Huybers S, Naber TH, Bindels RJ, Hoenderop JG. Prednisolone-induced Ca 2ϩ malabsorption is caused by diminished expression of the epithelial Ca 2ϩ channel TRPV6. Am J Physiol Gastrointest Liver Physiol 292: G92-G97, 2007. First published August 10, 2006; doi:10.1152/ajpgi.00317.2006.-Glucocorticoids, such as prednisolone, are often used in clinic because of their anti-inflammatory and immunosuppressive properties. However, glucocorticoids reduce bone mineral density (BMD) as a side effect. Malabsorption of Ca 2ϩ in the intestine is supposed to play an important role in the etiology of low BMD. To elucidate the mechanism of glucocorticoid-induced Ca 2ϩ malabsorption, the present study investigated the effect of prednisolone on the expression and activity of proteins responsible for active intestinal Ca 2ϩ absorption including the epithelial Ca 2ϩ channel TRPV6, calbindin-D9K, and the plasma membrane ATPase PMCA1b. Therefore, C57BL/6 mice received 10 mg/kg body wt prednisolone daily by oral gavage for 7 days and were compared with control mice receiving vehicle only. An in vivo 45 Ca 2ϩ absorption assay indicated that intestinal Ca 2ϩ absorption was diminished after prednisolone treatment. We showed decreased duodenal TRPV6 and calbindin-D9K mRNA and protein abundance in prednisolone-treated compared with control mice, whereas PMCA1b mRNA levels were not altered. Importantly, detailed expression studies demonstrated that in mice these Ca 2ϩ transport proteins are predominantly localized in the first 2 cm of the duodenum. Furthermore, serum Ca 2ϩ and 1,25-dihydroxyvitamin D 3 [1,25(OH)2D3] concentrations remained unchanged by prednisolone treatment. In conclusion, these data suggest that prednisolone reduces the intestinal Ca 2ϩ absorption capacity through diminished duodenal expression of the active Ca 2ϩ transporters TRPV6 and calbindin-D 9K independent of systemic 1,25(OH)2D3.1,25-dihydroxyvitamin D3; duodenum; epithelial calcium channel 2; calcium transporter 1 REDUCED BONE MINERAL DENSITY (BMD) is particularly present in the elderly and women, which implies that age and gender are important risk factors for developing low BMD. However, in clinical practice low BMD is frequently observed in several patient groups, including inflammatory bowel disease (IBD) patients. Estimates of osteopenia in IBD range from 31 to 59% and osteoporosis from 5 to 41%. Various studies exploring the cause of low BMD in IBD found a significant correlation between glucocorticoid treatment and decreased BMD (3,5,17,28,29). Glucocorticoids, such as prednisolone, are wellknown drugs for their potent anti-inflammatory and immunosuppressive properties. As a consequence, glucocorticoids are widely used in clinic as drugs to treat inflammatory conditions such as IBD. To date, glucocorticoids are generally accepted to reduce BMD, despite the fact that in a number of studies an effect on bone mass could not be observed (5, 11) or could be observed only in male glucocorticoid users (31).This effect of glucocorticoids on BMD is caused by the c...

This study provides detailed mRNA expression patterns of various claudins throughout the human gastrointestinal tract. Analysis of expression levels of claudins in patients with CD, active and inactive UC shows that changes in expression are confined to specific intestinal segments and strongly depend on inflammatory activity.

Our results imply that TNF(DeltaARE/+) mice have a disturbed Ca(2+) homeostasis characterized by reduced duodenal and renal Ca(2+) transporters, diminished 1,25(OH)(2)D(3) levels, and increased bone resorption associated with profound bone abnormalities.

BackgroundCurcumin is a spice and a coloring food compound with a promising role in colon cancer prevention. Curcumin protects against development of colon tumors in rats treated with a colon carcinogen, in colon cancer cells curcumin can inhibit cell proliferation and induce apoptosis, it is an anti-oxidant and it can act as an anti-inflammatory agent. The aim of this study was to elucidate mechanisms and effect of curcumin in colon cancer cells using gene expression profiling.MethodsGene expression changes in response to curcumin exposure were studied in two human colon cancer cell lines, using cDNA microarrays with four thousand human genes. HT29 cells were exposed to two different concentrations of curcumin and gene expression changes were followed in time (3, 6, 12, 24 and 48 hours). Gene expression changes after short-term exposure (3 or 6 hours) to curcumin were also studied in a second cell type, Caco-2 cells.ResultsGene expression changes (>1.5-fold) were found at all time points. HT29 cells were more sensitive to curcumin than Caco-2 cells. Early response genes were involved in cell cycle, signal transduction, DNA repair, gene transcription, cell adhesion and xenobiotic metabolism. In HT29 cells curcumin modulated a number of cell cycle genes of which several have a role in transition through the G2/M phase. This corresponded to a cell cycle arrest in the G2/M phase as was observed by flow cytometry. Functional groups with a similar expression profile included genes involved in phase-II metabolism that were induced by curcumin after 12 and 24 hours. Expression of some cytochrome P450 genes was downregulated by curcumin in HT29 and Caco-2 cells. In addition, curcumin affected expression of metallothionein genes, tubulin genes, p53 and other genes involved in colon carcinogenesis.ConclusionsThis study has extended knowledge on pathways or processes already reported to be affected by curcumin (cell cycle arrest, phase-II genes). Moreover, potential new leads to genes and pathways that could play a role in colon cancer prevention by curcumin were identified.

BackgroundAs acetylsalicylic acid is metabolized by UDP-glucuronosyltransferase 1A6 (UGT1A6) and cytochrome P450 2C9 (CYP2C9), interindividual differences in activity of these enzymes may modulate the effects and side-effects of acetylsalicylic acid. The objective of this study was to assess whether polymorphisms in UGT1A6 and CYP2C9 genes are related to the prevalence of upper gastrointestinal symptoms in cardiovascular patients using acetylsalicylic acid for secondary prevention of ischaemic hear t disease. MethodsBlood samples were taken from acetylsalicylic acid using patients admitted to the Coronary Care Unit. Dyspepsia-related health was evaluated at week 2, using a validated upper gastrointestinal complaint questionnaire. A subset of 160 patients responded to a survey and were eligible to participate in this study. DNA was isolated and UGT1A6 and CYP2C9 genotypes were determined using polymerase chain reaction restricted fragment length polymorphism techniques. ResultsSeventy per cent of the patients returned the questionnaire. UGT1A6 and CYP2C9 variant polymorphisms were found in 103 (63%) and 56 (35%) patients, respectively. There was no association between gastrointestinal symptoms and UGT1A6 (OR = 0.80, 95% CI = 0.41-1.56) or CYP2C9 polymorphisms (OR = 0.85, 95% CI = 0.44-1.67). ConclusionsThere was no association between polymorphisms in genes encoding for acetylsalicylic acid metabolizing enzymes on the prevalence of gastric complaints in cardiovascular patients on acetylsalicylic acid.