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A requiem for the cholecystokinin provocation test?

ABSTRACT: BACKGROUND: The cholecystokinin provocation test (CCKPT) has been claimed to predict a better symptomatic result after cholecystectomy in patients with acalculous biliary pain. AIMS: To examine the predictive value of the CCKPT for symptom relief after cholecystectomy in both CCKPT positive and negative patients. PATIENTS AND METHODS: Fifty eight patients with acalculous biliary pain underwent CCKPT with serial ultrasound gall bladder volumetry. CCKPT positive patients were offered cholecystectomy; negative patients were reassessed and were offered a cholecystectomy if symptoms persisted. Six months after cholecystectomy, the CCKPT was repeated. RESULTS: Of 32 CCKPT positive patients, 27 underwent cholecystectomy and of these, 18 (67%) became symptom-free. Postoperatively, 20 of 25 patients converted to CCKPT negative but five remained CCKPT positive and were symptomatic. Of the 26 CCKPT negative patients, nine became symptom-free without cholecystectomy; six of 14 (42.8%) patients undergoing cholecystectomy became asymptomatic and remained CCKPT negative. Cholecystectomy seemed to reduce symptoms in both groups, but there was no significant difference in the symptomatic outcome between preoperative CCKPT positive and negative patients. CONCLUSIONS: In this study, cholecystokinin provocation testing did not predict symptomatic benefit from cholecystectomy and we suggest it should no longer be used in the evaluation of patients with acalculous biliary pain.

SUBMITTER: Smythe A

PROVIDER: S-EPMC1727273 | biostudies-other | 1998 Oct

REPOSITORIES: biostudies-other

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Cholecystokinin

Project description: Not available

| S-EPMC2884643 | biostudies-literature

Cholecystokinin activates orexin/hypocretin neurons through the cholecystokinin A receptor.

Project description:Orexin A and B are neuropeptides implicated in the regulation of sleep/wakefulness and energy homeostasis. The regulatory mechanism of the activity of orexin neurons is not precisely understood. Using transgenic mice in which orexin neurons specifically express yellow cameleon 2.1, we screened for factors that affect the activity of orexin neurons (a total of 21 peptides and six other factors were examined) and found that a sulfated octapeptide form of cholecystokinin (CCK-8S), neurotensin, oxytocin, and vasopressin activate orexin neurons. The mechanisms that underlie CCK-8S-induced activation of orexin neurons were studied by both calcium imaging and slice patch-clamp recording. CCK-8S induced inward current in the orexin neurons. The CCKA receptor antagonist lorglumide inhibited CCK-8S-induced activation of orexin neurons, whereas the CCKB receptor agonists CCK-4 (a tetrapeptide form of cholecystokinin) and nonsulfated CCK-8 had little effect. The CCK-8S-induced increase in intracellular calcium concentration was eliminated by removing extracellular calcium but not by an addition of thapsigargin. Nifedipine, omega-conotoxin, omega-agatoxin, 4-ethylphenylamino-1,2-dimethyl-6-methylaminopyrimidinium chloride, and SNX-482 had little effect, but La3+, Gd3+, and 2-aminoethoxydiphenylborate inhibited CCK-8S-induced calcium influx. Additionally, the CCK-8S-induced inward current was dramatically enhanced in the calcium-free solution and was inhibited by the cation channel blocker SKF96365, suggesting an involvement of extracellular calcium-sensitive cation channels. CCK-8S did not induce an increase in intracellular calcium concentration when membrane potential was clamped at -60 mV, suggesting that the calcium increase is induced by depolarization. The evidence presented here expands our understanding of the regulation of orexin neurons and the physiological role of CCK in the CNS.

| S-EPMC6725310 | biostudies-literature

Cholecystokinin, gastrin, cholecystokinin/gastrin receptors, and bitter taste receptor TAS2R14: trophoblast expression and signaling.

Project description:We investigated expression of cholecystokinin (CCK) in humans and mice, and the bitter taste receptor TAS2R14 in the human placenta. Because CCK and gastrin activate the CCKBR receptor, we also explored placental gastrin expression. Finally, we investigated calcium signaling by CCK and TAS2R14. By RT-PCR, we found CCK/Cck and GAST/Gast mRNA expression in both normal human and mouse placentas, as well as in human trophoblast cell lines (TCL). Although both Cckar and -br mRNA were expressed in the mouse placenta, only CCKBR mRNA was detected in the human placenta and TCL. mRNA expression for TAS2R14 was also observed in the human placenta and TCL. Using immunohistochemistry, CCK protein was localized to the syncytiotrophoblast (ST) and extravillous trophoblast (EVT) in the human term placenta, and to trophoblast glycogen cells in mouse and human placentas. Gastrin and TAS2R14 proteins were also observed in ST and EVT of the human placenta. Both sulfated and nonsulfated CCK elicited a comparable rise in intracellular calcium in TCL, consistent with CCKBR expression. Three TAS2R14 agonists, flufenamic acid, chlorhexidine, and diphenhydramine, also evoked rises in intracellular calcium in TCL. These results establish CCK, gastrin, and their receptor(s) in both human and mouse placentas, and TAS2R14 in the human placenta. Both CCK and TAS2R14 agonists increased intracellular calcium in human TCL. Although the roles of these ligands and receptors, and their potential cross talk in normal and pathological placentas, are currently unknown, this study opens new avenues for placental research.

| S-EPMC6589605 | biostudies-literature

Cholecystokinin induces crowing in chickens.

Project description:Animals that communicate using sound are found throughout the animal kingdom. Interestingly, in contrast to human vocal learning, most animals can produce species-specific patterns of vocalization without learning them from their parents. This phenomenon is called innate vocalization. The underlying molecular basis of both vocal learning in humans and innate vocalization in animals remains unknown. The crowing of a rooster is also innately controlled, and the upstream center is thought to be localized in the nucleus intercollicularis (ICo) of the midbrain. Here, we show that the cholecystokinin B receptor (CCKBR) is a regulatory gene involved in inducing crowing in roosters. Crowing is known to be a testosterone (T)-dependent behavior, and it follows that roosters crow but not hens. Similarly, T-administration induces chicks to crow. By using RNA-sequencing to compare gene expression in the ICo between the two comparison groups that either crow or do not crow, we found that CCKBR expression was upregulated in T-containing groups. The expression of CCKBR and its ligand, cholecystokinin (CCK), a neurotransmitter, was observed in the ICo. We also showed that crowing was induced by intracerebroventricular administration of an agonist specific for CCKBR. Our findings therefore suggest that the CCK system induces innate vocalization in roosters.

| S-EPMC6408447 | biostudies-literature

Elasmobranchs express separate cholecystokinin and gastrin genes.

Project description:The peptide hormone gastrin was long believed to be specific for higher vertebrates, whereas its homologue, cholecystokinin (CCK), has been assumed to represent the original ancestor of the CCK/gastrin family. To trace the divergence of the CCK/gastrin family beyond birds, reptiles, and amphibians we have now examined sharks. Distinct CCK and gastrin peptides were identified in two shark species, the spiny dogfish (Squalus acanthias) and the porbeagle (Lamna cornubica). The corresponding genes and cDNAs were isolated and sequenced from the spiny dogfish. Comparison with several vertebrate species show that the CCK gene and peptide structures have been considerably more conserved than the corresponding gastrin structures. Alignment of the dogfish prepropeptides displays similarities that support the hypothesis that they share a common ancestor. Our findings move the CCK/gastrin family segregation back to at least 350 million years ago. This event must have occurred before, or perhaps during, the evolution of cartilagenous fishes, probably concomitant with the occurrence of gastric acid secretion.

| S-EPMC23343 | biostudies-literature

Cholecystokinin plays a novel protective role in diabetic kidney through anti-inflammatory actions on macrophage: anti-inflammatory effect of cholecystokinin.

Project description:Inflammatory process is involved in the pathogenesis of diabetic nephropathy. In this article, we show that cholecystokinin (CCK) is expressed in the kidney and exerts renoprotective effects through its anti-inflammatory actions. DNA microarray showed that CCK was upregulated in the kidney of diabetic wild-type (WT) mice but not in diabetic intracellular adhesion molecule-1 knockout mice. We induced diabetes in CCK-1 receptor (CCK-1R) and CCK-2R double-knockout (CCK-1R(-/-),-2R(-/-)) mice, and furthermore, we performed a bone marrow transplantation study using CCK-1R(-/-) mice to determine the role of CCK-1R on macrophages in the diabetic kidney. Diabetic CCK-1R(-/-),-2R(-/-) mice revealed enhanced albuminuria and inflammation in the kidney compared with diabetic WT mice. In addition, diabetic WT mice with CCK-1R(-/-) bone marrow-derived cells developed more albuminuria than diabetic CCK-1R(-/-) mice with WT bone marrow-derived cells. Administration of sulfated cholecystokinin octapeptide (CCK-8S) ameliorated albuminuria, podocyte loss, expression of proinflammatory genes, and infiltration of macrophages in the kidneys of diabetic rats. Furthermore, CCK-8S inhibited both expression of tumor necrosis factor-? and chemotaxis in cultured THP-1 cells. These results suggest that CCK suppresses the activation of macrophage and expression of proinflammatory genes in diabetic kidney. Our findings may provide a novel strategy of therapy for the early stage of diabetic nephropathy.

| S-EPMC3314350 | biostudies-literature

Hypoxia induced cholecystokinin gene expression in 3D engineered muscle.

Project description:At high altitude, hypoxic atmosphere decreases the oxygen partial pressure (pO2) in the body, inducing several metabolic changes in tissues and cells. Furthermore, it exerts potent anorectic effects, thus causing energy deficit. Two decades ago, a marked increase in the level of resting plasma cholecystokinin (CCK) was observed at Mt. Kanchenjunga basecamp (BC) located at 5,100 m above the sea level, compared to sea-level control values. Interestingly, acute exercise also raises plasma CCK and exerts potent anorectic effects under normoxic conditions. However, the molecular mechanism underlying these effects has not yet been established. We employed acute electrical pulse stimulation (EPS), followed by a microarray analysis, to discover novel myokines in 3D engineered muscle. Acute EPS efficiently affects the contractile function, inducing a decline of the contractile force. Surprisingly, microarray analysis revealed an EPS-induced activation of the cholecystokinin receptor (CCKR)-mediated signaling. Furthermore, Cck was constitutively expressed in 3D engineered muscle, and was upregulated by hypoxic conditions. Notably, a hypoxia responsive element (HRE) was detected in the Cck promoter of mice and humans. Our results suggested that, under hypoxic conditions, Hif-1a binding to HRE transactivated Cck expression in mice and humans. Furthermore, the plasma CCK elevation after acute exercise or at high altitude might be partly attributed to myogenic cells.

2021-04-13 | GSE135373 | GEO

Targeting cholecystokinin-2 receptor for pancreatic cancer chemoprevention.

Project description:Gastrin signaling mediated through cholecystokinin-2 receptor (CCK2R) and its downstream molecules is altered in pancreatic cancer. CCK2R antagonists, YF476 (netazepide) and JNJ-26070109, were tested systematically for their effect on pancreatic intraepithelial neoplasia (PanIN) progression to pancreatic ductal adenocarcinoma (PDAC) in KrasG12D mice. After dose selection using wild-type mice, six-week-old p48Cre/+ -LSL-KrasG12D (22-24 per group) genetically engineered mice (GEM) were fed AIN-76A diets containing 0, 250, or 500 ppm JNJ-26070109 or YF-476 for 38 weeks. At termination, pancreata were collected, weighed, and evaluated for PanINs and PDAC. Results demonstrated that control-diet-fed mice showed 69% (males) and 33% (females) incidence of PDAC. Administration of low and high dose JNJ-26070109 inhibited the incidence of PDAC by 88% and 71% (P < .004) in male mice and by 100% and 24% (P > .05) in female mice, respectively. Low and high dose YF476 inhibited the incidence of PDAC by 74% (P < .02) and 69% (P < .02) in male mice and by 45% and 33% (P > .05) in female mice, respectively. Further, transcriptome analysis showed downregulation of Cldn1, Sstr1, Apod, Gkn1, Siglech, Cyp2c44, Bnc1, Fmo2, 623169, Kcne4, Slc27a6, Cma1, Rho GTPase activating protein 18, and Gpr85 genes in JNJ-26070109-treated mice compared with untreated mice. YF476-treated mouse pancreas showed downregulation of Riks, Zpbp, Ntf3, Lrrn4, Aass, Skint3, Kcnb1, Dgkb, Ddx60, and Aspn gene expressions compared with untreated mouse pancreas. Overall, JNJ-26070109 showed better chemopreventive efficacy than YF476. However, caution is recommended when selecting doses, as the agents appeared to exhibit gender-specific effects.

| S-EPMC6721979 | biostudies-literature

Permanent Photodynamic Activation of the Cholecystokinin 2 Receptor.

Project description:The cholecystokinin 2 receptor (CCK2R) is expressed in the central nervous system and peripheral tissues, playing an important role in higher nervous and gastrointestinal functions, pain sensation, and cancer growth. CCK2R is reversibly activated by cholecystokinin or gastrin, but whether it can be activated permanently is not known. In this work, we found that CCK2R expressed ectopically in CHO-K1 cells was permanently activated in the dark by sulfonated aluminum phthalocyanine (SALPC / AlPcS4, 10-1,000 nM), as monitored by Fura-2 fluorescent calcium imaging. Permanent CCK2R activation was also observed with AlPcS2, but not PcS4. CCK2R previously exposed to SALPC (3 and 10 nM) was sensitized by subsequent light irradiation (> 580 nm, 31.5 mW·cm-2). After the genetically encoded protein photosensitizer mini singlet oxygen generator (miniSOG) was fused to the N-terminus of CCK2R and expressed in CHO-K1 cells, light irradiation (450 nm, 85 mW·cm-2) activated in-frame CCK2R (miniSOG-CCK2R), permanently triggering persistent calcium oscillations blocked by the CCK2R antagonist YM 022 (30 nM). From these data, it is concluded that SALPC is a long-lasting CCK2R agonist in the dark, and CCK2R is photogenetically activated permanently with miniSOG as photosensitizer. These properties of SALPC and CCK2R could be used to study CCK2R physiology and possibly for pain and cancer therapies.

| S-EPMC7072308 | biostudies-literature

Cholecystokinin-A signaling regulates automaticity of pacemaker cardiomyocytes.

Project description:Aims: The behavior of pacemaker cardiomyocytes (PCs) in the sinoatrial node (SAN) is modulated by neurohormonal and paracrine factors, many of which signal through G-protein coupled receptors (GPCRs). The aims of the present study are to catalog GPCRs that are differentially expressed in the mammalian SAN and to define the acute physiological consequences of activating the cholecystokinin-A signaling system in isolated PCs. Methods and results: Using bulk and single cell RNA sequencing datasets, we identify a set of GPCRs that are differentially expressed between SAN and right atrial tissue, including several whose roles in PCs and in the SAN have not been thoroughly characterized. Focusing on one such GPCR, Cholecystokinin-A receptor (CCKAR), we demonstrate expression of Cckar mRNA specifically in mouse PCs, and further demonstrate that subsets of SAN fibroblasts and neurons within the cardiac intrinsic nervous system express cholecystokinin, the ligand for CCKAR. Using mouse models, we find that while baseline SAN function is not dramatically affected by loss of CCKAR, the firing rate of individual PCs is slowed by exposure to sulfated cholecystokinin-8 (sCCK-8), the high affinity ligand for CCKAR. The effect of sCCK-8 on firing rate is mediated by reduction in the rate of spontaneous phase 4 depolarization of PCs and is mitigated by activation of beta-adrenergic signaling. Conclusion: (1) PCs express many GPCRs whose specific roles in SAN function have not been characterized, (2) Activation of the cholecystokinin-A signaling pathway regulates PC automaticity.

| S-EPMC10764621 | biostudies-literature

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