scholarly journals A new p65 isoform that bind the glucocorticoid hormone and is expressed in inflammation liver diseases and COVID-19

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Gaetano Spinelli ◽  
Giuseppa Biddeci ◽  
Anna Artale ◽  
Francesca Valentino ◽  
Giuseppe Tarantino ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Hepatic Cirrhosis ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
Wild Type ◽  
Inflammatory Agent ◽  
Anti Inflammatory ◽  
Corticosteroid Hormone ◽  
Spliced Variant ◽  
Nuclear Factor Kb

AbstractInflammation is a physiological process whose deregulation causes some diseases including cancer. Nuclear Factor kB (NF-kB) is a family of ubiquitous and inducible transcription factors, in which the p65/p50 heterodimer is the most abundant complex, that play critical roles mainly in inflammation. Glucocorticoid Receptor (GR) is a ligand-activated transcription factor and acts as an anti-inflammatory agent and immunosuppressant. Thus, NF-kB and GR are physiological antagonists in the inflammation process. Here we show that in mice and humans there is a spliced variant of p65, named p65 iso5, which binds the corticosteroid hormone dexamethasone amplifying the effect of the glucocorticoid receptor and is expressed in the liver of patients with hepatic cirrhosis and hepatocellular carcinoma (HCC). Furthermore, we have quantified the gene expression level of p65 and p65 iso5 in the PBMC of patients affected by SARS-CoV-2 disease. The results showed that in these patients the p65 and p65 iso5 mRNA levels are higher than in healthy subjects. The ability of p65 iso5 to bind dexamethasone and the regulation of the glucocorticoid (GC) response in the opposite way of the wild type improves our knowledge and understanding of the anti-inflammatory response and identifies it as a new therapeutic target to control inflammation and related diseases.

scholarly journals Polysaccharides from the fungus Scleroderma nitidum with anti-inflammatory potential modulate cytokine levels and the expression of Nuclear Factor kB

2012 ◽  
Vol 22 (1) ◽  
pp. 60-68 ◽  
Author(s):  
Marília S. Nascimento ◽  
Joedyson E. M. Magalhães ◽  
Thuane S. Pinheiro ◽  
Thayse Azevedo da Silva ◽  
Leonam Gomes Coutinho ◽  
...  
Keyword(s):  
Nuclear Factor ◽  
Cytokine Levels ◽  
Anti Inflammatory ◽  
Nuclear Factor Kb

Oxymatrine inhibits lipopolysaccharide-induced inflammation by down-regulating Toll-like receptor 4/nuclear factor-kappa B in macrophages

2015 ◽  
Vol 93 (4) ◽  
pp. 253-260 ◽  
Author(s):  
Yu Zhang ◽  
Ruhong Yan ◽  
Yae Hu
Keyword(s):  
Nitric Oxide ◽  
Interleukin 1 ◽  
Chinese Herb ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Anti Inflammatory

Oxymatrine (OMT) is the quinolizidine alkaloid extracted from the Chinese herb Sophora flavescens Ait. that has many pharmacological effects and is used for the treatment of some inflammatory diseases. In this study, RAW264.7 cells and THP-1 differentiated macrophages were pretreated with various concentrations of OMT at 2 h prior to treatment with lipopolysaccharide (LPS) (1.0 μg/mL) for different durations. We detected the anti-inflammatory effect of OMT in LPS-stimulated macrophages and investigated the molecular mechanism. We showed that OMT pretreatment significantly inhibited the LPS-induced secretion of nitric oxide (NO), interleukin-1 beta (IL-1β), and tumor necrosis factor-alpha (TNF-α) in supernatant, attenuated the mRNA levels of inducible nitric oxide synthase (iNOS), IL-1β, TNF-α, and Toll-like receptor 4 (TLR4), increased TLR4 and phosphorylation of inhibitor of kappa B-alpha (p-IBα) in cytosol, and decreased the nuclear level of nuclear factor-κB (NF-κB) p65 in macrophages. In conclusion, OMT exerts anti-inflammatory properties in LPS-stimulated macrophages by down-regulating the TLR4/NF-κB pathway.

The role of the α7nAChR-mediated cholinergic anti-inflammatory pathway in Hirschsprung associated enterocolitis

2020 ◽  
Author(s):  
Feng Chen ◽  
Xiaoyu Wei ◽  
Xiaohua Chen ◽  
Lei Xiang ◽  
Xinyao Meng ◽  
...  
Keyword(s):  
Western Blotting ◽  
Mrna Level ◽  
Underlying Mechanism ◽  
Mrna Levels ◽  
Wild Type ◽  
Inflammatory Pathway ◽  
Anti Inflammatory ◽  
Phosphorylated Stat3 ◽  
Morphology Changes

Abstract Background To investigate the role and the underlying mechanism of the α7nAChR-mediated cholinergic anti-inflammatory pathway in the pathogenesis of Hirschsprung(HSCR) associated enterocolitis（HAEC）. Methods Experimental group:twenty-one-day-old Ednrb-/- mice were selected (n=10), with comparable-age wild type(Ednrb+/+) mice controls (n=10). Intestinal samples were collected. The experimental colons were divided into narrow and dilated segments according to morphology changes. The control colons were divided into distal and proximal segments.Colon HE staining was used to judge HAEC.Acetylcholine levels in colon was measured using enzyme-linked immunosorbent assays. Detected phosphorylated Jak2 (p-Jak2), Jak2, phosphorylated Stat3 (p-Stat3), Stat3, phosphorylated IκBα (p-IκBα) and IκBα were studied by Western blotting; mRNA levels of Jak2, Stat3, and IκBα were detected by RT-qPCR. Results Colon HE staining indicated that HAEC mainly occured in the dilated segments of HSCR mice (Ednrb-/- mice) (EDNRB-P).Acetylcholine content in EDNRB-P was significantly lower than that in the narrow segments (EDNRB-D) (P<0.05). Western blotting showed that the Jak2, p-Jak2, Stat3 and p-Stat3 levels in EDNRB-D were significantly higher than those in EDNRB-P (P<0.05). The p-IκBα and IκBα levels in EDNRB-P were significantly higher than those in EDNRB-D(P<0.05). The mRNA levels of Jak2 and Stat3 in EDNRB-D were higher than those in EDNRB-P, but the IκBα mRNA level was significantly lower than that in EDNRB-P (P<0.05). Conclusions During HAEC, the inflammation in the dilated segment was more severe ,while in the narrow segment there was no obvious inflammatory reaction and the content of acetylcholine was higher, which was associated with the α7nAChR-mediated cholinergic anti-inflammatory pathway.

scholarly journals Tart Cherry Reduces Inflammation in Adipose Tissue of Zucker Fatty Rats and Cultured 3T3-L1 Adipocytes

Nutrients ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 1576 ◽  
Author(s):  
Shasika Jayarathne ◽  
April Stull ◽  
Alexandra Miranda ◽  
Shane Scoggin ◽  
Kate Claycombe-Larson ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Fatty Acid Synthase ◽  
Related Factor ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
Adipose Tissue Inflammation ◽  
Tart Cherry ◽  
Tissue Inflammation ◽  
Anti Inflammatory

Obesity increases adipose tissue inflammation and secretion of pro-inflammatory adipokines, which have systemic effects on the organism’s health status. Our objective was to dissect mechanisms of anti-inflammatory effects of tart cherry (TC) in adipose tissue of Zucker fatty rats, and cultured 3T3-L1 adipocytes. Rats were fed either a control diet, or 4% TC powder diets for eight weeks. Body and epididymal fat pad weights were not significantly different between control and TC groups. However, rats fed the TC diet had significantly reduced adipose tissue inflammation (p < 0.05), as determined by reduced mRNA levels of pro-inflammatory markers including interleukin-6 (IL-6), tumor necrosis factor alpha (TNFα), interleukin-1beta (IL-1β), monocyte chemoattractant protein 1 (MCP-1), inducible nitric oxide synthase (iNOS), and CD-11b, and increased mRNA levels of type-1 arginase (Arg-1) anti-inflammatory marker. Consistent with these in vivo results, TC significantly decreased expression of IL-6 mRNA and protein levels in lipopolysaccharide (LPS) stimulated adipocytes compared to those stimulated with LPS, but no TC. Moreover, both in vivo (rat adipose tissue) and in vitro (3T3-L1 adipocytes), phosphorylation of p65-NF-κB subunit was significantly reduced by TC. Additionally, TC decreased mRNA expression of fatty acid synthase (FASN), and increased expression of peroxisome proliferator-activated receptor alpha (PPARα), master regulator of lipid oxidation, and anti-oxidant markers nuclear factor erythroid-derived 2-related factor (NRFs) in both models. In conclusion, our findings indicate that TC downregulates inflammation in part via the nuclear factor kappa B (NF-κB) pathway in adipose tissue. Thus, TC may serve as a potential intervention to reduce obesity-associated inflammation.

scholarly journals A selective glucocorticoid receptor modulator attenuates lung inflammation and improves alveolarization in a neonatal rat model of bronchopulmonary dysplasia

2021 ◽  
Author(s):  
Shoichi Ishikawa ◽  
Tohru Ogihara ◽  
Shigeo Yamaoka ◽  
Jun Shinohara ◽  
Shigeru Kawabata ◽  
...  
Keyword(s):  
Side Effects ◽  
Glucocorticoid Receptor ◽  
Bronchopulmonary Dysplasia ◽  
Lung Inflammation ◽  
Inflammatory Cells ◽  
Mrna Levels ◽  
Compound A ◽  
Receptor Modulator ◽  
Anti Inflammatory ◽  
Tgf Β1

ABSTRACTBackgroundBronchopulmonary dysplasia (BPD) is a major problem for extremely preterm infants. Glucocorticoids effectively treat BPD; however, they have many side effects. Compound A (Cpd A) is a nonsteroidal Selective Glucocorticoid Receptor Modulator (SEGRM) that acts as a glucocorticoid receptor ligand without inducing the expression of glucocorticoid-response element-driven genes. Cpd A reportedly has anti-inflammatory properties with fewer side effects than glucocorticoids.MethodsUsing a bleomycin (Bleo)-induced BPD model, we evaluated the therapeutic effects of Cpd A. 0-day-old Sprague-Dawley rats were administered Bleo for 10 days and treated with dexamethasone (Dex) or Cpd A from day 0 to 13. We evaluated lung pathology by histology and the mRNA levels of interleukin (IL)-1β, transforming growth factor (TGF)-β1 and chemokines, CXCL1 and CCL2.ResultsBleo-treated mice had lungs with impaired alveolarization. Dex and Cpd A treatments improved the alveolar structure, attenuating the lung injury. Bleo-exposed lungs had increased inflammatory cells recruitment and inflammatory mediator mRNA levels. Cpd A treatment reduced inflammatory cells infiltration and CXCL1, CCL2 and TGF-β1 expression.ConclusionCpd A improved lung inflammation and alveolar maturation arrest, and restored histological and biochemical changes in a model of BPD. SEGRMs, including Cpd A, are promising candidates for the therapy of BPD.Impact Statement○What is the key message of your article?Compound A decreased lung inflammation and improved lung morphometric changes in Bleomycin-exposed lungs.○What does it add to the existing literature?Compound A has anti-inflammatory effects in an experimental model of BPD.○What is the impact?SEGRMs, including Cpd A, may be promising candidates for the therapy of BPD.

Abstract 551: Deficiency of Hepatic Nuclear Factor 4 Alpha Results in Impaired Metabolism of Endogenous Methylarginines and Beta-aminoisobutiric Acid - A Novel Mechanism of Cardiovascular Complications in Patients With Type 2 Diabetes?

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Dmitrii V Burdin ◽  
Alexey A Kolobov ◽  
Anton V Demyanov ◽  
Alexey A Soshnev ◽  
Chad N Broker ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Binding Site ◽  
Promoter Region ◽  
Core Promoter ◽  
Luciferase Reporter ◽  
Diabetic Patients ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
Wild Type

Introduction: Alanine-glyoxylate aminotransferase 2 (AGXT2) is the only known enzyme capable of degradation of all three endogenous methylarginines, which serve as markers and potentially mediators of cardiovascular disease. Recent studies also suggest that AGXT2 and its alternative substrate beta-aminoisobutyric acid (BAIB) play important role in lipid metabolism. The predicted core promoter region of mammalian AGXT2 promoter contains a highly conserved putative binding site for hepatic nuclear factor 4 alpha (HNF4A). Patients with severe deficiency in HNF4a develop maturity onset diabetes of young 1. Furthermore, polymorphisms of HNF4A are associated with increased risk of diabetes type 2. The aim of this study was to test the hypothesis that HNF4A is a major regulator of AGXT2 expression and activity. Methods and results: We demonstrated direct binding of HNF4A to the Agxt2 promoter region in hepatic cell line Hepa 1-6 using chromatin immunoprecipitation assays. Then we showed that mutations of the predicted HNF4A binding site in the Agxt2 core promoter result in up to 80% decrease in the promoter activity as assessed by luciferase reporter assays (p<0.001). We used siRNA-mediated knockdown of HNF4A to determine whether this factor is required for basal Agxt2 expression in Hepa 1-6 cells. Knockdown of HNF4A led to almost 50% reduction in Agxt2 mRNA levels compared to controls (p<0.01). We took advantage of the previously characterized inducible liver-specific Hnf4a knockout (KO) mice to determine whether HNF4A regulates Agxt2 expression in vivo and showed a 90% (p<0.001) decrease in liver Agxt2 expression and a 85% (p<0.01) decrease in liver AGXT2 activity towards methylarginines in Hnf4a KO mice compared with the wild-type littermates. Finaly, on a functional level, Hnf4a KO mice had significant amounts of BAIB present in plasma, whereas BAIB was not detectable in the plasma of the wild-type littermates. Conclusions: In our study we identified HNF4A as the major regulator of Agxt2 gene expression. This finding suggests that diabetic patients with HNF4A deficiency might have a unique mechanism for development of cardiovascular complication via AGXT2-dependent impairment of lipid metabolism and methylarginines-mediated vascular dysfunction.

Mapracorat, a selective glucocorticoid receptor agonist, upregulates RelB, an anti-inflammatory nuclear factor-kappaB protein, in human ocular cells

2014 ◽  
Vol 127 ◽  
pp. 290-298 ◽  
Author(s):  
Sherry L. Spinelli ◽  
Xia Xi ◽  
David H. McMillan ◽  
Collynn F. Woeller ◽  
Mary E. Richardson ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Receptor Agonist ◽  
Nuclear Factor Kappab ◽  
Nuclear Factor ◽  
Anti Inflammatory

Low Molecular Weight and Unfractionated Heparins Induce a down Regulation of Inflammation: Decreased Levels of Pro-Inflammatory Cytokines and Nuclear Factor-kB in LPS-Stimulated Human Monocytes.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3884-3884
Author(s):  
Helene M. Hochart ◽  
Vincent P. Jenkins ◽  
Barry D. White
Keyword(s):  
Molecular Weight ◽  
Inflammatory Cytokine ◽  
Autologous Serum ◽  
Low Molecular Weight ◽  
Nuclear Factor ◽  
Human Monocytes ◽  
Low Molecular Weight Heparins ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Nuclear Factor Kb

Abstract Unfractionated heparin (UFH) and low molecular weight heparin (LMWH) are highly sulphated proteoglycans widely applied as anticoagulant drugs. They represent pivotal agents for the prevention and treatment of thromboembolic disorders, pulmonary embolism, disseminated intravascular coagulation and unstable angina. Several different studies have suggested that aside from their anticoagulant capacity, heparins possess anti-inflammatory properties, however reports have been conflicting. UFH and sulfated heparin derivatives have been shown to inhibit pro-inflammatory cytokine gene expression in lipopolysaccharide (LPS)-stimulated human mononuclear cells and to inhibit the nuclear factor-kB (NF-κB) activation in a tumor necrosis factor alpha (TNF-α) stimulated human endothelial cell line. However, other studies indicate that heparin in fact amplifies the inflammatory cytokine release in monocytes. Nevertheless, heparin appeared in several clinical trials to have the potential to treat inflammatory bowel disease, arthritis, rhinitis, and human asthma, with an anti-inflammatory effect dissociable from its anticoagulant activity. In the present study, we assessed the effect of LPS stimulation on heparin pre-treated and untreated pure human monocytes. Cells were isolated from whole blood and resuspended in RPMI supplemented with 10% platelet free autologous serum, before addition of unfractionated and low molecular weight heparins (1IU=10μg/ml and 0.1IU=1μg/ml per million cells) 15 minutes before LPS stimulation (1ng per million cells). Pro-inflammatory cytokine levels produced were measured by ELISA and NF-κB translocation using the TransAM Chemi Transcription Factor Assay. The production of TNF-α, interleukin (IL)-8, IL-6 and IL-1β was upregulated by LPS, and their levels significantly reduced when the cells were exposed to heparin, up to 3 fold with 0.1IU UFH. LPS-induced NF-κB translocation from the cytoplasm to the nucleus was also significantly reduced in heparin pre-treated cells; even at low heparin doses, as shown by a 1.5-fold reduction induced with 0.1IU UFH. NF-κB activation, a critical phenomenon in host inflammatory response, is implicated in a wide range of inflammatory diseases and therefore represents an ideal and novel molecular target. Here we report that both unfractionated and low molecular weight heparins possess the equal ability to significantly reduce the monocytic inflammatory reaction through inhibition of NF-κB activation. This indicates a potential mechanism responsible, in part, for the protective effect of the drug in inflammatory disorders. In clinical practice, heparin use as an anti-inflammatory agent is restricted by its potential to induce bleeding complications. Further investigations are required to elucidate the precise mechanism of action of the drug at the cellular level, and optimise the development of non-anticoagulant variants.

scholarly journals Rice Protein Exerts Anti-Inflammatory Effect in Growing and Adult Rats via Suppressing NF-κB Pathway

2019 ◽  
Vol 20 (24) ◽  
pp. 6164
Author(s):  
Zhengxuan Wang ◽  
Mingcai Liang ◽  
Hui Li ◽  
Liang Cai ◽  
Lin Yang
Keyword(s):  
Nuclear Factor Κb ◽  
Interleukin 10 ◽  
Heme Oxygenase 1 ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
Adult Rats ◽  
Monocyte Chemoattractant Protein 1 ◽  
Rice Protein ◽  
Anti Inflammatory ◽  
Inflammatory Effect

To elucidate the effect of rice protein (RP) on the depression of inflammation, growing and adult rats were fed with caseins and RP for 2 weeks. Compared with casein, RP reduced hepatic accumulations of reactive oxygen species (ROS) and nitro oxide (NO), and plasma activities of alanine transaminase (ALT) and aspartate transaminase (AST) in growing and adult rats. Intake of RP led to increased mRNA levels, and protein expressions of phosphoinositide 3 kinase (PI3K), protein kinase B (Akt), nuclear factor-κB 1 (NF-αB1), reticuloendotheliosis viral oncogene homolog A (RelA), tumor necrotic factor α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and monocyte chemoattractant protein-1 (MCP-1) were decreased, whereas hepatic expressions of interleukin-10 (IL-10) and heme oxygenase 1 (HO-1) were increased by RP. The activation of NF-κB was suppressed by RP through upregulation of inhibitory κB α (IκBα), resulting in decreased translocation of nuclear factor-κB 1 (p50) and RelA (p65) to the nucleus in RP groups. The present study demonstrates that RP exerts an anti-inflammatory effect to inhibit ROS-derived inflammation through suppression of the NF-κB pathway in growing and adult rats. Results suggest that the anti-inflammatory capacity of RP is independent of age.

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