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)

Heavy metal treatment (2 X 1 mg/kg per day) for 3, 5, and 7 days resulted in progressive augmentation in the incorporation of [14C]thymidine into hepatic DNA. In contrast with the observed enhancement in DNA synthesis, cadmium exposure tended to produce a decrease in the activity of hepatic ornithine decarboxylase (EC 4.1.1.17) at 1, 3, or 5 days with the lowest (34% of control values) enzymic activity seen after 7 days. A similar reduction in the activity of S-adenosylmethionine decarboxylase (EC 4.1.1.50) was observed in livers of rats treated with cadmium for 1-7 days. Subacute exposure to cadmium significantly lowered the hepatic levels of spermidine and spermine whereas the endogenous concentrated of putrescine remained unaltered. In addition to the observed effects on the biosynthesis of polyamines and DNA, heavy metal treatment produced stimulation of the hepatic adenylate cyclase (EC 4.6.1.1)--cyclic AMP system. Significant increases in the activity of hepatic adenylate cyclase and endogenous cyclic AMP levels were detected as early as 1 day and the observed alterations persisted during the entire 1-week period of cadmium exposure. The depression in polyamine formation was accompanied by enhanced DNA biosynthesis as well as stimulation in the adenylate cyclase-cyclic AMP system of rat liver.
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PMID:Sequential changes in hepatic polyamine, deoxyribonucleic acid, and cyclic adenosine 3',5'-monophosphate metabolism after subacute exposure to cadmium in rats. 19 91

1. The activation of human peripheral blood lymphocytes by phytohaemagglutinin in vitro was accompanied by striking increases in the concentrations of the natural polyamines putrescine, spermidine and spermine. 2. The enhanced accumulation of polyamines could be almost totally abolished by dl-alpha-difluoromethylornithine, a newly discovered irreversible inhibitor of l-ornithine decarboxylase (EC 4.1.1.17), or by methylglyoxal bis(guanylhydrazone) {1,1'-[(methylethanediylidene)dinitrilo]diguanidine}, an inhibitor of S-adenosyl-l-methionine decarboxylase (EC 4.1.1.50). The inhibition of polyamine accumulation was associated with a marked suppression of DNA synthesis, which was partially or totally reversed by low concentrations of exogenous putrescine, spermidine, spermine and cadaverine and by higher concentrations of 1,3-diaminopropane. 3. In contrast with some earlier studies, we found that methylglyoxal bis(guanylhydrazone), at concentrations that were sufficient to prevent polyamine accumulation, also caused a clear inhibition of protein synthesis in the activated lymphocytes. Similar results were obtained with difluoromethylornithine. The decrease in protein synthesis caused by both compounds preceded the impairment of DNA synthesis. The inhibition of protein synthesis by difluoromethylornithine was fully reversed by exogenous putrescine, spermidine and spermine, and that caused by methylglyoxal bis(guanylhydrazone) by spermidine and spermine. In further support of the idea that the inhibition of protein synthesis by these compounds was related to the polyamine depletion, we found that difluoromethylornithine caused a dose-dependent decrease in the incorporation of [(14)C]leucine into lymphocyte proteins which closely correlated with the decreased concentrations of cellular spermidine. 4. Difluoromethylornithine and methylglyoxal bis(guanylhydrazone) also elicited a variable depression in the incorporation of [(3)H]uridine and [(14)C]adenine into total RNA. The apparent turnover of lymphocyte RNA remained essentially unchanged in spite of severe polyamine depletion brought about by difluoromethylornithine. 5. The present results, as well as confirming the anti-proliferative action of the inhibitors of polyamine biosynthesis, suggest that polyamine depletion may interfere with reactions at different levels of gene expression.
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PMID:Suppression of the formation of polyamines and macromolecules by DL-alpha-difluoromethylornithine and methylglyoxal bis(guanylhydrazone) in phytohaemagglutinin-activated human lymphocytes. 43 70

Adult rhesus monkeys were subjected to complete cerebral ischemia for one hour and subsequent recirculation for up to 24 h. Animals with signs of functional recovery (e.g. spontaneous EEG activity) exhibited a partial replenishment of cellular energy sources (ATP, phosphocreatine) and a progressive normalization of cerebral lactate levels. Glucose and pyruvate concentrations showed a transient increase over control values during the early stages of postischemic recirculation. Monkeys without functional recovery lacked a significant resynthesis of energy-rich compounds; adenine nucleotides continued to decrease and lactate concentrations were higher than in animals subjected to ischemia without recirculation. Cerebral polysome profiles remained unaltered during the ischemic period but in all animals a marked disaggregation of polyribosomes with a concomitant increase in ribosomal subunits occurred after the onset of recirculation. In monkeys with indications of functional recovery these changes were reversible but a normal polysome profile was only observed after 24 h of recirculation. The results obtained indicate a postischemic depression of protein synthesis due to an inhibition of peptide chain initiation. After recirculation of the brain for 3-6 h there was evidence for an induction of enzymes involved in polyamine synthesis (ornithine decarboxylase and S-adenosylmethionine decarboxylase). No changes in the activity of these enzymes were observed at the end of the ischemic period, indicating that during complete cerebral ischemia not only the synthesis but also the catabolism of proteins is inhibited.
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PMID:Resuscitation of the monkey brain after one hour complete ischemia. III. Indications of metabolic recovery. 115 69

When exposed to alpha-difluoromethylornithine (DFMO), an inhibitor of polyamine biosynthesis, Chinese hamster ovary cells become increasingly sensitive to the cytotoxic effects of elevated temperatures (D.J.M. Fuller and E.W. Gerner, Cancer Res., 42:5046-5049, 1982). This sensitization becomes marked at times greater than 24 h after drug removal, and by 48 h, polyamine-depleted cells that have been exposed to 43 degrees C for 90 min have clonogenic survival values more than two orders of magnitude lower than control populations. Dose response studies demonstrate that, when measured 36 h after removal of the drug, hyperthermic cytotoxicity is maximally potentiated by exposure to DFMO for times as short as 2 to 4 h. A drug concentration of 1 mM for 8 h also elicits maximal response. An additional 8-h drug treatment 24 h after the first fails to further reduce survival in response to heat shock, suggesting the effects of the first exposure are persistent. Intracellular putrescine pools are depleted by the drug within 8 h, and spermidine levels continue to decline for up to 50 h. Consistent with these observations, ornithine decarboxylase (EC 4.1.1.17) activity is found to be reduced for up to 48 h after drug removal. The concomitant depression of spermidine is reflected in the elevation of S-adenosylmethionine decarboxylase (EC 4.1.1.50), which is substrate limited. Putrescine and spermidine show no sign of reaccumulation until approximately 4 days after DFMO exposure. Exposure to exogenous putrescine reversed the sensitization to heat shock induced by DFMO. This effect is quite specific for putrescine (1.4-diaminobutane) and is not replicated by other diamine homologues ranging from 1.3-diaminopropane to 1.8-diaminooctane. Polyamine-depleted cells express thermotolerance with kinetics similar to control cells although overall survival levels are lower. These results suggest that the mechanism of induction and expression of thermotolerance is independent of the role of acid-soluble polyamine pools in cellular responses to heat shock.
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PMID:Sensitization of Chinese hamster ovary cells to heat shock by alpha-difluoromethylornithine. 310 26

The anti-proliferative effects of 1,1'-[(methylethanediylidene)dinitrilo]diguanidine [methylglyoxal bis(guanylhydrazone)] and 1,1'-[(metHYLETHANEDIYLIDENE)dinitrilo]bis-(3-aminoguaNIDINE) HAVE BEEN STUDIED IN Ehrlich ascites carcinoma cells grown in suspension cultures. Both compounds are potent inhibitors of S-adenosyl-L-methionine decarboxylase from the tumour cells. In the presence of putrescine (but not in its absence), the inhibition produced by 1,1'-[methylethanediylidene)dinitrilo]bis-(3-aminoguanadine) was apparently irreversible, as judged by persistent depression of the enzyme activity even after extensive dialysis. The two compounds produced similar increases in adenosylmethionine decarboxylase activity, which resulted from a striking stabilization of the enzyme in cells grown in the presence of the drugs. The inhibitory effect of the two diguanidine derivatives on the synthesis of DNA and protein became evident after an exposure of 4--8 h. At that time, the only change seen in tumour polyamines in cells grown in the presence of the inhibitors was an increase in cellular putrescine. To find out whether the compounds initially interfered with the energy production of the tumour cells, the cultures were grown in the presence of uniformly labelled glucose, and the formation of lactate, as well as the oxidation of the sugar into CO2, were measured. The activation of glycolysis upon dilution of the tumour cells with fresh medium and the subsequent formation of labelled CO2 were siliar in control cells and in cells exposed to methylglyoxal bis(buanylhydrazone), 1,1'-[(methylethanediylidene)dinitrilo]bis-(3-aminoguanidine) or diaminopropanol. Only a marginal decrease in the cellular content of ATP was found in cells exposed to the inhibitors for 24 h. The diguanidine-induced growth inhibition was fully reversed by low concentrations of exogenous polyamines. However, the possibility remained that the reversal by polyamines was due to a decrease of intracellular diguanidine concentration. Our results indicate that the mode of action of 1,1'-[(methylethanediylidene)dinitrilo]bis-(3-aminoguanidine) is fully comparable to that of methylglyoxal bis(guanylhydrazone), as regards stabilization of adenosylmethionine decarboxylase and the appearance of growth inhibition in Ehrlich ascites cells. The data tend to support the view that both compounds apparently have an early anti-proliferative effect unrelated to polyamine metabolism.
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PMID:Inhibition by derivatives of diguanidines of cell proliferation in Ehrlich ascites cells grown in cultures. 739 77

The activities of ornithine decarboxylase and S-adenosylmethionine decarboxylase, two of the enzymes involved in the synthesis of the polyamines, were found to be high in follicle-rich homogenates of sheep skin, and to be responsive to the nutrition of the animal. Systemic provision of the inhibitor of ornithine decarboxylase, alpha difluoromethylornithine, markedly altered the length, diameter, and composition of the fiber, the last being accompanied by an increase in the proportion of the fiber occupied by paracortical cells and an increase in the level of mRNA encoding a cysteine-rich family of keratin proteins. The growth of wool follicles cultured in media containing alpha-difluoromethylornithine was not inhibited, even at high concentrations. In contrast, low concentrations of methylglyoxal (bis)guanylhydrazone, the inhibitor of S-adenosylmethionine decarboxylase, completely inhibited fiber growth in culture follicles. Addition of spermidine to the media overcame this inhibition but spermine had no effect. Further evidence that spermine is not required for normal follicle function was provided by incubating follicles with the specific inhibitor of spermine synthase, n-butyl-1,3-diaminopropane. This inhibitor, even at high concentrations, had no effect on fiber growth in vitro. Spermidine partially overcame the growth depression that occurred in follicles cultured in methionine-deficient media, suggesting that part of the requirement for methionine is for spermidine synthesis in the follicle. These investigations provide strong evidence that the polyamines in general , and spermidine in particular, play a major role in hair growth.
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PMID:Inhibition of polyamine synthesis alters hair follicle function and fiber composition. 860 24