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1.
Sci Rep ; 14(1): 18804, 2024 08 13.
Artículo en Inglés | MEDLINE | ID: mdl-39138321

RESUMEN

Cell therapy for adrenocortical insufficiency can potentially provide steroid replacement in response to physiological stimuli. Previously, we reported that adipose tissue-derived stromal cells (ADSCs) are transformed into steroid-producing cells by overexpression of nuclear receptor subfamily 5 group A member 1 (NR5A1). The steroidogenic cells are characterized by the production of both adrenal and gonadal steroids. Cytotherapy for adrenocortical insufficiency requires cells with more adrenocortical characteristics. Considering the highly developed vascular network within the adrenal cortex, all adrenocortical cells are adjacent to and interact with vascular endothelial cells (VECs). In this study, NR5A1-induced steroidogenic cells derived from mouse ADSCs (NR5A1-ADSCs) were co-cultured with mouse VECs. Testosterone secretion in NR5A1-ADSCs was not altered; however, corticosterone secretion significantly increased while levels of steroidogenic enzymes significantly increased in the corticosterone synthesis pathway. Co-culture with lymphatic endothelial cells (LECs) or ADSCs, or transwell culture with NR5A1-ADSCs and VECs did not alter corticosterone production. VECs expressed higher levels of collagen and laminin than LECs. Culture in type-IV collagen and laminin-coated dishes increased corticosterone secretion in NR5A1-ADSCs. These results suggest that VECs may characterize ADSC-derived steroidogenic cells into a more corticosterone-producing phenotype, and VECs may be useful for generating adrenal steroidogenic cells from stem cells.


Asunto(s)
Tejido Adiposo , Técnicas de Cocultivo , Corticosterona , Células Endoteliales , Células Madre Mesenquimatosas , Animales , Corticosterona/metabolismo , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/citología , Células Endoteliales/metabolismo , Células Endoteliales/citología , Ratones , Tejido Adiposo/citología , Tejido Adiposo/metabolismo , Factor Esteroidogénico 1/metabolismo , Factor Esteroidogénico 1/genética , Células Cultivadas , Diferenciación Celular , Testosterona/metabolismo , Testosterona/biosíntesis
2.
Bull Exp Biol Med ; 177(1): 10-14, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38954295

RESUMEN

Spatial learning, memory, and reactivity of the hypothalamic-pituitary-adrenocortical system (HPA axis) were studied in adult male rats, whose mothers during pregnancy were subjected to acute moderate normobaric hypoxia, or repeated injections of buspirone, an agonist of type 1A serotonergic receptors (5HT1A), or their combination. Prenatal treatment with buspirone in rats with prenatal hypoxia impaired learning ability during the first day of 5-day training. A decrease in the effectiveness of long-term memory in comparison with short-term memory was revealed in two groups of rats: prenatal treatment with buspirone in combination with hypoxia and injection of physiological saline without hypoxia. The effectiveness of long-term memory and the level of corticosterone in response to stress did not differ between the groups, which can indicate adaptation of the 5HT1A receptor and the HPA axis to the prenatal buspirone and normobaric hypoxia during ontogeny.


Asunto(s)
Buspirona , Sistema Hipotálamo-Hipofisario , Hipoxia , Efectos Tardíos de la Exposición Prenatal , Buspirona/farmacología , Animales , Embarazo , Femenino , Ratas , Masculino , Efectos Tardíos de la Exposición Prenatal/metabolismo , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Hipoxia/fisiopatología , Hipoxia/metabolismo , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/metabolismo , Corticosterona/sangre , Corticosterona/metabolismo , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/metabolismo , Cognición/efectos de los fármacos , Cognición/fisiología , Ratas Wistar , Receptor de Serotonina 5-HT1A/metabolismo , Aprendizaje por Laberinto/efectos de los fármacos , Memoria a Largo Plazo/efectos de los fármacos , Memoria a Largo Plazo/fisiología , Estrés Fisiológico/efectos de los fármacos
3.
Int J Mol Sci ; 25(13)2024 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-39000204

RESUMEN

Fear conditioning evokes a physiologic release of glucocorticoids that assists learning. As a cochaperone in the glucocorticoid receptor complex, FKBP51 modulates stress-induced glucocorticoid signaling and may influence conditioned fear responses. This study combines molecular and behavioral approaches to examine whether locally reducing FKBP51 expression in the ventral hippocampus is sufficient to affect fear-related behaviors. We hypothesized that reducing FKBP51 expression in the VH would increase glucocorticoid signaling to alter auditory fear conditioning. Adult male rats were injected with an adeno-associated virus (AAV) vector expressing short hairpin - RNAs (shRNA) targeting FKBP5 into the ventral hippocampus to reduce FKBP5 levels or a control AAV. Infusion of FKBP5-shRNA into the ventral hippocampus decreased auditory fear acquisition and recall. Although animals injected with FKBP5-shRNA showed less freezing during extinction recall, the difference was due to a reduced fear recall rather than improved extinction. Reducing ventral hippocampus FKBP51 did not affect exploratory behavior in either the open field test or the elevated zero maze test but did increase passive behavior in the forced swim test, suggesting that the reduction in auditory fear recall was not due to more active responses to acute stress. Furthermore, lower ventral hippocampus FKBP51 levels did not alter corticosterone release in response to restraint stress, suggesting that the reduced fear recall was not due to lower corticosterone release. Our findings suggest FKBP51 in the ventral hippocampus plays a selective role in modulating fear-learning processes and passive behavioral responses to acute stress rather than hypothalamic-pituitary-adrenal axis reactivity or exploratory responses.


Asunto(s)
Miedo , Hipocampo , Proteínas de Unión a Tacrolimus , Animales , Masculino , Miedo/fisiología , Proteínas de Unión a Tacrolimus/metabolismo , Proteínas de Unión a Tacrolimus/genética , Hipocampo/metabolismo , Ratas , Corticosterona/metabolismo , Corticosterona/sangre , Ratas Sprague-Dawley , ARN Interferente Pequeño/metabolismo , ARN Interferente Pequeño/genética , Receptores de Glucocorticoides/metabolismo , Extinción Psicológica/fisiología
4.
PLoS One ; 19(7): e0299179, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39028705

RESUMEN

The African claw-toed frog, Xenopus laevis, is a well-established laboratory model for the biology of vertebrate oogenesis, fertilisation, and development at embryonic, larval, and metamorphic stages. For ovulation, X. laevis females are usually injected with chorionic gonadotropin, whereupon they lay typically hundreds to thousands of eggs in a day. After being rested for a minimum of three months, animals are re-used. The literature suggests that adult females can lay much larger numbers of eggs in a short period. Here, we compared the standard "single ovulation" protocol with a "double ovulation" protocol, in which females were ovulated, then re-ovulated after seven days and then rested for three months before re-use. We quantified egg number, fertilisation rate (development to cleavage stage), and corticosterone secretion rate as a measure of stress response for the two protocol groups over seven 3-month cycles. We found no differences in egg number-per-ovulation or egg quality between the groups and no long-term changes in any measures over the 21-month trial period. Corticosterone secretion was elevated by ovulation, similarly for the single ovulation as for the first ovulation in the double-ovulation protocol, but more highly for the second ovulation (to a level comparable to that seen following shipment) in the latter. However, both groups exhibited the same baseline secretion rates by the time of the subsequent cycle. Double ovulation is thus transiently more stressful/demanding than single ovulation but within the levels routinely experienced by laboratory X. laevis. Noting that "stress hormone" corticosterone/cortisol secretion is linked to physiological processes, such as ovulation, that are not necessarily harmful to the individual, we suggest that the benefits of a doubling in egg yield-per-cycle per animal without loss of egg quality or signs of acute or long-term harm may outweigh the relatively modest and transient corticosterone elevation we observed. The double ovulation protocol therefore represents a potential new standard practice for promoting the "3Rs" (animal use reduction, refinement and replacement) mission for Xenopus research.


Asunto(s)
Corticosterona , Fertilización , Ovulación , Xenopus laevis , Animales , Femenino , Ovulación/fisiología , Corticosterona/metabolismo , Óvulo , Gonadotropina Coriónica/administración & dosificación
5.
Mol Metab ; 87: 101986, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38992428

RESUMEN

OBJECTIVE: During infection, metabolism and immunity react dynamically to promote survival through mechanisms that remain unclear. Pro-opiomelanocortin (POMC) cleavage products are produced and released in the brain and in the pituitary gland. One POMC cleavage product, alpha-melanocyte-stimulating hormone (α-MSH), is known to regulate food intake and energy expenditure and has anti-inflammatory effects. However, it is not known whether α-MSH is required to regulate physiological anti-inflammatory responses. We recently developed a novel mouse model with a targeted mutation in Pomc (Pomctm1/tm1 mice) to block production of all α-MSH forms which are required to regulate metabolism. To test whether endogenous α-MSH is required to regulate immune responses, we compared acute bacterial lipopolysaccharide (LPS)-induced inflammation between Pomctm1/tm1 and wild-type Pomcwt/wt mice. METHODS: We challenged 10- to 14-week-old male Pomctm1/tm1 and Pomcwt/wt mice with single i.p. injections of either saline or low-dose LPS (100 µg/kg) and monitored immune and metabolic responses. We used telemetry to measure core body temperature (Tb), ELISA to measure circulating cytokines, corticosterone and α-MSH, and metabolic chambers to measure body weight, food intake, activity, and respiration. We also developed a mass spectrometry method to measure three forms of α-MSH produced in the mouse hypothalamus and pituitary gland. RESULTS: LPS induced an exaggerated immune response in Pomctm1/tm1 compared to Pomcwt/wt mice. Both groups of mice were hypoactive and hypothermic following LPS administration, but Pomctm1/tm1 mice were significantly more hypothermic compared to control mice injected with LPS. Pomctm1/tm1 mice also had reduced oxygen consumption and impaired metabolic responses to LPS compared to controls. Pomctm1/tm1 mice had increased levels of key proinflammatory cytokines at 2 h and 4 h post LPS injection compared to Pomcwt/wt mice. Lastly, Pomcwt/wt mice injected with LPS compared to saline had increased total α-MSH in circulation 2 h post injection. CONCLUSIONS: Our data indicate endogenous α-MSH contributes to the inflammatory immune responses triggered by low-dose LPS administration and suggest that targeting the melanocortin system could be a potential therapeutic for the treatment of sepsis or inflammatory disease.


Asunto(s)
Inflamación , Lipopolisacáridos , Proopiomelanocortina , alfa-MSH , Animales , alfa-MSH/metabolismo , alfa-MSH/farmacología , Lipopolisacáridos/farmacología , Ratones , Masculino , Proopiomelanocortina/metabolismo , Inflamación/metabolismo , Ratones Endogámicos C57BL , Corticosterona/metabolismo , Corticosterona/sangre
6.
J Exp Biol ; 227(15)2024 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-39022893

RESUMEN

Social status directly affects the health of humans and other animals. Low status individuals receive more antagonistic encounters, have fewer supportive relationships and have worse health outcomes. However, the physiological and cellular processes that mediate the relationship between the social environment and health are incompletely known. Epigenetic regulation of the hypothalamic-pituitary-adrenal (HPA) axis, the neuroendocrine pathway that activates in response to stressors, may be one process that is sensitive to the social environment. Here, we experimentally manipulated plumage, a key social signal in female tree swallows (Tachycineta bicolor) and quantified methylation of four genes in the HPA axis before and after treatment. We found that dulling the white breast plumage affected methylation in one gene, CRHR1; however, the effect depended on the original brightness of the bird. Methylation in this gene was correlated with baseline corticosterone levels, suggesting that DNA methylation of CRHR1 helps regulate glucocorticoid production in this species. Methylation in two other genes, FKBP5 and GR, changed over the course of the experiment, independent of treatment. These results show that methylation of these genes is labile into adulthood and suggest that epigenetic regulation of the HPA axis could help birds respond to current environmental conditions.


Asunto(s)
Metilación de ADN , Plumas , Sistema Hipotálamo-Hipofisario , Receptores de Hormona Liberadora de Corticotropina , Golondrinas , Animales , Femenino , Plumas/fisiología , Golondrinas/genética , Golondrinas/fisiología , Receptores de Hormona Liberadora de Corticotropina/genética , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipotálamo-Hipofisario/fisiología , Proteínas de Unión a Tacrolimus/genética , Proteínas de Unión a Tacrolimus/metabolismo , Corticosterona/sangre , Corticosterona/metabolismo , Sistema Hipófiso-Suprarrenal/metabolismo , Sistema Hipófiso-Suprarrenal/fisiología , Epigénesis Genética , Estrés Fisiológico/genética , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Proteínas Aviares/genética , Proteínas Aviares/metabolismo
7.
Sci Rep ; 14(1): 13787, 2024 06 14.
Artículo en Inglés | MEDLINE | ID: mdl-38877207

RESUMEN

Cultural and genetic inheritance combine to enable rapid changes in trait expression, but their relative importance in determining trait expression across generations is not clear. Birdsong is a socially learned cognitive trait that is subject to both cultural and genetic inheritance, as well as being affected by early developmental conditions. We sought to test whether early-life conditions in one generation can affect song acquisition in the next generation. We exposed one generation (F1) of nestlings to elevated corticosterone (CORT) levels, allowed them to breed freely as adults, and quantified their son's (F2) ability to copy the song of their social father. We also quantified the neurogenetic response to song playback through immediate early gene (IEG) expression in the auditory forebrain. F2 males with only one corticosterone-treated parent copied their social father's song less accurately than males with two control parents. Expression of ARC in caudomedial nidopallium (NCM) correlated with father-son song similarity, and patterns of expression levels of several IEGs in caudomedial mesopallium (CMM) in response to father song playback differed between control F2 sons and those with a CORT-treated father only. This is the first study to demonstrate that developmental conditions can affect social learning and neurogenetic responses in a subsequent generation.


Asunto(s)
Corticosterona , Aprendizaje , Vocalización Animal , Animales , Vocalización Animal/fisiología , Masculino , Aprendizaje/fisiología , Corticosterona/metabolismo , Femenino , Pinzones/fisiología , Prosencéfalo/metabolismo , Prosencéfalo/fisiología , Genes Inmediatos-Precoces
8.
J Reprod Immunol ; 164: 104276, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38896933

RESUMEN

Many endocrine or non-endocrine factors are involved in sperm production. Although reproductive hormones are very important for the initiation and maintenance of spermatogenesis, other factors, such as inflammation and oxidative stress, affect spermatogenesis. The aim of this study is to evaluate the relationships between sperm parameters and hormones, oxidative stress, and inflammation status. We conducted this study on 40 rats. Sperm parameters (motility, abnormal sperm rate, and dead sperm rate), oxidative stress (malondialdehyde, glutathione, glutathione peroxidase, and catalase), inflammation (NF-κß, TNF-α, IL-1ß, IL-6, and IL-10), and hormone parameters (follicle-stimulating hormone, luteinizing hormone, testosterone, melatonin, and corticosterone) were determined. Relationships between mentioned parameters were investigated by canonical correlation analysis. Canonical correlation coefficients for these data sets (sperm-oxidative stress, sperm-inflammation, and sperm-hormone parameters) were found to be strongly significant (rc= 0.875, p<0.001; rc= 0.868, p<0.001; rc= 0.886, p<0.001, respectively). The rate of explanation of oxidative stress, inflammation parameters and hormones by sperm parameters was 61.80 %, 56.10 % and 63.90 %, respectively. Canonical correlation analysis results have revealed that dead sperm rate is mostly related to nuclear factor-kappa beta (NF-κß), catalase, and corticosterone. CCA, which has taken into account the multiple relationships, has revealed that multidimensional evaluation of data sets can provide important and innovative information to researchers for the assessment of relationships between sperm, oxidative stress, inflammation, and hormone parameters.


Asunto(s)
Inflamación , Estrés Oxidativo , Espermatozoides , Masculino , Animales , Estrés Oxidativo/inmunología , Ratas , Espermatozoides/inmunología , Espermatozoides/metabolismo , Inflamación/inmunología , Espermatogénesis/inmunología , Testosterona/sangre , Testosterona/metabolismo , Motilidad Espermática , Citocinas/metabolismo , Corticosterona/sangre , Corticosterona/metabolismo , Ratas Wistar , FN-kappa B/metabolismo , Hormona Luteinizante/sangre , Hormona Luteinizante/metabolismo , Hormona Folículo Estimulante/sangre , Hormona Folículo Estimulante/metabolismo
9.
J Reprod Immunol ; 164: 104288, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38924811

RESUMEN

Thymic atrophy affects T cell generation and migration to the periphery, thereby affecting T cell pool diversity. However, the mechanisms underlying thymic atrophy have not been fully elucidated. Here, gonadotropin-releasing hormone (GnRH) immunization and surgical castration did not affect thymocyte proliferation, but significantly reduced the apoptosis and increased the survival rate of CD4-CD8-, CD4+CD8+, CD4+CD8-, and CD4-CD8+ thymocytes. Following testosterone supplementation in rats subjected to GnRH immunization and surgical castration, thymocyte proliferation remained unchange, but the apoptosis of CD4-CD8-, CD4+CD8+, CD4+CD8-, and CD4-CD8+ thymocytes significantly increased. Transcriptome analyses of the thymus after GnRH immunization and surgical castration showed a significant reduction in the thymus's response to corticosterone. Cholesterol metabolism and the synthesis and secretion of corticosterone were significantly reduced. Analysis of the enzyme levels involved in the corticosterone synthesis pathway revealed that corticosterone synthesis in thymocytes was significantly reduced after GnRH immunization and surgical castration, whereas exogenous testosterone supplementation relieved this process. Testosterone promoted thymocyte apoptosis in a concentration-dependent manner, and induced corticosterone secretion in vitro. Blocking the intracellular androgen receptor (AR) signaling pathway did not significantly affect thymocyte apoptosis, but blocking the glucocorticoid receptor (GR) signaling pathway significantly reduced it. Our findings indicate that testosterone regulates thymus remodeling by affecting corticosterone synthesis in thymocytes, which activates GR signal transduction and promotes thymocyte apoptosis.


Asunto(s)
Apoptosis , Receptores de Glucocorticoides , Transducción de Señal , Testosterona , Timocitos , Timo , Animales , Masculino , Testosterona/metabolismo , Apoptosis/inmunología , Ratas , Transducción de Señal/inmunología , Transducción de Señal/efectos de los fármacos , Timo/inmunología , Timo/metabolismo , Timo/patología , Receptores de Glucocorticoides/metabolismo , Timocitos/inmunología , Timocitos/metabolismo , Hormona Liberadora de Gonadotropina/metabolismo , Corticosterona/metabolismo , Corticosterona/sangre , Células Cultivadas , Ratas Sprague-Dawley , Receptores Androgénicos/metabolismo , Orquiectomía
10.
Brain Behav Immun ; 120: 464-470, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38925419

RESUMEN

The ability to detect and respond to sickness in others promotes survival. Here we show that mouse dams respond to immune challenged pups by mirroring their inflammatory response. Dams with pups subjected to immune challenge displayed a marked induction of inflammatory mediators in both the brain and the periphery, accompanied by an increase in maternal behaviors and corticosterone levels. This social transmission of inflammation did not require physical contact, and it contributed to the stress hormone response in the dams. In adult dyads, interaction with an immune challenged cagemate did not elicit robust inflammatory signaling but induced an increased responsiveness to a subsequent immune challenge. The identification of social transmission of inflammation, or inflammatory responsiveness, may open new avenues for research on social behavior, just like the description of similar phenomena such as observational fear and transmitted pain has done.


Asunto(s)
Corticosterona , Inflamación , Conducta Social , Animales , Ratones , Inflamación/inmunología , Inflamación/metabolismo , Femenino , Corticosterona/sangre , Corticosterona/metabolismo , Ratones Endogámicos C57BL , Encéfalo/metabolismo , Encéfalo/inmunología , Conducta Materna/fisiología , Masculino , Conducta Animal/fisiología
11.
J Endocrinol ; 262(2)2024 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-38829241

RESUMEN

Glucocorticoids modulate glucose homeostasis, acting on metabolically active tissues such as liver, skeletal muscle, and adipose tissue. Intracellular regulation of glucocorticoid action in adipose tissue impacts metabolic responses to obesity. ATP-binding cassette family C member 1 (ABCC1) is a transmembrane glucocorticoid transporter known to limit the accumulation of exogenously administered corticosterone in adipose tissue. However, the role of ABCC1 in the regulation of endogenous glucocorticoid action and its impact on fuel metabolism has not been studied. Here, we investigate the impact of Abcc1 deficiency on glucocorticoid action and high-fat-diet (HFD)-induced obesity. In lean male mice, deficiency of Abcc1 increased endogenous corticosterone levels in skeletal muscle and adipose tissue but did not impact insulin sensitivity. In contrast, Abcc1-deficient male mice on HFD displayed impaired glucose and insulin tolerance, and fasting hyperinsulinaemia, without alterations in tissue corticosterone levels. Proteomics and bulk RNA sequencing revealed that Abcc1 deficiency amplified the transcriptional response to an obesogenic diet in adipose tissue but not in skeletal muscle. Moreover, Abcc1 deficiency impairs key signalling pathways related to glucose metabolism in both skeletal muscle and adipose tissue, in particular those related to OXPHOS machinery and Glut4. Together, our results highlight a role for ABCC1 in regulating glucose homeostasis, demonstrating diet-dependent effects that are not associated with altered tissue glucocorticoid concentrations.


Asunto(s)
Tejido Adiposo , Corticosterona , Dieta Alta en Grasa , Resistencia a la Insulina , Proteínas Asociadas a Resistencia a Múltiples Medicamentos , Músculo Esquelético , Obesidad , Animales , Masculino , Dieta Alta en Grasa/efectos adversos , Ratones , Obesidad/metabolismo , Obesidad/genética , Obesidad/etiología , Tejido Adiposo/metabolismo , Resistencia a la Insulina/fisiología , Corticosterona/sangre , Corticosterona/metabolismo , Músculo Esquelético/metabolismo , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Ratones Noqueados , Ratones Endogámicos C57BL , Glucosa/metabolismo
12.
Int J Mol Sci ; 25(10)2024 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-38791102

RESUMEN

Congenital Adrenal Hyperplasia (CAH) is an autosomal recessive disorder impairing cortisol synthesis due to reduced enzymatic activity. This leads to persistent adrenocortical overstimulation and the accumulation of precursors before the blocked enzymatic step. The predominant form of CAH arises from mutations in CYP21A2, causing 21-hydroxylase deficiency (21-OHD). Despite emerging treatment options for CAH, it is not always possible to physiologically replace cortisol levels and counteract hyperandrogenism. Moreover, there is a notable absence of an effective in vivo model for pre-clinical testing. In this work, we developed an animal model for CAH with the clinically relevant point mutation p.R484Q in the previously humanized CYP21A2 mouse strain. Mutant mice showed hyperplastic adrenals and exhibited reduced levels of corticosterone and 11-deoxycorticosterone and an increase in progesterone. Female mutants presented with higher aldosterone concentrations, but blood pressure remained similar between wildtype and mutant mice in both sexes. Male mutant mice have normal fertility with a typical testicular appearance, whereas female mutants are infertile, exhibit an abnormal ovarian structure, and remain in a consistent diestrus phase. Conclusively, we show that the animal model has the potential to contribute to testing new treatment options and to prevent comorbidities that result from hormone-related derangements and treatment-related side effects in CAH patients.


Asunto(s)
Hiperplasia Suprarrenal Congénita , Modelos Animales de Enfermedad , Esteroide 21-Hidroxilasa , Animales , Hiperplasia Suprarrenal Congénita/genética , Hiperplasia Suprarrenal Congénita/patología , Hiperplasia Suprarrenal Congénita/metabolismo , Esteroide 21-Hidroxilasa/genética , Esteroide 21-Hidroxilasa/metabolismo , Ratones , Femenino , Masculino , Humanos , Corticosterona/metabolismo , Corticosterona/sangre , Aldosterona/metabolismo , Glándulas Suprarrenales/metabolismo , Glándulas Suprarrenales/patología , Mutación , Progesterona/metabolismo
13.
Redox Biol ; 73: 103196, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38772149

RESUMEN

Hippocampal neural stem/progenitor cells (NSPCs) are highly vulnerable to different stress stimuli, resulting in adult neurogenesis decline and eventual cognitive defects. Our previous study demonstrated that NOD-like receptor family pyrin domain-containing 6 (Nlrp6) highly expressed in NSPCs played a critical role in sustaining hippocampal neurogenesis to resist stress-induced depression, but the underlying mechnistms are still unclear. Here, we found that Nlrp6 depletion led to cognitive defects and hippocampal NSPC loss in mice. RNA-sequencing analysis of the primary NSPCs revealed that Nlrp6 deficiency altered gene expression profiles of mitochondrial energy generation and ferroptotic process. Upon siNlrp6 transfection, as well as corticosterone (CORT) exposure, downregulation of Nlrp6 suppressed retinoic acid-inducible gene I (RIG-1)/mitochondrial antiviral signaling proteins (MAVS)-mediated autophagy, but drove NSPC ferroptotic death. More interesting, short chain fatty acids (SCFAs) upregulated Nlrp6 expression and promoted RIG-1/MAVS-mediated mitophagy, preventing CORT-induced NSPC ferroptosis. Our study further demonstrates that Nlrp6 should be a sensor for RIG-1/MAVS-mediated mitophagy and play a critical role in maintain mitochondrial homeostasis of hippocampal NSPCs. These results suggests that Nlrp6 should be a potential drug target to combat neurodegenerative diseases relative with chronic stress.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Corticosterona , Proteína 58 DEAD Box , Ferroptosis , Mitofagia , Células-Madre Neurales , Animales , Ratones , Proteína 58 DEAD Box/metabolismo , Proteína 58 DEAD Box/genética , Corticosterona/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Células-Madre Neurales/metabolismo , Hipocampo/metabolismo , Mitocondrias/metabolismo , Transducción de Señal , Receptores de Superficie Celular
14.
Gen Comp Endocrinol ; 355: 114545, 2024 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-38701975

RESUMEN

In birds, patterns of development of the adrenocortical response to stressors vary among individuals, types of stressors, and species. Since there are benefits and costs of exposure to elevated glucocorticoids, this variation is presumably a product of selection such that animals modulate glucocorticoid secretion in contexts where doing so increases their fitness. In this study, we evaluated hypothalamo-pituitary-adrenal (HPA) activity in first-hatched free-living seabird nestlings that engage in intense sibling competition and facultative siblicide (black-legged kittiwakes, Rissa tridactyla). We sampled 5 day old chicks (of the ∼45 day nestling period), a critical early age when food availability drives establishment of important parent-offspring and intra-brood dynamics. We experimentally supplemented parents with food ("supplemented") and measured chick baseline corticosterone secretion and capacity to rapidly increase corticosterone in response to an acute challenge (handling and 15 min of restraint in a bag). We also used topical administration of corticosterone to evaluate the ability of chicks to downregulate physiologically relevant corticosterone levels on a short time scale (minutes). We found that 5 day old chicks are not hypo-responsive but release corticosterone in proportion to the magnitude of the challenge, showing differences in baseline between parental feeding treatments (supplemented vs non-supplemented), moderate increases in response to handling, and a larger response to restraint (comparable to adults) that also differed between chicks from supplemented and control nests. Topical application of exogenous corticosterone increased circulating levels nearly to restraint-induced levels and induced downregulation of HPA responsiveness to the acute challenge of handling. Parental supplemental feeding did not affect absorbance/clearance or negative feedback. Thus, while endogenous secretion of corticosterone in young chicks is sensitive to environmental context, other aspects of the HPA function, such as rapid negative feedback and/or the ability to clear acute elevations in corticosterone, are not. We conclude that 5 day old kittiwake chicks are capable of robust adrenocortical responses to novel challenges, and are sensitive to parental food availability, which may be transduced behaviorally, nutritionally, or via maternal effects. Questions remain about the function of such rapid, large acute stress-induced increases in corticosterone in very young chicks.


Asunto(s)
Charadriiformes , Corticosterona , Animales , Corticosterona/metabolismo , Corticosterona/sangre , Charadriiformes/fisiología , Charadriiformes/metabolismo , Sistema Hipotálamo-Hipofisario/metabolismo , Estrés Fisiológico , Sistema Hipófiso-Suprarrenal/metabolismo , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Femenino , Masculino
15.
Gen Comp Endocrinol ; 354: 114544, 2024 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-38705419

RESUMEN

Fecal samples are a non-invasive and relatively accessible matrix for investigating physiological processes in resident killer whale (Orcinus orca) populations. The high lipid content of the diet (primarily salmonids) leads to lower density fecal material and slower dispersion, facilitating sample collection. As fecal discharge is relatively infrequent and the volume of sample is variable, maximizing analytical options is an important consideration. Here we present an extraction methodology to measure hormones and lipid content from the same fecal aliquot. Lipid extractions are commonly conducted using chloroform and methanol from Folch or Bligh and Dyer (B&D), while alcohol is the primary solvent for hormone extraction. We evaluated the possibility of using the methanol layer from lipid extractions to assess fecal steroid hormone levels. Folch and B&D methanol residues were assayed form metabolites of progesterone (PMs) and corticosterone (GCs), and results were compared to aliquots extracted in 70 % ethanol. Hormone concentrations measured in the methanol layer from Folch and B&D extractions were 55 % to 79 % lower than concentrations in 70 % ethanol. We developed mathematical corrections, using linear regression models fitted to Folch or B&D methanol vs 70 % ethanol hormone concentrations (p < 0.01). Fecal concentrations of PMs and GCs from methanol extractions were biologically validated and are significantly higher in confirmed pregnant females compared to non-pregnant individuals (p < 0.05). This study demonstrates that lipid extraction protocols may be used for the analysis of multiple biomarkers, maximizing the use of small-volume samples.


Asunto(s)
Heces , Orca , Animales , Femenino , Corticosterona/metabolismo , Corticosterona/análisis , Heces/química , Lípidos/análisis , Progesterona/análisis , Progesterona/metabolismo , Orca/metabolismo
16.
Endocrinology ; 165(6)2024 Apr 29.
Artículo en Inglés | MEDLINE | ID: mdl-38712392

RESUMEN

Long-term ß-adrenoceptor (ß-AR) stimulation is a pathological mechanism associated with cardiovascular diseases resulting in endothelial and perivascular adipose tissue (PVAT) dysfunction. In this study, we aimed to identify whether ß-adrenergic signaling has a direct effect on PVAT. Thoracic aorta PVAT was obtained from male Wistar rats and cultured ex vivo with the ß-AR agonist isoproterenol (Iso; 1 µM) or vehicle for 24 hours. Conditioned culture medium (CCM) from Iso-treated PVAT induced a marked increase in aorta contractile response, induced oxidative stress, and reduced nitric oxide production in PVAT compared to vehicle. In addition, Iso-treated PVAT and PVAT-derived differentiated adipocytes exhibited higher corticosterone release and protein expression of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), an enzyme responsible for de novo synthesis of corticosterone. Macrophages exposed to Iso also exhibited increased corticosterone release in response to ß-AR stimulation. Incubation of Iso-treated PVAT and PVAT-derived differentiated adipocytes with ß3-AR antagonist restored aorta contractile function modulated by Iso-CCM and normalized 11ß-HSD1 protein expression. These results show that ß3-AR signaling leads to upregulation of 11ß-HSD1 in PVAT, thus increasing corticosterone release and contributing to impair the anticontractile function of this tissue.


Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1 , Corticosterona , Isoproterenol , Animales , Masculino , Ratas , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/genética , Adipocitos/metabolismo , Adipocitos/efectos de los fármacos , Tejido Adiposo/metabolismo , Agonistas Adrenérgicos beta/farmacología , Aorta Torácica/efectos de los fármacos , Aorta Torácica/metabolismo , Corticosterona/metabolismo , Medios de Cultivo Condicionados/farmacología , Isoproterenol/farmacología , Óxido Nítrico/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas Wistar , Receptores Adrenérgicos beta/metabolismo
17.
Integr Comp Biol ; 64(1): 15-26, 2024 Jul 26.
Artículo en Inglés | MEDLINE | ID: mdl-38734888

RESUMEN

There is a large body of evidence linking increased noise to negative health effects for animals. Anthropogenic noise induces behavioral and physiological reactions across a range of taxa and increased traffic noise affects glucocorticoid (GC) hormones associated with the stress response in amphibians. GCs help to maintain homeostasis while balancing energetic trade-offs between reproduction, growth, and activity. Stressors during early development can impact fitness at later life stages. We measured growth, activity, and GCs in response to high levels of traffic noise in two tadpole species that differ in life history: Acris crepitans and Rana berlandieri. We predicted that earlier exposures to traffic noise will slow down the development and alter the behavior and GC concentrations differently than later exposures. Subjects were initially either exposed to natural levels of traffic noise for 8 days (early exposure) or a white noise control (later exposure), then the treatment was switched. Activity was measured via focal sampling and tadpoles were categorized as active if movement was detected. Tadpoles exposed to white noise initially maintained mass and activity throughout the experiment and early exposure to traffic noise had a greater impact on mass, activity, and GCs. Tadpoles exposed to traffic noise initially lost mass, with A. crepitans regaining mass but not R. berlandieri. When exposed earlier to traffic noise, R. berlandieri increased movement when shifted to the white noise treatment while A. crepitans did not significantly change activity. Acris creptians had higher corticosterone release rates compared to R. berlandieri, and in both species, release rates were higher for tadpoles exposed to noise earlier. The longer-lived R. berlandieri allocated more of their energetic resources into activity, while the shorter-lived A. crepitans allocated energy toward growth. Rana berlandieri and A. crepitans utilized different coping strategies to contend with early exposure to traffic noise, potentially due to differences in life histories. Our findings suggest that these tadpoles employ different coping mechanisms to modulate stress responses in noise-polluted environments, and these mechanisms could influence their fitness later in life. Further study is needed to understand the impact in more sensitive tadpole species.


Asunto(s)
Glucocorticoides , Larva , Animales , Larva/crecimiento & desarrollo , Larva/fisiología , Glucocorticoides/metabolismo , Ruido del Transporte/efectos adversos , Ranidae/fisiología , Ranidae/crecimiento & desarrollo , Especificidad de la Especie , Anuros/fisiología , Anuros/crecimiento & desarrollo , Corticosterona/metabolismo , Estrés Fisiológico
18.
Sci Rep ; 14(1): 12430, 2024 05 30.
Artículo en Inglés | MEDLINE | ID: mdl-38816541

RESUMEN

Dietary trans 10, cis 12-conjugated linoleic acid (t10c12-CLA) is a potential candidate in anti-obesity trials. A transgenic mouse was previously successfully established to determine the anti-obesity properties of t10c12-CLA in male mice that could produce endogenous t10c12-CLA. To test whether there is a different impact of t10c12-CLA on lipid metabolism in both sexes, this study investigated the adiposity and metabolic profiles of female Pai mice that exhibited a dose-dependent expression of foreign Pai gene and a shift of t10c12-CLA content in tested tissues. Compared to their gender-match wild-type littermates, Pai mice had no fat reduction but exhibited enhanced lipolysis and thermogenesis by phosphorylated hormone-sensitive lipase and up-regulating uncoupling proteins in brown adipose tissue. Simultaneously, Pai mice showed hepatic steatosis and hypertriglyceridemia by decreasing gene expression involved in lipid and glucose metabolism. Further investigations revealed that t10c10-CLA induced excessive prostaglandin E2, adrenaline, corticosterone, glucagon and inflammatory factors in a dose-dependent manner, resulting in less heat release and oxygen consumption in Pai mice. Moreover, fibroblast growth factor 21 overproduction only in monoallelic Pai/wt mice indicates that it was sensitive to low doses of t10c12-CLA. These results suggest that chronic t10c12-CLA has system-wide effects on female health via synergistic actions of various hormones.


Asunto(s)
Corticosterona , Dinoprostona , Epinefrina , Factores de Crecimiento de Fibroblastos , Glucagón , Ácidos Linoleicos Conjugados , Ratones Transgénicos , Animales , Femenino , Factores de Crecimiento de Fibroblastos/metabolismo , Factores de Crecimiento de Fibroblastos/genética , Ratones , Ácidos Linoleicos Conjugados/farmacología , Ácidos Linoleicos Conjugados/metabolismo , Corticosterona/metabolismo , Dinoprostona/metabolismo , Glucagón/metabolismo , Epinefrina/metabolismo , Termogénesis/efectos de los fármacos , Termogénesis/genética , Masculino , Metabolismo de los Lípidos/efectos de los fármacos , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Pardo/efectos de los fármacos , Hígado Graso/metabolismo , Hígado Graso/genética , Lipólisis/efectos de los fármacos , Hipertrigliceridemia/metabolismo , Hipertrigliceridemia/genética , Adiposidad/efectos de los fármacos
19.
Int J Mol Sci ; 25(10)2024 May 16.
Artículo en Inglés | MEDLINE | ID: mdl-38791468

RESUMEN

Maternal type 2 diabetes mellitus (T2DM) has been shown to result in foetal programming of the hypothalamic-pituitary-adrenal (HPA) axis, leading to adverse foetal outcomes. T2DM is preceded by prediabetes and shares similar pathophysiological complications. However, no studies have investigated the effects of maternal prediabetes on foetal HPA axis function and postnatal offspring development. Hence, this study investigated the effects of pregestational prediabetes on maternal HPA axis function and postnatal offspring development. Pre-diabetic (PD) and non-pre-diabetic (NPD) female Sprague Dawley rats were mated with non-prediabetic males. After gestation, male pups born from the PD and NPD groups were collected. Markers of HPA axis function, adrenocorticotropin hormone (ACTH) and corticosterone, were measured in all dams and pups. Glucose tolerance, insulin and gene expressions of mineralocorticoid (MR) and glucocorticoid (GR) receptors were further measured in all pups at birth and their developmental milestones. The results demonstrated increased basal concentrations of ACTH and corticosterone in the dams from the PD group by comparison to NPD. Furthermore, the results show an increase basal ACTH and corticosterone concentrations, disturbed MR and GR gene expression, glucose intolerance and insulin resistance assessed via the Homeostasis Model Assessment (HOMA) indices in the pups born from the PD group compared to NPD group at all developmental milestones. These observations reveal that pregestational prediabetes is associated with maternal dysregulation of the HPA axis, impacting offspring HPA axis development along with impaired glucose handling.


Asunto(s)
Sistema Hipotálamo-Hipofisario , Sistema Hipófiso-Suprarrenal , Estado Prediabético , Animales , Femenino , Masculino , Embarazo , Ratas , Hormona Adrenocorticotrópica/sangre , Hormona Adrenocorticotrópica/metabolismo , Corticosterona/sangre , Corticosterona/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Sistema Hipotálamo-Hipofisario/metabolismo , Resistencia a la Insulina , Sistema Hipófiso-Suprarrenal/metabolismo , Estado Prediabético/metabolismo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Ratas Sprague-Dawley , Receptores de Glucocorticoides/metabolismo , Receptores de Glucocorticoides/genética , Receptores de Mineralocorticoides/metabolismo , Receptores de Mineralocorticoides/genética
20.
Biochemistry ; 63(8): 1026-1037, 2024 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-38564530

RESUMEN

The mitochondrial enzyme cytochrome P450 11B2 (aldosterone synthase) catalyzes the 3 terminal transformations in the biosynthesis of aldosterone from 11-deoxycorticosterone (DOC): 11ß-hydroxylation to corticosterone, 18-hydroxylation, and 18-oxidation. Prior studies have shown that P450 11B2 produces more aldosterone from DOC than from the intermediate corticosterone and that the reaction sequence is processive, with intermediates remaining bound to the active site between oxygenation reactions. In contrast, P450 11B1 (11ß-hydroxylase), which catalyzes the terminal step in cortisol biosynthesis, shares a 93% amino acid sequence identity with P450 11B2, converts DOC to corticosterone, but cannot synthesize aldosterone from DOC. The biochemical and biophysical properties of P450 11B2, which enable its unique 18-oxygenation activity and processivity, yet are not also represented in P450 11B1, remain unknown. To understand the mechanism of aldosterone biosynthesis, we introduced point mutations at residue 320, which partially exchange the activities of P450 11B1 and P450 11B2 (V320A and A320V, respectively). We then investigated NADPH coupling efficiencies, binding kinetics and affinities, and product formation of purified P450 11B1 and P450 11B2, wild-type, and residue 320 mutations in phospholipid vesicles and nanodiscs. Coupling efficiencies for the 18-hydroxylase reaction with corticosterone as the substrate failed to correlate with aldosterone synthesis, ruling out uncoupling as a relevant mechanism. Conversely, corticosterone dissociation rates correlated inversely with aldosterone production. We conclude that intermediate dissociation kinetics, not coupling efficiency, enable P450 11B2 to synthesize aldosterone via a processive mechanism. Our kinetic data also suggest that the binding of DOC to P450 11B enzymes occurs in at least two distinct steps, favoring an induced-fit mechanism.


Asunto(s)
Aldosterona , Esteroide 11-beta-Hidroxilasa , Esteroide 11-beta-Hidroxilasa/química , Esteroide 11-beta-Hidroxilasa/genética , Esteroide 11-beta-Hidroxilasa/metabolismo , Corticosterona/metabolismo , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Citocromo P-450 CYP11B2/genética , Citocromo P-450 CYP11B2/química , Citocromo P-450 CYP11B2/metabolismo , Catálisis , Cinética
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