scholarly journals MicroRNA-511-3p mediated modulation of the peroxisome proliferator-activated receptor gamma (PPARγ) controls LPS-induced inflammatory responses in human monocyte derived DCs

2020 ◽  
Author(s):  
Dennis Awuah ◽  
Alisa Ruisinger ◽  
Meshal Alobaid ◽  
Chidimma Mbadugha ◽  
Amir M. Ghaemmaghami
Keyword(s):  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Human Monocyte ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Peroxisome Proliferator Activated Receptor ◽  
Inflammatory Cytokine Production ◽  
And Function ◽  
First Time ◽  
Selection Of

AbstractThe peroxisome proliferator activated receptor gamma (PPARγ) is a ligand activated transcription factor expressed in dendritic cells (DCs), where it exerts anti-inflammatory responses against TLR4-induced inflammation. Recently, microRNA-511 (miR-511) has also emerged as a key player in controlling TLR4-mediated signalling, and in regulating the function of DCs. Interestingly, PPARγ has been previously highlighted as a putative target of miR-511 activity; however the link between miR-511 and PPARγ and its influence on human DC function within the context of LPS-induced inflammatory responses is unknown. Using a selection of miR-511-3p-specific inhibitors and mimics, we demonstrate for the first time that up or downregulation of miR-511-3p inversely correlates with PPARγ mRNA levels and transcriptional activity following treatment with PPARγ synthetic agonist rosiglitazone (RSG), in the presence or absence of LPS. Additionally, we show that PPARγ activation with RSG modulates LPS-induced DC activation and downregulates pro-inflammatory cytokine production following downregulation of miR-511-3p. Lastly, PPARγ activation was shown to suppress LPS-mediated induction of indoleamine 2,3-dioxygenase (IDO) activity in DCs, most likely due to changes in miR-511-3p expression. These data suggest that PPARγ-induced modulation of DC phenotype and function is influenced by miR-511-3p expression, which may serve as a potential therapeutic target against inflammatory diseases.

scholarly journals MicroRNA-511-3p Mediated Modulation of the Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) Controls LPS-Induced Inflammatory Responses in Human Monocyte Derived DCs

Immuno ◽  
2022 ◽  
Vol 2 (1) ◽  
pp. 104-117
Author(s):  
Dennis Awuah ◽  
Alisa Ruisinger ◽  
Meshal Alobaid ◽  
Chidimma Mbadugha ◽  
Amir M. Ghaemmaghami
Keyword(s):  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Human Monocyte ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Peroxisome Proliferator Activated Receptor ◽  
Inflammatory Cytokine Production ◽  
Pparγ Agonist ◽  
And Function ◽  
First Time

The peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor expressed in dendritic cells (DCs), where it exerts anti-inflammatory responses against TLR4-induced inflammation. Recently, microRNA-511 (miR-511) has also emerged as a key player in controlling TLR4-mediated signalling and in regulating the function of DCs. Interestingly, PPARγ has been previously highlighted as a putative target of miR-511 activity; however, the link between miR-511 and PPARγ and its influence on human DC function within the context of LPS-induced inflammatory responses is unknown. Using a selection of miR-511-3p-specific inhibitors and mimics, we demonstrate for the first time that knockdown or overexpression of miR-511-3p inversely correlates with PPARγ mRNA levels and affects its transcriptional activity following treatment with rosiglitazone (RSG; PPARγ agonist), in the presence or absence of LPS. Additionally, we show that PPARγ-mediated suppression of DC activation and pro-inflammatory cytokine production in miR-511-3p knockdown DCs is abrogated following overexpression of miR-511-3p. Lastly, PPARγ activation suppressed LPS-mediated induction of indoleamine 2,3-dioxygenase (IDO) activity in DCs, most likely due to changes in miR-511-3p expression. Our data thus suggests that PPARγ-induced modulation of DC phenotype and function is influenced by miR-511-3p expression, which may serve as a potential therapeutic target against inflammatory diseases.

scholarly journals Attenuation of Colon Inflammation through Activators of the Retinoid X Receptor (Rxr)/Peroxisome Proliferator–Activated Receptor γ (Pparγ) Heterodimer

2001 ◽  
Vol 193 (7) ◽  
pp. 827-838 ◽  
Author(s):  
Pierre Desreumaux ◽  
Laurent Dubuquoy ◽  
Sophie Nutten ◽  
Michel Peuchmaur ◽  
Walter Englaro ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Synergistic Effects ◽  
Survival Rates ◽  
Nuclear Factor Κb ◽  
Retinoid X Receptor ◽  
Trinitrobenzene Sulfonic Acid ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Peroxisome Proliferator Activated Receptor ◽  
Colon Inflammation

The peroxisome proliferator–activated receptor γ (PPARγ) is highly expressed in the colon mucosa and its activation has been reported to protect against colitis. We studied the involvement of PPARγ and its heterodimeric partner, the retinoid X receptor (RXR) in intestinal inflammatory responses. PPARγ1/− and RXRα1/− mice both displayed a significantly enhanced susceptibility to 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis compared with their wild-type littermates. A role for the RXR/PPARγ heterodimer in the protection against colon inflammation was explored by the use of selective RXR and PPARγ agonists. TNBS-induced colitis was significantly reduced by the administration of both PPARγ and RXR agonists. This beneficial effect was reflected by increased survival rates, an improvement of macroscopic and histologic scores, a decrease in tumor necrosis factor α and interleukin 1β mRNA levels, a diminished myeloperoxidase concentration, and reduction of nuclear factor κB DNA binding activity, c-Jun NH2-terminal kinase, and p38 activities in the colon. When coadministered, a significant synergistic effect of PPARγ and RXR ligands was observed. In combination, these data demonstrate that activation of the RXR/PPARγ heterodimer protects against colon inflammation and suggest that combination therapy with both RXR and PPARγ ligands might hold promise in the clinic due to their synergistic effects.

scholarly journals PPARγin Bacterial Infections: A Friend or Foe?

PPAR Research ◽  
2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Aravind T. Reddy ◽  
Sowmya P. Lakshmi ◽  
Raju C. Reddy
Keyword(s):  
Bacterial Infections ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
Antibacterial Properties ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Therapeutic Modalities ◽  
Anti Inflammatory ◽  
And Function

Peroxisome proliferator-activated receptorγ(PPARγ) is now recognized as an important modulator of leukocyte inflammatory responses and function. Its immunoregulatory function has been studied in a variety of contexts, including bacterial infections of the lungs and central nervous system, sepsis, and conditions such as chronic granulomatous disease. Although it is generally believed that PPARγactivation is beneficial for the host during bacterial infections via its anti-inflammatory and antibacterial properties, PPARγagonists have also been shown to dampen the host immune response and in some cases exacerbate infection by promoting leukocyte apoptosis and interfering with leukocyte migration and infiltration. In this review we discuss the role of PPARγand its activation during bacterial infections, with focus on the potential of PPARγagonists and perhaps antagonists as novel therapeutic modalities. We conclude that adjustment in the dosage and timing of PPARγagonist administration, based on the competence of host antimicrobial defenses and the extent of inflammatory response and tissue injury, is critical for achieving the essential balance between pro- and anti-inflammatory effects on the immune system.

scholarly journals The 5,7-Dimethoxyflavone Suppresses Sarcopenia by Regulating Protein Turnover and Mitochondria Biogenesis-Related Pathways

Nutrients ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 1079 ◽  
Author(s):  
Changhee Kim ◽  
Jae-Kwan Hwang
Keyword(s):  
Muscle Mass ◽  
Protein Turnover ◽  
Inflammatory Responses ◽  
Biological Activities ◽  
Muscle Disease ◽  
Initiation Factor ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Necrosis Factor Alpha ◽  
Peroxisome Proliferator Activated Receptor

Sarcopenia is a muscle disease featured by the loss of muscle mass and dysfunction with advancing age. The 5,7-dimethoxyflavone (DMF), a major flavone found in Kaempferia parviflora, has biological activities, including anti-diabetes, anti-obesity, and anti-inflammation. However, its anti-sarcopenic effect remains to be elucidated. This current study investigated the inhibitory activity of DMF on sarcopenia. Eighteen-month-old mice were orally administered DMF at the dose of 25 mg·kg−1·day−1 or 50 mg·kg−1·day−1 for 8 weeks. DMF not only stimulated grip strength and exercise endurance but also increased muscle mass and volume. Besides, DMF stimulated the phosphatidylinositol 3-kinase-Akt pathway, consequently activating the mammalian target of rapamycin-eukaryotic initiation factor 4E-binding protein 1-70-kDa ribosomal protein S6 kinase pathway for protein synthesis. DMF reduced the mRNA expression of E3 ubiquitin ligase- and autophagy-lysosomal-related genes involved in proteolysis via the phosphorylation of Forkhead box O3. DMF upregulated peroxisome proliferator-activated receptor-gamma coactivator 1 alpha, nuclear respiratory factor 1, and mitochondrial transcription factor A along with the increase of relative mitochondrial DNA content. DMF alleviated inflammatory responses by reducing the tumor necrosis factor-alpha and interleukin-6 serum and mRNA levels. Collectively, DMF can be used as a natural agent to inhibit sarcopenia via improving protein turnover and mitochondria function.

scholarly journals Serum- and Glucocorticoid-Inducible Kinase 1 (SGK1) Regulates Adipocyte Differentiation via Forkhead Box O1

2010 ◽  
Vol 24 (2) ◽  
pp. 370-380 ◽  
Author(s):  
Natalia Di Pietro ◽  
Valentine Panel ◽  
Schantel Hayes ◽  
Alessia Bagattin ◽  
Sunitha Meruvu ◽  
...  
Keyword(s):  
Cellular Localization ◽  
Adipocyte Differentiation ◽  
Binding Protein ◽  
Ectopic Expression ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Peroxisome Proliferator Activated Receptor ◽  
Fatty Acid Binding ◽  
Mesenchymal Precursor Cells ◽  
And Function

Abstract The serum and glucocorticoid-inducible kinase 1 (SGK1) is an inducible kinase the physiological function of which has been characterized primarily in the kidney. Here we show that SGK1 is expressed in white adipose tissue and that its levels are induced in the conversion of preadipocytes into fat cells. Adipocyte differentiation is significantly diminished via small interfering RNA inhibition of endogenous SGK1 expression, whereas ectopic expression of SGK1 in mesenchymal precursor cells promotes adipogenesis. The SGK1-mediated phenotypic effects on differentiation parallel changes in the mRNA levels for critical regulators and markers of adipogenesis, such as peroxisome proliferator-activated receptor γ, CCAAT enhancer binding protein α, and fatty acid binding protein aP2. We demonstrate that SGK1 affects differentiation by direct phosphorylation of Foxo1, thereby changing its cellular localization from the nucleus to the cytosol. In addition we show that SGK1−/− cells are unable to relocalize Foxo1 to the cytosol in response to dexamethasone. Together these results show that SGK1 influences adipocyte differentiation by regulating Foxo1 phosphorylation and reveal a potentially important function for this kinase in the control of fat mass and function.

scholarly journals Expression and regulation of sterol 27-hydroxylase (CYP27A1) in human macrophages: a role for RXR and PPARγ ligands

2005 ◽  
Vol 385 (3) ◽  
pp. 823-830 ◽  
Author(s):  
Carmel M. QUINN ◽  
Wendy JESSUP ◽  
Jenny WONG ◽  
Leonard KRITHARIDES ◽  
Andrew J. BROWN
Keyword(s):  
Human Monocyte ◽  
Cell Types ◽  
Human Macrophage ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Macrophage Cell ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Levels ◽  
Cholesterol Levels ◽  
Elimination Pathway

CYP27A1 (sterol 27-hydroxylase) catalyses an important sterol elimination pathway in the human macrophage, and consequently may protect against atherosclerosis. We studied the expression and regulation of CYP27A1 in a human macrophage-like cell-line, THP-1, and primary HMDMs (human monocyte-derived macrophages). In both macrophage cell types, we found that CYP27A1 expression is independent of cellular cholesterol levels and of LXR (liver X receptor)-dependent control of transcription. However, the RXR (retinoid X receptor) ligand, 9-cis-retinoic acid, upregulates CYP27A1 expression. Of the RXR heterodimeric partners tested, PPAR (peroxisome-proliferator-activated receptor) γ ligands significantly increased CYP27A1 mRNA levels. Its reversal by a PPARγ antagonist demonstrated the specificity of this effect. Interestingly, HMDMs express markedly higher levels of CYP27A1 than THP-1 macrophages, and this difference was reflected in both protein levels and enzyme activities between the two cell types. In conclusion, stimulation of CYP27A1 by PPARγ may represent a key previously unrecognized mechanism by which PPARγ protects against atherosclerosis.

scholarly journals Protective Effects of Salidroside on Mitochondrial Functions against Exertional Heat Stroke-Induced Organ Damage in the Rat

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Wei Zhang ◽  
Ming Peng ◽  
Yang Yang ◽  
Zhangwu Xiao ◽  
Bin Song ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Multiorgan Failure ◽  
Heat Stroke ◽  
Organ Damage ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Protective Effects ◽  
Exertional Heat Stroke ◽  
Peroxisome Proliferator Activated Receptor ◽  
Mitochondrial Functions

Exertional heat stroke (EHS) results in a constellation of systemic inflammatory responses resulting in multiorgan failure and an extremely high mortality. The present study was designed to evaluate the protective effects of salidroside on EHS by improving mitochondrial functions in the rat model. Liver and heart mitochondria were observed by transmission electron microscopy and mitochondrial membrane potential (ΔΨm) was detected by a fluorescent probe. Intramitochondrial free Ca2+concentration, mitochondrial respiratory control ratio (RCR), reactive oxygen species (ROS) levels, superoxide dismutase (SOD), and malondialdehyde (MDA) activity were detected by the corresponding kits. RT-PCR was performed to estimate peroxisome proliferator-activated receptor-γcoactivator-1α(PGC-1α) and manganese form of SOD (MnSOD) mRNA expression. The results demonstrated that salidroside was able to relieve EHS damage by reducing the swelling of mitochondria, ROS levels, and MDA activity, as well as increasing ΔΨm, RCR, free Ca2+concentration, SOD, PGC-1α, and MnSOD mRNA levels. In conclusion, salidroside has protective effects on mitochondrial functions against exertional heat stroke-induced organ damage in the rat.

scholarly journals PPAR-gamma induced AKT3 expression increases levels of mitochondrial biogenesis driving prostate cancer

Oncogene ◽  
2021 ◽  
Vol 40 (13) ◽  
pp. 2355-2366
Author(s):  
Laura C. A. Galbraith ◽  
Ernest Mui ◽  
Colin Nixon ◽  
Ann Hedley ◽  
David Strachan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Mitochondrial Biogenesis ◽  
Nuclear Export ◽  
Epithelial To Mesenchymal Transition ◽  
Ppar Gamma ◽  
Peroxisome Proliferator ◽  
Serine Threonine Kinase ◽  
Peroxisome Proliferator Activated Receptor ◽  
Mesenchymal Transition ◽  
And Function

AbstractPeroxisome Proliferator-Activated Receptor Gamma (PPARG) is one of the three members of the PPAR family of transcription factors. Besides its roles in adipocyte differentiation and lipid metabolism, we recently demonstrated an association between PPARG and metastasis in prostate cancer. In this study a functional effect of PPARG on AKT serine/threonine kinase 3 (AKT3), which ultimately results in a more aggressive disease phenotype was identified. AKT3 has previously been shown to regulate PPARG co-activator 1 alpha (PGC1α) localisation and function through its action on chromosome maintenance region 1 (CRM1). AKT3 promotes PGC1α localisation to the nucleus through its inhibitory effects on CRM1, a known nuclear export protein. Collectively our results demonstrate how PPARG over-expression drives an increase in AKT3 levels, which in turn has the downstream effect of increasing PGC1α localisation within the nucleus, driving mitochondrial biogenesis. Furthermore, this increase in mitochondrial mass provides higher energetic output in the form of elevated ATP levels which may fuel the progression of the tumour cell through epithelial to mesenchymal transition (EMT) and ultimately metastasis.

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