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)

The gene encoding amylin is implicated in the generation of amyloid in the islets of Langerhans of diabetics and is believed to be regulated by the homeodomain transcription factor PDX-1. Although gastric mucosa also produces amylin, studies on its cellular site of production have yielded highly divergent results, localizing this peptide to either gastrin, serotonin, or somatostatin cells or to combinations thereof. Using region-specific amylin antisera in combination with reverse transcriptase-polymerase chain reaction, we now document that the majority of cells expressing amylin correspond to somatostatin cells. Only a small subpopulation of gastrin cells contained immunoreactive amylin. Studies of PDX-1-deficient mice, which fail to develop gastrin cells while possessing normal numbers of somatostatin cells, revealed no detectable change in gastric amylin expression. These data show that neither normal gastrin cell development nor PDX-1 expression is needed for gastric amylin expression.
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PMID:Gastric amylin expression. Cellular identity and lack of requirement for the homeobox protein PDX-1. A study in normal and PDX-1-deficient animals with a cautionary note on antiserum evaluation. 1042 81

Gastrin stimulates gastric acid secretion by acting on the cholecystokinin B/gastrin receptor (CCK-BR). The localization of this receptor at the cellular level showed conflicting results in animal studies and has not been described in man by immunohistochemistry. The aim of the present study is to characterize the precise cellular location of the CCK-BR in the human stomach. Polyclonal antisera were raised against different epitopes of the CCK-BR molecule and used for immunohistochemical investigations. CCK-BR mRNA was detected in paraffin tissue sections by the highly sensitive method of in situ reverse transcriptase-polymerase chain reaction (RT-PCR). Using immunohistochemistry, CCK-BR could successfully be localized in gastric parietal cells. In the majority of parietal cells, CCK-BR immunoreactivity was present a he basolateral cell membrane domain. In some parietal cells, a granular pattern of immunoreactivity was exclusively confined to the cytoplasm of the cells. CCK-BR mRNA was found in parietal cells and in enterochromaffin-like (ECL) cells by means of in situ RT-PCR. No expression of CCK-BR was found in the gastric antral mucosa. Our data support the concept that gastrin stimulates gastric acid secretion directly via CCK-B receptors on parietal cells and indirectly by inducing histamine release from histamine-containing ECL cells, which contributes to acid secretion by parietal cells.
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PMID:Expression and cell-specific localization of the cholecystokinin B/gastrin receptor in the human stomach. 1074 70

gamma-Aminobutyric acid (GABA) is a neurotransmitter that also occurs in a few non-neuronal cell types, where it may serve as a paracrine modulator. GABA is biosynthesized from glutamate by glutamate decarboxylase (GAD) and from putrescine via diamine oxidase (DAO). GAD is demonstrable in several GABA-positive cell types but is undetectable in the GABA-containing gastrin cells and somatostatin cells of the antropyloric mucosa of the stomach. Using two antisera raised against synthetic peptides corresponding to two different regions of rat DAO, we now demonstrate strong reactivity for DAO in gastrin-positive cells of the rat antropyloric mucosa, whereas somatostatin-positive cells as well as other structures of the antrum are unreactive. Western blotting analysis of antrum and colon demonstrate that both antisera react with a single band of 85 kD, consistent with the predicted molecular weight of DAO. Expression of DAO mRNA in the antrum is demonstrated by reverse transcriptase polymerase chain reaction (RT-PCR). Our results strongly indicate that gastrin cells produce GABA via DAO-catalyzed oxidation of putrescine, and experimental data moreover suggest that the biosynthesis of GABA is regulated by the prandial state. Because GABA modulates release of somatostatin, these results point to a new mechanism of paracrine interaction between gastrin cells and somatostatin cells.
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PMID:Immunocytochemical evidence suggesting that diamine oxidase catalyzes biosynthesis of gamma-aminobutyric acid in antropyloric gastrin cells. 1082 Jan 57

Although physiological functions of the CCK-B/gastrin receptor are well explored, little is known about its role during healing. Here, we evaluated the role of this receptor in the rat oxyntic mucosa following the introduction of a cryoulcer. In this model, we located and quantified CCK-B/gastrin receptors by reverse transcriptase PCR and receptor autoradiography. Rats with cryoulcers were treated with placebo, omeprazole, the CCK-B/gastrin receptor antagonist YF-476, omeprazole plus YF-476, gastrin-17, and gastrin 17 plus YF-476. During wound healing, CCK-B/gastrin receptors were specifically expressed and localized to the regenerative mucosal ulcer margin. This high expression was limited in time, and the pattern of expression of CCK-B/gastrin receptors correlated closely with the proliferative activity of the regenerative mucosa. Functionally, omeprazole and gastrin-17 caused profound hypergastrinemia, increased cell proliferation in the mucosal ulcer margin and accelerated the late ulcer healing phase. These effects were completely reversed by cotherapy with YF-476. These in vivo and vitro data suggest that CCK-B/gastrin receptors in regenerative rat gastric oxyntic mucosa enhance trophic effects during wound healing.
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PMID:Cholecystokinin-B/gastrin receptors enhance wound healing in the rat gastric mucosa. 1103 62

Small-cell lung cancer (SCLC) synthesises a wide range of neuropeptides and their corresponding receptors. Together, these can form autocrine growth loops. Non-small-cell lung cancer (NSCLC) does not generally share this neuroendocrine phenotype. In this study, we tested the hypothesis that multiple neuropeptides and their receptors are co-expressed in SCLC, constituting potential autocrine loops. Expression of mRNA for arginine vasopressin, gastrin, cholecystokinin, gastrin-releasing peptide, endothelin and neurotensin, together with their cognate receptors, was evaluated by reverse transcriptase-polymerase chain reaction (RT-PCR) in a panel of human lung cancer cell lines. We have assessed those neuropeptides and neuropeptide receptors that could be used as potential early markers to detect lung cancer cells both as micrometastases in blood and within dysplasia in bronchial biopsies. We establish that although no cell line expressed all neuropeptides, co-expression of neuropeptides and their receptors is common in SCLC but not in NSCLC. We conclude that mRNA for the neuropeptides gastrin-releasing peptide and arginine vasopressin and the cholecystokinin receptor B were most SCLC-specific and RT-PCR for these markers could be used to distinguish between SCLC and NSCLC.
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PMID:Use of RT-PCR to detect co-expression of neuropeptides and their receptors in lung cancer. 1142 90

Acid secretion first appears in the stomach during the later stages of fetal development. Gastric acid secretion is regulated by the stimulatory effects of gastrin, histamine, acetylcholine and the inhibitory actions of somatostatin on their respective receptors. A semi-quantitative reverse transcriptase-polymerase chain reaction method for the determination of changes in mRNA expression for these receptors was developed and correlated with known changes in gastric acidity. Glyceraldehyde-3-phosphate dehydrogenase (GAP-DH) was used as a reference and an internal standard. The antrum and fundus from four age groups were assayed: 80 days of gestation, 110 days of gestation, term (145 days) and adult animals. The CCK B/gastrin and the histamine (H(2)) receptor mRNA were significantly lower in samples from the fundus of fetuses, from 80 and 110 days of gestation when compared with the adult fundus. Histamine receptor mRNA in the antrum was also significantly lower in the 80 and 110 days of gestation samples relative to the term fetal antrum. Somatostatin II receptor mRNA levels in the antrum decreased with increasing age with no change in the fundus. These findings suggest that changes in receptor gene expression, may be responsible for the diminished gastric acidity and responsiveness observed in the fetal stomach.
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PMID:Expression of receptors regulating gastric acidity in the developing sheep stomach. 1149 84

Helicobacter pylori (HP) infection is usually accompanied by an increased plasma level of gastrin, a potent mitogen able to induce cyclooxygenase (COX)-2. This study examined (a) the seroprevalence of HP, its cytotoxic protein, CagA, and cytokines (tumor necrosis factor alpha, interleukins 1beta and 8) in 80 patients with colorectal cancers, before and after the removal of tumor, compared with 160 age- and gender-matched controls; (b) the gene expression of gastrin and its receptors (CCKB-R) in the cancer tissue, (c) the plasma levels and tumor tissue contents of gastrin, and (d) the mRNA expression of COX-1, COX-2, and apoptotic proteins (Bax and Bcl2) in cancer tissue and intact colonic mucosa. Anti-HP IgG, anti-CagA IgG seroprevalence, and cytokine levels were analyzed by enzyme-linked immunosorbent assay tests; gene expressions of gastrin, CCKB-R, COX-1, COX-2, Bax, and Bcl2 by reverse transcriptase polymerase chain reaction; and gastrin by radioimmunoassay. The seroprevalence of HP, especially that expressing CagA, was significantly higher in cancer patients than in controls and did not change 1 week after tumor resection while plasma cytokines were significantly reduced after this operation. Both gastrin and CCKB-R mRNA were detected in the cancer tissue and the resection margin; similarly, COX-2 mRNA was expressed in most of cancers and their resection margin but not in intact colonic mucosa, where only COX-1 was detected. The colorectal cancer tissue contained several folds more immunoreactive gastrin than cancer resection margin and many folds more than the intact colonic mucosa. We conclude that colon adenocarcinoma and its resection margin overexpress gastrin, its receptors, CCKB-R, and COX-2, and that HP infection may contribute to colonic cancerogenesis via overexpression of gastrin and COX-2, which may account for the stimulation of the tumor growth and the reduction in apoptosis as documented by enhanced mRNA expression of anti-apoptotic Bcl2 over proapoptotic Bax proteins.
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PMID:Helicobacter pylori infection, gastrin, cyclooxygenase-2, and apoptosis in colorectal cancer. 1151 78

Melatonin, a major hormone of pineal gland, was recently shown to attenuate acute gastric lesions induced by strong irritants because of the scavenging of free radicals but its role in ulcer healing has been little investigated. In this study we compared the effects of intragastric (i.g.) administration of melatonin and its precursor, L-tryptophan, with or without concurrent treatment with luzindole, a selective antagonist of melatonin MT2 receptors, on healing of chronic gastric ulcers induced by serosal application of acetic acid (ulcer area 28 mm2). The involvement of endogenous prostaglandins (PG), nitric oxide (NO) and sensory nerves in ulcer healing action of melatonin and L-tryptophan was studied in rats treated with indomethacin and NG-nitro-L-arginine (L-NNA) to suppress, respectively, cyclo-oxygenases (COX) and NO synthases or in those with functionally deactivated sensory nerves with capsaicin. The influence of melatonin on gastric secretion during ulcer healing was tested in separate group of rats with gastric ulcer equipped with gastric fistulas (GF). At day 8 and 15 upon the ulcer induction, the area of gastric ulcers was measured by planimetry, the mucosal blood flow (GBF) was determined by H2-gas clearance technique and gastric luminal NO2-/NO3- levels was assessed by Griess reaction. Plasma melatonin and gastrin levels were measured by specific radioimmunoassay (RIA). Biopsy mucosal samples were taken for expression of constitutive NO-synthase (cNOS) and inducible NOS (iNOS) by reverse transcriptase-polymerase chain reaction (RT-PCR). Melatonin (2.5-20 mg/kg-d i.g.) and L-tryptophan (25-100 mg/kg-d i.g.) dose-dependently accelerated ulcer healing, the dose inhibiting by 50% (ED50) of ulcer area being 10 and 115 mg/kg, respectively. This inhibitory effect of melatonin (10 mg/kg-d i.g.) and L-tryptophan (100 mg/kg-d i.g.) on ulcer healing was accompanied by a significant rise in the GBF at ulcer margin and an increase of plasma melatonin. luminal NO2-/NO3- and plasma gastrin levels. Gastric acid and pepsin outputs were significantly inhibited during the ulcer healing in melatonin-treated gastric mucosa as compared with those in vehicle-treated animals. Luzindole abolished completely the healing effects of melatonin and L-tryptophan and attenuated significantly the rise in plasma gastrin evoked by the hormone and its precursor. Indomethacin (5 mg/kg-d i.p). that blocked PG biosynthesis by 90% or L-NAME (20 mg/kg i.v), inhibitor of NOS. that suppressed luminal NO release, attenuated significantly melatonin and L-tryptophan-induced acceleration of ulcer healing and accompanying rise in GBF at ulcer margin and luminal NO release. The melatonin-induced acceleration of ulcer healing, hyperemia at ulcer margin and increase in the release of NO were enhanced when L-arginine but not D-arginine was added to L-NAME. The ulcer healing and the GBF effects of melatonin and L-tryptophan were significantly impaired in rats with capsaicin-induced denervation of sensory nerves and both, ulcer healing and the hyperemia at ulcer margin were restored in these rats by addition of exogenous CGRP to melatonin and L-tryptophan. Expression of cNOS mRNA was detected by RT-PCR in the intact gastric mucosa as well as at the edge of gastric ulcers treated with both, vehicle and melatonin, while iNOS mRNA that was undetectable in the intact gastric mucosa, appeared during ulcer healing and especially this was strongly up-regulated in the melatonin-treated gastric mucosa. We conclude that (1) exogenous melatonin and that derived from its precursor, L-tryptophan, accelerate ulcer healing probably via interaction with MT2 receptors; (2) this ulcer healing action is caused by an enhancement by melatonin of the microcirculation at the ulcer margin possibly mediated by COX-derived PG and NO because of overexpression of iNOS and (3) gastrin, which exhibits trophic activity in the gastric mucosa and calcitonin gene related peptide (CGRP), released from sensory nerves, may also contribute to the ulcer healing action of melatonin.
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PMID:Role of prostaglandins, nitric oxide, sensory nerves and gastrin in acceleration of ulcer healing by melatonin and its precursor, L-tryptophan. 1207 98

[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

Melatonin attenuates acute gastric lesions induced by topical strong irritants because of scavenging of free radicals, but its role in the pathogenesis of stress-induced gastric lesions has been sparingly investigated. In this study we compared the effects of intragastric (i.g.) or intracerebroventricular (i.c.v.) administration of melatonin and its precursor, L-tryptophan, with or without concurrent treatment with luzindole, a selective antagonist of melatonin MT2 receptors, on gastric lesions induced by water immersion and restraint stress (WRS). The involvement of pineal gland, endogenous prostaglandins (PG) and sensory nerves in gastroprotective action of melatonin and L-tryptophan against WRS was studied in intact or pinealectomized rats or those treated with indomethacin or rofecoxib to suppress cyclooxygenase (COX)-1 and COX-2, respectively, and with capsaicin to induce functional ablation of the sensory nerves. In addition, the influence of i.c.v. and i.g. melatonin on gastric secretion was tested in a separate group of rats equipped with gastric fistulas. At 3.5 hr after the end of WRS, the number of gastric lesions was counted, the gastric blood flow (GBF) was determined by H2-gas clearance technique and plasma melatonin and gastrin levels were measured by specific radioimmunoassay (RIA). Biopsy mucosal samples were taken for determination of expression of mRNA for COX-1 and COX-2 by reverse transcriptase-polymerase chain reaction (RT-PCR) and of the mucosal generation of prostaglandin E2 (PGE2) by RIA. Melatonin applied i.g. (1.25-10 mg/kg) or i.c.v. (1.25-10 microg/kg) dose-dependently inhibited gastric acid secretion and significantly attenuated the WRS-induced gastric damage. This protective effect of melatonin was accompanied by a significant rise in the GBF and plasma melatonin and gastrin levels and in mucosal generation of PGE2. Pinealectomy, which suppressed plasma melatonin levels, aggravated the gastric lesions induced by WRS and these effects were counteracted by i.g. or i.c.v. application of melatonin. Luzindole abolished completely the gastroprotective effects of melatonin and L-tryptophan and attenuated significantly the rise in GBF evoked by the indoleamine and its precursor. Indomethacin and rofecoxib, which diminished PGE2 biosynthesis by c. 90 and 75% or capsaicin denervation, attenuated significantly melatonin- and L-tryptophan-induced protection and the rise in the GBF. Both the protection and the hyperemia were restored by addition of exogenous CGRP to capsaicin-denervated animals. COX-1 mRNA was detected by RT-PCR in the intact and melatonin-treated gastric mucosa, while COX-2 mRNA, which was undetectable in the intact gastric mucosa, appeared in WRS-exposed mucosa, especially in the melatonin-treated animals and this was accompanied by increased generation of PGE2 in gastric mucosa. Pinealectomy downregulated COX-2 mRNA and this effect was reversed by supplementation of pinealectomized animals with melatonin. We conclude that, (a) exogenous melatonin and its precursor, L-tryptophan, attenuates WRS-induced gastric lesions via interaction with MT2 receptors, (b) this protective action of melatonin is because of an enhancement of gastric microcirculation, probably mediated by PGE2 derived from COX-2 overexpression and activity, the activation of brain-gut axis involving CGRP released from sensory nerves, and the release of gastrin and (c) the pineal plays an important role in the limitation of WRS-induced gastric lesions via releasing melatonin, which exerts gastroprotective and hyperemic activities against stress ulcerogenesis.
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PMID:Importance of the pineal gland, endogenous prostaglandins and sensory nerves in the gastroprotective actions of central and peripheral melatonin against stress-induced damage. 1620 93


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