Cholecystokinin and cholecystokinin-A receptor: An attractive treatment strategy for biliary dyskinesia?

Biliary dyskinesia is a relatively common gastrointestinal disease that is increas-ing in incidence as living standards improve.However,its underlying pathogenesis remains unclear,hindering the development of therapeutic drugs.Recently,“Expression and functional study of cholecystokinin-A receptors on the interstitial Cajal-like cells of the guinea pig common bile duct”demonstrated that cholecystokinin(CCK)regulates the contractile function of the common bile duct through interaction with the CCK-A receptor in interstitial Cajal-like cells,contributing to improving the academic understanding of biliary tract dynamics and providing emerging directions for the pathogenesis and clinical management of biliary dyskinesia.This letter provides a brief overview of the role of CCK and CCK-A receptors in biliary dyskinesia from the perspective of animal experiments and clinical studies,and discusses prospects and challenges for the clinical application of CCK and CCK-A receptors as potential therapeutic targets.

Expression profile of cholecystokinin type-A receptor in gallbladder cancer and gallstone disease

BACKGROUND:Regulatory peptide receptors have attracted the interest of oncologists as a new promising approach for cancer pathology,imaging and therapy.Although cholecystokinin (CCK) is a potent modulator of gallbladder contractility and plays a potential role in pancreatic carcinogenesis through CCK type-A receptor (CCKAR),its role in gallbladder cancer (GBC) is still unknown and immunohistochemical detection of CCKAR in the gallbladder has not yet been reported.This novel case-control study aimed to investigate the expression profile of CCKAR in GBC and gallstone disease (GSD).METHODS:This study included 162 samples of gallbladder:94 from GBC and 68 from GSD.Expression of CCKAR was analyzed by immunohistochemistry and immunoblotting.The results were statistically correlated with disease history including age,sex,presence of gallstone,stage and differentiation.RESULTS:CCKAR was positive in 30/68 (44.1%) of GSD and 72/94 (76.6%) of GBC samples.Fifty-one of the 72 (70.8%) CCKAR-positive GBC samples showed over-expression.Interestingly,consistent results also appeared in the immunoblotting study.CONCLUSIONS:CCKAR expression was significantly increased in GBC compared to GSD.Moreover,CCKAR expression was associated with the degree of tumor differentiation,i.e.,less expression in poorly-differentiated tumors.Thus,it has future prognostic and therapeutic implications in the management of GBC.

Investigation of cholecystokinin receptors in the human lower esophageal sphincter

AIM:To compare the binding of cholecystokinin(CCK)-8to CCK receptors in sling and clasp fibers of the human lower esophageal sphincter.METHODS:Esophageal sling and clasp fibers were isolated from eight esophagectomy specimens,resected for squamous cell carcinoma in the upper two thirds of the esophagus,which had been maintained in oxygenated Kreb’s solution.Western blot was used to measure CCK-A and CCK-B receptor subtypes in the two muscles.A radioligand binding assay was used to determine the binding parameters of 3H-CCK-8S to the CCK receptor subtypes.The specificity of binding was determined by the addition of proglumide,which blocks the binding of CCK to both receptor subtypes.RESULTS:There was no significant difference between the sling and clasp fibers of the human lower esophageal sphincter in the amount of CCK-A[integratedoptical density(IOD)value:22.65±0.642 vs 22.328±1.042,P=0.806]or CCK-B receptor protein(IOD value:13.20±0.423 vs 12.45±0.294,P=0.224)as measured by Western blot.The maximum binding of radio-labeled CCK-8S was higher in the sling fibers than in the clasp fibers(595.75±3.231 cpm vs 500.000±10.087 cpm,P<0.001)and dissociation constant was lower(Kd:1.437±0.024 nmol/L vs 1.671±0.024nmol/L,P<0.001).The IC50 of the receptor specific antagonists were lower for the CCK-A receptors than for the CCK-B(P<0.01).CONCLUSION:CCK binding modulates the contractile function of the lower esophageal sphincter through differential binding to the CCK-A receptor on the sling and clasp fibers.

Simotang enhances gastrointestinal motility,motilin and cholecystokinin expression in chronically stressed mice

AIM:To investigate the effect of Simotang(Decoction of Four Powered Drugs) on gastrointestinal motility,motilin and cholecystokinin expression in chronically stressed mice.METHODS:Forty mice were randomly divided into control group,stress group(model group),mosapride group and Simotang group,10 in each group.A variety of unpredictable stimulations were used to induce chronic stress in mice.Then,the mice were treated with distilled water,mosapride or Simotang for 7 d.Gastric emptying and intestinal propulsion function were detected.Serum level of motilin was measured by enzyme-linked immunosorbent assay.Expression of cholecystokinin(CCK) in intestine,spinal cord and brain of mice was detected by immunohistochemistry and semi-quantitative reverse transcription polymerase chain reaction,respectively.RESULTS:Simotang improved the gastric emptying and intestinal propulsion in chronically stressed mice.Furthermore,the serum motilin level was significantly higher and the expression levels of CCK-positive cells and genes were significantly lower in intestine,spinal cord and brain of Simotang group than in those of model group(P<0.05).No significant difference was found in serum motilin level and expression levels of CCK-positive cells and genes between the mosapride and Simotang groups.CONCLUSION:Simotang enhances the gastrointestinal motility in chronically stressed mice by regulating the serum motilin level and the expression of cholecystokinin.

Effect of cholecystokinin and secretin on contractile activity of isolated gastric muscle strips in guinea pigs

AIM To study the effect of cholecystokinin-octapeptide（CCK-8）and secretin on contractileactivity of isolated gastric muscle strips inguinea pigs.METHODS Each isolated gastric muscle stripwas suspended in a tissue chamber containing5 mL Krebs solution constantly warmed by waterjacked at 37℃ and supplied with a mixed gas of95% O2 and 5% CO2 After incubating for lhunder 1 g tension,varied concentrations of CCK-8 and secretin were added respectively in thetissue chamber and the contractile response wasmeasured isometrically on ink-writing recorders.RESULTS CCK-8 could increase①all regionalcircular and longitudinal muscular tension at rest（fundus LM 19.7%±2.1%,P【0.01;fundus CM16.7%±2.2%,P【0.01;gastric body LM 16.8%±2.3%,P【0.01;body CM 12.7%±2.6%,P【0.01;antrum LM 12.3%±1.3%,P【0.01;antrum CM 16.7%±4.5%,P【0.01;pylous CM12.7%±5.0%,P【0.05）;②contractilefrequencies of body LM,both LM and CM ofantrum and pylorus CM（5.1/min±0.2/min to5.6/min±0.2/min,5.9/min±0.2/min to 6.6/min±0.l/min,5.4/min±0.3/min to 6.3/min±0.4/rain,1.3/min±0.2/min to 2.3/min±0.3/min,respectively,P【0.05）;③the mean contractileamplitude of antral circular muscle（58.6%±18.4%,P【0.05）and ④the motility index ofpylorus CM（145.0%±23.8%,P【0.01）,butdecrease the mean contractile amplitude ofgastric body and antral LM（-10.3%±3.3%,-10.5%±4.6%,respectively,P【0.05）.All the CCK-8 effects were not blocked by atropine orindomethacin.Secretin had no effect on gastricsmooth muscle activity.CONCLUSION CCK-8 possessed bothexcitatory and inhibitory action on contractileactivity of different regions of stomach in guineapigs.Its action was not mediated via cholinergicM receptor and endogenous prostagiandinreceptor,

Effect of endogenous cholecystokinin on the course of acute pancreatitis in rats

AIM: To examine the effects of pancreatic rest, stimulation and rest/stimulation on the natural course of recovery after acute pancreatitis. METHODS: Acute hemorrhagic pancreatitis(AP) was induced in male rats by intraductal infusion of 40 μl/100 g body weight of 3% sodium taurocholate. All rats took food ad libitum. At 24 h after induction of AP, rats were divided into four groups: control(AP-C), pancreas rest(AP-R), stimulation(AP-S), and rest/stimulation(AP-R/S). Rats in the AP-C, AP-R and AP-S groups received oral administration of 2 ml/kg body weight saline, cholecystokinin(CCK)-1 receptor antagonist, and endogenous CCK release stimulant, respectively, twice daily for 10 d, while those in the AP-R/S group received twice daily CCK-1 receptor antagonist for the first 5 d followed by twice daily CCK release stimulant for 5 d. Rats without any treatment were used as control group(Control). Biochemical andhistological changes in the pancreas, and secretory function were evaluated on day 12 at 24 h after the last treatment. RESULTS: Feeding ad libitum(AP-C) delayed biochemical, histological and functional recovery from AP. In AP-C rats, bombesin-stimulated pancreatic secretory function and HOMA-β-cell score were significantly lower than those in other groups of rats. In AP-R rats, protein per DNA ratio and pancreatic exocrine secretory function were significantly low compared with those in Control rats. In AP-S and AP-R/S rats, the above parameters recovered to the Control levels. Bombesinstimulated pancreatic exocrine response in AP-R/S rats was higher than in AP-S rats and almost returned to control levels. In the pancreas of AP-C rats, destruction of pancreatic acini, marked infiltration of inflammatory cells, and strong expression of α-smooth muscle actin, tumor necrosis factor-α and interleukin-1β were seen. Pancreatic rest reversed these histological alterations, but not atrophy of pancreatic acini and mild infiltration of inflammatory cells. In AP-S and AP-R/S rats, the pancreas showed almost normal architecture. CONCLUSION: The favorable treatment strategy for AP is to keep the pancreas at rest during an early stage followed by pancreatic stimulation by promoting endogenous CCK release.

Serotonin transporter and cholecystokinin in diarrhea-predominant irritable bowel syndrome: Associations with abdominal pain, visceral hypersensitivity and psychological performance

BACKGROUND Visceral hypersensitivity and psychological performance are the main pathophysiological mechanisms of irritable bowel syndrome(IBS).Previous studies have found that cholecystokinin(CCK)can enhance colon movement and that serotonin transporter(SERT)is a transmembrane transport protein with high affinity for 5-hydroxytryptamine,which can rapidly reuptake 5-hydroxytryptamine and then regulate its action time and intensity.We speculate that SERT and CCK might play a role in the pathogenesis of diarrheapredominant IBS(IBS-D)by affecting visceral sensitivity and the brain-gut axis.AIM To determine SERT and CCK levels in IBS-D patients diagnosed using Rome IV criteria and to analyze their associations with abdominal pain,visceral hypersensitivity and psychological performance.METHODS This study collected data from 40 patients with IBS-D at the China-Japan Friendship Hospital from September 2017 to April 2018 and 18 healthy controls.The severity of abdominal pain,visceral sensitivity and psychological performance were evaluated in IBS-D patients and healthy controls,the levels of SERT and CCK in plasma and colonic mucosa were evaluated,and the correlations between them were analyzed.RESULTS There were significant differences in the initial sensation threshold(31.00±8.41 mL vs 52.22±8.09 mL,P<0.001),defecating sensation threshold(51.75±13.57 mL vs 89.44±8.73 mL,P<0.001)and maximum tolerable threshold(97.25±23.64 mL vs 171.11±20.83 mL,P<0.001)between the two groups.IBS-D patients had more severe anxiety(7.78±2.62 vs 2.89±1.02,P<0.001)and depressive(6.38±2.43 vs 2.06±0.73,P<0.001)symptoms than healthy controls.Significant differences were also found in mucosal CCK(2.29±0.30 vs 1.66±0.17,P<0.001)and SERT(1.90±0.51 vs 3.03±0.23,P<0.001)between the two groups.There was a significant positive correlation between pain scores and mucosal CCK(r=0.96,0.93,0.94,P<0.001).Significant negative correlations between anxiety(r=-0.98;P<0.001),depression(r=-0.99;P<0.001),pain evaluation(r=-0.96,-0.93,-0.95,P<0.001)and mucosal SERT were observed.CONCLUSION IBS-D patients had psychosomatic disorders and visceral hypersensitivity.SERT and CCK might be involved in the pathogenesis of IBS-D by regulating the braingut axis and affecting visceral sensitivity.This provides a new potential method for identifying a more specific and effective therapeutic target.

Purification and characterization of cholecystokinin from the skin of salamander Tylototriton verrucosus

As a group of intestinal hormones and neurotransmitters, cholecystokinins（CCKs） regulate and affect pancreatic enzyme secretion, gastrointestinal motility, pain hypersensitivity, digestion and satiety, and generally contain a DYMGWMDFG sequence at the C-terminus. Many CCKs have been reported in mammals. However, only a few have been reported in amphibians, such as Hyla nigrovittata, Xenopus laevis, and Rana catesbeiana, with none reported in urodele amphibians like newts and salamanders. Here, a CCK called CCK-TV was identified and characterized from the skin of the salamander Tylototriton verrucosus. This CCK contained an amino acid sequence of DYMGWMDF-NH2 as seen in other CCKs. A c DNA encoding the CCK precursor containing 129 amino acid residues was cloned from the c DNA library of T. verrucosus skin. The CCK-TV had the potential to induce the contraction of smooth muscle strips isolated from porcine gallbladder, eliciting contraction at a concentration of 5.0x10-11 mol/L and inducing maximal contraction at a concentration of 2.0x10-6 mol/L. The EC50 was 13.6 nmol/L. To the best of our knowledge, this is the first report to identify the presence of a CCK in an urodele amphibian.

Peroxynitrite-induced expression of inducible nitric oxide synthase and activated apoptosis via nuclear factor-kappa B pathway in retinal pigment epithelial cells and antagonism of cholecystokinin octapeptide-8 in vitro

AIM: To explore that if peroxynitrite induced the expression of inducible nitric oxide synthase (iNOS)via nuclear factor-kappa B (NF-kappa B)pathway in retinal pigment epithelial (RPE) cells and the antagonism of cholecystokinin octapeptide-8 (Melatonin, CCK-8) in vitro. METHODS: RPE cells were obtained from eyes of C57BL/6 mouse and divided into control, peroxynitrite and CCK-8 groups. Control group was treated with saline, peroxynitrite group was treated with peroxynitrite, and CCK-8 group was treated with CCK-8 after added with peroxynitrite. All changes were observered at 6, 12 and 24 hours after treatment. Gene array analysis, Reverse Transcription Polymerase Chain Reaction (RT-PCR) were used to determine the expression of inducible nitric oxide synthase ( iNOS)mRNA in RPE cells. Western blotting was used to test the apoptosis of RPE cells. Immunofluorescent staining was used to determine the NF-kappa B pathway signal transduction. RESULTS: Compared to the control group, the expression of iNOS mRNA was up-regulated in peroxynitrite group and down-regulated in CCK-8 group with gene array analysis. Apoptosis was increased in peroxynitrite group and decreased in CCK-8 group with western blotting. The NF-kappa B pathway signal transduction was more and more stronger in the peroxynitrite group. But in CCK-8 group, little stronger could be observed at 12 hours, then weak at 24 hours with immunofluorescent staining (P<0.001). CONCLUSION: This study suggested that apoptosis of RPE cells was partly induced by peroxynitrite, which may be the new way of oxidative damage to the RPE cells. The NF-kappa B signal transduction may affect and reinforce apoptosis mediated by peroxynitrite. CCK-8 decreased apoptosis of RPE cells induced by peroxynitrite and is a potential agent for therapy of retinopathy. The mechanism of CCK-8 dealing with RPE cells may be related to its direct inhibition of the formation of iNOS to produce peroxynitrite and antagnism of damage of peroxynitrite to the RPE cells.

Chemical Reactivity Properties, Drug-Likeness Features and Bioactivity Scores of the Cholecystokinin Peptide Hormone

Five density functionals, CAM-B3LYP, LC-ωPBE, MN12SX, N12SX and ωB97XD, in connection with the Def2TZVP basis set were assessed together with the SMD solvation model for the calculation of the molecular and chemical reactivity properties of the Cholecystokinin peptide hormone (CCK-8) in the presence of water. All the chemical reactivity descriptors for the systems were calculated via Conceptual Density Functional Theory (CDFT). The potential bioavailability and druggability as well as the bioactivity scoresfor CCK-8 were predicted through different methodologies already reported in the literature which have been previously validated during the study of different peptidic systems. The conclusion was that the CCK-8 peptide will be moderately bioactive regarding all the interactions.

Effect of cholecystokinin octapeptide on mean pulmonary artery pressure in endotoxic shock rats

Objective:To investigate the effects of CCK-8 on mean pulmonary artery pressure in rats with endotoxic shock.Methods:Male SD rats were randomized into seven groups(n=6):control group,model group,LPS+CCK-8 group,CCK-8 group,CCK-1R antagonist group,CCK-2R antagonist group,DFSO+PF group.The rats were induced to lethal endotoxic shock by an injection of LPS(30 mg.kg-1).CCK-8(50μg.kg-1)was administered 30 min after LPS injection.Either a specific CCK-1R antagonist or CCK-2R antagonist was injected before CCK-8 treatment.The mean arterial pressure(MAP)and mean pulmonary artery pressure(MPAP)were collected by a multi-channel data physiological recorder.As well as the 8h mortality was recorded.Results:Compared with control group,the MAP were significantly continuously lower and the MPAP significantly higher in model group.Administration of CCK-8 significantly delayed the LPS-induced not only decreases in MAP but also rises in MPAP,while reduceing the mortality.In addition,the specific antagonist at the CCK-2 receptor(CCK-2R)abrogated the action of CCK-8 significantly.Conclusion:while the LPS-induced hypotension delayed,CCK-8 could effectively alleviate the LPS-induced rises in MPAP via the CCK-2 receptor in ES rat model,while reduceing the mortality.

Effects of cholecystokinin octapeptide receptor on lung injury in endotoxemia rats

Objective:To investigate the effects of CCK-8 receptor on lung injury in endotoxemia rats. Methods: Male SD rats were randomized into four groups (n=6): control group (LPS+CCK-8 group), CCK-1R antagonist group, CCK-2R antagonist group, DFSO+PF group. The rats were injected by LPS (5 mg.kg-1). CCK-8 (20 μg.kg-1) was administered 30 min after LPS injection. Either a specific CCK-1R antagonist or CCK-2R antagonist (0.5.kg-1) was injected before CCK-8 treatment (after LPS 20min). The tidal volume (TV) was collected by a multi-channel data physiological recorder. The lung injury was observed by light and electron microscopy. The concentrations of TNF-α、IL-1 and IL-6 in lung homogenates were measured by ELISA kits.Rresults: Compared with control group, the TV were significantly lower and the lung injuries were more serious in CCK-2R antagonist group. As well as the concentrations of TNF-α、IL-1 and IL-6 in lung homogenates were higher.Conclusion: CCK-2 receptor plays a major role in the effect of CCK-8 on lung injury in ETM rats.

Cholecystokinin in the Pathogenesis of Bulimia Nervosa

Objective: This review aims to describe the role of the hormone cholecystokinin (CCK) in the pathogenesis of bulimia nervosa (BN), the perpetuation of this illness and the possibility of its use as a target for future therapeutic advances. Methods: Search for cholecystokinin AND bulimia nervosa in Pubmed Central, with no limits, identified 38 articles published up to the present date. Results: It is well established that CCK is altered in the pathogenesis of BN, and that its main role is in the perpetuation of the disorder rather than the cause of it. Discussion: Additional studies will be needed to further understand the mechanisms by which CCK regulates orexigenic pathways. If an orally active, longer acting analogue of CCK could be developed, it would be of significant interest as an appetite suppressant and a key adjuvant in the treatment of patients suffering from BN, particularly in refractory cases.

Synthesis of Cholecystokinin Peptide CCK-4 Exclusively by Enzymatic Methods

The synthesis of CCK - 4 (H - Trp- Met- Asp- Phe- NH2 ) by using enzym es exclusively was described.As protection group for the amino group we used the Phenylacetyl group (Phac) which had been cleaved at the end of the synthesis with Penicillin G Amidase (PGA ) without affecting the peptide bonds.Thus,beginning with Phac- Trp- OH we had successfully synthesized the target peptide with following4 enzymes,α- Chym otrypsin,Papain,Therm olysin and PGA in four reac- tion steps.All reactions were carried out in aqueous buffer in reasonable yields(>6 5 % ) .FAB- MS or FD- MS verified the correct molecular mass of all peptides.

Gallbladder motor function, plasma cholecystokinin and cholecystokinin receptor of gallbladder in cholesterol stone patients

AIM: To study the interactive relationship of gallbladder motor function, plasma cholecystokinin (CCK) and cholecystokinin A receptor (CCK-R) of gallbladder in patients with cholesterol stone disease.METHODS: Gallbladder motility was studied by ultrasonography in 33 patients with gallbladder stone and 10 health subjects as controls. Plasma CCK concentration was measured by radioimmunoassay in fasting status (CCK-f) and in 30 min after lipid test meal (CCK-30).Radioligand method was employed to analyze the amount and activity of CCK-R from 33 gallstone patients having cholecystectomy and 8 persons without gallstone died of severe trauma as controls.RESULTS: The percentage of cholesterol in the gallstone composition was more than 70%. The cholesterol stone type was indicated for the patients with gallbladder stone in this study. Based on the criterion of gallbladder residual fraction of the control group, 33 gallstone patients were divided into two subgroups, contractor group (14 cases)and non-contractor group (19 cases), The concentration of CCK-30 was significantly higher in non-contractor group than that in both contractor group and control group (55.86±3.86 pmol/l vs 37.85±0.88 pmol/l and 37.95±0.74 pmol/L, P＜0.01), but there was no difference between contractor group and control group. Meanwhile no significant difference of the concentration of CCK-f could be observed among three groups. The amount of CCK-R was lower in non-contractor group than those in both control group and contractor group (10.27±0.94 fmol/mg vs24.59±2.39 fmol/mg and 22.66±0.55 fmol/mg, P＜0.01).The activity of CCK-R shown as KD in non-contractor group decreased compared to that in control group and contractor group. Only was the activity of CCK-R lower in contractor group than that in control group. The ejection fraction correlated closely with the amount of CCK-R (r = 0.9683,P＜0.01), and the concentration of CCK-30 correlated negatively with the amount of CCK-R closely (r = -0.9627,P＜0.01).CONCLUSION: The distinctive interactive relationship of gallbladder emptying, plasma CCK and CCK-R in gallbladder from this study suggested that the defect of CCK-R may be a key point leading to the impairment of gallbladder motor function and the pathogenesis of cholesterol gallstoneformation may differ in two subgroups of gallstone patient,gallbladder non-contractor group or contractor group.

大黄鱼(Pseudosciaena crocea)leptin和cholecystokinin基因的克隆和表达特性研究

本文克隆了两种大黄鱼(Pseudosciaena crocea)摄食调控因子胆囊收缩素(CCK)、瘦素(LEP)基因的全长序列,并对其表达特性进行了研究。结果表明,克隆得到CCK基因属硬骨鱼类的CCK1亚家族,全长900nt,编码137个氨基酸,与其他鱼类的CCK1相比序列组成非常保守,特别是在20氨基酸的信号肽和8个氨基酸的CCK-8活性结构区域;而克隆得到LEP基因属硬骨鱼类的LEPA亚家族,全长1290nt,编码161个氨基酸,与其他鱼类LEP相比基因同源性较差,但在3D结构上却保留了LEP经典的4个α螺旋特征。两种因子在所检测的所有组织中均有表达,但尤以脑、胃、肠消化道、肝脏等摄食及能量平衡相关组织中表达活性最高。8天的饥饿能使大黄鱼脑、消化道组织的CCK和肝脏、脂肪组织中的LEP表达显著降低(P<0.05)。该结果说明CCK和LEP可能在大黄鱼的摄食生理和能量平衡中起着重要的调控作用;本研究将为深入了解鱼类食欲调控的神经内分泌机理提供基础。

Cholecystokinin hyperresponsiveness in functional dyspepsia

机能性消化不良(FD ) 是还不明确的病原学的普通混乱。消化不良的症状通常是联系的饭并且建议一个协会到胃肠(官方补给) 感觉运动的机能障碍。缩胆囊素(CCK ) 是在胃肠的功能起一个重要规章的作用的确定的大脑勇气肽。它禁止胃的活动性并且经由辣椒辣素倒空敏感迷走神经小径。倒空上的效果经由它近似的胃和幽门上的行动。CCK 也涉及食物摄取的规定。导致饱足经由迷走神经 afferents 响应饭和幕在内脏被释放。而且， CCK 也被显示了涉及恐慌的混乱，焦虑和疼痛的致病。另外的 neurotransmitters 象血清素那样并且也不肾上腺素可以在官方补给的活动的协作与 CCK 被含有。另外， CCK 的静脉内的管理被观察了在 FD 复制症状，这效果能被颠茄碱和 loxiglumide 两个都堵住(CCK -- 一个对手) 。对 CCK 的改变的回答可能为通常观察的胃的感觉运动的机能障碍负责，是可能的，它然后可以与消化不良的症状的开始被联系。

Role of cholecystokinin and central serotonergic receptors in functional dyspepsia

机能性消化不良的症状被上面的腹的不快或疼痛描绘，早饱足，饭后的充分，膨胀，恶心并且呕吐。它非常是长期的混乱，与症状 3 瞬间每器质性病的年，和没有证据。不正常的活动性，改变的内脏的感觉，和精神分析聚会因素都作为主要 pathophysiological 机制被识别了。这些 pathophysiological 机制交往生产观察症状，这被相信。消化不良基于主导的症状被分成了三亚群。象 Dysmotility 一样消化不良描述其综合征通常与一个胃的感觉运动的机能障碍有关的病人的亚群。大脑勇气肽缩胆囊素(CCK ) 和血清素(5-HT ) 分享某些生理的效果。被显示了胃的倒空减少并且影响饱足。而且， CCK 导致了取决于的厌食可能经由中央小径行动的 serotonergic 功能。我们相信和一只亢奋的应答的海角工作到 CCK 或他们的相互作用的中央 serotonergic 受体的畸形可能为在机能性消化不良(FD ) 的症状的开始负责。

Control of gallbladder contractions by cholecystokinin through cholecystokinin-A receptors on gallbladder interstitial cells of cajal

AIM: To identify the cholecystokinin (CCK)-A receptors (CCK-AR) on the guniea pig gallbladder interstitial cells of cajal (ICC) and to study CCK-8 induced gallbladder muscle strip contractions through the CCK-AR. METHODS: The existence of CCK-AR was examined by immunohistofluorescence on sectioned tissue and cultured cells. In vitro contractile response of guinea pig gallbladder muscle strips and the strips with ICC removed were also studied with CCK-8 receptors added. RESULTS: In tissue sections, intensely CCKAR- immunoreactive interstitial cells were found mainly in the muscular layers. In cultured cell sections, distinctive double staining of C-kit and CCK-AR ICCs were found. When we removed the ICC of the gallbladder, CCK-8 induced muscle strip contraction dose response curve significantly shifted to the right. CONCLUSION: We proved that both the existence of CCK-AR on the guinea pig gallbladder ICC and CCK evoked contraction are mediated through direct action on CCK-AR on the gallbladder ICC.

Effects of psychological stress on small intestinal motility and expression of cholecystokinin and vasoactive intestinal polypeptide in plasma and small intestine in mice

AIM: To investigate the effects of psychological stress on small intestinal motility and expression of cholecystokinin(CCK) and vasoactive intestinal polypeptide (VIP) in plasma and small intestine, and to explore the relationship between small intestinal motor disorders and gastrointestinal hormones under psychological stress.METHODS: Thirty-six mice were randomly divided into psychological stress group and control group. A mouse model with psychological stress was established by housing the mice with a hungry cat in separate layers of a two-layer cage. A semi-solid colored marker (carbon-ink) was used for monitoring small intestinal transit. CCK and VIP levels in plasma and small intestine in mice were measured by radioimmunoassay (RIA).RFSULTS: Small intestinal transit was inhibited (52.18±19.15%vs 70.19±17.79%, P＜0.01) in mice after psychological stress, compared to the controls. Small intestinal CCK levels in psychological stress mice were significantly lower than those in the control group (0.75±0.53 μg/g vs 1.98±1.17 μg/g,P＜0.01), whereas plasma CCK concentrations were not different between the groups. VIP levels in small intestine were significantly higher in psychological stress mice than those in the control group (8.45±1.09 μg/g vs 7.03±2.36 μg/g,P＜0.01), while there was no significant difference in plasma VTP levels between the two groups.CONCLUSION: Psychological stress inhibits the small intestinal transit, probably by down-regulating CCK and up-regulating VIP expression in small intestine.