RESUMO
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.
Assuntos
Bombesina , Neoplasias Colorretais , Humanos , Camundongos , Animais , Peptídeos/metabolismo , Colecistocinina/metabolismo , Neoplasias Colorretais/etiologia , Gastrinas/metabolismo , Peptídeos e Proteínas de Sinalização IntercelularRESUMO
Metabolic programming may be induced by reduction or enhancement of litter size, which lead to neonatal over or undernutrition, respectively. Changes in neonatal nutrition can challenge some regulatory processes in adulthood, such as the hypophagic effect of cholecystokinin (CCK). In order to investigate the effects of nutritional programming on the anorexigenic function of CCK in adulthood, pups were raised in small (SL, 3 pups per dam), normal (NL, 10 pups per dam), or large litters (LL, 16 pups per dam), and on postnatal day 60, male rats were treated with vehicle or CCK (10 µg/Kg) for the evaluation of food intake and c-Fos expression in the area postrema (AP), nucleus of solitary tract (NTS), and paraventricular (PVN), arcuate (ARC), ventromedial (VMH), and dorsomedial (DMH) nuclei of the hypothalamus. Overnourished rats showed increased body weight gain that was inversely correlated with neuronal activation of PaPo, VMH, and DMH neurons, whereas undernourished rats had lower body weight gain, inversely correlated with increased neuronal activation of PaPo only. SL rats showed no anorexigenic response and lower neuron activation in the NTS and PVN induced by CCK. LL exhibited preserved hypophagia and neuron activation in the AP, NTS, and PVN in response to CCK. CCK showed no effect in c-Fos immunoreactivity in the ARC, VMH, and DMH in any litter. These results indicate that anorexigenic actions, associated with neuron activation in the NTS and PVN, induced by CCK were impaired by neonatal overnutrition. However, these responses were not disrupted by neonatal undernutrition. Thus, data suggest that an excess or poor supply of nutrients during lactation display divergent effects on programming CCK satiation signaling in male adult rats.
Assuntos
Desnutrição , Hipernutrição , Ratos , Masculino , Animais , Núcleo Hipotalâmico Paraventricular/metabolismo , Colecistocinina/farmacologia , Colecistocinina/metabolismo , Ratos Wistar , Núcleo Solitário/metabolismo , Ratos Sprague-Dawley , Hipotálamo/metabolismo , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Hipernutrição/metabolismo , Peso Corporal , Ingestão de AlimentosRESUMO
Eating behavior is regulated by central and peripheral signals, which interact to modulate the response to nutrient intake. Central control is mediated by the hypothalamus through neuropeptides that activate the orexigenic and anorexigenic pathways. Energy homeostasis depends on the efficiency of these regulatory mechanisms. This neuroendocrine regulation of hunger and appetite can be modulated by nutritional sensors such as adenosine monophosphate-activated protein kinase (AMPK). Thus, this systematic review discusses the literature on correlations between AMPK and hypothalamic neuropeptides regarding control of eating behavior. Lilacs, PubMed/Medline, ScienceDirect, and Web of Science were searched for articles published from 2009 to 2021 containing combinations of the following descriptors: "eating behavior," "hypothalamus," "neuropeptide," and "AMPK." Of the 1330 articles found initially, 27 were selected after application of the inclusion and exclusion criteria. Of the selected articles, 15 reported decreased AMPK activity, due to interventions using angiotensin II infusion, fructose, glucose, cholecystokinin, leptin, or lipopolysaccharide (LPS) injection; dietary control through a low-protein diet or a high-fat diet (60 % fat); induction of hyperthyroidism; or injection of AMPK inhibitors. Seven studies showed a decrease in neuropeptide Y (NPY) through CV4 AICAR administration; fructose, glucose, leptin, or angiotensin II injections; or infusion of LPS from Escherichia coli and liver kinase B1 (LKB1) overexpression. Eleven studies reported a decrease in food consumption due to a decrease in AMPK activity and/or hypothalamic neuropeptides such as NPY. The results indicate that there is a relationship between AMPK and the control of eating behavior: a decrease in AMPK activity due to a dietary or non-dietary stimulus is associated with a consequent decrease in food intake. Furthermore, AMPK activity can be modulated by glucose, thyroid hormones, estradiol, leptin, and ghrelin.
Assuntos
Leptina , Neuropeptídeos , Leptina/metabolismo , Grelina/metabolismo , Neuropeptídeo Y/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Lipopolissacarídeos/metabolismo , Angiotensina II/metabolismo , Hipotálamo/metabolismo , Neuropeptídeos/metabolismo , Comportamento Alimentar , Ingestão de Alimentos , Colecistocinina/metabolismo , Glucose/metabolismo , Hormônios Tireóideos/metabolismo , Estradiol/metabolismo , Monofosfato de Adenosina/metabolismo , FrutoseRESUMO
Dourado (Salminus brasiliensis) is a large carnivorous fish with high commercial value for which sustainable aquaculture relies on the substitution of expensive dietary animal protein sources in aquafeeds, in particular fish meal (FM), by cheaper plant protein, such as soy protein concentrate (SPC). This study aimed at evaluating feed intake and gene expression of appetite- regulating hormones [orexin, cocaine and amphetamine regulated transcript (CART), leptin, cholecystokinin (CCK) and peptide YY (PYY)] in the intestine, pyloric caeca and hypothalamus of juvenile dourado fed diets containing graded levels of SPC and FM as dietary protein sources for a period of three weeks. Increasing dietary plant protein contents reduced daily feed consumption and the expressions of the anorexigenic hormone CCK in the anterior intestine and in pyloric caeca and PYY in pyloric caeca. No changes were detected in the hypothalamic expression of appetite-regulating hormones, suggesting that gastrointestinal hormones are more involved in the decrease in feeding induced by plant protein diets than central appetite-regulating systems.
Assuntos
Apetite , Caraciformes , Ração Animal/análise , Animais , Apetite/genética , Caraciformes/genética , Colecistocinina/genética , Colecistocinina/metabolismo , Dieta/veterinária , Ingestão de Alimentos/fisiologia , Expressão Gênica , Proteínas de SojaRESUMO
Cholecystokinin (CCK), the most abundant brain neuropeptide, is involved in relevant behavioral functions like memory, cognition, and reward through its interactions with the opioid and dopaminergic systems in the limbic system. CCK excites neurons by binding two receptors, CCK1 and CCK2, expressed at low and high levels in the brain, respectively. Historically, CCK2 receptors have been related to the induction of panic attacks in humans. Disturbances in brain CCK expression also underlie the physiopathology of schizophrenia, which is attributed to the modulation by CCK1 receptors of the dopamine flux in the basal striatum. Despite this evidence, neither CCK2 receptor antagonists ameliorate human anxiety nor CCK agonists have consistently shown neuroleptic effects in clinical trials. A neglected aspect of the function of brain CCK is its neuromodulatory role in mental disorders. Interestingly, CCK is expressed in pivotal inhibitory interneurons that sculpt cortical dynamics and the flux of nerve impulses across corticolimbic areas and the excitatory projections to mesolimbic pathways. At the basal striatum, CCK modulates the excitability of glutamate, the release of inhibitory GABA, and the discharge of dopamine. Here we focus on how CCK may reduce rather than trigger anxiety by regulating its cognitive component. Adequate levels of CCK release in the basal striatum may control the interplay between cognition and reward circuitry, which is critical in schizophrenia. Hence, it is proposed that disturbances in the excitatory/ inhibitory interplay modulated by CCK may contribute to the imbalanced interaction between corticolimbic and mesolimbic neural activity found in anxiety and schizophrenia.
Assuntos
Ansiedade , Colecistocinina , Esquizofrenia , Humanos , Receptor de Colecistocinina B , Receptores da ColecistocininaRESUMO
PURPOSE: The current study explored the involvement of neurogenic pathway-linked cholecystokinin (CCK) release in RIP-induced cardioprotection in rats. METHODS: Male Wistar rats were subjected to four cycles of alternate episodes of ischemia and reperfusion (five min each) to induce RIP. Thereafter, the hearts were subjected to global ischemia and reperfusion ex vivo. The myocardial damage was assessed by quantifying the levels of heartspecific biochemicals i.e. LDH-1, CK-MB and cTnT. Apoptotic cell injury was assessed by measuring the levels of caspase-3 and Bcl-2. The levels of CCK were measured in the plasma following RIP. RESULTS: Exposure to RIP significantly increased the plasma levels of CCK and attenuated IR-induced myocardial injury. Administration of CCK antagonist, proglumide significantly attenuated RIP-induced cardioprotection. Administration of hexamethonium, a ganglion blocker, abolished RIP-induced increase in plasma CCK levels and cardioprotective effects. Exogenous delivery of CCK-8 restored the effects of RIP in hexamethonium treated animals. CONCLUSION: RIP activates the neurogenic pathway that may increase the plasma levels of CCK, which may act on the heart-localized CCK receptors to produce cardioprotection against I/R injury.
Assuntos
Precondicionamento Isquêmico Miocárdico , Infarto do Miocárdio , Traumatismo por Reperfusão Miocárdica , Animais , Colecistocinina , Creatina Quinase , Membro Posterior , Masculino , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Ratos , Ratos WistarRESUMO
Overfeeding and rapid weight gain during early life are risk factors for the development of obesity in adulthood. This metabolic malprogramming may be mediated by endocrine disturbances during critical periods of development. Cholecystokinin (CCK) acts on the central nervous system by elevating thermogenesis and the activity of anorectic neurons, modulating overall energy balance. Therefore, we tested the hypothesis that postnatal overfeeding impaired CCK effects. Pups were raised in either a litter of three (neonatal overnutrition/small litter group) or 12 (controls/normal litter group) pups per dam to study the effects of postnatal overfeeding on the central and peripheral CCK systems in adulthood. Rats raised in small litters became overweight during lactation and remained overweight as adults, with increased adiposity and plasma levels of lipids, glucose, insulin, and leptin. Neonatally over-nourished rats showed attenuation of gastric emptying and anorexigenic response to CCK, suggesting that offspring from the SL group may present CCK resistance as adult male rats. Consistent with this idea, overweight rats displayed impaired central response in c-Fos immunoreactivity on the nucleus tractus solitarius, area postrema, paraventricular nucleus, central amygdala, arcuate nucleus, and dorsomedial hypothalamus in response to peripheral CCK at adulthood. The small litter group of adult male rats also exhibited reduced norepinephrine- and CCK-stimulated thermogenesis. Unresponsiveness to the effects of CCK may contribute to overweight and metabolic dysfunctions observed in postnatally over-nourished adult rats. Thus, the involvement of an impaired CCK system, among other neurohormonal failures, may contribute to the development of obesity.
Assuntos
Adiposidade , Sistema Nervoso Central/fisiopatologia , Colecistocinina/metabolismo , Sistema Endócrino/fisiopatologia , Hipernutrição/fisiopatologia , Tecido Adiposo/metabolismo , Animais , Animais Recém-Nascidos , Mapeamento Encefálico , Metabolismo Energético , Feminino , Esvaziamento Gástrico , Glucose/metabolismo , Homeostase , Hipotálamo , Leptina/sangue , Lipídeos/química , Masculino , Obesidade/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Wistar , Termogênese , Aumento de PesoRESUMO
Goblet cells (GCs) and endocrine cells (ECs) play an important role in intestine physiology, and few studies currently exist for Amazonian fishes. This study aimed to quantify the distribution of GCs and ECs producing cholecystokinin-8 and neuropeptide Y, assessed by mucin histochemistry and peptides immunohistochemistry, in the intestine of two Amazonian species with different feeding habits Tambaqui (Colossosoma macropomum) and hybrid catfish (Pseudoplatystoma reticulatum × Leiarius marmoratus), an omnivore and carnivore, respectively. A systematic literature review correlating feeding habit and GC and EC distribution was also included to contribute to the comparative study. The results of this study provided novel information about the gut cells of Tambaqui and hybrid catfish. Both, GCs and ECs can be found sweeping the entire intestine of Tambaqui and hybrid catfish although the cells can be more concentrated in certain segments. The GCs and ECs in Tambaqui were more uniformly distributed in the midgut segments (T1, T2, and T3). Unlike, in hybrid catfish GCs were more concentrated in the hindgut (C4) and ECs mainly in the two midgut segments (C1 and C2) of hybrid catfish. Based on the comparison between Tambaqui, hybrid catfish, and other fishes in the literature review, we suggest that cell distribution can be partially explained by feeding habits, carnivorous vs. omnivorous.
Assuntos
Peixes-Gato/genética , Células Endócrinas/citologia , Água Doce , Hibridização Genética , Intestinos/citologia , Animais , Contagem de Células , Colecistocinina/metabolismo , Mucinas/metabolismo , Neuropeptídeo Y/metabolismo , Fragmentos de Peptídeos/metabolismo , Revisões Sistemáticas como AssuntoRESUMO
The intestinal mucosa plays a critical role in the organism, acting as an interface between the lamina propria and the harmful antigens in the lumen. Sepsis is associated with primary injury to the intestinal mucosa, which in turn induces bacterial translocation and hyperpermeability. Cholecystokinin (CCK) is a peptide synthesized by several cell types, whose immunomodulatory activity has been reported in experimental models of inflammation. We hypothesized that the CCK treatment could modulate the inflammatory response and protect the integrity of the intestinal barrier in endotoxemic rats. Ten minutes before the endotoxemia induction by lipopolysaccharide (LPS) administration, rats were pretreated with CCK at two doses (0.4 µg/kg or 40âµg/kg). Mucosal permeability, bacterial translocation, cytokines production, histology injury, and expression of tight junction (TJ) proteins were the parameters assessed. In the early phase of endotoxemia, rats exhibited impaired intestinal barrier function, increased mucosal permeability, bacterial translocation, and also hyperactivation of the inflammatory response. On the other hand, the pretreatment with CCK modulated the mucosal production of pro-inflammatory cytokines and increased the expression of seal-forming TJ proteins (occludin, claudin-1 and junctional adhesion molecule (JAM-A)) only in the colon and also, reduced the bacterial counts in the mesenteric lymph nodes. However, CCK has a site-specific mechanism of action in the colon via CCK-1R, which is upregulated by the CCK treatment. In synergy with previous findings from our research group, the present results demonstrated that CCK preserves the integrity of the intestinal mucosa and might be a promising hormonal adjuvant therapy for the treatment of sepsis.
Assuntos
Colecistocinina/uso terapêutico , Enteropatias/induzido quimicamente , Enteropatias/tratamento farmacológico , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Lipopolissacarídeos/toxicidade , Animais , Enteropatias/metabolismo , Masculino , Ratos , Ratos Wistar , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismoRESUMO
Abstract Purpose: The current study explored the involvement of neurogenic pathway-linked cholecystokinin (CCK) release in RIP-induced cardioprotection in rats. Methods: Male Wistar rats were subjected to four cycles of alternate episodes of ischemia and reperfusion (five min each) to induce RIP. Thereafter, the hearts were subjected to global ischemia and reperfusion ex vivo. The myocardial damage was assessed by quantifying the levels of heartspecific biochemicals i.e. LDH-1, CK-MB and cTnT. Apoptotic cell injury was assessed by measuring the levels of caspase-3 and Bcl-2. The levels of CCK were measured in the plasma following RIP. Results: Exposure to RIP significantly increased the plasma levels of CCK and attenuated IR-induced myocardial injury. Administration of CCK antagonist, proglumide significantly attenuated RIP-induced cardioprotection. Administration of hexamethonium, a ganglion blocker, abolished RIP-induced increase in plasma CCK levels and cardioprotective effects. Exogenous delivery of CCK-8 restored the effects of RIP in hexamethonium treated animals. Conclusion: RIP activates the neurogenic pathway that may increase the plasma levels of CCK, which may act on the heart-localized CCK receptors to produce cardioprotection against I/R injury.