Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015674 (chronic fatigue syndrome)
 2,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dysregulation in the negative feedback of the hypothalamus-pituitary-adrenal (HPA) system is observed in a subgroup of major depression. Recent studies have postulated that tricyclic antidepressant treatment increases the glucocorticoid receptor (GR) in the brain and that such GR up-regulation normalizes the hyperactivity of HPA systems. The GR is associated with heat-shock proteins (HSPs) as a functional complex with a high affinity for steroid binding. In this study, we have examined the effects of chronic fixed (restraint) stress (CFS) and chronic variable stress (CVS) on the subcellular localization of GR and HSP90 in rat hippocampus using an immunoblotting procedure. A single restraint stress for 1-2 h and a single treatment with dexamethasone (DEX) 0.5 mg/kg, s.c. induced a translocation of the cytosolic GR to nuclei. Long-term treatment with DEX 0.1 mg/kg, s.c. for 14 days caused a significant decrease in both cytosolic and nucleic GR. There was no significant change in either cytosolic or nucleic GR after CFS for 14 days. However, CVS for 14 days increased both cytosolic GRs and HSP90 while nucleic GR was not changed. CFS for 14 days had no influence on the DEX-induced translocation of GR to nuclei, whereas GR translocation by DEX was not observed after CVS for 14 days. Gel filtration chromatography of the hippocampal cytosol after CVS indicated an increase in monomeric GR (approximately 90 kDa) and a decrease in the GR-HSP complex (approximately 300 kDa). Since CVS has been reported to increase serum corticosterone in rats, our results suggest that CVS prevents formation of the GR-HSP complex. A new intracellular environment rather than excessive serum corticosterone caused by CVS may contribute to inhibition of the formation of GR-HSP complex. It is proposed that the CVS could be an appropriate model for disturbance in the negative feedback control of HPA systems.
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PMID:[Influence of chronic variable stress (CVS) on the association of glucocorticoid receptor with heat-shock protein (HSP) 90 in rat hippocampus]. 948 79

Chronic fatigue syndrome (CFS) is a common and disabling problem; although most likely of biopsychosocial origin, the nature of the pathophysiological components remains unclear. There has been a wealth of interest in the endocrinology of this condition, which will be reviewed in this article. Most studied has been the hypothalamic-pituitary-adrenal (HPA) axis; although the quality of many studies is poor, the overall balance of evidence points to reduced cortisol output in at least some patients, with some evidence that this is linked to symptom production or persistence. There is evidence for heightened negative feedback and glucocorticoid receptor function and for impaired ACTH and cortisol responses to a variety of challenges. However, there is no evidence for a specific or uniform dysfunction of the HPA axis. Given the many factors that may impinge on the HPA axis in CFS, such as inactivity, sleep disturbance, psychiatric comorbidity, medication, and ongoing stress, it seems likely that HPA axis disturbance is heterogeneous and of multifactorial etiology in CFS. Studies assessing GH, dehydroepiandrostenedione and its sulfate, melatonin, leptin, and neuroendocrine-monoamine interactions are also reviewed. There is some evidence from these studies to suggest alterations of dehydroepiandrostenedione sulfate function and abnormal serotonin function in CFS, but whether these changes are of functional importance remains unclear. To obtain a clearer assessment of the etiological and pathophysiological relevance of endocrine changes in CFS, it is suggested that more prospective cohort studies be undertaken in groups at high risk for CFS, that patients with CFS are followed up into recovery, and that multidimensional assessments are undertaken to unravel the influence of the various confounding factors on the observed endocrine changes in CFS.
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PMID:The neuroendocrinology of chronic fatigue syndrome. 1270 Jan 81

Koso-san (Xiang-Su-San in Chinese), a Kampo (Japanese herbal) medicine, is used clinically in East Asia for the treatment of depression-like symptoms associated with the initial stage of the common cold, allergic urticaria due to food ingestion, irritable bowel syndrome, chronic fatigue syndrome, insomnia, and autonomic imbalance. However, the antidepressant-like activity of Koso-san has never been evaluated scientifically. In this study, ddY mice subjected to a combination of forced swimming and chronic mild stresses were termed depression-like model mice. The degree of the depression-like state was measured by the animal's duration of immobility using the forced swimming test (FST). Oral administration of Koso-san (1.0 g/kg/body wt./day, 9 days) significantly shortened the duration of immobility of the depression-like model mice in the FST; however, locomotor activity was not affected. Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis plays an important role in the pathophysiology of depression. Levels of corticotropin-releasing hormone mRNA expression in the hypothalamus and proopiomelanocortin mRNA expression in the pituitary were significantly increased, and glucocorticoid receptor protein expression in the hypothalamus paraventricular nucleus was downregulated in the depression-like model mice. However, Koso-san ameliorated these alterations to the normal conditions. The results of this study suggest that Koso-san shows the antidepressant-like effect through suppressing the hyperactivity of the HPA axis in depression-like model mice.
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PMID:Antidepressant-like activity of a Kampo (Japanese herbal) medicine, Koso-san (Xiang-Su-San), and its mode of action via the hypothalamic-pituitary-adrenal axis. 1651 52

Chronic fatigue syndrome (CFS) is a significant public health problem of unknown etiology, the pathophysiology has not been elucidated, and there are no characteristic physical signs or laboratory abnormalities. Some studies have indicated an association of CFS with deregulation of immune functions and hypothalamic-pituitary-adrenal (HPA) axis activity. In this study, we examined the association of sequence variations in the glucocorticoid receptor gene (NR3C1) with CFS because NR3C1 is a major effector of the HPA axis. There were 137 study participants (40 with CFS, 55 with insufficient symptoms or fatigue, termed as ISF, and 42 non-fatigued controls) who were clinically evaluated and identified from the general population of Wichita, KS. Nine single nucleotide polymorphisms (SNPs) in NR3C1 were tested for association of polymorphisms and haplotypes with CFS. We observed an association of multiple SNPs with chronic fatigue compared to non-fatigued (NF) subjects (P < 0.05) and found similar associations with quantitative assessments of functional impairment (by the SF-36), with fatigue (by the Multidimensional Fatigue Inventory) and with symptoms (assessed by the Centers for Disease Control Symptom Inventory). Subjects homozygous for the major allele of all associated SNPs were at increased risk for CFS with odds ratios ranging from 2.61 (CI 1.05-6.45) to 3.00 (CI 1.12-8.05). Five SNPs, covering a region of approximately 80 kb, demonstrated high linkage disequilibrium (LD) in CFS, but LD gradually declined in ISF to NF subjects. Furthermore, haplotype analysis of the region in LD identified two associated haplotypes with opposite alleles: one protective and the other conferring risk of CFS. These results demonstrate NR3C1 as a potential mediator of chronic fatigue, and implicate variations in the 5' region of NR3C1 as a possible mechanism through which the alterations in HPA axis regulation and behavioural characteristics of CFS may manifest.
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PMID:Glucocorticoid receptor polymorphisms and haplotypes associated with chronic fatigue syndrome. 1674 Jan 43

Fatigue during adolescence is associated with somatic and psychological complaints that resemble the pattern of symptoms described for chronic fatigue syndrome (CFS). Studies in CFS and other stress-related syndromes suggested a dysfunction of the interactions between the hypothalamic-pituitary-adrenal axis (HPA-axis) and the immune system, i.e. a changed glucocorticoid (GC) receptor sensitivity of immune cells, to exist. Here we investigated whether severely fatigued girls from a healthy population have altered cortisol production and immune cell sensitivity for the synthetic GC, dexamethasone (DEX). In a longitudinal design, we examined ex vivo DEX sensitivity of monocytes and of T-cell mitogen-induced responses of severely fatigued (N=65) and non-fatigued girls (N=60). Fatigued girls reported more severe comorbid complaints than non-fatigued participants across three measurements during 1 year (T1: spring, T2: autumn, T3: spring) and had higher plasma cortisol levels throughout the study. DEX sensitivity of T-cell mitogen-induced responses showed seasonal variation with increased sensitivity in autumn compared to spring. No systematic variation of monocyte glucocorticoid receptor (GR) sensitivity was observed. Significant rank correlations of DEX sensitivity of T-cell mitogen-induced responses between the three assessments during the year suggest a stable trait of immune function. Groups did not differ in DEX sensitivity on any of the read outs. However, in a persistently fatigued subgroup, sensitivity to DEX was significantly reduced on the level of interferon (IFN)-gamma production. These results show that although fatigued participants had severe (comorbid) complaints, only in the case when symptoms persisted, altered GC sensitivity of immune cells was observed.
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PMID:Glucocorticoid sensitivity of immune cells in severely fatigued adolescent girls: a longitudinal study. 1824 1

The hypothalamic-pituitary-adrenal (HPA) axis is a major system maintaining body homeostasis by regulating the neuroendocrine and sympathetic nervous systems as well modulating immune function. Recent work has shown that the complex dynamics of this system accommodate several stable steady states, one of which corresponds to the hypocortisol state observed in patients with chronic fatigue syndrome (CFS). At present these dynamics are not formally considered in the development of treatment strategies. Here we use model-based predictive control (MPC) methodology to estimate robust treatment courses for displacing the HPA axis from an abnormal hypocortisol steady state back to a healthy cortisol level. This approach was applied to a recent model of HPA axis dynamics incorporating glucocorticoid receptor kinetics. A candidate treatment that displays robust properties in the face of significant biological variability and measurement uncertainty requires that cortisol be further suppressed for a short period until adrenocorticotropic hormone levels exceed 30% of baseline. Treatment may then be discontinued, and the HPA axis will naturally progress to a stable attractor defined by normal hormone levels. Suppression of biologically available cortisol may be achieved through the use of binding proteins such as CBG and certain metabolizing enzymes, thus offering possible avenues for deployment in a clinical setting. Treatment strategies can therefore be designed that maximally exploit system dynamics to provide a robust response to treatment and ensure a positive outcome over a wide range of conditions. Perhaps most importantly, a treatment course involving further reduction in cortisol, even transient, is quite counterintuitive and challenges the conventional strategy of supplementing cortisol levels, an approach based on steady-state reasoning.
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PMID:Model-based therapeutic correction of hypothalamic-pituitary-adrenal axis dysfunction. 1916 14

Gene expression data and genotype variation data are now capable of providing genome-wide patterns across many different clinical conditions. However, the separate analysis of these data has limitations in elucidating the complex network of gene interactions underlying complex traits, such as common human diseases. More information about the identity of key driver genes of common diseases comes from integrating these two heterogeneous types of data. We developed a two-step procedure to characterize complex diseases by integrating genotype variation data and gene expression data. The first step elucidates the causal relationship among genetic variation, gene expression level, and disease. Based on the causal relationship determined at the first step, the second step identifies significant gene expression traits whose effects on disease status or whose responses to disease status are modified by the specific genotype variation. For the selected significant genes, a pathway enrichment analysis can be performed to identify the genetic mechanism of a complex disease. The proposed two-step procedure was shown to be an effective method for integrating three different levels of data, i.e., genotype variation, gene expression and disease status. By applying the proposed procedure to a chronic fatigue syndrome (CFS) dataset, we identified a list of potential causal genes for CFS, and found an evidence for difference in genetic mechanisms of the etiology between CFS without 'a major depressive disorder with melancholic features' (CFS) and CFS with 'a major depressive disorder with melancholic features' (CFS-MDD/m). Especially, the SNPs within NR3C1 gene were shown to differently influence the susceptibility of developing CFS and CFS-MDD/m through integrative action with gene expression levels.
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PMID:An integrated approach to infer causal associations among gene expression, genotype variation, and disease. 1954 Mar 36

Serotonergic neurotransmission plays a key role in the pathophysiology of neuropsychiatric illnesses. The functional significance of a promoter polymorphism, -1438G/A (rs6311), in one of the major genes of this system (serotonin receptor 2A, HTR2A) remains poorly understood in the context of epigenetic factors, transcription factors and endocrine influences. We used functional and structural equation modeling (SEM) approaches to assess the contributions of the polymorphism (rs6311), DNA methylation and clinical variables to HTR2A expression in chronic fatigue syndrome (CFS) subjects from a population-based study. HTR2A was up-regulated in CFS through allele-specific expression modulated by transcription factors at critical sites in its promoter: an E47 binding site at position -1,438, (created by the A-allele of rs6311 polymorphism), a glucocorticoid receptor (GR) binding site encompassing a CpG at position -1,420, and Sp1 binding at CpG methylation site -1,224. Methylation at -1,420 was strongly correlated with methylation at -1,439, a CpG site that is dependent upon the G-allele of rs6311 at position -1,438. SEM revealed a strong negative interaction between E47 and GR binding (in conjunction with cortisol level) on HTR2A expression. This study suggests that the promoter polymorphism (rs6311) can affect both transcription factor binding and promoter methylation, and this along with an individual's stress response can impact the rate of HTR2A transcription in a genotype and methylation-dependent manner. This study can serve as an example for deciphering the molecular determinants of transcriptional regulation of major genes of medical importance by integrating functional genomics and SEM approaches. Confirmation in an independent study population is required.
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PMID:Functional genomics of serotonin receptor 2A (HTR2A): interaction of polymorphism, methylation, expression and disease association. 2094 51

Hypocortisolism is a frequent finding in individuals with chronic fatigue syndrome (CFS) with other research findings implying potential dysregulation of glucocorticoid signaling. Glucocorticoid signaling is under the influence of several pathways, several of which are of interest in the study of CFS. Oxidative stress and decreased antioxidant capacity are known to disrupt the hypothalamic-pituitary-adrenal (HPA) axis (Epel et al., 2004) and the presence of histone deacetylases (HDAC) could also impact glucocorticoid signaling. The intent of this pilot study was to investigate the relationship among oxidative stress elements, select HDAC's (2/3) and glucocorticoid receptor signaling in an elderly sample with CFS. Findings suggest increased histone deacetylase activity, lower total antioxidant power, in the context of decreased plasma cortisol and increased plasma dehydroepiandrosterone concomitant with decreased expression of the encoding gene for the glucocorticoid receptor. These findings support the presence of HPA axis dysregulation in elderly individuals with CFS.
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PMID:Increased HDAC in association with decreased plasma cortisol in older adults with chronic fatigue syndrome. 2154 89

In complex multisymptom disorders like fibromyalgia syndrome (FMS) and chronic fatigue syndrome (CFS) that are defined primarily by subjective symptoms, genetic and gene expression profiles can provide very useful objective information. This paper summarizes research on genes that may be linked to increased susceptibility in developing and maintaining these disorders, and research on resting and stressor-evoked changes in leukocyte gene expression, highlighting physiological pathways linked to stress and distress. These include the adrenergic nervous system, the hypothalamic-pituitary-adrenal axis and serotonergic pathways, and exercise responsive metabolite-detecting ion channels. The findings to date provide some support for both inherited susceptibility and/or physiological dysregulation in all three systems, particularly for catechol-O-methyl transferase (COMT) genes, the glucocorticoid and the related mineralocorticoid receptors (NR3C1, NR3C2), and the purinergic 2X4 (P2X4) ion channel involved as a sensory receptor for muscle pain and fatigue and also in upregulation of spinal microglia in chronic pain models. Methodological concerns for future research, including potential influences of comorbid clinical depression and antidepressants and other medications, on gene expression are also addressed.
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PMID:Genetics and Gene Expression Involving Stress and Distress Pathways in Fibromyalgia with and without Comorbid Chronic Fatigue Syndrome. 2211 Sep 41


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