AIM:To investigate the potential therapeutic significance of ghrelin and growth hormone releasing peptide 6 (GHRP-6) in diabetic mice with gastric motility disorders. METHODS: A diabetic mouse model was established by...AIM:To investigate the potential therapeutic significance of ghrelin and growth hormone releasing peptide 6 (GHRP-6) in diabetic mice with gastric motility disorders. METHODS: A diabetic mouse model was established by intraperitoneal (ip) injection of alloxan. Diabetic mice were injected ip with ghrelin or GHRP-6 (20-200 μg/kg), and the effects on gastric emptying were measured after intragastric application of phenol red. The effect of atropine, NG-nitro-L-arginine methyl ester hydrochloride (L-NAME) or D-Lys3-GHRP-6 (a growth hormone secretagogue receptor (GHS-R) antagonist) on the gastroprokinetic effect of ghrelin or GHRP-6 (100 μg/kg) was also investigated. The effects of ghrelin or GHRP-6 (0.01-10 μmol/L) on spontaneous or carbachol-induced contractile amplitude were also investigated in vitro, in gastric fundic circular strips taken from diabetic mice. The presence of growth hormone secretagogue receptor 1a transcripts in the fundic strips of diabetic mice was detected by reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: We established a diabetic mouse model with delayed gastric emptying. Ghrelin and GHRP-6 accelerated gastric emptying in diabetic mice with gastroparesis. In the presence of atropine or L-NAME, which delayed gastric emptying, ghrelin and GHRP-6 (100 μg/kg) failed to accelerate gastric emptying. D-Lys3-GHRP-6 also delayed gastric emptying induced by the GHS-R agonist. Ghrelin and GHRP-6 increased the carbachol-induced contractile amplitude in gastric fundicstrips taken from diabetic mice. RT-PCR confirmed the presence of GHS-R mRNA in the strip preparations. CONCLUSION: Ghrelin and GHRP-6 increase gastric emptying in diabetic mice with gastroparesis, perhaps by activating peripheral cholinergic pathways in the enteric nervous system.展开更多
BACKGROUND： Changes in the cardiac autonomic nerve are considered to be important factors in the mechanisms of heart failure. It is possible to reduce or slow down nerve degeneration and necrosis, provided that patie...BACKGROUND： Changes in the cardiac autonomic nerve are considered to be important factors in the mechanisms of heart failure. It is possible to reduce or slow down nerve degeneration and necrosis, provided that patients take effective neuroprotectants during the early stages of heart failure. Moreover, it is possible to relieve the pathological process and reduce the risk of death. OBJECTIVE： To study the effect of growth hormone releasing peptide （GHRP） on cardiac cholinergic nerve fiber density distribution in a rat model of heart failure, and verify whether GHRP can ameliorate denervation. DESIGN, TIME AND SETTING： A randomized controlled study was performed at the Key Laboratory of Anatomy, Harbin Medical University, between June and October 2009. MATERIALS： Fifty adult, healthy, female, Wistar rats, weighing （200± 20） g, were randomly divided into GHRP （n = 30）, model （n = 10）, and sham operation （n = 10） groups. GHRP-2 was made in Shanghai, China （batch No. z071212-03）. METHODS： Acute myocardial infarction was established by ligating the left anterior descending coronary artery in the GHRP and model groups. Five weeks later, myocardial function was detected using color ultrasound electrocardiograph a successful marker of chronic heart failure models Ejection fraction 〈 60% was considered to be However, the left anterior descending coronary artery was not ligated in the sham operation group. The GHRP group was injected with 100 μ g/kg GHRP-2, and the other two groups were injected with the same volume of physiological saline, once per day. MAIN OUTCOME MEASURES： After 4 weeks, pathological changes in cardiac cholinergic nerve fibers were detected under optic microscopy following hematoxylin/eosin staining. In addition, density distribution was measured using a multi-function color pathological image system. RESULTS： In the sham operation group, myocardial cells were regular, uniformly stained, and no inflammatory cells were present. In the model group, myocardial cells were unevenly stained, exhibited nuclear atrophy, degeneration, dissolution, or disappearance. In the GHRP group, myocardial damage was less than in the model group; cardiac muscle fibers exhibited slight degeneration. The myocardium in the sham operation group was serried, spreading the cholinergic innervations along the cardiac fiber. In the model group, there was a decreased number of cholinergic nerve fibers decreased, which also became shorter and smaller, compared with the sham operation group （P 〈 0.01）. In the GHRP group, cholinergic positive nerve fibers were significantly increased compared with the model group （P 〈 0.01）, but still less than the sham surgery group （P 〈 0.05）. CONCLUSION： GHRP delayed denervation and reduced nerve reconstitution following heart failure in rats.展开更多
Benign prostatic hyperplasia(BPH)is a pathologic condition of the prostate described as a substantial increase in its number of epithelial and stromal cells.BPH may significantly reduce the quality of life due to the ...Benign prostatic hyperplasia(BPH)is a pathologic condition of the prostate described as a substantial increase in its number of epithelial and stromal cells.BPH may significantly reduce the quality of life due to the initiation of bladder outlet obstruction and lower urinary tract syndromes.Current medical therapies mostly consist of inhibitors of 5α-reductase orα1-adrenergic blockers;their efficacy is often insufficient.Antagonistic analogs of neuropeptide hormones are novel candidates for the management of BPH.At first,antagonists of luteinizing hormone-releasing hormone(LHRH)have been introduced to the therapy aimed to reduce serum testosterone levels.However,they have also been found to produce an inhibitory activity on local LHRH receptors in the prostate as well as impotence and other related side effects.Since then,several preclinical and clinical studies reported the favorable effects of LHRH antagonists in BPH.In contrast,antagonists of growth hormone-releasing hormone(GHRH)and gastrin-releasing peptide(GRP)have been tested only in preclinical settings and produce significant reduction in prostate size in experimental models of BPH.They act at least in part,by blocking the action of respective ligands produced locally on prostates through their respective receptors in the prostate,and by inhibition of autocrine insulin-like growth factors-Ⅰ/Ⅱand epidermal growth factor production.GHRH and LHRH antagonists were also tested in combination resulting in a cumulative effect that was greater than that of each alone.This article will review the numerous studies that demonstrate the beneficial effects of antagonistic analogs of LHRH,GHRH and GRP in BPH,as well as suggesting a potential role for somatostatin analogs in experimental therapies.展开更多
Background Diabetic gastroparesis is a disabling condition with no consistently effective treatment. In normal animals, both ghrelin and its synthetic peptide, growth hormone releasing peptide 6 （GHRP-6）, increase g...Background Diabetic gastroparesis is a disabling condition with no consistently effective treatment. In normal animals, both ghrelin and its synthetic peptide, growth hormone releasing peptide 6 （GHRP-6）, increase gastric emptying. Thus, we investigated the potential therapeutic significance of ghrelin and GHRP-6 in diabetic guinea pigs with gastric motility disorders. Methods A diabetic guinea pig model was produced by intraperitoneal （i.p.） injection of streptozotocin （STZ, 280 mg/kg）. Diabetic guinea pigs were injected i.p. with ghrelin or GHRP-6 （10-100 μg/kg）, and the effects on gastric emptying were measured after intragastric application of phenol red. The effect of atropine or a growth hormone secretagogue receptor （GHS-R） antagonist, D-Lys^3-GHRP-6, on the gastroprokinetic effects of ghrelin or GHRP-6 （100 μg/kg） was also investigated. Further, the in vitro effects of ghrelin or GHRP-6 （0.01-10 μmol/L） on spontaneous or carbachol-induced contractile amplitude in gastric fundic circular strips taken from diabetic guinea pigs were examined. Growth hormone secretagogue receptor transcripts in the fundic strips of diabetic guinea pigs were detected by reverse transcriptase polymerase chain reaction （RT-PCR）. Results We established a guinea pig model of delayed gastric emptying. Ghrelin （20, 50, or 100 μg/kg） and GHRP-6 （20, 50, or 100 μg/kg） accelerated gastric emptying in diabetic guinea pigs with gastroparesis （n=6, P 〈0.05）. In the presence of atropine, which delayed gastric emptying, ghrelin and GHRP-6 （100 μg/kg） failed to accelerate gastric emptying （n=6, P 〈0.05）. D-Lys^3-GHRP-6 also delayed gastric emptying induced by the GHS-R agonist （n=6, P 〈0.05）. Ghrelin and GHRP-6 increased the carbachol-induced contractile amplitude in gastric fundic strips taken from diabetic guinea pigs （n=6, P〈0.05）. RT-PCR confirmed the presence of GHS-R mRNA in the strip preparations. Conclusions Ghrelin and GHRP-6 increased gastric emptying in diabetic guinea pigs with gastroparesis, potentially, by activating the peripheral cholinergic pathways in the enteric nervous system.展开更多
N-hydroxysuccinimide (HOSU) active esters have gained wide application in peptide synthesis, especially in the synthesis of longer peptides by segment conden sation, for they can avoid racemization during coupling pro...N-hydroxysuccinimide (HOSU) active esters have gained wide application in peptide synthesis, especially in the synthesis of longer peptides by segment conden sation, for they can avoid racemization during coupling processes. However, the HOSU active ester method is prone to side reactions, forming undesirable by-products such as succinimide-oxycarbonyl-alanine N-hydroxysuccinimide ester (Ⅰ) in activating steps and compound (Ⅱ) in the coupling steps sterically hindered by amino acids (proline, valine, isoleucine, etc.).展开更多
基金National Nature Science Foundation of China, No. 30400429
文摘AIM:To investigate the potential therapeutic significance of ghrelin and growth hormone releasing peptide 6 (GHRP-6) in diabetic mice with gastric motility disorders. METHODS: A diabetic mouse model was established by intraperitoneal (ip) injection of alloxan. Diabetic mice were injected ip with ghrelin or GHRP-6 (20-200 μg/kg), and the effects on gastric emptying were measured after intragastric application of phenol red. The effect of atropine, NG-nitro-L-arginine methyl ester hydrochloride (L-NAME) or D-Lys3-GHRP-6 (a growth hormone secretagogue receptor (GHS-R) antagonist) on the gastroprokinetic effect of ghrelin or GHRP-6 (100 μg/kg) was also investigated. The effects of ghrelin or GHRP-6 (0.01-10 μmol/L) on spontaneous or carbachol-induced contractile amplitude were also investigated in vitro, in gastric fundic circular strips taken from diabetic mice. The presence of growth hormone secretagogue receptor 1a transcripts in the fundic strips of diabetic mice was detected by reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: We established a diabetic mouse model with delayed gastric emptying. Ghrelin and GHRP-6 accelerated gastric emptying in diabetic mice with gastroparesis. In the presence of atropine or L-NAME, which delayed gastric emptying, ghrelin and GHRP-6 (100 μg/kg) failed to accelerate gastric emptying. D-Lys3-GHRP-6 also delayed gastric emptying induced by the GHS-R agonist. Ghrelin and GHRP-6 increased the carbachol-induced contractile amplitude in gastric fundicstrips taken from diabetic mice. RT-PCR confirmed the presence of GHS-R mRNA in the strip preparations. CONCLUSION: Ghrelin and GHRP-6 increase gastric emptying in diabetic mice with gastroparesis, perhaps by activating peripheral cholinergic pathways in the enteric nervous system.
基金Supported by:the Natural Science Foundation of Heilongjiang Province,No. D2006-24Post-graduate Scientific and Technological Innovation Program of Heilongjiang Province,No. YJSCX2007-0077HLJ+1 种基金Research Fund of Heilongjiang Provincial Education Department,No. 11511241Scientific Research Fund of Heilongjiang Provincial Education Department,No. 11531386
文摘BACKGROUND： Changes in the cardiac autonomic nerve are considered to be important factors in the mechanisms of heart failure. It is possible to reduce or slow down nerve degeneration and necrosis, provided that patients take effective neuroprotectants during the early stages of heart failure. Moreover, it is possible to relieve the pathological process and reduce the risk of death. OBJECTIVE： To study the effect of growth hormone releasing peptide （GHRP） on cardiac cholinergic nerve fiber density distribution in a rat model of heart failure, and verify whether GHRP can ameliorate denervation. DESIGN, TIME AND SETTING： A randomized controlled study was performed at the Key Laboratory of Anatomy, Harbin Medical University, between June and October 2009. MATERIALS： Fifty adult, healthy, female, Wistar rats, weighing （200± 20） g, were randomly divided into GHRP （n = 30）, model （n = 10）, and sham operation （n = 10） groups. GHRP-2 was made in Shanghai, China （batch No. z071212-03）. METHODS： Acute myocardial infarction was established by ligating the left anterior descending coronary artery in the GHRP and model groups. Five weeks later, myocardial function was detected using color ultrasound electrocardiograph a successful marker of chronic heart failure models Ejection fraction 〈 60% was considered to be However, the left anterior descending coronary artery was not ligated in the sham operation group. The GHRP group was injected with 100 μ g/kg GHRP-2, and the other two groups were injected with the same volume of physiological saline, once per day. MAIN OUTCOME MEASURES： After 4 weeks, pathological changes in cardiac cholinergic nerve fibers were detected under optic microscopy following hematoxylin/eosin staining. In addition, density distribution was measured using a multi-function color pathological image system. RESULTS： In the sham operation group, myocardial cells were regular, uniformly stained, and no inflammatory cells were present. In the model group, myocardial cells were unevenly stained, exhibited nuclear atrophy, degeneration, dissolution, or disappearance. In the GHRP group, myocardial damage was less than in the model group; cardiac muscle fibers exhibited slight degeneration. The myocardium in the sham operation group was serried, spreading the cholinergic innervations along the cardiac fiber. In the model group, there was a decreased number of cholinergic nerve fibers decreased, which also became shorter and smaller, compared with the sham operation group （P 〈 0.01）. In the GHRP group, cholinergic positive nerve fibers were significantly increased compared with the model group （P 〈 0.01）, but still less than the sham surgery group （P 〈 0.05）. CONCLUSION： GHRP delayed denervation and reduced nerve reconstitution following heart failure in rats.
基金Supported by The Medical Research Service of the Veterans Affairs Department,Departments of Pathology and Medicine,Division of Hematology/Oncology,Sylvester Comprehensive Cancer Center,University of Miami,Miller School of Medicine,the South Florida Veterans Affairs Foundation for Research and Education(all to Schally AV)the L Austin Weeks Endowment for Urologic Research(to Block NL)+2 种基金in part by a grant from the Urology Care Foundation Research Scholars Program and the American Urological Association(AUA)Southeastern Section(to Rick FG)by a stipend program of the Department of Medicine,Dresdenby the Helmholtz Alliance ICEMED(Imaging and Curing Environmental Metabolic Diseases)through the Initiative and Networking Fund of the Helmholtz Association(to Popovics P)
文摘Benign prostatic hyperplasia(BPH)is a pathologic condition of the prostate described as a substantial increase in its number of epithelial and stromal cells.BPH may significantly reduce the quality of life due to the initiation of bladder outlet obstruction and lower urinary tract syndromes.Current medical therapies mostly consist of inhibitors of 5α-reductase orα1-adrenergic blockers;their efficacy is often insufficient.Antagonistic analogs of neuropeptide hormones are novel candidates for the management of BPH.At first,antagonists of luteinizing hormone-releasing hormone(LHRH)have been introduced to the therapy aimed to reduce serum testosterone levels.However,they have also been found to produce an inhibitory activity on local LHRH receptors in the prostate as well as impotence and other related side effects.Since then,several preclinical and clinical studies reported the favorable effects of LHRH antagonists in BPH.In contrast,antagonists of growth hormone-releasing hormone(GHRH)and gastrin-releasing peptide(GRP)have been tested only in preclinical settings and produce significant reduction in prostate size in experimental models of BPH.They act at least in part,by blocking the action of respective ligands produced locally on prostates through their respective receptors in the prostate,and by inhibition of autocrine insulin-like growth factors-Ⅰ/Ⅱand epidermal growth factor production.GHRH and LHRH antagonists were also tested in combination resulting in a cumulative effect that was greater than that of each alone.This article will review the numerous studies that demonstrate the beneficial effects of antagonistic analogs of LHRH,GHRH and GRP in BPH,as well as suggesting a potential role for somatostatin analogs in experimental therapies.
基金This study was supported by a grant from National Natural Science Foundation of China （No. 30400429）.
文摘Background Diabetic gastroparesis is a disabling condition with no consistently effective treatment. In normal animals, both ghrelin and its synthetic peptide, growth hormone releasing peptide 6 （GHRP-6）, increase gastric emptying. Thus, we investigated the potential therapeutic significance of ghrelin and GHRP-6 in diabetic guinea pigs with gastric motility disorders. Methods A diabetic guinea pig model was produced by intraperitoneal （i.p.） injection of streptozotocin （STZ, 280 mg/kg）. Diabetic guinea pigs were injected i.p. with ghrelin or GHRP-6 （10-100 μg/kg）, and the effects on gastric emptying were measured after intragastric application of phenol red. The effect of atropine or a growth hormone secretagogue receptor （GHS-R） antagonist, D-Lys^3-GHRP-6, on the gastroprokinetic effects of ghrelin or GHRP-6 （100 μg/kg） was also investigated. Further, the in vitro effects of ghrelin or GHRP-6 （0.01-10 μmol/L） on spontaneous or carbachol-induced contractile amplitude in gastric fundic circular strips taken from diabetic guinea pigs were examined. Growth hormone secretagogue receptor transcripts in the fundic strips of diabetic guinea pigs were detected by reverse transcriptase polymerase chain reaction （RT-PCR）. Results We established a guinea pig model of delayed gastric emptying. Ghrelin （20, 50, or 100 μg/kg） and GHRP-6 （20, 50, or 100 μg/kg） accelerated gastric emptying in diabetic guinea pigs with gastroparesis （n=6, P 〈0.05）. In the presence of atropine, which delayed gastric emptying, ghrelin and GHRP-6 （100 μg/kg） failed to accelerate gastric emptying （n=6, P 〈0.05）. D-Lys^3-GHRP-6 also delayed gastric emptying induced by the GHS-R agonist （n=6, P 〈0.05）. Ghrelin and GHRP-6 increased the carbachol-induced contractile amplitude in gastric fundic strips taken from diabetic guinea pigs （n=6, P〈0.05）. RT-PCR confirmed the presence of GHS-R mRNA in the strip preparations. Conclusions Ghrelin and GHRP-6 increased gastric emptying in diabetic guinea pigs with gastroparesis, potentially, by activating the peripheral cholinergic pathways in the enteric nervous system.
文摘N-hydroxysuccinimide (HOSU) active esters have gained wide application in peptide synthesis, especially in the synthesis of longer peptides by segment conden sation, for they can avoid racemization during coupling processes. However, the HOSU active ester method is prone to side reactions, forming undesirable by-products such as succinimide-oxycarbonyl-alanine N-hydroxysuccinimide ester (Ⅰ) in activating steps and compound (Ⅱ) in the coupling steps sterically hindered by amino acids (proline, valine, isoleucine, etc.).
文摘目的探讨不同病因矮小症患儿血清生长激素释放肽(Ghrelin)、胰岛素样生长因子-1(insulinlike growth factor-1,IGF-1)水平变化及其临床意义。方法选取2016年1月至2022年1月南通大学附属医院如皋分院收治的212例矮小症患儿,根据不同病因分为生长激素缺乏症组(n=60)、特发性矮小症组(n=46)、Turner综合征组(n=38)、先天性甲状腺功能减退症组(n=32)和宫内发育迟缓组(n=36),另选取同期于本院行体检证实身高同性别、同年龄标准范围内的106例健康儿童作为对照组。比较不同病因矮小症患儿与对照组的人口学特征和骨龄年龄差(bone age difference,BAD)、身高标准差分值(heightstandard deviation score,Ht SDS)、年生长速率(growth velocity,GV)和生长激素(growth hormone,GH)峰值等生长发育指标及青春前期和青春期的血清Ghrelin、IGF-1水平。采用受试者操作特征(receiveroperating characteristic,ROC)曲线分析血清Ghrelin、IGF-1水平对特发性矮小症的鉴别诊断价值。统计学方法采用单因素方差分析、LSD-t检验及χ^(2)检验。结果特发性矮小症组青春期患儿比例为65.2%,明显高于其他4组(P值均<0.05),其中青春期患儿比例从高至低依次为宫内发育迟缓组(41.7%)、先天性甲状腺功能减退症组(40.6%)、生长激素缺乏症组(35.0%)和Turner综合征组(31.6%);特发性矮小症组BAD为(1.4±0.3)岁,明显高于其他4组(P值均<0.05),其中BAD值从高至低依次为生长激素缺乏症组[(1.2±0.2)岁]、先天性甲状腺功能减退症组[(1.1±0.2)岁]、Turner综合征组[(0.7±0.1)岁]和宫内发育迟缓组[(0.3±0.1)岁]。特发性矮小症组GV值为[(3.7±0.8)cm/年],明显高于其他4组(P值均<0.05),其中GV值从高至低依次为生长激素缺乏症组[(2.2±0.7)cm/年]、宫内发育迟缓组[(2.1±0.6)cm/年]、先天性甲状腺功能减退症组[(1.7±0.5)cm/年]和Turner综合征组[(1.2±0.4)cm/年]。生长激素缺乏症组GH峰值为[(6.4±0.3)μg/L],明显低于其他4组(P值均<0.05),其中GH峰值从低至高依次为宫内发育迟缓组[(13.4±3.2)μg/L]、Turner综合征组[(14.2±2.1)μg/L]、特发性矮小症组[(14.7±2.5)μg/L]和先天性甲状腺功能减退症组[(15.6±2.9)μg/L]。Turner综合征组Ghrelin水平显著高于生长激素缺乏症组、特发性矮小症组、先天性甲状腺功能减退症组和宫内发育迟缓组(P值均<0.05);先天性甲状腺功能减退症组IGF-1水平显著低于生长激素缺乏症组、特发性矮小症组、Turner综合征组和宫内发育迟缓组(P值均<0.05)。特发性矮小症组青春前期的血清Ghrelin、IGF-1水平均明显低于青春期(P值均<0.05)。ROC曲线分析结果显示,血清Ghrelin、IGF-1鉴别诊断特发性矮小症的曲线下面积(area under the curve,AUC)分别为0.776、0.733,联合检测鉴别诊断特发性矮小症的AUC为0.839,灵敏度为90.0%,特异性为65.6%(P<0.001)。结论不同病因矮小症患儿血清Ghrelin、IGF-1水平均存在异常表达,特发性矮小症患儿在青春前期和青春期的血清Ghrelin、IGF-1水平差异明显,血清Ghrelin、IGF-1联合检测对特发性矮小症的鉴别诊断具有较好的诊断效能。
