Browse
Submit Data
Databases
API
Help

Dataset Information

17 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A new arthritis therapy with oxidative burst inducers.

ABSTRACT:

Background

Despite recent successes with biological agents as therapy for autoimmune inflammatory diseases such as rheumatoid arthritis (RA), many patients fail to respond adequately to these treatments, making a continued search for new therapies extremely important. Recently, the prevailing hypothesis that reactive oxygen species (ROS) promote inflammation was challenged when polymorphisms in Ncf1, that decrease oxidative burst, were shown to increase disease severity in mouse and rat arthritis models. Based on these findings we developed a new therapy for arthritis using oxidative burst-inducing substances.

Methods and findings

Treatment of rats with phytol (3,7,11,15-tetramethyl-2-hexadecene-1-ol) increased oxidative burst in vivo and thereby corrected the effect of the genetic polymorphism in arthritis-prone Ncf1(DA) rats. Importantly, phytol treatment also decreased the autoimmune response and ameliorated both the acute and chronic phases of arthritis. When compared to standard therapies for RA, anti-tumour necrosis factor-alpha and methotrexate, phytol showed equally good or better therapeutic properties. Finally, phytol mediated its effect within hours of administration and involved modulation of T cell activation, as injection prevented adoptive transfer of disease with arthritogenic T cells.

Conclusions

Treatment of arthritis with ROS-promoting substances such as phytol targets a newly discovered pathway leading to autoimmune inflammatory disease and introduces a novel class of therapeutics for treatment of RA and possibly other chronic inflammatory diseases.

SUBMITTER: Hultqvist M

PROVIDER: S-EPMC1564167 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Superoxide dismutase 3 limits collagen-induced arthritis in the absence of phagocyte oxidative burst.

Project description:Extracellular superoxide dismutase (SOD3), an enzyme mediating dismutation of superoxide into hydrogen peroxide, has been shown to reduce inflammation by inhibiting macrophage migration into injured tissues. In inflamed tissues, superoxide is produced by the phagocytic NOX2 complex, which consists of the catalytic subunit NOX2 and several regulatory subunits (e.g., NCF1). To analyze whether SOD3 can regulate inflammation in the absence of functional NOX2 complex, we injected an adenoviral vector overexpressing SOD3 directly into the arthritic paws of Ncf1(?/?) mice with collagen-induced arthritis. SOD3 reduced arthritis severity in both oxidative burst-deficient Ncf1(?/?) mice and also in wild-type mice. The NOX2 complex independent anti-inflammatory effect of SOD3 was further characterized in peritonitis, and SOD3 was found to reduce macrophage infiltration independently of NOX2 complex functionality. We conclude that the SOD3-mediated anti-inflammatory effect on arthritis and peritonitis operates independently of NOX2 complex derived oxidative burst.

| S-EPMC3317049 | biostudies-literature

Vav proteins control MyD88-dependent oxidative burst.

Project description:The importance of reactive oxygen intermediate (ROI) production in antimicrobial responses is demonstrated in human patients who suffer from chronic granulomatous disease (CGD) due to defective NADPH oxidase function. Exactly how bacterial products activating Toll-like receptors (TLRs) induce oxidative burst is unknown. Here, we identify the Vav family of Rho guanine nucleotide exchange factors (GEFs) as critical mediators of LPS-induced MyD88-dependent activation of Rac2, NADPH oxidase, and ROI production using mice deficient in Vav1, Vav2, and Vav3. Vav proteins are also required for p38 MAPK activation and for normal regulation of proinflammatory cytokine production, but not for other MyD88-controlled effector pathways such as those involving JNK, COX2, or iNOS and the production of reactive nitrogen intermediates (RNIs). Thus, our data indicate that Vav specifically transduces a subset of signals emanating from MyD88.

| S-EPMC1852252 | biostudies-literature

Enhanced autoimmunity, arthritis, and encephalomyelitis in mice with a reduced oxidative burst due to a mutation in the Ncf1 gene.

Project description:The Ncf1 gene was recently identified as a strong regulator of severe arthritis in rat. This finding was surprising, because the disease-promoting allele mediated a lower level of reactive oxygen species in NADPH oxidase-expressing cells. We have now investigated a splice mutation of the Ncf1 gene in B10.Q mice, causing a truncated and nonfunctional Ncf1 protein. We found that the mutated Ncf1 led to a more severe and chronic relapsing collagen-induced arthritis. Enhanced IgG and delayed-type hypersensitivity responses against type II collagen were seen, indicating increased activity of autoreactive T cells. Interestingly, female Ncf1-mutated mice spontaneously developed severe arthritis during the postpartum period. The arthritis was accompanied by an increased antibody response to type II collagen, with the same fine specificity as in collagen-induced arthritis. The enhancing effect of the mutated Ncf1 could also be shown to be more general in that it enhanced myelin oligodendrocyte glycoprotein protein-induced experimental autoimmune encephalomyelitis, a model for multiple sclerosis. These results show that Ncf1, a gene important for oxidative burst, regulates the susceptibility and severity of both arthritis and encephalomyelitis and modulates, directly or indirectly, the level of T cell-dependent autoimmune responses.

| S-EPMC515111 | biostudies-literature

Oxidative damage and respiratory burst in Multiple Sclerosis

2011-10-13 | GSE32915 | GEO

Oxidative damage and respiratory burst in Multiple Sclerosis

Project description:In this project we focused on white matter injury in relapsing remitting MS. We concentrated on material obtained from patients who suffered from fulminant active MS to identify possible sources for ROS production in relation to demyelination and neurodegeneration. To identify possible sources for ROS production in relation to demyelination and neurodegeneration in MS, we used genome wide microarray analysis of gene expression in carefully dissected lesion areas of patients with fulminant acute MS. Preceding the gene expression profiling all cases were characterized histologically and areas of interest were identified. We included 4 control cases, 2 active MS cases were we separated 3 distinct lesions areas (NAWM, initial lesion and early demyelinated lesion) and 1 active MS case were we separated 2 distinct lesion areas (NAWM and early demyelinated lesion). The RNA was isolated from those areas, amplified and hybridized to Agilent G4112A whole genome microarrays.

2011-10-12 | E-GEOD-32915 | biostudies-arrayexpress

Selective activation of PFKL suppresses the phagocytic oxidative burst.

Project description:In neutrophils, nicotinamide adenine dinucleotide phosphate (NADPH) generated via the pentose phosphate pathway fuels NADPH oxidase NOX2 to produce reactive oxygen species for killing invading pathogens. However, excessive NOX2 activity can exacerbate inflammation, as in acute respiratory distress syndrome (ARDS). Here, we use two unbiased chemical proteomic strategies to show that small-molecule LDC7559, or a more potent designed analog NA-11, inhibits the NOX2-dependent oxidative burst in neutrophils by activating the glycolytic enzyme phosphofructokinase-1 liver type (PFKL) and dampening flux through the pentose phosphate pathway. Accordingly, neutrophils treated with NA-11 had reduced NOX2-dependent outputs, including neutrophil cell death (NETosis) and tissue damage. A high-resolution structure of PFKL confirmed binding of NA-11 to the AMP/ADP allosteric activation site and explained why NA-11 failed to agonize phosphofructokinase-1 platelet type (PFKP) or muscle type (PFKM). Thus, NA-11 represents a tool for selective activation of PFKL, the main phosphofructokinase-1 isoform expressed in immune cells.

| S-EPMC8802628 | biostudies-literature

Oxidative burst: an early plant response to pathogen infection.

Project description:As plants are confined to the place where they grow, they have to develop a broad range of defence responses to cope with pathogenic infections. The oxidative burst, a rapid, transient, production of huge amounts of reactive oxygen species (ROS), is one of the earliest observable aspects of a plant's defence strategy. First this Review describes the chemistry of ROS (superoxide radical, hydrogen peroxide and hydroxyl radical). Secondly, the role of ROS in defence responses is demonstrated, and some important issues are considered, such as: (1) which of the ROS is a major building element of the oxidative burst; (2) the spatial and temporal regulation of the oxidative burst; and (3) differences in the plant's responses to biotic and abiotic elicitation. Thirdly, the relationships between the oxidative burst and other plant defence responses are indicated. These include: (1) an oxygen consumption, (2) the production of phytoalexins, (3) systemic acquired resistance, (4) immobilization of plant cell wall proteins, (5) changes in membrane permeability and ion fluxes and (6) a putative role in hypersensitive cell death. Wherever possible, the comparisons with models applicable to animal systems are presented. Finally, the question of the origin of ROS in the oxidative burst is considered, and two major hypotheses, (1) the action of NADPH oxidase system analogous to that of animal phagocytes, and (2) the pH-dependent generation of hydrogen peroxide by a cell wall peroxidase, are presented. On the basis of this material, a third 'unifying' hypothesis is presented, where transient changes in the pH of the cell wall compartment are indicated as a core phenomenon in evoking ROS production. Additionally, a germin/oxalate oxidase system which generates H2O2 in response to pathogenic infection is also described.

| S-EPMC1218243 | biostudies-other

Functional genomics identifies negative regulatory nodes controlling phagocyte oxidative burst.

Project description:The phagocyte oxidative burst, mediated by Nox2 NADPH oxidase-derived reactive oxygen species, confers host defense against a broad spectrum of bacterial and fungal pathogens. Loss-of-function mutations that impair function of the Nox2 complex result in a life-threatening immunodeficiency, and genetic variants of Nox2 subunits have been implicated in pathogenesis of inflammatory bowel disease (IBD). Thus, alterations in the oxidative burst can profoundly impact host defense, yet little is known about regulatory mechanisms that fine-tune this response. Here we report the discovery of regulatory nodes controlling oxidative burst by functional screening of genes within loci linked to human inflammatory disease. Implementing a multi-omics approach, we define transcriptional, metabolic and ubiquitin-cycling nodes controlled by Rbpj, Pfkl and Rnf145, respectively. Furthermore, we implicate Rnf145 in proteostasis of the Nox2 complex by endoplasmic reticulum-associated degradation. Consequently, ablation of Rnf145 in murine macrophages enhances bacterial clearance, and rescues the oxidative burst defects associated with Ncf4 haploinsufficiency.

| S-EPMC4518307 | biostudies-literature

Rac-dependent feedforward autoactivation of NOX2 leads to oxidative burst.

Project description:NADPH oxidase 2 (NOX2) produces the superoxide anion radical (O2-), which has functions in both cell signaling and immune defense. NOX2 is a multimeric-protein complex consisting of several protein subunits including the GTPase Rac. NOX2 uniquely facilitates an oxidative burst, which is described by initially slow O2- production, which increases over time. The NOX2 oxidative burst is considered critical to immune defense because it enables expedited O2- production in response to infections. However, the mechanism of the initiation and progression of this oxidative burst and its implications for regulation of NOX2 have not been clarified. In this study, we show that the NOX2 oxidative burst is a result of autoactivation of NOX2 coupled with the redox function of Rac. NOX2 autoactivation begins when active Rac triggers NOX2 activation and the subsequent production of O2-, which in turn activates redox-sensitive Rac. This activated Rac further activates NOX2, amplifying the feedforward cycle and resulting in a NOX2-mediated oxidative burst. Using mutagenesis-based kinetic and cell analyses, we show that enzymatic activation of Rac is exclusively responsible for production of the active Rac trigger that initiates NOX2 autoactivation, whereas redox-mediated Rac activation is the main driving force of NOX2 autoactivation and contributes to generation of ∼98% of the active NOX2 in cells. The results of this study provide insight into the regulation of NOX2 function, which could be used to develop therapeutics to control immune responses associated with dysregulated NOX2 oxidative bursts.

| S-EPMC8353492 | biostudies-literature

Fetal globin gene inducers: novel agents and new potential.

Project description:Inducing expression of endogenous fetal globin (gamma-globin) gene expression to 60-70% of alpha globin synthesis produces beta-thalassemia trait globin synthetic ratios and can reduce anemia to a mild level. Several classes of therapeutics have induced gamma-globin expression in beta-thalassemia patients and subsequently raised total hemoglobin levels, demonstrating proof-of-concept of the approach. Butyrate treatment eliminated transfusion requirements in formerly transfusion-dependent patients with treatment for as long as seven years. However, prior generation inducers were not readily applicable for widespread use. Currently, a novel oral dual-action therapeutic, sodium 2,2-dimethylbutyrate, is in clinical trials, an oral decitabine formulation is under development, and agents with complementary mechanisms of action can be applied in combined regimens. Identification of three major genetic trait loci which modulate clinical severity provides avenues for developing tailored regimens. These refinements offer renewed potential to apply fetal globin induction as a treatment approach in patient-friendly regimens that can be used worldwide.

| S-EPMC3913055 | 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