Cholecystokinin facilitates motor skill learning by modulating neuroplasticity in the motor cortex.

Cholecystokinin (CCK) is an essential modulator for neuroplasticity in sensory and emotional domains. Here, we investigated the role of CCK in motor learning using a single pellet reaching task in mice. Mice with a knockout of Cck gene (Cck-/-) or blockade of CCK-B receptor (CCKBR) showed defective motor learning ability; the success rate of retrieving reward remained at the baseline level compared to the wildtype mice with significantly increased success rate. We observed no long-term potentiation upon high-frequency stimulation in the motor cortex of Cck-/- mice, indicating a possible association between motor learning deficiency and neuroplasticity in the motor cortex. In vivo calcium imaging demonstrated that the deficiency of CCK signaling disrupted the refinement of population neuronal activity in the motor cortex during motor skill training. Anatomical tracing revealed direct projections from CCK-expressing neurons in the rhinal cortex to the motor cortex. Inactivation of the CCK neurons in the rhinal cortex that project to the motor cortex bilaterally using chemogenetic methods significantly suppressed motor learning, and intraperitoneal application of CCK4, a tetrapeptide CCK agonist, rescued the motor learning deficits of Cck-/- mice. In summary, our results suggest that CCK, which could be provided from the rhinal cortex, may surpport motor skill learning by modulating neuroplasticity in the motor cortex.

Heterosynaptic plasticity of the visuo-auditory projection requires cholecystokinin released from entorhinal cortex afferents.

The entorhinal cortex is involved in establishing enduring visuo-auditory associative memory in the neocortex. Here we explored the mechanisms underlying this synaptic plasticity related to projections from the visual and entorhinal cortices to the auditory cortex in mice using optogenetics of dual pathways. High-frequency laser stimulation (HFS laser) of the visuo-auditory projection did not induce long-term potentiation. However, after pairing with sound stimulus, the visuo-auditory inputs were potentiated following either infusion of cholecystokinin (CCK) or HFS laser of the entorhino-auditory CCK-expressing projection. Combining retrograde tracing and RNAscope in situ hybridization, we show that Cck expression is higher in entorhinal cortex neurons projecting to the auditory cortex than in those originating from the visual cortex. In the presence of CCK, potentiation in the neocortex occurred when the presynaptic input arrived 200 ms before postsynaptic firing, even after just five trials of pairing. Behaviorally, inactivation of the CCK+ projection from the entorhinal cortex to the auditory cortex blocked the formation of visuo-auditory associative memory. Our results indicate that neocortical visuo-auditory association is formed through heterosynaptic plasticity, which depends on release of CCK in the neocortex mostly from entorhinal afferents.

Gut hormones and appetite regulation.

PURPOSE OF REVIEW: Various gut hormones interact with the brain through delicate communication, thereby influencing appetite and subsequent changes in body weight. This review summarizes the effects of gut hormones on appetite, with a focus on recent research. RECENT FINDINGS: Ghrelin is known as an orexigenic hormone, whereas glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin (CCK), postprandial peptide YY (PYY), and oxyntomodulin (OXM) are known as anorexigenic hormones. Recent human studies have revealed that gut hormones act differently in various systems, including adipose tissue, beyond appetite and energy intake, and even involve in high-order thinking. Environmental factors including meal schedule, food contents and quality, type of exercise, and sleep deprivation also play a role in the influence of gut hormone on appetite, weight change, and obesity. Recently published studies have shown that retatrutide, a triple-agonist of GLP-1, GIP, and glucagon receptor, and orforglipron, a GLP-1 receptor partial agonist, are effective in weight loss and improving various metabolic parameters associated with obesity. SUMMARY: Various gut hormones influence appetite, and several drugs targeting these receptors have been reported to exert positive effects on weight loss in humans. Given that diverse dietary and environmental factors affect the actions of gut hormones and appetite, there is a need for integrated and largescale long-term studies in this field.

Distribution of cionin, a cholecystokinin/gastrin family peptide, and its receptor in the central nervous system of Ciona intestinalis type A.

The cholecystokinin (CCK)/gastrin family peptides are involved in regulation of feeding and digestion in vertebrates. In the ascidian Ciona intestinalis type A (Ciona robusta), cionin, a CCK/gastrin family peptide, has been identified. Cionin is expressed exclusively in the central nervous system (CNS). In contrast, cionin receptor expression has been detected in the CNS, digestive tract, and ovary. Although cionin has been reported to be involved in ovulation, its physiological function in the CNS remains to be investigated. To elucidate its neural function, in the present study, we analyzed the expression of cionin and cionin receptors in the CNS. Cionin was expressed mainly in neurons residing in the anterior region of the cerebral ganglion. In contrast, the gene expressin of the cionin receptor gene CioR1, was detected in the middle part of the cerebral ganglion and showed a similar expression pattern to that of VACHT, a cholinergic neuron marker gene. Moreover, CioR1 was found to be expressed in cholinergic neurons. Consequently, these results suggest that cionin interacts with cholinergic neurons as a neurotransmitter or neuromodulator via CioR1. This study provides insights into a biological role of a CCK/gastrin family peptide in the CNS of ascidians.

Acetylcholine Engages Distinct Amygdala Microcircuits to Gate Internal Theta Rhythm.

Acetylcholine (ACh) is released from basal forebrain cholinergic neurons in response to salient stimuli and engages brain states supporting attention and memory. These high ACh states are associated with theta oscillations, which synchronize neuronal ensembles. Theta oscillations in the basolateral amygdala (BLA) in both humans and rodents have been shown to underlie emotional memory, yet their mechanism remains unclear. Here, using brain slice electrophysiology in male and female mice, we show large ACh stimuli evoke prolonged theta oscillations in BLA local field potentials that depend upon M3 muscarinic receptor activation of cholecystokinin (CCK) interneurons (INs) without the need for external glutamate signaling. Somatostatin (SOM) INs inhibit CCK INs and are themselves inhibited by ACh, providing a functional SOM→CCK IN circuit connection gating BLA theta. Parvalbumin (PV) INs, which can drive BLA oscillations in baseline states, are not involved in the generation of ACh-induced theta, highlighting that ACh induces a cellular switch in the control of BLA oscillatory activity and establishes an internally BLA-driven theta oscillation through CCK INs. Theta activity is more readily evoked in BLA over the cortex or hippocampus, suggesting preferential activation of the BLA during high ACh states. These data reveal a SOM→CCK IN circuit in the BLA that gates internal theta oscillations and suggest a mechanism by which salient stimuli acting through ACh switch the BLA into a network state enabling emotional memory.

Cholecystokinin (CCK): a neuromodulator with therapeutic potential in Alzheimer's and Parkinson's disease.

Cholecystokinin (CCK) is a neuropeptide modulating digestion, glucose levels, neurotransmitters and memory. Recent studies suggest that CCK exhibits neuroprotective effects in Alzheimer's disease (AD) and Parkinson's disease (PD). Thus, we review the physiological function and therapeutic potential of CCK. The neuropeptide facilitates hippocampal glutamate release and gates GABAergic basket cell activity, which improves declarative memory acquisition, but inhibits consolidation. Cortical CCK alters recognition memory and enhances audio-visual processing. By stimulating CCK-1 receptors (CCK-1Rs), sulphated CCK-8 elicits dopamine release in the substantia nigra and striatum. In the mesolimbic pathway, CCK release is triggered by dopamine and terminates reward responses via CCK-2Rs. Importantly, activation of hippocampal and nigral CCK-2Rs is neuroprotective by evoking AMPK activation, expression of mitochondrial fusion modulators and autophagy. Other benefits include vagus nerve/CCK-1R-mediated expression of brain-derived neurotrophic factor, intestinal protection and suppression of inflammation. We also discuss caveats and the therapeutic combination of CCK with other peptide hormones.

Role of CFTR in diabetes-induced pancreatic ductal fluid and HCO3 - secretion.

Type 1 diabetes is a disease of the endocrine pancreas; however, it also affects exocrine function. Although most studies have examined the effects of diabetes on acinar cells, much less is known regarding ductal cells, despite their important protective function in the pancreas. Therefore, we investigated the effect of diabetes on ductal function. Diabetes was induced in wild-type and cystic fibrosis transmembrane conductance regulator (CFTR) knockout mice following an i.p. administration of streptozotocin. Pancreatic ductal fluid and HCO3 - secretion were determined using fluid secretion measurements and fluorescence microscopy, respectively. The expression of ion transporters was measured by real-time PCR and immunohistochemistry. Transmission electron microscopy was used for the morphological characterization of the pancreas. Serum secretin and cholecystokinin levels were measured by an enzyme-linked immunosorbent assay. Ductal fluid and HCO3 - secretion, CFTR activity, and the expression of CFTR, Na+ /H+ exchanger-1, anoctamine-1 and aquaporin-1 were significantly elevated in diabetic mice. Acute or chronic glucose treatment did not affect HCO3 - secretion, but increased alkalizing transporter activity. Inhibition of CFTR significantly reduced HCO3 - secretion in both normal and diabetic mice. Serum levels of secretin and cholecystokinin were unchanged, but the expression of secretin receptors significantly increased in diabetic mice. Diabetes increases fluid and HCO3 - secretion in pancreatic ductal cells, which is associated with the increased function of ion and water transporters, particularly CFTR. KEY POINTS: There is a lively interaction between the exocrine and endocrine pancreas not only under physiological conditions, but also under pathophysiological conditions The most common disease affecting the endocrine part is type-1 diabetes mellitus (T1DM), which is often associated with pancreatic exocrine insufficiency Compared with acinar cells, there is considerably less information regarding the effect of diabetes on pancreatic ductal epithelial cells, despite the fact that the large amount of fluid and HCO3 - produced by ductal cells is essential for maintaining normal pancreatic functions Ductal fluid and HCO3 - secretion increase in T1DM, in which increased cystic fibrosis transmembrane conductance regulator activation plays a central role. We have identified a novel interaction between T1DM and ductal cells. Presumably, the increased ductal secretion represents a defence mechanism in the prevention of diabetes, but further studies are needed to clarify this issue.

Satiety: a gut-brain-relationship.

Many hormones act on the hypothalamus to control hunger and satiety through various pathways closely associated with several factors. When food is present in the gastro intestinal (GI) tract, enteroendocrine cells (EECs) emit satiety signals such as cholecystokinin (CCK), glucagon like peptide-1 (GLP-1) and peptide YY (PYY), which can then communicate with the vagus nerve to control food intake. More specifically, satiety has been shown to be particularly affected by the GLP-1 hormone and its receptor agonists that have lately been acknowledged as a promising way to reduce weight. In addition, there is increasing evidence that normal flora is also involved in the peripheral, central, and reward system that impact satiety. Moreover, neurologic pathways control satiety through neurotransmitters. In this review, we discuss the different roles of each of the GLP-1 hormone and its agonist, gut microbiomes, as well as neurotransmitters and their interconnected relation in the regulation of body's satiety homeostasis.

Implicating the cholecystokinin B receptor in liver stem cell oncogenesis.

Hepatocellular carcinoma (HCC) is the fastest-growing cause of cancer-related deaths worldwide. Chronic inflammation and fibrosis are the greatest risk factors for the development of HCC. Although the cell of origin for HCC is uncertain, many theories believe this cancer may arise from liver progenitor cells or stem cells. Here, we describe the activation of hepatic stem cells that overexpress the cholecystokinin-B receptor (CCK-BR) after liver injury with either a DDC diet (0.1% 3, 5-diethoxy-carbonyl 1,4-dihydrocollidine) or a NASH-inducing CDE diet (choline-deficient ethionine) in murine models. Pharmacologic blockade of the CCK-BR with a receptor antagonist proglumide or knockout of the CCK-BR in genetically engineered mice during the injury diet reduces the expression of hepatic stem cells and prevents the formation of three-dimensional tumorspheres in culture. RNA sequencing of livers from DDC-fed mice treated with proglumide or DDC-fed CCK-BR knockout mice showed downregulation of differentially expressed genes involved in cell proliferation and oncogenesis and upregulation of tumor suppressor genes compared with controls. Inhibition of the CCK-BR decreases hepatic transaminases, fibrosis, cytokine expression, and alters the hepatic immune cell signature rendering the liver microenvironment less oncogenic. Furthermore, proglumide hastened recovery after liver injury by reversing fibrosis and improving markers of synthetic function. Proglumide is an older drug that is orally bioavailable and being repurposed for liver conditions. These findings support a promising therapeutic intervention applicable to patients to prevent the development of HCC and decrease hepatic fibrosis.NEW & NOTEWORTHY This investigation identified a novel pathway involving the activation of hepatic stem cells and liver oncogenesis. Receptor blockade or genetic disruption of the cholecystokinin-B receptor (CCK-BR) signaling pathway decreased the activation and proliferation of hepatic stem cells after liver injury without eliminating the regenerative capacity of healthy hepatocytes.

Substance P, NPY, CCK and their receptors in five brain regions in major depressive disorder with transcriptomic analysis of locus coeruleus neurons.

Major depressive disorder (MDD) is a serious disease and a burden to patients, families and society. Rodent experiments and human studies suggest that several neuropeptide systems are involved in mood regulation. The aim of this study is two-fold: (i) to monitor, with qPCR, transcript levels of the substance P/tachykinin (TAC), NPY and CCK systems in bulk samples from control and suicide subjects, targeting five postmortem brain regions including locus coeruleus (LC); and (ii) to analyse expression of neuropeptide family transcripts in LC neurons of 'normal' postmortem brains by using laser capture microdissection with Smart-Seq2 RNA sequencing. qPCR revealed distinct regional expression patterns in male and female controls with higher levels for the TAC system in the dorsal raphe nucleus and LC, versus higher transcripts levels of the NPY and CCK systems in prefrontal cortex. In suicide patients, TAC, TAC receptors and a few NPY family transcript levels were increased mainly in prefrontal cortex and LC. The second study on 'normal' noradrenergic LC neurons revealed expression of transcripts for GAL, NPY, TAC1, CCK, and TACR1 and many other peptides (e.g. Cerebellin4 and CARTPT) and receptors (e.g. Adcyap1R1 and GPR173). These data and our previous results on suicide brains indicates that the tachykinin and galanin systems may be valid targets for developing antidepressant medicines. Moreover, the perturbation of neuropeptide systems in MDD patients, and the detection of further neuropeptide and receptor transcripts in LC, shed new light on signalling in noradrenergic LC neurons and on mechanisms possibly associated with mood disorders.

A new experimental rat model of nocebo-related nausea involving double mechanisms of observational learning and conditioning.

AIM: The nocebo effect, such as nausea and vomiting, is one of the major reasons patients discontinue therapy. The underlying mechanisms remain unknown due to a lack of reliable experimental models. The goal of this study was to develop a new animal model of nocebo-related nausea by combining observational learning and Pavlovian conditioning paradigms. METHODS: Male Sprague-Dawley rats with nitroglycerin-induced migraine were given 0.9% saline (a placebo) or LiCl (a nausea inducer) following headache relief, according to different paradigms. RESULTS: Both strategies provoked nocebo nausea responses, with the conditioning paradigm having a greater induction impact. The superposition of two mechanisms led to a further increase in nausea responses. A preliminary investigation of the underlying mechanism revealed clearly raised peripheral and central cholecystokinin (CCK) levels, as well as specific changes in the 5-hydroxytryptamine and cannabinoid systems. Brain networks related to emotion, cognition, and visceral sense expressed higher c-Fos-positive neurons, including the anterior cingulate cortex (ACC), insula, basolateral amygdala (BLA), thalamic paraventricular nucleus (PVT), hypothalamic paraventricular nucleus (PVN), nucleus tractus solitarius (NTS), periaqueductal gray (PAG), and dorsal raphe nucleus-dorsal part (DRD). We also found that nausea expectances in the model could last for at least 12 days. CONCLUSION: The present study provides a useful experimental model of nocebo nausea that might be used to develop potential molecular pathways and therapeutic strategies for nocebo.

Effect of pregnancy on the expression of nutrient-sensors and satiety hormones in mice.

Small intestinal satiation pathways involve nutrient-induced stimulation of chemoreceptors leading to release of satiety hormones from intestinal enteroendocrine cells (ECCs). Whether adaptations in these pathways contribute to increased maternal food intake during pregnancy is unknown. To determine the expression of intestinal nutrient-sensors and satiety hormone transcripts and proteins across pregnancy in mice. Female C57BL/6J mice (10-12 weeks old) were randomized to mating and then tissue collection at early- (6.5 d), mid- (12.5 d) or late-pregnancy (17.5 d), or to an unmated age matched control group. Relative transcript expression of intestinal fatty acid, peptide and amino acid and carbohydrate chemoreceptors, as well as gut hormones was determined across pregnancy. The density of G-protein coupled receptor 93 (GPR93), free fatty acid receptor (FFAR) 4, cholecystokinin (CCK) and glucagon-like peptide1 (GLP-1) immunopositive cells was then compared between non-pregnant and late-pregnant mice. Duodenal GPR93 expression was lower in late pregnant than non-pregnant mice (P < 0.05). Ileal FFAR1 expression was higher at mid- than at early- or late-pregnancy. Ileal FFAR2 expression was higher at mid-pregnancy than in early pregnancy. Although FFAR4 expression was consistently lower in late-pregnant than non-pregnant mice (P < 0.001), the density of FFAR4 immunopositive cells was higher in the jejunum of late-pregnant than non-pregnant mice. A subset of protein and fatty acid chemoreceptor transcripts undergo region-specific change during murine pregnancy, which could augment hormone release and contribute to increased food intake. Further investigations are needed to determine the functional relevance of these changes.

Identification and target of action of cholecystokinin-releasing peptides from simulated digestion hydrolysate of wheat protein.

BACKGROUND: Wheat protein intake leads to improved appetite control. However, the active components causing appetite in wheat have not been fully clarified. Gut cholecystokinin (CCK) plays a vital role in appetite control. This study aimed to investigate the ability of wheat protein digest (WPD) to stimulate CCK secretion and clarify the active components and target of action. RESULTS: WPD was prepared by a simulated gastrointestinal digestion model. WPD treatment with a concentration of 5 mg mL-1 significantly stimulated CCK secretion in enteroendocrine STC-1 cells (P < 0.05). Furthermore, oral gavage with WPD in mice significantly increased plasma CCK level at 60 min (P < 0.01). Preparative C18 column separation was used to isolate peptide fractions associated with CCK secretion and peptide sequences were identified by liquid chromatography-tandem mass spectrometry. A new CCK-releasing peptide, RYIVPL, that potently stimulated CCK secretion was successfully identified. After pretreatment with a specific calcium-sensing receptor (CaSR) antagonist, NPS 2143, CCK secretion induced by WPD or RYIVPL was greatly suppressed, suggesting that CaSR was involved in WPD- or RYIVPL-induced CCK secretion. CONCLUSION: The present study demonstrated that WPD has an ability to stimulate CCK secretion in vitro and in vivo, and determined that peptide RYIVPL in WPD could stimulate CCK secretion through CaSR. © 2023 Society of Chemical Industry.

Entorhinohippocampal cholecystokinin modulates spatial learning by facilitating neuroplasticity of hippocampal CA3-CA1 synapses.

The hippocampus is broadly impacted by neuromodulations. However, how neuropeptides shape the function of the hippocampus and the related spatial learning and memory remains unclear. Here, we discover the crucial role of cholecystokinin (CCK) in heterosynaptic neuromodulation from the medial entorhinal cortex (MEC) to the hippocampus. Systematic knockout of the CCK gene impairs CA3-CA1 LTP and space-related performance. The MEC provides most of the CCK-positive neurons projecting to the hippocampal region, which potentiates CA3-CA1 long-term plasticity heterosynaptically in a frequency- and NMDA receptor (NMDAR)-dependent manner. Selective inhibition of MEC CCKergic neurons or downregulation of their CCK mRNA levels also impairs CA3-CA1 LTP formation and animals' performance in the water maze. This excitatory extrahippocampal projection releases CCK upon high-frequency excitation and is active during animal exploration. Our results reveal the critical role of entorhinal CCKergic projections in bridging intra- and extrahippocampal circuitry at electrophysiological and behavioral levels.

Expression and functional study of cholecystokinin-A receptors on the interstitial Cajal-like cells of the guinea pig common bile duct.

BACKGROUND: Many studies have shown that interstitial Cajal-like cell (ICLC) abnormalities are closely related to a variety of dynamic gastrointestinal disorders. ICLCs are pacemaker cells for gastrointestinal movement and are involved in the transmission of nerve impulses. AIM: To elucidate the expression profile and significance of cholecystokinin-A (CCK-A) receptors in ICLCs in the common bile duct (CBD), as well as the role of CCK in regulating CBD motility through CCK-A receptors on CBD ICLCs. METHODS: The levels of tyrosine kinase receptor (c-kit) and CCK-A receptors in CBD tissues and isolated CBD cells were quantified using the double immunofluorescence labeling technique. The CCK-mediated enhancement of the movement of CBD muscle strips through CBD ICLCs was observed by a muscle strip contraction test. RESULTS: Immunofluorescence showed co-expression of c-kit and CCK-A receptors in the CBD muscularis layer. Observations of isolated CBD cells showed that c-kit was expressed on the surface of ICLCs, the cell body and synapse were colored and polygonal, and some cells presented protrusions and formed networks adjacent to the CBD while others formed filaments at the synaptic terminals of local cells. CCK-A receptors were also expressed on CBD ICLCs. At concentrations ranging from 10-6 mol/L to 10-10 mol/L, CCK promoted CBD smooth muscle contractility in a dose-dependent manner. In contrast, after ICLC removal, the contractility mediated by CCK in CBD smooth muscle decreased. CONCLUSION: CCK-A receptors are highly expressed on CBD ICLCs, and CCK may regulate CBD motility through the CCK-A receptors on ICLCs.

High-calorie diets uncouple hypothalamic oxytocin neurons from a gut-to-brain satiation pathway via κ-opioid signaling.

Oxytocin-expressing paraventricular hypothalamic neurons (PVNOT neurons) integrate afferent signals from the gut, including cholecystokinin (CCK), to adjust whole-body energy homeostasis. However, the molecular underpinnings by which PVNOT neurons orchestrate gut-to-brain feeding control remain unclear. Here, we show that mice undergoing selective ablation of PVNOT neurons fail to reduce food intake in response to CCK and develop hyperphagic obesity on a chow diet. Notably, exposing wild-type mice to a high-fat/high-sugar (HFHS) diet recapitulates this insensitivity toward CCK, which is linked to diet-induced transcriptional and electrophysiological aberrations specifically in PVNOT neurons. Restoring OT pathways in diet-induced obese (DIO) mice via chemogenetics or polypharmacology sufficiently re-establishes CCK's anorexigenic effects. Last, by single-cell profiling, we identify a specialized PVNOT neuronal subpopulation with increased κ-opioid signaling under an HFHS diet, which restrains their CCK-evoked activation. In sum, we document a (patho)mechanism by which PVNOT signaling uncouples a gut-brain satiation pathway under obesogenic conditions.

In vitro gastrointestinal digestion of buckwheat (Fagopyrum esculentum Moench) protein: release and structural characteristics of novel bioactive peptides stimulating gut cholecystokinin secretion.

Satiety hormone cholecystokinin (CCK) plays a vital role in appetite inhibition. Its secretion is regulated by dietary components. The search for bioactive compounds that stimulate CCK secretion is currently an active area of research. The objective of this study was to evaluate the ability of buckwheat (Fagopyrum esculentum Moench) protein digest (BPD) to stimulate CCK secretion in vitro and in vivo and clarify the structural characteristics of peptides stimulating CCK secretion. BPD was prepared by an in vitro gastrointestinal digestion model. The relative molecular weight of BPD was <10 000 Da, and peptides with <3000 Da accounted for 70%. BPD was rich in essential amino acids Lys, Leu, and Val but lacked sulfur amino acids Met and Cys. It had a stimulatory effect on CCK secretion in vitro and in vivo. Chromatographic separation was performed to isolate peptide fractions involved in CCK secretion, and five novel CCK-releasing peptides including QFDLDD, PAFKEEHL, SFHFPI, IPPLFP, and RVTVQPDS were successfully identified. A sequence length range of 6-8 and marked hydrophobicity (18-28) were observed among the most CCK-releasing peptides. The present study demonstrated for the first time that BPD could stimulate CCK secretion and clarify the structural characteristics of bioactive peptides having CCK secretagogue activity in BPD.

NEUROENDOCRINE PEPTIDES IN THE PATHOGENESIS OF COLORECTAL CARCINOMA.

Colorectal carcinoma (CRC) is the third most frequent neoplasm worldwide and the second leading cause of mortality. Neuroendocrine peptides such as glucagon, bombesin, somatostatin, cholecystokinin, and gastrin as well as growth factors such as platelet-derived growth factor, epidermal growth factor, insulin-like growth factor, and fibroblast growth factor have been postulated as being involved in carcinogenesis. The fact that these neuroendocrine peptides are involved in the development of CRC through the activation of growth factors that stimulate a series of molecular pathways that activate oncogenic signaling mechanisms is emphasized in this review. Peptides such as CCK1, serotonin, and bombesin have been found to be over-expressed in human tumor tissues. Meanwhile, the expression of peptides such as GLP2 has been seen mainly in murine models. The information contained in this review provides a better understanding of the role these peptides play in the pathogenesis of CRC for basic and clinical science studies.

In vitro gastrointestinal digestion of highland barley protein: identification and characterization of novel bioactive peptides involved in gut cholecystokinin secretion.

BACKGROUND: The satiety hormone cholecystokinin (CCK) plays an important role in food intake inhibition. Its secretion is regulated by dietary components. The search for bioactive compounds that induce CCK secretion is currently an active area of research. The objective of this study was to evaluate the ability of highland barley protein digest (HBPD) to stimulate CCK secretion in vitro and in vivo and identify the responsible peptide sequences. RESULTS: HBPD was prepared by in vitro gastrointestinal digestion model. Peptides of <1000 Da in HBPD accounted for 82%. HBPD was rich in essential amino acids Leu, Phe and Val, but lack in sulfur amino acids Met and Cys. HBPD treatment at a concentration of 5 mg mL-1 significantly stimulated CCK secretion from enteroendocrine STC-1 cells (P < 0.05). Moreover, oral gavage with HBPD in mice significantly increased plasma CCK level. Chromatographic separation was performed to isolate peptide fractions involved in CCK secretion and peptide sequence was determined by ultra-performance liquid chromatography-tandem mass spectrometry. Two novel CCK-releasing peptides, PDLP and YRIVPL, were pointed out for their outstanding CCK secretagogue activity. CONCLUSION: This study demonstrated for the first time that HBPD had an ability to stimulate CCK secretion in vitro and in vivo and determined the bioactive peptides exerting CCK secretagogue activity in HBPD. © 2023 Society of Chemical Industry.

CCK and GLP-1 response on enteroendocrine cells of semi-dynamic digests of hydrolyzed and intact casein.

A semi-dynamic gastrointestinal device was employed to explore the link between protein structure and metabolic response upon digestion for two different substrates, a casein hydrolysate and the precursor micellar casein. As expected, casein formed a firm coagulum that remained until the end of the gastric phase while the hydrolysate did not develop any visible aggregate. Each gastric emptying point was subjected to a static intestinal phase where the peptide and amino acid composition changed drastically from that found during the gastric phase. Gastrointestinal digests from the hydrolysate were characterized by a high abundancy of resistant peptides and free amino acids. Although all gastric and intestinal digests from both substrates induced the secretion of cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1) in STC-1 cells, GLP-1 levels were maximum in response to gastrointestinal digests from the hydrolysate. The enrichment of protein ingredients with gastric-resistant peptides by enzymatic hydrolysis is proposed as strategy to deliver protein stimuli to the distal gastrointestinal tract to control food intake or type 2 diabetes.