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Targeted therapies for Glioblastoma multiforme (GBM): State-of-the-art and future prospects 治疗多形性胶质母细胞瘤(GBM)的靶向疗法:最新进展与未来展望。
IF 3.5 4区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-11-01 DOI: 10.1002/ddr.22261
Smera Satish, Maithili Athavale, Prashant S. Kharkar

Glioblastoma multiforme (GBM) remains one of the most aggressive and lethal forms of brain cancer, characterized by rapid growth and resistance to conventional therapies. The present review explores the latest advancements in targeted therapies for GBM, emphasizing the critical role of the blood-brain barrier (BBB), blood-brain-tumor barrier, tumor microenvironment, and genetic mutations in influencing treatment outcomes. The impact of the key hallmarks of GBM, for example, chemoresistance, hypoxia, and the presence of glioma stem cells on the disease progression and multidrug resistance are discussed in detail. The major focus is on the innovative strategies aimed at overcoming these challenges, such as the use of monoclonal antibodies, small-molecule inhibitors, and novel drug delivery systems designed to enhance drug penetration across the BBB. Additionally, the potential of immunotherapy, specifically immune checkpoint inhibitors and vaccine-based approaches, to improve patient prognosis was explored. Recent clinical trials and preclinical studies are reviewed to provide a comprehensive overview of the current landscape and future prospects in GBM treatment. The integration of advanced computational models and personalized medicine approaches is also considered, aiming to tailor therapies to individual patient profiles for better efficacy. Overall, while significant progress has been made in understanding and targeting the complex biology of GBM, continued research and clinical innovation are imperative to develop more effective and sustainable therapeutic options for patients battling this formidable disease.

多形性胶质母细胞瘤(GBM)仍然是最具侵袭性和致命性的脑癌之一,其特点是生长迅速且对传统疗法具有抗药性。本综述探讨了 GBM 靶向疗法的最新进展,强调了血脑屏障 (BBB)、血脑屏障、肿瘤微环境和基因突变在影响治疗效果方面的关键作用。详细讨论了 GBM 的主要特征(如化疗耐药、缺氧和胶质瘤干细胞的存在)对疾病进展和多药耐药性的影响。主要重点是旨在克服这些挑战的创新策略,如使用单克隆抗体、小分子抑制剂和新型给药系统,以增强药物在 BBB 的穿透力。此外,还探讨了免疫疗法,特别是免疫检查点抑制剂和基于疫苗的方法在改善患者预后方面的潜力。本文回顾了最近的临床试验和临床前研究,全面概述了 GBM 治疗的现状和未来前景。此外,还考虑了先进计算模型和个性化医学方法的整合,旨在根据患者的个体情况定制治疗方案,以提高疗效。总之,虽然在理解和针对 GBM 复杂的生物学特性方面取得了重大进展,但要为与这种可怕疾病作斗争的患者开发出更有效、更可持续的治疗方案,继续研究和临床创新势在必行。
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引用次数: 0
Knockdown of ENO1 promotes autophagy dependent-ferroptosis and suppresses glycolysis in breast cancer cells via the regulation of CST1. 敲除ENO1可通过调控CST1促进乳腺癌细胞的自噬依赖性铁变态反应并抑制糖酵解。
IF 3.5 4区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-11-01 DOI: 10.1002/ddr.70004
Guoliang Huang, Lian Lu, Yuhong You, Jie Li, Kaixiang Zhang

Autophagy-dependent ferroptosis and glycolysis play a significant role in tumor development. α-Enolase (ENO1), a glycolytic enzyme, has been demonstrated to function as a crucial modulator in breast cancer (BC). However, the specific mechanism by which ENO1 influences the ferroptosis and glycolysis of BC remains unclear. qRT-PCR, along with western blot analysis was applied to investigate ENO1 and cystatin SN (CST1) expression in BC cells. Glycolysis level was measured by extracellular acidification rate (ECAR), lactate production, glucose consumption, and western blot analysis. Ferroptosis was evaluated by iron and lipid peroxidation assay, DCFH-DA staining, and western blot analysis. Immunofluorescence, together with western blot analysis was adopted for assessing cell autophagy and mTOR signaling pathway. Cell apoptosis and Ki67 level were measured by TUNEL and immunohistochemistry, respectively. ENO1 had abundant existence in BC cell lines. ENO1 silencing inhibited glycolysis but promoted ferroptosis and autophagy. In addition, autophagy inhibitor 3-MA reversed the impacts of ENO1 silencing on glycolysis and ferroptosis. Meanwhile, mTOR activator MHY1485 demonstrated opposing effects on autophagy. Moreover, CST1 could be extensively found in BC cell lines, and its overexpression reversed the effects of ENO1 silencing on glycolysis and ferroptosis. In vivo experiments illustrated that ENO1 deletion suppressed BC tumor growth, increased the apoptosis rate, restrained cell proliferation, and glycolysis, but promoted ferroptosis and autophagy, as well as reducing CST1 and mTOR signaling. To sum up, ENO1 silencing mediated a utophagy-dependent ferroptosis and glycolysis in BC cells by regulating CST1.

自噬依赖性铁蛋白沉积和糖酵解在肿瘤发生发展中起着重要作用。α-烯醇化酶(ENO1)是一种糖酵解酶,已被证实在乳腺癌(BC)中发挥着重要的调节作用。qRT-PCR和Western印迹分析被用来研究ENO1和胱抑素SN(CST1)在乳腺癌细胞中的表达。糖酵解水平通过细胞外酸化率(ECAR)、乳酸生成、葡萄糖消耗和 Western 印迹分析进行测量。通过铁和脂质过氧化测定、DCFH-DA 染色和 Western 印迹分析评估铁变态反应。免疫荧光和 Western 印迹分析用于评估细胞自噬和 mTOR 信号通路。细胞凋亡和Ki67水平分别通过TUNEL和免疫组化进行检测。ENO1在BC细胞系中大量存在。沉默ENO1可抑制糖酵解,但促进铁突变和自噬。此外,自噬抑制剂3-MA能逆转ENO1沉默对糖酵解和铁突变的影响。同时,mTOR 激活剂 MHY1485 对自噬的影响则相反。此外,CST1广泛存在于BC细胞系中,其过表达可逆转ENO1沉默对糖酵解和铁突变的影响。体内实验表明,ENO1缺失抑制了BC肿瘤的生长,增加了细胞凋亡率,抑制了细胞增殖和糖酵解,但促进了铁代谢和自噬,并减少了CST1和mTOR信号传导。综上所述,ENO1沉默通过调节CST1介导了依赖于吞噬细胞的铁代谢和糖酵解。
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引用次数: 0
PARP7i Clinical Candidate RBN-2397 Exerts Antiviral Activity by Modulating Interferon-β Associated Innate Immune Response in Macrophages. PARP7i 临床候选药物 RBN-2397 通过调节巨噬细胞中与干扰素-β 相关的先天性免疫反应而发挥抗病毒活性。
IF 3.5 4区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-11-01 DOI: 10.1002/ddr.70013
Xiaoli Du, Jiawei Zhou, Yi Zhou, Yulong Chen, Yanhua Kang, Dongjiu Zhao, Xiang-Yang Ye, Liwei Wang, Tian Xie, Hang Zhang

Polyadenosine diphosphate-ribose polymerase 7 (PARP7) acts as a suppressor of the type I interferon (IFN) signaling pathway via suppressing TANK-binding protein 1 (TBK1). Research study indicates that inhibition of PARP7 could potentially regulate tumor immunity. However, the effect of PARP7 inhibition on innate antiviral immunity in macrophages as well as the underlying mechanism have not been demonstrated else well. We report herein that PARP7 inhibitor clinical candidate RBN-2397 could augment type I interferon (IFN-I) production in macrophages by elevating retinoic acid-inducible gene I (RIG-I) and stimulator of interferon genes (STING) signaling pathways. Treatment with RBN-2397 leads to increased pattern recognition ligands-induced interferon-β production in primary bone marrow-derived macrophages (BMDM) and RAW264.7 cells. Additionally, RBN-2397 suppresses viral replication efficiency in macrophages infected by vesicular stomatitis virus (VSV) and amplifies the expression of interferon-stimulated chemokine genes (ISGs). Mechanistically, RBN-2397 promotes TBK1 phosphorylation, consequently leading to the amplified activation of RIG-I and STING signaling pathways. Furthermore, RBN-2397 enhances the phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT2 induced by IFN-α/β and the expression of chemokine genes in macrophages in response to IFN stimulation. In vivo experiments demonstrated that RBN-2397 enhances innate antiviral immunity in mice infected with VSV, resulting in increased serum IFN-β levels, reduced viral loads, and alleviated pulmonary inflammatory responses of the VSV-infected mice. In conclusion, our findings highlight the potential of RBN-2397 as a promising antiviral therapeutic agent for enhancing the IFN-relative antiviral immune defense in host.

多聚腺苷二磷酸核糖聚合酶 7(PARP7)通过抑制 TANK 结合蛋白 1(TBK1)而成为 I 型干扰素(IFN)信号通路的抑制因子。研究表明,抑制 PARP7 有可能调节肿瘤免疫。然而,抑制 PARP7 对巨噬细胞先天性抗病毒免疫的影响及其机制尚未得到证实。我们在本文中报告了 PARP7 抑制剂临床候选药物 RBN-2397 可通过提高视黄酸诱导基因 I(RIG-I)和干扰素基因刺激器(STING)信号通路来增强巨噬细胞中 I 型干扰素(IFN-I)的产生。用 RBN-2397 处理原代骨髓源性巨噬细胞(BMDM)和 RAW264.7 细胞,可增加模式识别配体诱导的干扰素-β的产生。此外,RBN-2397 还能抑制受水泡性口炎病毒(VSV)感染的巨噬细胞的病毒复制效率,并扩大干扰素刺激的趋化因子基因(ISGs)的表达。从机理上讲,RBN-2397 可促进 TBK1 磷酸化,从而导致 RIG-I 和 STING 信号通路的激活。此外,RBN-2397 还能增强 IFN-α/β 诱导的信号转导及转录激活因子 1(STAT1)和 STAT2 的磷酸化,以及巨噬细胞在 IFN 刺激下趋化因子基因的表达。体内实验证明,RBN-2397 可增强感染 VSV 小鼠的先天性抗病毒免疫,从而提高血清 IFN-β 水平,降低病毒载量,并减轻 VSV 感染小鼠的肺部炎症反应。总之,我们的研究结果凸显了 RBN-2397 作为一种有前景的抗病毒治疗药物在增强宿主 IFN 相关抗病毒免疫防御方面的潜力。
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引用次数: 0
MLLT3 knockdown suppresses proliferation and cell mobility in human lung adenocarcinoma. 敲除 MLLT3 可抑制人肺腺癌的增殖和细胞移动性。
IF 3.5 4区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-11-01 DOI: 10.1002/ddr.70010
Wenbo Shi, Tongyangzi Zhang, Li Zhang, Wanzhen Li, Zhiwei Chen, Xianghuai Xu

Lung cancer is emerging as one of the most frequently encountered malignancies around the world that carries high morbidity and mortality. Lung adenocarcinoma (LUAD) has become the most common subtype of lung cancer. MLLT3 or named AF9 was first characterized in acute myeloid leukemia and can downregulate the expression of several critical genes. The aim of this study was to explore the function of MLLT3 in the progression of LUAD and related molecular mechanisms. Immunohistochemistry was employed to assess MLLT3 expression in LUAD tissues, while quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were utilized to detect MLLT3 expression levels in lung adenocarcinoma cell lines. These results revealed a significant overexpression of MLLT3 in LUAD cell lines and tissues. We further uncovered an association between MLLT3 expression profiles in LUAD tissues and metastasis, as well as TNM stage. Survival analysis showed that elevated MLLT3 correlated with a poorer survival rate. We also found that MLLT3 knockdown repressed LUAD cells invasion, migration, and proliferation in vitro, while inducing cell cycle arrest and apoptosis of LUAD cells. Moreover, knocking down MLLT3 inhibited tumor growth in vivo. Specific markers of apoptosis, cell cycle, epithelial-mesenchymal transition (EMT), and MLLT3-induced signaling were examined by Western blot. We demonstrated that MLLT3 knockdown inhibited the activity of the EGFR-MAPK/ERK signaling pathway, and MLLT3 might be a novel diagnostic biomarker and therapeutic target in lung adenocarcinomas.

肺癌是全球最常见的恶性肿瘤之一,发病率和死亡率都很高。肺腺癌(LUAD)已成为肺癌最常见的亚型。MLLT3(又称 AF9)最早出现在急性髓性白血病中,能下调多个关键基因的表达。本研究旨在探讨 MLLT3 在 LUAD 进展过程中的功能及相关分子机制。研究采用免疫组织化学方法评估 MLLT3 在 LUAD 组织中的表达,并采用实时定量聚合酶链反应(qRT-PCR)和 Western 印迹法检测 MLLT3 在肺腺癌细胞系中的表达水平。这些结果表明,MLLT3 在 LUAD 细胞系和组织中明显过表达。我们进一步发现了 LUAD 组织中 MLLT3 表达谱与转移以及 TNM 分期之间的关联。生存分析表明,MLLT3 的升高与较差的生存率相关。我们还发现,在体外敲除 MLLT3 可抑制 LUAD 细胞的侵袭、迁移和增殖,同时诱导 LUAD 细胞的细胞周期停滞和凋亡。此外,敲除 MLLT3 还能抑制肿瘤在体内的生长。我们用 Western 印迹法检测了细胞凋亡、细胞周期、上皮-间质转化(EMT)和 MLLT3 诱导的信号转导的特定标志物。我们证明,MLLT3敲除抑制了表皮生长因子受体-MAPK/ERK信号通路的活性,MLLT3可能是肺腺癌的一种新型诊断生物标记物和治疗靶点。
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引用次数: 0
Agmatine: An Emerging Approach for Neuroprotection in Recurrent Ischemic Stroke Events in a Murine Model 阿格马丁在小鼠模型中对复发性缺血性中风事件进行神经保护的新方法
IF 3.5 4区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-29 DOI: 10.1002/ddr.70012
M. L. Miranda-Mosqueda, S. Y. Ruiz-Oropeza, J. A. González-Barrios, R. Jaimez, Fernando Peña-Ortega, C. Gómez-Acevedo

This study investigates the effect of agmatine on reducing mortality, neurobehavioral alterations, infarct size, and expression of pro-inflammatory cytokines in mice subjected to bilateral carotid thrombosis. Under pentobarbital anesthesia, the left common carotid artery was exposed to 6% FeCl3. Thirty-two days later, the same procedure was performed on the right common carotid artery. Subsequently, Agmatine (100 mg/kg) was administered 15 min after the second procedure, and in another experimental group, the dose of Agmatine was repeated at 72 h. Administration of agmatine extended survival in ischemic animals up to 72 h for the single-dose group and up to 96 h for the repeated-dose group, without significant increases in neurological deficits or infarct area size. This neurobehavioral effect was also observed in sham animals treated with agmatine. In ischemic animals, agmatine administration improved digging behavior and reduced recovery times, consistently shorter in those animals treated with repeated doses. RT-PCR analyses revealed a positive regulation of the cytokine IL-1β in agmatine-treated animals, which has been associated with recovery stages. The results suggest that the observed effect may be attributed to the multiple interactions of agmatine with ischemic cascade events, highlighting its anti-inflammatory role.

本研究探讨了阿马汀对降低双侧颈动脉血栓形成小鼠死亡率、神经行为改变、梗塞面积和促炎细胞因子表达的影响。在戊巴比妥麻醉下,将左侧颈总动脉暴露于 6% FeCl3。32 天后,对右侧颈总动脉进行同样的操作。单剂量组的缺血动物存活时间延长至 72 小时,重复剂量组的缺血动物存活时间延长至 96 小时,但神经功能缺损或梗死面积大小没有显著增加。用阿格马汀治疗的假动物也观察到了这种神经行为效应。在缺血动物中,服用阿司匹林可改善挖掘行为并缩短恢复时间,重复剂量组的恢复时间更短。RT-PCR分析显示,在服用了阿司马汀的动物体内,细胞因子IL-1β受到了正向调节,而这种调节与恢复阶段有关。结果表明,所观察到的效果可能是由于阿司马汀与缺血级联事件的多重相互作用,突出了其抗炎作用。
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引用次数: 0
Molecular docking, DFT and antiproliferative properties of 4-(3,4-dimethoxyphenyl)−3-(4-methoxyphenyl)−1-phenyl-1H-pyrazolo[3,4-b]pyridine as potent anticancer agent with CDK2 and PIM1 inhibition potency 4-(3,4-二甲氧基苯基)-3-(4-甲氧基苯基)-1-苯基-1H-吡唑并[3,4-b]吡啶作为具有 CDK2 和 PIM1 抑制效力的强效抗癌剂的分子对接、DFT 和抗增殖特性。
IF 3.5 4区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-28 DOI: 10.1002/ddr.70009
Faizah A. Binjubair, Basma S. Almansour, Noha I. Ziedan, Alaa A.-M. Abdel-Aziz, Sara T. Al-Rashood, Mohamed K. Elgohary, Mahmoud S. Elkotamy, Hatem A. Abdel-Aziz

Due to the limited effeteness and safety concerns associated with current cancer treatments, there is a pressing need to develop novel therapeutic agents. 4-(3,4-Dimethoxyphenyl)−3-(4-methoxyphenyl)−1-phenyl-1H-pyrazolo[3,4-b]pyridine (3) was synthesized and Initially screened on 59 cancer cell lines showed promising anticancer activity, so, it was chosen for a 5-dose experiment by the NCI/USA. The GI50 values ranged from 1.04 to 8.02 μM on the entire nine panels (57 cell lines), with a GI50 of 2.70 μM for (MG-MID) panel, indicating an encouraging action. To further explore the molecular attributes of compound 3, we optimized its structure using DFT with the B3LYP/6-31 + + G(d,p) basis set. We have considered vibrational analysis, bond lengths and angles, FMOs, and MEP for the structure. Additionally, pharmacokinetic assessments were conducted using various in-silico platforms to evaluate the compound safety. A molecular modeling study created a kinase profile on 44 different kinases. This allowed us to study our compound's binding affinity to these kinases and compare it to the co-crystallized one. Our findings revealed compound 3 exhibited better binding for half of the tested kinases, suggesting its potential as a multi-kinase inhibitor. To further validate our computational results, we tested compound 3 for its inhibitory effects on CDK2 and PIM1. Compound 3 exhibited an IC50 of 0.30 µM for CDK2 inhibition, making it five times less active than Roscovitine, which has an IC50 of 0.06 µM. However, compound 3 demonstrated slightly better inhibition of PIM1 compared to Staurosporine. These findings suggest that compound 3 is a promising anticancer agent with the potential for further development into a highly active compound.

由于目前的癌症治疗方法疗效有限且存在安全隐患,因此迫切需要开发新型治疗药物。我们合成了 4-(3,4-二甲氧基苯基)-3-(4-甲氧基苯基)-1-苯基-1H-吡唑并[3,4-b]吡啶 (3),并对 59 种癌症细胞株进行了初步筛选,结果显示其具有良好的抗癌活性。在整个九个小组(57 个细胞系)中,其 GI50 值介于 1.04 至 8.02 μM 之间,其中(MG-MID)小组的 GI50 值为 2.70 μM,表明其具有令人鼓舞的作用。为了进一步探索化合物 3 的分子属性,我们使用 B3LYP/6-31 + + G(d,p) 基集进行了 DFT 结构优化。我们考虑了结构的振动分析、键长和键角、FMO 和 MEP。此外,我们还利用各种体内平台进行了药代动力学评估,以评价化合物的安全性。分子建模研究建立了 44 种不同激酶的激酶谱。这使我们能够研究化合物与这些激酶的结合亲和力,并将其与共晶体化合物进行比较。我们的研究结果表明,化合物 3 与半数受测激酶的结合力更强,这表明它具有作为多激酶抑制剂的潜力。为了进一步验证计算结果,我们测试了化合物 3 对 CDK2 和 PIM1 的抑制作用。化合物 3 抑制 CDK2 的 IC50 值为 0.30 µM,比 IC50 值为 0.06 µM 的 Roscovitine 低五倍。不过,与 Staurosporine 相比,化合物 3 对 PIM1 的抑制效果稍好。这些研究结果表明,化合物 3 是一种很有前途的抗癌剂,有望进一步开发成为一种高活性化合物。
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引用次数: 0
RNA sequencing comparing centenarian and middle-aged women lymphoblastoid cell lines identifies age-related dysregulated expression of genes encoding selenoproteins, heat shock proteins, CD99, and BID 通过对百岁老人和中年女性淋巴母细胞系进行 RNA 测序比较,发现与年龄有关的硒蛋白、热休克蛋白、CD99 和 BID 编码基因表达失调。
IF 3.5 4区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-24 DOI: 10.1002/ddr.70011
Irena Voinsky, Ofir Goldenberg-Bogner, Ifat Israel-Elgali, Hadas Volkov, Monika Puzianowska-Kuźnicka, Noam Shomron, David Gurwitz

Women typically live longer than men, and constitute the majority of centenarians. We applied RNA-sequencing (RNA-seq) of blood-derived lymphoblastoid cell lines (LCLs) from women aged 60-80 years and centenarians (100-105 years), validated the RNA-seq findings by real-time PCR, and additionally measured the differentially expressed genes in LCLs from young women aged 20-35 years. Top RNA-seq genes with differential expression between the age groups included three selenoproteins (GPX1, SELENOW, SELENOH) and three heat shock proteins (HSPA6, HSPA1A, HSPA1B), with the highest expression in LCLs from young women, indicating that young women are better protected from oxidative stress. The expression of two additional genes, BID encoding BH3-interacting domain death agonist and CD99 encoding CD99 antigen, showed unique age dependence, with similar expression levels in young and centenarian women while exhibiting higher and lower expression levels, respectively, in LCLs from women aged 60-80 years compared with the two other age groups. This age-related differential expression of BID and CD99 suggests elevated inflammation susceptibility in middle-aged women compared with either young or centenarian women. Our findings, once validated with human peripheral blood mononuclear cells and further cell types, may lead to novel healthy aging diagnostics and therapeutics.

女性的寿命通常比男性长,而且在百岁老人中占大多数。我们对来自 60-80 岁女性和百岁老人(100-105 岁)的血源性淋巴母细胞系(LCLs)进行了 RNA 序列分析(RNA-seq),并通过实时 PCR 验证了 RNA-seq 结果,此外还测定了来自 20-35 岁年轻女性的 LCLs 中的差异表达基因。不同年龄组之间存在差异表达的顶级RNA-seq基因包括三种硒蛋白(GPX1、SELENOW、SELENOH)和三种热休克蛋白(HSPA6、HSPA1A、HSPA1B),其中年轻女性的LCL中表达量最高,这表明年轻女性在氧化应激方面的保护能力更强。另外两个基因,即编码 BH3-相互作用结构域死亡激动剂的 BID 和编码 CD99 抗原的 CD99 的表达表现出独特的年龄依赖性,在年轻女性和百岁女性中的表达水平相似,而在 60-80 岁女性的 LCL 中的表达水平则分别高于和低于其他两个年龄组。与年龄相关的 BID 和 CD99 表达差异表明,与年轻女性或百岁女性相比,中年女性对炎症的易感性更高。我们的发现一旦在人类外周血单核细胞和其他细胞类型中得到验证,可能会带来新的健康老龄化诊断和治疗方法。
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引用次数: 0
Role of BIX01294 in the intracranial inhibition of H3K9 methylation lessens neuronal loss in vascular dementia model BIX01294 在颅内抑制 H3K9 甲基化中的作用可减轻血管性痴呆模型中神经元的损失。
IF 3.5 4区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-23 DOI: 10.1002/ddr.70001
Fardin Sehati, Saereh Hosseindoost, Mina Ranjbaran, Fatemeh Nabavizadeh, Seyed-Morteza Karimian, Soheila Adeli, Elham Zahedi, Leila Chodari, Ghorbangol Ashabi

Dementia develops as a result of multiple factors, including cerebrovascular disease which is called vascular dementia (VD). Histone-3 lysine-9 dimethylation (H3K9me2) broadly increases during VD and inhibits neuroprotective gene expressions. So, we aimed to determine how H3K9me2 inhibitor (BIX01294) affects neuronal damage in VD. An in vivo model of VD was used followed by BIX01294 treatment. Behavioral tests, hematoxylin, and eosin (H&E), Congo red, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were carried out. Hippocampal phosphorylated cyclic-AMP responsive element binding protein (p-CREB), c-fos, brain-derived neurotrophic factor (BDNF), and H3K9me2, were detected by western blot analysis technique. Neurological deficit and anxiety-related behavior significantly reduced in the treatment group compared to the VD group (p < 0.05). BIX01294 improved spatial and passive avoidance memory (p < 0.01 and p < 0.05, respectively) compared to the VD group. Treatment with BIX01294 restored the level of p-CREB/CREB ratio (p < 0.05), cfos (p < 0.01), BDNF (p < 0.01), and suppressed H3K9me2 (p < 0.001) when compared to the VD group. BIX01294 microinjection reduced the apoptosis level in TUNEL staining (p < 0.05), and raised neural cell count in H&E staining (p < 0.01); amyloid beta accumulation significantly decreased in the treatment group (p < 0.05) compared to the VD group. In conclusion, long-term treatment with a low dose of BIX01294 can prevent the progression of neuronal loss in VD model by raising the expression of neurotrophic factors, and reducing the apoptosis level.

痴呆症的发生是多种因素共同作用的结果,其中包括被称为血管性痴呆(VD)的脑血管疾病。组蛋白-3 赖氨酸-9 二甲基化(H3K9me2)在血管性痴呆期间广泛增加,并抑制神经保护基因的表达。因此,我们旨在确定 H3K9me2 抑制剂(BIX01294)如何影响 VD 中的神经元损伤。我们使用体内 VD 模型,然后用 BIX01294 治疗。进行了行为测试、苏木精和伊红(H&E)、刚果红和末端脱氧核苷酸转移酶 dUTP 缺口标记(TUNEL)染色。海马磷酸化环-AMP反应元件结合蛋白(p-CREB)、c-fos、脑源性神经营养因子(BDNF)和H3K9me2通过Western印迹分析技术进行检测。与 VD 组相比,治疗组的神经功能缺损和焦虑相关行为明显减少(p
{"title":"Role of BIX01294 in the intracranial inhibition of H3K9 methylation lessens neuronal loss in vascular dementia model","authors":"Fardin Sehati,&nbsp;Saereh Hosseindoost,&nbsp;Mina Ranjbaran,&nbsp;Fatemeh Nabavizadeh,&nbsp;Seyed-Morteza Karimian,&nbsp;Soheila Adeli,&nbsp;Elham Zahedi,&nbsp;Leila Chodari,&nbsp;Ghorbangol Ashabi","doi":"10.1002/ddr.70001","DOIUrl":"10.1002/ddr.70001","url":null,"abstract":"<p>Dementia develops as a result of multiple factors, including cerebrovascular disease which is called vascular dementia (VD). Histone-3 lysine-9 dimethylation (H3K9me2) broadly increases during VD and inhibits neuroprotective gene expressions. So, we aimed to determine how H3K9me2 inhibitor (BIX01294) affects neuronal damage in VD. An in vivo model of VD was used followed by BIX01294 treatment. Behavioral tests, hematoxylin, and eosin (H&amp;E), Congo red, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were carried out. Hippocampal phosphorylated cyclic-AMP responsive element binding protein (p-CREB), c-fos, brain-derived neurotrophic factor (BDNF), and H3K9me2, were detected by western blot analysis technique. Neurological deficit and anxiety-related behavior significantly reduced in the treatment group compared to the VD group (<i>p</i> &lt; 0.05). BIX01294 improved spatial and passive avoidance memory (<i>p</i> &lt; 0.01 and <i>p</i> &lt; 0.05, respectively) compared to the VD group. Treatment with BIX01294 restored the level of p-CREB/CREB ratio (<i>p</i> &lt; 0.05), cfos (<i>p</i> &lt; 0.01), BDNF (<i>p</i> &lt; 0.01), and suppressed H3K9me2 (<i>p</i> &lt; 0.001) when compared to the VD group. BIX01294 microinjection reduced the apoptosis level in TUNEL staining (<i>p</i> &lt; 0.05), and raised neural cell count in H&amp;E staining (<i>p</i> &lt; 0.01); amyloid beta accumulation significantly decreased in the treatment group (<i>p</i> &lt; 0.05) compared to the VD group. In conclusion, long-term treatment with a low dose of BIX01294 can prevent the progression of neuronal loss in VD model by raising the expression of neurotrophic factors, and reducing the apoptosis level.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Design, synthesis, and evaluation of novel Indole-Based small molecules as sirtuin inhibitors with anticancer activities 设计、合成和评估具有抗癌活性的新型吲哚基小分子 sirtuin 抑制剂
IF 3.5 4区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-21 DOI: 10.1002/ddr.70008
Busra Binarci, Ensar Korkut Kilic, Tunca Dogan, Rengul Cetin Atalay, Deniz Cansen Kahraman, Sultan Nacak Baytas

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, driven mainly by chronic hepatitis infections and metabolic disorders, which highlights the urgent need for novel therapeutic strategies. Sirtuins, particularly SIRT1 are crucial in HCC pathogenesis, making it a promising drug target. Indole-based molecules show potential as therapeutic agents by interacting with key proteins like sirtuins involved in cancer progression. In this study, we designed and synthesized novel indole-based small molecules and investigated their potential sirtuin inhibitory action and anticancer activity on HCC cell lines. Four of the twenty-eight tested small molecules on different cancer types were selected (4 g, 4 h, 4o, and 7j) based on their structure–activity relationship and studied on a panel of HCC cell lines. Compounds had active drug-target interactions with SIRT1 or SIRT2 based on DEEPScreen DTI predictions and docking studies which confirmed that 4o, 4 g, and 7j were most potent in their interaction with SIRT1. Compound 4 g caused the highest sirtuin activity inhibition in vitro and induced G1 arrest and apoptosis in HCC cell lines.

肝细胞癌(HCC)是导致全球癌症相关死亡的主要原因,主要是由慢性肝炎感染和代谢紊乱引起的,这凸显了对新型治疗策略的迫切需求。Sirtuins,尤其是 SIRT1 在 HCC 发病机制中起着关键作用,因此是一个很有前景的药物靶点。吲哚类分子通过与参与癌症进展的 sirtuins 等关键蛋白相互作用,显示出作为治疗药物的潜力。在这项研究中,我们设计并合成了新型吲哚基小分子,并研究了它们对 HCC 细胞系潜在的 sirtuin 抑制作用和抗癌活性。根据其结构-活性关系,我们从 28 种不同癌症类型的测试小分子中选出了 4 种(4 g、4 h、4o 和 7j),并在一组 HCC 细胞系上进行了研究。根据 DEEPScreen DTI 预测和对接研究,化合物与 SIRT1 或 SIRT2 具有活跃的药物靶点相互作用,研究证实 4o、4 g 和 7j 与 SIRT1 的相互作用最为有效。化合物 4 g 在体外对 sirtuin 活性的抑制作用最强,并能诱导 HCC 细胞系 G1 停滞和凋亡。
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引用次数: 0
New S-substituted-3-phenyltetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one scaffold with promising anticancer activity profile through the regulation and inhibition of mutated B-RAF signaling pathway 通过调节和抑制突变的 B-RAF 信号通路,具有良好抗癌活性的新型 S-取代-3-苯基四氢苯并[4,5]噻吩并[2,3-d]嘧啶-4(3H)-酮支架
IF 3.5 4区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-18 DOI: 10.1002/ddr.70007
Safaa E. Seif, Wagnat W. Wardakhan, Rasha A. Hassan, Amr M. Abdou, Zeinab Mahmoud

Novel 3-phenyltetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivatives were synthesized and screened for their antiproliferative activity against a panel of 60 cancer cell lines. Derivatives 5b, 5f, and 9c showed significant antitumor activity at a single dose with mean growth inhibition of 55.62%, 55.79%, and 71.40%, respectively. These compounds were further investigated against HCT-116, colon cancer cell line, and FHC, normal colon cell line. Compound 9c showed the highest activity with IC50 = 0.904 ± 0.03 µM and SI = 20.42 excelling doxorubicin which scored IC50 = 2.556 ± 0.09 µM and SI = 6.19. Compound 9c was also the most potent against B-RAFWT and mutated B-RAFV600E with IC50 = 0.145 ± 0.005 and 0.042 ± 0.002 µM, respectively in comparison with vemurafenib with IC50 = 0.229 ± 0.008 and 0.038 ± 0.001 µM, respectively. The cell cycle analysis showed that 9c increased the cell population and induced an arrest in the cell cycle of HCT-116 cancer cells at the G0-G1 stage with 1.23-fold. Apoptosis evaluation showed that compound 9c displayed an 18.18-fold elevation in total apoptosis of HCT-116 cancer cells in comparison to the control. Compound 9c increased the content of caspase-3 by 3.52-fold versus the control. A molecular modeling study determined the binding profile and interaction of 9c with the B-RAF active site.

研究人员合成了新型 3-苯基四氢苯并[4,5]噻吩并[2,3-d]嘧啶衍生物,并筛选了它们对 60 种癌症细胞系的抗增殖活性。单剂量下,衍生物 5b、5f 和 9c 显示出显著的抗肿瘤活性,平均生长抑制率分别为 55.62%、55.79% 和 71.40%。这些化合物还针对结肠癌细胞株 HCT-116 和正常结肠细胞株 FHC 进行了进一步研究。化合物 9c 的活性最高,IC50 = 0.904 ± 0.03 µM,SI = 20.42,优于多柔比星,后者的 IC50 = 2.556 ± 0.09 µM,SI = 6.19。化合物9c对B-RAFWT和突变的B-RAFV600E也最有效,IC50分别为0.145 ± 0.005和0.042 ± 0.002 µM,而维莫非尼的IC50分别为0.229 ± 0.008和0.038 ± 0.001 µM。细胞周期分析表明,9c 增加了 HCT-116 癌细胞的细胞数量,并诱导细胞周期停滞在 G0-G1 阶段,增幅为 1.23 倍。凋亡评估显示,与对照组相比,化合物 9c 使 HCT-116 癌细胞的总凋亡率提高了 18.18 倍。与对照组相比,化合物 9c 使 Caspase-3 的含量增加了 3.52 倍。分子建模研究确定了 9c 与 B-RAF 活性位点的结合情况和相互作用。
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Drug Development Research
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