预约演示

更新于：2025-01-23

MAPK13

更新于：2025-01-23

基本信息

别名

MAP kinase 13、MAP kinase p38 delta、MAPK 13

+ [8]

简介

Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK13 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as pro-inflammatory cytokines or physical stress leading to direct activation of transcription factors such as ELK1 and ATF2. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. MAPK13 is one of the less studied p38 MAPK isoforms. Some of the targets are downstream kinases such as MAPKAPK2, which are activated through phosphorylation and further phosphorylate additional targets. Plays a role in the regulation of protein translation by phosphorylating and inactivating EEF2K. Involved in cytoskeletal remodeling through phosphorylation of MAPT and STMN1. Mediates UV irradiation induced up-regulation of the gene expression of CXCL14. Plays an important role in the regulation of epidermal keratinocyte differentiation, apoptosis and skin tumor development. Phosphorylates the transcriptional activator MYB in response to stress which leads to rapid MYB degradation via a proteasome-dependent pathway. MAPK13 also phosphorylates and down-regulates PRKD1 during regulation of insulin secretion in pancreatic beta cells.

关联

项与 MAPK13 相关的药物

SJF-6685

靶点

MAPK13 x p38α

作用机制

MAPK13抑制剂 [+1]

在研机构

Yale University [+1]

原研机构-

在研适应症

乳腺癌

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

BES-4612

靶点

MAPK13 x p38α

作用机制

MAPK13抑制剂 [+1]

在研机构

Arvinas, Inc. [+1]

原研机构-

在研适应症

乳腺癌

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

SJFδ

靶点

MAPK13

作用机制

MAPK13抑制剂 [+1]

在研机构

Arvinas, Inc. [+1]

原研机构

Yale University

在研适应症

乳腺癌

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 MAPK13 相关的临床结果

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100 项与 MAPK13 相关的转化医学

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0 项与 MAPK13 相关的专利（医药）

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227

项与 MAPK13 相关的文献（医药）

2025-01-01·Clinical and Translational Medicine

PINK1 modulates Prdx2 to reduce lipotoxicity‐induced apoptosis and attenuate cardiac dysfunction in heart failure mice with a preserved ejection fraction

Article

作者: Xu, Tianyu ; Zhou, Haobin ; Zeng, Qingchun ; Zhao, Qiming ; Ma, Zhuang ; Zeng, Xianghui ; Xu, Dingli ; Zhang, Hao ; Ren, Hao ; Mei, Xiyuan ; Yang, Qiling

AbstractIntroductionHeart failure with preserved ejection fraction (HFpEF) is a complex condition characterized by metabolic dysfunction and myocardial lipotoxicity. The roles of PTEN‐induced kinase 1 (PINK1) and peroxiredoxin‐2 (Prdx2) in HFpEF pathogenesis remain unclear.ObjectiveThis study aimed to investigate the interaction between PINK1 and Prdx2 to mitigate cardiac diastolic dysfunction in HFpEF.MethodsIn vivo, PINK1‐knockout mice and cardiac‐specific PINK1‐overexpressing transgenic mice were used to establish an HFpEF mouse model via a high‐fat diet and L‐NAME. Myocardial lipotoxicity was induced by palmitic acid in vitro. Immunoprecipitation, western blotting and immunofluorescence analysis were performed to elucidate the molecular mechanisms involved.ResultsWe determined that PINK1 and Prdx2 were downregulated in the HFpEF mouse model. In vivo, PINK1 ablation exacerbated the reduction in Prdx2 expression, worsening cardiac dysfunction in HFpEF mice. Conversely, PINK1 overexpression restored Prdx2 levels and decreased reactive oxygen species and apoptosis, thereby reducing fibrosis and inflammation and ameliorating cardiac diastolic dysfunction in HFpEF mice. In vitro, an interaction between the N‐terminal region (amino acids 1–133) of PINK1 and Prdx2 was identified. The overexpression of PINK1 induced Prdx2 expression and effectively attenuated palmitic acid‐induced apoptosis through the c‐Jun amino‐terminal kinase (JNK) and mitogen‐activated protein kinase (p38) pathways, whereas siRNA‐mediated Prdx2 knockdown abolished the protective effect of PINK1.ConclusionPINK1 alleviates lipotoxicity‐induced myocardial apoptosis and improves diastolic dysfunction in HFpEF through Prdx2, highlighting PINK1 overexpression as a potential therapeutic strategy for HFpEF.Key points

Our investigation discloses a pivotal relationship between PINK1 and Prdx2 in the context of HFpEF.

Notably, PINK1, in addition to its role in mitochondrial autophagy, can increase Prdx2 expression, effectively remove ROS and attenuate cardiomyocyte apoptosis by modulating the JNK and p38 pathways, thereby alleviating myocardial lipotoxicity and improving HFpEF cardiac function.

Our studies offer valuable insights, opening avenues for the development of innovative therapeutic strategies in the prevention and treatment of HFpEF.

2024-11-14·Translational Vision Science & Technology

Potential Drug Targets for Diabetic Retinopathy Identified Through Mendelian Randomization Analysis

Article

作者: Hu, Ziqing ; Wei, Jing ; Wang, Feiyan ; Liu, Huan

PurposeThis study aimed to investigate the causal effect of plasma proteins on diabetic retinopathy (DR) risk and identify potential drug targets for this disease.MethodsTwo-sample Mendelian randomization was performed to explore potential drug targets for DR. A total of 734 proteins were selected as instrumental variables. The Steiger filtering test and colocalization analysis were conducted to determine the causal direction and genetic pleiotropy. Plasma proteins from the decode study were used to validate the findings.ResultsEleven plasma proteins were associated with DR risk. Genetically predicted high levels of CCL3L1 (odds ratio [OR] = 0.582; 95% confidence interval [CI], 0.343-0.986; P = 0.044), PAM (OR = 0.782; 95% CI, 0.652-0.937; P = 0.008), GP1BA (OR = 0.793; 95% CI, 0.632-0.994; P = 0.044), GALNT16 (OR = 0.832; 95% CI, 0.727-0.952; P = 0.008), POGLUT1 (OR = 0.836; 95% CI = 0.703-0.995; P = 0.043), and DKK3 (OR = 0.859; 95% CI, 0.777-0.950; P = 0.003) have the protective effect on DR risk. Genetically predicted high levels of GFRA2 (OR = 1.104; 95% CI, 1.028-1.187; P = 0.007), PATE4 (OR = 1.405; 95% CI, 1.060-1.860; P = 0.018), GSTA1 (OR = 1.464; 95% CI, 1.163-1.842; P = 0.001), SIRPG (OR = 1.600, 95% CI, 1.244-2.057; P = 2.51E-04), and MAPK13 (OR = 1.731; 95% CI, 1.233-2.431; P = 0.002) were associated with an increased risk of DR. However, the colocalization analysis results suggested that SIRPG and GP1BA have a shared causal variant with DR.ConclusionsCCL3L1, PAM, GALNT16, POGLUT1, DKK3, GFRA2, PATE4, GSTA1, and MAPK13 were associated with DR risk and were identified as potential drug targets for DR.Translational RelevanceThe present study has highlighted the role of CCL3L1, PAM, GALNT16, POGLUT1, DKK3, GFRA2, PATE4, GSTA1, and MAPK13 in the development of DR.

2024-11-01·Molecular Nutrition & Food Research

Ruminant Trans Fatty Acid Intake Modulates Inflammation Pathways in the Adipose Tissue Transcriptome of C57BL/6 Mice

Article

作者: Mohammadi, Farzad ; Droit, Arnaud ; Beauparlant, Charles Joly ; Bertrand, Nicolas ; Rudkowska, Iwona ; Bianco, Stéphanie

ScopeThe study aims to analyze transcriptomic profiles in adipose tissues postconsumption of elaidic acid (EA; trans‐18:1n‐9) and trans‐palmitoleic acid (TPA; trans‐16:1n‐7), elucidating their different effects on inflammation and glucose metabolism.Methods and resultsTwenty C57BL/6 mice are divided into four groups. Each group receives one of the following formulations in drinking water: lecithin nanovesicles, nanovesicles containing either lecithin with EA or TPA (86:14 w/w), or water (control) for 28 days with a regular fat diet (18% calories from fat). Total RNA is extracted, and paired‐end sequencing is performed. TPA intake alters the expression of 351 genes compared to EA intake, including 11 downregulated and 340 upregulated genes (fold change [FC] >1.5, p < 0.05). TPA compares to EA upregulated: Slc5a8, Lcn2, Csf3, Scube1, Mapk13, Bdkrb2, Ctla2a, Slc2a1, Oas3, Cx3cl1, Oas2, Nlrp6, Pycard, Cyba, Ddr1, and Prkab1 and downregulated Fas gene. These genes are related to the NOD‐like receptor, lipid and atherosclerosis, IL‐17 signaling, TNF, nonalcoholic fatty liver disease, cytokine–cytokine receptor interaction, adipocytokine, glucagon, insulin resistance, and inflammatory mediator regulation of TRP channels signaling.ConclusionTPA intake has a distinct impact on the regulation of inflammation and diabetes‐related pathways in adipose tissue compared to EA.

项与 MAPK13 相关的新闻（医药）

2024-02-19

·奇点网

这回是替LDL说点儿好话。

*仅供医学专业人士阅读参考肿瘤浸润T细胞发生功能耗竭，会限制抗肿瘤免疫。但就在这些看起来无用甚至挡害的耗竭T细胞（Tex）中，科学家们发现存在一个特殊的群体，即以TCF1为表达特征的CD8+T细胞。TCF1是一种关键的转录因子，参与调节T细胞的分化、增殖以及免疫应答。肿瘤浸润的TCF1+CD8+T细胞表现出自我更新和长期存活的干细胞样特性，能够在长期抗原刺激下维持其功能，抵抗着T细胞走向终末耗竭。在免疫治疗中，TCF1+T细胞水平与患者的治疗反应和总体生存率呈正相关。一项发表在《癌症免疫治疗杂志》期刊上的最新研究发现[1]，常常与肥胖捆绑出现的低密度脂蛋白（LDL），竟然是启动T细胞干性的钥匙。华中科技大学同济医学院附属同济医院的兰培祥、陈刚和陈知水等人发现，LDL作用于T细胞表面的蛋白LRP11后，激活胞内信号通路，促进TCF1介导的转录重编程，从而增强T细胞的增殖和细胞毒性，延长其在肿瘤中效应功能的持续时间。直接补充LDL或使用LRP11激动性抗体，能够提高荷瘤小鼠的肿瘤浸润TCF1+T细胞水平，增强PD-1抑制剂疗效。论文首页截图很奇怪，明明高脂饮食相关的肥胖、体重指数（BMI）增加是公认的癌症风险因素，可为什么，临床上拥有这些特征的患者对免疫治疗的反应却是更为可观？肥胖悖论给肿瘤领域的科学家们设下了难题。在这项研究中，兰培祥、陈刚和陈知水等人首先发现，与对照组相比，高脂饮食的小鼠肿瘤生长速度较慢，肿瘤浸润淋巴细胞增加，尤其是TCF1+CD8+T细胞的增加最为显著。由于低密度脂蛋白（LDL）水平升高与高脂饮食引起的肥胖相关，研究团队将注意力转移到LDL身上来。体外结果显示，LDL处理可直接促进CD8+T细胞增殖，刺激CD8+T细胞持续释放大量具有杀伤作用的细胞因子。不仅如此，在结直肠癌小鼠模型实验中，研究团队以12mg/kg的剂量腹膜内注射PD-1抑制剂，40mg/kg的剂量注射LDL。结果发现，补充LDL能够显著增强PD-1抑制剂疗效，提高肿瘤浸润T细胞水平以及TCF1+CD8+T细胞的比例。补充LDL提高PD-1抑制剂疗效当然，大量补充LDL不太现实，LDL属于对心血管危害极大的坏胆固醇，咱们最好在协助癌症免疫治疗的同时，避免引狼入室，给心血管带来压力。于是，研究团队找到LDL助力抗肿瘤免疫背后的机制。他们发现，T细胞表面存在的膜受体LRP11能够充当传感器来接收细胞外的LDL信号，并激活细胞质中的激酶MAPK13。MAPK13进入细胞核后磷酸化TCF1，从而促进细胞干性相关基因表达，将T细胞转变成为免疫治疗的最佳内应。机制图如果使用遗传学手段将LRP11敲低表达，会抑制CD8+T细胞增殖以及毒性因子的表达。反过来，与补充LDL的效果相近，使用LRP11激动性抗体治疗结直肠癌小鼠，则可以协助抗肿瘤免疫。相比于PD-1抑制剂单独治疗（12mg/kg），与LRP11激动性抗体联用（20mg/kg）后肿瘤抑制效果进一步加强，肿瘤浸润CD8+T细胞水平提高，耗竭CD8+T细胞的增殖和毒性功能得到增强。LRP11激动性抗体增强PD-1抑制剂疗效也就是说，LRP11是干细胞样CD8阳性T细胞的细胞表面调节因子，通过胞内的LRP11-MAPK13信号通路唤醒TCF1，促进抗肿瘤免疫以及协助免疫治疗。或者换个角度来看，此次揭示的LDL抗肿瘤机制，或是为肥胖悖论又增加了一种新的解释。危害心血管的LDL可算做了次好人，引领我们寻找到扩充TCF1+T细胞亚群的方法。参考文献：[1]https://jitc-bmj-com.libproxy1.nus.edu.sg/content/12/1/e008367本文作者丨张艾迪

免疫疗法

2024-02-05

·今日头条

“神药PD1”新进展！同济大学发文：增强抗 PD1 免疫疗法新机制

本文为转化医学网原创，转载请注明出处作者：Sophia 导读：肿瘤浸润性T细胞进入耗竭或功能失调状态，限制了抗肿瘤免疫。在耗竭的 T 细胞中，具有祖细胞或干细胞样细胞特征的细胞亚群已被鉴定为对免疫治疗有反应的 TCF1 CD8 T 细胞。与TCF1控制肿瘤浸润干细胞样T细胞中的表观遗传和转录重编程的发现相反，对TCF1的调控知之甚少。新数据表明，体重指数升高与免疫治疗的结果有关。但是，该机制尚未明确。近日，同济医学院兰培祥、陈刚和陈知水共同在期刊《Journal for Immuno Therapy of Cancer》发表题为“LRP11 promotes stem-like T cells via MAPK13-mediated TCF1 phosphorylation, enhancing anti-PD1 immunotherapy”的文章，通过使用荷瘤小鼠模型，我们发现LDL诱导的肿瘤浸润TCF1PD1CD8 T细胞。使用基于细胞的嵌合受体筛选系统，我们发现 LRP11 与 LDL 相互作用并激活 TCF1。LRP11 激活增强了 TCF1PD1CD8 T 细胞介导的抗肿瘤免疫，这与 LRP11 阻断受损的 T 细胞功能一致。从机制上讲，LRP11 激活诱导 MAPK13 激活。然后，MAPK13 磷酸化 TCF1，导致干细胞样 T 细胞增加。 https://jitc-bmj-com.libproxy1.nus.edu.sg/content/12/1/e008367 研究背景 01 在肿瘤微环境中，免疫细胞，特别是T细胞，进入耗竭或功能失调状态，细胞因子产生减少，抑制性受体表达持续增加，如程序性细胞死亡蛋白1（PD1）（由Pdcd1编码）和TIM3（由Havcr2编码），限制免疫治疗，包括自体T细胞或嵌合抗原受体（CAR）T细胞的过继细胞治疗和抑制性受体的阻断，这在临床癌症治疗中取得了显著的成功。肿瘤中的干细胞样或祖细胞 Tex 细胞与免疫治疗后 T 细胞反应的长期维持和更好的患者预后相关。尽管肿瘤中富集了耗竭和功能失调的信号，例如持续抗原暴露、高抑制性配体和细胞因子，这些信号促进了 CD8 T 细胞耗竭，但干细胞样 Tex 细胞保持了对 PD1 阻断的比例和反应。重要的是，TCF1 充当控制 T 细胞命运和发育的主要调节因子。新数据表明， TCF1 CD8 T细胞存在于肿瘤或病毒感染的特定组织生态位中。TCF1 CD8 T细胞如何在生态位中接收信号尚不清楚。有趣的是，临床和实验数据表明，体重指数（BMI）升高与接受免疫治疗的患者的良好结果相关。尽管高水平的 PD1 表达被认为有助于这些结果，但增强 BMI 升高人群抗肿瘤免疫力的机制仍然未知。研究结果 02 最近的进展强调了TCF1在肿瘤组织和慢性病毒感染中的干细胞样T细胞中的关键作用。与控制肿瘤浸润干细胞样 T 细胞中转录重编程的 TCF1 的详细表征相比，对位于细胞核中的 TCF1 的调节知之甚少。在这里，我们发现LRP11（一种膜受体）充当传感器来接收细胞外信号并激活TCF1。LRP11激活增强了TCF1 CD8 T细胞介导的抗肿瘤免疫，增强了PD1阻断免疫疗法的抗肿瘤能力。从机制上讲，LRP11 激活诱导 MAPK13 激活。然后，MAPK13 磷酸化 TCF1。这导致CD8 T细胞的增殖和细胞毒性增强，并延长其在肿瘤中的效应功能的持续时间。它还增加了肿瘤浸润干细胞样T细胞的比例，从而增强了抗肿瘤免疫力（图 7）。干细胞样 TCF1CD8 T 细胞中 LRP11-MAPK13-TCF1 轴的汇总图。 MAPK13 信号通路的激活是通过 LDL 与膜受体 LRP11 的结合来实现的。一旦被磷酸化，MAPK13 进入细胞核并磷酸化 TCF1，从而促进干性相关基因的转录并增强 ICB 治疗。研究结论 03 总之，我们发现与高脂肪饮食诱导的肥胖相关的低密度脂蛋白（LDL）通过 LRP11 促进 CD8 T 细胞增殖和 TCF1 表达。同样，LRP11激动性抗体显示出强大的抗肿瘤能力。LRP11 阻断限制了 PD1 阻断免疫治疗期间的 TCF1 CD8 T 细胞。值得注意的是，LRP11 激活诱导 MAPK13 磷酸化并转运到细胞核中，其中 MAPK13 作为激酶发挥作用并促进 TCF1 磷酸化，导致 CD8 T 细胞中的转录重编程并增强 PD1 阻断免疫疗法。因此，LRP11-MAPK13 轴通过转录重编程促进干细胞样 TCF1 CD8 T 细胞，增强抗 PD1 免疫治疗。参考资料： https://jitc-bmj-com.libproxy1.nus.edu.sg/content/12/1/e008367 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。热门·直播/活动 🕓 上海｜3月01日-02日 ▶第三届长三角单细胞组学技术应用论坛暨空间组学前沿论坛将在上海召开，诚邀您的参与！点击对应文字查看详情

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