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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

2007-05-22 | GSE7826 | GEO

Novel Noncatalytic Substrate-Selective p38α-Specific MAPK Inhibitors with Endothelial-Stabilizing and Anti-Inflammatory Activity.

Project description:The p38 MAPK family is composed of four kinases of which p38α/MAPK14 is the major proinflammatory member. These kinases contribute to many inflammatory diseases, but the currently available p38 catalytic inhibitors (e.g., SB203580) are poorly effective and cause toxicity. We reasoned that the failure of catalytic p38 inhibitors may derive from their activity against noninflammatory p38 isoforms (e.g., p38β/MAPK11) and loss of all p38α-dependent responses, including anti-inflammatory, counterregulatory responses via mitogen- and stress-activated kinase (MSK) 1/2 and Smad3. We used computer-aided drug design to target small molecules to a pocket near the p38α glutamate-aspartate (ED) substrate-docking site rather than the catalytic site, the sequence of which had only modest homology among p38 isoforms. We identified a lead compound, UM101, that was at least as effective as SB203580 in stabilizing endothelial barrier function, reducing inflammation, and mitigating LPS-induced mouse lung injury. Differential scanning fluorimetry and saturation transfer difference-nuclear magnetic resonance demonstrated specific binding of UM101 to the computer-aided drug design-targeted pockets in p38α but not p38β. RNA sequencing analysis of TNF-α-stimulated gene expression revealed that UM101 inhibited only 28 of 61 SB203580-inhibited genes and 7 of 15 SB203580-inhibited transcription factors, but spared the anti-inflammatory MSK1/2 pathway. We provide proof of principle that small molecules that target the ED substrate-docking site may exert anti-inflammatory effects similar to the catalytic p38 inhibitors, but their isoform specificity and substrate selectivity may confer inherent advantages over catalytic inhibitors for treating inflammatory diseases.

| S-EPMC5649369 | biostudies-literature

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

Project description:Gene expression affected by TNFa was investigated, then, p38 inhibitor SB203580 was used to investigate p38 signal pathway. Experiment Overall Design: Fibroblast-like synoviocyte culture was treated with TNFa in the presence and absence of SB203580 and compared to the gene expression not treated with TNFa.

2008-06-15 | E-GEOD-7826 | biostudies-arrayexpress

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

Project description:Effect of stimulation with IL-1beta and p38 MAPK inhibition with SB203580 or Birb 796 on human articular osteoarthritic chondrocytes

2009-11-01 | E-MEXP-1434 | biostudies-arrayexpress

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

Project description:We could show that nephrotoxic genes show increased expression once MCT cells are treated with Cyclosporine A and p38 kinase inhibitor (SB203580) but not with a NFAT inhibitor (11R VIVIT).

2022-01-25 | GSE185146 | GEO

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

Project description:The main objective of the data analysis presented here is the investigation of the role of ABIN1 in antigenic responses of primary T cells. For this purpose, T cells from ABIN1-deficient mouse strain (GTKO) and WT mice were analyzed under different activation conditions. The effect of P38 MAPK inhibitor SB203580 (p38 inhibitor/p38i) was also analyzed. The results suggest that ABIN1 is a negative regulator of TCR-mediated activation and expression of the key effector molecules in primary CD8+ T cells, at least partly via the inhibition of the p38 pathway.

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Transcriptome analysis of inflammation-related gene expression in endothelial cells activated by complement MASP-1

Project description:Transcriptional profiling of human umbilical vein endothelial cells, treated with MASP-1, thrombin, LPS, histamine, TNFalpha, MASP-1+SB203580 (p38-MAPK inhibitor) or MASP-1+Bay-117082 (NFKB inhibitor). Goal was to determine the effect of MASP-1 on HUVECs, to compare this with the effect of other endothelial cell activators and to determine the MASP-1 induced signalling pathways.

2017-09-14 | GSE98114 | GEO

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.

2024-04-01 | GSE262079 | GEO

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

Project description:Epidermal keratinocytes respond to extracellular influences by activating cytoplasmic signal transduction pathways that change the transcriptional profiles of affected cells. To define responses to two such pathways, p38 and ERK, we used SB203580 and PD98059 as specific inhibitors, and identified the regulated genes after 1, 4, 24 and 48 hrs, using Affymetrix’ Hu133Av2 microarrays. Additionally, we compared genes specifically regulated by p38 and ERKs with those regulated by JNK and by all three pathways simultaneously. We find that the p38 pathway induces the expression of extracellular matrix and proliferation-associated genes, while suppressing microtubule-associated genes; the ERK pathway induces the expression of nuclear envelope and mRNA splicing proteins, while suppressing steroid synthesis and mitochondrial energy production enzymes. Both pathways promote epidermal differentiation and induce feedback inactivation of MAPK signaling. c-FOS, SRY and N-Myc appear to be the principal targets of the p38 pathway, Elk-1 SAP1 and HLH2 of ERK, while FREAC-4, ARNT and USF are common to both. The results for the first time comprehensively define the genes regulated by the p38 and ERK pathways in epidermal keratinocytes and suggest a list of targets potentially useful in therapeutic interventions. Human epidermal keratinocytes are grown in Keratinocyte Serum-Free Medium (Gibco) supplemented with 0.05 mg/ml bovine pituitary extract, 2.5 ng/ml epidermal growth factor, 0.09 mM CalCl2 and 1% penicillin/streptomycin (KGM). They are switched to Keratinocyte Serum Free-Media (Gibco) supplemented only with 1% penicillin/streptomycin (KBM) 24 h prior to commencing experiments. A set is left as controls, others treated with 5 uM JNK inhibitor SP600125, 15 uM p38 inhibitor SB203580, or 50 um ERK inhibitor PD98059. Timecourse of treated and parellel control samples over a 48 hr period was performed.

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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