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1.
Int J Mol Sci ; 25(10)2024 May 07.
Article in English | MEDLINE | ID: mdl-38791102

ABSTRACT

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.


Subject(s)
Adrenal Hyperplasia, Congenital , Disease Models, Animal , Steroid 21-Hydroxylase , Animals , Adrenal Hyperplasia, Congenital/genetics , Adrenal Hyperplasia, Congenital/pathology , Adrenal Hyperplasia, Congenital/metabolism , Steroid 21-Hydroxylase/genetics , Steroid 21-Hydroxylase/metabolism , Mice , Female , Male , Humans , Corticosterone/metabolism , Corticosterone/blood , Aldosterone/metabolism , Adrenal Glands/metabolism , Adrenal Glands/pathology , Mutation , Progesterone/metabolism
2.
Int J Mol Sci ; 25(10)2024 May 16.
Article in English | MEDLINE | ID: mdl-38791468

ABSTRACT

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.


Subject(s)
Adrenocorticotropic Hormone , Corticosterone , Hypothalamo-Hypophyseal System , Pituitary-Adrenal System , Prediabetic State , Rats, Sprague-Dawley , Animals , Hypothalamo-Hypophyseal System/metabolism , Pituitary-Adrenal System/metabolism , Female , Pregnancy , Prediabetic State/metabolism , Rats , Adrenocorticotropic Hormone/blood , Adrenocorticotropic Hormone/metabolism , Corticosterone/blood , Corticosterone/metabolism , Male , Receptors, Glucocorticoid/metabolism , Receptors, Glucocorticoid/genetics , Receptors, Mineralocorticoid/metabolism , Receptors, Mineralocorticoid/genetics , Prenatal Exposure Delayed Effects/metabolism , Diabetes Mellitus, Type 2/metabolism , Insulin Resistance
3.
Endocrinology ; 165(6)2024 Apr 29.
Article in English | MEDLINE | ID: mdl-38712392

ABSTRACT

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.


Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1 , Corticosterone , Isoproterenol , Rats, Wistar , Animals , Male , Rats , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , 11-beta-Hydroxysteroid Dehydrogenase Type 1/genetics , Isoproterenol/pharmacology , Corticosterone/metabolism , Adrenergic beta-Agonists/pharmacology , Adipose Tissue/metabolism , Aorta, Thoracic/drug effects , Aorta, Thoracic/metabolism , Adipocytes/metabolism , Adipocytes/drug effects , Receptors, Adrenergic, beta/metabolism , Oxidative Stress/drug effects , Nitric Oxide/metabolism , Culture Media, Conditioned/pharmacology
4.
Sci Rep ; 14(1): 12430, 2024 05 30.
Article in English | MEDLINE | ID: mdl-38816541

ABSTRACT

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.


Subject(s)
Corticosterone , Dinoprostone , Epinephrine , Fibroblast Growth Factors , Glucagon , Linoleic Acids, Conjugated , Mice, Transgenic , Animals , Female , Fibroblast Growth Factors/metabolism , Fibroblast Growth Factors/genetics , Mice , Linoleic Acids, Conjugated/pharmacology , Linoleic Acids, Conjugated/metabolism , Corticosterone/metabolism , Dinoprostone/metabolism , Glucagon/metabolism , Epinephrine/metabolism , Thermogenesis/drug effects , Thermogenesis/genetics , Male , Lipid Metabolism/drug effects , Adipose Tissue, Brown/metabolism , Adipose Tissue, Brown/drug effects , Fatty Liver/metabolism , Fatty Liver/genetics , Lipolysis/drug effects , Hypertriglyceridemia/metabolism , Hypertriglyceridemia/genetics , Adiposity/drug effects
5.
Gen Comp Endocrinol ; 354: 114544, 2024 08 01.
Article in English | MEDLINE | ID: mdl-38705419

ABSTRACT

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.


Subject(s)
Feces , Whale, Killer , Animals , Feces/chemistry , Whale, Killer/metabolism , Corticosterone/metabolism , Corticosterone/analysis , Progesterone/analysis , Progesterone/metabolism , Female , Lipids/analysis
6.
Nan Fang Yi Ke Da Xue Xue Bao ; 44(3): 411-419, 2024 Mar 20.
Article in Chinese | MEDLINE | ID: mdl-38597431

ABSTRACT

OBJECTIVE: To investigate the role of Rho/ROCK signaling pathway in mediating restraint stress-induced blood-brain barrier (BBB) injury in the amygdala of rats. METHODS: Sixty male SD rats were randomized equally into control group (with food and water deprivation for 6 h per day), restraint stress group (with restraint for 6 h per day), stress + fasudil treatment (administered by intraperitoneal injection at 1 mg/100 g 30 min before the 6-h restraint) group, and fasudil treatment alone group. The elevated plus-maze test was used to detect behavioral changes of the rats, serum corticosterone and S100B levels were determined with ELISA, and Evans Blue leakage in the brain tissue was examined to evaluate the changes in BBB permeability. The changes in expression levels of tight junction proteins in the amygdala were detected using immunofluorescence assay and Western blotting, and Rho/ROCK pathway activation was detected by Pull-down test and Western blotting. Ultrastructural changes of the cerebral microvascular endothelial cells were observed using transmission electron microscopy. RESULTS: Compared with those in the control group, the rats in restrain stress group and stress+fasudil group showed obvious anxiety-like behavior with significantly increased serum corticosterone level (P<0.001). Compared with those in the control group and stress+fasudil group, the rat models of restrain stress showed more obvious Evans Blue leakage and higher S100B expression (P<0.01) but lower expressions of tight junction proteins in the amygdala. Pull-down test and Western blotting confirmed that the expression levels of RhoA-GTP, ROCK2 and P-MLC 2 were significantly higher in stress group than in the control group and stress + fasudil group (P<0.05). Transmission electron microscopy revealed obvious ultrastructural changes in the cerebral microvascular endothelial cells in the rat models of restrain stress. CONCLUSION: Restraint stress induces BBB injury in the amygdala of rats by activating the Rho/ROCK signaling pathway.


Subject(s)
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs & derivatives , Blood-Brain Barrier , Endothelial Cells , Rats , Male , Animals , Blood-Brain Barrier/metabolism , Rats, Sprague-Dawley , Evans Blue/metabolism , Corticosterone/metabolism , Tight Junction Proteins/metabolism , Signal Transduction , rho-Associated Kinases/metabolism
7.
Nan Fang Yi Ke Da Xue Xue Bao ; 44(3): 515-522, 2024 Mar 20.
Article in Chinese | MEDLINE | ID: mdl-38597443

ABSTRACT

OBJECTIVE: To explore the inhibitory effect of saikosonin a (SSa) on pentylenetetrazol-induced acute epilepsy seizures in a mouse model of depression and explore the mechanism mediating this effect. METHODS: Male C57BL/6J mouse models of depression was established by oral administration of corticosterone via drinking water for 3 weeks, and acute epileptic seizures were induced by intraperitoneal injection of a single dose of pentylenetetrazole. The effect of intraperitoneal injection of SSa prior to the treatment on depressive symptoms and epileptic seizures were assessed using behavioral tests, epileptic seizure grading and hippocampal morphology observation. ELISA was used to detect blood corticosterone levels of the mice, and RTqPCR was performed to detect the pro- and anti-inflammatory factors. Microglia activation in the mice was observed using immunofluorescence staining. RESULTS: The mouse model of corticosterone-induced depression showed body weight loss and obvious depressive behaviors with significantly increased serum corticosterone level (all P < 0.05). Compared with those with pentylenetetrazole-induced epilepsy alone, the epileptic mice with comorbid depression showed significantly shorter latency of epileptic seizures, increased number, grade and duration of of seizures, reduced Nissl bodies in hippocampal CA1 and CA3 neurons, increased number of Iba1-positive cells, and significantly enhanced hippocampal expressions of IL-1ß, IL-10, TNF-α and IFN-γ. Pretreatment of the epileptic mice with SSa significantly prolonged the latency of epileptic seizures, reduced the number, duration, and severity of seizures, increased the number of Nissl bodies, decreased the number of Iba1-positive cells, and reduced the expression levels of IL-1ß, IL-10, TNF-α, and IFN-γ in the hippocampus (P < 0.05). CONCLUSION: Depressive state aggravates epileptic seizures, increases microglia activation, and elevates inflammation levels. SSA treatment can alleviate acute epileptic seizures in mouse models of depression possibly by suppressing microglia activation-mediated inflammation.


Subject(s)
Epilepsy , Oleanolic Acid/analogs & derivatives , Pentylenetetrazole , Saponins , Male , Mice , Animals , Pentylenetetrazole/adverse effects , Interleukin-10 , Microglia/metabolism , Tumor Necrosis Factor-alpha/metabolism , Depression , Corticosterone/metabolism , Corticosterone/pharmacology , Corticosterone/therapeutic use , Mice, Inbred C57BL , Seizures/chemically induced , Seizures/drug therapy , Seizures/metabolism , Epilepsy/chemically induced , Epilepsy/drug therapy , Epilepsy/metabolism , Hippocampus/metabolism , Inflammation/metabolism , Interleukin-1beta/metabolism , Disease Models, Animal
8.
Biochemistry ; 63(8): 1026-1037, 2024 Apr 16.
Article in English | MEDLINE | ID: mdl-38564530

ABSTRACT

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.


Subject(s)
Aldosterone , Steroid 11-beta-Hydroxylase , Steroid 11-beta-Hydroxylase/chemistry , Steroid 11-beta-Hydroxylase/genetics , Steroid 11-beta-Hydroxylase/metabolism , Corticosterone/metabolism , Cytochrome P-450 Enzyme System/genetics , Cytochrome P-450 Enzyme System/metabolism , Cytochrome P-450 CYP11B2/genetics , Cytochrome P-450 CYP11B2/chemistry , Cytochrome P-450 CYP11B2/metabolism , Catalysis , Kinetics
9.
PLoS One ; 19(4): e0302374, 2024.
Article in English | MEDLINE | ID: mdl-38635564

ABSTRACT

While chronic stress induces learning and memory impairments, acute stress may facilitate or prevent memory consolidation depending on whether it occurs during the learning event or before it, respectively. On the other hand, it has been shown that histone acetylation regulates long-term memory formation. This study aimed to evaluate the effect of two inhibitors of class I histone deacetylases (HDACs), 4-phenylbutyrate (PB) and IN14 (100 mg/kg/day, ip for 2 days), on memory performance in mice exposed to a single 15-min forced swimming stress session. Plasma corticosterone levels were determined 30 minutes after acute swim stress in one group of mice. In another experimental series, independent groups of mice were trained in one of three different memory tasks: Object recognition test, Elevated T maze, and Buried food location test. Subsequently, the hippocampi were removed to perform ELISA assays for histone deacetylase 2 (HDAC2) expression. Acute stress induced an increase in plasma corticosterone levels, as well as hippocampal HDAC2 content, along with an impaired performance in memory tests. Moreover, PB and IN14 treatment prevented memory loss in stressed mice. These findings suggest that HDAC2 is involved in acute stress-induced cognitive impairment. None of the drugs improved memory in non-stressed animals, indicating that HDACs inhibitors are not cognitive boosters, but rather potentially useful drugs for mitigating memory deficits.


Subject(s)
Corticosterone , Histone Deacetylases , Mice , Animals , Histone Deacetylases/metabolism , Corticosterone/metabolism , Learning , Memory Disorders/drug therapy , Memory Disorders/etiology , Memory Disorders/metabolism , Memory, Long-Term , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylase Inhibitors/therapeutic use , Histone Deacetylase Inhibitors/metabolism , Hippocampus/metabolism
10.
Stress ; 27(1): 2312467, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38557197

ABSTRACT

Chronic stress exposure during development can have lasting behavioral consequences that differ in males and females. More specifically, increased depressive behaviors in females, but not males, are observed in both humans and rodent models of chronic stress. Despite these known stress-induced outcomes, the molecular consequences of chronic adolescent stress in the adult brain are less clear. The stress hormone corticosterone activates the glucocorticoid receptor, and activity of the receptor is regulated through interactions with co-chaperones-such as the immunophilin FK506 binding proteins 5 (FKBP5). Previously, it has been reported that the adult stress response is modified by a history of chronic stress; therefore, the current study assessed the impact of chronic adolescent stress on the interactions of the glucocorticoid receptor (GR) with its regulatory co-chaperone FKBP5 in response to acute stress in adulthood. Although protein presence for FKBP5 did not differ by group, assessment of GR-FKBP5 interactions demonstrated that adult females with a history of chronic adolescent stress had elevated GR-FKBP5 interactions in the hippocampus following an acute stress challenge which could potentially contribute to a reduced translocation pattern given previous literature describing the impact of FKBP5 on GR activity. Interestingly, the altered co-chaperone interactions of the GR in the stressed female hippocampus were not coupled to an observable difference in transcription of GR-regulated genes. Together, these studies show that chronic adolescent stress causes lasting changes to co-chaperone interactions with the glucocorticoid receptor following stress exposure in adulthood and highlight the potential role that FKBP5 plays in these modifications. Understanding the long-term implications of adolescent stress exposure will provide a mechanistic framework to guide the development of interventions for adult disorders related to early life stress exposures.


Subject(s)
Receptors, Glucocorticoid , Stress, Psychological , Tacrolimus Binding Proteins , Animals , Female , Male , Rats , Corticosterone/metabolism , Hippocampus/metabolism , Receptors, Glucocorticoid/genetics , Receptors, Glucocorticoid/metabolism , Stress, Psychological/metabolism , Tacrolimus Binding Proteins/genetics , Tacrolimus Binding Proteins/metabolism
11.
Biomolecules ; 14(3)2024 Feb 23.
Article in English | MEDLINE | ID: mdl-38540689

ABSTRACT

Stress is known to induce a reduction in adult hippocampal neurogenesis (AHN) and anxiety-like behaviors. Glucocorticoids (GCs) are secreted in response to stress, and the hippocampus possesses the greatest levels of GC receptors, highlighting the potential of GCs in mediating stress-induced hippocampal alterations and behavior deficits. Herein, RNA-sequencing (RNA-seq) analysis of the hippocampus following corticosterone (CORT) exposure revealed the central regulatory role of the p21 (Cdkna1a) gene, which exhibited interactions with oxidative stress-related differentially expressed genes (DEGs), suggesting a potential link between p21 and oxidative stress-related pathways. Remarkably, p21-overexpression in the hippocampal dentate gyrus partially recapitulated CORT-induced phenotypes, including reactive oxygen species (ROS) accumulation, diminished AHN, dendritic atrophy, and the onset of anxiety-like behaviors. Significantly, inhibiting ROS exhibited a partial rescue of anxiety-like behaviors and hippocampal alterations induced by p21-overexpression, as well as those induced by CORT, underscoring the therapeutic potential of targeting ROS or p21 in the hippocampus as a promising avenue for mitigating anxiety disorders provoked by chronic stress.


Subject(s)
Corticosterone , Hippocampus , Corticosterone/pharmacology , Corticosterone/metabolism , Reactive Oxygen Species , Hippocampus/metabolism , Depression/drug therapy , Neurogenesis/physiology
12.
Science ; 383(6688): 1252-1259, 2024 Mar 15.
Article in English | MEDLINE | ID: mdl-38484078

ABSTRACT

Overgeneralization of fear to harmless situations is a core feature of anxiety disorders resulting from acute stress, yet the mechanisms by which fear becomes generalized are poorly understood. In this study, we show that generalized fear in mice results from a transmitter switch from glutamate to γ-aminobutyric acid (GABA) in serotonergic neurons of the lateral wings of the dorsal raphe. Similar change in transmitter identity was found in the postmortem brains of individuals with posttraumatic stress disorder (PTSD). Overriding the transmitter switch in mice prevented the acquisition of generalized fear. Corticosterone release and activation of glucocorticoid receptors mediated the switch, and prompt antidepressant treatment blocked the cotransmitter switch and generalized fear. Our results provide important insight into the mechanisms involved in fear generalization.


Subject(s)
Brain , Fear , Generalization, Response , Glutamic Acid , Stress Disorders, Post-Traumatic , Stress, Psychological , gamma-Aminobutyric Acid , Animals , Mice , Brain/metabolism , Fear/physiology , gamma-Aminobutyric Acid/metabolism , Neurons/metabolism , Stress Disorders, Post-Traumatic/metabolism , Stress, Psychological/metabolism , Glutamic Acid/metabolism , Corticosterone/metabolism , Receptors, Glucocorticoid/metabolism , Humans
13.
Article in English | MEDLINE | ID: mdl-38552775

ABSTRACT

There is an urgent need for novel antidepressants, given that approximately 30% of those diagnosed with depression do not respond adequately to first-line treatment. Additionally, monoaminergic-based antidepressants have a substantial therapeutic time-lag, often taking months to reach full therapeutic effect. Ketamine, an N-methyl-d-aspartate receptor (NMDAR) antagonist is the only current effective rapid-acting antidepressant, demonstrating efficacy within hours and lasting up to two weeks with an acute dose. Reelin, an extracellular matrix glycoprotein, has demonstrated rapid-acting antidepressant-like effects at 24 h, however the exact timescale of these effects has not been investigated. To determine the short and long-term effects of reelin, female Long Evans rats (n = 120) underwent a chronic corticosterone (CORT; or vehicle) paradigm (40 mg/kg, 21 days). On day 21, rats were treated with reelin (3µg; i.v.), ketamine (10 mg/kg; i.p.), both reelin and ketamine (same doses), or vehicle (saline). Behavioural and biological effects were then evaluated at 1 h, 6 h, 12 h, and 1 week after treatment. The 1-week cohort continued CORT injections to ensure the effect of chronic stress was not lost. Individually, both reelin and ketamine significantly rescued CORT-induced behaviour and hippocampal reelin expression at all timepoints. Ketamine rescued a decrease in dendritic maturity as induced by CORT. Synergistic effects of reelin and ketamine appeared at 1-week, suggesting a potential additive effect of the antidepressant-like actions. Taken together, this study provides further support for reelin-based therapeutics to develop rapid-acting antidepressant.


Subject(s)
Corticosterone , Ketamine , Animals , Female , Rats , Antidepressive Agents/pharmacology , Antidepressive Agents/therapeutic use , Corticosterone/metabolism , Depression/drug therapy , Depression/chemically induced , Hippocampus/metabolism , Ketamine/pharmacology , Ketamine/therapeutic use , Rats, Long-Evans , Reelin Protein/pharmacology , Reelin Protein/therapeutic use
14.
Adv Sci (Weinh) ; 11(18): e2307926, 2024 May.
Article in English | MEDLINE | ID: mdl-38460156

ABSTRACT

Prostanoids are endogenous lipid bioactive mediators that play essential roles in physiological processes such as glucocorticoid secretion. Here, it is found that the thromboxane (Tx)A2 receptor (TP) is highly expressed in the adrenal cortex of mice. Both global and adrenocortical-specific deletion of the TP receptor lead to increased adiposity in mice by elevating corticosterone synthesis. Mechanistically, the TP receptor deletion increases the phosphorylation of steroidogenic acute regulatory protein (StAR) and corticosterone synthesis in adrenal cortical cells by suppressing p-p38-mediated phosphorylation of 14-3-3γ adapter protein at S71. The activation of the p38 in the adrenal cortical cells by forced expression of the MKK6EE gene attenuates hypercortisolism in TP-deficient mice. These observations suggest that the TxA2/TP signaling regulates adrenal corticosterone homeostasis independent of the hypothalamic-pituitary-adrenal axis and the TP receptor may serve as a promising therapeutic target for hypercortisolism.


Subject(s)
Corticosterone , Phosphoproteins , Signal Transduction , Thromboxane A2 , Animals , Mice , Corticosterone/metabolism , Phosphoproteins/metabolism , Phosphoproteins/genetics , Thromboxane A2/metabolism , Adrenal Cortex/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism , p38 Mitogen-Activated Protein Kinases/genetics , Male , Mice, Inbred C57BL
15.
J Exp Zool A Ecol Integr Physiol ; 341(5): 587-596, 2024 06.
Article in English | MEDLINE | ID: mdl-38497306

ABSTRACT

There is a need to fully know the physiology of Eurasian beaver due to its essential role in environmental homeostasis. However, a "human factor" impacts this, including stress conditions and environmental pollution. Adrenal glands protect these all. The regulation of endocrine processes by nonclassical androgen and estrogen signaling, the first and fastest control, is still a matter of research. The specific analyses performed here in mature female and male beaver adrenals contained: anatomical and histological examinations, expression and localization of membrane androgen receptor (zinc transporter, Zinc- and Iron-like protein 9; ZIP9) and membrane estrogen receptor coupled with G protein (GPER), and measurement of zinc (Zn2+) and copper (Ca2+) ion levels and corticosterone levels. We revealed normal anatomical localization, size, and tissue histology in female and male beavers, respectively. Equally, ZIP9 and GPER were localized in the membrane of all adrenal cortex cells. The protein expression of these receptors was higher (p < 0.001) in male than female adrenal cortex cells. Similarly, Zn2+ and Ca2+ ion levels were higher (p < 0.05, p < 0.01) in male than female adrenal cortex. The increased corticosterone levels (p < 0.001) were detected in the adrenal cortex of females when compared to males. The present study is the first to report the presence of nonclassical androgen and estrogen signaling and its possible regulatory function in the adrenal cortex of Eurasian beavers. We assume that this first-activated and fast-transmitted regulation can be important in the context of the effect of environmental physical and chemical stressors especially on adrenal cortex cells. The beaver adrenals may constitute an additional supplementary model for searching for universal mechanisms of adrenal cortex physiology and diseases.


Subject(s)
Adrenal Cortex , Receptors, Androgen , Receptors, Estrogen , Rodentia , Signal Transduction , Animals , Female , Male , Receptors, Estrogen/metabolism , Receptors, Androgen/metabolism , Adrenal Cortex/metabolism , Signal Transduction/physiology , Rodentia/physiology , Corticosterone/blood , Corticosterone/metabolism , Zinc/metabolism , Copper/metabolism
16.
Microbiol Spectr ; 12(5): e0347323, 2024 May 02.
Article in English | MEDLINE | ID: mdl-38497712

ABSTRACT

This study aimed to explore alterations in growth performance, glycolipid metabolism disorders, intestinal mucosal barrier, cecal microbiota community, and metabolites in a chronic corticosterone (CORT)-induced stress (CCIS) broiler model. Results showed that compared with control (CON) broilers, in CCIS broilers: (i) the final body weight (BW), BW gain, and average daily gain were significantly reduced. (ii) The glycolipid metabolism disorder and impairement of intestinal immune barrier and physical barrier function were observed. (iii) Diversity and richness of cecal microbiota were obviously increased. From phylum to genus level, the abundances of Firmicutes and Faecalibacterium were significantly decreased, while the abundances of Proteobacteria, RuminococcaceaeUCG-005, and Escherichia coli (Shigella) were significantly increased. Microbial network analysis and function pathways prediction showed that cecal microbiota was mainly concentrated in translation, metabolism, nucleotide metabolism, and endocrine system. (iv) The main differential metabolites identified include steroids and their derivatives, amino acids, fatty acids, and carbohydrates; among which 37 metabolites were significantly upregulated, while 27 metabolites were significantly downregulated. These differential metabolites were mainly enriched in pathways related to steroid hormone biosynthesis and tyrosine metabolism. (v) Correlation between cecal microbiota and glycolipid metabolism indexes showed that BW and total cholesterol (TC) were positively correlated with Christensenellaceae_R.7_group and Escherichia_Shigella, respectively. Furthermore, the downregulated Faecalibacterium and Christensenellaceae were negatively correlated with the upregulated differentially expressed metabolites. These findings suggested that CCIS altered cecal microbiota composition and metabolites, which led to glycolipid metabolism disorder and impaired the nutritional metabolism and immune homeostasis, providing a theoretical basis for efforts to eliminate the harm of chronic stress to human health and animal production. IMPORTANCE: The study aimed to determine the influence of altered intestinal mucosal barrier, cecum flora community, and metabolites on anti-growth performance, glycolipid metabolism disorders of chronic corticosterone (CORT)-induced stress (CCIS) broilers. Compared with control (CON) broilers, in CCIS broilers: (i) anti-growth performance, glycolipid metabolism disorder, and impaired intestinal immune barrier and physical barrier function were observed. (ii) From phylum to genus level, the abundances of Firmicutes and Faecalibacterium were decreased; whereas, the abundances of Proteobacteria, RuminococcaceaeUCG-005, and Escherichia coli (Shigella) were increased. (iii) Differential metabolites in cecum were mainly enriched in steroid hormone biosynthesis and tyrosine metabolism. (iv) Body weight (BW) and total cholesterol (TC) were positively correlated with Christensenellaceae_R.7_group and Escherichia_Shigella, respectively, while downregulated Faecalibacterium and Christensenellaceae were negatively correlated with upregulated metabolites. Our findings suggest that CCIS induces anti-growth performance and glycolipid metabolism disorder by altering cecum flora and metabolites, providing a theoretical basis for efforts to eliminate the effect of chronic stress on human health and animal production.


Subject(s)
Bacteria , Cecum , Chickens , Corticosterone , Gastrointestinal Microbiome , Glycolipids , Intestinal Mucosa , Stress, Physiological , Animals , Chickens/microbiology , Chickens/growth & development , Corticosterone/metabolism , Glycolipids/metabolism , Intestinal Mucosa/metabolism , Intestinal Mucosa/microbiology , Cecum/microbiology , Cecum/metabolism , Bacteria/classification , Bacteria/metabolism , Bacteria/genetics , Bacteria/isolation & purification
17.
Gen Comp Endocrinol ; 352: 114490, 2024 06 01.
Article in English | MEDLINE | ID: mdl-38460737

ABSTRACT

Stressful experiences in early life can alter phenotypic expression later in life. For instance, in vertebrates, early life nutrient restriction can modify later life activity of the hypothalamic-pituitary-adrenal/interrenal axis (the HPI in amphibians), including the up- and downstream regulatory components of glucocorticoid signaling. Early life nutrient restriction can also influence later life behavior and metabolism (e.g., fat accumulation). Yet, less is known about whether nutrient stress-induced carryover effects on HPA/HPI axis regulation can vary across environmental contexts, such as the type of diet on which nutrient restriction occurs. Here, we experimentally address this question using the plains spadefoot toad (Spea bombifrons), whose larvae develop in ephemeral habitats that impose intense competition over access to two qualitatively distinct diet types: detritus and live shrimp prey. Consistent with diet type-specific carryover effects of early life nutrient restriction on later life HPI axis regulation, we found that temporary nutrient restriction at the larval stage reduced juvenile (i.e., post-metamorphic) brain gene expression of an upstream glucocorticoid regulator (corticotropin-releasing hormone) and two downstream regulators (glucocorticoid and mineralocorticoid receptors) only on the shrimp diet. These patterns are consistent with known diet type-specific effects of larval nutrient restriction on juvenile corticosterone and behavior. Additionally, larval nutrient restriction increased juvenile body fat levels. Our study indicates that HPA/HPI axis regulatory responses to nutrient restriction can vary remarkably across diet types. Such diet type-specific regulation of the HPA/HPI axis might provide a basis for developmental or evolutionary decoupling of stress-induced carryover effects.


Subject(s)
Corticotropin-Releasing Hormone , Glucocorticoids , Animals , Glucocorticoids/metabolism , Corticotropin-Releasing Hormone/metabolism , Hypothalamo-Hypophyseal System/metabolism , Corticosterone/metabolism , Anura/metabolism , Nutrients , Gene Expression , Pituitary-Adrenal System/metabolism , Receptors, Glucocorticoid/genetics , Receptors, Glucocorticoid/metabolism
18.
Front Immunol ; 15: 1330094, 2024.
Article in English | MEDLINE | ID: mdl-38361932

ABSTRACT

Microbiota plays a role in shaping the HPA-axis response to psychological stressors. To examine the role of microbiota in response to acute immune stressor, we stimulated the adaptive immune system by anti-CD3 antibody injection and investigated the expression of adrenal steroidogenic enzymes and profiling of plasma corticosteroids and their metabolites in specific pathogen-free (SPF) and germ-free (GF) mice. Using UHPLC-MS/MS, we showed that 4 hours after immune challenge the plasma levels of pregnenolone, progesterone, 11-deoxycorticosterone, corticosterone (CORT), 11-dehydroCORT and their 3α/ß-, 5α-, and 20α-reduced metabolites were increased in SPF mice, but in their GF counterparts, only CORT was increased. Neither immune stress nor microbiota changed the mRNA and protein levels of enzymes of adrenal steroidogenesis. In contrast, immune stress resulted in downregulated expression of steroidogenic genes (Star, Cyp11a1, Hsd3b1, Hsd3b6) and upregulated expression of genes of the 3α-hydroxysteroid oxidoreductase pathway (Akr1c21, Dhrs9) in the testes of SPF mice. In the liver, immune stress downregulated the expression of genes encoding enzymes with 3ß-hydroxysteroid dehydrogenase (HSD) (Hsd3b2, Hsd3b3, Hsd3b4, Hsd3b5), 3α-HSD (Akr1c14), 20α-HSD (Akr1c6, Hsd17b1, Hsd17b2) and 5α-reductase (Srd5a1) activities, except for Dhrs9, which was upregulated. In the colon, microbiota downregulated Cyp11a1 and modulated the response of Hsd11b1 and Hsd11b2 expression to immune stress. These data underline the role of microbiota in shaping the response to immune stressor. Microbiota modulates the stress-induced increase in C21 steroids, including those that are neuroactive that could play a role in alteration of HPA axis response to stress in GF animals.


Subject(s)
Hypothalamo-Hypophyseal System , Microbiota , Male , Mice , Animals , Hypothalamo-Hypophyseal System/metabolism , Cholesterol Side-Chain Cleavage Enzyme/genetics , Cholesterol Side-Chain Cleavage Enzyme/metabolism , Tandem Mass Spectrometry , Pituitary-Adrenal System/metabolism , Steroids/metabolism , Corticosterone/metabolism
19.
Cell ; 187(3): 764-781.e14, 2024 Feb 01.
Article in English | MEDLINE | ID: mdl-38306985

ABSTRACT

Pregnancy induces dramatic metabolic changes in females; yet, the intricacies of this metabolic reprogramming remain poorly understood, especially in primates. Using cynomolgus monkeys, we constructed a comprehensive multi-tissue metabolome atlas, analyzing 273 samples from 23 maternal tissues during pregnancy. We discovered a decline in metabolic coupling between tissues as pregnancy progressed. Core metabolic pathways that were rewired during primate pregnancy included steroidogenesis, fatty acid metabolism, and arachidonic acid metabolism. Our atlas revealed 91 pregnancy-adaptive metabolites changing consistently across 23 tissues, whose roles we verified in human cell models and patient samples. Corticosterone and palmitoyl-carnitine regulated placental maturation and maternal tissue progenitors, respectively, with implications for maternal preeclampsia, diabetes, cardiac hypertrophy, and muscle and liver regeneration. Moreover, we found that corticosterone deficiency induced preeclampsia-like inflammation, indicating the atlas's potential clinical value. Overall, our multi-tissue metabolome atlas serves as a framework for elucidating the role of metabolic regulation in female health during pregnancy.


Subject(s)
Metabolomics , Pregnancy , Animals , Female , Humans , Pregnancy/metabolism , Corticosterone/metabolism , Metabolome/physiology , Placenta/metabolism , Pre-Eclampsia , Primates/metabolism
20.
Brain Res Bull ; 208: 110903, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38367676

ABSTRACT

Chronic stress is a pervasive and complex issue that contributes significantly to various mental and physical health disorders. Using the previously established chronic unpredictable stress (CUS) model, which simulates human stress situations, it has been shown that chronic stress induces major depressive disorder (MDD) and memory deficiency. However, this established model is associated with several drawbacks, such as limited research reproducibility and the inability to sustain stress response. To resolve these issues, we developed a new CUS model (CUS+C) that included exogenous corticosterone exposure to induce continuous stress response. Thereafter, we evaluated the effect of this new model on brain health. Thus, we observed that the use of the CUS+C model decreased body and brain weight gain and induced an uncontrolled coat state as well as depressive-like behavior in adult mice. It also impaired learning memory function and cognitive abilities, reduced adult hippocampal neurogenesis as well as the number of hippocampal astrocytes, and downregulated glial fibrillary acidic protein expression in the brains of adult mice. These findings can promote the utilization and validity of the animal stress model and provide new information for the treatment of chronic stress-induced depressive and memory disorders.


Subject(s)
Corticosterone , Depressive Disorder, Major , Humans , Mice , Animals , Corticosterone/pharmacology , Corticosterone/metabolism , Depressive Disorder, Major/metabolism , Astrocytes/metabolism , Reproducibility of Results , Hippocampus/metabolism , Neurogenesis/physiology , Stress, Psychological , Depression/metabolism , Disease Models, Animal
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