ABSTRACT
BACKGROUND: Weight loss under hypoxic exposure is related to a reduction in food intake. Decreased gastric Ghrelin levels can reduce food intake, but whether digestive nutritional absorption disorders and dyslipidemia caused by obesity can be regulated through Ghrelin-growth hormone secretagogue receptor (GHSR) pathway under intermittent hypoxia is unclear yet. OBJECTIVE: To explore the effect of intermittent hypoxia exposure on Ghrelin-GHSR pathway in gastric tissues of obese mice. METHODS: Thirty C57BL/6J male mice were randomly divided into a control group (n=8) and a high fat diet group (n=22, fed with high fat diet). After 8 weeks high fat diet, obesity models were successfully established in 16 mice with high fat diet, and then were randomly divided into an obese control group (n=8) and an obese hypoxic group (n=8, 11.2% oxygen concentration, 8 hours per day, 6 times per week). The mice whose remaining body mass did not exceed the average body weight of the normal control group by 20% were discarded. After intervention, the serum biochemical indicators and Ghrelin level were tested; the Ghrelin and GHSR-1a mRNA expressions were tested by RT-PCR; gastric tissue morphology was observed by hematoxylin-eosin staining; the mean absorbance values of Ghrelin and Ghrelin O-acyltransferase (Goat) were measured by immunohistochemistry; the protein expressions of hypothalamic growth hormone secretagogue hormone receptor 1a (GHSR-1a), Ghrelin and Goat were detected by western blot. The study protocol was approved by the Sports Science Ethics Committee of Beijing Sport University, approval No. 2015021. RESULTS AND CONCLUSION: (1) The body mass of the obese control group was significantly higher than that of the control group and obese hypoxic group after 4-week hypoxic intervention. (2) The blood glucose, total cholesterol, and triacylglycerol levels were obviously higher in the obese control group than the control group. Compared with the obese control group, the blood glucose and total cholesterol levels were significantly lower in the obese hypoxic group, while the serum Ghrelin level was significantly higher in the obese hypoxic group. (3) The Ghrelin mRNA relative expression in gastric tissue of the obese control group was evidently lower than that of the obese hypoxic group, and the GHSR-1a mRNA expression in the hypothalamus was significantly lower in the obese control group than the control group. (4) The obese hypoxic group had a regular, dense and uniform distribution of gastric fundus gland main cells. (5) The mean absorbance values of Ghrelin and Goat as well as the protein contents of GHSR-1a, Ghrelin and Goat in the obese hypoxic group were evidently higher than those in the obese control group. These results indicate that 4-week hypoxic exposure can significantly increase the expression of Ghrelin and Goat in gastric tissue and GHSR-1a in the hypothalamus, decrease blood glucose level and body mass, and improve the adverse effects of obesity in obese mice.
ABSTRACT
[ ABSTRACT] AIM:To investigate the therapeutic effects of lentivirus-mediated shRNA targeting growth hormone secretagogue receptor 1a (GHSR1a) on colorectal cancer cell line SW480 both in vitro and in vivo.METHODS: Human GHSR1a sequence was used for the design of shRNA targeting GHSR1a, which was introduced to lentivirus, followed by transfection into SW480 cells.CCK-8 assay was performed to detect cell viability.The mRNA expression of GHSR1a and PTEN in colorectal cancer cells was detected by RT-PCR.The protein levels of GHSR1a, ghrelin, PTEN, p-AKT and p53 were determined by Western blot.Stable GHSR1a silencing in SW480 xenografts in nude mice was established.After the mice were sacrificed and weighted, immunohistochemistry was used to detect the positive expression of Ki-67 and PTEN in the tumors.RESULTS:GHSR1a was over-expressed in the malignant cells in comparison with the normal cells in vitro. The tumor specific lentivirus-mediated shRNA targeting GHSR1a gene and GHSR1a knockdown SW480 cells were success-fully constructed.After transfection with GHSR1a shRNA, the expression of GHSR1a at mRNA and protein levels was markedly inhibited in the SW480 cells.Furthermore, GHSR1a silencing by specific shRNA showed increased PTEN, inhi-bition of AKT phosphorylation and promotion of p53 release in the SW480 cells.In vivo results demonstrated that down-re-gulation of GHSR1a in the SW480 cells significantly decreased the expression of Ki-67 and increased the expression of PTEN in the tumor tissues, leading to a marked reduction in tumor weight in comparison to blank control or negative control tumors.CONCLUSION:Down-regulation of GHSR1a by shRNA technique inhibits the growth of colorectal cancer cell line and xenograft tumor through activation of the PTEN/PI3K/AKT signaling pathways.
ABSTRACT
Hexarelin, a synthetic growth hormone-releasing peptide, can bind to and activate the growth hormone secretagogue receptor (GHSR) in the brain similar to its natural analog ghrelin. However, the peripheral distribution of GHSR in the heart and blood vessels suggests that hexarelin might have direct cardiovascular actions beyond growth hormone release and neuroendocrine effects. Furthermore, the non-GHSR CD36 had been demonstrated to be a specific cardiac receptor for hexarelin and to mediate its cardioprotective effects. When compared with ghrelin, hexarelin is chemically more stable and functionally more potent. Therefore, it may be a promising therapeutic agent for some car-diovascular conditions. In this concise review, we discuss the current evidence for the cardiovascular action of hexarelin.
ABSTRACT
Objective To investigate the effects of ghrelin on colonic motility in mice.Methods The eflfects of ghrelin on colonic propulsive movement were detected by charcoal suspension pushing test after injection of normal saline and different doses of ghrelin(20,50,100,200 ng/g).The effects of atropine,NG-nitro-L-arginine methylester hydrochloride(L-NAME)or D-Lys3-GHRP-6 on the changes of colonic propulsive movement caused by ghrelin(100 ng/g)were also investigated.In vitro,the effects of different doses of ghrelin(0.01,0.1,1,10μmol/L)on the spontaneous contraction amplitude of proximal colonic circular muscle strips were studied.Results Ghrelin significantly accelerated the colonic propulsive movement in dose-dependent manner,but the efiect was significantly inhibited in the presence of atropine,L-NAME or D-Lys3-GHRP-6(t=10.230,12.560,11.590,P＜0.05).Administration of ghrelin significantly increased the contraction amplitude of colonic circular muscle strips.but this effect was inhibited when the colonic circular muscle strips were pretreated by tetrodotoxin.ConclusionsGhrelin can accelerate colonic propulsive movement by activating growth hormone secretagogue receptor of cholinergic excitatory pathways and nitrergic nervous pathways in the enteric nervous system of colon.