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Novel Non-catalytic Substrate-selective p38α-specific MAPK Inhibitors with Endothelial-Stabilizing and Anti-inflammatory Activity

ABSTRACT: We developed a novel substrate-selective inhibitor of p38 MAPK, UM101, and compared its effects on TNF-induced gene expression by human lung microvascular endothelial cells (HMVECLs) with the prototypical p38 catalytic inhibitor, SB203580

ORGANISM(S): Homo sapiens

PROVIDER: GSE93330 | GEO | 2017/01/10

SECONDARY ACCESSION(S): PRJNA360618

REPOSITORIES: GEO

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Gene expression affected by TNFa and SB203580

Project description:Gene expression affected by TNFa was investigated, then, p38 inhibitor SB203580 was used to investigate p38 signal pathway. Keywords: p38 signal response

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Transcription profiling of rat fibroblast-like synoviocyte cell cultures treated with TNFa and SB203580

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Transcription profiling of human articular osteoarthritic chondrocytes after stimulation with IL-1beta and p38 MAPK inhibition with SB203580 or Birb 796

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Real-time quantitative PCR analysis of murine kidney epithelial cell line (MCT) cells

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ABIN1 is a negative regulator of effector functions in cytotoxic T cells

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First-in-Class Substrate- and Function-Selective p38alpha Inhibitors with Anti-inflammatory and Endothelial-stabilizing Activities

Project description:We previously identified a small molecule, UM101, predicted to bind to the substrate-binding groove of MAPK14/p38a near the binding site of the proinflammatory substrate, MAPK-activated protein kinase (MK2). UM101 exhibited anti-inflammatory, endothelial-stabilizing, and lung-protective effects. We developed an analog of UM101, GEn-1124, with improved aqueous stability and p38a binding affinity. Compared with UM101, GEn-1124 has 60-fold greater p38a binding affinity as measured by Surface Plasmon Resonance (SPR), 66-fold greater aqueous solubility, enhanced barrier-stabilizing activity in thrombin-stimulated human pulmonary artery endothelial cells (hPAEC) in vitro, and greater lung protection in a mouse models of acute lung injury (ALI). GEn-1124 reduced lung injury and improved survival in a mouse model of ALI induced by intratracheal LPS instillation and exposure to febrile-range hyperthermia (FRH) from 10% to 40% and in a mouse influenza pneumonia model from 0% to 50%. RNASeq and pathway analysis of gene expression in TNFa-treated hPAEC showed that the gene-modifying effects of GEn-1124 were much more restricted to TNFa-inducible genes than SB203580. Gene expression pathway analysis, confocal immunofluorescence analysis of p38a and MK2 subcellular trafficking, and SPR analysis of phosphorylated p38a:MK2 binding affinity supports a novel mechanism of action. GEn-1124 destabilizes the phosphorylated p38a:MK2 complex, dissociates nuclear export of phosphorylated p38a and MK2, thereby promoting intranuclear phosphorylated p38a retention and intranuclear signaling, and accelerating inactivation of p38-free cytosolic MK2 by unopposed phosphatases.

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Transcriptional Profiling Defines the Roles of ERK and p38 Kinases in Epidermal Keratinocytes

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2013-09-05 | E-GEOD-50591 | biostudies-arrayexpress

Effect of p38 MAPK inhibitor SB203580 on gene expression in monocytic THP-1 cells stimulated with HIV gp120 or LPS.

Project description:Human monocytic THP-1 cells were exposed to HIV envelope protein gp120 or bacterial LPS in the presence and absence of a pharmacological inhibitor of the p38 mitogen-activated protein kinase (MAPK) for 4 and 24 hours. A microarray analysis was performed in order to assess differential gene expression at the RNA level. Human monocytic THP-1 cells were pre-treated for 15 min with 10 M-BM-5M SB203580 followed by exposure for 4 h or 24 h to 1 nM HIV gp120SF162 or 1 M-BM-5g/ml LPS. 0.1 % DMSO and 0.001 % BSA served as vehicle controls for SB203580 and gp120, respectively. The experimental samples were 1) control 4 h, 2) gp120 4 h, 3) LPS 4 h, 4) SB203580 (SB) 4 h, 5) SB+gp120 4 h, 6) SB+LPS 4 h, 7) control 24 h, 8) gp120 24 h, 9) LPS 24 h, 10) SB 24 h, 11) SB+gp120 24 h, 12) SB+LPS 24 h. RNA was isolated from three biological replicates for each experimental condition using an RNeasy kit commercially available from Qiagen (Valencia, CA). Roughly 2 X 106 cells were collected to obtain 500 ng M-bM-^@M-^S 2 M-BM-5g RNA. RNA quality (A260/A280 ratio ~1.8-2.0) was tested using the NanoDrop system from Thermo Scientific (Rockford, IL). High quality RNA was then provided to the Microarray/ QPCR Facility Core at Sanford-Burnham Medical Research Institute and DNA microarray was performed using the whole genome gene-expression analysis HumanHT-12 v4 Expression BeadChip kit from Illumina (San Diego, CA). Microarray results were further analyzed by Dr. Roy Williams (Bioinformatics Core, Sanford-Burnham Medical Research Institute) using the GeneSpring GX platform

2014-12-25 | E-GEOD-53712 | biostudies-arrayexpress

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Project description:Here, we aim to understand the role of P38 in the airway epithelial cells response to flagellin. We report the gene expression profile of pig airway epithelial cells cultured under air-liquid conditions, pre-incubated or not with the P38 inhibitor SB203580 (20 µM, Tocris Bioscience) for 1 h and then stimulated with 100 ng/ml of a mutated flagellin (FliCΔ174-400) for 2h or 24h. Our data show that flagellin stimulation induce the expression of pro-inflammatory cytokines mainly through the NFkB pathway, with little impact of P38 inhibition in the cells response.

2022-05-21 | GSE173768 | GEO

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