Showing papers on "Growth hormone secretagogue published in 2016"

Ghrelin and motilin receptors as drug targets for gastrointestinal disorders.

Abstract: The gastrointestinal tract is the major source of the related hormones ghrelin and motilin, which act on structurally similar G protein-coupled receptors. Nevertheless, selective receptor agonists are available. The primary roles of endogenous ghrelin and motilin in the digestive system are to increase appetite or hedonic eating (ghrelin) and initiate phase III of gastric migrating myoelectric complexes (motilin). Ghrelin and motilin also both inhibit nausea. In clinical trials, the motilin receptor agonist camicinal increased gastric emptying, but at lower doses reduced gastroparesis symptoms and improved appetite. Ghrelin receptor agonists have been trialled for the treatment of diabetic gastroparesis because of their ability to increase gastric emptying, but with mixed results; however, relamorelin, a ghrelin agonist, reduced nausea and vomiting in patients with this disorder. Treatment of postoperative ileus with a ghrelin receptor agonist proved unsuccessful. Centrally penetrant ghrelin receptor agonists stimulate defecation in animals and humans, although ghrelin itself does not seem to control colorectal function. Thus, the most promising uses of motilin receptor agonists are the treatment of gastroparesis or conditions with slow gastric emptying, and ghrelin receptor agonists hold potential for the reduction of nausea and vomiting, and the treatment of constipation. Therapeutic, gastrointestinal roles for receptor antagonists or inverse agonists have not been identified.

Periprandial changes and effects of short- and long-term fasting on ghrelin, GOAT, and ghrelin receptors in goldfish (Carassius auratus)

Abstract: The periprandial profile and effects of short- (7 days) and long-term (30 days) fasting on the ghrelinergic system were studied in goldfish (Carassius auratus). Plasma levels of acyl-ghrelin, desacyl-ghrelin, and ghrelin O-acyl transferase (GOAT) were analyzed by enzymoimmunoassays, and expression of preproghrelin, goat and growth hormone secretagogue receptors (ghs-r) was quantified by real-time PCR. Circulating levels of acyl-ghrelin and GOAT rise preprandially, supporting the role of acyl-ghrelin as a meal initiator in this teleost. Consistently, preproghrelin and ghs-r1a1 expression increases 1 h before feeding time in intestinal bulb, suggesting that this receptor subtype might be involved in the preprandial action of ghrelin in this tissue. Significant postfeeding variations are detected for preproghrelin in telencephalon, goat in telencephalon and hypothalamus, ghs-r1a1 in vagal lobe, ghs-r1a2 and ghs-r2a1 in hypothalamus and ghs-r2a2 in telencephalon and vagal lobe, especially in unfed fish. Short- and long-term fasting significantly increase preproghrelin expression in telencephalon and gut. Goat expression is upregulated by short-term fasting in telencephalon and hypothalamus, and by both short- and long-term fasting in gut. Expression of ghs-r increases by fasting in telencephalon, while an upregulation of type 2, but not type 1, receptors is observed in vagal lobe. In intestinal bulb, ghs-r1a2 transcripts increase after both short- and long-term fasting. These results show a high dependence of the ghrelinergic system on feeding and nutritional status in fish, and demonstrate for the first time a differential implication of the various components of this system suggesting different roles for the four ghrelinergic receptor subtypes.

Ghrelin and Motilin Control Systems in GI Physiology and Therapeutics.

Abstract: Ghrelin and motilin are released from gastrointestinal endocrine cells during hunger, to act through G protein-coupled receptors that have closely related amino acid sequences. The actions of ghrelin are more complex than motilin because ghrelin also exists outside the GI tract, it is processed to des-acyl ghrelin which has activity, ghrelin can exist in truncated forms and retain activity, the ghrelin receptor can have constitutive activity and is subject to biased agonism and finally additional ghrelin-like and des-acyl ghrelin receptors are proposed. Both ghrelin and motilin can stimulate gastric emptying, acting via different pathways, perhaps influenced by biased agonism at the receptors, but research is revealing additional pathways of activity. For example, it is becoming apparent that reduction of nausea may be a key therapeutic target for ghrelin receptor agonists and perhaps for compounds that modulate the constitutive activity of the ghrelin receptor. Reduction of nausea may be the mechanism through which gastroparesis symptoms are reduced. Intriguingly, a potential ability of motilin to influence nausea is also becoming apparent. Ghrelin interacts with digestive function through its effects on appetite, and ghrelin antagonists may have a place in treating Prader-Willi syndrome. Unlike motilin, ghrelin receptor agonists also have the potential to treat constipation by acting at the lumbosacral defecation centres. In conclusion, agonists of both ghrelin and motilin receptors hold potential as treatments for specific subsets of digestive system disorders.

A novel non-peptidic agonist of the ghrelin receptor with orexigenic activity in vivo

Abstract: Loss of appetite in the medically ill and ageing populations is a major health problem and a significant symptom in cachexia syndromes, which is the loss of muscle and fat mass. Ghrelin is a gut-derived hormone which can stimulate appetite. Herein we describe a novel, simple, non-peptidic, 2-pyridone which acts as a selective agonist for the ghrelin receptor (GHS-R1a). The small 2-pyridone demonstrated clear agonistic activity in both transfected human cells and mouse hypothalamic cells with endogenous GHS-R1a receptor expression. In vivo tests with the hit compound showed significant increased food intake following peripheral administration, which highlights the potent orexigenic effect of this novel GHS-R1a receptor ligand.

Comparative proteomic analysis of growth hormone secretagogue A233 treatment of murine macrophage cells J774A.2 indicates it has a role in antiviral innate response

Abstract: Background Growth hormone secretagogues (GHS), among other factors, regulate the release of GH. The biological activity of the secretagogue peptide A233 as a promoter of growth and innate immunity in teleost fish has previously been demonstrated, but its role in the immune system of mammals is not well understood. Methods The effect of the peptide was investigated in J774A.2 macrophage cells using a comparative proteomics approach after 6 and 12 h of peptide stimulation. Results The functional analysis of differentially modulated proteins showed that A233 peptide treatment appears to promote activation and ROS-dependent cytotoxic functions in macrophages and enhanced expression of antiviral protein complexes such as MAVS. In accordance with this hypothesis, we found that A233 treatment enhanced superoxide anion production and the IFN-γ level in J774A.2 cells and mouse splenocytes, respectively, and reduced viral load in a dengue virus mouse model of infection. Conclusions The growth hormone secretagogue A233 peptide promotes activation of ROS-dependent cytotoxic functions and exerts immunomodulatory effects that enable an antiviral state in a dengue virus mouse model. General Significance The increase of IFN-γ level and the differential modulation of antiviral proteins by the A233 peptide suggest that the molecule could activate an innate immune response with a possible further impact in the treatment of acute and chronic diseases.

Diversification and coevolution of the ghrelin/growth hormone secretagogue receptor system in vertebrates.

Abstract: The gut hormone ghrelin is involved in numerous metabolic functions, such as the stimulation of growth hormone secretion, gastric motility, and food intake. Ghrelin is modified by ghrelin O-acyltransferase (GOAT) or membrane-bound O-acyltransferase domain-containing 4 (MBOAT4) enabling action through the growth hormone secretagogue receptors (GHS-R). During the course of evolution, initially strong ligand/receptor specificities can be disrupted by genomic changes, potentially modifying physiological roles of the ligand/receptor system. Here, we investigated the coevolution of ghrelin, GOAT, and GHS-R in vertebrates. We combined similarity search, conserved synteny analyses, phylogenetic reconstructions, and protein structure comparisons to reconstruct the evolutionary history of the ghrelin system. Ghrelin remained a single-gene locus in all vertebrate species, and accordingly, a single GHS-R isoform was identified in all tetrapods. Similar patterns of the nonsynonymous (dN) and synonymous (dS) ratio (dN/dS) in the vertebrate lineage strongly suggest coevolution of the ghrelin and GHS-R genes, supporting specific functional interactions and common physiological pathways. The selection profiles do not allow confirmation as to whether ghrelin binds specifically to GOAT, but the ghrelin dN/dS patterns are more similar to those of GOAT compared to MBOAT1 and MBOAT2 isoforms. Four GHS-R isoforms were identified in teleost genomes. This diversification of GHS-R resulted from successive rounds of duplications, some of which remained specific to the teleost lineage. Coevolution signals are lost in teleosts, presumably due to the diversification of GHS-R but not the ghrelin gene. The identification of the GHS-R diversity in teleosts provides a molecular basis for comparative studies on ghrelin's physiological roles and regulation, while the comparative sequence and structure analyses will assist translational medicine to determine structure-function relationships of the ghrelin/GHS-R system.

Biological activity of a new Growth hormone secretagogue: study in fish and murine cell line

Abstract: Growth hormone (GH) has pleiotropic functions in all vertebrates. In addition to its essential role in the regulation of body growth and development, it can also influence reproduction, immunity, osmoregulation, and behavior Immune and neuroendocrine systems have bidirectional communications and it is well document the enhancing action of GH on teleost immune system .It is desirable controlled GH administration to allow growth and stimulation of the innate immune system of fish. In this study, we have characterized a chemical peptide compound, A228, designed by molecular modeling, which is able to perform the function of a GH peptide secretagogue . In pituitary cell culture, the peptide A228 induces GH secretion. It is able to increase superoxide production in tilapia peripheral blood leukocytes cultures and in a macrophage cell line J774 from mice, therefore using this molecule, innate immune system stimulation is obtained in vitro both in fish and in mammals cell cultures. In this paper is also shown the biological action in vivo of the molecule, to assess growth stimulation in tilapia larvae.

Multifactorial Regulation of GLH Hormones

Abstract: Growth hormone, prolactin and placental lactogen are known as the growth- and lactogenic hormone (GLH; e.g., GH, PRL, and PL) family, which maintain adaptive immunity , including cell-mediated immunity, antibody, and autoimmune reactions, as well as maintain thymus and bone marrow functions. Insulin-like growth factor-1 participates in the regulatory action of growth hormone and prolactin. GLH shares signal transduction pathways with type I (γ-c) cytokines . This indicates a functional overlap. Dopamine is the hypothalamic regulator of PRL and GH secretion and the HPA axis. This action regulates healing and recovery from a disease. During acute illness, corticotrophic hormone (CRH) stimulates the HPA axis and vasopressin (VP) helps to maintain acute illness. The pituitary gland secretes adrenal cortex-stimulating hormone (ACTH) and the adrenal gland secretes glucocorticoids (GC) and catecholamines (CAT). When the disease subsides, VP not CRH will regulate chronic inflammation and recovery. VP also maintains adaptive immunocompetence during homeostasis because it stimulates the HPA axis and also prolactin. Oxytocin is immunoregulatory. Thyroidectomy in rats suppresses immune function and thyroxin releases growth hormone and prolactin from transplanted pituitary grafts in rats and also restores immune function. This indicates that thyroxin is an important immunoregulator. The growth hormone secretagogue, ghrelin , is immunoregulatory.

Is ghrelin a glucagon-like peptide-1 secretagogue?

Abstract: Glucagon‐like peptide‐1 (GLP‐1), a 30‐amino acid peptide processed from proglucagon protein by prohormone convertase 1/3, plays important roles in glucose and energy metabolism, including glucose‐stimulated insulin secretion, inhibition of glucagon secretion and gut motility, and reduction of appetite. GLP‐1 receptor agonists have been widely used as antidiabetic drugs, and high‐dose liraglutide, a GLP‐1 receptor agonist, has been approved for the treatment of obesity in the USA. GLP‐1 is secreted by L cells, open‐type endocrine cells located primarily in the lower intestine that directly sense nutrients transported into the gut. GLP‐1 is released by various stimuli, including glucose, fats, protein, amino acids, long‐chain fatty acids, short‐chain fatty acids and bile acids1. GLP‐1 secretion is also regulated by the parasympathetic nervous system and circulating hormones, such as cholecystokinin, glucose‐dependent insulinotropic peptide, insulin, gastrin‐releasing peptide and leptin. Plasma GLP‐1 levels in humans increase postprandially, and reach a peak within 1 h, and then gradually decrease to basal levels. Some clinical studies, including our own, showed a biphasic pattern of plasma GLP‐1 concentrations, with an early postprandial peak at 15–30 min, and a second one at 90–120 min, whereas other studies described monophasic responses. This discrepancy appears to be attributable to differences in the methods used to measure GLP‐1 and the contents of the test meals. Ghrelin is a 28‐amino acid peptide first isolated from the stomach. Acylation of its third residue, Ser‐3, by the addition of a middle‐chain fatty acid, n‐octanoic acid, is essential for its biological activity, including the binding and activation of its receptor. Ghrelin stimulates feeding, gastric motility and secretion of growth hormone. Plasma ghrelin levels increase before meals and decrease afterward, the opposite pattern shown by plasma GLP‐1. Fasting plasma ghrelin levels are negatively correlated with body mass index in humans. Ghrelin administration has been reported to reduce glucose‐stimulated insulin secretion2, but in humans, ghrelin's effects on glucose metabolism and insulin secretion have not yet been fully clarified. Intravenous bolus administration of ghrelin under fasting conditions was found to induce hyperglycemia and reduce insulin secretion in humans3. These findings, however, were not observed in other studies. Continuous infusion of ghrelin to healthy subjects over 16 h resulted in hyperglycemia, a reduced early insulin response, and an increased second‐phase insulin response after meal. Further studies using various doses and timing of exogenously administered ghrelin are required to clarify ghrelin's effects on glucose metabolism in humans. Gagnon et al.4 recently reported that ghrelin enhanced GLP‐1 secretion after oral glucose tolerance tests (OGTTs) in mice. They administered ghrelin (200 nmol/kg bodyweight) or saline intraperitoneally 15 min before OGTT. Relative to saline, ghrelin preadministration significantly increased plasma GLP‐1 levels at 15 min after OGTT. Blood glucose levels at 60 and 90 min after OGTT were significantly lower in the ghrelin preadministration group. In addition, pretreatment with a ghrelin receptor antagonist reduced GLP‐1 secretion after OGTT and impaired glucose tolerance in wild‐type mice. High‐fat diet‐induced obese mice had lower basal plasma ghrelin levels and higher blood glucose levels after OGTT compared with controls, whereas ghrelin preadministration significantly increased plasma GLP‐1 levels after OGTT and improved glucose tolerance. Gagnon et al.4 also showed that ghrelin receptors were expressed in L cells, and that ghrelin directly stimulated GLP‐1 secretion from both murine and human L cell lines through an extracellular signal‐related kinase 1/2‐dependent pathway. These results suggest that ghrelin might function in the regulation of GLP‐1 secretion. This group also showed that ghrelin administration without an oral glucose load did not alter basal GLP‐1 levels, indicating that ghrelin is important for “priming” the L cells in preparation for glucose‐stimulated GLP‐1 secretion (Figure ​(Figure11). Figure 1 Relationship between stomach and lower intestine as mediated through gut peptides. Gagnon et al.4 reported that ghrelin is important for “priming” of L cells in preparation for glucose‐stimulated glucagon‐like peptide‐1 ... A variety of physiological phenomena are influenced by stratified hormonal secretion and feedback systems, such as the hypothalamus–pituitary–adrenal axis. When undigested nutrients reach the lower intestine, they cause inhibition of gastric emptying, small intestinal transit, gastric acid secretion, pancreatic enzyme secretion and bile acid secretion. This phenomenon in the gastrointestinal tract represents a negative feedback mechanism called the ileal brake (Figure​(Figure1).1). GLP‐1 and peptide YY are mediators of the ileal brake, and the distal intestine controls the functions of the upper gastrointestinal organs. Conversely, ghrelin's enhancement of GLP‐1 secretion might represent one of the anterograde regulatory systems in the gastrointestinal tract. Some early studies found that postprandial GLP‐1 secretion in diabetic patients was lower than that in healthy subjects, whereas a recent meta‐analysis showed no significant difference between the two groups in either Caucasian or Japanese subjects. Although the increases in GLP‐1 after either a meal or OGTT varied widely in previous reports, it is important to pay attention to the methods used to measure plasma GLP‐1, especially for active GLP‐1 levels; blood collected in tubes containing a dipeptidyl peptidase‐4 inhibitor, plasma extraction and antibodies used in ELISA kits5. Postprandial GLP‐1 secretion was reported to be lower or similar in obese subjects compared with lean controls. If ghrelin is important for postprandial GLP‐1 secretion in humans as well as in mice, GLP‐1 secretion after meals and after postprandial insulin secretion might be lower in obese subjects, because their plasma preprandial ghrelin levels are low. Even in lean subjects, postprandial GLP‐1 secretion might be low if the individuals eat snacks between meals or have short intervals between meals, because plasma ghrelin levels do not increase much during the short fasting periods. Ghrelin resistance, which is caused by high‐fat diets, could also further augment ghrelin's enhancing effect on postprandial GLP‐1 secretion in obese individuals. However, insulin secretion is generally increased by obesity, thus hyperinsulinemia cannot be explained only by ghrelin's enhancing effect on GLP‐1 secretion. Because the dose of ghrelin used in the report nu Gagnon et al.4 was pharmacological, it is uncertain whether physiological differences in plasma ghrelin levels influence human postprandial GLP‐1 secretion in individuals with obesity or diabetes, or who are in the postprandial state. Several kinds of orally available ghrelin receptor agonists, called growth hormone secretagogues, have been developed. For the treatment of obese patients with type 2 diabetes, preprandial ghrelin or growth hormone secretagogue administration might be useful to increase postprandial GLP‐1 secretion. However, administration of ghrelin or growth hormone secretagogues under fasting conditions will increase appetite. Thus, both therapies might be less than ideal for the treatment of type 2 diabetes in patients who are obese. In addition, in our preliminary animal experiment, the anorexigenic effect of GLP‐1 was cancelled when ghrelin was given 30 min before GLP‐1. The orexigenic effect of ghrelin was also cancelled when GLP‐1 was given 30 min before ghrelin (M. Nakazato, unpublished data). There are no data on whether ghrelin's enhancing effect on GLP‐1 secretion occurs with similar timing. Gagnon et al.4 administered ghrelin 15 min before OGTT, and the peak of enhanced GLP‐1 occurred at 15 min after OGTT; with this timing the anorexigenic effect of secreted GLP‐1 might not be apparent. To apply ghrelin's effect on GLP‐1 release to diabetes treatment, the dose, timing, adverse effects and administration route of ghrelin should be examined in the future. Clarifying all mechanisms of postprandial GLP‐1 secretion, including ghrelin's effect, is important to facilitate the development of a novel strategy for diabetes treatment.

A233 Peptide: A Growth Hormone Secretagogue that Promotes an Antiviral Signaling Pathway

Abstract: Rebeca Martinez1, Lazaro Gil2, Yassel Ramos3, Luis J Gonzalez3, Mario P Estrada1* and Vladimir Besada3* 1Animal Biotechnology Division, Center for Genetic Engineering and Biotechnology, Cuba 2Vaccines Division, Center for Genetic Engineering and Biotechnology, Havana, Cuba 3Department of Systems Biology, Center for Genetic Engineering and Biotechnology; Havana, Cuba *Corresponding authors: Vladimir Besada, Department of Systems Biology, Center for Genetic Engineering and Biotechnology; Havana, Cuba, Tel: +53-7250-41-50; Fax: +53-7271-8070; E-mail: vladimir.besada@cigb.edu.cu

Growth Hormone Releasing Peptide-2 Attenuation of Protein Kinase C-Induced Inflammation in Human Ovarian Granulosa Cells

Abstract: Cyclooxygenase-2 (COX-2) and interleukin-8 (IL-8) are two important inflammatory mediators in ovulation. Ghrelin may modulate inflammatory signaling via growth hormone secretagogue receptors. We investigated the role of ghrelin in KGN human ovarian granulosa cells using protein kinase C (PKC) activator phorbol 12, 13-didecanoate (PDD) and synthetic ghrelin analog growth hormone releasing peptide-2 (GHRP-2). GHRP-2 attenuated PDD-induced expression of protein and mRNA, the promoter activity of COX-2 and IL-8 genes, and the secretion of prostaglandin E2 (PGE2) and IL-8. GHRP-2 promoted the degradation of PDD-induced COX-2 and IL-8 proteins with the involvement of proteasomal and lysosomal pathways. PDD-mediated COX-2 production acts via the p38, c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways; PDD-mediated IL-8 production acts via the p38, JNK and ERK pathways. GHRP-2 reduced the PDD-induced phosphorylation of p38 and JNK and activator protein 1 (AP-1) reporter activation and PDD-induced NF-κB nuclear translocation and reporter activation. The inhibitors of mitogen-activated protein kinase phosphatase-1 (MKP-1) and protein phosphatase 2 (PP2A) reduced the inhibitory effect of GHRP-2 on PDD-induced COX-2 and IL-8 expression. Our findings demonstrate an anti-inflammatory role for ghrelin (GHRP-2) in PKC-mediated inflammation of granulosa cells, at least in part, due to its inhibitory effect on PKC-induced activation of p38, JNK and NF-κB, possibly by targeting to MKP-1 and PP2A.

Comparison of three chemiluminescence detection methods for growth hormone secretagogues competitive receptor assay in urine

Abstract: The list of growth hormone secretagogue (GHS) products is growing steadily, which presents a challenge in sports drug testing A method to alert on the abuse of emerging GHSs is relevant to support current target LC-MS methods In this area, our research team presented a useful competitive radioreceptor assay method However, as radioactive measurements are not implemented in all laboratories, an alternative competitive chemiluminescent receptor approach has been assessed with three different tags (alkaline phosphatase activity and horseradish peroxidase activity with their respective pre-luminescent substrates and acridinium) The method follows essentially the same sample preparation methodology of the initial radioactive approach, but exchanging the radioactive ghrelin ligand for ghrelin-biotin, which couples with streptavidin linked to the corresponding chemiluminescent tags The usefulness of the approach is shown, although the sensitivity achieved is borderline for the detection of current administration studies