Changhyun Lee

Effects of serum bilirubin on atherosclerotic processes.

Abstract This review highlights the protective roles of bilirubin against the atherosclerotic process. Bilirubin belongs to the superfamily of tetrapyrrolic compounds formed during heme catabolism. Although for decades bilirubin was considered to be a harmful waste product, recent epidemiologic studies have shown that serum bilirubin levels have consistently been inversely associated with cardiovascular disease (CVD), as well as cardiovascular risk factors such as metabolic syndrome and diabetes. These clinical studies are supported by in vitro and in vivo experimental data and have demonstrated that bilirubin not only has an ability to scavenge overproduced reactive oxygen species and inhibit vascular smooth muscle cell proliferation but, additionally, has anti-inflammatory effects. In this review, we will discuss the inverse association of serum bilirubin and CVD and cardiovascular risk factors established in various clinical studies. We also review detailed experimental studies about the effect of bilirubin on atherosclerotic processes. In vitro, animal and human studies have proved that bilirubin inhibits oxidation of cholesterol which is an important step of atherosclerosis. Bilirubin attenuates chemotactic activity of monocytes and strongly inhibits adhesion of leukocytes to venule and production of pro-inflammatory cytokines. Bilirubin has inhibited serum-driven smooth muscle cell cycle progression at the G1 phase. Lastly, we will discuss briefly the influence of bilirubin on lipoprotein composition and endothelial dysfunction.

The effect of intestinal alkaline phosphatase on intestinal epithelial cells, macrophages and chronic colitis in mice

AIMS Intestinal alkaline phosphatase (IAP) is an intestinal brush border enzyme that is shown to function as a gut mucosal defense factor, but its defensive mechanism remains unclear. The aims of this study were to evaluate the effect of IAP on intestinal epithelial cells and macrophages, and on chronic colitis in interleukin-10-deficient (IL-10(-/-)) mice. MAIN METHODS Human intestinal epithelial cells COLO 205 and peritoneal macrophages from IL-10(-/-) mice were pretreated with IAP and then stimulated with lipopolysaccharide (LPS). IL-8 secretion from COLO205 cells and TNF-α, IL-6, IL-12 from peritoneal macrophages were measured by ELISA. Electrophoretic mobility shift assay was used to assess the DNA binding activity of NF-κB and IκBα phosphorylation/degradation was evaluated by immunoblot assay in COLO 205. For the in vivo study, colitis was induced in IL-10(-/-) mice with piroxicam, the mice were then treated with 100 or 300 units of IAP by oral gavage for 2 weeks. Colitis was quantified by histopathologic scoring, and the phosphorylation of IκBα in the colonic mucosa was assessed using immunohistochemistry. KEY FINDINGS IAP significantly inhibited LPS-induced inflammatory cytokine production in both IECs and peritoneal macrophages. IAP also attenuated LPS-induced NF-κB binding activity and IκBα phosphorylation/degradation in IECs. Oral administration of IAP significantly reduced the severity of colitis and down-regulated colitis-induced IκBα phosphorylation in IL-10(-/-) mice. SIGNIFICANCE IAP may inhibit the activation of intestinal epithelial cells and peritoneal macrophages, and may attenuate chronic murine colitis. This finding suggests that IAP supplementation is a potential therapeutic option for inflammatory bowel disease.

Usefulness of the cytomegalovirus antigenemia assay in patients with ulcerative colitis.

Background/Aims Patients with ulcerative colitis (UC) are at high risk for cytomegalovirus (CMV) reactivation. The usefulness of the CMV antigenemia assay in active UC patients has rarely been studied. We assessed whether the assay detects CMV colitis and predicts clinical outcomes in patients with UC. Methods We retrospectively reviewed the medical records of patients hospitalized for moderate-to-severe UC from 2003 to 2012. Positive CMV antigenemia was defined as ≥1 pp65-positive cell per 2×105 polymorphonuclear neutrophils. CMV colitis was defined as the presence of inclusion bodies and/or positive immunohistochemistry in the colonic mucosa. The primary outcome was steroid refractoriness, defined as the absence of clinical improvement after intravenous high-dose steroid administration. Results A total of 43 patients were enrolled. CMV antigenemia was detected in 12 (27.9%) patients. Positive CMV antigenemia was significantly associated with CMV colitis (P =0.001). The sensitivity and specificity of positive CMV antigenemia for diagnosing CMV colitis were 66.7% and 87.1%, respectively. Steroid refractoriness was found in 11 of 12 (91.7%) and 12 of 31 (38.7%) patients with positive and negative CMV antigenemia, respectively (P =0.002). The independent predictors for steroid refractoriness were positive CMV antigenemia (adjusted odds ratio [OR], 7.73; 95% confidence interval [CI], 1.22-49.19; P =0.030) and a shorter duration from the diagnosis of UC (adjusted OR, 0.99; 95% CI, 0.98-0.99; P =0.025). Conclusions The CMV antigenemia assay shows low sensitivity but high specificity for detecting CMV colitis and may predict steroid-refractory UC. Early rescue therapy might be considered in UC patients positive for CMV antigenemia.

Sodium butyrate inhibits the NF-kappa B signaling pathway and histone deacetylation, and attenuates experimental colitis in an IL-10 independent manner

Abstract Butyrate is a bacterial metabolite of dietary fiber in the colon that has been used to treat inflammatory disease. However, the effect of oral supplementation with butyrate on colitis has not been fully explored. We evaluated the effects of and mechanisms underlying oral supplementation with butyrate on experimental murine colitis. In an in vitro study, we found that LPS induced the secretion of cytokines (i.e., IL‐8 in COLO 205; TNF‐&agr;, IL‐6, IL‐12, and IL‐10 in RAW 264.7; and TNF‐&agr;, IL‐6 and IL‐12 in peritoneal macrophages obtained from IL‐10‐deficient [IL‐10−/−] mice). Butyrate (100 &mgr;M and 500 &mgr;M) inhibited pro‐inflammatory cytokine production (i.e., IL‐8 in COLO205 and TNF‐&agr;, IL‐6 and IL‐12 in macrophages) but promoted anti‐inflammatory cytokine (i.e., IL‐10) production in RAW264.7 cells. Butyrate attenuated both the LPS‐induced degradation/phosphorylation of I&kgr;B&agr; and DNA binding of NF‐&kgr;B and enhanced histone H3 acetylation. To confirm that butyrate played a protective role in colitis, an acute colitis model was induced using dextran sulfate sodium (DSS) and a chronic colitis model was induced in IL‐10−/− mice. The administration of oral butyrate (100 mg/kg) significantly improved histological scores in both colitis models, including the IL‐10−/− mice. In immunohistochemical staining, I&kgr;B&agr; phosphorylation was attenuated, and histone H3 acetylation was reversed in the treated colons of both colitis models. Our results indicate that oral supplementation with butyrate attenuates experimental murine colitis by blocking NF‐&kgr;B signaling and reverses histone acetylation. These anti‐colitic effects of butyrate were IL‐10‐independent. Butyrate may therefore be a therapeutic agent for colitis. Graphical abstract Figure. No Caption available. HighlightsButyrate inhibits the production of TNF‐&agr;, IL‐6 and IL‐12 in macrophages.Butyrate inhibits NF‐&kgr;B signaling and histone deacetylation in IEC and macrophages.Oral supplementation with butyrate suppressed colitis, even in IL‐10−/− mice.Butyrate attenuated I&kgr;B&agr; phosphorylation and histone H3 deacetylation in the colon.The anti‐inflammatory effect of butyrate is IL‐10 independent.

Lupeol inhibits LPS-induced NF-kappa B signaling in intestinal epithelial cells and macrophages, and attenuates acute and chronic murine colitis

AIMS Lupeol, a natural pentacyclic triterpene, exhibits anti-inflammatory effects. However, its role in colitis has not been investigated. In the present study, we evaluated the effect of lupeol on the NF-κB signaling pathway and experimental colitis in mice. MAIN METHODS The human intestinal epithelial cells (IECs) COLO 205 and the murine macrophages RAW 264.7 were pretreated with lupeol and then stimulated with lipopolysaccharide (LPS). The production of inflammatory cytokines (IL-8 from COLO 205; IL-6, IL-12 and TNF-α from RAW 264.7) was determined by ELISA. The effect of lupeol on NF-κB pathway was examined by Western blot analysis of IκBα phosphorylation/degradation and an electrophoretic mobility shift assay (EMSA). For in vivo studies, dextran sulfate sodium (DSS)-induced acute colitis model and chronic colitis model in IL-10(-/-) mice were used. Colitis was quantified by disease activity index, colon length and histologic evaluation. KEY FINDINGS Lupeol strongly suppressed pro-inflammatory cytokine production in IECs and murine macrophages. It also inhibited LPS-induced IκBα phosphorylation/degradation and the DNA binding activity of NF-κB. The oral administration of lupeol significantly reduced the colitis activity and histologic scores in both acute and chronic murine colitis models. Furthermore, the up-regulation of IκBα phosphorylation in the colonic mucosa was attenuated in lupeol-treated mice. SIGNIFICANCE Lupeol blocks the NF-κB signaling in IECs and murine macrophages, and attenuate experimental murine colitis. These findings suggest that lupeol is a potential therapeutic agent for inflammatory bowel disease.

Risk and clinical characteristics of lymphoma in Korean patients with inflammatory bowel diseases: a multicenter study.

Background and Aims: Studies of lymphoma risk in Western inflammatory bowel disease (IBD) patients show conflicting results; however, none have examined the lymphoma risk and clinical characteristics of Asian IBD patients. Methods: Patients with lymphoma were identified in an IBD database from 3 tertiary referral centers in Seoul, Korea. The standardized incidence ratio (SIR) of lymphoma was estimated using data from the Korea Central Cancer Registry of the National Cancer Center. The risk of lymphoma in relation to specific medications was also explored. Results: Seven cases of lymphoma (0.1%) were identified in 6585 IBD patients. The median age at lymphoma diagnosis was 43 years (range, 33 to 70 y) and the median duration of IBD at lymphoma diagnosis was 96.1 months (range, 15.1 to 171.6 mo). Three patients had underlying ulcerative colitis and 4 had Crohn’s disease (CD). Non-Hodgkin lymphoma was diagnosed in 5 patients (71.4%) and Hodgkin disease (HD) in 2 patients (28.6%). The SIR of lymphoma was 2.03 [95% confidence interval (CI), 0.81-4.18] in the entire IBD patients. Both the SIR of lymphoma in CD patients (9.31; 95% CI, 1.13-33.62) and the SIR of HD (13.16; 95% CI, 1.59-47.53) in IBD patients were increased. The SIR of lymphoma in patients who were exposed to thiopurines was 5.93 (95% CI, 1.61-15.18). Conclusions: The risk of lymphoma in CD patients and the risk of HD in IBD patients seem to be increased in Korea. Thiopurine may be related with the risk of lymphoma in Korean IBD patients.

Characteristics and outcomes of endoscopically resected colorectal cancers that arose from sessile serrated adenomas and traditional serrated adenomas

Background/Aims The efficacy and safety of endoscopic resection of colorectal cancer derived from sessile serrated adenomas or traditional serrated adenomas are still unknown. The aims of this study were to verify the characteristics and outcomes of endoscopically resected early colorectal cancers developed from serrated polyps. Methods Among patients who received endoscopic resection of early colorectal cancers from 2008 to 2011, cancers with documented pre-existing lesions were included. They were classified as adenoma, sessile serrated adenoma, or traditional serrated adenoma according to the baseline lesions. Clinical characteristics, pathologic diagnosis, and outcomes were reviewed. Results Overall, 208 colorectal cancers detected from 198 patients were included: 198 with adenoma, five with sessile serrated adenoma, and five with traditional serrated adenoma. The sessile serrated adenoma group had a higher prevalence of high-grade dysplasia (40.0% vs. 25.8%, P<0.001) than the adenoma group. During follow-up, local recurrence did not occur after endoscopic resection of early colorectal cancers developed from serrated polyps. In contrast, two cases of metachronous recurrence were detected within a short follow-up period. Conclusions Cautious observation and early endoscopic resection are recommended when colorectal cancer from serrated polyp is suspected. Colorectal cancers from serrated polyp can be treated successfully with endoscopy.

Thirty-day mortality after percutaneous gastrostomy by endoscopic versus radiologic placement: a systematic review and meta-analysis

Background/Aims A percutaneous gastrostomy can be placed either endoscopically (percutaneous endoscopic gastrostomy, PEG) or radiologically (radiologically-inserted gastrostomy, RIG). However, there is no consistent evidence of the safety and efficacy of PEG compared to RIG. Recently, 30-day mortality has become considered as the most important surrogate index for evaluating the safety and efficacy of percutaneous gastrostomy. The aim of this meta-analysis was to compare the 30-day mortality rates between PEG and RIG. Methods Major electronic databases (MEDLINE, Embase, Scopus, and Cochrane library) were queried for comparative studies on the two insertion techniques of gastrostomy among adults with swallowing disturbance. The primary outcome was the 30-day mortality rate after gastrostomy insertion. Forest and funnel plots were generated for outcomes using STATA version 14.0. Results Fifteen studies (n=2,183) met the inclusion criteria. PEG was associated with a lower risk of 30-day mortality after tube placement compared with RIG (odds ratio, 0.60; 95% confidence interval [CI], 0.38–0.94; P=0.026). The pooled prevalence of 30-day mortality of PEG was 5.5% (95% CI, 4.0%–6.9%) and that of RIG was 10.5% (95% CI, 6.8%–14.3%). No publication bias was noted. Conclusions The present meta-analysis demonstrated that PEG is associated with a lower probability of 30-day mortality compared to RIG, suggesting that PEG should be considered as the first choice for long-term enteral tube feeding. Further prospective randomized studies are needed to evaluate and compare the safety of these two different methods of gastrostomy.

Clinical characteristics of primary gastric lymphoma detected during screening for gastric cancer in Korea.

The role of screening endoscopy in primary gastric lymphoma (PGL) has not been investigated. This study aimed to evaluate the clinical characteristics and outcomes of PGLs detected by screening endoscopy in the high prevalence area of Helicobacter pylori (H. pylori) infection.

Role of iRhom2 in intestinal ischemia-reperfusion-mediated acute lung injury

Intestinal ischemia-reperfusion (I/R) may cause acute systemic and lung inflammation. However, the detailed mechanism of this inflammatory cascade has not been fully elucidated. Inactive rhomboid protein 2 (iRhom2) is essential for the maturation of TNF-α converting enzyme (TACE), which is required for TNF-α secretion. We evaluated the role of iRhom2 in a mouse model of intestinal I/R using iRhom2 knockout (KO) and wild-type (WT) mice. Lung injury following intestinal I/R was significantly attenuated in iRhom2 KO mice compared with WT mice. After intestinal I/R, lungs from iRhom2 KO mice showed significantly lower myeloperoxidase (MPO) activity and markedly reduced cell apoptosis associated with a decreased level of active caspase 3 and decreased TUNEL staining compared with lungs from WT mice. TNF-α levels were elevated in the serum and lungs of WT mice with intestinal I/R and significantly reduced in iRhom2 KO mice with intestinal I/R. iRhom2 may play a critical role in the pathogenesis of acute lung injury (ALI) after intestinal I/R and thus may be a novel therapeutic target for ALI after intestinal I/R injury.