scholarly journals Neuroprotective Properties of a Novel Non-Thiazoledinedione Partial PPAR-γAgonist against MPTP

PPAR Research ◽  
2013 ◽  
Vol 2013 ◽  
pp. 1-16 ◽  
Author(s):  
Christine R. Swanson ◽  
Eric Du ◽  
Delinda A. Johnson ◽  
Jeffrey A. Johnson ◽  
Marina E. Emborg
Keyword(s):  
Antioxidant Response ◽  
Mechanisms Of Action ◽  
Peroxisome Proliferator ◽  
Placental Alkaline Phosphatase ◽  
Peroxisome Proliferator Activated Receptor ◽  
Reporter Mice ◽  
Neuroprotective Strategy ◽  
Human Placental Alkaline Phosphatase ◽  
Neuroprotective Treatment ◽  
Dose Dependent

Activation of the peroxisome proliferator activated receptor-gamma (PPAR)-γis proposed as a neuroprotective strategy to treat neurodegenerative disorders. In this study, we examined if LSN862 (LSN), a novel non-thiazoledinedione partial PPAR-γagonist, was neuroprotective in a mouse model of Parkinson’s disease (PD) and assessed possible mechanisms of action. LSN (3, 10, or 30 mg/kg) or vehicle was orally administered daily to C57BL/6 and antioxidant response element-human placental alkaline phosphatase (ARE-hPAP) reporter mice 3 days prior to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 30 mg/kg, i.p. ×  5 days) or PBS administration. LSN elicited a dose-dependent preservation of dopaminergic nigrostriatal innervation that was not associated with inhibition of MPTP metabolism or activation of Nrf2-ARE, although changes in NQO1 and SOD2 mRNA were observed. A significant dose-dependent downregulation in MAC-1 and GFAP positive cells was observed in MPTP + LSN-treated mice as well as significant downregulation of mRNA expression levels of these inflammatory markers. MPTP-induced increases in PPAR-γand PGC1αexpression were ameliorated by LSN dosing. Our results demonstrate that oral administration of LSN is neuroprotective against MPTP-induced neurodegeneration, and this effect is associated with downregulation of neuroinflammation, decreased oxidative stress, and modulation of PPAR-γand PGC1αexpression. These results suggest that LSN can be a candidate alternative non-thiazoledinedione partial PPAR-γagonist for neuroprotective treatment of PD.

scholarly journals Embryonic exposures to mono-2-ethylhexyl phthalate induce larval steatosis in zebrafish independent of Nrf2a signaling

2020 ◽  
pp. 1-9
Author(s):  
Karilyn E. Sant ◽  
Hadley M. Moreau ◽  
Larissa M. Williams ◽  
Haydee M. Jacobs ◽  
Anna M. Bowsher ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Hepatic Steatosis ◽  
Antioxidant Response ◽  
Abnormal Development ◽  
Fish Length ◽  
Peroxisome Proliferator ◽  
Primary Metabolite ◽  
Peroxisome Proliferator Activated Receptor ◽  
Expression Of Genes ◽  
Ethylhexyl Phthalate

Abstract Mono-2-ethylhexyl phthalate (MEHP) is the primary metabolite of the ubiquitous plasticizer and toxicant, di-2-ethylhexyl phthalate. MEHP exposure has been linked to abnormal development, increased oxidative stress, and metabolic syndrome in vertebrates. Nuclear factor, Erythroid 2 Like 2 (Nrf2), is a transcription factor that regulates gene expression in response to oxidative stress. We investigated the role of Nrf2a in larval steatosis following embryonic exposure to MEHP. Wild-type and nrf2a mutant (m) zebrafish embryos were exposed to 0 or 200 μg/l MEHP from 6 to either 96 (histology) or 120 hours post fertilization (hpf). At 120 hpf, exposures were ceased and fish were maintained in clean conditions until 15 days post fertilization (dpf). At 15 dpf, fish lengths and lipid content were examined, and the expression of genes involved in the antioxidant response and lipid processing was quantified. At 96 hpf, a subset of animals treated with MEHP had vacuolization in the liver. At 15 dpf, deficient Nrf2a signaling attenuated fish length by 7.7%. MEHP exposure increased hepatic steatosis and increased expression of peroxisome proliferator-activated receptor alpha target fabp1a1. Cumulatively, these data indicate that developmental exposure alone to MEHP may increase risk for hepatic steatosis and that Nrf2a does not play a major role in this phenotype.

scholarly journals Dysregulation of secretion of CXC α-chemokine CXCL10 in papillary thyroid cancer: modulation by peroxisome proliferator-activated receptor-γ agonists

2009 ◽  
Vol 16 (4) ◽  
pp. 1299-1311 ◽  
Author(s):  
Alessandro Antonelli ◽  
Silvia Martina Ferrari ◽  
Poupak Fallahi ◽  
Silvia Frascerra ◽  
Simona Piaggi ◽  
...  
Keyword(s):  
Primary Cultures ◽  
Cell Types ◽  
Interferon Γ ◽  
Antiproliferative Effect ◽  
Peroxisome Proliferator ◽  
Papillary Thyroid ◽  
Peroxisome Proliferator Activated Receptor ◽  
Similar Dose ◽  
Factor Α ◽  
Dose Dependent

In papillary thyroid carcinomas (PTCs), oncogenes activate a transcriptional program including the upregulation of CXCL10 chemokine, which stimulates proliferation and invasion. Furthermore, peroxisome proliferator-activated receptor-γ (PPARγ) activators thiazolidinediones (TZDs) modulate CXCL10 secretion in normal thyroid follicular cells (TFC), and inhibit PTC growth. Until now, no study has evaluated the effect of cytokines on CXCL10 secretion in PTCs, nor the effect of PPARγ activation. The combined effects of interferon γ (IFNγ) and tumor necrosis factor α (TNFα) stimulation on CXCL10 secretion in primary cells from PTCs and TFC were tested. Furthermore, the effect of PPARγ activation by TZDs, on CXCL10 secretion and proliferation in these cell types was studied. In primary cultures of TFC and PTCs CXCL10 production was absent under basal conditions; a similar dose-dependent secretion of CXCL10 was induced by IFNγ in both cell types. TNFα alone induced a slight but significant CXCL10 secretion only in PTCs. The stimulation with IFNγ+TNFα induced a synergistic CXCL10 release in both cell types; however, a secretion more than ten times higher was induced in PTCs. Treatment of TFC with TZDs dose-dependently suppressed IFNγ+TNFα-induced CXCL10 release, while TZDs stimulated CXCL10 secretion in PTCs. A significant antiproliferative effect by TZDs was observed only in PTCs. In conclusion, a dysregulation of CXCL10 secretion has been shown in PTCs. In fact, a CXCL10 secretion more than ten times higher has been induced by IFNγ+TNFα in PTCs with respect to TFC. Moreover, TZDs inhibited CXCL10 secretion in TFC and stimulated it in PTCs. The effect of TZDs on CXCL10 was unrelated to the significant antiproliferative effect in PTCs.

scholarly journals Cevoglitazar, a Novel Peroxisome Proliferator-Activated Receptor-α/γ Dual Agonist, Potently Reduces Food Intake and Body Weight in Obese Mice and Cynomolgus Monkeys

2010 ◽  
Vol 31 (3) ◽  
pp. 404-405
Author(s):  
Hong Chen ◽  
Beatriz Dardik ◽  
Ling Qiu ◽  
Xianglin Ren ◽  
Shari L. Caplan ◽  
...  
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Plasma Levels ◽  
Energy Homeostasis ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cynomolgus Monkeys ◽  
Dose Dependent ◽  
Dual Agonist

ABSTRACT Cevoglitazar is a dual agonist for the peroxisome proliferator-activated receptor (PPAR)-α and -γ subtypes. Dual activation of PPARα and -γ is a therapeutic approach in development for the treatment of type 2 diabetes mellitus and diabetic dyslipidemia. In this report, we show that, in addition to improving insulin sensitivity and lipid metabolism like other dual PPAR agonists, cevoglitazar also elicits beneficial effects on energy homeostasis in two animal models of obesity. In leptin-deficient ob/ob mice, administration of cevoglitazar at 0.5, 1, or 2 mg/kg for 18 d led to acute and sustained, dose-dependent reduction of food intake and body weight. Furthermore, plasma levels of glucose and insulin were normalized after 7 d of cevoglitazar treatment at 0.5 mg/kg. Plasma levels of free fatty acids and triglycerides were dose-dependently reduced. In obese and insulin-resistant cynomolgus monkeys, treatment with cevoglitazar at 50 and 500 μg/kg for 4 wk lowered food intake and body weight in a dose-dependent manner. In these animals, cevoglitazar also reduced fasting plasma insulin and, at the highest dose, reduced hemoglobin A1c levels by 0.4%. These preclinical results demonstrate that cevoglitazar holds promise for the treatment of diabetes and obesity-related disorders because of its unique beneficial effect on energy balance in addition to improving glycemic and metabolic control.

Peroxisome proliferators compete and ameliorate Hcy-mediated endocardial endothelial cell activation

2002 ◽  
Vol 283 (4) ◽  
pp. C1073-C1079 ◽  
Author(s):  
Matthew J. Hunt ◽  
Suresh C. Tyagi
Keyword(s):  
Fluorescence Quenching ◽  
Conformational Changes ◽  
Cell Activation ◽  
Intercellular Adhesion Molecule ◽  
Affinity Column ◽  
Peroxisome Proliferator ◽  
Endothelial Cell Activation ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Dose Dependent

To determine whether homocysteine (Hcy)-mediated activation of endocardial endothelial (EE) cells is ameliorated by peroxisome proliferator-activated receptor (PPAR), we isolated EE cells from mouse endocardium. Matrix metalloproteinase (MMP) activity and intercellular adhesion molecule (ICAM)-1 in EE cells were measured in the presence and absence of Hcy, and ciprofibrate (CF; PPAR-α agonist) or 15-deoxy-Δ12,14-prostaglandin J2 (PGJ2; PPAR-γ agonist) by zymography and Western blot analyses, respectively. Results suggest that Hcy-mediated MMP activation and ICAM-1 expression are ameliorated by CF and PGJ2. To test the hypothesis that Hcy competes with other ligands for binding to PPARα and -γ, we prepared cardiac nuclear extracts. Extracts were loaded onto an Hcy-cellulose affinity column. Bound proteins were eluted with CF and PGJ2. To determine conformational changes in PPAR upon binding to Hcy, we measured PPAR fluorescence at 334 nm. Dose-dependent increase in PPAR fluorescence demonstrated a primary binding affinity of 0.32 ± 0.06 μM. There was dose-dependent quenching of PPAR fluorescence by fluorescamine-homocysteine (F-Hcy). PPAR-α fluorescence quenching was abrogated by the addition of CF but not by PGJ2. PPAR-γ fluorescence quenching was abrogated by the addition of PGJ2 but not by CF. These results suggest that Hcy competes with CF and PGJ2 for binding to PPAR-α and -γ, respectively, indicating a role of PPAR in amelioration of Hcy-mediated EE dysfunction.

scholarly journals Protective Effects of Peroxisome Proliferator-Activated Receptor-αAgonist, Wy14643, on Hypoxia/Reoxygenation Injury in Primary Rat Hepatocytes

PPAR Research ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Ke Chen ◽  
Yuan-Hai Li ◽  
Si-Qi Xu ◽  
Sheng-Hong Hu ◽  
Lei Zhang
Keyword(s):  
Rat Hepatocytes ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Protective Effects ◽  
Primary Hepatocytes ◽  
Peroxisome Proliferator Activated Receptor ◽  
Group A ◽  
Reoxygenation Injury ◽  
Dose Dependent ◽  
Significant Protective Effect

This study investigates the effects and possible mechanism of an agonist of PPARα, Wy14643, on primary hepatocytes subjected to H/R injury in rats. H/R induced a significant increase ALT, AST, MDA in the culture medium and ROS in the hepatocytes. These effects were reversed by pretreatment with Wy14643 in the dose-dependent manner. The activity of SOD and the level of GSH in the hepatocytes were decreased after H/R, which were increased by Wy14643 pretreatment. Moreover, the mRNA expressions of PPARαsignificantly increased in H/R+Wy14643 groups when compared with that in H/R group. A PPARαagonist, Wy14643, exerts significant protective effect against H/R injury in primary hepatocytes via PPARαactivation and attenuating oxidative stress.

Differential effects of flavonoids on 3T3-L1 adipogenesis and lipolysis

2001 ◽  
Vol 280 (4) ◽  
pp. C807-C813 ◽  
Author(s):  
Anne W. Harmon ◽  
Joyce B. Harp
Keyword(s):  
Structural Similarity ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
Differential Effects ◽  
Triglyceride Accumulation ◽  
Induction Of Differentiation ◽  
Mitotic Clonal Expansion ◽  
Dose Dependent ◽  
Inhibit Cell Proliferation

Flavonoids, polyphenolic compounds that exist widely in plants, inhibit cell proliferation and increase cell differentiation in many cancerous and noncancerous cell lines. Because terminal differentiation of preadipocytes to adipocytes depends on proliferation of both pre- and postconfluent preadipocytes, we predicted that flavonoids would inhibit adipogenesis in the 3T3-L1 preadipocyte cell line. The flavonoids genistein and naringenin inhibited proliferation of preconfluent preadipocytes in a time- and dose-dependent manner. When added to 2-day postconfluent preadipocytes at the induction of differentiation, genistein inhibited mitotic clonal expansion, triglyceride accumulation, and peroxisome proliferator-activated receptor-γ expression, but naringenin had no effect. The antiadipogenic effect of genistein was not due to inhibition of insulin receptor subtrate-1 tyrosine phosphorylation. When added 3 days after induction of differentiation, neither flavonoid inhibited differentiation. In fully differentiated adipocytes, genistein increased basal and epinephrine-induced lipolysis, but naringenin had no significant effects. These data demonstrate that genistein and naringenin, despite structural similarity, have differential effects on adipogenesis and adipocyte lipid metabolism.

scholarly journals Protective effects of peroxisome proliferator-activated receptor agonists on human podocytes: proposed mechanisms of action

2012 ◽  
Vol 167 (3) ◽  
pp. 641-653 ◽  
Author(s):  
Gianluca Miglio ◽  
Arianna Carolina Rosa ◽  
Lorenza Rattazzi ◽  
Cristina Grange ◽  
Giovanni Camussi ◽  
...  
Keyword(s):  
Mechanisms Of Action ◽  
Peroxisome Proliferator ◽  
Protective Effects ◽  
Peroxisome Proliferator Activated Receptor ◽  
Receptor Agonists

Stimulation of NGF expression and secretion in 3T3-L1 adipocytes by prostaglandins PGD2, PGJ2, and Δ12-PGJ2

2005 ◽  
Vol 289 (1) ◽  
pp. E62-E67 ◽  
Author(s):  
Mònica Bulló ◽  
Muhammad R. Peeraully ◽  
Paul Trayhurn
Keyword(s):  
Mrna Level ◽  
Peroxisome Proliferator ◽  
Related Factors ◽  
Peroxisome Proliferator Activated Receptor ◽  
White Adipocytes ◽  
Cytokine Tumor Necrosis Factor ◽  
Factor Α ◽  
Dose Dependent Increase ◽  
Dose Dependent ◽  
Necrosis Factor

Nerve growth factor (NGF) has recently been shown to be secreted from white adipocytes, its production being strongly stimulated by the proinflammatory cytokine tumor necrosis factor-α. In this study, we have examined whether a series of prostaglandins and other inflammation-related factors also stimulate NGF expression and secretion by adipocytes, using 3T3-L1 cells. Although interleukin (IL)-1β, IL-10, and IL-18 each induced a small decrease in NGF mRNA level in 3T3-L1 adipocytes, there was no significant effect of these cytokines on NGF secretion. A small reduction in NGF expression and/or secretion was also observed with adiponectin and prostaglandins PGE2, PGF2α, and PGI2. In marked contrast, prostaglandin PGD2induced a major, dose-dependent increase (up to 20- to 40-fold) in NGF expression and secretion. The PGD2metabolites, PGJ2and Δ12-PGJ2, also induced major increases (up to 30-fold) in NGF production. A further metabolite of PGJ2, 15-deoxy-Δ12,14-PGJ2, a peroxisome proliferator-activated receptor-γ agonist, led paradoxically to a small increase in NGF mRNA level but a fall in NGF secretion. Both PGD2and PGJ2induced significant increases in NGF gene expression by 4 h after their addition. It is concluded that PGD2and the J series prostaglandins, PGJ2and Δ12-PGJ2, can play a significant role in the regulation of NGF production by white adipocytes. These results provide support for the view that NGF is an important inflammatory response protein, as well as a target-derived neurotrophin, in white adipose tissue.

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