Gao. Meijuan M; Yang. Jin J; Wei. Rui R; Liu. Guoqiang G; Zhang. Lin L; Wang. Haining H; Wang. Guang...
Ghrelin, an endogenous ligand for growth hormone secretagogue receptor (GHS-R), shows cardioprotective activity and regulates the differentiation of several mesoderm-derived cells, including myocytes, adipocytes and osteoblasts. The effect of ghrelin on cardiogenesis and its underlying mechanism, however, have not been studied in detail.
The effects of ghrelin on cardiomyocyte differentiation were tested both in human embryonic stem cells (hESCs) cultured in embryoid body (EB)-based differentiation protocol, and in hESCs transplanted into rat hearts. The signaling mechanisms of ghrelin were further investigated under the EB-based culture condition.
The generation of beating EBs and the expression of cardiac-specific markers including cardiac troponin I (cTnI) and α-myosin heavy chain (α-MHC) were 2 to 3-fold upregulated by ghrelin. Although GHS-R1α protein was expressed in differentiated EBs, the effects of exogenous ghrelin were unchanged by D-[lys(3)]-GHRP-6, a specific GHS-R1α antagonist. Moreover, des-acyl ghrelin, which does not bind to GHS-R1α, displayed similar effects with ghrelin. Importantly, activation of ERK1/2, but not Akt, was induced by ghrelin in the newly-formed EBs, and the ghrelin-induced effects of cardiomyocyte differentiation were abolished by adding specific ERK1/2 inhibitor PD98059, but not specific PI3K inhibitor Wortmannin. In addition, ghrelin promoted the differentiation of grafted hESCs into Sox9- and Flk1-positive mesodermal/cardiac progenitor cells in rat hearts.
These results suggest that ghrelin induces cardiomyocyte differentiation from hESCs via the activation of the ERK1/2 signaling pathway. Our study, therefore, indicates that using ghrelin may be an effective strategy to promote the differentiation of hESCs into cardiomyocytes.
Torsello. Antonio A; Bresciani. Elena E; Ravelli. Monica M; Rizzi. Laura L; Bulgarelli. Ilaria I; Ri...
The mechanisms of cardiovascular protective effects of ghrelin and its synthetic analogs are still largely unknown. Our first aim was to ascertain whether or not natural and synthetic ligands of GHS-R1a are capable of interfering with the activity of the renin-angiotensin system. Second, since polymorphisms in the ACE gene have been associated with Alzheimer's dementia (AD) and ACE is potentially involved in brain β-amyloid degradation, we also investigated the state of ghrelin axis and inflammatory markers in patients with AD and vascular dementia (VaD). Desacyl ghrelin, hexarelin, EP80317, and GHRP-6 all significantly inhibited ACE activity in vitro; by comparison, the efficacies of ghrelin and MK-0677 were significantly lower, suggesting that ACE-inhibiting activity is unrelated to ligand affinity to GHS-R1a. ACE was capable of cleaving Aβin vitro, reducing its ability to aggregate in fibrillar Aβ. Interestingly, this protective effect of ACE was blunted by enalapril but not hexarelin or EP80317. Desacyl ghrelin levels were lower in VaD subjects compared with AD and control subjects, whereas ghrelin and TNF-α levels were similar in all groups. VaD subjects demonstrated greater levels of mRNA for GHS-R1a, PPAR-γ and CD36 in peripheral blood lymphocytes compared with other groups. In conclusion, some GHSs are effective ACE-inhibitors, and this activity may contribute to their cardiovascular effects. Hexarelin or EP80317 do not inhibit the N-domain of ACE, which is also involved in the metabolism of β-amyloid, suggesting the possibility of developing new antihypertensive drugs with improved therapeutic potential.
Shepperd. Erin E; Peng. Chun C; Unniappan. Suraj S
Error: Malformed JSON response.
Abdel-Hakim. S M SM; Ibrahim. M Y MY; Ibrahim. H M HM; Ibrahim. M M MM
Error: Timeout.
Yamamoto. Kouichi K; Isogai. Yukihiro Y; Ishida. Takayuki T; Hagihara. Keisuke K
Error: Timeout.
Mondal. Anupom A; Koyama. Kouhei K; Mikami. Takashi T; Horita. Taichi T; Takemi. Shota S; Tsuda. Sac...
Error: Timeout.
Fernández-Oliva. Miguel M; Santana. Héctor H; Suardíaz. Reynier R; Gavín. Jos&#x...
Error: Timeout.
Lo. Yuan-Hao YH; Chen. Ying-Jie YJ; Chang. Chi-I CI; Lin. Yi-Wen YW; Chen. Chung-Yu CY; Lee. Maw-Ron...
Error: Timeout.
Gong. Yanling Y; Xu. Luo L; Guo. Feifei F; Pang. Mingjie M; Shi. Zhenyan Z; Gao. Shengli S; Sun. Xia...
Error: Timeout.
Gasco. V V; Corneli. G G; Rovere. S S; Croce. C C; Beccuti. G G; Mainolfi. A A; Grottoli. S S; Aimar...
Based on previous consensus statements, it has been widely accepted that the diagnosis of adult growth hormone deficiency (GHD) must be shown biochemically by provocative tests of GH secretion; in fact, the measurement of IGF-I as well as of other markers was considered unable to distinguish between normal and GHD subjects. The Insulin Tolerance Test (ITT) was indicated as that of choice and severe GHD defined by a GH peak lower than 3 microg/l. It is now recognized that, although normal IGF-I levels do not rule out severe GHD, very low IGF-I levels in patients highly suspected for GHD (i.e. patients with childhood-onset severe GHD or with multiple hypopituitarism acquired in adulthood) can be considered as definite evidence for severe GHD. However, patients suspected for adult GHD with normal IGF-I levels must be investigated by provocative tests. ITT remains a test of reference but it should be recognized that other tests are as reliable as ITT. Glucagon as classical test and, particularly, new maximal tests such as GHRH in combination with arginine or GH secretagogues (GHS) (i.e. GHRP-6) have well defined cut-off limits, are reproducible, able to distinguish between normal and GHD subjects. Overweight and obesity have confounding effect on the interpretation of the GH response to provocative tests. In adults cut-off levels of GH response below which severe GHD is demonstrated must be appropriate to lean, overweight and obese subjects to avoid false positive diagnosis in obese adults and false negative diagnosis in lean GHD patients.
Stengel. A A; Goebel-Stengel. M M; Wang. L L; Luckey. A A; Hu. E E; Rivier. J J; Taché. Y Y
Error: Malformed JSON response.
Del Barco. Diana García DG; Pérez-Saad. Héctor H; Rodríguez. Valia V; Marín...
Error: Malformed JSON response.
Proulx. Caroline C; Lubell. William D WD
Scientists described a new lab method to make modified versions of the GHRP‑6 peptide, but the work is focused on chemistry techniques and structural analysis, not on how the peptide works in the body or how to use it.
Proulx. Caroline C; Lubell. William D WD
The parallel synthesis of seven aza-1,2,3-triazole-3-alanine azapeptides of the Growth Hormone Releasing Peptide-6 (GHRP-6) was accomplished via a Cu-catalyzed azide-alkyne [3+2] cycloaddition on an aza-propargylglycine residue anchored on Rink amide resin. Circular dichroism spectroscopy in water demonstrated that azapeptides which possess an aza-1,2,3-triazole-3-alanine residue at the Trp(4) position of the GHRP-6 sequence adopt beta-turn conformations.
Tóth. Krisztián K; László. Kristóf K; Lukács. Edit E; Lénárd...
The brain-gut peptide acylated-ghrelin (A-Ghr) is a potent growth hormone (GH) secretagogue substance. A-Ghr is also known to influence on memory and learning processes. Its effect is mediated partly via GH secretagogue receptor (GHS-R) type 1a. The amygdaloid body (AMY) plays important role in memory and learning processes. Projections of ghrelinergic neurons were identified in the AMY, and previously we verified that A-Ghr infused into basolateral nucleus of the AMY (ABL) caused liquid food intake decrease. The aim of the present study was to examine the possible effects of A-Ghr in the ABL on learning. Male Wistar rats were examined in two-compartment passive avoidance paradigm. Animals were shocked with 0.4mA current and subsequently were microinjected bilaterally with 50 or 100 ng A-Ghr, 30 ng GHS-R antagonist d-Lys3-GHRP-6 (ANT), ANT+50 ng A-Ghr (dissolved in 0.15M sterile NaCl/0.4 microl) or vehicle into the ABL. Fifty nanogram A-Ghr significantly increased the latency time, the 100 ng and the ANT alone were ineffective. The effect of 50 ng A-Ghr was eliminated by the ANT pretreatment. Our results suggest that intraamygdaloid A-Ghr enhances learning processes and memory in aversive situations, and this effect can specifically be prevented by ANT pretreatment.
Park. Eun Ji EJ; Tak. Tae Hyuk TH; Na. Dong Hee DH; Lee. Kang Choon KC
The purpose of this study was to evaluate the effect of PEGylation on the stabilization of peptide in poly(D,L-lactide-co-glycolide) (PLGA) microspheres for sustained release delivery. As model peptide, growth hormone-releasing peptide-6 (GHRP-6) was conjugated with succinimidyl propionate monomethoxy poly(ethylene glycol) (PEG) with an average molecular weight of 2000 Da. The mono-PEG-GHRP-6 was separated by ion-exchange chromatography, and its molecular mass was identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). The microspheres encapsulating native GHRP-6 or mono-PEG-GHRP-6 were prepared using the single oil-in-water emulsion solvent evaporation method. During incubation in a 0.1 M phosphate buffer (pH 7.4) for one month at 37 degrees C, native GHRP-6 microspheres were identified to form several acylated peptides by reversed-phase HPLC and MALDI-TOF MS, whereas the mono-PEG-GHRP-6 microspheres was not affected from peptide acylation by PLGA. This study demonstrates that PEGylation can stabilize peptide against the acylation reaction occurred in PLGA microspheres.
Baquedano. Eva E; Chowen. Julie A JA; Argente. Jesús J; Frago. Laura M LM
GH and GH secretagogues (GHSs) are involved in many cellular activities such as stimulation of mitosis, proliferation and differentiation. As astrocytes are involved in developmental and protective functions, our aim was to analyse the effects of GH and GH-releasing hexapeptide on astrocyte proliferation and differentiation in the hypothalamus and hippocampus. Treatment of adult male Wistar rats with GH (i.v., 100 μg/day) for 1 week increased the levels of glial fibrillary acidic protein (GFAP) and decreased the levels of vimentin in the hypothalamus and hippocampus. These changes were not accompanied by increased proliferation. By contrast, GH-releasing hexapeptide (i.v., 150 μg/day) did not affect GFAP levels but increased proliferation in the areas studied. To further study the intracellular mechanisms involved in these effects, we treated C6 astrocytoma cells with GH or GH-releasing hexapeptide and the phosphatidylinositol 3'-kinase (PI3K) inhibitor, LY294002, and observed that the presence of this inhibitor reverted the increase in GFAP levels induced by GH and the proliferation induced by GH-releasing hexapeptide. We conclude that although GH-releasing hexapeptide is a GHS, it may exert GH-independent effects centrally on astrocytes when administered i.v., although the effects of both substances appear to be mediated by the PI3K/Akt pathway.
Vlasova. Maria A MA; Järvinen. Kristiina K; Herzig. Karl-Heinz KH
Ghrelin, a 28 aa growth-hormone-releasing peptide, has been shown to increase food intake and decrease arterial pressure in animals and in humans. Recently, a ghrelin antagonist (GhA), [d-Lys-3]-GHRP-6, was demonstrated to decrease food intake in mice, but its cardiovascular actions have not been described. In the present study, the effects of the GhA on cardiovascular parameters in conscious rats were investigated and the involvement of the sympathetic nervous system evaluated. Mean arterial pressure (MAP) and heart rate (HR) measurements were assessed by radiotelemetry. GhA was administered in doses of 2, 4 and 6 mg/kg subcutaneously (s.c.). MAP as well as HR was dose-dependently elevated after sc application of GhA. Sympathetic blockade of alpha-adrenoreceptors with phentolamine (3 mg/kg, s.c.) and simultaneous antagonism of beta(1)-adrenoreceptors with atenolol (10 mg/kg, s.c.) abolished the increase in MAP and HR induced by GhA (4 mg/kg, s.c.). Administration of phentolamine alone inhibited the increase of MAP, but not HR; atenolol alone abolished the elevation of both MAP and HR evoked by GhA. These results suggest that the peripheral injection of ghrelin antagonist increases arterial pressure and heart rate, at least in part, through the activation of the sympathetic nervous system. Therefore, the use of the ghrelin antagonist system as a therapeutic target for reduction in food intake might lead to serious side effects like elevated blood pressure in humans mostly already having an elevated blood pressure as part of their metabolic syndrome.
Zhang. Qingsheng Q; He. Meng M; Deng. Chao C; Wang. Hongqin H; Lian. Jiamei J; Huang. Xu-Feng XF
Excessive weight gain is a major metabolic side effect of second-generation antipsychotics (SGAs) in the treatment of schizophrenia. Ghrelin is an orexigenic hormone secreted mainly from the stomach, which can induce weight gain and hyperphagia through regulating neuropeptides at the hypothalamus. Accumulating evidence implicates a relationship between ghrelin signalling and SGA-induced hyperphagia and weight gain. We report that olanzapine (a SGA with high weight gain liability) potently and time-dependently up-regulate ghrelin and ghrelin signalling, leading to hyperphagia and weight gain in female Sprague-Dawley rats, an action reversed by i.c.v. injection of a ghrelin receptor (GHS-R1a) antagonist. These findings indicate a crucial role of ghrelin signalling in hyperphagia induced by olanzapine, supporting the notion that GHS-R1a antagonist may be useful for pharmacological treatment of SGA-induced weight gain resulted from hyperphagia.
Zhao. Hongqiong H; Thanthan. Sint S; Yannaing. Swe S; Kuwayama. Hideto H
The present study was designed to determine the dose-dependent effects of endothelin-3 (ET-3) on the secretion of ghrelin and growth hormone (GH) and characterize the receptors involved in these effects. Eight Holstein steers were randomly assigned to receive intravenous bolus injections of vehicle (0.1% bovine serum albumin in saline), bovine ET-3 (0.1, 0.4, 0.7 and 1.0microg/kg), IRL1620 (selective ET(B) receptor agonist, 2.0microg/kg), [d-Lys(3)]-GHRP-6 (GH secretagogue receptor type 1a [GHS-R1a] antagonist, 20.0microg/kg) and bovine ET-3 (1.0microg/kg) combined with [d-Lys(3)]-GHRP-6 (20.0microg/kg), respectively. Blood samples were collected at -30, -15, 0, 5, 10, 15, 20, 25, 30, 35, 40, 50 and 60min relative to injection time. Concentrations of acyl ghrelin, total ghrelin (acyl and des-acyl ghrelin) and GH in plasma were analyzed by a double antibody radioimmunoassay system. Concentrations of acyl and total ghrelin were significantly increased by ET-3 in a dose-dependent manner. Concentrations of GH were markedly elevated by administration of 0.4, 0.7 and 1.0microg/kg of ET-3, and the effect of 0.7microg/kg was greater than that of 1.0microg/kg. The minimum effective dose of ET-3 in the secretion of ghrelin and GH was 0.4microg/kg. IRL 1620 mimicked the effects of ET-3 on the secretion of ghrelin and GH in plasma. ET-3-induced elevation of plasma GH was blocked by [d-Lys(3)]-GHRP-6. These results indicate that ET-3 dose-dependently stimulates ghrelin release, and ET(B) receptors involve in these processes. Moreover, this study shows that endogenous ghrelin response to ET-3 increases GH secretion through GHS-R1a.