Search Results (98)

Obesity-driven inflammation disrupts gut barrier integrity and promotes inflammatory bowel disease (IBD). Emerging evidence highlights gut hormones—including glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), glucose-dependent insulinotropic polypeptide (GIP), peptide YY (PYY), cholecystokinin (CCK), and apolipoprotein A4 (APOA4)—as key regulators of metabolism and mucosal immunity. This review outlines known mechanisms and explores therapeutic prospects in IBD. GLP-1 improves glycemic control, induces weight loss, and preserves intestinal barrier function, while GLP-2 enhances epithelial repair and reduces pro-inflammatory cytokine expression in animal models of colitis. GIP facilitates lipid clearance, enhances insulin sensitivity, and limits systemic inflammation. PYY and CCK slow gastric emptying, suppress appetite, and attenuate colonic inflammation via neural pathways. APOA4 regulates lipid transport, increases energy expenditure, and exerts antioxidant and anti-inflammatory effects that alleviate experimental colitis. Synergistic interactions—such as GLP-1/PYY co-administration, PYY-stimulated APOA4 production, and APOA4-enhanced CCK activity—suggest that multi-hormone combinations may offer amplified therapeutic benefits. While preclinical data are promising, clinical evidence supporting gut hormone therapies in IBD remains limited. Dual GIP/GLP-1 receptor agonists improve metabolic and inflammatory parameters, but in clinical use, they are associated with gastrointestinal side effects that warrant further investigation. Future research should evaluate combination therapies in preclinical IBD models, elucidate shared neural and receptor-mediated pathways, and define optimal strategies for applying gut hormone synergy in human IBD. These efforts may uncover safer, metabolically tailored treatments for IBD, particularly in patients with coexisting obesity or metabolic dysfunction. Full article

This work aimed to evaluate two albumin affinity structure-containing peptide-radionuclide conjugate drugs, INER-PP-F11N-1 and INER-PP-F11N-2, for the diagnosis/treatment of cholecystokinin receptor subtype 2 (CCK2R)-overexpressing cancers. We developed In-111- and Lu-177-labeled INER-PP-F11N radiopharmaceuticals and compared them with the current PP-F11N to investigate metabolic stability, biodistribution, SPECT/CT imaging, and therapeutic responses in CCK2R-expressing tumor xenograft mice. The metabolic stability of [¹¹¹In]In/[¹⁷⁷Lu]Lu-INER-PP-F11N remained above 90% for up to 144 h after labeling, indicating that the compound is highly stable under in vitro conditions. INER-PP-F11N showed 27% and 11% higher cellular uptake and internalization than PP-F11N, respectively. In vivo SPECT/CT imaging confirmed that INER-PP-F11N could accumulate at the tumor site of mice 24 h after receiving the two radiopharmaceutical agents. Biodistribution analysis revealed a significantly greater tumor uptake and reduced accumulation of INER-PP-F11N in the kidneys compared with PP-F11N. Furthermore, INER-PP-F11N significantly inhibited the growth of the CCK2R-overexpressing tumors in mice. The INER-PP-F11N radiopharmaceutical was superior as a theragnostic agent compared with the current PP-F11N. Our study suggests that INER-PP-F11N may be an innovative radiopharmaceutical agent for CCK2R-overexpressing tumors. Full article

Caffeic acid phenethyl ester (CAPE) is identified to be an efficacious bioactive polyphenol in propolis for ameliorating glucose and lipid metabolism disorders and inflammation. In this study, an alcohol-induced zebrafish inflammation model was established. CAPE treatments at different concentrations (0.04, 0.2, and 1.0 μg/mL) were administered to alcohol-exposed zebrafish to investigate the underlying mechanisms of alleviating alcohol-induced liver inflammation using transcriptomic analysis and 16S rRNA gene sequencing methods. The results indicated that CAPE decreased the expressions of TNF-α and IL-1β and significantly increased the expression of IL-10 (p < 0.0001). Based on the KEGG enrichment analysis of transcriptomic sequencing, CAPE effectively alleviated the inflammation in zebrafish mainly through pancreatic secretion, complement and coagulation cascades, and protein digestion and absorption. Molecular docking supported the potential of CAPE in targeting cholecystokinin (CCK) A Receptor (CCKAR) and mediating the regulation of pancreatic secretion and related inflammation pathways. Moreover, intestinal microbiota analysis demonstrated that CAPE could improve the alcohol-induced microbiota disorder. Additionally, there was a significant correlation between the key genes related to lipid and sterol metabolism among the KEGG-enriched pathways and the specific intestinal microbial communities in zebrafish. Flavobacterium from Bacteroidota was significantly positively correlated with CEL1, CEL2, and LPIN (p < 0.01), which suggested that the anti-inflammatory function of CAPE was closely associated with the intestinal microbiota improvement. In conclusion, our findings demonstrated that CAPE could ameliorate liver inflammation in alcohol-induced zebrafish, which was mainly associated with the regulation of pancreatic secretion and intestinal microbiota disorder. This study emphasized the anti-inflammatory mechanisms of CAPE based on targeting the pancreatic secretion pathway, which will broaden the application of natural antioxidants in improving metabolic and inflammatory problems. Full article

Afferent vagal neurons convey gut–brain signals related to the mechanical and chemical sensing of nutrients, with the latter also mediated by gut hormones secreted from enteroendocrine cells. Cell bodies of these neurons are located in the nodose ganglia (NG), with the right NG playing a key role in metabolic regulation. Notably, glucagon-like peptide-1 receptor (GLP1R) neurons primarily innervate the muscle layer of the stomach, distant from glucagon-like peptide-1 (GLP-1)-secreting gut cells. However, the co-expression of gut hormone receptors in these NG neurons remains unclear. Using RNAscope combined with immunohistochemistry, we confirmed GLP1R expression in a large population of NG neurons, with Glp1r, cholecystokinin A receptor (Cckar), and Neuropeptide Y Y2 Receptor (Npy2r) being more highly expressed in the right NG, while neurotensin receptor 1 (Ntsr), G protein-coupled receptor (Gpr65), and 5-hydroxytryptamine receptor 3A (5ht3a) showed equal expressions in the left and right NG. Co-expression analysis demonstrated the following: (i) most Glp1r, Cckar, and Npy2r neurons co-expressed all three receptors; (ii) nearly all Ntsr1- and Gpr65-positive neurons co-expressed both receptors; and (iii) 5ht3a was expressed in subpopulations of all peptide-hormone-receptor-positive neurons. Retrograde labeling demonstrated that the anterior part of the stomach was preferentially innervated by the left NG, while the right NG innervated the posterior part. The entire gastrointestinal (GI) tract, including the distal colon, was strongly innervated by NG neurons. Most importantly, dual retrograde labeling with two distinct tracers identified a population of neurons co-expressing Glp1r, Cckar, and Npy2r that innervated both the stomach and the colon. Thus, neurons co-expressing GLP-1, cholecystokinin (CCK), and peptide YY (PYY) receptors, predominantly found in the right NG, sample chemical, nutrient-induced signals along the entire GI tract and likely integrate these with mechanical signals from the stomach. Full article

Background: Obesity is a multifactorial disease with detrimental effects on health and quality of life; unregulated satiety plays a crucial role in food intake and obesity development. Naringenin (NAR) has shown beneficial effects on lipid and carbohydrate metabolism, although its impact on adiposity and satiety remains unclear. This study reports a Western diet (WD)-induced obesity model in rats, wherein 100 mg/kg of NAR was administered as an anti-obesity agent for 8 weeks; oxidative stress, lipid profile, and satiety biomarkers were then studied, as well as in silico interaction between NAR and cholecystokinin (CCK) and ghrelin receptors. Results: NAR supplementation resulted in a significant decrease in retroperitoneal adipose tissue and liver weight, as compared to the untreated WD group (p < 0.05), potentially associated with a decreased feed efficiency. NAR also inhibited the development of dyslipidemia, particularly by reducing serum triglycerides (p < 0.05). NAR supplementation increased CCK serum levels in the basal diet group, an effect that was abolished by the WD (p < 0.05); likewise, no changes were determined on ghrelin (p > 0.05). In silico data shows that NAR is capable of interacting with the CCK and ghrelin receptors, which suggests a potential for it to modulate hunger/satiety signaling by interacting with them. Conclusions: We conclude that NAR has anti-obesogenic effects and may regulate CCK serum levels, although further research is still needed. Full article

Nutritional intake is closely linked to gonadal development, although the mechanisms by which food intake affects gonadal development are not fully understood. Cholecystokinin (CCK) is a satiety neuropeptide derived from the hypothalamus, and the present study observed that hypothalamic CCK expression is significantly influenced by food intake, which is mediated through blood glucose levels. Interestingly, CCK and its receptors were observed to exhibit a high expression in the hypothalamus–pituitary–gonad (HPG) axis of grass carp (Ctenopharyngodon idellus), suggesting that CCK is potentially involved in regulating fish reproduction through the HPG axis. Further investigations revealed that CCK could significantly stimulate the expression of gonadotropin-releasing hormone-3 (GnRH3) in the hypothalamus. In addition, single-cell RNA sequencing showed that cckrb was highly enriched in pituitary follicle-stimulating hormone (FSH) cells. Further study confirmed that CCK can significantly induce FSH synthesis and secretion in primary cultured pituitary cells. Additionally, with primary cultured ovary cells as a model, the in vitro experiment demonstrated that CCK directly induces the expression of lhr, fshr, and cyp19a1a mRNA. This indicates that hypothalamic CCK may act as a nutrient sensor involved in regulating gonadal development in teleosts. Full article

Background: Cholesterol gallstone disease (CGS) is often accompanied by gallbladder contraction dysfunction and chronic inflammation, but effective therapeutic options remain limited. This study investigates whether a low-intensity pulsed ultrasound (LIPUS) treatment can improve gallbladder motility and alleviate chronic inflammation while exploring the underlying mechanisms. Methods: Gallbladder motility was assessed through in vitro and in vivo contraction tests, while bile condition was evaluated by observing bile crystal clearance. Tissue analysis and Western blotting were performed to examine the expression of the cholecystokinin A receptor (CCKAR) and α-smooth muscle actin (α-SMA) as markers of gallbladder smooth muscle health and the inflammatory microenvironment. Blood cholesterol levels were measured via biochemical assays. Results: LIPUS treatment obviously enhanced gallbladder contractility in response to CCK-8 stimulation and accelerated bile crystal clearance. It also reduced inflammatory cell infiltration and tissue edema, and promoted new capillary formation in the gallbladder, mitigating the progression of CGS. Furthermore, LIPUS restored CCKAR expression and improved the thickness of the gallbladder smooth muscle layer, providing a structural basis for increased smooth muscle contractility. Conclusion: LIPUS improves gallbladder motility and reduces chronic inflammation in CGS by enhancing CCKAR expression and smooth muscle integrity. These findings highlight the potential of LIPUS as a non-invasive therapeutic approach for managing CGS. Full article

Background/Objectives: Dual-modality probes, combining positron emission tomography (PET) with fluorescence imaging (FI) capabilities in a single molecule, are of high relevance for the accurate staging and guided resection of tumours. We herein present a pair of candidates targeting the cholecystokinin-2 receptor (CCK2R), namely [⁶⁸Ga]Ga-CyTMG and [⁶⁸Ga]Ga-CyFMG. In these probes, the SulfoCy5.5 fluorophore and two units of a CCK2R-binding motif are coupled to the chelator acting as a core scaffold, triazacyclononane-phosphinic acid (TRAP), and Fusarinine C (FSC), respectively. Using this approach, we investigated the influence of these chelators on the final properties. Methods: The synthetic strategy to both precursors was based on the stoichiometric conjugation of the components via click chemistry. The characterization in vitro included the evaluation of the CCK2R affinity and internalization in A431-CCK2R cells. Ex vivo biodistribution as well as PET and FI studies were performed in xenografted mice. Results: ⁶⁸Ga labelling was accomplished with high radiochemical yield and purity for both precursors. A CCK2R affinity in the subnanomolar range of the conjugates and a receptor-specific uptake of the radioligands in cells were observed. In A431-CCK2R/A431-mock xenografted mice, the investigated compounds showed specific accumulation in the tumours and reduced off-target uptake compared to a previously developed compound. Higher accumulation and prolonged retention in the kidneys were observed for [⁶⁸Ga]Ga-CyTMG when compared to [⁶⁸Ga]Ga-CyFMG. Conclusions: Despite the promising targeting properties observed, further probe optimization is required to achieve enhanced imaging contrast at early timepoints. Additionally, the results indicate a distinct influence of the chelators in terms of renal accumulation and retention. Full article

Background/Objective: Obesity, clinically defined as a body mass index (BMI) of 30 kg/m² or higher, is a medical condition characterized by the excessive accumulation of body fat, which can lead to adverse health consequences. As a global public health issue with an escalating prevalence, controlling appetite and satiety is essential for regulating energy balance and managing body weight. Dietary proteins and peptides have gained interest in their potential to prevent and treat obesity by modulating satiety signals. This narrative review analyzes scientific evidence highlighting the role of dietary proteins and peptides in regulating satiety signals and investigates their therapeutic potential in preventing and treating obesity. Methods: A comprehensive literature search was conducted in multiple electronic databases, including PubMed, Scopus, and Web of Science. The search focused on articles examining the impact of dietary proteins and peptides on satiety and obesity, encompassing both preclinical and clinical trials. Results: Several studies have demonstrated a correlation between the intake of specific proteins or peptides from plant and animal sources and satiety regulation. These investigations identified mechanisms where amino acids and peptides interact with enteroendocrine cell receptors, activating intracellular signaling cascades that promote the release of anorexigenic gut hormones such as cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), and peptide YY (PYY). Both in vitro and in vivo assays have shown that these interactions contribute to appetite regulation and the sensation of satiety. Conclusions: Using proteins and peptides in the diet may be an effective strategy for regulating appetite and controlling body weight. However, more research—including clinical trials—is needed to understand the underlying mechanisms better and optimize the application of these bioactive compounds in preventing and treating obesity. Full article

This study investigated the role of cholecystokinin (cck) in the feeding regulation of largemouth bass (Micropterus salmoides) via peptide activation and antagonist inhibition. The results show that the cck gene was expressed in various tissues, with the highest expression level occurring in the brain. Feeding, continuous feeding, and refeeding after fasting could significantly improve the mRNA levels of cck in the brain. Moreover, the activation of cck via injecting an exogenous CCK peptide could inhibit feed intake by regulating the mRNA levels of anorexigenic and feed-promoting factors in the brain and intestine. Furthermore, the CCK peptide reduced feed intake; however, the presence of an antagonist (Ly225910-CCK1R and devazepide-CCK2R) could reverse this effect through regulating the mRNA levels of anorexigenic and feed-promoting factors in the brain and intestine. Treatment with devazepide + CCK (CCK2R) reversed feed intake more effectively than Ly225910 + CCK (CCK1R) treatment. In summary, cck could regulate the feed intake of largemouth bass through regulating feeding-related genes in the brain and intestine. In addition, cck required binding with the receptor to inhibit feed intake more effectively in largemouth bass, and the binding effect of CCK1R was better than that of CCK2R. Full article

A complication of diabetes is neuropathic pain, which is difficult to control with medication. We have confirmed that neuropathic pain due to mechanical allodynia in diabetic mice is mediated by a characteristic neuropeptide in the spinal cord. We evaluated the strength of mechanical allodynia in mice using von Frey filaments. When mice were intravenously injected with streptozotocin, mechanical allodynia appeared 3 days later. Antibodies of representative neuropeptides were intrathecally (i.t.) administered to allodynia-induced mice 7 days after the intravenous administration of streptozotocin, and allodynia was reduced by anti-cholecystokinin octapeptide antibodies, anti-nociceptin/orphanin FQ antibodies, and anti-hemokinin-1 antibodies. In contrast, i.t.-administered anti-substance P antibodies, anti-somatostatin antibodies, and anti-angiotensin II antibodies did not affect streptozotocin-induced diabetic allodynia mice. Mechanical allodynia was attenuated by the i.t. administration of CCK-B receptor antagonists and ORL-1 receptor antagonists. The mRNA level of CCK-B receptors in streptozotocin-induced diabetic allodynia mice increased in the spinal cord, but not in the dorsal root ganglion. These results indicate that diabetic allodynia is caused by cholecystokinin octapeptide, nociceptin/orphanin FQ, and hemokinin-1 released from primary afferent neurons in the spinal cord that transmit pain to the brain via the spinal dorsal horn. Full article

The poor prognosis for pancreatic ductal adenocarcinoma (PDAC) patients is due in part to the highly fibrotic nature of the tumors that impedes delivery of therapeutics, including nanoparticles (NPs). Our prior studies demonstrated that proglumide, a cholecystokinin receptor (CCKR) antagonist, reduced fibrosis pervading PanIN lesions in mice. Here, we further detail how the reduced fibrosis elicited by proglumide achieves the normalization of the desmoplastic tumor microenvironment (TME) and improves nanoparticle uptake. One week following the orthotopic injection of PDAC cells, mice were randomized to normal or proglumide-treated water for 3–6 weeks. Tumors were analyzed ex vivo for fibrosis, vascularity, stellate cell activation, vascular patency, and nanoparticle distribution. The histological staining and three-dimensional imaging of tumors each indicated a reduction in stromal collagen in proglumide-treated mice. Proglumide treatment increased tumor vascularity and decreased the activation of cancer-associated fibroblasts (CAFs). Additionally, PANC-1 cells with the shRNA-mediated knockdown of the CCK2 receptor showed an even greater reduction in collagen, indicating the CCK2 receptors on tumor cells contribute to the desmoplastic TME. Proglumide-mediated reduction in fibrosis also led to functional changes in the TME as evidenced by the enhanced intra-tumoral distribution of small (<12 nm) Rhodamine-loaded nanoparticles. The documented in vivo, tumor cell-intrinsic anti-fibrotic effects of CCK2R blockade in both an immunocompetent syngeneic murine PDAC model as well as a human PDAC xenograft model demonstrates that CCK2R antagonists, such as proglumide, can improve the delivery of nano-encapsulated therapeutics or imaging agents to pancreatic tumors. Full article

Chronic pancreatitis (CP) is a rare but debilitating condition with an 8-fold increased risk of developing pancreatic cancer. In addition to the symptoms that come from the loss of endocrine and exocrine function in CP, the management of chronic pain is problematic. We previously showed that the CCK-receptor antagonist called proglumide could decrease inflammation, acinar-ductal metaplasia, and fibrosis in murine models of CP. We hypothesized that proglumide would be safe and diminish pain caused by CP. A Phase 1 open-labeled safety study was performed in subjects with clinical and radiographic evidence of CP with moderate to severe pain. After a 4-week observation period, the subjects were treated with proglumide in 400 mg capsules three times daily (1200 mg per day) by mouth for 12 weeks, and then subjects returned for a safety visit 4 weeks after the discontinuation of the study medication. The results of three pain surveys (Numeric Rating Scale, COMPAT-SF, and NIH PROMIS) showed that the patients had significantly less pain after 12 weeks of proglumide compared to the pre-treatment observation phase. Of the eight subjects in this study, two experienced nausea and diarrhea with proglumide. These side effects resolved in one subject with doses reduced to 800 mg per day. No abnormalities were noted in the blood chemistries. A blood microRNA blood biomarker panel that corresponded to pancreatic inflammation and fibrosis showed significant improvement. We conclude that proglumide is safe and well tolerated in most subjects with CP at a dose of 1200 mg per day. Furthermore, proglumide therapy may have a beneficial effect by decreasing pain associated with CP. Full article

Polycystic ovary syndrome (PCOS), the most common endocrine disorder in women of reproductive age, constitutes a metabolic disorder frequently associated with obesity and insulin resistance (IR). Furthermore, women with PCOS often suffer from excessive anxiety and depression, elicited by low self-esteem due to obesity, acne, and hirsutism. These mood disorders are commonly associated with food cravings and binge eating. Hypothalamic signaling regulates appetite and satiety, deteriorating excessive food consumption. However, the hypothalamic function is incapable of compensating for surplus food in women with PCOS, leading to the aggravation of obesity and a vicious circle. Hyperandrogenism, IR, the reduced secretion of cholecystokinin postprandially, and leptin resistance defined by leptin receptors’ knockout in the hypothalamus have been implicated in the pathogenesis of hypothalamic dysfunction and appetite dysregulation. Diet modifications, exercise, and psychological and medical interventions have been applied to alleviate food disorders, interrupting the vicious circle. Cognitive–behavioral intervention seems to be the mainstay of treatment, while the role of medical agents, such as GLP-1 analogs and naltrexone/bupropion, has emerged. Full article

Background: Proton pump inhibitors (PPIs) are commonly prescribed long-acting drugs used to treat acid reflux, gastroesophageal reflux disease (GERD), and peptic ulcers. Recently, concerns have been raised about their safety, particularly due to the association between long-term PPI use and cancer development. Multiple comprehensive studies have consistently suggested a noteworthy link between prolonged PPI usage and an increased risk of developing gastric, esophageal, colorectal, and pancreatic cancers, yet the precise underlying mechanism remains elusive. Methods: First, we review the extensive body of research that investigates the intricate relationship between cancer and PPIs. Then, we predict PPI toxicity using the prodrug structures with the ProTox-II webserver. Finally, we predict the relative risk of cancer for each PPI, using PubMed citation counts of each drug and keywords related to cancer. Results: Our review indicates that prolonged PPI use (exceeding three months) is significantly associated with an elevated risk of cancer, while shorter-term usage (less than three months) appears to pose a comparatively lower risk. Our review encompasses various proposed mechanisms, such as pH and microbiome alterations, vitamin and mineral malabsorption, hypergastrinemia, and enterochromaffin-like cell proliferation, while ProTox-II also suggests aryl hydrocarbon receptor binding. Potentially, the PubMed citations count suggests that the PPIs omeprazole and lansoprazole are more associated with cancer than pantoprazole and esomeprazole. In comparison, the H2R blocker, famotidine, is potentially less associated with cancer than PPIs, and may serve as a safer alternative treatment for periods beyond 3 months. Conclusions: Despite the well-established cancer risk associated with PPIs, it is notable that these medications continue to be widely prescribed for periods longer than 3 months. Thus, it is of paramount importance for clinicians and patients to thoughtfully evaluate the potential risks and benefits of long-term PPI usage and explore alternative treatments before making informed decisions regarding their medical management. Full article