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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pyruvate and K-ferricyanide stimulation of net ATP and 2,3-bisphosphoglycerate synthesis is very probably due to enhancement of glyceraldehyde 3-phosphate dehydrogenase activity. Significant peculiarities in the K-ferricyanide effect and its depression by non-penetrating-SH inhibitors at low concentrations were noted and suggested that membrane-bound enzymes play a substantial part in the synthesis of ATP and 2,3-bisphosphoglycerate. Experiments with isolated ghosts showed their ATP-and 2,3-bis-phosphogylcerate-building capacity. Pulse-labeling with 32P-Pi and determination of specific radioactive in intracellular inorganic phosphate and ATP-gamma-P demonstrated that the ferricyanide-stimulated compartment utilizes only intracellular inorganic phosphate for ATP (and 2,3-bisphosphoglycerate) synthesis, and does so only when extracellular inorganic phosphate is present.
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PMID:The role of red cell membrane in the regulation of glycolysis and the 2,3-bisphosphoglycerate-cycle. 59 59

Doxorubicin (Adriamycin, ADR) is an effective antineoplastic agent with a major side effect of dilated cardiomyopathy. Previously we showed ADR selectively decreased alpha cardiac (alpha c) actin mRNA in the rat heart when compared to other mRNAs examined in heart and skeletal muscle. The present study determined if this effect was selective for mRNAs within the thin filament, related to inhibitory effects on mitochondrial transcription, and modified by pretreatment with the cardioprotective chelating agent ICRF-187. Adult Sprague-Dawley rats received ADR at 8 mg/kg intraperitoneally (ip) with or without pretreatment with ICRF-187 given at 80 mg/kg ip. After 3 days, rats were killed and myocardial RNA was extracted, electrophoresed, transferred to nitrocellulose, and hybridized with the [32]cDNA probes alpha c actin, troponin C (TnC), BamHI fragment of mouse mitochondria (MM), and glyceraldehyde-3-phosphate dehydrogenase (G3PD). Results showed a major depressive effect of ADR on rat myocardial alpha c actin mRNA. No depression of the other mRNAs examined (TnC, MM, or G3PD) was seen. ICRF-187 did not modify the effect. We conclude that the ADR-induced decrease in alpha c actin mRNA was: (1) selective within the thin filament; (2) not related to inhibitory effects on mitochondrial transcription; and (3) not related to free radical formation. Possible subcellular mechanisms are discussed.
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PMID:Selective alterations in rat cardiac mRNA induced by doxorubicin: possible subcellular mechanisms. 170 8

Modern research in male contraception is focusing on 4 areas: 1) hormonal control of spermatogenesis, the complex processes of spermiogenesis in the testis where the spermatogonia stem cells mitotically divide into spermatocytes, which meiotically divide into nondividing spermatids, which become the spermatozoa; 2) direct (nonhormonal) inhibition of spermatogenesis; 3) the suppression of sperm maturation in the epididymis; and 4) the immunological suppression of fertility through the identification of an antisperm antibody. Hormonal suppression of spermatogenesis requires depression of testosterone levels in the testis, either by direct inhibition of the Leydig cells or by inhibition of the hypothalamic production of luteinizing hormone-releasing hormone, which induces the pituitary secretion of luteinizing hormone, which induces the secretion of testosterone. Testosterone suppression in the testis must be accompanied by exogenous androgen supplements or there will be loss of libido and potency. Preparations under investigation in the hormonal suppression of spermatogenesis include monthly injections of 200 mg depot medroxyprogesterone acetate with 200 mg testosterone enanthate; danazol with testosterone enanthate; anabolic steroids, such as 19-NT-hydroxyphenylpropionate; cyproterone acetate, an antiandrogen with progestational effects; and luteinizing hormone-releasing hormone agonists, which down-regulate pituitary receptors, or luteinizing hormone-releasing hormone antagonists, which competitively block receptor activation. None of these preparations have yet struck a balance where they can completely but reversibly block spermatogenesis at doses which do not have toxic or feminizing effects. 3 nonhormonal agents which suppress sperm production are gossypol, extract of Trypterigium wilfordii, and tolnidamine. Gossypol, an extract of cottonseed oil, has been widely studied in China and has been found 99% effective in producing azoospermia or severe oligospermia. However, it is extremely toxic, damages cells in the seminiferous epithelium, and causes hypokalemia. Over time, its effects become irreversible, and its mutagenicity and teratogenicity are not known. Agents which suppress sperm maturation in the epididymis act after cell division is complete and hence are not mutagenic, but they are extremely toxic. Alpha-chlorohydrin and 6-chloro-6 deoxysugars act by inhibiting the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase with the result that sperm cannot metabolize sugar. The sulfonamide compound, sulfasalazine, disrupts sperm motility by a mechanism not yet known. The development of a contraceptive vaccine relies on the identification of the antigenic determinants on sperm surface. Even if such a vaccine could be developed, there remains the problem of reversibility. None of the methods now being studied have demonstrated that they can reliably prevent unwanted pregnancy, and none have been around long enough for their longterm side effects to be known.
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PMID:Male contraception: current status and future prospects. 307 64

Inhibition of ADP phosphorylation by both glycolysis and mitochondria in P388D1 cells exposed to H2O2 is described. Net glucose uptake and lactate production were inhibited by oxidant exposure (ED50 = 50-100 microM). Glycolysis was specifically inactivated at the glyceraldehyde-3-phosphate dehydrogenase step by three independent mechanisms: (a) direct inactivation of the intracellular enzyme (ED50 approximately equal to 100 microM); (b) reduction of the intracellular concentration and redox potential of its nicotinamide cofactors; and (c) a cytosolic pH shift further from the enzyme optima. Consistent with inhibition of glycolysis at the glyceraldehyde-3-phosphate dehydrogenase step, a rise in the intracellular concentration of glyceraldehyde 3-phosphate, dihydroxyacetone phosphate, and fructose 1,6-bisphosphate was observed. The calculated combined inhibition of glyceraldehyde-3-phosphate dehydrogenase activity could be reasonably correlated with the depression in glycolytic flux rate with the appropriate modeling. The steady-state contribution by mitochondria to the total intracellular ATP pool was indirectly determined by the use of various metabolic inhibitors and was found to rapidly decline following exposure to 300-800 microM H2O2. The inhibition of ADP phosphorylation appeared to be related more to the direct inhibition of the ATPase-synthase complex rather than to the diminished capacity of the respiratory chain for coupled electron transport. Both the estimated rates of ADP phosphorylation by glycolysis and mitochondria and the estimated rate of ATP hydrolysis by ongoing metabolism were utilized to model the approximate decline in intracellular ATP expected at 15-min exposure to various H2O2 concentrations. Theoretical calculations and the measured intracellular ATP status were in good agreement. Oxidant exposure for 15 min resulted in dose-dependent killing of the cells (ED50 = 500 microM), indicating a close correlation between H2O2-mediated loss of intracellular ATP and cell viability. The possible contribution of impaired energy homeostasis during oxidant-mediated injury to the process of cell dysfunction and death is discussed.
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PMID:Mechanisms of oxidant-mediated cell injury. The glycolytic and mitochondrial pathways of ADP phosphorylation are major intracellular targets inactivated by hydrogen peroxide. 333 86

The effects of ischemia on mitochondrial function and the unidirectional rate of ATP synthesis (Pi----ATP rate) were studied using a Langendorff-perfused heart preparation and 31P NMR spectroscopy. There was significant postischemic depression of mechanical function assessed as the heart rate pressure product, and the myocardial oxygen consumption rate at a given rate pressure product was elevated. Experiments performed on glucose- and pyruvate-perfused hearts demonstrated the presence of a large contribution to the unidirectional Pi----ATP rate catalyzed by glyceraldehyde-3-phosphate dehydrogenase and phosphoglycerate kinase. This rate was much greater than the maximal glucose utilization rate in the myocardium, demonstrating that the glyceraldehyde-3-phosphate dehydrogenase/phosphoglycerate kinase reactions are near equilibrium both before and after ischemia. In the pyruvate-perfused postischemic hearts, the glycolytic contribution was eliminated and the net rate of ATP synthesis by oxidative phosphorylation was measurable. Despite the reduced mechanical function and increased myocardial oxygen consumption rate, the ratio of the net rate of ATP synthesis by oxidative phosphorylation to oxygen consumption rate (the P:O ratio) was not altered subsequent to ischemia (2.34 +/- 0.12 and 2.36 +/- 0.09 in normal and postischemic hearts, respectively). Therefore, mitochondrial uncoupling cannot be the cause of postischemic depression in mechanical function; instead, the data suggest the existence of ischemia-induced inefficiency in ATP utilization.
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PMID:ATP synthesis kinetics and mitochondrial function in the postischemic myocardium as studied by 31P NMR. 339 29

Most of the eighteen vinylfurane derivatives studied fully inhibit the glycolysis of both Ehrlich ascites carcinoma (EAC) cells and respiratory deficient yeast Saccharomyces cerevisiae at concentrations lower than 0.5 mmol/l. The inhibition of glycolysis is a consequence of some thiol enzymes inactivation. This concerns namely hexokinase (EC 2.7.1.1), glyceraldehyde-3-phosphate dehydrogenase (EC 1.2.1.12) and especially 6-phosphofructokinase (EC 2.7.1.11). Interference of vinylfurans with energy metabolism resulted in the depression of biosynthetic processes followed (14C-precursors incorporation into proteins and nucleic acids) and finally in the loss of EAC cell transplantability.
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PMID:The inhibitory effect of vinylfurans on the glycolysis in tumor and yeast cells. 702 57

The cerebral metabolic effects of intravenous administration of 1000 mg/kg gamma-hydroxybutyrate (GHB) were studied by sequential measurement of the cerebral contents of selected glycolytic-citric acid cycle intermediates and energy phosphates in lightly anesthetized rats. The initial change in the glycolytic pathway occurred by 2.5 min, with increases of tissue glucose-6-phosphate and decreases of fructose-1,6- diphosphate which indicated an inhibition of phosphofructokinase. This pattern was transient and was replaced at 5--15 min by increasing tissue glucose and decreasing glucose-6-phosphate which indicated an inhibition of hexokinase. The initial inhibition of phosphofructokinase was associated with functional depression, an isoelectric EEG and an increase of the tissue phosphocreatine which suggested that the observed metabolic pattern was an adaptation to the reduced energy needs of neuronal depression. Within 2.5 min of GHB injection tissue alpha-ketoglutarate and aspartate showed significant increases which suggested a shift in the aspartate aminotransferase reaction. Preliminary calculations indicated that the probable cause of this shift was an increase in oxaloacetate content due to GHB oxidation. The cytoplasmic NADH/NAD+ ratio remained unchanged throughout the entire exposure to GHB (2.5--180 min) and thus gave no support for the hypothesis that GHB interfers with glycolysis via the restriction of free cytoplasmic NAD+ required for the glyceraldehyde phosphate dehydrogenase step.
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PMID:Sequential alterations of cerebral carbohydrate metabolism associated with gamma-hydroxybutyrate. 735 98

Conditions to induce and parameters to evaluate sublethal oxidative stress of cultured human fibroblasts have been investigated in the attempt to identify markers for a more accurate quantification of cell injury. Sublethal oxidative stress was obtained by treating fibroblasts with 0.5 mM H2O2 in DMEM plus 5% FCS for times not exceeding 60 min. Under these conditions cells remained viable throughout long-term incubation, showing no appreciable release of cytosolic enzymes into the medium. On the contrary, exposures of fibroblasts to 0.5 mM H2O2 for times > 60 min induced a lethal cell injury which was fully expressed 2 days later by massive monolayer wasting and leakage of cytosolic components. Early metabolic effects of sublethal stress consisted of a rapid and significant fall of both ATP and NAD+ pools. Concomitantly, there was a moderate increase (about threefold) in both ADP-ribosyl transferase activity and free [Ca2+]i, while the specific activity of glyceraldehyde-3-phosphate dehydrogenase was partially decreased upon treatment. Oxidative injury also caused delayed effects consisting of a large depression of both protein and DNA synthesis. However, while the former was partially restored within 10 days of incubation, the latter remained severely impaired, as encountered in a growth-arrested population. Microfilaments of H2O2-treated cells appeared to be morphologically altered due to partial fragmentation of cytoskeleton actin which, however, was still maintained in the polymerized form as F-actin. Moreover, sublethally injured fibroblasts exhibited a reduced adhesiveness to plastic once they were detached and reseeded into new dishes. Relative adhesion efficiencies (number of adherent cells at 16 h as a percentage of seeded cells) were found to correlate inversely with times of exposure to H2O2. This finding allowed the identification of a biological parameter which showed itself to be very sensitive to oxidative stress and was also useful for developing an assay to grade sublethal injury to fibroblasts.
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PMID:Induction, effects, and quantification of sublethal oxidative stress by hydrogen peroxide on cultured human fibroblasts. 784 83

A cDNA clone which contains the near-complete open reading frame (ORF) encoding glyceraldehyde-3-phosphate dehydrogenase (GAPDH, EC 1.2.1.12) was obtained by screening a muscle cDNA library of jerboa (Jaculus orientalis), a true hibernating rodent, with a PCR-amplified 0.5-kb genomic DNA probe from an internal region of the gene. The 1.1-kb cDNA clone consists of a 927-bp ORF which codifies for 309 aa, about 93% of the original GapC gene encoding the 36-kDa protein, and a 3'-noncoding region of 167 bp. The full-length aa sequence of GAPDH was achieved by sequencing the N-terminal region of the purified protein completing the missing part in the cDNA clone. Both nt and aa sequences exhibit a high degree of homology to other mammalian GAPDHs. The expression of the GapC gene was studied in skeletal muscle and liver of euthermic and hibernating jerboas both on the mRNA level by Northern blot hybridization using the cDNA clone as a probe and on the protein level by Western blot immunodetection using an antibody raised against muscle GAPDH. A clear decrease (about threefold) in the amount of GapC mRNA, a single 1.2-kb transcript, was observed in muscle of hibernating jerboa when compared with the same tissue from the euthermic animal. This mRNA level decrease directly correlates with a reduction in both protein amount and specific activity in crude protein extracts. In contrast, both GAPDH protein and GapC mRNA levels remained unchanged in liver from euthermic and hibernating jerboas although the enzymatic activity was also about threefold lower in the hibernating tissue. These result, together with previous data obtained from protein studies [Soukri et al. (1995) Biochim. Biophys. Acta 1243, 161-168 and (1996) 1292, 177-187] indicate that jerboa GAPDH is regulated by different mechanisms during hibernation in these tissues, that is, at transcriptional level in muscle and at posttranslational level in liver. The reduced GAPDH activity should result in both cases in a decrease of the glycolytic flux that would eventually contribute to the dramatic metabolic depression of this dormant state.
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PMID:Occurrence of a differential expression of the glyceraldehyde-3-phosphate dehydrogenase gene in muscle and liver from euthermic and induced hibernating jerboa (Jaculus orientalis). 897 22

Recent research suggests that antidepressants exert their clinical action in depression via the restoration of glucocorticoid receptor (GR) function with a subsequent normalization of the altered feed-back regulation of the hypothalamic-pituitary adrenocortical (HPA) system. We, therefore, studied the effects of amitriptyline, a standard antidepressant, and of the glucocorticoid dexamethasone, which has recently been reported to possess antidepressive properties, on glucocorticoid receptor mRNA (GR-mRNA) derived from blood cells of healthy male volunteers. Whole blood samples were exposed in vitro for 24 h to amitriptyline and dexamethasone, the mRNA was extracted, transcripts of the 'house-keeping gene' glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and the GR-gene were subjected to reverse transcriptase-polymerase chain reaction (RT-PCR) and semiquantitatively determined by subsequent densitometry. In a concentration of 10 nM, amitriptyline induced a significant increase in GR-mRNA (GR/GAPDH ratio) to 186 +/- 31% of the control condition, while a concentration of 10 microM of amitriptyline resulted in an increase of GR-mRNA (GR/GAPDH ratio) to 165 +/- 36%. Dexamethasone also up-regulated blood cell GR-mRNA (GR/GAPDH ratio) levels at a concentration of 10 nM to 184 +/- 29%, whereas an incubation with 10 microM apparently resulted in toxic effects on blood cells with a decreased amount of total mRNA samples recovered. In conclusion, we here show an increase of GR-mRNA in human blood cells after treatment with amitriptyline and dexamethasone, pointing to a direct action of these substances on GR-gene expression in a human system.
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PMID:Regulation of glucocorticoid receptor-mRNA in human blood cells by amitriptyline and dexamethasone. 1040 68


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