Takanori Yamada

Twice‐daily dosing of esomeprazole effectively inhibits acid secretion in CYP2C19 rapid metabolisers compared with twice‐daily omeprazole, rabeprazole or lansoprazole

Twice‐daily dosing of proton pump inhibitors (PPIs) is used to treat Helicobacter pylori or acid‐related diseases, such as gastro‐oesophageal reflux disease (GERD) refractory to standard dose of a PPI. Genetic polymorphisms of CYP2C19 are involved to different extents in the metabolism of four kinds of PPIs (omeprazole, lansoprazole, rabeprazole and esomeprazole) available in Japan.

Sitafloxacin-based third-line rescue regimens for Helicobacter pylori infection in Japan.

Quinolone‐based regimens have been used as the rescue for eradication of Helicobacter pylori. Sitafloxacin is known to have low minimum inhibitory concentration for H. pylori. Here, we compared two sitafloxacin‐based eradication regimens as rescue for the eradication of H. pylori.

Ability of rabeprazole to prevent gastric mucosal damage from clopidogrel and low doses of aspirin depends on CYP2C19 genotype

BACKGROUND & AIMS Low doses of aspirin can injure the gastric mucosa. It is not clear whether other drugs such as the antiplatelet agent clopidogrel also cause gastric mucosal injury or exacerbate aspirin-induced injury, or whether proton pump inhibitors prevent damage. METHODS Twenty Japanese subjects with different CYP2C19 genotypes were randomly assigned to groups that were given a low dose of aspirin (100 mg; A), clopidogrel (75 mg; C), low dose of aspirin and clopidogrel (AC), or low dose of aspirin in combination with clopidogrel and rabeprazole (10 mg; ACR) once daily for 7 days. Subjects underwent gastroduodenoscopy and platelet tests on days 3 and 7; gastric mucosal damage was assessed by using the modified Lanza score (MLS). We performed 24-hour intragastric pH monitoring on day 7 of each regimen. We also analyzed the effects of the AC regimen on 30 patients with different CYP2C19 genotypes. RESULTS Subjects in groups A, C, and AC had significantly higher levels of gastric mucosal damage on days 3 and 7, compared with baseline. The median MLS for the AC group was similar to that of the A group. Helicobacter pylori-negative subjects in the ACR group with different CYP2C19 genotypes had significant differences in MLS, intragastric pH, and platelet function. Gastric mucosal injury was inhibited equally among H pylori-positive subjects in the ACR group. Rabeprazole did not appear to affect platelet function or intragastric pH in subjects given clopidogrel. CONCLUSIONS Clopidogrel and low doses of aspirin cause a similar degree of gastric mucosal damage. Rabeprazole prevented this damage without reducing the antiplatelet function of clopidogrel. However, its prophylactic effect varies with CYP2C19 genotype in H pylori-negative subjects.

Norepinephrine suppresses IFN-γ and TNF-α production by murine intestinal intraepithelial lymphocytes via the β1 adrenoceptor

We examined whether norepinephrine (NE) had direct effects on cytokine production by murine intestinal intraepithelial lymphocytes (IELs), compared with splenocytes. CD3⁺ IELs and CD3⁺ splenocytes expressed α(1B), α(1D), α(2C), β₁, β₂, and β₃ adrenoceptors (ARs). NE significantly suppressed IFN-γ and TNF-α production by IELs and splenocytes ex vivo. The suppressive effects of NE in IELs were reversed by β₁ AR antagonist CGP-20712A, whereas those in splenocytes were reversed by β₂ AR antagonist ICI118,551. In IELs, β₁ AR agonist xamoterol mimicked the suppressive effects of NE. These results indicated NE regulates intestinal mucosal immune responses mediated by IELs via β₁ AR.

Cytokine responses of intraepithelial lymphocytes are regulated by histamine H2 receptor

BackgroundsHistamine participates in the immune regulation of several gastrointestinal diseases. However, the effect of histamine on intestinal intraepithelial lymphocytes (IELs), the front line of the intestinal mucosal immune system, is not well understood. We examined whether histamine has a direct effect on cytokine production by IELs and the involvement of histamine receptor subtypes.MethodsMurine IELs were activated by PMA plus ionomycin with/without histamine. Secreted cytokines were measured and compared with those of splenocytes. Intracellular cytokines were detected by flow cytometry. Expression of histamine receptor subtypes in IELs was examined by RT-PCR.ResultsHistamine H1 receptor (H1R), H2R, and H4R, but not H3R mRNA were expressed on IELs. Histamine significantly decreased Th1-cytokine (IFN-γ, TNF-α, and IL-2) and also IL-4 production in IELs as well as splenocytes. The selective H2R antagonist famotidine, but not the H1R antagonist pyrilamine nor the H3R/H4R antagonist thioperamide, competes with the inhibitory effect of histamine on these cytokine production in IELs. These suppressive effects of histamine were mimicked by a selective H2R/H4R agonist dimaprit. Further, these suppressive effects of histamine for Th1-cytokine and IL-4 did not accompany the enhancement of IL-10 production or IL-10 mRNA level in IELs. Intracellular cytokine analysis revealed that the number of IFN-γ-producing αβ T cells was significantly reduced by histamine in IELs.ConclusionsHistamine has a direct suppressive effect on IEL-derived cytokines via H2R, which would have a crucial role in the suppression of local immunoregulation in the intestinal epithelium.

Effect of dosing schemes of amoxicillin on eradication rates of Helicobacter pylori with amoxicillin-based triple therapy

In standard regimens for Helicobacter pylori infection, amoxicillin is dosed twice daily, although the bactericidal effect of amoxicillin depends on the %time‐above‐MIC. We aimed to examine whether dosing schemes of amoxicillin influenced eradication rates of amoxicillin‐based regimens.

A distinct expression pattern of the long 3'-untranslated region dicer mRNA and its implications for posttranscriptional regulation in colorectal cancer.

OBJECTIVES:Reduced expression of Dicer is associated with global downregulation of microRNAs. Primary Dicer transcripts can be processed at two alternative polyadenylation sites, generating two pools of messenger RNAs (mRNAs) that carry either a long or a short 3′-untranslated regions (3′UTRs), that both encode the same Dicer protein. The short 3′UTR Dicer mRNA is not regulated by miR-103/107. The aim of this study was to investigate the expression of total Dicer mRNA, long 3′UTR Dicer mRNA, and miR-103 in colorectal cancer (CRC).METHODS:Paired tumor and normal mucosal specimens were obtained from 66 patients with CRC. Real-time reverse transcription PCR of long 3′UTR Dicer mRNA, total Dicer mRNA and miR-103 was carried out using the TaqMan Expression assay and the TaqMan MicroRNA assay.RESULTS:The median expression level of coding Dicer mRNA in the tumors was significantly lower than that in normal mucosa (P<0.001). There was no significant difference in expression levels of long 3′UTR Dicer mRNA between the tumors and the normal mucosa (P=0.90). The median expression ratio of long 3′UTR Dicer mRNA to total Dicer mRNA in tumors was significantly higher than in normal mucosa (P<0.001). There was no significant difference in expression levels of miR-103 between the tumors and normal mucosa (P=0.17). There was no significant correlation between clinicopathological findings, such as stage, tumor location, and histological grade and expression levels of total Dicer mRNA, long 3′UTR Dicer mRNA, or expression ratio of long 3′UTR Dicer mRNA to total Dicer mRNA.CONCLUSIONS:These results suggest that both transcriptional and posttranscriptional dysregulation of Dicer expression may be involved in colon carcinogenesis.

Influence of prostate stem cell antigen gene polymorphisms on susceptibility to Helicobacter pylori-associated diseases: a case-control study.

Patients with duodenal ulcer have a reduced risk of developing gastric cancer compared to those without. Recently, the prostate stem cell antigen (PSCA) rs2294008 C>T polymorphism was found to be associated with different pathogenesis of duodenal ulcer and gastric cancer developments. However, whether PSCA rs2294008 C>T polymorphism is associated with severity of gastric mucosal atrophy is unclear. We examined the influence of the PSCA rs2294008 C>T polymorphism on susceptibility to H. pylori‐related diseases and the relationships between PSCA polymorphism and gastric mucosal atrophy.

Guggulsterone, a Plant-Derived Inhibitor of NF-TB, Suppresses CDX2 and COX-2 Expression and Reduces the Viability of Esophageal Adenocarcinoma Cells

Background/Aims: Induction by bile acid of caudal type homeobox 2 (CDX2) and cyclooxygenase-2 (COX-2) expression via nuclear factor-TB (NF-TB) activation is a critical event in the development of Barretts esophagus (BE) and esophageal adenocarcinoma (EAC). Guggulsterone (GS) is a plant sterol that inhibits NF-TB activity. Here, we evaluated whether GS has either or both chemopreventive or therapeutic effects against EAC. Methods: Two EAC cells lines were treated with deoxycholic acid (DCA) in the presence of GS or vehicle. The levels of transcription and translation of ITBE, CDX2, and COX-2 were determined. Prostaglandin E2 (PGE2) levels, cell viability, and cell cycle distribution were assessed as well. Results: GS inhibited DCA-induced ITBE phosphorylation. GS and the NF-TB inhibitor BAY11-7085 suppressed DCA-induced CDX2 and COX-2 expression in EAC cells. GS also suppressed basal transcription levels of CDX2 and COX-2 and reduced constitutive synthesis of COX-2 and PGE2. Further, GS reduced the viability of EAC cells, increased their numbers in the apoptotic sub-G1 fraction. Conclusion: GS suppressed DCA-induced and NF-TB-dependent activation of CDX2 and COX-2 expression. Further, GS also reduced the viability of EAC cells. GS may serve as candidate for preventing and treating EAC and BE. i 2014 S. Karger AG, Basel

Statins directly suppress cytokine production in murine intraepithelial lymphocytes

Statins, inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, are known not only as cholesterol-lowering agents but also as anti-inflammatory mediators. However, their regulatory effect on intestinal mucosal immunity remains unclear. The present study examined the possible direct effects of statin on intestinal intraepithelial lymphocytes (IELs), the front line cells of the intestinal mucosal immune system. Murine IELs were isolated from the small intestines of C57BL/6 mice. IELs activated with anti-CD3/CD28 monoclonal antibodies produced interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-2, and IL-4 in significant numbers; however, they did not produce IL-5. Both simvastatin and lovastatin suppressed IEL production of IFN-γ, TNF-α, IL-2, and IL-4 in a dose-dependent manner, whereas 48-h treatment with high concentrations (5 × 10(-5)M) of simvastatin and lovastatin did not affect the number of IELs. The suppressive effect of the simvastatin was significantly restored by the addition of mevalonate, farnesyl pyrophosphate ammonium salt, and geranylgeranyl pyrophosphate ammonium salt, which are downstream metabolites of HMG-CoA. These findings suggest that statins have direct suppressive effects on the production of T helper 1-cytokines and IL-4 in IELs; these effects are associated with inhibition of the mevalonate pathway to some extent.