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)

[Arg(6),D-Trp(7,9),N(me)Phe(8)]-substance P (6-11) (SP-G) is a novel anticancer agent that has recently completed phase I clinical trials. SP-G inhibits mitogenic neuropeptide signal transduction and small cell lung cancer (SCLC) cell growth in vitro and in vivo. Using the SCLC cell line series GLC14, 16 and 19, derived from a single patient during the clinical course of their disease and the development of chemoresistance, it is shown that there was an increase in responsiveness to neuropeptides. This was paralleled by an increased sensitivity to SP-G. In a selected panel of tumour cell lines (SCLC, non-SCLC, ovarian, colorectal and pancreatic), the expression of the mitogenic neuropeptide receptors for vasopressin, gastrin-releasing peptide (GRP), bradykinin and gastrin was examined, and their sensitivity to SP-G tested in vitro and in vivo. The tumour cell lines displayed a range of sensitivity to SP-G (IC(50) values from 10.5 to 119 microM). The expression of the GRP receptor measured by reverse transcriptase-polymerase chain reaction, correlated significantly with growth inhibition by SP-G. Moreover, introduction of the GRP receptor into rat-1A fibroblasts markedly increased their sensitivity to SP-G. The measurement of receptor expression from biopsy samples by polymerase chain reaction could provide a suitable diagnostic test to predict efficacy to SP-G clinically. This strategy would be of potential benefit in neuropeptide receptor-expressing tumours in addition to SCLC, and in tumours that are relatively resistant to conventional chemotherapy.
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PMID:Increased gastrin-releasing peptide (GRP) receptor expression in tumour cells confers sensitivity to [Arg6,D-Trp7,9,NmePhe8]-substance P (6-11)-induced growth inhibition. 1277 99

To examine the possible role of the bradykinin-NO system in the action of ACE inhibitors, we studied the effects of imidapril, an ACE inhibitor, on inflammatory vascular injury by using AT1a-receptor-deficient (AT1aKO) mice. A polyethylene cuff was placed around the femoral artery of AT1aKO mice and wild-type (WT; C57BL/6J) mice. Neointimal area in cross sections of the artery was measured 14 days after cuff placement. A low dose of imidapril (1 mg/kg per day), which did not affect blood pressure, was administered by gavage. Expression of monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor (TNF)-alpha was detected by immunohistochemical staining and reverse transcriptase-polymerase chain reaction (RT-PCR) 7 days after the operation. Neointimal formation, vascular smooth muscle cell proliferation, and expression of MCP-1 and TNF-alpha were attenuated in the injured artery in AT1aKO mice compared with those in WT mice. Imidapril inhibited neointimal formation, DNA synthesis of vascular smooth muscle cells, and expression of MCP-1 and TNF-alpha in AT1aKO mice as well as in WT mice. In addition, imidapril increased tissue cGMP content after cuff placement. These inhibitory effects of imidapril were significantly reduced or abolished by a bradykinin receptor antagonist, Hoechst 140, or an NO synthase inhibitor, L-NAME, both in WT and AT1aKO mice. Treatment with imidapril did not change AT2 receptor and ACE expression detected by RT-PCR in the injured artery. These results indicate that not only blockade of angiotensin II production but also activation of the bradykinin-NO system plays an important role in the beneficial effects of imidapril on vascular remodeling.
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PMID:Important role of nitric oxide in the effect of angiotensin-converting enzyme inhibitor imidapril on vascular injury. 1296 79

Kawasaki disease (KD) is an acute inflammatory disorder of children frequently associated with the development of coronary artery abnormalities. Although a great deal is known about inflammatory and immune responses in acute KD, the mechanisms linking the immune response to vascular changes are not known. To gain further insight into this process, we performed a microarray gene expression analysis on RNA isolated from the peripheral blood mononuclear cells of four patients with KD during both their acute and convalescent phases. Forty-seven genes of 7129 genes examined showed an increased expression in three or all four patients in the acute compared with the convalescent phase of KD. Fourteen of these genes were significantly (p < 0.05) up-regulated, including several inflammatory response genes (e.g. S-100 A9 protein) and also anti-inflammatory genes (e.g. TSG-6). Of greatest interest, the adrenomedullin (ADM) gene, known to be associated with coronary artery vasodilation, was up-regulated in the acute phase of KD (p = 0.024). Up-regulation of ADM in the acute phase of KD was confirmed in peripheral blood mononuclear cells of 11 additional KD patients by reverse transcriptase-PCR (p < 0.01). Isolated blood monocytes but not lymphocytes were demonstrated by real-time PCR to have increased ADM mRNA (p = 0.01). Plasma ADM protein level in 32 additional KD patients was also confirmed to be higher in acute KD compared with convalescent KD (p < 0.032). It is interesting that from microarray results, other molecules known to be associated with coronary dilation, including nitric oxide, prostacyclin, acetylcholine, bradykinin, substance P, and serotonin, were not elevated in acute KD. Our current study suggests that ADM-expressing monocytes that infiltrate the coronary vascular wall may be the cause of coronary dilation in the acute phase of KD.
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PMID:Adrenomedullin is highly expressed in blood monocytes associated with acute Kawasaki disease: a microarray gene expression study. 1553 34

The use of HIV protease inhibitors (PIs) may be associated with cardiovascular diseases in HIV-infected patients. The objective of this study was to determine the effects of the HIV PI ritonavir on vasomotor function and endothelial nitric oxide synthase (eNOS) expression. Porcine coronary artery rings were incubated with ritonavir for 24 hours. Vasomotor function was studied with a myograph tension system in response to U46619 (contraction), bradykinin (endothelium-dependent relaxation), and sodium nitroprusside (SNP) (endothelium-independent relaxation). The vessel tension contraction after challenge with U46619 showed a significant decrease in 15- and 30-microM ritonavir-treated rings (P < 0.05). In response to bradykinin at 10 M, ritonavir (15 and 30 microM) reduced the relaxation by 27% and 78%, respectively, as compared with controls (P < 0.05). No alterations in the relaxation response were observed in the presence of SNP (10 M). The mRNA and protein levels of eNOS of the artery rings were determined by reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry, respectively. The eNOS mRNA showed a 54% and 65% reduction for 15- and 30-microM ritonavir-treated rings, respectively (P < 0.05). The eNOS protein levels were also substantially decreased in these groups. In parallel, human coronary artery endothelial cells (HCAECs) were studied. HCAECs treated with ritonavir showed significant reductions in mRNA and protein levels of eNOS (P < 0.05). Thus, ritonavir significantly impairs vasomotor function and reduces eNOS expression in porcine coronary artery endothelial cells as well as HCAECs. This study suggests that ritonavir may contribute to coronary artery disease formation in antiviral therapy for HIV-infected patients.
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PMID:Effects of HIV protease inhibitor ritonavir on vasomotor function and endothelial nitric oxide synthase expression. 1590 30

Genistein (4,5,7-trihydroxyisoflavone), a phytoestrogen with selective estrogen receptor modulator properties, has received a great deal of attention over the last few years because of its potentially preventive roles against cardiovascular diseases. However, the precise molecular mechanisms for this modulation are not fully elucidated. In this study, we investigated (both in vivo and in vitro) the relationship between genistein and the changes of angiotensin-converting enzyme (ACE) in rat aortic endothelial cells (RAECs), serum and tissue (aorta). ACE expression was assessed by the immunofluorescence and the reverse transcriptase-polymerase chain reaction (RT-PCR) assay. Serum and tissue ACE activity was detected with a commercial kit. Genistein exhibited a concentration-dependent inhibitory effect on the expression of ACE, particularly at higher concentrations (24.70+/-1.20 at 100microM, P<0.01, and 18.22+/-0.92 at 200microM, P<0.01 compared with the control group 50.49+/-5.19). The estrogen receptor blocker tamoxifen at 100microM attenuated this effect of genistein. The extracellular signal-regulated kinase 1/2 (ERK1/2) blocker PD98059 also markedly inhibited this effect. The observations in vivo were highly consistent with the data in RAECs. These results indicate that genistein inhibits the expression of ACE via estrogen receptor and subsequently ERK1/2 signaling pathway in RAECs. Our results suggest that the down-regulation of ACE with a consequent change in the circulating levels of angiotensin II (Ang II), vasorelaxant angiotensin-(1-7) [Ang-(1-7)] and bradykinin plays an important role in cardiovascular effects of genistein through the ERK1/2 pathway.
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PMID:Effects of genistein on angiotensin-converting enzyme in rats. 1662 61

Kinins are biologically active peptides that are powerful mediators of cellular inflammation. They mimic the cardinal signs of inflammation by inducing vasodilatation and by increasing vascular permeability and pain. Neutrophils are chemoattracted to sites of inflammation by several stimuli. However, the evidence concerning the chemotactic effect of kinin peptides has been contradictory. We analyzed the chemotactic effect of kinin B(1) receptor agonists on neutrophils isolated from peripheral blood of human healthy subjects. Chemotaxis was performed using the migration under agarose technique. To test the effect of B(1) receptor agonists, each assay was carried out overnight at 37 degrees C in 5% CO(2)-95% air on neutrophils primed with 1 ng/ml interleukin-1beta. Simultaneous experiments were performed using unprimed cells or cells challenged with formyl-Met-Leu-Phe (fMLP). A clear chemotactic activity was observed when primed neutrophils were challenged with Lys-des[Arg(9)]-bradykinin (LDBK) or des[Arg(9)]-bradykinin at 10(-10) M but not when unprimed cells were used. A reduction in the chemotactic response was observed after priming of cells in the presence of 0.5 mM cycloheximide and 10 mug/ml brefeldin A, suggesting that some protein biosynthesis is required. Techniques such as reverse transcriptase-polymerase chain reaction and in situ hybridization confirmed the expression of the B(1) receptor mRNA, and immunocytochemistry and autoradiography demonstrated the expression of the B(1) receptor protein. In contrast to other chemoattractants such as fMLP, cytosolic intracellular calcium did not increase in response to the B(1) receptor agonist LDBK. A generation of kinin B(1) receptor agonists during the early phase of acute inflammation may favor the recruitment of neutrophils to the inflammatory site.
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PMID:Activation of kinin B1 receptors induces chemotaxis of human neutrophils. 1667 Jan 23

Small mammalian proteins called the prokineticins [prokineticin 1 (PK1) and PK2] and two corresponding G-protein-coupled receptors [prokineticin receptor 1 (PKR1) and PKR2] have been identified recently, but the physiological role of the PK/PKR system remains mostly unexplored. Bv8, a protein extracted from frog skin, is a convenient and potent agonist for both PKR1 and PKR2, and injection of Bv8 in vivo causes a potent and long-lasting hyperalgesia. Here, we investigate the cellular basis of hyperalgesia caused by activation of PKRs. Bv8 caused increases in [Ca]i in a population of isolated dorsal root ganglion (DRG) neurons, which we identified as nociceptors, or sensors for painful stimuli, from their responses to capsaicin, bradykinin, mustard oil, or proteases. Bv8 enhanced the inward current carried by the heat and capsaicin receptor, transient receptor potential vanilloid 1 (TRPV1) via a pathway involving activation of protein kinase Cepsilon (PKCepsilon), because Bv8 caused translocation of PKCepsilon to the neuronal membrane and because PKC antagonists reduced both the enhancement of current carried by TRPV1 and behavioral hyperalgesia in rodents. The neuronal population expressing PKRs consisted partly of small peptidergic neurons and partly of neurons expressing the N52 marker for myelinated fibers. Using single-cell reverse transcriptase-PCR, we found that mRNA for PKR1 was mainly expressed in small DRG neurons. Exposure to GDNF (glial cell line-derived neurotrophic factor) induced de novo expression of functional receptors for Bv8 in a nonpeptidergic population of neurons. These results show that prokineticin receptors are expressed in nociceptors and cause heat hyperalgesia by sensitizing TRPV1 through activation of PKCepsilon. The results suggest a role for prokineticins in physiological inflammation and hyperalgesia.
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PMID:Sensitization of transient receptor potential vanilloid 1 by the prokineticin receptor agonist Bv8. 1668 2

Bradykinin and its kinin B(2) receptor are autocrine and paracrine mediators in foetal membranes and decidua. As a first step we characterized the intracellular morphology of decidual cells. Cultured decidua tissue-derived cells immunolabel for vimentin fibrils, and are considered to be of mesenchymal origin. They show characteristics of macrophages and can be distinguished from endothelial cells and cells of the trophoblast lineage. These cellular features were determined by means of immunocytochemistry. Furthermore cultured decidua tissue-derived cells express kinin B(2) receptors and in this context we demonstrated its expression at mRNA level by in situ reverse transcriptase polymerase chain reaction. Following stimulation with bacterial lipopolysaccharide, we have observed a marginal upregulation of the expression of kinin B(1) receptors and carboxypeptidase M by quantitative RT-PCR. Equilibrium binding experiments with [(3)H]des-Arg(10)-kallidin, the kinin B(1) receptor agonist, did not result in detectable binding sites.
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PMID:Kinin receptors in stimulated and characterized decidua tissue-derived cells. 1716 23

The aim of this study was to explore the effect of 0NO-54918-07, a stable prostacyclin analogue, on the current-voltage (IV) curve and the intracellular Ca2+ concentration [Ca2+]i of NG108-15 neuroblastoma x glioma hybrid cells. The IV curve was measured with ramp pulses from -70 to 0 mV, and [Ca2+]i was determined with Fura 2. Bath application of 0.2 muM ONO-54918-07 reversibly increased the holding current at -70 mV by -81.1 +/- 14.8 pA (mean +/- SEM, n = 35) and the slope of the IV curve between -70 and -50 mV by the factor 2.24 +/- 0.24. The effect of 0.2 microM prostaglandin PGE1 was similar (DeltaI (hold) = -96.1 +/- 29.9 pA, g/g (control) = 2.72 +/- 0.44, n = 9). ONO-54918-07 concentrations of 0.04, 2 and 6 microM were also effective. From the dose-response curve, the concentration for the half maximal effect was obtained as 0.054 microM. When cells did not respond to ONO-54918-07, an effect could sometimes be elicited by a ramp pulse or by a second ONO-54918-07 application 30-50 min after the first. The effect of ONO-54918-07 was not affected by pre-treatment with the EP1 antagonists ONO-8713 or SC-51089. However, a 14-40 min pre-treatment with 1 microM RO3244794, a selective prostacyclin receptor (IP) antagonist, abolished the effect of 0.2 microM PGE1. The effect of 0.2 microM ONO-54918-07 vanished completely in the presence of 5 microM RO32446794. ONO-54918-07 and PGE1 produced a slow increase in [Ca2+]i that lasted at least 6 min. Delta[Ca2+]i induced by both substances reached approximately 12% of the peak Delta[Ca2+]i induced by application of bradykinin. In only a few cells, PGE1 produced a brief, transient rise of [Ca2+]i. Using reverse transcriptase polymerase chain reaction, a prominent expression of the IP was detected in NG108-15 cells. It is concluded that ONO-54918-07 mimics the effect of PGE1, supporting the notion that the PGE1 effect on NG108-15 cells is mediated by IP receptors.
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PMID:ONO-54918-07, a stable prostacyclin analogue, mimics the effect of prostaglandin PGE1 on NG108-15 cells. 1795 10

Low-frequency ultrasound (LFU) and bradykinin (BK) have been shown separately to increase the permeability of the blood-tumor barrier (BTB) in the rat model of C6 glioma. This study examined the hypothesis that the combination of LFU and low-dose BK has a synergistic effect on increasing the permeability of BTB and explored the possible underlying mechanism including the involvement of tight junction (TJ). The rats were divided into six groups: control group, LFU group, BK group, 2/3LFU + 1/2BK group, 5/6LFU + 2/3BK group, and LFU + BK group. The BTB permeability was assessed by Evans blue extravasation. The mRNA and protein expressions of TJ-related proteins ZO-1, occludin, and claudin-5 were determined by reverse transcriptase-polymerase chain reaction, immunohistochemistry, immunolocalization, and Western blot test. BTB permeability increased in all the experimental groups, accompanied by opening of local TJ of the BTB, observed by transmission electron microscopy, and decreased mRNA and protein expressions of ZO-1, occludin, and claudin-5. In addition, there was a further increase in BTB permeability and a further reduction in the expressions of TJ-related proteins in 5/6LFU + 2/3BK and LFU + BK groups, compared with LFU or BK group. These results indicate that LFU and low-dose BK applied in combination act in a synergistic manner to increase BTB permeability. The down-regulation of TJ-related proteins ZO-1, occludin, and claudin-5 may be one of the underlying mechanisms of the increase in BTB permeability induced by LFU and BK.
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PMID:Synergistic effect of low-frequency ultrasound and low-dose bradykinin on increasing permeability of the blood-tumor barrier by opening tight junction. 1932 37


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