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)

Cells of macrophage lineage represent a key target of human immunodeficiency virus (HIV) in addition to CD4-lymphocytes. The absolute number of infected macrophages in the body is relatively low compared to CD4-lymphocytes. Nevertheless, the peculiar dynamics of HIV replication in macrophages, their long-term survival after HIV infection, and their ability to spread virus particles to bystander CD4-lymphocytes, make evident their substantial contribution to the pathogenesis of HIV infection. In addition, infected macrophages are able to recruit and activate CD4-lymphocytes through the production of both chemokines and virus proteins (such as nef). In addition, the activation of the oxidative pathway in HIV-infected macrophages may lead to apoptotic death of bystander, not-infected cells. Finally, macrophages are the most important target of HIV in the central nervous system. The alteration of neuronal metabolism induced by infected macrophages plays a crucial role in the pathogenesis of HIV-related encephalopathy. Taken together, these results strongly support the clinical relevance of therapeutic strategies able to interfere with HIV replication in macrophages. In vitro data show the potent efficacy of all nucleoside analogues inhibitors of HIV-reverse transcriptase in macrophages. Nevertheless, the limited penetration of some of these compounds in sequestered districts, coupled with the scarce phosphorylation ability of macrophages, suggests that nucleoside analogues carrying preformed phosphate groups may have a potential role against HIV replication in macrophages. This hypothesis is supported by the great anti-HIV activity of tenofovir and other acyclic nucleoside phosphonates in macrophages that may provide a rationale for the remarkable efficacy of tenofovir in HIV-infected patients. Non-nucleoside reverse transcriptase inhibitors (NNRTI) do not affect HIV-DNA chain termination, and for this reason their antiviral activity in macrophages is similar to that found in CD4-lymphocytes. Interestingly, protease inhibitors (PIs), acting at post-integrational stages of virus replication, are the only drugs able to interfere with virus production and release from macrophages with established and persistent HIV infection (chronically-infected cells). Since this effect is achieved at concentrations and doses higher than those effective in de-novo infected CD4-lymphocytes, it is possible that lack of adherence to therapy, and/or suboptimal dosage leading to insufficient concentrations of PIs may cause a resumption of virus replication from chronically-infected macrophages, ultimately resulting in therapeutic failure. For all these reasons, therapeutic strategies aimed to achieve the greatest and longest control of HIV replication should inhibit HIV not only in CD4-lymphocytes, but also in macrophages. Testing new and promising antiviral compounds in such cells may provide crucial hints about their efficacy in patients infected by HIV.
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PMID:Macrophages and HIV infection: therapeutical approaches toward this strategic virus reservoir. 1210 27

This is the first description of a persistent subclinical nodavirus infection in the Atlantic halibut Hippoglossus hippoglossus. Juvenile fish (1 to 5 g) were sampled at 4, 5 and 8 mo of age at a fish farm in Norway during and after weaning. None showed clinical signs of viral encephalopathy and retinopathy (VER) or other disease. Pathological changes and/or nodavirus were detected by light microscopy, immunohistochemistry, reverse transcriptase polymerase chain reaction (RT-PCR) and transmission electron microscopy in all fish examined. High numbers of virus particles were found in macrophage-like cells in the central nervous system, including brain and retina (CNS). The virus particles displayed the icosahedral shape and size (approximately 25 nm) characteristic of nodaviruses. The virus-infected cells formed focal cell aggregates and were seen in all regions of the brain and all nuclear cell layers of the retina. The cytoplasm of the infected cells was filled with membrane-enclosed inclusions packed with virus particles. Some virus particles lay along membranes and formed membrane-bound necklace-like arrangements. The virus-infected cells of the retina also contained pigment granula located generally inside virus inclusions and sometimes forming a coating around the virus particles. All frontal parts with the eyes and brain and 50% of the mid-parts, which included the abdominal organs, were found positive for nodavirus with RT-PCR. Pathological changes in these persistently nodavirus-infected fish differ from earlier descriptions in Atlantic halibut during outbreaks of VER. Vertical transmission from infected spawners is believed to be a major route for nodavirus infection. Detection of nodavirus in subclinical infected fish and a better understanding of its pathogenesis are important in order to prevent the spread of nodavirus in the fish-farming industry.
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PMID:Pathological changes in juvenile Atlantic halibut Hippoglossus hippoglossus persistently infected with nodavirus. 1221 72

A growing body of evidence suggests that alterations in N-methyl-D-asparate NMDA-mediated excitatory neurotransmission may be involved in the pathophysiology of hepatic encephalopathy (HE) in acute liver failure (ALF). The NMDA receptor requires glycine as a positive allosteric modulator. One of the glycine transporters Glyt-1 is expressed primarily in astrocytes of the cerebral cortex in association with regions of high NMDA receptor expression. As astrocytic transporters regulate the amino acid concentrations within excitatory synapses, the expression of Glyt-1 was studied in cortical preparations from rats with ischemic liver failure induced by portacaval anastomosis followed 24 hr later by hepatic artery ligation and from appropriate sham-operated controls. Expression of Glyt-1 mRNA, studied by reverse transcriptase-polymerase chain reaction, was significantly decreased in the brain at coma stages of encephalopathy (to approximately 50% of control) concomitant with a significant threefold increase of extracellular glycine, measured by in vivo cerebral microdialysis. These findings suggest that loss of expression of the Glyt-1 transporter may cause an impairment of regulation of glycine concentration at synaptic level and contribute to an overactivation of the NMDA receptor in ALF. The use of NMDA receptor antagonists, aimed specifically at the glycine modulatory site, could offer novel approaches to the prevention and treatment of HE in ALF.
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PMID:Reduced expression of astrocytic glycine transporter (Glyt-1) in acute liver failure. 1260 3

Increased travel to exotic destinations around the world is escalating the risk that an emerging virus may be imported into the UK. Rabies should be considered in the differential diagnosis of any encephalitic illness presenting in an appropriate epidemiological context. Molecular diagnostic tests that can rapidly discriminate rabies from other suspected infections will influence the use of anti-rabies prophylaxis for potential contacts with the victim. In 2001, the UK had two confirmed human rabies cases, imported from the Philippines and Nigeria, respectively. In case one, hemi-nested reverse transcriptase polymerase chain reaction (hn-RT-PCR) and automated sequencing confirmed the presence of rabies virus (RABV) within both the saliva and skin specimens within 36 h of sample submission. Subsequent phylogenetic analysis using a partial sequence of the nucleoprotein (N-) gene segment demonstrated that the virus was closely related to that of canine variants currently circulating in the Philippines. In the second case, the fluorescent antibody test and reverse transcriptase polymerase chain reaction (RT-PCR) confirmed the diagnosis on post-mortem tissue. Phylogenetic analysis of two genomic segments of this isolate confirmed that it was a classical RABV (genotype 1) of the Africa 2 subgroup. These cases have highlighted the capability of molecular diagnostic tests for the rapid identification and subsequent genotyping of RABV to host and geographical location. In the first instance, rabies diagnosis often rests on clinical and epidemiological grounds. Negative tests, even late in the illness, do not exclude the diagnosis as these tests are never optimal and are entirely dependent on the nature and quality of the sample supplied. For this reason, rapid molecular detection and virus typing will be essential in considering the appropriate medical treatment regimen for a patient. In addition, an early diagnosis may decrease the number of unnecessary contacts with the patient and reduce the requirement for invasive and costly interventions. Rabies should form part of a differential diagnosis for any patient presenting with a history of travel to a rabies endemic country and displaying an undiagnosed encephalopathy.
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PMID:Risk factors associated with travel to rabies endemic countries. 1267 34

Spotted wolffish Anarhichas minor (approx. 0.7 g) were found to be susceptible to infection with a nodavirus isolated from Atlantic halibut (AHNV) by bath-challenge. During the acute stage of infection, 4 to 8 wk post-challenge, viral encephalopathy and retinopathy (VER) were diagnosed by histopathology, immunohistochemistry (IHC) and reverse transcriptase-polymerase chain reaction (RT-PCR). Accumulated mortality was 52% in the challenged group. The surviving fish were sampled 16 wk post-challenge, by which time they had grown to approximately 17 g. No clinical signs of VER were observed in these fish. RT-PCR examination revealed the presence of nodavirus in several organs of the survivors, but no immunopositive cells were detected by IHC. Nodavirus was reisolated from fish at the last sampling in SSN-1 cells, showing that nodavirus retains virulence in persistently infected wolffish for at least 16 wk post-bath-challenge.
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PMID:Acute and persistent experimental nodavirus infection in spotted wolffish Anarhichas minor. 1473 19

Hypoxia causes dysfunction of excitatory and inhibitory neurotransmission, often resulting in encephalopathy, seizures or myoclonus. We evaluated the effects of hypoxia on GABAA receptor (GABAAR) function and expression in an in vitro model of neuronal hypoxia. NT2-N cells, derived from the human NT2 teratocarcinoma cell line, were exposed to < or =1% O2 for 8 h and then used immediately for experiments or allowed to recover under normoxic conditions (95% air/5% CO2) for 24, 48 or 96 h. Hypoxic treatment did not cause obvious morphological changes or cell death. In whole-cell patch-clamp recordings, the GABA current EC50 was unchanged, however, maximal GABA-evoked currents changed in a biphasic manner. Maximal GABA currents were significantly increased immediately after hypoxia, but were significantly reduced after 48 h normoxic recovery, and then returned to baseline after 96 h recovery. Maximal potentiation of 10 microM GABA currents by diazepam was increased 48 h after hypoxia, but potentiation by zolpidem was decreased. Barbiturate enhancement and zinc inhibition of GABA currents were unchanged. Semiquantitative reverse transcriptase (RT)-PCR showed decreased alpha1, alpha5, beta2 and gamma2 subunit mRNA after hypoxia. Hypoxic exposure altered GABAAR physiology and subunit mRNA expression, which may correlate with symptoms observed after hypoxia in vivo.
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PMID:Hypoxia alters GABAA receptor function and subunit expression in NT2-N neurons. 1497 87

Following a natural outbreak of viral encephalopathy and retinopathy (VER) at a commercial farm in Norway, surviving Atlantic halibut, Hippoglossus hippoglossus, were sequentially studied for distribution of nodavirus, immune response and histopathology over 1 year. Typical clinical signs and histopathology of VER were observed during the acute stage of the disease. Most of the surviving fish became subclinical carriers of nodavirus with clusters of nodavirus-containing cells in the central nervous system. Four random samplings of presumably healthy fish were performed from two fish groups, with low and high growth rates respectively, over a 7-month period. Immunohistochemical (IHC) examination revealed a higher number of nodavirus-positive cells in fish with a low growth rate than in fish with a high growth rate. All IHC positive fish were also reverse transcriptase polymerase chain reaction (RT-PCR) positive for nodavirus and for nodavirus antibodies detected by enzyme-linked immunosorbent assay (ELISA) at all sampling points. The percentage of PCR- and ELISA-positive fish remained high throughout the year, while the number of IHC-positive fish decreased, especially in the group with a high growth rate. Several other histopathological changes were observed, including pericarditis, steatitis, changes in liver and kidney, and necrosis of the intestinal wall. None of these findings seemed to be related to the nodavirus infection. Nodavirus was reisolated in cell culture from subclinically infected fish one year after the acute VER outbreak, which indicates that the virus was still infectious.
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PMID:A sequential study of pathological findings in Atlantic halibut, Hippoglossus hippoglossus (L), throughout one year after an acute outbreak of viral encephalopathy and retinopathy. 1518 73

Betanodaviruses are the causative agents of viral nervous necrosis (VNN) or viral encephalopathy and retinopathy (VER) in cultured marine fish. A total of 131 apparently healthy fish from 30 species were collected in two geographically remote aquaculture areas, Yashima Bay (Kagawa Prefecture) and Tamanoura Bay (Nagasaki Prefecture), in Japan. The brains of fish were examined by reverse transcriptase-polymerase chain reaction (RT-PCR) and nested PCR to detect the coat protein gene of betanodavirus. In Yashima Bay, two and 13 of 20 cultured fish were positive for nodavirus in RT-PCR and nested PCR, respectively, and four of five wild fish were positive only in nested PCR. In Tamanoura Bay, 28 and 99 of 106 wild fish were positive for the virus in RT-PCR and nested PCR, respectively. All the sequences of the nested PCR products (177 nt) from 27 fish species (10 cultured and 17 wild) were highly homologous to each other (99-100%) and were closely related to that of the known betanodavirus, redspotted grouper nervous necrosis virus (RGNNV). These results illustrate that large populations of cultured and wild marine fish in aquaculture areas are subclinically infected with genetically closely related betanodaviruses, suggesting an importance of such infected fish as a carrier or reservoir of betanodaviruses.
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PMID:PCR-based detection of betanodaviruses from cultured and wild marine fish with no clinical signs. 1548 25

The introduction of highly active antiretroviral therapy (HAART) for treatment of human immunodeficiency virus (HIV) infection has led to substantial reduction in morbidity and near-complete suppression of HIV-1 replication. But since HAART is unlikely to eradicate HIV-1, antiviral therapy may be required a lifelong, leading to an increase in attention on the long-term safety of HAART. A major toxicity of HAART is the mitochondrial toxicity. Mitochondrial toxicity becomes apparent particularly over the medium-term to long-term therapy and is attributed to treatment with nucleoside reverse transcriptase inhibitors (NRTIs), leading to a wide range of severe adverse events in HIV-infected patients. These include lactic acidosis, hepatic steatosis, neuropathy, (cardio-) myopathy, pancreatitis, and probably lipodystrophy. Furthermore, lactic acidosis and encephalopathy have been reported in children exposed in-utero and/or postnatally to NRTIs. Mitochondrial toxicity could pose a major threat to long-term success of HIV-therapy, and is of great concern for children exposed in-utero and/or postnatally to NRTIs. Therefore, investigation of mitochondrial toxicity of new compounds or new combinations is of growing interest for the clinical application of antiretroviral agents. However, at present no standardized and validated screening model system exists for the investigation of NRTI-induced mitochondrial toxicity. There is a need for the generation of a relevant in vitro assay system that can assess the mitochondrial toxicity in early preclinical development. This paper gives an overview of cell culture models currently used for the investigation of NRTI-induced mitochondrial toxicity and discusses the relevance and suitability of these models for prediction of clinical toxicity.
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PMID:Cell culture models for the investigation of NRTI-induced mitochondrial toxicity. Relevance for the prediction of clinical toxicity. 1640 76

Chronic degenerative brain disease in diabetes, known as 'diabetic encephalopathy', is a recognized complication that can occur due to long-standing diabetes in patients. It is defined by chronic cognitive disturbance and it is thought to relate to regional tissue pathological changes in the brain. Furthermore, hyperglycemia induced activation of the AGE (S)/RAGE/NF-kappaB pathway may play an important role in the pathogenesis of the degenerative changes seen in the diabetic hippocampus. To help prevent the development of and to potentially treat this brain disease, effective interventions directed toward key molecular target(s) are required. Grape seed proanthocyanidin extracts (GSPE), which are the anti-oxidants derived from grape seeds, have been reported to possess a variety of potent properties. As a consequence, they may have therapeutic effects in the prevention and treatment of complications in patients with diabetes. In this study, we firstly examined whether GSPE could attenuate the structural degenerative changes in the diabetic hippocampus in a rodent model of diabetes. Secondly, we addressed if such effects of GSPE may be occurring through modulation of the receptor for advanced glycation end products (RAGE) and/or nuclear factor-kappa BP65 (NF-kappaBP65). Hippocampi from GSPE treated STZ induced diabetic rats were immunohistochemically stained for glial fibrillary acidic protein, RAGE and NF-kappaBP65 and for morphological observations. Western blot was used to detect the proteins of RAGE and NF-kappaBP65. Real time, reverse transcriptase coupled to polymerase chain reaction was used for quantitative determination of mRNA for RAGE and NF-kappaBP65. Analysis of data showed that long term chronic hyperglycemia caused the overexpression of AGE (S)/RAGE and NF-kappaBp65 in the CA region of hippocampus in STZ induced diabetic rats. GSPE decreased the expression of RAGE and NF-kappaBP65 at a daily oral dosage of 250 mg/kg. This study provides indication that GSPE can prevent structural changes of diabetes in the rat brain and it suggests that GSPE might be a useful remedy in the treatment of diabetic encephalopathy. In addition, it implicates the potential pathological role of RAGE and NF-kappaBP65 in diabetic encephalopathy.
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PMID:Oral administration of grape seed proanthocyanidin extracts downregulate RAGE dependant nuclear factor- kappa BP65 expression in the hippocampus of streptozotocin induced diabetic rats. 1827 52


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