Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017168 (gastroesophageal reflux disease)
 11,783 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitric oxide (NO) has been implicated as a potential causative factor for endogenous p53 mutations in gastrointestinal malignancy. To investigate the role of NO in esophageal adenocarcinoma (EADC), we studied patterns of p53 mutations, expression of inducible nitric oxide synthase (iNOS) and the tissue accumulation of nitrotyrosine (NTS), a stable reaction product of NO and a marker for cellular protein damage, in human premalignant and malignant esophageal epithelia. Tissues were obtained from patients with gastroesophageal reflux disease (GERD)-induced esophagitis (n = 76), Barrett's esophagus (BE; n = 119) and primary EADC (n = 54). DNA sequencing was used to characterize p53 mutations, RT-PCR to study iNOS mRNA expression, and immunohistochemistry to study NTS. Relative to self-matched normal epithelia, a progressive increase in iNOS mRNA expression was seen in GERD (30%; 23/76), BE (48%; 57/119), and EADC (63%; 34/54) tissues (P < 0.001). Among patients with EADC, elevated levels of NTS immunoreactivity were more frequent in tumors with p53 mutations (11/21; 52%) compared with tumors with wild-type p53 (9/33; 27%; P = 0.063), and specifically in tumors with p53 mutations at CpG dinucleotides (10/12; 83%) compared with non-CpG p53 mutations (1/9; 11%; P = 0.008). The increasing frequency of iNOS (mRNA) overexpression in GERD, BE and EADC supports the hypothesis that an active inflammatory process, most likely a consequence of GERD, underlies molecular progression to EADC. The highly significant association between NTS, reflecting chronic NO-induced cellular protein damage, and endogenous p53 mutations at CpG dinucleotides, provides further evidence for a molecular link between chronic inflammation and esophageal malignancy.
Mol Carcinog 2008 Apr
PMID:Inducible nitric oxide synthase, nitrotyrosine and p53 mutations in the molecular pathogenesis of Barrett's esophagus and esophageal adenocarcinoma. 1784 24

Inhibition of gastric acid secretion is the mainstay of the treatment of gastroesophageal reflux disease and peptic ulceration; therapies to inhibit acid are among the best-selling drugs worldwide. Highly effective agents targeting the histamine H2 receptor were first identified in the 1970s. These were followed by the development of irreversible inhibitors of the parietal cell hydrogen-potassium ATPase (the proton pump inhibitors) that inhibit acid secretion much more effectively. Reviewed here are the chemistry, biological targets and pharmacology of these drugs, with reference to their current and evolving clinical utilities. Future directions in the development of acid inhibitory drugs include modifications of current agents and the emergence of a novel class of agents, the acid pump antagonists.
Cell Mol Life Sci 2008 Jan
PMID:Molecular mechanisms in therapy of acid-related diseases. 1792 53

It is anticipated that unraveling the human genome will have a direct impact on the management of specific diseases. Variations or mutations in genes involved in drug metabolism or disease pathophysiology in gastroenterology and hepatology are expected to have effect on response to therapy. The spectrum of diseases is vast. Thus, we focus this review on clinical pharmacogenetics of inflammatory bowel disease, Helicobacter pylori infections, gastroesophageal reflux disease, irritable bowel syndrome, liver transplantation, and colon cancer. Although only a few genotyping tests are used regularly in clinical practice, we anticipate that in the future there will be more routine use of many of the tests described in this review.
Methods Mol Biol 2008
PMID:Pharmacogenomics in gastrointestinal disorders. 1837 Feb 39

Venous leg ulcers are an important medical issue due to their high incidence in the elderly and the lack of a standard curative approach. Apart from surgical therapy, different medical treatments to effect ulcer wound repair and regeneration are currently being investigated. Sucralfate is a cytoprotective agent employed to prevent or treat several gastrointestinal diseases such as gastroesophageal reflux, gastritis, peptic ulcer, stress ulcer and dyspepsia. In this study we evaluated the efficacy, safety and tolerability of topical sucralfate (SUC-LIS 95) on the healing of chronic venous leg ulcers in 50 patients by a double-blind, placebo-controlled, randomized study. Our results indicated that the daily application of SUC-LIS 95 to non-infected post-phlebitis/vascular ulcers, for a median period of 42.0 days, led to complete healing in 95.6% of patients, against only 10.9% of cases with a matched placebo. A significant improvement was obtained in the SUC-LIS 95-treated patient group with regard to local tissue inflammation as well as pain and burning, and consequently, in ulcer size and the evolution of granulation tissue. Our findings were corroborated for selected patients by the morphological analysis of biopsies obtained before and after treatment. Using ultrastructural analysis we demonstrated that the topical use of SUC-LIS 95 was able to affect neoangiogenesis, increase wound contraction, promote re-epithelialization of the wound area and diminish the inflammatory reaction. Overall, our results indicated that patients with chronic venous ulcers show improvement after the use of topical sucralfate.
Int J Mol Med 2008 Jul
PMID:Topical treatment of chronic venous ulcers with sucralfate: a placebo controlled randomized study. 1857 71

Esophageal cancer is a significant worldwide health problem because of its poor prognosis and high incidence in certain parts of the world. Tobacco smoke and alcohol consumption are significant risk factors for esophageal squamous cell carcinoma, whereas frequent gastroesophageal reflux and subsequent inflammatory reactions play a role in causing the adenocarcinoma. Esophageal carcinogenesis involves multiple genetic alterations. A large body of knowledge has been generated regarding molecular alterations associated with esophageal carcinogenesis. These alterations include aberrant cell cycle control, DNA repair, cellular enzymes, growth factor receptors, and nuclear receptors. This chapter reviews the most frequent gene alterations and their correlation with risk factors as well as the prevention strategies in esophageal cancer.
Methods Mol Biol 2009
PMID:Risk factors and gene expression in esophageal cancer. 1910 88

Barrett's oesophagus (BO) and oesophageal adenocarcinoma (OAC) are regarded as complications of gastro-oesophageal reflux disease, although all the factors that contribute to the development of these lesions are unknown. Acid suppressive drugs are widely used for symptomatic therapy of reflux disease but may induce hypersecretion of gastrin peptides. Amidated gastrin (G-17) has been shown to be a growth factor for OAC cells. We have examined the effects of glycine-extended gastrin (G-Gly), an alternative product of progastrin processing on apoptosis in the QhERT Barrett's oesophageal cell line and OE33 and BIC-1 OAC cells. G-Gly inhibited serum-starvation and camptothecin-induced apoptosis in all three cell lines, G-17 was only effective in OE33 cells. By contrast to the effects of G-17, the anti-apoptotic effect of G-Gly was independent of both the CCK(2) receptor and cyclo-oxygenase-2 activity. G-Gly stimulated JAK2 phosphorylation and kinase activity and JAK2-dependent STAT3 phosphorylation and transcriptional activity. G-Gly also increased mRNA and protein levels of the anti-apoptotic proteins survivin and BCL2L1 but did not affect the levels of BAD, BAX or BCL-2. Novel small molecule inhibitors of JAK2 and STAT3 as well as STAT3 siRNA blocked the anti-apoptotic effects of G-Gly and inhibited the induction of survivin and BCL2L1 in OE33 cells. We conclude that G-Gly inhibits apoptosis in BO and OAC via mechanisms distinct from those activated by G-17 and involving JAK2 and STAT3 activation. Release of gastrin peptides in response to acid suppressive therapy may adversely influence the dynamics of the epithelium in BO.
J Mol Endocrinol 2009 Apr
PMID:Glycine-extended gastrin inhibits apoptosis in Barrett's oesophageal and oesophageal adenocarcinoma cells through JAK2/STAT3 activation. 1915 90

Previous studies addressing the effects of acid reflux and PPI therapy on gene expression in oesophageal epithelium concentrated on inflamed tissue. We aimed to determine changes in gene expression in non-inflamed oesophageal epithelium of GERD patients. Therefore, we included 20 GERD patients with pathological total 24-hr acid exposure of 6-12% and SAP > or = 95%. Ten patients discontinued PPI treatment (PPI-), 10 took pantoprazole 40 mg bid (PPI+). Ten age/sex-matched healthy controls were recruited. Biopsies were taken from non-inflamed mucosa 6 cm and 16 cm proximal to the squamocolumnar junction (SCJ). Gene expression profiling of biopsies from 6 cm was performed on Human Genome U133 Plus 2.0 arrays (Affymetrix). Genes exhibiting a fold change >1.4 (t-test P-value < 1(E)- 4) were considered differentially expressed. Results were confirmed by real-time RT-PCR. In PPI- patients, 92 microarray probesets were deregulated. The majority of the corresponding genes were associated with cell-cell contacts, cytoskeletal reorganization and cellular motility, suggesting facilitation of a migratory phenotype. Genes encoding proteins with anti-apoptotic or anti-proliferative functions or stress-protective functions were also deregulated. No probesets were deregulated in PPI+ patients. QPCR analysis of 20 selected genes confirmed most of the deregulations in PPI- patients, and showed several deregulated genes in PPI+ patients as well. In the biopsies taken at 16 cm QPCR revealed no deregulations of the selected genes. We conclude that upon acid exposure, oesophageal epithelial cells activate a process globally known as epithelial restitution: up-regulation of anti-apoptotic, anti-oxidant and migration associated genes. Possibly this process helps maintaining barrier function.
J Cell Mol Med 2009 May
PMID:In GERD patients, mucosal repair associated genes are upregulated in non-inflamed oesophageal epithelium. 1941 90

The mutants P235A and F236A have been generated and their crystal structure was determined to resolutions of 2.38 and 2.35 A, respectively, in order to understand the residues involved in the formation of the novel arched P-loop of subunit A of the A-ATP synthase from Pyrococcus horikoshii OT3. Both the structures show unique, altered conformations for the P-loop. Comparison with the previously solved wild type and P-loop mutant S238A structures of subunit A showed that the P-loop conformation for these two novel mutants occupy intermediate positions, with the wild type fully arched and the well-relaxed S238A mutant structures taking the extreme positions. Even though the deviation is similar for both mutants, the curvature of the P-loop faces the opposite direction. Deviations in the GER-loop, lying above the P-loop, are similar for both mutants, but in F236A, it moves towards the P-loop by around 2 A. The curvature of the loop region V392-V410, located directly behind the P-loop, moves close by 3.6 A towards the P-loop in the F236A structure and away by 2.5 A in the P235A structure. Two major deviations were observed in the P235A mutant, which are not identified in any of the subunit A structures analyzed so far, one being a wide movement of the N-terminal loop region (R90-P110) making a rotation of 80 degrees and the other being rigid-body rotation of the C-terminal helices from Q520-A588 by around 4 degrees upwards. Taken together, the data presented demonstrate the concerted effects of the critical residues P235A, F236, and S238 in the unique P-loop conformation of the A-ATP synthases.
J Mol Biol 2010 Sep 03
PMID:The critical roles of residues P235 and F236 of subunit A of the motor protein A-ATP synthase in P-loop formation and nucleotide binding. 2061 20

Gastroesophageal reflux represents a physiological phenomenon in the first year of life. The reflux associated with clinical complications is defined as "gastroesophageal reflux disease" (GERD), that may be esophageal or extra-esophageal, as is for respiratory problems. Nuclear medicine investigations have given an important contribution to the diagnostic assessment and therapeutical management of GERD in children, by means of the following procedures: scintigraphy of the gastroduodenal transit and reflux detection, scintigraphic quantification of gastric emptying, scintigraphy of the esophageal transit, radioisotopic salivagram, scintigraphy of lung perfusion, ventilation and of mucociliary clearance. All of these investigations are among the less irradiating nuclear medicine procedures, therefore particularly adapted to paediatrics. The main clinical advantages of this body of information include: improvements in the management of many asthmatic children, surgical anti-reflux intervention success-rate increase, prompt regional lung alterations detection for preventing stable tissue damage, and many others.
Q J Nucl Med Mol Imaging 2010 Aug
PMID:Gastro-esophageal studies in relationship to respiratory problems. 2082 5

A metaplastic change where normal squamous mucosa of the esophagus is replaced by columnar mucosa is considered an adaptive process to withstand the chronic gastroesophageal reflux injury. However, this phenotypic switch in the esophageal mucosa is associated with an increased propensity to undergo neoplastic transformation. In this chapter, we review the molecular alterations that are relevant to metaplastic and neoplastic transformations in the esophagus and also discuss the mechanisms that could potentially contribute to this transformation.
Prog Mol Biol Transl Sci 2010
PMID:Molecular determinants of metaplastic and neoplastic transformation in the esophageal epithelium. 2107 40


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