Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.7 (DNA polymerase)
 17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nervous system tissues from a number of patients with idiopathic neurological disorders were examined for biochemical evidence of RNA tumor virus infection. RNase-sensitive DNA polymerase activity was found in a cytoplasmic particulate fraction from two patients with Guamanian amyotrophic lateral sclerosis (ALS) but not in brains from two normal U.S. individuals. The buoyant density of the enzyme-containing fraction was 1.16-1.18 g/ml and could be converted to a denser region of the gradient (1.24 g/ml) by treatment with the nonionic surfactant, Sterox. The cation and detergent requirements for the endogenous RNase-sensitive DNA polymerase reaction were determined. The early (5 min) endogenous reverse transcriptase product was analyzed by cesium sulfate gradient centrifugation. RNase- and heat-sensitive RNA-DNA hybrids were detected in the product analysis of two ALS, one Parkinsonism-dementia (PD) brain, and two brains from asymptomatic Chamorros but not in brains from normal U.S. individuals and a number of patients with neuro-psychiatric disorders. The DNA product was a 4.5S heteropolymer that hybridized more extensively to RNA extracted from the enzyme-containing pellet from PD brain as compared to a similar fraction from normal U.S. brain. The DNA product appeared to be unrelated to Rausvher or visna virus 70S RNA as determined by RNA-[-3H]DNA hybridization.
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PMID:RNA-instructed DNA polymerase activity in a cytoplasmic particulate fraction in brains from Guamanian patients. 4 90

Polymerase chain reaction (PCR) was prospectively performed with cerebrospinal fluid (CSF) from 51 patients whose CSF was available for analysis and was submitted for viral culture and/or herpes simplex virus (HSV) serology and 20 patients whose CSF was submitted exclusively to the Clinical Biochemistry Laboratory. Primers were used that flanked a 92 bp segment of the HSV DNA polymerase gene (35 cycles). Amplified products were electrophoresed on agarose gel, blotted onto nylon membrane, and probed with a 32P-labelled sequence internal to the primers. For nested PCR, 1 microliter of PCR product was amplified for an additional 35 cycles before electrophoresis and Southern blot analysis. Review of the clinical records revealed that 15 patients had central nervous system (CNS) infections. Specific HSV DNA sequences were detected in CSF specimens of three of the individuals [PCR(2), nested PCR(1)]. Two of these patients had disseminated HSV infection including encephalitis and one patient had aseptic meningitis. The diagnoses of the 12 patients with CNS infection who did not have HSV DNA detected in CSF included encephalitis [varicella-zoster virus (1), cytomegalovirus (1), Mycoplasma pneumoniae (1)], meningitis [Neisseria meningitidis (1), Coccidioides immitis (1), Enterovirus (1), aseptic meningitis (1)], varicella-zoster radiculitis (2), human immunodeficiency virus dementia (2), and transverse myelitis due to Epstein-Barr virus (1). Importantly, HSV DNA was also not detected in the CSF of the 36 patients who did not have CNS infection and 20 samples submitted exclusively to the Clinical Biochemistry Laboratory. Our findings demonstrate the utility of PCR as a rapid, non-invasive method for the routine laboratory diagnosis of CNS infection due to HSV.
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PMID:A prospective study of the polymerase chain reaction for detection of herpes simplex virus in cerebrospinal fluid submitted to the clinical virology laboratory. 133 47

Several dideoxynucleosides, including 3'-azido-2',3'-dideoxythymidine (zidovudine, azidothymidine, AZT), 2',3'-dideoxycytidine (ddC), and 2',3'-dideoxyinosine (ddI), have been shown to be potent inhibitors of human immunodeficiency virus (HIV) replication in human T cells and macrophages. These compounds undergo anabolic phosphorylation within target cells to a 3'-triphosphate moiety; as triphosphates, they act at the level of HIV DNA polymerase (reverse transcriptase). AZT has been shown to reduce the morbidity and mortality of patients with severe HIV infection and to at least temporarily ameliorate certain cases of HIV-induced dementia. In phase 1 studies, ddC and ddI have been shown to induce immunologic and virologic improvements in patients with AIDS or related disorders; phase 2 studies of ddC and ddI are underway. The use of these drugs can be associated with toxicity. AZT can cause bone marrow toxicity or myositis with prolonged use, ddC can cause peripheral neuropathy at high doses, and ddI can cause sporadic pancreatitis and peripheral neuropathy at high doses. For each compound, however, a therapeutic window exists in which an anti-HIV effect can be attained without short-term toxicity in most patients. Dose-intensity appears to be an important determinant of the toxicity of dideoxynucleosides. Studies are underway to explore how the therapeutic profiles of these compounds may be enhanced by attention to scheduling or through the use of combination therapy.
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PMID:Initial clinical experience with dideoxynucleosides as single agents and in combination therapy. 207 27

1. RNA was purified from postmortem human brains, and the poly A+ RNA was isolated by oligo dT cellulose. 2. Double stranded cDNA was synthesized using reverse transcriptase, RNAse H and DNA polymerase. 3. cDNA was cloned in the lambda GT 11 expression vector, and libraries containing between 1 and 2 millions clones were obtained. 92 to 98% of the plaques contained a recombinant phage. 4. Such libraries will allow the molecular characterization of cDNA and corresponding proteins which play a key role in brain functions and in particular which could be involved in the etiology of Alzheimer's dementia.
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PMID:Cloning of the cDNA from normal brain and brain of patients with Alzheimer's disease in the expression vector lambda GT 11. 246 41

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

Some drugs are routinely prescribed for dementia that sets in either due to normal ageing or due to neurodegenerative disorders. We have studied the effect of three of these drugs, Donepezil hydrochloride, Rivastigmine tartrate and Nootropyl, on the activity of DNA polymerases beta, a crucial enzyme in the base excision repair pathway, the most important mode of DNA repair in brain. All the three drugs inhibited DNA polymerase beta activity to varying degrees although the affects of Donepezil being the least and inconsistent. The drugs preferentially bind to and inhibit the activities of 8 kDa domain of DNA polymerase beta that is known to possess the dRP lyase activity. The function of 31 kDa domain dealing with template driven addition of nucleotides at 3' end of the primer is not adversely affected. The inhibitory action of most widely used dementia drugs on DNA repair potential signifies that pharma sector needs to consider this aspect especially while designing drugs targeted towards brain.
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PMID:On the inhibitory affect of some dementia drugs on DNA polymerase Beta activity. 1818 93

Neurologic diseases tend to target various areas of the central nervous system (CNS) and can therefore result in paralysis, dementia, and death. Neurodegenerative diseases distinguish themselves from other diseases by affecting nerve cells, which unlike many other cells in our body cannot regenerate when severely injured. The discovery of RNA interference (RNAi) has enabled scientist to design new therapeutic approaches based on specific gene silencing rather than the canonical gene therapy through gene augmentation. Two types of molecules can be used for viral vector-mediated gene silencing: short hairpin RNAs (shRNAs) and artificial microRNAs (miRNAs) that have the ability to enter the RNAi pathway. Although both shRNAs and miRNAs can be used to silence genes, they enter the RNAi pathway at different points. Unlike shRNAs, miRNAs require an additional cleavage step inside the nucleus before being exported to the cytoplasm. These molecules can then be incorporated into the RNA-induced silencing complex (RISC) which utilizes sequence complementarity to recognize target mRNAs and activate either translational repression, in the case of partial complementarity, or induce mRNA cleavage in the case of complete complementarity. Elevated amounts of shRNAs, which are commonly driven by strong polymerase III promoters, can cause saturation of the endogenous RNAi machinery due to competition between endogenous and artificial molecules. Switching to a DNA polymerase II promoter is an alternative to reduce shRNA production, thereby reducing toxicity. Even though the molecules are designed to target specific mRNAs there may be off-target effects due to nonspecific binding that must be accounted for during the design process. In this chapter we discuss the design and in vitro screening of shRNAs and artificial miRNAs.
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PMID:Design of shRNA and miRNA for Delivery to the CNS. 2661 79