scholarly journals Saturated fatty acid combined with lipopolysaccharide stimulates a strong inflammatory response in hepatocytes in vivo and in vitro

2018 ◽  
Vol 315 (5) ◽  
pp. E745-E757 ◽  
Author(s):  
Yanchun Li ◽  
Zhongyang Lu ◽  
Ji Hyun Ru ◽  
Maria F. Lopes-Virella ◽  
Timothy J. Lyons ◽  
...  
Keyword(s):  
Gene Expression ◽  
Fatty Acid ◽  
Liver Disease ◽  
Inflammatory Response ◽  
Saturated Fatty Acid ◽  
Proinflammatory Gene ◽  
Strong Inflammatory Response ◽  
Proinflammatory Gene Expression

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and consumption of high-fat diet (HFD) is a risk factor for NAFLD. The HFD not only increases intake of saturated fatty acid (SFA) but also induces metabolic endotoxemia, an HFD-associated increase in circulating lipopolysaccharide (LPS). Although it is known that SFA or LPS promote hepatic inflammation, a hallmark of NAFLD, it remains unclear how SFA in combination with LPS stimulates host inflammatory response in hepatocytes. In this study, we performed both in vivo and in vitro experiments to investigate the effect of SFA in combination with LPS on proinflammatory gene expression in hepatocytes. Our animal study showed that feeding low-density lipoprotein-deficient mice HFD enriched with SFA and injection of low-dose LPS cooperatively stimulated IL-6 expression in livers. To understand how SFA and LPS interact to promote IL-6 expression, our in vitro studies showed that palmitic acid (PA), a major SFA, and LPS exerted synergistic effect on the expression of IL-6 in hepatocytes. Furthermore, coculture of hepatocytes with macrophages resulted in a greater IL-6 expression than culture of hepatocytes without macrophages in response to the combination of PA and LPS. Finally, we observed that LPS and PA increased ceramide production by cooperatively stimulating ceramide de novo synthesis, which played an essential role in the synergistic stimulation of proinflammatory gene expression by LPS and PA. Taken together, this study showed that SFA in combination with LPS stimulated a strong inflammatory response in hepatocytes in vivo and in vitro.

In vitro proinflammatory gene expression predicts in vivo telomere shortening: A preliminary study

2018 ◽  
Vol 96 ◽  
pp. 179-187 ◽  
Author(s):  
Jue Lin ◽  
Jie Sun ◽  
Stephanie Wang ◽  
Jeffrey M. Milush ◽  
Chris A.R. Baker ◽  
...  
Keyword(s):  
Gene Expression ◽  
Telomere Shortening ◽  
Proinflammatory Gene ◽  
Preliminary Study ◽  
Proinflammatory Gene Expression

scholarly journals Activation of TAF9 via Danshensu-Induced Upregulation of HDAC1 Expression Alleviates Non-alcoholic Fatty Liver Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Ruiwen Wang ◽  
Zhecheng Wang ◽  
Ruimin Sun ◽  
Rong Fu ◽  
Yu Sun ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Liver Disease ◽  
Fatty Liver ◽  
Protective Effect ◽  
Fatty Liver Disease ◽  
Cell Model ◽  
Signaling Mechanism ◽  
Alcoholic Fatty Liver

Fatty acid β-oxidation is an essential pathogenic mechanism in nonalcoholic fatty liver disease (NAFLD), and TATA-box binding protein associated factor 9 (TAF9) has been reported to be involved in the regulation of fatty acid β-oxidation. However, the function of TAF9 in NAFLD, as well as the mechanism by which TAF9 is regulated, remains unclear. In this study, we aimed to investigate the signaling mechanism underlying the involvement of TAF9 in NAFLD and the protective effect of the natural phenolic compound Danshensu (DSS) against NAFLD via the HDAC1/TAF9 pathway. An in vivo model of high-fat diet (HFD)-induced NAFLD and a palmitic acid (PA)-treated AML-12 cell model were developed. Pharmacological treatment with DSS significantly increased fatty acid β-oxidation and reduced lipid droplet (LD) accumulation in NAFLD. TAF9 overexpression had the same effects on these processes both in vivo and in vitro. Interestingly, the protective effect of DSS was markedly blocked by TAF9 knockdown. Mechanistically, TAF9 was shown to be deacetylated by HDAC1, which regulates the capacity of TAF9 to mediate fatty acid β-oxidation and LD accumulation during NAFLD. In conclusion, TAF9 is a key regulator in the treatment of NAFLD that acts by increasing fatty acid β-oxidation and reducing LD accumulation, and DSS confers protection against NAFLD through the HDAC1/TAF9 pathway.

scholarly journals Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation

Science ◽  
2018 ◽  
Vol 362 (6416) ◽  
pp. 834-839 ◽  
Author(s):  
Torkild Visnes ◽  
Armando Cázares-Körner ◽  
Wenjing Hao ◽  
Olov Wallner ◽  
Geoffrey Masuyer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Cell ◽  
Nuclear Factor Κb ◽  
Cell Recruitment ◽  
Inflammatory Conditions ◽  
Molecule Inhibitor ◽  
Proinflammatory Gene ◽  
Factor Α ◽  
Proinflammatory Gene Expression

The onset of inflammation is associated with reactive oxygen species and oxidative damage to macromolecules like 7,8-dihydro-8-oxoguanine (8-oxoG) in DNA. Because 8-oxoguanine DNA glycosylase 1 (OGG1) binds 8-oxoG and because Ogg1-deficient mice are resistant to acute and systemic inflammation, we hypothesized that OGG1 inhibition may represent a strategy for the prevention and treatment of inflammation. We developed TH5487, a selective active-site inhibitor of OGG1, which hampers OGG1 binding to and repair of 8-oxoG and which is well tolerated by mice. TH5487 prevents tumor necrosis factor–α–induced OGG1-DNA interactions at guanine-rich promoters of proinflammatory genes. This, in turn, decreases DNA occupancy of nuclear factor κB and proinflammatory gene expression, resulting in decreased immune cell recruitment to mouse lungs. Thus, we present a proof of concept that targeting oxidative DNA repair can alleviate inflammatory conditions in vivo.

scholarly journals Antioxidant mimetics modulate oxidative stress and cellular signaling in airway epithelial cells infected with respiratory syncytial virus

2012 ◽  
Vol 303 (11) ◽  
pp. L991-L1000 ◽  
Author(s):  
Yashoda M. Hosakote ◽  
Narayana Komaravelli ◽  
Nicolas Mautemps ◽  
Tianshuang Liu ◽  
Roberto P. Garofalo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Cell Damage ◽  
Cellular Signaling ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Proinflammatory Gene ◽  
Syncytial Virus ◽  
Proinflammatory Gene Expression

Respiratory syncytial virus (RSV) is one of the most common causes of bronchiolitis and pneumonia among infants and young children worldwide. In previous investigations, we have shown that RSV infection induces rapid generation of reactive oxygen species (ROS), which modulate viral-induced cellular signaling, and downregulation of antioxidant enzyme (AOE) expression, resulting in oxidative stress in vitro and in vivo, which plays a pathogenetic role in RSV-induced lung disease. In this study, we determined whether pharmacological intervention with synthetic catalytic scavengers could reduce RSV-induced proinflammatory gene expression and oxidative cell damage in an in vitro model of infection. Treatment of airway epithelial cells (AECs) with the salen-manganese complexes EUK-8 or EUK-189, which possess superoxide dismutase, catalase, and glutathione peroxidase activity, strongly reduced RSV-induced ROS formation by increasing cellular AOE enzymatic activity and levels of the lipid peroxidation products F2-8-isoprostane and malondialdehyde, which are markers of oxidative stress. Treatment of AECs with AOE mimetics also significantly inhibited RSV-induced cytokine and chemokine secretion and activation of the transcription factors nuclear factor-κB and interferon regulatory factor-3, which orchestrate proinflammatory gene expression. Both EUKs were able to reduce viral replication, when used at high doses. These results suggest that increasing antioxidant cellular capacities can significantly impact RSV-associated oxidative cell damage and cellular signaling and could represent a novel therapeutic approach in modulating virus-induced lung disease.

scholarly journals In vitro response of macrophages to ceramic scaffolds used for bone regeneration

2016 ◽  
Vol 13 (120) ◽  
pp. 20160346 ◽  
Author(s):  
Pamela L. Graney ◽  
Seyed-Iman Roohani-Esfahani ◽  
Hala Zreiqat ◽  
Kara L. Spiller
Keyword(s):  
Gene Expression ◽  
Inflammatory Response ◽  
Bone Regeneration ◽  
Bone Repair ◽  
Principal Component ◽  
Human Monocyte ◽  
Macrophage Phenotype ◽  
In Vitro Response

Macrophages, the primary cells of the inflammatory response, are major regulators of healing, and mediate both bone fracture healing and the inflammatory response to implanted biomaterials. However, their phenotypic contributions to biomaterial-mediated bone repair are incompletely understood. Therefore, we used gene expression and protein secretion analysis to investigate the interactions in vitro between primary human monocyte-derived macrophages and ceramic scaffolds that have been shown to have varying degrees of success in promoting bone regeneration in vivo . Specifically, baghdadite (Ca 3 ZrSi 2 O 9 ) and strontium–hardystonite–gahnite (Sr–Ca 2 ZnSi 2 O 7 –ZnAl 2 O 4 ) scaffolds were chosen as two materials that enhanced bone regeneration in vivo in large defects under load compared with clinically used tricalcium phosphate–hydroxyapatite (TCP–HA). Principal component analysis revealed that the scaffolds differentially regulated macrophage phenotype. Temporal changes in gene expression included shifts in markers of pro-inflammatory M1, anti-inflammatory M2a and pro-remodelling M2c macrophage phenotypes. Of note, TCP–HA scaffolds promoted upregulation of many M1-related genes and downregulation of many M2a- and M2c-related genes. Effects of the scaffolds on macrophages were attributed primarily to direct cell–scaffold interactions because of only minor changes observed in transwell culture. Ultimately, elucidating macrophage–biomaterial interactions will facilitate the design of immunomodulatory biomaterials for bone repair.

The mechanism of lowering cholesterol absorption by calcium studied by using an in vitro digestion model

2016 ◽  
Vol 7 (1) ◽  
pp. 151-163 ◽  
Author(s):  
Liliya Vinarova ◽  
Zahari Vinarov ◽  
Slavka Tcholakova ◽  
Nikolai D. Denkov ◽  
Simeon Stoyanov ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Saturated Fatty Acid ◽  
Serum Cholesterol ◽  
In Vitro Digestion ◽  
Cholesterol Absorption ◽  
Lipid Digestion

Ca2+decreases strongly cholesterol and saturated fatty acid bioaccessibility duringin vitrolipid digestion, explaining the lowering of serum cholesterolin vivo.

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