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Norisoboldine, a natural aryl hydrocarbon receptor agonist, alleviates TNBS-induced colitis in mice, by inhibiting the activation of NLRP3 inflammasome

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Chinese Journal of Natural Medicines 2018年第3期16卷 161-174页

作者： LV Qi WANG Kai QIAO Si-Miao DAI Yue WEI Zhi-Feng Department of Pharmacology of Chinese Materia Medica China Pharmaceutical University

Although the etiology of inflammatory bowel disease is still uncertain, increasing evidence indicates that the excessive activation of NLRP3 inflammasome plays a major role. Norisoboldine(NOR), an alkaloid isolated from Radix Linderae, has previously been demonstrated to inhibit inflammation and IL-1β production. The present study was to examine the effect of NOR on colitis and the underlying mechanism related to NLRP3 inflammasome activation. Our results showed that NOR alleviated colitis symptom in mice induced by 2, 4, 6-trinitrobenzene sulfonic acid(TNBS). Moreover, it significantly reduced expressions of cleaved IL-1β, NLRP3 and cleaved Caspase-1 but not ASC in colons of mice. In THP-1 cells, NOR suppressed the expressions of NLRP3, cleaved Caspase-1 and cleaved IL-1β but not ASC induced by lipopolysaccharide(LPS) and adenosine triphosphate(ATP). Furthermore, NOR could activate aryl hydrocarbon receptor(AhR) in THP-1 cells, inducing CYP1 A1 mR NA expression, and promoting dissociation of Ah R/HSP90 complexes, association of AhR and ARNT, Ah R nuclear translocation, XRE reporter activity and binding activity of Ah R/ARNT/XRE. Both siA hR and α-naphthoflavone(α-NF) markedly diminished the inhibition of NOR on NLRP3 inflammasome activation. In addition, NOR elevated Nrf2 level and reduced ROS level in LPS-and ATP-stimulated THP-1 cells, which was reversed by either si AhR or α-NF treatment. Finally, correlations between activation of AhR and attenuation of colitis, inhibition of NLRP3 inflammasome activation and up-regulation of Nrf2 level in colons were validated in mice with TNBS-induced colitis. Taken together, NOR ameliorated TNBS-induced colitis in mice through inhibiting NLRP3 inflammasome activation via regulating AhR/Nrf2/ROS signaling pathway.

关键词： Norisoboldine 煽动性的肠疾病 NLRP3 inflammasome 芳基烃受体

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Disease impact on the quality of life of children with inflammatory bowel disease

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World Journal of Gastroenterology 2017年第6期23卷 1067-1075页

作者： Giorgos Chouliaras Daphne Margoni Konstantina Dimakou Smaragdi Fessatou Ioanna Panayiotou Eleftheria Roma-Giannikou First Department of Pediatrics National and Kapodistrian University of Athens'Aghia Sophia'Children’s Hospital11527 AthensGreece

AIM To assess the impact of disease characteristics on the quality of life (QOL) in children with inflammatory bowel diseases(IBD).METHODS This was a cross-sectional study conducted at the First Department of Pediatrics of the University of Athens at the "Aghia Sophia" Children's Hospital. Children diagnosed with Crohn's disease (CD) or ulcerative colitis (UC), who were followed as outpatients or during a hospitalization, participated, after informed consent was obtained from their legal representative. QOL was assessed by the IMPACT-III questionnaire. Demographic data and disease characteristics were also collected. Statistical analyses included parametric(Student's t-test and Pearson's r) and non-parametric(Mann-Whitney test, Fisher's test and Spearman's rho) procedures.RESULTS Ninety-nine patients (UC: 37, 73.0% females, CD: 62, 51.6% females), aged 12.8±2.6 years were included.Overall, as well as, sub-domain scores did not differ between UC and CD(overall score: 73.9±13.3 vs 77.5±11.2, respectively, P=0.16). In the entire sample, total score was related to physician's global assessment(PGA, patients classified as "mild/moderate" active disease had, on average, 14.8±2.7 points lower total scores compared to those "in remission", P<0.001) and age at IMPACT completion (Pearson's r=0.29, P=0.05). Disease activity assessed by the indices Pediatric Ulcerative Colitis activity index, Pediatric Crohn's disease activity index or PGA was significantly associated with all subdomains scores. Presence of extraintestinal manifestations had a negative impact on emotional and social functioning domains.CONCLUSION Disease activity is the main correlate of QOL in children with IBD, underlining the importance of achieving and sustaining clinical

关键词：煽动性的肠疾病 ulcerative 大肠炎 Crohns 疾病生活的质量 IMPACT-III 孩子

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Inflammatory bowel disease: An evaluation of health information on the internet

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World Journal of Gastroenterology 2017年第9期23卷 1676-1696页

作者： Samy A Azer Thekra I AlOlayan Malak A AlGhamdi Malak A AlSanea Curriculum Development and Research Unit Medical Education DepartmentCollege of MedicineKing Saud UniversityRiyadh 11461Saudi Arabia

AIM To evaluate the quality and accuracy of websites written to the public on inflammatory bowel disease(IBD)(Crohn's disease and ulcerative colitis) and assess their readability level.METHODS Google?, Bing?, and Yahoo? search engines were searched independently by three researchers in December 2014. Only English-language websites were selected on the basis of predetermined inclusion and exclusion criteria. Researchers independently evaluated the quality of each website by using the DISCERN and the HONcode instruments. The readability levels were calculated using two formulas; the Flesch-Kincaid Grade Level Index, and the Coleman-Liau Readability Index. The agreement between the evaluators was calculated using Cohen kappa coefficient.RESULTS Eighty-four websites were finally identified. Scores varied from a minimum DISCERN score of 18 to a maximum of 68 [mean ± SD, 42.2 ± 10.7; median = 41.5, interquartile range, interquartile range (IQR) = 15.8] and a minimum score of HONcode of 0.14 and a maximum of 0.95 (mean ± SD, 0.16 ± 0.19; median = 0.45, IQR = 0.29). Most of these websites were reviewed in 2014 and 2015 (n = 51). The creators of these websites were: universities and research centers(n = 25, 30%), foundations and associations (n = 15, 18%), commercial and pharmaceutical companies(n =25, 30%), charities and volunteer work(n = 9, 10%), and non-university educational bodies (n = 10, 12%). The Flesch-Kincaid Grade Level readability score(mean ± SD) was 11.9 ± 2.4 and the Coleman-Liau Readability Index score was 12.6 ± 1.5. Significant correlation was found between the two readability scores (R2 = 0.509, P = 0.001). The overall agreement between evaluators measured by Cohen kappa coefficient was in the range of 0.804-0.876; rated as "Good".CONCLUSION The DISCERN and the HONcode scores of websites varied and the readability levels of most websites were above the public readability level. The study highlights the areas that need further improvement and development in patient education online materials about IBD.

关键词：煽动性的肠疾病因特网病人信息证据病人教育联机资源

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Chronological age when health care transition skills are mastered in adolescents/young adults with inflammatory bowel disease

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World Journal of Gastroenterology 2017年第18期23卷 3349-3355页

作者： Natalie Stollon Yi Zhong Maria Ferris Suneet Bhansali Brian Pitts Eniko Rak Maureen Kelly Sandra Kim Miranda AL van Tilburg School of Social Work University of Washington Department of Economics University of North Carolina Department of Pediatrics University of North CarolinaSchool of Medicine Department of Pediatrics NYU School of Medicine Department of Allied Health Sciences University of North CarolinaSchool of Medicine Department of Pediatrics Children's Hospital of Pittsburgh Department of Clinical Research Campbell UniversityCollege of Pharmacy and Health Sciences Department of Gastroenterology and Hepatology the University of North CarolinaSchool of Medicine

AIM To describe the longitudinal course of acquisition of healthcare transition skills among adolescents and young adults with inflammatory bowel diseases.METHODS We recruited adolescents and young adults(AYA) with inflammatory bowel diseases(IBD), from the pediatric IBD clinic at the University of North Carolina. Participants completed the TRx ANSITION Scale? at least once during the study period(2006-2015). We used the electronic medical record to extract participants' clinical and demographic data. We used ordinary least square regressions with robust standard error clustered at patient level to explore the variations in the levels and growths of healthcare transition readiness.RESULTS Our sample(n = 144) ranged in age from 14-22 years. Age was significantly and positively associated with both the level and growth of TRx ANSITION Scale? scores(P < 0.01). Many healthcare transition(HCT) skills were acquired between ages 12 and 14 years, but others were not mastered until after age 18, including self-management skills.CONCLUSION This is one of the first studies to describe the longitudinal course of HCT skill acquisition among AYA with IBD, providing benchmarks for evaluating transition interventions.

关键词：煽动性的肠疾病 Crohns 疾病 Ulcerative 大肠炎儿科保健转变

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Transition of pediatric to adult care in inflammatory bowel disease: Is it as easy as 1, 2, 3?

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World Journal of Gastroenterology 2017年第20期23卷 3624-3631页

作者： Anita Afzali Ghassan Wahbeh Division of Gastroenterology University of WashingtonHarborview Medical CenterSeattleWashington Division of Gastroenterology Seattle Children's HospitalUniversity of WashingtonSeattleWashington

Inflammatory bowel disease(IBD)is a heterogeneous group of chronic diseases with a rising prevalence in the pediatric population,and up to 25%of IBD patients are diagnosed before 18 years of age.Adolescents with IBD tend to have more severe and extensive disease and eventually require graduation from pediatric care toadult services.The transition of patients from pediatric to adult gastroenterologists requires careful preparation and coordination,with involvement of all key players to ensure proper collaboration of care and avoid interruption in care.This can be challenging and associated with gaps in delivery of care.The pediatric and adult health paradigms have inherent differences between health care models,as well as health care priorities in IBD.The readiness of the young adult also influences this transition of care,with often times other overlaps in life events,such as school,financial independence and moving away from home.These patients are therefore at higher risk for poorer clinical disease outcomes.The aim of this paper is to review concepts pertinent to transition of care of young adults with IBD to adult care,and provides resources appropriate for an IBD pediatric to adult transition of care model.

关键词：煽动性的肠疾病青少年年轻成年人转移照顾转变到成年照顾

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Systemic interleukin-9 in inflammatory bowel disease: Association with mucosal healing in ulcerative colitis

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World Journal of Gastroenterology 2017年第22期23卷 4039-4046页

作者： Malgorzata Matusiewicz Katarzyna Neubauer Iwona Bednarz-Misa Sabina Gorska Malgorzata Krzystek-Korpacka Department of Medical Biochemistry Wroclaw Medical University Department of Gastroenterology and Hepatology Wroclaw Medical University Laboratory of Medical Microbiology Ludwik Hirszfeld Institute of Immunology and Experimental TherapyPolish Academy of Sciences

AIM To evaluate circulating IL9 in inflammatory bowel disease and disease-associated anemia/cachexia and assess its potential as a mucosal healing marker.METHODS Serum IL9 as well as other cytokines(IL1β, IL6, IL13, IFNγ, TNFα, and VEGF-A) were determined in 293 individuals: 97 patients with Crohn's disease(CD) and 74 with ulcerative colitis(UC) and in 122 apparently healthy controls. The clinical activity of CD and UC was expressed in terms of the Crohn's Disease Activity Index(CDAI) and the Mayo Scoring System(MDAI), respectively, and the severity of bowel inflammation in UC patients was assessed using Mayo endoscopic score. Cytokine concentrations were measured by a flow cytometry-based method using Luminex x MAP? technology. Highsensitive C-reactive protein concentrations(hs CRP) were determined in CD and UC patients using the enhanced immunoturbidimetric method.RESULTS Systemic IL9 was significantly lower in healthy individuals [9 pg/m L(95%CI: 8.2-10)] than in patients with inflammatory bowel disease(IBD): both inactive [14.3 pg/m L(11.9-19.9)] and active [27.6 pg/m L(24.5-32), P < 0.0001]. Cytokine concentrations were significantly higher in active CD [27.4 pg/m L(23.4-32.2)] and in active UC [32.7 pg/m L(27-38.9)] compared to inactive diseases [15.9 pg/m L(10.8-23.4) in CD and 19.4 pg/m L(13.9-27.1) in UC, P = 0.001]. IL9 correlated weakly with CDAI(ρ = 0.32, P = 0.003) and MDAI(ρ = 0.35, P = 0.002) and strongly with endoscopic inflammation in UC(ρ = 0.74, P < 0.0001). As a negative marker of mucosal healing(MH), IL9 had an accuracy superior to hs CRP and IL6 [97%(P < 0.0001), 67%(P = 0.071), and 55%(P = 0.525), respectively]. IL9 was significantly higher in cachectic IBD patients [30.25 pg/m L(24.4-37.5) vs 21.88 pg/m L(18-26.5), P = 0.026] and negatively correlated with hemoglobin concentrations(ρ =-0.27, P < 0.001). Multiple regression showed IL1β and IL13 to be the independent predictors of circulating IL9 in healthy individuals, IFNγ or IL6 in active and inactive UC, respectively, and IL13 and VEGF-A

关键词： Interleukin 9 Mucosal 愈合 Biomarker 煽动性的肠疾病 Crohns 疾病 Ulcerative 大肠炎极度瘦弱贫血症

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Potential role of nutraceutical compounds in inflammatory bowel disease

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World Journal of Gastroenterology 2017年第14期23卷 2483-2492页

作者： Tiziana Larussaa Maria Imeneoa Francesco Luzza Department of Health Sciences University of Catanzaro 'Magna Graecia'

Conventional therapies for inflammatory bowel diseases(IBD) involve combinations of pharmacologic agents such as aminosalicylates, azathioprine, and corticosteroids. Recently, the therapeutic scenario has been heavily increased by the introduction of agents including monoclonal antibodies targeted to specific proinflammatory cytokines, to adhesion molecules, and the induction of anti-inflammatory cytokines and T-cell activation. However, the use of these drugs is accompanied by a certain number of side effects, with some of them being quite severe, rising concerns about the safety profile. Furthermore, the cost of these emerging therapeutic strategies is significant, considering the increasing incidence and the chronic trend of IBD. Nutraceuticals is a broad term used to describe any product derived from food sources claiming extra health benefits beyond the intrinsic nutritional value found in foods. The beneficial effects of nutraceutical compounds in human health have been emerging in the last decades. Although few clinical trials have been performed in IBD patients, nutraceuticals, such as herbal products or vitamins, are generally accepted as safer alternative/supplementation to conventional therapy. In vitro and IBD-animal models studies have shown their involvement in several biological processes, including antioxidant defenses, cell proliferation, gene expression, which could account for a role in the maintenance of the mucosal barrier integrity, the control of the inflammatory pathways and the modulation of the immune response. These data suggest a wide spectrum of positive effects exerted by nutraceuticals, with a high potential for a therapeutic use in humans. In the present review, the beneficial effects of the most investigated nutraceutical compounds in the setting of human IBD are discussed.

关键词：煽动性的肠疾病 Ulcerative 大肠炎 Crohns 疾病 Nutraceuticals Probiotics Phytochemicals Herbals 功能的食物

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Investigation of mitigating effect of colon-specific prodrugs of boswellic acid on 2,4,6-trinitrobenzene sulfonic acidinduced colitis in Wistar rats: Design, kinetics and biological evaluation

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World Journal of Gastroenterology 2017年第7期23卷 1147-1162页

作者： Ajinkya Sarkate Suneela S Dhaneshwar Department of Pharmaceutical Chemistry Poona College of PharmacyBharati Vidyapeeth UniversityMaharashtra 411038India

AIM To develop a colon-targeting bioreversible delivery system for β-boswellic acid(BBA) and explore utility of its prodrugs in 2,4,6-trinitrobenzene sulfonic acid(TNBS)-induced colitis in rats.METHODS Synthesis of 4 co-drugs of BBA with essential amino acids was achieved by CDI coupling, followed by their spectral characterization. In vitro kinetics were studied by HPLC in aqueous buffers, homogenates of gastrointestinal tract and fecal matter. In vivo kinetic studies were performed in Wistar rat plasma, urine and feces. The prodrugs were screened in TNBS-induced colitis modeled Wistar rats. Statistical significance was assumed at P < 0.05, P < 0.01, P < 0.001 when compared with disease controls using one-way and two-way ANOVAs.RESULTS Prodrugs were stable in 0.05 mol/L HCl buffer(p H 1.2) and stomach homogenates. Negligible hydrolysis was observed in phosphate buffer and intestinal homogenates. Substantial release(55%-72% and 68%-86%) of BBA was achieved in rat fecal matter and homogenates of colon. In vivo studies of BBA with L-tryptophan(BT) authenticated colon-specific release of BBA. But, surprisingly substantial concentration of BBA was seen to reach the systemic circulation due to probable absorption through colonic mucosa. Sitespecifically enhanced bioavailability of BBA could be achieved in colon, which resulted in demonstration of significant mitigating effect on TNBS-induced colitis in rats without inducing any adverse effects on stomach, liver and pancreas. Prodrug of BT was found to be 1.7%(P < 0.001) superior than sulfasalazine in reducing the inflammation to colon among all prodrugs tested. CONCLUSION The outcome of this study strongly suggests that these prodrugs might have dual applicability to inflammatory bowel disease and chronotherapy of rheumatoid arthritis.

关键词：煽动性的肠疾病 Boswellic 酸互补、其他的药指向冒号相互的 prodrugs 氨基酸导致 TNBS 的大肠炎

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Role of new endoscopic techniques in inflammatory bowel disease management: Has the change come?

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World Journal of Gastroenterology 2017年第24期23卷 4324-4329页

作者： loredana goran lucian negreanu ana maria negreanu Internal Medicine Ⅱ Gastroenterology department University Hospital Carol Davila University of Medicine

Despite significant therapeutic progress in recent years,inflammatory bowel disease(IBD),which includes Crohn’s disease and ulcerative colitis,remains a challenge regarding its pathogenesis and long-term complications.New concepts have emerged in the management of this disease,such as the"treat-totarget"concept,in which mucosal healing plays a key role in the evolution of IBD,the risk of recurrence and the need for surgery.Endoscopy is essential for the assessment of mucosal inflammation and plays a pivotal role in the analysis of mucosal healing in patients with IBD.Endoscopy is also essential in the detection of dysplasia and in the identification of the risk of colon cancer.The current surveillance strategy for dysplasia in IBD patients indicates white-light endoscopy with non-targeted biopsies.The new chromoendoscopy techniques provide substantial benefits for both clinicians and patients.Narrow-band imaging(NBI)has similar rates of dysplastic lesion detection as whitelight endoscopy,and it seems that NBI identifies more adenoma-like lesions.Because it is used instinctively by many endoscopists,the combination of these two techniques might improve the rate of dysplasia detection.Flexible spectral imaging color enhancement can help differentiate dysplastic and non-dysplastic lesions and can also predict the risk of recurrence,which allows us to modulate the treatment to gain better control of the disease.The combination of noninvasive serum and stool biomarkers with endoscopy will improve the monitoring and limit the evolution of IBD because it enables the use of a personalized approach to each patient based on that patient’s history and risk factors.

关键词： Chromoendoscopy 灵活光谱成像颜色改进煽动性的肠疾病发育异常 Mucosal 愈合缩小乐队成像

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Overexpression of fibrinogen-like protein 2 protects against T cell-induced colitis

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World Journal of Gastroenterology 2017年第15期23卷 2673-2684页

作者： Agata Bartczak Jianhua Zhang Oyedele Adeyi Achiya Amir David Grant Reginald Gorczynski Nazia Selzner Andrzej Chruscinski Gary A Levy Multi Organ Transplant Program University Health Network Department of Laboratory Medicine and Pathology University Health Network Gastroenterology Hepatology and Nutrition DivisionThe Hospital for Sick Children

AIM To determine the effect of overexpression of fibrinogenlike protein 2(FGL2) on regulatory T cell(Treg) and effector T(Teff) cell function on T cell-induced colitis in Rag1-/-mice.METHODS Treg and Teff cells from fgl2-/-, fgl2+/+, and fgl2 Tg mice were purified by FACS. They were studied in vitro for immunosuppressive activity and cell proliferation and in vivo for their effects on the development and prevention of T cell-induced colitis in Rag1-/-mice. RESULTS In vitro, fgl2 Tg Treg had enhanced immunosuppressive activity, and fgl2 Tg Teff had reduced proliferation to alloantigen stimulation. Transfer of Teff from C57Bl/6J mice(fgl2+/+) into Rag1-/-mice produced both clinical and histologic colitis with dense infiltrates of CD3+ T cells, crypt abscesses and loss of goblet cells. Fgl2 Tg Treg prevented the development of T cell-induced colitis, whereas fgl2+/+ and fgl2-/-Treg were only partially protective. In mice that received fgl2 Tg Treg, the ratio of Foxp3+ to CD3+ cells was increased both in the colon and in mesenteric lymph nodes, and Teff cell proliferation as determined by staining with Ki67 was reduced. Teff cells from fgl2 Tg mice did not produce colitis. CONCLUSION Here we show that fgl2 Tg Teff are hypoproliferative and do not induce colitis. We further demonstrate that fgl2 Tg Treg prevent colitis in contrast to fgl2+/+ Treg, which were only partially protective. These studies collectively provide a rationale for exploring the use of FGL2 or Treg expressing high levels of FGL2 in the treatment of inflammatory bowel disease.

关键词：像纤维蛋白原的蛋白质 2 大肠炎规章的 T 房间转基因的老鼠煽动性的肠疾病

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