Titanium and zirconia particle-induced pro-inflammatory gene expression in cultured macrophages and osteolysis, inflammatory hyperalgesia and edema in vivo

In this study we investigated the role of astragaloside IV (AS-IV), one of the major active constituents purified from the Chinese medicinal herbAstragalus membranaceus, in LPS-induced acute inflammatory responses in micein vivoand examined possible underlying mechanisms. Mice were assigned to four groups: vehicle-treated control animals; AS-IV-treated animals (10 mg/kg b.w. AS-IV daily i.p. injection for 6 days); LPS-treated animals; and AS-IV plus LPS-treated animals. We found that AS-IV treatment significantly inhibited LPS-induced increases in serum levels of MCP-1 and TNF by 82% and 49%, respectively. AS-IV also inhibited LPS-induced upregulation of inflammatory gene expression in different organs. Lung mRNA levels of cellular adhesion molecules, MCP-1, TNFα, IL-6, and TLR4 were significantly attenuated, and lung neutrophil infiltration and activation were strongly inhibited, as reflected by decreased myeloperoxidase content, when the mice were pretreated with AS-IV. Similar results were observed in heart, aorta, kidney, and liver. Furthermore, AS-IV significantly suppressed LPS-induced NF-κB and AP-1 DNA-binding activities in lung and heart. In conclusion, our data provide newin vivoevidence that AS-IV effectively inhibits LPS-induced acute inflammatory responses by modulating NF-κB and AP-1 signaling pathways. Our results suggest that AS-IV may be useful for the prevention or treatment of inflammatory diseases.

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BET protein inhibition regulates macrophage chromatin accessibility and microbiota-dependent colitis

10.1101/2021.07.15.452570 ◽

2021 ◽

Author(s):

Michelle Hoffner O'Connor ◽

Ana Berglind ◽

Meaghan M Kennedy ◽

Benjamin P Keith ◽

Zachary J Lynch ◽

...

Keyword(s):

Gene Expression ◽

Regulatory Elements ◽

Chromatin Accessibility ◽

Inflammatory Gene Expression ◽

Chronic Inflammatory Response ◽

Inflammatory Gene ◽

Bet Inhibitor ◽

Dna Regulatory Elements ◽

Induced Changes

Introduction: In colitis, macrophage functionality is altered compared to homeostatic conditions. Loss of IL-10 signaling results in an inappropriate and chronic inflammatory response to bacterial stimulation. It remains unknown if inhibition of bromodomain and extra-terminal domain (BET) proteins alters usage of DNA regulatory elements responsible for driving inflammatory gene expression. We determined if the BET inhibitor, (+)-JQ1, could suppress inflammatory activation of macrophages in Il10-/- mice. Methods: We performed ATAC-seq and RNA-seq on Il10-/- bone marrow-derived macrophages (BMDMs) cultured in the presence or absence of lipopolysaccharide (LPS) and with or without treatment with (+)-JQ1 and evaluated changes in chromatin accessibility and gene expression. Germ-free Il10-/- mice were treated with (+)-JQ1, colonized with fecal slurries and underwent histological and molecular evaluation 14-days post colonization. Results: Treatment with (+)-JQ1 suppressed LPS-induced changes in chromatin at distal regulatory elements associated with inflammatory genes, particularly in regions that contain motifs for AP-1 and IRF transcription factors. This resulted in the attenuation of inflammatory gene expression. Treatment with (+)-JQ1 in vivo reduced severity of colitis as compared with vehicle-treated mice. Conclusion: We identified the mechanism of action associated with a new class of compounds that may mitigate aberrant macrophage responses to bacteria in colitis.

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Abstract 361: Oxidized Phospholipids Are Proinflammatory and Proatherogenic

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.36.suppl_1.361 ◽

2016 ◽

Vol 36 (suppl_1) ◽

Author(s):

Xuchu Que ◽

Calvin Yeang ◽

Ming-Yow Hung ◽

Fumihiro Yamaguchi ◽

Cody J Diehl ◽

...

Keyword(s):

Gene Expression ◽

Inflammatory Responses ◽

Biological Effects ◽

Progressive Increase ◽

Oxidized Phospholipids ◽

Single Chain ◽

Inflammatory Gene Expression ◽

Inflammatory Gene ◽

Novel Strategy

Oxidized phospholipids (OxPL) are ubiquitously generated during inflammation, and found on apoptotic cells, OxLDL, and Lp(a). They facilitate uptake of OxLDL by macrophages (Mac) and mediate cellular inflammatory responses. The E06 natural IgM binds to the PC of OxPL, neutralizing biological effects and inhibiting OxLDL uptake by Mac. To determine the role of OxPL in atherogenesis, we generated transgenic mice expressing a single chain variant (scFv) of E06 in Ldlr background (E06-Tg). E06-scFv was secreted into plasma, bound to OxLDL and had sufficient titer to inhibit OxLDL uptake into Mac. E06-Tg or Ldlr mice were fed 1% Chol diet for 4, 7 or 12 months (n=12-15 mice/group). Plasma Chol was ~ 1600 mg/dL in all mice. Atherosclerosis decreased in E06-Tg mice: En face lesions decreased 57%, 34% and 28%, and aortic root lesions decreased 55%, 41% and 26% at 4, 7 and 12-months, respectively. OxLDL uptake by Macs was decreased: Thus, in E06-Tg mice, the uptake by peritoneal Mac of fluorescently-labeled OxLDL injected ip was decreased ~ 50%, as was peritoneal Mac Chol content. As Macs secrete E06-scFv, we performed BMT from E06-Tg donors into irradiated Ldlr recipients (n=10-12): This also decreased lesions 31% compared to BMT from control donors, even though plasma titers of E06-scFv were ~10% of Tg mice. Overexpression of E06-scFv was anti-inflammatory: Thus, in E06-Tg mice, both peritoneal and aortic wall resident macrophages exhibited decreased inflammatory gene expression, and phenotypic switches from M1 to M2 analyzed by RNAseq and FACS. Further, in E06-Tg mice, plasma SAA levels were reduced 32%, and hepatic steatosis was also decreased (-50% in both TG and Chol), as was hepatic inflammatory gene expression. Finally, E06-scFv attenuated both a progressive increase in aortic valve gradient (via echocardiography) and calcification in aged Ldlr mice. The E06-scFv lacks functional effects of an intact antibody other than the ability to “neutralize” OxPL. Thus, these data demonstrate that OxPL are profoundly proatherogenic and proinflammatory, which E06 counteracts in vivo . Neutralizing OxPL may therefore reduce the progression of atherosclerosis and cardiovascular events and more generally, represents a novel strategy to safely attenuate inflammation.

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Gallic acid regulates adipocyte hypertrophy and suppresses inflammatory gene expression induced by the paracrine interaction between adipocytes and macrophages in vitro and in vivo

Nutrition Research ◽

10.1016/j.nutres.2019.09.007 ◽

2020 ◽

Vol 73 ◽

pp. 58-66 ◽

Cited By ~ 1

Author(s):

Miori Tanaka ◽

Ayako Sugama ◽

Kanako Sumi ◽

Kozue Shimizu ◽

Yoshimi Kishimoto ◽

...

Keyword(s):

Gene Expression ◽

Gallic Acid ◽

Inflammatory Gene Expression ◽

Inflammatory Gene ◽

Adipocyte Hypertrophy ◽

Paracrine Interaction

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Targeted adenovirus mediated inhibition of NF-κB-dependent inflammatory gene expression in endothelial cells in vitro and in vivo

Journal of Controlled Release ◽

10.1016/j.jconrel.2012.12.016 ◽

2013 ◽

Vol 166 (1) ◽

pp. 57-65 ◽

Cited By ~ 13

Author(s):

J.M. Kułdo ◽

S.A. Ásgeirsdóttir ◽

P.J. Zwiers ◽

A.R. Bellu ◽

M.G. Rots ◽

...

Keyword(s):

Gene Expression ◽

Endothelial Cells ◽

Inflammatory Gene Expression ◽

Inflammatory Gene

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Effect of quercetin on inflammatory gene expression in mice liver in vivo – role of redox factor 1, miRNA-122 and miRNA-125b

Pharmacological Research ◽

10.1016/j.phrs.2012.02.007 ◽

2012 ◽

Vol 65 (5) ◽

pp. 523-530 ◽

Cited By ~ 74

Author(s):

Christine Boesch-Saadatmandi ◽

Anika E. Wagner ◽

Siegfried Wolffram ◽

Gerald Rimbach

Keyword(s):

Gene Expression ◽

Inflammatory Gene Expression ◽

Inflammatory Gene ◽

Mice Liver

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Surfactant protein-D modulation of pulmonary macrophage phenotype is controlled by S-nitrosylation

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00506.2018 ◽

2019 ◽

Vol 317 (5) ◽

pp. L539-L549 ◽

Cited By ~ 4

Author(s):

Chang-Jiang Guo ◽

Elena N. Atochina-Vasserman ◽

Elena Abramova ◽

Ley Cody Smith ◽

Michael F. Beers ◽

...

Keyword(s):

Gene Expression ◽

Surfactant Protein ◽

Surfactant Protein D ◽

Macrophage Phenotype ◽

Oligomeric State ◽

Inflammatory Gene Expression ◽

Inflammatory Gene ◽

Cellular Recruitment

Surfactant protein-D (SP-D) is a regulator of pulmonary innate immunity whose oligomeric state can be altered through S-nitrosylation to regulate its signaling function in macrophages. Here, we examined how nitrosylation of SP-D alters the phenotypic response of macrophages to stimuli both in vivo and in vitro. Bronchoalveolar lavage (BAL) from C57BL6/J and SP-D-overexpressing (SP-D OE) mice was incubated with RAW264.7 cells ± LPS. LPS induces the expression of the inflammatory genes Il1b and Nos2, which is reduced 10-fold by SP-D OE-BAL. S-nitrosylation of the SP-D OE-BAL (SNO-SP-D OE-BAL) abrogated this inhibition. SNO-SP-D OE-BAL alone induced Il1b and Nos2 expression. PCR array analysis of macrophages incubated with SP-D OE-BAL (±LPS) shows increased expression of repair genes, Ccl20, Cxcl1, and Vcam1, that was accentuated by LPS. LPS increases inflammatory gene expression, Il1a, Nos2, Tnf, and Ptgs2, which was accentuated by SNO-SP-D OE-BAL but inhibited by SP-D OE-BAL. The transcription factor NF-κB was identified as a target for SNO-SP-D by IPA, which was confirmed by Trans-AM ELISA in vitro. In vivo, SP-D overexpression increases the burden of infection in a Pneumocystis model while increasing cellular recruitment. Expression of iNOS and the production of NO metabolites were significantly reduced in SP-D OE mice relative to C57BL6/J. Inflammatory gene expression was increased in infected C57BL6/J mice but decreased in SP-D OE. SP-D oligomeric structure was disrupted in C57BL6/J infected mice but unaltered within SP-D OE. Thus SP-D modulates macrophage phenotype and the balance of multimeric to trimeric SP-D is critical to this regulation.

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Are Fried Foods Unhealthy? The Dietary Peroxidized Fatty Acid, 13-HPODE, Induces Intestinal Inflammation In Vitro and In Vivo

Antioxidants ◽

10.3390/antiox9100926 ◽

2020 ◽

Vol 9 (10) ◽

pp. 926 ◽

Cited By ~ 1

Author(s):

Esra’a Keewan ◽

Chandrakala Aluganti Narasimhulu ◽

Michael Rohr ◽

Simran Hamid ◽

Sampath Parthasarathy

Keyword(s):

Gene Expression ◽

Fatty Acid ◽

Intestinal Epithelium ◽

Intestinal Inflammation ◽

Inflammatory Disorder ◽

Inflammatory Gene Expression ◽

Inflammatory Gene ◽

Gut Mucosa

Inflammatory Bowel Disease (IBD) is a chronic inflammatory disorder characterized by progressive inflammation and the erosion of the gut mucosa. Although the exact cause of IBD is unknown, multiple factors contribute to its complex pathogenesis. Diet is one such factor and a strong correlation exists between the western-style, high fat diets (HFDs) and IBD incidence rates. In this study, we propose that the peroxidized fatty acid components of HFDs could contribute to inflammation of the gut. The inflammatory nature of peroxidized linoleic acid (13-HPODE), was confirmed in vitro by analyzing pro-inflammatory gene expression in Caco-2 cells via RT-PCR and ELISA. Additionally, peroxide induced apoptosis was tested by Annexin-V fluorescent staining, while permeability was tested by FITC-dextran flux and TEER. The 13-HPODE-induced inflammation of intestinal epithelium was evaluated in vivo by analyzing pro-inflammatory cytokines under acute and chronic conditions after feeding 13-HPODE to C57BL/6J mice. Our data show that 13-HPODE significantly induced pro-inflammatory gene expression of TNF-α and MCP-1 in vitro, most notably in differentiated Caco-2 cells. Further, acute and chronic 13-HPODE treatments of mice similarly induced pro-inflammatory cytokine expression in the epithelium of both the proximal and distal small intestines, resident immune cells in Peyer’s patches and peritoneal macrophages. The results of this study not only confirm the pro-inflammatory properties of peroxidized fats on the gut mucosa, but for the first time demonstrate their ability to differentially induce pro-inflammatory gene expression and influence permeability in the intestinal epithelium and mucosal cells. Collectively, our results suggest that the immunogenic properties of HFD’s in the gut may be partly caused by peroxide derivatives, providing potential insight into how these diets contribute to exacerbations of IBD.

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