更新于：2024-11-01

PSAP

更新于：2024-11-01

基本信息

别名

A1 activator、Cerebroside sulfate activator、Co-beta-glucosidase

+ [22]

简介

Saposin-A and saposin-C stimulate the hydrolysis of glucosylceramide by beta-glucosylceramidase (EC 3.2.1.45) and galactosylceramide by beta-galactosylceramidase (EC 3.2.1.46). Saposin-C apparently acts by combining with the enzyme and acidic lipid to form an activated complex, rather than by solubilizing the substrate. Saposin-B stimulates the hydrolysis of galacto-cerebroside sulfate by arylsulfatase A (EC 3.1.6.8), GM1 gangliosides by beta-galactosidase (EC 3.2.1.23) and globotriaosylceramide by alpha-galactosidase A (EC 3.2.1.22). Saposin-B forms a solubilizing complex with the substrates of the sphingolipid hydrolases. Saposin-D is a specific sphingomyelin phosphodiesterase activator (EC 3.1.4.12). Saposins are specific low-molecular mass non-enzymic proteins, they participate in the lysosomal degradation of sphingolipids, which takes place by the sequential action of specific hydrolases. Behaves as a myelinotrophic and neurotrophic factor, these effects are mediated by its G-protein-coupled receptors, GPR37 and GPR37L1, undergoing ligand-mediated internalization followed by ERK phosphorylation signaling.

关联

项与 PSAP 相关的药物

CDD-3290

靶点

PSAP

作用机制

PSAP inhibitors

在研机构

Baylor College of Medicine

原研机构

Baylor College of Medicine

在研适应症

避孕

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

CN115850423

专利挖掘

靶点

PSAP

作用机制-

在研机构

BGI Research

原研机构

BGI Research

在研适应症

感染

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 PSAP 相关的临床结果

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100 项与 PSAP 相关的转化医学

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0 项与 PSAP 相关的专利（医药）

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685

项与 PSAP 相关的文献（医药）

2025-01-01·Journal of Affective Disorders

Intermittent escitalopram treatment and reactive aggression in women with premenstrual irritability and anger: A crossover study

Article

作者: Gröndal, Maria ; Luke, Timothy J ; Eriksson, Elias ; Näslund, Jakob ; Englund, Christin ; Winblad, Stefan ; Ask, Karl

BACKGROUNDSelective serotonin reuptake inhibitors (SSRI) are the primary treatment for premenstrual mood symptoms and particularly effective in reducing reactive aggression in the forms of irritability and anger. The present study examined whether behavioral responses in laboratory measures of reactive aggression are influenced by medication with the SSRI escitalopram in women reporting high levels of premenstrual irritability/anger.METHODSParticipants (N = 34) rated the cardinal mood symptoms of premenstrual dysphoric disorder over three menstrual cycles. During the second and third cycles, participants received escitalopram (20 mg) or placebo in a single-blind, cross-over design. In the luteal phase of the intervention cycles, participants completed two aggression tasks: The Anger-Infused Ultimatum Game (AI-UG) and the Point Subtraction Aggression Paradigm (PSAP). Additionally, they rated expression and control of anger using the State-Trait Anger Expression Inventory-2 (STAXI-2) once in the luteal phase and once in the follicular phase.RESULTSWhile irritability/anger was reduced in the treatment (vs. placebo) cycle, no effect of escitalopram was detected in the PSAP. Escitalopram decreased reactive aggressive behavior in the AI-UG but only for a subset of participants who experienced a sharp premenstrual rise in outwardly expressed anger and/or did not experience a premenstrual rise in inwardly expressed anger.LIMITATIONSThe participants' symptoms were based on the severity of only premenstrual irritability/anger, limiting the generalizability to the broader group of PMDD patients.CONCLUSIONThe results suggest that the behavioral consequences of severe premenstrual irritability/anger are not easily captured by traditional measures of reactive aggression and underline the importance of considering individual differences in symptom expression.

2024-12-01·Cellular and Molecular Life Sciences

The exon junction complex is required for DMD gene splicing fidelity and myogenic differentiation

Article

作者: Tuffery-Giraud, Sylvie ; Cossée, Mireille ; Carnac, Gilles ; Van Goethem, Charles ; Miro, Julie ; Notarnicola, Cécile ; Koenig, Michel ; Da Cunha, Dylan ; Hugon, Gérald

AbstractDeposition of the exon junction complex (EJC) upstream of exon-exon junctions helps maintain transcriptome integrity by preventing spurious re-splicing events in already spliced mRNAs. Here we investigate the importance of EJC for the correct splicing of the 2.2-megabase-long human DMD pre-mRNA, which encodes dystrophin, an essential protein involved in cytoskeletal organization and cell signaling. Using targeted RNA-seq, we show that knock-down of the eIF4A3 and Y14 core components of EJC in a human muscle cell line causes an accumulation of mis-splicing events clustered towards the 3′ end of the DMD transcript (Dp427m). This deregulation is conserved in the short Dp71 isoform expressed ubiquitously except in adult skeletal muscle and is rescued with wild-type eIF4A3 and Y14 proteins but not with an EJC assembly-defective mutant eIF4A3. MLN51 protein and EJC-associated ASAP/PSAP complexes independently modulate the inclusion of the regulated exons 71 and 78. Our data confirm the protective role of EJC in maintaining splicing fidelity, which in the DMD gene is necessary to preserve the function of the critical C-terminal protein–protein interaction domain of dystrophin present in all tissue-specific isoforms. Given the role of the EJC in maintaining the integrity of dystrophin, we asked whether the EJC could also be involved in the regulation of a mechanism as complex as skeletal muscle differentiation. We found that eIF4A3 knockdown impairs myogenic differentiation by blocking myotube formation. Collectively, our data provide new insights into the functional roles of EJC in human skeletal muscle.

2024-10-18·Biochemistry

Molecular Characterization of Ancient Prosaposin-like Proteins from the Protist Dictyostelium discoideum.

Article

作者: Ortjohann, Marius ; Leippe, Matthias

To combat the permanent exposure to potential pathogens every organism relies on an immune system. Important factors in innate immunity are antimicrobial peptides (AMPs) that are structurally highly diverse. Some AMPs are known to belong to the saposin-like proteins (SAPLIPs), a group of polypeptides with a broad functional spectrum. The model organism Dictyostelium discoideum possesses a remarkably large arsenal of potential SAPLIPs, which are termed amoebapore-like peptides (Apls), but the knowledge about these proteins is very limited. Here, we report about the biochemical characterization of AplE1, AplE2, AplK1, and AplK2, which are derived from the two precursor proteins AplE and AplK, thereby resembling prosaposins of vertebrates. We produced these Apls as recombinant polypeptides in Escherichia coli using a self-splicing intein to remove an affinity tag used for purification. All recombinant Apls exhibited pore-forming activity in a pH-dependent manner, as evidenced by liposome depolarization, showing higher activities the more acidic the setting was. Lipid preference was detected for negatively charged phospholipids and in particular for cardiolipin. Antimicrobial activity against various bacteria was found to be inferior in classical microdilution assays. However, all of the Apls studied permeabilized the cytoplasmic membrane of live Bacillus subtilis. Collectively, we assume that the selected Apls interact by their cationic charge with negatively charged bacterial membranes in acidic environments such as phagolysosomes and eventually lyse the target cells by pore formation.

项与 PSAP 相关的新闻（医药）

2024-02-23

·生物谷

Science：新方法重新暴露癌症抗原以增强肿瘤免疫疗法

肿瘤组织中含有大量垂死细胞，它们会脱落含有肿瘤抗原的小囊泡。称为树突细胞的免疫细胞会摄取这些囊泡，处理抗原，并在其表面呈递抗原碎片，从而教会T细胞识别和攻击这些抗原。成功的癌症免疫疗法涉及激活患者自身的 T 细胞，以识别肿瘤表面上称为抗原的特征性蛋白并对其进行攻击。但有些肿瘤有一个诀窍：它们通过阻止其抗原的显示来躲避免疫系统的攻击。在一项新的研究中，来自美国哈佛医学院等研究机构的研究人员在小鼠身上找到了绕过这种防御的方法。他们指出其中的关键在于一种名为prosaposin的蛋白。这些发现为开发附加疗法提供了一种策略，从而使癌症免疫疗法更加有效。相关研究结果近期发表在Science期刊上，论文标题为“Hyperglycosylation of prosaposin in tumor dendritic cells drives immune escape”。肿瘤组织中含有大量垂死细胞，它们会脱落含有肿瘤抗原的小囊泡。称为树突细胞的免疫细胞会摄取这些囊泡，处理抗原，并在其表面呈递抗原碎片，从而教会T细胞识别和攻击这些抗原。这些作者发现，如果没有prosaposin，树突细胞就无法分解囊泡，并将肿瘤抗原作为一种教学工具呈递给免疫系统。具体来说，他们发现树突细胞需要一种叫做saposins的蛋白，而saposins由prosaposin形成。论文通讯作者作者、波士顿儿童医院细胞与分子医学项目儿科副教授Florian Winau解释说，“我们发现，要消化这些囊泡并将肿瘤抗原释放出来以呈递给免疫系统，就需要saposins。” 让肿瘤抗原无所遁形 Winau及其同事们发现，肿瘤通过在prosaposin中加入糖分子链，使其抗原无法被免疫系统识别。这使得树突细胞分泌prosaposin，耗尽了它们的saposins供应。这样，树突细胞就无法消化囊泡，并释放出里面的肿瘤抗原。这些作者的下一步是尝试重新添加prosaposin。在皮肤癌黑色素瘤的小鼠模型中，他们给这些小鼠静脉注射了一种靶向树突细胞的抗体。这种疗法使得它们的免疫系统再次检测到肿瘤抗原并激活 T 细胞。图片来自Science, 2024, doi:10.1126/science.adg1955 当这些作者将prosaposin与免疫检查点抑制剂药物结合使用时，他们发现肿瘤生长有所减少。不过要确认基于prosaposin的治疗是否对人类有效，还需要进一步的研究。 Winau及其同事们已经申请了这项技术的专利。他们与一家行业合作伙伴合作，设计了一种靶向系统来递送prosaposin，并希望开发出一种候选药物，在人体临床试验中进行测试。在另一个项目中，他们正在开发一种诊断测试，用于检测人体血液中糖分子链修饰的prosaposin。他们的目标指出当患者的肿瘤抗原呈递受损、肿瘤正在逃避免疫攻击时，需要改变治疗。（生物谷 Bioon.com）参考资料： Pankaj Sharma et al. Hyperglycosylation of prosaposin in tumor dendritic cells drives immune escape. Science, 2024, doi:10.1126/science.adg1955. Re-exposing a cancer protein to enhance immunotherapyhttps://medicalxpress.com/news/2024-02-exposing-cancer-protein-immunotherapy.html

免疫疗法

2024-01-12

·药明康德

前沿 | Nature、Science重磅三连，揭露肿瘤疯狂生长秘诀！

▎药明康德内容团队编辑近期，《自然》和《科学》杂志共带来了3项肿瘤领域的重磅研究，从不同角度为我们解析为何肿瘤能够逃脱免疫系统的监管、实现快速生长，并且每项研究都提供了用于未来肿瘤治疗的潜在靶点和新策略。让免疫细胞识别肿瘤DNA损伤其中，发表于《自然》杂志的新研究由北卡罗莱纳大学研究团队完成，该篇论文解答了肿瘤中的一个关键问题——肿瘤存在如此之多的DNA损伤，为何对DNA稳定性极其敏感的免疫细胞不会清除掉它们呢？要知道，我们的身体每时每刻都可能遭受外来病原体的攻击，一些外来的DNA病毒，以及各种原因导致的DNA损伤都会被免疫系统视为威胁或者废弃物，这些异常的DNA信息会提示免疫细胞及时工作，将这些坏东西清除出去。该过程非常依赖一种名为环GMP-AMP 合成酶（cGAS）的蛋白，之前的研究发现，cGAS蛋白平时会与组蛋白结合，并不能游离到环境中识别损伤DNA片段。在新论文中，作者发现了帮助cGAS从组蛋白解脱出来的分子MRE11。MRE11本身也会参与DNA监测和修复，但这是首次有研究发现它还能助力cGAS的释放。▲MRE11与cGAS合作是抑制肿瘤生长的关键（图片来源：参考资料[1]）由于肿瘤细胞中cGAS经常处于不活跃状态，它们才能得以逃脱掉免疫系统的追踪。但新研究发现的这一机制有望从MRE11下手，重新激活肿瘤中的cGAS。研究还发现，MRE11能与游离的cGAS相互作用，促使细胞发生坏死性凋亡。接下来，作者计划在临床试验中测试，激活这一信号通路能否改善免疫治疗的效果。如何暴露肿瘤抗原？《科学》杂志的一篇论文主要关注了肿瘤的抗原呈递机制。肿瘤抗原呈递是引起T细胞免疫反应的关键。T细胞需要识别肿瘤表面一些特异性的抗原，才会启动杀伤程序。然而许多肿瘤也意识到这一点，学会了隐藏自己表面的抗原，这也是癌细胞逃避免疫系统的一种常见手段。为了应对这一情况，树突状细胞（DC）承担了抗原呈递的工作，它们会通过吞没肿瘤抗原，然后经过处理后呈递在自己表面来引起T细胞的注意。来自哈佛医学院的研究团队发现，这一过程中，鞘脂激活蛋白原（pSAP）起着重要作用，树突状细胞溶酶体中的pSAP以及它的单体同源物负责将肿瘤细胞的凋亡小体进行分解，然后促成抗原呈递和激活T细胞。图片来源：123RF不过在肿瘤微环境中，肿瘤产生的转化生长因子β会诱导pSAP高糖基化，这将抑制pSAP的后续处理和分泌，最终导致树突状细胞呈递抗原的过程关闭。作者在检查黑色素瘤患者的肿瘤样本时也发现，其中的树突状细胞内部有着pSAP高糖基化。而在树突状细胞中恢复pSAP可以提升免疫治疗的效果，这也为未来的肿瘤疗法提供了全新的思路。揭秘叛变的免疫细胞另外一项《科学》研究由新加坡科技研究局（A*STAR）与上海交大医学院附属仁济医院等研究机构合作完成，研究关注了中性粒细胞在肿瘤免疫反应的作用。中性粒细胞会在感染或损伤后迅速被招募到相关区域，这一过程在肿瘤病理发生时同样会发生。不过当中性粒细胞持续浸润到肿瘤中时，患者的预后往往较差，这也预示着这些免疫细胞的状态发生了改变。新研究发现，中性粒细胞进入肿瘤内部后会经历不可逆的表观遗传变化以及转录组、蛋白组学修饰，这会导致它们转变为一种独特的终末分化状态。▲浸润到肿瘤的中性粒细胞会促进肿瘤血管生成（图片来源：参考资料[3]）这些细胞不会帮助杀伤肿瘤，它们主要发挥促进血管生成的作用，这对肿瘤生长是有利的。作者在多种肿瘤中发现了类似的变化，这也提示靶向这些中性粒细胞或是增强免疫疗法效果的潜在方法。综上，这些研究分别从cGAS、树突状细胞和中性粒细胞3个方向发现了肿瘤持续生长的原因，可见癌细胞为了繁殖壮大使用了许多不同通路的生存策略。而科学家挖掘到的这些细节也将为未来的肿瘤治疗研发奠定基础。参考资料：[1] MRE11 liberates cGAS from nucleosome sequestration during tumorigenesis. Nature (2024). DOI: https://doi.org/10.1038/s41586-023-06889-6[2] Hyperglycosylation of prosaposin in tumor dendritic cells drives immune escape. Science (2024), DOI: 10.1126/science.adg1955[3] Deterministic reprogramming of neutrophils within tumors. Science (2024), DOI: 10.1126/science.adf6493本文来自药明康德内容微信团队，欢迎转发到朋友圈，谢绝转载到其他平台。如有开设白名单需求，请在“学术经纬”公众号主页回复“转载”获取转载须知。其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。更多推荐点个“在看”再走吧~

免疫疗法