Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Using the time sharing fluorometer/reflectometer the measurement of NADH fluorescence as well as the reflected light was obtained from the surface of the awake rat brain cortex. The light was transferred to and from the brain via a flexible light pipe (made of quartz fibers) connected to a cannula implanted permanently above the brain. Exposing the rat to pure nitrogen atmosphere increased the fluorescence (reduction of NADH) by 32.3 +/- 6.1% in comparison to the normoxic fluorescence level. During cortical spreading depression (SD) the NADH fluorescence decreased (oxidation of NADH) by 17.3 +/- 2.8%. Exposing the rat to nitrogen after SD was elicited blocked the oxidation cycle observed during SD. Exposing the awake ras to 10, 7.5 or 5% O2 did not block the response of the brain to spreading depression or to Metrazol applied locally to the cortex. Under hypoxic conditions the brain showed a typical response to SD, namely, an oxidation cycle of NADH except that the duration of the cycle was longer and the decrease in the NADH level was smaller. The EEG activity recovered to normal even under 5%. The same effect of hypoxia was found when Metrazol was applied and epileptic activity was developed.
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PMID:Metabolic responses of the awake cerebral cortex to anoxia hypoxia spreading depression and epileptiform activity. 16 66

The relationship between bipolar disorder and chromosome 11 markers remains uncertain. Whilst re-analysis of the Amish pedigree weakened previous evidence for close linkage (but could not exclude the possibility of genetic heterogeneity), a recent French study has found a significant association between this condition and tyrosine hydroxylase polymorphisms. We aimed to determine if bipolar disorder in two large Australian pedigrees (of Irish and English extraction respectively) was linked to these markers. Of the 84 family members available for testing, nine were diagnosed as bipolar I, one as bipolar II and six had recurrent unipolar depression. Linkage of bipolar disorder and recurrent depression to the chromosome 11p15 markers c-Harvey ras, insulin and tyrosine hydroxylase was tested using a series of genetic models with varying penetrance levels. Additionally, linkage was examined using a series of levels of definitions of affective status (ranging from bipolar I alone to all affective illnesses). Close linkage to these markers was strongly excluded using each model and definition. The findings also persisted when a wide range of rates of 'sporadic' (non-genetic) presentations of illness were incorporated in the analysis. These results are consistent with other recent studies indicating that bipolar disorder is not linked to chromosomal region 11p15.
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PMID:Close linkage of bipolar disorder to chromosome 11 markers is excluded in two large Australian pedigrees. 167 74

Expression of a transforming Ha-ras gene in NIH 3T3 cells transfected with an inducible Ha-ras construct leads to a rapid desensitization of the intracellular Ca2(+)-mobilizing system to bombesin and serum growth factors. Half-maximal depression of the Ca2+ response is observed 2 h after induction of p21ras. A maximum is obtained after 6 h. Bombesin-induced elevation of inositol 1,4,5-trisphosphate formation is also depressed in cells expressing Ha-ras. This, however, is a relatively late phenomenon and not yet detectable when maximal depression of the Ca2+ signal is observed. We conclude that the rapid densensitization of the Ca2(+)-releasing system to bombesin by Ha-ras is not caused by down-modulation or uncoupling of phospholipase C-coupled bombesin receptors. The inositol 1,4,5-trisphosphate-mediated release of intracellular Ca2+ is reduced in permeabilized cells expressing the Ha-ras oncogene. A depletion of intracellular Ca2+ stores by Ha-ras is unlikely since (i) the Ha-ras-induced growth factor-independent stimulation of inositol phosphate formation occurs several hours after reduction of the Ca2+ response and (ii) the Ca2+ load of intracellular nonmitochondrial Ca2+ stores was found to be unaffected by Ha-ras. We conclude that the desensitization of the Ca2(+)-mobilizing system is caused either by partial inhibition of inositol 1,4,5-trisphosphate-regulated Ca2+ channels or by interference of Ha-ras with Ca2+ translocation between intracellular Ca2+ compartments.
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PMID:Mechanism of desensitization of the Ca2(+)-mobilizing system to bombesin by Ha-ras. Independence from down-modulation of agonist-stimulated inositol phosphate production. 184 54

An overview was presented of our approach of inhibition of de novo and salvage pathways in pyrimidine and purine metabolism. 1. Combination of acivicin, an inhibitor of de novo biosynthesis, and dipyridamole, a transport inhibitor, provided synergistic cytotoxicity in hepatoma and colon carcinoma cells. 2. AZT, a competitive inhibitor of the salvage enzyme, thymidine kinase, and 5-FU or MTX provided synergistic cytotoxicity in hepatoma 3924A. In human colon carcinoma HT-29 cells AZT and methotrexate yielded synergistic cytotoxicity and thymidine and hypoxanthine together provided protection from the action of these drugs. 3. These observations are significant because in rat hepatoma 3924A and in human cell lines HT-29, HL-60 and K562 thymidine kinase activity was 16- to 67-fold higher than that of dTMP synthase. Therefore, inhibition of dTMP synthase activity alone may provide poor responses because the salvage pathways can circumvent this block. 4. In leukemic patients treated with tiazofurin, an inhibitor of IMP dehydrogenase, the rate-limiting enzyme of GTP biosynthesis, and with allopurinol, which inhibits GPRT activity through raising plasma hypoxanthine levels, synergistic therapeutic results were obtained. The responses in sensitive patients entailed a decrease in IMP dehydrogenase activity and GTP concentration in leukemic cells and down-regulation of the ras and myc oncogenes. The down-regulation of the ras oncogene by tiazofurin through the decrease of GTP concentration has now been shown in K562, HL-60 and hepatoma cells and in patients with chronic granulocytic leukemia in blast crisis. Tiazofurin may be useful in studies on selective depression of the expression of the ras oncogene. 5. In 27 consecutive patients 50% responded positively to tiazofurin treatment. From this group, 10 out of 12 patients (83%) with chronic granulocytic leukemia in blast crisis responded to tiazofurin treatment.
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PMID:Regulation of de novo and salvage pathways in chemotherapy. 187 99

Expression of the transforming Ha-ras oncogene in MMTV-LTR transfected NIH 3T3 cells leads to a growth factor independent activation of the Na+/H(+)-antiporter. The activation of the antiporter is insensitive to the protein kinase inhibitor staurosporine and equally expressed in protein kinase C-depleted cells. It is concluded that the Ha-ras induced activation of the antiporter occurs by a protein kinase C-independent mechanism. An inhibition of the Na+/H(+)-antiporter by dimethylamiloride or a reduction of the extracellular [Na+] concentration results in a depression of the bombesin induced release of Ca2+ from intracellular stores. These results are explained by a steep pH-dependence of the Ca2(+)-mobilizing system which exhibits a maximum at pH 7.1 in the system studied here. Stimulation by growth factors of quiescent cells with a resting pH below 7 results in a shift of the cytosolic pH towards the optimum for the Ca2+ release. In agreement with the proposed interrelationship, pHi and [Ca2+]i rise and peak simultaneously after addition of bombesin to G0 arrested cells.
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PMID:Mechanism and biological significance of the Ha-ras-induced activation of the Na+/H(+)-antiporter. 216

NIH3T3 cells were transfected with activated Ha-ras and the corresponding proto-oncogene was subjected to transcriptional control by recombination in vitro with MMTV-LTR. Induction of p21ras expression in quiescent cells by dexamethasone causes an increased turnover of phosphatidylinositol 4,5-bisphosphate with a concomitant rise in inositol phosphates, and an activation of the Na+/H+-antiporter. Addition of serum growth factors to dexamethasone treated cells does not result in an additional stimulation of phosphatidylinositol metabolism or Na+/H+-exchange. There is also a desensitization to exogenous growth factors of the intracellular Ca2+-mobilizing system, leading to a depression of the transitory increase in cytosolic Ca2+ after addition of serum growth factors. None of these effects are seen after expression of the Ha-ras proto-oncogene. Results are discussed as indicating a constitutive growth factor independent activation of growth factor signal transduction by the activated Ha-ras.
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PMID:Effect of Ha-ras on phosphatidylinositol metabolism, Na+/H+-antiporter and mobilization of intracellular calcium. 285 46

Manic depression is a severe cyclic mental illness that can be unipolar or bipolar and has a lifetime risk of approximately 7 per 1,000 in most populations. Families with multiple cases of manic depression have been described that are compatible with both autosomal dominant and X-linked modes of genetic transmission. Psychoactive antidepressant and stimulant drugs that help to ameliorate depression and mania are thought to act by affecting catecholamine neurotransmitter systems such as adrenaline, noradrenaline and dopamine, amongst others. Mutations affecting the tyrosine hydroxylase (TH) gene, which encodes the rate-limiting enzyme for the synthesis of these three neurotransmitters, might therefore be responsible for causing the manic depressive phenotype. We have studied three Icelandic kindreds amongst whom it appears that a single autosomal dominant disease allele is segregating. In these families there were 44 cases amongst 73 individuals at risk. Genetic linkage studies were carried out using clones encoding tyrosine hydroxylase the variable portion of the Harvey-ras-1 (HRAS1) locus and the variable region of the insulin gene (INS). All three markers are closely linked on chromosome 11 and were used to observe the segregation of restriction fragment length polymorphisms (RFLPs) in the three affected kindreds. We found no evidence for linkage to these markers in any of the three families. In contrast, Gerhard et al. found linkage between manic depression and HRAS1 in a single large Amish kindred. We conclude that there is genetic heterogeneity of linkage in manic depression. Therefore mutations at different loci are responsible for the manic depressive phenotype in the Amish and in Iceland.
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PMID:Molecular genetic evidence for heterogeneity in manic depression. 288 Dec 10

Studies were undertaken to define the existence of specific T3-binding sites in the synaptosomal fraction of rat cerebral cortex. Development-related changes of the synaptosomal T3-binding sites were compared with those of nuclear T3 receptors in rat cerebral cortex. Scatchard analysis was compatible with the existence of two sets of high affinity T3-binding sites: K1, with a mean (+/- SE) apparent dissociation constant (Kd) of 3.22 +/- 0.63 x 10(-11) M and a mean (+/- SE) maximum binding capacity (MBC) of 3.2 +/- 0.3 pg T3/mg protein, and K2, with a K4 of 2.64 +/- 0.15 x 10(-9) M and a MBC of 218.3 +/0 15.0 pg T3/mg protein. When compared to T3, 27-, 135-, 500-, and 1000-fold higher concentrations of T4, 3,5-diiodothyronine (3,5-T2), triiodothyroacetic acid, and rT3, respectively, were needed to obtain 50% depression of the synaptosomal T3 binding. Tetraiodothyroacetic acid, 3,3'-T2, 3'5'-T2, 3-monoiodothyronine (3-T1), 3'-T1, and thyronine had little effect. The MBC of T3 nuclear receptors was the highest at 2 days of age and significantly decreased thereafter, although an almost constant K4 was observed in all age groups studied. On the contrary, the MBC of the higher affinity synaptosomal T3-binding sites was low in 2-day-old rats (20.3 +/- 1.2 pg T3/g tissue) and increased thereafter to the level in young adult ras (50.4 +/- 2.2 pg T3/g tissue). However, the Kd of synaptosomal T3-binding sites was also unchanged in all age groups studied. These findings clearly indicate that there exist specific T3-binding sites in synaptosomes from rat cerebral cortex.
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PMID:High affinity 3,5,3'-L-triiodothyronine binding to synaptosomes in rat cerebral cortex. 706 May 25

Unipolar depression, alcoholism and suicide have become more common over the past decades. Genetic studies have attempted to link (bipolar) affective disorder to the short arm of chromosome 11 (where the loci for insulin, insulin growth factor (IGF), tyrosine hydroxylase (TH) and h-ras-oncogene are located) but these have failed. Since TH and the insulin receptor require phosphorylation by protein kinases, then a defect of the h-ras-oncogene or its products (p21) could disorder both these systems and compromise catecholaminergic transmission in neurones and energy flow in glial cells. This could lead not only to a predisposition to depression ('trait markers') but to neurotoxic damage, predisposed by inadequate cytosol Mg2+ levels of hypometabolism. Tyrosine, tryptophan and phenylalanine hydroxylases all require tetrahydrobiopterin (BH4) which allosterically regulates its own activity as well as that of these enzymes. Anything which impairs this cofactor could lead to overt depression in predisposed individuals, and the heterocyclic amines are being increasingly implicated. These substances are derived from fried and broiled meats, azo food dyes, soft drinks and hard candies, but particularly from cigarette and petroleum fumes. The heterocyclic amines can inhibit aromatic-l-amino-acid-decarboxylase (AADC) as well as the hydroxylases reversibly, but BH4 is inhibited noncompetitively. Thus, susceptible individuals (those with inherited defective protein kinase phosphorylation) might be 'tipped over' by chronic exposure to these neurotoxins. The rising incidence of unipolar depression-associated morbidity could be significantly linked to increasing levels of heterocyclic amines in the developed nations.
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PMID:The 'cerebral diabetes' paradigm for unipolar depression. 814 51

The purpose of this paper was to clarify critical aspects of the behavior of signal transduction activity in normal and cancer cells. 1. Signal transduction activity in the conversion of phosphatidylinositol through PI and PIP kinases and PLC to IP3 is regulated at multiple sites. In liver, hepatomas and human carcinomas PIP kinase is the rate limiting enzyme and PLC activity is present in great excess. 2. The steady-state signal transduction activity as measured by the three enzyme activities and IP3 concentration was markedly up-regulated in rat hepatomas of different growth rates. The steady-state specific activities of the three signal transduction enzymes were elevated in ovarian carcinomas as compared to normal ovary. Increased enzyme activities were also observed in human breast carcinoma cells as compared to normal human breast parenchymal cells. In breast, ovarian and rat hepatoma cells as they go through lag, log and plateau phases, IP3 concentration in the early lag phase increased 4.5- to 20-fold and PI and PIP kinase activities peaked in mid-log phase. These events returned to baseline levels in the plateau phase. PLC activity did not change. 3. The bone marrow PI and PIP kinase activities in 3-day starvation were decreased to 13% and IP3 concentration was reduced to 24%; at 1-day refeeding they returned to normal. PLC activity changed little. These alterations are in line with the rapid t1/2 degradation rates (12 min) of PI and PIP kinases observed in studies with cycloheximide. By contrast, PLC has a long half-life. 4. The molecular action of tiazofurin entails inhibition of IMP DH activity, decrease in GTP and IP3 concentrations, reduction of ras and myc oncogene expression, and signal transduction enzyme activities. These events are followed by induced differentiation and apoptosis. There are also decreases in enzyme activities which have rapid turnover, including TdR kinase, dTMP synthase, and GPRT. In vitro studies indicated that these events are abrogated by addition of guanine which restores GTP concentrations. Therefore, most or all these events were brought about by the reduced GTP concentration in the tiazofurin target cells. 5. Quercetin and genistein are able to inhibit PI and PIP kinase activities and reduce IP3 concentration in vivo and in tissue culture systems. These flavonoids are also inhibitors of cell proliferation and clonogenic ability in rat hepatoma 3924A and in human OVCAR-5 and MDA-MB-435 cells. Quercetin down-regulated the expression of c-myc and Ki-ras oncogenes and led to induced differentiation and apoptosis in K562 cells. Genistein reduced IP3 concentration in vivo and in the tissue culture system. Genistein is antiproliferative and has cytototoxicity in human carcinoma cells. All three drugs, tiazofurin, quercetin and genistein, act, in part at least, through depression of cellular IP3 concentration although the mechanisms may not be identical. 6. Quercetin and genistein, which attack different targets and different phases of the cell cycle, proved to be synergistic in OVCAR-5 cells. The impact of tiazofurin, genistein and quercetin is of interest because the drugs crucially inhibit the display of the neoplastic program of cells and lead to induced differentiation and apoptosis.
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PMID:Regulation of the signal transduction program by drugs. 938 80


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