更新于：2024-09-19

HCFC1

更新于：2024-09-19

基本信息

别名

C1 factor、CFF、HCF

+ [23]

简介

Transcriptional coregulator (By similarity). Involved in control of the cell cycle (PubMed:10629049, PubMed:10779346, PubMed:15190068, PubMed:16624878, PubMed:23629655). Also antagonizes transactivation by ZBTB17 and GABP2; represses ZBTB17 activation of the p15(INK4b) promoter and inhibits its ability to recruit p300 (PubMed:10675337, PubMed:12244100). Coactivator for EGR2 and GABP2 (PubMed:12244100, PubMed:14532282). Tethers the chromatin modifying Set1/Ash2 histone H3 'Lys-4' methyltransferase (H3K4me) and Sin3 histone deacetylase (HDAC) complexes (involved in the activation and repression of transcription, respectively) together (PubMed:12670868). Component of a THAP1/THAP3-HCFC1-OGT complex that is required for the regulation of the transcriptional activity of RRM1 (PubMed:20200153). As part of the NSL complex it may be involved in acetylation of nucleosomal histone H4 on several lysine residues (PubMed:20018852). Recruits KMT2E/MLL5 to E2F1 responsive promoters promoting transcriptional activation and thereby facilitates G1 to S phase transition (PubMed:23629655). Modulates expression of homeobox protein PDX1, perhaps acting in concert with transcription factor E2F1, thereby regulating pancreatic beta-cell growth and glucose-stimulated insulin secretion (By similarity). May negatively modulate transcriptional activity of FOXO3 (By similarity). (Microbial infection) In case of human herpes simplex virus (HSV) infection, HCFC1 forms a multiprotein-DNA complex with the viral transactivator protein VP16 and POU2F1 thereby enabling the transcription of the viral immediate early genes.

关联

100 项与 HCFC1 相关的临床结果

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100 项与 HCFC1 相关的转化医学

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0 项与 HCFC1 相关的专利（医药）

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699

项与 HCFC1 相关的文献（医药）

2024-10-01·Experimental Eye Research

Hyperreflective choroidal foci in diabetic eyes with and without macular edema: Novel insights on diabetic choroidopathy

Article

作者: Midena, Giulia ; Frizziero, Luisa ; Midena, Edoardo ; Danieli, Luca ; Pilotto, Elisabetta

Histopathologic studies of diabetic choroid suggest that diabetic choroidopathy is a key aspect secondary to diabetes. Recently, hyperreflective choroidal foci (HCF) have been introduced as novel optical coherence tomography (OCT) parameter. The aim of this study was to identify and quantify HCF in diabetic subjects with retinopathy, with or without diabetic macular edema (DME). Eighty-five diabetic subjects with different degrees of DR were enrolled: 37 without DME and 48 with DME. All subjects underwent full ophthalmologic examination including spectral domain optical coherence tomography (OCT). OCT images were analyzed to quantify and localize HCF. Each image was analyzed by two independent, masked examiners. OCT images showed that all subjects (100%) had HCF in the different layers of the choroid. The number of HCF was significantly higher in diabetics with DME versus those without DME (p<.0001). HCF showed variable size, shape and location inside the choroid. They were mainly located in choriocapillaris and Sattler's layer, on the edges of blood vessels. The intraobserver and interobserver agreement was almost perfect (ICC >0.9). This study suggests that hyperreflective foci in the choroid of subjects with DR may be accurately identified with structural OCT. Their number significantly increases with the progression of DME. These HCF may represent, as in the retina, a sign of infiltration of inflammatory cells (mainly migrating microglia) into the choroid, according to the hypothesis raised by Jerry Lutty. HCF may confirm in vivo the histopathologic findings suggesting that diabetic choroidopathy may be primarily a neuroinflammatory disorder.

2024-07-01·Annals of Vascular Surgery

The Influence of Diabetes on Thrombotic Profiles and Outcomes on Patients with Peripheral Artery Disease

Article

作者: Hagos, Fanah ; Zacharias, Nikolaos ; Yeng, Tina ; Hansraj, Natasha ; Patel, Shiv ; Dua, Anahita ; Lee, Ivy ; Rodriguez, Adriana ; Ghandour, Samir ; Hall, Ryan ; Suarez, Sasha ; Young, Elizabeth ; Agrawal, Aniket

BACKGROUNDElevated glycated hemoglobin (HbA1c) is associated with vascular complications, including arterial thrombosis post-revascularization. However, the objective relationship between levels of HbA1c and coagulation profiles has not been established. This study aims to determine the association between specific coagulation parameters and variations in HbA1c in patients undergoing lower extremity revascularization.METHODSPatients with Peripheral Artery Disease (PAD) undergoing revascularization were prospectively evaluated between December 2020 and July 2023. Patients were categorized based on their HbA1c levels, and their thromboelastography with platelet mapping (TEG-PM) results were compared at baseline, post-operatively day 1, 1 month, 3 months and 6 months. The parameters included Maximum Amplitude (MA) with both adenosine diphosphate (ADP) and arachidonic acid (AA), as well as ADP and AA percent aggregation indicating clot strength. The study further assessed the differences in these parameters between groups with varying HbA1c levels through the use of unpaired Student t test for pairwise analysis and Mann-Whitney U tests.RESULTSAmong 830 samples, those with HbA1c above 6.5 demonstrated a significant increase in ADP MA (52.6 vs. 43.5, p<0.01), AA MA (36.6 vs. 29.65, p<0.05), clot strength without platelets ActF MA (activator F: 13.10 vs. 10.80, p<0.01), and heparin neutralized uninhibited clot strength from thrombin activation HKH MA (heparinized kaolin with heparinase: 61.10 vs. 57.70, p<0.01) values at baseline. Post-operatively, patients with HbA1c levels greater than 6.5 had higher median functional fibrinogen CFF FLEV levels (citrated functional fibrinogen: 40.95 vs. 371.35, p<0.05) and higher formation of fibrin in response to stimulation of thrombin by tissue factor CFF MA values (22.90 vs. 20.40, p<0.05) when measured within 36 hours of intervention, with these trends staying consistent during the 1-month follow-up visit. The trend analysis revealed a progressive increase in ADP MA values with rising HbA1c values, indicating a unit increase in the thrombotic risk relationship. Regression analysis showed a positive relationship between HbA1c and both ADP MA (a 2.261 unit increase for each unit increase in HbA1c) and AA MA. The R-square values indicate that HbA1c only explains a small percentage of the variance in these parameters, suggesting the confounding influence of other factors contributing to thrombosis.CONCLUSIONElevated HbA1c levels appear to be associated with pro-thrombotic tendencies in clot dynamics as measured by TEG-PM, particularly in parameters related to platelet function. HbA1c explains a limited proportion of the variability in these measures, emphasizing the need for a comprehensive approach to evaluating clotting profiles in patients. This study lays the groundwork for further investigation into personalized antithrombotic strategies for patients with varying HbA1c levels.

2024-05-28·Proceedings of the National Academy of Sciences

Dissecting OGT’s TPR domain to identify determinants of cellular function

Article

作者: Janetzko, John ; Gibbs, Bettine E ; Potter, Sarah C ; Fei, George Q ; Haggarty, Stephen J ; Paulo, Joao A ; Joiner, Cassandra M ; Levine, Zebulon G ; Hammel, Forrest A ; Walker, Suzanne

O-GlcNAc transferase (OGT) is an essential mammalian enzyme that glycosylates myriad intracellular proteins and cleaves the transcriptional coregulator Host Cell Factor 1 to regulate cell cycle processes. Via these catalytic activities as well as noncatalytic protein–protein interactions, OGT maintains cell homeostasis. OGT’s tetratricopeptide repeat (TPR) domain is important in substrate recognition, but there is little information on how changing the TPR domain impacts its cellular functions. Here, we investigate how altering OGT’s TPR domain impacts cell growth after the endogenous enzyme is deleted. We find that disrupting the TPR residues required for OGT dimerization leads to faster cell growth, whereas truncating the TPR domain slows cell growth. We also find that OGT requires eight of its 13 TPRs to sustain cell viability. OGT-8, like the nonviable shorter OGT variants, is mislocalized and has reduced Ser/Thr glycosylation activity; moreover, its interactions with most of wild-type OGT’s binding partners are broadly attenuated. Therefore, although OGT’s five N-terminal TPRs are not essential for cell viability, they are required for proper subcellular localization and for mediating many of OGT’s protein–protein interactions. Because the viable OGT truncation variant we have identified preserves OGT’s essential functions, it may facilitate their identification.

项与 HCFC1 相关的新闻（医药）

2022-06-12

·医药魔方

Sionna：开发新型CFTR靶向小分子药物，向百亿美元“重磅药物”发起挑战

创新是生物医药领域发展的命脉。如何将一项创新技术、一个创新靶点转换为一类创新疗法是科学界、产业界、投资界共同探讨的命题。根据医药魔方PharmaInvest数据库，过去几年，每年都有数百家致力于各类创新疗法开发的公司在资本的支持下开启新药研发征程，且这种创新驱动的新药研发热潮在未来几年，甚至几十年有明显的延续之势。医药魔方《创星》栏目，根据PharmaInvest独有的评分系统，筛选最值得关注的一批“创新之星”，从科学基础、技术优势、研发潜力等多个维度，洞悉新锐公司获资本青睐的原因，同时，也将总结同领域的全球竞争概况，辅助国内创新药同行的决策判断。2019年一部名叫《五尺天涯》的电影在美国上映，讲述了一位患有罕见病的女孩在医院治疗过程中，与患有同样病症的男孩相识相知，共同与疾病作斗争的故事。电影中男女主角所患有的疾病即是一种称为“囊性纤维化（cystic fibrosis，CF）”的罕见病。这是一种会影响患者呼吸系统和消化系统的致命性的罕见遗传病，是由于囊性纤维化跨膜传导调节因子（CFTR）的基因突变所导致。当CFTR基因突变时，会导致CFTR蛋白功能失调，机体内氯化物在细胞内外的转移会受到干扰，从而导致患者各个器官形成稠厚的黏液，影响器官的正常功能。根据囊性纤维化基金会（CFF）的统计数据，目前全球范围内约有7万例CF患者，其中美国的患者人数就超过3万例。尽管引起CF的突变种类非常多，但在过去的几十年中，CF领域的药物研发还是取得了很大的进展，这其中Vertex医药公司占据了非常重要的地位。早在十年前，Vertex就为CF患者带来了第一个针对囊性纤维化相关基因突变的药物。2012年，依伐卡托（ivacaftor）获得美国FDA批准，成为第一个从根本上治疗CF的药物，主要针对G551D突变的CF患者；2015年，Vertex的另一款CF组合药物Orkambi（lumacaftor/ ivacaftor）获批，可针对双拷贝F508del突变的CF患者；2018年，Vertex开发的第3种对因治疗CF疾病的组合药物Symdeko（tezacaftor/ivacaftor）获批，为携带残留功能突变的CF患者提供了更多选择；2019年，CF患者迎来了里程碑式的一刻，Vertex开发的创新疗法Trikafta（elexacaftor/ tezacaftor/ ivacaftor）获FDA批准上市，这是一款具有治疗90% CF患者潜力的突破性疗法，可以将CF从进行性疾病转变为更易于控制的慢性疾病，并被《Science》杂志评为2019年度十大科学突破。Trikafta自上市以来，累计销售额已达到近100亿美元，仅2021年的销售额就达到近60亿美元，可见其市场空间还是非常大的。然而，尽管这些药物已经为多数CF患者提供了对因治疗的药物选择，但目前的疗法尚无法完全恢复患者CFTR蛋白的正常功能，对于这一未被满足的需求，新兴的治疗思路与技术也层出不穷。2022年4月19日，一家专注于CFTR靶向新型小分子药物开发的公司Sionna Therapeutics宣布完成了1.11亿美元的B轮融资，该轮融资是由知名风投机构奥博资本领投，RA Capital、Atlas Venture等知名机构以及囊性纤维化基金会（CFF）跟投。其中值得一提的是，在针对CF的药物开发过程中，CFF在其中扮演了非常重要的角色。最初在1989年，CFTR基因也是在CFF的资助下被发现并报道，后来CFF又支持了多款针对CF药物的开发与上市，这次CFF的跟投也足以看出基金会对该公司的重视。来源：SionnaSionna公司成立于2019年，公司着眼于CF药物开发的终极目标是使患者CFTR功能完全正常化。由于大多数CF患者都携带F508del突变，该突变位于CFTR蛋白的NBD1结构域内，会严重破坏CFTR的稳定性和功能，并阻止其正常运输到细胞表面。目前的疗法并未完全纠正F508del-CFTR和其他类似突变的不稳定性。因此，针对这一目前仍遥不可及的目标，Sionna公司积极布局了其专有的技术与产品管线，他们采取的策略是针对NBD1结构域来开发CF小分子药物。CFTR蛋白的NBD1结构域在CFTR向细胞表面的折叠和运输中起到关键作用，NBD1也一直被认为是一个“无法成药”的靶点。Sionna公司正在开发的小分子疗法，旨在通过稳定NBD1结构域来恢复CFTR的功能，以实现CFTR功能的完全正常化，这是现有的CF调节剂缺乏的关键机制，也是Sionna公司当前最具亮点的一项技术创新。Sionna公司管线（来源：Sionna）Sionna目前正在开发针对NBD1的CFTR调节剂以及其他的互补调节剂，公司计划在未来12月内为其第一个NBD1靶向项目SION-638和靶向ICL4的项目SION-109提交IND申请。临床预测性CF模型已证明Sionna的NBD1靶向小分子与其他互补调节剂结合有可能使F508del-CFTR蛋白的功能和稳定性正常化。此轮融资也将帮助Sionna将其核心管线进一步推向临床。Sionna首席医疗官Charlotte McKee博士（来源：Sionna）Sionna的领导团队在CF药物开发方面有着非常丰富的经验，公司的首席医疗官Charlotte McKee博士曾在Vertex公司担任CF药物临床开发副总裁，参与了Vertex多个CF重磅产品的开发，拥有20多年的临床试验和药物开发经验，因此无疑是Sionna公司的中坚力量。资深的领导团队结合突破性的治疗技术，将为Sionna公司的产品开发奠定坚实的基础，该公司未来的产品开发进展也非常值得期待。已上市针对CF的CFTR靶向药物（来源：医药魔方NextPharma）开发针对CF的CFTR靶向药物的主要玩家（来源：医药魔方NextPharma）根据医药魔方NextPharma数据库，目前共有7款针对CF的CFTR靶向药物获批上市，均为Vertex公司开发。除此之外，针对CF的在研CFTR靶向药物大都还处在临床早期阶段。目前国内仅有3家企业布局了CF这一疾病领域，其中仑胜医药与优锐医药的相关产品均为许可引进，目前分别处于I期与Ⅱ期临床阶段，另一家公司为朗煜医药，其原研的针对CF的药品管线已授权给Path BioAnalytics公司，目前处在Ⅱ期临床阶段。当前国内布局CF领域的企业为数不多的原因其实也与国内CF患者的数量密切相关，由于CF的发病率具有种族差异，在白种人中发病率相对较高，而在亚洲人中发病率很低，因此CF在国内就成为更为罕见的疾病。对于这部分罕见病患者来说，也需要更多国产新药的开发。除小分子药物之外，目前针对CF疾病也出现了很多其他的前沿技术，例如通过递送编码CFTR的mRNA或利用编码核酸酶的mRNA（如CRISPR-Cas9和gRNA）的基因编辑疗法来治疗CF等等，也希望这些新兴技术能够为国内的药物开发提供更多新的思路。《创星》系列：Septerna：GPCR药物研发颠覆者，诺奖得主的下一程Ceptur Therapeutics：U1衔接子技术新锐，主攻新一代RNA靶向疗法Kelonia Therapeutics：新一代LVV技术加持，让体内CAR-T走进现实参考资料：[1] https://www.sionnatx.com[2]https://www.prnewswire.com/news-releases/sionna-therapeutics-launches-with-111-million-series-b-financing-to-advance-pipeline-of-novel-small-molecules-with-the-potential-to-fully-restore-cftr-function-in-cystic-fibrosis-301527741.html[3] https://www.cff.org[4] Zhang T, Tian X, Xu KF. Cystic fibrosis: a rare disease emerging in China. Sci China Life Sci. 2020 Jul;63(7):1082-1084. doi: 10.1007/s11427-020-1620-x. Epub 2020 Feb 20. PMID: 32103413.[5]https://vis-sciencemag-org.libproxy1.nus.edu.sg/breakthrough2019/finalists/#Darkness-made-visible大礼包100个新靶点（后台回复靶点，获取相关Excel）2022 AACR资料包（后台回复AACR，获取资料合集）2022 ASCO资料包（后台回复ASCO，获取值得收藏的20份PPT）

小分子药物创新药免疫疗法信使RNA基因疗法