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

Barrett's esophagus is a complication of gastroesophageal reflux disease in which metaplastic, intestinal-type epithelium containing mucin-producing goblet cells with characteristic staining on histology replaces the squamous epithelium normally found in the esophagus. This condition is named after the British thoracic surgeon, N. R. Barrett. Treatment in various stages of the disease continues to provoke controversy. Different surgical procedures are suggested in dysplasia free patients, in low grade dysplasia, high grade dysplasia and adenocarcinoma. Instead of the widely accepted surgical procedure with high grade dysplasia and early carcinoma we suggest an intervention which is oncologically radical, functionally adequate and less inconvenient and stressing for the patients: left side thoraco-laparotomy, distal esophageal and proximal (lesser curvature) gastric resection with adequate lymphadenectomy and reconstruction with esophago-jejuno-gastric interposition.
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PMID:[Surgical management of Barrett's esophagus]. 1655 Jul 96

A 43-year-old white man presented with an 8-month history of redness and swelling on the back of the neck. He also noted a decrease in range of motion of his upper body. There was no improvement with a 4-week course of topical corticosteroids. Review of systems was negative for polydipsia, polyuria, polyphagia, and bone pain. His medical history included depression, gastroesophageal reflux disease, and microdiscectomy. His medications included sertraline and omeprazole. Physical examination revealed a 20-cm erythematous, indurated plaque on the posterior part of the upper back and neck (Figure 1). A lack of skin wrinkling was noted with lateral pressure. Biopsy revealed a periadnexal and mild interface dermatitis with an increase in connective tissue mucin as demonstrated with colloidal iron (Figures 2A and 2B). Serum protein electrophoresis, hemoglobin A1C, and antinuclear antibody titer were within normal limits. A diagnosis of tumid lupus erythematosus mimicking scleredema was made. Hydroxychloroquine therapy was started at a dose of 200 mg and, at 2 months' follow-up, the patient's symptoms and appearance were improved.
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PMID:Tumid lupus erythematosus: an unusual scleredema-like presentation. 1660 43

MUC4 (mucin 4) is a membrane-bound mucin overexpressed in the early steps of oesophageal carcinogenesis and implicated in tumour progression. We previously showed that bile acids, main components of gastro-oesophageal reflux and tumour promoters, up-regulate MUC4 expression [Mariette, Perrais, Leteurtre, Jonckheere, Hemon, Pigny, Batra, Aubert, Triboulet and Van Seuningen (2004) Biochem. J. 377, 701-708]. HNF (hepatocyte nuclear factor) 1alpha and HNF4alpha transcription factors are known to mediate bile acid effects, and we previously identified cis-elements for these factors in MUC4 distal promoter. Our aim was to demonstrate that these two transcription factors were directly involved in MUC4 activation by bile acids. MUC4, HNF1alpha and HNF4alpha expressions were evaluated by immunohistochemistry in human oesophageal tissues. Our results indicate that MUC4, HNF1alpha and HNF4alpha were co-expressed in oesophageal metaplastic and adenocarcinomatous tissues. Studies at the mRNA, promoter and protein levels indicated that HNF1alpha regulates endogenous MUC4 expression by binding to two cognate cis-elements respectively located at -3332/-3327 and -3040/-3028 in the distal promoter. We also showed by siRNA (small interfering RNA) approach, co-transfection and site-directed mutagenesis that HNF1alpha mediates taurodeoxycholic and taurochenodeoxycholic bile acid activation of endogenous MUC4 expression and transcription in a dose-dependent manner. In conclusion, these results describe a new mechanism of regulation of MUC4 expression by bile acids, in which HNF1alpha is a key mediator. These results bring new insights into MUC4 up-regulation in oesophageal carcinoma associated with bile reflux.
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PMID:Regulation of the human mucin MUC4 by taurodeoxycholic and taurochenodeoxycholic bile acids in oesophageal cancer cells is mediated by hepatocyte nuclear factor 1alpha. 1703 83

Tegaserod, a 5-HT4 partial agonist, was shown to reduce esophageal acid exposure in patients with gastroesophageal reflux disease; however, its mechanism of action is poorly understood. Therefore, we have examined the effect of tegaserod on luminal bicarbonate and mucin secretion in the isolated perfused pig esophagus. We also studied its role in esophageal protection using SMG-bearing pig esophagus in comparison to the rabbit esophagus, which is devoid of them. The tissues were mounted in Ussing chambers, and acid injury was replicated by exposing the lumen to acid (pH 1.6) or acid/pepsin (pH 2.5). In pig esophagus, tegaserod increased bicarbonate secretion, but had no effect on basal mucin secretion. In Ussing chambers, tegaserod reduced injury to pig, but not rabbit esophagus exposed to acid (pH 2.5) plus pepsin. These results indicate that tegaserod stimulates SMG bicarbonate secretion, an effect that likely accounts for the observed protection against acid-pepsin injury to pig, but not rabbit, esophagus.
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PMID:The effect of tegaserod on esophageal submucosal glands bicarbonate and mucin secretion. 1827 Aug 37

Melatonin is implicated in sustaining the esophageal integrity in gastro-esophageal reflux disease. However, the role of its synthetic precursor l-tryptophan is not clear in this pathology. The present study was designed to explore the effects of l-tryptophan on esophageal damage following reflux esophagitis (RE)-establishment and concurrent alterations in factors possibly influencing esophageal integrity such as esophageal melatonin level, luminal acidity, H(+)K(+)-ATPase activity, mucin and gastric PGE(2) levels. RE was established in rats by simultaneous ligation of pylorus region and fore-stomach. RE significantly decreased the esophageal-melatonin level and the expression of its synthesizing enzymes: arylalkylamine-N-acetyltransferase (AA-NAT) and hydroxyindole-O-methyltransferase (HIOMT). Administration of l-tryptophan significantly decreased the RE-induced esophageal mucosal damage, without altering the levels of melatonin. l-Tryptophan pretreatment also normalized the esophageal mucosal damage caused by melatonin receptor antagonist-luzindole. Simultaneously, l-tryptophan significantly increased the RE-decreased expression of AA-NAT with insignificant effect on HIOMT gene expression. In contrast, l-tryptophan per se caused a significant elevation in the esophageal melatonin level, with no significant effect on the expression of AA-NAT and HIOMT enzymes. Further, l-tryptophan significantly normalized the RE-induced changes in the gastric juice volume, acidity and pH. However, it did not significantly inhibit the H(+)K(+)-ATPase activity in vitro. Also, l-tryptophan significantly increased the RE-reduced mucin level, COX-2 activity and thereby PGE(2) levels. Interestingly, indomethacin (PGE(2) synthesis blocker), aggravated the RE-induced tissue injury with simultaneous changes in the gastric volume, acidity, pH and mucin content, which l-tryptophan failed to reverse, suggesting that the attenuating effect of l-tryptophan on gastric secretions could be PGE(2) driven. Thus the current study provide evidences that protective functions of l-tryptophan against RE is independent of its conversion into melatonin, and possibly involve mobilization of factors such as COX-2 derived PGE(2) and mucin that counterbalance the detrimental effect of gastric acid on esophageal mucosa, signifying the therapeutic efficacy of l-tryptophan against the esophageal pathologies.
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PMID:Melatonin independent protective role of l-tryptophan in experimental reflux esophagitis in rats. 2152 45

Esophageal adenocarcinoma (EAC) has become a major concern in Western countries due to rapid rises in incidence coupled with very poor survival rates. One of the key risk factors for the development of this cancer is the presence of Barrett's esophagus (BE), which is believed to form in response to repeated gastro-esophageal reflux. In this study we performed comparative, genome-wide expression profiling (using Illumina whole-genome Beadarrays) on total RNA extracted from esophageal biopsy tissues from individuals with EAC, BE (in the absence of EAC) and those with normal squamous epithelium. We combined these data with publically accessible raw data from three similar studies to investigate key gene and ontology differences between these three tissue states. The results support the deduction that BE is a tissue with enhanced glycoprotein synthesis machinery (DPP4, ATP2A3, AGR2) designed to provide strong mucosal defenses aimed at resisting gastro-esophageal reflux. EAC exhibits the enhanced extracellular matrix remodeling (collagens, IGFBP7, PLAU) effects expected in an aggressive form of cancer, as well as evidence of reduced expression of genes associated with mucosal (MUC6, CA2, TFF1) and xenobiotic (AKR1C2, AKR1B10) defenses. When our results are compared to previous whole-genome expression profiling studies keratin, mucin, annexin and trefoil factor gene groups are the most frequently represented differentially expressed gene families. Eleven genes identified here are also represented in at least 3 other profiling studies. We used these genes to discriminate between squamous epithelium, BE and EAC within the two largest cohorts using a support vector machine leave one out cross validation (LOOCV) analysis. While this method was satisfactory for discriminating squamous epithelium and BE, it demonstrates the need for more detailed investigations into profiling changes between BE and EAC.
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PMID:Whole genome expression array profiling highlights differences in mucosal defense genes in Barrett's esophagus and esophageal adenocarcinoma. 2182 65

MUC4 is a membrane-bound mucin known to participate in tumor progression. It has been shown that MUC4 pattern of expression is modified during esophageal carcinogenesis, with a progressive increase from metaplastic lesions to adenocarcinoma. The principal cause of development of esophageal adenocarcinoma is the gastro-esophageal reflux, and MUC4 was previously shown to be upregulated by several bile acids present in reflux. In this report, our aim was thus to determine whether MUC4 plays a role in biological properties of human esophageal cancer cells. For that stable MUC4-deficient cancer cell lines (shMUC4 cells) were established using a shRNA approach. In vitro (proliferation, migration and invasion) and in vivo (tumor growth following subcutaneous xenografts in SCID mice) biological properties of shMUC4 cells were analyzed. Our results show that shMUC4 cells were less proliferative, had decreased migration properties and did not express S100A4 protein when compared with MUC4 expressing cells. Absence of MUC4 did not impair shMUC4 invasiveness. Subcutaneous xenografts showed a significant decrease in tumor size when cells did not express MUC4. Altogether, these data indicate that MUC4 plays a key role in proliferative and migrating properties of esophageal cancer cells as well as is a tumor growth promoter. MUC4 mucin appears thus as a good therapeutic target to slow-down esophageal tumor progression.
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PMID:The MUC4 membrane-bound mucin regulates esophageal cancer cell proliferation and migration properties: Implication for S100A4 protein. 2188 95

Acid, pepsin and other noxious material reach the esophageal mucosa and interact with the luminal aspect of the squamous epithelium. The first protective barrier to these potentially injurious substances is the mucus buffer layer that covers the mucosa. In healthy people, the esophagus has a protective surface adherent mucus gel barrier. Levels of mucin glycoprotein are considerably increased in response to acid and pepsin. A wide spectrum of mucin genes are expressed in normal esophageal mucosa, squamous cell carcinoma of the esophagus, Barrett epithelium and esophageal adenocarcinoma. The mucins MUC5AC and MUC6 are expressed to a similar degree in Barrett metaplasia and gastric mucosa, as is MUC2 in Barrett intestinal metaplasia and small bowel mucosa. Increased expression of MUC1 is associated with progression from dysplasia to adenocarcinoma of the esophagus. Thus, mucins have an important role in the defense of esophageal mucosa against the acid, pepsin and bile that are present in the refluxate. Changes in the expression of mucins occur in patients with GERD, and might lead to the development of new drugs.
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PMID:The role of mucin in GERD and its complications. 2206 20

Mucin hypersecretion is a key pathological feature of inflammatory respiratory diseases. Previous studies have reported that acids (gastroesophageal reflux or environmental exposure) induce many respiratory symptoms and are implicated in the pathophysiology of obstructive airway diseases. To understand these mechanisms, we measured acid-induced mucin secretion in human bronchial epithelial cells. In the present study, acid induced inward currents of transient receptor potential vanilloid (TRPV)1 and mucin 5AC (MUC5AC) secretion dose dependently, which were inhibited by TRPV1 antagonist capsazepine in a concentration-dependent manner. TRPV1 agonist capsaicin mediated a concentration-dependent increase in TRPV1 inward currents and MUC5AC secretion. Furthermore, capsaicin enhanced acid-induced TRPV1 inward currents and MUC5AC secretion. Acid-induced Ca(2+) influx was prevented by capsazepine dose dependently and enhanced by capsaicin. Pretreatment only with capsaicin also increased the Ca(2+) concentration in a concentration-dependent manner. These data suggest that pharmacological inhibition of calcium-permeable TRPV1 receptors could be used to prevent acid-induced mucin secretion, thereby providing a potential mechanism to reduce their toxicity.
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PMID:Transient receptor potential vanilloid 1 receptors mediate acid-induced mucin secretion via Ca2+ influx in human airway epithelial cells. 2256 28

MUC1 is a membrane-bound mucin known to participate in tumor proliferation. It has been shown that MUC1 pattern of expression is modified during esophageal carcinogenesis, with a progressive increase from metaplasia to adenocarcinoma. The principal cause of development of esophageal adenocarcinoma is gastro-esophageal reflux and MUC1 was previously shown to be up-regulated by several bile acids present in reflux. In this report, our aim was thus to determine whether MUC1 plays a role in biological properties of human esophageal cancer cells. For that, a stable MUC1-deficient esophageal cancer cell line was established using a shRNA approach. In vitro (proliferation, migration and invasion) and in vivo (tumor growth following subcutaneous xenografts in SCID mice) biological properties of MUC1-deficient cells were analyzed. Our results show that esophageal cancer cells lacking MUC1 were less proliferative and had decreased migration and invasion properties. These alterations were accompanied by a decreased activity of NFKB p65, Akt and MAPK (p44/42, JNK and p38) pathways. MCM6 and TSG101 tumor-associated markers were also decreased. Subcutaneous xenografts showed a significant decrease in tumor size when cells did not express MUC1. Altogether, the data indicate that MUC1 plays a key role in proliferative, migrating and invasive properties of esophageal cancer cells as well as in tumor growth promotion. MUC1 mucin appears thus as a good therapeutic target to slow down esophageal tumor progression.
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PMID:The MUC1 mucin regulates the tumorigenic properties of human esophageal adenocarcinomatous cells. 2500 15


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