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Expression of protease-activated receptor 2 in ulcerative colitis

Although tryptase released from mast cells might play a key role in the pathogenesis of ulcerative colitis (UC), the role of protease-activated receptor 2 (PAR2), tryptase receptor, remains unclear in the pathogenesis of this disease. The expressions of PAR2 and tumor necrosis factor (TNF) &agr; in nine UC tissues and nine normal tissues were examined by immunohistochemistry. TNF-&agr; levels secreted from human leukemic mast cell line (HMC-1) after the treatment of PAR2 agonists were also measured by enzyme-linked immunosorbent assay. The PAR2 and TNF-&agr; proteins were more significantly detectable in UC tissues than in normal tissues. Furthermore, 65.2% of PAR2+ cells and 66.4% of TNF-&agr;+ cells in UC tissues were tryptase-positive cells. In other words, 60.6% and 46.3% of tryptase-positive cells in UC tissues were PAR2+ cells and TNF-&agr;+ cells, respectively. A &khgr;2 analysis showed correlation (p < 0.007) between PAR2 and TNF-&agr; in tryptase-positive mast cells. Moreover, PAR2 agonists significantly induced the TNF-&agr; secretion from HMC-1. These results indicate that the activation of the mast cells through PAR2 may be involved in the pathogenesis of UC.

Isoliquiritigenin, from Dalbergia odorifera, up-regulates anti-inflammatory heme oxygenase-1 expression in RAW264.7 macrophages.

Abstract.Objectives:Isoliquiritigenin (ISL), one of the major constituents of Dalbergia odorifera T. Chen (Leguminosae), is reported to exert anti-inflammatory effects, but the relevant anti-inflammatory mechanisms are not completely understood. Heme oxygenase-1 (HO-1) has been proven to be involved in the resolution of inflammatory responses. In this study, we investigated whether ISL could induce HO-1 expression in RAW264.7 macrophages, and if so, whether HO-1 could mediate the anti-inflammatory effects of ISL.Methods:The protein expression of inducible nitric oxide synthase and HO-1 was analyzed by western blot analysis. The production of nitric oxide (NO) and interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) was assayed by Griess and ELISA, respectively. The TNF-α and HO-1 mRNA expression was analyzed by northern blot analysis.Results:ISL markedly suppressed LPS-induced NO, IL-1β, and TNF-α production. ISL induced HO-1 expression through the extracellular signal-regulated kinase1/2 pathway in RAW264.7 macrophages. The effects of ISL on LPS-induced NO and TNF-α production were reversed by the HO-1 inhibitor, tin protoporphyrin.Conclusions:ISL is an effective HO-1 inducer capable of inhibiting macrophage-derived inflammation.

The aqueous extract of Solanum melongena inhibits PAR2 agonist-induced inflammation.

BACKGROUND Solanum melongena L. (Solanaceae) has antioxidant, analgesic, hypolipidemic and antiallergic activity. METHODS The anti-inflammatory effects of the water extract of the S. melongena (SMWE) were investigated in PAR2-mediated mouse paw edema. Paw edema was induced by injection of trypsin or trans-cinnamoyl-LIGRLO-NH(2) (tc-NH(2)) into the hindpaw of mice. The SMWE (1, 5, 10, and 100 mg/kg) was orally administered 1 h before induction of inflammation. RESULTS At doses of 5, 10, and 100 mg/kg, the SMWE showed significant inhibition of both paw edema and vascular permeability. The SMWE (10 mg/kg) significantly also inhibited PAR2 agonist-induced myeloperoxidase (MPO) activity and tumor necrosis factor (TNF)-alpha expression in paw tissue. CONCLUSION These results demonstrate that the SMWE inhibits PAR2 agonist-induced mouse paw edema.

Increased expression of MIP-3α/CCL20 in peripheral blood mononuclear cells from patients with ulcerative colitis and its down-regulation by sulfasalazine and glucocorticoid treatment

Background: CCL20 expression is known to increase in the mucosal tissues of inflammatory bowel diseases (IBDs). Moreover, the discovery of Nod2 as the IBD1 susceptibility gene has underscored the significance of blood mononuclear cells in IBD pathogenesis. Methods: This study addresses whether CCL20 expression is similarly altered in peripheral blood mononuclear cells (PBMCs) of patients with ulcerative colitis (UC), a major type of IBD in Korea. Results: Expression of CCL20 was significantly up‐regulated in the PBMCs of patients with UC compared with those of normal healthy controls. Interestingly, untreated UC groups expressed higher levels of CCL20 mRNA than either treated UC or normal control groups, suggesting that CCL20 could be modulated by anti‐inflammatory drugs. Accordingly, a strong association between CCL20 levels and disease activity index was observed. Supporting these findings, results from a 3‐month follow‐up study revealed that the UC groups treated with 5‐aminosalicylic acid and glucocorticoid exhibited dramatic decreases of CCL20 mRNA in PBMCs, accompanied by ameliorated disease states. Moreover, tumor necrosis factor‐&agr;− or interleukin‐1&bgr;‐induced CCL20 secretion was greatly diminished by 5‐aminosalicylic acid and/or glucocorticoid treatment of human intestinal epithelial HT‐29 cells. Of note, CCR6+ cell populations were significantly reduced in the blood of severe patients with UC compared with normal controls, whereas no significant changes in CCR6+ cell populations were observed in the blood of patients with mild UC or acute colitis. Conclusions: Collectively, these findings suggest that CCL20 expression in blood mononuclear cells is associated with altered immune and inflammatory responses in patients with UC.

Catalposide, a compound isolated from Catalpa Ovata, attenuates induction of intestinal epithelial proinflammatory gene expression and reduces the severity of trinitrobenzene sulfonic acid-induced colitis in mice

Certain irinoid-producing plants have been used as herbal anti-inflammatory remedies. Here we evaluated whether catalposide (CATP), a single compound isolated from irinoid-producing plant Catalpa ovata, has a potential for preventing or ameliorating diseases characterized by mucosal inflammation. Preliminary microarray-based gene expression test revealed that CATP, which alone did not significantly affect expression of any of the >8,000 genes analyzed, attenuated the expression of tumor necrosis factor-alpha (TNF-alpha)-induced proinflammatory genes including interleukin-8 (IL-8) in human intestinal epithelial HT-29 cells. Down-regulation of IL-8 mRNA accumulation was also reflected by the decreased IL-8 secretion in CATP-treated HT-29 cells. The signal transduction study revealed that CATP significantly attenuates TNF-alpha-mediated p38 and extracellular signal-regulated kinase (ERK) phosphorylation. Further, CATP reduced NF-kappaB-mediated transcriptional activation as well as Ikappa-Balpha degradation. To establish the in vivo relevance of these findings, we examined whether CATP could affect intestinal inflammation in vivo using the mouse model of trinitrobenzene sulfonic acid (TNBS)-induced inflammatory colitis. Intrarectal administration of CATP dramatically reduced the weight loss, colonic damage, and mucosal ulceration that characterize TNBS colitis. Moreover, CATP suppressed the expression of TNF-alpha, interleukin-1beta, and intercellular adhesion molecule-1 along with the inhibition of NF-kappa B p65 translocation into nucleus in TNBS colitis. Collectively, current results demonstrate that CATP may be an effective agent for the treatment of diseases characterized by mucosal inflammation.

Iron chelator induces MIP-alpha/CCL20 in human intestinal epithelial cells: implication for triggering mucosal adaptive immunity.

A previous report by this laboratory demonstrated that bacterial iron chelator (siderophore) triggers inflammatory signals, including the production of CXC chemokine IL-8, in human intestinal epithelial cells (IECs). Microarray-based gene expression profiling revealed that iron chelator also induces macrophage inflammatory protein 3 α (MIP-3α)/ CC chemokine-ligand 20 (CCL20). As CCL20 is chemotactic for the cells involved in host adaptive immunity, this suggests that iron chelator may stimulate IECs to have the capacity to link mucosal innate and adaptive immunity. The basal medium from iron chelator deferoxamine (DFO)-treated HT-29 monolayers was as chemotactic as recombinant human CCL20 at equivalent concentrations to attract CCR6+ cells. The increase of CCL20 protein secretion appeared to correspond to that of CCL20 mRNA levels, as determined by real-time quantitative RT-PCR. The efficacy of DFO at inducing CCL20 mRNA was also observed in human PBMCs and in THP-1 cells, but not in human umbilical vein endothelial cells. Interestingly, unlike other proinflammatory cytokines, such as TNF-α and IL-1β, a time-dependent experiment revealed that DFO slowly induces CCL20, suggesting a novel mechanism of action. A pharmacologic study also revealed that multiple signaling pathways are differentially involved in CCL20 production by DFO, while some of those pathways are not involved in TNF-α-induced CCL20 production. Collectively, these results demonstrate that, in addition to some bacterial products known to induce host adaptive immune responses, direct chelation of host iron by infected bacteria may also contribute to the initiation of host adaptive immunity in the intestinal mucosa.

Randomized trial comparing oral sulfate solution with 4‐L polyethylene glycol administered in a split‐dose as preparation for colonoscopy

The present study aimed to evaluate the non‐inferiority of low‐volume oral sulfate solution (OSS) to 4‐L polyethylene glycol (PEG) solutions administered in a split‐dose regimen as bowel preparation for colonoscopy. The safety and tolerability were also compared between the two regimens.

Do surveillance intervals in patients with more than 5 adenomas at index colonoscopy be shorter than those in patients with 3‐4 adenomas? : A KASID Study

There is controversy about the surveillance interval after colonoscopy when 5–10 adenomas have been found on index colonoscopy. This study aimed to investigate the risk of colorectal neoplasm (CRN) according to the number of adenomas at index colonoscopy.

Clinical outcomes of endoscopic resection for colorectal laterally spreading tumors with advanced histology

BackgroundColorectal laterally spreading tumors (LSTs) are large, flat neoplasms that are usually treated using different endoscopic techniques based on their morphology, size, and histology. The aim of this study was to evaluate the clinical outcomes of LSTs with advanced histology treated by endoscopic resection.MethodsA total of 246 LSTs with advanced histology [i.e., high-grade dysplasia (HGD) and adenocarcinoma (AC)] treated by endoscopic resection [i.e., endoscopic mucosal resection (EMR), EMR-precutting (EMR-P), and endoscopic submucosal dissection (ESD)] were enrolled. Clinicopathological characteristics were collected by review of patient’s medical records.ResultsThe en bloc resection and R0 resection rates were 75.6% and 85.0%, respectively. The bleeding and perforation rates were 10.2% and 2.4%, respectively. The frequency of cancerous pit pattern and bleeding was significantly higher in LSTs with AC than in LSTs with HGD. The R0 resection rate in LSTs with HGD was significantly higher than that in LSTs with AC. The frequency of cancerous pit patterns in LST cases with submucosal AC was significantly higher than those with intramucosal AC. The mean size of the LSTs was significantly larger in ESD group than in EMR or EMR-P groups. The frequencies of nodular mixed subtype, cancerous pit patterns, and en bloc resection rates were significantly higher in the ESD group than in the EMR or EMR-P groups. However, the frequency of perforation was significantly higher in EMR-P group than in EMR or ESD groups.ConclusionsThese results indicate that ESD is a more acceptable treatment approach for resection of colorectal LSTs of larger size, with nodular mixed subtype, having a cancerous pit pattern or AC, using either en bloc or curative resection methods, compared to EMR or EMR-P procedures.

Clinicopathological feature and treatment outcome of patients with colorectal laterally spreading tumors treated by endoscopic submucosal dissection

Background/Aims Endoscopic submucosal dissection (ESD) is an advanced technique that can be used to treat precancerous and early colorectal neoplasms by facilitating en bloc resection regardless of tumor size. In our study, we investigated the clinicopathological feature and the treatment outcome of patients with colorectal laterally spreading tumors (LSTs) that were treated by ESD. Methods The study enrolled all of 210 patients with colorectal LSTs who underwent ESD. Clinical outcomes were analyzed by retrospectively reviewing medical records. Results A cancerous pit pattern (Vi/Vn) was more common in pseudo-depressed (PD) subtype than in flat elevated (FE) subtype. The incidence of adenocarcinoma in the PD subtype and nodular mixed (NM) subtypes was significantly higher than in the homogenous (HG) subtype and FE subtype. The en bloc and R0 resection rates were 89.0% and 85.7%, respectively. The bleeding and perforation rates were 5.2% and 1.9%, respectively. The mean procedure time was much longer in the PD subtype than in the FE subtype. The en bloc resection rate was significantly higher in the NM subtype than in the HG subtype. However, there were no statistically significant differences in mean procedure time, en bloc resection rate, R0 resection rate, bleeding rate, or perforation rate between LST-granular and LST-nongranular types. Conclusions These results indicate that ESD is acceptable for treating colorectal LSTs concerning en bloc resection, curative resection, and risk of complications. Careful consideration is required for complete resection of the PD subtype and NM subtype because of their higher malignant potential.