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 Targeting the EZH2-PPAR Axis Is a Potential Therapeutic Pathway for Pancreatic Cancer

PPAR Research ◽  
2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Jilong Hu ◽  
Zhinan Zheng ◽  
Jia Lei ◽  
Yuxin Cao ◽  
Qiyun Li ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cyclin D1 ◽  
Caspase 3 ◽  
Synergistic Effects ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Agonist ◽  
Combined Use

Enhancer of zeste homolog 2 (EZH2) is abnormally highly expressed in pancreatic cancer (PC). However, it is not ideal to treat PC by inhibiting EZH2. This study reported that the combined use of pan-peroxisome proliferator-activated receptor (PPAR) agonist could significantly improve the anti-PC effect of EZH2 inhibitor. In vitro, PC cell lines PANC-1 and AsPC-1 were cultured, and MTT and flow cytometry were performed to observe the effects of pan-PPAR agonist bezafibrate and EZH2 selective inhibitor GSK126 on cell viability and apoptosis. In vivo, CDXs of PANC-1 and AsPC-1 were established to observe the effects of bezafibrate and GSK126 on bearing tumors. Western blotting was performed to detect the protein expressions of H3K27me3, β-catenin, p-β-catenin, cyclin D1, c-Myc, and cleaved caspase 3 in vitro and in vivo. The results showed that bezafibrate significantly improved the effects of GSK126 on proliferation inhibition and apoptosis promotion in vitro and the growth suppression of CDX tumors in vivo. It also significantly enhanced the effects of GSK126 on upregulating the expression level of p-β-catenin and that of cleaved caspase 3 in vitro and in vivo. In parallel, downregulation of the expression levels of H3K27me3, β-catenin, cyclin D1, and c-Myc was also observed in vitro or in vivo. These results suggest that the combination of bezafibrate and GSK126 has synergistic effects on PC, and the molecular mechanism may be related to the enhanced inhibition of the Wnt/β-catenin signaling pathway. We believe that targeting the EZH2-PPAR axis is a potential therapeutic pathway for PC.

scholarly journals Altered Biosynthesis of Neuropeptide Processing Enzyme Carboxypeptidase E after Brain Ischemia: Molecular Mechanism and Implication

2004 ◽  
Vol 24 (6) ◽  
pp. 612-622 ◽  
Author(s):  
An Zhou ◽  
Manabu Minami ◽  
Xiaoman Zhu ◽  
Sylvia Bae ◽  
John Minthorne ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Brain Ischemia ◽  
Cortical Neurons ◽  
Focal Cerebral Ischemia ◽  
Proteolytic Processing ◽  
Carboxypeptidase E ◽  
Processing Enzyme ◽  
The Impact

In this study, using both in vivo and in vitro ischemia models, the authors investigated the impact of brain ischemia on the biosynthesis of a key neuropeptide-processing enzyme, carboxypeptidase E (CPE). The response to brain ischemia of animals that lacked an active CPE was also examined. Combined in situ hybridization and immunocytochemical analyses for CPE showed reciprocal changes of CPE mRNA and protein, respectively, in the same cortical cells in rat brains after focal cerebral ischemia. Western blot analysis revealed an accumulation of the precursor protein of CPE in the ischemic cortex in vivo and in ischemic cortical neurons in vitro. Detailed metabolic labeling experiments on ischemic cortical neurons showed that ischemic stress caused a blockade in the proteolytic processing of CPE. When mice lacking an active CPE protease were subjected to a sublethal episode of focal cerebral ischemia, abundant TUNEL-positive cells were seen in the ischemic cortex whereas only a few were seen in the cortex of wild-type animals. These findings suggest that ischemia has an adverse impact on the neuropeptide-processing system in the brain and that the lack of an active neuropeptide-processing enzyme exacerbates ischemic brain injury.

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.

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.

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.

Peroxisome proliferator-activated receptor-γ-agonist, rosiglitazone, promotes angiogenesis after focal cerebral ischemia

2006 ◽  
Vol 1093 (1) ◽  
pp. 208-218 ◽  
Author(s):  
Kon Chu ◽  
Soon-Tae Lee ◽  
Ja-Seong Koo ◽  
Keun-Hwa Jung ◽  
Eun-Hee Kim ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Focal Cerebral Ischemia ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor
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