更新于：2024-11-01

AKR1B1

更新于：2024-11-01

基本信息

别名

AKR1B1、Aldehyde reductase、aldo-keto reductase family 1 member B

+ [7]

简介

Catalyzes the NADPH-dependent reduction of a wide variety of carbonyl-containing compounds to their corresponding alcohols. Displays enzymatic activity towards endogenous metabolites such as aromatic and aliphatic aldehydes, ketones, monosacharides, bile acids and xenobiotics substrates. Key enzyme in the polyol pathway, catalyzes reduction of glucose to sorbitol during hyperglycemia (PubMed:1936586). Reduces steroids and their derivatives and prostaglandins. Displays low enzymatic activity toward all-trans-retinal, 9-cis-retinal, and 13-cis-retinal (PubMed:12732097, PubMed:19010934, PubMed:8343525). Catalyzes the reduction of diverse phospholipid aldehydes such as 1-palmitoyl-2-(5-oxovaleroyl)-sn -glycero-3-phosphoethanolamin (POVPC) and related phospholipid aldehydes that are generated from the oxydation of phosphotidylcholine and phosphatdyleethanolamides (PubMed:17381426). Plays a role in detoxifying dietary and lipid-derived unsaturated carbonyls, such as crotonaldehyde, 4-hydroxynonenal, trans-2-hexenal, trans-2,4-hexadienal and their glutathione-conjugates carbonyls (GS-carbonyls) (PubMed:21329684).

关联

项与 AKR1B1 相关的药物

Epalrestat

依帕司他

靶点

AKR1B1

作用机制

AKR1B1抑制剂

在研机构

Alfresa Pharma Corp. [+2]

原研机构

Alfresa Pharma Corp.

在研适应症

糖尿病性神经病变

非在研适应症-

最高研发阶段批准上市

首次获批国家/地区

日本

首次获批日期1992-01-21

Bendazac Lysine

苄达赖氨酸

靶点

AKR1B1

作用机制

AKR1B1抑制剂

在研机构

浙江莎普爱思药业股份有限公司

原研机构

浙江莎普爱思药业股份有限公司

在研适应症

白内障 [+1]

非在研适应症-

最高研发阶段批准上市

首次获批国家/地区-

首次获批日期1800-01-20

Govorestat

靶点

AKR1B1

作用机制

AKR1B1抑制剂

在研机构

Advanz Pharma Corp. Ltd. [+1]

原研机构

Affitech A/S

在研适应症

半乳糖血症 [+3]

非在研适应症-

最高研发阶段申请上市

首次获批国家/地区-

首次获批日期1800-01-20

项与 AKR1B1 相关的临床试验

CTR20243317 / RecruitingN/A

依帕司他片在中国成年健康受试者中的一项随机、开放、空腹单次给药、两制剂、两序列、两周期交叉的生物等效性研究

主要研究目的：单次口服50mg（空腹）受试制剂依帕司他片T（规格：50mg/片，湖南千金湘江药业股份有限公司生产）与参比制剂依帕司他片R（KINEDAK®，规格：50mg/片，小野药品工业株式会社生产），观察两种制剂在受试者体内的药代动力学特征，评估空腹状态下分别口服两种制剂的生物等效性次要研究目的：观察受试制剂T和参比制剂R单次口服50mg（空腹）在中国成年健康受试者中的安全性。

开始日期2024-09-10

申办/合作机构

湖南千金湘江药业股份有限公司

CTR20241582 / CompletedN/A

依帕司他片在中国成年健康受试者中的一项随机、开放、空腹单次给药、两制剂、两序列、两周期交叉的生物等效性研究

主要研究目的：考察空腹状态下单次口服1片受试制剂依帕司他片（规格：50 mg/片，海南赛立克药业有限公司生产，海南斯达制药有限公司提供）与参比制剂依帕司他片[商品名：KINEDAK，规格：50 mg/片，アルフレッサファーマ株式会社（Alfresa Pharma Corporation）生产，海南斯达制药有限公司提供]在中国成年健康受试者体内的相对生物利用度，分析两种制剂的药代动力学参数，评价两制剂的生物等效性。次要研究目的：评价空腹状态下单次口服1片受试制剂和参比制剂依帕司他片（规格：50 mg/片）在中国成年健康受试者中的安全性。

开始日期2024-06-28

申办/合作机构

海南斯达制药有限公司

CTR20242135 / CompletedN/A

依帕司他片（50mg）在中国健康受试者中空腹给药条件下随机、开放、单剂量、两序列、两周期、双交叉生物等效性试验。

主要研究目的：按有关生物等效性试验的规定，选择アルフレッサファーマ株式会社为持证商的依帕司他片（商品名：KINEDAK；规格：50mg）为参比制剂，对广东九明制药有限公司生产并提供的受试制剂依帕司他片（规格：50mg）进行空腹给药人体生物等效性试验，比较受试制剂中药物的吸收速度和吸收程度与参比制剂的差异是否在可接受的范围内，评价两种制剂在空腹给药条件下的生物等效性。次要研究目的：观察健康受试者口服受试制剂依帕司他片（规格：50mg）和参比制剂依帕司他片（商品名：KINEDAK；规格：50mg）的安全性。

开始日期2024-06-26

申办/合作机构

广东九明制药有限公司

100 项与 AKR1B1 相关的临床结果

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100 项与 AKR1B1 相关的转化医学

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0 项与 AKR1B1 相关的专利（医药）

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3,623

项与 AKR1B1 相关的文献（医药）

2024-12-01·Journal of Ethnopharmacology

Exploring the mechanism of Pueraria lobata (Willd.) Ohwi in the regulation of obesity

Article

作者: Guo, Xiulan ; Wang, Binbin ; Li, Maolin ; Wang, Xiaodong ; Wang, Guoze ; Luo, Peng ; Mao, Jingxin

ETHNOPHARMACOLOGICAL RELEVANCEPueraria lobata (Willd.) Ohwi is a traditional medicinal and edible homologous plant rich in flavonoids, triterpenes, saponins, polysaccharides and other chemical components. At present, studies have shown that PR has the effect of lowering blood sugar, improving insulin sensitivity and inhibiting obesity. However, the specific mechanism of PR inhibits obesity is still unclear, and there are few researches on the anti-obesity effect of PR through the combination of network pharmacology and experiment.AIM OF THE STUDYPharmacology, molecular docking technology and experimental verification through the network, revealing the Pueraria lobata radix (PR) the material basis of obesity and the potential mechanism.METHODS AND RESULTSThe present study used network pharmacology techniques to investigate the therapeutic effect and mechanism of action of PR. Through relevant databases, a total of 6 main chemical components and 257 potential targets were screened. Protein interaction analysis shows that AKT1, AKR1B1, PPARG, MMP9, TNF, TP53, BAD, and BCL2 are core targets. Enrichment analysis shows that the pathway of PR in preventing obesity involves the cancer signaling pathway and the PI3K-Akt signaling pathway, which may be the main pathways of action. Further molecular docking verification indicates that its core target exhibits good binding activity with 4 compounds: formononectin, purerin, 7,8,4 '- trihydroxide and daidzein. Using the ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) technology to detected and confirmed these main compounds. Cell experiment results revealed that puerarin inhibits cell proliferation and differentiation in a concentration dependent manner, significantly promoting cell apoptosis and affecting cell migration. Animal experiments have shown that puerarin reduces food intake and weight gain in mice. It was found that puerarin can upregulate HDL and downregulate TC, TG, and LDL blood biochemical indicators. Western blot results showed that puerarin significantly inhibited the expression of AKT1, AKR1B1, MMP9, TNF, TP53, BCL2, PPARG, and significantly increased the expression of BAD protein at both cellular and animal levels.CONCLUSIONThe present study established a method for measuring PR content and predicted its active ingredients and their mechanisms of action in the treatment of obesity, providing a theoretical basis for further research.

2024-12-01·Molecular Biology Reports

High glucose combined with lipopolysaccharide stimulation inhibits cell proliferation and migration of human HaCaT keratinocytes by impacting redox homeostasis and activating the polyol pathway

Article

作者: Zhou, Shufan ; Xie, Zhenhui ; Zhang, Qiu ; Tang, Songtao ; Liu, Lei

BACKGROUNDHigh glucose level and chronic inflammation are characteristic features of diabetic cutaneous wounds. Keratinocytes make up the epidermis and play an important role in skin repair. However, metabolomic changes of keratinocytes in chronic diabetic ulcers have not been fully studied.METHODS AND RESULTSThis study used high levels of glucose combined with lipopolysaccharide to treat human HaCaT keratinocytes. Untargeted metabolomic combined with colorimetric assays were used to explore the changes of keratinocyte metabolites and related metabolic pathways caused by high glucose and lipopolysaccharide. Results demonstrated that high glucose combined with lipopolysaccharide treatment increased intracellular reactive oxygen species and impaired proliferation and migration of keratinocytes. Untargeted metabolomics analysis identified a total of 273 differential metabolites. Redox metabolism associated metabolites were largely altered. Reduced nicotinamide adenine dinucleotide, gamma-glutamylcysteine, superoxide dismutase activity and SOD2 gene expression were significantly upregulated while nicotinamide adenine dinucleotide, glutathione, glutathione peroxidase, several types of lysophosphatidylcholine, lysophosphatidylinositol, and GPR55 gene expression were downregulated. Alterations of glutathione and nicotinamide adenine dinucleotide were verified by colorimetric assays. For the first time, high glucose and LPS were observed to boost the levels of fructose, aldose reductase and sorbitol dehydrogenase of the polyol pathway in HaCaT cells. Further treatment of HaCaT with fructose leading to inhibition of cell proliferation and migration.CONCLUSIONSOur data suggest high glucose combined with lipopolysaccharide significantly altered redox homeostasis associated metabolites and activate the polyol pathway in keratinocytes to impact cell proliferation and migration, providing new strategies for the treatment of chronic diabetic ulcers.

2024-12-01·Molecular Biology Reports

Vitamin C alleviates hyperglycemic stress in retinal pigment epithelial cells

Article

作者: Chang, Kun-Che ; Liu, Chia-Chun ; Alahmari, Hamid ; Rodriguez, Paul ; Lin, Venice Y ; Rubin, Elizabeth

BACKGROUNDRetinal pigment epithelial cells (RPECs) are a type of retinal cells that structurally and physiologically support photoreceptors. However, hyperglycemia has been shown to play a critical role in the progression of diabetic retinopathy (DR), which is one of the leading causes of vision impairment. In the diabetic eye, the high glucose environment damages RPECs via the induction of oxidative stress, leading to the release of excess reactive oxygen species (ROS) and triggering apoptosis. In this study, we aim to investigate the antioxidant mechanism of Vitamin C in reducing hyperglycemia-induced stress and whether this mechanism can preserve the function of RPECs.METHODS AND RESULTSARPE-19 cells were treated with high glucose in the presence or absence of Vitamin C. Cell viability was measured by MTT assay. Cleaved poly ADP-ribose polymerase (PARP) was used to identify apoptosis in the cells. ROS were detected by the DCFH-DA reaction. The accumulation of sorbitol in the aldose reductase (AR) polyol pathway was determined using the sorbitol detection assay. Primary mouse RPECs were isolated from adult mice and identified by Rpe65 expression. The mitochondrial damage was measured by mitochondrial membrane depolarization. Our results showed that high glucose conditions reduce cell viability in RPECs while Vitamin C can restore cell viability, compared to the vehicle treatment. We also demonstrated that Vitamin C reduces hyperglycemia-induced ROS production and prevents cell apoptosis in RPECs in an AR-independent pathway.CONCLUSIONSThese results suggest that Vitamin C is not only a nutritional necessity but also an adjuvant that can be combined with AR inhibitors for alleviating hyperglycemic stress in RPECs.

项与 AKR1B1 相关的新闻（医药）

2024-10-18

·今日头条

【Nature子刊】上海六院等合作揭示AKR1B1驱动果糖代谢，助力癌细胞恶性转化

【导读】果糖代谢已成为癌细胞增殖的重要因素，但果糖对癌细胞的潜在机制和来源，仍不完全清楚。在这项研究中，团队证明了癌细胞可以通过AKR1B1介导的多元醇途径的过程，将葡萄糖转化为果糖。 2024年10月15日，上海交通大学医学院附属第六人民医院、上海中医药大学附属龙华医院等团队在期刊《Cell Death & Differentiation》上合作发表了题为“AKR1B1-dependent fructose metabolism enhances malignancy of cancer cells”的研究论文。研究结果强调了内源性果糖在癌细胞恶性肿瘤中的关键作用，并支持进一步研究AKR1B1作为潜在癌症治疗靶点的必要性。 https://www.nature.com/articles/s41418-024-01393-4 膳食果糖与肿瘤 01 最近的研究发现，膳食果糖与肿瘤促进有关。然而，内源性果糖驱动这些病理的机制仍不清楚。在正常生理条件下，多元醇途径存在于大多数体细胞中，通过两步过程将约3%的细胞内葡萄糖转化为果糖。第一步，使用NADPH和醛糖还原酶（AKR1B1）将葡萄糖还原为山梨醇。第二步通过山梨醇脱氢酶（SORD）的作用，将山梨醇转化为果糖，并将NAD转化为NADH。癌细胞迁移可以通过两种不同的模式发生：单细胞迁移和集体迁移。癌细胞具有固有的可塑性，使它们能够根据微环境调整迁移模式。癌细胞运动至关重要的因素，可能包括代谢稳态、细胞骨架动力学和细胞收缩力。这项研究旨在探讨癌细胞产生内源性果糖的分子机制，以及该类型果糖在代谢稳态和恶性肿瘤中的作用。 AKR1B1介导的果糖代谢通过RhoA-ROCK2通路增强癌细胞迁移 02 AKR1B1的缺失显著抑制了癌细胞迁移，伤口愈合证明了这一点。通过补充果糖，可以逆转AKR1B1-KO引起的迁移能力受损。在过表达AKR1B1的细胞中，观察到一致的结果，因为该基因的强制表达增强了HCT116和BxPC3肿瘤细胞的迁移能力。此外，内源性果糖代谢受损的A549和U87细胞向肺或肝组织的转移减少。NC A549细胞表现出向肺部转移的趋势，而NC U87细胞表现出对肝转移的偏好。 AKR1B1缺失在A549和U87细胞中，显著下调了RhoA和ROCK2的表达。AKR1B1消融对这两种细胞系之间EMT标志物的表达，产生不同的影响，包括E-钙粘蛋白和N-钙粘蛋白。一致地，用AKR1B1抑制剂epalrestat处理，也降低了这些细胞系中RhoA和ROCK2的表达，但没有降低E-钙粘蛋白和波形蛋白的表达。这些结果表明，AKR1B1-KO可以抑制RhoA-ROCK2通路。相比之下，果糖添加以剂量依赖性方式，显著恢复了A549和U87细胞AKR1B1-KO中RhoA和ROCK2的表达。来自TCGA数据库的ROCK2高表达，预测了泛癌患者的OS更差。综上所述，AKR1B1可能通过激活RhoA-ROCK2通路，在促进肿瘤转移中发挥关键作用。既往研究报道，RhoA-ROCK2通路主要介导肿瘤细胞中的单细胞转移模式。因此，可以合理地假设， AKR1B1可能通过促进肿瘤细胞的分离来促进转移。 AKR1B1介导的葡萄糖果糖，通过RhoA-ROCK2通路增强癌细胞迁移。总结 03 1. 果糖作为癌细胞代谢燃料：研究发现，外源性果糖可以作为癌细胞的碳源，癌细胞对果糖有很强的依赖性。 2. AKR1B1在果糖代谢中的作用： AKR1B1介导的多元醇通路在癌细胞中高度活跃，是葡萄糖转化为果糖的关键机制。 3. AKR1B1作为潜在治疗靶点：抑制AKR1B1活性可能是治疗癌症的可行且安全的方法，尤其在糖尿病患者中。 4. 多元醇途径与癌症风险：高血糖水平增强AKR1B1表达，可能解释糖尿病患者癌症风险升高的原因。 5. AKR1B1的临床潜力： AKR1B1介导的内源性果糖代谢在癌细胞增殖和迁移中起重要作用，表明AKR1B1是潜在的治疗靶点。参考资料： 1.Goncalves MD, Lu C, Tutnauer J, Hartman TE, Hwang SK, Murphy CJ, et al. High-fructose corn syrup enhances intestinal tumor growth in mice. Science. 2019;363:1345–9. 2.Chen WL, Wang YY, Zhao A, Xia L, Xie G, Su M, et al. Enhanced fructose utilization mediated by SLC2A5 is a unique metabolic feature of acute myeloid leukemia with therapeutic potential. Cancer cell. 2016;30:779–91. 【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 🕓 线上｜10月15日/10月22日 ▶ 代谢组学在精准医学方向的研究应用线上高峰论坛 🕓 上海｜11月15日-16日 ▶ 2024第一届中国类器官转化医学大会 🕓 上海｜11月21日-24日 ▶ 第七届上海国际肿瘤内科学论坛 🕓 上海 / 北京 / 重庆等 + 同步线上直播｜2024年12月-2025年03月 ▶ 中国转化医学产业大会点击对应文字查看详情

临床结果

2024-09-20

·佰傲谷BioValley

FDA取消召开Adcomm，公司股价大涨69%

近日，Applied Therapeutics公布了其核心管线Govorestat新药申请(NDA)审查的积极消息。 FDA通知公司，不再需要召开专家咨询委员会会议（adcomm）来针对Govorestat进行讨论，该会议之前原定于2024年10月9日举行。这一举动令Applied大松一口气，因为去年Govorestat未能通过一项III期临床（ACTION-Galactosemia ），并且上市申请审评期还在今年3月还被FDA延长三个月。取消在adcom上对该药的投票表决，已经表明了监管态度。不用在adcomm中走一遭，Govorestat被上市通过的概率将大大提升。 FDA表示优先审查计划将如期进行，PDUFA目标行动日仍定在2024年11月28日。受此消息鼓舞，公司股价上涨了近70%。 Govorestat是Applied Therapeutics最为核心的管线，如果获得批准，将成为Applied的首个商业产品。 Govorestat是一种具有中枢神经系统渗透性的醛糖还原酶抑制剂（ARI），被开发用于治疗多种罕见的神经系统疾病，包括半乳糖血症、山梨醇脱氢酶缺乏症（SORD）和磷酸甘露糖变位酶2-先天性糖基化障碍（PMM2-CDG）。半乳糖血症是Govorestat首发适应症。如果Govorestat获得批准，将成为首个用于治疗半乳糖血症的药物。 2024年2月，govorestat治疗半乳糖血症的NDA获得了FDA受理，并获得了优先审评。 NDA申请得到了半乳糖醇快速和持续降低的支持，包括针对2-17岁半乳糖血症儿童的Ⅲ期临床数据ACTION-Galactosemia Kid、以及针对成人半乳糖血症患者的ACTION-GalactosemiaⅠ/Ⅱ期临床数据。 Applied亦向欧洲药品管理局（EMA）递交治疗半乳糖血症的上市许可申请(MAA)，目前正在接受EMA人用药品委员会(CHMP)的审查。公司预计EMA将在2024年第四季度做出审批决定。此外，Govorestat在其他适应症中取得了临床积极结果。今年2月，Applied 公布了Govorestat治疗SORD缺乏症的Ⅲ期临床INSPIRE试验12个月中期分析结果，该试验达到了主要终点和几个关键次要终点。与安慰剂相比，Govorestat在山梨醇水平持续下降具有统计学意义。此外，govorestat在CMT健康指数（CMT-HI）方面也产生了显著的统计学意义，患者的下肢功能、活动能力、感觉功能和上肢功能的改善。安全性和耐受性良好，治疗组和安慰剂组的不良事件发生率相似。基于迄今为止的临床数据，公司计划与FDA讨论针对该适应症的新药上市申请。官网中还有有两条管线AT-001和AT-003，业均为醛糖还原酶抑制剂。AT-001已经推进到了临床Ⅲ期阶段，不过最近报告的消息看起来不算好，2024年1月4日，AT-001治疗糖尿病心肌病ARISE-HF的Ⅲ期临床中主要终点没有达到。 AT-003是一款具有眼球内的渗透性的ARI，目前还在临床前阶段，用于治疗糖尿病性视网膜病变。从经营现状看来，Govorestat尽快取得上市批准也是十分急迫的了。参考出处： https://firstwordpharma.com/story/5841711 https://ir.appliedtherapeutics.com/news-releases/news-release-details/applied-therapeutics-provides-regulatory-update-govorestat https://ir.appliedtherapeutics.com/static-files/2f5dd433-9a82-40b9-ae3f-3da06ce5bff8 本周好文推荐如需转载请联系佰傲谷并在醒目位置注明出处 · · · · · · · ·

临床3期优先审批临床2期申请上市引进/卖出

2024-09-18

·FierceBiotech

FDA scraps adcomm for Applied's rare disease drug ahead of November decision

The Nov. 28 approval decision deadline for Applied Therapeutics’ metabolic disorder drug govorestat is still in place. After pushing back the decision date for Applied Therapeutics’ metabolic disorder drug govorestat, the FDA has now decided that a planned advisory committee meeting won’t be required.The agency had originally expected an approval decision for the aldose reductase inhibitor for the end of August, but, by March, the FDA had bumped this back three months to Nov. 28. At the time, the regulator told Applied that more time was needed to examine supplemental analyses of already submitted data and determined that the additional info constitutes a major amendment to the new drug application.Applied announced Wednesday morning that while the Nov. 28 deadline is still in place, the FDA had informed the biotech during a late-cycle review meeting that the advisory committee meeting to discuss the application—which had been penciled in for Oct. 9—is no longer required.“We are incredibly pleased by the ongoing collaborative dialogue with the FDA during the NDA review process, and we look forward to continuing to work together with the agency to bring the first potential treatment to classic galactosemia patients,” Applied’s CEO Shoshana Shendelman, Ph.D., said.“Our commitment to the cassic galactosemia community is further supported by our thoughtful commercial preparation, focused on establishing an effective patient access program, high physician awareness and strong payor engagement,” Shendelman added. While analysts at William Blair said the FDA's decision was “unexpected,” they branded it as good news.“We view this outcome as favorable for Applied as it suggests that the regulators are comfortable with the totality of the clinical data submitted to make a regulatory decision on or prior to the November 28 PDUFA,” the analysts said in a Sept. 18 note.Applied’s confidence in govorestat has survived a phase 3 trial last year that showed the drug was no better than placebo at improving a composite of four measures—including language skills, self-care capabilities and more—among children with galactosemia. The rare disease can cause developmental delays, speech problems and motor function abnormalities.Despite the failure, the New York-based biotech argued at the time that the data showed “consistent and sustained clinical benefit on activities of daily living, behavioral symptoms, cognition, adaptive behavior and tremor” and went ahead with filing a new drug application with the FDA.Applied had planned to ask for U.S. approval on the strength of biomarker data, only for the FDA to say it would likely need evidence the drug candidate improves clinical outcomes to receive a positive decision. The phase 3 trial gave Applied evidence of the effect of govorestat, also known as AT-007, on clinical outcomes.