RESUMEN
The study was carried out electrophysiological effects of hydrocortisone for protection on the prelimbic cortex (PrL) neurons in rats, particularly in response to high-frequency stimulation (HFS) of the Caudate-Putamen nuclear complex (CPu) on the models of Parkinson's disease (PD). The study involved 19 rats of the Albino line, each weighing 250 gr. The rats were divided into three experimental groups: intact, rotenone model of Parkinson's disease (PD), and rats with PD but treated with hydrocortisone for protection. Extracellular recording was conducted to measure the impulse activity of single neurons in the prelimbic cortex (PrL) particularly in response to high-frequency stimulation (HFS) of the Caudate-Putamen nuclear complex (CPu) on the models of PD and PD treated with hydrocortisone for protection. In rats with the PD model, there was a decrease in post-stimulus synaptic depressor tetanic effects compared to the norm. This means that the ability of synapses to depress their activity after stimulation was reduced in PD. Conversely, excitatory effects increased in PD rats compared to the norm. This indicates an increase in the excitatory response of neurons in the PD model. When hydrocortisone was applied in PD rats, the frequency of impulse activity dropped sharply, even falling below the levels observed in the normal condition. This indicates that hydrocortisone treatment mitigated the heightened neural activity induced by PD, possibly returning it to a more normal state. Overall, these findings suggest that PD alters synaptic responses and neural activity in the PrL, and hydrocortisone treatment seems to reverse some of these effects.
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Hidrocortisona , Animales , Hidrocortisona/farmacología , Ratas , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/fisiopatología , Sinapsis/efectos de los fármacos , Neuronas/efectos de los fármacos , Modelos Animales de Enfermedad , Masculino , Rotenona/farmacología , Estimulación EléctricaRESUMEN
OBJECTIVE: To investigate the protective effects of Gumibao recipe on glucocorticoid-included bone microcirculatory endothelial cell (BMEC) injury, and elucidate the possible underlying mechanism. METHODS: BMECs were treated with different concentrations of hydrocortisone at different time points, and the viability as well as migration of BMECs were evaluated; furthermore, the release of LDH, levels of VEGF, PAI-1, t-PA, and the content of NO by BMECs have been evaluated by commercially available kits; moreover, the expressions of eNOS, p-PI3K, p-Akt and p-mTOR in BMECs were examined by WB methods. Next, hydrocortisone treated BMECs were co-treated with Gumibao recipe, and the viability, migration and autophagy of BMECs were evaluated. RESULTS: 0.2 mg/ml and 0.3 mg/ml hydrocortisone significantly decreased viability and migration ability of BMECs, and also impeded the endothelial function of BMECs by decreasing the levels of VEGF, t-PA, the content of NO, and increasing the level of PAI-1. Gumibao medicated serum markedly increased the viability and migration of BMECs, and also increased the levels of VEGF, t-PA, the content of NO, meanwhile decreased the level of PAI-1 in 0.3 mg/ml hydrocortisone treated BMECs; moreover, glucocorticoids inhibited the autophagy of BMECs, and Gumibao recipe significantly increased the autophagy of BMECs; meanwhile, autophagy inhibitor 3-MA partially blocked the protective effects of Gumibao recipe. Finally, gumibao recipe partially abrogated the inhibitory effects of hydrocortisone on the activation of PI3K/Akt/mTOR singling, and these effects were further counteracted by PI3K and mTOR inhibitor NVP-BEZ235. CONCLUSIONS: We reported for the first time the protective effects of Gumibao recipe on glucocorticoid-included BMECs injury, and the possible underlying mechanism may be regulating the autophagy of BMECs via PI3K/AKT/mTOR signaling pathway.
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Autofagia , Supervivencia Celular , Medicamentos Herbarios Chinos , Células Endoteliales , Glucocorticoides , Microcirculación , Animales , Células Endoteliales/efectos de los fármacos , Autofagia/efectos de los fármacos , Glucocorticoides/farmacología , Microcirculación/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Movimiento Celular/efectos de los fármacos , Hidrocortisona/farmacología , Masculino , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Huesos/efectos de los fármacos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Inhibidor 1 de Activador Plasminogénico/metabolismo , HumanosRESUMEN
Stress-induced increases in cortisol can stimulate or inhibit brain cell proliferation, but the mechanisms behind these opposing effects are unknown. We tested the hypothesis that 11ß-hydroxysteroid dehydrogenase type 2 (Hsd11b2), a glucocorticoid-inactivating enzyme expressed in neurogenic regions of the adult zebrafish brain, mitigates cortisol-induced changes to brain cell proliferation, using one of three stress regimes: a single 1 min air exposure (acute stress), two air exposures spaced 24â h apart (repeat acute stress) or social subordination (chronic stress). Plasma cortisol was significantly elevated 15â min after air exposure and recovered within 24â h after acute and repeat acute stress, whereas subordinate fish exhibited significant and sustained elevations relative to dominant fish for 24â h. Following acute stress, brain hsd11b2 transcript abundance was elevated up to 6â h after a single air exposure but was unchanged by repeat acute stress or social subordination. A sustained increase in brain Hsd11b2 protein levels occurred after acute stress, but not after repeat or chronic stress. Following acute and repeat acute stress, brain pcna transcript abundance (a marker of cell proliferation) exhibited a prolonged elevation, but was unaffected by social subordination. Interestingly, the number of telencephalic BrdU+ cells increased in fish after a single air exposure but was unchanged by repeat acute stress. Following acute and repeat acute stress, fish expressed lower brain glucocorticoid and mineralocorticoid receptor (gr and mr) transcript abundance while subordinate fish exhibited no changes. Taken together, these results demonstrate stressor-specific regulation of Hsd11b2 in the zebrafish brain that could modulate rates of cortisol catabolism contributing to observed differences in brain cell proliferation.
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11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2 , Encéfalo , Proliferación Celular , Hidrocortisona , Estrés Fisiológico , Pez Cebra , Animales , Pez Cebra/metabolismo , Pez Cebra/fisiología , Hidrocortisona/farmacología , Hidrocortisona/metabolismo , Proliferación Celular/efectos de los fármacos , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/metabolismo , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/genética , Encéfalo/metabolismo , Masculino , Proteínas de Pez Cebra/metabolismo , Proteínas de Pez Cebra/genética , FemeninoRESUMEN
BACKGROUND: An elevated endogenous cortisol level due to the peripartum stress is one of the risk factors of postpartum bovine uterine infections. Selenium is a trace element that elicits anti-inflammation and antioxidation properties. This study aimed to reveal the modulatory effect of selenium on the inflammatory response of primary bovine endometrial stromal cells in the presence of high-level cortisol. The cells were subjected to lipopolysaccharide to establish cellular inflammation. The mRNA expression of toll-like receptor 4 (TLR4), proinflammatory factors, and selenoproteins was measured with qPCR. The activation of NF-κB and MAPK signalling pathways was detected with Western blot and immunofluorescence. RESULTS: The pretreatment with sodium selenite (2 and 4 µΜ) resulted in a down-regulation of TLR4 and genes encoding proinflammatory factors, including interleukin (IL)-1ß, IL-6, IL-8, tumour necrosis factor α, cyclooxygenase 2, and inducible nitric oxide synthase. Selenium inhibited the activation of NF-κB and the phosphorylation of mitogen-activated protein kinase kinase, extracellular signal-regulated kinase, p38MAPK and c-Jun N-terminal kinase/stress-activated protein kinase. The suppression of those genes and pathways by selenium was more significant in the presence of high cortisol level (30 ng/mL). Meanwhile the gene expression of glutathione peroxidase 1 and 4 was promoted by selenium, and was even higher in the presence of cortisol and selenium. CONCLUSIONS: The anti-inflammatory action of selenium is probably mediated through NF-κB and MAPK, and is augmented by cortisol in primary bovine endometrial stromal cells.
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Antiinflamatorios , Endometrio , Hidrocortisona , Selenio , Células del Estroma , Animales , Bovinos , Femenino , Endometrio/efectos de los fármacos , Endometrio/metabolismo , Endometrio/citología , Hidrocortisona/farmacología , Células del Estroma/efectos de los fármacos , Células del Estroma/metabolismo , Selenio/farmacología , Antiinflamatorios/farmacología , FN-kappa B/metabolismo , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 4/genética , Células Cultivadas , Lipopolisacáridos/farmacologíaRESUMEN
The production and release of cortisol during stress responses are key regulators of growth in teleosts. Understanding the molecular responses to cortisol is crucial for the sustainable farming of rainbow trout (Oncorhynchus mykiss) and other salmonid species. While several studies have explored the genomic and non-genomic impacts of cortisol on fish growth and skeletal muscle development, the long-term effects driven by epigenetic mechanisms, such as cortisol-induced DNA methylation, remain unexplored. In this study, we analyzed the transcriptome and genome-wide DNA methylation in the skeletal muscle of rainbow trout seven days after cortisol administration. We identified 550 differentially expressed genes (DEGs) by RNA-seq and 9059 differentially methylated genes (DMGs) via whole-genome bisulfite sequencing (WGBS) analysis. KEGG enrichment analysis showed that cortisol modulates the differential expression of genes associated with nucleotide metabolism, ECM-receptor interaction, and the regulation of actin cytoskeleton pathways. Similarly, cortisol induced the differential methylation of genes associated with focal adhesion, adrenergic signaling in cardiomyocytes, and Wnt signaling. Through integrative analyses, we determined that 126 genes showed a negative correlation between up-regulated expression and down-regulated methylation. KEGG enrichment analysis of these genes indicated participation in ECM-receptor interaction, regulation of actin cytoskeleton, and focal adhesion. Using RT-qPCR, we confirmed the differential expression of lamb3, itga6, limk2, itgb4, capn2, and thbs1. This study revealed for the first time the molecular responses of skeletal muscle to cortisol at the transcriptomic and whole-genome DNA methylation levels in rainbow trout.
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Metilación de ADN , Hidrocortisona , Músculo Esquelético , Oncorhynchus mykiss , Estrés Fisiológico , Transcriptoma , Animales , Oncorhynchus mykiss/genética , Oncorhynchus mykiss/metabolismo , Hidrocortisona/metabolismo , Hidrocortisona/farmacología , Músculo Esquelético/metabolismo , Músculo Esquelético/efectos de los fármacos , Estrés Fisiológico/genética , Epigénesis Genética , Epigenómica/métodos , Perfilación de la Expresión Génica , Proteínas de Peces/genética , Proteínas de Peces/metabolismoRESUMEN
Glucocorticoids (GCs) are widely used as powerful anti-inflammatory and immunosuppressive therapeutics in multiple pathological conditions. However, compelling evidence indicates that they might promote neurodegeneration by altering mitochondrial homeostatic processes. Although the effect of dexamethasone on cell survival and homeostasis has been widely investigated, the effect of other glucocorticoids needs to be explored in more detail. In this report, we have compared the neurotoxicity induced by dexamethasone, prednisolone, betamethasone, and hydrocortisone in cultured neuroblastoma cells, through the analysis of several parameters such as cell viability, ER stress, oxidative stress, and mitochondrial fusion and fission markers. Interestingly, we have found that synthetic glucocorticoids may impact neuronal viability by affecting different cellular responses, suggesting that their therapeutic use should be consciously decided after careful consideration of benefits and detrimental effects.
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Supervivencia Celular , Glucocorticoides , Neuroblastoma , Estrés Oxidativo , Glucocorticoides/farmacología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Neuroblastoma/patología , Línea Celular Tumoral , Humanos , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Estrés del Retículo Endoplásmico/fisiología , Dexametasona/farmacología , Hidrocortisona/farmacología , Prednisolona/farmacología , Betametasona/farmacología , Neuronas/efectos de los fármacos , Neuronas/metabolismoRESUMEN
This is an animal model study to investigate changes in hemostasis during endotoxemic shock and to determine whether the combination of inhaled nitric oxide (iNO) + intravenous hydrocortisone had an effect on clot formation and fibrinolysis. iNO selectively decreases pulmonary artery pressure, without affecting cardiac index or systemic vascular resistance; however, the results of studies on the possible consequences of iNO administration on coagulation are inconsistent and require further research. Thirty-four piglets were included. Administering endotoxin caused severe hypodynamic shock. Half of the animals received iNO (30 ppm) + hydrocortisone, starting 3 h after endotoxin infusion and continuing to the end of the study. All animals developed coagulation disorders, manifested by a tendency to hypocoagulation; at the same time, fibrinolysis was impaired. Coagulation and fibrinolysis disorders persisted after endotoxin infusion was discontinued, with worse severity in the animals that died before the study was terminated. Administering iNO + hydrocortisone did not cause further changes in coagulation and fibrinolysis parameters, either during or after the endotoxin challenge, suggesting that potential therapeutic interventions with iNO to lower pulmonary arterial pressure will not affect hemostasis.
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Coagulación Sanguínea , Modelos Animales de Enfermedad , Fibrinólisis , Hidrocortisona , Óxido Nítrico , Choque Séptico , Tromboelastografía , Animales , Hidrocortisona/administración & dosificación , Hidrocortisona/uso terapéutico , Hidrocortisona/farmacología , Óxido Nítrico/metabolismo , Fibrinólisis/efectos de los fármacos , Porcinos , Coagulación Sanguínea/efectos de los fármacos , Choque Séptico/tratamiento farmacológico , Administración por Inhalación , Endotoxinas/administración & dosificación , Humanos , Trastornos de la Coagulación Sanguínea/tratamiento farmacológicoRESUMEN
The mineralocorticoid receptor (MR, NR3C2) mediates ion and water homeostasis in epithelial cells of the distal nephron and other tissues. Aldosterone, the prototypical mineralocorticoid, regulates electrolyte and fluid balance. Cortisol binds to MR with equal affinity to aldosterone, but many MR-expressing tissues inactivate cortisol to cortisone via 11ß-hydroxysteroid dehydrogenase type 2 (HSD11B2). Dysregulated MR activation contributes to direct cardiovascular tissue insults. Besides aldosterone and cortisol, a variety of MR agonists and/or HSD11B2 inhibitors are putative players in the pathophysiology of low-renin hypertension (LRH), and cardiovascular and metabolic pathology. We developed an in vitro human MR (hMR) model, to facilitate screening for MR agonists, antagonists, and HSD11B2 inhibitors. The CV1 monkey kidney cells were transduced with lentivirus to stably express hMR and an MR-responsive gaussia luciferase gene. Clonal populations of MR-expressing cells (CV1-MRluc) were further transduced to express HSD11B2 (CV1-MRluc-HSD11B2). CV1-MRluc and CV1-MRluc-HSD11B2 cells were treated with aldosterone, cortisol, 11-deoxycorticosterone (DOC), 18-hydroxycorticosterone (18OHB), 18-hydroxycortisol (18OHF), 18-oxocortisol (18oxoF), progesterone, or 17-hydroxyprogesterone (17OHP). In CV1-MRLuc cells, aldosterone and DOC displayed similar potency (EC50: 0.45â¯nM and 0.30â¯nM) and maximal response (31- and 23-fold increase from baseline) on hMR; 18oxoF and 18OHB displayed lower potency (19.6â¯nM and 56.0â¯nM, respectively) but similar maximal hMR activation (25- and 27-fold increase, respectively); cortisol and corticosterone exhibited higher maximal responses (73- and 52-fold, respectively); 18OHF showed no MR activation. Progesterone and 17OHP inhibited aldosterone-mediated MR activation. In the MRluc-HSD11B2 model, the EC50 of cortisol for MR activation increased from 20â¯nM (CV1-MRLuc) to â¼2000â¯nM, while the EC50 for aldosterone remained unchanged. The addition of 18ß-glycyrrhetinic acid (18ß-GA), a HSD11B2 inhibitor, restored the potency of cortisol back to â¼70â¯nM in CV1-hMRLuc-HSD11B2 cells. Together, these two cell models will facilitate the discovery of novel MR-modulators, informing MR-mediated pathophysiology mechanisms and drug development efforts.
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11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2 , Aldosterona , Antagonistas de Receptores de Mineralocorticoides , Receptores de Mineralocorticoides , Receptores de Mineralocorticoides/metabolismo , Receptores de Mineralocorticoides/genética , Receptores de Mineralocorticoides/agonistas , Humanos , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/metabolismo , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/genética , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/antagonistas & inhibidores , Aldosterona/metabolismo , Antagonistas de Receptores de Mineralocorticoides/farmacología , Animales , Hidrocortisona/metabolismo , Hidrocortisona/farmacología , Línea CelularRESUMEN
BACKGROUND: The human stress response is characterized by increases in neuromodulators, including norepinephrine (NE) and cortisol. Both neuromodulators can enter the brain and affect neurofunctional responses. Two brain areas associated with stress are the amygdala and the hippocampus. The precise influence of NE and cortisol on the amygdala and hippocampal resting state functional connectivity (RSFC) is poorly understood. AIMS: To investigate the influence of NE and cortisol on the amygdala and hippocampal RSFC. METHODS: We recruited 165 participants who received 10 mg yohimbine and/or 10 mg hydrocortisone in a randomized, placebo-controlled design. With seed-based analyses, we compared RSFC of the hippocampus and amygdala separately between the three groups that received medication versus placebo. RESULTS: We found no differences between yohimbine and placebo condition or between hydrocortisone and placebo condition regarding amygdala or hippocampal FC. Compared with placebo, the yohimbine/hydrocortisone condition showed increased amygdala and hippocampal RSFC with the cerebellum. Also, they had increased hippocampal RSFC with the amygdala and cerebral white matter. DISCUSSION: The group with elevated NE and cortisol showed significantly increased RSFC between the amygdala, hippocampus, and cerebellum compared to placebo. These three brain areas are involved in associative learning and emotional memory, suggesting a critical role for this network in the human stress response. Our results show that NE and cortisol together may influence the strength of this association. Compared to placebo, we found no differences in the groups receiving only one medication, suggesting that increasing one neuromodulator alone may not induce differences in neurofunctional responses. The study procedure has been registered at clinicaltrials.gov (ID: NCT04359147).
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Amígdala del Cerebelo , Hipocampo , Hidrocortisona , Imagen por Resonancia Magnética , Norepinefrina , Estrés Psicológico , Yohimbina , Humanos , Hipocampo/efectos de los fármacos , Hipocampo/diagnóstico por imagen , Hidrocortisona/metabolismo , Hidrocortisona/farmacología , Masculino , Amígdala del Cerebelo/efectos de los fármacos , Amígdala del Cerebelo/diagnóstico por imagen , Norepinefrina/metabolismo , Yohimbina/farmacología , Adulto , Femenino , Adulto Joven , Estrés Psicológico/fisiopatología , Método Doble CiegoRESUMEN
Hyperthermia along with hydrocortisone (HC) are proven teratogens that can negatively influence embryo development during early pregnancy. Proliferation of cells is one of the main developmental processes during the early embryogenesis. This study was focused on testing the effect of elevated temperature and HC addition on proliferation of cells in in vitro cultures. The V79-4 cell line was treated with HC and cultured in vitro at 37 °C or 39 °C, respectively. To reveal the effect of both factors, the proliferation of cells cultured under different conditions was evaluated using various approaches (colony formation assay, generation of growth curves, computation of doubling times, and mitotic index estimation). Our results indicate that a short-term exposure to elevated temperature slightly stimulates and a long-term exposure suppresses cell proliferation. However, HC (0.1 mg/ml) acts as a stimulator of cell proliferation. Interestingly, the interaction of HC and long-term elevated temperature (39 °C) exposure results in at least partial compensation of the negative impact of elevated temperature by HC addition and in higher proliferation if compared with cells cultured at 39 °C without addition of HC.
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Proliferación Celular , Fibroblastos , Hidrocortisona , Proliferación Celular/efectos de los fármacos , Hidrocortisona/farmacología , Fibroblastos/efectos de los fármacos , Fibroblastos/citología , Fibroblastos/metabolismo , Animales , Células Cultivadas , Temperatura , Cricetulus , CalorRESUMEN
Without the protective shielding of Earth's atmosphere, astronauts face higher doses of ionizing radiation in space, causing serious health concerns. Highly charged and high energy (HZE) particles are particularly effective in causing complex and difficult-to-repair DNA double-strand breaks compared to low linear energy transfer. Additionally, chronic cortisol exposure during spaceflight raises further concerns, although its specific impact on DNA damage and repair remains unknown. This study explorers the effect of different radiation qualities (photons, protons, carbon, and iron ions) on the DNA damage and repair of cortisol-conditioned primary human dermal fibroblasts. Besides, we introduce a new measure, the Foci-Integrated Damage Complexity Score (FIDCS), to assess DNA damage complexity by analyzing focus area and fluorescent intensity. Our results show that the FIDCS captured the DNA damage induced by different radiation qualities better than counting the number of foci, as traditionally done. Besides, using this measure, we were able to identify differences in DNA damage between cortisol-exposed cells and controls. This suggests that, besides measuring the total number of foci, considering the complexity of the DNA damage by means of the FIDCS can provide additional and, in our case, improved information when comparing different radiation qualities.
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Roturas del ADN de Doble Cadena , Reparación del ADN , Fibroblastos , Hidrocortisona , Humanos , Fibroblastos/efectos de la radiación , Fibroblastos/metabolismo , Roturas del ADN de Doble Cadena/efectos de la radiación , Hidrocortisona/farmacología , Radiación Ionizante , Células Cultivadas , Daño del ADNRESUMEN
Increased cortisol levels in the preovulatory follicular fluid suggests a role of glucocorticoid in human ovulation. However, the mechanisms through which cortisol regulates the ovulatory process remain poorly understood. In this study, we examined the upregulation of f5 mRNA by glucocorticoid and its receptor (Gr) in the preovulatory follicles of zebrafish. Our findings demonstrate a significant increase in 11ß-hydroxysteroid dehydrogenase type 2 (hsd11b2), a cortisol response gene, in preovulatory follicles. Additionally, hydrocortisone exerts a dose- and time-dependent upregulation of f5 mRNA in these follicles. Importantly, this stimulatory effect is Gr-dependent, as it was completely abolished in gr-/- mutants. Furthermore, site-directed mutagenesis identified a glucocorticoid response element (GRE) in the promoter of zebrafish f5. Interestingly, successive incubation of hydrocortisone and the native ovulation-inducing steroid, progestin (17α,20ß-dihydroxy-4-pregnen-3-one, DHP), further enhanced f5 expression in preovulatory follicles. Overall, our results indicate that the dramatic increase of f5 expression in preovulatory follicles is partially attributable to the regulation of glucocorticoid and Gr.
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Glucocorticoides , Hidrocortisona , Folículo Ovárico , Receptores de Glucocorticoides , Regulación hacia Arriba , Pez Cebra , Animales , Pez Cebra/genética , Pez Cebra/metabolismo , Folículo Ovárico/metabolismo , Folículo Ovárico/efectos de los fármacos , Femenino , Glucocorticoides/farmacología , Regulación hacia Arriba/efectos de los fármacos , Receptores de Glucocorticoides/metabolismo , Receptores de Glucocorticoides/genética , Hidrocortisona/farmacología , Hidrocortisona/metabolismo , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo , Ovulación/efectos de los fármacos , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/metabolismo , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/genética , Regiones Promotoras GenéticasRESUMEN
INTRODUCTION: Selective attention to salient emotional information can enable an advantage in the face of danger. The present study aims to investigate the influence of the stress neuromodulators, norepinephrine and cortisol, on selective attention processes to fearful faces and its neuronal activation. METHODS AND MATERIALS: We used a randomized, double-blind, placebo-controlled design. 167 healthy men between 18 and 35 years (mean [SD] age: 25.23 [4.24] years) participated in the study. Participants received either: (A) yohimbine (n= 41), (B) hydrocortisone (n = 41), (C) yohimbine and hydrocortisone (n = 42) or (D) placebo only (n= 43) and participated in a dot-probe task with fearful and neutral faces in an fMRI scanner. RESULTS: We found an attentional bias toward fearful faces across all groups and related neuronal activation in the left cuneus. We did not find any differences between experimental treatment groups in selective attention and its neuronal activation. DISCUSSION: Our results provide evidence that fearful faces lead to an attentional bias with related neuronal activation in the left cuneus. We did not replicate formerly reported activation in the amygdala, intraparietal sulcus, dorsal anterior cingulate cortex, and thalamus. Suitability of the dot-probe task for fMRI studies and insignificant treatment effects are discussed.
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Atención , Expresión Facial , Miedo , Hidrocortisona , Imagen por Resonancia Magnética , Yohimbina , Humanos , Masculino , Imagen por Resonancia Magnética/métodos , Adulto , Miedo/efectos de los fármacos , Miedo/fisiología , Hidrocortisona/metabolismo , Hidrocortisona/farmacología , Yohimbina/farmacología , Método Doble Ciego , Adulto Joven , Atención/efectos de los fármacos , Atención/fisiología , Adolescente , Sesgo Atencional/efectos de los fármacos , Sesgo Atencional/fisiología , Reconocimiento Facial/efectos de los fármacos , Reconocimiento Facial/fisiología , Encéfalo/efectos de los fármacos , Encéfalo/diagnóstico por imagen , Encéfalo/fisiología , Amígdala del Cerebelo/efectos de los fármacos , Amígdala del Cerebelo/diagnóstico por imagen , Amígdala del Cerebelo/fisiología , Emociones/efectos de los fármacos , Emociones/fisiologíaRESUMEN
Multifunctional delivery systems capable of modulating drug release and exerting adjunctive pharmacological activity have attracted particular attention. Chitosan (CS) and pomegranate seed oil (PO) appear to be attractive bioactive components framing the strategy of complex therapy and multifunctional drug carriers. This research is aimed at evaluating the potential of CS in combination with PO in studies on topical emulgels containing hydrocortisone as a model anti-inflammatory agent. Its particular goal was to distinguish alterations in anti-inflammatory action followed with drug dissolution or penetrative behavior between the designed formulations that differ in CS/PO weight ratio. All formulations favored hydrocortisone release with up to a two-fold increase in the drug dissolution rate within first 5 h as compared to conventional topical preparations. The clear effect of CS/PO on the emulgel biological performance was observed, and CS was found to be prerequisite for the modulation of hydrocortisone absorption and accumulation. In turn, a greater amount of PO played the predominant role in the inhibition of hyaluronidase activity and enhanced the anti-inflammatory effect of preparation E-3. Emulgels showed a negligible reduction in mouse fibroblasts' L929 cell viability, confirming their non-irritancy with skin cells. Overall, the designed formulation with a CS/PO ratio of 6:4 appeared to be the most promising topical carrier for the effective treatment of inflammatory skin diseases among the tested subjects.
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Quitosano , Granada (Fruta) , Animales , Ratones , Humanos , Hidrocortisona/farmacología , Antiinflamatorios/farmacología , Aceites de Plantas/farmacologíaRESUMEN
Hypercortisolism is known to affect platelet function. However, few studies have approached the effect of exogenous cortisol on human platelets, and the results obtained are conflicting and unconvincing. In this study, the effect of exogenous cortisol on several parameters indicative of oxidative status in human platelets has been analysed. We have found that cortisol stimulates ROS production, superoxide anion formation, and lipid peroxidation, with these parameters being in strict correlation. In addition, cortisol decreases GSH and membrane SH-group content, evidencing that the hormone potentiates oxidative stress, depleting platelet antioxidant defence. The involvement of src, syk, PI3K, and AKT enzymes in oxidative mechanisms induced by cortisol is shown. The main sources of ROS in cells can include uncontrolled increase of NADPH oxidase activity and uncoupled aerobic respiration during oxidative phosphorylation. Both mechanisms seem to be involved in ROS formation induced by cortisol, as the NADPH oxidase 1 inhibitor 2(trifluoromethyl)phenothiazine, and rotenone and antimycin A, complex I and III inhibitor, respectively, significantly reduce oxidative stress. On the contrary, the NADPH oxidase inhibitor gp91ds-tat, malate and NaCN, complex II and IV inhibitor, respectively, have a minor effect. It is likely that, in human platelets, oxidative stress induced by cortisol can be associated with venous and arterial thrombosis, greatly contributing to cardiovascular diseases.
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Hidrocortisona , Estrés Oxidativo , Humanos , Hidrocortisona/farmacología , Especies Reactivas de Oxígeno , Plaquetas , NADPH OxidasasRESUMEN
Introduction: Stress may pose a serious challenge to immune homeostasis. Stress however also may prepare the immune system for challenges such as wounding or infection, which are likely to happen during a fight or flight stress response. Methods: In common carp (Cyprinus carpio L.) we studied the stress-induced redistribution of neutrophils into circulation, and the expression of genes encoding CXC chemokines known to be involved in the regulation of neutrophil retention (CXCL12) and redistribution (CXCL8), and their receptors (CXCR4 and CXCR1-2, respectively) in blood leukocytes and in the fish hematopoietic organ - the head kidney. The potential involvement of CXC receptors and stress hormone receptors in stress-induced neutrophil redistribution was determined by an in vivo study with selective CXCR inhibitors and antagonists of the receptors involved in stress regulation: glucocorticoid/mineralocorticoid receptors (GRs/MRs), adrenergic receptors (ADRs) and the melanocortin 2 receptor (MC2R). Results: The stress-induced increase of blood neutrophils was accompanied by a neutrophil decrease in the hematopoietic organs. This increase was cortisol-induced and GR-dependent. Moreover, stress upregulated the expression of genes encoding CXCL12 and CXCL8 chemokines, their receptors, and the receptor for granulocytes colony-stimulation factor (GCSFR) and matrix metalloproteinase 9 (MMP9). Blocking of the CXCR4 and CXCR1 and 2 receptors with selective inhibitors inhibited the stress-induced neutrophil redistribution and affected the expression of genes encoding CXC chemokines and CXCRs as well as GCSFR and MMP9. Discussion: Our data demonstrate that acute stress leads to the mobilization of the immune system, characterized by neutrophilia. CXC chemokines and CXC receptors are involved in this stress-induced redistribution of neutrophils from the hematopoietic tissue into the peripheral blood. This phenomenon is directly regulated by interactions between cortisol and the GR/MR. Considering the pivotal importance of neutrophilic granulocytes in the first line of defense, this knowledge is important for aquaculture, but will also contribute to the mechanisms involved in the stress-induced perturbation in neutrophil redistribution as often observed in clinical practice.
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Carpas , Neutrófilos , Animales , Metaloproteinasa 9 de la Matriz/metabolismo , Hidrocortisona/farmacología , Hidrocortisona/metabolismo , Granulocitos , Receptores de Quimiocina/metabolismoRESUMEN
Winter is an energetically challenging period for many animals in temperate regions because of the relatively harsh environmental conditions and reduction in food availability during this season. Moreover, stressors experienced by individuals in the fall can affect their subsequent foraging strategy and energy stores after exposure has ended, referred to as carryover effects. We used exogenous cortisol manipulation of wild juvenile brown trout (Salmo trutta) in the fall to simulate a physiological stress response and then investigated short-term (2 weeks) and long-term (4 months) effects on condition metrics (hepatosomatic index and water muscle content), diet (stomach contents and stable isotopes), and morphology during growth in freshwater. We revealed some short-term impacts, likely due to handling stress, and long-term (seasonal) changes in diet, likely reflecting prey availability. Unfortunately, we had very few recaptures of cortisol-treated fish at long-term sampling, limiting detailed analysis about cortisol effects at that time point. Nonetheless, the fish that were sampled showed elevated stable isotopes, suggestive of a cortisol effect long after exposure. This is one of few studies to investigate whether cortisol influences foraging and morphology during juvenile growth, thus extending the knowledge of proximate mechanisms influencing ecologically-relevant phenotypes.
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Hidrocortisona , Trucha , Animales , Hidrocortisona/farmacología , Estaciones del Año , Trucha/fisiología , Dieta/veterinaria , IsótoposRESUMEN
Anxiety is among the most prevalent mental disorders present in the general population. Benzodiazepines are the most commonly prescribed drugs for the treatment of anxiety. Using zebrafish as a model organism, we investigated the anxiolytic activity of JM-20, a novel hybrid molecule with a 1,5-benzodiazepine ring fused to a dihydropyridine moiety. Firstly, we carried out some assays to analyze the possible toxicity mediated by JM-20. For this, zebrafish were exposed to different JM-20 concentrations (0-5 µM) for 96 h. Then, using the novel tank test, we evaluated both locomotor and anxiety-like behavior of the animals. Furthermore, brain, liver and plasma were removed to assess toxicity parameters. JM-20 exposure did not cause changes on novel tank, and also did not alter brain viability, hepatic LDH and plasma ALT levels. Afterward, we investigated whether a pre-exposure to JM-20 would prevent the anxiogenic effect evoked by caffeine. In the novel tank test, caffeine significantly decreased the time spent at the top, as well as the number of transitions to the top area. Moreover, caffeine decreased both the total and average time spent in the lit area, as well as increased the number of risk episodes evaluated by the light-dark test. Whole-body cortisol levels were also increased by caffeine exposure. Interestingly, pre-treatment with JM-20 abolished all alterations induced by caffeine. The anxiolytic effect profile of JM-20 was similar to those found for diazepam (positive control). Our findings show, for the first time, the anxiolytic effect of JM-20 in zebrafish, and its relationship with cortisol regulation.
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Ansiolíticos , Humanos , Animales , Ansiolíticos/farmacología , Cafeína/toxicidad , Pez Cebra/fisiología , Hidrocortisona/farmacología , Conducta Animal , FenotipoRESUMEN
BACKGROUND: Glucocorticoid (GR) and mineralocorticoid (MR) receptors are highly expressed in cardiac tissue, and both can be activated by corticosteroids. MR activation, in acute myocardial infarction (AMI), worsens cardiac function, and increase NHE activity contributing to the deleterious process. In contrast, effects of GR activation are not fully understood, probably because of the controversial scenario generated by using different doses or potencies of corticosteroids. AIMS: We tested the hypothesis that an acute dose of hydrocortisone (HC), a low-potency glucocorticoid, in a murine model of AMI could be cardioprotective by regulating NHE1 activity, leading to a decrease in oxidative stress. MATERIALS AND METHODS: Isolated hearts from Wistar rats were subjected to regional ischemic protocol. HC (10 nmol/L) was added to the perfusate during early reperfusion. Infarct size and oxidative stress were determined. Isolated papillary muscles from non-infarcted hearts were used to evaluate HC effect on sodium-proton exchanger 1 (NHE1) by analysing intracellular pH recovery from acute transient acidosis. RESULTS: HC treatment decreased infarct size, improved cardiac mechanics, reduced oxidative stress after AMI, while restoring the decreased level of the pro-fusion mitochondrial protein MFN-2. Co-treatment with the GR-blocker Mifepristone avoided these effects. HC reduced NHE1 activity by increasing the NHE1 pro-inhibiting Ser648 phosphorylation site and its upstream kinase AKT. HC restored the decreased AKT phosphorylation and anti-apoptotic BCL-2 protein expression detected after AMI. CONCLUSIONS: Our results provide the first evidence that acute HC treatment during early reperfusion induces cardioprotection against AMI, associated with a non-genomic HC-triggered NHE1 inhibition by AKT and antioxidant action that might involves mitochondrial dynamics improvement.
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Infarto del Miocardio , Daño por Reperfusión , Ratas , Ratones , Animales , Miocardio/metabolismo , Antioxidantes/farmacología , Antioxidantes/metabolismo , Hidrocortisona/farmacología , Hidrocortisona/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Glucocorticoides/farmacología , Glucocorticoides/metabolismo , Ratas Wistar , Intercambiadores de Sodio-Hidrógeno , Infarto del Miocardio/prevención & control , Infarto del Miocardio/metabolismo , Daño por Reperfusión/metabolismoRESUMEN
Amphibious fishes on land encounter higher oxygen (O2) availability and novel energetic demands, which impacts metabolism. Previous work on the amphibious mangrove killifish (Kryptolebias marmoratus) has shown that cortisol becomes elevated in response to air exposure, suggesting a possible role in regulating metabolism as fish move into terrestrial environments. We tested the hypothesis that cortisol is the mechanism by which oxidative processes are upregulated during the transition to land in amphibious fishes. We used two groups of fish, treated fish (+metyrapone, a cortisol synthesis inhibitor) and control (-metyrapone), to determine the impact of cortisol during air exposure (0 and 1 h, 7 days) on O2 consumption, terrestrial locomotion, the phenotype of red skeletal muscle, and muscle lipid concentration. Metyrapone-treated fish had an attenuated elevation in O2 consumption rate during the water to air transition and an immediate reduction in terrestrial exercise performance relative to control fish. In contrast, we found no short- (0 h) or long-term (7 days) differences between treatments in the oxidative phenotype of red muscles, nor in muscle lipid concentrations. Our results suggest that cortisol stimulates the necessary increase in aerobic metabolism needed to fuel the physiological changes that amphibious fishes undergo during the acclimation to air, although further studies are required to determine specific mechanisms of cortisol regulation.