预约演示

更新于：2025-05-07

ENT2

更新于：2025-05-07

基本信息

别名

36 kDa nucleolar protein HNP36、Delayed-early response protein 12、DER12

+ [10]

简介

Bidirectional uniporter involved in the facilitative transport of nucleosides and nucleobases, and contributes to maintaining their cellular homeostasis (PubMed:10722669, PubMed:12527552, PubMed:12590919, PubMed:16214850, PubMed:21795683, PubMed:9396714, PubMed:9478986). Functions as a Na(+)-independent, passive transporter (PubMed:9478986). Involved in the transport of nucleosides such as inosine, adenosine, uridine, thymidine, cytidine and guanosine (PubMed:10722669, PubMed:12527552, PubMed:12590919, PubMed:16214850, PubMed:21795683, PubMed:9396714, PubMed:9478986). Also able to transport purine nucleobases (hypoxanthine, adenine, guanine) and pyrimidine nucleobases (thymine, uracil) (PubMed:16214850, PubMed:21795683). Involved in nucleoside transport at basolateral membrane of kidney cells, allowing liver absorption of nucleoside metabolites (PubMed:12527552). Mediates apical nucleoside uptake into Sertoli cells, thereby regulating the transport of nucleosides in testis across the blood-testis-barrier (PubMed:23639800). Mediates both the influx and efflux of hypoxanthine in skeletal muscle microvascular endothelial cells to control the amount of intracellular hypoxanthine available for xanthine oxidase-mediated ROS production (By similarity). Non functional nucleoside transporter protein for adenosine or thymidine transport. Does not express on cell membrane.

关联

项与 ENT2 相关的药物

GMAB-D31N/3pRNA (Gennao)

靶点

ENT2 x RIG-I

作用机制

ENT2抑制剂 [+1]

在研机构

Gennao Bio

原研机构

Yale University

在研适应症

黑色素瘤

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

GMAB-7001

靶点

ENT2 x RIG-I

作用机制

ENT2抑制剂 [+1]

在研机构

Gennao Bio

原研机构

Gennao Bio

在研适应症

实体瘤

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

V66-Exatecan

靶点

ENT2 x Top I

作用机制

ENT2抑制剂 [+1]

在研机构-

原研机构

Yale School of Medicine

在研适应症-

非在研适应症-

最高研发阶段-

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 ENT2 相关的临床结果

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100 项与 ENT2 相关的转化医学

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0 项与 ENT2 相关的专利（医药）

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249

项与 ENT2 相关的文献（医药）

2025-04-01·Journal of Hepatology

Oral-gut microbiome interactions in advanced cirrhosis: characterisation of pathogenic enterotypes and salivatypes, virulence factors and antimicrobial resistance

Article

作者: Edwards, Lindsey A. ; Begum, Neelu ; Patel, Vishal C. ; Lee, Sunjae ; Cai, Haizhuang ; Mohamad, Merianne ; Stamouli, Marilena ; Moyes, David L ; Chokshi, Shilpa ; Curtis, Mike ; Proctor, Gordon ; Mardinoglu, Adil ; Shoaie, Saeed ; Curtis, Michael A ; Zamalloa, Ane ; Harzandi, Azadeh ; Patel, Vishal C ; Shawcross, Debbie L ; Williams, Roger ; Witherden, Elizabeth ; Moyes, David ; McPhail, Mark J. ; McPhail, Mark J ; Arefaine, Bethlehem ; Edwards, Lindsey A ; Shawcross, Debbie L. ; Uhlen, Mathias

BACKGROUND & AIMSCirrhosis complications are often triggered by bacterial infections with multidrug-resistant organisms. Alterations in the gut and oral microbiome in decompensated cirrhosis (DC) influence clinical outcomes. We interrogated: (i) gut and oral microbiome community structures, (ii) virulence factors (VFs) and antimicrobial resistance genes (ARGs) and (iii) oral-gut microbial overlap in patients with differing cirrhosis severity.METHODSFifteen healthy controls (HCs), as well as 26 patients with stable cirrhosis (SC), 46 with DC, 14 with acute-on-chronic liver failure (ACLF) and 14 with severe infection without cirrhosis participated. Metagenomic sequencing was undertaken on paired saliva and faecal samples. 'Salivatypes' and 'enterotypes' based on genera clustering were assessed against cirrhosis severity and clinical parameters. VFs and ARGs were evaluated in oral and gut niches, and distinct resistotypes identified.RESULTSSalivatypes and enterotypes revealed a greater proportion of pathobionts with concomitant reduction in autochthonous genera with increasing cirrhosis severity and hyperammonaemia. Increasing overlap between oral and gut microbiome communities was observed in DC and ACLF vs. SC and HCs, independent of antimicrobial, beta-blocker and gastric acid-suppressing therapies. Two distinct gut microbiome clusters harboured genes encoding for the PTS (phosphoenolpyruvate:sugar phosphotransferase system) and other VFs in DC and ACLF. Substantial ARGs (oral: 1,218 and gut: 672) were detected (575 common to both sites). The cirrhosis resistome was distinct, with three oral and four gut resistotypes identified, respectively.CONCLUSIONSThe degree of oral-gut microbial community overlap, frequency of VFs and ARGs all increase significantly with cirrhosis severity, with progressive dominance of pathobionts and loss of commensals. Despite similar antimicrobial exposure, patients with DC and ACLF have reduced microbial richness compared to patients with severe infection without cirrhosis, supporting the additive pathobiological effect of cirrhosis.IMPACT AND IMPLICATIONSThis research underscores the crucial role of microbiome alterations in the progression of cirrhosis in an era of escalating multidrug resistant infections, highlighting the association and potential impact of increased oral-gut microbial overlap, virulence factors, and antimicrobial resistance genes on clinical outcomes. These findings are particularly significant for patients with decompensated cirrhosis and acute-on-chronic liver failure, as they reveal the intricate relationship between microbiome alterations and cirrhosis complications. This is relevant in the context of multidrug-resistant organisms and reduced oral-gut microbial diversity that exacerbate cirrhosis severity, drive hepatic decompensation and complicate treatment. For practical applications, these insights could guide the development of targeted microbiome-based therapeutics and personalised antimicrobial regimens for patients with cirrhosis to mitigate infectious complications and improve clinical outcomes.

2024-12-01·IUBMB Life

Extracellular adenosine oppositely regulates the purinome machinery in glioblastoma and mesenchymal stem cells

Article

作者: Giacomelli, Chiara ; Bertilacchi, Maria Sofia ; Pietrobono, Deborah ; Trincavelli, Maria Letizia ; Marchetti, Laura ; Russo, Lara ; Martini, Claudia

AbstractGlioblastoma (GB) is a lethal brain tumor that rapidly adapts to the dynamic changes of the tumor microenvironment (TME). Mesenchymal stem/stromal cells (MSCs) are one of the stromal components of the TME playing multiple roles in tumor progression. GB progression is prompted by the immunosuppressive microenvironment characterized by high concentrations of the nucleoside adenosine (ADO). ADO acts as a signaling molecule through adenosine receptors (ARs) but also as a genetic and metabolic regulator. Herein, the effects of high extracellular ADO concentrations were investigated in a human glioblastoma cellular model (U343MG) and MSCs. The modulation of the purinome machinery, i.e., the ADO production (CD39, CD73, and adenosine kinase [ADK]), transport (equilibrative nucleoside transporters 1 (ENT1) and 2 (ENT2)), and degradation (adenosine deaminase [ADA]) were investigated in both cell lines to evaluate if ADO could affect its cell management in a positive or negative feed‐back loop. Results evidenced a different behavior of GB and MSC cells upon exposure to high extracellular ADO levels: U343MG were less sensitive to the ADO concentration and only a slight increase in ADK and ENT1 was evidenced. Conversely, in MSCs, the high extracellular ADO levels reduced the ADK, ENT1, and ENT2 expression, which further sustained the increase of extracellular ADO. Of note, MSCs primed with the GB‐conditioned medium or co‐cultured with U343MG cells were not affected by the increase of extracellular ADO. These results evidenced how long exposure to ADO could produce different effects on cancer cells with respect to MSCs, revealing a negative feedback loop that can support the GB immunosuppressive microenvironment. These results improve the knowledge of the ADO role in the maintenance of TME, which should be considered in the development of therapeutic strategies targeting adenosine pathways as well as cell‐based strategies using MSCs.

2024-10-01·Drug Metabolism and Disposition

Development of a Novel HEK293 Cell Model Lacking SLC29A1 to Study the Pharmacology of Endogenous SLC29A2-Encoded Equilibrative Nucleoside Transporter Subtype 2

Article

作者: Hubbard, Basil P ; Cromwell, Christopher ; Shahid, Nayiar ; Hammond, James R

Equilibrative nucleoside transporters (ENTs) mediate the transmembrane flux of endogenous nucleosides and nucleoside analogs used clinically. The predominant subtype, ENT1, has been well characterized. However, the other subtype, ENT2, has been less well characterized in its native milieu due to its relatively low expression and the confounding influence of coexpressed ENT1. We created a cell model where ENT1 was removed from human embryonic kidney (HEK293) cells using CRISPR/cas9 [ENT1 knockout (KO) cells]; this cell line has ENT2 as the only functional purine transporter. Transporter function was assessed through measurement of [³H]2-chloroadenosine uptake. ENT1 protein was quantified based on the binding of [³H]nitrobenzylthioinosine, and ENT1/ENT2 protein was detected by immunoblotting. Changes in expression of relevant transporters and enzymes involved in purine metabolism were examined by quantitative polymerase chain reaction. Wild-type HEK293 cells and ENT1KO cells had a similar expression of SLC29A2/ENT2 transcript/protein and ENT2-mediated [³H]2-chloroadenosine transport activity (V_max values of 1.02 ± 0.06 and 1.50 ± 0.22 pmol/μl/s, respectively). Of the endogenous nucleosides/nucleobases tested, adenosine had the highest affinity (K_i) for ENT2 (2.6 μM), while hypoxanthine was the only nucleobase with a submillimolar affinity (320 μM). A range of nucleoside/nucleobase analogs were also tested for their affinity for ENT2 in this model, with affinities (K_i) ranging from 8.6 μM for ticagrelor to 2,300 μM for 6-mercaptopurine. Our data suggest that the removal of endogenous ENT1 from these cells does not change the expression or function of ENT2. This cell line should prove useful for the analysis of novel drugs acting via ENT2 and to study ENT2 regulation. SIGNIFICANCE STATEMENT: We have created a cell line whereby endogenous ENT2 can be studied in detail in the absence of the confounding influence of ENT1. Loss of ENT1 has no impact on the expression and function of ENT2. This novel cell line will provide an ideal model for studying drug interactions with ENT2 as well as the cellular regulation of ENT2 expression and function.

项与 ENT2 相关的新闻（医药）

2025-02-07

·浙江大学药学院

浙江大学药学院团队在Nature Communications报道SLC29A1和SLC29A2介导的烟酰胺跨细胞膜转运机制

烟酰胺（Nicotinamide）是维生素B3的主要形式，因其代谢调控、细胞保护和修复、特别是抗衰老作用，被广泛应用于保健品、膳食添加剂和化妆品中。烟酰胺在细胞内转变为烟酰胺腺嘌呤二核苷酸（NAD+）发挥作用。因烟酰胺水溶性大，难以借助简单扩散穿过细胞膜磷脂双分子层，因此其进入细胞需由转运体协助，但介导烟酰胺跨细胞膜转运的转运体尚未阐明。 2025年1月30日，浙江大学药学院蒋惠娣教授团队在《Nature Communications》发表了题为“SLC29A1 and SLC29A2 are human nicotinamide cell membrane transporters”的研究成果。该文介绍了由SLC29A1和SLC29A2基因编码的平衡型核苷转运体ENT1和ENT2介导的烟酰胺跨细胞膜转运机制。研究团队应用抑制剂、特异性敲低、过表达、分子对接和点突变等技术明确了SLC29A1和SLC29A2对烟酰胺跨细胞膜转运的贡献，并借助代谢组学、液质联用等手段进一步明确SLC29A1和SLC29A2对烟酰胺代谢以及细胞内烟酰胺和NAD+水平的调控作用；借助转录组学揭示SLC29A1和SLC29A2对烟酰胺生化功能的调控，并验证了SLC29A1和SLC29A2通过转运烟酰胺实现对细胞能量代谢和细胞衰老的调控。图1 SLC29A1/2（ENT1/2）介导烟酰胺（NAM）跨细胞膜转运并调控其生化功能浙江大学药学院为论文第一署名单位；蒋惠娣教授团队博士研究生陈铭扬和硕士研究生袁略翔为共同第一作者，蒋惠娣教授和周慧副教授为共同通讯作者。供稿：药物代谢和药物分析研究所责任编辑：金成庆审核：王毅点击名片，关注我们

2024-08-15

·生物谷

《细胞发现》：温州医科大学团队发现40Hz光照促进大脑清除垃圾蛋白的新机制！

40Hz多感官刺激如果可以作为一种新型非侵入性策略，调节并增强脑类淋巴流动，将为相关疾病的治疗带来极大的改善。近日，来自温州医科大学附属眼视光医院陈江帆教授的研究成果，将40Hz感官刺激促进脑内致病蛋白清除的机制进行了更新升级。他们发现40Hz光闪烁增强了脑类淋巴的流入和流出，并且发现腺苷-A2A受体（A2AR）信号传导是脑类淋巴流动增强的神经化学基础。研究发表在Cell Discovery杂志上。脑类淋巴系统的运转依赖于脑脊液（CSF）的流动和星形胶质细胞末端足的水通道蛋白-4（AQP4）极化，使脑脊液和间质液（ISF）进行液体交换，帮助大脑清除代谢废物。利用荧光示踪剂，研究人员可以看到40Hz光闪烁显著增加了野生型小鼠脑脊液流动，基底前脑、前额叶、上丘和海马等区域表现出显著的脑脊液灌注速度加快，淋巴流入和流出增强。 40Hz光闪烁增强淋巴流入和流出 AQP4作为血管周围空间的外部屏障，在40Hz光闪烁30分钟后，极化显著增加，意味着更有效地定位在星形胶质细胞末端足处，有助于增强脑内的液体流动和类淋巴的废物清除功能。与此同时，小鼠的动脉血管运动和脑血流量显著增加，有助于增强类淋巴流入。当然，研究人员也关注了小鼠的心血管健康。虽然血管运动增强，但是40Hz光闪烁没有造成小鼠的血压和心率显著上升，不会影响整体的心血管状态。脑血流量增加接下来，研究人员进一步探索40Hz光闪烁影响脑类淋巴流动的潜在机制。在之前的研究中，陈教授团队已经发现40Hz光闪烁可以增强胞外腺苷水平。而腺苷作为一种神经调质，在睡眠调控、心血管和炎症反应等功能中扮演着重要角色，并且与受体A2AR结合可以调节脑血流量。因此，研究人员针对小鼠腺苷水平进行了分析。腺苷的跨膜转运依赖于两种不同的转运蛋白ENT1和ENT2。40Hz光闪烁30分钟后，小鼠脑脊液细胞外腺苷水平显著升高，脑类淋巴流动增强；分别对两种转运蛋白基因进行敲除，发现只有ENT2缺失影响了40Hz诱导的腺苷水平增加和脑类淋巴流动增强，并且在ENT2缺失小鼠中也没有发现AQP4的极化增加或者动脉血管运动增强。 ENT2缺失影响40Hz诱导的脑淋巴流动、血管运动和脑血流量增加进一步对40Hz光闪烁诱导后的野生型小鼠大脑进行分析，可以看到全脑提取物中的ENT2密度增加以及A2AR密度增加，说明腺苷和A2AR在40Hz光闪烁促进脑类淋巴流动中的重要作用。总的来说，研究证明40Hz光闪烁通过ENT2介导的腺苷释放和A2AR激活增强了野生型小鼠的脑类淋巴流动。机制示意图在多种衰老相关疾病以及神经系统疾病中，都存在脑类淋巴系统功能减退，从而导致认知能力下降和蛋白质病变。40Hz多感官刺激如果可以作为一种新型非侵入性策略，调节并增强脑类淋巴流动，将为相关疾病的治疗带来极大的改善。

2024-08-12

·奇点网

接着奏乐接着舞！

*仅供医学专业人士阅读参考40Hz的神话还在继续。高频感觉刺激作为非侵入性策略，其调节大脑功能的作用正在被广泛接受。对于40Hz的光闪烁或者声音刺激在治疗阿尔茨海默病（AD）中的神奇表现，奇点糕从刚开始的大吃一惊到逐渐习惯，再之后有一阵子听不到40Hz的消息还有点想念。40Hz光闪烁治疗AD的临床试验已经在积极进行中，而对于相关机制的探索也从未停止。就在今年2月份，顶刊《自然》上的一项研究提出，40Hz多感官刺激可以促进AD小鼠脑脊液（CSF）和间质液（ISF）交换，加速淀粉样蛋白的淋巴清除。近日，来自温州医科大学附属眼视光医院陈江帆教授的研究成果，将40Hz感官刺激促进脑内致病蛋白清除的机制进行了更新升级。他们发现40Hz光闪烁增强了脑类淋巴的流入和流出，并且发现腺苷-A2A受体（A2AR）信号传导是脑类淋巴流动增强的神经化学基础。研究发表在Cell Discovery杂志上。脑类淋巴系统的运转依赖于脑脊液（CSF）的流动和星形胶质细胞末端足的水通道蛋白-4（AQP4）极化，使脑脊液和间质液（ISF）进行液体交换，帮助大脑清除代谢废物。利用荧光示踪剂，研究人员可以看到40Hz光闪烁显著增加了野生型小鼠脑脊液流动，基底前脑、前额叶、上丘和海马等区域表现出显著的脑脊液灌注速度加快，淋巴流入和流出增强。40Hz光闪烁增强淋巴流入和流出AQP4作为血管周围空间的外部屏障，在40Hz光闪烁30分钟后，极化显著增加，意味着更有效地定位在星形胶质细胞末端足处，有助于增强脑内的液体流动和类淋巴的废物清除功能。与此同时，小鼠的动脉血管运动和脑血流量显著增加，有助于增强类淋巴流入。当然，研究人员也关注了小鼠的心血管健康。虽然血管运动增强，但是40Hz光闪烁没有造成小鼠的血压和心率显著上升，不会影响整体的心血管状态。脑血流量增加接下来，研究人员进一步探索40Hz光闪烁影响脑类淋巴流动的潜在机制。在之前的研究中，陈教授团队已经发现40Hz光闪烁可以增强胞外腺苷水平。而腺苷作为一种神经调质，在睡眠调控、心血管和炎症反应等功能中扮演着重要角色，并且与受体A2AR结合可以调节脑血流量。因此，研究人员针对小鼠腺苷水平进行了分析。腺苷的跨膜转运依赖于两种不同的转运蛋白ENT1和ENT2。40Hz光闪烁30分钟后，小鼠脑脊液细胞外腺苷水平显著升高，脑类淋巴流动增强；分别对两种转运蛋白基因进行敲除，发现只有ENT2缺失影响了40Hz诱导的腺苷水平增加和脑类淋巴流动增强，并且在ENT2缺失小鼠中也没有发现AQP4的极化增加或者动脉血管运动增强。ENT2缺失影响40Hz诱导的脑淋巴流动、血管运动和脑血流量增加进一步对40Hz光闪烁诱导后的野生型小鼠大脑进行分析，可以看到全脑提取物中的ENT2密度增加以及A2AR密度增加，说明腺苷和A2AR在40Hz光闪烁促进脑类淋巴流动中的重要作用。总的来说，研究证明40Hz光闪烁通过ENT2介导的腺苷释放和A2AR激活增强了野生型小鼠的脑类淋巴流动。机制示意图在多种衰老相关疾病以及神经系统疾病中，都存在脑类淋巴系统功能减退，从而导致认知能力下降和蛋白质病变。40Hz多感官刺激如果可以作为一种新型非侵入性策略，调节并增强脑类淋巴流动，将为相关疾病的治疗带来极大的改善。参考文献：https://www.nature.com/articles/s41421-024-00701-z

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