Glucocorticoids In Mice Research Articles

Decreased Brain pH Underlies Behavioral and Brain Abnormalities Induced by Chronic Exposure to Glucocorticoids in Mice.

Depressed patients may exhibit glucocorticoid hypersecretion, suggesting that elevated levels of glucocorticoids may play an important role in the pathophysiology of depression. Some postmortem brain studies have shown decreased pH and increased lactate levels in psychiatric patients, implying involvement of these factors in the pathogenesis. To investigate the effects of glucocorticoids on brain pH and lactate levels, and their roles in depressive symptoms, brain pH and lactate were examined in mice treated with corticosterone (CORT), the major bioactive glucocorticoid in rodents. A single administration of CORT decreased hippocampal pH after 24 h. Three weeks of CORT treatment decreased pH in the prefrontal cortex (PFC), striatum, and hippocampus (HC), whereas intake of pH 9.0 drinking water increased pH in these brain regions. pH and lactate levels were correlated in the PFC and HC of mice treated with CORT for 3 weeks. The suppression of body weight gain and decrease in adrenal weight observed after 3 weeks of CORT treatment were not alleviated by pH 9.0 water. However, an increase in immobility time in the forced swim test and a decrease in neurogenesis in the hippocampus were alleviated. The decrease in brain pH and increase in immobility time in the forced swim test and a decrease in neurogenesis in the hippocampus induced by CORT treatment were abolished by co-treatment with the glucocorticoid receptor (GR) antagonist mifepristone. These findings indicate that decreased brain pH via GRs may be related to glucocorticoid-induced depression-like behavior and decreased hippocampal neurogenesis.

Inhibition of Thyroid Hormone Signaling in the Zona Incerta Alters Basal Metabolic Rate, Behavior, and Serum Glucocorticoids in Male Mice.

Background: It has long been known that thyroid disease can lead to changes in energy metabolism, thermoregulation, and anxiety behavior. While these actions have been partially attributed to thyroid hormone (TH) receptor α1 (TRα1) action in the brain, the precise neuroanatomical substrates have remain elusive. Methods: We used PET-CT scans to identify brain regions affected by TH. We then inhibited TRα1 signaling specifically in the most affected region, the zona incerta (ZI), a still mysterious region previously implicated in thermogenesis and anxiety. To this end, we used an adeno-associated virus (AAV) expressing a dominant-negative TRα1R384C in wild-type mice and phenotyped the animals. Finally, we used tyrosine hydroxylase-Cre mice to test specifically the contribution of ZI dopaminergic neurons. Results: Our data showed that AAV-mediated inhibition of TRα1 signaling in the ZI lead to increased energy expenditure at thermoneutrality, while body temperature regulation remained unaffected. Moreover, circulating glucocorticoid levels were increased, and a mild habituation problem was observed in the open field test. No effects were observed when TRα1 signaling was selectively inhibited in dopaminergic neurons. Conclusions: Our findings suggest that altered TH signaling in the ZI is not involved in body temperature regulation but can affect basal metabolism and modulates stress responses.

New anti-inflammatory mechanism of glucocorticoids uncovered

Glucocorticoids (GCs) are potent anti-inflammatory drugs. A new study by Auger et al. found that GCs increase itaconate, an anti-inflammatory tricarboxylic acid (TCA) cycle intermediate, by promoting movement of cytosolic pyruvate dehydrogenase (PDH) to mitochondria. Itaconate was sufficient for mediating the anti-inflammatory effects of GCs in mice, overriding the notion that nuclear glucocorticoid receptor (GR) are necessary for inflammation inhibition.

TERT mediates the U-shape of glucocorticoids effects in modulation of hippocampal neural stem cells and associated brain function.

Glucocorticoids (GCs) are steroidal hormones produced by the adrenal cortex. A physiological-level GCs have a crucial function in maintaining many cognitive processes, like cognition, memory, and mood, however, both insufficient and excessive GCs impair these functions. Although this phenomenon could be explained by the U-shape of GC effects, the underlying mechanisms are still not clear. Therefore, understanding the underlying mechanisms of GCs may provide insight into the treatments for cognitive and mood-related disorders. Consecutive administration of corticosterone (CORT, 10 mg/kg, i.g.) proceeded for 28 days to mimic excessive GCs condition. Adrenalectomy (ADX) surgery was performed to ablate endogenous GCs in mice. Microinjection of 1 μL of Ad-mTERT-GFP virus into mouse hippocampus dentate gyrus (DG) and behavioral alterations in mice were observed 4 weeks later. Different concentrations of GCs were shown to affect the cell growth and development of neural stem cells (NSCs) in a U-shaped manner. The physiological level of GCs (0.01 μM) promoted NSC proliferation invitro, while the stress level of GCs (10 μM) inhibited it. The glucocorticoid synthesis blocker metyrapone (100 mg/kg, i.p.) and ADX surgery both decreased the quantity and morphological development of doublecortin (DCX)-positive immature cells in the DG. The physiological level of GCs activated mineralocorticoid receptor and then promoted the production of telomerase reverse transcriptase (TERT); in contrast, the stress level of GCs activated glucocorticoid receptor and then reduced the expression of TERT. Overexpression of TERT by AD-mTERT-GFP reversed both chronic stresses- and ADX-induced deficiency of TERT and the proliferation and development of NSCs, chronic stresses-associated depressive symptoms, and ADX-associated learning and memory impairment. The bidirectional regulation of TERT by different GCs concentrations is a key mechanism mediating the U-shape of GC effects in modulation of hippocampal NSCs and associated brain function. Replenishment of TERT could be a common treatment strategy for GC dysfunction-associated diseases.

TMIC-67. GLIOBLASTOMA AUGMENTS SYSTEMIC IMMUNUNOSUPPRESSION UPON LOSS OF TESTOSTERONE VIA ALTERATION OF GLUCOCORTICOIDS PRODUCTION

Abstract While sex differences in incidence, genetics, and immune changes are established in glioblastoma (GBM), the specific contribution of sex hormones to these differences has not been fully explored. Testosterone has been shown to have a pro-tumorigenic effect on human and mouse GBM tumor cells. However, the systemic effect of testosterone in an immune competent model has not been tested. To test this, we performed castration or sham surgery on C57BL/6 male mice, followed by intracranial implantation of syngeneic glioma cells. Surprisingly, castrated mice exhibited more aggressive tumor growth compared to sham surgery controls, and this castration-induced aggressiveness could be reversed by administering exogenous testosterone. This finding was further confirmed by chemically blocking androgen receptor signaling using enzalutamide. We observed a significant increase in adrenocorticotropic hormone (ACTH) levels in the serum from castrated mice compared to the sham group after tumor implantation. Additionally, mass spectrometry analysis detected elevated levels of circulating glucocorticoids in castrated mice, and pharmacological blockade of glucocorticoid receptor using mifepristone reversed the shorted survival in castrated mice, but not in sham control. Flow analysis revealed decreased production of anti-tumor cytokines such as IFN-γ and TNF-α in CD4+ and CD8+ T cells from tumors and lymph nodes in castrated mice, suggesting systemic immunosuppression in these animals. Indeed, castration of immune-compromised mice, specifically NSG and RAG1KO strains, did not result in reduced survival. Moreover, when GBM cells were subcutaneously implanted into the flank, tumor growth in castrated mice was decelerated compared to sham controls. We also observed significantly lower ACTH levels in the flank tumor model compared to the brain tumor model, indicating a brain-specific effect of steroid hormones on tumor control. Taken together, these findings demonstrate that testosterone regulates T cell function through glucocorticoids, ultimately affecting GBM growth in a site-specific manner.

SAT011 Neonatal Endotoxin Exposure Has Long-term Effects On Glucocorticoid Regulation In Blood And Lymphoid Organs Of Mice

Abstract Disclosure: A. Mazurenko: None. M. Salehzadeh: None. S.R. Lim: None. K.K. Soma: None. Glucocorticoids (GCs) are steroid hormones that play vital roles in immunity. GCs are produced by the adrenal glands and also by lymphoid organs, such as bone marrow, thymus, and spleen. There is a period of decreased adrenocortical activity in neonatal humans and mice termed the stress hyporesponsive period (SHRP), which protects developing tissues from high circulating GCs and allows for fine-tuning of GC levels in lymphoid organs. In neonatal mice, GC levels increase acutely in response to the bacterial endotoxin, lipopolysaccharide (LPS). Yet, it is not known how early-life LPS exposure affects systemic and local GC levels in adulthood. We assessed whether LPS administration during the SHRP (‘first hit’) affects GC regulation in blood and lymphoid organs in adulthood when challenged again with LPS (‘second hit’). We administered LPS (50 μg/kg i.p.) or saline (vehicle control) to male and female C57BL/6J neonatal mice (PND 4 and 6, within the SHRP). We then split the mice into two groups and administered LPS (50 μg/kg i.p.) or saline to adults (PND90) (2x2 design). We collected whole blood, bone marrow, thymus, and spleen 4 hr after LPS administration at PND90. We used liquid chromatography tandem mass spectrometry (LC-MS/MS) to measure 7 steroids, including 11-deoxycorticosterone (DOC; corticosterone precursor), corticosterone (main active GC in mice), and 11-dehydrocorticosterone (DHC; corticosterone metabolite). Preliminary results show that neonatal LPS treatment altered LPS-stimulated corticosterone levels (but not baseline corticosterone levels) in adult mice. Specifically, neonatal LPS treatment increased blood corticosterone levels in LPS-treated adult males, but not females. In contrast, neonatal LPS treatment increased thymus and spleen corticosterone levels in LPS-treated adult females. There were no effects of neonatal LPS treatment on DOC and DHC levels in adult males. In contrast, neonatal LPS treatment increased thymus DOC and spleen DHC levels in LPS-treated adult females. Altogether, our results suggest that LPS exposure during the SHRP has long-term effects on GC regulation in the blood and lymphoid organs when challenged with a ‘second hit’ in adulthood. This research offers vital insights into understanding the development and regulation of the immune and endocrine systems. Critically, this study demonstrates that lymphoid organs modulate local GC levels independently of circulating GC levels. More generally, these data elucidate the long-lasting programming effects of an immunological stressor, such as neonatal sepsis, early in life. Presentation: Saturday, June 17, 2023

Suppression of mir-150–5p attenuates the anti-inflammatory effect of glucocorticoids in mice with ulcerative colitis

Glucocorticoids have been widely used in the treatment of ulcerative colitis, but not all patients benefit from this therapy due to hormone resistance. Mir-150–5p has been reported to enhance the efficacy of glucocorticoids, and low serum mir-150–5p expression has been linked to glucocorticoid resistance in ulcerative colitis patients. The aim of this study was to elucidate the mechanisms of mir-150–5p regulation on glucocorticoid resistance. An ulcerative colitis mouse model was used to evaluate changes in ulcerative colitis symptoms, inflammatory factors, and glucocorticoid resistance-related gene expression. The results showed that mir-150–5p suppression with antagomirs did not significantly interfere with or enhance the induction of ulcerative colitis symptoms by dextran sulfate sodium, but it did attenuate the inflammation inhibitory effect of dexamethasone by abnormally regulating the expression of IL-17a, IL-10, IL-2 and IL-6 levels and myeloperoxidase activity. Mir-150–5p inhibition also induced a glucocorticoid-resistant gene expression profile in colon tissues of ulcerative colitis mice, with upregulation of p-ERK, p-JNK, and HSP90 and downregulation of p-GRa, FKBP4, and HDAC2 expression. Our results indicate that mir-150–5p suppression attenuates the anti-inflammatory effect of glucocorticoids and may function as a driver element in ulcerative colitis glucocorticoid resistance. Availability of data and materialsAll data and figures analyzed in this study are available from the corresponding author by request.

Sex Differences in Long-term Outcome of Prenatal Exposure to Excess Glucocorticoids—Implications for Development of Psychiatric Disorders

Exposure to prenatal insults, such as excess glucocorticoids (GC), may lead to pathological outcomes, including neuropsychiatric disorders. The aim of the present study was to investigate the long-term effects of in utero exposure to the synthetic GC analog dexamethasone (Dex) in adult female offspring. We monitored spontaneous activity in the home cage under a constant 12 h/12 h light/dark cycle, as well as the changes following a 6-h advance of dark onset (phase shift). For comparison, we re-analysed data previously recorded in males. Dex-exposed females were spontaneously more active, and the activity onset re-entrained slower than in controls. In contrast, Dex-exposed males were less active, and the activity onset re-entrained faster than in controls. Following the phase shift, control females displayed a transient reorganisation of behaviour in light and virtually no change in dark, while Dex-exposed females showed limited variations from baseline in both light and dark, suggesting weaker photic entrainment. Next, we ran bulk RNA-sequencing in the suprachiasmatic nucleus (SCN) of Dex and control females. SPIA pathway analysis of ~ 2300 differentially expressed genes identified significantly downregulated dopamine signalling, and upregulated glutamate and GABA signalling. We selected a set of candidate genes matching the behaviour alterations and found consistent differential regulation for ~ 73% of tested genes in SCN and hippocampus tissue samples. Taken together, our data highlight sex differences in the outcome of prenatal exposure to excess GC in adult mice: in contrast to depression-like behaviour in males, the phenotype in females, defined by behaviour and differential gene expression, is consistent with ADHD models.

T Cell Energy Metabolism Is a Target of Glucocorticoids in Mice, Healthy Humans, and MS Patients.

Glucocorticoids (GCs) are used to treat inflammatory disorders such as multiple sclerosis (MS) by exerting prominent activities in T cells including apoptosis induction and suppression of cytokine production. However, little is known about their impact on energy metabolism, although it is widely accepted that this process is a critical rheostat of T cell activity. We thus tested the hypothesis that GCs control genes and processes involved in nutrient transport and glycolysis. Our experiments revealed that escalating doses of dexamethasone (Dex) repressed energy metabolism in murine and human primary T cells. This effect was mediated by the GC receptor and unrelated to both apoptosis induction and Stat1 activity. In contrast, treatment of human T cells with rapamycin abolished the repression of metabolic gene expression by Dex, unveiling mTOR as a critical target of GC action. A similar phenomenon was observed in MS patients after intravenous methylprednisolon (IVMP) pulse therapy. The expression of metabolic genes was reduced in the peripheral blood T cells of most patients 24 h after GC treatment, an effect that correlated with disease activity. Collectively, our results establish the regulation of T cell energy metabolism by GCs as a new immunomodulatory principle.

OR07-3 Hormone-Controlled Cooperative Binding of Transcription Factors Within Enhancer Clusters Drives Synergistic Induction of Fasting-Regulated Genes

Abstract During fasting, hepatocytes produce glucose in response to hormonal signals. Glucagon and glucocorticoids are principal hormones secreted during fasting that cooperate in regulating glucose production via increasing hepatic gluconeogenesis. However, how these hormone signals are integrated in hepatocytes and translated to a biological output is unknown. We used genome-wide profiling of gene expression, enhancer dynamics and transcription factor binding in primary mouse hepatocytes to uncover the mode of cooperation between glucagon and corticosterone (the major glucocorticoid in mice). We found that compared to a single treatment with either hormone alone, a dual treatment initiates a pro-gluconeogenic gene program in hepatocytes by synergistically inducing gluconeogenic genes. We show that the mechanism driving synergistic gene expression is based on glucagon-mediated enhancer activation, leading to increased binding of the glucocorticoid receptor (GR) upon corticosterone stimulation. This was shown by glucagon-dependent increases in the active enhancer mark H3K27ac at GR binding sites (both signals were measured genome-wide via chromatin immunoprecipitation sequencing). Thus, glucagon-dependent enhancer activation, mediated by the glucagon-activated transcription factor CREB, assists GR loading to specific enhancers located near synergistic gluconeogenic genes. This 'assisted loading' mechanism is enhancer-specific as GR was able to efficiently bind other enhancers without assistance by CREB. Interestingly, we found that the glucagon-CREB axis does not only activate single enhancers but is also able to activate entire enhancer clusters. Indeed, CREB binding in one enhancer unit within a cluster, led to cluster-wide enhancer activation, thereby assisting the loading of GR in other enhancer units within the cluster that are unbound by CREB directly. These chromatin and gene expression changes collectively lead to synergistic glucose production from hepatocytes in the presence of glucagon and corticosterone. In summary, we show that hepatocytes integrate extracellular signals by an enhancer-specific mechanism: glucagon activates enhancers, thereby assisting the loading of GR upon stimulation by corticosterone. This chromatin-bound integration of endocrine signals leads to synergistic gene induction and a tailored response to fasting. Presentation: Saturday, June 11, 2022 12:00 p.m. - 12:15 p.m.

Flattening of circadian glucocorticoid oscillations drives acute hyperinsulinemia and adipocyte hypertrophy.

Disruption of circadian glucocorticoid oscillations in Cushing's disease and chronic stress results in obesity and adipocyte hypertrophy, which is believed to be a main source of the harmful effects of obesity. Here, we recapitulate stress due to jet lag or work-life imbalances by flattening glucocorticoid oscillations in mice. Within 3days, mice achieve a metabolic state with persistently high insulin, but surprisingly low glucose and fatty acids in the bloodstream, that precedes a more than 2-fold increase in brown and white adipose tissue mass within 3weeks. Transcriptomic and Cd36-knockout mouse analyses show that hyperinsulinemia-mediated de novo fatty acid synthesis and Cd36-mediated fatty acid uptake drive fat mass increases. Intriguingly, this mechanism by which glucocorticoid flattening causes acute hyperinsulinemia and adipocyte hypertrophy is unexpectedly beneficial in preventing high levels of circulating fatty acids and glucose for weeks, thus serving as a protective response to preserve metabolic health during chronic stress.

Role of Macrophages and Plasminogen Activator Inhibitor-1 in Delayed Bone Repair Induced by Glucocorticoids in Mice.

Glucocorticoids delay fracture healing and induce osteoporosis. However, the mechanisms by which glucocorticoids delay bone repair have yet to be clarified. Plasminogen activator inhibitor-1 (PAI-1) is the principal inhibitor of plasminogen activators and an adipocytokine that regulates metabolism. We herein investigated the roles of macrophages in glucocorticoid-induced delays in bone repair after femoral bone injury using PAI-1-deficient female mice intraperitoneally administered with dexamethasone (Dex). Dex significantly decreased the number of F4/80-positive macrophages at the damaged site two days after femoral bone injury. It also attenuated bone injury-induced decreases in the number of hematopoietic stem cells in bone marrow in wild-type and PAI-1-deficient mice. PAI-1 deficiency significantly weakened Dex-induced decreases in macrophage number and macrophage colony-stimulating factor (M-CSF) mRNA levels at the damaged site two days after bone injury. It also significantly ameliorated the Dex-induced inhibition of macrophage phagocytosis at the damaged site. In conclusion, we herein demonstrated that Dex decreased the number of macrophages at the damaged site during early bone repair after femoral bone injury partly through PAI-1 and M-CSF in mice.

WNT7B overexpression rescues bone loss caused by glucocorticoids in mice.

Glucocorticoids, widely prescribed for anti-inflammatory and immunosuppressive purposes, are the most common secondary cause for osteoporosis and related fractures. Current anti-resorptive and anabolic therapies are insufficient for treating glucocorticoid-induced osteoporosis due to contraindications or concerns of side effects. Glucocorticoids have been shown to disrupt Wnt signaling in osteoblast-lineage cells, but the efficacy for Wnt proteins to restore bone mass after glucocorticoid therapy has not been examined. Here by using two mouse genetic models wherein WNT7B expression is temporally activated by either tamoxifen or doxycycline in osteoblast-lineage cells, we show that WNT7B recovers bone mass following glucocorticoid-induced bone loss, thanks to increased osteoblast number and function. However, WNT7B overexpression in bone either before or after glucocorticoid treatments does not ameliorate the abnormal accumulation of body fat. The study demonstrates a potent bone anabolic function for WNT7B in countering glucocorticoid-induced bone loss.

642 REDD1 (regulated in development and DNA damage 1) is essential for skin wound healing

The major adverse effects of topical glucocorticoids (GCs) are skin atrophy and impaired wound healing, especially pronounced in older patients. Previously we showed that knockout of REDD1, a negative regulator of mTOR/Akt signaling, protects skin from GCs-induced atrophy. Here we investigated whether REDD1 status affected wound healing delay induced by GCs using REDD1 KO and isogenic C57Blx129 12-15-month-old mice. Wound healing in untreated REDD1 KO mice was slightly delayed compared to WT animals. Glucocorticoid fluocinolone acetonide (FA) significantly delayed wound healing in WT and especially in REDD1 KO mice. As expected, FA inhibited keratinocyte proliferation near the wound edge in WT animals. In contrast, in REDD1 KO, FA increased the proliferation by ∼50-70%, resulting in epidermal hyperplasia above the level induced by wounding. The complex process of wound healing involves increased keratinocyte migration and proliferation at the wound edge. Thus, we accessed the effect of REDD1 on proliferation and motility using human HaCaT keratinocytes with CRISPR/Cas9-generated REDD1 KO. In a scratch assay, the wound closed faster in REDD1 KO than in WT/Cas9 cells. However, when proliferation was inhibited by Mitomycin C, WT and REDD1 KO keratinocytes showed similar migration activity. In correlation with in vivo results, REDD1 KO HaCaT cells became resistant to FA anti-growth effects. RNA-seq analysis of the WT and REDD1 KO HaCaT transcriptome revealed significant alteration of FA molecular signature and consistent upregulation of cell cycle regulators CDK1, CCNA2, CCNB1, CCNB2 and proliferation marker PCNA in REDD1 KO keratinocytes. Overall, REDD1 regulated keratinocyte growth but not motility, suggesting that abnormal, non-controlled keratinocyte proliferation during skin wound healing could be an undelaying mechanism of significant wound healing delay induced by GCs in REDD1 KO mice.

Loss of CREBRF Reduces Anxiety-like Behaviors and Circulating Glucocorticoids in Male and Female Mice.

Glucocorticoid signaling controls many key biological functions ranging from stress responses to affective states. The putative transcriptional coregulator CREB3 regulatory factor (CREBRF) reduces glucocorticoid receptor levels in vitro, suggesting that CREBRF may impact behavioral and physiological outputs. In the present study, we examined adult male and female mice with global loss of CREBRF (CrebrfKO) for anxiety-like behaviors and circulating glucocorticoids in response to various acute stress conditions. Results demonstrate that both male and female CrebrfKO mice have preserved locomotor activity but reduced anxiety-like behaviors during the light-dark box and elevated plus maze. These behavioral phenotypes were associated with lower plasma corticosterone after restraint stress. Further studies using unhandled female mice also demonstrated a loss of the diurnal circulating corticosterone rhythm in CrebrfKO mice. These results suggest that CREBRF impacts anxiety-like behavior and circulating glucocorticoids in response to acute stressors and serves as a basis for future mechanistic studies to define the impact of CREBRF in glucocorticoid-associated behavioral and physiological responses.

Analysis of Genetically Regulated Gene Expression Identifies a Prefrontal PTSD Gene, SNRNP35, Specific to Military Cohorts

To reveal post-traumatic stress disorder (PTSD) genetic risk influences on tissue-specific gene expression, we use brain and non-brain transcriptomic imputation. We impute genetically regulated gene expression (GReX) in 29,539 PTSD cases and 166,145 controls from 70 ancestry-specific cohorts and identify 18 significant GReX-PTSD associations corresponding to specific tissue-gene pairs. The results suggest substantial genetic heterogeneity based on ancestry, cohort type (military versus civilian), and sex. Two study-wide significant PTSD associations are identified in European and military European cohorts; ZNF140 is predicted to be upregulated in whole blood, and SNRNP35 is predicted to be downregulated in dorsolateral prefrontal cortex, respectively. In peripheral leukocytes from 175 marines, the observed PTSD differential gene expression correlates with the predicted differences for these individuals, and deployment stress produces glucocorticoid-regulated expression changes that include downregulation of both ZNF140 and SNRNP35. SNRNP35 knockdown in cells validates its functional role in U12-intron splicing. Finally, exogenous glucocorticoids in mice downregulate prefrontal Snrnp35 expression.

Something Else to Stress about: Perinatal Stress Attenuates CD8+ T Cell Activity in Adults

Early-life stress has adverse health effects, but the underlying mechanisms are unclear. Hong et al. demonstrate that perinatal exposure to glucocorticoids in mice reprograms the neuroendocrine stress pathway. This results in reduced glucocorticoid levels in adults, leading to attenuated anti-tumor and anti-bacterial CD8+ T cell responses.

PAI-1 is involved in delayed bone repair induced by glucocorticoids in mice.

Glucocorticoid (GC) treatments induce osteoporosis and chronic GC treatments have been suggested to induce delayed bone repair; however, the mechanisms by which GC induces delayed bone repair remain unclear. We herein investigated the roles of plasminogen activator inhibitor-1 (PAI-1) in GC-induced effects on bone repair after femoral bone injury using female mice with a PAI-1 deficiency and their wild-type counterparts. Dexamethasone (Dex) increased plasma PAI-1 levels as well as PAI-1 mRNA levels in the adipose tissues and muscles of wild-type mice. PAI-1 deficiency significantly blunted Dex-induced delayed bone repair in mice. Moreover, PAI-1 deficiency significantly blunted Runx2 mRNA levels suppressed by Dex as well as Dex-induced osteoblast apoptosis at the damaged site 7days after bone injury in mice. On the other hand, PAI-1 deficiency did not affect adipogenic gene expression enhanced by Dex at the damaged site 7days after bone injury in mice. In conclusion, we herein showed for the first time that PAI-1 is involved in delayed bone repair after bone injury induced by GC in mice. PAI-1 may influence early stage osteoblast differentiation and apoptosis during the osteoblastic restoration phase of the bone repair process.

No island-effect on glucocorticoid levels for a rodent from a near-shore archipelago

Island rodents are often larger and live at higher population densities than their mainland counterparts, characteristics that have been referred to as “island syndrome”. Island syndrome has been well studied, but few studies have tested for island-mainland differences in stress physiology. We evaluated island syndrome within the context of stress physiology of white-footed mice (Peromyscus leucopus) captured from 11 islands and five mainland sites in Thousand Islands National Park, Ontario, Canada. Stress physiology was evaluated by quantifying corticosterone (a stress biomarker), the primary glucocorticoid in mice, from hair and its related metabolites from fecal samples. White-footed mice captured in this near-shore archipelago did not display characteristics of island syndrome, nor differences in levels of hair corticosterone or fecal corticosterone metabolites compared with mainland mice. We suggest that island white-footed mice experience similar degrees of stress in the Thousand Islands compared with the mainland. Although we did not find evidence of island syndrome or differences in glucocorticoid levels, we identified relationships between internal (sex, body mass) and external (season) factors and our hormonal indices of stress in white-footed mice.

Gender and Age Differences in the Suppressive Effect of a 50 Hz Electric Field on the Immobilization-Induced Increase of Plasma Glucocorticoid in Mice.

We developed an experimental system to characterize the suppressive effect of extremely low-frequency (ELF) electric fields (EFs) on the stress response. We assessed differences in the EF effects by age and gender. Control, EF-alone, immobilization-alone, and co-treated groups were subjected to an EF (50 Hz, 10 kV/m). Co-treated mice were exposed to the EF for 60 min, with immobilization during the latter half. Our results indicate that the suppressive effects of ELF EFs on the stress response in immobilized mice occur regardless of gender or age. As stress plays an important role in the onset and progression of various diseases, these findings may have broad implications for understanding the efficacy of EFs in animal, and perhaps human, health. Bioelectromagnetics. 2020;41:156-163. © 2019 Bioelectromagnetics Society.