RESUMEN
Research suggests that both tuberculosis (TB) and type 2 diabetes mellitus (T2DM) have an immuno-endocrine imbalance characterized by dysregulated proinflammatory molecules and hormone levels (high cortisol/DHEA ratio), impeding an effective immune response against Mycobacterium tuberculosis (Mtb) driven by cytokines, antimicrobial peptides (AMPs), and androgens like DHEA. Insulin, sulfonylurea derivatives, and metformin are commonly used glucose-lowering drugs in patients suffering from TB and T2DM. For this comorbidity, metformin is an attractive target to restore the immunoendocrine mechanisms dysregulated against Mtb. This study aimed to assess whether metformin influences cortisol and DHEA synthesis in adrenal cells and if these hormones influence the expression of proinflammatory cytokines and AMPs in Mtb-infected macrophages. Our results suggest that metformin may enhance DHEA synthesis while maintaining cortisol homeostasis. In addition, supernatants from metformin-treated adrenal cells decreased mycobacterial loads in macrophages, which related to rising proinflammatory cytokines and AMP expression (HBD-2 and 3). Intriguingly, we find that HBD-3 and LL-37 can modulate steroid synthesis in adrenal cells with diminished levels of cortisol and DHEA, highlighting the importance of crosstalk communication between adrenal hormones and these effectors of innate immunity. We suggest that metformin's effects can promote innate immunity against Mtb straight or through modulation of corticosteroid hormones.
Asunto(s)
Citocinas , Deshidroepiandrosterona , Hidrocortisona , Macrófagos , Metformina , Mycobacterium tuberculosis , Metformina/farmacología , Humanos , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/microbiología , Macrófagos/inmunología , Mycobacterium tuberculosis/efectos de los fármacos , Hidrocortisona/metabolismo , Deshidroepiandrosterona/farmacología , Citocinas/metabolismo , Inmunidad Innata/efectos de los fármacos , Células THP-1 , Interacciones Huésped-Patógeno , Células Cultivadas , Hipoglucemiantes/farmacología , Glándulas Suprarrenales/metabolismo , Glándulas Suprarrenales/efectos de los fármacos , Glándulas Suprarrenales/microbiología , Mediadores de Inflamación/metabolismoRESUMEN
The dopaminergic system of zebrafish is complex and the numerous pathways and receptors in the central nervous system (CNS) are being extensively studied. A critical factor for the synthesis, activation and release of catecholamines (CAs) is the presence of tyrosine hydroxylase, an enzyme which converts L-tyrosine into levodopa. Levodopa thus is the intermediary in the synthesis of dopamine (DA) and norepinephrine (NE) and promotes its release; therefore, CAs play an important role in the CNS with hormonal functions. Here, we use levodopa/carbidopa to clarify the involvement of the dopaminergic pathway in the stress response in zebrafish submitted to an acute stress challenge. Acute stress was induced by chasing fish with a net for 2 min and assessed by measuring whole-body cortisol levels. Two experiments were carried out, the first with exposure to levodopa/carbidopa and the second with exposure to AMPT and levodopa/carbidopa. Levodopa/carbidopa balances the stress response through its action on the zebrafish hypothalamic-pituitary-adrenal (HPA) axis. Changes in cortisol levels suggest that DA was related to the balance of the stress response and that NE decreased this response. These effects were specific to stress since levodopa/carbidopa did not induce changes in cortisol in non-stressed fish.
Asunto(s)
Glándulas Suprarrenales/efectos de los fármacos , Carbidopa/farmacología , Agonistas de Dopamina/farmacología , Dopamina/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Levodopa/farmacología , Estrés Fisiológico , Pez Cebra/metabolismo , Glándulas Suprarrenales/metabolismo , Animales , Neuronas Dopaminérgicas/metabolismo , Combinación de Medicamentos , Inhibidores Enzimáticos/farmacología , Femenino , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisario/metabolismo , Masculino , Tirosina 3-Monooxigenasa/antagonistas & inhibidores , Tirosina 3-Monooxigenasa/metabolismo , Proteínas de Pez Cebra/antagonistas & inhibidores , Proteínas de Pez Cebra/metabolismo , alfa-Metiltirosina/farmacologíaRESUMEN
SUMMARY: The Viperidae venoms are composed of a mixture of constituents with enzymatic and non-enzymatic actions, which act on ultrastructural components of cells and tissues. Here, the number of mitochondria, mitochondrial area and the number of mitochondrial cristae from adrenal glands cortex treated with snake venoms were tested after 3, 6 and 24 hours of venom injections. The mitochondria quantitative changes showed a statistically significant decrease, in the number of mitochondria past 3, 6 and 24 h. There was an increase in the mitochondrial area after 6 h, where Crotalus vegrandis venom did not present significant differences with Crotalus pifanorum or Bothrops venezuelensis venoms. After 24 h, there was an escalation of mitochondrial area in all tested venoms. The number of mitochondrial cristae after 3 h did not present important differences with the control treatment. After 6 h, the number of mitochondrial cristae initiated to decrease under the activities of the 3 venoms action, until 24 h of observation. In the qualitative observations it was possible to witness an intense damage of the mitochondria, with loss and swelling of membranes, disappearance of cristae and the appearance of myelin figures, which started at 3 h after the Crotalus and Bothrops venoms injections. These damages probably were due to cytotoxic effects of phospholipases, metalloproteases and/or other proteolytic activities present in Viperidae snake venoms, being more evident in Crotalus venoms. As far as we know, these results define a novel finding that suggest that Viperidae snake venoms are extremely toxic to mammalian mitochondria.
RESUMEN: Los venenos de Viperidae tienen acciones enzimáticas y no enzimáticas, que actúan sobre la estructura celular. Aquí se probaron, a las 3, 6 y 24 horas de la inyección del veneno, el número de mitocondrias, el área mitocondrial y el número de crestas mitocondriales de la corteza de las glándulas adrenales. Los cambios cuantitativos de las mitocondrias mostraron una disminución en el número de mitocondrias a las 3, 6 y 24 h. Hubo un aumento en el área mitocondrial a las 6 h, donde el veneno de la serpiente Crotalus vegrandis no presentó diferencias significativas con los venenos de Crotalus pifanorum o Bothrops venezuelensis. Después de 24 h, hubo un aumento del área mitocondrial en todos los venenos. El número de crestas mitocondriales a las 3 h no presentó alteraciones o diferencias importantes con el tratamiento de control. Después de 6 h, el número de crestas mitocondriales comenzó a disminuir bajo la acción de los 3 venenos, hasta las 24 h de observación. En las observaciones cualitativas se observó un daño intenso de las mitocondrias, con pérdida y edema de las membranas, desaparición de las cristae y aparición de figuras mielínicas, que comenzó a las 3 h después de las inyecciones de veneno de Crotalus y Bothrops. Estos daños se debieron factiblemente a los efectos citotóxicos de componentes proteolíticos de los venenos. Creemos que estos resultados definen un nuevo y original hallazgo, que sugiere que los venenos de serpiente Viperidae son extremadamente tóxicos para las mitocondrias de mamíferos.
Asunto(s)
Animales , Ratones , Venenos de Víboras/toxicidad , Viperidae/fisiología , Glándulas Suprarrenales/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Glándulas Suprarrenales/ultraestructura , Crotalus , Bothrops , Mitocondrias/ultraestructuraAsunto(s)
Glándulas Suprarrenales/diagnóstico por imagen , Astenia/diagnóstico por imagen , Diarrea/diagnóstico por imagen , Paracoccidioidomicosis/diagnóstico por imagen , Vómitos/diagnóstico por imagen , Glándulas Suprarrenales/efectos de los fármacos , Glándulas Suprarrenales/microbiología , Glándulas Suprarrenales/patología , Anfotericina B/uso terapéutico , Astenia/tratamiento farmacológico , Astenia/microbiología , Astenia/patología , Diarrea/tratamiento farmacológico , Diarrea/microbiología , Diarrea/patología , Fludrocortisona/uso terapéutico , Humanos , Hidrocortisona/uso terapéutico , Itraconazol/uso terapéutico , Masculino , Persona de Mediana Edad , Paracoccidioides/efectos de los fármacos , Paracoccidioides/crecimiento & desarrollo , Paracoccidioides/patogenicidad , Paracoccidioidomicosis/tratamiento farmacológico , Paracoccidioidomicosis/microbiología , Paracoccidioidomicosis/patología , Tomografía Computarizada por Rayos X , Vómitos/tratamiento farmacológico , Vómitos/microbiología , Vómitos/patologíaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Cyperus rotundus L. (Cyperaceae) is considered one of the most widely distributed plant species in the world, especially in tropical and subtropical regions. In addition, it is commonly used in India, China and Japan in traditional medicine to treat different diseases, including dermatitis and other skin disorders. AIM OF THE STUDY: To investigate the topical anti-inflammatory activity of C. rotundus rhizome ethanolic extract in models of acute and chronic dermatitis. MATERIALS AND METHODS: Phytochemical analysis was carried out using High-performance liquid chromatography-ultraviolet detection (HPLC/UV) to determine the presence of quercetin and chlorogenic acid in C. rotundus extract. Topical anti-inflammmatory effects of C. rotundus extract were evaluated on arachidonic acid (AA) and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin inflammation in mice. Skin biopsies were collected and submitted to histological and enzymatic analysis to evaluate the C. rotundus effect in leukocyte migration into inflamed tissue. Antiproliferative activity of C. rotundus was confirmed by PCNA immunostained cell analysis. Systemic and possible adverse effects of topical treatment with C. rotundus were evaluated by the skin atrophy and same organ weights. In addition, the glucocorticoid receptor (GR) antagonist mifepristone was used to investigate possible GR-mediated mechanisms of action. RESULTS: The phytochemical analysis show that C. rotundus ethanol extract contains 45 µg/g of chlorogenic acid. Topical treatment with C. rotundus extract reduced ear edema and cellular infiltrate in acute and chronic skin inflammation models. Moreover, mice topically treated with C. rotundus exhibited decrease in TPA-induced keratinocyte hyperproliferation. Relevantly, topical treatment with C. rotundus did not caused skin atrophy or changes in lymphoid organ weight. The anti-inflammatory effect of C. rotundus was not influenced by the GR antagonist. CONCLUSION: The results here demonstrate for the first time the topical anti-inflammatory and antiproliferative efficacy of C. rotundus extract, suggesting that the extract could be a potential new therapeutic tool for the treatment of inflammatory skin disorders.
Asunto(s)
Antiinflamatorios/uso terapéutico , Cyperus , Dermatitis por Contacto/tratamiento farmacológico , Extractos Vegetales/uso terapéutico , Glándulas Suprarrenales/efectos de los fármacos , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacología , Ácido Araquidónico , Atrofia/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Edema/tratamiento farmacológico , Edema/metabolismo , Femenino , Irritantes , Queratinocitos/efectos de los fármacos , Ganglios Linfáticos/efectos de los fármacos , Ratones , Fitoquímicos/análisis , Fitoquímicos/uso terapéutico , Fitoterapia , Extractos Vegetales/química , Extractos Vegetales/farmacología , Rizoma , Piel/efectos de los fármacos , Piel/patología , Bazo/efectos de los fármacos , Acetato de Tetradecanoilforbol , Timo/efectos de los fármacosRESUMEN
Microcirculation maintenance is associated with microRNAs. Nevertheless, the role of microRNAs induced by training in preventing dexamethasone (DEX)-induced microvascular rarefaction remains unknown. The study aim was to investigate if training-induced microRNAs are able to improve microcirculation proteins and prevent DEX-induced microvascular rarefaction. Rats underwent training for 8 weeks and then were treated with DEX (50 µg/kg per day, s.c.) for 14 days. Arterial pressure was measured and tibialis anterior (TA) muscle was collected for analyses. DEX induced hypertension concomitantly with capillary density loss (CD, -23.9%) and decrease of VEGF (-43.0%), p-AKT/AKT (-39.6%) and Bcl-2 (-23.0%) and an increase in caspase-3-cleaved protein level (+34.0%) in TA muscle. Training upregulated microRNA-126 expression (+13.1%), prevented VEGF (+61.4%), p-AKT/AKT (+37.7%), Bcl-2 (+7.7%) decrease and caspase-3-cleaved (-23.1%) increase associated with CD (+54.7%) reduction and hypertension prevention. MiRNA-126 upregulation, induced by training, plays a role in controlling microcirculation, which may be a potential target against DEX-induced microvascular rarefaction.
Asunto(s)
Dexametasona/farmacología , MicroARNs/genética , Microcirculación/genética , Condicionamiento Físico Animal , Regulación hacia Arriba/genética , Glándulas Suprarrenales/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Capilares/efectos de los fármacos , Capilares/fisiología , Hemodinámica/efectos de los fármacos , Masculino , MicroARNs/metabolismo , Microcirculación/efectos de los fármacos , Músculo Esquelético/irrigación sanguínea , Tamaño de los Órganos/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas Wistar , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Sensitized stress-induced corticosterone (CORT) secretion in chronically stressed rats involves 5-HT7 receptor activation. The effect of 14-day chronic CORT and vehicle (VEH) administration on 5-HT7 receptor expression in adrenal glands, adrenal 5-HT content, and adrenocorticotropic hormone and CORT secretion was analysed. On day 15, VEH- and CORT-treated animals were perfused or decapitated without stress exposure (0 min) or after 10 and 30 min of restraint for collection of trunk blood and tissues. 5-HT7 receptor-like immunoreactivity (5-HT7R-LI), 5-HT7 receptor protein, and mRNA levels were determined by immunohistochemistry, Western blot, and reverse transcription polymerase chain reaction assays, respectively; 5-HT levels and hormones were quantified using HPLC and ELISA kits, respectively. An undisturbed control group was included for most experimental comparisons. Chronic CORT strongly increased 5-HT7R-LI in the outer adrenal cortex, as well as 5-HT7 receptor protein and mRNA in whole adrenal glands; adrenal 5-HT content also increased in these animals. Decreased adrenocorticotropic hormone and CORT secretion at 30 min of restraint occurred in CORT-treated rats. The results support the notion that chronic stress-induced increase of adrenocortical 5-HT7 receptors and adrenal 5-HT content is a glucocorticoid-dependent phenomenon; the development of magnified stress-induced 5-HT7 receptor-mediated CORT responses in chronically stressed animals nevertheless likely involves additional mechanisms.
Asunto(s)
Glándulas Suprarrenales/efectos de los fármacos , Corticosterona/administración & dosificación , Receptores de Serotonina/metabolismo , Estrés Psicológico/metabolismo , Glándulas Suprarrenales/metabolismo , Hormona Adrenocorticotrópica/análisis , Hormona Adrenocorticotrópica/metabolismo , Animales , Corticosterona/metabolismo , Modelos Animales de Enfermedad , Humanos , Sistema Hipotálamo-Hipofisario/metabolismo , Masculino , Sistema Hipófiso-Suprarrenal/metabolismo , Ratas , Receptores de Serotonina/análisis , Restricción Física/psicología , Serotonina/análisis , Serotonina/metabolismo , Estrés Psicológico/etiología , Estrés Psicológico/psicologíaRESUMEN
INTRODUCTION: Glucocorticoid release by adrenals has been described as significant to survive sepsis. The activation of transient receptor potential vanilloid type 1 (TRPV1) inhibited ACTH-induced glucocorticoid release by adrenal glands in vitro. OBJECTIVE: The aim of this study was to investigate if capsaicin, an activator of TRPV1, would prevent LPS-induced glucocorticoid production by adrenals. METHODS: Male Swiss-Webster mice were treated with capsaicin intraperitoneally (0.2 or 2 mg/kg) 30 min before LPS injection. All analyses were performed 2 h after the LPS stimulation, including plasma corticosterone and peritoneal IL-1ß and TNF-α levels. Furthermore, murine adrenocortical Y1 cells were used to assess the effects of capsaicin on LPS-induced corticosterone production in vitro. RESULTS: Capsaicin (2 mg/kg, i.p.) significantly reduced plasma corticosterone levels and adrenal hypertrophy induced by LPS without alter the levels of pro-steroidogenic cytokines IL-1ß and TNF-α in peritoneal cavity of mice, while the dose of 0.2 mg/kg of capsaicin did not interfere with adrenal steroidogenesis, attested by RIA and ELISA, respectively. Y1 cells express TRPV1, measured by immunofluorescence and western blot, and capsaicin decreased LPS-induced corticosterone production by these cells in vitro. Capsaicin also induces calcium mobilization in Y1 cells in vitro. CONCLUSIONS: These findings suggest that capsaicin inhibits corticosterone production induced by LPS by acting directly on adrenal cells producing glucocorticoids, in a mechanism probably associated with induction of a cytoplasmic calcium increase in these cells.
Asunto(s)
Glándulas Suprarrenales/efectos de los fármacos , Calcio/metabolismo , Capsaicina/farmacología , Glucocorticoides/biosíntesis , Lipopolisacáridos/farmacología , Glándulas Suprarrenales/metabolismo , Animales , Líquido Ascítico/metabolismo , Línea Celular , Corticosterona/biosíntesis , Interleucina-1beta/metabolismo , Masculino , Ratones , Canales Catiónicos TRPV/agonistas , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Chronic stress exposure commonly increases adrenals weight and changes their morphology. This study aimed to compare four methods to delimitate the cortical and medullary layers of adrenals glands in Nelore bulls. Fresh adrenals did not present differentiation between layers. Then, frozen adrenals were distributed in plastics bags with fixative Bouin (G1), 96ºGL ethylic alcohol (G2), 10% formaldehyde (G3), or 2.5% glutaraldehyde (G4). After 12 hours of fixation, the G1 adrenal glands did not show the entire cortical layer marked by Bouin's solution. For G2 and G3 there was a poor contrast, while for G4 there was a reasonable contrast. After 24 hours of fixation, G1 had an excellent contrast between layers, while G2 and G4 had a reasonable contrast and G3 a very bad contrast. After 48 hours it was difficult to differentiate cortical and medullar layers for G1; for Group 2 we get a reasonable contrast; and for G3 the contrast was bad. For G4 the contrast was not as sharp due to the medulla became dark. It was concluded that fixation of adrenals must be done in Bouin's solution for 24 hours to obtain an effective evaluation of the adrenals' morphometry.
Asunto(s)
Ácido Acético/farmacología , Glándulas Suprarrenales/anatomía & histología , Glándulas Suprarrenales/efectos de los fármacos , Etanol/farmacología , Fijadores/farmacología , Formaldehído/farmacología , Glutaral/farmacología , Picratos/farmacología , Animales , BovinosRESUMEN
OBJECTIVES: This study aimed to evaluate the chronic topical anti-inflammatory activity of the pharmaceutical formulation ProHLP containing the hexane fraction of Lacistema pubescens (HLP). It was also investigated the possible cutaneous and systemic adverse effects of HLP and ProHLP in mice when compared to dexamethasone. METHODS: The chronic topical anti-inflammatory activity was determined by croton oil multiple application-induced mouse ear oedema model. Histopathological analyses of ear tissue samples sensitized with croton oil were performed. Cutaneous atrophy induced by HLP and topical glucocorticoid treatments and excision skin wounds model to evidenced possible adverse reactions were also determined. KEY FINDINGS: ProHLP significantly reduced the mice ear oedema and considerably accelerated the wound-healing process. Also, HLP did not lead cutaneous atrophy and preserved the clinical aspect of the thymus, adrenal and spleen, unlike dexamethasone. CONCLUSIONS: The results suggested that ProHLP is an efficient and safer pharmaceutical formulation to treat chronic inflammatory diseases.
Asunto(s)
Antiinflamatorios/administración & dosificación , Dexametasona/administración & dosificación , Modelos Animales de Enfermedad , Edema/tratamiento farmacológico , Extractos Vegetales/administración & dosificación , Administración Tópica , Glándulas Suprarrenales/efectos de los fármacos , Glándulas Suprarrenales/patología , Animales , Antiinflamatorios/efectos adversos , Antiinflamatorios/aislamiento & purificación , Enfermedad Crónica , Dermatitis/tratamiento farmacológico , Dermatitis/patología , Dexametasona/efectos adversos , Edema/patología , Masculino , Ratones , Extractos Vegetales/efectos adversos , Extractos Vegetales/aislamiento & purificación , Timo/efectos de los fármacos , Timo/patología , Resultado del TratamientoRESUMEN
INTRODUCTION: Bisphenol A (BPA) is a well-known endocrine disrupting compound. Although several studies have investigated the effect of BPA exposure and reproductive hormones in humans, results have been inconsistent. OBJECTIVE: To explore the cross-sectional relationship between bisphenol A (BPA) exposure and reproductive hormones/cortisol among peripubertal boys. MATERIAL AND METHODS: Urinary BPA and serum hormones were assessed in 172 boys belonging to the INMA "Environment and Childhood" Granada birth cohort in their follow-up at 9-11years of age. BPA concentrations were quantified by liquid chromatography-mass spectrometry, and levels of serum total testosterone (TT), luteinizing hormone (LH), follicle-stimulating hormone (FSH) and cortisol were measured by electrochemiluminescence immunoassay. RESULT(S): After adjustment for confounders, linear regression models showed that each natural-log unit increase in urinary BPA concentrations was associated with a 19% increase in geometric mean (GM) serum TT levels, and a 16% decrease in GM serum cortisol levels. When urinary BPA concentrations were categorized in tertiles, boys in the 3rd tertile showed 49% higher TT levels and 23% lower cortisol concentrations compared to boys in the 1st tertile. Additionally, urinary BPA concentrations were also significantly associated with higher TT:LH and TT:cortisol ratios, but not with serum LH or FSH levels. CONCLUSION(S): Our results suggest the possible endocrine disrupting potential of BPA during this important period of development. Although action at the testis or pituitary cannot be ruled out, our findings are compatible with a possible involvement of BPA at the adrenal gland, resulting in a differential production of androgens/cortisol. However, given the cross-sectional design of our study, the heterogeneous results reported in the literature, and the scant experimental research on BPA effects at the adrenal gland, the present findings should be interpreted with caution.
Asunto(s)
Compuestos de Bencidrilo/orina , Hormona Folículo Estimulante/sangre , Hidrocortisona/sangre , Hormona Luteinizante/sangre , Fenoles/orina , Testosterona/sangre , Glándulas Suprarrenales/efectos de los fármacos , Niño , Estudios Transversales , Exposición a Riesgos Ambientales/análisis , Humanos , Masculino , EspañaRESUMEN
Neonatal lambs, as with human and other neonates, have low arrhythmic endogenous levels of melatonin for several weeks until they start their own pineal rhythm of melatonin production at approximately 2 weeks of life. During pregnancy, daily rhythmic transfer of maternal melatonin to the fetus has important physiological roles in sheep, nonhuman primates, and rats. This melatonin rhythm provides a circadian signal and also participates in adjusting the physiology of several organs in preparation for extrauterine life. We propose that the ensuing absence of a melatonin rhythm plays a role in neonatal adaptation. To test this hypothesis, we studied the effects of imposing a high-amplitude melatonin rhythm in the newborn lamb on (1) clock time-related changes in cortisol and plasma variables and (2) clock time-related changes of gene expression of clock genes and selected functional genes in the adrenal gland and heart. We treated newborn lambs with a daily oral dose of melatonin (0.25 mg/kg) from birth to 5 days of age, recreating a high-amplitude melatonin rhythm. This treatment suppressed clock time-related changes of plasma adrenocorticotropic hormone, cortisol, clock gene expression, and functional genes in the newborn adrenal gland. In the heart, it decreased heart/body weight ratio, increased expression of Anp and Bnp, and resulted in different heart gene expression from control newborns. The interference of this postnatal melatonin treatment with the normal postnatal pattern of adrenocortical function and heart development support a physiological role for the window of flat postnatal melatonin levels during the neonatal transition.
Asunto(s)
Glándulas Suprarrenales/metabolismo , Ritmo Circadiano/fisiología , Melatonina/sangre , Miocardio/metabolismo , Glándulas Suprarrenales/efectos de los fármacos , Animales , Animales Recién Nacidos , Factor Natriurético Atrial/genética , Factor Natriurético Atrial/metabolismo , Femenino , Expresión Génica/efectos de los fármacos , Corazón/efectos de los fármacos , Corazón/fisiología , Masculino , Melatonina/farmacología , Melatonina/fisiología , Péptido Natriurético Encefálico/genética , Proteínas Circadianas Period/genética , OvinosRESUMEN
OBJECTIVES: Cohabitation with Ehrlich tumor-bearing (ETB) mice induced behavioral, neurochemical, hormonal, and immune effects in the conspecifics as a consequence of stress-induced activation of the sympathetic nervous system (SNS) with catecholamine release. In the current study, the nonspecific ß-AR blocker d,l-propranolol and the specific ß2-AR blocker ICI-118.551 were employed as pharmacological tools to assess the extent to which catecholamines participated in the effects induced by cohabitation with ETB mice. METHODS: Two experiments were performed, 1 with d,l-propranolol treatment and the other with ICI-118.551. One mouse in the experimental group was called the "companion of the sick partner" (CSP) since it was forced to live in the same cage with 2 (experiment 1) or 1 (experiment 2) cage mate that had been i.p. injected with 5 × 106 Ehrlich tumor cells. RESULTS: The d,l-propranolol treatment, but not the ICI-118.551 treatment, attenuated the effects of cohabitation with 2 ETB mice on both open-field behavior and the hypothalamic levels and turnover rate of norepinephrine. The 2 ß-AR blockers were unable to change the serum corticosterone levels and adrenal weights of the CSP mice; however, these drugs abrogated the effects of cohabitation on neutrophil oxidative burst and phagocytosis. Finally, an increase in the 5-HT turnover rate was observed in the olfactory bulb of CSP mice compared to their respective controls, an effect that was not modified by ß-AR blockade. CONCLUSION: These results confirm and strengthen our hypothesis that the SNS is involved in the effects induced by cohabitation with ETB mice and point towards ß2-AR participation in the immune effects analyzed.
Asunto(s)
Adrenérgicos/farmacología , Carcinoma de Ehrlich/inmunología , Carcinoma de Ehrlich/psicología , Relaciones Interpersonales , Glándulas Suprarrenales/efectos de los fármacos , Animales , Carcinoma de Ehrlich/tratamiento farmacológico , Carcinoma de Ehrlich/metabolismo , Catecolaminas/metabolismo , Corticosterona/sangre , Modelos Animales de Enfermedad , Conducta Exploratoria/efectos de los fármacos , Femenino , Citometría de Flujo , Conducta de Enfermedad/efectos de los fármacos , RatonesRESUMEN
The aim of this study was to evaluate the morphometry and the gene expression of Ki-67, VEGF and caspase 3 and the stress oxidative in the adrenal gland of ovariectomized rats treated with estrogen or isoflavones. We used 15 Wistar rats ovariectomized treated with isoflavones or estrogen during 30 days. At the end of the treatment, the left adrenal gland was removed for subsequent histological studies and the right was used to evaluate gene expression of angiogenesis (VEGF-A), cell proliferation (Ki-67), apoptose (caspase 3 clivated) and oxidative stress. Treatment with estrogen showed a largest increase in the layers of the adrenal cortex than with isoflavones. These hypertrofic effects agree with higher expression elevation of Ki67 and VEGF, which did not occur with the caspase 3, indicating that isoflavones have great proliferative effect on the adrenal gland. Similar results were also observed on superoxide quantification show that isoflavone has a protective effect against oxidative stress. Our results indicate positively the trophic therapeutic potential of isoflavones has a protective effect and can contribute to the development of effective therapies to decrease the symptoms of menopause.
Asunto(s)
Glándulas Suprarrenales/efectos de los fármacos , Estrógenos/farmacología , Isoflavonas/farmacología , Animales , Femenino , Menopausia , Ovariectomía , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/farmacología , Ratas , Ratas Wistar , Útero/efectos de los fármacosRESUMEN
We evaluated the effects of air pollution on the adrenal cortex using 30 female mice divided into two groups of fifteen animals each. One group was conditioned daily in a chamber with exposure to particulate matter (PM) 2.5 µm (GExp). Animals were exposed on daily basis in an ambient particles concentrator during the period of time enough to reach an accumulated dose of 600 µg/m3, which corresponds to a 24-h exposure of 25 µg/m3 that approximates to the annual mean of PM2.5 in São Paulo. The other group was allocated to another chamber with filtered air (GCrt). After euthanasia, the adrenals underwent histological processing and immunohistochemistry staining for Ki-67 and cleaved caspase-3. Histomorphometry of the adrenal glands in GExp showed increased thickness of the zona glomerulosa, while in GCrt; the adrenal glands from GExp had higher Ki-67 immunostaining scores in the zona reticularis than those from GCrt. The adrenal from GExp showed higher cleaved caspase-3 immunoreactivity in the zona fasciculata than the unexposed group (GCrt). The homeostasis index indicated higher cell proliferation in the zona glomerulosa and zona reticularis in GExp than in GCrt. Our data indicate that PM2.5 air pollution induces alterations on cell kinetics in mouse adrenal glands.
Asunto(s)
Glándulas Suprarrenales/efectos de los fármacos , Contaminación del Aire/efectos adversos , Material Particulado/efectos adversos , Glándulas Suprarrenales/metabolismo , Glándulas Suprarrenales/patología , Animales , Caspasa 3/metabolismo , Femenino , Homeostasis , Antígeno Ki-67/metabolismo , Ratones Endogámicos BALB CRESUMEN
We investigated arsenite exposure on the reproductive axis of dams (during pregnancy and at cyclicity resumption) and their offspring. Pregnant rats were exposed to 5 (A5) or 50ppm (A50) of sodium arsenite in drinking water from gestational day 1 (GD1) until sacrifice at GD18 or two months postpartum. Offspring were exposed to the same treatment as their mothers from weaning to adulthood. A50-pregnant rats gained less weight, showed increased testosterone and estradiol but pregnancy was unaffected. After lactation, arsenic-exposed dams presented compromised cyclicity, decreased estradiol, increased follicle-stimulating hormone (FSH), less preovulatory follicles and presence of ovarian cysts, suggesting impaired reproduction. A50-offspring presented lower body weight; A50-female-offspring showed elevated gonadotropin releasing hormone (GnRH), FSH and testosterone, while A50-males showed diminished GnRH/FSH, but normal testosterone. We conclude that arsenite at the present exposure levels did not compromise pregnancy outcome while it negatively affected reproductive physiology in postpartum dams and their offspring.
Asunto(s)
Arsenitos/toxicidad , Efectos Tardíos de la Exposición Prenatal , Compuestos de Sodio/toxicidad , Glándulas Suprarrenales/efectos de los fármacos , Glándulas Suprarrenales/metabolismo , Animales , Arsénico/metabolismo , Femenino , Hormonas/metabolismo , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Lactancia , Hígado/metabolismo , Masculino , Intercambio Materno-Fetal , Ovario/efectos de los fármacos , Ovario/metabolismo , Hipófisis/efectos de los fármacos , Hipófisis/metabolismo , Embarazo , Ratas , Ratas Sprague-Dawley , Reproducción/efectos de los fármacos , Maduración Sexual/efectos de los fármacosRESUMEN
Chronic unpredictable mild stress (CUMS) elicits aspects of cognitive and behavioral alterations that can be used to model comparable aspects of depression in humans. The aim of the present study was to investigate the antidepressant-like potential of 7-fluoro-1,3-diphenylisoquinoline-1-amine (FDPI), a novel isoquinoline compound, in CUMS, a model that meets face, construct and predictive criteria for validity. Swiss mice were subjected to different stress paradigms daily for a period of 35 days to induce the depressive-like behavior. The animals received concomitant FDPI (0.1 and 1mg/kg, intragastric) or paroxetine (8mg/kg, intraperitoneal) and CUMS. The behavioral tests (splash test, tail suspension test, modified forced swimming test and locomotor activity) were performed. The levels of cytokines, corticosterone and adrenocorticotropic (ACTH) hormones were determined in the mouse prefrontal cortex and serum. The synaptosomal [(3)H] serotonin (5-HT) uptake, nuclear factor (NF)-κB, tyrosine kinase receptor (TrkB) and pro-brain-derived neurotrophic factor (BDNF) levels were determined in the mouse prefrontal cortex. CUMS induced a depressive-like behavior in mice, which was demonstrated in the modified forced swimming, tail suspension and splash tests. FDPI at both doses prevented depressive-like behavior induced by CUMS, without altering the locomotor activity of mice. FDPI at the highest dose prevented the increase in the levels of NF-kB, pro-inflammatory cytokines, corticosterone and ACTH and modulated [(3)H]5-HT uptake and the proBDNF/TrkB signaling pathway altered by CUMS. The present findings demonstrated that FDPI elicited an antidepressant-like effect in a model of stress-induced depression.
Asunto(s)
Antidepresivos/uso terapéutico , Depresión/tratamiento farmacológico , Depresión/etiología , Quinolinas/uso terapéutico , Estrés Psicológico/complicaciones , Glándulas Suprarrenales/efectos de los fármacos , Animales , Antidepresivos/farmacología , Citocinas/metabolismo , Depresión/metabolismo , Modelos Animales de Enfermedad , Aseo Animal/efectos de los fármacos , Suspensión Trasera/psicología , Hormonas/metabolismo , Locomoción , Masculino , Ratones , Paroxetina/uso terapéutico , Corteza Prefrontal/metabolismo , Corteza Prefrontal/patología , Quinolinas/farmacología , Serotonina/farmacocinética , Natación/psicología , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismo , Tritio/farmacocinéticaRESUMEN
The aim of this study was to evaluate the effects of metoclopramide-induced hyperprolactinemia on the prolactin (PRL) and prolactin receptor's (PRLR) expression in the adrenal. For this purpose, a total of 12 animals with intact ovaries were allocated to two groups: G1 (saline solution) and G2 (metoclopramide). A total of 30 oophorectomized animals was randomized to five subgroups: G3 (saline solution), G4 (metoclopramide), G5 (metoclopramide + 17ß-estradiol), G6 (metoclopramide + progesterone), and G7 (metoclopramide + 17ß-estradiol + progesterone). Immunohistochemical analyses were evaluated semi-quantitatively. For PRLR, the area fraction of labeled cells (ALC) varied from 1 (0-10%) to 3 (> 50%). Based on the mean of the immunostaining intensity, G2 and G4 showed strong expression; G6 and G7 presented a mild reaction; and G1, G3, and G5 exhibited a weak reaction. Concerning PRL, the ALC varied from 1 (0-10%) to 3 (> 50%), and groups G6 and G7 showed a strong reaction; G2, G4, and G5 showed a mild reaction; and G1 and G3 exhibited a weak reaction. These findings suggest that metoclopramide-induced hyperprolactinemia increases PRL expression in the adrenal glands of mice. Furthermore, progesterone alone or in association with estrogen also increases PRL expression, but to a lesser extent.
Asunto(s)
Glándulas Suprarrenales/química , Hiperprolactinemia/inducido químicamente , Metoclopramida/administración & dosificación , Prolactina/análisis , Receptores de Prolactina/análisis , Glándulas Suprarrenales/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Estradiol/administración & dosificación , Estrógenos/sangre , Femenino , Hiperprolactinemia/metabolismo , Inmunohistoquímica , Ratones , Ovariectomía , Progesterona/administración & dosificación , Progesterona/sangre , Prolactina/sangreRESUMEN
Adrenal chromaffin cells (CCs) from spontaneously hypertensive rats (SHRs) secrete more catecholamine (CA) upon stimulation than CCs from normotensive Wistar Kyoto rats (WKY). Unitary CA exocytosis events, both spontaneous and stimulated, were amperometrically recorded from cultured WKY and SHR CCs. Both strains display spontaneous amperometric spikes but SHR CCs produce more spikes and of higher mean amplitude. After a brief stimulation with high K(+) or caffeine which produces voltage-gated Ca(2+) influx or intracellular Ca(2+) release, respectively, more spikes and of greater mean amplitude and unitary charge were recorded in SHR CCs. Consequently, peak cumulative charge was ~2-fold higher in SHR CCs. Ryanodine (10 µM), a specific blocker of the ryanodine receptors reduced depolarization-induced peak cumulative charge by ~10 % in WKY and ~77 % in SHR CCs, suggesting, a larger contribution of Ca(2+)-induced Ca(2+) release to CA exocytosis in SHR CCs. Accordingly, Ca(2+) imaging showed larger [Ca(2+)]i signals induced both by depolarization and caffeine in SHR CCs. Distribution amplitude histograms showed that small amperometric spikes (0-50 pA) are more frequent in WKY than in SHR CCs. Conversely, medium (50-190 pA) and large (190-290 pA) spikes are more numerous in SHR than in WKY CCs. This study reveals that the enhanced CA secretion in SHR CCs results from a combination of (1) larger depolarization-induced Ca(2+) transients, due to a greater Ca(2+)-induced intracellular Ca(2+) release, (2) more exocytosis events per time unit, and (3) a greater proportion of medium and large amperometric spikes probably due to a higher mean CA content per granule. Enhanced CA release by excessive amplification by Ca(2+) induced Ca(2+) release and larger granule catecholamine content contributes to the increased CA plasma levels and vasomotor tone in SHRs.
Asunto(s)
Glándulas Suprarrenales/metabolismo , Señalización del Calcio/efectos de los fármacos , Calcio/metabolismo , Calcio/farmacología , Catecolaminas/metabolismo , Células Cromafines/metabolismo , Glándulas Suprarrenales/efectos de los fármacos , Animales , Presión Sanguínea/efectos de los fármacos , Cafeína/farmacología , Células Cultivadas , Células Cromafines/efectos de los fármacos , Exocitosis , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Inhibidores de Fosfodiesterasa/farmacología , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Rianodina/farmacología , Canal Liberador de Calcio Receptor de Rianodina/efectos de los fármacosRESUMEN
The disruption to glucose homeostasis upon glucocorticoid (GC) treatment in adult male rats has not been fully characterized in older rats or in females. Thus, we evaluated the age- and gender-related changes in glucose homeostasis in GC-treated rats. We injected male and female rats at 3 months and 12 months of age with either dexamethasone (1.0 mg/kg body mass, intraperitoneally) or saline, daily for 5 days. All of the GC-treated rats had decreased body mass and food intake, and adrenal hypotrophy. Increased glycemia was observed in all of the GC-treated groups and only the 3-month-old female rats were not glucose intolerant. Dexamethasone treatment resulted in hyperinsulinemia and hypertriacylglyceridemia in all of the GC-treated rats. The glucose-stimulated insulin secretion (GSIS) was higher in all of the dexamethasone-treated animals, but it was less pronounced in the older animals. The ß-cell mass was increased in the younger male rats treated with dexamethasone. We conclude that dexamethasone treatment induces glucose intolerance in both the 3- and 12-month-old male rats as well as hyperinsulinemia and augmented GSIS. Three-month-old female rats are protected from glucose intolerance caused by GC, whereas 12-month-old female rats developed the same complications that were present in 3- and 12-month-old male rats.