Resveratrol restores intracellular transport in cystic fibrosis epithelial cells

We have demonstrated previously that intracellular transport is impaired in cystic fibrosis (CF) epithelial cells. This impairment is related to both growth and inflammatory regulation in CF cell and animal models. Understanding how transport in CF cells is regulated and identifying means to manipulate that regulation are key to identifying new therapies that can address key CF phenotypes. It was hypothesized that resveratrol could replicate these benefits since it interfaces with multiple pathways identified to affect microtubule regulation in CF. It was found that resveratrol treatment significantly restored intracellular transport as determined by monitoring both cholesterol distribution and the distribution of rab7-positive organelles in CF cells. This restoration of intracellular transport is due to correction of both microtubule formation rates and microtubule acetylation in cultured CF cell models and primary nasal epithelial cells. Mechanistically, the effect of resveratrol on microtubule regulation and intracellular transport was dependent on peroxisome proliferator-activated receptor-γ signaling and its ability to act as a pan-histone deacetylase (HDAC) inhibitor. Resveratrol represents a candidate compound with known anti-inflammatory properties that can restore both microtubule formation and acetylation in CF epithelial cells.

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Peroxisome proliferator-activated receptor-γ in cystic fibrosis lung epithelium

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.90276.2008 ◽

2008 ◽

Vol 295 (2) ◽

pp. L303-L313 ◽

Cited By ~ 38

Author(s):

Aura Perez ◽

Anna M. van Heeckeren ◽

David Nichols ◽

Sanhita Gupta ◽

Jean F. Eastman ◽

...

Keyword(s):

Cystic Fibrosis ◽

Epithelial Cells ◽

Acute Infection ◽

Airway Epithelial Cells ◽

Peroxisome Proliferator ◽

Airway Epithelial ◽

Peroxisome Proliferator Activated Receptor ◽

Pparγ Agonists

The pathophysiology of cystic fibrosis (CF) inflammatory lung disease is not well understood. CF airway epithelial cells respond to inflammatory stimuli with increased production of proinflammatory cytokines as a result of increased NF-κB activation. Peroxisome proliferator-activated receptor-γ (PPARγ) inhibits NF-κB activity and is reported to be reduced in CF. If PPARγ participates in regulatory dysfunction in the CF lung, perhaps PPARγ ligands might be useful therapeutically. Cell models of CF airway epithelium were used to evaluate PPARγ expression and binding to NF-κB at basal and under conditions of inflammatory stimulation by Pseudomonas aeruginosa or TNFα/IL-1β. An animal model of CF was used to evaluate the potential of PPARγ agonists as therapeutic agents in vivo. In vitro, PPARγ agonists reduced IL-8 and MMP-9 release from airway epithelial cells in response to PAO1 or TNFα/IL-1β stimulation. Less NF-κB bound to PPARγ in CF than normal cells, in two different assays; PPARγ agonists abrogated this reduction. PPARγ bound less to its target DNA sequence in CF cells. To test the importance of the reported PPARγ inactivation by phosphorylation, we observed that inhibitors of ERK, but not JNK, were synergistic with PPARγ agonists in reducing IL-8 secretion. In vivo, administration of PPARγ agonists reduced airway inflammation in response to acute infection with P. aeruginosa in CF, but not wild-type, mice. In summary, PPARγ inhibits the inflammatory response in CF, at least in part by interaction with NF-κB in airway epithelial cells. PPARγ agonists may be therapeutic in CF.

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WY-14 643, a Selective PPARα Agonist, Induces Proinflammatory and Proangiogenic Responses in Human Ocular Cells

International Journal of Toxicology ◽

10.1177/1091581810376674 ◽

2010 ◽

Vol 29 (5) ◽

pp. 496-504 ◽

Cited By ~ 7

Author(s):

Jin-Zhong Zhang ◽

Keith W. Ward

Keyword(s):

Epithelial Cells ◽

Inflammatory Cytokines ◽

Peroxisome Proliferator ◽

Cytokine Release ◽

Corneal Epithelial Cells ◽

Peroxisome Proliferator Activated Receptor ◽

Corneal Epithelial ◽

Factor Α ◽

Endothelial Growth Factor ◽

Pparα Agonist

Peroxisome proliferator-activated receptor α (PPARα) agonism in ocular inflammation has not been thoroughly investigated. The objective of this investigation was to determine the effect of WY-14 643, a selective PPARα agonist, on inflammatory cytokine release in human ocular cells. Stimulation of primary human corneal epithelial cells, keratocytes, and retinal endothelial cells with 1 to 10 ng/mL interleukin 1β (IL-1β) resulted in a significant increase in numerous inflammatory cytokines, including IL-6, IL-8, and tumor necrosis factor α (TNF-α); and dexamethasone was able to significantly inhibit these effects. However, WY-14 643 did not effectively block IL-1β-induced cytokine release in ocular cells; rather, significant increases in IL-1β-induced inflammatory cytokines were observed in these cells but not in aortic smooth muscle cells. WY-14 643 also significantly upregulated vascular endothelial growth factor (VEGF) expression in corneal epithelial cells and keratocytes. These studies demonstrate for the first time that PPARα agonism may be proinflammatory and proangiogenic in a variety of ocular cells and suggest that therapeutic applications of such agents in ophthalmology may be limited.

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Retraction: Down-regulated peroxisome proliferator-activated receptor γ (PPARγ) in lung epithelial cells promotes a PPARγ agonist-reversible proinflammatory phenotype in chronic obstructive pulmonary disease (COPD).

Journal of Biological Chemistry ◽

10.1074/jbc.rx118.007042 ◽

2019 ◽

Vol 294 (1) ◽

pp. 69-69 ◽

Cited By ~ 1

Author(s):

Sowmya P. Lakshmi ◽

Aravind T. Reddy ◽

Yingze Zhang ◽

Frank C. Sciurba ◽

Rama K. Mallampalli ◽

...

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Epithelial Cells ◽

Pulmonary Disease ◽

Lung Epithelial Cells ◽

Chronic Obstructive ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Obstructive Pulmonary Disease ◽

Pparγ Agonist ◽

Lung Epithelial

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Circadian Gene PER2 Silencing Downregulates PPARG and SREBF1 and Suppresses Lipid Synthesis in Bovine Mammary Epithelial Cells

Biology ◽

10.3390/biology10121226 ◽

2021 ◽

Vol 10 (12) ◽

pp. 1226

Author(s):

Yujia Jing ◽

Yifei Chen ◽

Shan Wang ◽

Jialiang Ouyang ◽

Liangyu Hu ◽

...

Keyword(s):

Lipid Metabolism ◽

Epithelial Cells ◽

Circadian Clock ◽

Lipid Droplets ◽

Mammary Epithelial Cells ◽

Lipid Synthesis ◽

Mammary Epithelial ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Bovine Mammary Epithelial Cells

PER2, a circadian clock gene, is associated with mammary gland development and lipid synthesis in rodents, partly via regulating peroxisome proliferator-activated receptor gamma (PPARG). Whether such a type of molecular link existed in bovines was unclear. We hypothesized that PER2 was associated with lipid metabolism and regulated cell cycles and apoptosis in bovine mammary epithelial cells (BMECs). To test this hypothesis, BMECs isolated from three mid-lactation (average 110 d postpartum) cows were used. The transient transfection of small interfering RNA (siRNA) was used to inhibit PER2 transcription in primary BMECs. The silencing of PER2 led to lower concentrations of cellular lipid droplets and triacylglycerol along with the downregulation of lipogenic-related genes such as ACACA, FASN, LPIN1, and SCD, suggesting an overall inhibition of lipogenesis and desaturation. The downregulation of PPARG and SREBF1 in response to PER2 silencing underscored the importance of circadian clock signaling and the transcriptional regulation of lipogenesis. Although the proliferation of BMECs was not influenced by PER2 silencing, the number of cells in the G2/GM phase was upregulated. PER2 silencing did not affect cell apoptosis. Overall, the data provided evidence that PER2 participated in the coordination of mammary lipid metabolism and was potentially a component of the control of lipid droplets and TAG synthesis in ruminant mammary cells. The present data suggested that such an effect could occur through direct effects on transcriptional regulators.

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