BackgroundThe colitis-associated cancer exhibits different characteristics according to sex in the initiation and progression of the tumors. The aim of this study was to investigate the sex-associated difference in the azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colitis-associated cancer model.MethodsThe AOM/DSS ICR mouse model was established to compare male with female, and then the severity of colitis-associated carcinogenesis was examined macroscopically and histologically regarding the number, size, and location of tumors. Subsequently, levels of colonic mucosal cytokine, interleukin (IL)-1β and myeloperoxidase (MPO) were assessed.ResultsAt the 16th week, the tumor multiplicity and the pro-inflammatory factors differed according to sex. The total tumor number was significantly higher in male (P = 0.020) and the number of large tumors (diameter > 2 mm) was higher in male (P = 0.026). In male, the tumors located more in distal colon (P = 0.001). MPO was significantly higher in AOM/DSS-treated male mice compared to the control group (P = 0.003), whereas the corresponding female group showed no significant change (P = 0.086). Colonic IL-1β level significantly increased in AOM/DSS groups compared to control groups both in male and female (male, P = 0.014; female, P = 0.005). It was higher in male group; however, there was no statistical significance (P = 0.226).ConclusionsIn AOM/DSS murine model, colitis-associated colon tumorigenesis are induced more severely in male mice than female probably by way of inflammatory mediators such as IL-1β and MPO. The sex-related differences at the animal model of colon cancer suggest the importance of approach to disease with sex-specific medicine in human.

Background and aim Various drugs have been developed for inflammatory bowel disease (IBD), but still there are limitations in the treatment due to the insufficient responses and significant adverse effects of immunosuppressant. Apocynin is an NADPH-oxidase inhibitor with established safety profiles. We aimed to investigate the protective efficacy of apocynin in IBD using chemical-induced mouse colitis model. Method We induced experimental colitis by administrating 5% dextran sulfate sodium (DSS) to 8-week old BALB/c mouse for 11 days. Apocynin (400 mg/kg) or sulfasalazine (150 mg/kg) were administeredduring7 days. We monitored bodyweight daily and harvested colon and spleen at day 11 to check weight and length. We also examined histopathologic change and pro-, anti-inflammatory cytokines and enzymes from harvested colons (iNOS, COX-2, TNF-α, MCP-1, p-NrF2, and HO-1). Result Apocynin significantly alleviated weight reduction induced by DSS treatment (21.64 ± 0.55 for Apocynin group vs. 20.33 ± 0.90 for DSS group, p = 0.005). Anti-inflammatory efficacy of apocynin was also shown by the recovery of colon weight and length. Histopathologic examination revealed significantly reduced inflammatory foci and erosions by apocynin treatment. Colonic expression of iNOS, COX-2, TNF-α, and MCP-1 was decreased significantly in the apocynin treated group. Anti-inflammatory mediators Nrf2 and HO-1 were activated significantly in apocynin treated mouse. Conclusion Apocynin showed significant anti-inflammatory efficacy against chemically induced colonic inflammation. This study also revealed the unique action of apocynin compared to the currently prescribed drug, sulfasalazine. Given its excellent safety profile and potent efficacy with novel action mechanism, apocynin can be a new therapeutic molecule for the IBD treatment, which can be added to the currently available drugs.

Apocynin, an inhibitor of NADPH oxidase, exhibits anti-inflammatory properties in ulcerative colitis. However, the underlying mechanism by which apocynin exerts this effect has not been clearly demonstrated. The objective of this study was to elucidate the anti-inflammatory mechanism of apocynin in lipopolysaccharide (LPS)-challenged RAW264.7 macrophage cells. Apocynin inhibited LPS-induced extracellular secretion of the pro-inflammatory mediators, nitric oxide (NO) and PGE2 and the expression of inducible nitric oxide synthase and cyclooxygenase-2. Apocynin also suppressed LPS-induced secretion of the pro-inflammatory cytokine, tumor necrosis factor-α and LPS-induced degradation of IκB, which retains NF-κB in the cytoplasm, consequently inhibiting the transcription of pro-inflammatory genes by NF-κB in the nucleus. To elucidate the underlying anti-inflammatory mechanism of apocynin, the involvement of the mitogen-activated protein (MAP) kinases, c-jun N-terminal kinase, extracellular signal-regulated kinases, and p38 was examined. Apocynin attenuated LPS-induced activation of all three MAP kinases in a concentration-dependent manner. The present study demonstrates apocynin exerts anti-inflammatory activity via the suppression of MAP kinase signaling pathways in LPS-challenged RAW264.7 macrophage cells. Drug Dev Res, 2016. © 2016 Wiley Periodicals, Inc.

Background and study aims: Many patients with acute gastrointestinal bleeding present with anemia and frequently require red blood cell (RBC) transfusion. A restrictive transfusion strategy and a low hemoglobin (Hb) threshold for transfusion had been shown to produce acceptable outcomes in patients with acute upper gastrointestinal bleeding. However, most patients are discharged with mild anemia owing to the restricted volume of packed RBCs (pRBCs). We investigated whether discharge Hb influences the outcome in patients with acute nonvariceal upper gastrointestinal bleeding. Patients and methods: We retrospectively analyzed patients with upper gastrointestinal bleeding who had received pRBCs during hospitalization between January 2012 and January 2014. Patients with variceal bleeding, malignant lesion, stroke, or cardiovascular disease were excluded. We divided the patients into 2 groups, low (8 g/dL ≤ Hb < 10 g/dL) and high (Hb ≥ 10 [g/dL]) discharge Hb, and compared the clinical course and Hb changes between these groups. Results: A total of 102 patients met the inclusion criteria. Fifty patients were discharged with Hb levels < 10 g/dL, whereas 52 were discharged with Hb levels > 10 g/dL. Patients in the low Hb group had a lower consumption of pRBCs and shorter hospital stay than did those in the high Hb group. The Hb levels were not fully recovered at outpatient follow-up until 7 days after discharge; however, most patients showed Hb recovery at 45 days after discharge. The rate of rebleeding after discharge was not significantly different between the 2 groups. Conclusions: In patients with acute upper gastrointestinal bleeding, a discharge Hb between 8 and 10 g/dL was linked to favorable outcomes on outpatient follow-up. Most patients recovered from anemia without any critical complication within 45 days after discharge.

Deubiquitinating enzymes (DUBs) play an important role in the ubiquitin-proteasome system (UPS) by eliminating ubiquitins from substrates and inhibiting proteasomal degradation. Protein phosphatase methylesterase 1 (PME-1) inactivates protein phosphatase 2A (PP2A) and enhances the ERK and Akt signaling pathways, which increase cell proliferation and malignant cell transformation. In this study, we demonstrate that USP36 regulates PME-1 through its deubiquitinating enzyme activity. USP36 increases PME-1 stability, and depletion of USP36 decreases the PME-1 expression level. Furthermore, we demonstrate that USP36 promotes the ERK and Akt signaling pathways. In summary, it is suggested that USP36 regulates PME-1 as a DUB and participates in the ERK and Akt signaling pathways.