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Sistema Endocrino , Humanos , Animales , Sistema Endocrino/fisiología , Sistema InmunológicoRESUMEN
The close interaction between fetal and maternal cells during pregnancy requires multiple immune-endocrine mechanisms to provide the fetus with a tolerogenic environment and protection against any infectious challenge. The fetal membranes and placenta create a hyperprolactinemic milieu in which prolactin (PRL) synthesized by the maternal decidua is transported through the amnion-chorion and accumulated into the amniotic cavity, where the fetus is bedded in high concentrations during pregnancy. PRL is a pleiotropic immune-neuroendocrine hormone with multiple immunomodulatory functions mainly related to reproduction. However, the biological role of PRL at the maternal-fetal interface has yet to be fully elucidated. In this review, we have summarized the current information on the multiple effects of PRL, focusing on its immunological effects and biological significance for the immune privilege of the maternal-fetal interface.
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Decidua , Prolactina , Embarazo , Femenino , Humanos , Placenta , Membranas Extraembrionarias , Líquido AmnióticoRESUMEN
One of the most challenging aspects of long-term research based on microorganisms is the maintenance of isolates under ex situ conditions, particularly the conservation of phytopathological characteristics. Our research group has worked for more than 10 years with Gaumannomyces graminis var. tritici (Ggt), the main biotic factor affecting wheat. In this sense we preserved the microorganisms in oil overlaid. However, several strains preserved for a long time lost their pathogenicity. These strains show white and non-infective mycelia. In this sense, we hypothesized that this is attributable to low melanin content. Melanin is a natural pigment mainly involved in UV protection, desiccation, salinity, oxidation, and fungal pathogenicity. Therefore, understanding the melanin role on Ggt pathogenicity is fundamental to developing melanin activation strategies under laboratory studies. In this study, we induce melanin activation by UV-A light chamber, 320 to 400 nm (T1) and temperature changes of 30 °C, 15 °C, and 20 °C (T2). Fungal pathogenicity was evaluated by determination of blackening roots and Ggt was quantified by real-time PCR in inoculated wheat plants. Results revealed that Ggt grown under UV-A (T1) conditions showed around 40% higher melanin level with a concomitant effect on root infection (98% of blackened roots) and 4-fold more Ggt genome copy number compared with the control (non-infective mycelia) being T1, a more inductor factor compared with T2. These findings would support the role of melanin in pathogenicity in darkly pigmented fungi such as Ggt and could serve as a basis for activating pathogenicity under laboratory conditions.
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OBJECTIVE: To assess the association of diabetes and mental, behavioral, and developmental disorders in youth, we examined the magnitude of overlap between these disorders in children and adolescents. STUDY DESIGN: In this cross-sectional study, we calculated prevalence estimates using the 2016-2019 National Survey of Children's Health. Parents reported whether their child was currently diagnosed with diabetes or with any of the following mental, behavioral, or developmental disorders: attention-deficit/hyperactivity disorder, autism spectrum disorder, learning disability, intellectual disability, developmental delay, anxiety, depression, behavioral problems, Tourette syndrome, or speech/language disorder. We present crude prevalence estimates weighted to be representative of the US child population and adjusted prevalence ratios (aPRs) adjusted for age, sex, and race/ethnicity. RESULTS: Among children and adolescents (aged 2-17 years; n = 121â312), prevalence of mental, behavioral, and developmental disorders varied by diabetes status (diabetes: 39.9% [30.2-50.4]; no diabetes: 20.3% [19.8-20.8]). Compared with children and adolescents without diabetes, those with diabetes had a nearly 2-fold higher prevalence of mental, behavioral, and developmental disorders (aPR: 1.72 [1.31-2.27]); mental, emotional, and behavioral disorders (aPR: 1.90 [1.38-2.61]) and developmental, learning, and language disorders (aPR: 1.89 [1.35-2.66]). CONCLUSIONS: These results suggest that approximately 2 in 5 children and adolescents with diabetes have a mental, behavioral, or developmental disorder. Understanding potential causal pathways may ultimately lead to future preventative strategies for mental, behavioral, and developmental disorders and diabetes in children and adolescents.
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Discapacidades del Desarrollo , Diabetes Mellitus , Trastornos Mentales , Humanos , Masculino , Femenino , Niño , Trastornos Mentales/epidemiología , Discapacidades del Desarrollo/epidemiología , Prevalencia , Diabetes Mellitus/epidemiología , Trastorno del Espectro Autista , Discapacidades para el Aprendizaje , Estudios Transversales , Adolescente , Estados Unidos/epidemiologíaRESUMEN
Glutamate is one of the most abundant amino acids in the blood. Besides its role as a neurotransmitter in the brain, it is a key substrate in several metabolic pathways and a primary messenger that acts through its receptors outside the central nervous system (CNS). The two main types of glutamate receptors, ionotropic and metabotropic, are well characterized in CNS and have been recently analyzed for their roles in non-neural organs. Glutamate receptor expression may be particularly important for tumor growth in organs with high concentrations of glutamate and might also influence the propensity of such tumors to set metastases in glutamate-rich organs, such as the liver. The study of glutamate transporters has also acquired relevance in the physiology and pathologies outside the CNS, especially in the field of cancer research. In this review, we address the recent findings about the expression of glutamatergic system components, such as receptors and transporters, their role in the physiology and pathology of cancer in non-neural organs, and their possible use as biomarkers and therapeutic targets.
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Neoplasias , Humanos , Biomarcadores , Glutamatos , Sistema Nervioso Central , AminoácidosRESUMEN
Gaeumannomyces graminis var. tritici is a soilborne pathogen that causes "take-all" disease, affecting cereal roots. In wheat, G. graminis var. tritici is the most important biotic factor, causing around 30 to 50% losses of yield. Chemical control of this fungal disease is difficult because G. graminis var. tritici is able to reside for a long time in soils. Therefore, the development of environmentally friendly biotechnological strategies to diminish the incidence of soilborne diseases is highly desirable. Natural products are a promising strategy for biocontrol of plant pathogens. A special emphasis is on medicinal plants due to their reported fungitoxic effects. Drimys winteri (canelo) is a medicinal plant that is widely used by the Mapuche ethnic group from Chile due to its anti-inflammatory activity. In addition, inhibitory effects of canelo against phytopathogenic fungi and pest insects have been reported. In this study, we isolated, purified, and identified six drimane sesquiterpenoid compounds from canelo (drimenin, drimenol, polygodial, isodrimeninol, valdiviolide, and drimendiol). Then, we evaluated their antimicrobial effects against G. graminis var. tritici. Compounds were identified by comparing Fourier-transform infrared spectroscopy (FTIR) data and the retention time in thin-layer chromatography (TLC) with those of pure standards. The putative antagonistic effects were confirmed by assessing hyphal cell wall damage using confocal microscopy and lipid peroxidation. Here, we reported the high potential of drimane sesquiterpenoids as natural antifungals against G. graminis var. tritici. Polygodial and isodrimeninol were the most effective, with 50% lethal concentrations (LC50s) between 7 and 10 µg ml-1 and higher levels of fungal lipid peroxidation seen. Accordingly, natural sesquiterpenoids purified from canelo are biologically active against G. graminis var. tritici and could be used as natural biofungicides for sustainable agriculture.IMPORTANCE More than two billion tons of pesticides are used every year worldwide. An interesting sustainable alternative to control plant pathogens is the use of natural products obtained from plants, mainly medicinal plants that offer secondary metabolites important to human/animal health. In this study, we isolated and identified six pure drimane sesquiterpenoids obtained from the bark of Drimys winteri Additionally, we evaluated their antifungal activities against Gaeumannomyces graminis (the main biotic factor affecting cereal production, especially wheat) by assessing fungal cell wall damage and lipid peroxidation. The compounds obtained showed important antifungal properties against G. graminis var. tritici, mainly isodrimenol, which was the second-most-active compound after polygodial, with an LC50 against G. graminis var. tritici of around 9.5 µg ml-1 This information could be useful for the development of new natural or hemisynthetic antifungal agents against soilborne phytopathogens that could be used in green agriculture.
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Antifúngicos/farmacología , Ascomicetos/efectos de los fármacos , Drimys/química , Corteza de la Planta/química , Sesquiterpenos/farmacología , Pared Celular/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Sesquiterpenos Policíclicos/farmacologíaRESUMEN
Human lead (Pb) exposure induces many adverse health effects, including some related to lead accumulation in organs. Although lead bio-distribution in the body has been described, the molecular mechanism underlying distribution and excretion is not well understood. The transport of essential and toxic metals is principally mediated by proteins. How lead affects the expression of metal transporter proteins in the principal metal excretory organs, i.e., the liver and kidney, is unknown. Considering that co-administration of melatonin and lead reduces the toxic effects of lead and lead levels in the blood in vivo, we examined how lead and co-administration of lead and melatonin affect the gene and protein expression of metal transporter proteins (ZIP8, ZIP14, CTR1 and DMT1) in these organs. Rats were exposed intraperitoneally to lead or lead-melatonin. Our results show that Pb exposure induces changes in the protein and gene expression of ZIP8, ZIP14 and CTR1. Alterations in the copper/zinc ratio found in the blood, liver and kidney were likely related to these changes. With DMT1 expression (gene and protein), a positive correlation was found with lead levels in the kidney. Co-administration of melatonin and lead reduced lead-induced DMT1 expression through an unknown mechanism. This effect of melatonin relates to reduced lead levels in the blood and kidney. The metal transport protein function and our results suggest that DMT1 likely contributes to lead accumulation in organs. These data further elucidate the effects of lead on Cu and Zn and the molecular mechanism underlying lead bio-distribution in animals.
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Proteínas Portadoras/biosíntesis , Proteínas Portadoras/genética , Cobre/análisis , Regulación de la Expresión Génica/efectos de los fármacos , Plomo/farmacología , Melatonina/farmacología , Zinc/análisis , Animales , Proteínas Portadoras/metabolismo , Plomo/análisis , Masculino , Espectrometría de Masas , Melatonina/análisis , Ratas , Ratas WistarRESUMEN
Physiological activity in healthy conditions requires a coordinated interaction between the molecular circadian clock and the network of biochemical pathways. An important metabolic parameter in the interface between these two entities is the redox state. Among the redox coenzymes that regulate the fluxes of enzymatic reactions is the NADP+/NADPH pair. Indeed, the main biosynthetic pathways need NADPH to serve as an electron donor for cellular anabolic transformations. The existence of a metabolic circadian clock is well established, and it was first identified in mammalian red blood cells. The metabolic circadian clock is independent of transcriptional activity and is sustained by the enzymatic complex peroxiredoxin/thioredoxin/NADPH. This complex shows 24-h redox fluctuations metabolizing H2O2 in various tissues and species (fungi, insects, and mammals). Although this NADPH-sensitive metabolic clock is autonomous in erythrocytes that lack a nucleus, it functions in concert with the transcriptional circadian clock in other cell types to accomplish the task of timing cellular physiology. During carcinogenesis, circadian alterations influence cell cycle onset and promote tumoral growth. These alterations also deregulate cellular energetics through a process known as aerobic glycolysis, or the Warburg effect. The Warburg effect is a typical response of cancer cells in which the metabolism turns into glycolysis even in the presence of functional mitochondria. This alteration has been interpreted as a cellular strategy to increase biomass during cancer, and one of its main factors is the availability of NADPH. This minireview explores the potential role of NADPH as a circadian and cancer-promoting metabolite.
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BACKGROUND: little is known on the influences of normal menstrual cycle on prolactin gene expression in immune cells. AIM OF THE STUDY: to determine the effects of the ovarian cycle on prolactin and its receptor expression. METHODS: peripheral blood mononuclear cells (PBMC) were obtained from twenty-six normal menstruating women at different intervals of their menstrual cycle. The PBMC were incubated during 24 h in the presence or absence of Concanavalin-A (Con-A) and the gene expression of PRL, PRLR and cytokines was evaluated by qPCR. Prolactin, IL-2 and cAMP were determined in each culture by specific immunoassays. RESULTS: neither PRL nor its receptor expression in PBMC changed significantly among groups, including the cytokines (IL-2, IL-10, and IFNG) studied. Similar results, among groups, were obtained, when PRL expression was stimulated by PGE2 or 8-Br-cAMP. Concanavalin A-stimulated PBMC expressed significantly less prolactin and a significant negative correlation between secreted IL-2 and PRL expression was found. The presence of anti-IL-2 antibodies in Con-A stimulated-cultures significantly increased PRL expression when compared to control cells regardless the hormonal status. CONCLUSIONS: these data suggest that the menstrual cycle does not significantly modulate or influence prolactin and cytokines gene expression in PBMC, and indicate that IL-2 may be involved in the Con-A regulation of PRL expression in immune cells.
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Concanavalina A/metabolismo , Citocinas/metabolismo , Expresión Génica/fisiología , Leucocitos Mononucleares/metabolismo , Ciclo Menstrual/metabolismo , Receptores de Prolactina/metabolismo , Adulto , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Femenino , Humanos , Interferón gamma/metabolismo , Interleucina-10/metabolismo , Interleucina-2/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Adulto JovenRESUMEN
BACKGROUND: Food allergy is deemed to have a worldwide prevalence ranging from 2 to 10 %. OBJECTIVE: To determine the frequency of skin reactivity to food allergens by age groups. METHODS: Cross-sectional, descriptive, prolective, observational study. Patients aged from 2 to 64 years with symptoms consistent with allergic disease were included. Skin prick tests were carried out with food allergens. Frequencies and percentages were estimated. RESULTS: One-hundred and ninety-one patients were included, out of which 63.4% were females. Mean age was 22.5 years; 19.3 % showed positive skin reactivity to at least one food. Distribution by age group was as follows: preschool children 13.5 %, schoolchildren 24.3 %, adolescents 2.7 % and adults 59.5 %. Diagnoses included allergic rhinitis in 84.3 %, asthma in 19.4 %, urticaria in 14.1 % and atopic dermatitis in 8.4 %. Positive skin reactivity frequency distribution in descending order was: soybeans with 5.2 %, peach with 4.7 %, grapes, orange and apple with 3.6 %, nuts with 3.1 %, pineapple, avocado, tomato and tuna with 2.6 %. CONCLUSION: The frequency of skin reactivity to food allergens was similar to that reported in the national and Latin American literature, but sensitization to each specific allergen varied for each age group.
Antecedentes: Se considera que la alergia alimentaria tiene una prevalencia mundial de 2 a 10 %. Objetivo: Determinar la frecuencia de reactividad cutánea hacia alérgenos alimentarios por grupos de edad. Métodos: Estudio observacional, descriptivo, transversal y prolectivo. Se incluyeron pacientes de 2 a 64 años de edad con cuadro compatible de enfermedad alérgica. Se efectuaron pruebas por punción cutánea con alérgenos alimentarios. Se estimaron frecuencias y porcentajes. Resultados: Se incluyeron 191 pacientes, 63.4 % fue del sexo femenino. La edad promedio fue 22.5 años; 19.3 % mostró reactividad cutánea positiva al menos a un alimento. La distribución por grupo etario fue la siguiente: preescolares 13.5 %, escolares 24.3 %, adolescentes 2.7 % y adultos 59.5 %. Los diagnósticos fueron rinitis alérgica 84.3 %, asma 19.4 %, urticaria 14.1 % y dermatitis atópica 8.4 %. La distribución de la frecuencia de reactividad cutánea positiva en orden descendente fue 5.2 % a soya, 4.7 % a durazno, 3.6 % a uva, naranja y manzana, 3.1 % a nuez y 2.6 % a piña, aguacate, tomate y atún. Conclusión: La frecuencia de reactividad cutánea para alérgenos alimentarios fue similar a la informada en la literatura nacional y latinoamericana, pero la sensibilización para cada alérgeno específico varió en cada grupo etario.
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Alérgenos/inmunología , Hipersensibilidad a los Alimentos/etiología , Alimentos/efectos adversos , Pruebas Cutáneas , Adolescente , Adulto , Factores de Edad , Niño , Preescolar , Estudios Transversales , Método Doble Ciego , Femenino , Hipersensibilidad a los Alimentos/inmunología , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Adulto JovenRESUMEN
During pregnancy, prolactin (PRL) is a neuro-immuno-cytokine that contributes actively to the crosstalk between the immune and endocrine systems and, thus, to the creation of an immune-privileged milieu. This work aims to analyze the capacity of PRL to modulate the synthesis and secretion of pro-inflammatory markers associated with labor. Studies were conducted using human fetal membranes at term mounted in a model of two independent chambers. The choriodecidual region was stimulated with 500-ng/mL lipopolysaccharide (LPS), and the amnion and choriodecidual region were co-simulated with different concentrations of PRL that can arise during pregnancy: 250, 500, 1000, and 4000ng/mL. Following these co-treatments, the tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, and IL-10 levels were measured in both compartments. As expected, treatment with LPS induced all cytokines to increase. Co-stimulation with the highest tested concentration of PRL induced significant decreases in TNF-α in the choriodecidual region and IL-1ß in both regions of the fetal membranes. PRL did not modified the IL-6 and IL-10 secretion profile. These findings, coupled with clinical evidence, suggest that the high level of PRL in the amniotic cavity is involved the mechanism by which the fetal-placental unit regulates the equilibrium between pro- and anti-inflammatory modulators.
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Amnios/inmunología , Antiinflamatorios/metabolismo , Decidua/inmunología , Prolactina/metabolismo , Células Cultivadas , Femenino , Humanos , Inmunomodulación , Mediadores de Inflamación/metabolismo , Interleucina-10/metabolismo , Lipopolisacáridos/inmunología , Neuroinmunomodulación , Técnicas de Cultivo de Órganos , Circulación Placentaria , EmbarazoRESUMEN
BACKGROUND: Allergic diseases diagnosis must be based on adequate allergological anamnesis and an immunological sensitization test; the most sensitive and specific is the skin prick test. OBJECTIVE: To determine the frequency of skin reactivity to aeroallergens, by age groups, in patients of the Department of Allergy and Clinical Immunology of the Hospital Universitario de Puebla, in Mexico. METHODS: A cross-sectional study was conducted that included patients aged 2 to 64 years with symptoms suggestive of allergic disease, in which skin prick tests with aeroallergens were performed; the diagnostic criteria were those of international guidelines. Frequencies, percentages and dispersion measures were calculated. RESULTS: Of 173 patients, 63 % were females. Mean age was 22.3 years. The frequency of skin reactivity for Quercus sp. was 12.72 %, for Periplaneta americana, 9.83 %, for Dermatophagoides farinae, 9.25 %, for Cynodon dactylon, 8.09 %, for Blatella germanica, 8.09 %, for Holcus halepensis, 6.94 %, for Dermatophagoides pteronyssinus, 6.36 %, for Schinus molle, 5.78 %, for Fraxinus uhdei, 5.20 %, for Lolium perenne, 5.20 %, for Ambrosia eliator, 5.20 % and for Artemisa tridentata, 4.62 %. CONCLUSION: Although Dermatophagoides are the most frequently reported aeroallergens, the most common aeroallergen in this study was pollen, probably owing to geographical and environmental factors, although this was not observed in the analysis by age groups.
Antecedentes: El diagnóstico de las enfermedades alérgicas debe basarse en la historia clínica alergológica adecuada y en una prueba inmunológica de sensibilización; la de mayor sensibilidad y especificidad es la prueba cutánea por punción. Objetivo: Determinar la frecuencia de la reactividad cutánea hacia aeroalérgenos, por grupos etarios, en pacientes del Servicio de Alergia e Inmunología Clínica del Hospital Universitario de Puebla, México. Métodos: Se realizó estudio transversal que incluyó a pacientes de 2 a 64 años de edad, con síntomas sugestivos de enfermedad alérgica, en quienes se realizaron pruebas cutáneas con aeroalérgenos; los criterios diagnósticos fueron los de las guías internacionales. Se calcularon frecuencias, porcentajes y medidas de dispersión. Resultados: De 173 pacientes, 63 % fue del sexo femenino. La edad media fue de 22.3 años. La frecuencia de la reactividad cutánea para Quercus sp. fue 12.72 %, Periplaneta americana 9.83 %, Dermatophagoides farinae 9.25 %, Cynodon dactylon 8.09 %, Blatella germanica 8.09 %, Holcus halepensis 6.94 %, Dermatophagoides pteronyssinus 6.36 %, Schinus molle 5.78 %, Fraxinus uhdei 5.20 %, Lolium perenne 5.20 %, Ambrosia eliator 5.20 % y Artemisa tridentata 4.62 %. Conclusión: Los Dermatophagoides son los aeroalérgenos más identificados, pero en el presente estudio fue más común un polen, probablemente debido a factores geográficos-medioambientales, aunque no fue así en el análisis por grupos etarios.
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Alérgenos/inmunología , Hipersensibilidad/diagnóstico , Pruebas Cutáneas , Adolescente , Adulto , Factores de Edad , Antígenos Dermatofagoides/inmunología , Niño , Preescolar , Estudios Transversales , Femenino , Humanos , Hipersensibilidad/inmunología , Masculino , Persona de Mediana Edad , Polen/inmunología , Evaluación de Síntomas , Adulto JovenRESUMEN
Rhythms of approximately 24 h are pervasive in most organisms and are known as circadian. There is a molecular circadian clock in each cell sustained by a feedback system of interconnected "clock" genes and transcription factors. In mammals, the timing system is formed by a central pacemaker, the suprachiasmatic nucleus, in coordination with a collection of peripheral oscillators. Recently, an extensive interconnection has been recognized between the molecular circadian clock and the set of biochemical pathways that underlie the bioenergetics of the cell. A principle regulator of metabolic networks is the flow of electrons between electron donors and acceptors. The concomitant reduction and oxidation (redox) reactions directly influence the balance between anabolic and catabolic processes. This review summarizes and discusses recent findings concerning the mutual and dynamic interactions between the molecular circadian clock, redox reactions, and redox signaling. The scope includes the regulatory role played by redox coenzymes (NAD(P)+/NAD(P)H, GSH/GSSG), reactive oxygen species (superoxide anion, hydrogen peroxide), antioxidants (melatonin), and physiological events that modulate the redox state (feeding condition, circadian rhythms) in determining the timing capacity of the molecular circadian clock. In addition, we discuss a purely metabolic circadian clock, which is based on the redox enzymes known as peroxiredoxins and is present in mammalian red blood cells and in other biological systems. Both the timing system and the metabolic network are key to a better understanding of widespread pathological conditions such as the metabolic syndrome, obesity, and diabetes.
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Relojes Circadianos/fisiología , Ritmo Circadiano/fisiología , Transducción de Señal/fisiología , Animales , Disulfuro de Glutatión/metabolismo , Humanos , NADP/metabolismo , Oxidación-Reducción , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Besides its classical biological effects on calcium and phosphorus homeostasis, calcitriol, the active vitamin D metabolite, has a broad variety of actions including anticancer effects that are mediated either transcriptionally and/or via non-genomic pathways. In the context of cancer, calcitriol regulates the cell cycle, induces apoptosis, promotes cell differentiation and acts as anti-inflammatory factor within the tumor microenvironment. In this review, we address the different mechanisms of action involved in the antineoplastic effects of calcitriol.
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Antineoplásicos/farmacología , Calcitriol/farmacología , Neoplasias/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , HumanosRESUMEN
Daytime restricted feeding (DRF) is an experimental protocol that influences the circadian timing system and underlies the expression of a biological clock known as the food entrained oscillator (FEO). Liver is the organ that reacts most rapidly to food restriction by adjusting the functional relationship between the molecular circadian clock and the metabolic networks. γ-Aminobutyric acid (GABA) is a signaling molecule in the liver, and able to modulate the cell cycle and apoptosis. This study was aimed at characterizing the expression and activity of the mostly mitochondrial enzyme GABA transaminase (GABA-T) during DRF/FEO expression. We found that DRF promotes a sustained increase of GABA-T in the liver homogenate and mitochondrial fraction throughout the entire day-night cycle. The higher amount of GABA-T promoted by DRF was not associated to changes in GABA-T mRNA or GABA-T activity. The GABA-T activity in the mitochondrial fraction even tended to decrease during the light period. We concluded that DRF influences the daily variations of GABA-T mRNA levels, stability, and catalytic activity of GABA-T. These data suggest that the liver GABAergic system responds to a metabolic challenge such as DRF and the concomitant appearance of the FEO.
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4-Aminobutirato Transaminasa/metabolismo , Restricción Calórica , Ritmo Circadiano , Hígado/enzimología , 4-Aminobutirato Transaminasa/genética , Animales , Western Blotting , Regulación Enzimológica de la Expresión Génica , Masculino , Mitocondrias/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas Wistar , Fracciones Subcelulares/metabolismo , Ácido gamma-AminobutíricoRESUMEN
The hormone prolactin (PRL) regulates neuroendocrine and emotional stress responses. It is found in the hypothalamus, where the protein is partially cleaved to vasoinhibins, a family of N-terminal antiangiogenic PRL fragments ranging from 14 to 18kDa molecular masses, with unknown effects on the stress response. Here, we show that the intracerebroventricular administration of a recombinant vasoinhibin, containing the first 123 amino acids of human PRL that correspond to a 14kDa PRL, exerts anxiogenic and depressive-like effects detected in the elevated plus-maze, the open field, and the forced swimming tests. To investigate whether stressor exposure affects the generation of vasoinhibins in the hypothalamus, the concentrations of PRL mRNA, PRL, and vasoinhibins were evaluated in hypothalamic extracts of virgin female rats immobilized for 30min at different time points after stress onset. The hypothalamic levels of PRL mRNA and protein were higher at 60min but declined at 360min to levels seen in non-stressed animals. The elevation of hypothalamic PRL did not correlate with the stress-induced increase in circulating PRL levels, nor was it modified by blocking adenohypophyseal PRL secretion with bromocriptine. A vasoinhibin having an electrophoretic migration rate corresponding to 17kDa was detected in the hypothalamus. Despite the elevation in hypothalamic PRL, the levels of this hypothalamic vasoinhibin were similar in stressed and non-stressed rats. Stress reduced the rate of cleavage of PRL to this vasoinhibin as shown by the incubation of recombinant PRL with hypothalamic extracts from stressed rats. These results suggest that vasoinhibins are potent anxiogenic and depressive factors and that stress increases PRL levels in the hypothalamus partly by reducing its conversion to vasoinhibins. The reciprocal interplay between PRL and vasoinhibins may represent an effective mechanism to regulate anxiety and depression.
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Conducta Animal/efectos de los fármacos , Proteínas de Ciclo Celular/farmacología , Hipotálamo/metabolismo , Prolactina/metabolismo , Animales , Ansiedad/metabolismo , Conducta Animal/fisiología , Depresión/metabolismo , Femenino , Ratas , Ratas WistarRESUMEN
Calcitriol, the hormonal form of vitamin D(3), exerts immunomodulatory effects through the vitamin D(3) receptor (VDR) and increases prolactin (PRL) expression in the pituitary and decidua. Nevertheless, the effects of calcitriol upon lymphocyte PRL have not been evaluated. Therefore, we investigated calcitriol effects upon PRL in resting and phytohemagglutinin-activated human peripheral blood mononuclear cells (PBMNC) and Jurkat T lymphoma cells. Immunoblots showed constitutive expression of the 50-kDa VDR species in activated PBMNC and Jurkat cells, while a 75-kDa species was recognized in both resting and activated-PBMNC. Only in resting PBMNC calcitriol significantly stimulated PRL expression in a dose-dependent manner. The positive control CYP24A1, a highly VDR-responsive gene, was stimulated by calcitriol, effect that was stronger in resting than in activated-PBMNC (P<0.05), and without effect in Jurkat cells. Calcitriol upregulation of PRL and CYP24A1 was significantly inhibited by the VDR antagonist TEI-9647. EMSA showed that resting PBMNC contain a protein that binds to DR3-type VDRE. Cell activation reduced basal CYP24A1 while induced CYP27B1, VDR and pregnane X receptor (PXR) expression. In summary, calcitriol stimulated PRL and CYP24A1 gene expression in quiescent lymphocytes through a VDR-mediated mechanism. Our results suggest that the 75-kDa VDR species could be participating in calcitriol-mediated effects, and that activation induces factors such as PXR that restrain VDR transcriptional processes. This study supports the presence of a functional VDR in quiescent lymphocytes, providing evidence to reevaluate the VDR paradigm that assumes that lymphocytes respond to calcitriol only after activation. Altogether, our results offer new insights into the mechanisms whereby PRL is regulated in immune cells.
Asunto(s)
Calcitriol/fisiología , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/fisiología , Prolactina/metabolismo , Adulto , Animales , Calcitriol/farmacología , Expresión Génica/efectos de los fármacos , Humanos , Leucocitos Mononucleares/citología , Masculino , Receptor X de Pregnano , Prolactina/genética , Receptores de Calcitriol/metabolismo , Receptores de Esteroides/genética , Receptores de Esteroides/metabolismo , Esteroide Hidroxilasas/genética , Esteroide Hidroxilasas/metabolismo , Vitamina D3 24-Hidroxilasa , Vitaminas/farmacologíaRESUMEN
Human placenta synthesizes and metabolizes 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)/calcitriol] through the activity of 25-hydroxyvitamin D(3)-1alpha-hydroxylase (CYP27B1) and 1,25(OH)(2)D(3)-24-hydroxylase (CYP24A1), the two key enzymes for Vitamin D metabolism. In this study, calcitriol rapidly generated intracellular cAMP accumulation in cultured human syncytiotrophoblast cells, which in turn enhanced hCG secretion, a marker of trophoblast endocrine activity. The effects of 1,25(OH)(2)D(3) upon the expression of CYP27B1 and CYP24A1 were also investigated. 1,25(OH)(2)D(3) and activators of the PKA signaling system decreased the expression of CYP27B1, whereas increased CYP24A1 gene transcription. The use of a selective inhibitor of PKA (H-89) prevented the effects of calcitriol on CYP27B1 gene and hCG secretion, but not on CYP24A1 transcription. Addition of ZK 159222, a Vitamin D receptor (VDR) antagonist, blocked the calcitriol-mediated upregulation of 24-hydroxylase gene expression but did not affect calcitriol-induced downregulation of CYP27B1 gene or hCG stimulation. In addition, our study also demonstrated a role of calcitonin on Vitamin D hydroxylases gene regulation in placenta. The overall data suggest that calcitriol downregulates CYP27B1 expression via a cAMP-dependent signaling pathway, whereas upregulates 24-hydroxylase gene expression through a VDR-dependent mechanism.
Asunto(s)
25-Hidroxivitamina D3 1-alfa-Hidroxilasa/metabolismo , Calcitriol/farmacología , AMP Cíclico/fisiología , Regulación Enzimológica de la Expresión Génica , Trofoblastos/enzimología , 8-Bromo Monofosfato de Adenosina Cíclica/farmacología , Células Cultivadas , AMP Cíclico/metabolismo , Humanos , Placenta/enzimología , Receptores de Calcitriol , Esteroide Hidroxilasas/metabolismo , Trofoblastos/fisiología , Vitamina D3 24-Hidroxilasa , Vitaminas/farmacologíaRESUMEN
Prolactin (PRL) is a 23 kDa protein hormone that is produced and secreted by the pituitary lactotrophs. Although PRL was initially regarded as an exclusive pituitary hormone, many nonpituitary tissues were later found to contain and produce this hormone. The most established extrapituitary sites that produce PRL are the decidua, the immune system, brain and endometrium. In the immune system, PRL acts as a cytokine where it plays an important role in human immune responses, including in autoimmune diseases. Here, we will discuss the regulation of PRL gene expression in human lymphocytes and review the functions of PRL made by the immune cells, including its involvement in autoimmunity.