RESUMEN
BACKGROUND: A tight immune and metabolic regulation underlies the early maternal-placental interaction to assist the energetic dynamic demands of the fetus throughout pregnancy. The vasoactive intestinal peptide (VIP) holds biochemical, metabolic and immune properties consistent with a regulatory role during pregnancy. AIM: Here we overview critical aspects of embryo implantation and placental development with special focus on the immune and metabolic effects of VIP expressed by decidual and trophoblast cells. CONTENT: During decidualization, endometrial stromal cells undergo reticular stress and trigger unfolded protein response (UPR) that enable expansion of their endoplasmic reticulum and immunomodulatory factor synthesis. These processes appear differentially affected in recurrent abortion and in vitro fertilization failure suggesting their relevance in reproductive pathologies. Similarly, defective placentation associates with altered immune, vascular and trophoblast interaction resulting in complicated pregnancies that threaten maternal and neonatal health and underlie metabolic programming of adult life. We discuss the most recent research on decidual, trophoblast and immune cell interaction on the light of VIP regulation. Its role in decidualization and UPR associated with a sterile inflammatory response and angiogenesis is discussed. Evidence on VIP modulation of cytotrophoblast cell function, metabolism and immune profile is revised as well as the shaping of decidual leukocyte phenotype and function from decidualization to term. IMPLICATIONS: The broad spectrum of effects of VIP from implantation to term in normal and pathological conditions summarized here might contribute to the identification of novel biomarkers for diagnosis and pharmacological targeting.
Asunto(s)
Placenta , Péptido Intestinal Vasoactivo , Biomarcadores/metabolismo , Decidua/metabolismo , Implantación del Embrión , Femenino , Humanos , Placenta/metabolismo , Placentación , Embarazo , Células del Estroma/metabolismo , Trofoblastos , Péptido Intestinal Vasoactivo/metabolismoRESUMEN
The arcuate nucleus of hypothalamus (ARC) integrates circulating factors that signal energy status. The vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are widely distributed in the periphery and central nervous systems (CNS) and play important roles on energy balance. The present study aimed to investigate the responses of microinjection of VIP and PACAP in the ARC on metabolic changes and food intake. In addition, the activity of neurons in the ARC following intracerebroventricular (ICV) microinjection of these peptides was also evaluated. Microinjection of VIP or PACAP in the ARC decreased fasting-induced hyperphagia and food intake, decreased total lipids, and increased free fatty acids plasma concentrations. VIP microinjection in the ARC induced hyperglycemia and decreased total cholesterol level; and PACAP reduced triglycerides concentration. ICV microinjection of VIP and PACAP enhanced neuronal activation in the ARC, associated with lower fasting-induced hyperphagia and plasma metabolic changes (only VIP). These results suggest that VIP and PACAP play important roles in ARC, inducing hypophagia and peripheral metabolic changes, as hyperglycemia, increased free fatty acids and decreased total lipids plasma levels.
Asunto(s)
Núcleo Arqueado del Hipotálamo , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa , Péptido Intestinal Vasoactivo , Animales , Núcleo Arqueado del Hipotálamo/metabolismo , Conducta Alimentaria , Hipotálamo/metabolismo , Lípidos/sangre , Neuronas/metabolismo , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/metabolismo , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/farmacología , Péptido Intestinal Vasoactivo/metabolismo , Péptido Intestinal Vasoactivo/farmacologíaRESUMEN
Hypothalamic kisspeptin neurons are the primary modulators of gonadotropin-releasing hormone (GnRH) neurons. It has been shown that circadian rhythms driven by the suprachiasmatic nucleus (SCN) contribute to GnRH secretion. Kisspeptin neurons are potential targets of SCN neurons due to reciprocal connections with the anteroventral periventricular and rostral periventricular nuclei (AVPV/PeN) and the arcuate nucleus of the hypothalamus (ARH). Vasoactive intestinal peptide (VIP), a notable SCN neurotransmitter, modulates GnRH secretion depending on serum estradiol levels, aging or time of the day. Considering that kisspeptin neurons may act as interneurons and mediate VIP's effects on the reproductive axis, we investigated the effects of VIP on hypothalamic kisspeptin neurons in female mice during estrogen negative feedback. Our findings indicate that VIP induces a TTX-independent depolarization of approximately 30% of AVPV/PeN kisspeptin neurons in gonad-intact (diestrus) and ovariectomized (OVX) mice. In the ARH, the percentage of kisspeptin neurons that were depolarized by VIP was even higher (approximately 90%). An intracerebroventricular infusion of VIP leds to an increased percentage of kisspeptin neurons expressing the phosphoSer133 cAMP-response-element-binding protein (pCREB) in the AVPV/PeN. On the other hand, pCREB expression in ARH kisspeptin neurons was similar between saline- and VIP-injected mice. Thus, VIP can recruit different signaling pathways to modulate AVPV/PeN or ARH kisspeptin neurons, resulting in distinct cellular responses. The expression of VIP receptors (VPACR) was upregulated in the AVPV/PeN, but not in the ARH, of OVX mice compared to mice on diestrus and estradiol-primed OVX mice. Our findings indicate that VIP directly influences distinct cellular aspects of the AVPV/PeN and ARH kisspeptin neurons during estrogen negative feedback, possibly to influence pulsatile LH secretion.
Asunto(s)
Kisspeptinas , Péptido Intestinal Vasoactivo , Animales , Estradiol/metabolismo , Estradiol/farmacología , Estrógenos/metabolismo , Estrógenos/farmacología , Retroalimentación , Femenino , Hormona Liberadora de Gonadotropina/metabolismo , Hipotálamo/metabolismo , Kisspeptinas/metabolismo , Ratones , Neuronas/metabolismo , Péptido Intestinal Vasoactivo/metabolismo , Péptido Intestinal Vasoactivo/farmacologíaRESUMEN
Cell-cell interaction and active migration (and invasion) of parasites into skin host-cell(s) are key steps for successful infection by Leishmania. Chemotaxis constitutes a primordial chapter of Leishmania-host cell interaction, potentially modulated by neuropeptides released into the skin due, for example, to the noxious stimuli represented by the insect bite. Herein we have evaluated in vitro the effect of sensory (Substance P, SP) and autonomic (Vasoactive Intestinal Peptide, VIP, and Neuropeptide Y, NPY) neuropeptides on parasite taxis, and investigated the potential modulatory effect of SP on Leishmania (Viannia) braziliensis-macrophage interaction. We demonstrated that VIP (10-10 M) and NPY (10-9 M) are chemorepellent to the parasites, while SP (10-8 M) produces a chemoattractant response. SP did not affect macrophage viability but seems to impair parasite-macrophage interaction as it decreased promastigote adherence to macrophages. As this effect is blocked by ([D-Pro 2, D-Trp7,9]-Substance P (10-6 M), the observed action may be mediated by neurokinin-1 (NK1) transmembrane receptors. VIP and NPY repellent chemotactic effect is impaired by their corresponding receptor antagonists. Additionally, they suggest that SP may be a key molecule to guide promastigote migration towards, and interaction, with dendritic cells and macrophage host cells.
Asunto(s)
Leishmania braziliensis/metabolismo , Neuropéptido Y/metabolismo , Sustancia P/metabolismo , Péptido Intestinal Vasoactivo/metabolismo , Animales , Quimiotaxis , Flagelos/ultraestructura , Leishmania braziliensis/fisiología , Leishmania braziliensis/ultraestructura , Macrófagos , RatonesRESUMEN
The transport of nutrients across the placenta involves trophoblast cell specific transporters modulated through the mammalian target of rapamycin (mTOR). The vasoactive intestinal peptide (VIP) has embryotrophic effects in mice and regulates human cytotrophoblast cell migration and invasion. Here we explored the effect of VIP on glucose and System A amino acid uptake by human trophoblast-derived cells (Swan 71 and BeWo cell lines). VIP activated D-glucose specific uptake in single cytotrophoblast cells in a concentration-dependent manner through PKA, MAPK, PI3K and mTOR signalling pathways. Glucose uptake was reduced in VIP-knocked down cytotrophoblast cells. Also, VIP stimulated System A amino acid uptake and the expression of GLUT1 glucose transporter and SNAT1 neutral amino acid transporter. VIP increased mTOR expression and mTOR/S6 phosphorylation whereas VIP silencing reduced mTOR mRNA and protein expression. Inhibition of mTOR signalling with rapamycin reduced the expression of endogenous VIP and of VIP-induced S6 phosphorylation. Our findings support a role of VIP in the transport of glucose and neutral amino acids in cytotrophoblast cells through mTOR-regulated pathways and they are instrumental for understanding the physiological regulation of nutrient sensing by endogenous VIP at the maternal-foetal interface.
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Aminoácidos Neutros/metabolismo , Glucosa/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Trofoblastos/metabolismo , Péptido Intestinal Vasoactivo/metabolismo , Transporte Biológico/fisiología , Línea Celular , Femenino , Humanos , Placenta/metabolismo , Embarazo , ARN Mensajero/metabolismo , Transducción de Señal/fisiologíaRESUMEN
INTRODUCTION: The balance between the host proinflammatory immune response and the counteracting anti-inflammatory and reparative responses supposedly determine the outcome of periapical lesions. In this scenario, the vasoactive intestinal peptide (VIP) may exert a protective role because of its prominent immunoregulatory capacity. In this study, we investigated (in a cause-and-effect manner) the potential involvement of VIP in the development of human and experimental periapical lesions. METHODS: Periapical granulomas (n = 124) and control samples (n = 48) were comparatively assessed for VIP and multiple immunologic/activity marker expression through real-time polymerase chain reaction. Experimental periapical lesions (C57Bl/6 wild-type mice) were evaluated regarding endogenous VIP expression correlation with lesion development and the effect of recombinant VIP therapy in lesion outcome. CCR4KO and IL4KO strains and anti-glucocorticoid-induced TNFR-related protein inhibition were used to test the involvement of Treg and Th2 cells in VIP-mediated effects. RESULTS: VIP expression was more prevalent in periapical granulomas than in controls, presenting a positive association with immunoregulatory factors and an inverse association/correlation with proinflammatory mediators and the receptor activator of nuclear factor kappa B ligand/osteoprotegerin ratio. Endogenous VIP expression up-regulation was temporally associated with lesion immunoregulation and a decline of bone loss. VIP therapy in mice prompted the arrest of lesion development, being associated with an anti-inflammatory and proreparative response that limits the proinflammatory, Th1, Th17, and osteoclastogenic response in the periapex. The VIP protective effect was dependent of Treg migration and activity and independent of interleukin 4. CONCLUSIONS: Our results show that VIP overexpression in human and experimental periapical lesions is associated with lesion inactivity and that VIP therapy results in the attenuation of experimental lesion progression associated with the immunosuppressive response involving Treg cells.
Asunto(s)
Granuloma Periapical , Péptido Intestinal Vasoactivo , Animales , Humanos , Ratones , Ratones Endogámicos C57BL , Granuloma Periapical/metabolismo , Linfocitos T Reguladores , Células Th17 , Péptido Intestinal Vasoactivo/metabolismoRESUMEN
A network of cell-cell communications through contact and soluble factors supports the maternal-placental interaction and provides a suitable environment for fetal growth. Trophoblast cells take center stage at these loops: they interact with maternal leukocytes to sustain the varying demands of gestation, and they synthesize hormones, cytokines among other factors that contribute to the maintenance of immune homeostasis. Here, we discuss vasoactive intestinal peptide (VIP) and its potential as a regulatory neuropeptide in pregnancy. VIP is synthesized by trophoblast cells; it regulates trophoblast cell function and interaction with the major immune cell populations present in the pregnant uterus. VIP activity produces an anti-inflammatory microenvironment by modulating the functional profile of monocytes, macrophages, and regulatory T cells. Trophoblast VIP inhibits neutrophil extracellular trap formation and accelerates neutrophil apoptosis, enabling their silent clearance by phagocytic cells. The effects of VIP on the trophoblast-immune interaction are consistent with its regulatory role throughout pregnancy for immune homeostasis maintenance. These observations may provide new clues for pharmacological targeting of pregnancy complications associated with exacerbated inflammation.
Asunto(s)
Comunicación Celular/fisiología , Homeostasis/inmunología , Linfocitos T Reguladores/inmunología , Trofoblastos/metabolismo , Péptido Intestinal Vasoactivo/metabolismo , Apoptosis/inmunología , Trampas Extracelulares/inmunología , Femenino , Humanos , Inflamación/inmunología , Macrófagos/inmunología , Monocitos/inmunología , Neutrófilos/inmunología , EmbarazoRESUMEN
The vasoactive intestinal peptide (VIP) expression is lower in cardiac chagasic patients and is related to worse cardiac function. The reduction of VIP in patients with Chagas disease may be a result of its enhanced degradation. To test this hypothesis, the tryptase and chymase expression was evaluated. We also related VIP levels with interleukin-17 (IL-17) expression since VIP may modulate IL-17 production. Plasma levels of chymase were higher in chagasic patients. Conversely, VIP/chymase and VIP/tryptase ratios were lower in chagasic patients when compared to non-infected individuals. Besides, the VIP/chymase ratio was lower in chagasic cardiac patients in comparison with the indeterminate group. A positive correlation between tryptase and chymase levels was observed in chagasic cardiac patients. In relation to IL-17, we observed a higher expression of this cytokine in the cardiac form of the disease than in the indeterminate form. IL-17/VIP ratio was higher in the cardiac form in comparison with non-infected or indeterminate form. These results suggest that the low levels of VIP observed in chagasic patients could be due to an increased production of chymase and/or to the additive effect of the interaction between chymase and tryptase in the cardiac form. Moreover, the decreased VIP expression may contribute to the increase of IL-17 in chagasic cardiac patients.
Asunto(s)
Cardiomiopatía Chagásica/metabolismo , Interleucina-17/metabolismo , Péptido Intestinal Vasoactivo/metabolismo , Cardiomiopatía Chagásica/sangre , Quimasas/sangre , Estudios Transversales , Humanos , Triptasas/sangre , Péptido Intestinal Vasoactivo/sangreRESUMEN
We previously found that acute exercise inhibited the gastric emptying of liquid in awake rats by causing an acid-base imbalance. In the present study, we investigated the involvement of the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway, vasoactive intestinal peptide (VIP), and corticotropin-releasing factor (CRF) peptide in this phenomenon. Male rats were divided into exercise or sedentary group and were subjected to a 15-min swim session against a load (2.5 or 5% b.w.). The rate of gastric emptying was evaluated after 5, 10, or 20 min postprandially. Separate groups of rats were treated with vehicle (0.9% NaCl, 0.1 mL/100 g, ip) or one of the following agents: atropine (1.0 mg/kg, ip), the NO non-selective inhibitor Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME; 10.0 mg/kg, ip), or the selective cGMP inhibitor 1H-(1,2,4)oxadiazole[4,3-a]quinoxalin-1-one (ODQ; 5.0 mg/kg, ip), the i-NOS non-specific inhibitor (aminoguanidine; 10.0 mg/kg, ip), the corticotropin-releasing factor receptor antagonist (astressin; 100 µg/kg, ip), or the vasoactive intestinal peptide (VIP) receptor antagonist Lys1, Pro2,5, Arg3,4, Tyr6 (100 µg/kg, ip). Compared to sedentary rats, both the 2.5 and 5% exercise groups exhibited higher (P<0.05) values of blood lactate and fractional gastric dye recovery. Corticosterone and NO levels increased (P<0.05) in the 5% exercised rats. Pretreatment with astressin, VIP antagonist, atropine, L-NAME, and ODQ prevented the increase in gastric retention caused by exercise in rats. Acute exercise increased gastric retention, a phenomenon that appears to be mediated by the NO-cGMP pathway, CRF, and VIP receptors.
Asunto(s)
Hormona Liberadora de Corticotropina/metabolismo , Vaciamiento Gástrico/fisiología , Guanosina Monofosfato/metabolismo , Óxido Nítrico/metabolismo , Condicionamiento Físico Animal/fisiología , Péptido Intestinal Vasoactivo/metabolismo , Animales , Atropina/farmacología , Corticosterona/sangre , Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Hormona Liberadora de Corticotropina/farmacología , Inhibidores Enzimáticos/farmacología , Vaciamiento Gástrico/efectos de los fármacos , Guanosina Monofosfato/antagonistas & inhibidores , Ácido Láctico/sangre , Masculino , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico/antagonistas & inhibidores , Fragmentos de Péptidos/farmacología , Periodo Posprandial/efectos de los fármacos , Periodo Posprandial/fisiología , Distribución Aleatoria , Ratas Wistar , Valores de Referencia , Reproducibilidad de los Resultados , Conducta Sedentaria , Factores de Tiempo , Péptido Intestinal Vasoactivo/antagonistas & inhibidoresRESUMEN
Vasoactive intestinal peptide (VIP) and corticotrophin-releasing factor (CRF) are anorexigenic neuropeptides that act in the hypothalamus to regulate food intake. Intracerebroventricular (ICV) microinjection of VIP promotes increased plasma adrenocorticotrophic hormone (ACTH) and corticosterone, indicating that VIP activates hypothalamic-pituitary-adrenal axis. The aim of this study was to evaluate the interaction between VIP and CRF, by verifying the effects of ICV administration of VIP on the activity of neurons and CRF mRNA expression in paraventricular nucleus of hypothalamus (PVN). In addition, it was evaluated the effects of pretreatment with CRF type 1 receptor (CRFR1) antagonist (Antalarmin, ANT) or CRF type 2 receptor (CRFR2) antagonist (Antisauvagine-30, AS30) on VIP-induced changes on food intake and plasma parameters of male rats. Compared to Saline group, VIP increased not only the number of Fos-related antigens (FRA)-immunoreactive neurons in the PVN but also CRF mRNA levels in this nucleus. Both ANT and AS30 treatment attenuated the inhibition of food intake promoted by VIP, ANT showing a more pronounced effect. Both antagonists also attenuated VIP-induced reduction and enhancement of free fatty acids and corticosterone plasma levels, respectively, and only AS30 was able to attenuate the hyperglycemia. These results suggest that CRF is an important mediador of VIP effects on energy balance, and CRFR1 and CRFR2 are involved in these responses.
Asunto(s)
Hormona Liberadora de Corticotropina/fisiología , Trastornos de Alimentación y de la Ingestión de Alimentos/sangre , Trastornos de Alimentación y de la Ingestión de Alimentos/inducido químicamente , Péptido Intestinal Vasoactivo/efectos adversos , Hormona Adrenocorticotrópica/sangre , Animales , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Corticosterona/sangre , Hormona Liberadora de Corticotropina/genética , Hormona Liberadora de Corticotropina/metabolismo , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Ácidos Grasos/sangre , Trastornos de Alimentación y de la Ingestión de Alimentos/genética , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/metabolismo , Hipotálamo/metabolismo , Masculino , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/metabolismo , Ratas , Ratas Wistar , Péptido Intestinal Vasoactivo/metabolismoRESUMEN
Gastrointestinal symptoms are the first signs of fluoride (F) toxicity. In the present study, the jejunum of rats chronically exposed to F was evaluated by proteomics, as well as by morphological analysis. Wistar rats received water containing 0, 10 or 50 mgF/L during 30 days. HuC/D, neuronal Nitric Oxide (nNOS), Vasoactive Intestinal Peptide (VIP), Calcitonin Gene Related Peptide (CGRP), and Substance P (SP) were detected in the myenteric plexus of the jejunum by immunofluorescence. The density of nNOS-IR neurons was significantly decreased (compared to both control and 10 mgF/L groups), while the VIP-IR varicosities were significantly increased (compared to control) in the group treated with the highest F concentration. Significant morphological changes were seen observed in the density of HUC/D-IR neurons and in the area of SP-IR varicosities for F-treated groups compared to control. Changes in the abundance of various proteins correlated with relevant biological processes, such as protein synthesis, glucose homeostasis and energy metabolism were revealed by proteomics.
Asunto(s)
Fluoruros/efectos adversos , Yeyuno/efectos de los fármacos , Animales , Péptido Relacionado con Gen de Calcitonina/metabolismo , Duodeno/metabolismo , Proteína 3 Similar a ELAV/metabolismo , Sistema Nervioso Entérico/efectos de los fármacos , Intestino Delgado/metabolismo , Masculino , Minerales/metabolismo , Óxido Nítrico/análisis , Óxido Nítrico/metabolismo , Proteómica/métodos , Ratas , Ratas Wistar , Sustancia P/metabolismo , Péptido Intestinal Vasoactivo/metabolismoRESUMEN
The decidualization process involves phenotype and functional changes on endometrial cells and the modulation of mediators with immunoregulatory properties as the vasoactive intestinal peptide (VIP). We investigate VIP contribution to the decidualization program and to immunoregulation throughout the human embryo implantation process. The decidualization of Human endometrial stromal cell line (HESC) with Medroxyprogesterone-dibutyryl-cAMP increased VIP/VPAC-receptors system. In fact, VIP could induce decidualization increasing differentiation markers (IGFBP1, PRL, KLF13/KLF9 ratio, CXCL12, CXCL8 and CCL2) and allowing Blastocyst-like spheroids (BLS) invasion in an in vitro model of embryo implantation. Focus on the tolerogenic effects, decidualized cells induced a semi-mature profile on maternal dendritic cells; restrained CD4+ cells recruitment while increased regulatory T-cells recruitment. Interestingly, the human blastocyst conditioned media from developmentally impaired embryos diminished the invasion and T-regulatory cells recruitment in these settings. These evidences suggest that VIP contributes to the implantation process inducing decidualization, allowing BLS invasion and favoring a tolerogenic micro-environment.
Asunto(s)
Decidua/metabolismo , Implantación del Embrión/inmunología , Péptido Intestinal Vasoactivo/metabolismo , Biomarcadores/metabolismo , Blastocisto/citología , Línea Celular , Microambiente Celular/efectos de los fármacos , Medios de Cultivo Condicionados/farmacología , Implantación del Embrión/efectos de los fármacos , Endometrio/citología , Femenino , Humanos , Tolerancia Inmunológica , Modelos Biológicos , Células del Estroma/efectos de los fármacos , Células del Estroma/metabolismo , Trofoblastos/efectos de los fármacos , Trofoblastos/metabolismoRESUMEN
BACKGROUND: The intestinal mucosa plays an important role in the mechanical barrier against pathogens. During Toxoplasma gondii infection, however, the parasites invade the epithelial cells of the small intestine and initiate a local immune response. In the submucosal plexus, this response promotes an imbalance of neurotransmitters and induces neuroplasticity, which can change the integrity of the epithelium and its secretory function. This study evaluated the submucosal neurons throughout acute T. gondii infection and the relationship between possible alterations and the epithelial and immune defense cells of the mucosa. METHODS: Forty Wistar rats were randomly assigned to 8 groups (n = 5): 1 control group, uninfected, and 7 groups infected with an inoculation of 5000 sporulated T. gondii oocysts (ME-49 strain, genotype II). Segments of the ileum were collected for standard histological processing, histochemical techniques, and immunofluorescence. KEY RESULTS: The infection caused progressive neuronal loss in the submucosal general population and changed the proportion of VIPergic neurons throughout the infection periods. These changes may be related to the observed reduction in goblet cells that secret sialomucins and increase in intraepithelial lymphocytes after 24 hours, and the increase in immune cells in the lamina propria after 10 days of infection. The submucosa also presented fibrogenesis, characterizing injury and tissue repair. CONCLUSIONS AND INFERENCES: The acute T. gondii infection in the ileum of rats changes the proportion of VIPergic neurons and the epithelial cells, which can compromise the mucosal defense during infection.
Asunto(s)
Células Caliciformes/metabolismo , Íleon/metabolismo , Linfocitos Intraepiteliales/metabolismo , Neuronas/metabolismo , Toxoplasmosis/metabolismo , Péptido Intestinal Vasoactivo/metabolismo , Animales , Recuento de Células , Muerte Celular/fisiología , Células Caliciformes/microbiología , Células Caliciformes/patología , Íleon/microbiología , Íleon/patología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Linfocitos Intraepiteliales/microbiología , Linfocitos Intraepiteliales/patología , Masculino , Plexo Mientérico/metabolismo , Plexo Mientérico/microbiología , Plexo Mientérico/patología , Neuronas/microbiología , Neuronas/patología , Ratas , Ratas Wistar , Toxoplasma , Toxoplasmosis/microbiología , Toxoplasmosis/patologíaRESUMEN
Resumen: El neuroblastoma es un tumor maligno del sistema nervioso simpático periférico con presentación y curso clínico heterogéneo. Es el tercer tumor pediátrico más frecuente y el 90% de los casos se diagnostica antes de los 5 años. Los síntomas más comunes se deben a la compresión por la masa tumoral o al dolor óseo causado por la metástasis. La diarrea como síntoma principal es rara por lo que es difícil de diagnosticar en la etapa temprana de la enfermedad. Se presenta el caso clínico de una paciente de 2 años en la que luego de 8 meses de estudio por diarrea crónica se diagnóstica ganglioneuroblastoma secretor de VIP. Se debe plantear como diagnóstico diferencial en los pacientes menores de 3 años con diarrea crónica intratable luego de haber descartado otras etiologías.
Summary: Neuroblastoma is a malignant tumor of the peripheral sympathetic nervous system with heterogeneous clinical presentation and course. It is the third most frequent pediatric tumor and in 90% of cases it is diagnosed before 5 years of age. The most typical symptoms result from the tumor compression or bone pain caused by methastasis. Diarrhea as the main symptom is unusual, and thus it is hard to diagnose in early stages of the disease. We report the case of a 2-year-old patient who, after 8 months of study for chronic diarrhea was diagnosed with VIP-secreting ganglioneuroblastoma. It is necessary for this condition to be considered as a differential diagnosis in patients younger than 3 years old with chronic diarrhea with no evolution, after other etiologies are ruled out.
Asunto(s)
Humanos , Ganglioneuroblastoma/diagnóstico , Disentería/etiología , Péptido Intestinal Vasoactivo/metabolismo , Ganglioneuroblastoma/complicaciones , Diagnóstico DiferencialRESUMEN
Microglial cells are responsible for immune surveillance within the CNS. They respond to noxious stimuli by releasing inflammatory mediators and mounting an effective inflammatory response. This is followed by release of anti-inflammatory mediators and resolution of the inflammatory response. Alterations to this delicate process may lead to tissue damage, neuroinflammation, and neurodegeneration. Chronic pain, such as inflammatory or neuropathic pain, is accompanied by neuroimmune activation, and the role of glial cells in the initiation and maintenance of chronic pain has been the subject of increasing research over the last two decades. Neuropeptides are small amino acidic molecules with the ability to regulate neuronal activity and thereby affect various functions such as thermoregulation, reproductive behavior, food and water intake, and circadian rhythms. Neuropeptides can also affect inflammatory responses and pain sensitivity by modulating the activity of glial cells. The last decade has witnessed growing interest in the study of microglial activation and its modulation by neuropeptides in the hope of developing new therapeutics for treating neurodegenerative diseases and chronic pain. This review summarizes the current literature on the way in which several neuropeptides modulate microglial activity and response to tissue damage and how this modulation may affect pain sensitivity.
Asunto(s)
Inflamación/metabolismo , Microglía/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Neuropéptidos/metabolismo , Dolor/metabolismo , Adrenomedulina/metabolismo , Animales , Péptido Relacionado con Gen de Calcitonina/metabolismo , Ghrelina/metabolismo , Humanos , Mediadores de Inflamación , Leptina/metabolismo , Activación de Macrófagos , Neuralgia/metabolismo , Neuroglía/metabolismo , Neuropéptido Y/metabolismo , Proopiomelanocortina/metabolismo , Taquicininas/metabolismo , Péptido Intestinal Vasoactivo/metabolismoRESUMEN
Trophoblast cells migrate and invade the decidual stroma in a tightly regulated process to maintain immune homeostasis at the maternal-placental interface during the first weeks of pregnancy. Locally synthesized factors modulate trophoblast cell function and their interaction with maternal leukocytes to promote the silent clearance of apoptotic cells. The vasoactive intestinal peptide (VIP) is a pleiotropic polypeptide with trophic and anti-inflammatory effects in murine pregnancy models. We explored the effect of VIP on two human first trimester trophoblast cell lines, particularly on their migration, invasiveness and interaction with phagocytic cells, and the signalling and regulatory pathways involved. We found that VIP enhanced trophoblast cell migration and invasion through the activation of high affinity VPAC receptors and PKA-CRE signalling pathways. VIP knocked-down trophoblast cells showed reduced migration in basal and leukemic inhibitor factor (LIF)-elicited conditions. In parallel, VIP-silenced trophoblast cells failed to induce the phagocytosis of apoptotic bodies and the expression of immunosuppressant markers by human monocytes. Our results suggest that VIP-mediated autocrine pathways regulate trophoblast cell function and contribute to immune homeostasis maintenance at placentation and may provide new clues for therapeutic intervention in pregnancies complicated by defective deep placentation.
Asunto(s)
Comunicación Autocrina , Fagocitos/citología , Trofoblastos/citología , Péptido Intestinal Vasoactivo/metabolismo , Línea Celular , Movimiento Celular , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Embarazo , Primer Trimestre del Embarazo , Proteínas Quinasas/metabolismo , Receptores del Polipéptido Activador de la Adenilato-Ciclasa Hipofisaria/metabolismo , Transducción de Señal , Péptido Intestinal Vasoactivo/genéticaRESUMEN
AIM: To assess the effects of ME-49 Toxoplasma gondii (T. gondii) strain infection on the myenteric plexus and external muscle of the jejunum in rats. METHODS: Thirty rats were distributed into two groups: the control group (CG) (n = 15) received 1 mL of saline solution orally, and the infected group (IG) (n = 15) inoculated with 1 mL of saline solution containing 500 oocysts of M-49 T. gondii strain orally. After 36 d of infection, the rats were euthanized. Infection with T. gondii was confirmed by blood samples collected from all rats at the beginning and end of the experiment. The jejunum of five animals was removed and submitted to routine histological processing (paraffin) for analysis of external muscle thickness. The remaining jejunum from the others animals was used to analyze the general population and the NADH-diaphorase, VIPergic and nitrergic subpopulations of myenteric neurons; and the enteric glial cells (S100-IR). RESULTS: Serological analysis showed that animals from the IG were infected with the parasite. Hypertrophy affecting jejunal muscle thickness was observed in the IG rats (77.02 ± 42.71) in relation to the CG (51.40 ± 12.34), P < 0.05. In addition, 31.2% of the total number of myenteric neurons died (CG: 39839.3 ± 5362.3; IG: 26766.6 ± 2177.6; P < 0.05); hyperplasia of nitrergic myenteric neurons was observed (CG: 7959.0 ± 1290.4; IG: 10893.0 ± 1156.3; P < 0.05); general hypertrophy of the cell body in the remaining myenteric neurons was noted [CG: 232.5 (187.2-286.0); IG: 248.2 (204.4-293.0); P < 0.05]; hypertrophy of the smallest varicosities containing VIP neurotransmitter was seen (CG: 0.46 ± 0.10; IG: 0.80 ± 0.16; P < 0.05) and a reduction of 25.3% in enteric glia cells (CG: 12.64 ± 1.27; IG: 10.09 ± 2.10; P < 0.05) was observed in the infected rats. CONCLUSION: It was concluded that infection with oocysts of ME-49 T. gondii strain caused quantitative and plastic alterations in the myenteric plexus of the jejunum in rats.
Asunto(s)
Yeyuno/inervación , Músculo Liso/inervación , Plexo Mientérico/parasitología , Plasticidad Neuronal , Toxoplasma/patogenicidad , Toxoplasmosis/parasitología , Animales , Biomarcadores/metabolismo , Dihidrolipoamida Deshidrogenasa/metabolismo , Modelos Animales de Enfermedad , Masculino , Plexo Mientérico/metabolismo , Plexo Mientérico/fisiopatología , Neuroglía/metabolismo , Neuroglía/parasitología , Neuronas Nitrérgicas/metabolismo , Neuronas Nitrérgicas/parasitología , Ratas Wistar , Factores de Tiempo , Toxoplasmosis/fisiopatología , Péptido Intestinal Vasoactivo/metabolismoRESUMEN
The physiology of hepatic hematopoiesis is largely unknown, although studies have indicated that vasoactive intestinal polypeptide (VIP) is involved in this disease. To validate this hypothesis, we assessed the effects of VIP on human cord blood CD34+ cells. We also measured VIP levels and the capacity of vasoactive intestinal polypeptide receptor (VIPR) to bind to VIP in the rat liver during different developmental phases. VIP inhibited the proliferation of cord blood-derived CD34(+) cells from concentrations of 10-7-10-12 M. The highest suppression was achieved with 10-8 M VIP at day 10. Intracellular levels of tumor necrosis factor (TNF)-α and transforming growth factor (TGF)-ß1 in CD34(+) cells treated with VIP were increased by 50.70 and 43.46%, respectively. Variations in VIP levels in the rat fetal liver generally increased rapidly with the stage of fetal development. In addition, the affinity of VIPR for VIP increased from relatively low levels in the rat fetal liver and peaked at birth, after which it gradually decreased. VIP had a suppressive effect on the proliferation of human cord blood-derived CD34(+) cells, partially by increasing the production of TNF-α and TGF-ß. Low VIP levels in the fetal liver and gradually increasing levels after birth may in part be responsible for suppressing hematopoietic stem cell and progenitor proliferation in the liver.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Células Madre Hematopoyéticas/efectos de los fármacos , Factor de Crecimiento Transformador beta1/biosíntesis , Factor de Necrosis Tumoral alfa/biosíntesis , Péptido Intestinal Vasoactivo/farmacología , Animales , Animales Recién Nacidos , Antígenos CD34/metabolismo , Células Cultivadas , Relación Dosis-Respuesta a Droga , Ensayo de Inmunoadsorción Enzimática , Sangre Fetal/citología , Expresión Génica/efectos de los fármacos , Células Madre Hematopoyéticas/metabolismo , Humanos , Hígado/embriología , Hígado/crecimiento & desarrollo , Hígado/metabolismo , Ratas Sprague-Dawley , Receptores de Péptido Intestinal Vasoactivo/genética , Receptores de Péptido Intestinal Vasoactivo/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Tiempo , Péptido Intestinal Vasoactivo/metabolismoRESUMEN
The nerve growth factor (NGF) and other neurotrophins, and the neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) are largely present in human tissue and can exert modulatory activities on nervous, endocrine and immune system functions. NGF, VIP and PACAP receptors are expressed systemically in organisms, and thus these mediators exhibit pleiotropic natures. The human immunodeficiency virus type 1 (HIV-1), the causal agent of the acquired immunodeficiency syndrome (AIDS), infects immune cells, and its replication is modulated by a number of endogenous factors that interact with HIV-1-infected cells. NGF, VIP and PACAP can also affect HIV-1 virus particle production upon binding to their receptors on the membranes of infected cells, which triggers cell signaling pathways that modify the HIV-1 replicative cycle. These molecules exert opposite effects on HIV-1 replication, as NGF and other neurotrophins enhance and VIP and PACAP reduce viral production in HIV-1-infected human primary macrophages. The understanding of AIDS pathogenesis should consider the mechanisms by which the replication of HIV-1, a pathogen that causes chronic morbidity, is influenced by neurotrophins, VIP and PACAP, i.e. molecules that exert a broad spectrum of physiological activities on the neuroimmunoendocrine axis. In this review, we will present the main effects of these two groups of mediators on the HIV-1 replicative cycle, as well as the mechanisms that underlie their abilities to modulate HIV-1 production in infected immune cells, and discuss the possible repercussion of the cross talk between NGF and both neuropeptides on the pathogenesis of HIV-1 infection.
Asunto(s)
Infecciones por VIH/metabolismo , VIH-1/fisiología , Interacciones Huésped-Parásitos/fisiología , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/metabolismo , Péptido Intestinal Vasoactivo/metabolismo , Replicación Viral/fisiología , Animales , HumanosRESUMEN
PROBLEM: Impaired pregnancy in non-obese diabetic (NOD) mice was related to limited vascular remodeling and autoimmune background. Vasoactive intestinal peptide (VIP) has anti-inflammatory and immunosuppressant effects, so we explored its ability to modulate the immune microenvironment at the early maternal-placental interface and improve pregnancy in NOD mice. METHOD OF STUDY: Implantation sites were isolated from pregnant NOD mice at gestational day 9.5 and were incubated with VIP for evaluation of cytokine or transcription factor expression by RT-PCR, immunoblotting, and immunohistochemistry. Alternatively, pregnant mice were injected with VIP at day 6.5 and studied at day 9.5. RESULTS: VIP and VPAC receptors were detected in viable implantation sites. VIP immunostaining was found predominantly on trophoblast giant cells. The in vitro treatment of viable implantation sites with VIP increased IL-10, TGF-ß, and Foxp3 expression. Sites with resorption processes presented lower VIP expression, reduced suppressant markers, and increased IL-17 and RORγT expression compared with viable sites and VIP reduced RORγT expression. Pregnant mice treated with VIP at day 6.5 presented an even distribution of viable implantation sites with an increased expression of IL-10, TGF- ß, and Foxp3. CONCLUSION: VIP induces an immunosuppressant profile at the early maternal-placental interface of NOD mice and improves pregnancy outcome.