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Background & Aims: Pancreatic stellate cells have some similarities to hepatic stellate cells and an intrinsic renin-angiotensin system is present in the pancreas and is enhanced in acute pancreatitis and chronic pancreatic hypoxia. We assessed the effects of lisinopril, an angiotensin-converting enzyme (ACE) inhibitor, on spontaneously occurring chronic pancreatitis. Methods: Lisinopril in drinking water (20, 50, or 200 mg/L) was administered to 10-week-old male Wistar Bonn/Kobori (WBN/Kob) rats for 10 weeks and then the inflammatory parameters, fibrosis, serum and pancreatic ACE activity, and expression of transforming growth factor-β1 (TGF-β1) messenger RNA (mRNA) as well as positive immunostaining for α-smooth muscle actin (α-SMA) were assessed. Results: Lisinopril attenuated gross alterations in the pancreas. This protective effect was confirmed quantitatively by significant increases in pancreatic weights and decreases in pancreatic myeloperoxidase (MPO) activity (an index of granulocyte infiltration), pancreatic hydroxyproline content (an index of collagen deposition), ratio of fibrous tissue, and histologic scores. Lisinopril significantly reduced serum ACE activity but it did not affect pancreatic activity. High doses of lisinopril suppressed the overexpression of TGF-β1 mRNA measured by reverse-transcription polymerase chain reaction (RT-PCR) and decreased the number of α-SMA-positive cells (activated pancreatic stellate cells) in the pancreas. Conclusions: Lisinopril alleviated chronic pancreatitis and fibrosis in male WBN/Kob rats. It suppressed the expression of TGF-β1 mRNA, resulting in the prevention of pancreatic stellate cell activation, which may be involved in the observed protection. We propose that an ACE inhibitor may be useful for treating chronic pancreatitis.

Background & Aims Cells of tumors associated with chronic inflammation frequently have altered patterns of DNA methylation, including hepatocellular carcinomas. Chronic hepatitis has also been associated with aberrant DNA methylation, but little is known about their relationship. Methods Pyrosequencing was used to determine the methylation status of cultured Huh7.5.1 hepatoma cells after hepatitis C virus (HCV) infection. We also studied mice with severe combined immunodeficiency carrying the urokinase-type plasminogen activator transgene controlled by an albumin promoter (urokinase-type plasminogen activator/severe combined immunodeficient mice), in which up to 85% of hepatocytes were replaced by human hepatocytes (chimeric mice). Mice were given intravenous injections of hepatitis B virus (HBV) or HCV, liver tissues were collected, and DNA methylation profiles were determined at different time points after infection. We also compared methylation patterns between paired samples of hepatocellular carcinomas and adjacent nontumor liver tissues from patients. Results No reproducible changes in DNA methylation were observed after infection of Huh7.5.1 cells with HCV. Livers from HBV- and HCV-infected mice had genome-wide, time-dependent changes in DNA methylation, compared with uninfected urokinase-type plasminogen activator/severe combined immunodeficient mice. There were changes in 160 ± 63 genes in HBV-infected and 237 ± 110 genes in HCV-infected mice. Methylation of 149 common genes increased in HBV- and HCV-infected mice; methylation of some of these genes also increased in hepatocellular carcinoma samples from patients compared with nontumor tissues. Expression of Ifng , which is expressed by natural killer cells, increased significantly in chimeric livers, in concordance with induction of DNA methylation, after infection with HBV or HCV. Induction of Ifng was reduced after administration of an inhibitor of natural killer cell function (anti−asialo GM1). Conclusions In chimeric mice with humanized livers, infection with HBV and HCV appears to activate a natural kill cell−dependent innate immune response. This contributes to the induction and accumulation of aberrant DNA methylation in human hepatocytes.

19.85, 13.14, 8.94 μmol/L in MKN45 at 24, 48, and 72 hours, respectively. MK-2206 enhanced apoptosis in SGC-7901 and increased the expression level of cleaved PARP. The combination therapy of MK-2206 and doxorubicin or 5-fluorouracil, showed a synergistic pattern of combination indexes in SGC-7901 and MKN45 cells, indicating an enhanced inhibition by MK-2206 co-treatment. Furthermore, a small dose (1 μmol/L) of MK-2206 was sufficient for complete inhibition of chemotherapeutic-alteration of pAkt expression and significant enhancement of pro-apoptosis effect through the activation of caspase pathway. Conclusion MK-2206 could effectively inhibit gastric cancer cell growth by attenuation of Akt phosphorylation. Additionally, MK-2206 could synergistically enhance the antitumor effect of doxorubicin or 5-fluorouracil via caspase-dependent apoptosis.

Background & Aims: The epidermal growth factor (EGF) receptor (EGFR) can be transactivated by many factors including G-protein-coupled receptor agonists and cytokines. Although this EGFR transactivation reportedly requires a disintegrin and metalloproteinase (ADAM) that sheds the ectodomain of EGFR ligands, the detailed mechanisms are still unknown. This study evaluated the mechanism of interleukin (IL)-8- and IL-1β-dependent shedding of the EGFR ligand in KATO III cells. Methods: We established transfectants stably expressing alkaline phosphatase-tagged heparin-binding EGF-like growth factor (HB-EGF), transforming growth factor α, or amphiregulin precursors, and depleted ADAM proteins, using short interfering RNA against ADAM10, 12, or 17. We assessed shedding of EGFR ligands by measuring AP activities in the conditioned media after IL-1β or IL-8 stimulation. EGFR activation was examined by immunoprecipitation and Western blotting using antiphosphotyrosine antibody. KB-R7785 and anti-IL-8 neutralizing antibody were used to inhibit activities of ADAMs and IL-8 action, respectively. Results: IL-8 dose dependently released the EGFR ligands and transiently phosphorylated EGFR, with a peak at 15 minutes. KB-R7785 completely blocked IL-8-induced shedding and EGFR transactivation. Depletion of ADAM10 also dramatically reduced IL-8-induced shedding and EGFR transactivation, but depletion of ADAM12 and 17 did not. IL-1β dose dependently enhanced shedding of HB-EGF, which was not blocked by KB-R7785 in the early phase. In the late phase, however, the EGFR transactivation was blocked by KB-R7785 and abrogated by anti-IL-8 neutralizing antibody. Conclusions: IL-8 induces shedding of EGFR ligands because of an ADAM10-dependent pathway in gastric cancer cells, whereas IL-1β acts principally by an ADAM-independent pathway. IL-1β-dependent prolonged EGFR transactivation involves multiple pathways, including an IL-8-dependent pathway.

Efficacy and Safety of Rikkunshito, a Japanese Herbal Medicine, on the Treatment of Functional Dyspepsia: A Multi-Center, Double-Blind, Randomized, Placebo-Controlled Study Hidekazu Suzuki, Juntaro Matsuzaki, Yasushi Fukushima, Fumio Suzaki, Kunio Kasugai, Toshihiro Nishizawa, Yuji Naito, Toshihiko Hayakawa, Takeshi Kamiya, Takashi Ando, Hideo Yoshida, Yoshifumi Tokura, Hiroshi Nagata, Masao Kobayakawa, Mikiji Mori, Kimihiko Kato, Hiroshi Hosoda, Toru Takebayashi, Soichiro Miura, Naomi Uemura, Takashi Joh, Toshifumi Hibi, Jan F. Tack

BACKGROUND and AIM: Randomized controlled trials had shown a high efficacy of PPIs in healing and maintenance therapy for RE. However, their efficacy needs to be reassessed using recent real-life evidence because factors that may contribute to refractory RE, such as advanced age and absence of H. pylori infection, are becoming more prevalent in Japan. We retrospectively surveyed endoscopic findings of RE before and after ≥8 weeks of PPI administration, and analyzed factors that may affect endoscopic healing. METHOD: This multicenter retrospective survey in 41 institutions in Japan included adult (≥20 years) patients with RE defined as grade A-D by Los Angeles classification and treated for ≥8 weeks with a PPI (omeprazole, lansoprazole, or rabeprazole), who then underwent second endoscopy. Patients with malignancy, esophageal stricture, eosinophilic esophagitis, achalasia, malabsorption, or history of gastrointestinal resection or vagotomy were excluded. Using medical records for endoscopies between August 2005 and July 2010, eligible records were reviewed and analyzed for endoscopic findings, duration and dose of PPI use, comorbidities

BACKGROUND&AIMS: The efficacy of proton pump inhibitor (PPI) for functional dyspepsia (FD) in Japan, in which the acid secretion is thought to be less than Western people, is unknown. The aims of this study was to compare the therapeutic effects of Rabeprazole (RPZ) and Itopride (ITO), and to investigate the randomized open-labeled trial in Japanese FD patients. METHODS: 151 consecutive patients diagnosed as FD by Rome III criteria, were randomly assigned to either 4-week treatment with RPZ or with ITO. Dyspeptic symptoms were evaluated with questionnaires, additional abdominal pain and indigestion score in Gastrointestinal Symptom Rating Scale as a FD symptom score (FD score) at pretreatment and 1, 2, and 4 weeks after the treatment. The efficacy endpoint is the change rates based on pretreatment in FD score at each time-points. We also conducted sub-analysis of epigastric pain syndrome (EPS) and postprandial distress syndrome (PDS). RESULTS: At all time-points, RPZ group was more higher improvement rates than ITO group significantly (Figure). RPZ group showed significant rapid improvement in FD score within 1 week, and persisted until after 4 weeks, but, significant improvement in FD score was only seen after 4 weeks with ITO. With RPZ improved FD symptoms in both EPS and PDS, significantly, whereas the significant improvement with ITO was only seen in PDS. CONCLUSIONS: These results showed that acid suppressive therapy with PPI is more useful than with PDS as well as with EPS in Japanese FD patients.