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)

Thiazolidinyl- and perhydrothiazinyl-ethyl-N-mustard-phosphamide esters were designed to act as highly specific suicide inactivators of DNA polymerase alpha holoenzymes. Acute and subacute toxicity of these drugs in mice was very small. By daily i.p. injection, on day 0-4 mice were cured of P 388 lymphatic leukaemia with no depression of blood leucocytes. The findings suggest that suicide inactivators of DNA polymerase alpha holoenzyme may be promising drugs for low toxicity cancer chemotherapy.
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PMID:Low toxicity cancer chemotherapy by suicide inactivation of DNA polymerase alpha holoenzyme: first results with new thiazolidinyl- and perhydrothiazinyl-ethyl-N-mustard-phosphamide esters. 338 44

Previous results from this laboratory have shown that thymidylate deprivation results in dramatic elevation of intracellular dUTP and incorporation of dUMP into DNA. The goal of the present studies was to determine whether the latter changes may play a part in the associated cytotoxicity ("thymineless death"), which is ordinarily assumed to be a direct result of reduced intracellular dTTP. The approach used here was to increase intracellular dUTP without allowing dTTP to diminish and observe the effects on cell viability. dUMP pools were expanded by exposure of cells to deoxyuridine [in cell growth medium containing hypoxanthine, methotrexate, and thymidine (HAT medium)], resulting in accumulation of dUTP to levels that approached those of dTTP, which were at, or higher than, the levels in untreated cells. In conjunction with this the cells became nonviable, and newly synthesized DNA was fragmented, both of which occur with thymidylate depletion and, we assume, result from the active process of excision repair at the many uracil-containing sites in DNA. The results indicate that, although the relative importance of low dTTP remains unknown, elevated dUTP can account for the cytotoxicity caused by thymidine starvation. Most of the "dTTP" measured by the DNA polymerase assay in cells treated with methotrexate (MTX) (plus purine supplement) was, in fact, dUTP, which may explain some previous observations of only modest depression of dTTP in cells treated with MTX or similarly acting drugs.
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PMID:DNA fragmentation and cytotoxicity from increased cellular deoxyuridylate. 352 74

BW A515U (6-Deoxyacyclovir) is a pro-drug of acyclovir and almost 100% is absorbed orally. 250 mg orally 6-hourly for 10 days was given to 4 hepatitis B surface antigen/e antigen-positive carriers. No consistent effect on productive viral replication, as determined by serum DNA polymerase and DNA levels was observed. The changes that occurred in these markers and transaminases in 1 patient were attributed to a spontaneous depression of productive viral replication.
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PMID:A pilot study of BW A515U (6-deoxyacyclovir) in chronic hepatitis B virus infection. 359 53

Previous work from this laboratory has shown that the cytosine-containing T4 deoxyribonucleic acid (DNA) made by deoxycytidine triphosphatase (dCTPase) amber mutants is extensively degraded, and that nucleases controlled by genes 46 and 47 participate in this process. In this paper, we examine other consequences of a defective dCTPase. Included are studies of DNA synthesis and phage production, and of the control of both early and late protein synthesis after infection of Escherichia coli B with various T4 mutants defective in genes 56 (dCTPase), 42 (dCMP hydroxymethylase), 1 (deoxynucleotide kinase), 43 (DNA polymerase), 30 (polynucleotide ligase), 46 and 47 (DNA breakdown) or e(lysozyme). By varying the temperature of infection with a temperature-sensitive dCTPase mutant, we have been able to control intracellular dCTPase activity, and thus vary the cytosine content of the phage DNA. We have produced and characterized viable T4 phage in which cytosine replaces 20% of the 5-hydroxymethylcytosine (HMC) in the DNA. We present evidence which suggests that intact, cytosine-containing T4 DNA is much less efficient than is normal T4 DNA in directing the synthesis of tail-fiber antigen. Lysozyme production is much less affected by progressively decreasing dCTPase activity; however, complete substitution of cytosine is correlated with a depression of lysozyme synthesis greater than expected from the defective synthesis of DNA. Low but significant lysozyme synthesis is observed late after infection of E. coli B with T4 amber mutants defective in a number of genes controlling DNA synthesis. The "20% cytosine" T4 phage, once produced, can initiate an apparently normal infection at permissive temperatures; the synthesis of early enzymes, DNA, and phage does not appear to be impaired. Two roles for HMC in T4 DNA have been indicated previously: (i) involvement in host-controlled restriction of the phage, in which glucosylation of the hydroxymethyl group plays a crucial role (16, 29, 53, 58), and (ii) protection of vegetative DNA against phage-controlled nucleases, a protection not dependent on glucosylation (41, 66, 67). A third role is suggested by our present results: transcription of at least some late genes can occur only from HMC-containing DNA and not from cytosine-containing DNA.
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PMID:Biological effects of substituting cytosine for 5-hydroxymethylcytosine in the deoxyribonucleic acid of bacteriophage T4. 430 78

Biochemical studies on a new antitumor antibiotic, CI-920, have been directed toward understanding its mode of action. The most striking effect brought on by CI-920 was a marked inhibition of macromolecular synthesis. L1210 leukemia cells exposed to 10 microM CI-920 exhibited a decreased rate of DNA, RNA, and protein synthesis within 45 min, and maximal inhibition occurred within 60 min. The reduction in nucleic acid synthesis was not due to precursor depletion, since ribonucleoside and deoxyribonucleoside triphosphate levels in cells exposed to 10 microM CI-920 for 2 h either remained unchanged relative to control cells or were elevated, suggesting a block more directly at the level of nucleotide incorporation. Nevertheless, CI-920 (50 microM) had no effect on DNA or RNA polymerase activity as assessed in permeabilized L1210 cells. However, if viable cells were exposed to 20 microM CI-920 for 1 h prior to permeabilization and then the polymerases assayed in the absence of drug, there was a 60% depression in enzyme activity. The inhibition of RNA polymerase appears to result from an effect on the enzyme rather than the template, since inhibition of RNA polymerase activity in cell-free systems from drug-treated cells could not be restored by addition of excess DNA template. DNA polymerase, however, was at least partially restored by addition of template and therefore was inconclusive in this respect. The data, then, suggest that CI-920 inhibits nucleic acid synthesis directly at the level of nucleotide incorporation, either by direct inhibition of DNA or RNA polymerase or by inactivation of an essential component of these enzyme systems. Since the drug in its parent form did not inhibit nucleic acid synthesis in cell-free systems the effects may possibly be mediated through conversion of this agent to another chemical form within viable cells.
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PMID:Studies on the biochemical mechanism of the novel antitumor agent, CI-920. 654 19

It has been suggested that increased fragile site expression in lymphocyte cultures can be used as a marker for genetic predisposition to cancer. We wished to determine whether aphidicolin (APC), an inhibitor of the DNA repair enzyme DNA polymerase alpha, could be used as a reliable biomarker in identification of DNA repair capacity in unaffected individuals at high risk from breast cancer families. PHA-stimulated lymphocyte cultures, with and without APC, were set up in 65 individuals, of whom 14 were breast cancer patients, 26 were unaffected individuals from breast cancer families, and 25 were controls. A significant proportion of breast cancer patients and unaffected individuals from familial breast cancer (FBC) families exhibited premature separation of centromeres (PSC) and aneuploidy in the untreated cultures. In the APC treated cultures, almost all such individuals exhibited a marked depression of mitotic index and increased aneuploidy, as compared to controls. Our results indicate that these individuals have defective DNA repair capacity. Such individuals could thus have a much higher risk of cancer as compared to persons exhibiting PSC and aneuploidy or DNA repair defects alone. We propose that APC may be a valuable biomarker in identifying individuals with genetic predisposition to cancer from FBC families.
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PMID:Reduced DNA repair capacity in breast cancer patients and unaffected individuals from breast cancer families. 953 Mar 43

Genome replication generally requires primases, which synthesize an initial oligonucleotide primer, and DNA polymerases, which elongate the primer. Primase and DNA polymerase activities are combined, however, in newly identified replicases from archaeal plasmids, such as pRN1 from Sulfolobus islandicus. Here we present a structure-function analysis of the pRN1 primase-polymerase (prim-pol) domain. The crystal structure shows a central depression lined by conserved residues. Mutations on one side of the depression reduce DNA affinity. On the opposite side of the depression cluster three acidic residues and a histidine, which are required for primase and DNA polymerase activity. One acidic residue binds a manganese ion, suggestive of a metal-dependent catalytic mechanism. The structure does not show any similarity to DNA polymerases, but is distantly related to archaeal and eukaryotic primases, with corresponding active-site residues. We propose that archaeal and eukaryotic primases and the prim-pol domain have a common evolutionary ancestor, a bifunctional replicase for small DNA genomes.
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PMID:Structure of a bifunctional DNA primase-polymerase. 1473 Mar 55

The aim of this article is to clarify the relationships between aging or age-related diseases and magnesium (Mg). The mutation of mitochondrial DNA can occur in both aging and Mg deficiency, resulting in peroxidation, intracellular Ca(2+) accumulation and apoptosis. The capability against peroxidation decreases in aging and Mg deficiency. DNA polymerase I, RNA polimerase and DNA helicase require Mg for their activities. Under Mg deficiency the replication, transcription and translation of DNA become erroneous. The dysfunctions of vascular endothelial cell occur in aging and Mg deficiency. In comparison between adult and old rats using the rings of rat thoracic aortae, vasorelaxation by acetylcholine and isoproterenol is lower in old rats, but can be improved through high Mg concentration. Although women with menopause are suffered from osteoporosis due to estrogen deficiency, bone fragility increases with additive Mg deficiency. High Ca intake is recommended for women with menopause, but adequate Mg intake is necessary to lower dietary Ca/Mg ratio, because the high ratio prompts blood coagulation. About lipid metabolism Mg can play a statin-like activity. Mg deficiency is complicated with lifestyle-related diseases, osteoporosis, bone fragility, depression and elderly dementia.
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PMID:[Aging and magnesium]. 1627 11

A 4-year-old donkey was evaluated for progressive neurological abnormalities consisting of depression, stupor, weakness, and recumbency. Diagnostic evaluation for viral involvement identified an asinine herpesvirus in DNA extracted from deep pharyngeal swabs. Specific primers were designed based on comparison with equine herpesviral DNA polymerase sequences and yielded an 875-base pair product from the donkey. This sequence had complete identity with short sequences of asinine herpesvirus previously identified in donkeys with interstitial pneumonia. Amino acid analysis of the entire sequence indicated high similarity with Equid herpesvirus 7 (91%), Zebra herpesvirus 1 (90%), and Equid herpesvirus 2 (89%). With supportive treatment and physical therapy, the donkey gradually recovered over 5 days of hospitalization and returned to normal function. The current case illustrates the potential of a novel asinine herpesvirus to induce neurological disease in donkeys and provides a large viral sequence allowing confident assignment of this virus to the subfamily Gammaherpesvirinae.
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PMID:Herpesvirus-associated neurological disease in a donkey. 1898 38

Bipolar disorder (BPD) is characterized by vulnerability to episodic depression and mania and spontaneous cycling. Because of marked advances in candidate-gene and genome-wide association studies, the list of risk genes for BPD is growing rapidly, creating an unprecedented opportunity to understand the pathophysiology of BPD and to develop novel therapeutics for its treatment. However, genetic findings are associated with major unresolved issues, including whether and how risk variance leads to behavioral abnormalities. Although animal studies are key to resolving these issues, consensus is needed regarding how to define and monitor phenotypes related to mania, depression and mood swing vulnerability in genetically manipulated rodents. In this study we discuss multiple facets of this challenging area, including theoretical considerations, available tests, limitations associated with rodent behavioral modeling and promising molecular-behavioral findings. These include CLOCK, glycogen synthase kinase 3beta (GSK-3beta), glutamate receptor 6 (GluR6), extracellular signal-regulated kinase-1 (ERK1), p11 (or S100A10), vesicular monoamine transporter 2 (VMAT2 or SLC18A2), glucocorticoid receptors (GRs), Bcl-2-associated athanogene-1 (BAG1) and mitochondrial DNA polymerase-gamma (POLG). Some mutant rodent strains show behavioral clusters or activity patterns that cross-species phenocopy objective/observable facets of mood syndromes, and changes in these clustered behaviors can be used as outcome measures in genetic-behavioral research in BPD.
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PMID:Translational research in bipolar disorder: emerging insights from genetically based models. 2014 20


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