Browse
Submit Data
Databases
API
Help

Dataset Information

8 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Anti-inflammatory effects of N-cyclooctyl-5-methylthiazol-2-amine hydrobromide on lipopolysaccharide-induced inflammatory response through attenuation of NLRP3 activation in microglial cells.

ABSTRACT: Microglial activation is closely associated with neuroinflammatory pathologies. The nucleotide-binding and oligomerization domain-like receptor containing a pyrin domain 3 (NLRP3) inflammasomes are highly organized intracellular sensors of neuronal alarm signaling. NLRP3 inflammasomes activate nuclear factor kappa-B (NF-κB) and reactive oxygen species (ROS), which induce inflammatory responses. Moreover, NLRP3 dysfunction is a common feature of chronic inflammatory diseases. The present study investigated the effect of a novel thiazol derivative, N-cyclooctyl-5-methylthiazol-2-amine hydrobromide (KHG26700), on inflammatory responses in lipopolysaccharide (LPS)-treated BV-2 microglial cells. KHG26700 significantly attenuated the expression of several pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-1β, and interleukin-6, in these cells, as well as the LPS-induced increases in NLRP3, NF-κB, and phospho-IkBα levels. KHG26700 also suppressed the LPS-induced increases in protein levels of autophagy protein 5 (ATG5), microtubule- associated protein 1 light chain 3 (LC3), and beclin-1, as well as downregulating the LPS-enhanced levels of ROS, lipid peroxidation, and nitric oxide. These results suggest that the anti-inflammatory effects of KHG26700 may be due, at least in part, to the regulation of the NLRP3-mediated signaling pathway during microglial activation. [BMB Reports 2021; 54(11): 557-562].

SUBMITTER: Kim EA

PROVIDER: S-EPMC8633521 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Lipopolysaccharide induces inflammatory microglial activation through CD147-mediated matrix metalloproteinase expression.

Project description:Microglia-mediated neuroinflammation plays a vital role in the pathophysiological processes of multiple neurodegenerative diseases. Lipopolysaccharide (LPS) is an environmental poison that can induce inflammatory microglial activation. Matrix metalloproteinases (MMPs) are vital factors regulating microglial activation, and CD147 is a key MMP inducer, which can induce inflammation by inducing MMPs. However, whether it is involved in the regulation of microglial activation has not been reported. In this study, the role of CD147 in LPS-induced microglial inflammatory activation was investigated by establishing in vivo and in vitro models. The results suggested that LPS-induced microglial activation was accompanied by the induction of CD147 expression while the inhibition of CD147 expression could inhibit LPS-induced microglial inflammatory activation. In addition, the results also indicated that the role of CD147 in LPS-induced pro-inflammatory activation of microglia was related to its downstream MMP-3, MMP-8, and autophagy. Furthermore, the inhibition of MMP-3, MMP-8, and autophagy attenuated LPS-induced inflammatory activation of microglia. At the same time, there was a certain interaction between MMPs and autophagy, which is shown that inhibiting the expression of MMPs could inhibit autophagy, whereas inhibiting autophagy could inhibit the expression of MMPs. Taken together, we provided the first evidence that CD147/MMPs can be involved in LPS-induced inflammatory activation of microglia through an autophagy-dependent manner.

| S-EPMC9761036 | biostudies-literature

The Anti-diabetic Drug Gliquidone Modulates Lipopolysaccharide-Mediated Microglial Neuroinflammatory Responses by Inhibiting the NLRP3 Inflammasome.

Project description:The sulfonylurea drug gliquidone is FDA approved for the treatment of type 2 diabetes. Binding of gliquidone to ATP-sensitive potassium channels (SUR1, Kir6 subunit) in pancreatic β-cells increases insulin release to regulate blood glucose levels. Diabetes has been associated with increased levels of neuroinflammation, and therefore the potential effects of gliquidone on micro- and astroglial neuroinflammatory responses in the brain are of interest. Here, we found that gliquidone suppressed LPS-mediated microgliosis, microglial hypertrophy, and proinflammatory cytokine COX-2 and IL-6 levels in wild-type mice, with smaller effects on astrogliosis. Importantly, gliquidone downregulated the LPS-induced microglial NLRP3 inflammasome and peripheral inflammation in wild-type mice. An investigation of the molecular mechanism of the effects of gliquidone on LPS-stimulated proinflammatory responses showed that in BV2 microglial cells, gliquidone significantly decreased LPS-induced proinflammatory cytokine levels and inhibited ERK/STAT3/NF-κB phosphorylation by altering NLRP3 inflammasome activation. In primary astrocytes, gliquidone selectively affected LPS-mediated proinflammatory cytokine expression and decreased STAT3/NF-κB signaling in an NLRP3-independent manner. These results indicate that gliquidone differentially modulates LPS-induced microglial and astroglial neuroinflammation in BV2 microglial cells, primary astrocytes, and a model of neuroinflammatory disease.

| S-EPMC8587901 | biostudies-literature

Microglial Pro-Inflammatory and Anti-Inflammatory Phenotypes Are Modulated by Translocator Protein Activation.

Project description:A key role of the mitochondrial Translocator Protein 18 KDa (TSPO) in neuroinflammation has been recently proposed. However, little is known about TSPO-activated pathways underlying the modulation of reactive microglia. In the present work, the TSPO activation was explored in an in vitro human primary microglia model (immortalized C20 cells) under inflammatory stimulus. Two different approaches were used with the aim to (i) pharmacologically amplify or (ii) silence, by the lentiviral short hairpin RNA, the TSPO physiological function. In the TSPO pharmacological stimulation model, the synthetic steroidogenic selective ligand XBD-173 attenuated the activation of microglia. Indeed, it reduces and increases the release of pro-inflammatory and anti-inflammatory cytokines, respectively. Such ligand-induced effects were abolished when C20 cells were treated with the steroidogenesis inhibitor aminoglutethimide. This suggests a role for neurosteroids in modulating the interleukin production. The highly steroidogenic ligand XBD-173 attenuated the neuroinflammatory response more effectively than the poorly steroidogenic ones, which suggests that the observed modulation on the cytokine release may be influenced by the levels of produced neurosteroids. In the TSPO silencing model, the reduction of TSPO caused a more inflamed phenotype with respect to scrambled cells. Similarly, during the inflammatory response, the TSPO silencing increased and reduced the release of pro-inflammatory and anti-inflammatory cytokines, respectively. In conclusion, the obtained results are in favor of a homeostatic role for TSPO in the context of dynamic balance between anti-inflammatory and pro-inflammatory mediators in the human microglia-mediated inflammatory response. Interestingly, our preliminary results propose that the TSPO expression could be stimulated by NF-?B during activation of the inflammatory response.

| S-EPMC6770267 | biostudies-literature

Anti-Inflammatory Activity of Panduratin A against LPS-Induced Microglial Activation.

Project description:Uncontrolled and excessive microglial activation is known to contribute to inflammation-mediated neurodegeneration. Therefore, reducing neurotoxic microglial activation may serve as a new approach to preventing neurodegeneration. Here, we investigated the anti-inflammatory effects of panduratin A against microglial activation induced by lipopolysaccharides (LPS) in the SIMA9 microglial cell line. We initially examined the anti-inflammatory properties of panduratin A by measuring LPS-induced nitric oxide (NO) production and the levels of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6). Panduratin A significantly reduced NO levels and pro-inflammatory cytokines' production and secretion. In addition, panduratin A enhanced the production of anti-inflammatory cytokines IL-4 and IL-10. The anti-inflammatory effects of panduratin A are related to the suppression of the NF-κB signaling pathway. Together, these results demonstrate the anti-inflammatory properties of panduratin A against LPS-induced microglial activation, suggesting panduratin A has the potential to be further developed as a new agent for the prevention of neuroinflammation-associated neurodegenerative diseases.

| S-EPMC9599841 | biostudies-literature

New phenanthrenequinones from Cymbidium ensifolium roots and their anti-inflammatory activity on lipopolysaccharide-activated BV2 microglial cells.

Project description:The roots of Cymbidium ensifolium yielded a total of 17 compounds, comprising two new compounds (1-2), one new natural product (3), and 14 known compounds (4-17). The structures of new compounds were determined through the analysis of their spectroscopic data, including NMR, MS, UV, FT-IR, optical rotation, and CD. The anti-inflammatory activity of the isolated pure compounds was assessed using lipopolysaccharide-activated BV2 microglial cells. Compounds 1, 3, 6, 12, 14, and 16 showed the ability to reduce LPS induced NO release in BV2 microglial cells, with IC50 values of 9.95 ± 2.13, 8.77 ± 3.78, 2.39 ± 0.91, 6.69 ± 2.94, 2.96 ± 1.38, 8.42 ± 2.99 μM, respectively and reduced the secretion of proinflammatory mediators (TNF-α, IL-6, MCP-1) in a concentration-dependent manner. Furthermore, the mechanistic role of the compound 3 was determined, which demonstrated its ability to inhibit the nuclear factor-κB (NF-κB) pathway through decreasing phosphorylation of p65 subunits.

| S-EPMC11375963 | biostudies-literature

Inhibition of NADPH oxidase promotes alternative and anti-inflammatory microglial activation during neuroinflammation.

Project description:Like macrophages, microglia are functionally polarized into different phenotypic activation states, referred as classical and alternative. The balance of the two phenotypes may be critical to ensure proper brain homeostasis, and may be altered in brain pathological states, such as Alzheimer's disease. We investigated the role of NADPH oxidase in microglial activation state using p47(phox) and gp91(phox) -deficient mice as well as apocynin, a NADPH oxidase inhibitor during neuroinflammation induced by an intracerebroventricular injection of LPS or A?????. We showed that NADPH oxidase plays a critical role in the modulation of microglial phenotype and subsequent inflammatory response. We demonstrated that inhibition of NADPH oxidase or gene deletion of its functional p47(phox) subunit switched microglial activation from a classical to an alternative state in response to an inflammatory challenge. Moreover, we showed a shift in redox state towards an oxidized milieu and that subpopulations of microglia retain their detrimental phenotype in Alzheimer's disease brains. Microglia can change their activation phenotype depending on NADPH oxidase-dependent redox state of microenvironment. Inhibition of NADPH oxidase represents a promising neuroprotective approach to reduce oxidative stress and modulate microglial phenotype towards an alternative state.

| S-EPMC3386526 | biostudies-literature

Adjudin attenuates lipopolysaccharide (LPS)- and ischemia-induced microglial activation.

Project description:Neuroinflammation caused by microglial activation plays a key role in ischemia, neurodegeneration and many other CNS diseases. In this study, we found that Adjudin, a potential non-hormonal male contraceptive, exhibits additional function to reduce the production of proinflammatory mediators. Adjudin significantly inhibited LPS-induced IL-6 release and IL-6, IL-1β, TNF-α expression in BV2 microglial cells. Furthermore, Adjudin exhibited anti-inflammatory properties by suppression of NF-κB p65 nuclear translocation and DNA binding activity as well as ERK MAPK phosphorylation. To determine the in vivo effect of Adjudin, we used a permanent middle cerebral artery occlusion (pMCAO) mouse model and found that Adjudin could reduce ischemia-induced CD11b expression, a marker of microglial activation. Furthermore, Adjudin treatment attenuated brain edema and neurological deficits after ischemia but did not reduce infarct volume. Thus, our data suggest that Adjudin may be useful for mitigating neuroinflammation.

| S-EPMC4108195 | biostudies-literature

NLRP3 Inflammasome Blockade Reduces Cocaine-Induced Microglial Activation and Neuroinflammation.

Project description:Cocaine use disorder is a major health crisis that is associated with increased oxidative stress and neuroinflammation. While the role of NLRP3 inflammasome in mediating neuroinflammation is well-recognized, whether cocaine induces this response remains unexplored. Based on the premise that cocaine induces both reactive oxygen species (ROS) as well as microglial activation, we hypothesized that cocaine-mediated microglial activation involves both ROS and NLRP3 signaling pathways. We examined activation of the NLRP3 pathway in microglia exposed to cocaine, followed by validation in mice administered either cocaine or saline for 7 days, with or without pretreatment with the NLRP3 inhibitor, MCC950, and in postmortem cortical brain tissues of chronic cocaine-dependent humans. We found that microglia exposed to cocaine exhibited significant induction of NLRP3 and mature IL-1β expression. Intriguingly, blockade of ROS (Tempol) attenuated cocaine-mediated priming of NLRP3 and microglial activation (CD11b). Blockade of NLRP3 by both pharmacological (MCC950) as well as gene silencing (siNLRP3) approaches underpinned the critical role of NLRP3 in cocaine-mediated activation of inflammasome and microglial activation. Pretreatment of mice with MCC950 followed by cocaine administration for 7 days mitigated cocaine-mediated upregulation of mature IL-1β and CD11b, in both the striatum and the cortical regions. Furthermore, cortical brain tissues of chronic cocaine-dependent humans also exhibited upregulated expression of the NLRP3 pathway mediators compared with non-cocaine dependent controls. Collectively, these findings suggest that cocaine activates microglia involving the NLRP3 inflammasome pathway, thereby contributing to neuroinflammation. NLRP3 can thus be considered as a potential therapeutic target for alleviating cocaine-mediated neuroinflammation.

| S-EPMC8026688 | biostudies-literature

Costunolide Plays an Anti-Neuroinflammation Role in Lipopolysaccharide-Induced BV2 Microglial Activation by Targeting Cyclin-Dependent Kinase 2.

Project description:Hyperactivation of microglia in the brain is closely related to neuroinflammation and leads to neuronal dysfunction. Costunolide (CTL) is a natural sesquiterpene lactone with wide pharmacological activities including anti-inflammation and antioxidation. In this study, we found that CTL significantly inhibited the production of inflammatory mediators including nitric oxide, IL-6, TNF-α, and PGE2 in lipopolysaccharide (LPS)-stimulated BV2 microglia. Moreover, CTL effectively attenuated IKKβ/NF-κB signaling pathway activation. To identify direct cellular target of CTL, we performed high-throughput reverse virtual screening assay using scPDB protein structure library, and found cyclin-dependent kinase 2 (CDK2) was the most specific binding protein for CTL. We further confirmed the binding ability of CTL with CDK2 using cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) assays. Surface plasmon resonance analysis also supported that CTL specifically bound to CDK2 with a dissociation constant at micromole level. Furthermore, knocking down CDK2 obviously reversed the anti-inflammation effect of CTL via AKT/IKKβ/NF-κB signaling pathway on BV-2 cells. Collectively, these results indicate that CTL inhibits microglia-mediated neuroinflammation through directly targeting CDK2, and provide insights into the role of CDK2 as a promising anti-neuroinflammation therapeutic target.

| S-EPMC7355650 | biostudies-literature

Identification of new molecular targets for PET imaging of the microglial anti-inflammatory activation state.

Project description:Microglia are potential targets for therapeutic intervention in neurological and neurodegenerative diseases affecting the central nervous system. In order to assess the efficacy of therapies aimed to reduce the tissue damaging activities of microglia and/or to promote the protective potential of these cells, suitable pre-clinical and clinical tools for the in vivo analysis of microglia activities and dynamics are required. The aim of this work was to identify new translational markers of the anti-inflammatory / protective state of microglia for the development of novel PET tracers. Methods: New translational markers of the anti-inflammatory/protective activation state of microglia were selected by bioinformatic approaches and were in vitro and ex vivo validated by qPCR and immunohistochemistry in rodent and human samples. Once a viable marker was identified, a novel PET tracer was developed. This tracer was subsequently confirmed by autoradiography experiments in murine and human brain tissues. Results: Here we provide evidence that P2RY12 expression increases in murine and human microglia following exposure to anti-inflammatory stimuli, and that its expression is modulated in the reparative phase of experimental and clinical stroke. We then synthesized a novel carbon-11 labeled tracer targeting P2RY12, showing increased binding in brain sections of mice treated with IL4, and low binding to brain sections of a murine stroke model and of a stroke patient. Conclusion: This study provides new translational targets for PET tracers for the anti-inflammatory/protective activation state of microglia and shows the potential of a rationale-based approach. It therefore paves the way for the development of novel non-invasive methodologies aimed to monitor the success of therapeutic approaches in various neurological diseases.

| S-EPMC6276082 | 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