Transcriptome analysis of porcine endometrium after LPS-induced inflammation: effects of the PPAR-gamma ligands in vitro†

2020 ◽  
Author(s):  
Karol Mierzejewski ◽  
Łukasz Paukszto ◽  
Aleksandra Kurzyńska ◽  
Zuzanna Kunicka ◽  
Jan Paweł Jastrzębski ◽  
...  
Keyword(s):  
Luteal Phase ◽  
Ppar Gamma ◽  
Peroxisome Proliferator ◽  
Rna Seq ◽  
Peroxisome Proliferator Activated Receptor ◽  
Genes Expression ◽  
Microbial Infections ◽  
Pparγ Agonists ◽  
Vitro Effect

Abstract Female fertility depends greatly on the capacity of the uterus to recognize and eliminate microbial infections, a major reason of inflammation in the endometrium in many species. This study aimed to determine the in vitro effect of peroxisome proliferator-activated receptor gamma (PPARγ) ligands on the transcriptome genes expression and alternative splicing in the porcine endometrium in the mid-luteal phase of the estrous cycle during LPS-stimulated inflammation using RNA-seq technology. The endometrial slices were incubated in vitro in the presence of LPS and PPARγ agonists—PGJ2 or pioglitazone and antagonist—T0070907. We identified 222, 3, 4, and 62 differentially expressed genes after LPS, PGJ2, pioglitazone, or T0070907 treatment, respectively. In addition, we detected differentially alternative spliced events: after treatment with LPS-78, PGJ2-60, pioglitazone-52, or T0070907-134. These results should become a basis for further studies explaining the mechanism of PPARγ action in the reproductive system in pigs.

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

2008 ◽  
Vol 295 (2) ◽  
pp. L303-L313 ◽  
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.

PPARγ Agonists in Combination Cancer Therapies

2020 ◽  
Vol 20 (3) ◽  
pp. 197-215
Author(s):  
Piotr Mrowka ◽  
Eliza Glodkowska-Mrowka
Keyword(s):  
Targeted Therapy ◽  
Therapeutic Potential ◽  
Pharmacological Therapy ◽  
Treatment Modalities ◽  
Peroxisome Proliferator ◽  
Tumoricidal Activity ◽  
Peroxisome Proliferator Activated Receptor ◽  
Anticancer Efficacy ◽  
Pparγ Agonists

: Peroxisome proliferator-activated receptor-gamma (PPARγ) is a nuclear receptor acting as a transcription factor involved in the regulation of energy metabolism, cell cycle, cell differentiation, and apoptosis. These unique properties constitute a strong therapeutic potential that place PPARγ agonists as one of the most interesting and widely studied anticancer molecules. : Although PPARγ agonists exert significant, antiproliferative and tumoricidal activity in vitro, their anticancer efficacy in animal models is ambiguous, and their effectiveness in clinical trials in monotherapy is unsatisfactory. However, due to pleiotropic effects of PPARγ activation in normal and tumor cells, PPARγ ligands interact with many antitumor treatment modalities and synergistically potentiate their effectiveness. The most spectacular example is a combination of PPARγ ligands with tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML). In this setting, PPARγ activation sensitizes leukemic stem cells, resistant to any previous form of treatment, to targeted therapy. Thus, this combination is believed to be the first pharmacological therapy able to cure CML patients. : Within the last decade, a significant body of data confirming the benefits of the addition of PPARγ ligands to various antitumor therapies, including chemotherapy, hormonotherapy, targeted therapy, and immunotherapy, has been published. Although the majority of these studies have been carried out in vitro or animal tumor models, a few successful attempts to introduce PPARγ ligands into anticancer therapy in humans have been recently made. In this review, we aim to summarize shines and shadows of targeting PPARγ in antitumor therapies.

scholarly journals Development of an In Vitro Screening Platform for the Identification of Partial PPARγ Agonists as a Source for Antidiabetic Lead Compounds

Molecules ◽  
2018 ◽  
Vol 23 (10) ◽  
pp. 2431 ◽  
Author(s):  
Lars Porskjær Christensen ◽  
Rime Bahij El-Houri
Keyword(s):  
Side Effects ◽  
Target Genes ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
In Silico Docking ◽  
Lead Compounds ◽  
Ppar Γ ◽  
Pparγ Agonists ◽  
Screening Platform

Type 2 diabetes (T2D) is a metabolic disorder where insulin-sensitive tissues show reduced sensitivity towards insulin and a decreased glucose uptake (GU), which leads to hyperglycaemia. Peroxisome proliferator-activated receptor (PPAR)γ plays an important role in lipid and glucose homeostasis and is one of the targets in the discovery of drugs against T2D. Activation of PPARγ by agonists leads to a conformational change in the ligand-binding domain, a process that alters the transcription of several target genes involved in glucose and lipid metabolism. Depending on the ligands, they can induce different sets of genes that depends of their recruitment of coactivators. The activation of PPARγ by full agonists such as the thiazolidinediones leads to improved insulin sensitivity but also to severe side effects probably due to their behavior as full agonists. Partial PPARγ agonists are compounds with diminished agonist efficacy compared to full agonist that may exhibit the same antidiabetic effect as full agonists without inducing the same magnitude of side effects. In this review, we describe a screening platform for the identification of partial PPARγ agonists from plant extracts that could be promising lead compounds for the development of antidiabetic drugs. The screening platform includes a series of in vitro bioassays, such as GU in adipocytes, PPARγ-mediated transactivation, adipocyte differentiation and gene expression as well as in silico docking for partial PPARγ agonism.

scholarly journals Potential role for peroxisome proliferator-activated receptor γ in regulating luteal lifespan in the rat

Reproduction ◽  
2007 ◽  
Vol 133 (1) ◽  
pp. 187-196 ◽  
Author(s):  
Nicole Tinfo ◽  
Carolyn Komar
Keyword(s):  
Corpora Lutea ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Luteal Cells ◽  
Progesterone Production ◽  
Chain Cleavage ◽  
Major Player ◽  
Luteal Tissue ◽  
Pparγ Agonists

Peroxisome proliferator-activated receptor γ (PPARγ) has been shown to stimulate progesterone production by bovine luteal cells. We previously reported higher expression of PPARγ in old compared with new luteal tissue in the rat. The following studies were conducted to determine the role of PPARγ in rat corpora lutea (CL) and test the hypothesis that PPARγ plays a role in the metabolism of progesterone and/or luteal lifespan. Ovaries were removed from naturally cycling rats throughout the estrous cycle, and pseudopregnant rats. mRNA for PPARγ and P450 side-chain cleavage (SCC) was localized in luteal tissue byin situhybridization, and protein corresponding to PPARγ and macrophages identified by immunohistochemistry. Luteal tissue was cultured with agonists (ciglitazone, prostaglandin J2) or an antagonist (GW-9662) of PPARγ. Progesterone was measured in media by RIA and levels of mRNA for 20α-hydroxysteriod dehydrogenase (HSD) and bcl-2 were measured in luteal tissue after culture by RT-PCR. An inverse relationship existed between the expression of mRNA for SCC and PPARγ. There was no effect of PPARγ agonists or the antagonist on luteal progesterone productionin vitro, or levels of mRNA for 20α-HSD. PPARγ protein was localized to the nuclei of luteal cells and did not correspond with the presence of macrophages. In new CL, ciglitazone decreased mRNA for bcl-2 on proestrus, estrus, and metestrus. Interestingly, GW-9662 also decreased mRNA for bcl-2 on proestrus and diestrus in old and new CL, and on metestrus in new CL. These data indicate that PPARγ is not a major player in luteal progesterone production or metabolism but may be involved in regulating luteal lifespan.

In Situ Localization of PPAR Gamma and Uncoupling Protein in Mouse Embryo Sections Using Digoxigenin-Labeled Riboprobes

1996 ◽  
Vol 54 ◽  
pp. 32-33
Author(s):  
C. Jennermann ◽  
S. A. Kliewer ◽  
D. C. Morris
Keyword(s):  
Alkaline Phosphatase ◽  
Room Temperature ◽  
Uncoupling Protein ◽  
Ppar Gamma ◽  
Nuclear Hormone Receptor ◽  
Full Length ◽  
Northern Analysis ◽  
Peroxisome Proliferator

Peroxisome proliferator-activated receptor gamma (PPARg) is a member of the nuclear hormone receptor superfamily and has been shown in vitro to regulate genes involved in lipid metabolism and adipocyte differentiation. By Northern analysis, we and other researchers have shown that expression of this receptor predominates in adipose tissue in adult mice, and appears first in whole-embryo mRNA at 13.5 days postconception. In situ hybridization was used to find out in which developing tissues PPARg is specifically expressed.Digoxigenin-labeled riboprobes were generated using the Genius™ 4 RNA Labeling Kit from Boehringer Mannheim. Full length PPAR gamma, obtained by PCR from mouse liver cDNA, was inserted into pBluescript SK and used as template for the transcription reaction. Probes of average size 200 base pairs were made by partial alkaline hydrolysis of the full length transcripts. The in situ hybridization assays were performed as described previously with some modifications. Frozen sections (10 μm thick) of day 18 mouse embryos were cut, fixed with 4% paraformaldehyde and acetylated with 0.25% acetic anhydride in 1.0M triethanolamine buffer. The sections were incubated for 2 hours at room temperature in pre-hybridization buffer, and were then hybridized with a probe concentration of 200μg per ml at 70° C, overnight in a humidified chamber. Following stringent washes in SSC buffers, the immunological detection steps were performed at room temperature. The alkaline phosphatase labeled, anti-digoxigenin antibody and detection buffers were purchased from Boehringer Mannheim. The sections were treated with a blocking buffer for one hour and incubated with antibody solution at a 1:5000 dilution for 2 hours, both at room temperature. Colored precipitate was formed by exposure to the alkaline phosphatase substrate nitrobluetetrazoliumchloride/ bromo-chloroindlylphosphate.

scholarly journals Adipocyte PHLPP2 inhibition prevents obesity-induced fatty liver

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
KyeongJin Kim ◽  
Jin Ku Kang ◽  
Young Hoon Jung ◽  
Sang Bae Lee ◽  
Raffaela Rametta ◽  
...  
Keyword(s):  
Fatty Liver ◽  
Whole Body ◽  
Acid Oxidation ◽  
Chow Diet ◽  
Peroxisome Proliferator ◽  
Obese Mice ◽  
Ph Domain ◽  
Peroxisome Proliferator Activated Receptor

AbstractIncreased adiposity confers risk for systemic insulin resistance and type 2 diabetes (T2D), but mechanisms underlying this pathogenic inter-organ crosstalk are incompletely understood. We find PHLPP2 (PH domain and leucine rich repeat protein phosphatase 2), recently identified as the Akt Ser473 phosphatase, to be increased in adipocytes from obese mice. To identify the functional consequence of increased adipocyte PHLPP2 in obese mice, we generated adipocyte-specific PHLPP2 knockout (A-PHLPP2) mice. A-PHLPP2 mice show normal adiposity and glucose metabolism when fed a normal chow diet, but reduced adiposity and improved whole-body glucose tolerance as compared to Cre- controls with high-fat diet (HFD) feeding. Notably, HFD-fed A-PHLPP2 mice show increased HSL phosphorylation, leading to increased lipolysis in vitro and in vivo. Mobilized adipocyte fatty acids are oxidized, leading to increased peroxisome proliferator-activated receptor alpha (PPARα)-dependent adiponectin secretion, which in turn increases hepatic fatty acid oxidation to ameliorate obesity-induced fatty liver. Consistently, adipose PHLPP2 expression is negatively correlated with serum adiponectin levels in obese humans. Overall, these data implicate an adipocyte PHLPP2-HSL-PPARα signaling axis to regulate systemic glucose and lipid homeostasis, and suggest that excess adipocyte PHLPP2 explains decreased adiponectin secretion and downstream metabolic consequence in obesity.

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