ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 2 2010
M. Montalto
Aliment Pharmacol Ther 2010; 32: 209,214 Summary Background, Non-steroidal anti-inflammatory drugs (NSAIDs) can cause serious gastrointestinal side effects. Faecal calprotectin assay represents a simple and practical method for diagnosis of NSAID enteropathy. Intestinal micro-organisms are necessary for the development of NSAID-induced small bowel lesions and hence it has been suggested that probiotics could protect against NSAID enteropathy. Aim, To evaluate the effect of a probiotic mixture in comparison with placebo on faecal calprotectin concentrations (FCCs) in healthy volunteers receiving indomethacin. Methods, In a double-blind, cross-over trial, 20 healthy volunteers ingested a daily dose of probiotic mixture (VSL#3) or placebo for 21 days. From day 16 to day 19, all subjects were also administered 50 mg/day of indomethacin. FCCs were measured the day before starting probiotic/placebo ingestion (T0), and every day from day 15 to day 21. Results, During dosing with probiotic, median FCCs were significantly increased only at day 17 with respect to T0 values, whereas during dosing with placebo, they were significantly increased at every day from day 17 to day 21 with respect to T0 values. Conclusions, Treatment with VSL#3 before and during indomethacin therapy significantly reduces FCCs in healthy subjects with respect to placebo, suggesting that this approach could be useful in decreasing indomethacin-induced intestinal inflammation. [source]

Intestinal and hepatic metabolism of glutamine and citrulline in humans

THE JOURNAL OF PHYSIOLOGY, Issue 2 2007
Marcel C. G. Van De Poll
Glutamine plays an important role in nitrogen homeostasis and intestinal substrate supply. It has been suggested that glutamine is a precursor for arginine through an intestinal,renal pathway involving inter-organ transport of citrulline. The importance of intestinal glutamine metabolism for endogenous arginine synthesis in humans, however, has remained unaddressed. The aim of this study was to investigate the intestinal conversion of glutamine to citrulline and the effect of the liver on splanchnic citrulline metabolism in humans. Eight patients undergoing upper gastrointestinal surgery received a primed continuous intravenous infusion of [2- 15N]glutamine and [ureido- 13C,2H2]citrulline. Arterial, portal venous and hepatic venous blood were sampled and portal and hepatic blood flows were measured. Organ specific amino acid uptake (disposal), production and net balance, as well as whole body rates of plasma appearance were calculated according to established methods. The intestines consumed glutamine at a rate that was dependent on glutamine supply. Approximately 13% of glutamine taken up by the intestines was converted to citrulline. Quantitatively glutamine was the only important precursor for intestinal citrulline release. Both glutamine and citrulline were consumed and produced by the liver, but net hepatic flux of both amino acids was not significantly different from zero. Plasma glutamine was the precursor of 80% of plasma citrulline and plasma citrulline in turn was the precursor of 10% of plasma arginine. In conclusion, glutamine is an important precursor for the synthesis of arginine after intestinal conversion to citrulline in humans. [source]

Reg IV is an independent prognostic factor for relapse in patients with clinically localized prostate cancer

CANCER SCIENCE, Issue 8 2008
Shinya Ohara
Regenerating islet-derived family, member 4 (REG4, which encodes Reg IV) is a candidate marker for cancer and inflammatory bowel disease. We investigated the potential prognostic role of Reg IV immunostaining in clinically localized prostate cancer (PCa) after radical prostatectomy. Immunohistochemical staining of Reg IV was performed in 98 clinically localized PCa tumors obtained during curative radical prostatectomy. Intestinal and neuroendocrine differentiation was investigated by MUC2 and chromogranin A immunostaining, respectively. The prognostic significance of immunohistochemical staining for these factors on prostate-specific antigen (PSA)-associated recurrence was assessed by Kaplan,Meier analysis and a Cox regression model. Phosphorylation of the epidermal growth factor receptor (EGFR) by Reg IV was analyzed by Western blot. In total, 14 (14%) of the 98 PCa cases were positive for Reg IV staining. Reg IV positivity was observed frequently in association with MUC2 (P = 0.0182) and chromogranin A positivity (P = 0.0012). Univariate analysis revealed that Reg IV staining (P = 0.0004), chromogranin A staining (P = 0.0494), Gleason score (P < 0.0001) and preoperative PSA concentration (P = 0.0167) were significant prognostic factors for relapse-free survival. Multivariate analysis indicated that Reg IV staining (P = 0.0312), Gleason score (P = 0.0014) and preoperative PSA concentration (P = 0.0357) were independent predictors of relapse-free survival. In the LNCaP cell line, EGFR phosphorylation was induced by the addition of Reg IV-conditioned medium. These results suggest that Reg IV expression is an independent prognostic indicator of relapse after radical prostatectomy. (Cancer Sci 2008; 99: 1570,1577) [source]

Intestinal double-positive CD4+CD8+ T,cells are highly activated memory cells with an increased capacity to produce cytokines

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2006
Bapi Pahar Dr.
Abstract Peripheral blood and intestinal CD4+CD8+ double-positive (DP) T,cells have been described in several species including humans, but their function and immunophenotypic characteristics are still not clearly understood. Here we demonstrate that DP T,cells are abundant in the intestinal lamina propria of normal rhesus macaques (Macaca mulatta). Moreover, DP T,cells have a memory phenotype and are capable of producing different and/or higher levels of cytokines and chemokines in response to mitogen stimulation compared to CD4+ single-positive T,cells. Intestinal DP T,cells are also highly activated and have higher expression of CCR5, which makes them preferred targets for simian immunodeficiency virus/HIV infection. Increased levels of CD69, CD25 and HLA-DR, and lower CD62L expression were found on intestinal DP T,cells populations compared to CD4+ single-positive T,cells. Collectively, these findings demonstrate that intestinal and peripheral blood DP T,cells are effector cells and may be important in regulating immune responses, which distinguishes them from the immature DP cells found in the thymus. Finally, these intestinal DP T,cells may be important target cells for HIV infection and replication due to their activation, memory phenotype and high expression of CCR5. [source]

Down-regulation of reduced folate carrier may result in folate malabsorption across intestinal brush border membrane during experimental alcoholism

FEBS JOURNAL, Issue 24 2007
Abid Hamid
Folate plays a critical role in maintaining normal metabolic, energy, differentiation and growth status of all mammalian cells. The intestinal folate uptake is tightly and diversely regulated, and disturbances in folate homeostasis are observed in alcoholism, attributable, in part, to intestinal malabsorption of folate. The aim of this study was to delineate the regulatory mechanisms of folate transport in intestinal absorptive epithelia in order to obtain insights into folate malabsorption in a rat model of alcoholism. The rats were fed 1 g·kg,1 body weight of ethanol daily for 3 months. A reduced uptake of [3H]folic acid in intestinal brush border membrane was observed over the course of ethanol administration for 3 months. Folate transport exhibited saturable kinetics and the decreased intestinal brush border membrane folate transport in chronic alcoholism was associated with an increased Km value and a low Vmax value. Importantly, the lower intestinal [3H]folic acid uptake in ethanol-fed rats was observed in all cell fractions corresponding to villus tip, mid-villus and crypt base. RT-PCR analysis for reduced folate carrier, the major folate transporter, revealed that reduced folate carrier mRNA levels were decreased in jejunal tissue derived from ethanol-fed rats. Parallel changes were observed in reduced folate carrier protein levels in brush border membrane along the entire crypt,villus axis. In addition, immunohistochemical staining for reduced folate carrier protein showed that, in alcoholic conditions, deranged reduced folate carrier localization was observed along the entire crypt,villus axis, with a more prominent effect in differentiating crypt base stem cells. These changes in functional activity of the membrane transport system were not caused by a general loss of intestinal architecture, and hence can be attributed to the specific effect of ethanol ingestion on the folate transport system. The low folate uptake activity observed in ethanol-fed rats was found to be associated with decreased serum and red blood cell folate levels, which might explain the observed jejunal genomic hypomethylation. These findings offer possible mechanistic insights into folate malabsorption during alcoholism. [source]

Inhibition of recombinant human maltase glucoamylase by salacinol and derivatives

FEBS JOURNAL, Issue 12 2006
Elena J. Rossi
Inhibitors targeting pancreatic ,-amylase and intestinal ,-glucosidases delay glucose production following digestion and are currently used in the treatment of Type II diabetes. Maltase-glucoamylase (MGA), a family 31 glycoside hydrolase, is an ,-glucosidase anchored in the membrane of small intestinal epithelial cells responsible for the final step of mammalian starch digestion leading to the release of glucose. This paper reports the production and purification of active human recombinant MGA amino terminal catalytic domain (MGAnt) from two different eukaryotic cell culture systems. MGAnt overexpressed in Drosophila cells was of quality and quantity suitable for kinetic and inhibition studies as well as future structural studies. Inhibition of MGAnt was tested with a group of prospective ,-glucosidase inhibitors modeled after salacinol, a naturally occurring ,-glucosidase inhibitor, and acarbose, a currently prescribed antidiabetic agent. Four synthetic inhibitors that bind and inhibit MGAnt activity better than acarbose, and at comparable levels to salacinol, were found. The inhibitors are derivatives of salacinol that contain either a selenium atom in place of sulfur in the five-membered ring, or a longer polyhydroxylated, sulfated chain than salacinol. Six-membered ring derivatives of salacinol and compounds modeled after miglitol were much less effective as MGAnt inhibitors. These results provide information on the inhibitory profile of MGAnt that will guide the development of new compounds having antidiabetic activity. [source]

Expression and regulation of alkaline phosphatases in human breast cancer MCF-7 cells

FEBS JOURNAL, Issue 5 2000
Lai-Chen Tsai
The effect of retinoic acid and dexamethasone on alkaline phosphatase (AP) expression was investigated in human breast cancer MCF-7 cells. Cellular AP activity was induced significantly by retinoic acid or dexamethasone in a time-dependent and dose-dependent fashion. A marked synergistic induction of AP activity was observed when the cells were incubated with both agents simultaneously. Two AP isozymes, tissue-nonspecific (TNAP) and intestinal (IAP), were shown to be expressed in MCF-7 cells as confirmed by the differential rate of thermal inactivation of these isozymes and RT-PCR. Based on the two-isozyme thermal-inactivation model, the specific activities for TNAP and IAP in each sample were analyzed. TNAP activity was induced only by retinoic acid and IAP activity was induced only by dexamethasone. Whereas dexamethasone conferred no significant effect on TNAP activity, retinoic acid was shown to inhibit IAP activity by , 50%. Interestingly, TNAP was found to be the only isozyme activity superinduced when the cells were costimulated with retinoic acid and dexamethasone. Northern blot and RT-PCR analysis were then used to demonstrate that the steady-state TNAP mRNA level was also superinduced, which indicates that the superinduction is regulated at the transcriptional or post-transcriptional levels. In the presence of the glucocorticoid receptor antagonist RU486, the dexamethasone-mediated induction of IAP activity was blocked completely as expected. However, the ability of RU486 to antagonize the action of glucocorticoid was greatly compromised in dexamethasone-mediated superinduction of TNAP activity. Furthermore, in the presence of retinoic acid, RU486 behaved as an agonist, and conferred superinduction of TNAP gene expression in the same way as dexamethasone. Taken together, these observations suggest that the induction of IAP activity by dexamethasone and the superinduction of TNAP by dexamethasone were mediated through distinct regulatory pathways. In addition, retinoic acid plays an essential role in the superinduction of TNAP gene expression by enabling dexamethasone to exert its agonist activity, which otherwise has no effect. [source]

p16 Immunoreactivity in unusual types of cervical adenocarcinoma does not reflect human papillomavirus infection

HISTOPATHOLOGY, Issue 3 2010
Oisin Houghton
Houghton O, Jamison J, Wilson R, Carson J & McCluggage W G (2010) Histopathology,57, 342,350 p16 Immunoreactivity in unusual types of cervical adenocarcinoma does not reflect human papillomavirus infection Aims:, The association between human papillomavirus (HPV) and cervical carcinoma is well known, with HPV being identifiable in almost all cervical squamous carcinomas and most adenocarcinomas. However, the prevalence of HPV in unusual morphological types of cervical adenocarcinoma has not been investigated extensively. The aim was to determine HPV status in a series of primary cervical adenocarcinomas, enriched for unusual morphological types. The relationship between HPV and p16 immunoreactivity in these neoplasms was also investigated, as it is generally assumed that in cervical neoplasms diffuse p16 expression is predictive of the presence of high-risk HPV. Methods and results:, Sixty-three cervical adenocarcinomas, comprising those of usual type (n = 43), minimal deviation type (n = 4), gastric type (n = 3), intestinal type (n = 3), mesonephric type (n = 3), clear cell type (n = 4), serous type (n = 2) and hepatoid type (n = 1) underwent linear array HPV genotyping and immunohistochemistry for p16. Overall, HPV was identified in 32 of 56 cases (57%) in which sufficient DNA was present for analysis. The most common HPV types were 16 and 18, with these being identified in 20 and 18 cases, respectively, either alone or in combination. Seventy-eight per cent of usual-type adenocarcinomas were HPV-positive, as was the single serous carcinoma in which there was sufficient DNA for analysis. In contrast, all minimal deviation adenocarcinomas and those of gastric, intestinal, mesonephric and clear cell types were HPV-negative, as was the single hepatoid carcinoma. All usual-type adenocarcinomas exhibited p16 immunoreactivity (diffuse staining in all but one case), as did 11 of 20 of those of unusual morphological type (five focal, six diffuse). Conclusions:, Most, but not all, cervical adenocarcinomas of usual type contain HPV, but those of unusual morphological type are almost always HPV-negative. This has implications for the efficacy of HPV vaccination in the prevention of cervical adenocarcinoma. A significant proportion of cervical adenocarcinomas are p16-positive in the absence of HPV, illustrating that in these neoplasms diffuse p16 immunoreactivity is not a reliable surrogate marker of the presence of high-risk HPV. [source]

Defective arachidonate release and PGE2 production in Gi,2-deficient intestinal and colonic subepithelial myofibroblasts

INFLAMMATORY BOWEL DISEASES, Issue 3 2006
Robert Andrew Edwards MD
Abstract Background: Mice lacking the pertussis toxin-sensitive G-protein subunit Gi,2 spontaneously develop colitis and colon cancer. In the gut, arachidonate-derived prostaglandin E2 (PGE2) modulates intestinal immune responses and epithelial restitution and is derived largely from subepithelial myofibroblasts. Methods: We tested whether known decreases in arachidonate release in cells lacking Gi,2 would result in decreased PGE2 production and tissue PGE2 levels. PGE2 levels were significantly decreased in the colon of Gi,2,/, mice. Results: Gi,2,/, myofibroblasts from the small intestine and colon both released ,50% less arachidonate and 3- to 7-fold less PGE2 and 6-keto PGF1, in response to adenosine triphosphate, thrombin, tumor necrosis factor-,, or lipopolysaccharide, in a partially cyclooxygenase (COX)-2-dependent manner. Decreased arachidonate release did not appear to be caused by a defect in cPLA2 translocation in the absence of Gi,2. Basal myofibroblast COX-1 and COX-2 expression was downregulated in Gi,2,/, cells. No differences in proliferation rates were found between serum-starved or serum-activated wild-type (WT) and Gi,2,/, myofibroblasts. Finally, treatment of Gi,2,/, mice with the EP4 -specific PGE2 receptor agonist ONO-AE1-329 significantly decreased the severity of established colitis. Conclusions: These findings confirm a requirement for Gi,2 in intestinal and colonic myofibroblast-derived prostanoid production and confirm the importance of mucosal PGE2 in the suppression of colitis. [source]

Mammalian target of rapamycin is activated in human gastric cancer and serves as a target for therapy in an experimental model

INTERNATIONAL JOURNAL OF CANCER, Issue 8 2007
Sven A. Lang
Abstract The mammalian target of rapamycin (mTOR) has become an interesting target for cancer therapy through its influence on oncogenic signals, which involve phosphatidylinositol-3-kinase and hypoxia-inducible factor-1, (HIF-1,). Since mTOR is an upstream regulator of HIF-1,, a key mediator of gastric cancer growth and angiogenesis, we investigated mTOR activation in human gastric adenocarcinoma specimens and determined whether rapamycin could inhibit gastric cancer growth in mice. Expression of phospho-mTOR was assessed by immunohistochemical analyses of human tissues. For in vitro studies, human gastric cancer cell lines were used to determine S6K1, 4E-BP-1 and HIF-1, activation and cancer cell motility upon rapamycin treatment. Effects of rapamycin on tumor growth and angiogenesis in vivo were assessed in both a subcutaneous tumor model and in an experimental model with orthotopically grown tumors. Mice received either rapamycin (0.5 mg/kg/day or 1.5 mg/kg/day) or diluent per intra-peritoneal injections. In addition, antiangiogenic effects were monitored in vivo using a dorsal-skin-fold chamber model. Immunohistochemical analyses showed strong expression of phospho-mTOR in 60% of intestinal- and 64% of diffuse-type human gastric adenocarcinomas. In vitro, rapamycin-treatment effectively blocked S6K1, 4E-BP-1 and HIF-1, activation, and significantly impaired tumor cell migration. In vivo, rapamycin-treatment led to significant inhibition of subcutaneous tumor growth, decreased CD31-positive vessel area and reduced tumor cell proliferation. Similar significant results were obtained in an orthotopic model of gastric cancer. In the dorsal-skin-fold chamber model, rapamycin-treatment significantly inhibited tumor vascularization in vivo. In conclusion, mTOR is frequently activated in human gastric cancer and represents a promising new molecular target for therapy. © 2007 Wiley-Liss, Inc. [source]

A history of cancer in the husband does not increase the risk of breast cancer

INTERNATIONAL JOURNAL OF CANCER, Issue 12 2006
Eva Negri
Abstract Spouses share the home environment, and dietary and other lifestyle habits. Furthermore, a cancer diagnosis in the husband is a stressful event for the wife also. Thus, a history of cancer in the husband may be an indicator of breast cancer risk. We investigated the issue in a large Italian multicentric case-control study on 2,588 women with incident breast cancer and 2,569 female hospital controls, admitted for acute, non neoplastic diseases. The adjusted odds ratio (OR) was 1.0 (95% confidence interval, CI, 0.7,1.4) for a history of any type of cancer in the husband, 1.0 (95% 0.4,2.7) for stomach, 0.7 (95% 0.2,2.3) for intestinal (chiefly colorectal), 0.9 (95% CI 0.5,1.7) for lung, and 1.3 (95% CI 0.4,4.3) for prostate cancer. The OR was close to unity also when data were analyzed in separate strata of patient's or husband's age, patient's education, or vital status of the husband. This study suggests that women whose husband had a diagnosis of cancer are not at increased risk of breast cancer, although results for individual cancer sites should be interpreted with caution, due to small numbers. © 2006 Wiley-Liss, Inc. [source]

The aggregation-promoting factor of Lactobacillus crispatus M247 and its genetic locus

JOURNAL OF APPLIED MICROBIOLOGY, Issue 4 2004
H. Marcotte
Abstract Aims:, Characterization of the aggregation-promoting factor (APF) of the human intestinal isolate Lactobacillus crispatus M247 and its homologous nonaggregating mutant Mu5. Methods and Results:, Western blot analysis revealed that the supernatant of both M247 and Mu5 contains a 28-kDa protein which cross reacts with the antiserum produced against the APF of Lact. gasseri 4B2. The apf genes of M247 and Mu5 strains were identical and were shown to be 672 nucleotides in length and encoding a protein of 223 amino acids with a predicted molecular weight of 24·0 kDa. Conclusion:, Our results shows that the lost of aggregation in Mu5 is not related to a defect in secretion of the APF protein or a mutation in the apf gene. Significance and Impact of the Study:, These results suggest that the mutation in Mu5 may be contained in another molecule involved in aggregation such as a possible receptor for APF. [source]

Genetic heterogeneity and functional properties of intestinal bifidobacteria

JOURNAL OF APPLIED MICROBIOLOGY, Issue 3 2004
J. Mättö
Abstract Aims:, The aim of the present study was to compare several molecular methods for the identification and genotyping of bifidobacteria, and further to investigate genetic heterogeneity and functional properties of bifidobacterial isolates from intestinal samples of Finnish adult subjects. Methods and Results:, A total of 153 intestinal bifidobacterial isolates were included in initial screening and 34 isolates were further characterized. Identification results obtained with PCR,ELISA and ribotyping were well in accordance with each other, while randomly amplified polymorphic DNA (RAPD) gave tentative identification only to Bifidobacterium bifidum and to 65% of the B. longum isolates. The most commonly detected species were B. longum biotype longum followed by B. adolescentis and B. bifidum. In addition, B. animalis (lactis), B. angulatum and B. pseudocatenulatum were found. Ribotyping and pulsed-field gel electrophoresis (PFGE) proved to be discriminatory methods for bifidobacteria, but also RAPD revealed intraspecies heterogeneity. Besides two B. animalis (lactis) isolates with very close similarity to a commercially available probiotic strain, none of the intestinal isolates showed optimal survival in all tolerance (acid, bile and oxygen) or growth performance tests. Conclusions:, Several species/strains of bifidobacteria simultaneously colonize the gastrointestinal tract of healthy Finnish adults and intestinal Bifidobacterium isolates were genetically heterogeneous. Functional properties of bifidobacteria were strain-dependent. Significance and Impact of the Study:, Applicability of ribotyping with the automated RiboPrinter® System for identification and genotyping of bifidobacteria was shown in the present study. [source]

Preparation and in vitro evaluation of new pH-sensitive hydrogel beads for oral delivery of protein drugs

JOURNAL OF APPLIED POLYMER SCIENCE, Issue 5 2010
I. M. El-Sherbiny
Abstract New biodegradable pH-responsive hydrogel beads based on chemically modified chitosan and sodium alginate were prepared and characterized for the controlled release study of protein drugs in the small intestine. The ionotropic gelation reaction was carried out under mild aqueous conditions, which should be appropriate for the retention of the biological activity of an uploaded protein drug. The equilibrium swelling studies were carried out for the hydrogel beads at 37°C in simulated gastric (SGF) and simulated intestinal (SIF) fluids. Bovine serum albumin (BSA), a model for protein drugs was entrapped in the hydrogels and the in vitro drug release profiles were established at 37°C in SGF and SIF. The preliminary investigation of the hydrogel beads prepared in this study showed high entrapment efficiency (up to 97%) and promising release profiles of BSA. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2010 [source]

Methotrexate induction of human sulfotransferases in Hep G2 and Caco-2 cells

JOURNAL OF APPLIED TOXICOLOGY, Issue 5 2005
Xinrong Chen
Abstract Methotrexate (MTX) was the first antifolate drug developed for the treatment of cancer. It is also effective in treating inflammatory and autoimmune diseases. Sulfotransferases are phase II drug-metabolizing enzymes and their induction by hormones and endogenous molecules is relatively well known, although xenobiotic drug induction of sulfotransferases has not been well studied. In the present investigation, MTX is shown to be a xenobiotic inducer of human sulfotransferases in transformed human liver (Hep G2) and intestinal (Caco-2) cells. Following MTX treatment, various sulfotransferases were induced in both cell lines. Enzyme assay, Western blot and reverse-transcription polymerase chain reaction (RT-PCR) results demonstrated that protein and mRNA expressions of human simple phenol sulfotransferase (P-PST), human monoamine sulfotransferase (M-PST), human dehydroepiandrosterone sulfotransferase (DHEA-ST) and human estrogen sulfotransferase (EST) were induced in Hep G2 cells; M-PST and DHEA-ST were induced in Caco-2 cells. Inductions in both cell lines were dose dependent. Enzyme activity and Western blot results were in good agreement with RT-PCR results, suggesting that the induction is at the gene transcription level. Folic acid had a significantly lesser effect on sulfotransferases compared with MTX. Interestingly, the induction of different sulfotransferases by MTX was inhibited by high doses of folic acid at both protein and mRNA levels in Hep G2 cells. Methotrexate is the first antifolate and apoptosis-inducing drug to show induction of sulfotransferases in Hep G2 cells and Caco-2 cells. The inhibition by folic acid suggests a possible mechanism for MTX induction. Copyright © 2005 John Wiley & Sons, Ltd. [source]

Analysis of SOX10 mutations identified in Waardenburg-Hirschsprung patients: Differential effects on target gene regulation

JOURNAL OF CELLULAR BIOCHEMISTRY, Issue 3 2003
Kwok Keung Chan
Abstract SOX10 is a member of the SOX gene family related by homology to the high-mobility group (HMG) box region of the testis-determining gene SRY. Mutations of the transcription factor gene SOX10 lead to Waardenburg-Hirschsprung syndrome (Waardenburg-Shah syndrome, WS4) in humans. A number of SOX10 mutations have been identified in WS4 patients who suffer from different extents of intestinal aganglionosis, pigmentation, and hearing abnormalities. Some patients also exhibit signs of myelination deficiency in the central and peripheral nervous systems. Although the molecular bases for the wide range of symptoms displayed by the patients are still not clearly understood, a few target genes for SOX10 have been identified. We have analyzed the impact of six different SOX10 mutations on the activation of SOX10 target genes by yeast one-hybrid and mammalian cell transfection assays. To investigate the transactivation activities of the mutant proteins, three different SOX target binding sites were introduced into luciferase reporter gene constructs and examined in our series of transfection assays: consensus HMG domain protein binding sites; SOX10 binding sites identified in the RET promoter; and Sox10 binding sites identified in the P0 promoter. We found that the same mutation could have different transactivation activities when tested with different target binding sites and in different cell lines. The differential transactivation activities of the SOX10 mutants appeared to correlate with the intestinal and/or neurological symptoms presented in the patients. Among the six mutant SOX10 proteins tested, much reduced transactivation activities were observed when tested on the SOX10 binding sites from the RET promoter. Of the two similar mutations X467K and 1400del12, only the 1400del12 mutant protein exhibited an increase of transactivation through the P0 promoter. While the lack of normal SOX10 mediated activation of RET transcription may lead to intestinal aganglionosis, overexpression of genes coding for structural myelin proteins such as P0 due to mutant SOX10 may explain the dysmyelination phenotype observed in the patients with an additional neurological disorder. © 2003 Wiley-Liss, Inc. [source]

Vasopressin decreases intestinal mucosal perfusion: a clinical study on cardiac surgery patients in vasodilatory shock

ACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 5 2009
A. NYGREN
Background: Low to moderate doses of vasopressin have been used in the treatment of cathecholamine-dependent vasodilatory shock in sepsis or after cardiac surgery. We evaluated the effects of vasopressin on jejunal mucosal perfusion, gastric-arterial pCO2 gradient and the global splanchnic oxygen demand/supply relationship in patients with vasodilatory shock after cardiac surgery. Methods: Eight mechanically ventilated patients, dependent on norepinephrine to maintain mean arterial pressure (MAP) ,60 mmHg because of septic/post-cardiotomy vasodilatory shock and multiple organ failure after cardiac surgery, were included. Vasopressin was sequentially infused at 1.2, 2.4 and 4.8 U/h for 30-min periods. Norepinephrine was simultaneously decreased to maintain MAP at 75 mmHg. At each infusion rate of vasopressin, data on systemic hemodynamics, jejunal mucosal perfusion, jejunal mucosal hematocrit and red blood cell velocity (laser Doppler flowmetry) as well as gastric-arterial pCO2 gradient (gastric tonometry) and splanchnic oxygen and lactate extraction (hepatic vein catheter) were obtained. Results: The cardiac index, stroke volume index and systemic oxygen delivery decreased and systemic vascular resistance and systemic oxygen extraction increased significantly, while the heart rate or global oxygen consumption did not change with increasing vasopressin dose. Jejunal mucosal perfusion decreased and the arterial-gastric-mucosal pCO2 gradient increased, while splanchnic oxygen or lactate extraction or mixed venous,hepatic venous oxygen saturation gradient were not affected by increasing infusion rates of vasopressin. Conclusions: Infusion of low to moderate doses of vasopressin in patients with norepinephrine-dependent vasodilatory shock after cardiac surgery induces an intestinal and gastric mucosal vasoconstriction. [source]

Confocal endomicroscopy for phenotypic diagnosis of gastric cancer

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 4 2010
Kakunori Banno
Abstract Background and Aim:, Relationships between mucin phenotype and malignant potential in gastric cancers have attracted attention. We attempted to assess the possibility of obtaining phenotypic diagnoses by confocal endomicroscopy. Methods:, Confocal images of target lesions were obtained in 29 of 40 patients with gastric cancer. Appearances of the brush border, goblet cells, and gastric foveolar epithelium were investigated with immunohistochemical staining using CD10, MUC2, and human gastric mucin to evaluate phenotypic expression in gastric carcinomas. Confocal images were compared with immunohistochemical findings for goblet cells and brush borders. Results:, Both the endoscopists and the pathologist obtained high accuracy rates for differential diagnosis. Sensitivity and specificity for goblet cells were 85.7% and 92.3% (Endoscopist A), and 85.7% and 88.5% (Endoscopist B). The ,-value for correspondence between two endoscopists for the diagnosis of goblet cells in confocal images was 0.73. Sensitivity and specificity for the brush border were 93.8% and 91.7% (Endoscopist A), and 81.3% and 91.7% (Endoscopist B). The ,-value for correspondence between two endoscopists for diagnosis of the brush border in confocal images was 0.79. Intestinal phenotypic gastric cancers show a brush border, goblet cells, or both. Sensitivity and specificity for the intestinal phenotype in confocal endomicroscopy were 90.9% and 77.8% (Endoscopist A), and 86.4% and 83.3% (Endoscopist B). Conclusion:, The confocal endomicroscopic diagnosis of the mucin phenotype in gastric cancers was limited to intestinal and mixed phenotypes, but may be useful for the diagnosis of mucin phenotype and differential diagnosis. [source]

Role of interleukin-18 in the development of acute pulmonary injury induced by intestinal ischemia/reperfusion and its possible mechanism

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 2 2007
Yong-jie Yang
Abstract Background and Aims:, Lung injury is an important target for the systemic inflammatory response associated with intestinal ischemia/reperfusion (I/R). In the present study, the role of interleukin (IL)-18 in the development of acute pulmonary injury induced by intestinal I/R and its possible mechanism in relation to the increased activity of inducible nitric oxide synthase and tumor necrosis factor (TNF)-, were investigated. Methods:, Mice were randomly divided into three groups: normal control group without operation; sham group with sham operation; and I/R group in which mice underwent superior mesenteric artery occlusion for 30 min followed by reperfusion for 3 h. Each group received pretreatment with exogenous IL-18, anti-IL-18 neutralizing antibody or L-NIL, the selective inhibitor of inducible nitric oxide synthase, 30 min before ischemia. The expression of TNF-, was detected by reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). Lung injury was evaluated by means of Evans blue dye (EBD) concentration, myeloperoxidase (MPO) activity and morphological analysis. Results:, The experimental results showed that both in the sham-operated and I/R groups of animals, pretreatment with exogenous IL-18 clearly enhanced pulmonary MPO activity, microvascular leakage and the expression of TNF-, mRNA and protein. In contrast, IL-18 did not increase the TNF-, level and degree of lung injury, although it clearly enhanced the pulmonary MPO activity in normal animals. Meanwhile, IL-18 antibody given prior to ischemia led to a reduction in the sequestration of neutrophils, extravasation of EBD and downregulation of the serum level of TNF-, in the I/R group of animals. In addition, selective inhibition of inducible nitric oxide synthase (iNOS) that inhibited plasma extravasation and pulmonary injury without affecting the MPO activity could be demonstrated in all treated animals. Conclusions:, These data suggested a role of IL-18 in the activation and sequestration of neutrophils in lungs. Our results were consistent with the hypothesis that increased sequestration of neutrophils and microvascular leakage might, respectively, relate to the increased IL-18 level and the elevation of TNF-,/iNOS activity, and these two aspects might synergically contribute to intestinal I/R-induced pulmonary dysfunction. [source]

Physiologically based predictions of the impact of inhibition of intestinal and hepatic metabolism on human pharmacokinetics of CYP3A substrates

JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 1 2010
Frederique Fenneteau
Abstract The first objective of the present study was to predict the pharmacokinetics of selected CYP3A substrates administered at a single oral dose to human. The second objective was to predict pharmacokinetics of the selected drugs in presence of inhibitors of the intestinal and/or hepatic CYP3A activity. We developed a whole-body physiologically based pharmacokinetics (WB-PBPK) model accounting for presystemic elimination of midazolam (MDZ), alprazolam (APZ), triazolam (TRZ), and simvastatin (SMV). The model also accounted for concomitant administration of the above-mentioned drugs with CYP3A inhibitors, namely ketoconazole (KTZ), itraconazole (ITZ), diltiazem (DTZ), saquinavir (SQV), and a furanocoumarin contained in grape-fruit juice (GFJ), namely 6,,7,-dihydroxybergamottin (DHB). Model predictions were compared to published clinical data. An uncertainty analysis was performed to account for the variability and uncertainty of model parameters when predicting the model outcomes. We also briefly report on the results of our efforts to develop a global sensitivity analysis and its application to the current WB-PBPK model. Considering the current criterion for a successful prediction, judged satisfied once the clinical data are captured within the 5th and 95th percentiles of the predicted concentration,time profiles, a successful prediction has been obtained for a single oral administration of MDZ and SMV. For APZ and TRZ, however, a slight deviation toward the 95th percentile was observed especially for Cmax but, overall, the in vivo profiles were well captured by the PBPK model. Moreover, the impact of DHB-mediated inhibition on the extent of intestinal pre-systemic elimination of MDZ and SMV has been accurately predicted by the proposed PBPK model. For concomitant administrations of MDZ and ITZ, APZ and KTZ, as well as SMV and DTZ, the in vivo concentration,time profiles were accurately captured by the model. A slight deviation was observed for SMV when coadministered with ITZ, whereas more important deviations have been obtained between the model predictions and in vivo concentration,time profiles of MDZ coadministered with SQV. The same observation was made for TRZ when administered with KTZ. Most of the pharmacokinetic parameters predicted by the PBPK model were successfully predicted within a two-fold error range either in the absence or presence of metabolism-based inhibition. Overall, the present study demonstrated the ability of the PBPK model to predict DDI of CYP3A substrates with promising accuracy. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:486,514, 2010 [source]

In Vivo use of the P450 inactivator 1-aminobenzotriazole in the rat: Varied dosing route to elucidate gut and liver contributions to first-pass and systemic clearance

JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 6 2006
Timothy J. Strelevitz
Abstract The small intestine is regarded as an absorptive organ in the uptake of orally administered drugs, but also has the ability to metabolize drugs by both phase 1 and phase 2 reactions. The amount of drug that reaches the systemic circulation can be reduced by both intestinal and hepatic metabolism. 1-Aminobenzotriazole (ABT) is an irreversible inhibitor of cytochrome P450s. Through in vivo and in vitro studies, ABT has been evaluated for its utility in studying intestinal metabolism in rats. Rats have been exposed to ABT through varied routes of administration followed by p.o. and i.v. administration of midazolam (MDZ), a CYP3A substrate. The MDZ bioavailablity in rats dosed orally and in rats dosed intravenously with ABT is 58.5% and 0.7%, respectively (%F,=,2.3% w/o ABT). The approximately 80-fold difference between the two groups suggests the majority of the extraction occurs in the intestine following an oral dose. To further study the utility of ABT, the antihistamine fexofenadine (Fex), which is not significantly metabolized and is a substrate for the uptake and efflux transporters, OATP and P-gp, was tested in rat. There was no change in oral or systemic exposure of Fex when animals were predosed with ABT, suggesting that ABT does not affect these transporters. These findings may lead to a better understanding of the interdependent role of absorption and metabolism and the specificity of ABT. This method should have utility in drug discovery for the identification of factors limiting oral bioavailability. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 95:1334,1341, 2006 [source]

Advances and potential applications of chitosan derivatives as mucoadhesive biomaterials in modern drug delivery

JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 8 2006
Shruti Chopra
Pharmaceutical technologists have been working extensively on various mucoadhesive polymeric systems to create an intimate and prolonged contact at the site of administration. Chitosan is one of the most promising polymers because of its non-toxic, polycationic biocompatible, biodegradable nature, and particularly due to its mucoadhesive and permeation enhancing properties. Due to its potential importance in controlled drug delivery applications, pharmaceutical scientists have exploited this mucoadhesive polymer. However, chitosan suffers from limited solubility at physiological pH and causes presystemic metabolism of drugs in intestinal and gastric fluids in the presence of proteolytic enzymes. These inherent drawbacks of chitosan have been overcome by forming derivatives such as carboxylated, various conjugates, thiolated, and acylated chitosan, thus providing a platform for sustained release formulations at a controlled rate, prolonged residence time, improved patient compliance by reducing dosing frequency, enhanced bioavailability and a significant improvement in therapeutic efficacy. We have explored the potential benefits of these improved chitosan derivatives in modern drug delivery. [source]

Dose-response efficacy of caraway (Carum carvi L.) on tissue lipid peroxidation and antioxidant profile in rat colon carcinogenesis

JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 8 2006
Muthaiyan Kamaleeswari
Colon cancer is a leading cause of cancer death and its prevention is of great interest throughout the world. This study was conducted to examine the efficacy of different doses of dietary caraway (Carum carvi L.) on tissue lipid peroxidation (LPO) and antioxidant profile in rat colon carcinogenesis. Wistar male rats were divided into 6 groups and were fed a modified pellet diet for the whole of 30 weeks. To induce colon cancer, rats were given a weekly subcutaneous injection of 1,2-dimethylhydrazine (DMH) at a dose of 20 mg kg,1 (based on body weight) for the first 15 weeks. Caraway was supplemented every day orally at doses of 30, 60 and 90 mg kg,1 for different groups of rats for the total period of 30 weeks. All rats were sacrificed at the end of 30 weeks, the colons were examined visually for masses and were subsequently evaluated histologically. The results showed diminished levels of intestinal, colonic and caecal LPO products, such as conjugated dienes (CD), lipid hydroperoxides (LOOH) and thiobarbituric acid reactive substances (TBARS) and also the antioxidants superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH) and glutathione reductase (GR) in DMH treated rats, which were significantly reversed (P < 0.05) on caraway supplementation. Moreover, enhanced activity of intestinal, colonic and caecal glutathione peroxidase (GPx), glutathione S-transferase (GST) and colonic ascorbic acid and ,-tocopherol levels were observed in carcinogen-treated rats, which were significantly (P < 0.05) reduced on caraway supplementation. Thus, our study showed that caraway supplementation at a dose of 60 mg kg,1 had a modulatory role on tissue LPO, antioxidant profile and prevented DMH-induced histopathological lesions in colon cancer rats. [source]

Mucoadhesive and penetration enhancement properties of three grades of hyaluronic acid using porcine buccal and vaginal tissue, Caco-2 cell lines, and rat jejunum

JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 9 2004
Giuseppina Sandri
The influence of the molecular weight on mucoadhesive and penetration enhancement properties of three grades of hyaluronic acid (1878, 693 and 202 kDa) has been evaluated. The mucoadhesive properties were investigated using buccal and vaginal porcine mucosa by means of a tensile stress method and using rat jejunum by means of an inclined plane method. The mucoadhesive performances observed using animal tissues were compared with the mucoadhesive properties observed using submaxillary or gastric mucin dispersions. The penetration enhancement properties were investigated using porcine buccal epithelium membrane or vaginal tissue and a cell monolayer (Caco-2 cell line). Chitosan hydrochloride, already described as a penetration enhancer towards buccal and vaginal mucosae and Caco-2 cell monolayers, was used as reference. Aciclovir (acyclovir), a poorly soluble and absorbable drug, commonly used in the treatment of Herpes simplex virus (type I and II), was used as the model drug. Unlike chitosan hydrochloride, which does not show any mucoadhesive potential at pH close to neutrality (buccal and intestinal), all hyaluronic acid grades show mucoadhesive properties in all the environments considered (buccal, vaginal and intestinal). In all cases, a decrease in molecular weight of hyaluronic acid produced an increase in the mucoadhesive performance. The hyaluronic acid with the lowest molecular weight (202 kD) exhibited the best penetration enhancement properties, that, depending on the substrate under consideration, was either comparable with or even better than chitosan hydrochloride. Therefore, this grade would be the most promising for buccal, vaginal and intestinal delivery of aciclovir. [source]

The influence of citalopram on interdigestive gastrointestinal motility in man

ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 2 2010
P. Janssen
Aliment Pharmacol Ther 2010; 32: 289,295 Summary Background, Administration of 5-hydroxytryptamine (5HT) and selective 5HT receptor ligands modifies interdigestive motility in animals and in man. Aim, To study the effect of citalopram, a selective 5-HT reuptake inhibitor, on interdigestive motility in man. Methods, In 20 healthy subjects, antroduodenojejunal motor activity was studied manometrically. Basal interdigestive motor activity was recorded until the passage of two activity fronts. Ten minutes after the second activity front, placebo or 20 mg of citalopram was administered intravenously in a double-blind randomized fashion. Recording continued until the passage of two more activity fronts had occurred. Results, Administration of citalopram induced a premature small intestinal phase 3 after 35 ± 6.4 min, compared to 120 ± 17 min after placebo P < 0.01. Citalopram shortened MMC cycle length at the expense of phase 1 and phase 2 and significantly increased the motility index during phase 2 in the antrum and the small intestine. Conclusions, In the interdigestive state in man, intravenous administration of the selective 5-HT reuptake inhibitor citalopram induces a premature intestinal phase 3 and suppresses gastric activity fronts. Phase 2 motility is stimulated both in the stomach and in the small bowel after citalopram. These data suggest that 5HT is involved in the control of interdigestive motility. [source]

In situ evaluation of the protein value of wheat grain corrected for ruminal microbial contamination

JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE, Issue 4 2009
José M Arroyo
Abstract BACKGROUND: Uncorrected and microbial corrected in situ estimates of ruminal effective degradability (RED) of dry matter (DM), organic matter (OM) and crude protein (CP) and intestinal effective digestibility (IED) of DM and CP of a wheat grain sample were obtained by a simplified method using a sample pooled from rumen-incubated residues representing rumen outflow of undegraded food. Uncorrected values of RED of DM and CP were also obtained by the usual mathematical integration method. The study was performed in three rumen and duodenum cannulated wethers. RESULTS: Uncorrected values of RED of CP were similar either for the mathematical integration or this simplified method (82.4% vs. 82.2%). Microbial contamination in the rumen led to small underestimations (P < 0.05) of RED of DM (87.9% vs. 88.1%) and CP (82.2% vs. 82.8%) and to small overestimations (P < 0.05) of IED for DM (66.5% vs. 66.1%) and CP (87.7% vs. 87.3%). Accumulative errors resulted in overestimations (P < 0.05) of the intestinal digested fractions of DM (1.8%) and CP (4.0%). CONCLUSION: Corrected values of intestinal digested CP show that the protein value of wheat is closely related to the microbial protein synthesis derived from its OM rumen fermentation. This synthesis and the content of intestinal digested undegraded protein may be respectively higher and lower than is usually assumed in feed tables. Copyright © 2009 Society of Chemical Industry [source]

Review article: new receptor targets for medical therapy in irritable bowel syndrome

ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2010
M. CAMILLERI
Summary Background, Despite setbacks to the approval of new medications for the treatment of irritable bowel syndrome, interim guidelines on endpoints for irritable bowel syndrome (IBS) trials have enhanced interest as new targets for medical therapy are proposed based on novel mechanisms or chemical entities. Aims, To review the approved lubiprostone, two targets that are not meeting expectations (tachykinins and corticotrophin-releasing hormone), the efficacy and safety of new 5-HT4 agonists, intestinal secretagogues (chloride channel activators, and guanylate cyclase-C agonists), bile acid modulation, anti-inflammatory agents and visceral analgesics. Methods, Review of selected articles based on PubMed search and clinically relevant information on mechanism of action, safety, pharmacodynamics and efficacy. Results, The spectrum of peripheral targets of medical therapy addresses chiefly the bowel dysfunction of IBS and these effects are associated with pain relief. The pivotal mechanisms responsible for the abdominal pain or visceral sensation in IBS are unknown. The new 5-HT4 agonists are more specific than older agents and show cardiovascular safety to date. Secretory agents have high specificity, low bioavailability and high efficacy. The potential risks of agents ,borrowed' from other indications (such as hyperlipidaemia, inflammatory bowel disease or somatic pain) deserve further study. Conclusions, There is reason for optimism in medical treatment of IBS with a spectrum of agents to treat bowel dysfunction. However, visceral analgesic treatments are still suboptimal. [source]

Association between entero-hepatic Helicobacter species and Crohn's disease: a prospective cross-sectional study

ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 3 2009
D. LAHARIE
Summary Background, The pathogenesis of Crohn's disease (CD) involved microbial factors. Some Helicobacter species, the so-called entero-hepatic Helicobacters (EHH), can naturally colonize the intestinal surface and have been detected in humans. Aim, To look for an association between CD and the presence of EHH DNA in intestinal biopsies. Methods, Two groups of patients were included prospectively in a multicentre cross-sectional study: CD patients with an endoscopic post-operative recurrence within 2 years following a surgical resection and controls screened for colorectal polyps or cancer. Intestinal biopsies were taken for Helicobacter culture and Helicobacter 16S DNA detection. If positive, the EHH species were identified with specific PCRs, sequencing and denaturing gradient gel electrophoresis. Results, In the 165 included patients (73 CD and 92 controls), Helicobacter cultures were negative. PCR was positive in 44% of CD and 47% of controls. After age-adjustment, CD was significantly associated with EHH in intestinal biopsies (OR = 2.58; 95%CI: 1.04,6.67). All EHH species detected were identified as Helicobacter pullorum and the closely related species Helicobacter canadensis. Conclusion, Crohn's disease is associated with the presence of EHH species DNA in intestinal biopsies after adjustment for age. Whether these species play a role in the pathophysiology of CD remains to be determined. [source]

Antimicrobial Use in the Treatment of Calf Diarrhea

JOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 1 2004
Peter D. Constable
Calves with diarrhea often have small intestinal overgrowth with Escherichia coli bacteria, regardless of the inciting cause for the diarrhea, and 30% of systemically ill calves with diarrhea have bacteremia, predominantly because of E coli. Antimicrobial treatment of diarrheic calves should therefore be focused against E coli in the small intestine and blood, the 2 sites of infection. Fecal bacterial culture and antimicrobial susceptibility testing is not recommended in calves with diarrhea because fecal bacterial populations do not accurately reflect small intestinal or blood bacterial populations and because the break points for susceptibility test results have not been validated. Antimicrobial efficacy is therefore best evaluated by the clinical response of a number of calves to treatment, with calves randomly assigned to treatment groups. Amoxicillin, chlortetracycline, neomycin, oxytetracycline, streptomycin, sulfachloropyridazine, sulfamethazine, and tetracycline administered PO are currently labeled in the United States for the treatment of calf diarrhea. On the basis of published evidence for the oral administration of these antimicrobial agents, only amoxicillin can be recommended for the treatment of diarrhea. Dosage recommendations are amoxicillin trihydrate (10 mg/kg PO q12h) or amoxicillin trihydrate-clavulanate potassium (12.5 mg combined drug/kg PO q12h) for at least 3 days; the latter constitutes extra-label drug use. Parenteral administration of broad-spectrum ,-lactam antimicrobials,eftiofur (2.2mg/kg IM orSCq12h) and amoxicillin or ampicillin (10 mg/kg IM q12h),rpotentiatedsulfonamides(25 mg/kg IV or IM q24h) is recommended for treating calves with diarrhea and systemic illness; both constitute extra-label drug use. In calves with diarrhea and no systemic illness (normal appetite for milk, no fever), it is recommended that the health of the calf be monitored and that oral or parenteral antimicrobials not be administered. [source]

Hypoxia-inducible factor-1 alpha and vascular endothelial growth factor expression in ischaemic colitis and ulcerative colitis

ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 2006
T. OKUDA
Summary Background Hypoxia-inducible factor-1 alpha (HIF-1 alpha) is a transcriptional factor induced by ischaemic crisis in many tissues. Vascular endothelial growth factor (VEGF) is an important growth factor that plays a major role in angiogenesis. Aim We examined the aetiology and pathophysiology of human ischaemic colitis and ulcerative colitis from the viewpoint of the expression of these two ischaemic factors. Methods Thirty-two patients with ischaemic colitis, 16 with ulcerative colitis and 25 normal controls underwent colonoscopy. Biopsy samples were taken from a colitis lesion and a normal region in the same patient. In the normal controls, four biopsy samples were obtained from each subject. Biopsy samples were subjected to real-time polymerase chain reaction. Results Hypoxia-inducible factor and VEGF were overexpressed in ischaemic colitis lesions and quickly decreased to normal levels in the healing phase. In contrast, HIF but not VEGF was overexpressed in active ulcerative colitis lesions. In the remission phase of ulcerative colitis, VEGF decreased to low levels, although HIF was continuously overexpressed. Conclusions Overexpression of HIF and VEGF contribute to the tolerance of ischaemia in patients with active ischaemic colitis. The inconsistency in their expression might be associated with the chronic intestinal damage characteristic of ulcerative colitis. [source]