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)

Multiple voltage-gated sodium channels are the primary mediators of cell excitability. They are multimers that consist of the pore-forming alpha subunit and auxiliary beta subunits. Although ion permeability and voltage sensing are primarily determined by the alpha subunit, beta subunits are important modulators of sodium channel function. The purpose of this study was to assess the effect of axotomy on the expression of beta subunits (beta(1), beta(2) and beta(3)) and coexpression of Na(v)1.3 and beta(3) subunits in the dorsal root ganglion (DRG). We used sciatic nerve transection models or spared nerve injury (SNI) models in the rat. In reverse transcriptase-polymerase chain reaction analysis, there were no significant differences between contralateral and ipsilateral DRGs of beta(1) and beta(2) mRNA 3 days after axotomy. beta(3) mRNA expression in ipsilateral DRGs increased significantly compared with contralateral DRGs 3 days after axotomy. In in situ hybridization histochemistry, beta(1) mRNA was predominantly expressed in medium- to large-size neurons, whereas beta(2) mRNA was expressed in small- to large-size neurons. There were no significant differences in beta(1) and beta(2) mRNA between contralateral and ipsilateral DRGs 3 days after axotomy. In contrast, beta(3) mRNA was mainly expressed in small neurons and occasionally in medium- to large-size neurons, and beta(3) mRNA expression in small c-type neurons in ipsilateral DRGs was increased significantly compared with contralateral DRGs. We examined beta(3) mRNA expression with one of alpha subunits, Na(v)1.3-ir, in DRG neurons after axotomy using the double labeling method. We found a high percentage of coexpression in injured DRG neurons: 83.6+/-2.8% of neurons expressing beta(3) mRNA were labeled for Na(v)1.3-ir; 70.1+/-3.1% of Na(v)1.3-ir neurons expressed beta(3) mRNA. We also examined the expression of beta(3) mRNA in DRG neurons in the SNI model, a neuropathic pain model. We used activating transcription factor 3 to identify axotomized neurons, and found that beta(3) mRNA up-regulation occurred mainly in axotomized neurons in the neuropathic pain model. These data strongly suggest that beta(3) expression in injured DRG neurons following axotomy might be an important pathomechanism of post-nerve injury pain in primary sensory neurons.
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PMID:Expression of auxiliary beta subunits of sodium channels in primary afferent neurons and the effect of nerve injury. 1452 2

Vascular endothelial growth factor (VEGF) is a glycoprotein that plays an important role in neovascularization and increases vascular permeability. We reported that VEGF is involved in motion pain of patients with rotator cuff disease by causing synovial proliferation in the subacromial bursa (SAB). The present study investigates whether VEGF is also involved in the development of shoulder contracture in diabetics with rotator cuff disease. We examined 67 patients with rotator cuff disease, including 36 with complete cuff tears, 20 with incomplete tears, and 11 without apparent tears (subacromial bursitis). The patients were into groups according to the presence or absence of diabetes (14 type II diabetics and 53 non-diabetics). Specimens of the synovium of the SAB were obtained from all patients during surgery. Expression of the VEGF gene in the synovium of the subacromial bursa was evaluated by using the reverse transcriptase polymerase chain reaction. The VEGF protein was localized by immunohistochemistry, and the number of vessels was evaluated based on CD34 immunoreactivity. The results showed that VEGF mRNA was expressed in significantly more diabetics (100%, 14/14) than in non-diabetics (70%, 37/53) (P=0.0159, Fisher's test). Investigation of VEGF isoform expression revealed VEGF121 in all 14 diabetics and in 37 of the 53 non-diabetics, VEGF165 in 12 of the 14 diabetics and in 21 of the 53 non-diabetics, and VEGF189 in 1 of the 14 diabetics and in 2 of the 53 non-diabetics. No VEGF206 was expressed in either group. VEGF protein was localized in both vascular endothelial cells and synovial lining cells. The mean number of VEGF-positive vessels and the vessel area were also significantly greater in the diabetics (p<0.015, Mann-Whitney U test). Synovial proliferation and shoulder joint contracture were more common in the diabetics (P=0.0329 and P=0.073, respectively; Fisher's test). The mean preoperative range of shoulder motion significantly differed in terms of elevation between two groups: 103.8 degrees in diabetics and 124.9 degrees in no diabetics (p=0.0039 Mann-Whitney U test). In contrast, external rotation did not significantly differ: 44 degrees in diabetics and 49 degrees in non-diabetics (p=0.4957, Mann-Whitney U test). These results suggest that VEGF121 and VEGF165 expression in the SAB is responsible for the development of shoulder joint contracture, especially in elevation, among type II diabetic patients with rotator cuff disease.
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PMID:Vascular endothelial growth factor 121 and 165 in the subacromial bursa are involved in shoulder joint contracture in type II diabetics with rotator cuff disease. 1455 30

To elucidate the underlying mechanisms involved in AIDS therapy-induced peripheral neuropathy, we have developed a model of nucleoside analog reverse transcriptase inhibitor-induced painful peripheral neuropathy in the rat, using 2',3'-dideoxycytidine (ddC), 2',3'-dideoxyinosine (ddI) and 2',3'-didehydro-3'-deoxythymidine (d4T), AIDS chemotherapeutic drugs that are also components of AIDS highly active anti-retroviral therapy. Administration of ddC, ddI and d4T produced dose-dependent mechanical hypersensitivity and allodynia. Peripheral administration of inhibitors of protein kinase A, protein kinase C, protein kinase G, p42/p44-mitogen-activated protein kinase (ERK1/2) and nitric oxide synthase, which have demonstrated anti-hyperalgesic effects in other models of metabolic and toxic painful peripheral neuropathies, had no effect on ddC-, ddI- and d4T-induced hypersensitivity. Since suramin, an anti-parasitic and anti-cancer drug, which shares with the anti-retroviral nucleoside analogs, mitochondrial toxicity, altered regulation of intracellular calcium, and a sensory neuropathy in humans, also produced mechanical hypersensitivity that was not sensitive to the above second messenger inhibitors we evaluated the role of intracellular calcium. Intradermal or spinal injection of intracellular calcium modulators (TMB-8 and Quin-2), which had no effect on nociception in control rats, significantly attenuated and together eliminated ddC and suramin-induced mechanical hypersensitivity. In electrophysiology experiments in ddC-treated rats, C-fibers demonstrated alterations in pattern of firing as indicated by changes in the distribution of interspike intervals to sustained suprathreshold stimuli without change in mechanical activation thresholds or in number of action potentials in response to threshold and suprathreshold stimulation. This study provides evidence for a novel, calcium-dependent, mechanism for neuropathic pain in a model of AIDS therapy-induced painful peripheral neuropathy.
Pain 2004 Jan
PMID:Novel mechanism of enhanced nociception in a model of AIDS therapy-induced painful peripheral neuropathy in the rat. 1471 1

Petasites hybridus is used in Chinese herbal medicine. S-petasin is a bioactive compound isolated from leaves or roots of P. hybridus, which has been used to relieve gastrointestinal pain, lung disease, and spasms of urogenital tract. We have demonstrated that S-petasin inhibited corticosterone release from rat zona fasiculata-reticularis cells. However, the mechanism and molecular effects of S-petasin on zona fasiculata-reticularis cells are still unclear. This study explored the effects of S-petasin on cellular adenosine 3':5'-cyclic monophosphate (cAMP) production, the functions of steroidogenic enzymes including cytochrome P450 side-chain cleavage enzyme (P450scc), 11beta-hydroxylase, and the expression levels of steroidogenic acute regulatory protein or P450scc. In this experiment, zona fasciculata-reticularis cells were incubated with S-petasin in the presence or absence of adrenocorticotropin (ACTH), 8-bromo-adenosine 3':5'-cyclic monophosphate (8-Br-cAMP), forskolin, 25-OH-cholesterol, deoxycorticosterone at 37 degrees C for 0.5, 1 or 3 h. The media were used to measure the concentration of corticosterone or pregnenolone by radioimmunoassay. The cells were used to measure the content of cAMP by radioimmunoassay and extracted protein for Western blot or messenger RNA (mRNA) for reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. Our data demonstrated that (1) S-petasin inhibits ACTH- or forskolin-stimulated cellular cAMP production, (2) S-petasin increased the Michaelis constants of P450scc and 11beta-hydroxylase and (3) S-petasin decreased the expression levels and mRNA of steroidogenic acute regulatory protein. In summary, the actions of S-petasin mediate the inhibition of cAMP formation, decrease the activities of key enzymes P450scc and 11beta-hydroxylase, and reduce mRNA of steroidogenic acute regulatory protein and expression of steroidogenic acute regulatory protein.
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PMID:Effects of S-petasin on cyclic AMP production and enzyme activity of P450scc in rat zona fasciculata-reticularis cells. 1506 52

In this study we compared the alpha-calcitonin gene-related peptide (alphaCGRP) and betaCGRP expression patterns in wild-type and knockout mice by using quantitative reverse transcriptase polymerase chain reaction and immunohistochemistry. In dorsal root ganglia and spinal cord of wild-type animals, alphaCGRP mRNA was about two times more abundant than betaCGRP mRNA. The betaCGRP mRNA was the only isoform expressed in the intestine. In alphaCGRP knockout mice, we found no change in betaCGRP mRNA levels in dorsal root ganglia and spinal cord compared with wild-type controls, but a twofold decrease in the intestine. CGRP immunoreactivity (IR) was detected in many small and some large neurons in the dorsal root ganglia, was found in sensory fibers and motor neurons in the spinal cord, and labeled neuromuscular junctions in wild-type mice. In the dorsal root ganglia of alphaCGRP knockout mice, punctate betaCGRP-IR again was predominantly found in small neurons. In the spinal cord, betaCGRP-IR fibers were localized to the outermost layer of the dorsal horn. IR was found in the cell bodies of motor neurons, but it was undetectable in neuromuscular junctions. In the intestine, CGRP-IR was localized to neurons of the myenteric plexus and to fibers in the mucosal folds, with similar staining intensity in both wild-type and knockout mice. Finally, CGRP-IR was undetectable in preganglionic fibers and postganglionic sympathetic neurons in mice from both genotypes. Our results indicate that alphaCGRP and betaCGRP are variably coexpressed in different functional aspects of the mouse nervous system. This pattern suggests distinct roles for betaCGRP in pain, neuromuscular, and gastrointestinal systems.
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PMID:Analysis of the cellular expression pattern of beta-CGRP in alpha-CGRP-deficient mice. 1523 65

Prostaglandins (PGs) formed via the cyclooxygenase (COX) pathway mediate hyperalgesia in sensory nerve endings. To investigate the role of the COX isoforms in pain transmission we recently studied nociception in COX-isozyme-deficient mice using models of "sharp" rapidly transmitted pain (hot-plate) and slowly developing, diffuse pain (writhing) [Ballou L, Botting RM, Goorha S, Zhang J, Vane JR. Nociception in cyclooxygenase isozyme-deficient mice. Proc Natl Acad Sci USA 2000;97:10272]. Our results demonstrated that COX-1 (and not COX-2) was the primary isoform involved in nociception in both model systems. Given the importance of dorsal root ganglia (DRG) in pain transmission we examined the expression patterns of COX-1, -2 and the recently described variant of COX-1 retaining intron-1, originally referred to as "COX-3" but hereafter referred to as COX-1 variant (COX-1v), in mouse L4 or L5 DRG taken from normal and COX-isozyme-deficient mice. Messenger RNA and protein for COX isoforms from DRG, spinal cord as well as, heart, brain, kidney, spleen and skin of adult mice were isolated and analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot analysis, respectively. Patterns of COX-isoform expression were determined using immunohistochemical techniques. We found that COX-1 and COX-1v were both expressed in neurons while COX-2 expression was completely undetectable in the DRG. Immunohistochemical analysis of COX expression in DRG of mice exhibiting the chronic pain and inflammation associated with collagen-induced arthritis (CIA) expressed COX-1 and COX-1v while no COX-2 could be detected. For purposes of comparison, COX-1v mRNA was also expressed in heart, brain, spinal cord, kidney, spleen and skin. Together, these data support a role for COX-1 and perhaps COX-1v, not COX-2, as the primary producers of PGs in mouse DRG in normal and in mice subject to chronic pain and inflammation. These data also suggest potential alternative analgesic mechanisms of action for the newly developed, COX-2 selective inhibitors and the nonsteroidal anti-inflammatory drugs (NSAIDs) in pain transmission in the peripheral nervous system.
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PMID:Nociception and the differential expression of cyclooxygenase-1 (COX-1), the COX-1 variant retaining intron-1 (COX-1v), and COX-2 in mouse dorsal root ganglia (DRG). 1556 Jan 14

Whereas small-fibre sensory neuropathies might ultimately lead to cell death and loss of sensation, they first progress through a phase, which might last for years, characterized by the presence of analgesia-resistant neuropathic dysesthesias and pain. Much previous research has addressed these two phases as separate phenomena mediated by presumably discrete biochemical mechanisms. We hypothesized that activity in signalling pathways that ultimately lead to apoptosis plays a critical role in the generation of neuropathic pain, before death of sensory neurons becomes apparent. We have tested the hypothesis that activator and effector caspases, defining components of programmed cell death (apoptosis) signalling pathways, also contribute to pain-related behaviour in animals with small-fibre peripheral neuropathies and that the death receptor ligand, tumour necrosis factor-alpha, and its downstream second messenger, ceramide, also produce pain-related behaviour via this mechanism. In two models of painful peripheral neuropathy, HIV/AIDS therapy (induced by the nucleoside reverse transcriptase inhibitor, dideoxycytidine), and cancer chemotherapy (induced by vincristine) peripheral neuropathy, and for pain-related behaviour induced by tumour necrosis factor-alpha and its second messenger, ceramide, inhibition of both activator (1, 2, 8 and 9) and effector (3) caspases attenuates neuropathic pain-related behaviour, although has no effect in streptozotocin-diabetic neuropathy and control rats. We conclude that during a latent phase, before apoptotic cell death is manifest, the caspase signalling pathway can contribute to pain in small-fibre peripheral neuropathies, and that inflammatory/immune mediators also activate these pathways. This suggests that these pathways are potential targets for novel pharmacological agents for the treatment of inflammatory as well as neuropathic pain.
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PMID:Caspase signalling in neuropathic and inflammatory pain in the rat. 1557 43

The reverse transcriptase polymerase chain reaction (RT-PCR) technique was used to examine the changes of the expression of 5-hydroxytryptamine (5-HT) receptors in the rat lumbar dorsal root ganglion (DRG) following subcutaneous bee venom (BV) injection into the plantar surface of the unilateral hindpaw. In the DRG ipsilateral to the BV injection, significant increase of mRNA levels of 5-HT(1A), 5-HT(1B), 5-HT(2A) and 5-HT(3) receptor subtypes were observed at 1 and 4h after the BV injection, while increase of 5-HT(2C), 5-HT(4), 5-HT(6) and 5-HT(7) receptor subtype mRNAs was detected at 4h only. No such changes were observed in the expressions of 5-HT(1D), 5-HT(1F) and 5-HT(5A) receptor subtype mRNAs. Upregulation of 5-HT(1A), 5-HT(1B) and 5-HT(2A) receptor subtype mRNAs was also observed in the contralateral DRG at 4 h. The presence of 5-HT(1E), 5-HT(2B) and 5-HT(5B) receptor subtype mRNAs was not detected in the rat DRG. The present results suggest that different sets of 5-HT receptor subtypes work at different stages of the inflammatory pain induced by subcutaneous BV injection.
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PMID:Changes of 5-HT receptor subtype mRNAs in rat dorsal root ganglion by bee venom-induced inflammatory pain. 1566 20

(1) The current first-line treatment for HIV infection is a combination of at least two nucleoside (or nucleotide) inhibitors of HIV reverse transcriptase, and one non nucleoside inhibitor or at least one HIV protease inhibitor. (2) Emtricitabine is the eighth nucleoside/nucleotide inhibitor to be marketed in France. It has a similar chemical structure to lamivudine. (3) Evaluation of emtricitabine use in adults contains data from four comparative trials, two in treatment-naive patients and two in patients who were already receiving a virologically effective treatment. Emtricitabine combination therapy was no more effective than lamivudine combination therapy on either viral load or the CD4+ lymphocyte count. (4) Only non comparative trials are available in children. (5) In clinical trials, the adverse effects of emtricitabine were similar to those of lamivudine, including headache, pain, fatigue, fever, abdominal pain, nausea, vomiting, and diarrhea. (6) Viral strains resistant to emtricitabine are also resistant to lamivudine, and vice versa. (7) Emtricitabine, like other nucleoside inhibitors (lamivudine, didanosine, tenofovir), can be taken once a day by mouth. (8) In practice, emtricitabine is indistinguishable from lamivudine and does not offer any advance for patients living with HIV/AIDS.
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PMID:Emtricitabine: new preparation. An antiretroviral very similar to lamivudine. 1587 41

Hyperpolarization-activated cation channels of the HCN gene family are crucial for the regulation of cell excitability. Importantly, these channels play a pivotal role in the control of cardiac and neuronal pacemaker activity. Dysfunction of HCN channels has been associated with human diseases, including cardiac arrhythmia, epilepsy, and neuropathic pain. The properties of three HCN channel isoforms (HCN1, HCN2, and HCN4) have been extensively investigated. By contrast, due to the lack of an efficient heterologous expression system, the functional characteristics of HCN3 were by and large unknown so far. Here, we have used lentiviral gene transfer to overexpress HCN3 in HEK293T cells. HCN3 currents revealed slow activation and deactivation kinetics and were effectively blocked by extracellular Cs+ and the bradycardic agent ivabradine. Cyclic AMP and cGMP had no significant impact on activation kinetics but induced a 5-mV shift of the half-maximal activation voltage (V0.5) to more hyperpolarized potentials. A negative shift of V0.5 induced by cyclic nucleotides is an unprecedented feature within the HCN channel family. The expression of HCN3 in mouse brain was examined by Western blot analysis using a specific antibody. High levels of protein were detected in olfactory bulb and hypothalamus. In contrast, only very low expression was found in cortex. Using reverse transcriptase PCR transcripts of HCN3 were also detected in heart ventricle. In conclusion, the distinct expression pattern in conjunction with the unusual biophysical properties implies that HCN3 may play an unique role in the body.
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PMID:The murine HCN3 gene encodes a hyperpolarization-activated cation channel with slow kinetics and unique response to cyclic nucleotides. 1592 85


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