Browse
Submit Data
Databases
API
Help

Dataset Information

16 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Nrf2 Regulates Anti-Inflammatory A20 Deubiquitinase Induction by LPS in Macrophages in Contextual Manner.

ABSTRACT: The aberrant regulation of inflammatory gene transcription following oxidant and inflammatory stimuli can culminate in unchecked systemic inflammation leading to organ dysfunction. The Nrf2 transcription factor dampens cellular stress and controls inflammation by upregulating antioxidant gene expression and TNFα-induced Protein 3 (TNFAIP3, aka A20) deubiquitinase by controlling NF-kB signaling dampens tissue inflammation. Here, we report that Nrf2 is required for A20 induction by inflammatory stimuli LPS in monocyte/bone marrow derived macrophages (MDMΦs) but not in lung-macrophages (LDMΦs). LPS-induced A20 expression was significantly lower in Nrf2^-/- MDMΦs and was not restored by antioxidant supplementation. Nrf2 deficiency markedly impaired LPS-stimulated A20 mRNA expression Nrf2^-/- MDMΦs and ChIP assays showed Nrf2 enrichment at the promoter Nrf2^-/- MDMΦs upon LPS stimulation, demonstrating that Nrf2 directly regulates A20 expression. Contrary to MDMΦs, LPS-stimulated A20 expression was not largely impaired in Nrf2^-/- LDMΦs ex vivo and in vivo and ChIP assays showed lack of increased Nrf2 binding at the A20 promoter in LDMΦ following LPS treatment. Collectively, these results demonstrate a crucial role for Nrf2 in optimal A20 transcriptional induction in macrophages by endotoxin, and this regulation occurs in a contextual manner.

SUBMITTER: Potteti HR

PROVIDER: S-EPMC8228212 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Anti-Inflammatory Activity of Bryophytes Extracts in LPS-Stimulated RAW264.7 Murine Macrophages.

Project description:Bryophytes produce rare and bioactive compounds with a broad range of therapeutic potential, and many species are reported in ethnomedicinal uses. However, only a few studies have investigated their potential as natural anti-inflammatory drug candidate compounds. The present study investigates the anti-inflammatory effects of thirty-two species of bryophytes, including mosses and liverworts, on Raw 264.7 murine macrophages stimulated with lipopolysaccharide (LPS) or recombinant human peroxiredoxin (hPrx1). The 70% ethanol extracts of bryophytes were screened for their potential to reduce the production of nitric oxide (NO), an important pro-inflammatory mediator. Among the analyzed extracts, two moss species significantly inhibited LPS-induced NO production without cytotoxic effects. The bioactive extracts of Dicranum majus and Thuidium delicatulum inhibited NO production in a concentration-dependent manner with IC50 values of 1.04 and 1.54 µg/mL, respectively. The crude 70% ethanol and ethyl acetate extracts were then partitioned with different solvents in increasing order of polarity (n-hexane, diethyl ether, chloroform, ethyl acetate, and n-butanol). The fractions were screened for their inhibitory effects on NO production stimulated with LPS at 1 ng/mL or 10 ng/mL. The NO production levels were significantly affected by the fractions of decreasing polarity such as n-hexane and diethyl ether ones. Therefore, the potential of these extracts to inhibit the LPS-induced NO pathway suggests their effective properties in attenuating inflammation and could represent a perspective for the development of innovative therapeutic agents.

| S-EPMC8953629 | biostudies-literature

Acylphloroglucinol Derivatives from Garcinia multiflora with Anti-Inflammatory Effect in LPS-Induced RAW264.7 Macrophages.

Project description:Two new acylphloroglucinol derivatives, 13,14-didehydroxygarcicowin C (1) and 13,14-didehydroxyisoxanthochymol (2), have been isolated from the stems of Garcinia multiflora, together with seven known compounds (3?9). The structures of new compounds 1 and 2 were elucidated by MS and extensive 1D/2D NMR spectroscopic analyses. Among the isolates, 13,14-didehydroxy-isoxanthochymol (2) and sampsonione B (3) exhibited inhibition against lipopolysaccharide (LPS)-induced NF-?B activation in macrophages at 30 ?M with relative luciferase activity values (inhibitory %) of 0.75 ± 0.03 (24 ± 4%) and 0.12 ± 0.03 (88 ± 4%), respectively. Additionally, sampsonione B (3) reduced LPS-induced nitric oxide (NO) production in murine RAW264.7 macrophages and did not induce cytotoxicity against RAW 264.7 cells after 24 h treatment. Compound 3 is worth further investigation and may be expectantly developed as an anti-inflammatory drug candidate.

| S-EPMC6222856 | biostudies-other

Anti-inflammatory effect of Irisin on LPS-stimulated macrophages through inhibition of MAPK pathway.

Project description:This study aimed to investigate the effect of irisin on LPS-induced inflammation in RAW 264.7 macrophages through inhibition of the mitogen-activated protein kinase (MAPK) pathway. A network pharmacology-based approach, combined with molecular docking and in vitro validation were performed to identify the biological activity, key targets, and potential pharmacological mechanisms of irisin against LPS-induced inflammation. By matching 100 potential genes of irisin with 1893 ulcerative colitis (UC) related genes, 51 common genes were obtained. Using protein-protein interaction networks (PPI) and component-target network analysis,10 core genes of irisin on UC were further identified. The results of gene ontology (GO) enrichment analysis showed that the molecular mechanisms of irisin on UC were mainly related to major enrichment in the categories of response to xenobiotic stimulus, response to the drug, and negative regulation of gene expression. Molecular docking results showed good binding activity for almost all core component targets. More importantly, MTT assay and flow cytometry results showed that LPS-induced cytotoxicity was reversed by irisin, after coincubation with irisin, the level of IL-12 and IL-23 decreased in LPS-stimulated RAW264.7 macrophages. Irisin pretreatment significantly inhibited the phosphorylation of ERK and AKT and increased the expression of PPAR alpha and PPAR gamma. LPS-induced enhancement of phagocytosis and cell clearance were reversed by irisin pretreatment. Irisin ameliorated LPS-induced inflammation by inhibiting cytotoxicity and apoptosis, and this protective effect may be mediated through the MAPK pathway. These findings confirmed our prediction that irisin plays an anti-inflammatory role in LPS-induced inflammation via the MAPK pathway.

| S-EPMC10226406 | biostudies-literature

Anti-Inflammatory Activity and ROS Regulation Effect of Sinapaldehyde in LPS-Stimulated RAW 264.7 Macrophages.

Project description:We evaluated the anti-inflammatory effects of SNAH in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages by performing nitric oxide (NO) assays, cytokine enzyme-linked immunosorbent assays, Western blotting, and real-time reverse transcription-polymerase chain reaction analysis. SNAH inhibited the production of NO (nitric oxide), reactive oxygen species (ROS), tumor necrosis factor (TNF)-α, and interleukin (IL)-6. Additionally, 100 μM SNAH significantly inhibited total NO and ROS inhibitory activity by 93% (p < 0.001) and 34% (p < 0.05), respectively. Protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) stimulated by LPS were also decreased by SNAH. Moreover, SNAH significantly (p < 0.001) downregulated the TNF-α, IL-6, and iNOS mRNA expression upon LPS stimulation. In addition, 3-100 µM SNAH was not cytotoxic. Docking simulations and enzyme inhibitory assays with COX-2 revealed binding scores of -6.4 kcal/mol (IC50 = 47.8 μM) with SNAH compared to -11.1 kcal/mol (IC50 = 0.45 μM) with celecoxib, a known selective COX-2 inhibitor. Our results demonstrate that SNAH exerts anti-inflammatory effects via suppression of ROS and NO by COX-2 inhibition. Thus, SNAH may be useful as a pharmacological agent for treating inflammation-related diseases.

| S-EPMC7570554 | biostudies-literature

Sargachromenol Purified from Sargassum horneri Inhibits Inflammatory Responses via Activation of Nrf2/HO-1 Signaling in LPS-Stimulated Macrophages.

Project description:In this study, we isolated sargachromenol (SC) from Sargassum horneri and evaluated its anti-inflammatory effect in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. SC did not show cytotoxicity at all concentrations and effectively increased the cell viability by reducing the nitric oxide (NO) and intracellular reactive oxygen species (ROS) production in LPS-stimulated RAW 264.7 macrophages. In addition, SC decreased the mRNA expression levels of inflammatory cytokines (IL-1β, IL-6, and TNF-α) and inflammatory mediators (iNOS and COX-2). Moreover, SC suppressed the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) and mitogen-activated protein kinase (MAPK) signaling, whereas activated the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) signaling in LPS-stimulated RAW 264.7 macrophages. Interestingly, the anti-inflammatory effect of SC was abolished by the inhibition of HO-1 in LPS-stimulated RAW 264.7 macrophages. According to the results, this study suggests that the antioxidant capacity of SC leads to its anti-inflammatory effect and it potentially may be utilized in the nutraceutical and pharmaceutical sectors.

| S-EPMC8466374 | biostudies-literature

Anti-Inflammatory Activity of Kurarinone Involves Induction of HO-1 via the KEAP1/Nrf2 Pathway.

Project description:Kurarinone, a flavonoid isolated from the roots of Sophora flavescens, was suggested to exert potent antioxidant and immunosuppressive effects. However, the underlying mechanisms remain unclear. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor that regulates the antioxidant defense system with anti-inflammatory activity. In the present study, we demonstrated that kurarinone activated Nrf2 and increased the expression of antioxidant enzymes, including heme oxygenase-1 (HO-1). Mechanistically, kurarinone downregulated the expression of kelch-like ECH-associated protein 1 (KEAP1), subsequently leading to the activation of Nrf2. Kurarinone also inhibited the expression of the inflammatory cytokine, interleukin (IL)-1β, and inducible nitric oxide synthase (iNos) in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. The overexpression of HO-1 suppressed the LPS-induced production of inflammatory mediators in RAW264.7 cells, and the immunosuppressive effects of kurarinone were partially inhibited by a treatment with Tin Protomorphyrin IX (TinPPIX), an inhibitor of HO-1. These results indicate that kurarinone activates the KEAP1/Nrf2 pathway to induce HO-1 expression, thereby exerting immunosuppressive effects.

| S-EPMC7554885 | biostudies-literature

Potential anti-inflammatory effect of inulin in an inflammatory cell model (mouse macrophages with LPS)

Project description:A potential anti-inflammatory effect of inulin, a fructan found in thousands of plant species, has been described. In this study we look at the effect of inulin, at the proteome level, in a murine cellular model of inflammation. Our interest is focused on describing the molecular mechanisms involved in this possible anti-inflammatory bioactivity.

2023-03-11 | PXD032759 | Pride

Regulation of NF-κB signaling by the A20 deubiquitinase.

Project description:The NF-κB transcription factor is a central mediator of inflammatory and innate immune signaling pathways. Activation of NF-κB is achieved by K63-linked polyubiquitination of key signaling molecules which recruit kinase complexes that in turn activate the IκB kinase (IKK). Ubiquitination is a highly dynamic process and is balanced by deubiquitinases that cleave polyubiquitin chains and terminate downstream signaling events. The A20 deubiquitinase is a critical negative regulator of NF-κB and inflammation, since A20-deficient mice develop uncontrolled and spontaneous multi-organ inflammation. Furthermore, specific polymorphisms in the A20 genomic locus predispose humans to autoimmune disease. Recent studies also indicate that A20 is an important tumor suppressor that is inactivated in B-cell lymphomas. Therefore, targeting A20 may form the basis of novel therapies for autoimmune disease and lymphomas.

| S-EPMC3532050 | biostudies-other

Semi-Mechanism-Based Pharmacodynamic Model for the Anti-Inflammatory Effect of Baicalein in LPS-Stimulated RAW264.7 Macrophages.

Project description:Monitoring of the inhibition of TNF-?, IL-6, iNOS, and NO is used to effectively evaluate anti-inflammatory drugs. Baicalein was found to have good anti-inflammatory activities, but its detailed cellular pharmacodynamic events have not been expatiated by any other study. The inflammatory mediators, including TNF-?, IL-6, iNOS, and NO production in RAW264.7 macrophage induced by LPS, were measured. It was found that these data showed a sequential pattern on time and based on these points a cellular pharmacodynamic model was developed and tested. TNF-? and IL-6 were quantified by ELISA, NO was detected by Griess and iNOS expression was measured by Western blot. The pharmacodynamic model was developed using a NLME modeling program Monolix® 2016R1.The results showed that baicalein quickly suppressed release of TNF-? in a concentration-dependent manner, and consequently causing the diminution of IL-6 and iNOS/NO. The pharmacodynamic model simulation successfully described the experimental data, supporting the hypothesis that IL-6 and iNOS /NO release after LPS stimulation is mediated by TNF-? rather than LPS directly. The pharmacodynamic model allowed a well understanding of the cellular pharmacodynamic mechanism of baicalein in the treatment of inflammatory diseases.

| S-EPMC6058255 | biostudies-literature

Anti-Inflammatory Effects of Ginsenoside Rb3 in LPS-Induced Macrophages Through Direct Inhibition of TLR4 Signaling Pathway.

Project description:Panax ginseng has therapeutic effects on various inflammation-related diseases. Ginsenoside Rb3 (GRb3), a natural compound with anti-inflammatory and immunomodulatory properties, is one of the main active panaxadiol extracted from Panax ginseng. We explored whether GRb3 inhibited LPS-mediated inflammation through TLR4/NF-κB/MAPK signaling in macrophages. GRb3 attenuated NO and PGE2 production by attenuating iNOS and COX2 expression. GRb3 also suppressed pro-inflammatory cytokines levels, including IL-1β, IL-6, and TNF-α. Moreover, GRb3 administration significantly suppressed NF-κB (p65) nuclear translocation and the phosphorylation levels of p65, IκBα, JNK, p38, and ERK dose-dependently. Molecular docking demonstrated that GRb3 could dock onto the hydrophobic binding site of TLR4/MD2 complex, with a binding energy of -8.79 kcal/mol. Molecular dynamics (MD) displayed stable TLR4-MD2-GRb3 modeling. GRb3 dose-dependently inhibited LPS binding to cell membranes and blocked TLR4 expression. Surface plasmon resonance imaging (SPRi) revealed that GRb3 had an excellent binding affinity to TLR4/MD2 complex. Notably, resatorvid (TAK242), a selective TLR4 inhibitor, did not increase the repressive influence of GRb3 in RAW264.7 macrophages. Moreover, TLR4 overexpression partially reversed the repressive roles of GRb3 on the NF-κB/MAPK pathway and inflammatory mediators. Collectively, our study strongly indicated that GRb3 attenuated LPS-mediated inflammation through direct inhibition of TLR4 signaling. A novel insight into the underlying mechanism of anti-inflammatory effects of GRb3 in macrophages was confirmed.

| S-EPMC8987581 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data