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1.
PLoS One ; 15(5): e0233863, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32470053

RESUMO

Adaptive regulation of epithelial transporters to nutrient intake is essential to decrease energy costs of their synthesis and maintenance, however such regulation is understudied. Previously we demonstrated that the transport function of the basolateral amino acid uniporter LAT4 (Slc43a2) is increased by dephosphorylation of serine 274 (S274) and nearly abolished by dephosphorylation of serine 297 (S297) when expressed in Xenopus oocytes. Phosphorylation changes in the jejunum of food-entrained mice suggested an increase in LAT4 transport function during food expectation. Thus, we investigated further how phosphorylation, expression and localization of mouse intestinal LAT4 respond to food-entrained diurnal rhythm and dietary protein content. In mice entrained with 18% protein diet, LAT4 mRNA was not submitted to diurnal regulation, unlike mRNAs of luminal symporters and antiporters. Only in duodenum, LAT4 protein expression increased during food intake. Concurrently, S274 phosphorylation was decreased in all three small intestinal segments, whereas S297 phosphorylation was increased only in jejunum. Interestingly, during food intake, S274 phosphorylation was nearly absent in ileum and accompanied by strong phosphorylation of mTORC1 target S6. Entraining mice with 8% protein diet provoked a shift in jejunal LAT4 localization from the cell surface to intracellular stores and increased S274 phosphorylation in both jejunum and ileum during food anticipation, suggesting decreased transport function. In contrast, 40% dietary protein content led to increased LAT4 expression in jejunum and its internalization in ileum. Ex vivo treatments of isolated intestinal villi fraction demonstrated that S274 phosphorylation was stimulated by protein kinase A. Rapamycin-sensitive insulin treatment and amino acids increased S297 phosphorylation, suggesting that the response to food intake might be regulated via the insulin-mTORC1 pathway. Ghrelin, an oscillating orexigenic hormone, did not affect phosphorylation of intestinal LAT4. Overall, we show that phosphorylation, expression and localization of intestinal mouse LAT4 responds to diurnal and dietary stimuli in location-specific manner.


Assuntos
Sistema L de Transporte de Aminoácidos/metabolismo , Sistema y+ de Transporte de Aminoácidos/metabolismo , Ritmo Circadiano , Proteínas na Dieta/farmacologia , Alimentos , Intestinos/fisiologia , Aminoácidos/metabolismo , Animais , Antiporters/metabolismo , Ritmo Circadiano/efeitos dos fármacos , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Grelina/administração & dosagem , Grelina/farmacologia , Insulina/metabolismo , Intestino Delgado/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos Endogâmicos C57BL , Microvilosidades/efeitos dos fármacos , Microvilosidades/metabolismo , Fosforilação/efeitos dos fármacos , Fosfosserina/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Frações Subcelulares/metabolismo , Simportadores/metabolismo , Serina-Treonina Quinases TOR/metabolismo
2.
Chem Biol Interact ; 322: 109059, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32171850

RESUMO

Fatty liver is the earliest and most common response of the liver to consumption of excessive alcohol. Steatosis can predispose the fatty liver to develop progressive liver damage. Chief among the many mechanisms involved in development of hepatic steatosis is dysregulation of insulin-mediated adipose tissue metabolism. Particularly, it is the enhanced adipose lipolysis-derived free fatty acids and their delivery to the liver that ultimately results in hepatic steatosis. The adipose-liver axis is modulated by hormones, particularly insulin and adiponectin. In recent studies, we demonstrated that an alcohol-induced increase in serum ghrelin levels impairs insulin secretion from pancreatic ß-cells. The consequent reduction in circulating insulin levels promotes adipose lipolysis and mobilization of fatty acids to the liver to ultimately contribute to hepatic steatosis. Because many tissues, including adipose tissue, express ghrelin receptor we hypothesized that ghrelin may directly affect energy metabolism in adipocytes. We have exciting new preliminary data which shows that treatment of premature 3T3-L1 adipocytes with ghrelin impairs adipocyte differentiation and inhibits lipid accumulation in the tissue designed to store energy in the form of fat. We further observed that ghrelin treatment of differentiated adipocytes significantly inhibited secretion of adiponectin, a hepatoprotective hormone that reduces lipid synthesis and promotes lipid oxidation. These results were corroborated by our observations of a significant increase in serum adiponectin levels in ethanol-fed rats treated with a ghrelin receptor antagonist verses the un-treated ethanol-fed rats. Interestingly, in adipocytes, ghrelin also increases secretion of interleukin-6 (IL-6) and CCL2 (chemokine [C-C motif] ligand 2), cytokines which promote hepatic inflammation and progression of liver disease. To summarize, the alcohol-induced increase in serum ghrelin levels dysregulates adipose-liver interaction and promotes hepatic steatosis by increasing the free fatty acid released from adipose for hepatic uptake, and by altering adiponectin and cytokine secretion. Taken together, our data indicates that targeting the activity of ghrelin may be a powerful treatment strategy.


Assuntos
Tecido Adiposo/metabolismo , Fígado Gorduroso Alcoólico/patologia , Grelina/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Células 3T3-L1 , Adipocinas/metabolismo , Adiponectina/sangue , Adiponectina/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Quimiocina CCL2/metabolismo , Etanol/farmacologia , Fígado Gorduroso Alcoólico/metabolismo , Fígado Gorduroso Alcoólico/veterinária , Interleucina-6/metabolismo , Masculino , Camundongos , Oligopeptídeos/farmacologia , PPAR gama/metabolismo , Ratos , Ratos Wistar
3.
Endocrinol. diabetes nutr. (Ed. impr.) ; 67(2): 89-101, feb. 2020. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-187433

RESUMO

Antecedentes y objetivo: En el hipotálamo existen poblaciones neuronales involucradas en la regulación de la ingesta, destacando la ghrelina como hormona orexígena (estimula el apetito). Después de los diferentes procedimientos de cirugía bariátrica se han observado cambios en los niveles plasmáticos de ghrelina, siendo los resultados de los estudios contradictorios. Existen muchas lagunas en cuanto al papel que desempeña la ghrelina en el proceso de pérdida de peso después de cirugía bariátrica. Nuestro objetivo es describir el comportamiento de ghrelina en ayunas, comparando los cambios acontecidos en 2 técnicas quirúrgicas (bypass gástrico versus gastrectomía vertical) y su correlación con la pérdida ponderal. Pacientes y método: Estudio observacional de cohortes analíticas prospectivo, donde se incluyen 54 pacientes (27 por cada técnica quirúrgica) y un período de seguimiento de 12 meses. Se analizaron datos demográficos, datos antropométricos, comorbilidades, pérdida ponderal y evolución del comportamiento de ghrelina en ayunas. Resultados: Con ambas técnicas quirúrgicas el comportamiento de ghrelina acilada fue similar, sin diferencias significativas entre bypass gástrico y gastrectomía vertical. Con ambos procedimientos se produce un ascenso de ghrelina acilada al 5.o día y caída posterior, para luego ir ascendiendo hasta alcanzar valores superiores a los preoperatorios a los 12 meses. Este aumento en los niveles de ghrelina no afecta a la pérdida ponderal, ya que al año de la cirugía con las 2 técnicas quirúrgicas se alcanza un 30% de pérdida de peso. Conclusiones: Observamos un incremento de los niveles de ghrelina acilada en ayunas al año de seguimiento con ambas técnicas quirúrgicas, cuando existe una pérdida ponderal del 30%


Background and objective: Neuronal populations involved in the regulation of food intake, particularly the orexigenic (appetite-stimulating) hormone ghrelin, are found in the hypothalamus. Changes in plasma ghrelin levels have been observed following different bariatric surgery procedures, but the results from different studies are contradictory. Much remains unknown regarding the role of ghrelin in the weight loss process following bariatric surgery. Our objective was to describe the behaviour of fasting ghrelin levels, comparing the changes occurring between 2 different surgical techniques (gastric bypass versus vertical sleeve gastrectomy) and their correlation with weight loss. Patients and method: A prospective, observational, analytic cohort study of 54 patients (27 for each surgical technique) with a 12-month follow-up period. We analysed demographic data, anthropometric data, comorbidities, weight loss and evolution of fasting ghrelin. Results: The behaviour of acylated ghrelin was similar with the 2 surgical techniques, with no significant differences between gastric bypass and vertical sleeve gastrectomy. With both procedures, there was an increase in acylated ghrelin on day 5 and a subsequent decrease, and levels then gradually increased to reach values at 12 months that were higher than those reported preoperatively. This increase in ghrelin levels did not affect weight loss, since one year post-surgery, 30% weight loss was achieved with both types of surgery. Conclusions: We observed an increase in fasting acylated ghrelin levels at one year of follow-up with both surgical techniques, with 30% weight los


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Grelina/administração & dosagem , Estudos de Coortes , Derivação Gástrica , Gastrectomia , Cirurgia Bariátrica/métodos , Grelina/metabolismo , Estudos Prospectivos , Antropometria , Índice de Massa Corporal , Perda de Peso , Grelina/farmacologia
4.
Fish Shellfish Immunol ; 98: 100-108, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31911288

RESUMO

Ghrelin is a peptide hormone secreted by gastrointestinal tract which regulates multiple physiological processes such as appetite, metabolism, growth and gonad development in fish. In the present study, the effects of ghrelin on hybrid tilapia infected with Aeromonas hydrophila are elucidated. Juvenile hybrid tilapia fish (20.0 ± 5.0 g) were intraperitoneally injected with 0, 0.1, 1.0, or 10.0 ng/g ghrelin/body weight synthetic ghrelin alone or in combination with A. hydrophila (0.5 × 106 CFU). At 10 days post treatment, the survival rate in the group that received 1.0 ng/g ghrelin/body weight ghrelin in combination with A. hydrophila was higher (66.66%) than that of the Ah group (13.33%) that received A. hydrophila alone. In tilapia that received ghrelin injections, reactive oxygen species (ROS) levels tended to increase at 5 h, while injection of 10.0 ng/g ghrelin/body weight ghrelin resulted in a significant decrease in ROS levels at 10 h. No changes in serum immune or antioxidant-related indicators were observed in fish injected with A. hydrophila compared to controls. However, ghrelin injection decreased Albumin (ALB), glutathione peroxidase (GSH-Px), lysozyme (LZM) and superoxide dismutase (SOD). Histological analysis showed that ghrelin injection alleviated the pathological changes in liver and spleen caused by A. hydrophila infection. Overall, the expression of HSP70, IL-1ß, and TGF-ß in the liver tended to upregulate compared to the control. In the kidney, HSP70, IL-1ß and TGF-ß levels were increased, and TNF-α expression levels were decreased compared to the control. The HSP70 level in the spleen was decreased, and IL-1ß, TGF-ß, and TNF-α were expressed at significantly higher levels in the spleen in the tilapia that received ghrelin injections. Taken together, our results indicate that injection with 1.0 ng/g ghrelin/body weight ghrelin may effectively protect juvenile hybrid tilapia against A. hydrophila infection by improving hematological indicators, maintaining normal histology and regulating cytokine gene expression.


Assuntos
Ciclídeos/imunologia , Resistência à Doença/imunologia , Doenças dos Peixes/prevenção & controle , Grelina/farmacologia , Infecções por Bactérias Gram-Negativas/veterinária , Imunidade Inata/efeitos dos fármacos , Aeromonas hydrophila/fisiologia , Animais , Relação Dose-Resposta a Droga , Doenças dos Peixes/imunologia , Grelina/administração & dosagem , Infecções por Bactérias Gram-Negativas/imunologia , Infecções por Bactérias Gram-Negativas/prevenção & controle , Distribuição Aleatória
5.
Chem Biol Interact ; 315: 108893, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31706954

RESUMO

This study aimed to investigate the effects of teaghrelin, an active ingredient of Chin-shin oolong tea, on murine C2C12 myoblast cells. Under high serum conditions, teaghrelin inhibited C2C12 cell proliferation, indicating a cell cycle arrest and cessation of proliferative progression. Teaghrelin promoted pro-differentiation of C2C12 cells as evidenced by a progressively elongated morphology, as well as the induction of muscle specific myogenin, myosin heavy chain (MHC), and MyoD. The formation of multinucleated myotubes, and the increase of MHC-positive immunoreactivity within the myotubes, further reflected a complete differentiation and maturation of the contractile skeletal muscle cells induced by teaghrelin. Like ghrelin, teaghrelin attenuated dexamethasone-decreased myotube diameter, indicating its protective effects against skeletal muscle atrophy. Additionally, the expressions of Atrogin-1 and MuRF-1 ubiquitin E3 ligase were reduced. In conclusion, the results highlight a possibility of developing teaghrelin as a functional food for the prevention or therapeutic treatment of disease-associated skeletal muscle atrophy.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Grelina/farmacologia , Fibras Musculares Esqueléticas/efeitos dos fármacos , Atrofia Muscular/tratamento farmacológico , Mioblastos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Chá/química , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Camundongos , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Proteína MyoD/metabolismo , Mioblastos/metabolismo , Miogenina/metabolismo , Cadeias Pesadas de Miosina/metabolismo , Substâncias Protetoras/farmacologia , Transdução de Sinais/efeitos dos fármacos , Ubiquitina-Proteína Ligases/metabolismo
6.
Arch Physiol Biochem ; 126(1): 31-40, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30320517

RESUMO

This study investigated the effect of acylated ghrelin (AG) deficiency after sleeve gastrectomy (SG) or chronic administration in control and SG-indiuced rats on platelet function, coagulation, and fibrinolysis. Administration of AG (100 µg/kg, subcutaneously) to control or SG rats significantly inhibited platelets aggregation and lowered levels of Von-Willebrand factor (vWF), fibrinogen, and thromboxane B2. Concomitantly, it decreased circulatory levels and aortic expression levels of plasminogen activator inhibitor-1 (PAI-1) and tissue factor (TF) and increased the aortic expression of the endothelial nitric oxidase (eNOS). However, AG inhibited angiotensin-II (ANGII)-induced upregulation of tissue factor pathway inhibitor (TPAI) and TF and increased activity of TF and increases eNOS expression in cultured endothelial cells, an effect that was abolished by the addition of D-[lys3]-GHRP-6, a selective AG receptor (GHSR-1a) blocker or L-Name, a potent eNOS inhibitor. In conclusion, AG has an anti-platelet, anti-coagulant, and fibrinolytic roles mediated through GHSR-1a to enhance nitric oxide synthesis.


Assuntos
Aorta/efeitos dos fármacos , Coagulação Sanguínea/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Gastrectomia/métodos , Grelina/farmacologia , Hemostáticos/farmacologia , Acilação , Angiotensina II/farmacologia , Animais , Aorta/citologia , Aorta/metabolismo , Esquema de Medicação , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Fibrinogênio/metabolismo , Expressão Gênica/efeitos dos fármacos , Grelina/análogos & derivados , Injeções Subcutâneas , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Oligopeptídeos/farmacologia , Inibidor 1 de Ativador de Plasminogênio/genética , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Agregação Plaquetária/efeitos dos fármacos , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Receptores de Grelina/antagonistas & inibidores , Receptores de Grelina/genética , Receptores de Grelina/metabolismo , Tromboxano B2/metabolismo , Fator de von Willebrand/metabolismo
7.
Gen Comp Endocrinol ; 285: 113294, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31585115

RESUMO

Motilin and ghrelin were identified in the pheasant by molecular cloning, and the actions of both peptides on the contractility of gastrointestinal (GI) strips were examined in vitro. Molecular cloning indicated that the deduced amino acid sequences of the pheasant motilin and ghrelin were a 22-amino acid peptide, FVPFFTQSDIQKMQEKERIKGQ, and a 26-amino acid peptide, GSSFLSPAYKNIQQQKDTRKPTGRLH, respectively. In in vitro studies using pheasant GI strips, chicken motilin caused contraction of the proventriculus and small intestine, whereas the crop and colon were insensitive. Human motilin, but not erythromycin, caused contraction of small intestine. Chicken motilin-induced contractions in the proventriculus and ileum were not inhibited by a mammalian motilin receptor antagonist, GM109. Neither atropine (a cholinergic receptor antagonist) nor tetrodotoxin (a neuron blocker) inhibited the responses of chicken motilin in the ileum but both drugs decreased the responses to motilin in the proventriculus, suggesting that the contractile mechanisms of motilin in the proventriculus was neurogenic, different from that of the small intestine (myogenic). On the other hand, chicken and quail ghrelin did not cause contraction in any regions of pheasant GI tract. Since interaction of ghrelin and motilin has been reported in the house musk shrew, interaction of two peptides was examined. The chicken motilin-induced contractions were not modified by ghrelin, and ghrelin also did not cause any contraction under the presence of motilin, suggesting the absence of interaction in both peptides. In conclusion, both the motilin system and ghrelin system are present in the pheasant. Regulation of GI motility by motilin might be common in avian species. However, absence of ghrelin actions in any GI regions suggests the avian species-related difference in regulation of GI contractility by ghrelin.


Assuntos
Aves/metabolismo , Trato Gastrointestinal/fisiologia , Grelina/farmacologia , Motilina/farmacologia , Contração Muscular/efeitos dos fármacos , Sequência de Aminoácidos , Animais , Atropina/farmacologia , Sequência de Bases , Galinhas , Clonagem Molecular , Feminino , Motilidade Gastrointestinal/efeitos dos fármacos , Motilidade Gastrointestinal/fisiologia , Trato Gastrointestinal/efeitos dos fármacos , Grelina/química , Grelina/genética , Humanos , Masculino , Motilina/química , Motilina/genética , Proventrículo/efeitos dos fármacos , Codorniz , Ratos , Receptores dos Hormônios Gastrointestinais/metabolismo , Receptores de Neuropeptídeos/metabolismo , Tetrodotoxina/farmacologia
9.
J Assist Reprod Genet ; 36(11): 2357-2366, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31650454

RESUMO

PURPOSE: Psychological stress exists widely in modern society and results in the disruption of testicular tight junctions, germ cell apoptosis, and the disorder of fertility hormones and even causes infertility. Ghrelin (GHRL), a 28-amino acid peptide secreted mainly by the stomach and pancreas, has been reported to alleviate male reproductive injury through inhibiting apoptosis. However, whether GHRL has a beneficial effect on psychological stress-induced testicular injury and the possible mechanisms remain poorly understood. METHODS: Male mice were immobilized in Decapicone bags for 3 h daily for 14 days treated with or without GHRL (i.p. 100 mg/kg body weight). Body weight and testicular weight were measured. Histological alterations and apoptosis were examined by H.E. staining and TUNEL staining, respectively. The expression of endoplasmic reticulum (ER) stress markers, inflammatory cytokines, Toll-like receptor 4 (TLR4), and nuclear factor-κB (NF-κB) in the testes was investigated. RESULTS: Exposure to stress caused testicular histological alterations, an elevation of the Johnsen score, and germ cell apoptosis, while GHRL partially alleviated the adverse effects. The expression of ER stress marker proteins, including GRP78, CHOP, ATF6, p-JNK, and XBP-1, was upregulated in the stress group; however, GHRL treatment significantly suppressed the activation of ER stress in the testes. GHRL also inhibited the expression of TNF-α, IL-1ß, IL-6, IL-10, TLR4, and NF-κB. CONCLUSIONS: GHRL alleviated testicular injury induced by ER stress and inflammation which is associated with the TLR4/NF-κB signaling pathway, and these findings may provide a novel strategy for preventing and treating reproductive dysfunction.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Grelina/farmacologia , Inflamação/tratamento farmacológico , Reprodução/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Citocinas/metabolismo , Feminino , Células Germinativas/efeitos dos fármacos , Células Germinativas/metabolismo , Marcação In Situ das Extremidades Cortadas/métodos , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Transdução de Sinais/efeitos dos fármacos
10.
Rev Assoc Med Bras (1992) ; 65(9): 1188-1192, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31618336

RESUMO

OBJECTIVE: We aimed to explore the effects of neuropeptides ghrelin, obestatin, and vasoactive intestinal peptide (VIP) on seizures and plasma concentrations of neuroinflammation biomarkers including calcitonin gene-related peptide (CGRP), substance-P (SP), and interleukin-1 beta (IL-1ß) in pentylenetetrazol-induced seizures in rats. METHODS: Ghrelin (80 µg/kg), obestatin (1 µg/kg), VIP (25 ng/kg) or saline were administered to rats intraperitoneally 30 min before pentylenetetrazole (PTZ, 50 mg/kg) injections. Stages of epileptic seizures were evaluated by Racine's scale, and plasma CGRP, SP, and IL-1ß concentrations were measured using ELISA. RESULTS: Both obestatin and VIP shortened onset-time of generalized tonic-clonic seizure, respectively, moreover VIP also shortened the onset-time of first myoclonic-jerk induced by PTZ. While PTZ increased plasma CGRP, SP and IL-1ß concentrations, ghrelin reduced the increases evoked by PTZ. While VIP further increased PTZ-evoked CGRP levels, it diminished IL-1ß concentrations. However, obestatin did not change CGRP, SP, and IL-1ß concentrations. CONCLUSION: Our results suggest that ghrelin acts as an anticonvulsant, obestatin acts as a proconvulsant, and VIP has dual action on epilepsy. Receptors of those neuropeptides may be promising targets for epilepsy treatment.


Assuntos
Convulsivantes/efeitos adversos , Neuropeptídeos/efeitos dos fármacos , Pentilenotetrazol/efeitos adversos , Hormônios Peptídicos/farmacologia , Convulsões/induzido quimicamente , Animais , Biomarcadores/sangue , Peptídeo Relacionado com Gene de Calcitonina/sangue , Peptídeo Relacionado com Gene de Calcitonina/efeitos dos fármacos , Modelos Animais de Doenças , Grelina/farmacologia , Inflamação , Interleucina-1beta/sangue , Interleucina-1beta/efeitos dos fármacos , Masculino , Mioclonia , Distribuição Aleatória , Ratos Wistar , Convulsões/metabolismo , Substância P/sangue , Substância P/efeitos dos fármacos , Fatores de Tempo , Peptídeo Intestinal Vasoativo/farmacologia
11.
Mol Med Rep ; 20(6): 5050-5058, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31638214

RESUMO

Ghrelin is an orexigenic hormone that is produced by gastric cells. Ghrelin stimulates food intake and increases gastric movement. In rat model, injected ß­hydroxybutyric acid (ß­HB) leads to a decrease in body weight. It has been reported that patients with gastric erosions are slower to evacuate the stomach. The aim of the present study was to investigate the effects of ghrelin and ß­HB on motility and inflammation in rat gastric antral smooth muscle cells (GASMCs). GASMCs were extracted from rat gastric antrum. Cell viability was determined using the Cell Counting Kit­8 assay. A reactive oxygen species (ROS) assay kit was used to analyze the levels of ROS using flow cytometry. Protein levels were determined using western blotting, and the expression levels of mRNAs were evaluated using reverse transcription­quantitative PCR. ß­HB inhibited the expression of myosin regulatory light polypeptide 9 (MYL9), myosin light chain kinase (MLCK), transforming protein RhoA (RhoA), Rho­associated protein kinase­1 (ROCK­1) and growth hormone secretagogue receptor (GHS­R). By contrast, ghrelin increased the expression of MYL9, MLCK, RhoA, ROCK­1 and GHS­R in ß­HB­treated GASMCs. ß­HB increased the levels of tumor necrosis factor (TNF)­α, interleukin (IL)­6 and ROS, and decreased the levels of manganese (Mn) superoxide dismutase (SOD), copper/zinc (Cu/Zn)SOD and catalase. Ghrelin decreased the expression of TNF­α, IL­6, ROS and catalase, whereas ghrelin promoted the expression of MnSOD and Cu/ZnSOD in ß­HB­treated GASMCs. Short interfering RNA targeting GHS­R inhibited the expression of MYL9, MLCK, RhoA and ROCK­1, and increased the levels of TNF­α, IL­6 and ROS in ß­HB­treated or ghrelin­treated GASMCs. The present study provided preliminary evidence that ß­HB inhibits the motility of GASMCs and promotes inflammation in GASMCs, whereas ghrelin decreases these effects. GHS­R acted as a primary regulator of motility and inflammation in GASMCs treated with ß­HB and ghrelin.


Assuntos
Ácido 3-Hidroxibutírico/farmacologia , Movimento Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Grelina/farmacologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Receptores de Grelina/genética , Animais , Biomarcadores , Sobrevivência Celular/efeitos dos fármacos , Suscetibilidade a Doenças , Feminino , Motilidade Gastrointestinal/efeitos dos fármacos , Motilidade Gastrointestinal/genética , Humanos , Masculino , Oxirredução , Ratos , Espécies Reativas de Oxigênio/metabolismo , Receptores de Grelina/metabolismo
12.
Proc Jpn Acad Ser B Phys Biol Sci ; 95(8): 459-467, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31611501

RESUMO

Ghrelin, a growth hormone-releasing peptide first discovered in rat stomach in 1999, is a ligand for the growth hormone secretagogue receptor. It participates in the regulation of diverse processes, including energy balance and body weight maintenance, and appears to be beneficial for the treatment of cardiovascular diseases. In animal models of chronic heart failure, ghrelin improves cardiac function and remodeling; these findings have been recapitulated in human patients. In other animal models, ghrelin effectively diminishes pulmonary hypertension. Moreover, ghrelin administration early after myocardial infarction decreased the frequency of fatal arrhythmia and improved survival rate. In ghrelin-deficient mice, endogenous ghrelin protects against fatal arrhythmia and promotes remodeling after myocardial infarction. Although the mechanisms underlying the effects of ghrelin on the cardiovascular system have not been fully elucidated, its beneficial effects appear to be mediated through regulation of the autonomic nervous system. Ghrelin is a promising therapeutic agent for cardiac diseases.


Assuntos
Sistema Cardiovascular/metabolismo , Grelina/metabolismo , Sequência de Aminoácidos , Animais , Sistema Nervoso Autônomo/metabolismo , Sistema Nervoso Autônomo/fisiologia , Sistema Cardiovascular/efeitos dos fármacos , Sistema Cardiovascular/fisiopatologia , Grelina/química , Grelina/farmacologia , Grelina/uso terapêutico , Cardiopatias/tratamento farmacológico , Cardiopatias/fisiopatologia , Humanos , Receptores de Grelina/metabolismo
13.
J Physiol Sci ; 69(6): 969-979, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31595463

RESUMO

The aim of this study was to investigate the effect of activated ghrelin with dietary octanoic acids or medium-chain triglyceride (MCT) administration to underweight patient with chronic obstructive pulmonary disease (COPD). Eleven severe and very severe COPD patients received a 5-day treatment with edible MCT. Sequentially, 10 patients received a 3-week combination treatment with MCT and intravenous acyl ghrelin. Five-day MCT treatment increased endogenous acyl ghrelin (p = 0.0049), but the total ghrelin level was unchanged. MCT-ghrelin combination treatment improved the peak oxygen uptake (p = 0.0120) during whole treatment course. This effect was attributed to the resultant improvements in cardiac function by O2 pulse, and to the difference between inspired and expired oxygen concentration rather than minute ventilation. Addition of dietary MCT to ghrelin treatment improved the aerobic capacity of underweight COPD patients, likely by mechanisms of increased O2 delivery through improvements in primary cardiocirculatory and muscular crosstalk.


Assuntos
Grelina/farmacologia , Pico do Fluxo Expiratório/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Magreza/tratamento farmacológico , Triglicerídeos/farmacologia , Quimioterapia Combinada , Grelina/administração & dosagem , Humanos , Triglicerídeos/administração & dosagem , Triglicerídeos/química
14.
Growth Horm IGF Res ; 48-49: 36-44, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31494533

RESUMO

OBJECTIVE: To investigate the anti-inflammatory property of ghrelin treatment on the Growth Hormone (GH)/Insulin-like Growth Factor-I (IGF-1) axis in Wistar rats that have undergone endotoxemia. DESIGN: In this randomized animal study, lipopolysaccharide (LPS) (5 mg/kg; intraperitoneal) was administered to induce endotoxemia, and ghrelin (15 nmol/kg; endovenous) was injected simultaneously. Blood and liver samples were collected 2 h, 6 h and 12 h after LPS administration for analysis. MEASUREMENTS: Tumor necrosis factor alpha (TNF-α), interleukin (IL)-1, beta (IL-1ß), and IL-6 from both blood and liver were determined by ELISA assay. Serum nitrate was determined by chemiluminescense. Growth hormone receptor (GHR) and growth hormone secretagogue receptor 1a (GHSR-1a) were determined by western blotting. GHR mRNA and IGF-1 mRNA were determined by RT-PCR. RESULTS: LPS administration induced a decrease in IGF-1 and GH serum levels, characterizing GH/IGF-1 axis disruption. Ghrelin treatment attenuated the decrease of serum levels of IGF-1 as well as the increase of TNF-α, IL-1ß, IL-6 and nitrate induced by LPS. The increase of induced GHSR-1a protein expression seen in the LPS group after 2 h remained until 6 h after ghrelin treatment. However, attenuation of the circulating IGF-1 decrease by ghrelin treatment was not accompanied by changes in GHR protein expression nor GHR and IGF-1 gene expression. CONCLUSION: Ghrelin was able to attenuate changes in the GH/IGF-1 axis observed during systemic inflammation, which may be due to the modulation of pro-inflammatory mediators release.


Assuntos
Endotoxemia/metabolismo , Grelina/farmacologia , Hormônio do Crescimento/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Receptores da Somatotropina/metabolismo , Animais , Citocinas/metabolismo , Endotoxemia/tratamento farmacológico , Endotoxemia/patologia , Lipopolissacarídeos/farmacologia , Masculino , Óxido Nítrico/metabolismo , Ratos , Ratos Wistar
15.
Endocr Regul ; 53(2): 65-70, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31517625

RESUMO

OBJECTIVE: Ghrelin, a 28 amino acid peptide, has diverse physiological roles. Phosphatidylino-sitol-bisphosphate 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) are involved in some of the recognized actions of ghrelin. It has been shown that ghrelin upregulates HOXB4 gene expression but the real mechanism of this effect is not clear. METHODS: Rat bone marrow stromal cells (BMSCs) were cultured in DMEM. BMSCs were treated with ghrelin (100 µM) for 48 h. Real-time PCR for HOXB4 was performed from Control (untreated BMSCs), BG (BMSCs treated with 100 µM ghrelin), PD (BMSCs treated with 10 µM PD98059, a potent inhibitor of mitogen-activated protein kinase, and 100 µM ghrelin), LY (BM-SCs treated with 10 µM LY294002, a strong inhibitor of phosphoinositide 3-kinase, and 100 µM ghrelin) and SY (BMSCs treated with 10 µM LY294002 plus 10 µM PD98059, and 100 µM ghrelin) groups. Relative gene expression changes were determined using Relative expression software tool 9 (REST 9). RESULTS: HOXB4 gene has been overexpressed in ghrelin-treated BMSCs (p<0.05). PI3K inhi-bition by LY294002 significantly downregulated the ghrelin-induced overexpression of HOXB4 (p<0.05). CONCLUSION: We can conclude that ghrelin, through PI3K/Akt pathway, may improve BMSC transplantation potency by reducing its apoptosis. Moreover, upregulating HOXB4 in BMSC and its possible differentiation to HSCs might in the future open the doors to new treatment for hematologic disorders. Therefore, activating the PI3K/Akt pathway, instead of using a non-specific inducer, could be the principal point to increase the efficiency of BMSC-based cell therapies in the future.


Assuntos
Genes Homeobox/genética , Grelina/fisiologia , Proteínas de Homeodomínio/genética , Células-Tronco Mesenquimais/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fatores de Transcrição/genética , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Células Cultivadas , Grelina/farmacologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/fisiologia , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Regulação para Cima/efeitos dos fármacos
16.
Toxicology ; 426: 152267, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31381934

RESUMO

Paraquat has relatively strong detrimental effects on humans and animals and can cause acute lung injury with high mortality. Ghrelin is a brain-gut peptide which plays important roles in regulating various physiological processes. This study investigated whether ghrelin could inhibit paraquat-induced lung injuries and attempted to elucidate the possible molecular mechanisms. A549 cells were preincubated with different concentrations of ghrelin and then treated with 200 µM of PQ for 24 h. Then cell survival, apoptosis, cellular oxidative stress and lipid peroxidation of A549 cells were detected after different treatments. Subsequently, we analyzed the mitochondrial membrane potential (ΔΨm) and measured caspase-3 activation in A549 cells. In addition, we investigated the activation of the MAPKs pathway and the function of p38-MAPK within mitochondrial apoptosis. Our study indicated that ghrelin administration improved cell viability and reduced apoptosis of PQ-treated A549 cells dose-dependently. Ghrelin treatment reduced the elevation of ROS and MDA, while improved GSH content in A549 cells after paraquat exposure. Moreover, we found that ghrelin dose-dependently increased ΔΨm and decreased caspase-3 activity. The phosphorylated p38 MAPK and JNK levels elevated following PQ exposure, while the phosphorylation of p38 MAPK decreased following ghrelin pretreatment. p38 MAPK siRNA or SB203580 pretreatment ameliorated PQ-caused cell injury and apoptosis related signals, however, the intracellular ROS production was not affected. N-Acetylcysteine (NAC), a classic antioxidant pretreatment decreased the phosphorylated p38 MAPK level and intracellular ROS production, alleviated cell injury, and inhibited apoptosis. The results showed that p38-MAPK pathway plays an important role in PQ-caused alveolar epithelial cell insult, and ghrelin might attenuate PQ-induced cell injury by inhibiting ROS-induced p38-MAPK modulated mitochondrial apoptotic pathway.


Assuntos
Apoptose/efeitos dos fármacos , Grelina/farmacologia , Herbicidas/toxicidade , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Paraquat/antagonistas & inibidores , Paraquat/toxicidade , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Células A549 , Caspase 3/biossíntese , Caspase 3/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/efeitos dos fármacos
17.
Anal Cell Pathol (Amst) ; 2019: 9627810, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31360627

RESUMO

This study investigated the effect of acylated synthetic ghrelin (AG) on the survival and proliferation of human chemosensitive ovarian cancer cells (A2780) and explored some mechanisms of action with a focus on the p53 apoptotic pathway and PI3K/Akt and NF-κB survival pathways. Human A2780 ovarian cancer cells were cultured with or without AG treatment in the presence or absence of cisplatin. In some cases, cisplatin+AG-treated cells were pre-incubated either with [D-Lys3]-GHRP-6, a ghrelin receptor antagonist, or with LY294002, a PI3K inhibitor. mRNA of ghrelin receptors(GHS-R1a and GHS-R1b), as well as, protein levels of GHS-R1a, were expressed abundantly in A2780 cells. AG treatment did not affect the mRNA and protein levels of GHS-R1a and GHS-R1b in both control and Cis-treated cells. However, while AG treatment had no effect on control cell viability, it significantly increased cell viability and proliferation and inhibited cell death in Cis-treated cells. In both control and Cis-treated cells, AG treatment significantly increased PI3K/Akt/mTOR signaling and enhanced the nuclear accumulation of NF-κB. Concomitantly, in both control and Cis-treated cells, AG significantly lowered the protein levels of p53, p-p53 (Ser16), PUMA, cytochrome C, and cleaved caspase-3. Interestingly, pre-incubating the cells with either [D-Lys3]-GHRP-6 or LY294002 completely abolished the above-mentioned effect of AG in both control and Cis-treated cells. In conclusion, the findings of this study show that AG promotes cell survival of the OC cells and renders them resistat to Cis therapy, an effect that is mediated by the activation of PI3K/Akt/mTOR and activation of NF-κB, and requires GHS-R1a.


Assuntos
Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Grelina/farmacologia , Neoplasias Ovarianas/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Acilação , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , NF-kappa B/metabolismo , Proteínas de Neoplasias/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Grelina/genética , Receptores de Grelina/metabolismo , Transdução de Sinais/efeitos dos fármacos
18.
J Korean Acad Nurs ; 49(3): 317-328, 2019 Jun.
Artigo em Coreano | MEDLINE | ID: mdl-31266928

RESUMO

PURPOSE: The purpose of this study was to identify the effect of ghrelin on memory impairment in a rat model of vascular dementia induced by chronic cerebral hypoperfusion. METHODS: Randomized controlled groups and the posttest design were used. We established the representative animal model of vascular dementia caused by bilateral common carotid artery occlusion and administered 80 µg/kg ghrelin intraperitoneally for 4 weeks. First, behavioral studies were performed to evaluate spatial memory. Second, we used molecular biology techniques to determine whether ghrelin ameliorates the damage to the structure and function of the white matter and hippocampus, which are crucial to learning and memory. RESULTS: Ghrelin improved the spatial memory impairment in the Y-maze and Morris water maze test. In the white matter, demyelination and atrophy of the corpus callosum were significantly decreased in the ghrelin-treated group. In the hippocampus, ghrelin increased the length of hippocampal microvessels and reduced the microvessels pathology. Further, we confirmed angiogenesis enhancement through the fact that ghrelin treatment increased vascular endothelial growth factor (VEGF)-related protein levels, which are the most powerful mediators of angiogenesis in the hippocampus. CONCLUSION: We found that ghrelin affected the damaged myelin sheaths and microvessels by increasing angiogenesis, which then led to neuroprotection and improved memory function. We suggest that further studies continue to accumulate evidence of the effect of ghrelin. Further, we believe that the development of therapeutic interventions that increase ghrelin may contribute to memory improvement in patients with vascular dementia.


Assuntos
Demência Vascular/tratamento farmacológico , Grelina/uso terapêutico , Animais , Demência Vascular/patologia , Modelos Animais de Doenças , Grelina/farmacologia , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Neovascularização Fisiológica , Distribuição Aleatória , Ratos , Ratos Wistar , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
19.
Mol Cells ; 42(6): 470-479, 2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31250620

RESUMO

Interstitial cells of Cajal (ICCs) are pacemaker cells that exhibit periodic spontaneous depolarization in the gastrointestinal (GI) tract and generate pacemaker potentials. In this study, we investigated the effects of ghrelin and motilin on the pacemaker potentials of ICCs isolated from the mouse small intestine. Using the whole-cell patch-clamp configuration, we demonstrated that ghrelin depolarized pacemaker potentials of cultured ICCs in a dose-dependent manner. The ghrelin receptor antagonist [D-Lys] GHRP-6 completely inhibited this ghrelin-induced depolarization. Intracellular guanosine 5'-diphosphate-ß-S and pre-treatment with Ca2+free solution or thapsigargin also blocked the ghrelin-induced depolarization. To investigate the involvement of inositol triphosphate (IP3), Rho kinase, and protein kinase C (PKC) in ghrelin-mediated pacemaker potential depolarization of ICCs, we used the IP3 receptor inhibitors 2-aminoethoxydiphenyl borate and xestospongin C, the Rho kinase inhibitor Y-27632, and the PKC inhibitors staurosporine, Go6976, and rottlerin. All inhibitors except rottlerin blocked the ghrelin-induced pacemaker potential depolarization of ICCs. In addition, motilin depolarized the pacemaker potentials of ICCs in a similar dose-dependent manner as ghrelin, and this was also completely inhibited by [D-Lys] GHRP-6. These results suggest that ghrelin induced the pacemaker potential depolarization through the ghrelin receptor in a G protein-, IP3-, Rho kinase-, and PKC-dependent manner via intracellular and extracellular Ca2+ regulation. In addition, motilin was able to depolarize the pacemaker potentials of ICCs through the ghrelin receptor. Therefore, ghrelin and its receptor may modulate GI motility by acting on ICCs in the murine small intestine.


Assuntos
Grelina/farmacologia , Células Intersticiais de Cajal/efeitos dos fármacos , Potenciais da Membrana/efeitos dos fármacos , Motilina/farmacologia , Acetofenonas/farmacologia , Amidas/farmacologia , Animais , Benzopiranos/farmacologia , Compostos de Boro/metabolismo , Cálcio/metabolismo , Carbazóis/farmacologia , Motilidade Gastrointestinal/fisiologia , Receptores de Inositol 1,4,5-Trifosfato/antagonistas & inibidores , Células Intersticiais de Cajal/fisiologia , Intestino Delgado/fisiologia , Compostos Macrocíclicos/farmacologia , Camundongos , Camundongos Endogâmicos ICR , Oligopeptídeos/metabolismo , Oxazóis/farmacologia , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo , Piridinas/farmacologia , Receptores de Grelina/antagonistas & inibidores , Receptores de Grelina/metabolismo , Transdução de Sinais , Estaurosporina/farmacologia , Tapsigargina/farmacologia , Quinases Associadas a rho/antagonistas & inibidores , Quinases Associadas a rho/metabolismo
20.
Am J Physiol Lung Cell Mol Physiol ; 317(3): L381-L391, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31242025

RESUMO

Ghrelin has proven to be protective against sepsis-induced acute lung injury (ALI) via anti-inflammatory effects. However, its mechanisms remain poorly understood. Alveolar macrophages (AMs) play a key role in mediating inflammatory responses during sepsis-induced ALI by secretion of cytokines and chemokines. This study was undertaken to investigate whether ghrelin suppresses inflammatory effects of AMs and therefore may help to attenuate sepsis-induced ALI. A sepsis model in rats was achieved using cecal ligation and puncture. Ghrelin treatment markedly improved histopathological changes in the lungs and reduced pulmonary inflammation in septic rats. NF-κB translocation and p-Akt and inducible nitric oxide synthase (iNOS) activities in AMs from septic rats were suppressed by ghrelin. In vitro data indicated that ghrelin decreased the levels of LPS-induced IL-1ß, TNF-α, and IL-6, NF-κB translocation, and iNOS and Akt activities of AMs. Furthermore, the NF-κB/iNOS pathway or Akt signaling was positively correlated with LPS-induced inflammatory production of AMs in vitro. In conclusion, ghrelin exerts a protective role against sepsis-induced ALI probably by reducing the production of inflammatory cytokines from AMs via inhibition of the NF-κB/iNOS pathway or Akt signaling.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Grelina/farmacologia , Macrófagos Alveolares/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Sepse/complicações , Lesão Pulmonar Aguda/patologia , Animais , Citocinas/metabolismo , Lipopolissacarídeos/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Macrófagos Alveolares/metabolismo , Masculino , Óxido Nítrico Sintase Tipo II/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Sepse/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos
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