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)

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

The average concentration of orotic acid in the milk of 412 Black and White bred cows from four Polish provinces was 0.618 +/- 0.233 mmol/l. There was no correlation between milk yield and concentration of orotic acid. A higher concentration of this pyrimidine in younger cows, and its increase during development of lactation was noted. The yearly pattern of orotic acid in milk and urine of four low-, and four high-orotate cows was examined. In spite of high average differences in milk orotate (0.397 and 0.813 mmol/l) no significant differences in urinary orotate (20.96 and 21.90 mumol/mmol creatinine) were observed. In both groups the lowest milk orotate level occurred in early lactation. The orotic acid content (mmol/l) in commercial milk products was as follows: skim milk--0.783; evaporated milk--0.538; cream 12% fat--0.367; buttermilk--0.449; yogurt--0.331; kefir--0.341; sour milk 2% fat--0.360; dried skim milk--1.042; Bebiko I (infant formula)--0.650. Leukemia led to the elevation (0.845 mmol/l), whereas mastitis to the depression (0.124 mmol/l) of milk orotic acid level.
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PMID:Variability of orotic acid concentration in cow's milk. 195 38

Patients with a recent myocardial infarction have a higher morbidity and mortality than comparable patients with chronic myocardial ischaemia. We postulated that this might be due to a reduced overall tolerance of the heart to cardioplegic arrest in the presence of a recent infarct. We postulated that orotic acid, a pyrimidine precursor which augments the rate of protein synthesis, might improve the response of the recently infarcted heart to cardioplegic arrest. Myocardial infarction was produced in rats by coronary ligation. The rats were then divided into two groups according to whether they were treated with oral orotic acid (10 mg/kg per day) or untreated. A sham-operated (non-infarcted) group served as normal controls. After 2 days, the hearts (n = 12 per group) underwent 1 h of cardioplegic arrest at 23 degrees C on the isolated working heart apparatus. Before arrest, maximum cardiac function in the untreated infarct group was lower than in the normal group (P less than 0.05), whereas in the treated group, function was similar to the normal group. After arrest there was severe depression of cardiac function in the untreated infarct group: only 57% recovery of the pre-arrest value compared with 86% in the normal group (P less than 0.001). In the orotic acid treated group, recovery (90%) was significantly greater than in the untreated group (P less than 0.001) and equivalent to the normal group. Oxygen utilisation, when corrected for external work, was higher in both infarct groups than in the normal group before and after arrest (P less than 0.05 in both cases). Total uridine nucleotide content of the infarcted and non-infarcted zones of the heart was increased. Treatment with orotic acid produced a further upward trend in uridine nucleotide levels. We conclude that an established, recent infarct reduces the overall tolerance of the heart to hypothermic cardioplegia. Treatment with orotic acid improves the function of the infarcted heart following cardioplegic arrest, and may therefore improve the results of urgent cardiac surgery in patients with myocardial infarction.
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PMID:The effect of orotic acid on the response of the recently infarcted rat heart to hypothermic cardioplegia. 201 59

Exposure of eukaryotic cells to ultraviolet light results in a temporary inhibition of DNA replication as well as a temporary blockage of DNA fork progression. Recently there has been considerable debate as to whether the (5-6)cyclobutane pyrimidine dimer, the pyrimidine(6-4)pyrimidone lesion or both are responsible for these effects. Using cell lines that repair both of these lesions (CHO AA8), only (6-4) lesions (CHO UV61) or neither (CHO UV5), we have shown that in rodent cells both lesions appear to play a role in both the inhibition of thymidine incorporation and the blockage of DNA fork progression. Specifically, after exposure to 2.5 J/m2, AA8 cells recover normal rates of DNA replication within 5 h after exposure, while UV5 cells exhibit a greater depression in thymidine incorporation for at least 10 h. UV61 cells, on the other hand, show an intermediate response, both with respect to the extent of the initial depression and the rate of recovery of thymidine incorporation. UV61 cells also exhibit an intermediate response with respect to blockage of DNA fork progression. In previous publications we have shown that UV5 cells exhibit extensive blockage of DNA fork progression and only limited recovery of this effect within the first 5 h after exposure to UV. In this report we show that UV61 cells exhibit a more extensive blockage of fork progression than is observed in AA8 cells. These blocks also appear to be removed (or overcome) more slowly than in the AA8 cells, but more rapidly than in UV5 cells. Taken together we conclude that both lesions appear to be involved in the initial depression in thymidine incorporation and the initial blockage of DNA fork progression in rodent cells. These data also indicate that (6-4) lesions may be responsible for the prolonged depression in thymidine incorporation and the prolonged blockage of DNA fork progression observed in UV5 cells.
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PMID:Effect of UV light on DNA replication and chain elongation in Chinese hamster UV61 cells. 236 97

An insect cell line, IAL-PID2, was exposed to UV and analyzed for its ability to incorporate [3H]-thymidine and to elongate replicon-sized DNA fragments. After exposure to 5 or 10 J/m2 UV, the cells exhibited a rapid and prolonged depression in the rate of thymidine incorporation. Photoreactivation reduced this depression but did not entirely reverse it. For exposures of 5 J/m2 or above, full recovery did not occur until 18 h after exposure. The blockage of fork progression after UV exposure was fluence-dependent, with replication segments after exposure to 20 J/m2 being shorter than those observed after exposure to 10 J/m2. Immediately after exposure to either 10 or 20 J/m2, photoreactivation reversed blockage of fork progression, indicating that the (5-6) cyclobutyl pyrimidine dimer is responsible for blockage. This also indicates that blockage of fork progression may not be the only factor responsible for the prolonged depression seen in thymidine incorporation. Three hours after exposure to either 10 or 20 J/m2, replication segments were still significantly shorter than control segments. Photoreactivation completely reversed blockage after exposure to 10 J/m2, but did not completely reverse blockage after exposure to 20 J/m2, indicating that at such fluences, other lesions may play a role in UV-induced blockage of fork progression.
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PMID:Effects of ultraviolet light on thymidine incorporation and DNA chain elongation in photoreactivable insect cells. 259 39

Recently, we reported that the distribution of ultraviolet light (u.v.) induced pyrimidine dimers in nucleosome core DNA has a striking 10.3(+/- 0.1) base periodicity and the regions of enhanced quantum yield map to positions where DNA strands are farthest from the core histone surface. Improvement of the mapping procedure has allowed us to analyze this distribution in more detail, and compare the distribution pattern for nucleosome cores from intact chromatin having different higher-order structures (from the 10 nm filament to the 30 nm fiber). At all levels of chromatin compaction, we observed the following. (1) The average periodicity in pyrimidine dimer yield is 10.3 bases. (2) The peak-to-peak spacing in this distribution is significantly different from 10.3 bases in the region covering three helix turns immediately 5' of the dyad axis. (3) There is a suppression of photoproduct formation in the region of the dyad axis, especially at position 84 from the 5' end. (4) The approximately 10 base ensembles have alternating peak intensities throughout core DNA. Furthermore, peak deconvolution analysis of the pyrimidine dimer pattern yielded a striking similarity in photoproduct yield for the different levels of chromatin compaction. Irradiation of isolated core DNA yields a much more random distribution of photoproducts, although a weak modulation pattern is observed (indicating that there is a non-random alignment of adjacent pyrimidines in our core DNA preparations). This pattern includes a depression in photoproduct yield near position 95, suggesting that the sequence in this region plays a role in nucleosome positioning. These results show that the u.v. photofootprint is a sensitive, diagnostic probe of core histone-DNA interactions in intact chromatin, and these interactions are not significantly altered by changes in the structural state of the chromatin fiber.
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PMID:Photofootprint of nucleosome core DNA in intact chromatin having different structural states. 322 2

The influence of trapidil (T) and two selected 5,7-disubstituted s-triazolo (1,5-a)pyrimidine derivatives (TD: AR 12456 and AR 12463) on arachidonic acid(AA)- and prostaglandin endoperoxide analogue U 46619-induced blood pressure changes in normotensive rats was investigated in comparison with the cyclooxygenase inhibitor acetylsalicylic acid (ASA) and the thromboxane A2 (TXA2) antagonist BM 13177. ASA and AR 12456 completely eliminated the second blood pressure depression after injection of AA and simultaneously diminished TXA2, TXB2 and 6-keto-PGF1a formation in murine blood, whereas BM 13177 prevented the return of the blood pressure to preinjection level after the initial brief fall in arterial pressure. BM 13177 and AR 12463 reduced the rise in U 46619-provoked blood pressure by 75% and 58%, respectively. Trapidil had no effect on blood pressure changes stimulated by AA and U 46619.
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PMID:Effects of trapidil and trapidil derivatives on arachidonic acid and prostaglandin endoperoxide analogue U 46619-induced blood pressure changes in rats. 324 2

Young adult male and female Wistar rats were inhalationally exposed head-only for 1 or 4 h to different anticholinesterase aerosols. The compounds tested were dichlorvos, fenamiphos, methamidophos, parathion, a pyrimidine thiophosphate and the carbamate propoxur. These compounds are direct or indirect inhibitors of cholinesterase activity. Immediately after termination of exposure to the compounds, the rats were anesthetized with barbiturate and subjected to pulmonary function tests. An acetylcholine provocation test was performed to correlate the effect of the cholinesterase inhibition and lung resistance. The results basically revealed that by inhalation exposure bronchoconstriction in the absence of acetylcholine provocation did not occur at toxicologically significant doses of the pesticides. An increase in lung resistance was observed only after provocation. However, measurements of plasma cholinesterase activity proved to be more sensitive than the provocation test. With regard to their diagnostic value, the results of the reported study may be summarized as follows (beginning with the most sensitive parameter): plasma cholinesterase activity depression greater than or equal to acetylcholine-induced bronchoconstriction greater than or equal to cholinergic symptoms greater than erythrocyte cholinesterase activity depression greater than pulmonary resistance without acetylcholine provocation.
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PMID:Effects of inhaled cholinesterase inhibitors on bronchial tonus and on plasma and erythrocyte acetylcholine esterase activity in rats. 367 30

1. Stimulation of the vagal non-adrenergic inhibitory innervation caused the release of adenosine and inosine into vascular perfusates from the stomachs of guinea-pigs and toads.2. Stimulation of portions of Auerbach's plexus isolated from turkey gizzard caused the release of adenosine triphosphate (ATP), adenosine diphosphate (ADP) and adenosine monophosphate (AMP).3. ATP, added to solutions perfused through the toad stomach vasculature, was broken down to adenosine, inosine and adenine.4. Of a series of purine and pyrimidine derivatives tested for inhibitory activity on the guinea-pig isolated taenia coli, ATP and ADP were the most potent.5. ATP caused inhibition of twelve other gut preparations previously shown to contain non-adrenergic inhibitory nerves. The inhibitory action of ATP was not prevented by tetrodotoxin.6. Quinidine antagonized relaxations of the guinea-pig taenia coli caused by catecholamines or adrenergic nerve stimulation. Higher concentrations of quinidine antagonized relaxations caused by ATP or non-adrenergic inhibitory nerve stimulation.7. When tachyphylaxis to ATP had been produced in the rabbit ileum, there was a consistent depression of the responses to non-adrenergic inhibitory nerve stimulation but not of responses to adrenergic nerve stimulation.8. It is suggested that ATP or a related nucleotide is the transmitter substance released by the non-adrenergic inhibitory innervation of the gut.
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PMID:Evidence that adenosine triphosphate or a related nucleotide is the transmitter substance released by non-adrenergic inhibitory nerves in the gut. 2788 76

The ultraviolet (UV) sensitivity of Escherichia coli B/r harvested at various times during growth in batch cultures was measured. The results showed a period of increased UV sensitivity in late log phase, just before the cultures entered stationary phase. This increase in sensitivity was associated with a decreased shoulder in the UV survival curves. The postirradiation division delay of survivors was shortest for cells harvested during the period of maximal sensitivity. This period of increased UV sensitivity during late log phase was not found in the radiation-sensitive, repair-deficient mutant B(s-1) (a strain which is unable to excise pyrimidine dimers from UV-damaged deoxyribonucleic acid). These results suggest that the variation in UV sensitivity of E. coli B/r as a function of time of harvesting of the cells from batch cultures is related to the varying capacities of these populations to repair UV-damaged deoxyribonucleic acid. Further experiments designed to elucidate the mechanism underlying this variation in UV sensitivity indicated that it arises from the partial depletion of nutrients in the medium during late log phase. We suggest that growth in such depleted media leads to a depression in the intercellular concentration or activity of one or more of the repair enzymes concerned with the repair of damaged deoxyribonucleic acid.
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PMID:Changes in the ultraviolet sensitivity of Escherichia coli during growth in batch cultures. 488 15


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