Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patients with endogenous depression (major affective disorder) frequently have high cortisol levels, but the diurnal rhythm is usually maintained and they do not develop the physical signs of Cushing's syndrome. On the other hand, depression is a frequent feature of Cushing's syndrome regardless of etiology, and it is often relieved when the cortisol levels are reduced, by whatever means. The mechanisms of the hypercortisolemia and resistance to dexamethasone suppression commonly found in endogenous depression are poorly understood; contrary to expectations, ACTH levels are not clearly elevated. There is a striking difference in the psychiatric features seen in endogenous hypercorticism compared to those seen after exogenous administration of glucocorticoids or ACTH. This suggests that either there are other stimulating or modifying factors besides ACTH or that the steroids stimulated by ACTH or other peptides differ from those in control subjects, i.e. there may be an alteration in the metabolism of steroids in depression. Little is known about the metabolic changes or the many steroids besides glucocorticoids produced by the hyperactive steroid-producing tissue. Preliminary studies suggest that major depression may be improved by steroid suppression. It is hypothesized that steroids themselves may be important in causing and perpetuating depression.
J Steroid Biochem Mol Biol 1991 May
PMID:Steroids and depression. 164 86

The hypercorticism frequently observed in major depression, unaccompanied by signs of Cushing's syndrome, is still poorly understood. One suicidal young woman, with very high cortisol levels and unusual resistance to dexamethasone suppression, is described. She was successfully treated with steroid suppressive drugs (aminoglutethimide, metyrapone), had a prompt and complete remission and has remained well for more than two years on no medication. This success prompted an on-going clinical trial of this therapy. The available drugs and a working hypothesis of their action are discussed.
J Steroid Biochem Mol Biol 1991 Aug
PMID:Treatment of major depression with steroid suppressive drugs. 188 84

Three measures of sequence dissimilarity have been compared on a computer-generated model system in which substitutions in random sequences were made at randomly selected sites and the replacement character was chosen at random from the set of characters different from the original occupant of the site. The three measures were the conventional mismatch count between aligned sequences (AMC = m) and two measures not requiring prior sequence alignment. The latter two measures were the squared Euclidean distance between vectors of counts of t-tuples (t = 1-6) of characters in the two sequences (multiplet distribution distances or MDD = d) and counts of characters not covered by word structures of statistically significant length common to the two sequences (common long words or CLW = SIB, SIS, or SAB). Average MDD distances were found to be two times average mismatch counts in the simulated sequences for all values of t from 1 to 6 and all degrees of substitution from one per sequence to so many as to produce, effectively, random sequences. This simple relation held independently of sequence length and of sequence composition. The relation was confirmed by exact results on small model systems and by formal asymptotic results in the limit of so few substitutions that no double hits occur and in the limit of two random sequences. The coefficient of variation for MDD distances was greater than that for mismatch counts for singlets but both measures approached the same low value for sextets. Needleman-Wunsch alignment produced incorrect mismatch counts at higher degrees of substitution. The model satisfied the conditions for the derivation of the Jukes-Cantor asymptotic adjustment, but its application produced increasingly bad results with increasing degrees of substitution in accord with earlier results on model and natural sequences. This fact was a consequence of the increase with increasing degrees of substitution of the sensitivity of the adjustment to error in the observations. Average CLW distances for a variety of common word structures were more or less parallel to MDD distances for appropriately long t-tuples. These results on model systems supported the validity of the two dissimilarity measures not requiring sequence alignment that was found in earlier work on natural sequences (Blaisdell 1989).
J Mol Evol 1989 Dec
PMID:Average values of a dissimilarity measure not requiring sequence alignment are twice the averages of conventional mismatch counts requiring sequence alignment for a computer-generated model system. 251

Increased cortisol secretion, caused by hyperactivity of the brain-pituitary-adrenal axis, and non-suppression of cortisol secretion following dexamethasone administration are two characteristics frequently associated with major depression or the depressed phase of bipolar illness. Antidepressants, irrespective of their selective inhibitory actions on the re-uptake of serotonin or of norepinephrine, modify glucocorticoid receptor messenger RNA concentrations in primary cultures of rat hypothalamic or amygdaloid neurons in a biphasic manner, with predominant stimulatory effects. This suggests a mechanism whereby antidepressants, by restoring the sensitivity of the limbic-hypothalamic system to glucocorticoid feedback inhibition, reverse the hyperactivity of the brain-pituitary-adrenal axis.
Brain Res Mol Brain Res 1989 Jul
PMID:Antidepressants regulate glucocorticoid receptor messenger RNA concentrations in primary neuronal cultures. 277 Apr 54

Repeated electroconvulsive stimulations represent one treatment modality for depressive disorders, but the mechanism leading to its effect is largely unknown. Studies of humans and rats have indicated that neuropeptide Y (NPY) is involved in major depression and anxiety. The purpose of the present investigation was to detect changes in the expression of preproNPY mRNA in the limbic cortex of rats exposed to electroconvulsive shocks (ECS) daily for 14 days. Twenty-four hours after the last ECS, the animals were sacrificed, brain sections were hybridized with a synthetic oligonucleotide probe complimentary to rat preproNPY mRNA. Semi-quantitative in situ hybridization histochemistry revealed an about ten-fold increase of preproNPY mRNA levels over the dentate gyrus and the piriform cortex in animals exposed to ECS compared to sham-treated controls. In the dentate gyrus dipped sections showed that the increase of gene expression took place in individual neurons in the polymorph layer. In the piriform cortex a moderate increase in the number of grains was observed over many individual cells in the pyramidal layer. These data show that the expression of preproNPY mRNA is markedly increased in specific brains regions after ECS, but whether this increase is a result of the ECS-induced seizures per se, or rather should be regarded as a protective adaptation to changes in neuronal activity pattern remains to be established.
Brain Res Mol Brain Res 1994 Jun
PMID:Electroconvulsive shocks increase the expression of neuropeptide Y (NPY) mRNA in the piriform cortex and the dentate gyrus. 809 71

This work evaluated in a population of heroin and heroin plus cocaine human addicts: 1. Norepinephrine (NE), epinephrine (Epi) and 3-methoxy-4-hydroxyphenylglycol (MHPG) (the principal metabolite of brain NE) plasma levels; 2. Monoamine oxidase (MAO) activity; and 3. 3H-imipramine specific binding to the amine carrier in platelets. NE plasma levels were significantly lower in the short-term heroin user groups (1-3 and 4-6 yr), a finding not observed in both long-term heroin user ( > 6 yr) and heroin plus cocaine user ( > 6 yr) groups. Epi levels changed in a similar manner, except that a significant increase was noted in heroin plus cocaine abusers. Conversely, dopamine and MHPG plasma levels increased with the duration of heroin use, and even more with cocaine abuse. Platelet MAO activity increased in all groups. Specific 3H-imipramine binding sites showed an increase after 3 yr of heroin abuse and in all heroin plus cocaine addicts. In conclusion, short-term use of heroin decreases NE or Epi release, but with prolonged use, a slow adaptation occurs. In contrast, cocaine inhibits the neuronal Epi uptake, even in a situation of long duration of abuse. Probably the amine levels additionally regulate the amine carrier, resulting in changes that show a different pattern from major depression. These drugs of abuse may also influence directly or indirectly related enzymatic systems.
Mol Neurobiol
PMID:Catecholamine and MHPG plasma levels, platelet MAO activity, and 3H-imipramine binding in heroin and cocaine addicts. 856 63

Cerebrospinal fluid (CSF) biochemical markers for Alzheimer disease (AD) would be of great value to improve the clinical diagnostic accuracy of the disorder. As abnormally phosphorylated forms of the microtubule-associated protein tau have been consistently found in the brains of AD patients, and since tau can be detected in CSF, two assays based on several well-defined monoclonal tau antibodies were used to study these proteins in CSF. One assay detects most normal and abnormal forms of tau (CSF-tau), while the other is highly specific for phosphorylated tau (CSF-PHFtau). A marked increase in CSF-PHFtau was found in AD (2230 +/- 930 pg/mL), as compared with controls (640 +/- 230 pg/mL; p < 0.0001), vascular dementia, VAD (1610 +/- 840 pg/mL; p < 0.05), frontal lobe dementia, FLD (1530 +/- 1000 pg/mL; p < 0.05), Parkinson disease, PD (720 +/- 590 pg/mL; p < 0.0001), and patients with major depression (230 +/- 130 pg/mL; p < 0.0001). Parallel results were obtained for CSF-tau. No less than 35/40 (88%) of AD patients had a CSF-PHFtau value higher than the cutoff level of 1140 pg/mL in controls. The present study demonstrates that elevated tau/PHFtau levels are consistently found in CSF of AD patients. However, a considerable overlap is still present with other forms of dementia, both VAD and FLD. CSF-tau and CSF-PHFtau may therefore be useful as a positive biochemical marker, to discriminate AD from normal aging, PD, and depressive pseudodementia. Further studies are needed to clarify the sensitivity and specificity of these assays, including follow-up studies with neuropathological examinations.
Mol Chem Neuropathol 1995 Dec
PMID:Tau protein in cerebrospinal fluid: a biochemical marker for axonal degeneration in Alzheimer disease? 874 26

The human serotonin transporter gene (hSERT) is a strong candidate for involvement in the pathogenesis of mood disorder and, using a UK Caucasian case-control sample, Collier et al found a significant association between bipolar disorder and the 12 allele of the VNTR polymorphism in intron 2 of this gene. In a European collaborative sample, Collier et al found a significant association between affective disorder and a functional deletion polymorphism in the promoter of hSERT. We have undertaken association studies using these polymorphisms in a British Caucasian sample comprising 171 DSM-IV bipolar probands, 80 DSM-IV major depression probands and 121 unrelated controls matched to bipolar probands for age, sex and ethnicity. We found no association between the promoter deletion and affective disorder but our findings with the VNTR polymorphism are similar to those of Collier and colleagues: we found a significant excess of the 12 repeat allele in bipolar probands (P = 0.031, one-tall) with a suggestion of a gene dosage effect (using genotypes bearing no 12 repeat allele as baseline, the increased risks conferred by genotypes bearing 12 repeat alleles were: heterozygote, OR = 1.24; homozygote, OR = 1.76). Our findings add to the evidence that variation at or near hSERT influences susceptibility to bipolar disorder in the British Caucasian population.
Mol Psychiatry 1997 Sep
PMID:Association studies of bipolar disorder at the human serotonin transporter gene (hSERT; 5HTT). 932 34

The glucocorticoid receptor (GR) is a ligand-regulated transcription factor that in its unactivated form resides primarily in the cytoplasm. After being bound by steroid, the GR undergoes a conformational change and translocates to the nucleus, where it influences gene transcription. Because the GR mediates negative feedback exerted by circulating glucocorticoid hormones on the hypothalamic-pituitary-adrenal (HPA) axis, it has been hypothesized that abnormalities in GR expression and/or function may underlie the HPA axis hyperactivity described in patients with major depression. In further support of this hypothesis, animal studies have shown that long term in vivo treatment with antidepressants enhances glucocorticoid feedback inhibition, possibly through a direct effect on the GR. To examine this latter possibility, we evaluated translocation of the GR from the cytoplasm to the nucleus after 24-hr in vitro treatment of L929 cells (mouse fibroblasts) with the tricyclic antidepressant desipramine (0.1-10 microM) in the presence or absence of the synthetic steroid dexamethasone. In addition, GR-mediated gene transcription was measured with the use of L929 cells stably transfected with the mouse mammary tumor virus-chloramphenicol acetyltransferase reporter gene. Desipramine was found to (i) induce GR translocation from the cytoplasm to the nucleus in the absence of steroids (with no effect alone on GR-mediated gene transcription) and (ii) potentiate dexamethasone-induced GR translocation and dexamethasone-induced GR-mediated gene transcription. Treatment with desipramine for 24-96 hr had no effect on the expression of GR protein as measured by cytosolic radioligand receptor binding. We suggest that one important aspect of the effects of antidepressants in vivo may be to facilitate GR-mediated feedback inhibition on the HPA axis, by facilitating GR translocation and function, and thereby reverse glucocorticoid hypersecretion in depression.
Mol Pharmacol 1997 Oct
PMID:Steroid-independent translocation of the glucocorticoid receptor by the antidepressant desipramine. 938 19

Pathological and biochemical studies indicate that beta-amyloid (betaA4) deposition is a hallmark in the pathogenesis of Alzheimer's disease (AD). Neuroimaging studies demonstrate that the respective cerebral changes primarily strike the temporal lobe and the amygdala-hippocampus complex and may be reliably assessed using quantitative magnetic resonance imaging (MRI). Therefore one may expect that reduced betaA4-levels are significantly correlated with measures of the temporal lobe rather than global cerebral atrophy in AD patients. To test this hypothesis in a clinical study, cerebrospinal fluid concentrations of total betaA4 and its major C-terminal variations betaA4 1-40 and betaA4 1-42 were compared with cerebral changes as assessed by quantitative magnetic resonance imaging (MRI). Significantly (P< 0.05) reduced betaA4 1-40 and betaA4 1-42 levels were found in the AD patients (17 female; six male; AD/NINCDS-ADRDA-criteria) in comparison to the patients with major depression (seven female; two male; DSM-III-R). Within the AD group, betaA4 and betaA4 1-42 levels were significantly correlated with the volume of the temporal lobes (r= 0.46 and r= 0.48, respectively) but none of the other volumetric measures. These findings indicate that changes in cerebral betaA4 levels contribute to temporal lobe atrophy in AD and support the possibility that betaA4 is central to the etiology of AD.
Mol Psychiatry
PMID:Cerebral changes and cerebrospinal fluid beta-amyloid in Alzheimer's disease: a study with quantitative magnetic resonance imaging. 939 97


1 2 3 4 5 6 7 8 9 10 Next >>