Hydrogen modulates signal transduction through manipulating oxidized phospholipid mediators
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Shigeo Ohta
PROVIDER: E-GEOD-62434 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:We previously reported that molecular hydrogen (H2) acts as a novel antioxidant to exhibits multiple-functions. Moreover, long-term drinking of H2-water (water infused with H2) enhanced energy expenditure to improve obesity and diabetes in db/db mice, accompanied with the increased gene expression of an energy metabolism stimulatory hepatic hormone, fibroblast growth factor 21 (FGF21); however, the molecular mechanism is unknown particularly on whether this gene regulation is a primary cause or the secondary consequence. Pathway analyses based on comprehensive gene expression revealed the increased expression in various genes involved in fatty acid and steroid metabolisms. As a transcription pathway, the PPARa signaling pathway was identified to up-regulate the genes by 14 day-ingestion of H2. As an early event, the gene expression of PGC-1a was transiently increased at day 3, followed by increased expression of FGF21. In wild-type mice that fed with fatty-diet, H2-water improved the level of plasma triglyceride and extended their life span. H2 was ingested by ad libitum drinking H2-water for 14 days or by oral administration of an H2-producing material MgH2 for 1, 3 or 7 days. Comprehensive gene expression profile in liver of db/db mice was analyzed by DNA microarray.
2015-08-06 | E-GEOD-71738 | biostudies-arrayexpress
Project description:Identification of circulating proteins from human plasma binding to oxidized phospholipids using pull-down proteomics. Enrichment of plasma proteins using OxPAPC and PAPC containing biotynilated liposomes. Identification of plasma proteins that inactivate toxic action of OxPLs.
2024-11-06 | PXD055177 | Pride
Project description:Oxidized phospholipids are thought to promote atherogenesis by stimulating endothelial cells (ECs) to produce inflammatory cytokines, such as IL-8. In studies with mouse models, we previously demonstrated that genetic variation in inflammatory responses of endothelial cells to oxidized lipids contributes importantly to atherosclerosis susceptibility. We now show that similar variations occur in cultured aortic ECs derived from multiple heart transplant donors. These variations were stably maintained between passages and, thus, reflect either genetic or epigenetic regulatory differences. Expression array analysis of aortic EC cultures derived from 12 individuals revealed that >1,000 genes were regulated by oxidized phospholipids. We have used the observed variations in the sampled population to construct a gene coexpression network comprised of 15 modules of highly connected genes. We show that several identified modules are significantly enriched in genes for known pathways and confirm a module enriched for unfolded protein response (UPR) genes using siRNA and the UPR inducer tunicamycin. On the basis of the constructed network, we predicted that a gene of unknown function (MGC4504) present in the UPR module is a target for UPR transcriptional activator ATF4. Our data also indicate that IL-8 is present in the UPR module and is regulated, in part, by the UPR. We validate these by using siRNA. In conclusion, we show that interindividual variability can be used to group genes into pathways and predict gene-gene regulatory relationships, thus identifying targets potentially involved in susceptibility to common diseases such as atherosclerosis. Twelve individual HAEC lines were treated in duplicate (in 35-mm dishes) for 4 h in media containing PAPC (40 μg/ml) or oxidized PAPC (OxPAPC) at 20 ug/ml or 40 μg/ml. Cytoplasmic RNA was isolated by using an RNAeasy kit (Qiagen) and analyzed on an Agilent 2100 Bioanalyzer (Agilent, Palo Alto, CA) to assess RNA integrity. Double-stranded cDNAs were synthesized from total RNA by using the cDNA Synthesis System (Invitrogen, Carlsbad, CA). Biotin-labeled cRNA was generated and used to probe Affymetrix (Santa Clara, CA) Human Genome U133 Plus 2.0 arrays according to the manufacturer’s recommendations (Affymetrix). The Microarray Suite 5.0 software (Affymetrix) was used to analyze image data and make the absolute call for each measurement. The array data were normalized with the median invariant method (31).
2011-06-13 | E-GEOD-29903 | biostudies-arrayexpress
Project description:Identify genes involved in regulation of inflammatory responses and gene-environemnt interactions, in macrophages from a set of mouse inbred strains termed the HMDP. The HMDP is a genetically diverse mapping panel comprised of classical inbred and recombinant inbred wild type mice. The RMA values of genes were used for genome wide association as described in Bennett et al Genome Research 2010. GWAS for expression in primary macrophages of mouse inbred strains. Macrophages were exposed to bacterial lipopolysaccharide (LPS), oxidized lipids (OxPAPC) or control treatment conditions.
2012-10-26 | E-GEOD-38705 | biostudies-arrayexpress
Project description:Long wavelength Ultraviolet (UVA-1) radiation causes oxidative stress that leads to the formation of noxious substances within the skin. As a defensive mechanism skin cells produce detoxifying enzymes and antioxidants when they detect modified molecules. We have recently shown that UVA-1 irradiation oxidizes the abundant membrane phospholipid 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (PAPC), which then induced the synthesis of the stress response protein heme oxygenase 1 (HO-1) in dermal fibroblasts. Here we examined the effects of UVA-1 and (UV-) oxidized phospholipids on the global gene expression in human dermal fibroblasts. We identified a cluster of genes that were co-induced by UVA-1-oxidized PAPC and UVA-1 radiation. The cluster included HO-1, glutamate-cysteine ligase modifier subunit (GCLM), aldo-keto reductases-1-C1 and -C2 (AKR1C1, AKR1C2), and interleukin 8 (IL8). These genes are members of the cellular stress response system termed âantioxidant responseâ or âPhase II detoxificationâ. Accordingly, the regulatory regions of all these genes contain binding sites for NF-E2-related factor 2 (Nrf2), a major regulator of the antioxidant response. Both UVA-1 irradiation and treatment with oxidized lipids led to increased nuclear accumulation of Nrf2. Silencing expression of Nrf2 using siRNA or using cells and tissue from Nrf2-deficient mice, we show that the induction of the co-regulated genes was suppressed. Expression of other canonical UVA-1-induced genes, including cyclooxygenase 2 (Cox2) and interleukin 6 (IL6) was unaltered in the absence of Nrf2. Together, our data show that UVA-1-mediated lipid oxidation induces induction of antioxidant response genes, which is dependent on the redox-regulated transcription factor Nrf2. To activate Nrf2 is a major strategy for novel antioxidant drugs, the skin photo-adaptation (SPA) inducers. Our finding that specific uv-oxidized lipids act similar sheds a new (ultraviolet) light on the usually detrimental âimageâ of UV generated lipid mediators. Experiment Overall Design: we profiled global mRNA expression levels in human dermal fibroblasts that had been treated with either UVA-1 or oxidized lipids. To investigate the effect of oxidized phospholipids on gene regulation, we used two preparations, which differed in their degree of oxidation; the minimally oxidized UV-PAPC resulting from UVA-1 irradiation of PAPC, and air-oxidized PAPC (OxPAPC), which represents the full spectrum of oxidation products (Gruber 07) (Reis et al., 2005). We irradiated dermal fibroblasts with UVA-1 (40J/cm²) or treated them with UV-PAPC, OxPAPC or native PAPC (100µg/ml each). We analyzed global gene expression four hours after stimulation with gene arrays (Affymetrix U133A Plus 2.0 Gene Chips).
2009-11-10 | E-GEOD-13606 | biostudies-arrayexpress
Project description:We have previously demonstrated that molecular hydrogen (H2) neutralizes hydroxyl radical (•OH) in cultured-cells and protects cells and tissues against oxidative stress. Growing evidence has confirmed that H2-consumption exhibits preventive and therapeutic effects in patients with various diseases as well as model animals. Moreover, a small amount of H2 modulates signal transduction for regulating the expression of various genes; however, the primary target of H2 for exhibiting a variety of phenotypes was completely unknown. Here we show that H2 at low amounts manipulates oxidized phospholipid mediators to modulate Ca2+-signal transduction and gene expression.
2014-10-17 | GSE62434 | GEO
Project description:Characteristic extinguishing of B-cell phenotype in cHL is believed to be a result of transcription factor network deregulation due to the overexpression of repressor proteins ID2 and ABF-1. KLF4 is a versatile transcription factor, participating in regulation of differentiation processes in various tissues. Epigenetic silencing of KLF4 in cHL hints that KLF4 is involved in the complex mechanism of extinguishing of B-cell phenotype in cHL. To clarify this issue we investigated transcriptome changes, induced by KLF4 activation in two cHL cell lines KM-H2 and L428. KM-H2-KLF-ER and L428-KLF-ER cells were incubated with 200 µM 4-OHT or vehicle (ethanol). The experiment was done twice. After 24 h, total RNA was isolated with RNeasy mini kit (QIAGEN). Microarray analyses were performed using 200 ng total RNA as starting material and 5.5 µg ssDNA per hybridization (GeneChip Fluidics Station 450; Affymetrix, Santa Clara, CA). The total RNAs were amplified and labeled following the Whole Transcript (WT) Sense Target Labeling Assay (http://www.affymetrix.com). Labeled ssDNA was hybridized to Human Gene 1.0 ST Affymetrix GeneChip arrays (Affymetrix, Santa Clara, CA). The chips were scanned with a Affymetrix GeneChip Scanner 3000 and subsequent images analyzed using Affymetrix® Expression Console Software (Affymetrix). Probe level data were obtained using the robust multichip average (RMA) normalization algorithm.
2010-10-22 | E-GEOD-21296 | biostudies-arrayexpress
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Project description:FOXO1 is highly expressed in normal B cells and in most types of non-Hodgkinl lymphoma. In Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma(cHL) expression of FOXO1 is low or absent. We overexpressed constitutively active mutant of FOXO1 fused in frame with estrogen receptor ligand-binding domain (FOXO1(3A)ER), which can be activated by 4-Hydroxytamoxifen (4-OHT), in cHL cell lines KM-H2 and L428. Activation of the FOXO1 with 4-OHT resulted in inhibition of proliferation and apoptosis. Using gene-expression array we found that FOXO1 activates transcription of known and potential tumor suppressor genes: CDKN1B, PMAIP1, BCL2L11, TNFSF10, FBXO32, CBLB). Of note, FOXO1 repressed transcription of several cytokines and cytokine receptors, which are known tobe involved in pathogenesis of cHL (e.g. CCL5, CXCR5, TNFRSF8). Taken togather our data indicate important role of FOXO1 repression in pathogenesis of cHL. KM-H2 and L428 cells expressing constitutively active mutant of human FOXO1 fused in frame with estrogen receptor ligand-binding domain were incubated with 200 µM 4-OHT or vehicle (ethanol). After 24 h, total RNA was isolated with RNeasy mini kit (QIAGEN). Microarray analyses were performed using 200 ng of total RNA as starting material and 5.5 µg ssDNA per hybridization (GeneChip Fluidics Station 450; Affymetrix, Santa Clara, CA). The total RNAs were amplified and labeled following the Whole Transcript (WT) Sense Target Labeling Assay (http://www.affymetrix.com). Labeled ssDNA was hybridized to Human Gene 1.0 ST Affymetrix GeneChip arrays (Affymetrix, Santa Clara, CA). The chips were scanned with a Affymetrix GeneChip Scanner 3000 and subsequent images analyzed using Affymetrix® Expression Console Software (Affymetrix). Probe level data were obtained using the robust multichip average (RMA) normalization algorithm.
2012-05-31 | E-GEOD-29545 | biostudies-arrayexpress
Project description:Human SZ95 sebocytes were transfected by lipofection with either scramble siRNA or OLR1 siRNA and after 24h were treated with 25µg/ml of UV-oxidized 1-palmitoyl-2-arachidonoyl-sn-phosphocholine (UVPAPC) for 7 hours. Phospholipid oxidation products (OxPL) are versatile stress signaling mediators in the skin. These lipid signaling molecules can be generated non-enzymatically or enzymatically by ultraviolet light, the major extrinsic skin aging factor. OxPL regulate cytoprotective, immunological and metabolic adaptation of the skin to oxidant stress. We here investigated whether the scavenger receptor Oxidized Low Density Lipoprotein Receptor 1 (OLR1, LOX-1) would have a function in cutaneous oxPL signaling. We found that OLR1 is expressed in several cutaneous cell types, most prominently in cells of the sebaceous gland and in keratinocytes. We repressed OLR1 expression with siRNA in SZ95 sebocytes, exposed cells to oxidized 1-palmitoyl-2-arachidonoyl-sn-phosphatiylcholine (PAPC) and performed transcriptomic profiling. Bioinformatic analysis revealed that OxPL exposure induced the Nrf2 antioxidant stress response and aldosterone signaling. The analysis also revealed that OLR1 is not required for the transcriptional regulation induced by oxidized PAPC, but interestingly, OLR1 knockdown affected expression of CNN2, HMRR, ITGB6 and KIF20A, all genes governing cell proliferation and motility. We identify sebocytes as cutaneous cells responsive to lipid mediated redox stress which is not dependent on the scavenger receptor OLR1.
2020-04-15 | GSE98335 | GEO