The Anti-Inflammatory Fungal Compound (S)-Curvularin Reduces Proinflammatory Gene Expression in an In Vivo Model of Rheumatoid Arthritis

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.

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Interleukin-26 enhances proinflammatory gene expression and its expression is increased in intestinal inflammation in vivo

Zeitschrift für Gastroenterologie ◽

10.1055/s-2007-988372 ◽

2007 ◽

Vol 45 (08) ◽

Author(s):

J Dambacher ◽

F Beigel ◽

A Kaul ◽

K Zitzmann ◽

D Haller ◽

...

Keyword(s):

Gene Expression ◽

Intestinal Inflammation ◽

Proinflammatory Gene ◽

Proinflammatory Gene Expression ◽

Interleukin 26

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Synthesis of a Novel Thiazolidinedione and Evaluation of Its Modulatory Effect on IFN-γ, IL-6, IL-17A, and IL-22 Production in PBMCs from Rheumatoid Arthritis Patients

BioMed Research International ◽

10.1155/2013/926060 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 12

Author(s):

Laurindo Ferreira da Rocha Junior ◽

Moacyr Jesus Barreto de Melo Rêgo ◽

Mariana Brayner Cavalcanti ◽

Michelly Cristiny Pereira ◽

Marina Galdino da Rocha Pitta ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Mrna Expression ◽

Mononuclear Cells ◽

Positive Control ◽

Peripheral Blood Mononuclear ◽

Murine Splenocytes ◽

Chronic Synovitis ◽

Proinflammatory Gene ◽

Anti Inflammatory ◽

Proinflammatory Gene Expression

Rheumatoid arthritis (RA) is an autoimmune disease frequently characterized by chronic synovitis of multiple joints. The pathogenesis of RA is complex and involves many proinflammatory cytokines as Th17 related ones. PPARγis a nuclear receptor activator that represses proinflammatory gene expression. Thus, this work aimed to synthetize a new thiazolidinedione (TZD) analogue based on a well-known anti-inflammatory and PPARγagonist activity of this ring and evaluate its anti-inflammatory activity. After chemical structure confirmation, the compound named 5-(5-bromo-2-methoxy-benzylidene)-3-(2-nitro-benzyl)-thiazolidine-2,4-dione TM17 was submitted to cytokine releasing inhibition and PPARγgenetic modulation assays. The new compound showed no toxicity on human and murine cells, decreasing IL-6 secretion by murine splenocytes and reducing IL-17A, IL-22, and IFN-γexpression in peripheral blood mononuclear cells from patients with RA. TM17 was more efficient in modulating the mRNA expression of PPARγthan its well-used TZD agonist rosiglitazone. Surprisingly, TM17 was efficient on IL-17A and IFN-γreduction, like the positive control methylprednisolone, and presented a better effect on IL-22 levels. In conclusion, PBMCs obtained from RA patients under TM17 treatment present a significant reduction in IL-17A, IL-22, and IFN-γlevels, but not IL-6 when compared with nontreated cells, as well as increase PPARγmRNA expression in absence of stimulus addressing it as a promising molecule in RA treatment.

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THRAP3 depletion reduces PPARγ mRNA and anti-inflammatory action in 3T3-L1 adipocytes

Journal of Molecular Endocrinology ◽

10.1530/jme-20-0334 ◽

2021 ◽

Author(s):

Juu-Chin Lu ◽

Chia-Yun Lu ◽

Ying-Yu Wu

Keyword(s):

Gene Expression ◽

Thyroid Hormone Receptor ◽

Peroxisome Proliferator ◽

Proinflammatory Response ◽

Peroxisome Proliferator Activated Receptor ◽

Protein Levels ◽

Erk Phosphorylation ◽

Proinflammatory Gene ◽

Anti Inflammatory ◽

Proinflammatory Gene Expression

Peroxisome proliferator-activated receptor γ (PPARγ) is the master transcriptional regulator of adipocytes and the cellular target of thiazolidinedione (TZD) drugs. Suppression of proinflammatory actions, including proinflammatory gene expression and lipolysis in adipocytes, contributes to PPARγ-mediated anti-diabetic effects of TZDs. However, adverse side effects largely limited the clinical use of TZDs, despite their potent insulin-sensitizing effects. Therefore, it is important to understand how PPARγ is regulated. Thyroid hormone receptor-associated protein 3 (THRAP3) was previously reported to promote diabetic gene expression by acting as a transcriptional coregulator of PPARγ in adipocytes. Therefore, we tested if THRAP3 modulated anti-inflammatory functions of PPARγ in 3T3-L1 adipocytes. THRAP3 depletion increased basal and tumor necrosis factor α (TNFα)-induced lipolysis, proinflammatory gene expression, and phosphorylation of extracellular signal-regulated kinases (ERKs), suggesting elevated proinflammatory response after THRAP3 depletion in adipocytes. Moreover, TZD-mediated suppression of TNFα-induced lipolysis, proinflammatory gene expression, and ERK phosphorylation were attenuated or alleviated after THRAP3 depletion. Interestingly, the mRNA and protein levels of PPARγ were greatly reduced in THRAP3-depleted adipocytes. Actinomycin D treatment revealed that the stability of PPARγ mRNA was greatly reduced by THRAP3 depletion in adipocytes. Thus, in addition to modulating PPARγ function, THRAP3 may directly regulate the transcript of PPARγ in differentiated adipocytes.

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

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00015.2018 ◽

2018 ◽

Vol 315 (5) ◽

pp. E745-E757 ◽

Cited By ~ 7

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.

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

Psychoneuroendocrinology ◽

10.1016/j.psyneuen.2018.06.020 ◽

2018 ◽

Vol 96 ◽

pp. 179-187 ◽

Cited By ~ 12

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

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BASELINE PROINFLAMMATORY GENE EXPRESSION IS RELATED TO ADVERSE LONG-TERM OUTCOMES AFTER TRANSCATHETER AORTIC VALVE REPLACEMENT

Journal of the American College of Cardiology ◽

10.1016/s0735-1097(21)02354-8 ◽

2021 ◽

Vol 77 (18) ◽

pp. 995

Author(s):

Deena Goldwater ◽

Mei Leng ◽

David Elashoff ◽

Teresa Seeman ◽

David Reuben ◽

...

Keyword(s):

Gene Expression ◽

Aortic Valve ◽

Aortic Valve Replacement ◽

Valve Replacement ◽

Transcatheter Aortic Valve Replacement ◽

Long Term Outcomes ◽

Transcatheter Aortic Valve ◽

Proinflammatory Gene ◽

Proinflammatory Gene Expression

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Capsaicin-Sensitive Peptidergic Sensory Nerves Are Anti-Inflammatory Gatekeepers in the Hyperacute Phase of a Mouse Rheumatoid Arthritis Model

International Journal of Molecular Sciences ◽

10.3390/ijms22041682 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1682

Author(s):

Bálint Botz ◽

Gábor Kriszta ◽

Kata Bölcskei ◽

Ádám István Horváth ◽

Attila Mócsai ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Morphological Changes ◽

Vascular Leakage ◽

Sensory Nerves ◽

Clinical Severity ◽

Severity Scores ◽

Clinical Scoring ◽

Anti Inflammatory ◽

Ros Burst

Capsaicin-sensitive peptidergic sensory nerves play complex, mainly protective regulatory roles in the inflammatory cascade of the joints via neuropeptide mediators, but the mechanisms of the hyperacute arthritis phase has not been investigated. Therefore, we studied the involvement of these afferents in the early, “black box” period of a rheumatoid arthritis (RA) mouse model. Capsaicin-sensitive fibres were defunctionalized by pretreatment with the ultrapotent capsaicin analog resiniferatoxin and arthritis was induced by K/BxN arthritogenic serum. Disease severity was assessed by clinical scoring, reactive oxygen species (ROS) burst by chemiluminescent, vascular permeability by fluorescent in vivo imaging. Contrast-enhanced magnetic resonance imaging was used to correlate the functional and morphological changes. After sensory desensitization, both early phase ROS-burst and vascular leakage were significantly enhanced, which was later followed by the increased clinical severity scores. Furthermore, the early vascular leakage and ROS-burst were found to be good predictors of later arthritis severity. We conclude that the anti-inflammatory role of peptidergic afferents depends on their activity in the hyperacute phase, characterized by decreased cellular and vascular inflammatory components presumably via anti-inflammatory neuropeptide release. Therefore, these fibres might serve as important gatekeepers in RA.

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