PPAR-γ ligands modulate effects of LPS in stimulated rat synovial fibroblasts

2002 ◽  
Vol 282 (1) ◽  
pp. C125-C133 ◽  
Author(s):  
Marie-Agnès Simonin ◽  
Karim Bordji ◽  
Sandrine Boyault ◽  
Arnaud Bianchi ◽  
Elvire Gouze ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Constitutive Expression ◽  
Synovial Fibroblasts ◽  
Binding Activity ◽  
Inos Mrna ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Tnf Α ◽  
Cox 2

This work demonstrated the constitutive expression of peroxisome proliferator-activated receptor (PPAR)-γ and PPAR-α in rat synovial fibroblasts at both mRNA and protein levels. A decrease in PPAR-γ expression induced by 10 μg/ml lipopolysaccharide (LPS) was observed, whereas PPAR-α mRNA expression was not modified. 15-Deoxy-Δ12,14-prostaglandin J2(15d-PGJ2) dose-dependently decreased LPS-induced cyclooxygenase (COX)-2 (−80%) and inducible nitric oxide synthase (iNOS) mRNA expression (−80%), whereas troglitazone (10 μM) only inhibited iNOS mRNA expression (−50%). 15d-PGJ2 decreased LPS-induced interleukin (IL)-1β (−25%) and tumor necrosis factor (TNF)-α (−40%) expression. Interestingly, troglitazone strongly decreased TNF-α expression (−50%) but had no significant effect on IL-1β expression. 15d-PGJ2 was able to inhibit DNA-binding activity of both nuclear factor (NF)-κB and AP-1. Troglitazone had no effect on NF-κB activation and was shown to increase LPS-induced AP-1 activation. 15d-PGJ2 and troglitazone modulated the expression of LPS-induced iNOS, COX-2, and proinflammatory cytokines differently. Indeed, troglitazone seems to specifically target TNF-α and iNOS pathways. These results offer new insights in regard to the anti-inflammatory potential of the PPAR-γ ligands and underline different mechanisms of action of 15d-PGJ2 and troglitazone in synovial fibroblasts.

Gabapentin Reduces Alcohol Intake in Rats by Regulating NF-κB Signaling Pathway Via PPAR γ

2021 ◽  
Author(s):  
Jing Li ◽  
Kewei Xu ◽  
Hao Ding ◽  
Qiaozhen Xi
Keyword(s):  
Locomotor Activity ◽  
Signaling Pathway ◽  
Specific Inhibitor ◽  
Underlying Mechanism ◽  
Ethanol Consumption ◽  
Diglycidyl Ether ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Tnf Α

Abstract Aims Increasing preclinical and clinical reports have demonstrated the efficacy of gabapentin (GBP) in treating alcohol use disorder (AUD). However, the mechanism of the effects of GBP in AUD is largely unknown. Herein, we sought to investigate the effect of GBP in a rat model of AUD and explore the underlying mechanism. Methods The intermittent access to 20% ethanol in a 2-bottle choice (IA2BC) procedure was exploited to induce high voluntary ethanol consumption in rats. The rats were treated daily for 20 days with different doses of GBP, simultaneously recording ethanol/water intake. The locomotor activity and grooming behavior of rats were also tested to evaluate the potential effects of GBP on confounding motor in rats. The levels of IL-1β and TNF-α in serum and hippocampus homogenate from the rats were detected by using ELISA. The expressions of peroxisome proliferator-activated-receptor γ (PPAR-γ) and nuclear factor-κB (NF-κB) in the hippocampus were determined by immunofluorescence and western blot. Results GBP reduced alcohol consumption, whereas increased water consumption and locomotor activity of rats. GBP was also able to decrease the levels of IL-1β and TNF-α in both serum and hippocampus, in addition to the expression of NF-κB in the hippocampus. Furthermore, these effects attributed to GBP were observed to disappear in the presence of bisphenol A diglycidyl ether (BADGE), a specific inhibitor of PPAR-γ. Conclusions Our findings revealed that GBP could activate PPAR-γ to suppress the NF-κB signaling pathway, contributing to the decrease of ethanol consumption and ethanol-induced neuroimmune responses.

15 Deoxy Δ12,14 PGJ2 Induces Procoagulant Activity in Cultured Human Endothelial Cells

2002 ◽  
Vol 87 (03) ◽  
pp. 523-529 ◽  
Author(s):  
Shaoping Xie ◽  
David O’Regan ◽  
Vijay Kakkar ◽  
Michael Scully
Keyword(s):  
Endothelial Cells ◽  
Peroxisome Proliferator ◽  
Endothelial Protein C Receptor ◽  
Peroxisome Proliferator Activated Receptor ◽  
Affinity Ligand ◽  
Ppar Γ ◽  
Tnf Α ◽  
Ea.Hy926 Cells ◽  
High Affinity Ligand ◽  
Feedback Regulator

Summary15 deoxy Δ12,14 PGJ2 (15d-PGJ2), a high affinity ligand of peroxisome proliferator-activated receptor γ (PPAR γ has been proposed to act as a negative feedback regulator of the inflammatory response. We investigated the effect of 15d-PGJ2 on the anticoagulant property of endothelial cells. 15d-PGJ2 stimulated a moderate but sustained increase in tissue factor (TF) activity in HUVECs and EA.hy926 cells while causing a partial loss of thrombomodulin (TM) activity. When cells were co-treated with 15d-PGJ2 and TNF-α, the subsequent elevation of TF activity was synergistically increased over that of cells treated with TNF-α, alone and the decline of TF activity after 24 h was less marked than TNF-α, alone. The induction of TF by 15d-PGJ2 alone and in combination with TNF-α, was reduced in the presence of PD 98059, suggesting the participation of the MEK/ERK pathway. The thiazolidinedione PPAR γ agonist ciglitazone had no effect on TF levels but reduced the expression of endothelial protein C receptor. The ability of 15d-PGJ2 to enhance a procoagulant phenotype arising from TNF-α, suggests a pro-inflammatory role for the prostaglandin.

scholarly journals Apple Flavonols Mitigate Adipocyte Inflammation and Promote Angiogenic Factors in LPS- and Cobalt Chloride-Stimulated Adipocytes, in Part by a Peroxisome Proliferator-Activated Receptor-γ-Dependent Mechanism

Nutrients ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1386 ◽  
Author(s):  
Danyelle M. Liddle ◽  
Meaghan E. Kavanagh ◽  
Amanda J. Wright ◽  
Lindsay E. Robinson
Keyword(s):  
Mrna Expression ◽  
Cobalt Chloride ◽  
Nuclear Factor Κb ◽  
Diglycidyl Ether ◽  
Low Grade ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Anti Inflammatory

Adipose tissue (AT) expansion induces local hypoxia, a key contributor to the chronic low-grade inflammation that drives obesity-associated disease. Apple flavonols phloretin (PT) and phlorizin (PZ) are suggested anti-inflammatory molecules but their effectiveness in obese AT is inadequately understood. Using in vitro models designed to reproduce the obese AT microenvironment, 3T3-L1 adipocytes were cultured for 24 h with PT or PZ (100 μM) concurrent with the inflammatory stimulus lipopolysaccharide (LPS; 10 ng/mL) and/or the hypoxia mimetic cobalt chloride (CoCl2; 100 μM). Within each condition, PT was more potent than PZ and its effects were partially mediated by peroxisome proliferator-activated receptor (PPAR)-γ (p < 0.05), as tested using the PPAR-γ antagonist bisphenol A diglycidyl ether (BADGE). In LPS-, CoCl2-, or LPS + CoCl2-stimulated adipocytes, PT reduced mRNA expression and/or secreted protein levels of inflammatory and macrophage chemotactic adipokines, and increased that of anti-inflammatory and angiogenic adipokines, which was consistent with reduced mRNA expression of M1 polarization markers and increased M2 markers in RAW 264.7 macrophages cultured in media collected from LPS + CoCl2-simulated adipocytes (p < 0.05). Further, within LPS + CoCl2-stimulated adipocytes, PT reduced reactive oxygen species accumulation, nuclear factor-κB activation, and apoptotic protein expression (p < 0.05). Overall, apple flavonols attenuate critical aspects of the obese AT phenotype.

Endotoxin downregulates peroxisome proliferator-activated receptor-γ via the increase in TNF-α release

2008 ◽  
Vol 294 (1) ◽  
pp. R84-R92 ◽  
Author(s):  
Mian Zhou ◽  
Rongqian Wu ◽  
Weifeng Dong ◽  
Asha Jacob ◽  
Ping Wang
Keyword(s):  
Gene Expression ◽  
Neutralizing Antibodies ◽  
Cecal Ligation ◽  
Polymyxin B ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Levels ◽  
Ppar Γ ◽  
Tnf Α ◽  
A Cell

The nuclear receptor peroxisome proliferator-activated receptor-γ (PPAR-γ) is anti-inflammatory in a cell-based system and in animal models of endotoxemia. We have shown that PPAR-γ gene expression is downregulated in macrophages after lipopolysaccharide (LPS) stimulation. However, it remains unknown whether hepatic PPAR-γ is altered in sepsis and, if so, whether LPS directly downregulates PPAR-γ. To study this, rats were subjected to sepsis by cecal ligation and puncture (CLP). Hepatic tissues were harvested at 5, 10, and 20 h after CLP. PPAR-γ gene expression and protein levels were determined by RT-PCR and Western blot analysis, respectively. The results showed that PPAR-γ gene expression decreased at 10 and 20 h and that its proteins levels were reduced at 20 h after CLP. PPAR-γ levels were also decreased in animals that were administered LPS. To determine the direct effects of LPS on PPAR-γ downregulation, LPS binding agent polymyxin B (PMB) was administered intramuscularly after CLP. The administration of PMB significantly reduced plasma levels of endotoxin, but it did not prevent the downregulation of PPAR-γ expression. We found that circulating levels of TNF-α still remained significantly elevated in PMB-treated septic animals. We, therefore, hypothesize that the decrease of PPAR-γ expression is TNF-α dependent. To investigate this, Kupffer cells (KCs) were isolated from normal rats and stimulated with LPS or TNF-α. TNF-α significantly attenuated PPAR-γ gene expression in KCs. Although LPS decreased PPAR-γ in KCs, the downregulatory effect of LPS was blocked by the addition of TNF-α-neutralizing antibodies. Furthermore, the administration of TNF-α-neutralizing antibodies to animals before the onset of sepsis prevented the downregulation of PPAR-γ in sepsis. We, therefore, conclude that LPS downregulates PPAR-γ expression during sepsis via an increase in TNF-α release.

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.

Suppression of PPAR-γ attenuates insulin-stimulated glucose uptake by affecting both GLUT1 and GLUT4 in 3T3-L1 adipocytes

2007 ◽  
Vol 293 (1) ◽  
pp. E219-E227 ◽  
Author(s):  
Wei Liao ◽  
M. T. Audrey Nguyen ◽  
Takeshi Yoshizaki ◽  
Svetlana Favelyukis ◽  
David Patsouris ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Insulin Signaling ◽  
Adipocyte Differentiation ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Tnf Α ◽  
Interfering Rna

Peroxisome proliferator-activated receptor-γ (PPAR-γ) plays a critical role in regulating insulin sensitivity and glucose homeostasis. In this study, we identified highly efficient small interfering RNA (siRNA) sequences and used lentiviral short hairpin RNA and electroporation of siRNAs to deplete PPAR-γ from 3T3-L1 adipocytes to elucidate its role in adipogenesis and insulin signaling. We show that PPAR-γ knockdown prevented adipocyte differentiation but was not required for maintenance of the adipocyte differentiation state after the cells had undergone adipogenesis. We further demonstrate that PPAR-γ suppression reduced insulin-stimulated glucose uptake without affecting the early insulin signaling steps in the adipocytes. Using dual siRNA strategies, we show that this effect of PPAR-γ deletion was mediated by both GLUT4 and GLUT1. Interestingly, PPAR-γ-depleted cells displayed enhanced inflammatory responses to TNF-α stimulation, consistent with a chronic anti-inflammatory effect of endogenous PPAR-γ. In summary, 1) PPAR-γ is essential for the process of adipocyte differentiation but is less necessary for maintenance of the differentiated state, 2) PPAR-γ supports normal insulin-stimulated glucose transport, and 3) endogenous PPAR-γ may play a role in suppression of the inflammatory pathway in 3T3-L1 cells.

scholarly journals Inhibitory Effects of a Novel PPAR-γ Agonist MEKT1 on Pomc Expression/ACTH Secretion in AtT20 Cells

PPAR Research ◽  
2018 ◽  
Vol 2018 ◽  
pp. 1-16 ◽  
Author(s):  
Rehana Parvin ◽  
Erika Noro ◽  
Akiko Saito-Hakoda ◽  
Hiroki Shimada ◽  
Susumu Suzuki ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Cushing’S Disease ◽  
Dna Interaction ◽  
Luciferase Assay ◽  
Cushing's Disease ◽  
Therapeutic Effects ◽  
Peroxisome Proliferator ◽  
Acth Secretion ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ

Although therapeutic effects of the peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists rosiglitazone and pioglitazone against Cushing’s disease have been reported, their effects are still controversial and inconsistent. We therefore examined the effects of a novel PPAR-γ agonist, MEKT1, on Pomc expression/ACTH secretion using murine corticotroph-derived AtT20 cells and compared its effects with those of rosiglitazone and pioglitazone. AtT20 cells were treated with either 1 nM~10 μM MEKT1, rosiglitazone, or pioglitazone for 24 hours. Thereafter, their effects on proopiomelanocortin gene (Pomc) mRNA expression were studied by qPCR and the Pomc promoter (−703/+58) activity was demonstrated by luciferase assay. Pomc mRNA expression and promoter activity were significantly inhibited by MEKT1 at 10 μM compared to rosiglitazone and pioglitazone. SiRNA-mediated PPAR-γ knockdown significantly abrogated MEKT1-mediated Pomc mRNA suppression. ACTH secretion from AtT20 cells was also significantly inhibited by MEKT1. Deletion/point mutant analyses of Pomc promoter indicated that the MEKT1-mediated suppression was mediated via NurRE, TpitRE, and NBRE at −404/-383, −316/-309, and −69/-63, respectively. Moreover, MEKT1 significantly suppressed Nur77, Nurr1, and Tpit mRNA expression. MEKT1 also was demonstrated to inhibit the protein-DNA interaction of Nur77/Nurr1-NurRE, Tpit-TpitRE, and Nur77-NBRE by ChIP assay. Taken together, it is suggested that MEKT1 could be a novel therapeutic medication for Cushing’s disease.

scholarly journals Sepsis-induced inhibition of neutrophil chemotaxis is mediated by activation of peroxisome proliferator-activated receptor-γ

Blood ◽  
2008 ◽  
Vol 112 (10) ◽  
pp. 4250-4258 ◽  
Author(s):  
Raju C. Reddy ◽  
Venkata R. Narala ◽  
Venkateshwar G. Keshamouni ◽  
Jami E. Milam ◽  
Michael W. Newstead ◽  
...  
Keyword(s):  
Actin Polymerization ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Extracellular Signal ◽  
Tnf Α ◽  
Human Pmns ◽  
Inflammatory Regulation

AbstractNeutrophils (polymorphonuclear leukocytes [PMNs]) are critical to the immune response, including clearance of infectious pathogens. Sepsis is associated with impaired PMN function, including chemotaxis. PMNs express peroxisome proliferator-activated receptor-γ (PPAR-γ), a ligand-activated nuclear transcription factor involved in immune and inflammatory regulation. The role of PPAR-γ in PMN responses, however, is not well characterized. We report that freshly isolated human PMNs constitutively express PPAR-γ, which is up-regulated by the sepsis-induced cytokines TNF-α and IL-4. PMN chemotactic responses to formylmethionyl-leucyl-phenylalanine (fMLP) and IL-8 were dose-dependently inhibited by treatment with the PPAR-γ ligands troglitazone and 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) and by transfection of PMN-like HL-60 cells with a constitutively active PPAR-γ construct. Inhibition of chemotaxis by PPAR-γ ligands correlated with decreases in extracellular signal-regulated kinase-1 and -2 activation, actin polymerization, and adherence to a fibrinogen substrate. Furthermore, PMN expression of PPAR-γ was increased in sepsis patients and mice with either of 2 models of sepsis. Finally, treatment with the PPAR-γ antagonist GW9662 significantly reversed the inhibition of PMN chemotaxis and increased peritoneal PMN recruitment in murine sepsis. This study indicates that PPAR-γ activation is involved in PMN chemotactic responses in vitro and may play a role in the migration of these cells in vivo.

scholarly journals Trace Elements, PPARs, and Metabolic Syndrome

2020 ◽  
Vol 21 (7) ◽  
pp. 2612 ◽  
Author(s):  
Yujie Shi ◽  
Yixin Zou ◽  
Ziyue Shen ◽  
Yonghong Xiong ◽  
Wenxiang Zhang ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Trace Elements ◽  
Mrna Expression ◽  
High Fat Diet ◽  
Binding Activity ◽  
Peroxisome Proliferator ◽  
Dna Binding Activity ◽  
Ppar Γ ◽  
Peroxisome Proliferator Activated Receptors ◽  
Structure Of Proteins

Metabolic syndrome (MetS) is a constellation of metabolic derangements, including central obesity, insulin resistance, hypertension, glucose intolerance, and dyslipidemia. The pathogenesis of MetS has been intensively studied, and now many factors are recognized to contribute to the development of MetS. Among these, trace elements influence the structure of proteins, enzymes, and complex carbohydrates, and thus an imbalance in trace elements is an independent risk factor for MetS. The molecular link between trace elements and metabolic homeostasis has been established, and peroxisome proliferator-activated receptors (PPARs) have appeared as key regulators bridging these two elements. This is because on one hand, PPARs are actively involved in various metabolic processes, such as abdominal adiposity and insulin sensitivity, and on the other hand, PPARs sensitively respond to changes in trace elements. For example, an iron overload attenuates hepatic mRNA expression of Ppar-α; zinc supplementation is considered to recover the DNA-binding activity of PPAR-α, which is impaired in steatotic mouse liver; selenium administration downregulates mRNA expression of Ppar-γ, thereby improving lipid metabolism and oxidative status in the liver of high-fat diet (HFD)-fed mice. More importantly, PPARs’ expression and activity are under the control of the circadian clock and show a robust 24 h rhythmicity, which might be the reasons for the side effects and the clinical limitations of trace elements targeting PPARs. Taken together, understanding the casual relationships among trace elements, PPARs’ actions, and the pathogenesis of MetS is of great importance. Further studies are required to explore the chronopharmacological effects of trace elements on the diurnal oscillation of PPARs and the consequent development of MetS.

scholarly journals The Effect of Biotinylated PAMAM G3 Dendrimers Conjugated with COX-2 Inhibitor (celecoxib) and PPARγ Agonist (Fmoc-L-Leucine) on Human Normal Fibroblasts, Immortalized Keratinocytes and Glioma Cells in Vitro

Molecules ◽  
2019 ◽  
Vol 24 (20) ◽  
pp. 3801 ◽  
Author(s):  
Łukasz Uram ◽  
Maria Misiorek ◽  
Monika Pichla ◽  
Aleksandra Filipowicz-Rachwał ◽  
Joanna Markowicz ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Treatment Strategies ◽  
Pge2 Production ◽  
Peroxisome Proliferator ◽  
Central Nervous System Tumor ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Pparγ Agonist ◽  
Cox 2

Glioblastoma multiforme (GBM) is the most malignant type of central nervous system tumor that is resistant to all currently used forms of therapy. Thus, more effective GBM treatment strategies are being investigated, including combined therapies with drugs that may cross the blood brain barrier (BBB). Another important issue considers the decrease of deleterious side effects of therapy. It has been shown that nanocarrier conjugates with biotin can penetrate BBB. In this study, biotinylated PAMAM G3 dendrimers substituted with the recognized anticancer agents cyclooxygenase-2 (COX-2) inhibitor celecoxib and peroxisome proliferator-activated receptor γ (PPARγ) agonist Fmoc-L-Leucine (G3-BCL) were tested in vitro on human cell lines with different p53 status: glioblastoma (U-118 MG), normal fibroblasts (BJ) and immortalized keratinocytes (HaCaT). G3-BCL penetrated efficiently into the lysosomal and mitochondrial compartments of U-118 MG cells and induced death of U-118 MG cells via apoptosis and inhibited proliferation and migration at low IC50 = 1.25 µM concentration, considerably lower than either drug applied alone. Comparison of the effects of G3-BCL on expression of COX-2 and PPARγ protein and PGE2 production of three different investigated cell line phenotypes revealed that the anti-glioma effect of the conjugate was realized by other mechanisms other than influencing PPAR-γ expression and regardless of p53 cell status, it was dependent on COX-2 protein level and high PGE2 production. Similar G3-BCL cytotoxicity was seen in normal fibroblasts (IC50 = 1.29 µM) and higher resistance in HaCaT cells (IC50 = 4.49 µM). Thus, G3-BCL might be a good candidate for the targeted, local glioma therapy with limited site effects.

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