更新于：2024-09-19

MGST2

更新于：2024-09-19

基本信息

别名

Glutathione peroxidase MGST2、GST2、Leukotriene C4 synthase MGST2

+ [6]

简介

Catalyzes several different glutathione-dependent reactions (PubMed:8703034, PubMed:9278457, PubMed:23409838, PubMed:26656251, PubMed:26066610). Catalyzes the glutathione-dependent reduction of lipid hydroperoxides, such as 5-HPETE (PubMed:9278457, PubMed:23409838). Has glutathione transferase activity, toward xenobiotic electrophiles, such as 1-chloro-2, 4-dinitrobenzene (CDNB) (PubMed:23409838, PubMed:8703034). Catalyzes also the conjugation of leukotriene A4 with reduced glutathione to form leukotriene C4 (LTC4) (PubMed:23409838, PubMed:26656251). Involved in oxidative DNA damage induced by ER stress and anticancer agents by activating LTC4 biosynthetic machinery in nonimmune cells (PubMed:26656251).

关联

项与 MGST2 相关的药物

HG-1067

靶点

MGST2

作用机制

MGST2基因调节剂

在研机构-

原研机构

Human Genome Sciences, Inc.

在研适应症-

非在研适应症

免疫系统疾病 [+1]

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 MGST2 相关的临床结果

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100 项与 MGST2 相关的转化医学

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0 项与 MGST2 相关的专利（医药）

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126

项与 MGST2 相关的文献（医药）

2024-05-13·European Heart Journal

Myocardial reperfusion injury exacerbation due to ALDH2 deficiency is mediated by neutrophil extracellular traps and prevented by leukotriene C4 inhibition

Article

作者: Hu, Jingjing ; Yang, Kun ; Wei, Xiang ; Gao, Rifeng ; Guo, Yansong ; Lyu, Yang ; Zhang, Peng ; Shi, Jiaran ; Chen, Juntao ; Hu, Kai ; Dong, Zhen ; Wei, Wei ; Chen, Yinyin ; Chen, Hanchuan ; Sun, Aijun ; Zhang, Liwei ; Ge, Junbo

AbstractBackground and AimsThe Glu504Lys polymorphism in the aldehyde dehydrogenase 2 (ALDH2) gene is closely associated with myocardial ischaemia/reperfusion injury (I/RI). The effects of ALDH2 on neutrophil extracellular trap (NET) formation (i.e. NETosis) during I/RI remain unknown. This study aimed to investigate the role of ALDH2 in NETosis in the pathogenesis of myocardial I/RI.MethodsThe mouse model of myocardial I/RI was constructed on wild-type, ALDH2 knockout, peptidylarginine deiminase 4 (Pad4) knockout, and ALDH2/PAD4 double knockout mice. Overall, 308 ST-elevation myocardial infarction patients after primary percutaneous coronary intervention were enrolled in the study.ResultsEnhanced NETosis was observed in human neutrophils carrying the ALDH2 genetic mutation and ischaemic myocardium of ALDH2 knockout mice compared with controls. PAD4 knockout or treatment with NETosis-targeting drugs (GSK484, DNase1) substantially attenuated the extent of myocardial damage, particularly in ALDH2 knockout. Mechanistically, ALDH2 deficiency increased damage-associated molecular pattern release and susceptibility to NET-induced damage during myocardial I/RI. ALDH2 deficiency induced NOX2-dependent NETosis via upregulating the endoplasmic reticulum stress/microsomal glutathione S-transferase 2/leukotriene C4 (LTC4) pathway. The Food and Drug Administration-approved LTC4 receptor antagonist pranlukast ameliorated I/RI by inhibiting NETosis in both wild-type and ALDH2 knockout mice. Serum myeloperoxidase–DNA complex and LTC4 levels exhibited the predictive effect on adverse left ventricular remodelling at 6 months after primary percutaneous coronary intervention in ST-elevation myocardial infarction patients.ConclusionsALDH2 deficiency exacerbates myocardial I/RI by promoting NETosis via the endoplasmic reticulum stress/microsomal glutathione S-transferase 2/LTC4/NOX2 pathway. This study hints at the role of NETosis in the pathogenesis of myocardial I/RI, and pranlukast might be a potential therapeutic option for attenuating I/RI, particularly in individuals with the ALDH2 mutation.

2024-02-08·Journal of Medicinal Chemistry1区 · 医学

Discovery of Artemisinins as Microsomal Prostaglandins Synthase-2 Inhibitors for the Treatment of Colorectal Cancer via Chemoproteomics

1区 · 医学

Article

作者: Xu, Jingyuan ; Deng, Zhangshuang ; Li, Qing ; Zhou, Yiqing ; Xue, Fuchong ; Wong, Nai-Kei ; Geng, Yiyun ; Li, Weichao ; Zhang, Yang

Colorectal cancer remains the second leading cause of cancer-related mortalities worldwide. While artemisinin (ART), a key active compound from the traditional Chinese medicinal herb Artemisia annua, has been recognized for its antiproliferative activity against colon cancer cells, its underlying molecular underpinnings remain elusive. Whereas promiscuity of heme-dependent alkylating of macromolecules, mainly proteins, has been seen pivotal as a universal and primary mode of action of ART in cancer cells, accumulating evidence suggests the existence of unique targets and mechanisms of actions contingent on cell or tissue specificities. Here, we employed photoaffinity probes to identify the specific targets responsible for ART's anti-colon cancer actions. Upon validation, microsomal prostaglandins synthase-2 emerged as a specific and reversible target of ART in HCT116 colorectal cancer cells, whose inhibition resulted in reduced cellular prostaglandin E₂ biosynthesis and cell growth. Our discovery opens new opportunities for pharmacological treatment of colon cancer.

2023-12-01·Journal of Dairy Science

Plant polyphenol extract supplementation affects performance, welfare, and the Nrf2-oxidative stress response in adipose tissue of heat-stressed dairy cows

Article

作者: Portnick, Y ; Lavon, Y ; Daddam, J R ; Pelech, I ; Kra, G ; Zachut, M ; Moallem, U ; Daniel, D

We examined the effects of a supplement of plant polyphenols extracts of green tea, capsicum, and fenugreek, and electrolytes ([Na⁺, K+]; AXT, Axion ThermoPlus, CCPA, France] during summer heat load on production, welfare, and oxidative stress proteins in adipose tissue (AT) of dairy cows. A total of 42 multiparous mid-lactation cows were divided into 3 groups during summer, and were fed for 2 wk either a standard milking cow diet (CTL, n = 14) or diets supplemented with 100 g/d of AXT (100AXT, n = 14), or 150 g/d of AXT (150AXT, n = 14), while being cooled 5 times a day. Then, half of the cows from each dietary treatment were cooled (CL) or not cooled (NCL) for 2 wk, after which the cooled and uncooled groups were switched for additional 2 wk. Cows were milked 3 times a day, and milk composition was analyzed at the end of each 2-wk period. Vaginal temperature (VT) was measured for 3 consecutive days in each period. Biopsies of subcutaneous AT were taken from 10 NCL cows (5 each of CTL and 150AXT) at the end of the period and examined by liquid chromatography-tandem mass spectrometry proteomics analysis. Data were analyzed with PROC MIXED of SAS (version 9.2, SAS Institute Inc.). The model included the effects of dietary treatment, cooling regimen, period, and their interactions. Protein and mRNA abundances and proteomic data (P ≤ 0.05 and fold change [FC] ± 1.5) were analyzed by t-test. Milk yields and 4% fat-corrected milk (FCM) were higher in 100AXT than in CTL; milk components were not different. Dry matter intake (DMI) was higher in 100AXT than in CTL. The effect of cooling and the interactions of period × cooling were significant for DMI, 4% FCM, energy-corrected milk, and milk/DMI. The proportion of time that VT was >39°C was lower in 100AXT and in 150AXT than in CTL. Daily rumination time was greater in 150AXT than in CTL, and lying time was greater in 100AXT and 150AXT than in CTL. Proteomics of AT demonstrated that 150AXT had increased abundances of peroxidasin (FC = 1.6), microsomal glutathione S-transferase 2 (FC = 2.5), and heme oxygenase 1 (FC = 3.6) compared with CTL. Top enriched canonical pathways included acute phase response signaling, Nrf2-mediated oxidative stress response, and lipopolysaccharide (LPS)/IL-1-mediated inhibition of RXR function. Immunoblots of AT showed a higher abundance of the transient receptor potential vanilloid 1 and of LPS binding protein in AT of 150AXT compared with CTL. Supplementation of AXT increased DMI, milk, and 4% FCM, lowered VT, improved welfare indices, and enriched the AT with Nrf2-oxidative stress response and acute phase response proteins in heat-stressed dairy cows.

项与 MGST2 相关的新闻（医药）

2024-05-11

·今日头条

再取突破！复旦大学葛均波院士、孙爱军教授等团队发布缺血性心脏病机制研究方面最新成果

本文为转化医学网原创，转载请注明出处作者：Sophia 导读：乙醛脱氢酶 2 （ALDH2）基因中的 Glu504Lys 多态性与心肌缺血/再灌注损伤（I/RI）密切相关。ALDH2 对 I/RI 期间中性粒细胞胞外陷阱（NET）形成（即 NETosis）的影响尚不清楚。本研究旨在探讨ALDH2在NETosis中对心肌I/RI发病机制的作用。近日，复旦大学附属中山医院葛均波院士、孙爱军教授团队与福建省立医院郭延松教授团队合作，在《European Heart Journal》 (IF 39.3)上发表了题为“Myocardial reperfusion injury exacerbation due to ALDH2 deficiency is mediated by neutrophil extracellular traps and prevented by leukotriene C4 inhibition”的研究成果。研究揭示了因乙醛脱氢酶2基因缺失而加重心肌缺血再灌注损伤的机制，即通过内质网应激/微粒体谷胱甘肽S转移酶2/白三烯C4信号通路介导中性粒细胞胞外诱捕网形成（NETosis）。研究团队发现一种使用抗哮喘类药物阻断以上机制发生的新策略，对防治心肌缺血再灌注损伤的治疗带来较好的临床转化前景。 https://academic-oup-com.libproxy1.nus.edu.sg/eurheartj/advance-article/doi/10.1093/eurheartj/ehae205/7658555?login=false 研究背景 01 通过经皮冠状动脉介入治疗（PCI）及时再灌注是急性心肌梗死（AMI）后挽救奄奄一息的心肌的最有效治疗选择之一。尽管早期再灌注，但仍有 7% 的患者死亡，22% 的幸存者可能在 AMI 后 1 年发展为慢性心力衰竭。心肌缺血/再灌注损伤（I/RI）是一种广泛认可的表型组，可发生在再灌注后，并导致高达 50% 的最终梗死面积。既往研究表明，免疫应答在I/RI过程中起着核心作用，早期免疫应答主要由先天免疫细胞介导，包括巨噬细胞和中性粒细胞。缺血/再灌注损伤可刺激受损心肌细胞（CM）释放核损伤相关分子模式（DAMP），例如高迁移率组 1 （HMGB1）和细胞外组蛋白，随后级联反应有利于免疫细胞的募集和激活。限制中性粒细胞浸润可增强心肌挽救率。中性粒细胞胞外陷阱（NET）是中性粒细胞生物学的一个新方面，最近有报道称会增加心肌 I/RI。作为对 DAMP 的响应，中性粒细胞的一个子集可以释放用组蛋白、细胞质和颗粒蛋白装饰的染色质结构。这个过程被称为NET形成（NETosis）。NETosis 可以增加细胞内钙并激活肽基拉吉宁脱亚胺酶 4 （PAD4），后者将特定的带正电荷的精氨酸残基转化为中性瓜氨酸残基。这通常发生在组蛋白上，导致瓜氨酸化组蛋白，例如瓜氨酸化组蛋白 H3 （citH3）。越来越多的证据表明，细胞毒性神经内分泌瘤的快速释放可能导致严重的心肌损伤和血管真菌。乙醛脱氢酶 2 （ALDH2）是一种关键的醇代谢酶。大约 30%–50% 的东亚人口（约占世界的 8%）携带 ALDH2 rs671 （Glu504Lys）多态性。ALDH2 rs671 G > A 多态性与各种心血管疾病的发病机制有关，包括心肌 I/RI。我们之前的研究表明 ALDH2 在各种心血管模型中的保护作用，包括 I/RI;然而，目前尚不清楚 ALDH2 是否参与 I/RI 期间的 NETosis。研究结果 02 本研究，我们在野生型ALDH2敲除、肽基拉吉宁脱亚胺酶4（Pad4）敲除和ALDH2/PAD4双敲除小鼠上构建了心肌I/RI小鼠模型，纳入了 308 例初次经皮冠状动脉介入治疗后的 ST 段抬高型心肌梗死患者。与对照组相比，在携带ALDH2基因突变的人中性粒细胞和ALDH2敲除小鼠的缺血性心肌中观察到增强的NETosis。PAD4敲除或NETosis靶向药物（GSK484，DNAse1）治疗可显著减轻心肌损伤的程度，特别是在ALDH2敲除中。从机制上讲，ALDH2 缺乏增加了与损伤相关的分子模式释放和对心肌 I/RI 期间 NET 诱导损伤的易感性。ALDH2 缺乏通过上调内质网应激/微粒体谷胱甘肽 S-转移酶 2/白三烯 C4 （LTC4）通路诱导 NOX2 依赖性 NETosis。美国食品药品监督管理局（FDA）批准的LTC4受体拮抗剂普兰鲁司特通过抑制野生型和ALDH2敲除小鼠的NETosis来改善I/RI。血清髓过氧化物酶-DNA复合物和LTC4水平对ST段抬高型心肌梗死患者初次经皮冠状动脉介入治疗后6个月的不良左心室重塑具有预测作用。 ALDH2 缺失会增加心肌 I/RI 期间的心肌 DAMP 释放。在 DAMP 的刺激下，ALDH2 缺失通过上调 ER 应激/Mgst2/LTC4 通路诱导 NOX2 依赖性 NET 形成，导致心肌 I/RI 加重。总之， ALDH2 缺乏症通过内质网应激/微粒体谷胱甘肽 S-转移酶 2/LTC4/NOX2 通路促进 NETosis，从而加剧心肌 I/RI。这项研究暗示了 NETosis 在心肌 I/RI 发病机制中的作用，普兰司特（pranlukast）可能是减轻 I/RI 的潜在治疗选择，尤其是在具有 ALDH2 突变的个体中。参考资料： https://academic-oup-com.libproxy1.nus.edu.sg/eurheartj/advance-article/doi/10.1093/eurheartj/ehae205/7658555?login=false https://mp.weixin.qq.com/s/mAUkrED7VWDFwrLWVZsNXg 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。热门·直播/活动 🕓 上海｜06月14日-16日 ▶ 第六届上海国际癌症大会将于6月14-16日在上海举办，学科交叉，共同推进肿瘤研究与诊治多模态！ 🕓 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欢迎您的参与！点击对应文字查看详情

临床研究

2024-04-30

·生物探索

EHJ | 葛均波/孙爱军/郭延松团队合作发现ALDH2基因缺失加重心肌缺血再灌注损伤的新机制

引言醛脱氢酶2 (ALDH2)基因Glu504Lys多态性与心肌缺血/再灌注损伤(I/RI)密切相关。在I/RI期间，ALDH2对中性粒细胞胞外陷阱(NET)形成(即NETosis)的影响尚不清楚。2024年4月26日，复旦大学附属中山医院葛均波院士/孙爱军教授团队与福建省立医院郭延松教授团队合作（杨坤、高日峰、陈汉川及胡静静为论文共同第一作者）在European Heart Journal（IF=39）在线发表题为“Myocardial reperfusion injury exacerbation due to ALDH2 deficiency is mediated by neutrophil extracellular traps and prevented by leukotriene C4 inhibition”的研究论文，该研究表明ALDH2缺乏引起的心肌再灌注损伤加重由中性粒细胞胞外陷阱介导，白三烯C4抑制剂可预防该疾病的进行。研究结果表明，与对照组相比，携带ALDH2基因突变的人中性粒细胞和ALDH2敲除小鼠的缺血心肌中观察到NETosis增强。PAD4敲除或使用NETosis靶向药物(GSK484，DNase1)治疗可显著减轻心肌损伤程度，特别是ALDH2敲除。在机制上，ALDH2缺乏增加了心肌I/RI期间损伤相关的分子模式释放和对NET诱导的损伤的易感性。ALDH2缺乏通过上调内质网应激/微粒体谷胱甘肽转移酶2/白三烯C4 (LTC4)途径诱导NOX2依赖性NETosiss。FDA的LTC4受体拮抗剂pranlukast通过抑制野生型和ALDH2敲除小鼠的NETosis来改善I/RI。血清髓过氧化物酶-DNA复合物和LTC4水平对ST段抬高型心肌梗死患者经皮冠状动脉介入治疗6个月后不良左心室重构具有预测作用。总之，ALDH2缺乏通过内质网应激/微粒体谷胱甘肽S-转移酶2/LTC4/NOX2途径促进NETosis，从而加剧心肌I/RI。该研究揭示了NETosis在心肌I/RI发病机制中的作用，而pranlukast可能是减轻I/RI的潜在治疗选择，特别是在ALDH2突变个体中。经皮冠状动脉介入治疗(PCI)是抢救急性心肌梗死(AMI)后濒死心肌最有效的治疗方法之一。尽管早期再灌注，仍有7%的患者死亡，22%的幸存者可能在AMI后1年发生慢性心力衰竭。心肌缺血/再灌注损伤(I/RI)是一种广泛认可的现象，可在再灌注后发生，占最终梗死面积的50%。既往研究表明，免疫应答在I/RI过程中起核心作用，早期免疫应答主要由先天免疫细胞介导，包括巨噬细胞和中性粒细胞。缺血/再灌注损伤可刺激受损心肌细胞(CMs)释放核损伤相关分子模式(DAMPs)，如高迁移率组框1 (HMGB1)和细胞外组蛋白，随后级联有利于免疫细胞的募集和激活，限制中性粒细胞浸润增强心肌挽救。中性粒细胞胞外陷阱(NETs)，中性粒细胞生物学的一个新方面，最近被报道增加心肌I/RI。作为对DAMPs的反应，一部分中性粒细胞可以释放由组蛋白、细胞质和颗粒蛋白修饰的染色质结构，这个过程被称为NET形成(NETosis)。NETosis可以增加细胞内钙，激活肽精氨酸脱亚胺酶4 (PAD4)，将特定的带正电的精氨酸残基转化为中性的瓜氨酸残基。模式图（Credit: European Heart Journal）醛脱氢酶2 (ALDH2)是一种重要的酒精代谢酶。大约30%-50%的东亚人口(约占世界人口的8%)携带ALDH2 rs671 (Glu504Lys)多态性。ALDH2 rs671 G > A多态性与多种心血管疾病的发病机制有关，包括心肌I/RI。之前的研究证实了ALDH2在多种心血管模型中的保护作用，包括I/ RI；然而，目前尚不清楚ALDH2是否参与I/RI期间的NETosis。该研究表明，ALDH2缺乏加剧了小鼠和患者的心肌I/RI，主要是通过内质网应激/Mgst2/LTC4/NOX2途径促进NETosis。药物治疗靶向NETosis或使用LTC4受体拮抗剂可能是减轻心肌I/RI的有希望的治疗方法，特别是在ALDH2突变个体中。原文链接https://doi-org.libproxy1.nus.edu.sg/10.1093/eurheartj/ehae205责编|探索君排版|探索君文章来源|“iNature”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Nature | 破除传统：为何我们需要重新思考肿瘤的命名方式热文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

临床研究