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)

Starting from the very simple molecule sulfamic acid, O-substituted-, N-substituted-, or di-/tri-substituted sulfamates may be obtained, which show specific biological activities which were or started to be exploited for the design of many types of therapeutic agents. Among them, sulfamate inhibitors of aminoacyl-tRNA synthetases (aaRSs) were recently reported, constituting completely new classes of antibiotics, useful in the fight of drug-resistant infections. Anti-viral agents incorporating sulfamate moieties have also been obtained, with at least two types of such derivatives investigated: the nucleoside/nucleotide human immunodeficiency virus (HIV) reverse transcriptase inhibitors, and the HIV protease inhibitors (PIs). In the increasing armamentarium of anti-cancer drugs, the sulfamates occupy a special position, with at least two important targets evidenced so far: the steroid sulfatases (STSs) and the carbonic anhydrases (CAs). An impressing number of inhibitors of STSs of the sulfamate type have been reported in the last years, with several compounds, such as 667COUMATE among others, progressing to clinical trials for the treatment of hormone-dependent tumors (breast and prostate cancers). This field is rapidly evolving, with many types of new inhibitors being constantly reported and designed in such a way as to increase their anti-tumor properties, and decrease undesired features (for example, estrogenicity, a problem encountered with the first generation such inhibitors, such as EMATE). Among the many isozymes of CAs, at least two, CA IX and CA XII, are highly overexpressed in tumors, being generally absent in the normal tissues. Inhibition of tumor-associated CAs was hypothesized to lead to novel therapeutic approaches for the treatment of cancer. Many sulfamates act as very potent (low nanomolar) CA inhibitors. The X-ray crystal structure of the best-studied isozyme, CA II, with three sulfamates (sulfamic acid, topiramate, and EMATE) has recently been reported, which allowed for a rationale drug design of new inhibitors. Indeed, low nanomolar CA IX inhibitors of the sulfamate type have been reported, although such compounds also act as efficient inhibitors of isozymes CA I and II, which are not associated with tumors. A large number of anti-convulsant sulfamates have been described, with one such compound, topiramate, being widely used clinically as anti-epileptic drug. By taking into consideration a side effect of topiramate, an anti-epileptic drug leading to weight loss in some patients, it has recently been proposed to use this drug and related sulfamates for the treatment of obesity. The rationale of this use is based on the inhibition of the mitochondrial CA isozyme, CA V, involved in lipogenesis. Some sulfamates were also shown to possess potent inhibitory activity against acyl coenzyme A:cholesterol acyltransferase, an enzyme involved in cholesterol metabolism. One such agent, avasimibe, is in advanced clinical trials for the treatment of hyperlipidemia and atherosclerosis. Thus, the sulfamate moiety offers very attractive possibilities for the drug design of various pharmacological agents, which are on one hand due to the relative ease with which such compounds are synthesized, and on the other one, due to the fact that biological activity of most of them is impressive.
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PMID:Sulfamates and their therapeutic potential. 1547 25

Synaptopodin is an actin-associated molecule found in a subset of telencephalic spines. It is an essential component of the spine apparatus, a Ca(2+)-storing organelle and has been implicated in synaptic plasticity (Deller et al. [2003] Proc Natl Acad Sci U S A 100:10494-10499). In the rodent hippocampus, Synaptopodin is distributed in a characteristic region- and lamina-specific manner. To learn more about the cellular basis underlying this distribution, the regional, laminar, and cellular localization of Synaptopodin and its mRNA were analyzed in mouse hippocampus. First, Synaptopodin puncta densities were quantified after immunofluorescent labeling using confocal microscopy. Second, the dendritic distribution of Synaptopodin-positive puncta was studied using three-dimensional confocal reconstructions of Synaptopodin-immunostained and enhanced green fluorescence protein (EGFP)-labeled principal neurons. Synaptopodin puncta located within dendrites of principal neurons were primarily found in spines (>95%). Analysis of dendritic segments located in different layers revealed lamina-specific differences in the percentage of Synaptopodin-positive spines. Densities ranged between 37% (outer molecular layer) and 14% (stratum oriens; CA1). Finally, synaptopodin mRNA expression was studied using in situ hybridization, laser microdissection, and quantitative reverse transcriptase-polymerase chain reaction. Expression levels were comparable between all regions. These data demonstrate a lamina-specific distribution of Synaptopodin within dendritic segments of identified neurons. Within dendrites, the majority of Synaptopodin-positive puncta were located in spines where they represent spine apparatuses. We conclude, that this organelle is distributed in a region- and layer-specific manner in the mouse hippocampus and suggest that differences in the activity of afferent fiber systems could determine its distribution.
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PMID:Lamina-specific distribution of Synaptopodin, an actin-associated molecule essential for the spine apparatus, in identified principal cell dendrites of the mouse hippocampus. 1589

Using a rat model of moderate hypothermic (26 degrees C-28 degrees C) cardiopulmonary bypass (CPB) with hemodilution, we investigated hippocampal apoptotic gene expression and neuronal apoptosis up to 6 h after CPB. The CPB was performed on male rats (380-400 g) under general anesthesia with isoflurane and fentanyl. The right atrium and tail artery were cannulated, and a peristaltic pump and membrane oxygenator were used for CPB. Two groups were studied: Group 1 consisted of fasted rats (n = 15) subjected to 60 min of moderate hypothermic nonpulsatile CPB; Group 2 consisted of sham-operated rats (n = 15). At 1 h after CPB, in 6 rats per group, hippocampus was processed for the apoptotic gene (bcl-2 and bax) messenger RNAs detection by reverse transcriptase polymerase chain reaction, and messenger RNA expression was determined by the ratio of the polymerase chain reaction product of bcl-2 or bax to the beta-actin gene. At 6 h after CPB, in 6 rats per group, hippocampus expression of Bcl-2 and bax protein was determined by immunohistochemistry, and neuronal apoptosis was detected by TUNEL. At 6 h after CPB, in three rats per group, changes in hippocampal CA1 neuronal ultra structure were determined with electron microscopy. Group 1 had increased ratios of bcl-2/beta-actin, bax/beta-actin, and bax/bcl-2 mRNA at 1 h after CPB (bcl-2/beta-actin, 0.82 +/- 0.14 versus 0.63 +/- 0.07; P = 0.03; bax/beta-actin, 1.04 +/- 0.14 versus 0.56 +/- 0.03; P = 0.00; bax/bcl-2, 1.31 +/- 0.12 versus 0.84 +/- 0.09; P = 0.02; Group 1 versus Group 2, respectively). Group 1 had increased bcl-2 and bax protein expression in hippocampal CA1 region at 6 h after CPB (bcl-2, 0.18 +/- 0.05 versus 0.09 +/- 0.01; P = 0.02; bax, 0.20 +/- 0.06 versus 0.04 +/- 0.02; P = 0.01; Group 1 versus Group 2, respectively). Group 1 had increased TUNEL staining in hippocampus CA1 at 6 h after CPB (0.14 +/- 0.02 versus 0.03 +/- 0.01; P = 0.00; Group 1 versus Group 2, respectively). In Group 1 CA1 hippocampus neurons, ultra-structural changes consistent with apoptosis occurred. In rats, moderate hypothermic CPB with hemodilution is associated with CA1 hippocampus bax and bcl-2 gene expression and neuronal apoptosis during the early post-CPB recovery period.
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PMID:Hippocampus bcl-2 and bax expression and neuronal apoptosis after moderate hypothermic cardiopulmonary bypass in rats. 1655 91

Mammalian O-mannosylation, although an uncommon type of protein modification, is essential for normal brain and muscle development. Defective O-mannosylation causes congenital muscular dystrophy with abnormal neuronal migration [Walker-Warburg syndrome (WWS)]. Here, we have identified and cloned rat Pomt1 and Pomt2, which are homologues of human POMT1 and POMT2, with identities of 86 and 90%, respectively, at the amino acid level. Coexpression of both genes was found to be necessary for enzymatic activity, as is the case with human POMT1 and POMT2. Northern blot and reverse transcriptase polymerase chain reaction (RT-PCR) analyses revealed that rat Pomt1 and Pomt2 are expressed in all tissues but most strongly in testis. In situ hybridization histochemistry of rat brain revealed that Pomt1 and Pomt2 mRNA are coexpressed in neurons (dentate gyrus and CA1-CA3 region of the hippocampus and cerebellar Purkinje cells). Two transcription-initiation sites were observed in rat Pomt2, resulting in two forms: a testis form and a somatic form. The two forms had equal protein O-mannosyltransferase activity when coexpressed with rat Pomt1. Coexpression studies also showed that the human and rat protein O-mannosyltransferases are interchangeable, providing further evidence for the closeness of their structures.
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PMID:Molecular cloning and characterization of rat Pomt1 and Pomt2. 1670 66

Osteopontin (OPN) is an adhesive glycoprotein linked to a variety of pathophysiological processes, with neuroprotective properties in ischemic injury. We examined the postischemic expression and localization of OPN in the rat brain after transient forebrain ischemia. The semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis showed that OPN expression in the hippocampal CA1 region was biphasic, peaking at day 3 after reperfusion and again between days 14 and 28. The two phases of OPN induction occurred in a time- and cell-dependent manner in the ischemic hippocampus. OPN mRNA expression in activated microglia was first induced 1 day after reperfusion, reached a peak at 3 days, and returned to basal levels by 7 days. In contrast, OPN expression in reactive astrocytes was first induced by 10 days after reperfusion in the hippocampal CA1. Astroglial OPN expression further increased, reaching a peak at day 14 and was maintained up to day 28, the latest time point we examined. OPN immunoreactivity in the ischemic hippocampus matched the mRNA induction patterns. OPN protein was first localized in the astroglial cytoplasm and later in the extracellular matrix of the hippocampal CA1. The temporal and cellular patterns of OPN induction in the ischemic hippocampus suggest a multifunctional capacity in the pathogenesis of ischemic injury, with the increased OPN production and secretion by reactive astrocytes being involved in subsequent tissue repair and reorganization.
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PMID:Transient microglial and prolonged astroglial upregulation of osteopontin following transient forebrain ischemia in rats. 1739 66

This study characterizes the distribution of the two tyrosine kinase receptors for vascular endothelial growth factor (VEGF), Flt-1 and Flk-1, in the rat hippocampus following transient forebrain ischemia. The semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of Flt-1 and Flk-1 in hippocampal CA1 showed upregulation of these receptors following ischemic injury. Expression of Flt-1 and Flk-1 mRNA was restricted to neurons in the pyramidal cell and granule cell layers in control animals; however, upregulation was detected in activated glial cells and in the vascular endothelial cells rather than in neurons, in ischemic hippocampi. Most of the activated glial cells expressing Flt-1 and Flk-1 were reactive astrocytes, although some were microglial cells. The spatiotemporal expression of Flt-1 in the ischemic hippocampus mirrored that of Flk-1 expression. Expression of mRNA for both receptors was induced after 12 h, appeared to be increased progressively until 3 days when the highest expression was reached, and was sustained for more than 2 weeks. Flt-1 and Flk-1 immunoreactivity in the ischemic hippocampus matched the mRNA induction patterns except for a somewhat delayed onset. These data suggest that VEGF may be involved in the glial response via specific VEGF receptors in the rat hippocampus following transient forebrain ischemia.
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PMID:Upregulation of vascular endothelial growth factor receptors Flt-1 and Flk-1 in rat hippocampus after transient forebrain ischemia. 1740 57

DYT1 dystonia is caused by a single GAG deletion in exon 5 of TOR1A, the gene encoding torsinA, a putative chaperone protein. In this study, central and peripheral nervous system perturbations (transient forebrain ischemia and sciatic nerve transection, respectively) were used to examine the systems biology of torsinA in rats. After forebrain ischemia, quantitative real-time reverse transcriptase-polymerase chain reaction identified increased torsinA transcript levels in hippocampus, cerebral cortex, thalamus, striatum, and cerebellum at 24 h and 7 days. Expression declined toward sham values by 14 days in striatum, thalamus and cortex, and by 21 days in cerebellum and hippocampus. TorsinA transcripts were localized to dentate granule cells and pyramidal neurons in control hippocampus and were moderately elevated in these cell populations at 24 h after ischemia, after which CA1 expression was reduced, consistent with the loss of this vulnerable neuronal population. Increased in situ hybridization signal in CA1 stratum radiatum, stratum lacunosum-moleculare, and stratum oriens at 7 days after ischemia was correlated with the detection of torsinA immunoreactivity in interneurons and reactive astrocytes at 7 and 14 days. Sciatic nerve transection increased torsinA transcript levels between 24 h and 7 days in both ipsilateral and contralateral dorsal root ganglia (DRG). However, increased torsinA immunoreactivity was localized to both ganglion cells and satellite cells in ipsilateral DRG but was restricted to satellite cells contralaterally. These results suggest that torsinA participates in the response of neural tissue to central and peripheral insults and its sustained up-regulation indicates that torsinA may contribute to remodeling of neuronal circuitry. The striking induction of torsinA in astrocytes and satellite cells points to the potential involvement of glial elements in the pathobiology of DYT1 dystonia.
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PMID:Glial elements contribute to stress-induced torsinA expression in the CNS and peripheral nervous system. 1853 41

We investigated the spatiotemporal expression of suppressor of cytokine signaling-3 (SOCS-3) in the rat hippocampus following transient forebrain ischemia using in situ hybridization and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. Messenger RNA for SOCS-3 was constitutively expressed in neurons of the pyramidal cell and granule cell layers in control animals; however, significant induction was detected in reactive astrocytes preferentially located in the CA1 and the dentate hilar regions of the ischemic hippocampus. SOCS-3 mRNA was induced within 3 days of ischemia and maintained for more than 2 weeks. The in situ hybridization data agreed with the semiquantitative RT-PCR analysis. These results demonstrate SOCS-3 induction occurs in reactive astrocytes of the post-ischemic hippocampus, suggesting that SOCS-3 is involved in regulating the astroglial reaction to an ischemic insult.
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PMID:Induction of suppressor of cytokine signaling-3 in astrocytes of the rat hippocampus following transient forebrain ischemia. 1858 73

Suppressor of cytokine signaling-2 (SOCS-2) has recently been identified as an important regulator involved in neuronal differentiation and maturation. However, the role of SOCS-2 in ischemia-induced hippocampal neurogenesis remains to be clarified. Here we investigated the spatiotemporal expression of SOCS-2 in the rat hippocampus following transient forebrain ischemia, and particular attention was paid to changes in the dentate gyrus. SOCS-2 mRNA was constitutively expressed in hippocampal neurons and astrocytes in control animals. However, its upregulation occurred specifically in reactive astrocytes in the hippocampus proper, in particular the CA1 and dentate hilar regions, at day 3 after reperfusion, and was sustained for more than 2 weeks. In addition to the CA1 and hilar regions, SOCS-2 was transiently increased in the subgranular zone (SGZ) of the dentate gyrus on days 3-7 after reperfusion. This correlated with the post-ischemic upregulation of SOCS-2 in the CA1 or dentate gyrus subfield, including the SGZ detected by semiquantitative reverse transcriptase-polymerase chain reaction analysis. The majority of the SOCS-2-expressing cells in the SGZ were co-labeled with glial fibrillary acidic protein (GFAP), and a subpopulation of GFAP/SOCS-2 double-labeled cells in the SGZ co-expressed the neural progenitor marker nestin, or the proliferation marker proliferating cellular nuclear antigen. In addition, a subset of SOCS-2-labeled cells in the SGZ expressed the immature neuronal marker polysialic acid-neural cell adhesion molecule. These data suggest that SOCS-2 may be involved in glial reactions, and possibly adult hippocampal neurogenesis during ischemic insults.
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PMID:Enhanced expression of SOCS-2 in the rat hippocampus after transient forebrain ischemia. 1946 88

There are ongoing concerns that antenatal corticosteroids, which are administered to women at high risk of delivering preterm to reduce the incidence of respiratory distress syndrome, have adverse effects on foetal brain development and subsequent effects on behaviour and learning, when administered as repeated courses. The present study aimed to examine whether repeated betamethasone treatment alters the expression of the key-rate limiting enzyme, 5alpha-reductase, in the synthetic pathway of the potent neuroactive steroid allopregnanolone in the brain and placenta and whether this effect is potentiated in growth restricted foetuses. To investigate this, pregnant guinea pigs carrying either control (sham surgery) or growth-restricted foetuses were treated with vehicle or betamethasone (1 mg/kg/day) for 4 days prior to sacrifice (65d). Placental insufficiency was induced by the ablation of uterine artery branches supplying each placenta at mid gestation, resulting in foetal growth restriction characterised by 'brain sparing'. Real-time reverse transcriptase polymerase chain reaction was used to determine relative 5alpha-reductase type 1 and 2 mRNA expression in the placenta and brain. Immunohistochemistry was used to examine the glial fibrillary acidic protein (GFAP) expression in the subcortical white matter, CA1 and dentate regions of the hippocampus. 5alpha-reductase type 2 mRNA expression in the brain was markedly reduced by betamethasone treatment in male foetuses compared to vehicle-treated controls but not in female foetuses. In addition, 5alpha-reductase type 1 expression in the brain was increased by growth restriction and/or betamethasone treatment in female foetuses but expression in males foetuses did not increase. 5alpha-reductase type 2 expression in the placenta was markedly reduced by betamethasone treatment compared to vehicle-treated control. Intrauterine growth restriction and betamethasone treatment reduced GFAP expression in the CA1 region of the hippocampus in the brains of male but not female foetuses. These data indicate that betamethasone treatment suppresses placental expression and has sexually dimorphic effects on expression of neuroactive steroid synthetic enzymes in the brain. These actions may lead to adverse effects on the developing brain, particularly in male foetuses, such as the observed effects on GFAP expression.
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PMID:The effect of betamethasone treatment on neuroactive steroid synthesis in a foetal Guinea pig model of growth restriction. 2004 84


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