更新于：2024-05-01

12/15-LOX

花生四烯酸15-脂氧合酶

更新于：2024-05-01

基本信息

别名

12-LOX、12/15-lipoxygenase、15-LOX

+ [9]

简介

Non-heme iron-containing dioxygenase that catalyzes the stereo-specific peroxidation of free and esterified polyunsaturated fatty acids generating a spectrum of bioactive lipid mediators (PubMed:1944593, PubMed:8334154, PubMed:17052953, PubMed:24282679, PubMed:25293588, PubMed:32404334). It inserts peroxyl groups at C12 or C15 of arachidonate ((5Z,8Z,11Z,14Z)-eicosatetraenoate) producing both 12-hydroperoxyeicosatetraenoate/12-HPETE and 15-hydroperoxyeicosatetraenoate/15-HPETE (PubMed:1944593, PubMed:8334154, PubMed:17052953, PubMed:24282679). It may then act on 12-HPETE to produce hepoxilins, which may show pro-inflammatory properties (By similarity). Can also peroxidize linoleate ((9Z,12Z)-octadecadienoate) to 13-hydroperoxyoctadecadienoate/13-HPODE (PubMed:8334154). May participate in the sequential oxidations of DHA ((4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoate) to generate specialized pro-resolving mediators (SPMs)like resolvin D5 ((7S,17S)-diHPDHA) and (7S,14S)-diHPDHA, that actively down-regulate the immune response and have anti-aggregation properties with platelets (PubMed:32404334). Can convert epoxy fatty acids to hydroperoxy-epoxides derivatives followed by an intramolecular nucleophilic substitution leading to the formation of monocyclic endoperoxides (PubMed:25293588). Plays an important role during the maintenance of self-tolerance by peroxidizing membrane-bound phosphatidylethanolamine which can then signal the sorting process for clearance of apoptotic cells during inflammation and prevent an autoimmune response. In addition to its role in the immune and inflammatory responses, this enzyme may play a role in epithelial wound healing in the cornea through production of lipoxin A4 (LXA(4)) and docosahexaenoic acid-derived neuroprotectin D1 (NPD1; 10R,17S-HDHA), both lipid autacoids exhibit anti-inflammatory and neuroprotective properties. Furthermore, it may regulate actin polymerization which is crucial for several biological processes such as the phagocytosis of apoptotic cells. It is also implicated in the generation of endogenous ligands for peroxisome proliferator activated receptor (PPAR-gamma), hence modulating macrophage development and function. It may also exert a negative effect on skeletal development by regulating bone mass through this pathway. As well as participates in ER stress and downstream inflammation in adipocytes, pancreatic islets, and liver (By similarity). Finally, it is also involved in the cellular response to IL13/interleukin-13 (PubMed:21831839).

关联

项与 12/15-LOX 相关的药物

Vatiquinone

靶点

12/15-LOX

作用机制

12/15-LOX抑制剂

在研机构

PTC Therapeutics, Inc.

原研机构

Edison Pharmaceuticals, Inc.

在研适应症

Friedreich共济失调 [+6]

非在研适应症

自闭症谱系障碍 [+7]

最高研发阶段临床3期

首次获批国家/地区-

首次获批日期1800-01-20

Utreloxastat

靶点

12/15-LOX

作用机制

12/15-LOX抑制剂

在研机构

PTC Therapeutics, Inc. [+1]

原研机构

BioElectron Technology Corp.

在研适应症

肌萎缩侧索硬化 [+1]

非在研适应症

帕金森病

最高研发阶段临床2/3期

首次获批国家/地区-

首次获批日期1800-01-20

ML-355

靶点

12/15-LOX

作用机制

12/15-LOX抑制剂

在研机构

Veralox Therapeutics, Inc.初创企业

原研机构

Veralox Therapeutics, Inc.初创企业

在研适应症-

非在研适应症

肝素诱导的血小板减少伴血栓形成

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 12/15-LOX 相关的临床试验

JPRN-jRCT2011230043 / Recruiting临床2期

A PHASE 2, RANDOMIZED, DOUBLE-BLIND, PLACEBOCONTROLLED,PARALLEL STUDY TO ASSESS THE EFFICACY,SAFETY, TOLERABILITY, PK, AND BIOMARKER EFFECTS OF PTC857 IN ADULT SUBJECTS WITH AMYOTROPHIC LATERAL SCLEROSIS (CARDINALS)

开始日期2023-10-12

申办/合作机构-

JPRN-jRCT2011230040 / Recruiting临床2期

A PHASE 2, RANDOMIZED, DOUBLE-BLIND, PLACEBOCONTROLLED,PARALLEL STUDY TO ASSESS THE EFFICACY,SAFETY, TOLERABILITY, PK, AND BIOMARKER EFFECTS OFPTC857 IN ADULT SUBJECTS WITH AMYOTROPHIC LATERALSCLEROSIS (CARDINALS)

开始日期2023-09-29

申办/合作机构-

NCT05785819 / Recruiting临床2期

A Randomized, Double-Blind, Phase 2 Pilot Study of VLX-1005 Versus Placebo in Participants With Suspected Heparin Induced Thrombocytopenia Treated With Background Standard of Care

The purpose of this study is to evaluate the efficacy and safety of VLX-1005, a 12-lipoxygenase (12-LOX) enzyme inhibitor in treating heparin induced thrombocytopenia (HIT). Participants with suspected HIT will receive the usual standard of care, and will be assigned randomly to either VLX-1005 or placebo treatment. The study will measure important outcomes including platelet count, stroke, pulmonary embolus (clot to the lungs) and bleeding.

开始日期2023-09-26

申办/合作机构

Veralox Therapeutics, Inc.初创企业

100 项与 12/15-LOX 相关的临床结果

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100 项与 12/15-LOX 相关的转化医学

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0 项与 12/15-LOX 相关的专利（医药）

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1,833

项与 12/15-LOX 相关的文献（医药）

2024-12-01·Journal of enzyme inhibition and medicinal chemistry

Development of novel ALOX15 inhibitors combining dual machine learning filtering and fragment substitution optimisation approaches, molecular docking and dynamic simulation methods.

Article

作者: Yinglin Liao ; Peng Cao ; Lianxiang Luo

The oxidation of unsaturated lipids, facilitated by the enzyme Arachidonic acid 15-lipoxygenase (ALOX15), is an essential element in the development of ferroptosis. This study combined a dual-score exclusion strategy with high-throughput virtual screening, naive Bayesian and recursive partitioning machine learning models, the already established ALOX15 inhibitor i472, and a docking-based fragment substitution optimisation approach to identify potential ALOX15 inhibitors, ultimately leading to the discovery of three FDA-approved drugs that demonstrate optimal inhibitory potential against ALOX15. Through fragment substitution-based optimisation, seven new inhibitor structures have been developed. To evaluate their practicality, ADMET predictions and molecular dynamics simulations were performed. In conclusion, the compounds found in this study provide a novel approach to combat conditions related to ferroptosis-related injury by inhibiting ALOX15.

2024-03-01·3 Biotech

Genome-wide runs of homozygosity signatures in diverse Indian goat breeds.

Article

作者: Dibyasha Kar ; Indrajit Ganguly ; Sanjeev Singh ; Avnish Kumar Bhatia ; S P Dixit

The present study analyzed ROH and consensus ROH regions in 102 animals of eleven diverse Indian goat (Capra hircus) breeds using whole genome sequencing. A total of 51,705 ROH and 21,271 consensus regions were identified. The mean number of ROH per animal was highest in the meat breed, Jharkhand Black (2693) and lowest in the pashmina breed, Changthangi (60). The average length of ROH (AL_ROH) was maximum in Kanniadu (974.11 Kb) and minimum in Tellicherry (146.98 Kb). Long ROH is typically associated with more recent inbreeding, whereas short ROH is connected to more ancient inbreeding. The overall ROH-based genomic inbreeding (F_ROH) was highest for Jharkhand Black (0.602) followed by Kanniadu (0.120) and Sangamneri (0.108) among all breeds. F_ROH of Jharkhand Black was higher than Kanniadu up to 5 Mb ROH length category. However, in > 20 Mb ROH length category, Kanniadu (0.98) exhibited significantly higher F_ROH than Jharkhand Black (0.46). This implies that Kanniadu had higher levels of recent inbreeding than Jharkhand Black. Despite this, due to the presence of both recent and ancient inbreeding, Jharkhand Black demonstrated higher overall F_ROH compared to Kanniadu. ROH patterns revealed dual purpose (meat and dairy) and pashmina breeds as less consanguineous while recent inbreeding was apparent in meat breeds. Analysis of ROH consensus regions identified selection sweeps in key genes governing intramuscular fat deposition, meat tenderisation, lean meat production and carcass weight (CDK4, ALOX15, CASP9, PRDM16, DVL1) in meat breeds; milk fat percentage and mammary gland development (POLD1, NOTCH2, ARHGAP35) in dual purpose (meat and dairy) breeds; while cold adaptation and hair follicle development (APOBEC1, DNAJC3, F2RL1, FGF9) in pashmina breed. MAPK, RAS, BMP and Wnt signaling pathways associated with hair follicle morphogenesis in Changthangi were also identified. PCA analysis based on ROH consensus regions revealed that meat breeds are more diverse than other goat breeds/populations.

Supplementary Information:

The online version contains supplementary material available at 10.1007/s13205-024-03921-y.

2024-02-22·International journal of biological macromolecules

Synergistic effect of spermidine and ciprofloxacin against Alzheimer's disease in male rat via ferroptosis modulation.

Article

作者: Menna Allah M Youssef ; Tarek M Mohamed ; Azza A Bakry ; Mai M El-Keiy

Alzheimer's disease (AD) is a prevalent form of neurodegenerative disease with a complex pathophysiology that remains not fully understood, and the exact mechanism of neurodegeneration is uncertain. Ferroptosis has been linked to the progression of degenerative diseases observed in AD models. The present study is designed to investigate the protective effects of spermidine, a potent antioxidant and iron chelator, and its synergistic interactions with ciprofloxacin, another iron chelator, in modulating ferroptosis and mitigating AD progression in rats. This study investigated AD-related biomarkers like neurotoxic amyloid beta (Aβ), arginase I, and serotonin. Spermidine demonstrated an anti-ferroptotic effect in the AD model, evident from the modulation of ferroptosis parameters such as hippocampus iron levels, reduced protein expression of transferrin receptor 1 (TFR1), and arachidonate 15-lipoxygenase (ALOX15). Additionally, the administration of spermidine led to a significant increase in protein expression of phosphorylated nuclear factor erythroid 2-related factor 2 (p-Nrf2) and upregulation of Cystine/glutamate transporter (SLC7A11) gene expression. Moreover, spermidine notably decreased p53 protein levels, acrolein, and gene expression of spermidine/spermine N1-acetyltransferase 1 (SAT1). Overall, our findings suggest that spermidine and/or ciprofloxacin may offer potential benefits against AD by modulating ferroptosis. Furthermore, spermidine enhanced the antioxidant efficacy of ciprofloxacin and reduced its toxic effects.

项与 12/15-LOX 相关的新闻（医药）

2024-04-02

·精准药物

各类细胞死亡的方式与机制总结

首先是各种死亡提出的时间表具体形式如下1、Apoptosis（凋亡）细胞凋亡，为一种细胞程序性死亡。相对于细胞坏死（necrosis），细胞凋亡是细胞主动实施的。细胞凋亡一般由生理或病理性因素引起。而细胞坏死则主要为缺氧造成，两者可以很容易通过观察区分开来。细胞凋亡的发现：细胞凋亡分为外源性和内源性细胞凋亡：细胞的凋亡分为“内源性凋亡”和“外源性凋亡”。简单的说起来外源性凋亡就是，当它细胞接受到外界通知它死亡的信号的时候，它通过一系列复杂的级联反应，自己将自己破坏，导致死亡。内源性凋亡就是它感应到自身内部出现了一些问题的时候（比如DNA遭到破坏），也可能触发它启动它的自杀程序，导致它的死亡。细胞凋亡的分子机制：细胞凋亡的检测方法：2、Necroptosis，坏死性凋亡坏死性凋亡是类似于细胞坏死的一种程序性细胞死亡。RIPK3激活MLKL是坏死性凋亡的关键调节通路。上游诱导因子死亡受体（DR）、TLR或病毒分别通过RIPK1、TICAM1和ZBP1诱导RIPK3的激活。另外，粘附受体（AR）通过一种未知的适配蛋白或激酶激活RIPK3。• 死亡受体配体通过RHIM 介导 RIPK1与 RIPK3的结合，促进特定信号复合物"坏死体"的形成，最终导致 MLKL 的激活。• TLR配体通过TICAM1介导RIPK3-MLK依赖性坏死的发生。• 某些病毒可以直接与 RIPK3结合，也可以促进宿主蛋白 ZBP1与 RIPK3的结合，最终激活 MLKL。• 干扰素 α 受体或粘附受体可以通过一种不依赖 RIPK1、TICAM1或 ZBP1的替代途径激活RIPK3。RIPK3活化后，介导MLKL c-末端假激酶结构域不同位点的磷酸化，导致MLKL构象变化，并与带正电荷的六磷酸肌醇（IP6）结合，随后募集到磷脂酰肌醇中，并在质膜中插入和多聚化，从而导致质膜透化，造成Necroptosis的发生。3、细胞焦亡（Pyroptosis）细胞焦亡是由炎性小体激活引起的，在炎症和免疫中起着重要的作用。炎性小体可以分为典型的CASP1依赖性炎症小体和非典型的CASP11依赖性炎症小体：• 典型的CASP1依赖性炎症小体可以被病原体相关分子模式（PAMPs），损伤相关分子模式（DAMPs）或其他免疫反应选择性激活。• 非典型的CASP11依赖性炎症小体由巨噬细胞、单核细胞或其他细胞细胞质中的LPS激活，该过程不依赖细胞膜的TLR4受体。GSDMD被CASP11或CASP1切割产生22kDa C-末端片段（GSDMD-C）和31kDa N-末端片段（GSDMD-N）；GSDMD-N产生后立即移位到质膜的内部小叶与磷脂结合，诱导孔的形成，最终导致细胞膜裂解。而GSDMD-C抑制GSDMD-N的这一活性。4、Ferroptosis（铁死亡）Ferroptosis是由铁积累和脂质过氧化驱动的，其特征在于线粒体变小、线粒体嵴减少、线粒体膜密度增加和线粒体膜破裂增加。ACSL4、LPCAT3与ALOXs（尤其是ALOX15）途径介导多不饱和脂肪酸（包括花生四烯酸）的氧化，这对于Ferroptosis的脂毒性是必需的；其中ACSL4的上调是ferroptosis的标志。相反，一些抗氧化系统，特别是 XC-系统（包括核心组件 SLC7A11）、GPX4、NFE2L2和某些热休克蛋白（如HSPs），抑制Ferroptosis脂质过氧化过程。对铁死亡感兴趣的同学，可以看一下这篇文献5、Parthanatos2023年发表的博士论文中，此种死亡方式还是以英文进行描述。Parthanatos是一种PARP1依赖性，由氧化应激诱导的DNA损伤激活。• AIFM1依赖型Parthanatos：活化的PARP1结合AIFM1，介导AIFM1从线粒体移位到细胞核，继而导致部分染色体的溶解。• AIFM1非依赖型Parthanatos：在某些条件下可发生，如干性黄斑变性。AIFM1依赖性和非依赖性parthanatos与其他RCD（如自噬依赖性细胞死亡和坏死性凋亡）之间的相互影响可能涉及DNA损伤相关的疾病，如神经退行性疾病，心肌梗塞和糖尿病。6、Entotic cell deathEntotic cell death是细胞“同类相食”的一种，一个细胞吞噬并杀死另一个细胞，其特征是细胞内细胞结构。Entotic cell death激活后通过LC3相关的吞噬作用（LAP）和组织蛋白酶B（CTSB）介导的溶酶体降解途径吞噬和杀死同类细胞。• 细胞粘附和细胞骨架重排通路（如肌动蛋白、肌球蛋白、RHOA和ROCK）在控制Entosis诱导作用中起重要作用。• 除细胞粘附和细胞骨架重排途径外，其他信号分子和调节因子（如CDC42）也通过不同的机制参与Entosis的调节。7、Netotic cell deathNetotic cell death是由NET驱动的,其受NADPH氧化酶介导的ROS产生和组蛋白瓜氨酸化的调节。NETosis是涉及多个信号和步骤的动态过程：• NADPH氧化酶介导的ROS产生；• 自噬；• 颗粒酶的释放和转运；• Cathelecidin家族多肽从细胞质到细胞核的易位。NETosis介导组蛋白瓜氨酸化，最终导致染色质去浓缩、核膜破坏和染色质纤维的释放。8、Lysosome-dependent cell death溶酶体依赖性细胞死亡溶酶体依赖性细胞死亡（LCD），也称为溶酶体细胞死亡，是由LMP释放的水解酶（组织蛋白酶）或铁来介导的一种RCD形式，其特征是溶酶体破裂。当细胞暴露于溶酶体洗涤剂、二肽甲酯、脂质代谢物和ROS时，溶酶体破裂，继而释放大量的水解酶，导致LCD的发生。其中组织蛋白酶在LCD中起主要作用，阻断组织蛋白酶的表达或活性可减轻LCD的发生。溶酶体膜透化还可以在细胞凋亡、自噬依赖性细胞死亡和Ferroptosis的情况下放大细胞死亡信号传导，从而增加了细胞死亡途径的复杂性。9、Autophagy-dependent cell death自噬依赖性细胞死亡自噬依赖性细胞死亡是由自噬分子机制驱动的一种RCD，其特征是自噬空泡化。Tat-Beclin 1诱导自噬依赖性细胞死亡的发生，该分子是一种自噬诱导肽，融合了 BECN1和 HIV Tat 的蛋白氨基酸。该过程可以通过阻断Tat-Beclin 1上游的Na+/K+ -ATP酶来抑制。自噬依赖性细胞死亡可能在神经毒性和缺氧缺血诱导的神经元死亡中起重要作用，提示这种类型的 RCD 可能作为神经保护的靶点。自噬依赖性细胞死亡是由自噬分子机制驱动的一种RCD，其特征是自噬空泡化。Tat-Beclin 1诱导自噬依赖性细胞死亡的发生，该分子是一种自噬诱导肽，融合了 BECN1和 HIV Tat 的蛋白氨基酸。该过程可以通过阻断Tat-Beclin 1上游的Na+/K+ -ATP酶来抑制。自噬依赖性细胞死亡可能在神经毒性和缺氧缺血诱导的神经元死亡中起重要作用，提示这种类型的 RCD 可能作为神经保护的靶点。10、AlkaliptosisAlkaliptosis是一种由细胞内碱化作用驱动的。已知IKBKB-NF-κB途径依赖性碳酸酐酶9（CA9）的下调可以诱导Alkaliptosis的发生。Alkaliptosis的具体分子作用机制仍不清楚。11、Oxeiptosis（氧死亡）Oxeiptosis是氧自由基诱导的不依赖半胱天冬酶的新型RCD，该过程由KEAP1-PGAM5-AIFM1途径驱动。过度活化的KEAP1可以NFE2L2非依赖性方式介导H2O2诱导的Oxeiptosis，通过KEAP1-PGAM5途径介导AIFM1 Ser116的去磷酸化。细胞死亡研究非常火热，也是我研究的一个方向，分享出来和大家一起学习。内容转载自医学检验知识速记，如有侵权，请联系删除声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓

临床1期临床终止

2023-11-12

·生物制品圈

干货分享 | 各类细胞死亡的方式与机制总结

首先是各种死亡提出的时间表具体形式如下1、Apoptosis（凋亡）细胞凋亡，为一种细胞程序性死亡。相对于细胞坏死（necrosis），细胞凋亡是细胞主动实施的。细胞凋亡一般由生理或病理性因素引起。而细胞坏死则主要为缺氧造成，两者可以很容易通过观察区分开来。细胞凋亡的发现：细胞凋亡分为外源性和内源性细胞凋亡：细胞的凋亡分为“内源性凋亡”和“外源性凋亡”。简单的说起来外源性凋亡就是，当它细胞接受到外界通知它死亡的信号的时候，它通过一系列复杂的级联反应，自己将自己破坏，导致死亡。内源性凋亡就是它感应到自身内部出现了一些问题的时候（比如DNA遭到破坏），也可能触发它启动它的自杀程序，导致它的死亡。细胞凋亡的分子机制：细胞凋亡的检测方法：2、Necroptosis，坏死性凋亡坏死性凋亡是类似于细胞坏死的一种程序性细胞死亡。RIPK3激活MLKL是坏死性凋亡的关键调节通路。上游诱导因子死亡受体（DR）、TLR或病毒分别通过RIPK1、TICAM1和ZBP1诱导RIPK3的激活。另外，粘附受体（AR）通过一种未知的适配蛋白或激酶激活RIPK3。• 死亡受体配体通过RHIM 介导 RIPK1与 RIPK3的结合，促进特定信号复合物"坏死体"的形成，最终导致 MLKL 的激活。• TLR配体通过TICAM1介导RIPK3-MLK依赖性坏死的发生。• 某些病毒可以直接与 RIPK3结合，也可以促进宿主蛋白 ZBP1与 RIPK3的结合，最终激活 MLKL。• 干扰素 α 受体或粘附受体可以通过一种不依赖 RIPK1、TICAM1或 ZBP1的替代途径激活RIPK3。RIPK3活化后，介导MLKL c-末端假激酶结构域不同位点的磷酸化，导致MLKL构象变化，并与带正电荷的六磷酸肌醇（IP6）结合，随后募集到磷脂酰肌醇中，并在质膜中插入和多聚化，从而导致质膜透化，造成Necroptosis的发生。3、细胞焦亡（Pyroptosis）细胞焦亡是由炎性小体激活引起的，在炎症和免疫中起着重要的作用。炎性小体可以分为典型的CASP1依赖性炎症小体和非典型的CASP11依赖性炎症小体：• 典型的CASP1依赖性炎症小体可以被病原体相关分子模式（PAMPs），损伤相关分子模式（DAMPs）或其他免疫反应选择性激活。• 非典型的CASP11依赖性炎症小体由巨噬细胞、单核细胞或其他细胞细胞质中的LPS激活，该过程不依赖细胞膜的TLR4受体。GSDMD被CASP11或CASP1切割产生22kDa C-末端片段（GSDMD-C）和31kDa N-末端片段（GSDMD-N）；GSDMD-N产生后立即移位到质膜的内部小叶与磷脂结合，诱导孔的形成，最终导致细胞膜裂解。而GSDMD-C抑制GSDMD-N的这一活性。4、Ferroptosis（铁死亡）Ferroptosis是由铁积累和脂质过氧化驱动的，其特征在于线粒体变小、线粒体嵴减少、线粒体膜密度增加和线粒体膜破裂增加。ACSL4、LPCAT3与ALOXs（尤其是ALOX15）途径介导多不饱和脂肪酸（包括花生四烯酸）的氧化，这对于Ferroptosis的脂毒性是必需的；其中ACSL4的上调是ferroptosis的标志。相反，一些抗氧化系统，特别是 XC-系统（包括核心组件 SLC7A11）、GPX4、NFE2L2和某些热休克蛋白（如HSPs），抑制Ferroptosis脂质过氧化过程。对铁死亡感兴趣的同学，可以看一下这篇文献5、Parthanatos2023年发表的博士论文中，此种死亡方式还是以英文进行描述。Parthanatos是一种PARP1依赖性，由氧化应激诱导的DNA损伤激活。• AIFM1依赖型Parthanatos：活化的PARP1结合AIFM1，介导AIFM1从线粒体移位到细胞核，继而导致部分染色体的溶解。• AIFM1非依赖型Parthanatos：在某些条件下可发生，如干性黄斑变性。AIFM1依赖性和非依赖性parthanatos与其他RCD（如自噬依赖性细胞死亡和坏死性凋亡）之间的相互影响可能涉及DNA损伤相关的疾病，如神经退行性疾病，心肌梗塞和糖尿病。6、Entotic cell deathEntotic cell death是细胞“同类相食”的一种，一个细胞吞噬并杀死另一个细胞，其特征是细胞内细胞结构。Entotic cell death激活后通过LC3相关的吞噬作用（LAP）和组织蛋白酶B（CTSB）介导的溶酶体降解途径吞噬和杀死同类细胞。• 细胞粘附和细胞骨架重排通路（如肌动蛋白、肌球蛋白、RHOA和ROCK）在控制Entosis诱导作用中起重要作用。• 除细胞粘附和细胞骨架重排途径外，其他信号分子和调节因子（如CDC42）也通过不同的机制参与Entosis的调节。7、Netotic cell deathNetotic cell death是由NET驱动的,其受NADPH氧化酶介导的ROS产生和组蛋白瓜氨酸化的调节。NETosis是涉及多个信号和步骤的动态过程：• NADPH氧化酶介导的ROS产生；• 自噬；• 颗粒酶的释放和转运；• Cathelecidin家族多肽从细胞质到细胞核的易位。NETosis介导组蛋白瓜氨酸化，最终导致染色质去浓缩、核膜破坏和染色质纤维的释放。8、Lysosome-dependent cell death溶酶体依赖性细胞死亡溶酶体依赖性细胞死亡（LCD），也称为溶酶体细胞死亡，是由LMP释放的水解酶（组织蛋白酶）或铁来介导的一种RCD形式，其特征是溶酶体破裂。当细胞暴露于溶酶体洗涤剂、二肽甲酯、脂质代谢物和ROS时，溶酶体破裂，继而释放大量的水解酶，导致LCD的发生。其中组织蛋白酶在LCD中起主要作用，阻断组织蛋白酶的表达或活性可减轻LCD的发生。溶酶体膜透化还可以在细胞凋亡、自噬依赖性细胞死亡和Ferroptosis的情况下放大细胞死亡信号传导，从而增加了细胞死亡途径的复杂性。9、Autophagy-dependent cell death自噬依赖性细胞死亡自噬依赖性细胞死亡是由自噬分子机制驱动的一种RCD，其特征是自噬空泡化。Tat-Beclin 1诱导自噬依赖性细胞死亡的发生，该分子是一种自噬诱导肽，融合了 BECN1和 HIV Tat 的蛋白氨基酸。该过程可以通过阻断Tat-Beclin 1上游的Na+/K+ -ATP酶来抑制。自噬依赖性细胞死亡可能在神经毒性和缺氧缺血诱导的神经元死亡中起重要作用，提示这种类型的 RCD 可能作为神经保护的靶点。自噬依赖性细胞死亡是由自噬分子机制驱动的一种RCD，其特征是自噬空泡化。Tat-Beclin 1诱导自噬依赖性细胞死亡的发生，该分子是一种自噬诱导肽，融合了 BECN1和 HIV Tat 的蛋白氨基酸。该过程可以通过阻断Tat-Beclin 1上游的Na+/K+ -ATP酶来抑制。自噬依赖性细胞死亡可能在神经毒性和缺氧缺血诱导的神经元死亡中起重要作用，提示这种类型的 RCD 可能作为神经保护的靶点。10、AlkaliptosisAlkaliptosis是一种由细胞内碱化作用驱动的。已知IKBKB-NF-κB途径依赖性碳酸酐酶9（CA9）的下调可以诱导Alkaliptosis的发生。Alkaliptosis的具体分子作用机制仍不清楚。11、Oxeiptosis（氧死亡）Oxeiptosis是氧自由基诱导的不依赖半胱天冬酶的新型RCD，该过程由KEAP1-PGAM5-AIFM1途径驱动。过度活化的KEAP1可以NFE2L2非依赖性方式介导H2O2诱导的Oxeiptosis，通过KEAP1-PGAM5途径介导AIFM1 Ser116的去磷酸化。细胞死亡研究非常火热，也是我研究的一个方向，分享出来和大家一起学习。识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

临床1期临床终止

2023-06-20

·GlobeNewswire-Health Care

Veralox Names Jonathan Mow as Chief Executive Officer as the Company Advances Development of First-in-Class Therapies for Immune-Mediated Diseases in Conjunction with Financing

-- New Financing of $24 Million Fully Funds the Phase 2 Clinical Program for Lead Candidate VLX-1005 -- Company Prepares to Evaluate VLX-1005 in Heparin-Induced Thrombocytopenia (HIT) FREDERICK, Md., June 20, 2023 (GLOBE NEWSWIRE) -- Veralox Therapeutics, a clinical-stage biotechnology company developing a new class of therapies targeting the 12-lipoxygenase (12-LOX) pathway to address some of medicine’s most persistent and serious immune-mediated diseases, today announced the appointment of Jonathan Mow as the company’s new chief executive officer. Mr. Mow’s appointment comes as Veralox secured $24 million in funding to advance VLX-1005 through a Phase 2a proof-of-concept study evaluating its impact on heparin-induced thromobcytopenia (HIT), a life-threatening rare disease caused by an aberrant immune response to heparin exposure. The investment round included new investors Pappas Capital and NYBC Ventures and existing investors Hatteras Venture Partners, Sanofi Ventures, JDRF T1D Fund and Genesys Capital, amongst others. In conjunction with the financing, the company welcomes Peter Young of Pappas Capital as a director and Meg Wood of NYBC Ventures as an observer. “VLX-1005 has great promise to revolutionize the treatment of HIT and other immune-mediated diseases,” Mr. Young said. “I am thrilled to join the board at such an exciting time, and to be working with a leader of Jonathan’s caliber to move into later stages of clinical development.” “This is an exciting time for Veralox as we head into our proof-of-concept Phase 2 study with VLX-1005 for HIT, a serious complication subsequent to heparin exposure that is accompanied by significant morbidity and mortality,” Mr. Mow said. “Our novel approach with 12-LOX inhibitors has great potential in this and other diseases and I would like to thank our investors for their financial support of our important mission and giving me the opportunity to lead this world-class effort and team.” Mr. Mow brings more than 25 years of accomplishments in biotechnology management to Veralox, most recently serving as CEO of PhaseBio Pharmaceuticals. At PhaseBio, he led the company’s scientific and business transformations, guiding the company from early-stage research to Phase 3 development, and through a successful initial public offering in 2018. Earlier in his career, Mr. Mow served as vice president, business development for Amylin Pharmaceuticals until its sale to Bristol-Myers Squibb in 2012; was co-founder and vice president, commercial and business development of Corus Pharma, Inc. until its acquisition by Gilead Sciences in 2006; and headed business development for PathoGenesis Corporation until its acquisition by Chiron Corporation in 2000. Mr. Mow has also held positions in marketing, marketing research and sales at Bristol-Myers Squibb, Wyeth/Lederle International and Syntex Laboratories. He holds a B.S. in mechanical engineering from University of California at Berkeley and M.B.A. from Carnegie Mellon University’s Tepper School of Business. About Veralox TherapeuticsVeralox Therapeutics Inc. is the clinical leader in developing first-in-class therapeutics targeting 12-lipoxygenase, pioneering a new class of therapies that treat the underlying pathologies of serious immune-inflammatory diseases with unmet medical needs. The company’s lead candidate, VLX-1005, is in development for the treatment of patients with heparin-induced thrombocytopenia (HIT). VLX-1005 has orphan drug designation in the United States and has been awarded Fast Track Designation by the U.S. Food and Drug Administration. Second generation therapeutic products are under development for type 1 diabetes and other immune-mediated and inflammatory diseases. For more information, visit our website: https://veralox.com/. Media Contact: Lisa GuitermanScient PR202-330-3431Lisa.guiterman@gmail.com

临床2期高管变更孤儿药快速通道