Studies have shown that cerebral ischemia activates neurogenesis and that stress inhibits neurogenesis.However,the role of stress hormone levels on neurogenesis following cerebral ischemia remains poorly understood.Th...Studies have shown that cerebral ischemia activates neurogenesis and that stress inhibits neurogenesis.However,the role of stress hormone levels on neurogenesis following cerebral ischemia remains poorly understood.The present study explored the possible regulatory mechanisms of adult neurogenesis under pathological conditions by examining changes and regulation of glucocorticoid receptors in adult rats subjected to transient unilateral middle cerebral artery suture occlusion.Corticosterone levels gradually increased following middle cerebral artery occlusion,and the number of glucocorticoid receptor-positive cells decreased.The number of5-bromodeoxyuridine-and nestin-positive cells significantly increased at 1 and 2 weeks after ischemia.A large number of doublecortin-positive cells migrated from the hippocampus to the cortex.At 3 weeks post-surgery,the number of 5-bromodeoxyuridine-and nestin-positive cells significantly reduced in the subventricular zone.Increased corticosterone levels decreased vascular endothelial cell proliferation and neurogenesis,and the number of glucocorticoid receptor-positive cells decreased.In the sham surgery group,vascular endothelial cell proliferation related to post-ischemic cerebral rehabilitation was not detected.Corticosterone levels increased,but the number and distribution of glucocorticoid receptor-positive cells were not changed.However,normal neuregenesis and migration of neural stem cells existed in the adult rat brain in the sham surgery group.Results suggested that glucocorticoid receptors influenced neurogenesis and were negatively regulated by glucocorticoid levels following focal cerebral ischemia and reperfusion.展开更多
Association between the reward caused by consuming drugs and the context in which they are consumed is essential in the formation of morphine-induced conditioned place preference(CPP).Glucocorticoid receptor(GRs)activ...Association between the reward caused by consuming drugs and the context in which they are consumed is essential in the formation of morphine-induced conditioned place preference(CPP).Glucocorticoid receptor(GRs)activation in different regions of the brain affects reward-based reinforcement and memory processing.A wide array of studies have demonstrated that blockage of GRs in some brain areas can have an effect on reward-related memory;however,to date there have been no systematic studies about the involvement of glucocorticoids(GCs)in morphine-related reward memory.Here,we used the GR antagonist RU38486 to investigate how GRs blockage affects the sensitization and CPP behavior during different phases of reward memory included acquisition,retrieval and reconsolidation.Interestingly,our results showed RU38486 has the ability to impair the acquisition,retrieval and reconsolidation of reward-based memory in CPP and sensitization behavior.But RU38486 by itself cannot induce CPP or conditioned place aversion(CPA)behavior.Our data provide a much more complete picture of the potential effects that glucocorticoids have on the reward memory of different phases and inhibit the sensitization behavior.展开更多
The leucocytic glucocorticoid receptors (GCR) were estimated in 20 patients with Yang-Defi-ciency Syndrome using a radioligand binding method and plasrna cortisol was measured at the same time. Re-sults showed that th...The leucocytic glucocorticoid receptors (GCR) were estimated in 20 patients with Yang-Defi-ciency Syndrome using a radioligand binding method and plasrna cortisol was measured at the same time. Re-sults showed that the levels of plasma cortisol and leucocytic GCR of patients were all significantly lower thanthe healthy control group, and the changes were more significant in 10 cases of hypofunction of endocrinopa-thy with manifestation of Yang-Deficiency and Yang-Doficiency patients aged < 40 years. The mechanism andrelationship between GCR and plasma cortisol were also discussed in this article.展开更多
BACKGROUND: The hippocampus regulates the hypothalamic-pituitary-adrenal axis through negative feedback. The hypothalamic paraventricular nucleus receives neuronal input from the hippocampus via the fomix, OBJECTIVE...BACKGROUND: The hippocampus regulates the hypothalamic-pituitary-adrenal axis through negative feedback. The hypothalamic paraventricular nucleus receives neuronal input from the hippocampus via the fomix, OBJECTIVE: To explore whether the negative feedback effect of the hippocampus on the hypothalamic-pituitary-adrenal axis is contributed to the inhibitory effect of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) in the hippocampus on the paraventricular nucleus via the fornix. DESIGN, TIME AND SETTING: Randomized, controlled, animal experiment. The study was performed at the Department of Histology and Embryology, China Medical University between September 2006 and September 2008. MATERIALS: Rabbit anti-rat anti-MR and rabbit anti-rat anti-GR antibodies were purchased from Santa Cruz Biotechnology, USA. Rabbit anti-rat anti-corticotrophin releasing hormone (CRH) and rabbit anti-rat anti-arginine vasopressin antibodies were purchased from Wuhan Boster. METHODS: A total of 90 male, Wistar rats were randomly divided into model and sham-surgery groups (n = 45). Fornix transection was performed in the model group, while the sham-surgery group underwent surgery, but no fornix transection. MAIN OUTCOME MEASURES: Immunohistochemistry was used to examine MR and GR expression in the hippocampus, as well as CRH and anti-arginine vasopressin in the paraventricular nucleus. Western blot was used to measure alterations in MR, GR, and CRH protein expression following fomix transection. RESULTS: Compared with the sham-surgery group, there were no obvious changes in MR and GR expression in the hippocampus, or CRH and anti-arginine vasopressin expression in the paraventdcular nucleus within 4 days of fornix transection. However, after 7-10 days, significantly decreased MR and GR expression in the hippocampus, and increased CRH and anti-arginine vasopmssin expression in the paraventricular nucleus were observed (P 〈 0.05-0.01). CONCLUSION: Negative feedback from the hippocampus on the hypothalamic-pituitary-adrenal axis might be mediated through the fornix, and the corticosterene actions mediated by hippocampal corticosteroid receptors indirectly modulated the hypothalamic-pituitary-adrenal axis.展开更多
Objective To explore the role of glucocorticoid (GC) receptor (GR) in rapamycin's reversion of GC resistance in humanGC-resistant T-acute lymphoblastic leukemia (ALL) CEM-C1 cells. Methods CEM-C1 cells were cul...Objective To explore the role of glucocorticoid (GC) receptor (GR) in rapamycin's reversion of GC resistance in humanGC-resistant T-acute lymphoblastic leukemia (ALL) CEM-C1 cells. Methods CEM-C1 cells were cultured in vitro and treated with rapamycin at different concentrations with or without 1 μmol/L dexamethasone (Dex). 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) test was performed to assess cell proliferation. The cell cycle and cell apoptosis were analyzed by flow cytometry. The expression of GRα mRNA was determined by real-time quantitative RT-PCR. The expression of GR, p-70S6K, Mcl-1, and Bim proteins was detected by Western blot. Results When incubated with rapamycin at different concentrations, CEM-C1 cells showed significant growth inhibition in a time- and concentration-dependent manner. The growth inhibition was synergistically increased when CEM-C1 cells were treated with rapamycin plus 1 μmol/L Dex. CEM-C1 cells treated with rapamycin alone showed no apparent apoptosis, and were arrested at G0/G1 phase. After the treatment with Dex plus rapamycin, CEM-C1 cells demonstrated apparent apoptosis and increased the cell cycle arrested at G0/G1 phase. Rapamycin combined with Dex up-regulated GRα, phosphorylated GR(p-GR), and pro-apoptotic protein Bim-EL in CEM-C1 cells, but inhibited the expression of p-p70S6K, a downstream target protein ofmTOR (mammalian target of rapamycin). Conclusion After the treatment with rapamycin plus Dex, Dex resistant CEM-C1 cells induce growth inhibition and apoptosis. The underlying mechanism may involve inhibition of the mTOR signaling pathway and also be associated with up-regulation of GR expression and activation of GC-GR signaling pathway.展开更多
Glucocorticoids(GCs)have been widely used as immunosuppressants and antiinflammatory agents to treat a variety of autoimmune and inflammatory diseases,and they fully exert their anti-inflammatory and immune-regulating...Glucocorticoids(GCs)have been widely used as immunosuppressants and antiinflammatory agents to treat a variety of autoimmune and inflammatory diseases,and they fully exert their anti-inflammatory and immune-regulating effects in the body.The effect of GCs on white blood cells is an important part of their action.GCs can cause changes in peripheral blood white blood cell counts by regulating the proliferation,differentiation,and apoptosis of white blood cells.Although the total number of white blood cells,neutrophil counts,lymphocytes,and eosinophils increases,the counts of basic granulocytes and macrophages decreases.In addition,GCs can regulate the activation and secretion of white blood cells,inhibit the secretion of a variety of pro-inflammatory cytokines,the expression of chemokines,and promote the production of anti-inflammatory cytokines.For patients on GC therapy,the effects of GCs on leukocytes were similar to the changes in peripheral blood caused by bacterial infections.Thus,we suggest that clinicians should be more cautious in assessing the presence of infection in children with long-term use of GCs and avoid overuse of antibiotics in the presence of elevated leukocytes.GCs work through genomic and non-genomic mechanisms in the human body,which are mediated by GC receptors.In recent years,studies have not fully clarified the mechanism of GCs,and further research on these mechanisms will help to develop new therapeutic strategies.展开更多
Glucocorticoids have been used in the treatment of prostate cancer to slow disease progression, improve pain control and offset side effects of chemo- and hormonal therapy. However, they may also have the potential to...Glucocorticoids have been used in the treatment of prostate cancer to slow disease progression, improve pain control and offset side effects of chemo- and hormonal therapy. However, they may also have the potential to drive prostate cancer growth via mutated androgen receptors or glucocorticoid receptors (GRs). In this review we examine historical and contemporary use of glucocorticoids in the treatment of prostate cancer, review potential mechanisms by which they may inhibit or drive prostate cancer growth, and describe potential means of defining their contribution to the biology of prostate cancer.展开更多
BACKGROUND: Studies have explored changes in neonatal rat glucocorticoid receptor (GR) expression changes following mature brain injury. OBJECTIVE: To investigate the temporal and special changes of GR during brai...BACKGROUND: Studies have explored changes in neonatal rat glucocorticoid receptor (GR) expression changes following mature brain injury. OBJECTIVE: To investigate the temporal and special changes of GR during brain development in rats with recurrent seizures. DESIGN, TIME AND SE'n'ING: A randomized, controlled animal experiment was performed at the Department of Pediatrics, Second Xiangya Hospital of Central South University, from February 2008 to March 2009. MATERIALS: Rabbit anti-rat GR monoclonal antibody was purchased from Santa Cruz Biotechnology, USA; goat anti-rabbit IgG was purchased from Zhongshan Goldenbridge Biotechnology, China. METHODS: A total of 48 Sprague-Dawley rats, 7 days old, were randomly assigned to control and seizure groups, with 24 animals in each group. Seizures were induced by inhalant flurothyl. MAIN OUTCOME MEASURES: Changes in GR protein expression in the rat cerebral cortex were detected by Western blotting analysis and immunohistochemistry. RESULTS: GR expression in the cerebral cortex of control rats significantly increased with aging (P 〈 0.05), and varied in the frontal lobe, temporal lobe, and parietal lobe. GR was predominantly expressed in the cytoplasm early and rapidly increased in the nuclei. GR protein expression in the cerebral cortex after seizure was lower in the cytoplasm at 15 days and in nuclear protein at 19 days. CONCLUSION: GR expression displayed temporal and spatial changes in brain development. Recurrent seizures in neonatal rats cause abnormal GR expression and might play an important role in developing brain injury.展开更多
AIM: To study whether the glucocorticoid receptor (GR/ NR3C1) gene haplotypes influence the steroid therapy outcome in inflammatory bowel disease (IBD). METHODS: We sequenced all coding exons and flanking intronic seq...AIM: To study whether the glucocorticoid receptor (GR/ NR3C1) gene haplotypes influence the steroid therapy outcome in inflammatory bowel disease (IBD). METHODS: We sequenced all coding exons and flanking intronic sequences of the NR3C1 gene in 181 IBD patients, determined the single nucleotide polymorphisms, and predicted the NR3C1 haplotypes. Furthermore, we investigated whether certain NR3C1 haplotypes are significantly associated with steroid therapy outcomes. RESULTS: We detected 13 NR3C1 variants, which led to the formation of 17 different haplotypes with a certainty of > 95% in 173 individuals. The three most commonly occurring haplotypes were included in the association analysis of the influence of haplotype on steroid therapy outcome or IBD activity. None of the NR3C1 haplotypes showed statistically signifi cant association with glucocorticoid therapy success. CONCLUSION: NR3C1 haplotypes are not related to steroid therapy outcome.展开更多
Objective:Xiaoyao san(XYS)is a classic traditional Chinese medicinal formula.It has been clinically administered to regulate liver function.However,its mechanisms in glucocorticoid-induced hepatic steatosis are unknow...Objective:Xiaoyao san(XYS)is a classic traditional Chinese medicinal formula.It has been clinically administered to regulate liver function.However,its mechanisms in glucocorticoid-induced hepatic steatosis are unknown.This study aimed to investigate whether XYS protects against corticosterone(CORT)-induced hepatic steatosis,and to explore its mechanism.Methods:High-fat diet mice induced with hepatic steatosis by 2mg/kg CORT were administered 2.56 g/kg or 5.12 g/kg XYS daily for 7 weeks.The effects of XYS on hepatic steatosis in mice were evaluated by H&E and Oil Red O staining and by measuring their plasma lipids(triglyceride,total cholesterol,and free fatty acids).The mechanism of XYS against hepatic steatosis was investigated by network pharmacology,immunohistochemistry,western blotting,and gain-of-function/loss-offunction experiments.Results:XYS alleviated CORT-induced steatosis,decreased plasma lipids,and inhibited glucocorticoid receptor(GR)activation in the liver.Network pharmacology data indicated that XYS may have mitigated hepatic steatosis via GR which mediated adipose differentiation-related protein(ADFP).Gain-of-function/loss-of-function experiments in vitro confirmed that GR positively regulated ADFP expression.Conclusions:XYS ameliorated CORT-induced hepatic steatosis by downregulating the GR/ADFP axis and inhibiting lipid metabolism.Our studies implicate that XYS is promising as a therapy for CORT-induced hepatic steatosis,and lay the foundation for designing novel prophylactic and therapeutic strategies on CORT-induced hepatic steatosis.展开更多
OBJECTIVE To investigate the anti-rheumatoid arthritis(RA)effect of Escin combined with low dose of GCs(dexameth⁃asone,Dex)and its underlying mechanism.METHODS Adjuvant-induced rheumatoid arthritis rats and LPS-injure...OBJECTIVE To investigate the anti-rheumatoid arthritis(RA)effect of Escin combined with low dose of GCs(dexameth⁃asone,Dex)and its underlying mechanism.METHODS Adjuvant-induced rheumatoid arthritis rats and LPS-injured RAW 264.7 were used to investigate the anti-RA effects of Escin combined with low dose Dex in vivo and in vitro.In vivo experiment:rats were randomly divided into model group(AIA),dexamethasone high dose(Dex,0.2 mg·kg^-1)group,dexamethasone low dose(Dex,0.05 mg·kg^-1)group,Escin 10 mg·kg^-1 group,Dex 0.05+Escin group,10 rats in each group,another 10 were used as normal control group.The vehicle and the corresponding drug were administered intragastrically(ig)daily for 14 d.In vitro experiment:LPS was used to stimulate RAW 264.7 macrophages for inflammatory models,which were divided into control group,LPS group,Dex with high dose(50 nmol·L^-1)group,and Dex with low dose(12.5 nmol·L^-1)group.In the Escin 10μmol·L^-1 group and the Dex+Escin(12.5 nmol·L^-1+10μmol·L^-1)group,the corresponding drugs were added to each well.After 2 h,LPS was added to induce inflammation.RESULTS Escin combined with low dose Dex significantly decreased arthritic index,serum IL-6 and TNF-α,improved paw swelling,and ameliorated the joint pathology immune organ pathology significantly.Gene chip results revealed that Nr3c1(GR)altered significantly.And that GR activation by Escin and low dose Dex was confirmed both in vivo and in vitro.Furthermore,Escin combined with low dose Dex also significant increase GR mRNA expression.However,when suppression of GR by its specific inhibitor,the anti-RA effect of Escin combined with low dose Dex was abolished.CONCLUSION Escin combined with Dex reduces the dose of Dex,and exerts significant anti-RA effects,which could also reduce the adverse effects of Dex.This combination might be attributed to GR activation.This study might provide a new combination drugs for the treatment of RA.展开更多
Chronic obstructive pulmonary disease is a common,highly disabling,and burdensome disease.Anti-inflammatory glucocorticoid medication plays a key role in its treatment;however,glucocorticoid resistance in patients wit...Chronic obstructive pulmonary disease is a common,highly disabling,and burdensome disease.Anti-inflammatory glucocorticoid medication plays a key role in its treatment;however,glucocorticoid resistance in patients with chronic obstructive pulmonary disease considerably weakens the effects of the treatment.Despite recent advances in determining the mechanism of glucocorticoid resistance in patients with chronic obstructive pulmonary disease,the role of traditional Chinese medicine in treating such patients remains unclear.In this review,we reviewed the mechanism of chronic obstructive pulmonary disease-related glucocorticoid resistance with reference to the glucocorticoid receptor,the important signaling pathways(phosphatidylinositol-3-kinase/protein kinase B signaling pathway,p38 mitogen-activated protein kinase signaling pathway,and interferon-γ/Janus kinase/stransducer and activator of transcription signaling pathway),histone deacetylase,nuclear transcription factor-κB,exosomes,and microRNA.Moreover,the methods of establishing the glucocorticoid resistance model associated with chronic obstructive pulmonary disease and advances in therapeutic approaches including traditional Chinese medicine to restore chronic obstructive pulmonary disease glucocorticoid sensitivity have also been reviewed.This review shows that traditional Chinese medicine reverses glucocorticoid resistance mainly by regulating the expression of glucocorticoid receptor,p38 mitogen-activated protein kinase signaling,histone deacetylase 2,and nuclear transcription factor-κB in chronic obstructive pulmonary disease models.Future research is suggested to evaluate traditional Chinese medicine understanding of chronic obstructive pulmonary disease-related glucocorticoid resistance in relation to exosomes,microRNA,and other signaling pathways.展开更多
Objective:To investigate the effect of Fufei Gushen Decoction on airway inflammation and glucocorticoid receptor in rats with chronic obstructive pulmonary disease.Methods:Fifty Wistar male rats were randomly divided ...Objective:To investigate the effect of Fufei Gushen Decoction on airway inflammation and glucocorticoid receptor in rats with chronic obstructive pulmonary disease.Methods:Fifty Wistar male rats were randomly divided into 5 groups:blank control group,COPD model group,Fufei Gushen Yin high,medium and low dose groups,10 rats in each group,except the blank control group,the remaining 4 groups were Smoked combined with lipopolysaccharide(LPS),cold air stimulation to create CODP rat model.After successful modeling,the blank control group and COPD model group were fed with distilled water 3ml/only,Fufei Gushen Yin high,medium and low dose groups were given 1.02,0.51,0.26g Chinese medicine granules/100g/day,respectively.2 times a day for 28 consecutive days.Samples were collected,hematoxylin-eosin(HE)staining was used to observe the pathological changes of lung tissue,and enzyme-linked immunosorbent assay(ELISA)was used to detect the tumor necrosis factor alpha(TNF-α)in the serum and right alveolar lavage fluid(BALF)of rats in each group.),the content of transforming growth factorβ1(TGF-β1),interleukin-17(IL-17A)and matrix metalloproteinase(MMP-9)and tissue inhibitor of metalloproteinase-1(TIMP-1)in the left lung tissue The expression level of real-time fluorescence quantitative polymerase chain reaction(Real-time PCR)rat left lung tissue GRmRNA,immunohistochemistry(IHC)to determine the expression level of left lung tissue glucocorticoid receptor(GR).Results:The content of TNF-α,TGF-β1 and IL-17A in the serum of COPD rats in Fufei Gushen Yin high,medium and low dose groups and BALF were significantly reduced compared with the COPD model group(P<0.05);The expressions of TIMP-1 and MMP-9 in tissues were lower than those in COPD model group(P<0.05);the expressions of GRmRNA and GR in lung tissues were higher than those in COPD model group(P<0.05),and were higher in Fufei Gushen Yin Among the middle-and low-dose groups,the middle-dose group has the most significant effect.Conclusion:Fufei Gushen Decoction can inhibit the release of inflammatory factors in lung tissue of COPD rats,improve airway inflammation and remodeling,and increase hormone sensitivity.展开更多
The homogeneity between the high-and low-affinity glucocorticoid receptors(GR_H and GR_L)was testified by immunoaffinity chromatography using Mab N250(recognizing the immunogenic domain at the N terminal of GR_H)and M...The homogeneity between the high-and low-affinity glucocorticoid receptors(GR_H and GR_L)was testified by immunoaffinity chromatography using Mab N250(recognizing the immunogenic domain at the N terminal of GR_H)and Mab BuGR1(recognizing the DNA binding domain of GR_H).The specific binding peak of 0.98μmol/L[~3H]triamcinolone acetonide(TA)was higher than that of 52.50nmol/L[~3H]TA.The re-sult suggests that the antigenic determinants of GR_L are similar to those of GR_H.ThecDNA of rat liver GR_H was introduced into GR_H-and GR_L-negative mouse fibroblast cellline E82.A3 by calcium phosphate coprecipitation.A number of clones which expressGR_H were selected with G418(400μg/ml).The results of radioligand binding assay indicatethat GR_H gene is expressed successfully and GR_L also may be encoded by GR_H gene.展开更多
The glucocorticoid receptor(GCR)and the mineralocorticoid receptor(MR)are members of the steroid receptor superfamily of hormone-dependent transcription factors.The receptors are structurally and functionally related....The glucocorticoid receptor(GCR)and the mineralocorticoid receptor(MR)are members of the steroid receptor superfamily of hormone-dependent transcription factors.The receptors are structurally and functionally related.They are localized in the cytosol and translocate into the nucleus after ligand binding.GCRs and MRs can be co-expressed within the same cell,and it is believed that the balance in GCR and MR expression is crucial for homeostasis and plays a key role in normal adaptation.In critical illness,the hypothalamic-pituitary-adrenal axis is activated,and as a consequence,serum cortisol concentrations are high.However,a number of patients exhibit relatively low cortisol levels for the degree of illness severity.Glucocorticoid(GC)actions are facilitated by GCR,whose dysfunction leads to GC tissue resistance.The MR is unique in this family in that it binds to both aldosterone and cortisol.Endogenous GCs play a critical role in controlling inflammatory responses in critical illness.Intracellular GC concentrations can differ greatly from blood levels due to the action of the two 11β-hydroxysteroid dehydrogenase isozymes,type 1 and type 2.11β-hydroxysteroid dehydrogenases interconvert endogenous active cortisol and intrinsically inert cortisone.The degree of expression of the two isozymes has the potential to dramatically influence local GC availability within cells and tissues.In this review,we will explore the clinical studies that aimed to elucidate the role of MR and GCR expression in the inflammatory response seen in critical illness.展开更多
Objective\ Exploring the alteration of glucocorticoid receptor (GCR) following forebrain ischemia in gerbils. Methods\ Establish a brain ischemia model by occluding bilateral common carotid. The GCR concentrations in ...Objective\ Exploring the alteration of glucocorticoid receptor (GCR) following forebrain ischemia in gerbils. Methods\ Establish a brain ischemia model by occluding bilateral common carotid. The GCR concentrations in forebrain tissue cytosol were detected by radioligand binding assay. The plasma concentrations of cortisol were determined by the method of competitive protein binding analysis. Results\ GCR concentrations had no significant change after 10 min ischemia (P>0 05), while decreased significantly in 1 h ischemia (P<0.01), and reduced more severely in 1 h ischemia followed by 3 h reperfusion (P<0.01). Plasma cortisol increased markedly in 10 min ischemia and 1 h ischemia (P<0.001), while decreased in 1 h ischemia followed by 3 h reperfusion. Conclusion\ GCR concentrations in brain decreased following forebrain ischemia in gerbil.展开更多
The central nervous system is susceptible to the modulation of various neurophysiological processes by the cytochrome P450 enzyme(CYP),which plays a crucial role in the metabolism of neurosteroids.The antiepileptic dr...The central nervous system is susceptible to the modulation of various neurophysiological processes by the cytochrome P450 enzyme(CYP),which plays a crucial role in the metabolism of neurosteroids.The antiepileptic drug phenytoin(PHT)has been observed to induce neuronal side effects in patients,which could be attributed to its induction of CYP expression and testosterone(TES)metabolism in the hippocampus.While pregnane X receptor(PXR)is widely known for its regulatory function of CYPs in the liver,we have discovered that the treatment of mice with pregnenolone 16α-carbonitrile(PCN),a PXR agonist,has differential effects on CYP expression in the liver and hippocampus.Specifically,the PCN treatment resulted in the induction of cytochrome P450,family 3,subfamily a,polypeptide 11(CYP3A11),and CYP2B10 expression in the liver,while suppressing their expression in the hippocampus.Functionally,the PCN treatment protected mice from PHT-induced hippocampal nerve injury,which was accompanied by the inhibition of TES metabolism in the hippocampus.Mechanistically,we found that the inhibition of hippocampal CYP expression and attenuation of PHT-induced neurotoxicity by PCN were glucocorticoid receptor dependent,rather than PXR independent,as demonstrated by genetic and pharmacological models.In conclusion,our study provides evidence that PCN can negatively regulate hippocampal CYP expression and attenuate PHT-induced hippocampal neurotoxicity independently of PXR.Our findings suggest that glucocorticoids may be a potential therapeutic strategy for managing the neuronal side effects of PHT.展开更多
Accumulating studies have proved that perinatal exposure to environmental dose causes long-term potentiation in anxiety/depression-related behaviors in rats. Hyperactivity of the hypothalamic-pituitary-adrenal (HPA)...Accumulating studies have proved that perinatal exposure to environmental dose causes long-term potentiation in anxiety/depression-related behaviors in rats. Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is one of the most consistent biological findings in anxiety- and depression-related disorders. The HPA axis is reported to be susceptible to developmental reprogramming. The present study focused on HPA reactivity in postnatal day (PND) 80 male rats exposed perinatally to environmental-dose BPA. When female breeders were orally administered 2 μg/(kg.day) BPA from gestation day 10 to lactation day 7, their offspring (PND 80 BPA-exposed rats) showed obvious anxiety/depression-like behaviors. Notably, significant increase in serum corticosterone and adrenocorticotropin, and corticotropin-releasing hormone mRNA were detected in BPA-exposed rats before or after the mild stressor. Additionally, the level of glucocorticoid receptor mRNA in the hippocampus, but not the hypothalamus, was decreased in BPA-exposed rats. The levels of hippocampal mineralocorticoid receptor mRNA, neuronal nitric oxide synthase and phosphorylated cAMP response element binding protein were increased in BPA-exposed rats. In addition, the testosterone level was in BPA-exposed rats. The results indicate that reprogramming-induced hyperactivity of the HPA axis is an important link between perinatal BPA exposure and persistent potentiation in anxiety and depression.展开更多
Acute spinal cord injury initiates a complex cascade of molecular events termed 'secondary injury', which leads to progressive degeneration ranging from early neuronal apoptosis at the lesion site to delayed degener...Acute spinal cord injury initiates a complex cascade of molecular events termed 'secondary injury', which leads to progressive degeneration ranging from early neuronal apoptosis at the lesion site to delayed degeneration of intact white matter tracts, and, ultimately, expansion of the initial injury. These secondary injury processes include, but are not limited to, inflammation, free radical-induced cell death glutamate excitotoxicity, phospholipase A2 activation, and induction of extrinsic and intrinsic apoptotic pathways, which are important targets in developing neuroprotective strategies for treatment of spinal cord injury. Recently, a number of studies have shown promising results on neuroprotection and recovery of function in rodent models of spinal cord injury using treatments that target secondary injury processes including inflammation, phospholipase A2 activation, and manipulation of the PTEN-AktJmTOR signaling pathway. The present review outlines our ongoing research on the molecular mechanisms of neuroprotection in experimental spinal cord injury and briefly summarizes our earlier findings on the therapeutic potential of pharmacological treatments in spinal cord injury.展开更多
基金the Scientific Research Foundation for Returned Overseas Chinese Scholars, State Education Ministry
文摘Studies have shown that cerebral ischemia activates neurogenesis and that stress inhibits neurogenesis.However,the role of stress hormone levels on neurogenesis following cerebral ischemia remains poorly understood.The present study explored the possible regulatory mechanisms of adult neurogenesis under pathological conditions by examining changes and regulation of glucocorticoid receptors in adult rats subjected to transient unilateral middle cerebral artery suture occlusion.Corticosterone levels gradually increased following middle cerebral artery occlusion,and the number of glucocorticoid receptor-positive cells decreased.The number of5-bromodeoxyuridine-and nestin-positive cells significantly increased at 1 and 2 weeks after ischemia.A large number of doublecortin-positive cells migrated from the hippocampus to the cortex.At 3 weeks post-surgery,the number of 5-bromodeoxyuridine-and nestin-positive cells significantly reduced in the subventricular zone.Increased corticosterone levels decreased vascular endothelial cell proliferation and neurogenesis,and the number of glucocorticoid receptor-positive cells decreased.In the sham surgery group,vascular endothelial cell proliferation related to post-ischemic cerebral rehabilitation was not detected.Corticosterone levels increased,but the number and distribution of glucocorticoid receptor-positive cells were not changed.However,normal neuregenesis and migration of neural stem cells existed in the adult rat brain in the sham surgery group.Results suggested that glucocorticoid receptors influenced neurogenesis and were negatively regulated by glucocorticoid levels following focal cerebral ischemia and reperfusion.
文摘Association between the reward caused by consuming drugs and the context in which they are consumed is essential in the formation of morphine-induced conditioned place preference(CPP).Glucocorticoid receptor(GRs)activation in different regions of the brain affects reward-based reinforcement and memory processing.A wide array of studies have demonstrated that blockage of GRs in some brain areas can have an effect on reward-related memory;however,to date there have been no systematic studies about the involvement of glucocorticoids(GCs)in morphine-related reward memory.Here,we used the GR antagonist RU38486 to investigate how GRs blockage affects the sensitization and CPP behavior during different phases of reward memory included acquisition,retrieval and reconsolidation.Interestingly,our results showed RU38486 has the ability to impair the acquisition,retrieval and reconsolidation of reward-based memory in CPP and sensitization behavior.But RU38486 by itself cannot induce CPP or conditioned place aversion(CPA)behavior.Our data provide a much more complete picture of the potential effects that glucocorticoids have on the reward memory of different phases and inhibit the sensitization behavior.
文摘The leucocytic glucocorticoid receptors (GCR) were estimated in 20 patients with Yang-Defi-ciency Syndrome using a radioligand binding method and plasrna cortisol was measured at the same time. Re-sults showed that the levels of plasma cortisol and leucocytic GCR of patients were all significantly lower thanthe healthy control group, and the changes were more significant in 10 cases of hypofunction of endocrinopa-thy with manifestation of Yang-Deficiency and Yang-Doficiency patients aged < 40 years. The mechanism andrelationship between GCR and plasma cortisol were also discussed in this article.
基金the Postdoctoral Science Foundation of China,No. 20060390301the National Natural Science Foundation of China,No.30600341the Ph.D.Program Foundation of Ministry of Education of China,No.20050159011
文摘BACKGROUND: The hippocampus regulates the hypothalamic-pituitary-adrenal axis through negative feedback. The hypothalamic paraventricular nucleus receives neuronal input from the hippocampus via the fomix, OBJECTIVE: To explore whether the negative feedback effect of the hippocampus on the hypothalamic-pituitary-adrenal axis is contributed to the inhibitory effect of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) in the hippocampus on the paraventricular nucleus via the fornix. DESIGN, TIME AND SETTING: Randomized, controlled, animal experiment. The study was performed at the Department of Histology and Embryology, China Medical University between September 2006 and September 2008. MATERIALS: Rabbit anti-rat anti-MR and rabbit anti-rat anti-GR antibodies were purchased from Santa Cruz Biotechnology, USA. Rabbit anti-rat anti-corticotrophin releasing hormone (CRH) and rabbit anti-rat anti-arginine vasopressin antibodies were purchased from Wuhan Boster. METHODS: A total of 90 male, Wistar rats were randomly divided into model and sham-surgery groups (n = 45). Fornix transection was performed in the model group, while the sham-surgery group underwent surgery, but no fornix transection. MAIN OUTCOME MEASURES: Immunohistochemistry was used to examine MR and GR expression in the hippocampus, as well as CRH and anti-arginine vasopressin in the paraventricular nucleus. Western blot was used to measure alterations in MR, GR, and CRH protein expression following fomix transection. RESULTS: Compared with the sham-surgery group, there were no obvious changes in MR and GR expression in the hippocampus, or CRH and anti-arginine vasopressin expression in the paraventdcular nucleus within 4 days of fornix transection. However, after 7-10 days, significantly decreased MR and GR expression in the hippocampus, and increased CRH and anti-arginine vasopmssin expression in the paraventricular nucleus were observed (P 〈 0.05-0.01). CONCLUSION: Negative feedback from the hippocampus on the hypothalamic-pituitary-adrenal axis might be mediated through the fornix, and the corticosterene actions mediated by hippocampal corticosteroid receptors indirectly modulated the hypothalamic-pituitary-adrenal axis.
基金supported by the research funds from the University Program for Changjiang Scholars and Innovative Research Team(No.IRT0935)the National Natural Science Fund Project(No.30973237)grants from the Department of Science and Technology of Sichuan Province(No.2008JY0029-1,No.07FG002-024,and No.2010JY0004)
文摘Objective To explore the role of glucocorticoid (GC) receptor (GR) in rapamycin's reversion of GC resistance in humanGC-resistant T-acute lymphoblastic leukemia (ALL) CEM-C1 cells. Methods CEM-C1 cells were cultured in vitro and treated with rapamycin at different concentrations with or without 1 μmol/L dexamethasone (Dex). 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) test was performed to assess cell proliferation. The cell cycle and cell apoptosis were analyzed by flow cytometry. The expression of GRα mRNA was determined by real-time quantitative RT-PCR. The expression of GR, p-70S6K, Mcl-1, and Bim proteins was detected by Western blot. Results When incubated with rapamycin at different concentrations, CEM-C1 cells showed significant growth inhibition in a time- and concentration-dependent manner. The growth inhibition was synergistically increased when CEM-C1 cells were treated with rapamycin plus 1 μmol/L Dex. CEM-C1 cells treated with rapamycin alone showed no apparent apoptosis, and were arrested at G0/G1 phase. After the treatment with Dex plus rapamycin, CEM-C1 cells demonstrated apparent apoptosis and increased the cell cycle arrested at G0/G1 phase. Rapamycin combined with Dex up-regulated GRα, phosphorylated GR(p-GR), and pro-apoptotic protein Bim-EL in CEM-C1 cells, but inhibited the expression of p-p70S6K, a downstream target protein ofmTOR (mammalian target of rapamycin). Conclusion After the treatment with rapamycin plus Dex, Dex resistant CEM-C1 cells induce growth inhibition and apoptosis. The underlying mechanism may involve inhibition of the mTOR signaling pathway and also be associated with up-regulation of GR expression and activation of GC-GR signaling pathway.
基金Supported by Provinces Co-construction Program of Medical Science and Technique Foundation of Henan Province,No.SB201901042Key Scientific Research Project of Colleges and Universities in Henan Province,No.21A320070.
文摘Glucocorticoids(GCs)have been widely used as immunosuppressants and antiinflammatory agents to treat a variety of autoimmune and inflammatory diseases,and they fully exert their anti-inflammatory and immune-regulating effects in the body.The effect of GCs on white blood cells is an important part of their action.GCs can cause changes in peripheral blood white blood cell counts by regulating the proliferation,differentiation,and apoptosis of white blood cells.Although the total number of white blood cells,neutrophil counts,lymphocytes,and eosinophils increases,the counts of basic granulocytes and macrophages decreases.In addition,GCs can regulate the activation and secretion of white blood cells,inhibit the secretion of a variety of pro-inflammatory cytokines,the expression of chemokines,and promote the production of anti-inflammatory cytokines.For patients on GC therapy,the effects of GCs on leukocytes were similar to the changes in peripheral blood caused by bacterial infections.Thus,we suggest that clinicians should be more cautious in assessing the presence of infection in children with long-term use of GCs and avoid overuse of antibiotics in the presence of elevated leukocytes.GCs work through genomic and non-genomic mechanisms in the human body,which are mediated by GC receptors.In recent years,studies have not fully clarified the mechanism of GCs,and further research on these mechanisms will help to develop new therapeutic strategies.
文摘Glucocorticoids have been used in the treatment of prostate cancer to slow disease progression, improve pain control and offset side effects of chemo- and hormonal therapy. However, they may also have the potential to drive prostate cancer growth via mutated androgen receptors or glucocorticoid receptors (GRs). In this review we examine historical and contemporary use of glucocorticoids in the treatment of prostate cancer, review potential mechanisms by which they may inhibit or drive prostate cancer growth, and describe potential means of defining their contribution to the biology of prostate cancer.
基金the National Natural Science Foundation of China,No.30400483the Natural Science Foundation of Hunan Province,No.07JJ5020
文摘BACKGROUND: Studies have explored changes in neonatal rat glucocorticoid receptor (GR) expression changes following mature brain injury. OBJECTIVE: To investigate the temporal and special changes of GR during brain development in rats with recurrent seizures. DESIGN, TIME AND SE'n'ING: A randomized, controlled animal experiment was performed at the Department of Pediatrics, Second Xiangya Hospital of Central South University, from February 2008 to March 2009. MATERIALS: Rabbit anti-rat GR monoclonal antibody was purchased from Santa Cruz Biotechnology, USA; goat anti-rabbit IgG was purchased from Zhongshan Goldenbridge Biotechnology, China. METHODS: A total of 48 Sprague-Dawley rats, 7 days old, were randomly assigned to control and seizure groups, with 24 animals in each group. Seizures were induced by inhalant flurothyl. MAIN OUTCOME MEASURES: Changes in GR protein expression in the rat cerebral cortex were detected by Western blotting analysis and immunohistochemistry. RESULTS: GR expression in the cerebral cortex of control rats significantly increased with aging (P 〈 0.05), and varied in the frontal lobe, temporal lobe, and parietal lobe. GR was predominantly expressed in the cytoplasm early and rapidly increased in the nuclei. GR protein expression in the cerebral cortex after seizure was lower in the cytoplasm at 15 days and in nuclear protein at 19 days. CONCLUSION: GR expression displayed temporal and spatial changes in brain development. Recurrent seizures in neonatal rats cause abnormal GR expression and might play an important role in developing brain injury.
基金Supported by The Swiss IBD Cohort Study (SNF Grant 33CSC0-108792)the Swiss National Science Foundation (Grant 32-120463/1)+2 种基金the Zurich University Research Priority Pro-gramme "Integrative Human Physiology" (ZIHP)the Center of Clinical Research at the University Hospital Zurichthe Novartis Foundation for Biomedical Research
文摘AIM: To study whether the glucocorticoid receptor (GR/ NR3C1) gene haplotypes influence the steroid therapy outcome in inflammatory bowel disease (IBD). METHODS: We sequenced all coding exons and flanking intronic sequences of the NR3C1 gene in 181 IBD patients, determined the single nucleotide polymorphisms, and predicted the NR3C1 haplotypes. Furthermore, we investigated whether certain NR3C1 haplotypes are significantly associated with steroid therapy outcomes. RESULTS: We detected 13 NR3C1 variants, which led to the formation of 17 different haplotypes with a certainty of > 95% in 173 individuals. The three most commonly occurring haplotypes were included in the association analysis of the influence of haplotype on steroid therapy outcome or IBD activity. None of the NR3C1 haplotypes showed statistically signifi cant association with glucocorticoid therapy success. CONCLUSION: NR3C1 haplotypes are not related to steroid therapy outcome.
基金the National Natural Science Foundation of China(Nos.81630104 and 81622050).
文摘Objective:Xiaoyao san(XYS)is a classic traditional Chinese medicinal formula.It has been clinically administered to regulate liver function.However,its mechanisms in glucocorticoid-induced hepatic steatosis are unknown.This study aimed to investigate whether XYS protects against corticosterone(CORT)-induced hepatic steatosis,and to explore its mechanism.Methods:High-fat diet mice induced with hepatic steatosis by 2mg/kg CORT were administered 2.56 g/kg or 5.12 g/kg XYS daily for 7 weeks.The effects of XYS on hepatic steatosis in mice were evaluated by H&E and Oil Red O staining and by measuring their plasma lipids(triglyceride,total cholesterol,and free fatty acids).The mechanism of XYS against hepatic steatosis was investigated by network pharmacology,immunohistochemistry,western blotting,and gain-of-function/loss-offunction experiments.Results:XYS alleviated CORT-induced steatosis,decreased plasma lipids,and inhibited glucocorticoid receptor(GR)activation in the liver.Network pharmacology data indicated that XYS may have mitigated hepatic steatosis via GR which mediated adipose differentiation-related protein(ADFP).Gain-of-function/loss-of-function experiments in vitro confirmed that GR positively regulated ADFP expression.Conclusions:XYS ameliorated CORT-induced hepatic steatosis by downregulating the GR/ADFP axis and inhibiting lipid metabolism.Our studies implicate that XYS is promising as a therapy for CORT-induced hepatic steatosis,and lay the foundation for designing novel prophylactic and therapeutic strategies on CORT-induced hepatic steatosis.
基金National Natural Science Foundation of China(8187303981973547)Natural Science Foundation of Shandong Province(ZR2017MH068)
文摘OBJECTIVE To investigate the anti-rheumatoid arthritis(RA)effect of Escin combined with low dose of GCs(dexameth⁃asone,Dex)and its underlying mechanism.METHODS Adjuvant-induced rheumatoid arthritis rats and LPS-injured RAW 264.7 were used to investigate the anti-RA effects of Escin combined with low dose Dex in vivo and in vitro.In vivo experiment:rats were randomly divided into model group(AIA),dexamethasone high dose(Dex,0.2 mg·kg^-1)group,dexamethasone low dose(Dex,0.05 mg·kg^-1)group,Escin 10 mg·kg^-1 group,Dex 0.05+Escin group,10 rats in each group,another 10 were used as normal control group.The vehicle and the corresponding drug were administered intragastrically(ig)daily for 14 d.In vitro experiment:LPS was used to stimulate RAW 264.7 macrophages for inflammatory models,which were divided into control group,LPS group,Dex with high dose(50 nmol·L^-1)group,and Dex with low dose(12.5 nmol·L^-1)group.In the Escin 10μmol·L^-1 group and the Dex+Escin(12.5 nmol·L^-1+10μmol·L^-1)group,the corresponding drugs were added to each well.After 2 h,LPS was added to induce inflammation.RESULTS Escin combined with low dose Dex significantly decreased arthritic index,serum IL-6 and TNF-α,improved paw swelling,and ameliorated the joint pathology immune organ pathology significantly.Gene chip results revealed that Nr3c1(GR)altered significantly.And that GR activation by Escin and low dose Dex was confirmed both in vivo and in vitro.Furthermore,Escin combined with low dose Dex also significant increase GR mRNA expression.However,when suppression of GR by its specific inhibitor,the anti-RA effect of Escin combined with low dose Dex was abolished.CONCLUSION Escin combined with Dex reduces the dose of Dex,and exerts significant anti-RA effects,which could also reduce the adverse effects of Dex.This combination might be attributed to GR activation.This study might provide a new combination drugs for the treatment of RA.
基金the Science and Technology Planning Project of Science and Technology Department of Sichuan Province(2021YJ0465)the 2020 Xinglin Scholars Scientific Research Promotion Plan of Chengdu University of Traditional Chinese Medicine,and the Hundred Talents Plan Project of Hospital of Chengdu University of Traditional Chinese Medicine(20-Q07).
文摘Chronic obstructive pulmonary disease is a common,highly disabling,and burdensome disease.Anti-inflammatory glucocorticoid medication plays a key role in its treatment;however,glucocorticoid resistance in patients with chronic obstructive pulmonary disease considerably weakens the effects of the treatment.Despite recent advances in determining the mechanism of glucocorticoid resistance in patients with chronic obstructive pulmonary disease,the role of traditional Chinese medicine in treating such patients remains unclear.In this review,we reviewed the mechanism of chronic obstructive pulmonary disease-related glucocorticoid resistance with reference to the glucocorticoid receptor,the important signaling pathways(phosphatidylinositol-3-kinase/protein kinase B signaling pathway,p38 mitogen-activated protein kinase signaling pathway,and interferon-γ/Janus kinase/stransducer and activator of transcription signaling pathway),histone deacetylase,nuclear transcription factor-κB,exosomes,and microRNA.Moreover,the methods of establishing the glucocorticoid resistance model associated with chronic obstructive pulmonary disease and advances in therapeutic approaches including traditional Chinese medicine to restore chronic obstructive pulmonary disease glucocorticoid sensitivity have also been reviewed.This review shows that traditional Chinese medicine reverses glucocorticoid resistance mainly by regulating the expression of glucocorticoid receptor,p38 mitogen-activated protein kinase signaling,histone deacetylase 2,and nuclear transcription factor-κB in chronic obstructive pulmonary disease models.Future research is suggested to evaluate traditional Chinese medicine understanding of chronic obstructive pulmonary disease-related glucocorticoid resistance in relation to exosomes,microRNA,and other signaling pathways.
基金Construction Project for Famous Doctors of Traditional Chinese Medicine of Ruikang Hospital Affiliated to Guangxi University of Traditional Chinese Medicine(No.[2019]18)。
文摘Objective:To investigate the effect of Fufei Gushen Decoction on airway inflammation and glucocorticoid receptor in rats with chronic obstructive pulmonary disease.Methods:Fifty Wistar male rats were randomly divided into 5 groups:blank control group,COPD model group,Fufei Gushen Yin high,medium and low dose groups,10 rats in each group,except the blank control group,the remaining 4 groups were Smoked combined with lipopolysaccharide(LPS),cold air stimulation to create CODP rat model.After successful modeling,the blank control group and COPD model group were fed with distilled water 3ml/only,Fufei Gushen Yin high,medium and low dose groups were given 1.02,0.51,0.26g Chinese medicine granules/100g/day,respectively.2 times a day for 28 consecutive days.Samples were collected,hematoxylin-eosin(HE)staining was used to observe the pathological changes of lung tissue,and enzyme-linked immunosorbent assay(ELISA)was used to detect the tumor necrosis factor alpha(TNF-α)in the serum and right alveolar lavage fluid(BALF)of rats in each group.),the content of transforming growth factorβ1(TGF-β1),interleukin-17(IL-17A)and matrix metalloproteinase(MMP-9)and tissue inhibitor of metalloproteinase-1(TIMP-1)in the left lung tissue The expression level of real-time fluorescence quantitative polymerase chain reaction(Real-time PCR)rat left lung tissue GRmRNA,immunohistochemistry(IHC)to determine the expression level of left lung tissue glucocorticoid receptor(GR).Results:The content of TNF-α,TGF-β1 and IL-17A in the serum of COPD rats in Fufei Gushen Yin high,medium and low dose groups and BALF were significantly reduced compared with the COPD model group(P<0.05);The expressions of TIMP-1 and MMP-9 in tissues were lower than those in COPD model group(P<0.05);the expressions of GRmRNA and GR in lung tissues were higher than those in COPD model group(P<0.05),and were higher in Fufei Gushen Yin Among the middle-and low-dose groups,the middle-dose group has the most significant effect.Conclusion:Fufei Gushen Decoction can inhibit the release of inflammatory factors in lung tissue of COPD rats,improve airway inflammation and remodeling,and increase hormone sensitivity.
文摘The homogeneity between the high-and low-affinity glucocorticoid receptors(GR_H and GR_L)was testified by immunoaffinity chromatography using Mab N250(recognizing the immunogenic domain at the N terminal of GR_H)and Mab BuGR1(recognizing the DNA binding domain of GR_H).The specific binding peak of 0.98μmol/L[~3H]triamcinolone acetonide(TA)was higher than that of 52.50nmol/L[~3H]TA.The re-sult suggests that the antigenic determinants of GR_L are similar to those of GR_H.ThecDNA of rat liver GR_H was introduced into GR_H-and GR_L-negative mouse fibroblast cellline E82.A3 by calcium phosphate coprecipitation.A number of clones which expressGR_H were selected with G418(400μg/ml).The results of radioligand binding assay indicatethat GR_H gene is expressed successfully and GR_L also may be encoded by GR_H gene.
文摘The glucocorticoid receptor(GCR)and the mineralocorticoid receptor(MR)are members of the steroid receptor superfamily of hormone-dependent transcription factors.The receptors are structurally and functionally related.They are localized in the cytosol and translocate into the nucleus after ligand binding.GCRs and MRs can be co-expressed within the same cell,and it is believed that the balance in GCR and MR expression is crucial for homeostasis and plays a key role in normal adaptation.In critical illness,the hypothalamic-pituitary-adrenal axis is activated,and as a consequence,serum cortisol concentrations are high.However,a number of patients exhibit relatively low cortisol levels for the degree of illness severity.Glucocorticoid(GC)actions are facilitated by GCR,whose dysfunction leads to GC tissue resistance.The MR is unique in this family in that it binds to both aldosterone and cortisol.Endogenous GCs play a critical role in controlling inflammatory responses in critical illness.Intracellular GC concentrations can differ greatly from blood levels due to the action of the two 11β-hydroxysteroid dehydrogenase isozymes,type 1 and type 2.11β-hydroxysteroid dehydrogenases interconvert endogenous active cortisol and intrinsically inert cortisone.The degree of expression of the two isozymes has the potential to dramatically influence local GC availability within cells and tissues.In this review,we will explore the clinical studies that aimed to elucidate the role of MR and GCR expression in the inflammatory response seen in critical illness.
文摘Objective\ Exploring the alteration of glucocorticoid receptor (GCR) following forebrain ischemia in gerbils. Methods\ Establish a brain ischemia model by occluding bilateral common carotid. The GCR concentrations in forebrain tissue cytosol were detected by radioligand binding assay. The plasma concentrations of cortisol were determined by the method of competitive protein binding analysis. Results\ GCR concentrations had no significant change after 10 min ischemia (P>0 05), while decreased significantly in 1 h ischemia (P<0.01), and reduced more severely in 1 h ischemia followed by 3 h reperfusion (P<0.01). Plasma cortisol increased markedly in 10 min ischemia and 1 h ischemia (P<0.001), while decreased in 1 h ischemia followed by 3 h reperfusion. Conclusion\ GCR concentrations in brain decreased following forebrain ischemia in gerbil.
基金supported in part by grants from the National Natural Science Foundation of China(Grant Nos.:81973405,82122071,and 82030111)to Dan XuHui Wang,the National Key R&D Program of China(Grant No.:2020YFA0803900)to Hui Wangthe Hubei Provincial Natural Science Foundation Outstanding Youth Found,China(Grant No.:2022CFA083).
文摘The central nervous system is susceptible to the modulation of various neurophysiological processes by the cytochrome P450 enzyme(CYP),which plays a crucial role in the metabolism of neurosteroids.The antiepileptic drug phenytoin(PHT)has been observed to induce neuronal side effects in patients,which could be attributed to its induction of CYP expression and testosterone(TES)metabolism in the hippocampus.While pregnane X receptor(PXR)is widely known for its regulatory function of CYPs in the liver,we have discovered that the treatment of mice with pregnenolone 16α-carbonitrile(PCN),a PXR agonist,has differential effects on CYP expression in the liver and hippocampus.Specifically,the PCN treatment resulted in the induction of cytochrome P450,family 3,subfamily a,polypeptide 11(CYP3A11),and CYP2B10 expression in the liver,while suppressing their expression in the hippocampus.Functionally,the PCN treatment protected mice from PHT-induced hippocampal nerve injury,which was accompanied by the inhibition of TES metabolism in the hippocampus.Mechanistically,we found that the inhibition of hippocampal CYP expression and attenuation of PHT-induced neurotoxicity by PCN were glucocorticoid receptor dependent,rather than PXR independent,as demonstrated by genetic and pharmacological models.In conclusion,our study provides evidence that PCN can negatively regulate hippocampal CYP expression and attenuate PHT-induced hippocampal neurotoxicity independently of PXR.Our findings suggest that glucocorticoids may be a potential therapeutic strategy for managing the neuronal side effects of PHT.
基金supported by China Postdoctoral Science Foundation(2013M540456)Jiangsu Planned Projects for Postdoctoral Research Funds(1301065B)+3 种基金Grants for 973(2014CB943303)NSFC(810710273117144081000482)
文摘Accumulating studies have proved that perinatal exposure to environmental dose causes long-term potentiation in anxiety/depression-related behaviors in rats. Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is one of the most consistent biological findings in anxiety- and depression-related disorders. The HPA axis is reported to be susceptible to developmental reprogramming. The present study focused on HPA reactivity in postnatal day (PND) 80 male rats exposed perinatally to environmental-dose BPA. When female breeders were orally administered 2 μg/(kg.day) BPA from gestation day 10 to lactation day 7, their offspring (PND 80 BPA-exposed rats) showed obvious anxiety/depression-like behaviors. Notably, significant increase in serum corticosterone and adrenocorticotropin, and corticotropin-releasing hormone mRNA were detected in BPA-exposed rats before or after the mild stressor. Additionally, the level of glucocorticoid receptor mRNA in the hippocampus, but not the hypothalamus, was decreased in BPA-exposed rats. The levels of hippocampal mineralocorticoid receptor mRNA, neuronal nitric oxide synthase and phosphorylated cAMP response element binding protein were increased in BPA-exposed rats. In addition, the testosterone level was in BPA-exposed rats. The results indicate that reprogramming-induced hyperactivity of the HPA axis is an important link between perinatal BPA exposure and persistent potentiation in anxiety and depression.
基金supported by National Institutes of Health(NIH/NINDS NS059622, NS052290, NS050243,NS073636)the Mari Hulman George Endowment Funds(XMX)the Indiana Spinal Cord and Brain Injury Research Funds(ISDH,Grant #A70-2-079609 and A70-9-079138)(NKL&XMX)
文摘Acute spinal cord injury initiates a complex cascade of molecular events termed 'secondary injury', which leads to progressive degeneration ranging from early neuronal apoptosis at the lesion site to delayed degeneration of intact white matter tracts, and, ultimately, expansion of the initial injury. These secondary injury processes include, but are not limited to, inflammation, free radical-induced cell death glutamate excitotoxicity, phospholipase A2 activation, and induction of extrinsic and intrinsic apoptotic pathways, which are important targets in developing neuroprotective strategies for treatment of spinal cord injury. Recently, a number of studies have shown promising results on neuroprotection and recovery of function in rodent models of spinal cord injury using treatments that target secondary injury processes including inflammation, phospholipase A2 activation, and manipulation of the PTEN-AktJmTOR signaling pathway. The present review outlines our ongoing research on the molecular mechanisms of neuroprotection in experimental spinal cord injury and briefly summarizes our earlier findings on the therapeutic potential of pharmacological treatments in spinal cord injury.