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1.
Chemosphere ; 262: 127841, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32784060

RESUMEN

Environmental pollutants suspected of disrupting the endocrine system are considered etiologic factors in the epidemic of metabolic disorders. As regulation of energy metabolism relies on the integrated action of a large number of hormones, we hypothesized that certain chemicals could trigger changes in glucocorticoid signaling. To this end, we exposed C57Bl6/J female and male mice between 5 and 20 weeks of age to a mixture of 2,3,7,8- tetrachlorodibenzo-p-dioxin (20 pg/kg body weight/day [bw/d]), polychlorobiphenyl 153 (200 ng/kg bw/d), di-[2-ethylhexyl]-phthalate (500 µg/kg bw/d) and bisphenol A (40 µg/kg bw/d). In female mice fed a standard diet (ST), we observed a decrease in plasma levels of leptin as well as a reduced expression of corticoid receptors Nr3c1 and Nr3c2, of leptin and of various canonical genes related to the circadian clock machinery in visceral (VAT) but not subcutaneous (SAT) adipose tissue. However, Nr3c1 and Nr3c2 mRNA levels did not change in high-fat-fed females exposed to pollutants. In ST-fed males, pollutants caused the same decrease of Nr3c1 mRNA levels in VAT observed in ST-fed females but levels of Nr3c2 and other clock-related genes found to be down-regulated in female VAT were enhanced in male SAT and not affected in male VAT. The expression of corticoid receptors was not affected in the livers of both sexes in response to pollutants. In summary, exposure to a mixture of pollutants at doses lower than the no-observed adverse effect levels (NoAELs) resulted in sex-dependent glucocorticoid signaling disturbances and clock-related gene expression modifications in the adipose tissue of ST-fed mice.


Asunto(s)
Contaminantes Ambientales/toxicidad , Glucocorticoides/metabolismo , Tejido Adiposo/metabolismo , Animales , Compuestos de Bencidrilo , Peso Corporal , Contaminantes Ambientales/metabolismo , Femenino , Expresión Génica , Leptina/sangre , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Fenoles , Dibenzodioxinas Policloradas/metabolismo , ARN Mensajero/metabolismo , Sensibilidad y Especificidad
2.
Phytomedicine ; 80: 153360, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33038867

RESUMEN

BACKGROUND: Curcumin is a naturally occurring polyphenol found in Curcuma longa with multiple therapeutic properties, such as anti-inflammatory, wound healing and anti-cancer effects. Curcuma longa is also used as a galactagogue to improve milk production during lactation. PURPOSE: To assess curcumin could have therapeutic potential for breastfeeding mothers, we investigated whether and how curcumin influences milk production in lactating mammary epithelial cells (MECs) at the cellular and molecular levels. METHODS: We prepared a lactating MEC culture model that produced milk components and formed less-permeable tight junctions (TJs) to investigate the molecular mechanism of curcumin on milk production, TJs, and inflammation in vitro. RESULTS: Curcumin downregulated milk production in lactation MECs concurrently with inactivation of lactogenesis-relating signaling (STAT5 and glucocorticoid receptor). The maintenance of a less-permeable TJ barrier was also confirmed, although the TJ protein claudin-4 increased. Curcumin inactivated NFκB and STAT3 signaling, which are closely involved in inflammatory responses in weaning and mastitis mammary glands. The expression levels of IL-1ß and TNF-α were also decreased by curcumin treatment. Furthermore, curcumin blocked activation of inflammatory signaling by lipopolysaccharide treatment in MECs, similar to those in MECs that were treated with diclofenac sodium. The drastic phosphorylation of ERK was induced by curcumin treatment in the absence of EGF. U0126, an inhibitor of ERK phosphorylation, attenuated the adverse effects of curcumin on lactating MECs. CONCLUSION: The results of the present study suggests that curcumin downregulates milk production via inactivation of STAT5 and GR signaling with concurrent suppression of inflammatory responses via STAT3 and NFκB signaling in MECs. These findings provide new insights into the role of curcumin as a mild suppressor of milk production without inflammatory damages in breastfeeding mothers.


Asunto(s)
Curcumina/farmacología , Células Epiteliales/efectos de los fármacos , Glándulas Mamarias Animales/citología , Leche/metabolismo , Animales , Caseínas/metabolismo , Células Cultivadas , Curcumina/efectos adversos , Células Epiteliales/metabolismo , Femenino , Glucocorticoides/metabolismo , Lactancia/efectos de los fármacos , Lactancia/metabolismo , Lipopolisacáridos/toxicidad , Glándulas Mamarias Animales/efectos de los fármacos , Glándulas Mamarias Animales/metabolismo , Mastitis/tratamiento farmacológico , Mastitis/metabolismo , Ratones Endogámicos ICR , FN-kappa B/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Uniones Estrechas/efectos de los fármacos
3.
Gene ; 766: 145128, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-32911026

RESUMEN

BACKGROUND: The pathogenesis of osteonecrosis of the femoral head (ONFH) is unclear. Our previous study demonstrated that upregulated miR-335 in bone microvascular endothelial cells (BMECs) might be associated with the disease of steroid-induced ONFH. Here, we study the preventive effect of ICA on steroid-induced ONFH in rats. METHOD: 90 rats were separated into three groups: control group, methylprednisolone (MPS) group, and MPS + Icariin (ICA) group. Four weeks later, histological analyses were performed. Thrombomodulin (TM) and vascular endothelial growth factor (VEGF) were tested. MiRNA-335 expression was screened in the three groups using Agilent Gene Spring GX software. Target genes of miRNA-335 were detected by bioinformatics analysis. The functions of BMECs were analyzed by scratch, angiogenesis and cell survival rate. RESULTS: ICA can prevent the occurrence of steroid-associated ONFH in rats and reduce the amount of TM and VEGF in serum induced by glucocorticoids. ICA could regulate the overexpression of miRNA-335 induced by glucocorticoids. We predicted the Gene ontology (GO) and signaling pathways of target genes. At 24 hours, we found that ICA significantly promoted BMECs migration abilities. We also found that ICA could promote the angioplasty ability of BMECs. ICA could improve the survival rate of BMECs after steroid-induced injury. CONCLUSIONS: ICA is effective to prevent the occurrence of steroidinduced ONFH. ICA has a protective effect against steroid-induced BMECs injury. ICA regulated the imbalance of miRNA-335 expression induced by the glucocorticoid in BMECs, which provides a new viewpoint to explore the mechanism of ICA in preventing steroid-induced ONFH.


Asunto(s)
Células Endoteliales/efectos de los fármacos , Necrosis de la Cabeza Femoral/tratamiento farmacológico , Cabeza Femoral/efectos de los fármacos , Flavonoides/farmacología , MicroARNs/metabolismo , Neovascularización Patológica/tratamiento farmacológico , Sustancias Protectoras/farmacología , Adipogénesis/efectos de los fármacos , Animales , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Endoteliales/metabolismo , Femenino , Cabeza Femoral/metabolismo , Necrosis de la Cabeza Femoral/inducido químicamente , Necrosis de la Cabeza Femoral/metabolismo , Glucocorticoides/metabolismo , Metilprednisolona/farmacología , Neovascularización Patológica/metabolismo , Osteocitos/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Esteroides/farmacología , Factor A de Crecimiento Endotelial Vascular/metabolismo
6.
Eur J Endocrinol ; 183(6): 669-676, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33112256

RESUMEN

Context: Obesity and cardiometabolic diseases are associated with higher long-term glucocorticoid levels, measured as scalp hair cortisol (HairF) and cortisone (HairE). Cardiometabolic diseases have also been associated with copeptin, a stable surrogate marker for the arginine-vasopressin (AVP) system. Since AVP is, together with corticotropin-releasing hormone (CRH) an important regulator of the hypothalamic-pituitary adrenal axis (HPA axis), we hypothesize that AVP contributes to chronic hypercortisolism in obesity. Objective: To investigate whether copeptin levels are associated with Higher HairF and HairE levels in obesity. Design: A cross-sectional study in 51 adults with obesity (BMI ≥30 kg/m2). Methods: Associations and interactions between copeptin, HairF, HairE, and cardiometabolic parameters were cross-sectionally analyzed. Results: Copeptin was strongly associated with BMI and waist circumference (WC) (rho = 0.364 and 0.530, P = 0.008 and <0.001, respectively), also after correction for confounders. There were no associations between copeptin and HairF or HairE on a continuous or dichotomized scale, despite correction for confounders. Conclusion: In patients with obesity, AVP seems not a major contributor to the frequently observed high cortisol levels. Other factors which stimulate the HPA axis or affect cortisol synthesis or breakdown may be more important than the influence of AVP on long-term glucocorticoid levels in obesity.


Asunto(s)
Cortisona/metabolismo , Síndrome de Cushing/etiología , Glicopéptidos/metabolismo , Hidrocortisona/metabolismo , Obesidad/metabolismo , Adulto , Arginina Vasopresina/metabolismo , Biomarcadores/metabolismo , Índice de Masa Corporal , Hormona Liberadora de Corticotropina/metabolismo , Estudios Transversales , Femenino , Glucocorticoides/metabolismo , Cabello/química , Humanos , Sistema Hipotálamo-Hipofisario/metabolismo , Masculino , Obesidad/complicaciones , Sistema Hipófiso-Suprarrenal/metabolismo
7.
J Pharmacol Exp Ther ; 375(3): 398-405, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33008869

RESUMEN

Glucocorticoids are extensively used for a variety of conditions, including those associated with dysregulation of immune and inflammatory responses as primary etiopathogenic factors. Indeed, the proinflammatory cytokine storm of coronavirus disease 2019 (COVID-19) is the latest condition for which the use of a glucocorticoid has been advocated. Recognition of serious adverse effects of glucocorticoids has led to research aimed at unraveling molecular basis by which they impact immune and inflammatory events with the ultimate objective of devising novel therapies to circumvent glucocorticoids-related adverse outcomes. Consequently, glucocorticoid-induced leucine zipper (GILZ) protein was discovered and is increasingly recognized as the pivotal regulator of the effects of glucocorticoids on immune and inflammatory responses. Importantly, the advent of GILZ-based options raises the prospect of their eventual therapeutic use for a variety of conditions accompanied with dysregulation of immune and inflammatory responses and associated target organ complications. Thus, the objective of this minireview is to describe our current understanding of the role of GILZ in the cardiovascular system and the kidney along with outcome of GILZ-based interventions on associated disorders. This information is also of relevance for emerging complications of COVID-19. SIGNIFICANCE STATEMENT: Glucocorticoid-induced leucine zipper (GILZ) was initially discovered as the pivotal mediator of immune regulatory/suppressive effects of glucocorticoids. Since the use of glucocorticoids is associated with serious adverse effects, GILZ-based formulations could offer therapeutic advantages. Thus, this minireview will describe our current understanding of the role of GILZ in the kidney and the cardiovascular system, which is of relevance and significance for pathologies affecting them, including the multiorgan complications of coronavirus disease 2019.


Asunto(s)
/metabolismo , Síndrome Cardiorrenal/complicaciones , Sistema Cardiovascular/metabolismo , Coronavirus/metabolismo , Riñón/metabolismo , Factores de Transcripción/metabolismo , Animales , /terapia , Regulación de la Expresión Génica , Glucocorticoides/metabolismo , Humanos , Leucina Zippers , Macrófagos/metabolismo , Transporte de Proteínas , ARN Mensajero , Receptores Toll-Like/metabolismo
8.
PLoS One ; 15(10): e0241085, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33095820

RESUMEN

In recent years, the ex situ population of the endangered black-footed ferret (Mustela nigripes; ferret) has experienced a decline in normal sperm morphology (from 50% to 20%), which may be linked to inbreeding depression and/or a dietary change. We examined the effects of adding carcass and vitamin E to the diet on stress and reproductive biomarkers in male ferrets (n = 42 males including 16 juveniles and 26 adults) housed at the U.S. Fish and Wildlife National Black-footed Ferret Conservation Center (Carr, CO, USA). Fecal samples (3x/week) were collected from November and December (pre-breeding season, no diet change), February through May (breeding season, diet change) and June (post-breeding season, diet change) and analyzed for fecal glucocorticoid metabolites (FGM) via a corticosterone enzyme immunoassay (EIA). A subset of samples from adult males (n = 15) were analyzed for fecal androgen metabolites (FAM) via a testosterone EIA. We first used a linear mixed effects model to identify the important fixed effects among meat treatment, vitamin E treatment, age class (juvenile or adult), and all possible interactions on each hormone. We then examined the important factor's effects across seasons using the non-parametric Friedman test. We found that age did not influence (p = 0.33) FGMs; however there was a significant effect of meat treatment on FGM (p = 0.04) and an effect of vitamin E on FAMs (p<0.10). When fed carcass, FGMs declined (p<0.001) from pre- to the during the breeding season time period, but was similar (p>0.05) between during and post-breeding season periods. Males that were not fed carcass had higher (p<0.05) FGMs during the breeding season compared to pre- and post-breeding season and FGMs were lower (p<0.05) in the post-breeding season compared to pre-breeding season. Males fed with carcass had lower (p<0.001) FGM than males that were not fed carcass during both the pre-breeding and the breeding season but not during the post-breeding season (p>0.05). Males supplemented with vitamin E had higher (p<0.001) FAM than non-supplemented males during the breeding season only. For both groups, FAM was highest (p<0.05) during the breeding season. In conclusion, adding carcass to the diet can reduce glucocorticoid production and adding vitamin E can increase testosterone during the breeding season, which may influence reproductive success.


Asunto(s)
Alimentación Animal , Especies en Peligro de Extinción , Hurones/fisiología , Reproducción/fisiología , Vitamina E/administración & dosificación , Animales , Suplementos Dietéticos , Heces/química , Conducta Alimentaria/fisiología , Glucocorticoides/análisis , Glucocorticoides/metabolismo , Masculino , Carne/efectos adversos , Reproducción/efectos de los fármacos , Estaciones del Año , Testosterona/análisis , Testosterona/metabolismo
9.
Sci Rep ; 10(1): 13682, 2020 08 13.
Artículo en Inglés | MEDLINE | ID: mdl-32792550

RESUMEN

The ability to respond appropriately to challenges is an important contributor to fitness. Variation in the regulation of glucocorticoid hormones, which mediate the phenotypic response to challenges, can therefore influence the ability to persist in a given environment. We compared stress responsiveness in four populations of tree swallows (Tachycineta bicolor) breeding under different environmental conditions to evaluate support for different selective pressures in driving the evolution of glucocorticoid regulation. In accordance with the environmental unpredictability hypothesis, stronger stress responses were seen in more unpredictable environments. Contrary to the reproductive value hypothesis, the stress response was not lower in populations engaging in more valuable reproductive attempts. Populations with stronger stress responses also had stronger negative feedback, which supports a "mitigating" rather than a "magnifying" effect of negative feedback on stress responses. These results suggest that combining a robust stress response with strong negative feedback may be important for persisting in unpredictable or rapidly changing environments.


Asunto(s)
Glucocorticoides/metabolismo , Golondrinas/fisiología , Animales , Cruzamiento , Retroalimentación Fisiológica , Selección Genética , Estrés Fisiológico , Golondrinas/metabolismo
10.
Proc Natl Acad Sci U S A ; 117(33): 20052-20062, 2020 08 18.
Artículo en Inglés | MEDLINE | ID: mdl-32747546

RESUMEN

In humans and other animals, harsh conditions in early life can have profound effects on adult physiology, including the stress response. This relationship may be mediated by a lack of supportive relationships in adulthood. That is, early life adversity may inhibit the formation of supportive social ties, and weak social support is itself often linked to dysregulated stress responses. Here, we use prospective, longitudinal data from wild baboons in Kenya to test the links between early adversity, adult social bonds, and adult fecal glucocorticoid hormone concentrations (a measure of hypothalamic-pituitary-adrenal [HPA] axis activation and the stress response). Using a causal inference framework, we found that experiencing one or more sources of early adversity led to a 9 to 14% increase in females' glucocorticoid concentrations across adulthood. However, these effects were not mediated by weak social bonds: The direct effects of early adversity on adult glucocorticoid concentrations were 11 times stronger than the effects mediated by social bonds. This pattern occurred, in part, because the effect of social bonds on glucocorticoids was weak compared to the powerful effects of early adversity on glucocorticoid levels in adulthood. Hence, in female baboons, weak social bonds in adulthood are not enough to explain the effects of early adversity on glucocorticoid concentrations. Together, our results support the well-established notions that early adversity and weak social bonds both predict poor adult health. However, the magnitudes of these two effects differ considerably, and they may act independently of one another.


Asunto(s)
Heces/química , Glucocorticoides/análisis , Papio/psicología , Conducta Social , Animales , Animales Salvajes/metabolismo , Femenino , Glucocorticoides/metabolismo , Estudios Longitudinales , Masculino , Apego a Objetos , Papio/metabolismo , Sistema Hipófiso-Suprarrenal/metabolismo , Estudios Prospectivos , Estrés Psicológico
11.
Sci Rep ; 10(1): 13736, 2020 08 13.
Artículo en Inglés | MEDLINE | ID: mdl-32792579

RESUMEN

We designed a retrospective observational study to identify factors associated with ocular hypertension [OHTN, defined as intraocular pressure (IOP) > 25 mmHg] after intravitreal dexamethasone (IVD) implantation in diabetic macular edema (DME) patients. We measured IOP monthly after placement of an IVD implant, and identified the trend of IOP, incidence of OHTN, and its associated systemic or ocular factors. On average, IOP was highest at 2 months after IVD implantation. Of 84 DME patients who received an IVD implant, 3 (3.57%) presented with an IOP ≥ 25 mmHg at 1 month after implantation, 6 (7.14%) at 2 months, and 2 (2.38%) at 3 months. Compared with the non-OHTN group, the OHTN group had significantly shorter axial lengths and were younger. Logistic regression analysis revealed that axial length < 23.00 mm and age < 57 years were associated with OHTN occurrence. Patients whose IOP was elevated > 30% or ≥ 20 mmHg at 1 month post-implantation, subsequently developed OHTN with statistical significance. In conclusion, shorter axial length and younger age were associated with OHTN occurrence after IVD implantation. Additionally, identifying levels or trends in IOP at 1 month after the IVD procedure may be helpful in predicting subsequent OHTN occurrence.


Asunto(s)
Dexametasona/administración & dosificación , Dexametasona/efectos adversos , Complicaciones de la Diabetes/tratamiento farmacológico , Edema Macular/tratamiento farmacológico , Hipertensión Ocular/inducido químicamente , Hipertensión Ocular/etiología , Complicaciones de la Diabetes/metabolismo , Femenino , Glaucoma/tratamiento farmacológico , Glaucoma/metabolismo , Glucocorticoides/metabolismo , Humanos , Presión Intraocular/efectos de los fármacos , Inyecciones Intravítreas , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Tomografía de Coherencia Óptica/métodos , Tonometría Ocular/métodos , Agudeza Visual/efectos de los fármacos
12.
Proc Natl Acad Sci U S A ; 117(35): 21667-21672, 2020 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-32817534

RESUMEN

Extensive pharmacologic, genetic, and epigenetic research has linked the glucocorticoid receptor (GR) to memory processes, and to risk and symptoms of posttraumatic stress disorder (PTSD). In the present study we investigated the epigenetic pattern of 12 genes involved in the regulation of GR signaling in two African populations of heavily traumatized individuals: Survivors of the rebel war in northern Uganda (n = 463) and survivors of the Rwandan genocide (n = 350). The strongest link between regional methylation and PTSD risk and symptoms was observed for NTRK2, which encodes the transmembrane receptor tropomyosin-related kinase B, binds the brain-derived neurotrophic factor, and has been shown to play an important role in memory formation. NTRK2 methylation was not related to trauma load, suggesting that methylation differences preexisted the trauma. Because NTRK2 methylation differences were predominantly associated with memory-related PTSD symptoms, and because they seem to precede traumatic events, we next investigated the relationship between NTRK2 methylation and memory in a sample of nontraumatized individuals (n = 568). We found that NTRK2 methylation was negatively associated with recognition memory performance. Furthermore, fMRI analyses revealed NTRK2 methylation-dependent differences in brain network activity related to recognition memory. The present study demonstrates that NTRK2 is epigenetically linked to memory functions in nontraumatized subjects and to PTSD risk and symptoms in traumatized populations.


Asunto(s)
Glicoproteínas de Membrana/genética , Receptor trkB/genética , Trastornos por Estrés Postraumático/genética , Adulto , Anciano , Encéfalo/metabolismo , Metilación de ADN/genética , Epigénesis Genética/genética , Femenino , Glucocorticoides/metabolismo , Humanos , Masculino , Glicoproteínas de Membrana/metabolismo , Memoria/fisiología , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Receptor trkB/metabolismo , Receptores de Glucocorticoides/metabolismo , Factores de Riesgo , Rwanda/epidemiología , Trastornos por Estrés Postraumático/metabolismo , Sobrevivientes , Uganda/epidemiología
13.
Proc Natl Acad Sci U S A ; 117(29): 17166-17176, 2020 07 21.
Artículo en Inglés | MEDLINE | ID: mdl-32632016

RESUMEN

Signaling of 17ß-estradiol (estrogen) through its two nuclear receptors, α and ß (ERα, ERß), is an important mechanism of transcriptional regulation. Although ERs are broadly expressed by cells of the immune system, the mechanisms by which they modulate immune responses remain poorly understood. ERß-specific signaling is reduced in patients with chronic inflammatory diseases, including systemic lupus erythematosus and inflammatory bowel disease, and our previous work suggests that dysregulation of ERß-specific signaling contributes to enhanced intestinal inflammation in female SAMP/YitFC mice, a spontaneous model of Crohn's disease-like ileitis. The present study builds on these prior observations to identify a nonredundant, immunoprotective role for ERß-specific signaling in TGF-ß-dependent regulatory T cell (Treg) differentiation. Using a strain of congenic SAMP mice engineered to lack global expression of ERß, we observed dramatic, female-specific exacerbation of intestinal inflammation accompanied by significant reductions in intestinal Treg frequency and function. Impaired Treg suppression in the absence of ERß was associated with aberrant overexpression of Tsc22d3 (GILZ), a glucocorticoid-responsive transcription factor not normally expressed in mature Tregs, and ex vivo data reveal that forced overexpression of GILZ in mature Tregs inhibits their suppressive function. Collectively, our findings identify a pathway of estrogen-mediated immune regulation in the intestine, whereby homeostatic expression of ERß normally functions to limit Treg-specific expression of GILZ, thereby maintaining effective immune suppression. Our data suggest that transcriptional cross-talk between glucocorticoid and steroid sex hormone signaling represents an important and understudied regulatory node in chronic inflammatory disease.


Asunto(s)
Receptor beta de Estrógeno/metabolismo , Estrógenos/metabolismo , Inflamación/inmunología , Intestinos/inmunología , Transducción de Señal/fisiología , Linfocitos T Reguladores/inmunología , Adolescente , Adulto , Animales , Enfermedad de Crohn/inmunología , Modelos Animales de Enfermedad , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/genética , Femenino , Glucocorticoides/metabolismo , Humanos , Ileítis/patología , Enfermedades Inflamatorias del Intestino/inmunología , Intestinos/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Factores de Transcripción/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Adulto Joven
14.
Acta Diabetol ; 57(11): 1383-1393, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-32647998

RESUMEN

AIMS: Steroid diabetes mellitus (SDM) is a metabolic syndrome caused by an increase in glucocorticoids, and its pathogenesis is unclear. 18F-FDG PET/CT can reflect the glucose metabolism of tissues and organs under living conditions. Here, PET/CT imaging of SDM and type 2 diabetes mellitus (T2DM) rats was used to visualize changes in glucose metabolism in the main glucose metabolizing organs and investigate the pathogenesis of SDM. METHODS: SDM and T2DM rat models were established. During this time, PET/CT imaging was used to measure the %ID/g value of skeletal muscle and liver to evaluate glucose uptake. The pancreatic, skeletal muscle and liver were analyzed by immunohistochemistry. RESULTS: SDM rats showed increased fasting blood glucose and insulin levels, hyperplasia of islet α and ß cells, increased FDG uptake in skeletal muscle accompanied by an up-regulation of PI3Kp85α, IRS-1, and GLUT4, no significant changes in liver uptake, and that glycogen storage in the liver and skeletal muscle increased. T2DM rats showed atrophy of pancreatic islet ß cells and decreased insulin levels, significantly reduced FDG uptake and glycogen storage in skeletal muscle and liver. CONCLUSIONS: The pathogenesis of SDM is different from that of T2DM. The increased glucose metabolism of skeletal muscle may be related to the increased compensatory secretion of insulin. Glucocorticoids promote the proliferation of islet α cells and cause an increase in gluconeogenesis in the liver, which may cause increased blood glucose.


Asunto(s)
Diabetes Mellitus Tipo 2/diagnóstico por imagen , Diabetes Mellitus/diagnóstico por imagen , Animales , Glucemia/metabolismo , Diabetes Mellitus/sangre , Diabetes Mellitus Tipo 2/sangre , Ayuno/sangre , Fluorodesoxiglucosa F18/administración & dosificación , Glucocorticoides/metabolismo , Transportador de Glucosa de Tipo 4/genética , Transportador de Glucosa de Tipo 4/metabolismo , Glucógeno/metabolismo , Humanos , Insulina/metabolismo , Proteínas Sustrato del Receptor de Insulina/genética , Proteínas Sustrato del Receptor de Insulina/metabolismo , Hígado/diagnóstico por imagen , Hígado/metabolismo , Masculino , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/metabolismo , Tomografía Computarizada por Tomografía de Emisión de Positrones , Ratas , Ratas Wistar
15.
Sci Rep ; 10(1): 11684, 2020 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-32669633

RESUMEN

Poor reproducibility is considered a serious problem in laboratory animal research, with important scientific, economic, and ethical implications. One possible source of conflicting findings in laboratory animal research are environmental differences between animal facilities combined with rigorous environmental standardization within studies. Due to phenotypic plasticity, study-specific differences in environmental conditions during development can induce differences in the animals' responsiveness to experimental treatments, thereby contributing to poor reproducibility of experimental results. Here, we studied how variation in weaning age (14-30 days) and housing conditions (single versus group housing) affects the phenotype of SWISS mice as measured by a range of behavioral and physiological outcome variables. Weaning age, housing conditions, and their interaction had little effect on the development of stereotypies, as well as on body weight, glucocorticoid metabolite concentrations, and behavior in the elevated plus-maze and open field test. These results are surprising and partly in conflict with previously published findings, especially with respect to the effects of early weaning. Our results thus question the external validity of previous findings and call for further research to identify the sources of variation between replicate studies and study designs that produce robust and reproducible experimental results.


Asunto(s)
Experimentación Animal/normas , Animales de Laboratorio/fisiología , Variación Biológica Individual , Vivienda para Animales/normas , Factores de Edad , Animales , Animales Recién Nacidos , Peso Corporal , Femenino , Glucocorticoides/metabolismo , Masculino , Aprendizaje por Laberinto/fisiología , Ratones , Fenotipo , Reproducibilidad de los Resultados , Destete
16.
Am J Physiol Heart Circ Physiol ; 319(2): H488-H506, 2020 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-32618516

RESUMEN

Although chronic stress is an important risk factor for cardiovascular diseases (CVD) onset, the underlying mechanisms driving such pathophysiological complications remain relatively unknown. Here, dysregulation of innate stress response systems and the effects of downstream mediators are strongly implicated, with the vascular endothelium emerging as a primary target of excessive glucocorticoid and catecholamine action. Therefore, this review article explores the development of stress-related endothelial dysfunction by focusing on the following: 1) assessing the phenomenon of stress and complexities surrounding this notion, 2) discussing mechanistic links between chronic stress and endothelial dysfunction, and 3) evaluating the utility of various preclinical models currently employed to study mechanisms underlying the onset of stress-mediated complications such as endothelial dysfunction. The data reveal that preclinical models play an important role in our efforts to gain an increased understanding of mechanisms underlying stress-mediated endothelial dysfunction. It is our understanding that this provides a good foundation going forward, and we propose that further efforts should be made to 1) more clearly define the concept of stress and 2) standardize protocols of animal models with specific guidelines to better indicate the mental complications that are simulated.


Asunto(s)
Enfermedades Cardiovasculares/etiología , Endotelio Vascular/fisiopatología , Estrés Psicológico/complicaciones , Animales , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/fisiopatología , Enfermedades Cardiovasculares/psicología , Catecolaminas/metabolismo , Enfermedad Crónica , Modelos Animales de Enfermedad , Endotelio Vascular/metabolismo , Glucocorticoides/metabolismo , Humanos , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipotálamo-Hipofisario/fisiopatología , Factores de Riesgo , Transducción de Señal , Estrés Psicológico/metabolismo , Estrés Psicológico/fisiopatología , Estrés Psicológico/psicología
17.
Nucleic Acids Res ; 48(15): 8393-8407, 2020 09 04.
Artículo en Inglés | MEDLINE | ID: mdl-32619221

RESUMEN

The glucocorticoid receptor is an important immunosuppressive drug target and metabolic regulator that acts as a ligand-gated transcription factor. Generally, GR's anti-inflammatory effects are attributed to the silencing of inflammatory genes, while its adverse effects are ascribed to the upregulation of metabolic targets. GR binding directly to DNA is proposed to activate, whereas GR tethering to pro-inflammatory transcription factors is thought to repress transcription. Using mice with a point mutation in GR's zinc finger, that still tether via protein-protein interactions while being unable to recognize DNA, we demonstrate that DNA binding is essential for both transcriptional activation and repression. Performing ChIP-Seq, RNA-Seq and proteomics under inflammatory conditions, we show that DNA recognition is required for the assembly of a functional co-regulator complex to mediate glucocorticoid responses. Our findings may contribute to the development of safer immunomodulators with fewer side effects.


Asunto(s)
Proteínas de Unión al ADN/genética , ADN/genética , Inflamación/genética , Receptores de Glucocorticoides/genética , Animales , ADN/metabolismo , Regulación de la Expresión Génica/genética , Glucocorticoides/genética , Glucocorticoides/metabolismo , Humanos , Inflamación/patología , Ratones , Dominios y Motivos de Interacción de Proteínas/genética , RNA-Seq , Activación Transcripcional/genética
18.
J Allergy Clin Immunol ; 146(2): 330-331, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32593491
19.
Vet J ; 258: 105456, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32564866

RESUMEN

The enzyme 11-beta-hydroxysteroid dehydrogenase isoenzyme 2 (11BHSD2) is responsible for converting the active glucocorticoid cortisol to inactive cortisone and in the renal medulla protects the mineralocorticoid receptor (MR) from activation by cortisol. Derangements in 11BHSD2 activity can result in reduced conversion of cortisol to cortisone, activation of the MR by cortisol and, consequently, sodium and water retention. The objective of this study was to examine glucocorticoid metabolism in canine congestive heart failure (CHF), specifically to evaluate whether renal 11BHSD2 activity and expression were altered. Dogs were prospectively recruited into one of two phases; the first phase (n=56) utilized gas chromatography-tandem mass spectrometry to examine steroid hormone metabolites normalised to creatinine in home-caught urine samples. Total serum cortisol was also evaluated. The second phase consisted of dogs (n=18) euthanased for refractory CHF or for behavioural reasons. Tissue was collected from the renal medulla for examination by quantitative reverse transcription polymerase chain reaction, immunohistochemistry and protein immune-blotting. Heart failure did not change urinary cortisol:cortisone ratio (P=0.388), or modify renal expression (P=0.303), translation (P=0.427) or distribution of 11BHSD2 (P=0.325). However, CHF did increase excretion of 5α-tetrahydrocortisone (P=0.004), α-cortol (P=0.002) and α-cortolone (P=0.009). Congestive heart failure modifies glucocorticoid metabolism in dogs by increasing 5α-reductase and 20α-hydroxysteroid dehydrogenase activity. Differences between groups in age, sex and underlying disease processes may have influenced these results. However, 11BHSD2 does not appear to be a potential therapeutic target in canine CHF.


Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/metabolismo , Enfermedades de los Perros/metabolismo , Glucocorticoides/metabolismo , Insuficiencia Cardíaca/veterinaria , Riñón/metabolismo , Animales , Cortisona/orina , Perros , Femenino , Cromatografía de Gases y Espectrometría de Masas/veterinaria , Insuficiencia Cardíaca/tratamiento farmacológico , Hidrocortisona/orina , Masculino , Estudios Prospectivos
20.
J Anim Sci ; 98(7)2020 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-32599620

RESUMEN

Glucocorticoids (GCs) induce the activation of the central adenosine 5'-monophosphate-activated protein kinase (AMPK) signaling pathway in birds. In this study, we aimed to investigate the effects of corticosterone (CORT) supplemented in diet on the central AMPK signaling pathway in broilers. The average daily gain was reduced by CORT treatment, and the average daily feed intake remained unchanged. Plasma glucose, triglyceride, total cholesterol, and CORT contents were increased by CORT administration. In addition, CORT treatment decreased the relative weights of heart, spleen, and bursa and increased the relative weights of liver and abdominal fat. The glycogen contents in the liver and breast muscle were higher in the chicks treated with CORT. CORT treatment upregulated the gene expression of mammalian target of rapamycin, glucocorticoid receptor, AMPKα2, neuropeptide Y(NPY), liver kinase B1 (LKB1), AMPKα1, and fatty acid synthase in the hypothalamus. Moreover, CORT treatment increased the protein levels of acetyl-coenzyme A carboxylase (ACC) phosphorylation and total AMPK and phosphorylated AMPK in the hypothalamus. Hence, CORT administration in the diet activated the LKB1-AMPK-NPY/ACC signaling pathway in the hypothalamus of broiler.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Pollos/fisiología , Corticosterona/administración & dosificación , Dieta/veterinaria , Transducción de Señal/efectos de los fármacos , Proteínas Quinasas Activadas por AMP/genética , Adenosina Monofosfato/metabolismo , Adenosina Monofosfato/farmacología , Animales , Pollos/metabolismo , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Glucocorticoides/metabolismo , Hipotálamo/metabolismo , Masculino , Neuropéptido Y/metabolismo , Músculos Pectorales/efectos de los fármacos , Músculos Pectorales/crecimiento & desarrollo
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