更新于：2024-11-01

HK1

更新于：2024-11-01

基本信息

别名

Brain form hexokinase、hexokinase 1、Hexokinase type I

+ [4]

简介

Catalyzes the phosphorylation of various hexoses, such as D-glucose, D-glucosamine, D-fructose, D-mannose and 2-deoxy-D-glucose, to hexose 6-phosphate (D-glucose 6-phosphate, D-glucosamine 6-phosphate, D-fructose 6-phosphate, D-mannose 6-phosphate and 2-deoxy-D-glucose 6-phosphate, respectively) (PubMed:1637300, PubMed:25316723, PubMed:27374331). Does not phosphorylate N-acetyl-D-glucosamine (PubMed:27374331). Mediates the initial step of glycolysis by catalyzing phosphorylation of D-glucose to D-glucose 6-phosphate (By similarity). Involved in innate immunity and inflammation by acting as a pattern recognition receptor for bacterial peptidoglycan (PubMed:27374331). When released in the cytosol, N-acetyl-D-glucosamine component of bacterial peptidoglycan inhibits the hexokinase activity of HK1 and causes its dissociation from mitochondrial outer membrane, thereby activating the NLRP3 inflammasome (PubMed:27374331).

关联

项与 HK1 相关的药物

Mito-lonidamine

靶点

CFTR x HK1

作用机制

CFTR抑制剂 [+1]

在研机构

University of Michigan College of Engineering [+1]

原研机构

Medical College of Wisconsin [+1]

在研适应症

肺癌

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

100 项与 HK1 相关的临床结果

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100 项与 HK1 相关的转化医学

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0 项与 HK1 相关的专利（医药）

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1,017

项与 HK1 相关的文献（医药）

2024-12-31·Gynecological Endocrinology

Enhanced glycolysis in the myometrium with ectopic endometrium of patients with adenomyosis: a preliminary study

Article

作者: Liu, Shanjia ; Guan, Yongge ; Huang, Shiya ; Liu, Xuehong ; Huang, Xueqian ; Li, Kunyin ; Ma, Hongxia ; Wang, Yishu ; Xie, Linling ; Wen, Xiaohui

OBJECTIVESThe objective of this study was to investigate the glycolytic activity of adenomyosis, which is characterized by malignant biological behaviors including abnormal cell proliferation, migration, invasion, cell regulation, and epithelial-mesenchymal transition.METHODSFrom January 2021 to August 2022, a total of 15 patients who underwent total hysterectomy for adenomyosis and 14 patients who had non-endometrial diseases, specifically with cervical squamous intraepithelial neoplasia and uterine myoma, were included in this study. Myometrium with ectopic endometrium from patients with adenomyosis while normal myometrium from patients in the control group were collected. All samples were confirmed by a histopathological examination. The samples were analyzed by liquid chromatography-mass spectrometry (LC-MS), real-time quantitative PCR, NAD+/NADH assay kit as well as the glucose and lactate assay kits.RESULTSEndometrial stroma and glands could be observed within the myometrium of patients in the adenomyosis group. We found that the mRNA expressions of HK1, PFKFB3, glyceraldehyde-3-phospate dehydrogenase (GAPDH), PKM2, and PDHA as well as the protein expressions of PFKFB3 were elevated in ectopic endometrial tissues of the adenomyosis group as compared to normal myometrium of the control group. The level of fructose 1,6-diphosphate was increased while NAD + and NAD+/NADH ratio were decreased compared with the control group. Besides, increased glucose consumption and lactate production were observed in myometrium with ectopic endometrium.CONCLUSIONSWe concluded that altered glycolytic phenotype of the myometrium with ectopic endometrium in women with adenomyosis may contribute the development of adenomyosis.

2024-12-01·Molecular Biology Reports

Protein kinase C iota promotes glycolysis via PI3K/AKT/mTOR signalling in high grade serous ovarian cancer

Article

作者: Roy, Adhiraj ; Mandal, Supratim ; Tyagi, Komal

BACKGROUNDEpithelial ovarian cancer, especially high grade serous ovarian cancer (HGSOC) is by far, the most lethal gynecological malignancy with poor prognosis and high relapse rate. Despite of availability of several therapeutic interventions including poly-ADP ribose polymerase (PARP) inhibitors, HGSOC remains unmanageable and identification of early detection biomarkers and therapeutic targets for this lethal malady is highly warranted. Aberrant expression of protein kinase C iota (PKCί) is implicated in many cellular and physiological functions involved in tumorigenesis including cell proliferation and cell cycle deregulation.METHODS AND RESULTSTwo high grade serous ovarian cancer cells SKOV3 and COV362 were employed in this study. PKCί was genetically knocked down or pharmacologically inhibited and several functional and biochemical assays were performed. We report that PKCί is overexpressed in HGSOC cells and patient tissue samples with a significant prognostic value. Pharmacological inhibition of PKCί by Na-aurothiomalate or its shRNA-mediated genetic knockdown suppressed HGSOC cell proliferation, EMT and induced apoptosis. Moreover, PKCί positively regulated GLUT1 and several other glycolytic genes including HK1, HK2, PGK1, ENO1 and LDHA to promote elevated glucose uptake and glycolysis in HGSOC cells. Mechanistically, PKCί drove glycolysis via PI3K/AKT/mTOR signalling. Na-aurothiomalate and highly selective, dual PI3K/mTOR inhibitor dactolisib could serve as novel anti-glycolytic drugs in HGSOC.CONCLUSIONTaken together, our results indicate PKCί/PI3K/AKT/mTOR signalling cascade could be a novel therapeutic target in a lethal pathology like HGSOC.

2024-12-01·Phytomedicine

Multi-omics analysis provides new insights into mechanism of didymin on non-alcoholic fatty liver disease in rats

Article

作者: Lin, Xing ; Huang, Quanfang ; Huang, Renbin ; Mo, Rou ; Fang, Bin

BACKGROUNDNon-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases accompanied by lipid and glucose metabolism disorder. Didymin has been reported to have various hepatoprotective effects, however, its potential effects and mechanisms on NAFLD remain unclear from the perspective of the whole.PURPOSETo investigate the underlying mechanism of didymin against NAFLD using multi-omics technologies.METHODSRats were fed with a high-fat diet (HFD) for 8 weeks to induce NAFLD, followed by didymin treatment for 8 weeks. Next, biochemical analysis and histopathological examinations were performed to evaluate the effects of didymin. The key regulating pathways were predicted using transcriptomics, metabolomics and proteomics, and the target pathways were then verified by detecting the key genes/proteins using various experiments.RESULTSDidymin markedly mitigated liver injury and excessive lipid droplet accretion. An integrative multi-omics analysis suggested that the PPAR signaling cascade and insulin signaling pathway might serve as pivotal mechanisms underlying the modulation of lipid and glucose homeostasis by didymin. Further dissection identified five pivotal genes (PPARα, PPARβ, FABP4, ANGPTL4, and PLIN2) and four genes (HK1, HK3, GCK, and PTPN1) as potential hubs within these pathways. Subsequent validation experiments, including qPCR and Western blot, demonstrated upregulated expression of PPARα and PPARβ, indicating the activation of the PPAR pathway by didymin. Concurrently, didymin appeared to modulate the insulin signaling pathway, as evidenced by the upregulated expression of HK1 and downregulated expression of PTPN1. Notably, the manipulation of PPARα, PPARβ, and PTPN1 expression in LO2 cells through silence or overexpression confirmed that didymin significantly reduced lipid accumulation, with its molecular targets likely being the PPAR and insulin pathways.CONCLUSIONSOur findings demonstrate that didymin has a protective effect on NAFLD, and its underlying mechanism may be associated with the regulation of the PPAR and insulin signaling pathways.

项与 HK1 相关的新闻（医药）

2024-08-13

·今日头条

新预后生物标记物！中山大学发文：鼻咽癌治疗的潜在靶点

【导读】近70%的鼻咽癌(NPC)治疗失败是由于远处转移，但其机制尚不清楚。RNA 5-甲基胞嘧啶(rna5 -methylcytosine, m5C)是一种新兴的调控基因表达的修饰方式，在肿瘤进展中发挥重要作用。然而，关于RNA m5C修饰在鼻咽癌转移中的潜在作用的信息很少。 8月8日，中山大学研究团队在期刊《Cell Death&Disease》上发表了研究论文，题为“ALYREF promotes the metastasis of nasopharyngeal carcinoma by increasing the stability of NOTCH1 mRNA”，在这项研究中，研究人员发现m5C阅读器的Aly/REF输出因子(ALYREF)在鼻咽癌中显著上调，其高表达与转移和不良预后相关。体外和体内研究发现，ALYREF过表达促进鼻咽癌细胞的肿瘤转移。机制上，m5c修饰的NOTCH1 mRNA被确定为ALYREF的靶点。另外，研究人员发现ALYREF以m5C修饰依赖的方式通过增强NOTCH1的RNA稳定性来上调其表达，从而促进NOTCH信号通路的激活，促进鼻咽癌的转移。总之，本研究数据揭示了ALYREF在鼻咽癌转移中的关键作用，并为鼻咽癌提供了一个潜在的治疗靶点。 https://www.nature.com/articles/s41419-024-06959-1 背景知识 01 鼻咽癌(NPC)在中国南部、东南亚和北非尤其流行，具有较高的侵袭和转移率。随着鼻咽癌治疗技术的进步，5年局部控制率已达95%。然而，20 ~ 30%的患者在根治性放化疗后仍会发生远处转移。尽管近期有进展，但一旦发生远处转移，预后仍然较差，中位无进展生存期为9.6 ~ 21.4个月。然而，鼻咽癌的转移机制仍不清楚，了解潜在的分子通路对于改善远处转移的控制具有重要意义。近年来，表观遗传修饰被证实在多种癌症的发生发展中发挥重要作用。5-甲基胞嘧啶(5-Methylcytosine, m5C)于20世纪70年代首次被报道，是真核生物mRNA中常见的一种转录后修饰，在mRNA稳定性、翻译效率和核输出等生物学过程中发挥重要作用。一系列调控因子已被证实参与RNA的m5C修饰，包括m5C甲基转移酶(NSUN1-7、DNMT1-2和DNMT3A-B)和去甲基化酶(TET2)。其中，NSUN2和NSUN6是催化哺乳动物mRNA m5C修饰的两种主要甲基转移酶，通过招募解读蛋白如y盒结合蛋白1 (YBX1)和Aly/REF输出因子(ALYREF)发挥其作用。此外，研究人员发现YBX1与AURKA mRNA结合以提高其在鼻咽癌细胞中的蛋白水平。先前的研究表明，ALYREF在促进m5c修饰的mRNA输出方面具有潜在的功能，并且它可能作为肿瘤生长和转移的正调节因子在癌细胞系中发挥作用。然而，ALYREF在NPC中的具体作用尚不清楚。进化保守的Notch通路在决定肿瘤细胞命运中发挥重要作用。在NOTCH受体家族的4个成员中，NOTCH1因其在肿瘤中的高突变率而被广泛研究。NOTCH1在细胞凋亡、转移、分化和增殖等重要过程中发挥重要作用。在鼻咽癌中，研究人员提出过表达NOTCH1可增强细胞的侵袭和迁移，但其潜在机制尚不清楚。最近的研究表明，Notch信号通路的激活与mettl3介导的m6A (n6 -甲基腺苷)mRNA修饰有关。然而，其他RNA修饰在Notch信号通路中的作用尚不清楚。 ALYREF促进鼻咽癌转移 02 为了探索ALYREF在鼻咽癌中的功能，研究人员使用siRNA敲低了SUNE1和SUNE2细胞中的ALYREF，之后研究人员进行了RNA测序分析。GSEA结果表明，敲低ALYREF可抑制肿瘤转移相关基因的表达。为了证实这些结果，研究人员在SUNE1和SUNE2细胞中敲低了ALYREF，以及在HK1和hon1细胞中过表达了ALYREF。迁移实验结果显示，敲低ALYREF可显著抑制SUNE1和SUNE2细胞的侵袭和迁移能力。相反，在HK1和hon1细胞中过表达ALYREF可增加其侵袭和迁移能力。另外，研究人员通过CCK-8实验检测ALYREF敲低和过表达对鼻咽癌细胞增殖的影响。数据显示，与相应的对照细胞相比，ALYREF敲低和过表达细胞的细胞活力没有显著改变，表明ALYREF促进鼻咽癌转移不是由于对细胞增殖的影响。除此之外，研究人员利用裸鼠肺转移模型来研究ALYREF在体内的功能。研究人员观察到，与载体对照组相比，ALYREF过表达组的荧光素酶信号更强，转移性肺结节更多，表明ALYREF过表达促进了HONE1细胞的肺转移。综上所述，这些结果揭示了ALYREF在促进鼻咽癌转移中的关键作用。 ALYREF促进鼻咽癌细胞的侵袭和转移 ALYREF通过激活NOTCH1信号通路发挥其致癌作用 03 为了研究ALYREF促进鼻咽癌转移的分子机制，研究人员对RNA-Seq数据进行了GSEA分析，结果显示ALYREF与Notch信号通路呈正相关。由于NOTCH1先前被发现可以促进鼻咽癌的转移，研究人员假设ALYREF可能通过激活Notch信号通路发挥其作用。然后，研究人员在ALYREF过表达的HONE1细胞和载体对照细胞中进行了Flag-RIP检测。研究人员发现，在hon1细胞中，ALYREF的过表达增加了NOTCH1的蛋白和mRNA水平。相反，敲低ALYREF可抑制SUNE1细胞中NOTCH1蛋白和mRNA的表达。此外，qRT-PCR和蛋白质免疫印迹实验结果显示，ALYREF敲低后，Notch信号通路的下游靶基因HES1和HEY1在SUNE1细胞中被显著抑制。研究人员通过组织学染色验证了转移性肺异种移植的存在，并证实了在ALYREF过表达的荷瘤小鼠中，与对照条件相比，NOTCH1蛋白水平升高。为了确定NOTCH1抑制是否可以逆转ALYREF的表型，研究人员用50 mg/L的新型r-分泌酶抑制剂LY3039478来阻断NOTCH1信号通路。LY3039478处理后，过表达ALYREF的HONE1细胞的侵袭和迁移能力明显减弱。综上所述，这些结果表明，ALYREF通过激活Notch信号通路促进鼻咽癌转移。研究小结 04 综上所述，本研究结果确定了ALYREF是鼻咽癌中一种新的致癌基因。研究发现，ALYREF的上调与鼻咽癌患者的转移和不良预后有关。在鼻咽癌细胞中，ALYREF通过m5c依赖的方式激活NOTCH1来促进转移。重要的是，本研究结果强调了ALYREF作为使用LY3039478治疗鼻咽癌的潜在生物标志物和治疗靶点。【参考资料】 https://www.nature.com/articles/s41419-024-06959-1 【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·直播/活动 🕓 线上｜08月15日 19:00-20:30 ▶ “脑类器官前沿：揭秘遗传机制，重塑神经退行性疾病研究未来”线上研讨会欢迎您的参与！ 🕓 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！ 🕓 上海｜11月15日-16日 ▶ 2024第一届中国类器官转化医学大会欢迎您的参与！点击对应文字查看详情

信使RNA临床结果寡核苷酸临床研究临床失败

2024-08-06

·Business Wire

BIOMAKERS and TOPAZIUM Unveil Groundbreaking AI Collaboration to Enhance NSCLC Immunotherapy

SAN FRANCISCO--( BUSINESS WIRE )-- BIOMAKERS , a Precision Medicine & Biotech Company that supports data-driven Drug Development globally, and TOPAZIUM , an AI-driven healthtech company specializing in drug discovery and human wellbeing, have announced the results of their innovative collaborative project. This partnership showcases the power of AI systems in leveraging real-world DNA sequencing data to identify novel targets aimed at improving the efficacy of immunotherapy for non-small cell lung cancer (NSCLC) treatment. The findings were presented at the prestigious 2024 American Society of Clinical Oncology (ASCO) meeting in Chicago. The study used Whole Exome Sequencing (WES) data from biopsies of squamous and adenocarcinoma NSCLC processed through BIOMAKERS ' advanced DNA sequencing platforms. The data was then analyzed using GFPrint™, a proprietary algorithm developed by TOPAZIUM , that generates virtual representations of tumor exomes in a latent space defined by the genetic features of the samples. “The advent of drugs targeting the PD-1/PD-L1 axis has revolutionized NSCLC treatment. Although promising, individual responses to these therapies can vary, and we believe this ongoing project will help to better understand mechanisms involved in PD1/PD-L1 expression, optimize treatment protocols, and identify which patients are most likely to benefit from these therapies. In this study, DNA sequencing and GFPrint™ were employed to identify mutations in genes linked to PD-L1 expression in NSCLC adenocarcinoma tumor samples,” said Dr. Rubén Salanova, Chief Medical Officer & Co-Founder of BIOMAKERS . “Using this strategy, we have identified a subpopulation of adenocarcinoma patients with increased PD-L1 expression levels, enriched in non-silent mutations of 10 genes of interest, mostly included in the HIF-1α signaling pathway. Notably, 6 of these mutated genes (PIK3R1, HK1, NOS2, NRAS, BRAF, ITGA1) were uniquely found in adenocarcinomas” said Juan Manuel Domínguez, Head of Preclinical & Biostatistics at TOPAZIUM . “All these newly identified genes deserve further studies to validate them as potential targets for pharmacological intervention concomitant with PD-1/PD-L1 blockade, and as potential biomarkers for patient selection to improve the efficiency of immunotherapy in NSCLC treatment,” added Andrea Mendoza, Head of R&D at BIOMAKERS . For more details, the abstract can be accessed at: https://ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.e13600 For more information about GFPrint™, visit: https://www.biorxiv.org/content/10.1101/2024.03.08.584090v4 About BIOMAKERS: BIOMAKERS is an Oncology Precision Medicine Company with a Comprehensive Genomic Platform and reach throughout LATAM, delivering care-changing solutions. In addition to its strong focus on physician support and patient care, their Life Science division partners with biopharma companies to advance R&D programs by providing support for Drug Discovery and Drug Development. This innovative work is enabled by direct partnerships with renowned Health Institutions across 17 different countries. contacto@biomakers.net About TOPAZIUM: TOPAZIUM is committed to supporting medical research with artificial intelligence (AI) through state-of-the-art analytical tools. They have developed a comprehensive AI engine that utilizes multiple medical data types to assist in identifying new disease patterns and the most promising therapeutic approaches, striving to achieve one of the most challenging global goals: health for all. info@topazium.com

免疫疗法ASCO会议临床研究

2024-04-20

·今日头条

诱导铁死亡抑制肿瘤生长！中南大学：揭示癌症治疗新选择

本文为转化医学网原创，转载请注明出处作者：Jerry 导读：以顺铂(DDP)为基础的放化疗是鼻咽癌的标准治疗方法之一。然而，DDP对患者的敏感性和副作用仍然是鼻咽癌治疗的主要障碍。 4月18日，中南大学研究人员在期刊《Cell Death&Disease》上发表了题为“Cancer-associated fibroblasts secrete FGF5 to inhibit ferroptosis to decrease cisplatin sensitivity in nasopharyngeal carcinoma through binding to FGFR2”的研究论文。本研究中，研究人员旨在研究癌症相关成纤维细胞(CAFs)通过调节铁死亡来调节DDP敏感性。研究人员证明了DDP在鼻咽癌细胞中诱导铁死亡，并通过在异种移植模型中诱导铁死亡抑制肿瘤生长。 https://www.nature.com/articles/s41419-024-06671-0 研究背景 01 鼻咽癌是一种常见于东南亚和中国南方的头颈部肿瘤。放化疗，特别是以顺铂(DDP)为基础的同步放化疗是鼻咽癌的标准治疗方法之一。不幸的是，化疗耐药仍然是鼻咽癌治疗的主要障碍。此外，以DDP为基础的化疗对患者有副作用，如呕吐、恶心、肾脏和听觉功能障碍。因此，确定组合靶点，从而降低DDP的有效剂量，提高DDP在鼻咽癌中的敏感性是很有意义的。铁死亡是一种以铁依赖性脂质过氧化为特征的新型细胞程序性死亡方式。越来越多的证据支持顺铂在不同的肿瘤中诱导铁死亡。最近的研究表明，顺铂可诱导鼻咽癌细胞发生铁死亡，但具体机制有待进一步探索。Keap1/Nrf2/HO-1通路在抑制铁死亡中发挥重要作用，并与顺铂耐药相关。然而，Keap1/Nrf2/HO-1信号通路介导的铁死亡是否参与鼻咽癌对顺铂的敏感性的调节仍未被研究。研究进展 02 为了研究DDP对鼻咽癌细胞铁死亡的影响，研究人员分别用不同剂量的DDP或DDP联合铁死亡抑制剂Ferrostatin-1处理2个人鼻咽癌细胞系NPC/HK1和C666-1细胞48 h。细胞计数试剂盒-8 (CCK-8)检测显示，DDP以剂量依赖性方式降低鼻咽癌细胞的存活率，而这种抑制作用被铁死亡抑制剂Ferrostatin-1所消除。SLC7A11/GPX4信号通路参与铁死亡的调控。蛋白质印迹和qRT-PCR结果显示，DDP呈剂量依赖性下调鼻鼻癌细胞中GPX4和SLC7A11蛋白和mRNA水平，而Ferrostatin-1则导致GPX4和SLC7A11的反弹。DDP增加了鼻咽癌细胞的丙二醛(MDA)、Fe2+水平和脂质过氧化，但降低了总谷胱甘肽(GSH)水平。这些影响也被Ferrostatin-1减弱。这些结果表明，DDP可诱导鼻咽癌细胞铁死亡。接下来，研究人员试图研究DDP在体内对肿瘤生长的作用。如图1A-C所示，DDP以剂量依赖性方式抑制NPC/HK1或C666-1细胞来源的异种移植瘤的生长，在DDP治疗后，肿瘤体积和重量下降，而这种作用被Ferrostatin-1部分消除。先前的研究表明，4-HNE被认为是脂质过氧化的指标。免疫组化(IHC)分析进一步表明，DDP在异种移植瘤中剂量依赖性上调4-HNE水平，而Ferrostatin-1在体内消除DDP诱导的4-HNE表达。与这些结果一致，DDP介导的异种移植瘤GPX4和SLC7A11表达的减少也被Ferrostatin-1所拯救。DDP增加了异种移植瘤中的MDA和Fe2+水平，但降低了GSH水平。这些作用也被Ferrostatin-1所消除。总的来说，这些数据表明，DDP通过诱导体内铁死亡来抑制肿瘤生长。图1：顺铂在体内通过诱导铁死亡抑制肿瘤生长研究结论 03 综上所述，研究人员证明了CAFs分泌FGF5通过调节FGFR2/Nrf2信号通路来抑制鼻咽癌的铁死亡和DDP敏感性，靶向FGF5/FGFR2/Nrf2信号通路可能增强鼻咽癌治疗的疗效和有效剂量。参考资料： https://www.nature.com/articles/s41419-024-06671-0 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

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