Pinosylvin and Monomethylpinosylvin, Constituents of an Extract from the Knot ofPinus sylvestris, Reduce Inflammatory Gene Expression and Inflammatory Responses in Vivo

2015 ◽  
Vol 63 (13) ◽  
pp. 3445-3453 ◽  
Author(s):  
Mirka Laavola ◽  
Riina Nieminen ◽  
Tiina Leppänen ◽  
Christer Eckerman ◽  
Bjarne Holmbom ◽  
...  
Keyword(s):  
Gene Expression ◽  
Inflammatory Responses ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene

scholarly journals Astragaloside IV Inhibits NF-κB Activation and Inflammatory Gene Expression in LPS-Treated Mice

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Wei-Jian Zhang ◽  
Balz Frei
Keyword(s):  
Gene Expression ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Cellular Adhesion ◽  
Mrna Levels ◽  
Astragaloside Iv ◽  
Chinese Medicinal Herb ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene

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.

Abstract 361: Oxidized Phospholipids Are Proinflammatory and Proatherogenic

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.

scholarly journals Transcription modulation by CDK9 regulates inflammatory genes and RIPK3-MLKL-mediated necroptosis in periodontitis progression

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Jiao Li ◽  
Jiahong Shi ◽  
Yue Pan ◽  
Yunhe Zhao ◽  
Fuhua Yan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Survival ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Acute Infection ◽  
Infection Process ◽  
Inhibitory Protein ◽  
Inflammatory Gene ◽  
Knock Down

AbstractCyclin-dependent kinase 9 (CDK9), one crucial molecule in promoting the transition from transcription pausing to elongation, is a critical modulator of cell survival and death. However, the pathological function of CDK9 in bacterial inflammatory diseases has never been explored. CDK9 inhibition or knock-down attenuated Porphyromonas gingivalis-triggered inflammatory gene expression. Gene-expression microarray analysis of monocytes revealed that knock-down of CDK9 not only affected inflammatory responses, but also impacted cell death network, especially the receptor-interacting protein kinase 3 (RIPK3)-mixed lineage kinase domain-like (MLKL)-mediated necroptosis after P. gingivalis infection. Inhibition of CDK9 significantly decreased necroptosis with downregulation of both MLKL and phosphorylated MLKL. By regulating caspase-8 and cellular FLICE inhibitory protein (cFLIP), key molecules in regulating cell survival and death, CDK9 affected not only the classic RIPK1-RIPK3-mediated necroptosis, but also the alternate TIR-domain-containing adapter-inducing interferon-β-RIPK3-mediated necroptosis. CDK9 inhibition dampened pro-inflammatory gene production in the acute infection process in the subcutaneous chamber model in vivo. Moreover, CDK9 inhibition contributed to the decreased periodontal bone loss and inflammatory response induced by P. gingivalis in the periodontal micro-environment. In conclusion, by modulating the RIPK3-MLKL-mediated necroptosis, CDK9 inhibition provided a novel mechanism to impact the progress of bacterial infection in the periodontal milieu.

scholarly journals TMIC-27. GLIOMA CELLS INDUCE ‘EPIGENETIC MEMORY’ IN MICROGLIA AND BLOCK INFLAMMATORY GENE EXPRESSION- IN VITRO AND IN VIVO FINDINGS

2018 ◽  
Vol 20 (suppl_6) ◽  
pp. vi262-vi262
Author(s):  
Bozena Kaminska ◽  
Marta Maleszewska ◽  
Aleksandra Steranka ◽  
Magdalena Smiech ◽  
Beata Kaza ◽  
...  
Keyword(s):  
Gene Expression ◽  
Glioma Cells ◽  
Epigenetic Memory ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene

scholarly journals Maternal high-fat diet induces sex-specific changes to glucocorticoid and inflammatory signaling in response to corticosterone and lipopolysaccharide challenge in adult rat offspring

2019 ◽  
Author(s):  
Sanoji Wijenayake ◽  
Mouly F. Rahman ◽  
Christine M.W. Lum ◽  
Wilfred C. De Vega ◽  
Aya Sasaki ◽  
...  
Keyword(s):  
Gene Expression ◽  
High Fat Diet ◽  
Maternal Obesity ◽  
Inflammatory Responses ◽  
Physiological Stress ◽  
High Fat ◽  
Inflammatory Gene Expression ◽  
Inflammatory Genes ◽  
Inflammatory Gene ◽  
Rat Offspring

ABSTRACTBackgroundAcute elevations in endogenous corticosterone (CORT) with psychosocial stress or exogenous administration potentiate inflammatory gene expression. Maternal obesity as a result of high-fat diet (HFD) consumption has been linked to higher basal levels of neuroinflammation, including increased expression of pro-inflammatory genes in the amygdala. These findings suggest that exposure to maternal HFD may elicit pro-inflammatory responses in the presence of an immune stressor such as lipopolysaccharide (LPS), a component of gram-negative bacteria, as well as acute elevated CORT.MethodsRat offspring were exposed to maternal HFD or control diet (CHD) throughout pre and postnatal development until weaning, when all offspring were provided CHD until adulthood. In adulthood, offspring were ‘challenged’ with administration of exogenous CORT, to simulate an acute physiological stress, LPS, to induce an immune stress, or both. qPCR was used to measure transcript abundance of CORT receptors and downstream inflammatory genes in the amygdala, hippocampus and prefrontal cortex, brain regions that mediate neuroendocrine and behavioral responses to stress.ResultsHFD female offspring exhibited elevations in anti-inflammatory transcripts, whereas HFD male offspring responded with greater pro-inflammatory gene expression to simultaneous CORT and LPS administration.ConclusionsThese findings suggest that exposure to maternal HFD leads to sex-specific alterations that may alter inflammatory responses in the brain, possibly as an adaptive response to basal inflammation.

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

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.

scholarly journals HDAC3 Regulates Gingival Fibroblast Inflammatory Responses in Periodontitis

2019 ◽  
Vol 99 (1) ◽  
pp. 98-106 ◽  
Author(s):  
K.B. Lagosz ◽  
A. Bysiek ◽  
J.M. Macina ◽  
G.P. Bereta ◽  
M. Kantorowicz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Inflammatory Mediators ◽  
Histone Deacetylases ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Gingival Fibroblast ◽  
Mrna Levels ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene ◽  
Inflammatory Activation

Histone deacetylases (HDACs) are important regulators of gene expression that are aberrantly regulated in several inflammatory and infectious diseases. HDAC inhibitors (HDACi) suppress inflammatory activation of various cell types through epigenetic and non-epigenetic mechanisms, and ameliorate pathology in a mouse model of periodontitis. Activation of gingival fibroblasts (GFs) significantly contributes to the development of periodontitis and the anaerobic bacterium Porphyromonas gingivalis plays a key role in driving chronic inflammation. Here, we analyzed the role of HDACs in inflammatory responses of GFs. Pan-HDACi suberoylanilide hydroxamic acid (SAHA) and/or ITF2357 (givinostat) significantly reduced TNFα- and P. gingivalis–inducible expression and/or production of a cluster of inflammatory mediators in healthy donor GFs ( IL1B, CCL2, CCL5, CXCL10, COX2, and MMP3) without affecting cell viability. Selective inhibition of HDAC3/6, but not specific HDAC1, HDAC6, or HDAC8 inhibition, reproduced the suppressive effects of pan-HDACi on the inflammatory gene expression profile induced by TNFα and P. gingivalis, suggesting a critical role for HDAC3 in GF inflammatory activation. Consistently, silencing of HDAC3 expression with siRNA largely recapitulated the effects of HDAC3/6i on mRNA levels of inflammatory mediators in P. gingivalis–infected GFs. In contrast, P. gingivalis internalization and intracellular survival in GFs remained unaffected by HDACi. Activation of mitogen-activated protein kinases and NFκB signaling was unaffected by global or HDAC3/6-selective HDACi, and new protein synthesis was not required for gene suppression by HDACi. Finally, pan-HDACi and HDAC3/6i suppressed P. gingivalis–induced expression of IL1B, CCL2, CCL5, CXCL10, MMP1, and MMP3 in GFs from patients with periodontitis. Our results identify HDAC3 as an important regulator of inflammatory gene expression in GFs and suggest that therapeutic targeting of HDAC activity, in particular HDAC3, may be clinically beneficial in suppressing inflammation in periodontal disease.

scholarly journals Prior hypoxia exposure enhances murine microglial inflammatory gene expression in vitro without concomitant H3K4me3 enrichment

2020 ◽  
Author(s):  
Elizabeth A. Kiernan ◽  
Andrea C. Ewald ◽  
Jonathan N. Ouellette ◽  
Tao Wang ◽  
Avtar Roopra ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chromatin Immunoprecipitation ◽  
Sleep Disordered Breathing ◽  
Inflammatory Responses ◽  
Hypoxic Exposure ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene ◽  
Hypoxia Exposure ◽  
Chromatin Immunoprecipitation Sequencing

ABSTRACTHypoxia is a component of multiple disorders, including stroke and sleep-disordered breathing, that often precede or are comorbid with neurodegenerative diseases. However, little is known about how hypoxia affects the ability of microglia, resident CNS macrophages, to respond to subsequent inflammatory challenges that are often present during neurodegenerative processes. We therefore tested the hypothesis that hypoxia would enhance or “prime” microglial pro-inflammatory gene expression in response to a later inflammatory challenge without programmatically increasing basal levels of pro-inflammatory cytokine expression. To test this, we pre-exposed immortalized N9 and primary microglia to hypoxia (1% O2) for 16 hrs and then challenged them with pro-inflammatory lipopolysaccharide (LPS) either immediately or 3-6 days following hypoxic exposure. We used RNA sequencing coupled with chromatin immunoprecipitation sequencing to analyze primed microglial inflammatory gene expression and modifications to histone H3 lysine 4 trimethylation (H3K4me3) at the promoters of primed genes. We found that microglia exhibited enhanced responses to LPS 3 days and 6 days post-hypoxia. Surprisingly however, the majority of primed genes were not enriched for H3K4me3 acutely following hypoxia exposure. Using the bioinformatics tool MAGICTRICKS and reversible pharmacological inhibition, we found that primed genes required the transcriptional activities of NF-ĸB. These findings provide evidence that hypoxia pre-exposure could lead to persistent and aberrant inflammatory responses in the context of CNS disorders.

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