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Background: Previously, we showed that M3 muscarinic receptor (M3R; gene name Chrm3) deficiency attenuates murine intestinal neoplasia, supporting the hypothesis that muscarinic receptors play an important role in intestinal tumorigenesis. Methods: To test this hypothesis, in the present study we treated mice with bethanechol, a non-selective muscarinic receptor agonist without nicotinic receptor activity, and examined its effects on azoxymethane (AOM)-induced colon neoplasia. Mice were provided with drinking water containing 400 μg/mL bethanechol chloride or water without additions (control) for a total of 20 weeks, a period that included the initial 6 weeks when mice received intraperitoneal injections of AOM. Results: When euthanized at week 20, control mice had 8.0 ± 1.3 tumors per animal, whereas bethanechol-treated mice had 10.4 ± 1.5 tumors per mouse (mean ± SE; P = 0.023), a 30% increase. Strikingly, tumor volume per animal was increased 52% in bethanechol-treated compared with control mice (179.7 ± 21.0 vs. 111. 8 ± 22.4 mm3; P = 0.047). On histological examination, bethenechol-treated mice also had more adenocarcinomas per animal (8.0 ± 1.0 vs. 4.1 ± 0.6 for control mice, P = 0.0042). Cell proliferation in both normal mucosa and adenocarcinomas was increased in bethanechol-treated compared to control mice. Also, in tumors, bethanechol treatment increased expression of Chrm3, Egfr and post-Egfr signaling molecules Myc and cyclin D1. Bethanechol treatment increased the thickness of normal colonic mucosa and the expression of selected matrix metalloproteinase (Mmp) genes, including Mmp7, Mmp10 and Mmp13. Conclusions: These findings support a prominent role for muscarinic receptors in colon neoplasia, and identify post-receptor signaling molecules as potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Purpose: To synthesize a trifluorinated bile acid that can be used for F magnetic resonance imaging (MRI) of bile acid enterohepatic circulation, characterize its in vitro transporter affinity, stability, and F-MRI signal, and assess its ability to concentrate in the gallbladder of C57BL/6 mice. Methods: Target compound CA-lys-TFA was synthesized and tested for affinity toward the apical sodium dependent bile acid transporter (hASBT) and the Na+/taurocholate cotransporting polypeptide (hNTCP). In a pilot study, fasted mice were gavaged with vehicle control, 150 mg/kg or 300 mg/kg CA-lys-TFA. CA-lys-TFA in gallbladder, liver and plasma at t = 5 h was quantified. Additionally, a 24-h time course (24 mice across eight time points) was studied using 50 mg/kg CA-lys-TFA. Results: CA-lys-TFA was a potent substrate of hASBT (Kt = 39.4 μM, normalized Vmax = 0.853) and hNTCP (Kt = 8.99 μM, normalized Vmax = 0.281). F MRI phantom imaging showed linear signal-concentration dependence. In vivo studies showed that rapid accumulation of CA-lys-TFA in the gallbladder was maximal within 4-7 h. Conclusions: These findings suggest that CA-lys-TFA, a fluorinated non-radioactive bile acid analogue, has potential for use in MRI to measure in vivo bile acid transport and diagnose bile acid malabsorption and other conditions associated with impaired bile acid transport. [ABSTRACT FROM AUTHOR]

Besides its essential role in controlling bile acid and lipid metabolism, the farnesoid X receptor (FXR) protects against intestinal tumorigenesis by promoting apoptosis and inhibiting cell proliferation. However, the mechanisms underlying these anti-proliferative actions of FXR remain to be elucidated. In the present study, we examined the effects of FXR activation (FXR overexpression and treatment with an FXR agonist GW4064) and inactivation (treatment with FXR siRNA and an FXR antagonist guggulsterone) on colon cancer cell proliferation in vitro using human colon cancer cell lines (H508, SNU- C4 and HT-29) and in vivo using xenografts in nude mice. Blocking FXR activity with guggulsterone stimulated time- and dose-dependent EGFR (Tyr845) phosphorylation and ERK activation. In contrast, FXR overexpression and activation with GW4064 attenuated cell proliferation by down-regulating EGFR (Tyr845) phosphorylation and ERK activation. Treatment with guggulsterone and GW4064 also caused dose-dependent changes in Src (Tyr416) phosphorylation. In stably- transfected human colon cancer cells, overexpression of FXR reduced EGFR, ERK, Src phosphorylation and cell proliferation, and in nude mice attenuated the growth of human colon cancer xenografts (64% reduction in tumor volume; 47% reduction in tumor weight; both P<0.01). Moreover, guggulsterone-induced EGFR and ERK phosphorylation and cell proliferation were abolished by inhibiting activation of Src, EGFR and MEK. Collectively these data support the novel conclusion that in human colon cancer cells Src-mediated cross-talk between FXR and EGFR modulates ERK phosphorylation, thereby regulating intestinal cell proliferation and tumorigenesis. [ABSTRACT FROM AUTHOR]

The aryl hydrocarbon receptor (AhR) mediates many toxic effects of environmental pollutants. AhR also interacts with multiple growth factor-driven signaling pathways. In the course of examining effects of growth factors on proliferation of human colon cancer cells, we identified cross talk between AhR and the epidermal growth factor receptor (EGFR). In the present work, we explored underlying signal transduction mechanisms and functional consequences of this interaction. With the use of two human colon cancer cell lines, H508 and SNU-C4, we examined the effects of AhR ligands including 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) on cell proliferation and activation of EGFR, ERK1/2, and Src kinases. In colon cancer cells, 5-day incubation with TCDD stimulated a twofold dose-dependent increase in cell proliferation that was detectable with 1 nM and maximal with 30 nM TCDD. TCDD induced dose- and time-dependent phosphorylation of EGFR (Tyr845) and ERK1/2; maximal phosphorylation was observed 5 to 10 min after addition of 30 nM TCDD. Both TCDD-induced ERK1/2 phosphorylation and cell proliferation were abolished by AhR small interfering RNA, AhR-specific inhibitor CH223191, Src kinase inhibitor PP2, neutralizing antibodies against matrix metalloproteinase 7, heparin-binding-EGF-like growth factor and EGFR, EGFR inhibitors (AG1478 and PD168393), and MEK1 inhibitor PD98059. Coimmunoprecipitation experiments revealed that AhR forms a protein complex with Src and regulates Src activity by phosphorylating Src (Tyr416) and dephosphorylating Src (Tyr527). These data support novel observations that, in human colon cancer cells, Src-mediated cross talk between aryl hydrocarbon and EGFR results in ERK1/2 activation, thereby stimulating cell proliferation. [ABSTRACT FROM AUTHOR]

M3 subtype muscarinic receptors (CHRM3) are over-expressed in colon cancer. In this study, we used Apcmin/+ mice to identify the role of Chrm3 expression in a genetic model of intestinal neoplasia, explored the role of Chrm3 in intestinal mucosal development and determined the translational potential of inhibiting muscarinic receptor activation. We generated Chrm3-deficient Apcmin/+ mice and compared intestinal morphology and tumor number in 12-week-old Apcmin/+Chrm3−/− and Apcmin/+Chrm3+/+ control mice. Compared with Apcmin/+Chrm3+/+ mice, Apcmin/+Chrm3−/− mice showed a 70 and 81% reduction in tumor number and volume, respectively (P < 0.01). In adenomas, β-catenin nuclear staining was reduced in Apcmin/+Chrm3−/− compared with Apcmin/+Chrm3+/+ mice (P < 0.02). Whereas Apc gene mutation increased the number of crypt and Paneth cells and decreased villus goblet cells, these changes were absent in Apcmin/+Chrm3−/− mice. To determine whether pharmacological inhibition of muscarinic receptor activation attenuates intestinal neoplasia, we treated 6-week-old Apcmin/+ mice with scopolamine butylbromide, a non-subtype-selective muscarinic receptor antagonist. After 8 weeks of continuous treatment, scopolamine butylbromide-treated mice showed a 22% reduction in tumor number (P = 0.027) and a 36% reduction in tumor volume (P = 0.004) as compared with control mice. Compared with Chrm3 gene ablation, the muscarinic antagonist was less efficacious, most probably due to shorter duration of treatment and incomplete blockade of muscarinic receptors. Overall, these findings indicate that interplay of Chrm3 and β-catenin signaling is important for intestinal mucosal differentiation and neoplasia and provide a proof-of-concept that pharmacological inhibition of muscarinic receptor activation can attenuate intestinal neoplasia in vivo. [ABSTRACT FROM AUTHOR]

Previously, we showed that ACh-induced proliferation of human colon cancer cells is mediated by transactivation of epidermal growth factor (EGF) receptors (EGFRs). In the present study, we elucidate the molecular mechanism underlying this action. ACh-induced proliferation of H508 colon cancer cells, which express exclusively M3 muscarinic receptors (M3Rs), was attenuated by anti-EGFR ligand binding domain antibody, a broad-spectrum matrix metalloproteinase (MMP) inhibitor, anti-MMP7 antibody, a diphtheria toxin analog that blocks release of an EGFR ligand [heparin-binding EGF-like growth factor (HBEGF)], and anti-HBEGF antibody. Conditioned media from ACh-treated H508 cells induced proliferation of SNU-C4 colon cancer cells that express EGFR but not M3R. These actions were attenuated by an EGFR inhibitor and by anti-EGFR and anti-HBEGF antibodies. In H508, but not SNU-C4, colon cancer cells, ACh caused a striking dose- and time-dependent increase in levels of MMP7 mRNA and MMP7 protein. Similarly, ACh induced robust MMP1 and MMP10 gene transcription. ACh-induced MMP1, MMP7, and MMP10 gene transcription was attenuated by atropine, anti-EGFR antibody, and chemical inhibitors of EGFR and ERK activation. In contrast, inhibitors of phosphatidylinositol 3-kinase and NF-κB activation did not alter MMP gene transcription. Collectively, these findings indicate that MMP7-catalyzed release of HBEGF mediates ACh-induced transactivation of EGFR and consequent proliferation of colon cancer cells. ACh-induced activation of EGFR and downstream ERK signaling also regulates transcriptional activation of MMP7, thereby identifying a novel feed-forward mechanism for neoplastic cell proliferation. [ABSTRACT FROM AUTHOR]

Emerging evidence indicates that muscarinic receptors and ligands play key roles in regulating cellular proliferation and cancer progression. Both neuronal and nonneuronal acetylcholine production results in neurocrine, paracrine, and autocrine promotion of cell proliferation, apoptosis, migration, and other features critical for cancer cell survival and spread. The present review comprises a focused critical analysis of evidence supporting the role of muscarinic receptors and ligands in cancer. Criteria are proposed to validate the biological importance of muscarinic receptor expression, activation, and postreceptor signaling. Likewise, criteria are proposed to validate the role of nonneuronal acetylcholine production in cancer. Dissecting cellular mechanisms necessary for muscarinic receptor activation as well as those needed for acetylcholine production and release will identify multiple novel targets for cancer therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: p53, a critical tumor suppressor, is commonly mutated in neoplasia, including colorectal cancer. To devise anti-cancer strategies targeting p53, it is crucial to understand the myriad cell-specific regulatory mechanisms in the p53 signaling pathway, and how these same regulatory mechanisms may be evaded by p53 mutants. This review focuses on colorectal cancer and considers the regulatory mechanisms underlying the actions of wild type p53 protein, emphasizing discoveries made in the last decade. We focus on the role of mouse double minute 2 homolog (MDM2), which modulates p53 protein levels by targeting p53 for protein degradation; other MDM2-independent mechanisms are also discussed. These regulatory mechanisms are further examined in the context of p53 missense mutants, which can evade canonical regulation. Lastly, we consider potential strategies for therapeutic targeting of p53 mutant-bearing cancers in preclinical testing or early-phase clinical trials. The role played by the key tumor suppressor gene p53 and the implications of p53 mutations for the development and progression of neoplasia continue to expand. This review focuses on colorectal cancer and the regulators of p53 expression and activity identified over the past decade. These newly recognized regulatory mechanisms include (1) direct regulation of mouse double minute 2 homolog (MDM2), an E3 ubiquitin-protein ligase; (2) modulation of the MDM2-p53 interaction; (3) MDM2-independent p53 degradation; and (4) inhibition of p53 nuclear translocation. We positioned these regulatory mechanisms in the context of p53 missense mutations, which not only evade canonical p53 degradation machinery but also exhibit gain-of-function phenotypes that enhance tumor survival and metastasis. Lastly, we discuss current and potential therapeutic strategies directed against p53 mutant-bearing tumors. [ABSTRACT FROM AUTHOR]

Cancers arising from gastrointestinal epithelial cells are common, aggressive, and difficult to treat. Progress in this area resulted from recognizing that the biological behavior of these cancers is highly dependent on bioactive molecules released by neurocrine, paracrine, and autocrine mechanisms within the tumor microenvironment. For many decades after its discovery as a neurotransmitter, acetylcholine was thought to be synthesized and released uniquely from neurons and considered the sole physiological ligand for muscarinic receptor subtypes, which were believed to have similar or redundant actions. In the intervening years, we learned this former dogma is not tenable. (1) Acetylcholine is not produced and released only by neurons. The cellular machinery required to synthesize and release acetylcholine is present in immune, cancer, and other cells, as well as in lower organisms (e.g., bacteria) that inhabit the gut. (2) Acetylcholine is not the sole physiological activator of muscarinic receptors. For example, selected bile acids can modulate muscarinic receptor function. (3) Muscarinic receptor subtypes anticipated to have overlapping functions based on similar G protein coupling and downstream signaling may have unexpectedly diverse actions. Here, we review the relevant research findings supporting these conclusions and discuss how the complexity of muscarinic receptor biology impacts health and disease, focusing on their role in the initiation and progression of gastric, pancreatic, and colon cancers. [ABSTRACT FROM AUTHOR]

Most colon cancers overexpress M[sub3] muscarinic receptors (M[sub3]R), and post-M[sub3]R signaling stimulates human colon cancer cell proliferation. Acetylcholine (ACh), a muscarinic receptor ligand traditionally regarded as a neurotransmitter, may be produced by nonneuronal cells. We hypothesized that ACh release by human colon cancer cells results in autocrine stimulation of proliferation. H508 human colon cancer cells, which have robust M[sub3]R expression, were used to examine effects of muscarinic receptor antagonists, acetylcholinesterase inhibitors, and choline transport inhibitors on cell proliferation. A nonselective muscarinic receptor antagonist (atropine), a selective M3R antagonist (ρ-fluorohexahydro-sila-difenidol hydrochloride), and a choline transport inhibitor (hemicholinum-3) all inhibited unstimulated H508 colon cancer cell proliferation by ∼40% (P < 0.005). In contrast, two acetylcholinesterase inhibitors (eserine-hemisulfate and bis-9-amino- 1 ,2,3,4-tetrahydroacridine) increased proliferation by 2.5- and 2-fold, respectively (P < 0.005). By using quantitative real-time PCR, expression of choline acetyltransferase (ChAT), a critical enzyme for ACh synthesis, was identified in H508, WiDr, and Caco-2 colon cancer cells. By using high-performance liquid chromatography-elec- trochemical detection, released ACh was detected in H508 and Caco-2 cell culture media. Immunohistochemistry in surgical specimens re- vealed weak or no cytoplasmic staining for ChAT in normal colon enterocytes (n = 25) whereas half of colon cancer specimens (n = 24) exhibited moderate to strong staining (P < 0.005). We conclude that ACh is an autocrine growth factor in colon cancer. Mechanisms that regulate colon epithelial cell production and release of ACh warrant further investigation. [ABSTRACT FROM AUTHOR]

Recent studies indicate that secondary bile acids promote colon cancer cell proliferation but their role in maintaining cell survival has not been explored. We found that deoxycholyltaurine (DCT) markedly attenuated both unstimulated and TNF-α-stimulated programmed cell death in colon cancer cells by a phosphatidylinositol 3-kinase (PI3K)-dependent mechanism. To examine the role of bile acids and PI3K signaling in maintaining colon cancer cell survival, we explored the role of signaling downstream of bile acid-induced activation of the epidermal growth factor receptor (EGFR) in regulating both apoptosis and proliferation of HT-29 and H508 human colon cancer cells. DCT caused dose- and time-dependent Akt (Ser473) phosphorylation, a commonly used marker of activated PI3K/Akt signaling. Both EGFR kinase and PI3K inhibitors attenuated DCT-induced Akt phosphorylation and Akt activation, as demonstrated by reduced phosphorylation of a GSK-3-paramyosin substrate. Transfection of HT-29 cells with kinase-dead EGFR (K721M) reduced DCT-induced Akt phosphorylation. In HT-29 cells, EGFR and PI3K inhibitors as well as transfection with dominant negative AKT attenuated DCT-induced cell proliferation. DCT-induced PI3K/Akt activation resulted in downstream phosphorylation of GSK-3 (Ser21/9) and BAD (Ser136), and nuclear translocation (activation) of NF-κB, thereby confirming that DCT-induced activation of PI3K/Akt signaling regulates both proproliferative and prosurvival signals. Collectively, these results indicate that DCT-induced activation of post-EGFR PI3K/Akt signaling stimulates both colon cancer cell survival and proliferation. J. Cell. Physiol. 215: 538–549, 2008. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

To obtain information on the concentration and spectrum of bile acids in human cecal content, samples were obtained from 19 persons who had died an unnatural death from causes such as trauma, homicide, suicide, or drug overdose. Bile acid concentration was measured via an enzymatic assay for 3α-hydroxy bile acids; bile acid classes were determined by electrospray ionization mass spectrometry and individual bile acids by gas chromatography mass spectrometry and liquid chromatography mass spectrometry. The 3α-hydroxy bile acid concentration (ε.mol bile acid/ml cecal content) was 0.4 ± 0.2 mM (mean ± SD); the total 3-hydroxy bile acid concentration was 0.6 ± 0.3 mM. The aqueous concentration of bile acids (supernatant after centrifugation) was identical, indicating that most bile acids were in solution. By liquid chromatography mass spectrometry, bile acids were mostly in unconjugated form (90 ± 9%, mean ± SD); sulfated, nonamidated bile acids were 7 ± 5%, and nonsulfated amidated bile acids (glycine or taurine conjugates) were 3 ± 7%. By gas chromatography mass spectrometry, 10 bile acids were identified: deoxycholic (34 ± 16%), lithocholic (26 ± 10%), and ursodeoxycholic (6 ± 9), as well as their primary bile acid precursors cholic (6 ± 9%) and chenodeoxycholic acid (7 ± 8%). In addition, 3β-hydroxy derivatives of some or all of these bile acids were present and averaged 27 ± 18% of total bile acids, indicating that 3β-hydroxy bile acids are normal constituents of cecal content. In the human cecum, deconjugation and dehydroxylation of bile acids are nearly complete, resulting in most bile acids being in unconjugated form at submicellar and subsecretory concentrations. [ABSTRACT FROM AUTHOR]

BACKGROUND: Despite increased emphasis on endoscopic performance indicators, e.g., cecal intubation rates, limited data from actual clinical practice have been published. OBJECTIVES: Retrospective database review to determine the rate and documentation of cecal intubation during colonoscopy at the University of Maryland Medical Center. METHODS: We reviewed 5,477 consecutive colonoscopies performed by 10 faculty gastroenterologists at a University hospital over a 6-yr period (March 1, 1999 to February 28, 2005). Unadjusted cecal intubation rates were analyzed as were rates that were adjusted based on the U.S. Multi-Society Task Force on Colorectal Cancer recommendations. We analyzed trends in overall and individual cecal intubation rates, circumstances that impact these rates, and the quality of documentation of cecal intubation. RESULTS: The overall adjusted cecal intubation rate for the entire 6 yr was 90.3%, and increased over the study period with the highest adjusted rate (93.7%) in the most recent year studied. There was no correlation between cecal intubation rate and patient age, gastroenterology fellow involvement, or endoscopist experience and number of procedures/year. In contrast, colon cancer screening, male gender, outpatient colonoscopy, and adequate bowel preparation predicted a higher cecal intubation rate. Written and photographic documentation of cecal intubation improved significantly after 2002. CONCLUSIONS: Our analysis revealed cecal intubation and documentation rates that meet current guidelines, and identified factors that may cause substantial variance in these rates depending on the nature of the practice. The present analysis confirms that computerized databases can be used to assess individual and group cecal intubation and documentation rates on an annual basis, and to make these data available to the public. [ABSTRACT FROM AUTHOR]

Abstract: Although epidemiological studies indicate an association between elevations in fecal bile acids and the development of colorectal cancer, the cellular mechanism for the proliferative actions of bile acids is not clear. Studies from other laboratories indicate a paradoxical pro-apoptotic action of bile acids on cell culture lines. Our previous studies indicate that cholinergic agonist-induced proliferation of colon cancer cells that express M3 muscarinic receptors (M3R) is mediated by transactivation of the epidermal growth factor receptor (EGFR) and that bile acids stimulate proliferation of colon cancer cells that express M3R. In the present study, we investigated the effects of bile acids on cell signaling and proliferation of a human colon cancer cell line (H508 cells) that abundantly expresses M3R and EGFR. Treatment with taurine and glycine conjugates of lithocholic and deoxycholic acids stimulated reversible activation of the p44/42 MAP kinase signaling cascade and proliferation of H508 cells. Bile acids did not stimulate proliferation of SNU-C4 colon cancer cells that express EGFR but not muscarinic receptors. Atropine, a muscarinic receptor inverse agonist, blocked bile acid-induced H508 cell proliferation. At concentrations that stimulate cell proliferation, conjugated bile acids did not activate caspase-3, a key mediator of apoptosis. Conjugated bile acids stimulated phosphorylation of EGFR Tyr992, thereby implicating EGFR transactivation in the cellular mechanism underlying their proliferative actions. This was confirmed by observing that inhibitors of EGFR activation and antibodies to the ligand-binding domain of EGFR blocked both the signaling and proliferative actions of bile acids. Collectively, these results suggest that in this colon cancer cell line, bile acid-induced colon cancer cell proliferation is M3R-dependent and is mediated by transactivation of EGFR. [Copyright &y& Elsevier]

Muscarinic cholinergic mechanisms play a key role in stimulating gastric pepsinogen secretion. Studies using antagonists suggested that the M3 receptor subtype (M3R) plays a prominent role in mediating pepsinogen secretion, but in situ hybridization indicated expression of M1 receptor (M1R) in rat chief cells. We used mice that were deficient in either the M1 (M1R-/-) or M3 (M3R-/-) receptor or that lacked both receptors (M1/3R-/-) to determine the role of M1R and M3R in mediating cholinergic agonistinduced pepsinogen secretion. Pepsinogen secretion from murine gastric glands was determined by adapting methods used for rabbit and rat stomach. In wild-type (WT) mice, maximal concentrations of carbachol and CCK caused a 3.0- and 2.5-fold increase in pepsinogen secretion, respectively. Maximal carbachol-induced secretion from M1R-/- mouse gastric glands was decreased by 25%. In contrast, there was only a slight decrease in carbachol potency and no change in efficacy when comparing M3R-/- with WT glands. To explore the possibility that both M1R and M3R are involved in carbachol-mediated pepsinogen secretion, we examined secretion from glands prepared from M1/3R-/- double-knockout mice. Strikingly, carbacholinduced pepsinogen secretion was nearly abolished in glands from M1/3R-/- mice, whereas CCK-induced secretion was not altered. In situ hybridization for murine M1R and M3R mRNA in gastric mucosa from WT mice revealed abundant signals for both receptor subtypes in the cytoplasm of chief cells. These data clearly indicate that, in gastric chief cells, a mixture of M1 and M3 receptors mediates cholinergic stimulation of pepsinogen secretion and that no other muscarinic receptor subtypes are involved in this activity. The development of a murine secretory model facilitates use of transgenic mice to investigate the regulation of pepsinogen secretion. [ABSTRACT FROM AUTHOR]

Besides their known physiological actions, bile acids are signaling molecules that alter cell function by interacting with muscarinic and nuclear receptors. Bile acid interaction with nuclear receptors modulates bile acid and cholesterol metabolism, whereas the potential consequences of muscarinic receptor activation are much broader. This review examines recent discoveries regarding bile acid interaction with muscarinic receptors. Selective and functional bile acid interaction has been reported with M3 receptors expressed in guinea pig gastric chief cells, human colon cancer cells, and transfected Chinese hamster ovary cells. Interaction of bile acids with chief cells may contribute to mucosal damage and other pathophysiological consequences of bile reflux. Bile acid-induced stimulation of muscarinic receptors on colon cancer cells may contribute to cellular proliferation and neoplasia. Potential consequences of bile acid interaction with muscarinic receptors on gastrointestinal myocytes, biliary epithelium, vascular endothelium and dermal neurons are discussed. Elucidation of molecular mechanisms underlying interaction of bile acids with muscarinic receptors may suggest new treatments for conditions that result from such interactions. [ABSTRACT FROM AUTHOR]

In the course of examining the actions of major human bile acids on cholinergic receptors, we discovered that conjugates of lithocholic acid are partial muscarinic agonists. In the present communication, we report that conjugates of deoxycholic acid (DC) act as cholinergic muscarinic receptor antagonists. Chinese hamster ovary (CHO) cells expressing rat M3-muscarinic receptors were used to test bile acids for inhibition of radioligand [N- [sup 3] H-methylscopolamine ([sup 3] H-NMS)] binding; alteration of inositol phosphate (IP) formation; mitogen-activated protein (MAP) kinase phosphorylation and cell toxicity. We observed approximately 18.8, 30.3 and 37.1% inhibition of [sup 3] H-NMS binding with DC and its glycine (DCG) and taurine (DCT) conjugates, respectively (all 100 μmol/l, p < 0.01). DCT and DCG inhibited acetylcholine-induced increases in IP formation and MAP kinase phosphorylation (p44 and p42 ERK). DCG and DCT did not alter trypan blue exclusion or lactate dehydrogenase release from CHO-M3 cells. We observed the following rank order of potency (IC[sub 50] μmol/l) for inhibition of [sup 3] H-NMS by muscarinic antagonists and bile acids: NMS (0.0004) > 4-DAMP (0.009) > atropine (0.012) > DCT (170) > DCG (250). None of the bile acids tested were hydrolyzed by recombinant cholinesterase. At concentrations achieved in human bile, DC derivatives are natural muscarinic antagonists.Copyright © 2002 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine the seroprevalence of Helicobacter pylori and risk factors for infection in gastrointestinal endoscopy personnel and those caring for developmentally disabled individuals. We administered a structured, one-page questionnaire. Helicobacter pylori status was determined serologically. In all, 107 health-care workers participated. Direct patient contact, exposure to gastrointestinal secretions, history of peptic ulcer, and acid-suppressing medicine use were more frequent among those who worked with the developmentally disabled. Seroprevalence of Helicobacter pylori was 24% in endoscopy personnel and 47% among those who cared for the developmentally disabled (P = 0.02). Bed-sharing with a sibling during childhood, working with the developmentally disabled, and direct patient contact were associated with Helicobacter pylori infection; exposure to patients' gastrointestinal secretions was not. We conclude that those caring for developmentally disabled individuals have a higher risk of occupational acquisition of Helicobacter pylori infection than endoscopy personnel. [ABSTRACT FROM AUTHOR]

Studies the role of the association of protein kinase (PKA) with A-kinase anchoring proteins (AKAP)150 in pepsinogen secretion guinea pig gastric chief cells. Identification of AKAP150 in guinea pig gastric chief cells; Association of AKAP150 and PKC; Effect of anchoring inhibitor peptide Ht31 on secretagogue-induced pepsinogen secretion.

Reports on the long-term outcome of medical and surgical therapies for gastroesophegeal reflux disease (GERD). Treatment of GERD; Incidence of death in severe cases; Methods of testing; Results; Conclusion.

Background: Extraintestinal Manifestations (EIMs) are a common and potentially debilitating complication of Inflammatory Bowel Diseases (IBD), sometimes requiring additional treatment beyond those used to control intestinal disease. IBD-associated arthritis (IAA), a form of spondyloarthritis, is associated with several factors including disease location, sex, and IBD type. However, much remains unknown about other clinical factors predicting development of EIMs. Our goal was to identify additional factors associated with IAA. Methods: Participants in the LOCATION-IBD cohort were included in this analysis. We performed univariate and multivariate analysis of demographics, clinical data, and patient-reported outcomes data. Results: The LOCATION-IBD cohort included 182 participants with (n = 53) and without (n = 110) joint EIMs and with joint pain of unclear etiology (n = 19). In a multivariate analysis comparing those with and without joint EIMs, female sex (OR = 2.5, p = 0.014), the presence of concomitant autoimmune and inflammatory disorders (OR = 2.5, p = 0.038), and Crohn's disease (OR = 2.9, p = 0.026) were associated with the presence of joint EIMs. Conclusion: This analysis reveals patients with IAA are more likely to have concomitant autoimmune disorders. Further studies are needed to confirm this association, understand the mechanisms underlying the common pathogenesis of these concurrent disorders, and evaluate their impact on the treatment of IAA. [ABSTRACT FROM AUTHOR]

Reviews the epidemiology and clinical problem of cholera. Definition of cholera; Information on the structure of cholera toxin; Details on the use of cholera toxin as a tool to examine regulation of the adenylyl cyclase system; Actions of cholera toxin; Treatment and prevention of cholera.