更新于：2024-11-01

THBS1

更新于：2024-11-01

基本信息

别名

Glycoprotein G、THBS、THBS-1

+ [8]

简介

Adhesive glycoprotein that mediates cell-to-cell and cell-to-matrix interactions (PubMed:2430973, PubMed:6489349, PubMed:15014436, PubMed:18285447). Multifunctional, involved in inflammation, angiogenesis, wound healing, reactive oxygen species (ROS) signaling, nitrous oxide (NO) signaling, apoptosis, senescence, aging, cellular self-renewal, stemness, and cardiovascular and metabolic homeostasis (PubMed:14568985, PubMed:1371676, PubMed:10613822, PubMed:11134179, PubMed:24511121, PubMed:29042481, PubMed:32679764). Negatively modulates dendritic cell activation and cytokine release, as part of an autocrine feedback loop, contributing to the resolution of inflammation and immune homeostasis (PubMed:14568985). Ligand for receptor CD47 (PubMed:8550562, PubMed:19004835). Modulates nitrous oxide (NO) signaling via CD47, hence playing a role as a pressor agent, supporting blood pressure (By similarity). Plays a role in endothelial cell senescence, acting via CD47, by increasing the abundance and activation of NADPH oxidase NOX1, and so generating excess ROS (PubMed:29042481). Inhibits stem cell self-renewal, acting via CD47 signaling, probably by regulation of the stem cell transcription factors POU5F1/OCT4, SOX2, MYC/c-Myc and KLF4 (By similarity). Negatively modulates wound healing, acting via CD47 (By similarity). Ligand for receptor CD36 (PubMed:1371676, PubMed:10613822, PubMed:11134179). Involved in inducing apoptosis in podocytes in response to elevated free fatty acids, acting via CD36 (By similarity). Plays a role in suppressing angiogenesis, acting, depending on context, via CD36 or CD47 (PubMed:1371676, PubMed:10613822, PubMed:32679764, PubMed:11134179). Promotes cellular senescence in a TP53-CDKN1A-RB1 signaling-dependent manner (PubMed:29042481). Ligand for immunoglobulin-like cell surface receptor SIRPA (PubMed:24511121). Involved in ROS signaling in non-phagocytic cells, stimulating NADPH oxidase-derived ROS production, acting via interaction with SIRPA (PubMed:24511121). Plays a role in metabolic dysfunction in diet-induced obesity, perhaps acting by exacerbating adipose inflammatory activity; its effects may be mediated, at least in part, through enhanced adipocyte proliferation (By similarity). Plays a role in ER stress response, via its interaction with the activating transcription factor 6 alpha (ATF6) which produces adaptive ER stress response factors (By similarity). May be involved in age-related conditions, including metabolic dysregulation, during normal aging (PubMed:29042481, PubMed:32679764).

关联

项与 THBS1 相关的药物

VT-1021

靶点

THBS1

作用机制

THBS1激动剂

在研机构

朴莱雷斯集团 [+5]

原研机构

Vigeo Therapeutics, Inc.

在研适应症

多形性胶质母细胞瘤 [+2]

非在研适应症-

最高研发阶段临床2/3期

首次获批国家/地区-

首次获批日期1800-01-20

HTPEP-001

靶点

THBS1

作用机制

THBS1拮抗剂

在研机构

成都惠泰生物医药有限公司

原研机构

成都惠泰生物医药有限公司

在研适应症

进行性肺纤维化 [+2]

非在研适应症-

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

SRI-35241

靶点

TGF-β x THBS1

作用机制

TGF-β抑制剂 [+1]

在研机构

Southern Research Institute

原研机构

Southern Research Institute

在研适应症

纤维化 [+1]

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

项与 THBS1 相关的临床试验

CTR20241874 / Recruiting临床1期

一项在健康受试者中评估吸入用HTPEP-001安全、耐受性和药代动力学的随机、双盲、安慰剂对照的I期临床研究

主要目的：评价在健康受试者中单次给予吸入用HTPEP-001后的安全性、耐受性。次要目的： 1.评价在健康受试者中单次给予吸入用HTPEP-001后的药代动力学特征； 2.评价在健康受试者中单次给予吸入用HTPEP-001的免疫原性。

开始日期2024-07-08

申办/合作机构

成都惠泰生物医药有限公司

NCT03970447 / Recruiting临床2/3期IIT

GBM AGILE: Global Adaptive Trial Master Protocol: an International, Seamless Phase II/III Response Adaptive Randomization Platform Trial Designed to Evaluate Multiple Regimens in Newly Diagnosed and Recurrent GBM

Glioblastoma (GBM) adaptive, global, innovative learning environment (GBM AGILE) is an international, seamless Phase II/III response adaptive randomization platform trial designed to evaluate multiple therapies in newly diagnosed (ND) and recurrent GBM.

开始日期2019-07-30

申办/合作机构

朴莱雷斯集团

[+5]

NCT03364400 / Active, not recruiting临床1期

A Phase 1 Study Evaluating the Safety, Pharmacology, and Preliminary Activity of VT1021 in Patients With Advanced Solid Tumors

This study is an an open-label Phase I trial of VT1021 in patients with advanced solid tumors. Patients must have recurrent or advanced cancer (i.e., solid tumors) for which standard therapy offers no curative potential.

开始日期2017-11-28

申办/合作机构

Vigeo Therapeutics, Inc.

100 项与 THBS1 相关的临床结果

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100 项与 THBS1 相关的转化医学

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0 项与 THBS1 相关的专利（医药）

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6,273

项与 THBS1 相关的文献（医药）

2025-01-01·Journal of Ethnopharmacology

Integrated lipidomic and transcriptomics to explore the effects of ethyl acetate extract of Herpetospermum pedunculosum on nonalcoholic fatty liver disease in mice

Article

作者: Tan, Rui ; Adiham, Akida ; Han, Cairong ; Zhang, Zhongrui ; Gong, Puyang ; Zhang, Boyu ; Gu, Jian

ETHNOPHARMACOLOGICAL RELEVANCEHerpetospermum pedunculosum (Ser.) C.B. Clarke (HP), a traditional Tibetan medicine used to treat hepatobiliary diseases, was confirmed that lignans-enriched ethyl acetate extract of HP (EAHP) could alleviate the hepatic injury by modern pharmacological evidence. However, the effects and potential mechanisms of EAHP against nonalcoholic fatty liver disease (NAFLD) are still unknown.AIM OF THE STUDYTo reveal the effects of EAHP on NAFLD and explore the potential mechanisms from the perspective of lipidomics and transcriptomics.MATERIALS AND METHODSUPLC‒Q-TOF‒MS analysis was carried out to investigate the chemical components of EAHP. A Choline-deficient, L-amino acid defined, high fat diet (CDAHFD) was used to establish a NAFLD mouse model. The anti-NAFLD effects of various dosages of EAHP were evaluated by biochemical indexes and histological analysis. Hepatic lipidomic and transcriptomic analysis and multiple bioinformatics methods were used to screen biomarkers and signaling pathways. The levels of the corresponding genes were verified by qPCR.RESULTS36 kinds of compounds were identified by UPLC‒Q-TOF‒MS analysis. Oral treatment with EAHP significantly decrease the liver index and the levels of ALT and AST in the serum. The measurements lipid content and Oil Red O staining results suggested that EAHP ameliorated lipid metabolism disorders by reducing the content of TG and LDL-C, increasing HDL-C in the liver. H&E staining and ELISA revealed that EAHP restored hepatic inflammatory infiltration and decrease the levels of IL-1β, IL-6, TNF-α, and increase IL-10 in the serum. Lipidomic analysis showed that EAHP could regulate CDAHFD-induced lipid metabolic disorder. The different lipid metabolites included TG, phosphatidyl choline (PC), diacylglycerol (DG), phosphatidylethanolamine (PE), phosphatidylinositol (PI), ceramide (Cer). Transcriptomic analysis revealed that Bmp8b, Nbl1, Rgma, Sphk1, Thbs1, and Ugt8a were important regulators, which were associated with TGF-β signaling pathway and sphingolipid metabolism. The expressions of above genes detected by were qPCR consistent with transcriptomic data.CONCLUSIONSThe ameliorative effects of EAHP on NAFLD are potentially attributable to the regulation of sphingolipid metabolism and TGF-β signaling pathway, etc., which results in abnormal hepatic lipid metabolism and inflammatory response.

2025-01-01·Vascular and Endovascular Surgery

Short-Term and Long-Term Fluvastatin Inhibit Effects of Thrombospondin-1 on Human Vascular Smooth Muscle Cells

Article

作者: Iwuchukwu, Chinenye ; Maier, Kristopher ; Ryabtsev, Boris ; Yuan, Helen L. ; Seymour, Keri ; Stein, Jeffrey J. ; Gahtan, Vivian ; Helkin, Alex

Introduction Vascular smooth muscle cells are important in intimal hyperplasia. Thrombospondin-1 is a matricellular protein involved in the vascular injury response. Statins are cholesterol lowering drugs that have beneficial cardiovascular effects. Statis have been shown to inhibit smooth muscle migration through the mevalonate pathway. This effect is thought to be mediated by small G protein Ras and Rho turnover which requires many hours. While many patients undergoing treatment for vascular disease are on statins, many are not. Thus immediate pretreatment with statins before surgery may be beneficial. We hypothesized that statins have effects independent of the mevalonate pathway and thus have an immediate effect. Methods Human vascular smooth muscle cells were pretreated for 20 h (long-term) or 20 min (short-term) with fluvastatin, or mevalonolactone plus fluvastatin. Thrombospondin-1-induced migration, activation of p42/p44 extracellular signal-regulated kinase, c-Src, focal adhesion kinase and PI3 kinase was determined. The effect of fluvastatin on thrombospondin-1-induced expression of THBS1, FOS, HAS2 and TGFB2 was examined. Results Both treatments inhibited thrombospondin-1-induced chemotaxis back to the control group. Mevalonolactone reversed the long-term statin effect by increasing migration but had no effect on the short-term statin response. p42/p44 extracellular signal-regulated kinase was activated by thrombospondin-1 and both treatments augmented activation. Neither treatment affected c-Src activity, but both inhibited focal adhesion kinase and PI3 kinase activity. Only long-term statin treatment inhibited THBS1 expression while both treatments inhibited FOS and TGFB2 expression. Neither treatment affected HAS2. FOS knockdown inhibited thrombospondin-1-induced HAS2 but not TGFβ2 gene expression. Conclusion Long-term fluvastatin inhibited thrombospondin-1-induced chemotaxis through the mevalonate pathway while short-term fluvastatin inhibited chemotaxis through an alternate mechanism. Short-term stains have immediate effects independent of the mevalonate pathway. Acute local treatment with statins followed by longer term therapy may limit the vascular response to injury.

2024-12-31·Clinical and Experimental Hypertension

Exploration and validation of signature genes and immune associations in septic cardiomyopathy

Article

作者: Wang, Jing ; Tan, Fangyan ; Liu, Han ; Chen, Wan ; Du, Jianlin ; Wang, Xiaojing ; Deng, Songbai ; Zhao, Zhengbo

An early and accurate diagnosis of septic cardiomyopathy is vital for improving the overall prognosis of sepsis. In our research, we aimed to identify signature genes and their immune connections in septic cardiomyopathy. By analyzing the mouse myocardial transcriptome from sepsis induced by cecum ligation and puncture (CLP), we identified four distinct k-means clusters. Further analysis of human myocardial datasets using Weighted Gene Co-expression Network Analysis (WGCNA) revealed a strong correlation between the MEturquoise module and septic cardiomyopathy (cor = 0.79, p < .001). Through the application of Cytoscape plug-in MCODE and comprehensive analysis, we pinpointed two signature genes, THBS1 and TIMP1. These genes demonstrated significant involvement in immune cell infiltration, as detected by CIBERSORT, and displayed promising prognostic potential as validated by external datasets. Our experimental validation confirmed the up-regulation of both THBS1 and TIMP1 in septic murine hearts, underscoring their positive association with septic cardiomyopathy.

项与 THBS1 相关的新闻（医药）

2024-09-19

·今日头条

可提高化疗药物疗效！上海交通大学刘辰莹/杜鹏团队：结直肠癌的联合治疗新策略

【导读】转录酶DDX21对于核糖体的生成至关重要，在结直肠癌（CRC）中表达上调，但DDX21的失调机制以及其在CRC中促进肿瘤形成的机制尚不为人所知。 9月17日，上海交通大学刘辰莹/杜鹏研究团队在期刊《Oncogene》上发表了题为“The RNA helicase DDX21 activates YAP to promote tumorigenesis and is transcriptionally upregulated by β-catenin in colorectal cancer”的研究论文，本研究中，研究人员发现DDX21是β-catenin的一个直接转录靶基因，并介导了β-catenin在结直肠癌中的促癌功能。结直肠癌组织中DDX21的表达与β-catenin的表达及活性相关，DDX21高表达与结直肠癌患者的不良预后相关。DDX21的缺失导致细胞质易位和YAP转录活性降低，抑制结直肠癌细胞的增殖和迁移，而YAP的重新激活可部分挽救这一作用。研究人员还发现核糖体应激可能通过ZAKα-MKK4/7-JNK轴上调DDX21的表达，诱导LATS的下调和YAP的激活。总之，本研究揭示了结直肠癌中DDX21的转录激活机制以及核糖体应激反应中YAP的激活，表明了涉及诱导核糖体应激和YAP抑制的联合治疗的潜力。 https://www.nature.com/articles/s41388-024-03160-8#Abs1 背景知识 01 DEAD-box RNA解旋酶调节RNA结构的形成，在各种生物过程中发挥重要作用，包括核糖体的生物发生，转录和翻译。DDX21是核仁DEAD-box RNA解旋酶家族成员，并首先被鉴定为c- jun依赖转录的转录辅因子。近年来的研究阐明了DDX21协调基因转录和核糖体RNA加工的机制，揭示了DDX21在核糖体生物发生的多个步骤中的关键作用。此外，DDX21可解析基因组R环，并在基因转录过程中协同SIRT7维持基因组稳定性。尤其是，DDX21只有在适当的表达水平才能促进双链断裂(DSB)修复。DDX21的异常高表达延迟了同源重组(HR)修复，导致基因组不稳定和随后的肿瘤发生。癌症分析表明，DEAD-box RNA解旋酶DDX21的表达在CRC的mRNA水平显著上调，促进CRC的转移和肿瘤生长。然而，在结直肠癌中，DDX21 mRNA表达上调的转录激活机制以及DDX21的下游效应分子在肿瘤发生和进展中的作用仍不清楚。 Hippo通路是一个保守的信号通路，参与哺乳动物的器官大小控制和组织稳态。转录共激活因子YAP/TAZ是Hippo通路的主要下游效应因子。YAP/TAZ的异常激活导致多种肿瘤的发生和侵袭表型，包括CRC。YAP/TAZ可以调控基因转录和细胞行为以应对多种细胞刺激和胁迫，如渗透胁迫、能量胁迫、内质网应激、氧化应激和热应激。核糖体应激(RQC)又称核糖体毒性应激(ISR)，是指核糖体功能和生物发生的损害，最终导致各种应激信号的激活，包括P53、核糖体毒性应激反应(RSR)、核糖体相关质量控制RQC)和综合应激反应(ISR)。RSR是一种由MAP3K20激酶ZAKα启动的丝裂原活化蛋白(MAP)激酶信号级联，并激活与应激相关的MAP激酶p38和JNK。然而，RSR和Hippo通路之间的生物学相关性以及ZAKα在CRC中对YAP活性的调节作用仍然不清楚。 DDX21促进YAP在结直肠癌发生中的致癌功能 02 之前的研究已经表明，作为7SK snRNP的重要组成部分，DDX21可以调节RNA的二级结构和核糖体RNA（rRNA）的合成，并促进转录延伸。为了探究DDX21在结直肠癌细胞中的转录效应，研究人员对敲除和对照HCT-116细胞进行了RNA-seq分析。与对照细胞相比，DDX21敲除HCT-116细胞中下调了69个基因，上调了118个基因（log2FC>1, p<0.05）。尤其是，基因集富集分析（GSEA）揭示，YAP靶基因集在DDX21敲除HCT-116细胞中的差异表达基因中富集。qPCR分析进一步证实，DDX21敲除HCT-116和RKO细胞中经典的YAP靶基因（如CTGF、CYR61、THBS1和AXL）的mRNA水平降低。相反，稳定过表达DDX21增加了YAP靶基因的表达。与上述结果一致，蛋白质免疫印迹实验分析显示，DDX21敲除细胞中磷酸化YAP-Ser127的水平升高。研究人员还观察到DDX21敲除HCT-116细胞胞质中出现弥散的YAP染色，这反映了YAP的胞质转位。值得注意的是，研究人员没有检测到DDX21与YAP/TAZ/TEAD复合物的相互作用（未显示数据）。因此，尽管有报道表明YAP控制转录延伸，但DDX21可能不直接参与YAP/TEAD靶基因的转录调控。YAP激活在多种癌症中常见，包括结直肠癌。因此，研究人员探讨了YAP是否介导了DDX21在CRC中的促癌效应。为此，研究人员建立了DDX21敲低HCT-116细胞，并过表达了恒定活性的YAP5SA。正如预期的那样，DDX21敲低抑制HCT-116细胞的增殖、克隆形成和细胞迁移的作用被过表达恒定活性的YAP5SA逆转。此外，研究人员建立了DDX21过表达的HCT-116和HIEC-6细胞，并进行了YAP敲低。正如预期的那样，YAP敲低消除了DDX21过表达诱导的YAP靶基因的上调表达。持续观察发现，DDX21过表达可显著增强HCT-116和HIEC-6细胞的增殖、克隆形成和细胞迁移能力，而YAP敲低则可显著降低上述效应。综上所述，这些数据表明DDX21在结直肠癌中发挥促癌作用，可能通过激活Hippo通路下游效应分子YAP来实现。 DDX21会增强YAP的活性，促进结直肠癌的发生研究小结 03 综上，本研究揭示了β-catenin在结直肠癌中转录激活DDX21, YAP/TEAD在响应核糖体应激时被激活，强调了靶向结直肠癌核仁DDX21和YAP/TEAD的联合策略的治疗潜力。【参考资料】 https://www.nature.com/articles/s41388-024-03160-8#Abs1 【关于投稿】转化医学网（360zhyx.com）是转化医学核心门户，旨在推动基础研究、临床诊疗和产业的发展，核心内容涵盖组学、检验、免疫、肿瘤、心血管、糖尿病等。如您有最新的研究内容发表，欢迎联系我们进行免费报道（公众号菜单栏-在线客服联系），我们的理念：内容创造价值，转化铸就未来！转化医学网（360zhyx.com）发布的文章旨在介绍前沿医学研究进展，不能作为治疗方案使用；如需获得健康指导，请至正规医院就诊。热门推荐活动点击免费报名 🕓 北京｜09月20日-21日 ▶ 第五届单细胞技术应用研讨会暨空间组学前沿研讨会 🕓 上海｜11月15日-16日 ▶ 2024第一届中国类器官转化医学大会点击对应文字查看详情

2024-08-14

·生物谷

Nat Commun：识别出一种与致白血病病毒相关疾病的新型潜在药物靶点

本文研究结果表明，Tax的稳定性依赖于KDR的活性，因此KDR的活性或能作为一种新型策略来靶向作用HTLV-1相关疾病患者机体中的Tax蛋白。人类T细胞白血病病毒1型（HTLV-1，Human T-cell leukemia virus type 1）感染与成人T细胞白血病/淋巴瘤（ATLL）和神经炎性疾病HTLV-1相关的脊髓病/热带痉挛性麻痹（HAM/TSP）的发展有关。近日，一篇发表在国际杂志Nature Communications上题为“The tyrosine kinase KDR is essential for the survival of HTLV-1-infected T cells by stabilizing the Tax oncoprotein”的研究报告中，来自宾夕法尼亚州立大学医学院等机构的科学家们通过研究发现了一种治疗与HTLV-1感染相关疾病的新型靶点。研究者表示，阻断能调节细胞功能的激酶或会导致细胞死亡，而这或许是由Tax蛋白的降解所引起的，Tax蛋白对于病毒基因表达、病毒的传播和被HTLV-1感染的细胞存活至关重要。 HTLV-1是一种逆转录病毒，其也是一类能通过将自身遗传物质拷贝插入到宿主细胞DNA中来劫持细胞的特殊病毒类型，如今其在全球感染了1000万至2000万人，感染者主要分布在日本南部、澳大利亚中部、撒哈拉以南非洲地区、南美洲、加勒比海和中东。大约10%的感染者会发展为ATLL和HAM/TSP。研究者Edward Harhaj教授说道，目前科学家们对HTLV-1尚未进行充分研究，而且缺乏治疗该病毒所引起疾病的疗法，本文研究结果或能帮助开发新型临床手段来靶向作用被HTLV-1感染的患者机体中的Tax蛋白。于是研究人员开始着手识别HTLV-1所感染细胞存活所需要的酶类，利用转化了病毒的人类细胞，研究人员进行了所谓的短发夹RNA筛选（a short hairpin RNA screen），其是一种能让研究人员挨个抑制编码激酶的600多个基因表达的特殊分子分析手段。研究结果表明，只有KDR（称之为VEGFR2的酪氨酸激酶）是细胞生存所必需的，为了验证研究人员的发现，研究者利用能靶向作用KDR的小分子抑制剂来处理细胞，包括一种被FDA批准的酪氨酸激酶抑制剂，当KDR的功能被阻断后，细胞就会发生死亡。识别出一种与致白血病病毒相关疾病的新型潜在药物靶点图片来源：Nature Communications (2024). DOI:10.1038/s41467-024-49737-5 研究者Harhaj说道，KDR并不在我们的研究范围内，因为其通常会在内皮细胞中表达，并调节血管的形成，如今我们惊讶地发现，其也会在T细胞中进行表达，T细胞是一类能保护机体抵御感染的白细胞，如今我们正债研究这种特殊类型的白血病，此前从来没有人认为其与这些特定细胞的存活有关。本文研究结果表明，KDR在HTLV-1感染细胞存活中所扮演的角色或许与Tax病毒蛋白有关，Tax对于病毒基因表达、病毒传播和癌症的发生至关重要，KDR的抑制会导致Tax发生降解，并会干扰致癌信号通路，从而导致细胞死亡，当研究人员抑制了HAM/TSP患者血液样本中的KDR时也观察到了相同的结果。研究人员对Tax蛋白研究了很长一段时间，但并没有人找到一种能靶向作用它的方法，如今研究人员发现了一种能靶向作用宿主激酶KDR的潜在手段，KDR不仅会在T细胞中表达，而且Tax还能开启其表达并拦截其功能，从而促使其稳定并保护其免于降解。这些研究发现或指明了开发ATLL和HAM/TSP疗法的潜在药物靶点，研究者认为，重新定向当前的KDR抑制剂或开发一种新型抑制剂或有望签字啊帮助减少HTLV-1的病毒载量，从而有望降低机体的患病风险。从临床上来讲，KDR抑制剂非常有效，无论是治疗患者还是给予病毒载量较高的个体来预防疾病，后期研究人员还将继续深入对其背后的作用机制进行研究。综上，本文研究结果表明，Tax的稳定性依赖于KDR的活性，因此KDR的活性或能作为一种新型策略来靶向作用HTLV-1相关疾病患者机体中的Tax蛋白。（生物谷Bioon.com）参考文献： Mohanty, S., Suklabaidya, S., Lavorgna, A. et al. The tyrosine kinase KDR is essential for the survival of HTLV-1-infected T cells by stabilizing the Tax oncoprotein. Nat Commun 15, 5380 (2024). doi：10.1038/s41467-024-49737-5

细胞疗法临床研究

2024-08-06

·生物探索

Nature | 焦亡细胞分泌物促进组织损伤修复

引言细胞焦亡是一种依赖于炎症小体激活的程序性细胞死亡形式，通常伴随着细胞膜破裂和炎性细胞因子的释放。与凋亡和坏死不同，焦亡以炎症反应为主要特征。炎症小体是一类多蛋白复合物，能够感知细胞内外的危险信号【1-4】。典型的炎症小体包括NLRP3、AIM2和NLRC4等。炎症小体的组装涉及两个诱导信号：1）由Toll样受体（TLR）配体引起的NF-κB激活炎症小体组分和促炎细胞因子的转录上调；2）由多种触发因素引起的炎症小体组装和caspase-1的激活【5, 6】。Caspase-1被激活后切割Gasdermin D（GSDMD），释放其N端结构域，这一结构域能够插入细胞膜，形成孔洞导致细胞膜破裂，同时这些孔洞还可以释放炎性细胞因子，从而引发炎症反应。通过中和IL-1β和IL-18等炎性细胞因子不能完全削弱焦亡和GSDMD激活的影响，表明还存在其他因素。然而，焦亡过程中还可能释放哪些其他小分子和代谢物及其对组织环境的影响仍不清楚。近日，来自比利时根特大学的Kodi S. Ravichandran课题组在Nature上发表了研究论文Oxylipins and metabolites from pyroptotic cells act as promoters of tissue repair。在本研究中，作者通过分析焦亡细胞分泌物发现了一类Oxylipins及其他小分子代谢物在促进组织修复中的重要作用，其中PGE2的释放促进了巨噬细胞在伤口的聚集从而加速了组织损伤修复。为了识别独立于IL-1β的焦亡分泌物作用，作者利用了NLRP1B炎症小体在无需TLR引发的情况下诱导焦亡的能力，在这一模型中，炭疽致死毒素（LeTox）通过NLRP1B炎症小体在骨髓来源的巨噬细胞（BMDMs）中诱导焦亡性细胞死亡，而不会引起IL-1β或IL-1α的释放，作者将这种焦亡定义为Pyro-1。为了研究Pyro-1分泌物如何与其他细胞进行交流，他们将LeTox处理的对照和Nlrp1b-Tg（Pyro-1）小鼠来源的BMDMs上清液加入到C57BL/6小鼠的初始BMDMs中孵育4小时，并进行了RNA-seq分析。研究发现，Pyro-1上清液显著富集了与细胞迁移、增殖和免疫反应相关的基因，其中包含了一些与伤口愈合和组织修复相关的基因，如Thbs1、Vegf、Nr4a1、S1pr1和Tgm2等；相比之下，脂质代谢基因呈下调趋势。并且作者发现这些诱导的基因特征是独立于IL-18的，敲除在BMDMs中持续表达的Il-18并不影响Pyro-1上清液诱导的基因表达。接下来，作者分析了Pyro-1上清液中小分子介质是否发挥作用。通过脂质组学分析，研究人员发现Pyro-1上清液中富含Oxylipins，包括PGE2。由于PGE2与伤口愈合有关，所以当添加来自Pyro-1的上清液时，作者发现Pyro-1上清液可以促进细胞划痕的愈合，细胞迁移也得到了有效增强，而这些效应都是独立于IL-18的。对PGE2释放动力学、来源以及释放方式进行研究后，发现：1）LeTox处理后90分钟就可以检测到PGE2，并在120分钟显著增加；2）在焦亡过程中COX1和COX2的活性诱导可能导致了新的PGE2合成和释放；3）焦亡细胞中的PGE2释放需要在焦亡过程中形成的GSDMD孔。此外，作者还研究了Pyro-1上清液在体外的生物活性，他们发现Pyro-1上清液也可以有效促进结肠伤口的愈合。作者更进一步的分析了Pyro-1上清液中小分子在伤口愈合中的作用。他们在小鼠全层皮肤损伤模型中进行了研究，这是因为该模型仅部分依赖于PGE2进行组织修复，使得作者能够研究PGE2及其他成分的贡献。皮内注射Pyro-1上清液时，在损伤后的第2天和第4天（修复的炎症阶段）可以观察到最大的有益效果。当通过添加阿司匹林（抑制PGE2合成）时也可以观察到部分的促进伤口愈合的效果，这表明其他成分也发挥了有助于组织修复的功能。机制上的研究表明，Pyro−1上清液处理的伤口显示出CD45+细胞和CD45-细胞的数量增加，这也符合了在伤口修复早期阶段通常伴随着巨噬细胞和中性粒细胞迅速渗入损伤部位的现象。这些巨噬细胞通过表达凝集素CD301和细胞因子IL-27来发挥促进组织修复的作用。总的来说，这篇文章探究了焦亡分泌的小分子和代谢物在组织环境中的生理功能，发现了焦亡细胞释放的PGE2和其他小分子在促进组织修复中的意料之外的有益效果。这些发现丰富了人们对焦亡这种程序性细胞死亡在组织中独特作用的认知。参考文献 1. Kesavardhana, S., Malireddi, R. S. & Kanneganti, T.-D. Caspases in cell death, inflammation, and gasdermin-induced pyroptosis. Annu. Rev. Immunol. 38, 567–595 (2020). 2. Mariathasan, S. et al. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature 430, 213–218 (2004). 3. Shi, J. et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526, 660–665 (2015). 4. Liu, X. et al. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature 535, 153–158 (2016). 5. Broz, P. & Dixit, V. M. Inflammasomes: mechanism of assembly, regulation and signalling. Nat. Rev. Immunol. 16, 407–420 (2016). 6. Bauernfeind, F. G. et al. Cutting edge: NF-κB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J. Immunol. 183, 787–791 (2009). https://doi.org/10.1038/s41586-024-07585-9 责编|探索君排版|探索君文章来源|“BioArt” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述