Paraoxonase-1 and arylesterase levels in patients with ulcerative colitis

Background and study aims

The role of oxidative stress in inflammatory bowel disease is increasingly recognised as an important factor. It is assumed that reduced levels of paraoxonase-1 (PON-1) and arylesterase (ARE) may lead to increased inflammation due to increased oxidative stress. This study aimed to investigate the relationship between ARE and PON-1 levels in ulcerative colitis (UC) patients and the difference in these levels in UC patients in comparison to the control group.

Evidence-based pathogenesis and treatment of ulcerative colitis: A causal role for colonic epithelial hydrogen peroxide

In this comprehensive evidence-based analysis of ulcerative colitis (UC), a causal role is identified for colonic epithelial hydrogen peroxide (H₂O₂) in both the pathogenesis and relapse of this debilitating inflammatory bowel disease. Studies have shown that H₂O₂ production is significantly increased in the non-inflamed colonic epithelium of individuals with UC. H₂O₂ is a powerful neutrophilic chemotactic agent that can diffuse through colonic epithelial cell membranes creating an interstitial chemotactic molecular “trail” that attracts adjacent intravascular neutrophils into the colonic epithelium leading to mucosal inflammation and UC. A novel therapy aimed at removing the inappropriate H₂O₂ mediated chemotactic signal has been highly effective in achieving complete histologic resolution of colitis in patients experiencing refractory disease with at least one (biopsy-proven) histologic remission lasting 14 years to date. The evidence implies that therapeutic intervention to prevent the re-establishment of a pathologic H₂O₂ mediated chemotactic signaling gradient will indefinitely preclude neutrophilic migration into the colonic epithelium constituting a functional cure for this disease. Cumulative data indicate that individuals with UC have normal immune systems and current treatment guidelines calling for the suppression of the immune response based on the belief that UC is caused by an underlying immune dysfunction are not supported by the evidence and may cause serious adverse effects. It is the aim of this paper to present experimental and clinical evidence that identifies H₂O₂ produced by the colonic epithelium as the causal agent in the pathogenesis of UC. A detailed explanation of a novel therapeutic intervention to normalize colonic H₂O₂, its rationale, components, and formulation is also provided.     

Effects of oral tacrolimus as a rapid induction therapy in ulcerative colitis

AIM:To determine the efficacy and safety of rapid induction therapy with oral tacrolimus without a meal in steroid-refractory ulcerative colitis(UC)patients.METHODS:This was a prospective,multicenter,observational study.Between May 2010 and August 2012,49 steroid-refractory UC patients(55 flare-ups)were consecutively enrolled.All patients were treated with oral tacrolimus without a meal at an initial dose of 0.1mg/kg per day.The dose was adjusted to maintain trough whole-blood levels of 10-15 ng/m L for the first 2 wk.Induction of remission at 2 and 4 wk after tacrolimus treatment initiation was evaluated using Lichtiger’s clinical activity index(CAI).RESULTS:The mean CAI was 12.6±3.6 at onset.Within the first 7 d,93.5%of patients maintained high trough levels(10-15 ng/m L).The CAI significantly decreased beginning 2 d after treatment initiation.At 2wk,73.1%of patients experienced clinical responses.After tacrolimus initiation,31.4%and 75.6%of patients achieved clinical remission at 2 and 4 wk,respectively.Treatment was well tolerated.CONCLUSION:Rapid induction therapy with oral tacrolimus shortened the time to achievement of appropriate trough levels and demonstrated a high remission rate 28 d after treatment initiation.Rapid induction therapy with oral tacrolimus appears to be a useful therapy for the treatment of refractory UC.     

Protective effect of naringenin on acetic acid-induced ulcerative colitis in rats

AIM:To evaluate the ameliorative effect of naringenin(NG)during ulcerative colitis(UC)in rats.METHODS:Rats were treated with three different doses(25,50 and 100 mg/kg per day)of NG and a single dose of mesalazine(MES,300 mg/kg per day)for seven days prior to ulcerative colitis induction by4%acetic acid(AA).Twenty four hours after AA rectal administration,animals were scarified and the colonic tissues were dissected.Colonic mucus content was estimated using Alcian blue dye binding technique.In colon tissues,levels of total glutathione sulphadryls(T-GSH),non-protein sulphadryls(NP-SH)and thiobarbituric acid reactive substances(TBARS)were evaluated.The activities of the antioxidant enzymes,catalase(CAT)and superoxide dismutase(SOD)were measured.Concentrations of nucleic acids(DNA and RNA)and total protein were also estimated in colon tissues.Colonic levels of tumor necrosis factor-(TNF-),interleukin-1(IL-1),interleukin-6(IL-6),prostaglandin E2(PGE2)and nitric oxide(NO)were estimated.In cross section of colitis tissue the histopathological changes were observed.RESULTS:Colonic mucus content was decreased in AA compared to controls(587.09±65.59 mg/kg vs941.78±68.41 mg/kg,P<0.001).AA administration markedly reduced T-GSH(5.25±0.37 nmol/L vs 3.04±0.24 nmol/L,P<0.01),NP-SH(3.16±0.04 nmol/L vs 2.16±0.30 nmol/L,P<0.01),CAT(6.77±0.40 U/mg vs 3.04±0.2 U/mg,P<0.01)and SOD(3.10±0.11U/mg vs 1.77±0.18 U/mg,P<0.01)while TBARS,TNF-,IL-1,IL-6,PGE2 and NO levels(15.09±3.84nmol/L vs 59.90±16.34 nmol/L,P<0.01;113.56±1.91 pg/mg vs 134.24±4.77 pg/mg,P<0.01;209.20±36.38 pg/mg vs 422.19±31.47 pg/mg,P<0.01;250.83±25.09 pg/mg vs 638.58±115.9 pg/mg,P<0.01;248.19±36.98 pg/mg vs 541.74±58.34 pg/mg,P<0.01 and 81.26±2.98 mmol/g vs 101.90±10.73 mmol/g,P<0.001)were increased in colon of rats with UC compared controls respectively.Naringenin supplementation,significantly and dose dependently increased the colonic mucus content.The elevated TBARS levels were significantly decreased(39.35±5.86n     

硫酸锌对溃疡性结肠炎治疗作用的实验研究

目的：建立一种慢性溃疡性结肠炎（Ｕｌｃｅｒａｔｉｖｅｃｏｌｉｔｉｓ，ＵＣ）的动物模型，并在此基础上观察硫酸锌灌肠治疗ＵＣ的疗效。方法：Ｗｉｓｔａｒ大鼠，给予含１．５％的ｓｏｄｉｕｍｄｅｘｔｒａｎｓｕｌｆａｔｅ水自由饮用，形成大鼠溃疡性结肠炎模型，给予硫酸锌灌肠治疗，内镜检查观察疗效。同时检测了治疗前后结肠粘膜ＳＯＤ活性、ＭＤＡ含量和锌含量。结果：硫酸锌灌肠应用治疗ＵＣ疗效与地塞米松相仿，治疗后结肠粘膜锌含量、ＳＯＤ活性增高，ＭＤＡ含量下降。结论：硫酸锌可用于溃疡性结肠炎的治疗，治疗作用与锌元素的局部对抗氧自由基的损害有关。     

A rare extraintestinal manifestation of ulcerative colitis: Tracheobronchitis associated with ulcerative colitis

We describe a 44 year-old woman who presented with dyspnea and cough 5 years after initial diagnosis of ulcerative colitis. The evaluation of patient showed findings of large airway inflammation with tracheal wall thickening and mucosal irregularities. The etiology was investigated and was diagnosed as tracheobronchitis that is a rare extraintestinal manifestation of ulcerative colitis. She was treated with systemic corticostreoids and rapid clinical improvement was detected.     

缺血性结肠炎与溃疡性结肠炎的对比分析

目的:研究缺血性结肠炎(ischemic colitis,IC)与溃疡性结肠炎(ulcerative colitis,UC)临床及组织病理学的差异,有助两者的鉴别诊断,利于临床治疗.方法:收集20例IC和30例UC患者,对其临床及组织病理学等资料进行对比分析.结果:IC组发病时间[(5±7)d]明显较UC组发病时间[(953±1354)d]短.IC组中65%的患者伴有高血压、冠状动脉性心脏病、心房颤动、房性早搏、腹部手术史等疾病史中的一项或几项,明显高于UC组的20%;IC组以急性发病、腹痛(85%)、血便(60%)及腹泻(50%)多见,而UC且以腹痛(83%)、腹泻(63%)、黏液脓血便(57%)及里急后重(20%)为主要临床表现;在内镜表现方面,IC多以沿肠系膜侧分布的纵形溃疡为主(60%),且病变多仅累及肠腔的1/4～1/2周(80%),呈节段性分布(60%),与邻近正常黏膜分界清楚(75%),而UC则以弥漫性地图状溃疡为主(43%),病变多累及肠腔全周(90%),炎性息肉明显多见(37%).在组织病理学方面,血管扩张充血(90%)、间质严重水肿(95%)在IC中多见,血管壁增厚(50%)是其特征性表现,隐窝脓肿(47%)则在UC中多见.两组以上差异均有统计学意义(P<0.05).结论:组织病理学特点、肠镜下表现以及患者临床特征的差异,为IC和UC的鉴别提供了有力依据.     

饮食与溃疡性结肠炎

饮食因素被认为是溃疡性结肠炎发病的危险因素.研究表明,过多摄入红肉,高脂肪和高蛋白饮食与本病的发病和复发有关联.另一方面,补充益生菌、鱼油和饮食纤维具有较好疗效.本文综述饮食因素在溃疡性结肠炎发病和治疗中作用的研究进展.     

溃疡性结肠炎的临床特点和治疗转归

目的分析溃疡性结肠炎患者的临床特点,探讨评价诊断方法、临床疗效及转归。方法回顾性分析自1989年10月至2005年6月在北京大学第三医院消化科住院的所有溃疡性结肠炎病例。填写调查表,统计病人的症状、诊断、分期、分型及治疗效果。结果共155例病人入选,男女比例为1·54∶1。平均年龄是41·8岁;发病高峰年龄20~30岁(44例,28·4%)。肠外表现较少见(12·9%)。轻度占32·3%,中度占41·3%,重度26·5%。病变范围以全结肠炎型最多(52·9%),分型以慢性复发型最多(39·4%),大部分病人都可以通过临床、内镜及病理(72·9%)得到确诊,病人经过内科保守治疗大多数都能缓解,少数需要手术治疗(4·5%),没有死亡病例。结论本组病人以轻中型为主,内科疗效较好,部分中重型病人需要使用激素和免疫抑制剂治疗,并发症(20例,12·9%)发生率和手术率(7例,4·5%)较低。     

Up-regulation of mitochondrial chaperone TRAP1 in ulcerative colitis associated colorectal cancer

AIM:To characterize tumor necrosis factor receptorassociated protein 1(TRAP1)expression in the progression of ulcerative colitis(UC)-associated colorectal cancer.METHODS:Chronic UC is an inflammatory bowel disease that predisposes to colorectal cancer.Immunohistochemical analysis was used to evaluate TRAP1expression on tissue microarrays containing colonic tissues from 42 UC progressors(patients with cancer or dysplasia)and 38 non-progressors(dysplasia/cancer free patients).Statistical analyses of the TRAP1immunohistochemistry staining were performed using Graph Pad Prism.Differences in the TRAP1 level between non-progressors and progressors were tested for statistical significance using the Mann-Whitney test.Receiver operating characteristic curve method was used to quantify marker performance in distinguishing diseased cases from controls.RESULTS:TRAP1 was up-regulated in the colon tissues from UC progressors,but not in the colon tissues from UC non-progressors.Moreover,up-regulation of TRAP1 preceded the neoplastic changes:it was present in both the dysplastic and non-dysplastic tissues of UC progressors.When TRAP1 staining in rectal tissue was used as a diagnostic marker,it could distinguish progressors from non-progressors with 59%sensitivity and 80%specificity.Our study further showed that the increase of TRAP1 expression positively correlated with the degree of inflammation in the colorectal cancer tissues,which could be related to the increased oxidation present in the colonic mucosa from UC progressors.We then investigated the cellular proteome changes underlying oxidative stress,and found that oxidative stress could induce up-regulation of TRAP1 along with several other negative modulators of apoptosis.CONCLUSION:These results suggest that oxidative stress in long standing UC could lead to the increase of cytoprotective protein TRAP1,which in turn could promote cancer progression by preventing or protecting the oxidative damaged epithelial cells from undergoing apoptosis.TRAP1 could be a potential diagnostic marker for UC associated colorectal cancer.     

Histological healing after infliximab induction therapy in children with ulcerative colitis

AIM: To verify the impact of induction therapy with infliximab(IFX) on mucosal healing in children with ulcerative colitis(UC).METHODS: The study included all UC pediatric patients treated with IFX at our center over the last10 years. The data were collected from patients' medical charts and analyzed retrospectively. A total of 16 patients with UC underwent colonoscopy with sample collection before and after three IFX injections.Pediatric Ulcerative Colitis Activity Index(PUCAI)was used to assess the clinical condition; endoscopic features were classified according to the Baron scale;and histological changes were evaluated according to the protocol of The British Society of Gastroenterology and Geboes Index. Clinical response was defined as a ≥ 20-point reduction in PUCAI index, and clinical remission as PUCAI index 10 points. Endoscopic mucosal remission was defined as completely normal(score 0) on the Baron scale. Histological remission was defined as grade 0 in the Geboes Index. To assess correlation between variables, Spearman's rank correlation coefficient was used.RESULTS: Clinical remission(PUCAI 10) at week 8 was achieved in 68.75% of investigated subjects. Endoscopic mucosal remission at week 8(Baron 0) was observed in 12.5% of patients. Histological remission(Geboes 0)after induction therapy with IFX was noticed in 18.75%cases. A general histological improvement, expressedby normal surface and crypt architecture, number of crypts, and lamina propria cellularity, was observed in six(37.5%) patients; there was no improvement in nine(56.25%) individuals, and worsening was observed in one(3.75%) case. Changes were not related to UC location. A reduction of inflammatory process was observed in 10(62.5%) patients; there were no changes in four(25%) individuals, and the inflammation became more severe in two(12.5 %) cases. Simultaneous clinical, endoscopic and histological improvement of parameters assessing disease activity at week 8 was noticed in six(37.5%) patients. 55.5% of investigated patients with normal mucosa seen on endoscopy showed no inflammation on histology. A Baron score of 2 and 3showed a good correlation with histology results(78.2%of patients with a Geboes Index ≥ 3).CONCLUSION: IFX has a positive histological effect in more than one-third of UC patients. IFX reduces intestinal inflammation and improves clinical condition.     

溃疡性结肠炎的临床特点和治疗转归

目的分析溃疡性结肠炎患者的临床特点，探讨评价诊断方法、临床疗效及转归。方法回顾性分析自1989年10月至2005年6月在北京大学第三医院消化科住院的所有溃疡性结肠炎病例。填写调查表，统计病人的症状、诊断、分期、分型及治疗效果。结果共155例病人入选，男女比例为1．54：1。平均年龄是41．8岁；发病高峰年龄20—30岁（44例，28．4％）。肠外表现较少见（12．9％）。轻度占32．3％，中度占41．3％，重度26．5％。病变范围以全结肠炎型最多（5209％），分型以慢性复发型最多（3904％），大部分病人都可以通过临床、内镜及病理（7209％）得到确诊，病人经过内科保守治疗大多数都能缓解，少数需要手术治疗（4．5％），没有死亡病例。结论本组病人以轻中型为主，内科疗效较好，部分中重型病人需要使用激素和免疫押制剂治疗，并发症（加例，12．9％）发生率和手术率（7例，4．5％）较低。     

溃疡性结肠炎免疫学发病机制进展

溃疡性结肠炎（UC）是一种肠道慢性非特异性炎症，病变主要位于结肠的黏膜和黏膜下层，多累及直肠和远端结肠。临床表现为腹泻、腹痛和黏液脓血便，并伴有一些肠外表现，如脱髓鞘疾病、多发性硬化症、视神经炎，骨质疏松嵋。等。UC病因不明，通常认为是环境、遗传及免疫等因素共同作用所致。我国本病发病率较低，但近年来本病也逐年呈上升趋势。在UC研究领域中，对免疫因素进展研究较快，本文就近年来免疫方面进展概述如下：     

TLRs在溃疡性结肠炎小鼠结肠中的表达研究

目的 观察溃疡性结肠炎（UC）小鼠模型结肠组织中TLR2、TLR4和TLR9的表达情况,为UC发病机制的研究提供新思路.方法 将6～8周龄健康雄性BALB/c小鼠随机分为两组：正常对照组（n=10）和UC模型组（n=10）,正常对照组小鼠蒸馏水自由饮用7d.UC模型组小鼠5％ DSS溶液自由饮用7d造模.7d后处死小鼠,采用实时荧光定量PCR方法检测各组小鼠结肠黏膜组织中TLR2、TLR4和TLR9 mRNA的表达情况.结果 正常对照组结肠组织中无TLR2、TLR4和TLR9 mRNA的表达,而UC组结肠组织中TLR2、TLR4和TLR9 mRNA表达明显,两组比较差异有统计学意义（P＜0.05）.结论 TLR2、TLR4、TLR9可能参与了UC的发病过程.     

Gaseous metabolites as therapeutic targets in ulcerative colitis

Diet therapies are currently under-utilised in optimising clinical outcomes for patients with active ulcerative colitis(UC). Furthermore, existing dietary therapies are framed by poorly defined mechanistic targets to warrant its success. There is good evidence to suggest that microbial production of gaseous metabolites, hydrogen sulfide(H2S) and nitric oxide(NO) are implicated in the development of mucosal inflammation in UC. On a cellular level, exposure of the colonic epithelium to excessive c...     

Lansoprazole-associated collagenous colitis： Diffuse mucosal cloudiness mimicking ulcerative colitis

There have only been a few reports on lansoprazole-associated collagenous colitis. Colonic mucosa of collagenous colitis is known to be endoscopically normal. We present a case of collagenous colitis where the mucosa showed diffuse cloudiness mimickin gulcerative colitis. A 70-year-old woman developed watery diarrhea four to nine times a day. She had interstitial pneumonia at 67 and reflux esophagitis at 70 years. Lansoprazole 30 mg/d had been prescribed for reflux esophagitis for nearly 6 mo. Lansoprazole was withdrawn due to its possible side effect of diarrhea. Colonoscopy disclosed diffuse cloudiness of the mucosa which suggested ulcerative colitis.Consequently sulfasalazine 2 g/d was started. The patient＇s diarrhea dramatically disappeared on the following day. However, biopsy specimens showed subepithelial collagenous thickening and infiltration of inflammatory cells in the lamina propria, confirming the diagnosis of collagenous colitis. One month after sulfasalazine therapy was initiated, colonoscopic and histological abnormalities resolved completely. Fivemonths later the diarrhea recurred. The findings on colonoscopy and histology were the same as before, confirming a diagnosis of collagenous colitis relapse. We found that the patient had begun to take lansoprazole again 3 mo ahead of the recent diarrhea.Withdrawal of lansoprazole promptly resolved the diarrhea. Endoscopic and histological abnormalities were also completely resolved, similar to the first episode. Retrospectively, the date of commencement of sulfasalazine and discontinuation of lansoprazole in the first episode was found to be the same. We conclude that this patient had lansoprazole-associated collagenous colitis.     

527例溃疡性结肠炎临床与病理分析

目的 评价临床、内镜及活检三者在溃疡性结肠炎(UC)诊断中的作用。方法 总结我院10年间经肠镜诊断为UC的病例，分析其临床、内镜表现及部分活检资料。结果 527例确诊为UC，其中误诊34例，结肠镜诊断正确率为93．9％。UC临床主要表现为腹泻(88％)、粘液脓血便(52％)。结肠镜表现以粘膜充血水肿(94％)、糜烂溃疡(75％)最多见，病变部位以直、乙结肠为主(51％)，呈弥漫性、连续性分布。活检特征性表现为炎症程度重(49％)，固有层弥漫性混合性炎细胞浸润(76％)、杯状细胞减少(71％)、隐窝扭曲(63％)、萎缩(47％)、隐窝炎(45％)、隐窝脓肿(36％)及绒毛状表面(39％)。结论 UC的诊断应强调临床、内镜及活检相结合。     

慢性应激对小鼠溃疡性结肠炎的影响

目的观察慢性束缚应激对葡聚糖酸钠(DSS)诱导的小鼠溃疡性结肠炎(UC)的影响。方法64只BALB/C小鼠分为6组,单纯应激组、正常对照组各16只,应激 2DSS组、应激 4DSS组、2DSS组、4DSS组各8只。采用自制的束缚笼对应激组小鼠建立慢性心理应激动物模型。采用小鼠自由饮用DSS溶液的方法建立UC模型。每日观察各组疾病活动指数(DAI)。并在实验结束后测量结肠组织损伤评分(HS)、髓过氧化物酶(MPO)活性。HS评分通过在光镜下观察结肠组织学改变得出。并用分光光度法测定结肠组织中MPO的活性。结果单纯应激组小鼠体重增长较正常对照组缓慢(P<0.05)。4DSS组小鼠DAI评分、HS评分及结肠组织MPO活性均较正常对照组增高(P<0.05)。应激 4DSS组上述指标较正常对照组变化更显著,与4DSS组比较亦增高(P<0.05)。2DSS组上述指标与正常对照组相比无明显区别(P>0.05)。应激 2DSS组上述指标较正常对照组增高(P<0.05)。结论慢性束缚应激可以使小鼠发生UC的易感性增加并加重DSS结肠炎的病理损伤。     

肠三叶因子与溃疡性结肠炎

溃疡性结肠炎（UC）是结肠与直肠的慢性非特异性炎症性疾病，与克罗恩病（CD）一起，统称为炎症性肠病（IBD）。溃疡性结肠炎以慢性、反复发作、病因不明为特征，1978年以来，资料统计结果表明，该病发病率在我国有明显上升的趋势。迄今，溃疡性结肠炎的病因和发病机制尚不十分清楚，但近年的一些研究结果具有重要的意义，尤其是对免疫调节所引起的各种细胞因子、炎症介质作用的研究。     

溃疡性结肠治的新思路

溃疡性结肠炎(ulcerative colitis)黏膜损伤无法修复的原因还没有阐明,至今无特异性治疗方法,造成该病病程迁延、无法治愈.通过研究结肠黏膜干细胞减少与病变黏膜损伤的关系以及骨髓干细胞随血液循环到达结肠黏膜并转分化为结肠黏膜干细胞和上皮细胞情况,有可能阐明溃疡性结肠炎黏膜损伤无法修复的原因及为从根本上治疗该病提供新思路.