Objective Coeliac disease (CeD) is a relatively common autoimmune disease in Caucasian populations, but is rarely reported in China. The metabolic characteristics of Chinese patients with coeliac disease remain insufficiently characterised. Therefore, this study attempted to describe the metabolic profile of a small cohort Chinese patients with coeliac disease.Methods Plasma samples and dietary pattern information were collected from 15 patients with CeD, 15 healthy volunteers, and 30 patients with inflammatory bowel disease (IBD). Plasma metabolomic analysis was performed using a pseudo-targeted metabolomics approach based on ultra-high-performance liquid chromatography coupled with triple quadrupole-linear ion trap mass spectrometry (UHPLC-QTRAP-MS). Dietary intake was assessed via food frequency questionnaires, and metabolomics data were adjusted according to energy and 17 specific nutrient covariates.Results Despite reporting significantly higher daily intakes of protein and carbohydrate when compared to controls or IBD patients, CeD patients exhibited a relative insufficiency of micronutrient niacin. Several distinct metabolic alterations were identified in CeD patients relative to healthy controls, independent of dietary intake. These included decreased metabolites in the pentose phosphate pathway and increased intermediates of the citric acid cycle. The abundances of L-proline, D-proline, microbiota-related aromatic amino acid metabolites, glycine-conjugated bile acids, and the plant sterol panuosterone were increased. In contrast, the abundances of several long-chain acylcarnitines were reduced despite higher fat intake. These metabolic alterations existed in CeD but not in IBD patients.Conclusions CeD patients in Northwest China exhibit a unique metabolic profile distinct from IBD and healthy controls, involving host central carbon metabolism, glycerophospholipid metabolism, gut microbiota, and other factors. This might underscore the multifactorial nature of coeliac disease, implicating other factors beyond genetics and gluten.

Objective To evaluate the prognostic value of WNT10B expression in colorectal cancer (CRC) for personalized management. Methods We analyzed a TCGA cohort of 644 CRC patients to assess differential expression of WNT family genes between 51 paired tumor-normal samples. Patients were stratified by WNT10B expression to compare overall survival (OS) and progression-free interval (PFI). Prognostic factors were identified via univariate and multivariate Cox regression. For validation, WNT10B protein expression was examined by immunohistochemistry in a separate cohort of 176 CRC patients who underwent surgery at our institution (2016-2020). Kaplan-Meier analysis and univariate Cox regression were used to correlate WNT10B levels with OS and disease-free survival (DFS). Results According to TCGA data, WNT10B was upregulated in CRC tumors. Elevated expression was correlated with reduced OS and PFI. Univariate analysis for OS implicated high WNT10B, age >65, lymph node/distant metastasis, positive margin, deep invasion, and abnormal CEA. For PFI, significant factors included high WNT10B, lymph node/distant metastasis, positive margin, deep invasion, and abnormal CEA. Multivariate analysis confirmed high WNT10B, age >65, and a positive margin as independent prognostic factors for OS. High WNT10B expression, distant metastasis, invasion depth and abnormal carcinoembryonic antigen level are the risk factors for independently predicting high tumor recurrence; Postoperative Kaplan-Meier analysis revealed that reduced WNT10B expression was associated with prolonged overall survival (OS), while disease-free survival (DFS) also tended to be longer in the low-expression group, although this trend did not reach statistical significance. Univariate Cox regression identified several factors adversely affecting OS, including elevated WNT10B expression, age ≥65 years, lymph node metastasis, distant metastasis, positive surgical margin, vascular invasion, and perineural invasion. Lymph node metastasis, distant metastasis, vascular invasion, and perineural invasion were also associated with increased recurrence risk. Multivariate analysis confirmed that age ≥65 years, distant metastasis, and vascular invasion were independent predictors of shorter OS. Distant metastasis emerged as an independent risk factor for tumor recurrence. Conclusion WNT10B is upregulated in colorectal cancer and correlates with unfavorable outcomes, suggesting its potential utility as a prognostic biomarker and therapeutic target.

Cancer is a noncommunicable disease burden and the second‐leading cause of death worldwide. Novel medications and drug possibilities are sought everyday throughout the world in pursuit of cancer therapy. Colorectal cancer as one of the leading cancers across the globe can be treated effectively using TCM via decreasing the incidence and increasing the survival of patients. Gallic acid (GA) is an effective polyphenol used in TCM to treat several disorders including cancer. Our hypothesis was set to determine that GA possesses cytotoxic effects on CRC cells and that apoptosis and/or autophagy could be the rationale behind the mechanism. Therefore, in the current study, we investigated the cytotoxic effects of GA on human colorectal adenocarcinoma HT‐29 cells and the mechanisms of such effects. The IC50 for the cytotoxic effects of GA as evidenced by the MTT assay was 37.08 μg/mL. The outcomes indicated that GA can cause changes in MMP and result in the formation or accumulation of exogenous ROS at the IC50 dose. Consequently, the polyphenol can induce mitochondrial‐ or ER‐stress‐induced apoptosis and canonical autophagy other than contributing to the induction of ferroptosis in HT‐29 cells as evidenced by quantitative PCR and western blotting. Our results indicate that GA is an effective cytotoxic agent for the management of CRC at the preclinical level and is a valuable candidate for clinical trials.

Purpose:Inflammatory bowel disease (IBD) is a serious disease that affects the metabolism and inflammatory responses of human beings. From the perspective of traditional Chinese medicine, damp-heat syndrome is one of the main syndromes of IBD. Rhizoma Paridis, also known as the root of Paris polyphylla, a well-known herbal medicine used in China, is used to treat IBD with damp-heat syndrome (IBD-DH). However, uncertainty still exists regarding the underlying mechanisms and the impact of Rhizoma Paridis on IBD-DH. Methods:The rats in the model (DAT) and medication administration (Rhizoma Paridis total saponins (RPTS) and Pennogenin (PN)) groups were given a high temperature and high humidity environment, high fat and high sugar diet combined with 2,4,6-trinitrobenzene sulfonic acid (TNBS) to establish the model of experimental colitis of damp-heat type, and the normal control group (RNC) rats were given a normal diet at normal temperature and humidity. Damp-heat control group (DNC) was set with the same condition as DAT without TNBS. Hematoxylin-Eosin (HE) staining was used to observe the histopathological morphology of the rat colorectum. The expression of the metabolism-related genes (Phospholipase A2 (sPLA2, cPLA2), and phosphatidylethanolamine N-methyltransferase (PEMT)) was assessed by using real-time quantitative PCR analysis (RT-qPCR). And the levels of the metabolism-related proteins (sPLA2, cPLA2), S100A8/9, Arg-1, and cytokines were detected by enzyme-linked immunosorbent assay (ELISA) kit. To investigate lipids and amino acids which closely associated with the IBD and IBD-DH, lipid pseudotargeted metabolomics with UHPLC-TQ/MS analysis method, as well as targeted quantitative amino acid analysis were performed. Results:Our data showed that RPTS (50 mg/kg) and PN (20 mg/kg) significantly ameliorated the severity of TNBS-induced colitis and downregulated the levels of circulating proinflammatory cytokines. Compared with RNC group, lipid pseudotargeted metabolomics demonstrated that glycerophospholipids, sphingolipids, carnitine, and glycerolipids were the four most perturbed lipid classes, and amino acids targeted metabolomics demonstrated that serine, N-acetylneuraminic acid, histidine, proline, taurine, and kynurenine changed significantly in DAT group . Correlation analyses showed tight associations between most of differential metabolites and proinflammatory cytokines. RPTS and PN both regulated glycerophospholipid metabolism and sphingolipid metabolism. However, both of them did not have a significant effect on amino acid modulation. RPTS and PN potentially regulated sPLA2, cPLA2, and PEMT. Conclusion:These results showed that RPTS (50 mg/kg) and PN (20 mg/kg) effectively alleviated rats' colitis of damp-heat type, affected cytokines, and altered lipid metabolism without significant modulation on amino acid metabolism.

重楼具有清热解毒、消肿止痛、化瘀止血、息风定惊等功效.国医大师徐景藩教授治疗内科疑难疾病时,常用重楼进行配伍,尤擅用其治疗溃疡性结肠炎,并总结重楼具有抑炎止痢、利咽止痛、调节免疫、抗萎防癌等功效,进而拓展重楼临证应用范围.现整理徐景藩教授运用重楼配伍诊治溃疡性结肠炎、扁桃体肿大、类风湿关节炎、慢性萎缩性胃炎四则医案,与飨同道.

Background Baicalin is an important active flavonoid isolated from the roots of Scutellaria baicalensis (S. baicalensis), a well-known traditional Chinese herb used in treating inflammatory bowel disease (IBD). The objectives of this study were to assess the potential benefit of baicalin in experimental colitis, as well as to investigate metabolic biomarkers of experimental colitis in conjunction with network pharmacology. Methods Using a widely utilized network pharmacology technique, baicalin’s targets and pathways were predicted. Simultaneously, experimental colitis was induced by intrarectal administration of TNBS. Histopathology examinations were performed to confirm pathological changes. Plasma samples were examined by using an untargeted metabolomics technique based on ultra-high performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS) to screen differential metabolites and associated metabolic pathways. Additionally, network pharmacology and integrated analysis of metabolomics were used to identify the primary targets. Results Through network pharmacology research, tumor necrosis factor (TNF), interleukin 6 (IL6), serine/threonine-protein kinase (AKT1), and other 7 proteins were found to be the main targets of baicalin against IBD. The untargeted metabolomics results showed that 47 metabolites in glycerophospholipids and sphingolipid metabolism were involved as key pathways in the experimental colitis model group. 19 metabolites, including Sphingomyelin (SM d42:2, SM d42:1, SM d34:1), Lysophosphatidic acids (LPA 18:4), 1-Palmitoylglycerophosphocholine, and 17(18)-EpETE were demonstrated as key metabolites for baicalin to exert effects. Moreover, udp-glucose ceramide glucosyltransferase (UGCG), sphingomyelin synthase 1 (SGMS1), and sphingosine kinase (SPHK1) were predicted as sphingolipids-linked targets of baicalin against experimental colitis by integrative analysis. Conclusion Based on these results, it implies that sphingolipid metabolism and sphingolipid signaling pathway might be acted as therapeutic mechanism for baicalin against experimental colitis.

Objective:To approach the effect and mechanism of rhizoma paridis total saponins（RPTS）on inflammation and coagulation in rats with 2,4,6-trinitrobenzene sulfonic acid（TNBS）-induced acute experimental colitis.Methods:50 male SD rats of SPF grade were randomly divided into normal control group（n=7）,TNBS model group（n=13）,Mesalazine group（n=10）,RPTS low-dose group（n=10）and RPTS high-dose group（n=10）.The rat model of acute experimental colitis was established by TNBS for 14 days.The indexes such as survival rate of final point,DAI score,CMDI score,TDI score,etc.were evaluated.The dose-efficacy relationship that RPTS was related to acute experimental colitis of rats was approached.The relevant indexes such as whole blood cell and coagulation,etc. were detected.CD40/CD40L indexes in plasma and liver tissue were detected by ELISA.mRNA levels of IL-1β and TNF-αin colon tissue was detected by RT-PCR.Results:The survival rate of final point was 76.9% in TNBS model group and 100% in RPTS low-dose group.The scores of DAI,CMDI and TDI of RPTS low-dose group were significantly decreased compared with TNBS model group（P ﹤ 0.05）.The expression level of CD40/CD40L in liver tissue,compared with TNBS model group,this expression level of Mesalazine group and RPTS low-dose group was significantly increased（P ﹤ 0.0001）.At the same time,in the detection of mRNA level of IL-1β in colon tissue,compared with TNBS model group,mRNA level of IL-1βof RPTS low-dose group was decreased（P﹤0.05）.Conclusion:RPTS can improve the symptoms of rats with TNBS-induced acute experimental colitis,has a good therapeutic effect,and improve the survival rate of final point of model rats;and the therapeutic effect of RPTS low-dose group is better.It may be that the immune mechanism of rats with experimental colitis is regulated and controlled by activating CD40/CD40L costimulatory factor,so as to alleviate the inflammatory reaction of the disease.

目的:通过重楼总皂苷(RPTS)对三硝基苯磺酸(TNBS)诱导的急性实验性结肠炎小鼠治疗作用及机制研究,以期为人类炎症性肠病治疗提供新策略.方法:将40只雄性SPF级BALB/c小鼠,随机分为正常对照(normal control,NC)组、TNBS模型(TNBS model,TM)组、美沙拉嗪(mesalazine,ME)组及重楼总皂苷(rhizoma paridis total saponins,RS)组,每组 10只.比较各组小鼠的一般情况、肠组织mRNA与蛋白表达情况以及血清细胞因子等指标.结果:通过RPTS的干预,与TM组比较,RS组TLR2、TLR4 及NF-κB的mRNA均降低(P<0.05);且IL-1β及TNF-α的mRNA表达呈现下降趋势.在IHC蛋白表达检测中,RS组相较于TM组TLR2及TLR4的蛋白水平均下降(P<0.05);在NF-κB的蛋白表达中,RS组相较TM组也呈现降低.在血清细胞因子中,与TM组比较,RS组TNF-α、CCL20/MIP-3α、CCL4/MIP-1β及IL-17 等多数细胞因子升高;CCL3/MIP-1α呈下降趋势.结论:RPTS对急性实验性结肠炎小鼠有治疗作用,提高了小鼠终点生存率,其机制可能与RPTS下调结肠黏膜局部TLR2&4/NF-κB炎性信号通路有关.同时,通过调节血清中细胞因子水平,发挥适度免疫调控机制进而对机体起到保护作用,以缓解模型鼠的全身炎症及免疫反应,其潜在机制有待进一步研究.

乳糜泻(CD)的病理机制尚不完全明确,可能由环境因素触发遗传易感个体肠道内的炎症反应所致.近年研究表明,CD患者肠道黏膜屏障功能异常及肠道微生物改变等多因素的协同作用,可导致肠道内环境稳态失衡,进而加重疾病严重程度.去麦胶饮食配合益生菌等药物的治疗,能调节肠道微生物群,有利于肠道黏膜屏障功能的修复,可有效缓解CD患者的临床症状.但是肠道菌群的组成及其是否为CD诱因的证据尚待进一步考量.深入探究CD的病理机制,针对病理因素进行靶向治疗,是预防及精准诊疗CD的新方向.本文从遗传及环境因素等方面着手,对CD的病理机制进行综述.

目的 三硝基苯磺酸(trinitrobenzenesulfonic acid,TNBS)诱导的实验性结肠炎模型中皮肤致敏是否必要尚无定论,拟探究皮肤致敏对其影响.方法 BALB/c小鼠随机分为空白(normol control,NC)组、皮肤致敏(skin presensitization,SP)组、无皮肤致敏(non-skin presensitization,NP)组,每组5只.比较两组模型及采用Luminex多功能液相芯片评估BAFF/BLys/TNFSF13B、TNF-α、ICAM-1/CD54和TIMP-1的差异.结果 与NC组比较,SP组及NP组小鼠,皮肤致敏后至灌肠前体质量均无显著差异;灌肠后SP组较NP组体质量降低(P<0.05).NP组脾脏质量(P<0.01)及脾脏指数(P<0.05)较NC组显著降低;SP组及NP组的疾病活动指数(disease activity index,DAI)评分较NC组均显著增加(P<0.05);SP组大体结肠形态损伤指数(colon macroscopic damage index,CMDI)评分及组织病理评分较NC组均显著升高(P<0.05);BAFF/BLys/TNFSF13B显示,SP组及NP组较NC组均显著增加(P<0.01),SP组与NP组比较,差异无显著性.结论 SP组及NP组均可建立小鼠急性实验性结肠炎的模型,但使用皮肤致敏建立的急性实验性结肠炎模型成模效果更佳.

Aims. This study aims to investigate the potential biomarkers of inflammatory bowel disease (IBD) and IBD with damp-heat syndrome (IBD-DH) by metabolomics. Methods. Plasma and urine samples were collected from 15 healthy controls and 30 IBD patients, including 15 IBD-DH and 15 IBD with spleen deficiency syndrome (IBD-SD), which was coded as SF8G and SF70 according to the International Classification of Diseases Eleventh Revision (ICD-11) issued by World Health Organization. Pseudotargeted metabolomics method was used based on ultra-high-performance liquid chromatography-high-resolution mass spectrometry and triple-quadrupole mass spectrometry. Results. Under the condition of false discovery rate (FDR) < 0.05, variable importance projection (VIP) > 1.0, and fold change (FC) > 1.5 or < 2/3, we found 57 plasma differential metabolites and 20 urinary differential metabolites in IBD. Then, with area under the curve (AUC) ≥ 0.85 and FC ≥ 2 or ≤ 0.3, 11 potential biomarkers were identified, such as acylcarnitine (ACar 20:4, ACar 18:1, and ACar 20:3), 3-indoleacetic acid, hippuric acid, and dehydroepiandrosterone sulfate, which is related to intestinal microbiota and immune response. However, less obvious differences were observed in IBD-DH when compared with IBD-SD. Under the condition of FDR < 0.2, VIP >1.0, and FC > 1.5 or < 2/3, we identified 16 plasma differential metabolites. In urine samples, IBD-DH and IBD-SD had the same metabolite pattern. With AUC ≥ 0.80, 7 differential plasma metabolites, mainly glycerophospholipids, were identified in IBD-DH. Kyoto Encyclopedia of Genes and Genomes analysis indicated that metabolic pathways, such as citrate cycle and amino acids metabolism, were mainly responsible for the distinction between IBD and healthy controls, whereas glycerophospholipid metabolism perturbation was not only a manifestation of IBD but also an important pathway to distinguish two subtypes defined by traditional medicine, IBD-DH and IBD-SD. Conclusion. In this study, we found that several metabolites of aromatic acids and lipid derivatives could act as potential biomarkers to discriminate IBD from healthy controls. Glycerophospholipids metabolites might be used to differentiate IBD-DH from IBD-SD.

如何利用真实世界证据(Real-world evidence,RWE)评价药物的有效性和安全性,已成为国内外药物研发和监管决策等方面共同关注的热点话题.真实世界研究(Real-world research/study,RWR/RWS)不同于临床实践,作为临床研究的一种类型,仍须基于医学伦理并科学开展,保护受试者权益仍是重中之重.知情同意是保障受试者权益的重要路径,做好知情同意非常关键.传统的知情同意方式在开展RWR/RWS过程中可能会导致招募困难或选择偏倚而降低研究结果的普适性,因此作者结合RWR/RWS的实际特点,探讨了在RWR/RWS范式下的知情同意方式的相关问题.

新版《药物临床试验质量管理规范》在2020年颁布并实施,以充分贯彻落实中央《关于深化审评审批制度改革鼓励药品医疗器械创新的意见》的精神,并适应人用药物注册技术要求国际协调会的规则.新版《药物临床试验质量管理规范》涉及伦理审查的重要更新之一在于,强调了申办者需要及时向伦理委员会提交可疑且非预期严重不良反应报告、其他潜在的严重安全性风险信息报告、研发期间安全性更新报告等安全性报告,对机构伦理审查能力提出了新的要求和挑战.作者结合欧盟、美国、英国等人用药物注册技术要求国际协调会成员国对安全性报告的伦理审查要求,探讨了我国在新形势下以注册为目的的药物临床试验安全性报告伦理审杏的要点.

新冠肺炎疫情给人类生命安全、经济社会发展造成巨大损害的同时,也对全球卫生紧急情况(GHE)下的科学研究提出了一系列挑战.2018年Nayha Sethi博士曾针对这一类困境,对传统的医学科学研究原则性指南和规则性指南进行了讨论,并提出最佳实践(Best Practice)及范例的概念,在实践水平上为研究决策指导提供了新的思路.在此介绍Sethi博士研究成果,希望能开拓我国研究者、政府管理者以及伦理审查相关人员对GHE期间研究决策的视野,并对中国GHE期间科研决策体系与模式的构建有所裨益.

目的：探讨蚤休复方对三硝基苯磺酸（TNBS）诱导的炎症性肠病（IBD）实验小鼠的治疗作用及其机制。方法：BALB/c小鼠随机分为正常对照组、模型组、柳氮磺吡啶组和蚤休复方组，后3组应用TNBS诱导建立小鼠IBD模型。造模同时柳氮磺吡啶组、蚤休复方组分别给予0.5g/kg柳氮磺吡啶10g/kg蚤休复方提取物灌胃，每日1次，连续28d。实验终点时分析小鼠存活率、疾病活动指数（DAI）、结肠重量/长度比值、结肠黏膜组织病理，以及采用MILLIPLEX R MAP的小鼠细胞因子/趋化因子磁珠试剂盒定量检测32种细胞因子和趋化因子。结果：与模型组比较，蚤休复方组小鼠存活率增高，结肠重量/长度比值降低，IBD疾病活动指数和结肠病理评分明显降低（P＜0.05）；在细胞因子的血清水平方面，蚤休复方组小鼠血清CCR5配体MIP-1ɑ明显低于模型组（P=0.045），而CXCR3配体CXCL9（MIG）、CXCL10（IP-10）和IL-12 P70显著高于模型组（P=0.006，P=0.027，P=0.030）。结论：蚤休复方提取物对TNBS诱导的IBD具有较好的治疗作用，其作用机制可能与IFN-γ协同刺激巨噬细胞产生CXCL9（MIG）、CXCL10（IP-10）等因子，进而影响T细胞活化、趋化，产生类TLR4激动剂作用相关。