Search

Abstract Intestinal fibrosis with stricture formation is a severe complication of Crohn's disease (CD). Though new therapeutic targets to enable the prevention or treatment of intestinal fibrosis are needed, markers of this condition and the basic mechanisms responsible have not been established. NADPH oxidase (NOX) 4 has already been reported to play a key role in models of fibrogenesis, including that of the lung. However, its importance in intestinal fibrogenesis remains unclear. In this study, we examined the role of NOX4 in collagen production by intestinal myofibroblasts stimulated with transforming growth factor (TGF)-β1. Using LmcMF cells, an intestinal subepithelial myofibroblast (ISEMF) line, we first examined the induction of collagen production by TGF-β1. Subsequently, we investigated the role of NOX4 in TGF-β1-induced collagen I production in these cells using SB525334 (an SMAD2/3 inhibitor), diphenyleneiodonium (an NOX inhibitor), and Nox4 small interfering RNA (siRNA). Production of collagen was assessed with Sirius red staining, and Nox4 expression was measured by quantitative real-time PCR. Reactive oxygen species (ROS) production was determined using DCFDA and fluorescent microscopy. We observed that TGF-β1 induced collagen production via NOX4 activation and ROS generation in LmcMF cells. Nox4 siRNA and inhibitors of TGF-β1 receptor and NOX significantly reduced TGF-β1-induced ROS and collagen production. Thus, in the present study, we revealed that collagen production in ISEMFs is induced via an NOX4-dependent pathway. This work supports a function for NOX4 in intestinal fibrogenesis and identifies it as a potential therapeutic target in recalcitrant fibrotic disorders of CD patients. Highlights • Intestinal fibrosis with stricture is severe complication of Crohn's disease. • TGF-β1-induced collagen production in intestinal myofibroblast is dependent on NOX4. • NOX inhibitor significantly diminished TGF-β1-induced ROS and collagen production. • NOX4 may constitute a therapeutic target in fibrotic disorders among Crohn's disease. [ABSTRACT FROM AUTHOR]

Dynamics of chromosomal ends during meiosis was examined using a tetrad F population derived from a cross between Setaria and Triticum isolates of Magnaporthe oryzae. Telomeric fragments were liberated by six restriction enzymes and detected with a telomere probe. Each fragment was assigned to one of the 14 chromosomal ends using chromosome-specific markers. Size shifts and non-Mendelian segregation (4:0, 3:1, 1:3, and 0:4) were frequently observed in these telomeric fragments and were considered to be caused by deletion, insertion, point mutation, and gene conversion. Similar results were obtained in another tetrad F population derived from a cross between Oryza and Triticum isolates. These results suggest that subtelomeric regions are unstable during meiosis and are prone to various rearrangements including gene conversion. [ABSTRACT FROM AUTHOR]

MFI metallosilicates AlMFI and FeMFI were prepared by hydrothermal synthesis, and Zn species were introduced into these MFI-type zeolites by ion exchange. Acetone-to-aromatics (ATA) reactions were carried out using the MFI-type zeolites before and after Zn ion exchange treatment. We examined the effects of zeolite Brønsted acid strength, Zn species, and Zn dose on (1) selective production of benzene-toluene-xylene (BTX) from acetone, and (2) catalyst lifetime. AlMFI selectively produced BTX due to its strong Brønsted acidity, and the introduction of Zn further enhanced its BTX selectivity. In contrast, FeMFI showed high selectivity for light olefins even after Zn ion exchange treatment. Increasing the Zn dose added to AlMFI did not improve its BTX selectivity but did suppress the catalytic deactivation rate. Together, the effects of Zn addition and AlMFI's strong Brønsted acidity resulted in highly selective BTX production and long catalyst lifetimes in the ATA reaction. [Display omitted] • Zn-containing AlMFI and FeMFI zeolites were prepared by ion exchange. • Catalytic performance in acetone-to-aromatics reaction was examined. • Introduction of Zn into AlMFI further enhanced BTX selectivity. • Increasing the Zn dose suppress the catalytic deactivation rate. • Combined effects of Zn and the strong acidity resulted in selective BTX production. [ABSTRACT FROM AUTHOR]

Background: Recent progress in ulcerative colitis (UC) treatment has been remarkable, and various medications have been applied. However, some patients with UC are refractory to treatment and convert to surgery. Aim: To investigate the role of colonic mucosal Wnt-5a expression in the pathogenesis of UC and the effect of bioactive Wnt-5a peptide on colitis in mice. Methods: Wnt-5a peptide was intraperitoneally administered to mice every day from the beginning of dextran sulfate sodium (DSS) treatment. The severity of colitis was evaluated based on body weight change, colonic length, and histological scores. Colonic mucosal TNF-α and KC mRNA expression levels were measured. This study included 70 patients with UC in clinical remission. Wnt-5a, TNFα, and IL-8 mRNA expression in the rectal mucosa were measured by quantitative real-time polymerase chain reaction using biopsy materials. Wnt-5a mRNA expression levels were compared between patients who relapsed and those in remission. We examined the correlation of Wnt-5a expression with TNF-α and IL-8 expression. Results: Wnt-5a peptide significantly attenuated the severity of DSS-induced colitis. Moreover, mucosal TNF-α and KC mRNA expression were significantly suppressed by Wnt-5a peptide treatment. Wnt-5a mRNA levels were significantly lower in patients with subsequent relapse than in those who remained in remission. Mucosal Wnt-5a was inversely correlated with TNF α and IL-8 expression. Conclusion: Wnt-5a peptide suppressed colitis in mice, and decreased Wnt-5a expression was strongly associated with relapse in patients with UC. Wnt-5a may have an inhibitory effect on mucosal inflammation in UC, and Wnt-5a peptide could be a new therapeutic strategy. [ABSTRACT FROM AUTHOR]

Background and Aim: Complete endoscopic mucosal healing is defined as a Mayo endoscopic subscore of 0. Some patients diagnosed with a Mayo endoscopic subscore 0 may present with subsequent clinical relapse. Here, we aimed to demonstrate mucosal cytokine profile as a predictor of clinical relapse in ulcerative colitis patients with a Mayo endoscopic subscore of 0 as a marker of mucosal healing. Methods: We conducted prospective observational pilot study to examine the relationship between mucosal cytokine expression and subsequent relapse of UC patients diagnosed with a Mayo endoscopic subscore of 0. We enrolled 55 patients, and expression of cytokines tumor necrosis factor‐α, interferon γ, interleukin‐1β, interleukin‐2, interleukin‐4, interleukin‐5, interleukin‐6, interleukin‐7, interleukin‐8, interleukin‐9, interleukin‐10, interleukin‐12, interleukin‐13, interleukin‐15, interleukin‐17A, interleukin‐17F, interleukin‐18, interleukin‐21, interleukin‐22, interleukin‐23, interleukin‐27, and interleukin‐33 was measured by quantitative real‐time PCR using rectal mucosa biopsy materials. Cytokine expression levels were compared between patients who relapsed between March 1, 2016, and March 30, 2020, of the study period and those who remained in remission. Results: Ten cytokines, including interleukin‐2, interleukin‐4, interleukin‐8, interleukin‐10, interleukin‐12, interleukin‐15, interleukin‐17A, interleukin‐21, interleukin‐23, and interleukin‐33, were significantly elevated in patients with subsequent relapse compared with those who remained in remission. Interleukin‐8 expression was the most useful predictor. Conclusions: In the rectal mucosa of ulcerative colitis patients with Mayo endoscopic subscore 0, levels of several cytokines were elevated in cases of subsequent relapse. Among these, interleukin‐8 expression was the most useful for predicting relapse. [ABSTRACT FROM AUTHOR]

[Display omitted] • Zn ion doped MFI type galloaluminosilicate zeolite (Zn/[Ga,Al]-MFI) was synthesized. • Zn/[Ga,Al]-MFI was the ideal catalyst for stable ethane dehydroaromatization. • The acidity tuned by a partial substitution of Ga for Al suppressed a coke formation. Ethane dehydroaromatization (EDA) reaction is one of the promising processes to meet the growing demand of aromatics in the future. Zn ion exchanged MFI type aluminosilicate zeolite (Zn/[Al]-MFI) shows high activity on EDA reaction. Zn ion and Brønsted acid derived from Al sites contribute to the high activity on EDA reaction, but excess strong acid sites promote coke formation, leading to rapid deactivation. Herein, we have developed a new synthesis method for Zn ion exchanged MFI type galloaluminosilicate zeolite (Zn/[Ga,Al]-MFI). The coke formation was suppressed by partially substituting Al with Ga since acidity derived from Ga sites are weaker than that derived from Al sites. Zn/[Ga,Al]-MFI was the ideal catalyst to achieve both high catalytic activity and stability on EDA reaction. Our work provides a new design direction of zeolite catalysts on EDA reaction, which can contribute to the progress on the transformation of light alkanes to value-added chemicals. [ABSTRACT FROM AUTHOR]

Magnaporthe oryzae is the causal agent of rice blast disease, a devastating problem worldwide. This fungus has caused breakdown of resistance conferred by newly developed commercial cultivars. To address how the rice blast fungus adapts itself to new resistance genes so quickly, we examined chromosomal locations of AVR-Pita, a subtelomeric gene family corresponding to the Pita resistance gene, in various isolates of M. oryzae (including wheat and millet pathogens) and its related species. We found that AVR-Pita (AVR-Pita1 and AVR-Pita2) is highly variable in its genome location, occurring in chromosomes 1, 3, 4, 5, 6, 7, and supernumerary chromosomes, particularly in rice-infecting isolates. When expressed in M. oryzae, most of the AVR-Pita homologs could elicit Pita-mediated resistance, even those from non-rice isolates. AVR-Pita was flanked by a retrotransposon, which presumably contributed to its multiple translocation across the genome. On the other hand, family member AVR-Pita3, which lacks avirulence activity, was stably located on chromosome 7 in a vast majority of isolates. These results suggest that the diversification in genome location of AVR-Pita in the rice isolates is a consequence of recognition by Pita in rice. We propose a model that the multiple translocation of AVR-Pita may be associated with its frequent loss and recovery mediated by its transfer among individuals in asexual populations. This model implies that the high mobility of AVR-Pita is a key mechanism accounting for the rapid adaptation toward Pita. Dynamic adaptation of some fungal plant pathogens may be achieved by deletion and recovery of avirulence genes using a population as a unit of adaptation. [ABSTRACT FROM AUTHOR]

Background and Aim: The Mayo Endoscopic Subscore (MES) and the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) are used to assess endoscopic mucosal healing in patients suffering from ulcerative colitis. Although mucosal healing is defined by MES 0, relapse of ulcerative colitis is often observed. Over a 48‐month period, this study investigated the efficacy of linked color imaging (LCI) in predicting the long‐term prognosis of ulcerative colitis patients diagnosed with MES 0. Methods: Overall, 26 patients in ulcerative colitis remission, diagnosed with MES 0, were enrolled. Using a LASEREO endoscopic system (Fujifilm Co., Tokyo, Japan), endoscopic colonic images were assessed with linked color imaging and the colitis endoscopic index of severity. Endoscopic LCI images were separated into three subgroups (A, no redness; B, redness with visible vessels; and C, redness without visible vessels). The Geboes score was used to evaluate histology; active mucosa was defined as GS > 2B.1. Results: Linked color imaging classification subdivided colonic mucosa, which had been diagnosed with MES 0, into two classes. The LCI‐A group did not relapse, and the non‐relapse rate was significantly higher (P = 0.018) than that in the LCI‐B group. No difference in relapse rates was observed between patients with a colitis endoscopic index of severity of 0 and 1 (P = 0.655). There was no statistical difference between the composition of LCI‐A group and the relapse rate between active and inactive mucosa diagnosed by Geboes score. Conclusions: This methodology can be used to evaluate mucosal healing and predict long‐term outcomes in ulcerative colitis patients. [ABSTRACT FROM AUTHOR]

Background: The role of IL-12/23 in the pathogenesis of ulcerative colitis (UC) is unclear. We analyzed mucosal IL-12/23 expression and its relationship with endoscopic severity, histological activity, and UC relapse.Methods: Rectal biopsies were collected from 70 UC patients with clinical remission. IL-12, IL-23, IFN-γ, IL-17A, and IL-17F mRNA expression was measured by real-time PCR. Endoscopic severity and histological activity were evaluated using the Mayo endoscopic subscore (MES) and the Geboes score, respectively.Results: The longest follow-up period was 51 months. Thirty-four patients relapsed during the study period. Samples from these subsequently relapsed patients formed the "relapse" group, while those from patients that did not relapse formed the "remission" group. IL-12 (P = 0.0003) and IL-23 (P = 0.014) mRNA expression was significantly higher in the relapse than the remission group. Expression of IL-23 (P = 0.015) but not IL-12 (P = 0.374) was correlated with MES. However, in patients with an MES of 0 and 1, IL-12 expression was statistically higher in the relapse than the remission group (P = 0.0015, P = 0.0342). IL-12 and IL-23 expression did not vary significantly between histologically active and inactive mucosa; both were higher in histologically inactive patients in the remission group (IL-12: P = 0.0002, IL-23: P = 0.046).Conclusions: Rectal IL-12 and IL-23 expression was elevated in the relapse group, but IL-12 was more strongly associated with UC relapse, irrespective of endoscopic severity and histological activity. Mucosal IL-12 was elevated in patients with deep mucosal healing. Our results suggest an important role of IL-12 in UC pathogenesis and the molecular mechanism of UC relapse. [ABSTRACT FROM AUTHOR]

Background and Aim: Daikenchuto, a traditional Japanese herbal medicine, has been reported to exhibit anti‐inflammatory effects against intestinal inflammation. However, whether daikenchuto has a therapeutic effect against intestinal mucosal injuries remains unclear. Thus, the aim of this study was to determine the effect of daikenchuto on intestinal mucosal healing. Methods: Colitis was induced in male Wistar rats by using trinitrobenzenesulfonic acid. Daikenchuto (900 mg/kg/day) was administered for 7 days after the induction of colitis. Thereafter, intestinal mucosal injuries were evaluated by determining the colonic epithelial regeneration ratio ([area of epithelial regeneration/area of ulcer] × 100). Restoration of rat intestinal epithelial cells treated with daikenchuto and its constituent herbs (Zanthoxylum fruit, processed ginger, and ginseng) and ginsenoside Rb1, which is a ginseng ingredient, was evaluated using a wound‐healing assay. Results: The colon epithelial regeneration ratio in the daikenchuto‐treated rats was significantly higher than that in the control rats. Daikenchuto, ginseng, and ginsenoside Rb1 enhanced wound healing, and the ginsenoside Rb1‐induced enhancement was inhibited by extracellular signal‐regulated kinase and Rho inhibitors. Conclusions: Daikenchuto and its constituent, ginsenoside Rb1, promoted wound healing. Because mucosal healing is one of the most important therapeutic targets in patients with inflammatory bowel disease, ginsenoside Rb1 may be a novel therapeutic agent against intestinal mucosal damage such as that occurring in intestinal bowel disease. [ABSTRACT FROM AUTHOR]

Peroxiredoxin 4 (PRDX4), a secretory protein that is preferentially retained in the endoplasmic reticulum (ER), is encoded by a gene located on the X chromosome and highly expressed in colonic tissue. In this study, we investigated the role of PRDX4 by means of male PRDX4-knockout (PRDX4-/y) mice in the development of intestinal inflammation using a dextran sulfate sodium (DSS)-induced colitis model. Acute colitis was induced with DSS (2.5% in drinking water) in wild-type (WT) and PRDX4-/y male C57BL/6 mice. Histological and biochemical analyses were performed on the colonic tissues. PRDX4 was mainly localized in the colonic epithelial cells in WT mice. The disease activity index (DAI) scores of PRDX4-/y mice were significantly higher compared to those of WT mice. Specifically, PRDX4-/y mice showed marked body weight loss and shortening of colon length compared to WT mice, whereas the myeloperoxidase levels were increased in PRDX4-/y compared to WT mice. In addition, the mRNA expression levels of TNF-α and IFN-γ were significantly higher in the colonic mucosa of PRDX4-/y compared to WT mice. Moreover, the levels of CHOP and activated caspase 3 were higher in the colonic tissues of PRDX4-/y compared to WT mice following treatment with DSS. The ER also showed greater expansion in PRDX4-/y than WT mice, which was consistent with severe ER stress under PRDX4 deficiency. Our results demonstrated that the lack of PRDX4 aggravated the colonic mucosal damage induced by DSS. Because PRDX4 functions as an ER thiol oxidase as well as an antioxidant, DSS induced oxidative damage and ER stress to a greater degree in PRDX4-/y than WT mice. These findings suggest that PRDX4 may represent a novel therapeutic molecule in intestinal inflammation. fx1 • ER-retained peroxiredoxin 4 (PRDX4) protein is highly expressed in the colon. • PRDX4 localizes to colonic epithelial cells. • PRDX4-/y mice show high disease severity of colitis. • The oxidative damage and ER stress are higher in PRDX4-/y than WT mice. • PRDX4 may represent a novel therapeutic molecule in intestinal inflammation. [ABSTRACT FROM AUTHOR]

Abstract: Background and Aim: Secreted protein acidic and rich in cysteine (SPARC) is a matricellular glycol that regulates cell proliferation, tissue repair, and tumorigenesis. Despite evidence linking SPARC to inflammation, the mechanisms are unclear. Accordingly, the role of SPARC in intestinal inflammation was investigated. Methods: Colitis was induced in wild‐type (WT) and SPARC knockout (KO) mice using trinitrobenzene sulfonic acid (TNBS). Colons were assessed for damage; leukocyte infiltration; Tnf, Ifng, Il17a, and Il10 mRNA expression; and histology. Cytokine profiling of colonic lamina propria mononuclear cells (LPMCs) was performed by flow cytometry. Naïve CD4+ T cells were isolated from WT and SPARC KO mouse spleens, and the effect of SPARC on Th17 cell differentiation was examined. Recombination activating gene 1 knockout (RAG1 KO) mice reconstituted with T cells from either WT or SPARC KO mice were investigated. Results: Trinitrobenzene sulfonic acid exposure significantly reduced bodyweight and increased mucosal inflammation, leukocyte infiltration, and Il17a mRNA expression in WT relative to SPARC KO mice. The percentage of IL17A‐producing CD4+ T cells among LPMCs from KO mice was lower than that in WT mice when both groups were exposed to TNBS. Th17 cell differentiation was suppressed in cells from SPARC KO mice. In the T cell transfer colitis model, RAG1 KO mice receiving T cells from WT mice were more severely affected than those reconstituted with cells from SPARC KO mice. Conclusions: Secreted protein acidic and rich in cysteine accelerates colonic mucosal inflammation via modulation of IL17A‐producing CD4+ T cells. SPARC is a potential therapeutic target for conditions involving intestinal inflammation. [ABSTRACT FROM AUTHOR]