scholarly journals Regulation of Epigenetic Modifications in the Placenta During Preeclampsia: PPARγ Influences H3K4me3 and H3K9ac in Extravillous Trophoblast Cells

2021 ◽  
Vol 22 (22) ◽  
pp. 12469
Author(s):  
Sarah Meister ◽  
Laura Hahn ◽  
Susanne Beyer ◽  
Corinna Paul ◽  
Sophie Mitter ◽  
...  
Keyword(s):  
Histone Modifications ◽  
Histone H3 ◽  
Extravillous Trophoblast ◽  
Trophoblast Invasion ◽  
Peroxisome Proliferator ◽  
Trophoblast Cells ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pparγ Agonist ◽  
Villous Trophoblast

The aim of this study was to analyze the expression of peroxisome proliferator-activated receptor γ (PPARγ) and retinoid X receptor α (RxRα), a binding heterodimer playing a pivotal role in the successful trophoblast invasion, in the placental tissue of preeclamptic patients. Furthermore, we aimed to characterize a possible interaction between PPARγ and H3K4me3 (trimethylated lysine 4 of the histone H3), respectively H3K9ac (acetylated lysine 9 of the histone H3), to illuminate the role of histone modifications in a defective trophoblast invasion in preeclampsia (PE). Therefore, the expression of PPARγ and RxRα was analyzed in 26 PE and 25 control placentas by immunohistochemical peroxidase staining, as well as the co-expression with H3K4me3 and H3K9ac by double immunofluorescence staining. Further, the effect of a specific PPARγ-agonist (Ciglitazone) and PPARγ-antagonist (T0070907) on the histone modifications H3K9ac and H3K4me3 was analyzed in vitro. In PE placentas, we found a reduced expression of PPARγ and RxRα and a reduced co-expression with H3K4me3 and H3K9ac in the extravillous trophoblast (EVT). Furthermore, with the PPARγ-antagonist treated human villous trophoblast (HVT) cells and primary isolated EVT cells showed higher levels of the histone modification proteins whereas treatment with the PPARγ-agonist reduced respective histone modifications. Our results show that the stimulation of PPARγ-activity leads to a reduction of H3K4me3 and H3K9ac in trophoblast cells, but paradoxically decreases the nuclear PPARγ expression. As the importance of PPARγ, being involved in a successful trophoblast invasion has already been investigated, our results reveal a pathophysiologic connection between PPARγ and the epigenetic modulation via H3K4me3 and H3K9ac in PE.

scholarly journals Human Chorionic Gonadotropin Produced by the Invasive Trophoblast But Not the Villous Trophoblast Promotes Cell Invasion and Is Down-Regulated by Peroxisome Proliferator-Activated Receptor-γ

Endocrinology ◽  
2007 ◽  
Vol 148 (10) ◽  
pp. 5011-5019 ◽  
Author(s):  
Karen Handschuh ◽  
Jean Guibourdenche ◽  
Vassilis Tsatsaris ◽  
Mickaël Guesnon ◽  
Ingrid Laurendeau ◽  
...  
Keyword(s):  
Chorionic Gonadotropin ◽  
Cell Invasion ◽  
Human Chorionic Gonadotropin ◽  
Primary Cultures ◽  
Trophoblast Invasion ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
Villous Trophoblast

A critical step in the establishment of human pregnancy is the invasion of the uterus wall by extravillous cytotrophoblasts (EVCTs) during the first trimester. It is well established that human chorionic gonadotropin hormone (hCG) is secreted by the endocrine syncytiotrophoblast (ST) into the maternal compartment. We recently reported that invasive EVCTs also produce hCG, suggesting an autocrine role in the modulation of trophoblast invasion. Here we analyzed the role of hCG secreted in vitro by primary cultures of invasive EVCT and noninvasive ST. We first demonstrated that LH/CG receptor was present in EVCTs in situ and in vitro as well as in an EVCT cell line (HIPEC65). We next showed that hCG secreted by EVCTs stimulated progesterone secretion by MA10 cells in a concentration-dependent manner. Incubation of HIPEC65 with EVCT supernatants induced a 10-fold increase in cell invasion, whereas ST supernatants had no effect. This stimulating effect was strongly decreased when hCG was depleted from EVCT supernatants containing a large amount of the hyperglycosylated form of hCG, which is almost undetectable in ST supernatants. Finally, we investigated the regulation of hCG expression by peroxisome proliferator-activated receptor (PPAR)-γ, a nuclear receptor shown to inhibit trophoblast invasion. Activation of PPARγ decreased α- and β-subunit transcript levels and total hCG secretion in primary EVCTs. Our results offer the first evidence that hCG secreted by the invasive trophoblast, likely the hyperglycosylated form of hCG, but not by the syncytiotrophoblast, promotes trophoblast invasion and may be a PPARγ target gene in trophoblast invasion process.

In vitro interaction between resistin and peroxisome proliferator-activated receptor γ in porcine ovarian follicles

2016 ◽  
Vol 28 (3) ◽  
pp. 357 ◽  
Author(s):  
Agnieszka Rak-Mardyła ◽  
Eliza Drwal
Keyword(s):  
Protein Expression ◽  
Ovarian Follicle ◽  
Hormone Secretion ◽  
Ovarian Follicles ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pparγ Agonist ◽  
Mrna And Protein Expression ◽  
Pparγ Expression

In the present study, using real-time polymerase chain reaction and immunoblotting methods, we quantified the expression of peroxisome proliferator-activated receptor (PPAR) γ, PPARα and PPARβ in different sized ovarian follicles (small (SF), medium (MF) and large (LF) follicles) in prepubertal and adult pigs. In prepubertal pigs, PPARγ and PPARα expression was highest in LF; however, PPARβ expression did not differ among SF, MF and LF. In mature pigs, only protein expression of PPARγ and PPARα increased during ovarian follicle development. Following identification of very high levels of PPARγ expression in LF in prepubertal and adult pigs, using in vitro culture of ovarian follicles, we determined the effect of resistin at 0.1, 1 and 10 ng mL–1 on PPARγ mRNA and protein expression and the effect of rosiglitazone at 25 and 50 µM (a PPARγ agonist) on resistin mRNA and protein expression. Resistin increased PPARγ expression in ovarian follicles in both prepubertal and adult pigs, whereas rosiglitazone had an inhibitory effect on resistin expression. The role of PPARγ in regulating the effects of resistin on ovarian steroidogenesis was investigated using GW9662 (a PPARγ antagonist at dose of 1 μM). In these studies, GW9662 reversed the effect of resistin on steroid hormone secretion. The data suggest that there is local cooperation between resistin and PPARγ expression in the porcine ovary. Resistin significantly increased the expression of PPARγ, whereas PPARγ decreased resistin expression; thus, PPARγ is a new key regulator of resistin expression and function.

scholarly journals PPARγ Regulates Triclosan Induced Placental Dysfunction

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 86
Author(s):  
Jing Li ◽  
Xiaojie Quan ◽  
Yue Zhang ◽  
Ting Yu ◽  
Saifei Lei ◽  
...  
Keyword(s):  
Cell Viability ◽  
Opposite Effect ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Placental Dysfunction ◽  
Promising Strategy ◽  
Pparγ Agonist ◽  
Tnf Α

Exposure to the antibacterial agent triclosan (TCS) is associated with abnormal placenta growth and fetal development during pregnancy. Peroxisome proliferator-activated receptor γ (PPARγ) is crucial in placenta development. However, the mechanism of PPARγ in placenta injury induced by TCS remains unknown. Herein, we demonstrated that PPARγ worked as a protector against TCS-induced toxicity. TCS inhibited cell viability, migration, and angiogenesis dose-dependently in HTR-8/SVneo and JEG-3 cells. Furthermore, TCS downregulated expression of PPARγ and its downstream viability, migration, angiogenesis-related genes HMOX1, ANGPTL4, VEGFA, MMP-2, MMP-9, and upregulated inflammatory genes p65, IL-6, IL-1β, and TNF-α in vitro and in vivo. Further investigation showed that overexpression or activation (rosiglitazone) alleviated cell viability, migration, angiogenesis inhibition, and inflammatory response caused by TCS, while knockdown or inhibition (GW9662) of PPARγ had the opposite effect. Moreover, TCS caused placenta dysfunction characterized by the significant decrease in weight and size of the placenta and fetus, while PPARγ agonist rosiglitazone alleviated this damage in mice. Taken together, our results illustrated that TCS-induced placenta dysfunction, which was mediated by the PPARγ pathway. Our findings reveal that activation of PPARγ might be a promising strategy against the adverse effects of TCS exposure on the placenta and fetus.

The Effect of the Immunosuppressant Drug, Tacrolimus, on Nitric Oxide Production in the Immortalized First Trimester Extra-Villous Trophoblast Cells

2020 ◽  
Author(s):  
Kassandra Coyle
Keyword(s):  
Mode Of Action ◽  
Low Dose ◽  
Normal Growth ◽  
First Trimester ◽  
Suppressive Effect ◽  
Trophoblast Invasion ◽  
Spiral Artery ◽  
Trophoblast Cells ◽  
Villous Trophoblast

The remodeling of uterine spiral arteries and subsequent placental formation are crucial for normal growth and development of the fetus. These processes are heavily dependent on the functioning of the extra-villous trophoblast cells and their ability to invade into the maternal decidual blood vessels. Reduced trophoblast invasion and shallow spiral artery remodeling can lead to a number of gestational complications including intrauterine growth restriction (IUGR). Therapeutic intervention with low dose immunosuppressant tacrolimus was able to prevent implantation failure and IUGR in obese and diabetic mice. Treatment with tacrolimus successfully aided in spiral artery modification that was conducive to a successful pregnancy. Further, tacrolimus has shown promise in restoring trophoblast cell functioning in the immortalized first trimester HTR8/SVneo extra-villous trophoblast cells cultured under preeclampsia-like conditions in vitro. However, the mode of action of tacrolimus has yet to be elucidated. Here we attempt to uncover the mode of action of tacrolimus by examining its effects on eNOS activity within the trophoblast cells. Cells were treated with tacrolimus (10 ng/mL), L-NAME (40 nM/mL) or a combination of both and subjected to analysis by several functional assays. The data obtained in this study is suggesting that L-NAME treatment has inhibitory effects on the levels of the pPGR, pSTAT3 and NO within the HTR8/SVneo cells. The use of low-dose tacrolimus abrogated the suppressive effect of L-NAME and restored the levels of the pPGR, pSTAT3, and NO within the cells.

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.

PPARγ controls pregnancy outcome through activation of EG-VEGF: new insights into the mechanism of placental development

2015 ◽  
Vol 309 (4) ◽  
pp. E357-E369 ◽  
Author(s):  
Vanessa Garnier ◽  
Wael Traboulsi ◽  
Aude Salomon ◽  
Sophie Brouillet ◽  
Thierry Fournier ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Trophoblast Cell ◽  
Extravillous Trophoblast ◽  
Trophoblast Invasion ◽  
Migration And Invasion ◽  
Placental Development ◽  
Human Trophoblast ◽  
Pparγ Agonist

PPARγ-deficient mice die at E9.5 due to placental abnormalities. The mechanism by which this occurs is unknown. We demonstrated that the new endocrine factor EG-VEGF controls the same processes as those described for PPARγ, suggesting potential regulation of EG-VEGF by PPARγ. EG-VEGF exerts its functions via prokineticin receptor 1 (PROKR1) and 2 (PROKR2). This study sought to investigate whether EG-VEGF mediates part of PPARγ effects on placental development. Three approaches were used: 1) in vitro, using human primary isolated cytotrophoblasts and the extravillous trophoblast cell line (HTR-8/SVneo); 2) ex vivo, using human placental explants ( n = 46 placentas); and 3) in vivo, using gravid wild-type PPARγ+/− and PPARγ−/− mice. Major processes of placental development that are known to be controlled by PPARγ, such as trophoblast proliferation, migration, and invasion, were assessed in the absence or presence of PROKR1 and PROKR2 antagonists. In both human trophoblast cell and placental explants, we demonstrated that rosiglitazone, a PPARγ agonist, 1) increased EG-VEGF secretion, 2) increased EG-VEGF and its receptors mRNA and protein expression, 3) increased placental vascularization via PROKR1 and PROKR2, and 4) inhibited trophoblast migration and invasion via PROKR2. In the PPARγ−/− mouse placentas, EG-VEGF levels were significantly decreased, supporting an in vivo control of EG-VEGF/PROKRs system during pregnancy. The present data reveal EG-VEGF as a new mediator of PPARγ effects during pregnancy and bring new insights into the fine mechanism of trophoblast invasion.

Peroxisome proliferator-activated receptor γ promotes neuroprotection by modulating cyclic D1 expression after focal cerebral ischemia

2010 ◽  
Vol 88 (7) ◽  
pp. 716-723 ◽  
Author(s):  
Lichun Pei ◽  
Yanqiao Zhang ◽  
Yina Zhang ◽  
Xiaojie Chu ◽  
Jingyuan Zhang ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Cyclin D1 ◽  
Cortical Neurons ◽  
Focal Cerebral Ischemia ◽  
Substantial Contribution ◽  
Cortical Region ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pparγ Agonist

Peroxisome proliferator-activated receptor γ (PPARγ) has been shown to protect against stroke and improve neurological outcome after cerebral ischemia. This study investigated whether activation of cerebral PPARγ improves recovery from focal cerebral ischemia by reducing expression of cyclin D1, which is associated with programmed neuron death. Focal cerebral ischemia was induced by 90 min of middle cerebral artery occlusion (MCAO), followed by reperfusion. Intracerebroventricular (i.c.v.) infusion of the PPARγ agonist ciglitazone, beginning 5 days before and continuing through 1 day after MCAO, reduced infarct size and cyclin D1 expression in the peri-infarct cortical region. Furthermore, primary cortical neurons treated with ciglitazone showed suppressed expression of cyclin D1 in response to hypoxia–reoxygenation. This protective effect was reversed after cotreatment with the selective PPAR-γ antagonist GW 9662 (2-chloro-5-nitrobenzanilide), clearly demonstrating the involvement of a PPARγ-dependent mechanism. Our data provide evidence that activation of neuronal PPARγ makes a substantial contribution to neuroprotection by preventing cyclin D1 up-regulation in vitro and in vivo.

scholarly journals Retinoid X Receptor Activation During Adipogenesis of Female Mesenchymal Stem Cells Programs a Dysfunctional Adipocyte

Endocrinology ◽  
2018 ◽  
Vol 159 (8) ◽  
pp. 2863-2883 ◽  
Author(s):  
Bassem M Shoucri ◽  
Victor T Hung ◽  
Raquel Chamorro-García ◽  
Toshi Shioda ◽  
Bruce Blumberg
Keyword(s):  
Endocrine Disrupting Chemicals ◽  
Receptor Activation ◽  
Retinoid X Receptor ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Obesity And Diabetes ◽  
Pparγ Agonist

Abstract Early life exposure to endocrine-disrupting chemicals (EDCs) is an emerging risk factor for the development of obesity and diabetes later in life. We previously showed that prenatal exposure to the EDC tributyltin (TBT) results in increased adiposity in the offspring. These effects linger into adulthood and are propagated through successive generations. TBT activates two nuclear receptors, the peroxisome proliferator–activated receptor (PPAR) γ and its heterodimeric partner retinoid X receptor (RXR), that promote adipogenesis in vivo and in vitro. We recently employed a mesenchymal stem cell (MSC) model to show that TBT promotes adipose lineage commitment by activating RXR, not PPARγ. This led us to consider the functional consequences of PPARγ vs RXR activation in developing adipocytes. We used a transcriptomal approach to characterize genome-wide differences in MSCs differentiated with the PPARγ agonist rosiglitazone (ROSI) or TBT. Pathway analysis suggested functional deficits in TBT-treated cells. We then compared adipocytes differentiated with ROSI, TBT, or a pure RXR agonist IRX4204 (4204). Our data show that RXR activators (“rexinoids,” 4204 and TBT) attenuate glucose uptake, blunt expression of the antidiabetic hormone adiponectin, and fail to downregulate proinflammatory and profibrotic transcripts, as does ROSI. Finally, 4204 and TBT treatment results in an inability to induce markers of adipocyte browning, in part due to sustained interferon signaling. Taken together, these data implicate rexinoids in the development of dysfunctional white adipose tissue that could potentially exacerbate obesity and/or diabetes risk in vivo. These data warrant further screening and characterization of EDCs that activate RXR.

scholarly journals Identification of a novel selective agonist of PPARγ with no promotion of adipogenesis and less inhibition of osteoblastogenesis

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Chang Liu ◽  
Tingting Feng ◽  
Ningyu Zhu ◽  
Peng Liu ◽  
Xiaowan Han ◽  
...  
Keyword(s):  
Side Effects ◽  
Distinct Group ◽  
Binding Mode ◽  
Peroxisome Proliferator ◽  
Molecular Compound ◽  
Site Mutation ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pparγ Agonist ◽  
A Site

Abstract Nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) plays an important role in the regulation of glucose homeostasis and lipid metabolism. However, current PPARγ-targeting drugs such as thiazolidinediones (TZDs) are associated with undesirable side effects. We identified a small molecular compound, F12016, as a selective PPARγ agonist by virtual screening, which showed moderate PPARγ agonistic activity and binding ability for PPARγ. F12016 did not activate other PPAR subtypes at 30 μM and selectively modulated PPARγ target gene expression. In diabetic KKAy mice, F12016 had insulin-sensitizing and glucose-lowering properties and suppressed weight gain. In vitro, F12016 effectively increased glucose uptake and blocked cyclin-dependent kinase 5-mediated phosphorylation of PPARγ at Ser273, but slightly triggered adipogenesis and less inhibited osteoblastogenesis than rosiglitazone. Moreover, compared with the full agonist rosiglitazone, F12016 had a distinct group of coregulators and a different predicted binding mode for the PPARγ ligand-binding domain. A site mutation assay confirmed the key epitopes, especially Tyr473 in AF-2. In summary, our study shows that F12016 is a non-TZD, novel selective PPARγ agonist without the classical lipogenic side effects, which may provide a new structural strategy for designing PPARγ ligands with advantages over TZDs.

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