BACKGROUND:Wumei Wan (WMW) has been used to address digestive disorder for centuries in traditional Chinese medicine. Previous studies have demonstrated its anti-colitis efficacy, but the underlying mechanism of its action remains to be further clarified.PURPOSE:To investigate the underlying mechanisms of WMW in the treatment of chronic ulcerative colitis (UC) through network pharmacology and experimental validation.METHODS:Traditional Chinese Medicine Systems Pharmacology (TCMSP) platform were used to identify the ingredients and potential targets of WMW. The microarray gene data GSE75214 datasets from GEO database was used to define UC-associated targets. Cytoscape3.7.2 was employed to construct the protein-protein interaction (PPI) network and compounds-disease targets network. GO enrichment analysis and KEGG pathway analysis were performed by R software for functional annotation. UPLC-TOF-MS/MS method was used to quantitatively analyze the active ingredients of WMW. For experimental validation, three cycles of 2% dextran sulfate sodium salt (DSS) were used to construct chronic colitis model. The hub targets and signal pathway were detected by qPCR, ELISA, western blotting , immunohistochemical and immunofluorescence.RESULTS:Through network analysis, 104 active ingredients were obtained from WMW, and 47 of these ingredients had potential targets for UC. A total of 41 potential targets of WMW and 13 hub targets were identified. KEGG analysis showed that WMW involved in advanced glycation end products-receptor of advanced glycation end products (AGE-RAGE) signaling pathway. Taxifolin, rutaecarpine, kaempferol, quercetin, and luteolin of WMW were the more highly predictive components related to the AGE-RAGE signaling pathway. In vivo validation, WMW improved DSS-induced colitis, reduced the expression of inflammatory cytokines and chemokines. Notably, it significantly decreased the mRNA expression of Spp1, Serpine1, Mmp2, Mmp9, Ptgs2, Nos2, Kdr and Icam1, which were associated with angiogenesis. In addition, we confirmed WMW inhibited RAGE expression and diminished DSS-induced epithelial barrier alterations CONCLUSION: Our results initially demonstrated the effective components and the strong anti-angiogenic activity of WMW in experimental chronic colitis. Sufficient evidence of the satisfactory anti-colitis action of WMW was verified in this study, suggesting its potential as a quite prospective agent for the therapy of UC.

目的 探讨黄葵敛疡汤灌肠对轻中度活动期溃疡性结肠炎(ulcerative colitis,UC)的临床疗效及安全性.方法 选取该院2016年1月-2020年6月UC患者101例,以黄葵敛疡汤灌肠为主治疗.比较治疗前后部分Mayo评分、中医证候积分、肠镜及炎症指标变化情况,判定临床疗效.结果 黄葵敛疡汤治疗UC的总有效率为74.20％(77/101),UC患者的部分Mayo评分、中医证候积分较治疗前显著降低(P＜0.01),腹泻、脓血便、腹痛、里急后重等单项证候积分也较前显著下降(P＜0.05).其中近期复查肠镜或炎症指标的UC患者,肠镜及粪便钙卫蛋白有显著改善(P＜0.05).结论 黄葵敛疡汤治疗轻中度活动期UC疗效确切,值得临床推广应用.

目的 以炎症小体NLRP3为切入点,探讨黄葵敛疡汤对溃疡性结肠炎(ulcerative colitis,UC)的治疗作用.方法 将50只C57BL/6小鼠随机分为正常组,模型组,美沙拉嗪组(0.82 g·kg-1),黄葵敛疡汤低、高剂量组(10.98、21.96 g·kg-1),每组10只.以2.5％葡聚糖硫酸钠(dextran sulfate sodium,DSS)溶液建立UC模型.观察并记录小鼠每日进食和饮水情况、统计疾病活动指数(disease activityindex,DAI)评分、测量结肠长度;采用苏木素-伊红(hematoxylin-eo-sin stain,HE)染色法观察小鼠结肠组织病理学变化;以实时荧光定量PCR法检测各组小鼠结肠组织中白细胞介素(IL)-1β、IL-18、IL-6、TNF-α、NLRP3、ASC和Caspase-1的mRNA表达;分别采用免疫组织化学染色法和蛋白免疫印迹法考察小鼠结肠组织中NLRP3蛋白表达.结果 与正常组相比,模型组小鼠DAI评分显著升高,肠壁组织明显破坏,NLRP3、ASC和Caspase-1 mRNA表达和蛋白表达明显升高(P＜0.05,P＜0.01);与模型组相比,各给药组小鼠结肠组织破坏明显得到改善,其中,黄葵敛疡汤高剂量组小鼠结肠组织中NLRP3、ASC和Caspase-1 mRNA表达和蛋白表达显著降低(P＜0.05,P＜0.01).结论 黄葵敛疡汤可通过抑制炎症小体NLRP3活化缓解DSS所致小鼠溃疡性结肠炎.

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.

白介素-1受体相关激酶家族(IRAKs)是一类丝氨酸-苏氨酸激酶,介导来自TLRs和白介素-1受体(IL-1R)的信号激活.IRAKs由4名成员组成:IRAK1、IRAK2、IRAKM、IRAK4,与先天免疫、适应性免疫和炎症的正向或负向调节密切相关.越来越多证据表明,IRAKs在炎症性肠病(IBD)发生发展中起重要免疫调节作用.本文就IRAKs的结构、功能、转录和调控及其在IBD中的作用进行综述,以期寻找新的IBD诊治靶点.

ABSTRACT Patients with ulcerative colitis (UC) have a high prevalence of mental disorders, such as depression and anxiety. Gut microbiota imbalance and disturbed metabolism have been suggested to play an important role in either UC or mental disorders. However, little is known about their detailed multi-omics characteristics in patients with UC and depression/anxiety. In this prospective observational study, 240 Chinese patients were enrolled, including 129 patients with active UC (69 in Phase 1 and 60 in Phase 2; divided into depression/non-depression or anxiety/non-anxiety groups), 49 patients with depression and anxiety (non-UC), and 62 healthy people. The gut microbiota of all subjects was analyzed using 16S rRNA sequencing. The serum metabolome and proteome of patients with UC in Phase 2 were analyzed using liquid chromatography/mass spectrometry. Associations between multi-omics were evaluated by correlation analysis. The prophylactic effect of candidate metabolites on the depressive-like behavior of mice with colitis was investigated. In total, 58% of patients with active UC had depression, while 50% had anxiety. Compared to patients with UC without depression/anxiety, patients with UC and depression/anxiety had lower fecal microbial community richness and diversity, with more Lactobacillales, Sellimonas, Streptococcus, and Enterococcus but less Prevotella_9 and Lachnospira. Most metabolites (e.g., glycochenodeoxycholate) were increased in the serum, while few metabolites, including 2ʹ-deoxy-D-ribose and L-pipecolic acid, were decreased, accompanied by a general reduction in immunoglobulin proteins. These related bacteria, metabolites, and proteins were highly connected. A prophylactic administration of 2ʹ-deoxy-D-ribose and L-pipecolic acid significantly reduced the depressive-like behaviors in mice with colitis and alleviated the inflammatory cytokine levels in their colon, blood and brain. This study has identified a comprehensive multi-omics network related to depression and anxiety in active UC. It is composed of a certain set of gut microbiota, metabolites, and proteins, which are potential targets for clinical intervention for patients with UC and depression/anxiety.

Major depressive disorder (MDD) is a neurasthenic disease, which is the second-largest burden of disease globally. Increasing studies have revealed that depression is associated with abnormalities in gut microbiota and metabolites. Several species of bacteria have been classified as psychobiotics, which confer mental health benefits through interactions with commensal gut microbiota. Therefore, it is essential to identify new psychobiotics and elucidate their mechanisms in the the treatment of depression. This study aims to evaluate the antidepressant effect of Akkermansia muciniphila (AKK) in a mouse model of depression induced by chronic restraint stress (CRS). C57BL/6 male mice were divided into three groups: mice subjected to CRS, mice not subjected to CRS, and mice treated with AKK for three weeks. Behavioral tests were performed, and hormone, neurotransmitter, and brain-derived neurotrophic factor (BDNF) levels were measured. Cecal microbiota was analyzed using 16S rRNA gene sequencing, and serum metabolites were detected using untargeted metabolomics. In addition, correlations between altered gut microbiota and metabolites with significant variations in serum associated with AKK ameliorating depression were analyzed using Pearson’s Correlation coefficient. The results revealed that AKK significantly ameliorated depressive-like behavior and restored abnormal variations in depression related molecular (corticosterone, dopamine and BDNF). Moreover, AKK altered chronic stress-induced gut microbial abnormalities. Untargeted metabolomics analysis revealed 23 potential biomarkers in serum that could be associated with the mechanisms underlying CRS-induced depression and the therapeutic effects of AKK. Pearson's correlation coefficient analysis revealed that AKK predominantly upregulated β-Alanyl-3-methyl-L-histidine and edaravone to relieve depression. Furthermore, β-Alanyl-3-methyl-L-histidine and edaravone exhibited the antidepressant phenotype in mice subjected to CRS. In conclusion, the study demonstrated that AKK ameliorates chronic stress-induced depressive symptoms in mice by regulating gut microbiota and metabolites. Funding Statement: This work was supported by the National Natural Science Foundation of China (No. 81873309). Declaration of Interests: There are no conflicts of interest to declare. Ethics Approval Statement: The experiments were conducted in accordance with the Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use Committee of the Nanjing University of Chinese Medicine.

Colorectal cancer (CRC) is the third most common type of cancer. Here, we studied the inhibitory effect of IRAK1 and IRAK4 as a preventive strategy using a colitis-induced tumorigenesis mouse model. CRC clinical data were obtained from the Gene Expression Omnibus (GEO). An experimental inflammation-dependent CRC model was induced by treatment with azoxymethane (AOM) and then dextran sodium sulfate (DSS) in C57BL/6 mice. Mice were administered an IRAK1/4 inhibitor by intraperitoneal injection at 3 mg/kg twice each week for 9 weeks. The IRAK1/4 inhibitor attenuated histological changes and prevented tumor growth. Tumor-associated proteins, including p65 and Ki-67, were downregulated by the IRAK1/4 inhibitor in AOM/DSS-treated mice. Additionally, IRAK1/4 inhibitor administration effectively decreased the expression of inflammatory cytokines. Furthermore, we observed that IRAK1/4 inhibitor treatment attenuated colitis-induced tumorigenesis by inhibiting epithelial-mesenchymal transition. These observations indicate that inhibition of IRAK1 and IRAK4 may suppress experimental colitis-induced tumorigenesis by inhibiting inflammatory responses and epithelial-mesenchymal transition.

Psychological disorders are associated with increased risk of severe inflammatory bowel disease (IBD) by causing gut microbiota dysbiosis and colonic mucosal barrier damage. However, the interaction between chronic restraint stress (CRS), gut microbiota composition, and colonic mucus remains unclear. We demonstrated that mice under CRS conditions exhibited alterations in microbiota composition, disruption of colonic mucus, and aggravation of colitis. In addition, the abundance of Akkermansia muciniphila was significantly decreased in mice under CRS and UC patients with depression, and positively associated with the expression of MUC2. After antibiotic treatment, the recipient mice colonized with CRS microbiota showed barrier defects and severe colitis. Administration of Akkermansia muciniphila was found to restore colonic mucus and modify the gut microbiota. We confirm that CRS-mediated gut microbiota dysbiosis results in colonic mucosal barrier damage and aggravation of colitis. Our results suggest that A. muciniphila is expected to be a potential probiotic to protect and treat colonic mucus that is involved in IBD with psychological disorders.

溃疡性结肠炎(UC)当前治疗策略能够大大改善患者临床结局,但是总体治疗效果仍远未达到最佳状态.中医药发挥整体调控,多靶点作用的优势,在UC治疗中具有显著的疗效.“证候”是中医领域研究的核心问题,但中医证候缺乏客观、量化指标制约中医学的发展和中医现代化的进程.系统生物学是一种整合性研究方法,通过研究生物系统中不同部分(基因、蛋白质、代谢物等)之间的相互关系和相互作用,从整体性、动态性、多维度的角度去解析生命活动过程及机制,其研究特点与中医药“整体观”、“辨证论治”十分契合,在中医药研究中发挥了重要作用.本文通过阐释系统生物学的UC中医证候研究现状,从系统生物学角度提出UC疾病研究的未来展望.

溃疡性结肠炎( ulcerative colitis,UC)是一种反复发作的慢性炎症性疾病,以腹痛、腹泻、黏液脓血便等为主要临床表现.UC确切的发病机制目前尚未明确,基因改变以及肠道免疫系统失调引起的肠黏膜持续性炎症,肠屏障功能改变可能是导致其发病的重要原因.炎症小体作为固有免疫的重要组成部分,在肠道微生物感染、黏膜免疫反应以及代谢过程的调节中发挥了关键作用[1].炎症小体包括NL-RP1、NLRP3、NLRC4、AIM2、NLRP6 等亚型,其中NLRP3是研究最为全面的亚型之一,正迅速成为肠道内稳态和肠道炎症反应的重要调节因子.本文聚焦NLRP3炎症小体与UC的关系,综述近年来中医药干预NLRP3炎症小体治疗UC的相关研究进展,更好地发挥中医药治疗优势.

Purpose Total flavone of Abelmoschus manihot (TFA), the effective constituents extracted from Flos Abelmoschus Manihot, has been reported to inhibit inflammation. However, the effect of TFA on ulcerative colitis (UC) progression in patients with depression is unknown. The purpose of our research was to explore the anti-UC effects of TFA in the context of depression in mice with UC by regulating the gut microbiota to drive the intestinal barrier. Methods In this study, chronic stress (CS) and dextran sodium sulfate (DSS) were used to induce depression and UC, respectively, in C57BL/6J mice. Fecal microbiota transplantation (FMT) was used to evaluate how treating mice modeling UC and depression with TFA effected their gut microbiota. Results Our results showed that TFA effectively improved UC aggravated by CS. In addition, TFA treatment improved the depression-like phenotype, the disturbed gut microbiota, and the intestinal barrier function in CS mice. It is worth noting that FMT from the CS mice to the receptor group further aggravated the damage of the intestinal barrier and the disturbance of the gut microbiota in the recipient DSS mice, thus further aggravating UC, however, treatment of the intervention of TFA in the CS fecal microbiota transplant with TFA also played its therapeutic outcome. Conclusion Taken together, our results show that CS disrupts the gut microbiota, triggers intestinal barrier injury and aggravates DSS colitis, while TFA is a promising drug for the treatment of UC in patients with depression.

目的:胫骨横向骨搬移术是近年来治疗糖尿病足的新兴疗法,目前已有大量研究证实其治疗糖尿病足疗效显著,且安全性较高,但仍缺乏相应的循证依据。文章以此对胫骨横向骨搬移术治疗糖尿病足进行Meta分析。方法:检索中国知网（CNKI）、维普（VIP）、万方（WanFang）、PubMed、Cochrane library和EMbase数据库中胫骨横向骨搬移术治疗糖尿病足的临床对照研究,检索时间均为建库至2020年2月,对所纳入研究进行严格的质量评价,利用RevMan 5.3软件对其截肢率、愈合率、愈合时间、皮温和目测类比疼痛评分进行Meta分析。结果:①共纳入8篇文献,共837例,治疗组为428例,对照组为409例;②文献质量评价结果显示:根据NOS量表对病例对照研究或队列研究进行质量评价,2篇均为7分;根据改良后Jadad量表对随机对照试验进行质量评价,有4项研究4分,2项研究2分;③Meta分析结果显示,胫骨横向骨搬移术治疗糖尿病足在截肢率上低于对照组（OR=0.12,95%CI:0.05-0.26,P ＜0.000 01）,并且在愈合率（OR=28.65,95%CI:16.45-49.88,P ＜0.000 01）、减少愈合时间（OR=-2.61,95%CI:-4.23至-0.98,P=0.002）、升高皮温（OR=2.44,95%CI:2.27-2.61,P＜0.000 01）、改善疼痛目测类比评分（SMD=-6.41,95%CI:-9.50至-3.32,P ＜0.000 1）等方面均优于对照组（P ＜0.000 01）。结论:胫骨横向骨搬移术治疗糖尿病足较常规治疗具有显著优势,且安全性较高。受纳入研究的数量和质量的限制,文章的上述结论尚待更多高质量的研究予以验证。

溃疡性结肠炎(UC)的发病机制与炎症通路的激活密切相关,其中Toll样受体4(TLR4)/髓样分化因子88(MyD88)/核因子-κB(NF-κB)信号通路在UC发病中起关键作用.综述了姜黄素、小檗碱、鸦胆子苦醇、黄芩苷、雷公藤多苷等中药活性成分及泄浊解毒方、乌梅丸、芍药汤、葛根芩连汤等中药复方制剂,通过干预TLR4/MyD88/NF-KB信号通路中不同细胞因子的结合及影响其表达水平,抑制NF-κB的活化,从而降低信号通路下游炎症因子的水平,缓解UC病情.参考文献50篇.

Akkermansia muciniphila(Akk菌)是一种新发现的热点菌,被证实与多种疾病存在负性相关,当前的研究主要集中在代谢性疾病相关领域.中药因含有纤维、多酚及多糖等成分,可以在疾病的防治中发挥益生元样作用.多种中药及其有效成分可通过调节肠道微生物的结构促进Akk菌功能的发挥,从而对疾病起到治疗作用.Akk菌被证实具有促进肠黏膜屏障修复、调节菌群代谢、影响"肠-肝轴"及"脑-肠轴"的作用.根据Akk菌的作用机制,总结当前研究中对Akk菌具备益生元样作用的中药单体、中药复方及其相应有效成分,以期为进一步研究中药对Akk菌作用的影响提供参考.

There are trillions and trillions of microorganisms in the human gut, and these microorganisms and their metabolites are closely related to human health. Recent studies have found that the abundance of Akkermansia muciniphila is decreased in many diseases. Supplementation of A. muciniphila is used to treat many diseases, suggesting it as a probiotic. Herbal medicines are considered as valuable asset of traditional Chinese medicine. Recent studies have revealed traditional Chinese medicine as a potential prebiotic agent for the treatment of many diseases. Hence, in this review, we aimed to provide a plausible mechanistic basis for the interactions between herbal medicines and A. muciniphila, and therapeutic benefits on this interaction in various illnesses.