Su1537 Overpressure Traumatic Brain Injury (TBI) Causes Intestinal Mucosal Microhemorrhage, Alters In Vivo Intestinal Permeability and Induces Brain and Intestinal Inflammatory Gene Expression in Rats

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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Neuroprotection with the proteasome inhibitor MLN519 in focal ischemic brain injury: Relation to nuclear factor κB (NF-κB), inflammatory gene expression, and leukocyte infiltration☆

Neurochemistry International ◽

10.1016/j.neuint.2006.03.018 ◽

2006 ◽

Vol 49 (2) ◽

pp. 106-112 ◽

Cited By ~ 62

Author(s):

A WILLIAMS ◽

J DAVE ◽

F TORTELLA

Keyword(s):

Gene Expression ◽

Brain Injury ◽

Proteasome Inhibitor ◽

Nuclear Factor Κb ◽

Ischemic Brain Injury ◽

Nuclear Factor ◽

Leukocyte Infiltration ◽

Ischemic Brain ◽

Inflammatory Gene Expression ◽

Inflammatory Gene

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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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