Jaeyoung Chun

High viremia, prolonged Lamivudine therapy and recurrent hepatocellular carcinoma predict posttransplant hepatitis B recurrence.

Hepatitis B virus (HBV) recurrence following orthotopic liver transplantation (OLT) is generally preventable by prophylaxis with hepatitis B immunoglobulin (HBIG) and lamivudine (LAM). However, HBV recurrence sometimes develops despite prophylaxis. This study assessed posttransplant outcomes and identified predictors of HBV recurrence. We analyzed the outcomes of 209 consecutive patients positive for hepatitis B surface antigen who underwent OLT, who received either combination prophylaxis with HBIG and LAM (89.0%) or HBIG monoprophylaxis (11.0%). The median follow‐up was 36.8 months (range, 1.0–84.4). Posttransplant HBV recurrence occurred in 22 patients (10.5%), including 13 patients with drug‐resistant mutations. HBV recurrence was observed in six patients after hepatocellular carcinoma (HCC) recurrence. Independent predictors of HBV recurrence were recurrent HCC (p < 0.001), LAM therapy >1.5 years (p = 0.001) and high HBV DNA titers (≥105 copies/mL) at OLT (p = 0.036). In conclusion, high viremia at OLT and prolonged exposure to LAM should be further stressed as main predictors of HBV recurrence.

Ursolic acid inhibits nuclear factor-κB signaling in intestinal epithelial cells and macrophages, and attenuates experimental colitis in mice☆

AIMS Ursolic acid (UA), a natural pentacyclic triterpenoid acid, has been reported to show immunomodulatory activity. This study investigated the effects of UA on nuclear factor-kappa B (NF-κB) signaling in cells and experimental murine colitis. MAIN METHODS Human intestinal epithelial cells (IECs) COLO 205 and peritoneal macrophages from IL-10-deficient (IL-10(-/-)) mice were pretreated with UA and then stimulated with tumor necrosis factor-α (TNF-α) and lipopolysaccharide (LPS), respectively. The expression of pro-inflammatory cytokines was determined by real-time RT-PCR and ELISA. The effect of UA on NF-κB signaling was examined by immunoblot analysis to detect IκBα phosphorylation/degradation and electrophoretic mobility shift assay to assess the DNA binding activity of NF-κB. For in vivo studies, dextran sulfate sodium (DSS)-induced acute colitis in C57BL/6 wild-type mice and chronic colitis in IL-10(-/-) mice were treated with or without UA. Colitis was quantified by histopathologic evaluation. Immunohistochemical staining for phosphorylated IκBα was performed in the colonic tissue. KEY FINDINGS UA significantly inhibited the production of pro-inflammatory cytokines, IκBα phosphorylation/degradation and NF-κB DNA binding activity in both IEC and IL-10(-/-) peritoneal macrophages stimulated with TNF-α and LPS, respectively. UA significantly reduced the severity of DSS-induced murine colitis, as assessed by the disease activity index, colon length, and histopathology. UA also significantly ameliorated the severity of colitis in IL-10(-/-) mice. Furthermore, UA suppressed IκBα phosphorylation in the colonic tissue. SIGNIFICANCE UA inhibits NF-κB activation in both IECs and macrophages, and attenuates experimental murine colitis. These results suggest that UA is a potential therapeutic agent for inflammatory bowel disease.

Complete Genome Sequence of Mycobacterium intracellulare Strain ATCC 13950T

Here we report the first complete genome sequence of Mycobacterium intracellulare ATCC 13950(T), a Mycobacterium avium complex (MAC) strain. This genome sequence will serve as a valuable reference for understanding the epidemiologic, biological, and pathogenic aspects of the disparity between MAC members.

Enalapril inhibits nuclear factor-κB signaling in intestinal epithelial cells and peritoneal macrophages and attenuates experimental colitis in mice ☆

AIMS Enalapril, an angiotensin-converting enzyme (ACE) inhibitor, has pleiotropic effects such as anti-inflammatory effects. This study investigated the effect of enalapril on the nuclear factor-kappa B (NF-κB) pathway and on experimental colitis. MAIN METHODS The human intestinal epithelial cell (IEC) line COLO 205 and peritoneal macrophages from C57BL/6 wild-type mice and IL-10-deficient (IL-10(-/-)) mice were prepared and subsequently stimulated with lipopolysaccharide (LPS) alone or LPS plus enalapril. The effect of enalapril on NF-κB signaling was examined by western blotting to detect IκBα phosphorylation/degradation; an electrophoretic mobility shift assay (EMSA) to assess the DNA binding activity of NF-κB; and ELISAs to qualify IL-8, TNF-α, IL-6, and IL-12 production. In in vivo studies, dextran sulfate sodium (DSS)-induced acute colitis in wild-type mice and chronic colitis in IL-10(-/-) mice were treated with or without enalapril. Colitis was quantified by histologic scoring, and the phosphorylation of IκBα in the colonic mucosa was assessed using immunohistochemistry. KEY FINDINGS Enalapril significantly inhibited LPS-induced IκBα phosphorylation/degradation, NF-κB binding activity, and pro-inflammatory cytokine production in both IEC and peritoneal macrophages. The administration of enalapril significantly reduced the severity of colitis, as assessed based on histology in both murine colitis models. Furthermore, in colon tissue, the up-regulation of IκBα phosphorylation with colitis induction was attenuated in enalapril-treated mice. SIGNIFICANCE Enalapril may block the NF-κB signaling pathway, inhibit the activation of IECs and macrophages, and attenuate experimental murine colitis by down-regulating IκBα phosphorylation. These findings suggest that enalapril is a potential therapeutic agent for inflammatory bowel disease.

Complete Genome Sequence of Mycobacterium intracellulare Clinical Strain MOTT-02

Here, we report the first complete genome sequence of the Mycobacterium intracellulare clinical strain MOTT-02, which was previously grouped in the INT2 genotype of M. intracellulare. This genome sequence will serve as a valuable reference for improving the understanding of the disparity in the virulence and epidemiologic traits between M. intracellulare genotypes.

Complete Genome Sequence of Mycobacterium intracellulare Clinical Strain MOTT-36Y, Belonging to the INT5 Genotype

Here we report the complete genome sequence of the Mycobacterium intracellulare clinical strain MOTT-36Y, previously grouped into the INT5 genotype among the 5 genotypes of M. intracellulare. This genome sequence will serve as a valuable reference for understanding the disparity in virulence and epidemiologic traits between M. intracellulare-related strains.

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.

Nimbolide Inhibits Nuclear Factor-КB Pathway in Intestinal Epithelial Cells and Macrophages and Alleviates Experimental Colitis in Mice

Nimbolide is a limonoid extracted from neem tree (Azadirachta indica) that has antiinflammatory properties. The effect of nimbolide on the nuclear factor‐kappa B (NF‐κB) pathway in intestinal epithelial cells (IECs), macrophages and in murine colitis models was investigated. The IEC COLO 205, the murine macrophage cell line RAW 264.7, and peritoneal macrophages from interleukin‐10‐deficient (IL‐10−/−) mice were preconditioned with nimbolide and then stimulated with tumor necrosis factor‐α (TNF‐α) or lipopolysaccharide. Dextran sulfate sodium‐induced acute colitis model and chronic colitis model in IL‐10−/− mice were used for in vivo experiments. Nimbolide significantly suppressed the expression of inflammatory cytokines (IL‐6, IL‐8, IL‐12, and TNF‐α) and inhibited the phosphorylation of IκBα and the DNA‐binding affinity of NF‐κB in IECs and macrophages. Nimbolide ameliorated weight loss, colon shortening, disease activity index score, and histologic scores in dextran sulfate sodium colitis. It also improved histopathologic scores in the chronic colitis of IL‐10−/− mice. Staining for phosphorylated IκBα was significantly decreased in the colon tissue after treatment with nimbolide in both models. Nimbolide inhibits NF‐κB signaling in IECs and macrophages and ameliorates experimental colitis in mice. These results suggest nimbolide could be a potentially new treatment for inflammatory bowel disease. Copyright