: 5576808, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34122616

RESUMO

Aim: To research the molecular mechanism of ghrelin in apoptosis, migratory, and invasion of gastric cancer (GC) cells. Methods: After GC AGS cells were handled with ghrelin (10-8 M), cyclooxygenase-2 inhibitor NS398 (100 µM), and Akt inhibitor perifosine (10uM), the rates of apoptosis were detected by TUNEL assay and flow cytometry assay. We assessed the expressions of PI3K, p-Akt, and COX-2 proteins by making use of Western blot analysis. The cell migratory and invasion were detected by using wound-healing and transwell analysis. Results: The migratory and invasion were increased in ghrelin-treated cells, while the rates of apoptosis were decreased. GC AGS cells treated with ghrelin showed an increase in protein expression of p-Akt, PI3K, and COX-2. After cells were treated with Akt inhibitor perifosine, the protein expression of p-Akt, PI3K, and COX-2 and the cell migratory, invasion, and apoptosis were partly recovered. After cells were treated with cyclooxygenase-2 inhibitor NS398, the protein expression of COX-2 and the cell migratory and invasion were decreased, while the rates of apoptosis were increased. Conclusion: Ghrelin regulates cell migration, invasion, and apoptosis in GC cells through targeting PI3K/Akt/COX-2. Ghrelin increases the expression of COX-2 in GC cells by targeting PI3K/Akt. Ghrelin is suggested to be one of the molecular targets in GC.


Assuntos
Ciclo-Oxigenase 2/metabolismo , Grelina/metabolismo , Neoplasias Gástricas/metabolismo , Apoptose , Linhagem Celular Tumoral , Movimento Celular , Biologia Computacional , Inibidores de Ciclo-Oxigenase 2/farmacologia , Progressão da Doença , Humanos , Invasividade Neoplásica , Nitrobenzenos/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Neoplasias Gástricas/etiologia , Neoplasias Gástricas/patologia , Sulfonamidas/farmacologia
10.
Int J Mol Sci ; 22(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065168

RESUMO

Increasing evidence links metabolic disorders with neurodegenerative processes including Alzheimer's disease (AD). Late AD is associated with amyloid (Aß) plaque accumulation, neuroinflammation, and central insulin resistance. Here, a humanized AD model, the 5xFAD mouse model, was used to further explore food intake, energy expenditure, neuroinflammation, and neuroendocrine signaling in the hypothalamus. Experiments were performed on 6-month-old male and female full transgenic (Tg5xFAD/5xFAD), heterozygous (Tg5xFAD/-), and non-transgenic (Non-Tg) littermates. Although histological analysis showed absence of Aß plaques in the hypothalamus of 5xFAD mice, this brain region displayed increased protein levels of GFAP and IBA1 in both Tg5xFAD/- and Tg5xFAD/5xFAD mice and increased expression of IL-1ß in Tg5xFAD/5xFAD mice, suggesting neuroinflammation. This condition was accompanied by decreased body weight, food intake, and energy expenditure in both Tg5xFAD/- and Tg5xFAD/5xFAD mice. Negative energy balance was associated with altered circulating levels of insulin, GLP-1, GIP, ghrelin, and resistin; decreased insulin and leptin hypothalamic signaling; dysregulation in main metabolic sensors (phosphorylated IRS1, STAT5, AMPK, mTOR, ERK2); and neuropeptides controlling energy balance (NPY, AgRP, orexin, MCH). These results suggest that glial activation and metabolic dysfunctions in the hypothalamus of a mouse model of AD likely result in negative energy balance, which may contribute to AD pathogenesis development.


Assuntos
Doença de Alzheimer/metabolismo , Metabolismo Energético/fisiologia , Hipotálamo/metabolismo , Doenças Metabólicas/metabolismo , Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Proteínas Amiloidogênicas/metabolismo , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Polipeptídeo Inibidor Gástrico/metabolismo , Grelina/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Insulina/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Placa Amiloide/metabolismo , Resistina/metabolismo
11.
FASEB J ; 35(7): e21368, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34125448

RESUMO

In the current study, we sought to determine the roles of histone deacetylase 5 (HDAC5) on the promotion of intestinal sepsis in a mouse model. Dual luciferase reporter gene assay was used to determine the binding relationship between HDAC5 and Ghrelin. Cecal ligation and puncture (CLP) was used as an animal model of intestinal sepsis. The roles of HDAC5 on intestinal sepsis were determined by HDAC5 knockdown, overexpression, and inhibitor (LMK-235) in vivo. Mice intestinal permeability and intestinal epithelial damage were evaluated, and HE staining was used to evaluate the intestinal mucosal injury index. Lipopolysaccharide (LPS)-treated intestinal-derived macrophages served as a cell model of sepsis, followed by the loss-of-function and gain-of-function assays. ELISA was used to determine the levels of inflammatory factors, and TUNEL staining was used to detect intestinal cell apoptosis. HDAC5 was upregulated in the intestine of sepsis patients. This increased HDAC5 expression was positively correlated with the expression of inflammatory factors TNF-α, IL-1ß, IL-6, and HMGB1, as well as the intestinal dysfunction-related factors IFABP. In sepsis mice, the expression of inflammatory factors was reduced by HDAC5 knockdown. HDAC5 knockdown also improved survival, morphology of intestinal tissue, intestinal permeability, and epithelial damage. Ghrelin was bound and inhibited by HDAC5, but E2F1 expression was increased by Ghrelin overexpression, leading to inhibition of the NF-κB pathway. Ghrelin and E2F1 expression were increased by the treatment with HDAC5 inhibitor LMK-235, which inhibited the NF-κB pathway to improve intestinal dysfunction in the sepsis model. In conclusion, HDAC5 inhibits Ghrelin to reduce E2F1 and thus activate the NF-κB pathway, thereby promoting intestinal sepsis.


Assuntos
Fator de Transcrição E2F1/metabolismo , Grelina/metabolismo , Histona Desacetilases/metabolismo , Enteropatias/patologia , NF-kappa B/metabolismo , Sepse/patologia , Animais , Modelos Animais de Doenças , Fator de Transcrição E2F1/genética , Regulação da Expressão Gênica , Grelina/genética , Histona Desacetilases/genética , Humanos , Enteropatias/genética , Enteropatias/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/genética , Sepse/genética , Sepse/metabolismo
12.
Front Immunol ; 12: 646775, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33968038

RESUMO

Intestinal barrier dysfunction is an important contributor to morbidity caused by sepsis. This study investigates the molecular mechanism by which Ghrelin affects intestinal dysfunction in rat model of sepsis. A rat model of sepsis was established by cecal ligation and puncture (CLP), revealing that Ghrelin was downregulated when sepsis occurs. Increases in the levels of inflammatory factors tumor necrosis factor α (TNF-α), interleukin-1 (IL-1ß), IL-6, gastrin, γ-H2AX and 8-OHdG was also detected in this model system, as was an overall increase in oxidative stress. Introduction of exogenous Ghrelin inhibited these increases in inflammatory response and oxidative stress, leading to a reduction of overall sepsis-induced intestinal dysfunction. Ghrelin was then shown to activate SIRT1 expression in vitro, while SIRT1 was found to co-express with KLF4, which in turn was predicted to bind to matrix metalloproteinase 2 (MMP2) promoter. Finally, gain- and loss-of-function experiment demonstrated that SIRT1 upregulated the expression of KLF4 to downregulate MMP2. Collectively, Ghrelin inhibits the oxidative stress and intestinal dysfunction to attenuate sepsis by activating SIRT1 and regulating a KLF4/MMP2 regulatory axis.


Assuntos
Grelina/genética , Enteropatias/genética , Fatores de Transcrição Kruppel-Like/genética , Metaloproteinase 2 da Matriz/genética , Sepse/genética , Sirtuína 1/genética , Animais , Western Blotting , Células CACO-2 , Regulação da Expressão Gênica , Grelina/metabolismo , Humanos , Enteropatias/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sepse/metabolismo , Transdução de Sinais/genética , Sirtuína 1/metabolismo
13.
J Med Chem ; 64(10): 6856-6876, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-33973470

RESUMO

Butyrylcholinesterase (BChE) has been considered as a potential therapeutic target for Alzheimer's disease (AD) because of its compensation capacity to hydrolyze acetylcholine (ACh) and its close association with Aß deposit. Here, we identified S06-1011 (hBChE IC50 = 16 nM) and S06-1031 (hBChE IC50 = 25 nM) as highly effective and selective BChE inhibitors, which were proved to be safe and long-acting. Candidate compounds exhibited neuroprotective effects and the ability to improve cognition in scopolamine- and Aß1-42 peptide-induced cognitive deficit models. The best candidate S06-1011 increased the level of ghrelin, a substrate of BChE, which can function as improving the mental mood appetite. The weight gain of the S06-1011-treated group remarkably increased. Hence, BChE inhibition not only plays a protective role against dementia but also exerts a great effect on treating and nursing care.


Assuntos
Butirilcolinesterase/química , Inibidores da Colinesterase/química , Fármacos Neuroprotetores/química , Peptídeos beta-Amiloides/farmacologia , Animais , Sítios de Ligação , Butirilcolinesterase/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/patologia , Modelos Animais de Doenças , Desenho de Fármacos , Grelina/metabolismo , Meia-Vida , Humanos , Camundongos , Camundongos Endogâmicos ICR , Simulação de Dinâmica Molecular , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Fragmentos de Peptídeos/farmacologia , Quinolinas/química , Quinolinas/metabolismo , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Regulação para Cima/efeitos dos fármacos
14.
Folia Histochem Cytobiol ; 59(2): 86-94, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33834452

RESUMO

INTRODUCTION: Ghrelin, originally isolated from the endocrine cells of the gastric mucosa, is also expressed in many peripheral tissues, including normal adrenals and adrenocortical tumors. It was shown that ghrelin stimulates proliferation and inhibits apoptosis of adrenocortical cells. In the current study, we compared ghrelin expression at the protein level in various adrenal tumors. We analyzed whether immunoreactive ghrelin could be considered as a potential marker for different types of adrenal tumors. MATERIAL AND METHODS: Study was carried out on 200 adrenal specimens arranged on microscope slide in tissue microarray format. We performed standardized immunohistochemical reactions with semiquantitative reaction intensity measurements. RESULTS: At the protein level, the expression of ghrelin was significantly reduced in adrenocortical adenocarcinoma in relation to the control group and pheochromocytoma as well as cancer-adjacent normal adrenal tissue. In contrast, a relatively high ghrelin expression was found in pheochromocytoma compared to all analyzed groups, with the exception of cancer-adjacent normal adrenal tissue. CONCLUSIONS: The ghrelin expression profile at the protein level may be associated with the type of adrenal tumor. In this context, our results suggest that adrenal immunoreactive ghrelin may be considered as a sensitive and specific marker for differentiating adrenocortical carcinoma from adrenocortical adenoma and pheochromocytoma.


Assuntos
Adenoma Adrenocortical/metabolismo , Biomarcadores Tumorais/metabolismo , Grelina/metabolismo , Glândulas Suprarrenais/metabolismo , Glândulas Suprarrenais/patologia , Adenoma Adrenocortical/patologia , Humanos , Imuno-Histoquímica , Neoplasias Neuroepiteliomatosas/metabolismo , Neoplasias Neuroepiteliomatosas/patologia , Feocromocitoma/metabolismo , Feocromocitoma/patologia , Curva ROC
15.
Arch Biochem Biophys ; 704: 108872, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33857472

RESUMO

The gastric peptide ghrelin has important functions in energy metabolism and cellular homeostasis by activating growth hormone secretagogue receptor type 1a (GHSR1a). The N-terminal residues of ghrelin orthologs from all vertebrates are quite conserved; however, in orthologs from Cavia porcellus and Phyllostomus discolor, Ser2 and Leu5 are replaced by a smaller Ala and a positively charged Arg, respectively. In the present study, we first demonstrated that the hydrophobic Leu5 is essential for the function of human ghrelin, because Ala replacement caused an approximately 100-fold decrease in activity. However, replacement of Leu5 by an Arg residue caused much less disruption; further replacement of Ser2 by Ala almost restored full activity, although the [S2A] mutation itself showed slight detriments, implying that the positively charged Arg5 in the [S2A,L5R] mutant might form alternative interactions with certain receptor residues to compensate for the loss of the essential Leu5. To identify the responsible receptor residues, we screened GHSR1a mutants in which all conserved negatively charged residues in the extracellular regions and all aromatic residues in the ligand-binding pocket were mutated separately. According to the decrease in selectivity of the mutant receptors towards [S2A,L5R]ghrelin, we deduced that the positively charged Arg5 of the ghrelin mutant primarily interacts with the essential aromatic Phe286 at the extracellular end of the sixth transmembrane domain of GHSR1a by forming cation-π and π-π interactions. The present study provided new insights into the binding mechanism of ghrelin with its receptor, and thus would facilitate the design of novel ligands for GHSR1a.


Assuntos
Grelina/química , Receptores de Grelina/química , Animais , Quirópteros , Grelina/genética , Grelina/metabolismo , Cobaias , Células HEK293 , Humanos , Ligação Proteica , Domínios Proteicos , Receptores de Grelina/genética , Receptores de Grelina/metabolismo
16.
Int J Mol Sci ; 22(7)2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33916403

RESUMO

Growth hormone secretagogue receptor 1a (GHS-R1a), which is one of the G protein-coupled receptors (GPCRs), is involved in various physiological actions such as energy consumption, growth hormone secretion promoting action, and cardiovascular protective action. The ligand was searched for as an orphan receptor for a while, but the ligand was found to be acylated ghrelin (ghrelin) discovered by Kangawa and Kojima et al. in 1999. Recently, it has also been reported that dysregulation of GHS-R1a mediates reduced feeding in various diseases. On the other hand, since the physiological effects of ghrelin have been studied exclusively in male mice, few studies have been conducted on gender differences in ghrelin reactivity. In this review, we describe (1) the characteristics of GHS-R1a, (2) the role of ghrelin in hypophagia due to stress or anticancer drugs, and (3) the gender differences in the physiological effects of GHS-R1a and the influence of stress on it.


Assuntos
Ingestão de Alimentos , Transtornos da Alimentação e da Ingestão de Alimentos/metabolismo , Grelina/metabolismo , Receptores de Grelina/metabolismo , Caracteres Sexuais , Transdução de Sinais , Animais , Transtornos da Alimentação e da Ingestão de Alimentos/patologia , Feminino , Humanos , Masculino , Camundongos
17.
Appetite ; 164: 105260, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-33848592

RESUMO

Nicotine has been shown to decrease appetite, food intake (FI) and body weight, but the mechanisms are unclear. The purpose of this review was to examine research on the effects of nicotine on energy balance by exploring physiological mechanisms and hormone regulation related to FI, subjective appetite and energy expenditure (EE). We searched PubMed and MEDLINE, and included articles investigating the effects of nicotine on central appetite regulation, FI, leptin, peptide-YY (PYY), ghrelin, glucagon-like peptide-1 (GLP-1), adiponectin, cholecystokinin (CCK), orexin, and EE. A total of 65 studies were included in the qualitative synthesis and review. Our findings suggest that the decrease in appetite and FI may be attributed to nicotinic alterations of neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) but the effect of nicotine on FI remains unclear. Furthermore, nicotine increases resting EE (REE) and physical activity EE (PAEE) in both smokers and non-smokers; and these increases may be a result of the catecholaminergic effect of nicotine. Decreases in body weight and appetite experienced by nicotine users results from increased EE and changes in the central hypothalamic regulation of appetite. There is not enough evidence to implicate a relationship between peripheral hormones and changes in appetite or FI after nicotine use. Although nicotine increases REE and PAEE, the effect of nicotine on other components of EE warrants further research. We conclude that further research evaluating the effect of nicotine on appetite hormones, FI and EE in humans is warranted.


Assuntos
Apetite , Metabolismo Energético , Nicotina , Regulação do Apetite , Ingestão de Energia , Grelina/metabolismo , Humanos , não Fumantes , Peptídeo YY/metabolismo , Fumantes
18.
Exp Neurol ; 341: 113708, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33771554

RESUMO

Leaky gut that is a condition reflecting intestinal barrier dysfunction has been attracting attention for its relations with many diseases such as irritable bowel syndrome or Alzheimer dementia. We have recently demonstrated that ghrelin acts in the brain to improve leaky gut via the vagus nerve. In the present study, we tried to clarify the precise central mechanisms by which ghrelin improves intestinal barrier function through the vagus nerve. Colonic permeability was estimated in vivo by quantifying the absorbed Evans blue in colonic tissue in rats. Adenosine receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), blocked the intracisternal ghrelin-induced improvement of intestinal hyperpermeability while dopamine, cannabinoid or opioid receptor antagonist failed to prevent it. Since DPCPX can block adenosine A1 and adenosine A2B receptors, we examined which subtype is involved in the mechanism. Intracisternal injection of adenosine A2B agonist but not adenosine A1 agonist improved colonic hyperpermeability, while peripheral injection of adenosine A2B agonist failed to improve it. Intracisternal adenosine A2B agonist-induced improvement of colonic hyperpermeability was blocked by vagotomy. Adenosine A2B specific antagonist, alloxazine blocked the ghrelin- or central vagal stimulation by 2-deoxy-d-glucose-induced improvement of intestinal hyperpermeability. These results suggest that activation of adenosine A2B receptors in the central nervous system is capable of improving intestinal barrier function through the vagal pathway, and the adenosine A2B receptors may mediate the ghrelin-induced improvement of leaky gut in a vagal dependent fashion. These findings may help us understand the pathophysiology in not only gastrointestinal diseases but also non-gastrointestinal diseases associated with the altered intestinal permeability.


Assuntos
Encéfalo/metabolismo , Grelina/metabolismo , Mucosa Intestinal/metabolismo , Receptor A2B de Adenosina/metabolismo , Nervo Vago/metabolismo , Agonistas do Receptor A2 de Adenosina/administração & dosagem , Antagonistas do Receptor A2 de Adenosina/administração & dosagem , Animais , Encéfalo/efeitos dos fármacos , Grelina/administração & dosagem , Humanos , Injeções Subcutâneas , Mucosa Intestinal/efeitos dos fármacos , Masculino , Permeabilidade/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Nervo Vago/efeitos dos fármacos
19.
Molecules ; 26(4)2021 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-33672773

RESUMO

A caloric surplus and a sedentary lifestyle are undoubtedly known to be the leading causes of obesity. Natural products represent valuable allies to face this problematic issue. This study was planned to assess the effect of a white grape (Vitis vinifera) juice extract (WGJe) in diet-induced obese zebrafish (Danio rerio). Fish were divided into four different diet groups: (i) normally fed (NF); (ii) overfed (OF); (iii) WGJe-supplemented NF (5 mL/L in fish water); (iv) WGJe-supplemented OF. Body mass index (BMI) was extrapolated each week. After the fourth week, euthanized zebrafish were processed for both microscopic evaluations and gene expression analyses. OF zebrafish showed higher BMI values with respect to NF counterparts, an effect that was hindered by WGJe treatment. Moreover, histological analyses showed that the area of the adipose tissue, as well as the number, size, and density of adipocytes was significantly higher in OF fish. On the other hand, WGJe was able to avoid these outcomes both at the subcutaneous and visceral levels, albeit to different extents. At the gene level, WGJe restored the altered levels of ghrelin and leptin of OF fish both in gut and brain. Overall, our results support the anti-obesity property of WGJe, suggesting its potential role in weight management.


Assuntos
Adipócitos/efeitos dos fármacos , Gorduras/antagonistas & inibidores , Grelina/antagonistas & inibidores , Leptina/antagonistas & inibidores , Extratos Vegetais/farmacologia , Vitis/química , Animais , Modelos Animais de Doenças , Gorduras/metabolismo , Sucos de Frutas e Vegetais/análise , Grelina/genética , Grelina/metabolismo , Leptina/genética , Leptina/metabolismo , Estrutura Molecular , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Peixe-Zebra
20.
Nutrients ; 13(3)2021 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-33673594

RESUMO

INTRODUCTION: Ghrelin is an orexigenic hormone which favors food-seeking behavior and has been postulated to be a biomarker of stress. We conducted a systematic review and meta-analysis on the evolution of ghrelin levels following acute stress. METHODS: The PubMed, Cochrane Library, Embase, and ScienceDirect databases were searched for studies reporting ghrelin levels before and after acute stress in humans. RESULTS: We included ten studies for a total of 348 patients. Acute stress (intervention) was always in a laboratory. Acute stress was psychological (Trier Social Stress Test), physical, or mixed (cold pressure test). The overall meta-analysis demonstrated an increase in ghrelin after the stress intervention (ES = 0.21, 95CI 0.09 to 0.34) compared with baseline levels. Stratification by time demonstrated an acute increase in ghrelin levels in the five minutes immediately following the initiation of stress (0.29, 0.10 to 0.48) but without any difference after. Obese individuals had a more significant (ES = 0.51, 95CI 0.18 to 0.84) and prolonged increase in ghrelin levels for up to 45 min compared with non-obese individuals who had a significant increase only five minutes after stress. Moreover, the ghrelin levels increased in response to stress with BMI (coefficient 0.028, 0.01 to 0.49; p = 0.013) and decreased with the time after the stress intervention (coefficient -0.007, -0.014 to -0.001; p = 0.025). CONCLUSION: Ghrelin is a biomarker of stress, with a short-term increase following acute stress. Obese individuals have both a higher and prolonged response, emphasizing the link between obesity and stress.


Assuntos
Grelina/sangue , Estresse Fisiológico/fisiologia , Estresse Psicológico/sangue , Biomarcadores/sangue , Grelina/metabolismo , Humanos , Estresse Psicológico/metabolismo
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