Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Modifications of the glutathione (GSH) intracellular level have been implicated in the regulation of human immunodeficiency virus (HIV) transcription and expression. In regard to this hypothesis, we have investigated the effects of valproic acid (VPA) on HIV replication. Indeed, it has been recently reported that VPA inhibits the human red blood cell glutathione reductase. In the supernatant of a CEM-SS T-lymphocytic cell line infected with the LAI strain of HIV-1, we observed an increase, in a dose-dependent fashion, of the reverse transcriptase activity after treatment of cells with VPA. VPA also induced HIV expression in the chronically infected monocytic U1 cell line which constitutively expresses low levels of virus, enhanced the HIV-long terminal repeat (LTR)-directed expression of beta-galactosidase in transiently transfected Jurkat T-cells, and potentiated the PMA effect on the LTR transactivation. GSH assays showed that VPA treatment led to a decrease in the intracellular level of this thiol compound in U937 (U1 parent-cell line) and in Jurkat T-cells. Work to understand the molecular mechanism of VPA-induced HIV transcription and expression are now in progress. VPA seems to be an adequate molecule to study the implications of a GSH decrease in the stimulation of HIV replication. However, a modification of the intracellular balance between reduced and oxidized glutathione, rather than a simple reduction of the intracellular glutathione level, could be of importance in the regulation of HIV replication and we are now testing this hypothesis. Finally, these findings already suggest that VPA, which is an anticonvulsive drug frequently prescribed for the management of various seizure disorders, should not be recommended for treatment of epilepsy or other related illnesses in HIV-positive individuals.
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PMID:Valproic acid reduces the intracellular level of glutathione and stimulates human immunodeficiency virus. 751 59

Why some patients with seizures are successfully treated with antiepileptic drugs (AEDs) and others prove medically intractable is not known. Inadequate intraparenchymal drug concentration is a possible mechanism of resistance to AEDs. The multiple drug resistance gene (MDR1) encodes P-glycoprotein, an energy-dependent efflux pump that exports planar hydrophobic molecules from the cell. If P-glycoprotein is expressed in brain of some patients with intractable epilepsy and AEDs are exported by P-glycoprotein, lower intraparenchymal drug concentrations could contribute to lack of drug response in such patients. Eleven of 19 brain specimens removed from patients during operation for intractable epilepsy had MDR1 mRNA levels > 10 times greater than those in normal brain, as determined by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) method. Immunohistochemistry for P-glycoprotein from 14 of the patients showed increased staining in capillary endothelium in samples from epileptic patients as compared with staining in normal brain samples. In epileptic brain specimens with high MDR1 mRNA levels, expression of P-glycoprotein in astrocytes also was identified. Last, steady-state intracellular phenytoin (PHT) concentrations in MDR1 expressing neuroectodermal cells was one fourth that in MDR1-negative cells. MDR1 expression is increased in brain of some patients with medically intractable epilepsy, suggesting that the patients' lack of response to medication may be caused by inadequate accumulation of AED in brain.
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PMID:MDR1 gene expression in brain of patients with medically intractable epilepsy. 800

A reverse transcriptase-polymerase chain reaction (RT-PCR) product obtained from ischemic rat brain RNA was used to screen a rat ischemic forebrain cDNA library for a cDNA clone containing the entire open reading frame for the inducible hsp70. The coding sequence for the rat hsp70 cDNA demonstrated significant similarities with the human hsp70 of Hunt and Morimoto (Proc Natl Acad Sci 82:6455-6459, 1985) and the mouse hsp70 of Hunt and Calderwood (Gene 87:199-204, 1990). The rat inducible hsp70 and constitutive hsc73 sequences are distinct. There was a low level of hsp70 mRNA expression in normal rat brain as in found in other tissues. hsp70 mRNA was markedly induced in rat brain 8 hours following global ischemia and kainic acid-induced seizures. Northern blots showed a approximately 2.9kb hsp70 mRNA band from control, kainic acid, and ischemic brains. RT-PCR confirmed the presence of hsp70 mRNA in normal rat brain. Since there are at least five human and six mouse inducible hsp70 genes known, many other rat hsp70 genes probably exist that could function in different cells or organelles or be induced under different circumstances.
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PMID:cDNA cloning and expression of stress-inducible rat hsp70 in normal and injured rat brain. 827 11

Zidovudine is a dideoxynucleoside analogue of thymidine. It acts by interfering with viral reverse transcriptase, thereby inhibiting human immunodeficiency virus (HIV) replication. Zidovudine has been shown in clinical trials to prolong survival of patients with acquired immune deficiency syndrome (AIDS) and advanced AIDS-related complex (ARC), and to delay progression to ARC or AIDS in patients with earlier disease. At the present time it is suggested that zidovudine be initiated when the CD4 lymphocyte count is less than 500 cells/mm3. Recent studies have suggested a delay in the development of AIDS in patients with CD4 counts over 500 cells/mm3, but ongoing studies will require confirmation. The adverse reactions associated with zidovudine have been well described. It appears that haematological toxicity is associated with both the dose and stage of disease. Anaemia may present more often within the first 3 months of therapy, whereas neutropenia can occur early or late. Mild headache and gastrointestinal intolerance may occur early and in some cases limit tolerance to the drug. A number of neurological adverse reactions have been reported rarely including seizures and dose-reduction encephalopathy. The most significant late adverse reaction is that of myopathy, which occurs in patients receiving zidovudine for more than 6 months. With careful monitoring, the adverse reactions of zidovudine are manageable and patient tolerance of the medication is acceptable.
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PMID:Zidovudine toxicity. Clinical features and management. 848 Dec 17

Amplification of viral nucleic acids from the cerebrospinal fluid (CSF) has considerably improved the diagnosis of several acute, subacute and chronic viral infections of the nervous system. In herpes simplex virus (HSV) encephalitis (HSE) the polymerase chain reaction (PCR) has become the method of choice for the rapid, non invasive diagnosis. Other herpes virus associated diseases which can now be reliably diagnosed are encephalitis, ventriculoencephalitis, polymyeloradiculitis, myelitis and an inflammatory polyradiculoneuropathy caused by cytomegalovirus (CMV), HSV, varicella-zoster virus (VZV) or Epstein-Barr virus (EBV), EBV associated primary B-cell-lymphoma of the brain, acute aseptic meningitis in young adults allied with VZV, and meningoencephalitis with recurrent seizures due to human herpes virus type 6 (HHV-6). In AIDS patients, PCR has helped to differentiate lesions either due to the human immunodeficiency virus (HIV) itself or to opportunistic infections such as progressive multifocal leukoencephalopathy (PML) caused by JC virus (JCV) or CMV related complications. HIV can be detected early in the course of infection in the CSF and the amount of proviral DNA in CSF cells seems to be correlated with the severity and/or progression of neurological signs and symptoms. Acute epidemic aseptic meningitis caused by enterovirus infections can now be reliably diagnosed and typed by reverse transcriptase PCR (RT-PCR). Meningitis cases caused by vaccination with the Jeryl Lynn and Urabe vaccine strain of mumps virus have been identified using RT-PCR and sequencing of the amplified products (amplicon).
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PMID:Clinical implications of nucleic acid amplification methods for the diagnosis of viral infections of the nervous system. 879 10

Subtypes I, II and III of sodium channel alpha-subunit mRNAs were analyzed in adult rat brain areas after kainate-induced seizures. Tissue samples were microdissected from occipital neocortex, CA1 and CA3 hippocampus areas and dentate gyrus. Three reverse transcriptase-polymerase chain reaction (RT-PCR) protocols were undertaken to amplify these mRNAs. Amplification products were then distinguished after digestion by restriction enzymes, electrophoresis separation and densitometric analysis of gel profiles. PCR 1 evidenced the relative percentage of mRNAs I, II and III as well as neonatal II and III subtype isoforms, which resulted from an alternative splicing. PCR 2 and 3 were performed to focus on the neonatal vs. adult ratio in II and III subtypes, respectively. Seizures were shown to induce an increase in both neonatal subtypes, which suggested an alteration at the splicing level. These changes exhibited a peculiar brain regional distribution, the maximal effect being observed in dentate gyrus and hippocampus CA1 area. In situ hybridization experiments, using a digoxigenin-labeled oligonucleotide probe-specific for neonatal II and III mRNAs, confirmed this increase in neonatal mRNA subtypes. These changes were transient, reaching a maximum 6 h after drug injection, then disappearing between 12 and 48 h. They were prevented by a pre-treatment of animals by MK-801, a non-competitive antagonist of NMDA receptors. This work, thus, suggested that KA-induced seizures can be accompanied by transient alteration in the splicing pattern of sodium channel alpha-subunit mRNAs which resulted in an increase in expression of their neonatal isoforms within localized areas of adult rat brain.
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PMID:Increase in mRNAs encoding neonatal II and III sodium channel alpha-isoforms during kainate-induced seizures in adult rat hippocampus. 907 59

The single-locus mutant mouse tottering (tg) is an established model for absence seizures. We have previously reported an impairment in GABA-induced chloride uptake in tg brain [Tehrani and Barnes, Epilepsy Res. 1995;22:13-21]. In order to determine if this alteration in GABAA receptor function can be related to specific receptor isoforms, we examined the radioligand binding properties of GABAA receptors and the expression of GABAA receptor subunit mRNAs in the cerebral cortex. Saturation binding of [3H]flunitrazepam revealed a significantly lower Kd value in tg cortical tissues (1.77 +/- 0.05 nM) in comparison to that for the background C57BL/6J strain (3.23 +/- 0.23 nM), while the Bmax values were indistinguishable. Biphasic displacement of [3H]flunitrazepam binding by 2-oxoquazepam showed that low affinity binding sites account for 36 +/- 7.6 and 51 +/- 7.5% of the total in control and tg, respectively. The level of [35S]-t-butylbicyclophosphorothionate (TBPS) binding to tg cortical membranes was 73.6 +/- 5.8% of that in controls. Paired measurements by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) revealed no significant differences in the levels of GABAA receptor alpha 1, alpha 3, alpha 5, beta 2, beta 3, gamma 2 or gamma 3 subunit mRNAs between tg and control cortex. However, tg tissues showed elevated levels of alpha 2- and beta 1-subunit mRNAs, representing 256 and 177%, respectively, those of controls. For the tg cortex, the enhanced expression of GABAA receptor alpha 2 and beta 1 subunits correlates with recombinant subtypes known to have low affinity for 2-oxoquazepam and impaired binding of TBPS. These aberrant properties of GABAA receptors could influence the development or propagation of phenotypic seizures in the tottering mouse.
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PMID:Aberrant expression of GABAA receptor subunits in the tottering mouse: an animal model for absence seizures. 933 86

Interleukin-1 beta (IL-1beta) is an inflammatory cytokine whose expression is elevated in brain during seizures, ischemia, and injury. Expression of IL-1beta and its receptor can also be observed in normal brain. Platelet-activating factor (PAF) is also a dual mediator that promotes neuronal plasticity responses as well as inflammation. We have determined the role of PAF in the regulation of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) genes by IL-1beta in rat primary hippocampal cultures. As assessed by reverse transcriptase/polymerase chain reaction (RT/PCR), recombinant mouse IL-1beta (1 nM) led to an induction of COX-2 mRNA which peaked at 2 hours, declined to baseline levels by 4 hours, began to rise again by 6 hours, and remained elevated at 24 hours post-treatment. iNOS mRNA was also induced, but unlike COX-2, its abundance peaked at 4 hours and decreased by 6 hours to a plateau lasting through 24 hours. Pretreatment with PAF antagonist BN50730 blocked induction of COX-2 mRNA by 2-hour IL-1beta treatment, and 2-hour treatment with the PAF analog mcPAF mimicked the effects of IL-1beta on COX-2 mRNA levels. Following injury, synaptic plasticity changes may be affected by IL-1beta-PAF-COX-2 neuronal signaling.
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PMID:Interleukin-1 beta activates expression of cyclooxygenase-2 and inducible nitric oxide synthase in primary hippocampal neuronal culture: platelet-activating factor as a preferential mediator of cyclooxygenase-2 expression. 1053 51

About one third of patients with HIV infection show neurological complications with considerable morbidity and high mortality. This is an actualized review of the most important neurological manifestations resulting from primary HIV infection, from secondary opportunistic infections, or as complications of antiretroviral therapy. The primary neurological manifestations, including HIV-associated dementia complex, myelopathies, peripheral neuropathies and myopathies, the more common opportunistic infections, primary central nervous system lymphoma and cerebrovascular diseases, are discussed in the light of new evidence in diagnosis, therapy and prognosis. Cognitive and psychiatric symptoms, visual changes, headache, seizures, dizziness, involuntary movements, gait disturbances, cranial neuropathies and focal deficits are the common neurological symptoms in HIV infection which are described under the aspect of differential diagnosis. It is important to bear in mind that nearly all information available to date on this subject concerns HIV patients in the period before combination therapies (including protease inhibitors). The introduction of highly active antiretroviral therapy (HAART) with protease inhibitors in 1995, and non-nucleoside reverse transcriptase inhibitors, have opened up new therapeutic modalities with a new emphasis on earlier detection and treatment of neurological complications. The prognosis of different HIV-associated neurological diseases has considerably improved, as recently shown in the case, for example, of progressive multifocal leucoencephalopathy.
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PMID:[Neurological complications of HIV infection. Review: new diagnostic, therapeutic and prognostic aspects]. 1081 41

Two children are described who presented with fever and generalized seizures, days 50 and 200, respectively, after matched unrelated donor-bone marrow transplantation. Upon antiepileptic treatment the seizures vanished but somnolence and fever remained. Magnetic resonance imaging (MRI) of the brain was performed and revealed transient asymmetric multifocal hyperintense lesions. Seizures were considered related to infection, and the cyclosporin A (CsA) treatment was not interrupted. Enterovirus was detected by reverse transcriptase-polymerase chain reaction in the spinal fluid of one patient and in the sputum of the other. Both children recovered completely within the next weeks without neurological sequel. This report shows that enteroviral meningoencephalitis can present with seizures during the post-transplant period. It highlights the importance of MRI for neuroimaging and of viral infections as differential diagnosis to CsA neurotoxicity.
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PMID:Enteroviral meningoencephalitis in immunocompromised children after matched unrelated donor-bone marrow transplantation. 1091 50


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