更新于：2024-05-01

DEFA6

defensin alpha 6

更新于：2024-05-01

基本信息

别名

DEF6、DEFA6、defensin alpha 6

+ [3]

简介

Host-defense peptide that contributes to intestinal innate immunity and mediates homeostasis at mucosal surfaces by forming higher-order oligomers that capture bacteria and prevent microbial invasion of the epithelium (PubMed:15616305, PubMed:25158166, PubMed:25354318, PubMed:28026958, PubMed:17088326). After binding to bacterial surface proteins, undergoes ordered self-assembly to form fibril-like nanonets that surround and entangle bacteria and thereby prevent bacterial invasion across the epithelial barrier (PubMed:22722251). Entangles and agglutinates Gram-negative bacteria, such as E.coli, S.typhimurium and Y.enterocolitica, and Gram-positive bacteria such as L.monocytogenes, thereby protecting the intestine against invasion by enteric bacterial pathogens (PubMed:27076903, PubMed:25158166, PubMed:22722251). Blocks adhesion of C.albicans to intestinal epithelial cells and thereby suppresses fungal invasion of epithelial cells and biofilm formation (PubMed:28026958). Under reducing conditions and in an acidic environment similar to the intestinal milieu, exhibits inhibitory activity against anaerobic bacteria such as B.adolescentis, L.acidophilus and B.breve, as well as B.longum and S.thermophilus, possibly by leading to alterations in bacterial cell envelope structures (PubMed:25354318). The disulfide-linked oxidized form exhibits negligible antimicrobial activity against Gram-negative and Gram-positive bacteria, as compared to the enteric defensin DEFA5 (PubMed:15616305, PubMed:17088326).

关联

100 项与 DEFA6 相关的临床结果

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100 项与 DEFA6 相关的转化医学

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0 项与 DEFA6 相关的专利（医药）

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352

项与 DEFA6 相关的文献（医药）

2024-02-06·Diseases of the colon and rectum

Innate Immunity Activation in Newly Diagnosed Ileocolonic Crohn's Disease: A Cohort Study.

Article

作者: Imerio Angriman ; Giovanni Bordignon ; Andromachi Kotsafti ; Claudia Mescoli ; Melania Scarpa ; Cesare Ruffolo ; Matteo Fassan ; Angelo Paolo Dei Tos ; Renata D'Incà ; Edoardo Savarino ; Fabiana Zingone ; Salvatore Pucciarelli ; Romeo Bardini ; Ignazio Castagliuolo ; Marco Scarpa

BACKGROUND:

Recent studies showed that early surgery for Crohn's disease leads to a lower recurrence rate. However, the underlying mechanism is unknown.

OBJECTIVE:

The study aims to analyze the innate immunity microenvironment in ileal mucosa according to Crohn's disease duration.

DESIGN:

A prospective cohort study.

SETTINGS:

Tertiary referral center for IBD surgery.

PATIENTS:

A total of 88 consecutive Crohn's disease patients undergoing ileocolonic resection were prospectively enrolled. Mucosal samples were obtained from both healthy and inflamed ileum. Data from a public dataset were analyzed as an external validation cohort.

MAIN OUTCOME MEASURES:

Neutrophil infiltration was evaluated at histology and macrophage subpopulation at immunohistochemistry. Expression of TLR2, TLR4, TLR5, DEFB1, DEFB4A, DEFB103, DEFA5 and DEFA6 was quantified by Real-Time qPCR. Concentrations of BDNF, CCL11, ICAM1, IL1A, IL1B, IL1RN, IL12 p40, IL12 p70, IL15, IL17A, IL23A, MMP3, CCL3, KITLG, VEGFA were determined with immunometric assay.

RESULTS:

Neutrophil infiltration is inversely correlated with disease duration. DEFB4A mRNA expression tended to be higher in late-stage Crohn's disease (p = 0.07). A higher number of macrophages expressed CD163 at low intensity in the late stage (p = 0.04). The concentration of IL15 (p = 0.02) and IL23A (p = 0.05) was higher in healthy ileal mucosa of early-stage patients. In the external cohort, expression of DEFB1 (p = 0.03) and DEFB4A (p = 0.01), IL2 (p = 0.04), and IL3 (p = 0.03) increased in late-stage patients.

LIMITATIONS:

A relatively small number of patients, especially in the newly diagnosed group.

CONCLUSIONS:

In newly diagnosed Crohn's disease, high levels of IL-15 and IL-23 in healthy mucosa suggest that innate immunity is the starter of acute inflammation. Moreover, M2 macrophages increase in healthy mucosa of late-stage Crohn's disease patients suggesting that reparative and profibrotic processes are predominant in the long term and in this phase, anti-inflammatory therapy may be less efficient. See Video Abstract.

2023-11-21·Proceedings of the National Academy of Sciences of the United States of America

FOXO inhibition rescues α-defensin expression in human intestinal organoids.

Article

作者: Serena J Eng ; Eric B Nonnecke ; Arthur J de Lorimier ; Mohamed R Ali ; Renée M Tsolis ; Charles L Bevins ; Paul Ashwood

To mediate critical host-microbe interactions in the human small intestine, Paneth cells constitutively produce abundant levels of α-defensins and other antimicrobials. We report that the expression profile of these antimicrobials is dramatically askew in human small intestinal organoids (enteroids) as compared to that in paired tissue from which they are derived, with a reduction of α-defensins to nearly undetectable levels. Murine enteroids, however, recapitulate the expression profile of Paneth cell α-defensins seen in tissue. WNT/TCF signaling has been found to be instrumental in the regulation of α-defensins, yet in human enteroids exogenous stimulation of WNT signaling appears insufficient to rescue α-defensin expression. By stark contrast, forkhead box O (FOXO) inhibitor AS1842856 induced the expression of α-defensin mRNA in enteroids by >100,000-fold, restoring DEFA5 and DEFA6 to levels comparable to those found in primary human tissue. These results newly identify FOXO signaling as a pathway of biological and potentially therapeutic relevance for the regulation of human Paneth cell α-defensins in health and disease.

2023-10-01·Materials today. Bio

Amyloid-like nanofibrous network confined and aligned ultrafine bimetallic nanozymes for smart antibacterial therapy.

Article

作者: Yonghai Feng ; Zerui Cheng ; Anne-Kathrine Kure Larsen ; Hui Shi ; Tongtong Sun ; Peng Zhang ; Mingdong Dong ; Lei Liu

Nanozyme-based antibacterial therapy (NABT) has emerged as a promising strategy to combat bacterial antimicrobial resistance. Engineering the noble metal nanozymes with strong bacterial capture and high catalytic activity for enhanced NABT is highly anticipated but still challenged. Herein, we developed hybrid nanozymes by engineering ultrafine bimetallic Au/Cu nanoparticles confined on the lysozyme amyloid-like nanofibrous networks (LNF). The introduction of copper in the nanozymes facilitates the H₂O₂ adsorption and reduces the energy barrier for activating the H₂O₂ decomposition to form •OH, meanwhile displaying the significantly enhanced POD-like activity under NIR irradiation. Taking advantage of the inherent supramolecular networks inspired from human defensin 6-trapping bacteria mechanism, the hybrid nanozymes effectively capture the bacteria and allow the catalytic attack around the bacterial surfaces to improve the antibacterial efficiency. Finally, the as-prepared nanozymes exhibit the preeminent bactericidal efficacy against bacteria, especially for drug-resistant bacteria both in vitro and in vivo, and the effect on wound healing.

项与 DEFA6 相关的新闻（医药）

2023-12-16

·今日头条

肠道细胞知多少？多文聚焦小细胞中的大学问

12月16日的《热心肠日报》，我们解读了 10 篇文献，关注：肠干细胞，组织再生，潘氏细胞，防御素，类器官，宿主-微生物互作，生物材料，组织工程。国内团队：果蝇羽化肌分泌皮质激素，引发肠干细胞不对称分裂 Developmental Cell——[11.8] ① 利用果蝇蛹期肠道为研究模型，探索启动肠道干细胞由对称分裂转向不对称分裂的信号；② 在蛹期肠道干细胞中进行全基因组RNAi筛选，发现蜕皮激素存在情况下EcR和Usp会促进E93表达而抑制Br表达，导致不对称分裂；③ 蛹蜕皮激素主要来源不是胸腺，是背侧内斜肌（DIOM），遗传和体外培养实验也证明DIOM在蛹期会产生蜕皮激素脉冲；④ 基因分析表明，抑制mTOR后DIOM无法重塑导致蜕皮激素脉冲消失，激活mTOR后DIOM重塑时间提前，脉冲产生时间提前。【主编评语】干细胞通过对称分裂扩增干细胞数目，通过不对称分裂产生终末分化的子代细胞。近日，华中科技大学同济医学院郭峥及团队在Developmental Cell发表最新研究，通过系列遗传和体外培养试验结合全基因组方法，发现果蝇负责执行出蛹的腹部背侧内斜肌会通过释放蜕皮激素来精确控制蛹期肠道干细胞由对称分裂到不对称分裂的发生及其时间，解决了百年来完全变态昆虫在蛹期的蜕皮激素信号来源问题，值得关注。（@九卿臣）【原文信息】 Eclosion muscles secrete ecdysteroids to initiate asymmetric intestinal stem cell division in Drosophila 2023-12-13, doi: 10.1016/j.devcel.2023.11.016 Cell子刊：果蝇肠干细胞如何丧失杂合性 Cell Reports——[8.8] ① 利用果蝇肠道模型研究成体干细胞中自发产生杂合性丧失（LOH）的潜在分子机制和驱动因素；② 老化的肠干细胞 (ISC) 会发生自发LOH，且随着年龄增长而增加；③ 致病性肠道细菌软腐欧文氏菌Ecc15而非嗜虫假单胞菌感染会促进DNA损伤并增加LOH；④ 全基因组测序揭示LOH主要是通过有丝分裂重组产生的；⑤ 分子特征和遗传证据表明LOH并非断裂诱导复制机制，而是通过基于双霍利迪连接体的修复进行交叉。【主编评语】杂合性丧失（LOH）发生在正常人体组织中且在病理遗传状况和癌症中普遍存在，其中单细胞酵母细胞中促进LOH的DNA修复机制已知晓，而多细胞生物体组织中的主要途径和环境触发因素尚不清楚。近日，发表在Cell Reports上的这篇文章，揭示了果蝇肠干细胞中LOH的分子基础和环境驱动因素。（@圆圈儿）【原文信息】 Molecular underpinnings and environmental drivers of loss of heterozygosity in Drosophila intestinal stem cells 2023-11-29, doi: 10.1016/j.celrep.2023.113485 Science子刊：部分重编程诱导肠道再生的分子机制 Science Advances——[13.6] ① 通过体内表达OSKM（Oct4、Sox2、Klf4和c-Myc）强制部分重编程，从而诱导肠上皮细胞去分化；② OSKM诱导的强制去分化具有类似肠道再生分子特征，如从稳态细胞向损伤反应性细胞类型的转变；③ 损伤反应样细胞具有再生干细胞和萎缩诱导的绒毛上皮细胞基因特征，并积极协助损伤后的组织再生；④ 与前列腺素内过氧化物合酶2（Ptgs2）诱导的正常肠道再生不同，OSKM通过上皮Ptgs1表达促进前列腺素E2的自主产生。【主编评语】损伤后的组织再生涉及体细胞的去分化，是一种自然的适应性重编程，导致具有胎儿样特征的损伤反应细胞出现，然而目前缺乏各种组织中部分重编程的再生效应分子机制。近日，发表在Science Advances上的这篇文章，发现Ptgs1介导的上皮前列腺素产生是体内部分重编程的关键，直接使肠上皮细胞采用胎儿特征而不涉及任何间充质辅助。（@圆圈儿）【原文信息】 Partial in vivo reprogramming enables injury-free intestinal regeneration via autonomous Ptgs1 induction 2023-11-24, doi: 10.1126/sciadv.adi8454 Science子刊：经典与非经典Wnt信号如何协调控制肠潘氏细胞分化？ Science Advances——[13.6] ① 鉴定发现Dishevelled相关形态发生激活剂1（Daam1）及其旁系同源物Daam2通过其N端结构域与Wnt抑制剂RNF43相互作用；② Daam1/2双敲除通过抑制RNF43依赖性的Wnt受体Frizzled内吞降解，从而激活经典Wnt信号传导；③ Daam1/2双敲除破坏非经典Wnt（Wnt/PCP）信号传导并增强经典Wnt信号传导，并进一步损害潘氏细胞分化；④ Daam1/2不对称地调节经典和非经典Wnt信号传导。【主编评语】潘氏细胞是构成肠道微环境的主要元素，可以提供各种生长因子如Wnt3来协调肠道干细胞稳态，不同的Wnt配体可以选择性地激活β-连环蛋白依赖（经典）或非依赖（非经典）信号传导，然而目前尚不清楚非经典Wnt信号传导如何影响肠上皮稳态和分化以及经典与非经典Wnt信号传导如何协调。近日，发表在Science Advances上的这篇文章，发现Daam1/2是协调经典和非经典Wnt信号传导的中心分子，对于潘氏细胞分化至关重要。（@圆圈儿）【原文信息】 Intestinal Paneth cell differentiation relies on asymmetric regulation of Wnt signaling by Daam1/2 2023-11-24, doi: 10.1126/sciadv.adh9673 Nature子刊：潘氏细胞化生的诱导机制 Nature Communications——[16.6] ① 研究由诱导型bcr-abl癌基因驱动的慢性粒细胞白血病（CML）小鼠模型中潘氏细胞化生（PCM）的进展；② 机制上，CML在胃肠道内诱导促炎状态，从而导致肠上皮细胞诱导IL-33产生；③ IL-33与受体ST2结合导致2型先天淋巴细胞（ILC2）激活产生IL-9，并驱动结肠PCM和小肠组织重塑（其特征是杯状和簇细胞增生以及粘膜肥大细胞扩张）；④ 肠炎触发ILC2/IL-9回路，诱导PCM并调节胃肠道中特化上皮细胞发育。【主编评语】潘氏细胞化生（PCM）通常出现在已有的胃肠道疾病中，然而诱导化生的机制途径以及PCM是否仅由胃肠道固有疾病引发尚不清楚。近日，发表在Nature Communications上的这篇文章，证明肠外疾病可触发ILC2/IL-9免疫回路，从而诱导PCM并调节胃肠道上皮细胞的命运决定。（@圆圈儿）【原文信息】 Interleukin-9 production by type 2 innate lymphoid cells induces Paneth cell metaplasia and small intestinal remodeling 2023-12-02, doi: 10.1038/s41467-023-43248-5 FOXO抑制剂或可增强潘氏细胞功能 PNAS——[11.1] ① 潘氏细胞可产生大量的α-防御素和其他抗菌素介导了人小肠中关键的宿主-微生物相互作用；② 这些抗菌素在人小肠类器官（enteroids）中的表达谱与在其来源的配对组织中的表达谱相比显著倾斜，α-防御素减少到几乎无法检测到的水平；③ 然而，在鼠类小肠类器官中，可以重现潘氏细胞α-防御素在组织中的表达谱；④ FOXO抑制剂AS1842856诱导人小肠类器官中α-防御素mRNA的表达增加超10万倍，将DEFA5和DEFA6恢复到与原始人体组织相当的水平。【主编评语】潘氏细胞分泌的α-防御素的一个关键功能是塑造肠道微生物群的组成。虽然微生物群可以显著促进健康宿主的生理，但微生物组成的扰动（即微生态失调）可能导致多种慢性疾病的发病机制，包括自闭症谱系障碍（ASD）、炎症性肠病(IBD)、肥胖、糖尿病和癌症。在克罗恩病中，潘氏细胞α-防御素的表达减少，并被认为是导致该病的微生态失调的原因之一。近期发表于PNAS的一项研究发现，FOXO抑制剂AS1842856在患者源性肠道类器官中重建了人α-防御素的天然组织水平，这一新发现表明FOXO信号轴可能是增强潘氏细胞功能的有价值的治疗靶点。（@注册营养师陈彬林）【原文信息】 FOXO inhibition rescues α-defensin expression in human intestinal organoids 2023-11-13, doi: 10.1073/pnas.2312453120 肠道类器官助力揭示罕见病发病机制 Journal of Clinical Investigation——[15.9] ① 通过胃肠道内窥镜可视化技术，观测到隐窝增大可能是Cronkhite-Canada综合征（CCS）患者独有的特征；② 从CCS患者体内分离肠道干细胞并制成人类肠道类器官（HIO），其表现出独特的出芽形态；③ CCS-HIO具有高度增殖性，并且能产生5-羟色胺的肠内分泌细胞数量增加，这些特征也在患者组织活检中观测到；④ HIO的修饰导致肠内分泌细胞增加，表现出CCS-HIO表型；⑤ 局部上皮5-羟色胺的产生与HIO增殖增加相关。【主编评语】 Cronkhite-Canada综合征（CCS）又称息肉-色素沉着-脱发-爪甲营养不良综合征，是一种极为罕见的非遗传性疾病，病因尚不清楚，以胃肠道多发息肉伴皮肤色素沉着、脱发、指趾甲萎缩等为主要临床特征，缺乏特异性治疗方法。该疾病发现迄今已有50余年，但其发病机制和最佳治疗方法仍然未知。Journal of Clinical Investigation最新研究性文章从CCS患者体内分离出肠道干细胞，构建人类肠道类器官，并揭示了5-羟色胺在肠上皮增殖中发挥关键作用。（@RZN）【原文信息】 Human intestinal organoids from Cronkhite-Canada syndrome patients reveal link between serotonin and proliferation 2023-11-01, doi: 10.1172/JCI166884 用原代肠道类器官检测宿主如何响应微生物刺激 Gut Microbes——[12.2] ① 从27个健康受试者的活检组织中构建小肠类器官，分解类器官并在层粘连蛋白511上培养，可产生绒毛基底膜（绒毛是上皮-微生物相互作用的主要部位），即产生体内与微生物互作的肠上皮细胞层；② 将上述肠上皮细胞层与菌进行共培养，会影响上皮细胞的转录状态，这个共培养体系可用于研究宿主对微生物的响应；③ 多个个体（n=9）的健康上皮对一系列益生菌菌株（BB-12R、LGGR、DSM33361和Bif195），表现出强烈的急性共通反应和菌株特异性反应。【主编评语】与微生物相互作用的研究大多来源于癌细胞系（如Caco-2），但这些癌症细胞系中的反应如何反映正常上皮的反应，以及是否存在微生物菌株特异性效应，需要进一步研究。Gut Microbes近期发表的文章，研究如何利用原代上皮类器官来检测宿主对微生物刺激的反应。（@章台柳）【原文信息】 Detecting host responses to microbial stimulation using primary epithelial organoids 2023-11-22, doi: 10.1080/19490976.2023.2281012 用于人肠类器官培养和治疗递送的工程合成基质（综述） Advanced Materials——[29.4] ① 多能干细胞或成体干细胞来源的人肠类器官（HIOs）可在体外研究人类发育、药物测试和疾病模型，并作为体内组织再生和治疗进展的细胞来源；② 合成水凝胶具有调节基质的机械和生化特性，比Matrigel-TM等生物衍生水凝胶具有优势，可设计为细胞外基质的类似物以支持HIOs生长和分化；③ HIOs被用于重建肠道移植物及体内递送至受伤的肠道部位；④ 使用合成水凝胶进行体外培养和体内递送将显著提高HIOs在药物筛选、疾病建模和治疗应用中的相关性。【主编评语】近日，发表在Advanced Materials上的这篇综述，讨论了合成水凝胶在人肠类器官（HIOs) 的体内外应用，包括概述多能干细胞或成体干细胞来源的人肠道类器官的生物学特性、设计合成基质时的不同设计注意事项、使用不同合成水凝胶用于体外HIOs培养和分化并总结了当前肠道再生的组织工程方法。（@圆圈儿）【原文信息】 Engineered Synthetic Matrices for Human Intestinal Organoid Culture And Therapeutic Delivery 2023-11-21, doi: 10.1002/adma.202307678 Nature Reviews：从零开始——肠道组织工程的进展与更新（综述） Nature Reviews Gastroenterology and Hepatology——[65.1] ① 肠道组织工程ITE具有治疗短肠症候群SBS的潜力；② 生成功能性全层肠移植物需要吸收性粘膜、平滑肌、肠神经和脉管系统等组件；③ 基于此，ITE的进展包括内皮细胞再编程和血管工程、使用患者来源的材料及使用小肠类器官改造结肠粘膜；④ ITE移植物需要根据患者及其病理进行个体化；⑤ 进行临床转化时，需考虑细胞来源的选择、是否追求同种异体或自体疗法以及良好生产规范要求；⑥ 引入脉管系统对于未来升级多层组织工程小肠以满足临床需求非常重要。【主编评语】 Nature Reviews Gastroenterology and Hepatology发表的综述，集中讨论了工程肠道移植的最新进展，特别探讨了临床转化时的关键因素和难题，并提供了其在治疗及其他领域中应用的未来场景。（@好雨）【原文信息】 Building gut from scratch — progress and update of intestinal tissue engineering 2022-03-03, doi: 10.1038/s41575-022-00586-x 感谢本期日报的创作者：九卿臣，圆圈儿，注册营养师陈彬林，RZN，章台柳，张小艳点击阅读过去10天的日报： 12-15 | 今日Science：菌群如何“排挤”病原体？生态学原理探究竟 12-14 | 今日Nature和Cell齐发，肠道菌群研究再掀小高潮 12-13 | 国内团队Cell子刊突破：调肠菌，改善肝癌患者手术预后！ 12-12 | 蜱虫叮咬使人对红肉过敏？JAMA解析α-gal综合征 12-11 | 《自然·综述》年度回顾：于君等详解癌症菌群研究新突破 12-10 | 限制性饮食如何影响健康？多文阐述背后的科学原理 12-09 | 黄秀娟等Lancet子刊突破：微生态干预可改善长新冠 12-08 | Cell连发3文，大肠癌基础和转化研究成焦点 12-07 | Nature重磅：用反向代谢组学方法，挖掘IBD中的微生物新分子 12-06 | 刘瑞欣、陈鹏等各取新突破，30分Cell子刊2文聚焦肠菌代谢与宿主健康