更新于：2024-09-19

HIF-1α

更新于：2024-09-19

基本信息

别名

缺氧诱导因子-1α亚单位、ARNT-interacting protein、Basic-helix-loop-helix-PAS protein MOP1

+ [15]

简介

Functions as a master transcriptional regulator of the adaptive response to hypoxia (PubMed:11292861, PubMed:11566883, PubMed:15465032, PubMed:16973622, PubMed:17610843, PubMed:18658046, PubMed:20624928, PubMed:22009797, PubMed:9887100, PubMed:30125331). Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor, HILPDA, and other genes whose protein products increase oxygen delivery or facilitate metabolic adaptation to hypoxia (PubMed:11292861, PubMed:11566883, PubMed:15465032, PubMed:16973622, PubMed:17610843, PubMed:20624928, PubMed:22009797, PubMed:9887100, PubMed:30125331). Plays an essential role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease (PubMed:22009797). Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters (By similarity). Activation requires recruitment of transcriptional coactivators such as CREBBP and EP300 (PubMed:9887100, PubMed:16543236). Activity is enhanced by interaction with NCOA1 and/or NCOA2 (PubMed:10594042). Interaction with redox regulatory protein APEX1 seems to activate CTAD and potentiates activation by NCOA1 and CREBBP (PubMed:10202154, PubMed:10594042). Involved in the axonal distribution and transport of mitochondria in neurons during hypoxia (PubMed:19528298). (Microbial infection) Upon infection by human coronavirus SARS-CoV-2, is required for induction of glycolysis in monocytes and the consequent pro-inflammatory state (PubMed:32697943). In monocytes, induces expression of ACE2 and cytokines such as IL1B, TNF, IL6, and interferons (PubMed:32697943). Promotes human coronavirus SARS-CoV-2 replication and monocyte inflammatory response (PubMed:32697943).

关联

项与 HIF-1α 相关的药物

Trientine Hydrochloride

盐酸曲恩汀

靶点

Cu x HIF-1α

作用机制

Cu调节剂 [+1]

在研机构

Univar Solutions, Inc. [+8]

原研机构

Bausch Health Americas, Inc.

在研适应症

肝豆状核变性 [+4]

非在研适应症-

最高研发阶段批准上市

首次获批国家/地区

美国

首次获批日期1985-11-08

EP-0057

靶点

HIF-1α x TOP1

作用机制

HIF-1α抑制剂 [+1]

在研机构

National Cancer Institute [+1]

原研机构

Ellipses Pharma Ltd.

在研适应症

铂耐药性卵巢癌 [+3]

非在研适应症

胃癌

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

TLC-388 HCl

靶点

HIF-1α x TOP1

作用机制

HIF-1α抑制剂 [+1]

在研机构

原研机构

在研适应症

非在研适应症

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

项与 HIF-1α 相关的临床试验

NCT06191965 / Not yet recruiting临床2/3期

Double Blind, Randomized, Placebo-Controlled Study of MitoQ as Adjunctive Treatment for Patients With Early-phase Schizophrenia-spectrum Disorder and Mitochondrial Dysfunction

The goal of this double-blind, placebo-controlled randomized clinical trial is to test the effect of 12 weeks of orally administered MitoQ (mitoquinol mesylate) supplementation on cognition in 50 people with early phase schizophrenia-spectrum disorders (E-SSD) who have mitochondrial dysfunction (called high risk, or HR). Cognitive impairments in SSD can cause significant disability. Yet, there are no effective treatments for cognitive impairments in SSD. It has been shown that alterations in a certain type of brain cell (parvalbumin interneurons, or PVI) underlie cognitive deficits in SSD. These PVI, which fire at a fast rate, utilize high amounts of energy from the mitochondria and are highly vulnerable to oxidative stress. MitoQ is an antioxidant. Research has shown that, in mice, MitoQ can reduce oxidative stress in the mitochondria. The main question that this clinical trial aims to answer is:
• Does MitoQ supplementation, compared to placebo, improve cognition in HR patients?
Secondary questions that this clinical trial aims to answer are the following: Does MitoQ supplementation, compared to placebo:
Improve positive and negative symptoms of SSD in HR patients?
Improve functioning in HR patients?
Improve/normalize blood markers of mitochondrial dysfunction in HR patients?
The investigators will enroll 100 individuals with E-SSD. These enrolled participants will participate in an initial screening visit to determine if they qualify for the actual clinical trial. At the screening visit, the investigators will ask about psychiatric history to determine diagnosis; ask about medical history; do a physical exam; collect blood and urine samples; do a pregnancy test; and ask participants to bring in their current medications in their original packaging so it is known what they are taking.
After the screening visit, the investigators will invite 50 HR patients (identified with a blood test) to continue with the clinical trial. Participants who qualify for the clinical trial will be asked to:
Take a supplement (MitoQ or placebo) once per day for 12 weeks in addition to their usual medications.
Come in for a study visit every 4 weeks over the 16-week study period. At these study visits, the investigators will do a physical exam; ask about symptoms and side effects; take blood and urine samples; and ask questions about general health and well-being, quality of life, mental health, emotional health, and mood. At visits 1 (baseline) and 4 (12 weeks), participants will also take a cognitive assessment.

开始日期2024-06-01

申办/合作机构

McLean Hospital, Inc.

[+2]

NCT06351683 / Recruiting临床2期IIT

Mito-LUTS: A Pilot Study of the Effect of MitoQ on Lower Urinary Tract Symptoms in Older Women With Metabolic Syndrome

The goal of this clinical trial is to test the effect of a supplement called MitoQ (mitoquinol mesylate) on bladder symptoms such as urgency and frequency in women aged 50-75 years old who have the metabolic syndrome. The main questions it aims to answer are:
Is the study design feasible and acceptable to participants?
Do participants taking the study drug get any improvement to their bladder symptoms compared to participants taking a placebo (a look-alike substance that contains no drug)?
Participants will take 2 capsules of the study drug every morning for 4 months, answer many questions about their health including questions about their bladder health, perform physical and cognitive testing, give blood and urine samples, collect urine over 24 hour periods 3 times over the 4 months of the study, complete 3 day bladder diaries about how much they drink and void, undergo electrocardiograms, have their vitals and measurements (weight, height, waist circumference) taken, participate in 4 visits to the clinical research area and participate in many phone calls of varying length. Researchers will compare participants who were taking capsules containing MitoQ and participants taking capsules not containing MitoQ to see if MitoQ improves their bladder symptoms (urgency, frequency, nocturia, incontinence, etc.)

开始日期2024-04-03

申办/合作机构

University of Connecticut Health Center

[+1]

NCT06027554 / Not yet recruiting临床2期IIT

The Mito-Frail Trial: Effects of MitoQ on Vasodilation, Mobility and Cognitive Performance in Frail Older Adults

The goal of this clinical trial is to test the effects of MitoQ supplementation in older adults and frail older adults with physical dysfunction and/or cognitive dysfunction. The main question[s] it aims to answer are:
To compare vascular function, oxidative stress levels, and physical and cognitive function among older adults and frail older adults with physical and cognitive dysfunction
To determine whether MitoQ supplementation has the potential to improve vascular function in central and cerebral vessels
To determine whether MitoQ supplementation can enhance physical and cognitive capabilities.

开始日期2024-02-28

申办/合作机构

University of Connecticut Health Center

[+2]

100 项与 HIF-1α 相关的临床结果

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100 项与 HIF-1α 相关的转化医学

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0 项与 HIF-1α 相关的专利（医药）

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22,571

项与 HIF-1α 相关的文献（医药）

2106-07-05·Oncotarget

Regulation of HK2 expression through alterations in CpG methylation of the HK2 promoter during progression of hepatocellular carcinoma

Article

作者: Kim, Seung Up ; Lee, Jong Doo ; Lee, Hyun Gyu ; Son, Taekwon ; Jeong, Youngtae ; Lee, Jae Myun ; Dong, Seung Myung ; Park, Jeon Han ; Kim, Hyemi ; Park, Young Nyun

Hexokinase 2 (HK2) is a rate-determining enzyme in aerobic glycolysis, a process upregulated in tumor cells. HK2 expression is controlled by various transcription factors and epigenetic alterations and is heterogeneous in hepatocellular carcinomas (HCCs), though the cause of this heterogeneity is not known. DNA methylation in the HK2 promoter CpG island (HK2-CGI) and its surrounding regions (shore and shelf) has not previously been evaluated, but may provide clues about the regulation of HK2 expression. Here, we compared HK2 promoter methylation in HCCs and adjacent non-cancerous liver tissues using a HumanMethylation450 BeadChip array. We found that, while the HK2-CGI N-shore was hypomethylated, thereby enhancing HK2 expression, the HK2-CGI was itself hypermethylated in some HCCs. This hypermethylation suppressed HK2 expression by inhibiting interactions between HIF-1α and a hypoxia response element (HRE) located at -234/-230. HCCs that were HK2negative and had distinct promoter CGI methylation were denoted as having a HK2-CGI methylation phenotype (HK2-CIMP), which was associated with poor clinical outcome. These findings indicate that HK2-CGI N-shore hypomethylation and HK2-CGI hypermethylation affect HK2 expression by influencing the interaction between HIF 1α and HRE. HK2-CGI hypermethylation induces HK2-CIMP and could represent a prognostic biomarker for HCC.

2025-04-01·Neural Regeneration Research

Perfluoropentane-based oxygen-loaded nanodroplets reduce microglial activation through metabolic reprogramming

Article

作者: Li, Yingjia ; Ji, Yunxiang ; Xu, Chuanhui ; Wang, Yezhong ; Ye, Yongyi ; Luo, Wanxian ; Li, Linxi

JOURNAL/nrgr/04.03/01300535-202504000-00032/figure1/v/2024-07-06T104127Z/r/image-tiff Microglia, the primary immune cells within the brain, have gained recognition as a promising therapeutic target for managing neurodegenerative diseases within the central nervous system, including Parkinson’s disease. Nanoscale perfluorocarbon droplets have been reported to not only possess a high oxygen-carrying capacity, but also exhibit remarkable anti-inflammatory properties. However, the role of perfluoropentane in microglia-mediated central inflammatory reactions remains poorly understood. In this study, we developed perfluoropentane-based oxygen-loaded nanodroplets (PFP-OLNDs) and found that pretreatment with these droplets suppressed the lipopolysaccharide-induced activation of M1-type microglia in vitro and in vivo, and suppressed microglial activation in a mouse model of Parkinson’s disease. Microglial suppression led to a reduction in the inflammatory response, oxidative stress, and cell migration capacity in vitro. Consequently, the neurotoxic effects were mitigated, which alleviated neuronal degeneration. Additionally, ultrahigh-performance liquid chromatography–tandem mass spectrometry showed that the anti-inflammatory effects of PFP-OLNDs mainly resulted from the modulation of microglial metabolic reprogramming. We further showed that PFP-OLNDs regulated microglial metabolic reprogramming through the AKT-mTOR-HIF-1α pathway. Collectively, our findings suggest that the novel PFP-OLNDs constructed in this study alleviate microglia-mediated central inflammatory reactions through metabolic reprogramming.

2025-01-01·Combinatorial Chemistry & High Throughput Screening

Integrated Network Pharmacology and In-silico Approaches to Decipher the Pharmacological Mechanism of Dioscorea septemloba Thunb in Treating Gout and Its Complications

Article

作者: Dai, Jie ; Chen, Xuan ; Hu, Jian ; Liu, Wen-Bin ; Du, Ning

Background:Dioscorea septemloba Thunb. (DST) has demonstrated therapeutic potential in the treatment of gout and its associated complications. However, the underlying mechanisms of DST’s pharmacological activity remain unclear. This study aims to investigate the pharmacological substances and network regulatory mechanisms of DST in treating gout and its complications using network pharmacology.Methods:According to ultra-high performance liquid chromatography coupled with hybrid quadrupole-Orbitrap mass spectrometry (UPLC-Q-Exactive Orbitrap-MS) data and Lipinski’s rule of five, 24 bioactive phytochemicals from DST were identified. The targets of gout were retrieved from Gene Expression Omnibus (GEO), GeneCards, and DisGeNET databases, followed by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG pathway) enrichment analysis. The Cytoscape network analysis was used to identify the primary pathological pathways and key targets. Finally, LeDock was used for molecular docking to verify the active components of DST and their core target proteins.Results:DST contains several core active ingredients, such as tetrahydroimidazo[1,2-a]pyridine- 2,5-dione, diosgenin, beta-sitosterol, dioscorol B, montroumarin and 9,10-dihydro-5,7- dimethoxy-3,4-phenanthrenediol. Moreover, these active components were found to strongly bind to the key targets for treating gout and its complications, including HSP90AA1, STAT3, PTGS2, PPARG, MTOR, HIF1A, MMP9, ESR1, and TLR4. As a result, DST alleviates gout and its complications by inhibiting xanthine dehydrogenase (XDH) to reduce uric acid levels and regulating the HIF-1α, EZH2/STAT3, and COX-2/PPAR-γ pathways to reduce inflammation. Additionally, it also plays an analgesic role by regulating the neuroactive ligand-receptor interaction pathway and calcium ion signaling pathway.Conclusion:This study has provided insights into the underlying mechanisms of DST in the treatment of gout and its complications, which could serve as a scientific foundation for its clinical translation.

142

项与 HIF-1α 相关的新闻（医药）

2024-08-25

·CPHI制药在线

木犀草素的药理作用研究进展

关注并星标CPHI制药在线木犀草素（Luteolin）是一种天然的黄酮类化合物，其外观呈现淡黄色，多为针状结晶，通常以糖基化形式存在于各种药材、蔬菜和水果中，如金银花、荆芥、紫苏、卷心菜、花椰菜、胡萝卜和石榴中。现代药理表明，木犀草素具有抗炎、抑菌、抗氧化、抗肿瘤等多种药理活性。 01 抗氧化黄酮类化合物可以清除氧自由基，是一种很强的O2捕捉剂和1O2 猝灭剂。黄酮类化合物结构中的酚羟基取代基位置和数目对其抗氧化能力有所影响，黄酮类化合物B环的邻二酚羟基是发挥抗氧化作用的结构基础，使得木犀草素的抗氧化剂活性大大增强。木犀草素可以提供氢原子与自由基反应生成稳定的化合物，避免ROS对细胞的损害，此外，它还可以促进核因子E2相关因子2（Nrf2）进入细胞核与抗氧化元件（ARE）结合，增强过氧化氢酶、超氧化物酶、谷胱甘肽过氧化物酶、血红素加氧酶1等抗氧化酶系活性，从而减少ROS的生成量。研究木犀草素清除UVA照射诱导的ROS的产生，结果表明木犀草可以清除ROS，对人皮肤成纤维细胞（HSF）具有保护作用，并且抑制了HIF-1α的产生，从而降低了UVA照射导致的HSF自噬。将人类永生化表皮（HaCaT）细胞暴露在100 μmol/L氧化氢的条件下，用不同剂量的木犀草素进行处理，结果表明木犀草素可以有效地防止过氧化氢诱导的细胞活力降低。进一步评估木犀草素对过氧化氢诱导的细胞凋亡的影响，结果表明木犀草素能抑制过氧化氢诱导的角质形成细胞凋亡。酸碱度（pH）值不同，木犀草素的抗氧化性也不同。在酸性条件下，木犀草素发挥抗氧化作用的最佳 pH 范围是3～4。相较于二丁基羟基甲苯，木犀草素抑制棕榈油形成丙二醛发挥的作用更大，因此抗氧化的能力更强。 02 抑菌大量研究表明，木犀草素对多种细菌具有抑制作用。实验证实，木犀草素可破坏细菌细胞壁的完整性，增加细胞膜的通透性，从而导致细胞形态发生改变。此外，木犀草素能够抑制细胞内 DNA拓扑异构酶的活性，从而降低细胞内总蛋白和核酸的含量，抑制细菌的增殖。还有研究表明，木犀草素可使大肠杆菌和阴沟肠杆菌细胞变为不规则形态，少数的大肠杆菌细胞出现扭曲甚至破裂。木犀草素具有较好的抗耐甲氧西林金葡菌活性，与喹诺酮类和氨基糖苷类抗菌药联用时具有协同效果，能够降低抗菌药的最小抑菌浓度，从而减轻其毒副作用。pH的大小也会影响木犀草素的抑菌作用。在pH 5.0～9.0的范围内木犀草素对金黄色葡萄球菌的最低抑菌浓度均小于0.24%，抑菌作用较强。随着pH的降低或升高，最低抑菌浓度有减少的趋势。高温以及短时热处理不会对其抗菌活性造成影响。木犀草素不仅抗菌谱广、抗菌活性强，还可以消除细菌耐药性，对治疗细菌感染特别是耐药菌感染效果较好。 03 抗炎炎症是损伤因子刺激机体后，由机体产生的防御反应。研究表明，木犀草素的抗炎作用主要发生在免疫细胞内部，尤其是巨噬细胞。通过MTT法和细胞死亡Elisa 法来评价木犀草素对RAW264. 7 巨噬细胞的活力和凋亡的影响。研究结果显示，20 μmol/L的木犀草素能够引起巨噬细胞的形态变化，使细胞缓慢收缩，并且可观察到凋亡小体的出现。在体内，木犀草素能够上调信号传导、转录活化因子 6( p-STAT6) 和抑制转录激活子3( p-STAT3) 从而改变巨噬细胞极化，从促炎性M1 表型转变为抗炎性 M2 表型；同时，细胞因子经历了从促炎到抗炎的转变，起到抑制炎症的作用。在尿酸钠引起的急性痛风性关节炎模型中，不同剂量的木犀草素能够明显降低小鼠的踝关节肿胀度，血清中的 IL-1β、IL-17、IL-6和TNF-α的含量也相对减少，且NF-κB 的蛋白水平和组织内 HMGB1mRNA的表达水平均相对降低，表明木犀草素可通过抑制 HMGB1-NF-κB信号通路来发挥抗炎活性，有望成为治疗痛风性关节炎的有效药物。通过诱导IκB激酶β（IKKβ）的磷酸化和激活来刺激内皮细胞，IKKβ的激活和NF-κB抑制蛋白-α（IκB-α）的磷酸化导致IκB-α蛋白的降解，从而激活NF-κB并调节多种炎症因子的表达。结果显示，木犀草素可降低IKKβ和IκB-α的磷酸化，抑制NF-κB的激活，降低TNF-α与IL-6基因表达。 04 抗肿瘤近年来，木犀草素对肿瘤的作用研究较多，其抗肿瘤作用机制较为复杂，既可以直接作用于肿瘤细胞的生长、增殖，还可以其它途径最终抑制肿瘤的发展。 ①抑制肿瘤细胞的增殖作用。研究发现，木犀草素可以通过干扰糖原合成酶激酶(GSK-3)、β连环蛋白和细胞周期蛋白D1的表达来抑制结肠癌细胞的增殖作用。研究木犀草素对人乳腺癌细胞(MCF-7) 的作用发现，木犀草素对MCF-7细胞的抑制作用不仅具有时间依赖性，也具有浓度依赖性。通过细胞周期分析发现，木犀草素主要将细胞的生长抑制在细胞周期S期，结合D-ibose、D-Galactose 和Phosphoric Acid等10种代谢差异物推测，木犀草素抑制细胞增殖的机制是阻滞磷酸戊糖代谢途径中酶的活性。 ②诱导肿瘤细胞凋亡作用。对人肝癌细胞(HepG2) 进行研究，通过流式细胞仪检测发现木犀草能够诱导细胞凋亡。分析发现，木犀草素可以降低HepG2细胞内iASPP水平，同时升高p53与ASPP2等促凋亡蛋白水平。另有实验结果证实，木犀草素对非小细胞肺癌细胞株A549具有明显的促凋亡作用和细胞周期阻滞作用，其机制与通过上调JNK磷酸化，继而激活线粒体凋亡途径，同时抑制NF-κB入核，使其不能发挥转录活性有关。 ③抗肿瘤转移作用。木犀草素处理卵巢癌细胞株HO-8910PM后，其MMP-9的分泌下降，ERK2蛋白的表达明显降低，这可能是肿瘤细胞的体外侵袭、运动能力呈剂量依赖性下降的主要机制。木犀草通过抑制β3整合蛋白的表达，防止表皮癌细胞间质转化，同时减慢A431表皮肿瘤细胞的生长速度，通过逆转间质转化过程而降低恶性黑色素瘤细胞的潜在浸润性。 ④对放化疗的增敏作用。木犀草素可作为放化疗的增敏剂，当与化疗药物联合应用时，可以提高肿瘤对化疗药物的敏感性，增强药物诱导肿瘤细胞凋亡的能力。 05 其他药理作用研究发现，木犀草素能以剂量依赖性的方式显著提高大鼠左心室的收缩力( P＜0. 05)。其潜在的机制可能是：木犀草素上调转录因子 SP1 的表达水平，以增强心肌肌浆网Ca2+-ATP 酶( SERCA2a) 的转录活性，从而减轻心肌缺血再灌注造成的损伤。此外，木犀草素还能够降低细胞内钙离子的浓度，从而扩张已收缩的肾动脉，进而降低血压，产生改善肾功能的作用，这为肾性高血压的治疗提供了一定的参考。木犀草素具有抗过敏作用，可以用来治疗哮喘和干燥性皮肤瘙痒；具有神经保护作用，可以增强神经系统的学习和记忆能力。参考资料 [1]詹鑫,徐帆,祝钧,等.木犀草素的生理作用及制剂研究进展[J].日用化学工业(中英文),2023,53(04):437-444. [2]胡泽香,佟雷,耿艳萌,等.木犀草素的药理活性及其制剂研究进展[J].中医临床研究,2022,14(10):141-145. [3]赵长祺,郭志义.木犀草素的药理作用研究进展[J].承德医学院学报,2015,32(02):148-150. 作者简介：小泥沙，食品科技工作者，食品科学硕士，现就职于国内某大型药物研发公司，从事营养食品的开发与研究。 END 【智药研习社直播预告】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~

2024-08-21

·今日头条

激活糖酵解！南京医科大学合作发文：发现肝癌进展新机制

【导读】尽管近年来肝细胞癌（HCC）的治疗取得了显著进展，但许多患者在中晚期被诊断出患有该疾病，从而失去了手术切除的机会。因此，寻找有效的HCC治疗靶点非常重要。 8月20日，南京医科大学与上海交通大学以及天津中医药大学研究人员合作在期刊《Advanced Science》上发表了研究论文，题为“GJB2 Promotes HCC Progression by Activating Glycolysis Through Cytoplasmic Translocation and Generating a Suppressive Tumor Microenvironment Based on Single Cell RNA Sequencing”，在这项研究中，研究人员通过单细胞RNA测序发现，间隙连接蛋白β-2（GJB2）在恶性细胞中高度富集，并且GJB2表达水平越高，预后越差。与正常肝组织相比，HCC癌细胞中GJB2的定位发生了变化。在癌细胞中，GJB2倾向于位于细胞质和细胞核中，而在正常组织中，GJB2主要位于细胞膜上。GJB2与糖酵解有关，通过诱导IκBa的泛素化降解来促进NF-κB通路，激活HIF-1α/GLUT-1/PD-L1通路。此外，GJB2敲低可重塑肿瘤免疫微环境，丹酚酸 B可抑制GJB2的活性。总之，GJB2通过在细胞质中的转位激活糖酵解，促进HCC进展，并产生抑制性肿瘤微环境。丹酚酸 B抑制GJB2的表达，增强抗PD1疗法的敏感性，这可能为开发HCC的新型联合治疗策略提供启示。 https://onlinelibrary.wiley.com/doi/10.1002/advs.202402115 背景知识 01 肝癌虽然在癌症类型中排名靠后，但却是第三大死亡原因。值得注意的是，HCC占所有肝癌病例的80%。全球范围内，2019年约有747000例HCC病例，较1990年增加了70%，该疾病导致了480000人死亡。对于HCC，早期诊断时的治疗方案通常非常有效。然而，肿瘤复发仍然是一个重大挑战。可用的治疗模式包括经动脉化疗栓塞术（TACE）、肝移植、消融疗法和外科切除。不幸的是，由于该疾病的无症状性，大多数HCC患者在晚期才被发现。对于这些个体，系统性药物通常是可行的选择，因为手术替代方案可能不可行。近年来，肿瘤免疫治疗，尤其是免疫检查点抑制剂(ICIs)的使用显著改变了HCC的临床管理。贝伐珠单抗和阿替利珠单抗联合治疗被证明比一线治疗索拉非尼更有效。尽管取得了这些进展，肝癌仍然是最具挑战性的癌症之一，由于其频繁复发和耐药。不幸的是，相当一部分HCC患者要么经历了免疫相关的副作用，要么没有从这些免疫疗法中获益。尽管如此，免疫治疗的快速发展为HCC患者带来了新的希望，但仍需进一步研究以提高治疗的敏感性。 GJB2促进肝癌细胞的增殖、侵袭和迁移 02 为了研究GJB2 mRNA对肝癌细胞的影响，研究人员设计了3条针对GJB2的shRNA序列，从而抑制GJB2 mRNA合成的来源。这些序列被用来下调肝癌细胞中GJB2的表达。随后，采用qRT-PCR方法检测GJB2的表达水平。值得注意的是，研究结果显示sh1表现出最高的敲低效率。研究人员用sh1序列验证GJB2蛋白的表达，发现在HCCLM3和Hep-3B细胞中，敲低GJB2后的蛋白表达低于对照sh-NC组。在CCK8和EdU实验中，敲低GJB2抑制肝癌细胞增殖。在迁移实验和划痕实验中，与对照组相比，sh-GJB2抑制相对迁移和侵袭率。 GJB2促进人癌细胞的体外增殖、侵袭和迁移另外，研究人员对GJB2的膜蛋白区域进行突变，发现与WT组相比，细胞表型提示突变组更促进HCC的进展，包括增殖，侵袭和迁移。下调GJB2的表达，尤其是在细胞质和细胞核中的表达，可有效抑制肝癌的增殖、侵袭和迁移。这一发现为靶向GJB2治疗HCC的潜在治疗策略提供了希望。可减缓HCC进展的丹酚酸 B 03 本研究通过计算机虚拟筛选人GJB2蛋白结构的胞外活性位点Site1，以获得与靶蛋白结合能力强的小分子化合物。将MCE文库中的化合物与靶蛋白Human GJB2进行对接后，综合对接分数、脂溶性、水溶性评价，初步筛选出5个最优化合物，分别为Militarine、丹酚酸B、Parishin B、VER-155008、RGX-104。研究人员选择丹酚酸B (Sal B)作为进一步研究的药物。在蛋白质免疫印迹实验中，研究人员发现Sal B可以抑制肿瘤细胞的NF-κB通路。在CCK8和EdU实验中，Sal B抑制肝癌细胞增殖。在迁移实验和划痕实验中，与对照组相比，Sal B抑制了相对迁移和侵袭率。说明丹酚酸B能抑制肝癌细胞的增殖、侵袭和迁移。研究人员将H22细胞注射到C57BL/6小鼠体内，第7天进行Sal B注射和抗PD1抗体治疗，观察其抗肿瘤能力。结果显示，与抗PD1组相比，Sal B+抗PD1组的肿瘤体积和重量明显减小。上述药物验证结果表明，Sal B可通过抑制GJB2活性增强抗PD1免疫治疗的敏感性，证实了其在肿瘤免疫治疗中的促进作用，并具有在HCC中临床转化的潜力。研究小结 04 根据单细胞RNA测序结果，GJB2在HCC恶性细胞中高度富集，GJB2蛋白的更高表达表明预后更差。机制上，GJB2通过细胞质转位激活糖酵解途径，在肿瘤微环境中产生抑制性作用，促进HCC进展。丹酚酸 B有效地抑制了GJB2的活性，并增强了抗PD1疗法的敏感性，这可能为开发HCC的新型联合治疗策略提供启示。【参考资料】 https://onlinelibrary.wiley.com/doi/10.1002/advs.202402115 【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21日 19:00-20:30 ▶ “肿瘤免疫与实时活细胞成像技术”在线研讨会欢迎您的参与！ 🕓 线上｜08月22日 19:00-20:30 ▶ “RNA原位杂交在临床病理诊断及相关研究中的应用”网络研讨会欢迎您的参与！ 🕓 上海｜09月11日 ▶ 微驭万物-单细胞空间组学技术前沿与临床应用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

免疫疗法

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

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