Both are significantly associated with an increased risk of developing gastric carcinoma among Caucasians but not among Asians or Hispanics. IL-1B–31 C allele or homozygous CC plus TT, or IL-1B +3954 T allele, however, are not associated with buy GDC-0449 an increased risk of developing gastric cancer but IL-1B–31 homozygous CC plus TT is significantly inversely associated with the risk of intestinal type gastric cancer. Genotyping methods and publication time could constitute the sources of heterogeneity across studies. Publication biases are not found in our meta-analysis.

Appendix S1 Scales for quality assessment. Appendix S2A Study characteristics of genotypes in gastric cancer cases and controls in the analysis of IL-1B –511 polymorphism. Appendix S2B Study characteristics of genotypes in gastric cancer cases and controls in the analysis of IL-1B –31 polymorphism. Appendix S2C Study characteristics of genotypes in gastric cancer cases and controls in the analysis of IL-1B+3954 polymorphism.

Appendix S2D Study characteristics of genotypes in gastric cancer cases and controls in the analysis Hormones antagonist of IL-1 RN VNTR polymorphism. Please note: Wiley-Blackwell are not responsible for the content or functionality of any supporting materials supplied by the authors. Any queries (other than missing material) should be directed to the corresponding author for the article. “
“Endogenous ligands such as high-mobility group box 1 (HMGB1) and nucleic acids are released by dying cells and bind Toll-like receptors (TLRs). Because TLR9 sits at the interface of microbial and sterile inflammation by detecting both bacterial

and endogenous DNA, we investigated its role 上海皓元医药股份有限公司 in a model of segmental liver ischemia–reperfusion (I/R) injury. Mice were subjected to 1 hour of ischemia and 12 hours of reperfusion before assessment of liver injury, cytokines, and reactive oxygen species (ROS). Wild-type (WT) mice treated with an inhibitory cytosine-guanosine dinucleotide (iCpG) sequence and TLR9−/− mice had markedly reduced serum alanine aminotransferase (ALT) and inflammatory cytokines after liver I/R. Liver damage was mediated by bone marrow–derived cells because WT mice transplanted with TLR9−/− bone marrow were protected from hepatic I/R injury. Injury in WT mice partly depended on TLR9 signaling in neutrophils, which enhanced production of ROS, interleukin-6 (IL-6), and tumor necrosis factor (TNF). In vitro, DNA released from necrotic hepatocytes increased liver nonparenchymal cell (NPC) and neutrophil cytokine secretion through a TLR9-dependent mechanism. Inhibition of both TLR9 and HMGB1 caused maximal inflammatory cytokine suppression in neutrophil cultures and conferred even greater protection from I/R injury in vivo. Conclusion: TLR9 serves as an endogenous sensor of tissue necrosis that exacerbates the innate immune response during liver I/R.

1 μg/mL demecolcine, a potent mitotic poison, in combination with 100 μM 5HT. After 5 days 5HT in SFM caused 7- to 8-fold higher values of MTT activity in Huh7 and HepG2, whereas selleck chemical serum deprivation led to complete

cell death (Fig. 1D,E). This clearly could not only be attributed to increased cell viability but also to an enhanced rate of proliferation. Initial proliferation in SFM was prevented by demecolcine. The combination of 5HT and demecolcine abolished cell proliferation, but importantly, MTT activity did not drop below the baseline of 100% MTT activity. Thus, we concluded that 5HT predominantly promotes cell survival of Huh7 and HepG2 and this prerequisite facilitates cell proliferation. To identify a potential target receptor that is involved in 5HT-mediated survival of HCC cells we tested different agonists and antagonists. A scheme of the experimental setup is shown in Supporting Fig. 2A. 5HT2 receptors belong to the Gq/11 family

of G-proteins. Their stimulation results in the activation of phospholipase C (PLC) and further downstream in the activation of protein kinase C (PKC).5 The use of a classical see more PKC activator, phorbol 12-myristate 13-acetate (PMA), in Huh7 cells could mimic the effect of 5HT in serum-free culture conditions, indicating that class 2 receptors are potentially involved in 5HT-mediated cell survival (Supporting Fig. 2B). After administration of specific agonists for the receptors 1/7 (5-CT), 2A (DOI), and 2B (α-Me-HTP), we concluded that the 2B receptor is responsible receptor for 5HT-mediated cytoprotection. This finding was further supported with ritanserin, a general 5HT2-receptor antagonist.

Ritanserin was able to reverse the cytoprotection conferred by 5HT, whereas antagonists targeted for the 5HT-1A, -2A, and -7 receptor MCE公司 failed to provide an effect on cell viability (Supporting Fig. 2C). The presence of HTR2B was demonstrated by western blotting (Supporting Fig. 2D). In time-dependent experiments 5HT caused significantly higher values of MTT activity in Huh7 and HepG2 cells after 120 hours of serum deprivation compared to untreated cells (Fig. 2A,C). The same effect was also found with α-Me-HTP, a selective 5HT2B agonist17, 18 (Fig. 3B,D). When SB204741 (SB204), a selective 5HT2B antagonist,17, 18 was added during incubation with 5HT or α-Me-HTP the effect was abolished in a dose-dependent manner (Fig. 2A-D). Taken together, these experiments identified (1) the 5HT2B receptor as a mediator of survival, and (2) demonstrated that 5HT mediates proliferation of HCC cells as a result of cytoprotection. The combined Hoechst/TUNEL and calcein/ethidium stainings (Fig. 1A) suggested either necrotic or apoptotic cell death after serum deprivation. Therefore, we measured caspase-3 activity in Huh7 under different conditions to elucidate the cytoprotective mechanism of 5HT. Interestingly, serum deprivation was not associated with any detectable caspase-3 activity (Fig. 3A).

1 μg/mL demecolcine, a potent mitotic poison, in combination with 100 μM 5HT. After 5 days 5HT in SFM caused 7- to 8-fold higher values of MTT activity in Huh7 and HepG2, whereas Autophagy Compound Library cost serum deprivation led to complete

cell death (Fig. 1D,E). This clearly could not only be attributed to increased cell viability but also to an enhanced rate of proliferation. Initial proliferation in SFM was prevented by demecolcine. The combination of 5HT and demecolcine abolished cell proliferation, but importantly, MTT activity did not drop below the baseline of 100% MTT activity. Thus, we concluded that 5HT predominantly promotes cell survival of Huh7 and HepG2 and this prerequisite facilitates cell proliferation. To identify a potential target receptor that is involved in 5HT-mediated survival of HCC cells we tested different agonists and antagonists. A scheme of the experimental setup is shown in Supporting Fig. 2A. 5HT2 receptors belong to the Gq/11 family

of G-proteins. Their stimulation results in the activation of phospholipase C (PLC) and further downstream in the activation of protein kinase C (PKC).5 The use of a classical Y-27632 mw PKC activator, phorbol 12-myristate 13-acetate (PMA), in Huh7 cells could mimic the effect of 5HT in serum-free culture conditions, indicating that class 2 receptors are potentially involved in 5HT-mediated cell survival (Supporting Fig. 2B). After administration of specific agonists for the receptors 1/7 (5-CT), 2A (DOI), and 2B (α-Me-HTP), we concluded that the 2B receptor is responsible receptor for 5HT-mediated cytoprotection. This finding was further supported with ritanserin, a general 5HT2-receptor antagonist.

Ritanserin was able to reverse the cytoprotection conferred by 5HT, whereas antagonists targeted for the 5HT-1A, -2A, and -7 receptor 上海皓元医药股份有限公司 failed to provide an effect on cell viability (Supporting Fig. 2C). The presence of HTR2B was demonstrated by western blotting (Supporting Fig. 2D). In time-dependent experiments 5HT caused significantly higher values of MTT activity in Huh7 and HepG2 cells after 120 hours of serum deprivation compared to untreated cells (Fig. 2A,C). The same effect was also found with α-Me-HTP, a selective 5HT2B agonist17, 18 (Fig. 3B,D). When SB204741 (SB204), a selective 5HT2B antagonist,17, 18 was added during incubation with 5HT or α-Me-HTP the effect was abolished in a dose-dependent manner (Fig. 2A-D). Taken together, these experiments identified (1) the 5HT2B receptor as a mediator of survival, and (2) demonstrated that 5HT mediates proliferation of HCC cells as a result of cytoprotection. The combined Hoechst/TUNEL and calcein/ethidium stainings (Fig. 1A) suggested either necrotic or apoptotic cell death after serum deprivation. Therefore, we measured caspase-3 activity in Huh7 under different conditions to elucidate the cytoprotective mechanism of 5HT. Interestingly, serum deprivation was not associated with any detectable caspase-3 activity (Fig. 3A).

43,44,182 At the time of diagnosis, cirrhosis is present in ∼25% of patients.183,184 Antibodies to SLA have emerged as possible prognostic markers that may identify patients with severe AIH who are prone to relapse after corticosteroid withdrawal.134,137-140,179,185 Type 2 AIH is characterized by the presence of anti-LKM1112 and/or

anti-LC1 and/or anti-LKM-3. Most patients with type 2 AIH are children, and serum immunoglobulin levels are usually elevated except for the concentration of IgA, which may be reduced.112 Concurrent immune diseases are common,112 progression to cirrhosis occurs,112 and an acute severe presentation is possible.58,64 Recommendations: 5. check details Classification of autoimmune hepatitis into two types based on the presence of ANA and SMA (type 1 AIH) or anti-LKM1 and anti-LC1 (type 2 AIH) can be used to characterize the clinical syndrome

or to indicate serological homogeneity in clinical investigations. Anti-LKM1 antibodies should be routinely investigated to avoid overlooking type 2 AIH. (Class IIa, Level C) PSC and PBC can have clinical, laboratory, histological, and genetic findings that resemble those of AIH,95,206-212 and AIH can have features that resemble each of these cholestatic syndromes.36,81,82,213-217 These nonspecific shared features can confound the codified diagnostic scoring system.13,76,78 The prevalence of AIH among patients with PSC was determined to be 21%-54% using the original scoring system,218,219 but this prevalence decreased to 8% in PSC when the revised original Midostaurin scoring system was

applied.206,220,221 Application of the original scoring system in a retrospective review of 141 patients with PBC showed that 19% and 0% scored as probable and definite AIH, respectively.222 Clinical 上海皓元 judgment is required to determine the predominant phenotype of the disease and to manage the process appropriately.95,223 AIH patients may demonstrate serological features that suggest another diagnosis. AMA occur in about 5% of AIH patients in the absence of other biliary features (“serological overlap”),178,224-228 and their presence may confound the clinical diagnosis. AMA may disappear226 or persist as long as 27 years without an evolution into PBC.227 The revised original scoring system can render a diagnosis of “probable AIH” in these patients, if other features of AIH are sufficiently strong.229,230 Other acute and chronic liver diseases of diverse etiologies that can have serological features of AIH include alcoholic231 and nonalcoholic fatty liver disease,232,233 acute234 and chronic54,235-241 viral hepatitis, and drug-induced hepatitis.242,243 Drugs such as minocycline,244-246 diclofenac,247,248 infliximab,249 propylthiouracil,250 atorvastatin,251 nitrofurantoin,252 methyl dopa,253 and isoniazid254 can cause a syndrome that resembles AIH replete with autoantibodies that generally disappear after discontinuation of the drug.

There were different esophageal motility appearances in the cases with different diseases. There was impaired LES relaxation in the DM RG7204 ic50 patient and peristaltic dysfunction in the CTD patient as the significant abnormal esophageal motility inspection. Almost half of the GERD patients were with

normal esophageal motilities. Key Word(s): 1. Dysphagia; 2. esophageal manometry; Table 1 EM DISEASE NORMAL NP ≥ 8 mmHg NE MED SED LOW-LESP EM: esophageal motility; NE: nutcracker esophagus; MED: mild peristaltic dysfunction; SED: severe peristaltic dysfunction Presenting Author: TANISA PATCHARATRAKUL Additional Authors: KESSARIN THANAPIROM, SUTEP GONLACHANVIT Corresponding Author: TANISA PATCHARATRAKUL Affiliations: King Chulalongkorn Memorial Hospital Objective: To compare the saliva swallowing

rate in patients with chronic throat burning/pain symptoms with healthy volunteers (HV) by using 24 hr esophageal pH-impedance monitoring. Methods: 9 HVs (4F, 29 ± 6 yr) and 20 patients (14F, 45 ± 13 yr) who were suspected of laryngopharyngeal reflux disease with disturbed throat burning/pain symptoms > 3 months, but had negative pH results were included. All were interviewed regarding gastrointestinal, upper respiratory tract and throat symptoms and underwent the pH-impedance monitoring during off treatment. Swallow events during meal ingestion or drinking were excluded. Saliva swallows were defined AZD1208 cost as the downward propagation of impedance

decreasing > 1/3 from baseline for > 2 consecutive channels and complete saliva swallows were defined as the decrease of impedance propagated downward to the most distal esophagus. Complete gas swallows were the propagation of rapidly increased impedance which increased > 3,000 Ohm from baseline to the most distal esophagus. Results: The MCE公司 pH impedance study duration was 22 ± 2 hrs for patients and 21 ± 1 hrs for HVs. The rate of all swallows (saliva and/or gas) was 18.5 ± 10.3 times/hr and 30.1 ± 9.2 times/hr in patients and HVs (p < 0.01), respectively. The rate of complete saliva and complete gas swallowing in patients was significantly lower than HVs (5.1 ± 5.0 vs. 12.9 ± 6.4; p = 0.001 and 2.6 ± 2.5 vs. 4.6 ± 1.9 times/hour; p < 0.05, respectively). During 2 hour-post-prandial period complete saliva swallowing rate in the patients was significantly lower than HVs (8.7 ± 6.7 vs. 14.8 ± 6.8 times/hour p < 0.05), whereas complete gas swallowing rate was not significantly different (6.7 ± 6.2 vs. 4.8 ± 2.2 times/hour p > 0.05). The proportion of incomplete/complete saliva swallowing rate was significantly higher in patients than controls (5.8 ± 7.0 vs. 1.4 ± 1.9, p < 0.05). Conclusion: In patients with chronic throat burning or pain, swallowing events were significantly less often than healthy volunteer, especially complete saliva swallowing rate with higher proportion of incomplete saliva swallowing.

Patients presenting with occult OGIB used antithrombotics significantly more often than the ones with visible OGIB (p = 0,049). We found no significant correlation between antithrombotics and P1 or P2 lesion findings in CE. However, when a sub-analysis was performed, there was a significant correlation between anticoagulant drugs and a higher incidence for P1-P2 lesions in the small bowel (p = 0,045). Conclusion: Antithrombotic drugs, whose usage was very frequent JNK inhibitor in vitro in patients presenting with OGIB, were significantly associated with an occult bleeding presentation.Both uncertain bleeding potential (P1)

and high bleeding potential (P2) small bowel lesions were more frequently found in the capsule enteroscopy when the patient was on anticoagulant drugs. Key Word(s): 1. Capsule enteroscopy; 2. OGIB; 3. Antiplatelet; 4. Anticoagulant; Presenting Author: LIANYING YU Additional Authors: QIYI WANG, WEIHONG SHA Corresponding Author: QIYI WANG Affiliations:

guangdong general hospital Objective: The aim of this study was evaluate the mechanisms and preventive effect of different kinds of propton pump inhibitor (PPI) on dual anti-platelet drugs induced gastrointestinal injury. Methods: Seventy male Sprague-Dawley HCS assay (SD) rats were divided into seven groups. Each group contained 10 rats. The rats in blank group received saline for 10ds. Dual anti-platelet therapy including aspirin (Asp) 100 mg/kg/d and clopidogrel (Clo) 75 mg/kg/d for 10ds were given to the rats as control group. Based on the dual anti-platelet therapy, the one in omeprazole (Ome), lansoprazole(Lan), esomeprazole (Eso), pantoprazole (Pan) and rabeprazole (Rab) groups were given Ome 20 mg /kg/d, Lan 20 mg/kg/d, Eso 20 mg/kg/d, Pan 40 mg/kg/d,

Rab 20 mg/kg/d for 10ds, respectively. After 10ds continuous medication, the Lesion index (LI), pathological 上海皓元 index (PI), ICAM-1, microvessel density (MVD) and PGE2 in gastric mucosal were estimated to evaluate the gastric mucosal injury. Results: Compared with control group, the LI and PI in all PPIs groups were decreased significantly, all p < 0.05. The ICAM-1 expressions in all PPI groups were significantly weaker than that in control group, all p < 0.05. The MVD in all PPIs groups were significantly lower than that in control group, all p < 0.05. But there was no difference among different PPIs groups for the above parameters. The PGE2 in gastric mucosa in control and all PPI groups decreased significantly as compared with blank group, all p < 0.05, but no difference was found among the control and all PPIs groups. Conclusion: PPIs can prevent dual anti-platelet drugs induced gastrointestinal injury. The prevention mainly relates to the increasing of intragastric pH but not relates to the improving of MVD and PGE2. Key Word(s): 1. PPIs; 2. clopidogrel; 3. gastric lesion; 4.

95 Total doses range from 4-24 g/day. All other medications must be given at least 1-2 hours before or after administration of these binding resins to avoid interference with their absorption. Side effects such as constipation and hyperchloridemia may occur. Rifampicin (150-300 mg twice a day) may also be effective RO4929097 order in patients intolerant to binding resins.96,97 Rifampicin is also a ligand for the nuclear receptor PXR, and ligand activation of this receptor induces expression of CYP isoforms that are capable

of detoxification of hydrophobic bile salts.98,99 Side effects of rifampicin include hepatic toxicity. Phenobarbital (1-5 mg/kg/day divided in three doses) also induces hepatic microsomal enzymes via activation of constitutive androstane receptor100 and therefore may facilitate detoxification and inactivation of putative peripheral pruritogens.101 However, long-term administration

of microsomal inducers may impair vitamin D metabolism. Alternatives are limited but include the opiate antagonists naloxone and naltrexone.91,102,103 Invasive procedures, including plasmapheresis and extracorporeal albumin dialysis using the Molecular Adsorbent Recirculating System (MARS), are reported to relieve severe pruritus,104 but both procedures may require hospitalization and significant input from renal dialysis staff. Severe pruritus can even be an indication for liver transplantation. Ursodeoxycholic acid (UDCA) is currently BMN 673 manufacturer the only established drug for the treatment of cholestatic liver disease, and it has cytoprotective, immunomodulatory, antiapoptotic, and choleretic effects.105 UDCA is also a strong agonist of PXR, an important nuclear receptor that up-regulates

CYP3A4.106 Experimental studies in rats have demonstrated that UDCA improves cholestasis induced by phalloidin, 17β-estradiol glucuronide, 上海皓元 and endotoxins.106-109 UDCA increases the expression of canalicular export pumps for bile salts (BSEP) and other organic anions including bilirubin (MRP2) which stimulates bile secretion.110,111 UDCA also stimulates the insertion of these export pumps into the canalicular membrane in a protein kinase C and p38 mitogen-activated protein kinase–dependent fashion.111,112 UDCA stimulates targeting of P-glycoprotein (MDR1) to the canalicular membrane, which could prevent cyclosporine-associated cholestatic effects.113 Although the mechanism of UDCA’s beneficial effect in cholestasis is not clearly understood, it is thought that its primary beneficial effect is decreasing the hydrophobicity of the bile acid pool by replacing toxic (e.g., hydrophobic) with nontoxic (e.g., hydrophilic) bile acids.105 UDCA is best administered at bedtime to avoid inhibition of its absorption when administered with cholestyramine or colestipol.

Table 1. Conventional white light gastroscopy findings Adenocarcinoma 2 Esophagitis SB203580 research buy 12 Hiatal hernia 9 Gastropathy (hyperemic) 71 Gastropathy (erosive) 7 Gastric atrophy 19 Metaplasia 2 Gastric ulcer 3 Of the 19 patients with endoscopic signs of atrophy 17 (90%) were confirmed by histology, in 14 patients (74 %) mild (OLGA stage I) and in 3 (16%) patients moderate (OLGA II) atrophy. Moreover 54 patients (67%) of endoscopically negative patients (n = 81) were diagnosed gastric mucosa atrophy histologically (47 (87%) = OLGA I, 6 (11%) = OLGA II and 1 (2%) = OLGA III. The negative predictive

value (NPV) is 34%. The sensitivity and specificity of endoscopy for the diagnosis of atrophy based on histological diagnosis of atrophy were 57.7% and 93.5%. Conclusion: Conventional white light endoscopy

cannot accurately diagnose atrophic gastritis in patients with changed serum pepsinogen tests (high risk group). Advanced endoscopy tecniques: magnification chromoendoscopy or narrow-band imaging (NBI)/flexible spectral imaging color enhancement (FICE) endoscopy with or without magnification may be offered in high risk patients as it improves diagnosis of such lesions. Key Word(s): 1. gastroscopy; 2. gastric atrophy; 3. serum pepsinogens; 4. diagnosis of atrophy; Presenting Author: RUSTEMOVIC NADAN Additional Authors: CUKOVIC-CAVKA SILVIJA, OPACIC MILORAD, BRINAR MARKO Corresponding Author: RUSTEMOVIC NADAN Affiliations: selleckchem Univ.Hospital Rebro Zagreb Objective: Recognition of specific IBD phenotype is sometimes difficult. The lack of specificity for the early diagnosis of pancreatic cancer(PC) based on symptoms that are also features of chronic pancreatitis(CP) requires histological proof. The aim of the study was to evaluate the real potentials of elastography in the field of inflammation and malignancy. Methods: A total of 55 IBD patients (30 with CD, 25 with UC), 48 patients with PC and 34 patients with CP

were included. Transrectal EUS-E was performed in all IBD patients, and standard EUS-E in other group. Results: A significant difference in strain ratio (SR) (median 1.18 vs 0.65; p = 0.0001) 上海皓元 was detected between CD and UC groups. Active CD patients had a significantly higher SR compared to active UC patients. A significant difference in SR was observed between patients with PC and CP. In patients with pancreatic disease, ROC curve analysis detected SR value of 11.85 that had a 97,5% sensitivity and 95% specificity for PC. Patients with PC had a significantly higher SR in comparison with patients with all IBD phenotypes (median 22.54 vs 0.82; p = 0.0001). Conclusion: EUS-E shows highly significant sensitivity and specificity for distinction between PC and CP. On the other hand, single endoscopy presentation often combined with histology is not conclusive enough for defining the phenotype of IBD in most cases.

Newer regimens are required to improve eradication rate. This study was designed to determine the efficacy of levofloxacin-based triple therapy as a second-line eradication therapy after failed triple therapy. Methods: Total of 58 patients with the mean age of 54.8 years who

previously failed to respond to 7–10 days of standard triple therapy as indicated by positive 13C-UBT or positive CLO-test were enrolled. Antral biopsy samples were obtained for culture and sensitivity using standard E-test for amoxicillin and levofloxacin resistance. Patients were received 10-day treatment of levofloxacin (500 mg) once a day plus lanzoprazole (30 mg) bid and amoxicillin 1000 mg OTX015 bid. 13C-UBT was performed 4 weeks after therapy to assess eradication. Results: Eradication rate of levofloxacin given once daily plus lanzoprazole and amoxicillin resulted in 82% eradication rate. In vitro levofloxacin resistance was not associated with eradication failure using this regimen as second-line therapy. Age and sex did not predict eradication failure. About 10% of patients reported side effects but none of the patients dropped out. Conclusion: Levofloxacin-based triple therapy using levofloxacin 500 mg once daily is effective in H.pylori eradication after failed triple therapy with eradication rate of 82%.

The regimen is simple and tolerable. Accumulative eradication rate with triple therapy followed by levofloxacin-based regimen is about 94%. In-vitro resistance, age, sex were not associated with eradication failure with this second-line therapy. Key Word(s): 1. levofloxacin; 2. H. pylori; 3. eradication; Presenting Author: learn more YAO-JONG YANG Additional Authors: CHING-CHUN CHUANG, HSIAO-BAI YANG, CHENG-CHAN LU, BOR-SHYANG

SHEU Corresponding Author: YAO-JONG YANG, BOR-SHYANG SHEU Affiliations: National Cheng Kung University Hospital; Ton-Yen General Hospital Objective: It has been reported that H. pylori infection is associated with increased expression of gastric Smad7 and NFκB. Probiotics is related to the changes of host immune responses to variable infections. The study aimed to examine whether probiotics can improve H. pylori-induced gastric inflammation MCE公司 through the inactivation of Smad7 and NFκB pathways. Methods: MKN45 and AGS cells were infected by Lactobacillus acidophilus isolated from yogurt and a clinical H. pylori strain (HP238) at various doses and time periods. The concentrations of TNF-α and IL-8 were measured by ELISA. RT-PCR was used to identify the Jak1, Stat1, and Smad7 RNAs with specific primers. Cytoplasmic Smad7, IκBα and nuclear NFκB p65 protein was detected by western blotting. Results: Challenge with H. pylori increased expressions of IL-8, TNF-α, NFκB, and Smad7, but not TGF-β1 in gastric epithelial cells in vitro. A higher dose (MOI 100) of L. acidophilus pre-treatment attenuated the H. pylori-induced IL-8 expressions, but not TGF-β1.

HEPATOLOGY 2010 Cytosolic

Ca2+ is a ubiquitous intracellular messenger.1 In the liver, Ca2+ signals have been linked to the regulation of such diverse functions PD0325901 cost as gene expression,2, 3 cell proliferation,4 apoptosis,5-7 paracellular permeability,8 glucose release,9, 10 and bile flow.11 Ca2+ signaling in hepatocytes is mainly controlled by the inositol 1,4,5-trisphosphate receptor (InsP3R), an InsP3-gated Ca2+ channel in the endoplasmic reticulum. InsP3Rs type I (InsP3R1) and type II (InsP3R2)12, 13 are the two InsP3R isoforms expressed in hepatocytes. InsP3R2 is the most highly expressed of these isoforms and is concentrated in the region of the endoplasmic reticulum near the canalicular membrane. Thus it is in close proximity to canalicular transporters,14 which selleck inhibitor are either inserted into the canalicular plasma membrane or localized to subplasmalemmal vesicles.15 Activation of InsP3Rs in the apical region of other epithelia generates a spatially restricted domain with Ca2+ concentrations as high as approximately 10 μM,16 which is sufficient to induce

vesicular exocytosis.17 Secretion of a wide variety of amphiphilic organic anions into bile, including bilirubin, glutathione S-conjugates, and oxidized glutathione, occurs through multidrug resistance-associated protein 2 (Mrp2), a member of the ATP binding cassette family of transporters.18 Mrp2 activity is partially regulated by its dynamic trafficking between the canalicular plasma membrane and a nearby endosomal compartment. Cholestatic agents such as estradiol,19 lipopolysaccharide,20 lithocholic acid,21 and phalloidin22 act in part by decreasing insertion of Mrp2 into the plasma membrane. Fusion of vesicles with the plasma membrane involves Ca2+-dependent proteins in nearly every cell type,23 and Ca2+ signals induced by tauroursodeoxycholic acid (TUDCA) have been linked to exocytosis in hepatocytes24, 25; yet the role of Ca2+ in regulating organic anion secretion is not known. Therefore, we investigated the role of InsP3R2-mediated Ca2+ release in the localization and activity of Mrp2. AM, fluo-4/acetoxymethyl ester; ANOVA,

analysis of variance; ATP, adenosine triphosphate; AVP, arg8-vasopressin; BAPTA, 1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid; cAMP, cyclic adenosine monophosphate; CMFDA, 5-chloromethylfluorescein 上海皓元 diacetate; InsP3R, inositol 1,4,5-triphosphate receptor; GFP, green fluorescent protein; KO, knockout; Mrp2, multidrug resistance-associated protein 2; PKC, protein kinase C; TIRF, total internal reflection fluorescence; TUDCA, tauroursodeoxycholic acid; WT, wild-type; TLCA, taurolithocholic acid. Male Swiss black wild-type (WT) mice obtained from Taconic Farms Inc (Hudson, NY) and InsP3R2 knockout (KO) mice described previously26 were used for experiments. Animals were maintained on a standard diet and housed under a 12-hour light/dark cycle. All animal procedures were approved by the Yale University Institutional Animal Care and Use Committee.