1,721,758 research outputs found
Effects of WY-14643 on Peroxisomal Enzyme Activity and Hormone Secretion in Immortalized Human Trophoblast Cells
Get PDFIn our previous report, clofibric acid increased both the enzyme activities of peroxisomes (catalase and fatty acyl-CoA oxidase) and the secretion of progesterone in immortalized human extravillous trophoblast cells (TCL-1) (F. Hashimoto et al., Biochem. Pharm., 68, 313 (2004)). WY-14643 is reported to be stronger inducer of peroxisomes in rodents than clofibric acid. Therefore, the effects of WY-14643 on the activities of peroxisomal enzymes and hormone secretion in TCL-1 were studied. After incubation for 3 d with WY-14643, WY-14643 (≧0.15 mM) suppressed the rate of increase in DNA and protein. The specific activities of catalase were increased by 0.1 mM WY-14643. The specific activities of fatty acyl-CoA oxidase were hardly changed by WY-14643. The concentration of progesterone in the medium was increased by 0.1 mM WY-14643, but human chorionic gonadotropin was decreased by 0.2 mM WY-14643. After a discontinuous Nycodenz-density gradient centrifugation of the light mitochondrial fraction of the cells, catalase activity was distributed in lower density fractions than cytochrome-c oxidase (a mitochondria marker enzyme) activity, but the distribution was not changed by WY-14643. These results suggest that WY-14643 inhibits the proliferation of trophoblast cells. The density of peroxisomes in human trophoblast cells is lower than that of mitochondria, and it is not affected by WY-14643. WY-14643 may increase the progesterone secretion. Effects of WY-14643 on metabolism of human trophoblast cells are different from those of clofibric acid
WY-14643 Regulates CYP1B1 Expression through Peroxisome Proliferator-Activated Receptor α-Mediated Signaling in Human Breast Cancer Cells
No full textHuman cytochrome P450 1B1 (CYP1B1)-mediated biotransformation of endobiotics and xenobiotics plays an important role in the progression of human breast cancer. In this study, we investigated the effects of WY-14643, a peroxisome proliferator-activated receptor α (PPARα) agonist, on CYP1B1 expression and the related mechanism in MCF7 breast cancer cells. We performed quantitative reverse transcription-polymerase chain reaction, transient transfection, and chromatin immunoprecipitation to evaluate the effects of PPARα on peroxisome proliferator response element (PPRE)-mediated transcription. WY-14643 increased the protein and mRNA levels of CYP1B1, as well as promoter activity, in MCF-7 cells. Moreover, WY-14643 plus GW6471, a PPARα antagonist, significantly inhibited the WY-14643-mediated increase in CYP1B1 expression. PPARα knockdown by a small interfering RNA markedly suppressed the induction of CYP1B1 expression by WY-14643, suggesting that WY-14643 induces CYP1B1 expression via a PPARα-dependent mechanism. Bioinformatics analysis identified putative PPREs (−833/−813) within the promoter region of the CYP1B1 gene. Inactivation of these putative PPREs by deletion mutagenesis suppressed the WY-14643-mediated induction of CYP1B1 promoter activation. Furthermore, WY-14643 induced PPARα to assume a form capable of binding specifically to the PPRE-binding site in the CYP1B1 promoter. Our findings suggest that WY-14643 induces the expression of CYP1B1 through activation of PPARα
Multifaceted Mechanisms of WY-14643 to Stabilize the Blood-Brain Barrier in a Model of Traumatic Brain Injury
Get PDFThe blood-brain barrier (BBB) is damaged during ischemic insults such as traumatic brain injury or stroke. This contributes to vasogenic edema formation and deteriorate disease outcomes. Enormous efforts are pursued to understand underlying mechanisms of ischemic insults and develop novel therapeutic strategies. In the present study the effects of PPARα agonist WY-14643 were investigated to prevent BBB breakdown and reduce edema formation. WY-14643 inhibited barrier damage in a mouse BBB in vitro model of traumatic brain injury based on oxygen/glucose deprivation in a concentration dependent manner. This was linked to changes of the localization of tight junction proteins. Furthermore, WY-14643 altered phosphorylation of kinases ERK1/2, p38, and SAPK/JNK and was able to inhibit proteosomal activity. Moreover, addition of WY-14643 upregulated PAI-1 leading to decreased t-PA activity. Mouse in vivo experiments showed significantly decreased edema formation in a controlled cortical impact model of traumatic brain injury after WY-14643 application, which was not found in PAI-1 knockout mice. Generally, data suggested that WY-14643 induced cellular responses which were dependent as well as independent from PPARα mediated transcription. In conclusion, novel mechanisms of a PPARα agonist were elucidated to attenuate BBB breakdown during traumatic brain injury in vitro
PPARα Agonist WY-14643 Relieves Neuropathic Pain through SIRT1-Mediated Deacetylation of NF-κB
No full textInflammation caused by neuropathy contributes to the development of neuropathic pain (NP), but the exact mechanism still needs to be understood. Peroxisome proliferator-activated receptor α (PPARα), an important inflammation regulator, might participate in the inflammation in NP. To explore the role of PPARα in NP, the effects of PPARα agonist WY-14643 on chronic constriction injury (CCI) rats were evaluated. The results showed that WY-14643 stimulation could decrease inflammation and relieve neuropathic pain, which was relative with the activation of PPARα. In addition, we also found that the SIRT1/NF-κB pathway was involved in the WY-14643-induced anti-inflammation in NP, and activation of PPARα increased SIRT1 expression, thus reducing the proinflammatory function of NF-κB. These data suggested that WY-14643 might serve as an inflammation mediator, which may be a potential therapy option for NP
PPARα Agonist WY-14643 Induces SIRT1 Activity in Rat Fatty Liver Ischemia-Reperfusion Injury
Get PDFIschemia-reperfusion injury (IRI) remains a frequent complication in surgery, especially in case of steatotic livers that present decreased tolerance towards IRI. Apart from its major role in metabolism, activation of peroxisome proliferator-activated receptor α (PPARα) has been related with positive effects on IRI. In addition, the deacetylase enzyme sirtuin 1 (SIRT1) has recently emerged as a promising target for preventing IRI, through its interaction with stress-related mechanisms, such as endoplasmic reticulum stress (ERS). Taking this into account, this study aims to explore whether PPARα agonist WY-14643 could protect steatotic livers against IRI through sirtuins and ERS signaling pathway. Obese Zucker rats were pretreated or not pretreated with WY-14643 (10 mg/kg intravenously) and then submitted to partial (70%) hepatic ischemia (1 hour) followed by 24 hours of reperfusion. Liver injury (ALT levels), lipid peroxidation (MDA), SIRT1 activity, and the protein expression of SIRT1 and SIRT3 and ERS parameters (IRE1α, peIF2, caspase 12, and CHOP) were evaluated. Treatment with WY-14643 reduced liver injury in fatty livers, enhanced SIRT1 activity, and prevented ERS. Together, our results indicated that PPARα agonist WY-14643 may exert its protective effect in fatty livers, at least in part, via SIRT1 induction and ERS prevention.Fellowship from AGAUR (2012FI B00382), Generalitat de Catalunya, Barcelona, Catalonia, Spain. Fondo de Investigaciones Sanitarias (FIS PI12/00519
PPAR α Agonist WY-14643 Induces SIRT1 Activity in Rat Fatty Liver Ischemia-Reperfusion Injury
No full textIschemia-reperfusion injury (IRI) remains a frequent complication in surgery, especially in case of steatotic livers that present decreased tolerance towards IRI. Apart from its major role in metabolism, activation of peroxisome proliferator-activated receptor α (PPARα) has been related with positive effects on IRI. In addition, the deacetylase enzyme sirtuin 1 (SIRT1) has recently emerged as a promising target for preventing IRI, through its interaction with stress-related mechanisms, such as endoplasmic reticulum stress (ERS). Taking this into account, this study aims to explore whether PPARα agonist WY-14643 could protect steatotic livers against IRI through sirtuins and ERS signaling pathway. Obese Zucker rats were pretreated or not pretreated with WY-14643 (10 mg/kg intravenously) and then submitted to partial (70%) hepatic ischemia (1 hour) followed by 24 hours of reperfusion. Liver injury (ALT levels), lipid peroxidation (MDA), SIRT1 activity, and the protein expression of SIRT1 and SIRT3 and ERS parameters (IRE1α, peIF2, caspase 12, and CHOP) were evaluated. Treatment with WY-14643 reduced liver injury in fatty livers, enhanced SIRT1 activity, and prevented ERS. Together, our results indicated that PPARα agonist WY-14643 may exert its protective effect in fatty livers, at least in part, via SIRT1 induction and ERS prevention.Eirini Pantazi thanks the fellowship from AGAUR (2012FI_B00382), Generalitat de Catalunya, Barcelona, Catalonia, Spain. The authors would like to thank the Fondo de Investigaciones Sanitarias (FIS PI12/00519) for the economic support.Peer Reviewe
Effect of intraperitoneally (IP) injected Wy-14643 on food intake.
No full text<p>(<b>A</b>) IP injected Wy-14643 (10, 20, 40 or 80 mg/kg/ml) dose-dependently reduced cumulative food intake (FI) in ad libitum HFD-fed rats (n=23). * Less than vehicle (<i>P</i> < 0.05), ** less than vehicle (<i>P</i> < 0.01), Mann-Whitney U test. (<b>B</b>) IP administered Wy-14643 (40 mg/kg/ml, n=10) did not reduce saccharin solution intake (% of total fluid intake) vs. water in a two-bottle preference test, whereas LiCl (60 mg/kg in 9.4 ml/kg H<sub>2</sub>O, n = 3) did. The height of each bar represents the median and the top and bottom of each bar shows 75th and 25th percentile respectively. * Significantly different from vehicle (<i>P</i> = 0.05).</p
Effect of intraperitoneally (IP) injected Wy-14643 on meal pattern.
No full text<p>IP administered Wy-14643 (40 mg/kg/ml) on meal patterns in ad libitum HFD-fed rats (n = 23). Wy-14643 increased the latency of the first meal (<b>A</b>) and decreased the second meal size (<b>E</b>), but did not significantly affect first meal size and duration (<b>B</b>, <b>C</b>), intermeal interval (<b>D</b>) and second meal duration (<b>F</b>). Data for first meal size are presented as median with percentiles and were analyzed with Wilcoxon Signed Ranks Test. Results for the other parameters (latency to eat, first meal duration, second meal size and duration) are presented as means ± SEM and were analyzed using a paired <i>t</i>-test. ** Significant difference (<i>P</i> < 0.01) compared to vehicle.</p
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