更新于：2024-05-01

DENR

density regulated re-initiation and release factor

更新于：2024-05-01

基本信息

别名

DENR、density regulated re-initiation and release factor、Density-regulated protein

+ [5]

简介

May be involved in the translation of target mRNAs by scanning and recognition of the initiation codon. Involved in translation initiation; promotes recruitmnet of aminoacetyled initiator tRNA to P site of 40S ribosomes. Can promote release of deacylated tRNA and mRNA from recycled 40S subunits following ABCE1-mediated dissociation of post-termination ribosomal complexes into subunits. Plays a role in the modulation of the translational profile of a subset of cancer-related mRNAs when recruited to the translational initiation complex by the oncogene MCTS1.

关联

项与 DENR 相关的药物

ASHA-091

靶点

UTRN

作用机制

DENR抑制剂 [+1]

在研机构

Asha Therapeutics LLC初创企业

原研机构

Asha Therapeutics LLC初创企业

在研适应症

肌萎缩侧索硬化 [+5]

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

IR-418

靶点-

作用机制

DENR抑制剂 [+1]

在研机构

西南医科大学

原研机构

西南医科大学

在研适应症

黑色素瘤

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

MB-0481

靶点-

作用机制

DENR抑制剂

在研机构

Mitobridge, Inc.

原研机构

Mitobridge, Inc.

在研适应症-

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 DENR 相关的临床结果

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100 项与 DENR 相关的转化医学

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0 项与 DENR 相关的专利（医药）

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135

项与 DENR 相关的文献（医药）

2024-02-05·Ecotoxicology and environmental safety

Corrigendum to "Parkin-mediated mitophagy protects against aluminum trichloride-induced hippocampal apoptosis in mice via the mtROS-NLRP3 pathway" [Ecotoxicol. Environ. Saf. 2023 Oct 1:264:115459.]

Article

作者: Huo, Siming ; Zhang, Xuliang ; Xu, Jinyu ; Zhang, Jian ; Du, Jiayu ; Li, Bo ; Song, Miao ; Shao, Bing ; Li, Yanfei ; Xu, Feibo

Silica nanoparticles (SiNPs) are widely used in the biomedical field and can enter the central nervous system through the blood-brain barrier, causing damage to hippocampal neurons. However, the specific mechanism remains unclear. In this experiment, HT22 cells were selected as the experimental model in vitro, and the survival rate of cells under the action of SiNPs was detected by MTT method, reactive oxygen species (ROS), lactate dehydrogenase (LDH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and adenosine triphosphate (ATP) were tested by the kit, the ultrastructure of the cells was observed by transmission electron microscope, membrane potential (MMP), calcium ion (Ca²⁺) and apoptosis rate were measured by flow cytometry, and the expressions of mitochondrial functional protein, mitochondrial dynein, mitochondrial autophagy protein as well as apoptosis related protein were detected by Western blot. The results showed that cell survival rate, SOD, CAT, GSH-Px, ATP and MMP gradually decreased with the increase of SiNPs concentration, while intracellular ROS, Ca²⁺, LDH and apoptosis rate increased with the increase of SiNPs concentration. In total cellular proteins,the expressions of mitochondrial functional proteins VDAC and UCP2 gradually increased, the expression of mitochondrial dynamic related protein DRP1 increased while the expressions of OPA1 and Mfn2 decreased. The expressions of mitophagy related proteins PINK1, Parkin and LC3Ⅱ/LC3Ⅰ increased and P62 gradually decreased, as well as the expressions of apoptosis related proteins Apaf-1, Cleaved-Caspase-3, Caspase-3, Caspase-9, Bax and Cyt-C. In mitochondrial proteins, the expressions of mitochondrial dynamic related proteins DRP1 and p-DRP1 were increased, while the expressions of OPA1 and Mfn2 were decreased. Expressions of mitochondrial autophagy associated proteins PINK1, Parkin, LC3II/LC3I increased, P62 decreased gradually, as well as the expressions of apoptosis related proteins Cleaved-Caspase-3, Caspase-3, and Caspase-9 increased, and Cyt-C expressions decreased. To further demonstrate the role of ROS and DRP1 in HT22 cell apoptosis induced by SiNPs, we selected the ROS inhibitor N-Acetylcysteine (NAC) and Dynamin-related protein 1 (DRP1) inhibitor Mdivi-1. The experimental results indicated that the above effects were remarkably improved after the use of inhibitors, further confirming that SiNPs induce the production of ROS in cells, activate DRP1, cause excessive mitochondrial division, induce mitophagy, destroy mitochondrial function and eventually lead to apoptosis.

2024-01-19·bioRxiv : the preprint server for biology

Efficacy of auxin-inducible protein degradation in C. elegans tissues using different auxins and TIR1-expressing strains.

作者: Nidhi Sharma ; Filipe Marques ; Paschalis Kratsios

The auxin-inducible degradation system has emerged as a powerful tool to deplete proteins of interest in cells and tissues of various model organisms, including C. elegans ^2-5 . Here, we present a detailed protocol to perform AID-driven spatiotemporal depletion of specific proteins in C. elegans tissues. First, we introduced the AID degron and a fluorescent reporter at two conserved proteins: (a) the transcription factor CFI-1 (human ARID3), which is expressed in the nucleus of multiple C. elegans neurons and head muscle cells ^6,7 , and (b) the broadly expressed translation initiation factor Y47D3A.21 (human DENR) that localizes in the cytoplasm. Second, we provide a step-by-step guide on how to generate C. elegans strains suitable for AID-mediated protein (CFI-1 and DENR) depletion. Third, we find that the degree of CFI-1 and DENR depletion in C. elegans tissues is comparable upon treatment with either natural auxin (indole-3-acetic acid (IAA) or a water-soluble synthetic auxin analog (K-NAA). Last, we compare the degree of AID-mediated CFI-1 depletion in C. elegans neurons when the transport inhibitor response 1 (TIR1), component of the SCF ubiquitin ligase complex, is provided in neurons or all somatic cells. Altogether, this protocol provides side-by-side comparisons of different auxins and TIR1-expressing lines. Such comparisons may benefit future studies of AID-mediated protein depletion in C. elegans .

Graphical abstract:

Image provided as pdf (together with Figures).

Highlights:

Efficient protein depletion in C. elegans tissues upon treatment with either natural or synthetic auxins. Pansomatic TIR1 expression leads to efficient depletion of CFI-1 and DENR.Panneuronal TIR1 expression leads to neuron-specific, yet variable CFI-1 depletion.The AID system is compatible with fluorescence microscopy, Western blotting and behavioral assays.

2024-01-08·Journal of molecular neuroscience : MN

Identification of SV2C and DENR as Key Biomarkers for Parkinson's Disease Based on Bioinformatics, Machine Learning, and Experimental Verification.

Article

作者: Jiecong Wu ; Wenqi Wu ; Ping Jiang ; Yuhao Xu ; Ming Yu

The objective of this study is to investigate the potential biomarkers and therapeutic target genes for Parkinson's disease (PD). We analyzed four datasets (GSE8397, GSE20292, GSE20163, GSE20164) from the Gene Expression Omnibus database. We employed weighted gene co-expression network analysis and differential expression analysis to select genes and perform functional analysis. We applied three algorithms, namely, random forest, support vector machine recursive feature elimination, and least absolute shrinkage and selection operator, to identify hub genes, perform functional analysis, and assess their clinical diagnostic potential using receiver operating characteristic (ROC) curve analysis. We employed the xCell website to evaluate differences in the composition patterns of immune cells in the GEO datasets. We also collected serum samples from PD patients and established PD cell model to validate the expression of hub genes using enzyme-linked immunosorbent assay and quantitative real-time polymerase chain reaction. Our findings identified SV2C and DENR as two hub genes for PD and decreased in PD brain tissue compared with controls. ROC analysis showed effectively value of SV2C and DENR to diagnose PD, and they were downregulated in the serum of PD patients and cell model. Functional analysis revealed that dopamine vesicle transport and synaptic vesicle recycling are crucial pathways in PD. Besides, the differences in the composition of immune cells, especially basophils and T cells, were discovered between PD and controls. In summary, our study identifies SV2C and DENR as potential biomarkers for diagnosing PD and provides a new perspective for exploring the molecular mechanisms of PD.

项与 DENR 相关的新闻（医药）

2023-08-07

·生物制品圈

靶向线粒体分裂蛋白Drp1的变构互作抑制剂设计

炎症细胞应激期间的线粒体功能障碍已被确定为一些未满足临床需求的疾病的重要驱动因素，例如败血症、神经退行性疾病和缺血性损伤等，不可控的细胞应激和炎症可能导致广泛的代谢崩溃和器官衰竭。因此，病理性线粒体裂变的药理学抑制是一种有希望的策略，可以平息过度活跃的炎症并预防多种细胞类型和疾病的线粒体功能障碍。线粒体分裂的主要驱动源是动力蛋白相关蛋白 1（dynamin-related protein 1，Drp1），它是一种大型的胞质GTP酶，可以从胞质转移到线粒体外膜，通过收缩环介导线粒体分裂。Drp1通过蛋白Fis1、Mff、MiD49和MiD51被招募到线粒体上。Drp1-Mff介导的裂变对于维持线粒体质量极为重要，而Drp1-Fis1则介导病理性线粒体裂变。目前虽已有一种Drp1-Fis1互作的选择性七肽抑制剂——P110，其展现出了良好的体外活性且无明显的体内毒性，但却受制于稳定性和难以口服而无法转化临床应用。最近，来自斯坦福大学医学院的研究团队发现P110结合在Drp1上的一个开关I相邻的凹槽（switch I-adjacent grove，SWAG），并筛选得到结合SWAG的小分子SC9，并在细胞和内毒素血症小鼠模型中模拟了P110的益处。首先，研究人员探究了P110的作用机制。P110的同源序列来自Drp1上开关1(switch I)的前半部分，而开关I是许多GTP酶中参与GTP水解的一段非结构化环，他们比对GTP结合前后的Drp1结构发现，GTP的结合会使switch I向GTP位点摆动从而打开一个凹槽，即SWAG。计算分析发现SWAG口袋成药潜力大，因此可针对该口袋设计小分子来调节Drp1的GTP酶活性和功能。为了评估SWAG作为潜在P110结合位点的作用，他们将Drp1上开关I上的两个残基D49和R53突变，发现会导致Drp1对cP110不再敏感，证明P110 结合依赖于 SWAG 残基 D49 和 R53 来调节 Drp1 GTP 酶活性。此外，体外环化的P110（cP110）能够减小Drp1 的GTP酶酶活的Vmax和Km值，并且GMPPCP（GTP类似物）能增强P110和Drp1的亲和力，说明P110作为Drp1的反竞争性抑制剂能稳固结合GTP形式的Drp1。接下来，他们在商业化合物集合文库虚拟筛选可能结合SWAG的小分子，并依据预测的亲和力排序命名，最终挑选出3个化合物SC1、SC3和SC9进行生化评估。与P110一样，SC1，SC3和SC9也是Drp1 WT的非竞争性抑制剂，在1μM 时，它们都降低了Drp1的Km和Vmax。D49A Drp1突变体被cP110，SC1和SC3抑制，但不受SC9抑制。与cP110一样，SC1和SC9对D49A/R53A双Drp1突变体的抑制活性显著降低。竞争性结合实验显示，SC1、SC3和SC9会与P110竞争结合Drp1寡聚体。另外，他们为了探究这些化合物的靶标选择性，对比检测了与Drp1有最高同源性的SWAG动力蛋白2（dynamin2, Dnm2）的GTPase酶活影响，发现cP110、SC3和SC9仅抑制Drp1的GTP酶活性。进而，研究人员研究了这些化合物是否拥有类似P110的细胞活性。他们使用细菌内毒素脂多糖（LPS）处理H9c2心肌细胞产生病理性的线粒体裂解表型，再用这些化合物处理，发现只有SC9能与P110一样维持线粒体的正常大小，SC1有微弱的恢复完整线粒体的作用，而SC3甚至会加剧线粒体的片段化，表现出细胞毒性。另外，LPS导致的线粒体膜电位下降也会受到P110和SC9的抑制，而SC1和SC3无效果。基于此，研究人员决定使用SC9进行后续研究，并发现SC9和P110一样能降低LPS诱导产生的高ROS水平的细胞数量至未处理的基线水平，即SC9能复刻P110在LPS诱导H9c2细胞产生的线粒体紊乱的治疗作用。接着他们探究了SC9的作用机制，看是否与P110一致。首先，他们检测了LPS诱导的与线粒体连接的Drp1寡聚体的含量，发现SC9和P110一样在不改变细胞整体Drp1含量情况下，将Drp1寡聚体的含量降低到空白对照组以下，即能阻断压力诱导的Drp1的寡聚化。另外，他们使用邻近连接实验检测了单细胞内Drp1-Fis1和Drp1-Mff的结合，SC9能减少LPS模拟的病理性Drp1-Fis1的结合水平，甚至比生理条件水平更低。而且SC9对介导线粒体生理性裂解的Drp1-Mff互作没有影响。由此可知，P110和SC9通过选择性抑制Drp1-Fis1相互作用阻断Drp1向线粒体移动。进一步对SC9在体外、细胞以及小鼠模型的活性表征发现，SC9抑制Drp1的GTP酶酶活的IC50为270 nM ± 60 nM，而抑制LPS诱导的细胞线粒体膜去极化的EC50为750 nM ± 290 nM。他们基于小鼠体重下降和小鼠败血症得分的两个指标，确认了SC9的剂量可以达到50mg/kg也不产生明显毒性。20mg/ml的单词腹腔注射后，血浆中的SC9浓度约为细胞实验EC50的17倍，说明该剂量可以在小鼠中产生药效，SC9在小鼠中透过血脑屏障的比例低，而两次注射SC9能延长SC9的半衰期；另外，他们还进行了标准安全毒理学筛查发现SC9无明显体内毒性。随后他们进行了LPS的盲法剂量递增实验，结果显示，虽然不同检测的最适LPS剂量不同，但SC9能增加检测的所有LPS剂量处理下的小鼠存活率，并且SC9治疗在LPS处理小鼠的体重、MSS、严重事件如呼吸困难的发生等指标都展现出良好效果。为了找到导致SC9这种治疗效果的参与调控的炎症因子，他们进行了小鼠免疫监测实验，发现SC9治疗的小鼠相比只有LPS处理的对照组的炎症因子水平明显下降，尤其是IL-13、IL-33R和M-CSF等，而抗炎因子如IL-10水平上升了28%。为了更好的建立临床内毒素血症的模型，研究人员在LPS诱导出内毒素血症的症状后，即LPS处理4h后再使用SC9治疗小鼠，导致脓毒症峰值评分降低 45%，说明SC9在诱导炎症反应后给药也仍然有效。综上，研究人员找到Drp1中的一个变构位点并命名为SWAG，并且发现了一个选择性结合SWAG位点从而抑制Drp1 GTP酶活的小分子SC9，该分子能选择性抑制病理性的Drp1-Fis1互作及其导致的线粒体紊乱并且与多肽抑制剂P110作用机制相同，并在LPS诱导的细胞和小鼠模型中都表现出良好的治疗效果。尽管SC9的半衰期较短且通过血脑屏障的能力较差，需要进一步的药物化学的优化，但该研究为其它GTPase的抑制剂开发提供了思路和途径，并且这种通过选择性抑制蛋白互作从而区分病理性和生理性线粒体裂解的化合物为解决许多疾病中线粒体失调导致的免疫代谢稳态提供了工具分子，对线粒体功能障碍引发的免疫代谢相关的疾病治疗和药物开发具有重要指导意义。参考文献：Rios, Luis, et al. "Targeting an allosteric site in dynamin-related protein 1 to inhibit Fis1-mediated mitochondrial dysfunction." Nat Commun. 2023, 14: 4356.

核酸药物