scholarly journals Estrogen Modulates Microglial Inflammatory Mediator Production via Interactions with Estrogen Receptor β

Endocrinology ◽  
2004 ◽  
Vol 145 (11) ◽  
pp. 5021-5032 ◽  
Author(s):  
Ann E. Baker ◽  
Vielska M. Brautigam ◽  
Jyoti J. Watters
Keyword(s):  
Nitric Oxide ◽  
Molecular Mechanisms ◽  
Mapk Pathway ◽  
Cyclooxygenase 2 ◽  
No Production ◽  
Transcriptional Responses ◽  
Neuroprotective Effects ◽  
Pathway Activation ◽  
Microglial Cell Line ◽  
Antiinflammatory Effects

Abstract Estrogens are well known to exert antiinflammatory effects outside the central nervous system (CNS). They have also been shown to exert neuroprotective effects in the CNS after several types of injury, including neurodegeneration. However, the molecular mechanisms by which these effects occur remain unclear. Because microglial hyperactivation and their production of neurotoxins is associated with many types of brain injury for which estrogens are beneficial, we sought to investigate the ability of estrogen to modulate microglial function. Furthermore, because little is known regarding the role of each of the two known estrogen receptors (ERs) in microglia, our studies were designed to test the hypothesis that 17β-estradiol (E2) exerts antiinflammatory effects in microglia, specifically via interactions with ERβ. We tested this hypothesis using the murine microglial cell line BV-2, which naturally expresses only ERβ. Our results indicate that not only does E2 decrease lipopolysaccharide (LPS)-stimulated nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) expression, it also reduces the expression of cyclooxygenase-2, a target for estrogen that has not previously been reported for ERβ. We also observed that LPS-stimulated TNFα mRNA was increased by estrogen. E2 exerts these effects within 30 min compared with typical estrogen transcriptional responses. Tamoxifen and ICI 182,780 differentially blocked the inhibitory effects of E2 on LPS-stimulated iNOS and cyclooxygenase-2. In addition, we show that E2 alters LPS-stimulated MAPK pathway activation, supporting the idea that alterations in the MAPKs may be a potential mechanism by which ERβ mediates decreased microglial activation.

The Signaling Pathways in Nitric Oxide Production by Neutrophils Exposed to N-nitrosodimethylamine

2018 ◽  
Vol 16 (2) ◽  
pp. 194-199
Author(s):  
Wioletta Ratajczak-Wrona ◽  
Ewa Jablonska
Keyword(s):  
Nitric Oxide ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Polymorphonuclear Neutrophils ◽  
Microbial Pathogens ◽  
Human Neutrophils ◽  
No Production ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

Background: Polymorphonuclear neutrophils (PMNs) play a crucial role in the innate immune system’s response to microbial pathogens through the release of reactive nitrogen species, including Nitric Oxide (NO). </P><P> Methods: In neutrophils, NO is produced by the inducible Nitric Oxide Synthase (iNOS), which is regulated by various signaling pathways and transcription factors. N-nitrosodimethylamine (NDMA), a potential human carcinogen, affects immune cells. NDMA plays a major part in the growing incidence of cancers. Thanks to the increasing knowledge on the toxicological role of NDMA, the environmental factors that condition the exposure to this compound, especially its precursors- nitrates arouse wide concern. Results: In this article, we present a detailed summary of the molecular mechanisms of NDMA’s effect on the iNOS-dependent NO production in human neutrophils. Conclusion: This research contributes to a more complete understanding of the mechanisms that explain the changes that occur during nonspecific cellular responses to NDMA toxicity.

scholarly journals The multi-site docking protein Grb2-associated binder 1 (Gab1) enhances interleukin-6-induced MAPK-pathway activation in an SHP2-, Grb2-, and time-dependent manner

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Hannes Bongartz ◽  
Karen Gille ◽  
Wiebke Hessenkemper ◽  
Katharina Mandel ◽  
Marc Lewitzky ◽  
...  
Keyword(s):  
Interleukin 6 ◽  
Molecular Mechanisms ◽  
Mapk Pathway ◽  
Sh2 Domain ◽  
Time Dependent ◽  
Signalling Pathways ◽  
Dependent Manner ◽  
Mapk Activation ◽  
Pathway Activation ◽  
Mapk Signalling

Abstract Background Cytokine-dependent activation of signalling pathways is tightly orchestrated. The spatiotemporal activation of signalling pathways dictates the specific physiological responses to cytokines. Dysregulated signalling accounts for neoplastic, developmental, and inflammatory diseases. Grb2-associated binder (Gab) family proteins are multi-site docking proteins, which expand cytokine-induced signal transduction in a spatial- and time-dependent manner by coordinating the recruitment of proteins involved in mitogen activated protein kinase (MAPK)/extracellular-signal regulated kinase (ERK) and phosphatidyl-inositol-3-kinase (PI3K) signalling. Interaction of Gab family proteins with these signalling proteins determines strength, duration and localization of active signalling cascades. However, the underlying molecular mechanisms of signal orchestration by Gab family proteins in IL-6-induced signalling are only scarcely understood. Methods We performed kinetic analyses of interleukin-6 (IL-6)-induced MAPK activation and analysed downstream responses. We compared signalling in wild-type cells, Gab1 knock-out cells, those reconstituted to express Gab1 mutants, and cells expressing gp130 receptors or receptor mutants. Results Interleukin-6-induced MAPK pathway activation can be sub-divided into an early Gab1-independent and a subsequent Gab1-dependent phase. Early Gab1-independent MAPK activation is critical for the subsequent initiation of Gab1-dependent amplification of MAPK pathway activation and requires binding of SH2 domain-containing phosphatase 2 (SHP2) to the interleukin-6 receptor complex. Subsequent and coordinated recruitment of Grb2 and SHP2 to Gab1 is essential for Gab1-dependent amplification of IL-6-induced late MAPK pathway activation and subsequent gene expression. Conclusions Overall, we elaborated the molecular requirements for Gab1-dependent, spatiotemporal orchestration of interleukin-6-dependent MAPK signalling. We discriminated IL-6-induced Gab1-independent, early activation of MAPK signalling and Gab1-dependent, sustained activation of MAPK signalling.

scholarly journals (−)-Epicatechin induces calcium and translocation independent eNOS activation in arterial endothelial cells

2011 ◽  
Vol 300 (4) ◽  
pp. C880-C887 ◽  
Author(s):  
Israel Ramirez-Sanchez ◽  
Lisandro Maya ◽  
Guillermo Ceballos ◽  
Francisco Villarreal
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Cardiovascular Effects ◽  
Mesenteric Arteries ◽  
No Production ◽  
Human Coronary Artery ◽  
Calmodulin Binding ◽  
Pathway Activation ◽  
Functional Relevance ◽  
Endothelial Nitric Oxide

The consumption of cacao-derived (i.e., cocoa) products provides beneficial cardiovascular effects in healthy subjects as well as individuals with endothelial dysfunction such as smokers, diabetics, and postmenopausal women. The vascular actions of cocoa are related to enhanced nitric oxide (NO) production. These actions can be reproduced by the administration of the cacao flavanol (−)-epicatechin (EPI). To further understand the mechanisms behind the vascular action of EPI, we investigated the effects of Ca2+ depletion on endothelial nitric oxide (NO) synthase (eNOS) activation/phosphorylation and translocation. Human coronary artery endothelial cells were treated with EPI or with bradykinin (BK), a well-known Ca2+-dependent eNOS activator. Results demonstrate that both EPI and BK induce increases in intracellular calcium and NO levels. However, under Ca2+-free conditions, EPI (but not BK) is still capable of inducing NO production through eNOS phosphorylation at serine 615, 633, and 1177. Interestingly, EPI-induced translocation of eNOS from the plasmalemma was abolished upon Ca2+ depletion. Thus, under Ca2+-free conditions, EPI can stimulate NO synthesis independent of calmodulin binding to eNOS and of its translocation into the cytoplasm. We also examined the effect of EPI on the NO/cGMP/vasodilator-stimulated phosphoprotein (VASP) pathway activation in isolated Ca2+-deprived canine mesenteric arteries. Results demonstrate that under these conditions, EPI induces the activation of this vasorelaxation-related pathway and that this effect is inhibited by pretreatment with nitro-l-arginine methyl ester, suggesting a functional relevance for this phenomenon.

scholarly journals MAPK pathway activation by chronic lead-exposure increases vascular reactivity through oxidative stress/cyclooxygenase-2-dependent pathways

2015 ◽  
Vol 283 (2) ◽  
pp. 127-138 ◽  
Author(s):  
Maylla Ronacher Simões ◽  
Andrea Aguado ◽  
Jonaína Fiorim ◽  
Edna Aparecida Silveira ◽  
Bruna Fernandes Azevedo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lead Exposure ◽  
Vascular Reactivity ◽  
Mapk Pathway ◽  
Cyclooxygenase 2 ◽  
Pathway Activation ◽  
Chronic Lead Exposure

IGF-I and insulin amplify IL-1β-induced nitric oxide and prostaglandin biosynthesis

1998 ◽  
Vol 274 (4) ◽  
pp. F673-F679 ◽  
Author(s):  
Zhonghong Guan ◽  
Shaavhree Y. Buckman ◽  
Lisa D. Baier ◽  
Aubrey R. Morrison
Keyword(s):  
Nitric Oxide ◽  
Mesangial Cells ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
No Production ◽  
Glomerular Mesangial Cells ◽  
Igf I ◽  
Mitogen Activated Protein ◽  
Transduction Mechanisms ◽  
Cox 2

The inflammatory cytokine interleukin-1β (IL-1β) induces both cyclooxygenase-2 (Cox-2) and the inducible nitric oxide synthase (iNOS) with concomitant release of PGs and nitric oxide (NO) by glomerular mesangial cells. In our current studies, we determine whether insulin and IGF-I are involved in the signal transduction mechanisms resulting in IL-1β-induced NO and PGE2biosynthesis in renal mesangial cells. We demonstrate that both insulin and IGF-I increase IL-1β-induced Cox-2 and iNOS protein expression, which in turn enhance PGE2 and NO production. Our data also indicate that both insulin and IGF-I enhance IL-1β-induced p38 mitogen-activated protein kinase (MAPK) phosphorylation and SAPK activation. These findings implicate the possible role of the MAPK pathway in mediating the effects of insulin and IGF-I on the upregulation of cytokine-stimulated NO and PG biosynthesis. Together, our results indicate that IGF-I and insulin may function to modulate the renal inflammatory process.

scholarly journals Identification of Potential Calorie Restriction-Mimicking Yeast Mutants with Increased Mitochondrial Respiratory Chain and Nitric Oxide Levels

2011 ◽  
Vol 2011 ◽  
pp. 1-16 ◽  
Author(s):  
Bin Li ◽  
Craig Skinner ◽  
Pablo R. Castello ◽  
Michiko Kato ◽  
Erin Easlon ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Calorie Restriction ◽  
Mitochondrial Respiration ◽  
Molecular Mechanisms ◽  
Mitochondrial Respiratory Chain ◽  
Yeast Cells ◽  
Mitochondrial Activity ◽  
No Production ◽  
Hypoxic Conditions ◽  
Yeast Mutants

Calorie restriction (CR) induces a metabolic shift towards mitochondrial respiration; however, molecular mechanisms underlying CR remain unclear. Recent studies suggest that CR-induced mitochondrial activity is associated with nitric oxide (NO) production. To understand the role of mitochondria in CR, we identify and studySaccharomyces cerevisiaemutants with increased NO levels as potential CR mimics. Analysis of the top 17 mutants demonstrates a correlation between increased NO, mitochondrial respiration, and longevity. Interestingly, treating yeast with NO donors such as GSNO (S-nitrosoglutathione) is sufficient to partially mimic CR to extend lifespan. CR-increased NO is largely dependent on mitochondrial electron transport and cytochrome c oxidase (COX). Although COX normally produces NO under hypoxic conditions, CR-treated yeast cells are able to produce NO under normoxic conditions. Our results suggest that CR may derepress some hypoxic genes for mitochondrial proteins that function to promote the production of NO and the extension of lifespan.

scholarly journals Prolactin activation of mammary nitric oxide synthase: molecular mechanisms

2002 ◽  
Vol 28 (1) ◽  
pp. 45-51 ◽  
Author(s):  
Keyword(s):  
Nitric Oxide ◽  
Protein Kinase ◽  
Intracellular Calcium ◽  
Molecular Mechanisms ◽  
Mammary Epithelial Cells ◽  
Calcium Ionophore ◽  
Mammary Epithelial ◽  
No Production ◽  
2B Protein ◽  
Oxide Synthase

Prolactin (PRL) is capable of stimulating both calcium and nitric oxide (NO) accumulation in mammary epithelial cells within 15min. A calcium ionophore was also able to stimulate NO levels to an extent similar to that generated by PRL. Furthermore, maximal concentrations of PRL and the ionophore were not additive, suggesting that they were both using the same pathway, i.e. calcium. Finally, the depletion of intracellular calcium completely abrogated the effect of PRL on NO production. No other pathway known to affect NO synthase (NOS) influenced the action of PRL. Specifically, manipulations of protein phosphatase 2B, protein kinase B (PKB), protein kinase C (PKC), and arginine transport did not alter the activation of NOS by PRL. Therefore, the ability of PRL to stimulate NO production at 15min can be completely explained by its ability to elevate intracellular calcium.

scholarly journals Atg32 dependent mitophagy sustains spermidine and nitric oxide required for heat stress tolerance in S. cerevisiae

2021 ◽  
Author(s):  
Jasvinder Kaur ◽  
Juliet Goldsmith ◽  
Alexandra Tankka ◽  
Sofía Bustamante Eguiguren ◽  
Alfredo A. Gimenez ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Heat Stress ◽  
Molecular Mechanisms ◽  
Physiological Role ◽  
No Production ◽  
Polyamine Biosynthesis ◽  
Adenosyl Methionine ◽  
Autophagic Degradation ◽  
Respiratory Growth ◽  
Induced Defects

In Saccharomyces cerevisiae, the selective autophagic degradation of mitochondria, termed mitophagy, is critically regulated by the adapter protein, Atg32. Despite our knowledge about the molecular mechanisms by which Atg32 controls mitophagy, its physiological roles in yeast survival and fitness remains less clear. Here, we demonstrate a requirement for Atg32 in promoting spermidine production during respiratory growth and heat-induced mitochondrial stress. During respiratory growth, mitophagy-deficient yeast exhibit profound heat-stress induced defects in growth and viability due to impaired biosynthesis of spermidine and its biosynthetic precursor S-Adenosyl-Methionine (SAM). Moreover, spermidine production is crucial for the induction of cytoprotective nitric oxide (NO) during heat stress. Hence, the re-addition of spermidine to Atg32 mutant yeast is sufficient to both enhance NO production and restore respiratory growth during heat stress. Our findings uncover a previously unrecognized physiological role for yeast mitophagy in spermidine metabolism and illuminate new interconnections between mitophagy, polyamine biosynthesis and NO signaling.

scholarly journals Nitric Oxide Synthase inhibition counteracts the stress-induced DNA methyltransferase 3b expression in the hippocampus of rats

2020 ◽  
Author(s):  
Izaque de Sousa Maciel ◽  
Amanda Juliana Sales ◽  
Plinio C Casarotto ◽  
Eero Castrén ◽  
Caroline Biojone ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Mrna Expression ◽  
Learned Helplessness ◽  
Hippocampal Neurons ◽  
Dna Methyltransferase ◽  
Molecular Mechanisms ◽  
Calcium Influx ◽  
No Production ◽  
Dna Methyltransferase 3B ◽  
Nos Inhibitors

AbstractIt has been postulated that activation of NMDA receptors (NMDAr) and nitric oxide (NO) production in the hippocampus is involved in the behavioral consequences of stress. Stress triggers NMDAr-induced calcium influx in limbic areas, such as the hippocampus, which in turn activates neuronal NO synthase (nNOS). Inhibition of nNOS or NMDAr activity can prevent stress-induced effects in animal models, but the molecular mechanisms behind this effect are still unclear. In this study, cultured hippocampal neurons treated with NMDA or dexamethasone showed increased of DNA methyltransferase 3b (DNMT3b) mRNA expression, which was blocked by pre-treatment with nNOS inhibitor nω-propyl-L-arginine (NPA). In rats submitted to the Learned Helplessness paradigm (LH), we observed that inescapable stress increased of DNMT3b mRNA expression at 1h and 24h in the hippocampus. The NOS inhibitors 7-NI and aminoguanidine (AMG) decreased the number of escape failures in LH, and counteracted the changes in hippocampal DNMT3b mRNA induced in this behavioral paradigm. Altogether, our data suggest that NO produced in response to NMDAr activation following stress upregulates DNMT3b in the hippocampus.

scholarly journals 1-Carbomethoxy-β-Carboline, Derived from Portulaca oleracea L., Ameliorates LPS-Mediated Inflammatory Response Associated with MAPK Signaling and Nuclear Translocation of NF-κB

Molecules ◽  
2019 ◽  
Vol 24 (22) ◽  
pp. 4042 ◽  
Author(s):  
Kim ◽  
Park ◽  
Jang ◽  
Lee ◽  
Park ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nuclear Translocation ◽  
Inflammatory Diseases ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Portulaca Oleracea ◽  
Mitogen Activated Protein Kinase ◽  
No Production ◽  
Ionization Mass ◽  
Anti Inflammatory

Portulaca oleracea is as a medicinal plant known for its neuroprotective, hepatoprotective, antidiabetic, antioxidant, anticancer, antimicrobial, antiulcerogenic, and anti-inflammatory activities. However, the specific active compounds responsible for the individual pharmacological effects of P. oleracea extract (95% EtOH) remain unknown. Here, we hypothesized that alkaloids, the most abundant constituents in P. oleracea extract, are responsible for its anti-inflammatory activity. We investigated the phytochemical substituents (compounds 1–22) using nuclear magnetic resonance (NMR) and electrospray ionization mass spectrometry (ESI-MS) and screened their effects on NO production in lipopolysaccharide (LPS)-induced macrophages. Compound 20, 1-carbomethoxy-β-carboline, as an alkaloid structure, ameliorated nitric oxide (NO) production, inducible nitric oxide synthase (iNOS), and proinflammatory cytokines associated with the mitogen-activated protein kinase (MAPK) pathways, p38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK). Subsequently, we observed that compound 20 suppressed nuclear translocation of nuclear factor κB (NF-κB) using immunocytochemistry. Moreover, we recently reported that compound 8, trans-N-feruloyl-3’, 7’-dimethoxytyramine, was originally purified from P. oleracea extracts. Our results suggest that 1-carbomethoxy-β-carboline, the most effective anti-inflammatory agent among alkaloids in the 95% EtOH extract of P. oleracea, was suppressing the MAPK pathway and nuclear translocation of NF-κB. Therefore, P. oleracea extracts and specifically 1-carbomethoxy-β-carboline may be novel therapeutic candidates for the treatment of inflammatory diseases associated with the activation of MAPKs and NF-κB.

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