scholarly journals Pioglitazone-Mediated Attenuation of Experimental Colitis Relies on Cleaving of Annexin A1 Released by Macrophages

2020 ◽  
Vol 11 ◽  
Author(s):  
Gustavo Henrique Oliveira da Rocha ◽  
Marina de Paula-Silva ◽  
Milena Fronza Broering ◽  
Pablo Rhasan dos Santos Scharf ◽  
Larissa Satiko Alcântara Sekimoto Matsuyama ◽  
...  
Keyword(s):  
Reactive Oxygen Species Generation ◽  
Experimental Colitis ◽  
Raw 264.7 ◽  
Peroxisome Proliferator ◽  
Annexin A1 ◽  
Peroxisome Proliferator Activated Receptor ◽  
Raw 264.7 Macrophages ◽  
Erk Phosphorylation ◽  
Potential Biomarker ◽  
Pioglitazone Treatment

Ulcerative colitis and Crohn’s disease are chronic inflammatory bowel diseases (IBDs) which burden health systems worldwide; available pharmacological therapies are limited and cost-intensive. Use of peroxisome proliferator activated-receptor γ (PPARγ) ligands for IBD treatment, while promising, lacks solid evidences to ensure its efficacy. Annexin A1 (AnxA1), a glucocorticoid-modulated anti-inflammatory protein, plays a key role on IBD control and is a potential biomarker of IBD progression. We here investigated whether effects of pioglitazone, a PPARγ ligand, rely on AnxA1 actions to modulate IBD inflammation. Experimental colitis was evoked by 2% dextran sodium sulfate (DSS) in AnxA1 knockout (AnxA1−/−) or wild type (WT) C57BL/6 mice. Clinical and histological parameters were more severe for AnxA−/− than WT mice, and 10 mg/kg pioglitazone treatment attenuated disease parameters in WT mice only. AnxA1 expression was increased in tissue sections of diseased WT mice, correlating positively with presence of CD68+ macrophages. Metalloproteinase-9 (MMP-9) and inactive 33 kDa AnxA1 levels were increased in the colon of diseased WT mice, which were reduced by pioglitazone treatment. Cytokine secretion, reactive oxygen species generation and MMP-9 expression caused by lipopolysaccharide (LPS) treatment in AnxA1-expressing RAW 264.7 macrophages were reduced by pioglitazone treatment, effects not detected in AnxA1 knockdown macrophages. LPS-mediated increase of AnxA1 cleaving in RAW 264.7 macrophages was also attenuated by pioglitazone treatment. Finally, pioglitazone treatment increased extracellular signal-regulated kinase (ERK) phosphorylation in AnxA1-expressing RAW 264.7 macrophages, but not in AnxA1-knockdown macrophages. Thus, our data highlight AnxA1 as a crucial factor for the therapeutic actions of pioglitazone on IBDs.

scholarly journals MAR1 suppresses inflammatory response in LPS-induced RAW 264.7 macrophages and human primary peripheral blood mononuclear cells via the SIRT1/PGC-1α/PPAR-γ pathway

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Wei Wang ◽  
Rong-Li Xu ◽  
Ping He ◽  
Rui Chen
Keyword(s):  
Inflammatory Response ◽  
Mononuclear Cells ◽  
Raw 264.7 ◽  
Peroxisome Proliferator ◽  
Peripheral Blood Mononuclear ◽  
Peroxisome Proliferator Activated Receptor ◽  
Raw 264.7 Macrophages ◽  
Ppar Γ ◽  
Tnf Α ◽  
Blood Mononuclear Cells

Abstract Background Sepsis is a complex syndrome characterized by a dysregulated inflammatory response to systemic infection and leads to shock, multiple organ failure and death especially if not recognized early and treated promptly. Previous studies have suggested Maresin 1 (MAR1) can alleviate systemic inflammation in sepsis, but its mechanism has not been clarified. Methods RAW 264.7 cells and human primary peripheral blood mononuclear cells (hPBMCs) were pretreated with LPS and MAR1. The mRNA expression and supernatant levels of pro-inflammatory cytokines, tumor necrosis factor (TNF-α), interleukin (IL)-1β and IL-6 were evaluated by RT-qPCR and ELISA, respectively. The expression levels of Sirtuin 1 (SIRT1), peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), and Peroxisome proliferator-activated receptor gamma (PPAR-γ) were determined by RT-qPCR and Western blot analysis, respectively. Results Our results show that LPS-induced inflammation increased the expression and secretion of proinflammatory cytokines TNF-α, IL-1β and IL-6 and induced suppression of SIRT1, PGC-1α, and PPAR-γ expression, which could be reversed by MAR1. And the effect of MAR1 was eliminated by repression of SIRT1/PPAR-γ and enhanced by PGC-1α overexpression. Conclusions MAR1 suppressed inflammatory response in LPS-induced RAW 264.7 macrophages and hPBMCs via the SIRT1/PGC-1α/PPAR-γ pathway.

Peroxisome proliferator-activated receptor-γ activation as a mechanism of preventive neuroprotection induced by pioglitazone treatment

2005 ◽  
Vol 25 (1_suppl) ◽  
pp. S506-S506
Author(s):  
Kimihiko Hattori ◽  
Tomokazu Shimazu ◽  
Ikuo Inoue ◽  
Nobuo Araki ◽  
Shigehiro Katayama ◽  
...  
Keyword(s):  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pioglitazone Treatment

scholarly journals PPARγin Inflammatory Bowel Disease

PPAR Research ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Vito Annese ◽  
Francesca Rogai ◽  
Alessia Settesoldi ◽  
Siro Bagnoli
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Potential Role ◽  
Intestinal Inflammation ◽  
Experimental Colitis ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Beneficial Effects ◽  
Inflammatory Bowel

Peroxisome proliferator-activated receptor gamma (PPARγ) is member of a family of nuclear receptors that interacts with nuclear proteins acting as coactivators and corepressors. The colon is a major tissue which expresses PPARγin epithelial cells and, to a lesser degree, in macrophages and lymphocytes and plays a role in the regulation of intestinal inflammation. Indeed, both natural and synthetic PPARγligands have beneficial effects in different models of experimental colitis, with possible implication in the therapy of inflammatory bowel disease (IBD). This paper will specifically focus on potential role of PPARγin the predisposition and physiopathology of IBD and will analyze its possible role in medical therapy.

scholarly journals Stigmasterol Restores the Balance of Treg/Th17 Cells by Activating the Butyrate-PPARγ Axis in Colitis

2021 ◽  
Vol 12 ◽  
Author(s):  
Shuting Wen ◽  
Long He ◽  
Zhuotai Zhong ◽  
Runyuan Zhao ◽  
Senhui Weng ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Th17 Cells ◽  
Experimental Colitis ◽  
Short Chain Fatty Acids ◽  
Peroxisome Proliferator ◽  
Inflammatory Disorder ◽  
T Helper 17 ◽  
Peroxisome Proliferator Activated Receptor ◽  
Chronic Inflammatory Disorder ◽  
Immune Imbalance

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder with gut microbiota disequilibrium and regulatory T (Treg)/T helper 17 (Th17) immune imbalance. Stigmasterol, a plant-derived sterol, has shown anti-inflammatory effects. Our study aimed to identify the effects of stigmasterol on experimental colitis and the related mechanisms. Stigmasterol treatment restored the Treg/Th17 balance and altered the gut microbiota in a dextran sodium sulfate (DSS)-induced colitis model. Transplantation of the faecal microbiota of stigmasterol-treated mice significantly alleviated inflammation. Additionally, stigmasterol treatment enhanced the production of gut microbiota-derived short-chain fatty acids (SCFAs), particularly butyrate. Next, human naïve CD4+ T cells sorted from IBD patients were cultured under Treg- or Th17-polarizing conditions; butyrate supplementation increased the differentiation of Tregs and decreased Th17 cell differentiation. Mechanistically, butyrate activated peroxisome proliferator-activated receptor gamma (PPARγ) and reprogrammed energy metabolism, thereby promoting Treg differentiation and inhibiting Th17 differentiation. Our results demonstrate that butyrate-mediated PPARγ activation restores the balance of Treg/Th17 cells, and this may be a possible mechanism, by which stigmasterol attenuates IBD.

scholarly journals Peroxisome Proliferator-Activated Receptor Alpha Mediates the Beneficial Effects of Atorvastatin in Experimental Colitis

2021 ◽  
Vol 12 ◽  
Author(s):  
Paulo José Basso ◽  
Helioswilton Sales-Campos ◽  
Viviani Nardini ◽  
Murillo Duarte-Silva ◽  
Vanessa Beatriz Freitas Alves ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Experimental Colitis ◽  
Predictive Biomarker ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
Beneficial Effects ◽  
Anti Inflammatory

The current therapeutic options for Inflammatory Bowel Diseases (IBD) are limited. Even using common anti-inflammatory, immunosuppressive or biological therapies, many patients become unresponsive to the treatments, immunosuppressed or unable to restrain secondary infections. Statins are cholesterol-lowering drugs with non-canonical anti-inflammatory properties, whose underlying mechanisms of action still remain poorly understood. Here, we described that in vitro atorvastatin (ATO) treatment was not toxic to splenocytes, constrained cell proliferation and modulated IL-6 and IL-10 production in a dose-dependent manner. Mice exposed to dextran sulfate sodium (DSS) for colitis induction and treated with ATO shifted their immune response from Th17 towards Th2, improved the clinical and histological aspects of intestinal inflammation and reduced the number of circulating leukocytes. Both experimental and in silico analyses revealed that PPAR-α expression is reduced in experimental colitis, which was reversed by ATO treatment. While IBD patients also downregulate PPAR-α expression, the responsiveness to biological therapy relied on the restoration of PPAR-α levels. Indeed, the in vitro and in vivo effects induced by ATO treatment were abrogated in Ppara-/- mice or leukocytes. In conclusion, the beneficial effects of ATO in colitis are dependent on PPAR-α, which could also be a potential predictive biomarker of therapy responsiveness in IBD.

scholarly journals Oxidized alkyl phospholipids stimulate sodium transport in proximal tubules via PPAR-dependent pathway

2021 ◽  
Author(s):  
Tomohito Mizuno ◽  
Nobuhiko Satoh ◽  
Shoko Horita ◽  
Hiroyuki Tsukada ◽  
Yusuke Sato ◽  
...  
Keyword(s):  
Volume Expansion ◽  
Bicarbonate Transport ◽  
Kidney Cortex ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Agonist ◽  
Extracellular Signal Regulated Kinase ◽  
Erk Phosphorylation ◽  
Extracellular Signal

The pleiotropic effects of oxidized phospholipids (oxPLs) have been identified. 1-O-hexadecyl-2-azelaoyl-sn-glycero-3-phosphocholine (azPC), an oxPL formed from alkyl phosphatidylcholines, is a potent peroxisome proliferator-activated receptor (PPAR) agonist. Although it has been reported that thiazolidinediones can induce volume expansion by enhancing renal sodium and water retention, the role of azPC, an endogenous PPAR agonist, in renal transport functions is unknown. In the present study, we investigated the effect of azPC on renal proximal tubule (PT) transport using isolated PTs and kidney cortex tissues. We showed that azPC rapidly stimulated Na+/HCO3- cotransporter 1 activity and luminal Na+/H+ exchanger (NHE) activities in a dose-dependent manner, at submicromolar concentrations, in isolated PTs from rats and humans. Additionally, the stimulatory effects were completely blocked by a specific PPAR antagonist, 2-chloro-5-nitro-N-phenylbenzamide (GW9662), and a mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor, PD98059. Treatment with an siRNA against PPAR significantly suppressed the expression of PPAR mRNA, and it completely blocked the stimulation of both Na+/HCO3- cotransporter 1 and NHE activities by azPC. Moreover, azPC induced extracellular signal-regulated kinase (ERK) phosphorylation in rat and human kidney cortex tissues, and the induced ERK phosphorylation by azPC was completely suppressed by GW9662 and PD98059. These results suggest that azPC stimulates renal PT sodium-coupled bicarbonate transport via the PPAR/MEK/ERK pathway. The stimulatory effects of azPC on PT transport may be partially involved in the development of volume expansion.

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