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We report two cases of the basal phalanx fractures of the thumb treated with absorbable mesh plates. In both cases, the mesh plates specifically tailored for each fracture were effective in obtaining bone union and healing. We conclude that absorbable mesh plates could be a practical option for phalangeal fractures, especially where proprietary pre-molded metallic plates do not neatly fit the reduced fracture area.
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Fijación Interna de Fracturas , Fracturas Óseas , Humanos , Fracturas Óseas/cirugía , Durapatita , Poliésteres , Placas ÓseasRESUMEN
INTRODUCTION: A non-surgical procedure for the treatment of Dupuytrens disease is a palmar injection of Collagenase Clostridium Histolyticum to the recommended depth of “around 2-3 mm”. However, there is little supporting evidence from the literature to substantiate this. The aim of this study was to evaluate the “optimal depth” for injection of Collagenase Clostridium Histolyticum by ultrasonography for the treatment of Dupuytrens disease. MATERIAL AND METHODS: A total of 43 patients were enrolled in this study. We marked the collagenase injection point on the skin above the cord before injection. We then measured the distance from the surface of the skin to the middle of the cord by ultrasonography long axis imaging and defined this as the “optimal depth”. RESULTS: The average depth from the skin to the centre of the cord was 2.4 mm. The average distance from the surface of the skin to the proximal surface of the cord was 1.0 mm and the average thickness of the cord was 2.7 mm. CONCLUSION: By precise measurement of individual cases utilising ultrasonography we were able to confirm that the recommendations for injection depth as provided by the supplier of Collagenase Clostridium Histolyticum (2-3 mm) were in agreement with our findings. However no objective guide was supplied as with regards to interindividual variability between patients and we suggest that the use of preliminary ultrasonography will likely provide improved outcomes.
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Clostridium histolyticum , Contractura de Dupuytren , Colagenasa Microbiana , Contractura de Dupuytren/diagnóstico por imagen , Contractura de Dupuytren/tratamiento farmacológico , Humanos , Resultado del Tratamiento , UltrasonografíaRESUMEN
Caloric restriction (CR) is known to retard aging and delay functional decline as well as the onset of diseases in most organisms. Ghrelin is secreted from the stomach in response to CR and regulates energy metabolism. We hypothesized that in CR ghrelin has a role in protecting aging-related diseases. We examined the physiological mechanisms underlying the ghrelin system during the aging process in three mouse strains with different genetic and biochemical backgrounds as animal models of accelerated or normal human aging. The elevated plasma ghrelin concentration was observed in both klotho-deficient and senescence-accelerated mouse prone/8 (SAMP8) mice. Ghrelin treatment failed to stimulate appetite and prolong survival in klotho-deficient mice, suggesting the existence of ghrelin resistance in the process of aging. However, ghrelin antagonist hastened death and ghrelin signaling potentiators rikkunshito and atractylodin ameliorated several age-related diseases with decreased microglial activation in the brain and prolonged survival in klotho-deficient, SAMP8 and aged ICR mice. In vitro experiments, the elevated sirtuin1 (SIRT1) activity and protein expression through the cAMP-CREB pathway was observed after ghrelin and ghrelin potentiator treatment in ghrelin receptor 1a-expressing cells and human umbilical vein endothelial cells. Furthermore, rikkunshito increased hypothalamic SIRT1 activity and SIRT1 protein expression of the heart in the all three mouse models of aging. Pericarditis, myocardial calcification and atrophy of myocardial and muscle fiber were improved by treatment with rikkunshito. Ghrelin signaling may represent one of the mechanisms activated by CR, and potentiating ghrelin signaling may be useful to extend health and lifespan.
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Ghrelina/metabolismo , Ghrelina/fisiología , Sirtuina 1/metabolismo , Envejecimiento/fisiología , Animales , Restricción Calórica , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/metabolismo , Medicamentos Herbarios Chinos/uso terapéutico , Hipotálamo , Ratones , Ratones Endogámicos ICR , Receptores de Ghrelina/genética , Transducción de Señal , Sirtuina 1/fisiologíaRESUMEN
Obesity is a serious public health problem throughout the world, affecting both developed societies and developing countries. The central nervous system has developed a meticulously interconnected circuitry in order to keep us fed and in an adequate nutritional state. One of these consequences is that an energy-dense environment favors the development of obesity. Neuropeptide Y (NPY) is one of the most abundant and widely distributed peptides in the central nervous system of both rodents and humans and has been implicated in a variety of physiological actions. Within the hypothalamus, NPY plays an essential role in the control of food intake and body weight. Centrally administered NPY causes robust increases in food intake and body weight and, with chronic administration, can eventually produce obesity. NPY activates a population of at least six G protein-coupled Y receptors. NPY analogs exhibit varying degrees of affinity and specificity for these Y receptors. There has been renewed speculation that ligands for Y receptors may be of benefit for the treatment of obesity. This review highlights the therapeutic potential of Y(1), Y(2), Y(4), and Y(5) receptor agonists and antagonists as additional intervention to treat human obesity.
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Obesidad/tratamiento farmacológico , Receptores de Neuropéptido Y/metabolismo , Animales , Animales Modificados Genéticamente , Ingestión de Alimentos , Metabolismo Energético , Variación Genética , Homeostasis , Humanos , Ligandos , Neuropéptido Y/metabolismo , Obesidad/genética , Obesidad/fisiopatología , Receptores de Neuropéptido Y/agonistas , Receptores de Neuropéptido Y/antagonistas & inhibidores , Receptores de Neuropéptido Y/genética , RoedoresRESUMEN
Restricting type of anorexia nervosa (AN-R) is a serious disorder affecting adolescents and young adults and decreases quality of life over a long period. Successful weight restoration is an important prognostic factor for disease outcome; however, the underlying mechanism of refeeding resistance, a core psychopathology relevant to 'ambivalent' eating behaviors, remains unclear in this disorder. Ghrelin plays an important role in the regulation of growth hormone release, appetite, and energy metabolism. However, the early progress of these patients and changes in the levels of acyl ghrelin and des-acyl ghrelin during treatment were not reported. The purpose of this study was to determine the changes in ghrelin levels (acyl and des-acyl) during early treatment. As a result, des-acyl ghrelin in AN-R patients is higher than in control subjects before the therapy, but it decreases with treatment. The plasma des-acyl ghrelin level in AN-R patients started decreasing more rapidly and in early stage of the hospitalization than ever reported, and after 8 weeks, it is significantly lower than in control subjects. It means that des-acyl ghrelin is sensitive and changeable with their nutrition state. Furthermore, the ratio of the acyl ghrelin to total ghrelin increases with 8 weeks treatment. Eight weeks after, energy intake of the AN-R patients is recovered near the normal range with a daily energy intake of 1 700+/-93.54 kcal. These findings may be valuable for future AN-R treatments in order to increase acyl ghrelin and decrease des-acyl ghrelin, thereby influencing the refeeding outcome.
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Anorexia Nerviosa/sangre , Anorexia Nerviosa/terapia , Conducta Alimentaria , Ghrelina/sangre , Pacientes Internos , Adulto , Femenino , Humanos , Factores de Tiempo , Adulto JovenRESUMEN
Neuromedin S (NMS) was recently identified as an endogenous ligand for the FM-4/TGR-1 receptor in the rat hypothalamus. No previous studies have examined the effect of NMS on gut motility. We examined the effects of intracerebroventricular administration of NMS on food intake in food-deprived and free-feeding mice, and on gastroduodenal motility by using a manometric method, and gastric emptying in mice. We found that NMS decreased food intake and the gastric emptying rate. It also disrupted the motor activity in the antrum and duodenum of conscious food-deprived mice. These results suggest that NMS influences gut motility as well as feeding behavior.
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Duodeno/fisiología , Conducta Alimentaria/efectos de los fármacos , Motilidad Gastrointestinal/efectos de los fármacos , Neuropéptidos/administración & dosificación , Animales , Duodeno/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Inyecciones Intraventriculares , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
AIMS: The purpose of this study was to evaluate the in vitro effects of apocynin, an inhibitor of nicotinamide adenine dinucleotide phosphate oxidase (NOX) and a downregulator of intracellular reactive oxygen species (ROS), on high glucose-induced oxidative stress on tenocytes. METHODS: Tenocytes from normal Sprague-Dawley rats were cultured in both control and high-glucose conditions. Apocynin was added at cell seeding, dividing the tenocytes into four groups: the control group; regular glucose with apocynin (RG apo+); high glucose with apocynin (HG apo+); and high glucose without apocynin (HG apo-). Reactive oxygen species production, cell proliferation, apoptosis and messenger RNA (mRNA) expression of NOX1 and 4, and interleukin-6 (IL-6) were determined in vitro. RESULTS: Expression of NOX1, NOX4, and IL-6 mRNA in the HG groups was significantly higher compared with that in the RG groups, and NOX1, NOX4, and IL-6 mRNA expression in the HG apo+ group was significantly lower compared with that in the HG apo- group. Cell proliferation in the RG apo+ group was significantly higher than in the control group and was also significantly higher in the HG apo+ group than in the HG apo- group. Both the ROS accumulation and the amounts of apoptotic cells in the HG groups were greater than those in the RG groups and were significantly less in the HG apo+ group than in the HG apo- group. CONCLUSION: Apocynin reduced ROS production and cell death via NOX inhibition in high-glucose conditions. Apocynin is therefore a potential prodrug in the treatment of diabetic tendinopathy.Cite this article: Bone Joint Res 2020;9(1):23-28.
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Citrin is the liver-type aspartate-glutamate carrier that resides within the inner mitochondrial membrane. Citrin deficiency (due to homozygous or compound heterozygous mutations in the gene SLC25A13) causes both adult-onset type II citrullinaemia (CTLN2) and neonatal intrahepatic cholestasis (NICCD). Clinically, CTLN2 is characterized by hyperammonaemia and citrullinaemia, whereas NICCD has a much more varied and transient presentation that can include multiple aminoacidaemias, hypoproteinaemia, galactosaemia, hypoglycaemia, and jaundice. Personal histories from CTLN2 patients have repeatedly described an aversion to carbohydrate-rich foods, and clinical observations of dietary and therapeutic outcomes have suggested that their unusual food preferences may be directly related to their pathophysiology. In the present study, we monitored the food intake of 18 Japanese citrin-deficient subjects whose ages ranged from 1 to 33 years, comparing them against published values for the general Japanese population. Our survey confirmed a marked decrease in carbohydrate intake, which accounts for a smaller proportion of carbohydrates contributing to the total energy intake (PFC ratio) as well as a shift towards a lower centile distribution for carbohydrate intake relative to age- and sex-matched controls. These results strongly support an avoidance of carbohydrate-rich foods by citrin-deficient patients that may lead to worsening of symptoms.
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Proteínas de Unión al Calcio/deficiencia , Colestasis Intrahepática/etiología , Citrulinemia/etiología , Carbohidratos de la Dieta/administración & dosificación , Preferencias Alimentarias , Transportadores de Anión Orgánico/deficiencia , Adolescente , Adulto , Niño , Preescolar , Grasas de la Dieta/administración & dosificación , Ingestión de Energía , Femenino , Glucosa/metabolismo , Humanos , Lactante , Masculino , Persona de Mediana Edad , NAD/metabolismoRESUMEN
OBJECTIVES: The aim of this study was to investigate the effect of hyperglycaemia on oxidative stress markers and inflammatory and matrix gene expression within tendons of normal and diabetic rats and to give insights into the processes involved in tendinopathy. METHODS: Using tenocytes from normal Sprague-Dawley rats, cultured both in control and high glucose conditions, reactive oxygen species (ROS) production, cell proliferation, messenger RNA (mRNA) expression of NADPH oxidase (NOX) 1 and 4, interleukin-6 (IL-6), matrix metalloproteinase (MMP)-2, tissue inhibitors of matrix metalloproteinase (TIMP)-1 and -2 and type I and III collagens were determined after 48 and 72 hours in vitro. In an in vivo study, using diabetic rats and controls, NOX1 and 4 expressions in Achilles tendon were also determined. RESULTS: In tenocyte cultures grown under high glucose conditions, gene expressions of NOX1, MMP-2, TIMP-1 and -2 after 48 and 72 hours, NOX4 after 48 hours and IL-6, type III collagen and TIMP-2 after 72 hours were significantly higher than those in control cultures grown under control glucose conditions. Type I collagen expression was significantly lower after 72 hours. ROS accumulation was significantly higher after 48 hours, and cell proliferation after 48 and 72 hours was significantly lower in high glucose than in control glucose conditions. In the diabetic rat model, NOX1 expression within the Achilles tendon was also significantly increased. CONCLUSION: This study suggests that high glucose conditions upregulate the expression of mRNA for NOX1 and IL-6 and the production of ROS. Moreover, high glucose conditions induce an abnormal tendon matrix expression pattern of type I collagen and a decrease in the proliferation of rat tenocytes.Cite this article: Y. Ueda, A. Inui, Y. Mifune, R. Sakata, T. Muto, Y. Harada, F. Takase, T. Kataoka, T. Kokubu, R. Kuroda. The effects of high glucose condition on rat tenocytes in vitro and rat Achilles tendon in vivo. Bone Joint Res 2018;7:362-372. DOI: 10.1302/2046-3758.75.BJR-2017-0126.R2.
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Corticotropin-releasing hormone (CRH) is the primary hypothalamic releasing factor that mediates the mammalian stress response. The CRH-binding protein (CRH-BP) is secreted from corticotropes, the pituitary CRH target cells, suggesting that the CRH-BP may modulate hypothalamic-pituitary-adrenal (HPA) axis activity by preventing CRH receptor stimulation. Transgenic mice were generated that constitutively express elevated levels of CRH-BP in the anterior pituitary gland. RNA and protein analyses confirmed the elevation of pituitary CRH-BP. Basal plasma concentrations of corticosterone and adrenocorticotropin hormone (ACTH) are unchanged, and a normal pattern of increased corticosterone and ACTH was observed after restraint stress. However, CRH and vasopressin (AVP) mRNA levels in the transgenic mice are increased by 82 and 35%, respectively, to compensate for the excess CRH-BP, consistent with the idea that CRH-BP levels are important for homeostasis. The transgenic mice exhibit increased activity in standard behavioral tests, and an altered circadian pattern of food intake which may be due to transgene expression in the brain. Alterations in CRH and AVP in response to elevated pituitary CRH-BP clearly demonstrate that regulation of CRH-BP is important in the function of the HPA axis.
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Proteínas Portadoras/metabolismo , Sistema Hipotálamo-Hipofisario/metabolismo , Estrés Fisiológico/fisiopatología , Hormona Adrenocorticotrópica/metabolismo , Animales , Ansiedad/fisiopatología , Arginina Vasopresina/metabolismo , Conducta Animal/fisiología , Ritmo Circadiano , Corticosterona/metabolismo , Hormona Liberadora de Corticotropina/metabolismo , Conducta Alimentaria/fisiología , Ratones , Ratones Transgénicos , Actividad Motora/fisiología , Adenohipófisis/metabolismo , Restricción FísicaRESUMEN
Neuropeptides are essential for the regulation of appetite and body weight within the hypothalamus. The understanding of the neuropeptide regulation of energy homeostasis has been greatly advanced by the recent discovery of leptin, the protein product of the obese gene (ob). Significant new insights into the relationship between peripheral adiposity signals and their impact on the hypothalamic neuropeptide signaling circuitry have provided some crucial missing links in the negative-feedback regulation of appetite and body weight. The neuropeptide Y orexigenic network is a final common pathway for this signaling cascade and, along with feeding-inhibitory neuropeptides such as melanocortin, corticotropin-releasing factor and glucagon-like peptide 1, it is a major target through which leptin exerts a regulatory tonic restraint on body adiposity.
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Peso Corporal/fisiología , Ingestión de Alimentos/fisiología , Hipotálamo/metabolismo , Neuropéptidos/fisiología , Proteínas/fisiología , Animales , Hormona Liberadora de Corticotropina/fisiología , Humanos , Leptina , Neuropéptido Y/fisiologíaRESUMEN
Progressive wasting is common in many types of cancer and is one of the most important factors leading to early death in cancer patients. Weight loss is a potent stimulus to food intake in normal humans and animals. The persistence of anorexia in cancer patients, therefore, implies a failure of this adaptive feeding response, although the weight loss in the patients differs from that found in simple starvation. Tremendous progress has been made in the last 5 years with regard to the regulation of feeding and body weight. It has been demonstrated that leptin, a hormone secreted by adipose tissue, is an integral component of the homeostatic loop of body weight regulation. Leptin acts to control food intake and energy expenditure via neuropeptidergic effector molecules within the hypothalamus. Complex interactions among the nervous, endocrine, and immune systems affect the loop and induce behavioral and metabolic responses. A number of cytokines, including tumor necrosis factor-alpha, interleukins 1 and 6, IFN-gamma, leukemia inhibitory factor, and ciliary neurotrophic factor have been proposed as mediators of the cachectic process. Cytokines may play a pivotal role in long-term inhibition of feeding by mimicking the hypothalamic effect of excessive negative feedback signaling from leptin. This could be done by persistent stimulation of anorexigenic neuropeptides such as corticotropin-releasing factor, as well as by inhibition of the neuropeptide Y orexigenic network that consists of opioid peptides and galanin, in addition to the newly identified melanin-concentrating hormone, orexin, and agouti-related peptide. Information is being gathered, although it is still insufficient, on such abnormalities in the hypothalamic neuropeptide circuitry in tumor-bearing animals that coincide with the development of anorexia and cachexia. Characterization of the feeding-associated gene products have revealed new biochemical pathways and molecular targets for pharmacological intervention that will likely lead to new treatments. Although therapeutic intervention using neuropeptide agonists/antagonists is now directed at obesity treatment, it may also have an effect on treating cancer anorexia-cachexia, especially when combined with other agents that have effects on muscle and protein breakdown.
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Anorexia/fisiopatología , Caquexia/fisiopatología , Neoplasias/fisiopatología , Neuropéptidos/fisiología , Animales , Peso Corporal , Humanos , Leptina , Neoplasias/mortalidad , Proteínas/fisiología , SíndromeRESUMEN
OBJECTIVES: Triamcinolone acetonide (TA) is widely used for the treatment of rotator cuff injury because of its anti-inflammatory properties. However, TA can also produce deleterious effects such as tendon degeneration or rupture. These harmful effects could be prevented by the addition of platelet-rich plasma (PRP), however, the anti-inflammatory and anti-degenerative effects of the combined use of TA and PRP have not yet been made clear. The objective of this study was to determine how the combination of TA and PRP might influence the inflammation and degeneration of the rotator cuff by examining rotator cuff-derived cells induced by interleukin (IL)-1ß. METHODS: Rotator cuff-derived cells were seeded under inflammatory stimulation conditions (with serum-free medium with 1 ng/ml IL-1ß for three hours), and then cultured in different media: serum-free (control group), serum-free + TA (0.1mg/ml) (TA group), serum-free + 10% PRP (PRP group), and serum-free + TA (0.1mg/ml) + 10% PRP (TA+PRP group). Cell morphology, cell viability, and expression of inflammatory and degenerative mediators were assessed. RESULTS: Exposure to TA significantly decreased cell viability and changed the cell morphology; these effects were prevented by the simultaneous administration of PRP. Compared with the control group, expression levels of inflammatory genes and reactive oxygen species production were reduced in the TA, PRP, and TA+PRP groups. PRP significantly decreased the expression levels of degenerative marker genes. CONCLUSIONS: The combination of TA plus PRP exerts anti-inflammatory and anti-degenerative effects on rotator cuff-derived cells stimulated by IL-1ß. This combination has the potential to relieve the symptoms of rotator cuff injury.Cite this article: T. Muto, T. Kokubu, Y. Mifune, A. Inui, R. Sakata, Y. Harada, F. Takase, M. Kurosaka. Effects of platelet-rich plasma and triamcinolone acetonide on interleukin-1ß-stimulated human rotator cuff-derived cells. Bone Joint Res 2016;5:602-609. DOI: 10.1302/2046-3758.512.2000582.
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Neuropeptide Y (NPY), one of the most abundant peptide transmitters in the mammalian brain, is assumed to play an important role in feeding and body weight regulation. However, there is little genetic evidence that overexpression or knockout of the NPY gene leads to altered body weight regulation. Previously, we developed NPY-overexpressing mice by using the Thy-1 promoter, which restricts NPY expression strictly within neurons in the central nervous system, but we failed to observe the obese phenotype in the heterozygote. Here we report that in the homozygous mice, overexpression of NPY leads to an obese phenotype, but only after appropriate dietary exposure. NPY-overexpressing mice exhibited significantly increased body weight gain with transiently increased food intake after 50% sucrose--loaded diet, and later they developed hyperglycemia and hyperinsulinemia without altered glucose excursion during 1 year of our observation period.
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Arginina/análogos & derivados , Encéfalo/fisiología , Sacarosa en la Dieta/farmacología , Neuropéptido Y/fisiología , Obesidad/fisiopatología , Envejecimiento , Animales , Arginina/farmacología , Ciclohexanos/farmacología , Ingestión de Energía/efectos de los fármacos , Homocigoto , Humanos , Ratones , Ratones Noqueados , Ratones Transgénicos , Neuropéptido Y/genética , Obesidad/inducido químicamente , Obesidad/genética , Fenotipo , Regiones Promotoras Genéticas , Receptores de Neuropéptido Y/antagonistas & inhibidores , Valores de Referencia , Antígenos Thy-1/genética , Xantenos/farmacologíaRESUMEN
OBJECTIVE: To examine the effects of the Kobe, Japan, earthquake, a life-threatening event, on stress and glycemic control in diabetic patients. PATIENTS AND METHODS: Hemoglobin A1c levels before and after the earthquake were evaluated in diabetic patients in Kobe (N = 157; magnitude, 7.2) and in Osaka, Japan, as a control (N = 277; magnitude, 4.2), where little damage to houses and traffic facilities occurred. Glycosylated hemoglobin levels were also compared with those of 2 years before and 1 year after the earthquake. The General Health Questionnaire (GHQ) and a self-administered questionnaire regarding damage to houses and relatives killed or injured were used to assess psychological and mental stresses on earthquake survivors. RESULTS: Glycemic control was aggravated in diabetic patients after the earthquake in Kobe but not in Osaka. THe GHQ scores were significantly higher in the patients in Kobe than those in Osaka. Increased hemoglobin A1c concentrations and high scores on the GHQ were especially evident in diabetic patients with severe damage to houses and/or with relatives killed or injured. CONCLUSION: These results suggest an association between chronic, life-threatening stress and the worsening of metabolic control in patients with diabetes mellitus.
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Glucemia/metabolismo , Diabetes Mellitus/sangre , Diabetes Mellitus/psicología , Desastres , Estrés Psicológico , Adulto , Anciano , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Japón , Masculino , Persona de Mediana Edad , Encuestas y CuestionariosRESUMEN
Ghrelin is known to be a critical stimulator of feeding behavior mainly via actions in the hypothalamus. However, its functional contribution to the control of energy homeostasis under chronic elevated conditions is unknown. Here we show that overproduction of ghrelin via an AAV viral delivery system in the hypothalamus leads to an increase in food intake associated with increases in body weight. However, this increase in food intake is only temporary and is diminished and no longer significant after 3 weeks. Analysis of brain sections of mice 6 weeks after AAV-ghrelin virus injection demonstrates unaltered neuropeptide Y levels but strongly up-regulated pro-opiomelanocortin levels indicating that a compensatory mechanism has been activated to counter regulate the feeding stimulatory actions of ghrelin. This demonstrates that control mechanism exists that is activated under conditions of prolonged high ghrelin levels, which could potentially be utilized to control feeding and the development of obesity.
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Ingestión de Alimentos/fisiología , Ghrelina/fisiología , Hipotálamo/metabolismo , Aumento de Peso/fisiología , Aciltransferasas/genética , Aciltransferasas/fisiología , Tejido Adiposo/crecimiento & desarrollo , Animales , Dependovirus/genética , Ingestión de Energía , Vectores Genéticos/farmacología , Ghrelina/biosíntesis , Ghrelina/genética , Células HEK293 , Humanos , Proteínas de la Membrana , Ratones , Proopiomelanocortina/biosíntesis , Proopiomelanocortina/genética , Proteínas Recombinantes de Fusión/metabolismo , Factores de TiempoRESUMEN
BACKGROUND: The gastrointestinal peptide hormone ghrelin was discovered in 1999 as the endogenous ligand of the growth hormone secretagogue receptor. Increasing evidence supports more complicated and nuanced roles for the hormone, which go beyond the regulation of systemic energy metabolism. SCOPE OF REVIEW: In this review, we discuss the diverse biological functions of ghrelin, the regulation of its secretion, and address questions that still remain 15 years after its discovery. MAJOR CONCLUSIONS: In recent years, ghrelin has been found to have a plethora of central and peripheral actions in distinct areas including learning and memory, gut motility and gastric acid secretion, sleep/wake rhythm, reward seeking behavior, taste sensation and glucose metabolism.
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We have shown previously that peptide YY (PYY) receptors are uniquely distributed in various mammalian brains and also have identified the receptor from porcine hippocampal membranes as a protein of 50,000 mol wt. To extend these observations, both the characteristics of PYY-receptor interaction and the structure of the receptor have been examined and compared with those of its sister peptide, neuropeptide Y (NPY), in the brains of various vertebrates including mammals (human, dog, guinea pig, rat, and mouse), birds (chicken), reptiles (snapping turtle), amphibians (bullfrog), and fish (yellowtail fish). The affinities and relative potencies of PYY as well as NPY receptors for pancreatic polypeptide (PP) family peptides were about the same in all species examined except for chickens. PYY and NPY bound to both the PYY and NPY receptors with high affinities, but porcine and avian PPs did not. In chicken brain, however, PYY, NPY, porcine PP, and avian PP all bound to the receptors with high affinity. Analysis of the equilibrium binding data for PYY receptors produced curvilinear Scatchard plots in all of the species, suggesting the existence of high and low affinity binding sites. Affinity cross-linking using disuccinimidyl suberate followed by electrophoretic analysis of ligand-receptor complexes characterized the molecular size of PYY and NPY receptors. [125I]PYY was cross-linked to a protein of 50,000 mol wt without sulfhydryl-bonded subunits on mammalian hippocampal membranes. A receptor protein with the same mol wt was identified in other brain areas, including hypothalamus and pituitary, PYY receptors in other vertebrate brains were similar in size to those of mammalian species except in chicken brain, where a receptor protein of 67,000 mol wt was observed. In addition, we also have demonstrated that the NPY receptor is a monomeric 50,000 and 55,000 mol wt protein in mammalian and fish brains, respectively. These findings indicate that brain PYY and NPY receptors in most vertebrate species from fish to man are pharmacologically and structurally similar and have been well conserved over a period of evolution of 400 million yr. The divergence of the receptors observed in chicken brain may reflect some change in their function.
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Evolución Biológica , Encéfalo/metabolismo , Receptores de Neurotransmisores/metabolismo , Vertebrados/metabolismo , Animales , Reactivos de Enlaces Cruzados , Humanos , Masculino , Peso Molecular , Neuropéptido Y/metabolismo , Péptido YY , Péptidos/metabolismo , Receptores de Neuropéptido Y , Receptores de Neurotransmisores/química , Succinimidas/metabolismoRESUMEN
We have previously identified the peptide-YY (PYY) receptor on porcine brain membranes as a 50-kDa protein after chemical cross-linking. PYY receptors are discretely distributed in the brain of various mammals, to which neuropeptide-Y (NPY), but not pancreatic polypeptide (PP), bind with great specificity. The present study was carried out in order 1) to identify and characterize the PYY receptor in the avian brain, 2) to compare it with the APP receptor that had been demonstrated in the cerebellum, and 3) to examine [125I]APP-binding activity in the porcine brain. [125I]PYY was bound to chicken brain membranes via high affinity (Kd = 2.19 x 10(-10) M) and low affinity (Kd = 1.93 x 10(-7) M) components. The binding sites were highly specific for PYY and APP as well as for NPY and PPP, coupled to a guanine nucleotide regulatory protein, and distributed in various brain areas, including the cerebellum. The C-terminal fragments of PYY, PYY-(17-36) and PYY-(24-36), exhibited low potency in inhibiting binding, but behaved like full agonists. Porcine brain membranes, on the other hand, possessed two orders of the APP-binding sites, a high affinity component (Kd = 4.24 x 10(-9) M) and a low affinity component (Kd = 3.08 x 10(-7) M). APP binding showed a high specificity for APP, but not for PPP, NPY, or PYY. The binding activity was highest in the pituitary gland, followed by the hippocampus, amygdala, cerebral cortex, hypothalamus, and cerebellum. Guanosine 5'-O-thiotriphosphate, a nonhydrolyzable GTP analog, did not inhibit the binding of [125I]APP to porcine or chicken brain membranes, which ran counter to the results of PYY receptors in both species. Cross-linking studies have demonstrated that receptor-bound [125I]APP is cross-linked to a protein of 67 kDa without disulfide-linked subunits in both porcine and chicken brain membranes. In the latter species, [125I]PYY and [125I]NPY were also cross-linked to the same 67-kDa proteins, which were different from the receptor proteins (50 kDa) in mammalian species. These results indicate that chicken brain has receptors specific for PYY and NPY, as was found in mammalian brains, and that PYY, NPY, and PP act in the brain through interaction at multiple receptor sites, which are similar to and shared by other members of the PP family. Furthermore, the finding that APP-binding sites in porcine brain are more specific than those in avian brain suggests that an endogenous peptide similar to APP may exist in porcine brain.
Asunto(s)
Encéfalo/metabolismo , Neuropéptido Y/metabolismo , Polipéptido Pancreático/metabolismo , Receptores de la Hormona Gastrointestinal/metabolismo , Receptores de Neurotransmisores/metabolismo , Animales , Unión Competitiva , Pollos , Cinética , Especificidad de Órganos , Receptores de Neuropéptido Y , Especificidad de la Especie , PorcinosRESUMEN
The expression and structure of the receptors for neuropeptide-Y (NPY) and peptide-YY (PYY) were studied in 16 human and rodent tumor cell lines derived from the neural crest by ligand binding and cross-linking techniques using [125I]Bolton-Hunter-NPY, [125I]PYY, and various forms of monoiodinated NPY and PYY. Although NPY-binding sites were observed in most of the tumor cells, PYY-binding sites were found only on the human neuroblastoma cell lines SMS-MSN, SMS-KAN, SK-N-MC, and MC-IXC and the human Ewing's sarcoma cell line SK-ES. The differential labeling of the NPY/PYY receptors on these cell lines suggests that the NPY/PYY receptors are more heterogeneous than previously described as the Y1, Y2, and Y3 receptor subtypes. Cross-linking studies demonstrate that the Y1 and Y2 receptors for NPY/PYY are structurally different (mol wt, 70 and 50 kilodaltons, respectively) and that the 70- and 50-kilodalton receptor proteins are coexpressed in certain tumor cell lines. This could explain at least in part why cell lines show a relative specificity for Y1/Y2 classification, observed as the inhibition by both C-terminal fragments and Y1-specific analogs on the NPY/PYY binding to membrane receptors. Collectively, the present study suggests further heterogeneity of the NPY/PYY receptors and the existence of multiple receptor proteins in the tumor cell lines derived from the neural crest.