TY - JOUR. T1 - Transcriptional regulation of nephrin gene by peroxisome proliferator-activated receptor-γ agonist. T2 - Molecular mechanism of the antiproteinuric effect of pioglitazone. AU - Benigni, Ariela. AU - Zoja, Carla. AU - Tomasoni, Susanna. AU - Campana, Marco. AU - Corna, Daniela. AU - Zanchi, Cristina. AU - Gagliardini, Elena. AU - Garofano, Elvira. AU - Rottoli, Daniela. AU - Ito, Takahito. AU - Remuzzi, Giuseppe. PY - 2006/6. Y1 - 2006/6. N2 - The renoprotective potential of the peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist pioglitazone was explored in an immune model of progressive nephropathy, passive Heymann nephritis (PHN), compared with that of an angiotensin II receptor antagonist, taken as standard therapy for renoprotection. PHN rats received orally vehicle, pioglitazone (10 mg/kg twice daily), or candesartan (1 mg/kg twice daily) from months 2 to 8. Pioglitazone reduced proteinuria as effectively as candesartan and limited renal functional and ...
TY - JOUR. T1 - Macrophage expression of peroxisome proliferator-activated receptor-α reduces atherosclerosis in low-density lipoprotein receptor-deficient mice. AU - Babaev, Vladimir R.. AU - Ishiguro, Hiroyuki. AU - Ding, Lei. AU - Yancey, Patricia G.. AU - Dove, Dwayne E.. AU - Kovacs, William J.. AU - Semenkovich, Clay F.. AU - Fazio, Sergio. AU - Linton, MacRae F.. N1 - Copyright: Copyright 2008 Elsevier B.V., All rights reserved.. PY - 2007/9. Y1 - 2007/9. N2 - BACKGROUND - The peroxisome proliferator-activated receptor-α (PPARα) plays important roles in lipid metabolism, inflammation, and atherosclerosis. PPARα ligands have been shown to reduce cardiovascular events in high-risk subjects. PPARα expression by arterial cells, including macrophages, may exert local antiatherogenic effects independent of plasma lipid changes. METHODS AND RESULTS - To examine the contribution of PPARα expression by bone marrow-derived cells in atherosclerosis, male and female low-density lipoprotein ...
TY - JOUR. T1 - Peroxisome proliferator-activated receptor-δ polymorphisms are associated with physical performance and plasma lipids. T2 - The HERITAGE Family Study. AU - Hautala, Arto J.. AU - Leon, Arthur S.. AU - Skinner, James S.. AU - Rao, D. C.. AU - Bouchard, Claude. AU - Rankinen, Tuomo. N1 - Copyright: Copyright 2009 Elsevier B.V., All rights reserved.. PY - 2007/5. Y1 - 2007/5. N2 - We tested the hypothesis that peroxisome proliferator-activated receptor-δ (PPARδ) gene polymorphisms are associated with cardiorespiratory fitness and plasma lipid responses to endurance training. Associations between the PPARδ exon 4 +15 C/T and exon 7 +65 A/G polymorphisms and maximal exercise capacity and plasma lipid responses to 20 wk of endurance training were investigated in healthy white (n = 477) and black (n = 264) subjects. In black subjects, the exon 4 = 15 C/C homozygotes showed a smaller training-induced increase in maximal oxygen consumption (P = 0.028) than the C/T and T/T genotypes. ...
The IUPHAR/BPS Guide to Pharmacology. Peroxisome proliferator-activated receptor-α - 1C. Peroxisome proliferator-activated receptors. Detailed annotation on the structure, function, physiology, pharmacology and clinical relevance of drug targets.
The mechanisms of the improvement of glucose homeostasis through angiotensin receptor blockers are not fully elucidated in hypertensive patients. We investigated the effects of telmisartan on insulin signaling and glucose uptake in cultured myotubes and skeletal muscle from wild-type and muscle-specific peroxisome proliferator-activated receptor (PPAR) δ knockout (MCK-PPARδ−/−) mice. Telmisartan increased PPARδ expression and activated PPARδ transcriptional activity in cultured C2C12 myotubes. In palmitate-induced insulin-resistant C2C12 myotubes, telmisartan enhanced insulin-stimulated Akt and Akt substrate of 160 kDa (AS160) phosphorylation as well as Glut4 translocation to the plasma membrane. These effects were inhibited by antagonizing PPARδ or phosphatidylinositol-3 kinase, but not by PPARγ and PPARα inhibition. Palmitate reducing the insulin-stimulated glucose uptake in C2C12 myotubes could be restored by telmisartan. In vivo experiments showed that telmisartan treatment ...
The mechanisms of the improvement of glucose homeostasis through angiotensin receptor blockers are not fully elucidated in hypertensive patients. We investigated the effects of telmisartan on insulin signaling and glucose uptake in cultured myotubes and skeletal muscle from wild-type and muscle-specific peroxisome proliferator-activated receptor (PPAR) δ knockout (MCK-PPARδ−/−) mice. Telmisartan increased PPARδ expression and activated PPARδ transcriptional activity in cultured C2C12 myotubes. In palmitate-induced insulin-resistant C2C12 myotubes, telmisartan enhanced insulin-stimulated Akt and Akt substrate of 160 kDa (AS160) phosphorylation as well as Glut4 translocation to the plasma membrane. These effects were inhibited by antagonizing PPARδ or phosphatidylinositol-3 kinase, but not by PPARγ and PPARα inhibition. Palmitate reducing the insulin-stimulated glucose uptake in C2C12 myotubes could be restored by telmisartan. In vivo experiments showed that telmisartan treatment ...
AIM To investigate the role of hepatic peroxisome proliferator-activated receptor-γ (PPAR-γ) in increased susceptibility to endotoxin-induced toxicity in rats with bile duct ligation during endotoxemia. METHODS Male Sprague-Dawley rats were subjected to bile duct ligation (BDL). Sham-operated animals served as controls. DNA binding were determined by polymerase chain reaction, Western blotting analysis, and electrophoretic mobility shift assay, respectively. BDL and sham-operated rats received a non-lethal dose of intraperitoneal lipopolysaccharide (LPS) injection (3 mg/kg, i.p.). Additionally, the potential beneficial effects of the PPAR-γ agonist rosiglitazone were determined in BDL and sham-operated rats treated with a non-lethal dose of LPS. Survival was assessed in BDL rats treated with a non-lethal dose of LPS and in sham-operated rats treated at a lethal dose of LPS (6 mg/kg, i.p.). RESULTS PPAR-γ activity in rats undergoing BDL was significantly lower than in the sham-controls. Hepatic
Ligands for peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) increase skeletal muscle fatty acid catabolism, improve insulin sensitivity, increase serum high-density lipoprotein cholesterol, elicit anti-inflammatory activity and induce terminal differentiation. Contradictory findings are also reported suggesting that PPARβ/δ ligands potentiate tumorigenesis by increasing cell proliferation, by inhibiting apoptosis through phosphorylation of Akt and by increasing cyclooxygenase-2 (COX2) and vascular endothelial growth factor (VEGF) expression. The contradictory findings could be due to differences in the model system (cancer cell line versus in vivo), differences in cell culture conditions (with and without serum) or differences in ligands. The present study examined the effect of two different PPARβ/δ ligands (GW0742 and GW501516) in human cancer cell lines (HT29, HCT116, LS-174T, HepG2 and HuH7) cultured in the presence or absence of serum and compared in vitro analysis with in ...
Breast cancer in women in the United States accounts for more deaths than any other malignancy (1) . The majority of these breast tumors originate from the ductile epithelia, and infiltrating ductal carcinomas account for ,70% of all of the breast cancers (2) . Current chemotherapies are accompanied by significant toxicity and benefit only a limited number of patients. The limited number of therapeutic options and the high degree of prevalence have stimulated the search for new and more selective molecular targets for the management of breast cancer. Cancer is the result of dysregulation of differentiation and apoptosis. The peroxisome proliferator-activated receptor-γ (PPARγ) as an important mediator of terminal differentiation in adipocytes (3 , 4) has led to the examination of its role in mediating similar programs in breast adenocarcinomas (5, 6, 7) .. PPARγ is a member of the nuclear hormone receptor superfamily and plays critical roles in adipogenesis (3 , 4 , 8) , insulin-mediated ...
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Peritoneal dialysis patients are at increased risk of cardiovascular morbidity and mortality and are related to the presence of accelerated atherosclerosis. Other than the traditional cardiovascular risk factors, there is increasing evidence that inflammation is associated with the development of atherosclerosis and cardiovascular events in both the general and dialysis population. C-reactive protein is predictive of higher all-cause mortality and cardiovascular mortality, independent of other cardiovascular risk factors and atherosclerotic vascular disease. As a considerable proportion of peritoneal dialysis patients showed elevated C-reactive protein, it raises an important question as to whether lowering C-reactive protein will have any cardiovascular and survival benefit in these patients. On the other hand, insulin resistance with associated hyperinsulinemia is frequently observed in chronic renal failure and dialysis patients. Although the exact mechanism of insulin resistance needs ...
PPAR Research is a peer-reviewed, Open Access journal that publishes original research and review articles on advances in basic research focusing on mechanisms involved in the activation of peroxisome proliferator-activated receptors (PPARs), as well as their role in the regulation of cellular differentiation, development, energy homeostasis and metabolic function. The journal also welcomes preclinical and clinical trials of drugs that can modulate PPAR activity, with a view to treating chronic diseases and disorders such as dyslipidemia, diabetes, adipocyte differentiation, inflammation, cancer, lung diseases, neurodegenerative disorders, and obesity.
Peroxisome proliferator-activated receptor-gamma (PPAR?) plays a critical role in lipid and glucose homeostasis. It is the target of many drug discovery studies, because of its role in various disease states including diabetes and cancer. Thiazolidinediones, a synthetic class of agents that work by activation of PPAR?, have been used extensively as insulin-sensitizers for the management of type 2 diabetes. In this study, a combination of QSAR and docking methods were utilised to perform virtual screening of more than 25 million compounds in the ZINC library. The QSAR model was developed using 1,517 compounds and it identified 42,378 potential PPAR? agonists from the ZINC library, and 10,000 of these were selected for docking with PPAR? based on their diversity. Several steps were used to refine the docking results, and finally 30 potentially highly active ligands were identified. Four compounds were subsequently tested for their in vitro activity, and one compound was found to have a K i values ...
Purpose.: Vascular endothelial growth factor (VEGF)-induced retinal vascular permeability contributes to diabetic macular edema (DME), a serious vision-threatening condition. Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) antagonist/reverse agonist, GSK0660, inhibits VEGF-induced human retinal microvascular endothelial cell (HRMEC) proliferation, tubulogenesis, and oxygen-induced retinal vasculopathy in newborn rats. These VEGF-induced HRMEC behaviors and VEGF-induced disruption of endothelial cell junctional complexes may well share molecular signaling events. Thus, we sought to examine the role of PPARβ/δ in VEGF-induced retinal hyperpermeability. Methods.: Transendothelial electrical resistance (TEER) measurements were performed on HRMEC monolayers to assess permeability. Claudin-1/Claudin-5 localization in HRMEC monolayers was determined by immunocytochemistry. Extracellular signal-regulated protein kinases 1 and 2 (Erk 1/2) phosphorylation, VEGF receptor 1 (VEGFR1) and R2 ...
Peroxisome proliferator-activated receptor-gamma (PPAR) is a nuclear transcription factor that regulates many genes and is involved in comprehensive natural functions. appearance claim that PPAR immunoassays may possibly not be suitable when used in combination with fresh homogenates of adipose and spleen tissues. Validation of the assay with each individual cells is recommended. Keywords: Immunoassay, peroxisome proliferator-activated receptor-gamma, rosiglitazone Intro Peroxisome proliferator-activated receptor-gamma (PPAR) is definitely a nuclear transcription element that regulates the manifestation of many genes. PPAR is definitely involved in large varieties of biological functions, including lipid and glucose metabolisms, anti-inflammatory effects, and has considerable cardiovascular effects.[1C5] Synthetic activators of PPAR, the thiazolidinediones (TZD), have been utilized for treatment of type II diabetes since the 1990s.[6] Dedication of PPAR activity and expression in various ...
Here, we investigated the mechanisms by which PPARδ agonists control expression of 14-3-3ε, a key antiinflammatory protein in endothelial cells.12 Our data not only provide evidence that PPARδ modulates expression of YWHAE gene and 14-3-3ε protein under resting conditions but also demonstrate that this nuclear receptor upregulates 14-3-3ε expression by targeting transcription via a PPRE-independent pathway involving colocalization of C/EBPβ and PPARδ on YWHAE promoter. Several lines of evidence support these conclusions. First, PPARδ agonists regulated YWHAE promoter activity in a concentration- and time-dependent manner. Concordantly, YWHAE promoter was upregulated by PPARδ overexpression, whereas specific PPARγ and PPARα ligands had no effect on YWHAE promoter under our experimental conditions. Second, PPARδ activation increased 14-3-3ε mRNA and protein expression in both primary and spontaneously transformed endothelial cell lines, whereas PPARδ knockdown depressed basal and ...
We investigated whether ancestral liver damage leads to heritable reprogramming of hepatic wound healing in male rats. We found that a history of liver damage corresponds with transmission of an epigenetic suppressive adaptation of the fibrogenic component of wound healing to the male F-1 and F-2 generations. Underlying this adaptation was less generation of liver myofibroblasts, higher hepatic expression of the antifibrogenic factor peroxisome proliferator-activated receptor gamma (PPAR-gamma) and lower expression of the profibrogenic factor transforming growth factor beta 1 (TGF-beta 1) compared to rats without this adaptation. Remodeling of DNA methylation and histone acetylation underpinned these alterations in gene expression. Sperm from rats with liver fibrosis were enriched for the histone variant H2A.Z and trimethylation of histone H3 at Lys27 (H3K27me3) at PPAR-gamma chromatin. These modifications to the sperm chromatin were transmittable by adaptive serum transfer from fibrotic rats to ...
Nitro-fatty acids (NO(2)-FA) are electrophilic signaling mediators formed by reactions of nitric oxide and nitrite. NO(2)-FA exert anti-inflammatory signaling actions through post-translational protein modifications. We report that nitro-oleic acid (OA-NO(2)) stimulates proMMP-7 and proMMP-9 proteolytic activity via adduction of the conserved cysteine switch domain thiolate. Biotin-labeled OA-NO(2) showed this adduction occurs preferentially with latent forms of MMP, confirming a role for thiol alkylation by OA-NO(2) in MMP activation. In addition to regulating pro-MMP activation, MMP expression was modulated by OA-NO(2) via activation of peroxisome proliferator-activated receptor-γ. MMP-9 transcription was decreased in phorbol 12-myristate 13-acetate-stimulated THP-1 macrophages to an extent similar to that induced by the peroxisome proliferator-activated receptor-γ agonist Rosiglitazone. This was affirmed using a murine model of atherosclerosis, ApoE(-/-) mice, where in vivo OA-NO(2) administration
In the present study, we examined PPARγ regulation by Ang II in mouse aortic VSMCs. The findings of this study demonstrate that Ang II decreases expression of PPARγ via AT1 receptors in VSMCs. Furthermore, this Ang II-induced decrease in PPARγ occurs via TGF-β1 and the p38 MAPK pathway. Ang II activated p38 via TGF-β1 and decreased PPARγ through HDAC3 without involving Smad signaling.. In this study, blockade of AT1 receptors with losartan inhibited Ang II-induced PPARγ reduction. AT1 receptors mediate most responses to Ang II, and this receptor subtype is predominantly expressed in VSMCs.25,26 AT1 receptor antagonists have been shown to activate PPARγ in various cell types, including adipocytes and VSMCs.27,28 Among the various AT1 receptor antagonists, telmisartan has been shown to activate PPARγ within a 10 μmol/L concentration,28 whereas the losartan activates PPARγ only at a high concentration (100 μmol/L).29 In our study, losartan at 10 μmol/L inhibited Ang II-induced PPARγ ...
Peroxisome proliferator-activated receptor gamma (PPAR-γ or PPARG), also known as the glitazone receptor, or NR1C3 (nuclear receptor subfamily 1, group C, member 3) is a type II nuclear receptor that in humans is encoded by the PPARG gene. PPARG is mainly present in adipose tissue, colon and macrophages. Two isoforms of PPARG are detected in the human and in the mouse: PPAR-γ1 (found in nearly all tissues except muscle) and PPAR-γ2 (mostly found in adipose tissue and the intestine). PPARG regulates fatty acid storage and glucose metabolism. The genes activated by PPARG stimulate lipid uptake and adipogenesis by fat cells. PPARG knockout mice fail to generate adipose tissue when fed a high-fat diet. This gene encodes a member of the peroxisome proliferator-activated receptor (PPAR) subfamily of nuclear receptors. PPARs form heterodimers with retinoid X receptors (RXRs) and these heterodimers regulate transcription of various genes. Four subtypes of PPARs are known: PPAR-alpha, PPAR-delta, ...
The present study demonstrates that both PPAR-α and PPAR-γ are expressed in various rat tissues, including blood vessels, heart, muscle, kidney, liver, and adipose tissue. There is a differential expression of PPAR-α and PPAR-γ during development in SHR, a genetic model of hypertension, compared with control WKY rats. We demonstrate for the first time that in aorta from young, prehypertensive SHR, PPAR-α and PPAR-γ levels are similar, whereas in mesenteric arteries from young SHR, PPAR-α and PPAR-γ levels were greater than in age-matched WKY. In established hypertension in adult SHR, however, PPAR-α and PPAR-γ levels in aorta and mesenteric arteries were greater than in age-matched WKY. Cell culture confirmed the expression of PPARs, particularly PPAR-γ, in VSMCs.. Expression of PPARs was primarily thought to be limited to tissues such as liver and fat, in which they participate in the regulation of lipid metabolism.18 Recently, it was suggested that PPAR activators not only regulate ...
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Cardiac hypertrophy is characterized by increased protein synthesis44 and size of existing cardiomyocytes,45 leading to increased cardiac muscle mass.46 Agonists of nuclear receptor PPAR-γ have been shown to inhibit both protein synthesis and cardiac hypertrophy induced by pressure overload.10,11 To elucidate the physiological function of PPAR-γ in cardiomyocytes, we used Cre-loxP system to genetically inactivate this gene specifically in cardiomyocytes of CM-PGKO mice.. CM-PGKO mice displayed age-progressive cardiac hypertrophy, indicating that PPAR-γ normally suppresses cardiomyocyte growth. Despite this hypertrophy, the resting cardiac systolic function in CM-PGKO mice was comparable to littermate control mice at the age of 6 months. In fact, at this time point, there may be a subtle improvement in systolic function over baseline, which may lead to the lower resting HR that was noted. Whether function will be maintained as these mice continue to age will need to be further evaluated. What ...
Until now, the transcriptional activity of CYP2A6 was investigated at up to -1.0 kb by luciferase assay (von Richter et al., 2004). Pitarque et al. (2005) demonstrated putative response elements for the transcriptional factors HNF-4α, C/EBPα and Oct-1 in the 5′-flanking sequence from -112 to -61. The constitutive expression of CYP2A6 is governed by the interplay between these factors (Pitarque et al., 2005). In the present study, we first investigated the transcriptional activity of a far upstream region, up to -6.8 kb of the CYP2A6 gene. The basal transcriptional activity of CYP2A6 was prominently decreased with the inclusion of the upstream region from -1013 to -185. The results were in accordance with a previous study by Pitarque et al. (2005) showing that the transcriptional activity was decreased by the inclusion of the upstream from -200. These results suggested that there might be a suppressor region(s) upstream from -200.. PXR and CAR bind to elements containing a direct repeat of ...
In this study, we demonstrated that activation of PPAR-α interrupted the earliest ET-1-induced events, ie, JNK activation, c-Jun phosphorylation, and c-Jun induction in cardiomyocytes. Because JNKs regulate the AP-1 DNA binding activity through phosphorylation of the 2 serine residues in the NH2-terminal region of c-Jun, 1 of the AP-1 components,19 fenofibrate, would inhibit AP-1 activity partly via JNK pathway inhibition. Activation of ERK has been implicated in features of the hypertrophic response in an in vitro model.10 Also in our study, ERKs were markedly activated by ET-1 in cardiomyocytes, but this was not affected by fenofibrate. Therefore, the inhibitory effect of fenofibrate on ET-1-related hypertrophic responses might be mediated through interfering with the JNK pathway rather than the ERK pathway.. We demonstrated that fenofibrate inhibited ET-1 promoter activity, preproET-1 mRNA expression, and hypertrophy in ET-1-stimulated cardiomyocytes. To gain additional insight into the ...
Impairment of the BBB is a critical event in the development and progression of several diseases that affect the CNS. We demonstrated here that increased BBB permeability with downregulation of TJ and AJ proteins was involved in T2DM-induced cognitive impairment. TJs present between cerebral endothelial cells perform diffusion barrier functions of the BBB and consist of many proteins, such as claudin 3, claudin 5, occludin, and ZO-1. On the other hand, AJs are required for the correct organization of TJs and are largely composed of VE-cadherin in endothelial cells.1 Therefore, alteration of the interaction between these TJ proteins and VE-cadherin plays an essential role in modulating BBB function. Our results are consistent with these ideas and previous observations, suggesting that reduced ZO-1 and occludin expression, for example, might contribute to enhanced BBB permeability in diabetes mellitus.10 However, further alterations of BBB ultrastructure in diabetic patients or animal models are a ...
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Genetic heterogeneity, lifestyle factors, gene-gene or gene-environment interactions are the determinants of T2D which puts Hispanics and populations with African ancestry at higher risk of developing T2D. In this dissertation, the genetic associations of PPARGC1A polymorphisms with T2D and its related phenotypes (metabolic markers) in Haitian Americans (cases=110, controls=116), African Americans (cases=120, controls=124) and Cuban Americans (cases=160, controls=181) of South Florida were explored. Five single nucleotide polymorphisms of gene PPARGC1A were evaluated in each ethnicity for their disease association. In Haitian Americans, rs7656250 (OR= 0.22, pp=0.03) had significant protective association with T2D but had risk association in African Americans for rs7656250 (OR=1.02, p=0.96) and rs4235308 (OR=2.53, p=0.03). We found that in Haitian American females, both rs7656250 (OR=0.23, pp=0.03) had protective association with T2D. In African American females, rs7656250 (OR=1.14, p=0.78) had risk
To examine the complex and multifactorial processes in early AVS in vivo, we combined a broad genomics-based approach with precise spatial resolution in a large animal model. To our knowledge, the present study is the first to examine the valve endothelium in the earliest stages of AVS and to identify a spatial shift of phenotype balance in response to a brief systemic insult. We found that the aortic side endothelium is much more responsive to HC than the adjacent ventricular side endothelium, and unexpectedly expressed overall protective pathways on the side vulnerable to AVS.. Differential endothelial responses to HC were identified using four different genomewide comparisons: two within-animal comparisons, in which the aortic and ventricular sides were compared; and two between-animal comparisons, in which the effect of HC on a single side of the valve was considered. These single-side analyses between NC and HC swine provided insight about the within-animal comparisons. For example, the ...
The metabolic nuclear receptors act as metabolic and toxicological sensors, enabling the organism to quickly adapt to environmental changes by inducing the appropriate metabolic genes and pathways. Ligands for these metabolic receptors are compounds from dietary origin, intermediates in metabolic pathways, drugs, or other environmental factors that, unlike classical nuclear receptor ligands, are present in high concentrations. Metabolic receptors are master regulators integrating the homeostatic control of (a) energy and glucose metabolism through peroxisome proliferator-activated receptor gamma (PPARgamma); (b) fatty acid, triglyceride, and lipoprotein metabolism via PPARalpha, beta/delta, and gamma; (c) reverse cholesterol transport and cholesterol absorption through the liver X receptors (LXRs) and liver receptor homolog-1 (LRH-1); (d) bile acid metabolism through the farnesol X receptor (FXR), LXRs, LRH-1; and (e) the defense against xeno- and endobiotics by the pregnane X receptor/steroid ...
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Results MiR-155 expression was significantly increased in the development of DAH. Disease progression was reduced in miR-155-/- mice and by in vivo silencing of miR-155 using miR-155 antagomir. MiR-155 silencing dampened pristane-induced ectopic activation of multiple inflammatory pathways, and reduced the expression of pro-inflammatory cytokines. Several negative regulators of nuclear factor (NF)-κB signalling were inhibited by pristane, and were re-activated in miR-155-/- mice. In particular, the anti-inflammatory factor peroxisome proliferator-activated receptor-α was identified as a direct target of miR-155. ...
The peroxisome proliferator-activated receptor gamma (PPARG), Pro12Ala and the insulin receptor substrate (IRS1), Gly972Arg confer opposite effects on insulin resistance and type 2 diabetes mellitus (T2DM). We investigated the independent and joint effects of PPARG Pro12Ala and IRS1 Gly972Arg on markers of insulin resistance and T2DM in an African population with elevated risk of T2DM. In all 787 (176 men) mixed-ancestry adults from the Bellville-South community in Cape Town were genotyped for PPARG Pro12Ala and IRS1 Gly972Arg by two independent laboratories. Glucose tolerance status and insulin resistance/sensitivity were assessed. Genotype frequencies were 10.4% (PPARG Pro12Ala) and 7.7% (IRS1 Gly972Arg). Alone, none of the polymorphisms predicted prevalent T2DM, but in regression models containing both alleles and their interaction term, PPARG Pro12 conferred a 64% higher risk of T2DM. Furthermore PPARG Pro12 was positively associated in adjusted linear regressions with increased 2-hour post-load
Peroxisome proliferator-activated receptor-γ (PPARγ) agonists, which have been used as insulin sensitizers in diabetic patients, may improve functions of endothelial cells (ECs). We investigated the effect of PPARγ on angiogenic activities of murine ECs and bone marrow-derived proangiogenic cells (PACs). PACs were isolated from bone marrow of 10-12 weeks old, wild type, db/db and PPARγ heterozygous animals. Cells were cultured on fibronectin and gelatin coated dishes in EGM-2MV medium. For in vitro stimulations, rosiglitazone (10 μmol/L) or GW9662 (10 μmol/L) were added to 80% confluent cell cultures for 24 hours. Angiogenic potential of PACs and ECs was tested in vitro and in vivo in wound healing assay and hind limb ischemia model. ECs and PACs isolated from diabetic db/db mice displayed a reduced angiogenic potential in ex vivo and in vitro assays, the effect partially rescued by incubation of cells with rosiglitazone (PPARγ activator). Correction of diabetes by administration of rosiglitazone
The aim of the present study was to examine the role of endogenous peroxisome proliferator-activated receptor-α (PPAR-α) ligand on the permeability and structure of small intestine tight junctions (TJs) in an animal model of experimental colitis, induced by dinitrobenzene sulfuric acid (DNBS). Four days after colitis induction with DNBS, the ileal TJs were studied by means of transmission electron microscopy using lanthanum nitrate and immunohistochemistry of occludin, zonula occludens 1, and claudin 2. Administration of DNBS to wild-type mice induced colon injury associated with a significant increase of plasma and colon tumor necrosis factor-α levels and with a significant increase of ileal permeability. Distal colitis in mice induced an increase of TJ permeability throughout the entire small intestine, and the extent of alterations correlates with colonic damage. Small intestinal permeability was associated with the presence of apoptosis (evaluated by FAS ligand expression and terminal ...
TY - JOUR. T1 - Peroxisome proliferator-activated receptor γ and its role in adipocyte homeostasis and thiazolidinedione-mediated insulin sensitization. AU - Wang, Qiong A.. AU - Zhang, Fang. AU - Jiang, Lei. AU - Ye, Risheng. AU - An, Yu. AU - Shao, Mengle. AU - Tao, Caroline. AU - Gupta, Rana K. AU - Scherer, Philipp E. PY - 2018/5/1. Y1 - 2018/5/1. N2 - Adipose tissue is a dynamic organ that makes critical contributions to whole-body metabolic homeostasis. Although recent studies have revealed that different fat depots have distinct molecular signatures, metabolic functions and adipogenic mechanisms, peroxisome proliferator-activated receptor γ (PPARγ) is still widely viewed as the master regulator of adipogenesis and critical for maintaining mature adipocyte function. Using an inducible, adipocyte-specific knockout system, we explored the role of PPARγ in mature adipocytes in vivo. Short-term PPARγ deficiency in adipocytes reduces whole-body insulin sensitivity, but adipocytes are ...
Nuclear receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the nuclear receptor binds to DNA specific PPAR response elements (PPRE) and modulates the transcription of its target genes, such as acyl-CoA oxidase. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. ARF6 acts as a key regulator of the tissue-specific adipocyte P2 (aP2) enhancer. Acts as a critical regulator of gut homeostasis by suppressing NF-kappa-B-mediated proinflammatory responses. Plays a role in the regulation of cardiovascular circadian rhythms by regulating the transcription of ARNTL/BMAL1 in the blood vessels (PubMed:19041764).
NCOR2, also known as SMRT, is a transcriptional corepressor that maintains the transcriptional silencing of certain target genes. NCOR2 expression and its occupancy on peroxisome proliferator-activated receptor (PPAR) target gene promoters are increased with age in major metabolic tissues. Shifting its repressive activity towards PPARs, by selectively disabling one of its two major receptor-interacting domains, resulted in premature ageing in mice and related metabolic diseases accompanied by reduced mitochondrial function and antioxidant gene expression. Additionally, in a preliminary analysis, several human polymorphisms were found to be associated with type 2 diabetes [2196]. ...
Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a member of the nuclear hormone receptor superfamily. It is expressed in adipocytes, immune cells, and cardiovascular cells that include cardiomyocytes, endothelial cells, and smooth mus
The angiotensin II type 1 receptor blocker (ARB) telmisartan was reported to activate the peroxisome proliferator-activated receptor-γ (PPARγ) in transactivation assays, whereas other ARBs, with the possible exception of irbesartan, did not (1). Telmisartan also induced adipogenesis and increased the expression of PPARγ target genes in preadipocyte fibroblasts (1), both of which are hallmark properties of PPARγ agonists.. We report a case of a 52-year-old man with hypertension, visceral obesity (BMI 34.4 kg/m2), and impaired glucose tolerance (pre-diabetes), in whom administration of telmisartan (80 mg/day) normalized blood pressure, improved insulin resistance, and reduced plasma triglycerides. During the 10 weeks after initiating telmisartan, … ...
We document here for the first time that endogenous ligands of PPARgamma may contribute to the protection against renal I/R injury afforded by LPS pretreatment in the rat.
Carbon monoxide (CO) dampens pro-inflammatory responses in a peroxisome proliferator-activated receptor-γ (PPARγ) and p38 mitogen-activated protein kinase (MAPK) dependent manner. Previously, we demonstrated that CO inhibits lipopolysaccharide (LPS
A Diabetes Outcome Progression Trial (ADOPT) was conceived in the hope that the seemingly inexorable decline in islet B-cell function described with metformin, sulfonylureas, and insulin in the UK Prospective Diabetes Study (UKPDS) might be stopped or inhibited to a major degree by peroxisome proliferator-activated receptor-γ agonists, in particular rosiglitazone (1,2). It was already well recognized that the rapid early efficacy of sulfonylureas in lowering glucose was not retained to 12 months, and that metformin and thiazolidinediones had slow onset of action over months, so the design of the study necessarily had to enable decline of measures of blood glucose control to be assessed for a considerable period from 1 year onwards. However, the extent (degree and time) to which this early efficacy of the sulfonylureas in protecting against hyperglycemia would persist was not accurately known. The study also provided a good opportunity to compare durability of effect of the three classes of ...
Allelic and genotypic distribution of polymorphisms in diacylglycerol acyltransferase 1 (DGAT1), fatty acid binding protein 4 (FABP4), fatty acid synthase (FASN), and peroxisome proliferator-activated receptor-γ coactivator-1α (PPARGC1A) genes were assessed in 679 Fleckvieh bulls. Single-locus genotype effects and the combined effect of the two polymorphisms within the FASN gene were evaluated for association with the intramuscular fat content and fatty acid profile determined in muscle and subcutaneous fat. The FASN (g.16024GNA) and FASN (g.17924ANG) polymorphisms were significantly associatedmainlywith C14:0, C16:0, and C18:1 n-9 concentrations aswell as with the atherogenic index. The proportion of explained phenotypic variation markedly increased when the effect of a combination of the two polymorphisms within the FASN gene was tested, with the highest values of 8.6% and 14.8%, respectively, observed for C14:0 in muscle and subcutaneous fat. With a focus on improving the fatty acid ...
TY - JOUR. T1 - The synthetic peroxisome proliferator-activated receptor-α agonist ciglitazone attenuates neuroinflammation and accelerates encapsulation in bacterial brain abscesses. AU - Kielian, Tammy. AU - Syed, Mohsin Md. AU - Liu, Shuliang. AU - Phulwani, Nirmal K.. AU - Phillips, Napoleon. AU - Wagoner, Gail. AU - Drew, Paul D.. AU - Esen, Nilufer. PY - 2008/4/1. Y1 - 2008/4/1. N2 - Brain abscesses result from a pyogenic parenchymal infection commonly initiated by Gram-positive bacteria such as Staphylococcus aureus. Although the host immune response elicited following infection is essential for effective bacterial containment, this response also contributes to the significant loss of brain parenchyma by necrosis that may be reduced by modulating the inflammatory response. Ciglitazone, a PPAR-γ agonist with anti-inflammatory properties, was evaluated for its ability to influence the course of brain abscess development when treatment was initiated 3 days following infection. ...
TY - JOUR. T1 - Inhibition of tumor necrosis factor-α-induced interleukin-6 expression by Telmisartan through cross-talk of peroxisome proliferator- activated receptor-γ with nuclear factor κB and CCAAT/Enhancer- Binding protein-β. AU - Tian, Qingping. AU - Miyazaki, Ryohei. AU - Ichiki, Toshihiro. AU - Imayama, Ikuyo. AU - Inanaga, Keita. AU - Ohtsubo, Hideki. AU - Yano, Kotaro. AU - Takeda, Kotaro. AU - Sunagawa, Kenji. N1 - Copyright: Copyright 2011 Elsevier B.V., All rights reserved.. PY - 2009/5/1. Y1 - 2009/5/1. N2 - Telmisartan, an angiotensin II type 1 receptor antagonist, was reported to be a partial agonist of peroxisome proliferator-activated receptor-γ. Although peroxisome proliferator-activated receptor-γ activators have been shown to have an anti-inflammatory effect, such as inhibition of cytokine production, it has not been determined whether telmisartan has such effects. We examined whether telmisartan inhibits expression of interleukin-6 (IL-6), a proinflammatory cytokine, ...
PPARγ is a ligand-binding transcription factor that has been reported to be implicated in lipid metabolism, immune function, and cellular growth and differentiation. It has been suspected to play a role in the pathophysiology of preeclampsia, although the mechanism is yet to be elaborated. This study aims to investigate the expression of PPARγ in early onset preeclampsia (EOPE), late onset preeclampsia (LOPE), and normal pregnancy. We conducted this study using primary trophoblastic cell culture incubated with serum from EOPE, LOPE, and normal pregnancy. The expression of PPARγ in these cells was analyzed using Western Blot. Statistical analysis was performed using one-way ANOVA and Bonferronis post hoc test. p | 0.05 is considered significant. Serum from normal pregnant women and EOPE did not induce any difference in the expression of PPAR-γ (p | 0.05). In contrast, expression of PPAR-γ was increased in those cells induced by serum from LOPE (p | 0.001). Therefore, we conclude that hypothetically
Pioglitazone is a thiazolidinedione compound with a mode of action as a peroxisome proliferator-activated receptor gamma agonist. Activation of this receptor causes increased transcriptional activity at a number of locations that are important to carbohydrate and lipid (fat) metabolism. Insulin resistance is reversed by enhancing the action of insulin, thereby promoting glucose utilization in peripheral tissues, suppressing gluconeogenesis in the liver, and reducing lipolysis at the adipocyte.. In previous studies of pioglitazone, peripheral edema (swelling in the hands, feet, and legs) was reported as an adverse event more often in pioglitazone groups and appears to be a dose dependent phenomenon with pioglitazone. The incidence of peripheral edema in monotherapy studies was 3.2% in pioglitazone patients compared with 0.7% placebo patients and was reported more by females than males. This incidence was higher when pioglitazone was combined with sulphonylurea or insulin (5.9% and 15.6%, ...
TY - JOUR. T1 - Inhibition of smooth muscle proliferation by urea-based alkanoic acids via peroxisome proliferator-activated receptor α-dependent repression of cyclin D1. AU - Ng, Valerie Y.. AU - Morisseau, Christophe. AU - Falck, John R.. AU - Hammock, Bruce D.. AU - Kroetz, Deanna L.. PY - 2006/11. Y1 - 2006/11. N2 - OBJECTIVE - Proliferation of smooth muscle cells is implicated in cardiovascular complications. Previously, a urea-based soluble epoxide hydrolase inhibitor was shown to attenuate smooth muscle cell proliferation. We examined the possibility that urea-based alkanoic acids activate the nuclear receptor peroxisome proliferator-activated receptor α (PPARα) and the role of PPARα in smooth muscle cell proliferation. METHODS AND RESULTS - Alkanoic acids transactivated PPARα, induced binding of PPARα to its response element, and significantly induced the expression of PPARα-responsive genes, showing their function as PPARα agonists. Furthermore, the alkanoic acids attenuated ...
TY - JOUR. T1 - Ligand for peroxisome proliferator-activated receptor γ (Troglitazone) has potent antitumor effect against human prostate cancer both in vitro and in vivo. AU - Kubota, Tetsuya. AU - Koshizuka, Kozo. AU - Williamson, Elizabeth A.. AU - Asou, Hiroya. AU - Said, Jonathan W.. AU - Holden, Stuart. AU - Miyoshi, Isao. AU - Koeffler, H. Phillip. N1 - Copyright: Copyright 2007 Elsevier B.V., All rights reserved.. PY - 1998/8/1. Y1 - 1998/8/1. N2 - Troglitazone, a thiazolidinedione derivative, is a widely used antidiabetic drug that binds and activates peroxisome proliferator-activated receptor γ (PPARγ) and enhances insulin sensitivity. It induces differentiation of adipocytes, which highly express PPARγ. We report that human prostate cancer cells expressed PPARγ at prominent levels and normal prostate tissues had very low expression. Dose-response clonogenic assays of the PC-3 prostate cancer cell line with troglitazone showed an antiproliferative effect (ED50, 3 x 10-7 M) and ...
TY - JOUR. T1 - 15-deoxy-Δ-Prostaglandin J 2 induces IL-8 and GM-CSF in a human airway epithelial cell line (NCI-H 292). AU - Chiba, Takahito. AU - Ueki, Shigeharu. AU - Ito, Wataru. AU - Kato, Hikari. AU - Takeda, Masahide. AU - Kayaba, Hiroyuki. AU - Furue, Masutaka. AU - Chihara, Junichi. PY - 2009/6/1. Y1 - 2009/6/1. N2 - Background: 15-Deoxy-Δ 12,14-prostaglandin J 2 (15d-PGJ 2), a major prostanoid metabolized from prostaglandin D 2 (PGD 2), plays an important role in various biological processes including inflammatory responses. 15d-PGJ 2 exerts its effects through two major receptors, chemoattractant receptor- homologous molecule expressed on Th2 cells (CRTH2) and peroxisome proliferator-activated receptor-γ (PPARγ). The 15d-PGJ 2/PPARγ system, in particular, regulates numerous biological processes including adipogenesis, apoptosis, and inflammation. Although our studies have shown that PGD 2 (metabolic precursor of 15d-PGJ 2) induces IL-8 and GM-CSF production, the role of 15d-PGJ 2 ...
TY - JOUR. T1 - Peroxisome proliferator-activated receptor γ level contributes to structural integrity and component production of elastic fibers in the aorta. AU - Tai, Haw Chih. AU - Tsai, Pei Jane. AU - Chen, Ju Yi. AU - Lai, Chao Han. AU - Wang, Kuan Chieh. AU - Teng, Shih Hua. AU - Lin, Shih Chieh. AU - Chang, Alice Y.W.. AU - Jiang, Meei Jyh. AU - Li, Yi Heng. AU - Wu, Hua Lin. AU - Maeda, Nobuyo. AU - Tsai, Yau Sheng. PY - 2016/6/1. Y1 - 2016/6/1. N2 - Loss of integrity and massive disruption of elastic fibers are key features of abdominal aortic aneurysm (AAA). Peroxisome proliferator-activated receptor γ (PPARγ) has been shown to attenuate AAA through inhibition of inflammation and proteolytic degradation. However, its involvement in elastogenesis during AAA remains unclear. PPARγ was highly expressed in human AAA within all vascular cells, including inflammatory cells and fibroblasts. In the aortas of transgenic mice expressing PPARγ at 25% normal levels (PpargC/- mice), we ...
Background: In Hashimotos thyroiditis (HT), there is evidence for activation of peripheral T-lymphocytes that predominantly express a T helper 1 (TH1) cytokine bias. However, the immunomodulatory factors involved in regulating this response have so far received scant attention. In this study, we examine the effects of the glucocorticoid, dexamethasone, and the peroxisome proliferator-activated receptor-γ (PPAR-γ) ligand, rosiglitazone on the expression of interferon (IFN)-γ (TH1) and interleukin (IL)-4 (TH2) by activated peripheral CD4+ and CD8+ lymphocytes in patients with HT (n = 10) and healthy control subjects (n = 12). Methods: Peripheral blood mononuclear cells (PBMC) were stimulated in vitro with phorbolmyristate acetate (PMA) and ionomycin in the presence or absence of varying doses of dexamethasone and rosiglitazone (0.01 µM, 1.0 µM, and 100 µM). Cytokine expression was determined by flow cytometry. Results: CD4+ and CD8+ IFN-γ expression was greater in HT than controls (14.87 ...
Background Peroxisome proliferator-activated receptors (PPARα, PPARγ, and PPARδ) are physiological sensors for glucose and lipid homeostasis. They are also the targets of synthetic drugs; such as fibrates as PPARα agonists which lower lipid level, and glitazones as PPARγ agonists which lower glucose level. As diabetes and metabolic diseases are often associated with high blood glucose and lipid levels, drugs that activate both PPARα/γ would be a logical approach. But synthetically developed PPARα/γ dual agonists and glitazones are showing side effects such as weight gain and edema. Therefore, natural compounds and their close derivatives are focused as future drugs against metabolic diseases. Presentation of hypothesis: Docosahexaenoic acid and eicosapentaenoic acid, which are the fatty acids abundant in fish oil, are traditionally used against metabolic diseases. These fatty acids act as PPAR agonists that transcript the genes involved in glucose and lipid homeostasis. Present ...
Peroxisome proliferator-activated receptor-gamma activators inhibit IFN-gamma-induced expression of the T cell-active CXC chemokines IP-10, Mig, and I-TAC in human endothelial cells. J Immunol. 2000 Jun 15; 164(12):6503-8 ...
A recent preclinical study has shown that not only maternal smoking but also grandmaternal smoking is associated with elevated pediatric asthma risk. Using a well-established rat model of in utero nicotine exposure, Rehan et al. have now demonstrated multigenerational effects of nicotine that could explain this grandmother effect. F1 offspring of nicotine-treated pregnant rats exhibited asthma-like changes to lung function and associated epigenetic changes to DNA and histones in both lungs and gonads. These alterations were blocked by co-administration of the peroxisome proliferator-activated receptor-γ agonist, rosiglitazone, implicating downregulation of this receptor in the nicotine effects. F2 offspring of F1 mated animals exhibited similar changes in lung function to that of their parents, even though they had never been exposed to nicotine. Thus epigenetic mechanisms appear to underlie the multigenerational transmission of a nicotine-induced asthma-like phenotype. These findings emphasize the
Aim: Peroxisome proliferator-activated receptor (PPAR) γ activation is associated with preferential lipoprotein lipase (LPL)-mediated fatty acid storage in peripheral subcutaneous fat depots. How PPARγ agonism acts upon the multi-level modulation of depot-specific lipid storage remains incompletely understood.. Methods: We evaluated herein triglyceride-derived lipid incorporation into adipose tissue depots, LPL mass and activity, mRNA levels and content of proteins involved in the modulation of LPL activity and fatty acid transport, and the expression/activity of enzymes defining adipose tissue lipogenic potential in rats treated with the PPARγ ligand rosiglitazone (30 mg kg−1 day−1, 23 days) after either a 10-h fasting period or a 17-h fast followed by 6 h of ad libitum refeeding.. Results: Rosiglitazone stimulated lipid accretion in subcutaneous fat (SF) ~twofold and significantly reduced that of visceral fat (VF) to nearly half. PPARγ activation selectively increased LPL mass, ...
TY - JOUR. T1 - Hyperglycemia, asymmetric dimethylarginine, and patient survival. T2 - Dysregulation of complex networks and the metabolic basis of disease. AU - Castillo, Leticia. AU - Al-Khadra, Eman. PY - 2005/3/1. Y1 - 2005/3/1. KW - Amino acid pool. KW - Asymmetric dimethylarginine. KW - Nutrients. KW - Peroxisome proliferator-activated receptor-γ. UR - http://www.scopus.com/inward/record.url?scp=14944354288&partnerID=8YFLogxK. UR - http://www.scopus.com/inward/citedby.url?scp=14944354288&partnerID=8YFLogxK. U2 - 10.1097/01.CCM.0000155775.30228.33. DO - 10.1097/01.CCM.0000155775.30228.33. M3 - Editorial. C2 - 15753766. AN - SCOPUS:14944354288. VL - 33. SP - 674. EP - 676. JO - Critical Care Medicine. JF - Critical Care Medicine. SN - 0090-3493. IS - 3. ER - ...
PPARγ is a member of the nuclear hormone receptor superfamily. It has been considered as a mediator regulating metabolism, anti-inflammation, and pro-proliferation in the Vascular Smooth Muscle Cells (VSMCs). Thiazolidinediones (TZDs), synthetic ligands of PPARγ, have anti-proliferative and pro-apoptotic effects on VSMCs, which prevent the formation and progression of atherosclerosis and restenosis following percutaneous coronary intervention (PCI). However, the underlying mechanism remains elusive. This present study therefore aimed to investigate the signaling pathway by which pioglitazone, one of TZDs, inhibits proliferation and induces apoptosis of VSMCs. The effects of pioglitazone on VSMC proliferation and apoptosis were studied. Cell proliferation was determined using BrdU incorporation assay. Cell apoptosis was monitored with Hoechst and Annexin V staining. The expression of caspases and cyclins was determined using real-time PCR and Western blot. Pioglitazone treatment and PPARγ
Title: From Dual Peroxisome Proliferator Activated Receptor Agonists to Selective Peroxisome Proliferator Activated Receptor Modulators. VOLUME: 2 ISSUE: 1. Author(s):Selcuk Dagdelen. Affiliation:Hambleden Court 9b, Burrow Road, St Francis Place, East Dulwich SE22 8DE, London/UK.. Keywords:Peroxisome proliferator activated receptors, dual PPAR agonists, SPPARMs, type 2 diabetes, metabolic syndrome, atherosclerosis, GW0072, FK614, AMG131, nTZDpa. Abstract: Worldwide epidemic of type 2 diabetes mellitus, obesity, dyslipidemia, hypertension and atherosclerosis (i.e. metabolic syndrome) still requires further treatment strategies. Life style change can be regarded as single evidenced option to manage these co-morbid conditions, at the same time. Peroxisome proliferator activated receptors (PPARs) are claimed to play critical roles in metabolic adaptation to changing environmental factors. PPAR alpha and gamma agonists are approved as hypolipidemic and antidiabetic agents, respectively. Combination ...
Migration and proliferation of vascular cells not only play an important role in the pathogenesis of atherosclerotic lesion formation, but also contribute to restenosis after therapeutic angioplasty. Therefore, pharmacological strategies for the prevention and/or treatment of atherosclerotic and restenotic vascular lesions are of great clinical interest. This involves substances that can be locally administered via stents, as well as agents that are already in clinical use for the treatment of metabolic risk factors. Among the latter, antidiabetic thiazolidinediones which function as ligands for the peroxisome proliferator-activated receptor gamma (PPARg), have been identified as promising drugs to target vascular lesion formation. PPARs constitute a group of novel regulators of gene expression, that exert several vascular effects. We report that vascular smooth muscle cell proliferation and migration is inhibited by PPARg-ligands. Investigating the signalling steps that are involved, we find ...
Peroxisome proliferator-activated receptor a and estrogen are believed to he involved in metabolic changes leading to obesity. To test this relationship, we divided female wildtype and PPAR alpha-deficient mice fed on a high fat diet into the following groups: mock-operated, ovariectomized (OVX), and E(2)-treated. The visceral white adipose tissue and plasma cholesterol levels were increased significantly in wild type OVX and decreased in the E(2)-treated group, but interestingly not in PPAR alpha-deficient mice. The mRNA levels of lipoprotein lipase in adipose tissue were also increased in only wild type OVX and decreased significantly in E(2)-treated mice. These novel results suggest the possibility of signaling crosstalk between PPAR alpha and E(2), causing obesity in vivo. [BMB reports 2009; 42(2): 91-95 ...
TY - JOUR. T1 - Indol-1-yl acetic acids as peroxisome proliferator-activated receptor agonists. T2 - Design, synthesis, structural biology, and molecular docking studies. AU - Mahindroo, Neeraj. AU - Wang, Chiung Chiu. AU - Liao, Chun Chen. AU - Huang, Chien Fu. AU - Lu, I. Lin. AU - Lien, Tzu Wen. AU - Peng, Yi Huei. AU - Huang, Wei Jan. AU - Lin, Ying Ting. AU - Hsu, Ming Chen. AU - Lin, Chia Hui. AU - Tsai, Chia Hua. AU - Hsu, John T A. AU - Chen, Xin. AU - Lyu, Ping Chiang. AU - Chao, Yu Sheng. AU - Wu, Su Ying. AU - Hsieh, Hsing Pang. PY - 2006/2/9. Y1 - 2006/2/9. N2 - A series of novel indole-based PPAR agonists is described leading to discovery of 10k, a highly potent PPAR pan-agonist. The structural biology and molecular docking studies revealed that the distances between the acidic group and the linker, when a ligand was complexed with PPARγ protein, were important for the potent activity. The hydrophobic tail part of 10k makes intensive hydrophobic interaction with the PPARγ protein ...
In the field of molecular biology, the peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes. PPARs play essential roles in the regulation of cellular differentiation, development, and metabolism (carbohydrate, lipid, protein), and tumorigenesis of higher organisms. Three types of PPARs have been identified: alpha, gamma, and delta (beta): α (alpha) - expressed in liver, kidney, heart, muscle, adipose tissue, and others β/δ (beta/delta) - expressed in many tissues but markedly in brain, adipose tissue, and skin γ (gamma) - although transcribed by the same gene, this PPAR through alternative splicing is expressed in three forms: γ1 - expressed in virtually all tissues, including heart, muscle, colon, kidney, pancreas, and spleen γ2 - expressed mainly in adipose tissue (30 amino acids longer than γ1) γ3 - expressed in macrophages, large intestine, white adipose tissue. PPARs ...
Transcriptional coactivator for steroid receptors and nuclear receptors. Greatly increases the transcriptional activity of PPARG and thyroid hormone receptor on the uncoupling protein promoter. Can regulate key mitochondrial genes that contribute to the program of adaptive thermogenesis. Plays an essential role in metabolic reprogramming in response to dietary availability through coordination of the expression of a wide array of genes involved in glucose and fatty acid metabolism. Induces the expression of PERM1 in the skeletal muscle in an ESRRA-dependent manner. Also involved in the integration of the circadian rhythms and energy metabolism. Required for oscillatory expression of clock genes, such as ARNTL/BMAL1 and NR1D1, through the coactivation of RORA and RORC, and metabolic genes, such as PDK4 and PEPCK. Isoform 4 specifically activates the expression of IGF1 and suppresses myostatin expression in skeletal muscle leading to muscle fiber hypertrophy.
PPAR Research is a peer-reviewed, Open Access journal that publishes original research and review articles on advances in basic research, as well as preclinical and clinical trials, involving Peroxisome Proliferator-Activated Receptors (PPARs).
Peroxisome proliferator-activated receptor(PPARagonists to promote tumorigenesis in some organs. elevated PDK1 Akt an infection [3-5] that tend exacerbated in sufferers with proinflammatory gene polymorphisms [6]. PPARs are ligand-dependent nuclear receptors that regulate appearance of the multiplicity of genes connected with metabolic disorders Rabbit polyclonal to Smad7. such as for example type II diabetes and lipodystrophies [7 8 PPARs contain the and isotypes that regulate not merely blood sugar and lipid fat burning capacity but also proliferation irritation and angiogenesis [9-13]. PPARexpression is normally increased in breasts colon and mind and neck malignancies [9 14 and it is associated with a far more intense phenotype in breasts cancer tumor MRS 2578 cells [18]. The selective PPARagonist type:entrez-nucleotide attrs :text:GW501516″ term_id :289075981″ term_text :GW501516″GW501516 works as a tumor promoter in mammary carcinogenesis [19] and digestive MRS 2578 tract ...
Herrmann J, Rubin D, Häsler R, Helwig U, Pfeuffer M, Auinger A, Laue C, Winkler P, Schreiber S, Bell D, Schrezenmeir J (2009); Lipids Health Dis., 8:35. doi: 10.1186/1476-511X-8-35. ...
Chronic pain presents a widespread and intractable medical problem. While numerous pharmaceuticals are used to treat chronic pain, drugs that are safe for extended use and highly effective at treating the most severe pain do not yet exist. Chronic pain resulting from nervous system injury (neuropathic pain) is common in conditions ranging from multiple sclerosis to HIV-1 infection to type II diabetes. Inflammation caused by neuropathy is believed to contribute to the generation and maintenance of neuropathic pain. Chemokines are key inflammatory mediators, several of which (MCP-1, RANTES, MIP-1α, fractalkine, SDF-1 among others) have been linked to chronic, neuropathic pain in both human conditions and animal models. The important roles chemokines play in inflammation and pain make them an attractive therapeutic target. Peroxisome proliferator-activated receptors are a family of nuclear receptors known for their roles in metabolism. Recent research has revealed that PPARs also play a role in
Search for abbreviations and long forms in lifescience, results along with the related PubMed / MEDLINE information and co-occurring abbreviations.
Glass, C.K. (2001) Potential roles of the peroxisome proliferator-activated receptorγ in macrophage biology and atherosclerosis. Journal of Endo-crinology, 169, 461-464. doi10.1677/joe.0.1690461
In atherosklerotischen Gefäßabschnitten kommt es durch Migration von Endothelzellen zur Neovaskularisation atherosklerotischer Plaques. Die Adhäsionsmoleküle E-Selectin, VCAM-1 und ICAM-1, die sowohl von luminalen, als auch von neovaskulären Endothelzellen exprimiert werden, vermitteln die Adhäsion von Leukozyten, die so durch die Endothel-Barriere hindurch an den Entzündungsort migrieren können. Peroxisome Proliferator-Activated Receptors (PPARs) sind ligand-aktivierte Kernrezeptoren, die als Transkriptionsfaktoren hauptsächlich an der Genregulation im Fett- und Glukosestoffwechsel beteiligt sind und zudem Wirkungen im kardiovaskulären System haben. In der vorliegenden Arbeit wurden die Effekte der PPAR-alpha-Liganden WY-14,643 und Fenofibrat und der PPAR-gamma-Liganden Troglitazon und Ciglitazon auf die Migration von Endothelzellen sowie die Beeinflussung der dabei involvierten Komponenten der Signaltransduktion und die Wirkung der PPAR-Liganden auf die Expression der endothelialen ...
Peroxisome proliferator-activated receptor (PPAR)-gamma ligands are insulin sensitizers, widely used in the treatment of type 2 diabetes. A consistent observation in preclinical species is the development of cardiac hypertrophy after short-term treatment with these agents. The mechanisms for this hy …
Adipocyte differentiation is a developmental process that is critical for metabolic homeostasis and nutrient signaling. The mammalian target of rapamycin (mTOR) mediates nutrient signaling to regulate cell growth, proliferation, and diverse cellular differentiation. It has been reported that rapamycin, the inhibitor of mTOR and an immunosuppressant, blocks adipocyte differentiation, but the mechanism underlying this phenomenon remains unknown. Here we show that mTOR plays a critical role in 3T3-L1 preadipocyte differentiation and that mTOR kinase activity is required for this process. Rapamycin specifically disrupted the positive transcriptional feedback loop between CCAAT/enhancer-binding protein-alpha and peroxisome proliferator-activated receptor-gamma (PPAR-gamma), two key transcription factors in adipogenesis, by directly targeting the transactivation activity of PPAR-gamma. In addition, we demonstrate for the first time that PPAR-gamma activity is dependent on amino acid sufficiency, ...
0068] RNA binding proteins as referred to in the methods (and which show a statistically significant change and a fold change of 1.5× either up or down in mesenchymal cells compared to control epithelial cells): RNA binding motif protein 35A; RNA binding motif protein 35B; poly(A) binding protein, cytoplasmic 1-like; ribosomal protein L3-like; eukaryotic translation initiation factor 5A-like 1; nuclear receptor subfamily 0, group B, member 1; RNA binding motif protein 47; peroxisome proliferator-activated receptor gamma, coactivator 1 beta; zinc finger protein 36, C3H type, homolog; splicing factor, arginine/serine-rich 16; tRNA splicing endonuclease 54 homolog; peroxisomal proliferator-activated receptor A interacting complex 285; DEAD (Asp-Glu-Ala-Asp) box polypeptide 51; ribonuclease P/MRP 25 kDa subunit; DEAD/H (Asp-Glu-Ala-Asp/His) box polypeptide 11 (CRL1-like helicase homolog); PRP40 pre-mRNA processing factor 40 homolog B; telomerase reverse transcriptase; pseudouridylate synthase-like ...
PubMed comprises more than 30 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.
2010). Zhang HL: Neuroprotective effects of pioglitazone in a rat model of permanent focal cerebral ischemia are associated with peroxisome proliferatoractivated receptor gamma-mediated suppression of nuclear factor kappa-B signaling pathway. Neuroscience ...
Because of their various metabolic and therapeutic actions, PPARs have become major drug targets (Berger et al., 2005; Staels and Fruchart, 2005). As clinical data continue to accumulate regarding current and emerging PPAR modulators, an important distinction must be maintained between the action of PPARs in vivo under normal physiologic and natural ligand production conditions and the effects of synthetic PPAR agonists, which may vary as a function of many pharmacologic and other parameters.. PPARα agonists, such as fibrates, effectively treat dyslipidemia and may have significant anti-inflammatory and antiatherosclerotic activity. Associated with their clinical effectiveness, PPARα agonists decrease plasma triglyceride levels by stimulating lipid uptake and catabolism and augment HDL-C levels by increasing the production, in the liver, of the apolipoproteins A-I and A-II, which are major components of HDL-C (Bays and Stein, 2003). PPARα agonists have also demonstrated anti-inflammatory ...
This gene encodes a member of the peroxisome proliferator-activated receptor (PPAR) subfamily of nuclear receptors. PPARs form heterodimers with retinoid X receptors (RXRs) and these heterodimers regulate transcription of various genes. Three subtypes of PPARs are known: PPAR-alpha, PPAR-delta, and PPAR-gamma. The protein encoded by this gene is PPAR-gamma and is a regulator of adipocyte differentiation. Additionally, PPAR-gamma has been implicated in the pathology of numerous diseases including obesity, diabetes, atherosclerosis and cancer. Alternatively spliced transcript variants that encode different isoforms have been described. [provided by RefSeq, Jul 2008 ...
TY - JOUR. T1 - PPARγ targeted oral cancer treatment and additional utility of genomics analytic techniques. AU - Handley, Nathan. AU - Eide, Jacob. AU - Taylor, Randall. AU - Wuertz, Beverly. AU - Gaffney, Patrick. AU - Ondrey, Frank. PY - 2017/4/1. Y1 - 2017/4/1. N2 - Objective: Peroxisome proliferator-activated receptor γ (PPARγ) agonists have been shown to have anti-proliferative, anti-angiogenic, and proapoptotic effects, leading to interest in their use as cancer therapeutics. Pioglitazone, a U.S. Food and Drug Administration-approved type II diabetes medication and PPARγ agonist, may have a role in adjuvant head-and-neck squamous cell carcinoma treatment or prevention. Therefore, the purpose of this study was: 1) to treat oral cavity cancer cells with the PPARγ activator, pioglitazone, to analyze gene expression changes; and 2) to compare those changes with our preexisting genomic data for development of hypothesis-driven additional basic and clinical studies. Study Design: ...
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The health benefits of botanicals is linked to their phytochemicals that often exert pleiotropic effects via targeting multiple molecular signaling pathways such as the peroxisome proliferator-activated receptors (PPARs) and the nuclear factor kappaB (NFκB). The PPARs are transcription factors that control metabolic homeostasis and inflammation while the NF-κB is a master regulator of inflammatory genes such as the inducible nitric-oxide synthase that result in nitric oxide (NO) overproduction. Extracts of Maerua subcordata (MS) and selected candidate constituents thereof, identified by liquid chromatography coupled to mass spectroscopy, were tested for their ability to induce PPARγ mediated gene expression in U2OS-PPARγ cells using luciferase reporter gene assay and also for their ability to inhibit lipopolysaccharide (LPS) induced NO production in RAW264.7 macrophages. While measuring the effect of test samples on PPARγ mediated gene expression, a counter assay that used U2OS-Cytotox cells was
Background Hemolytic uremic syndrome (HUS) resulting in acute kidney failure, is usually a condition linked to the production of primarily Shiga toxin 2 (Stx2) by some serotypes. investigated the likely site(s) of Stx2/antibody localization and clearance in intoxicated mice treated with antibody or placebo. Results Mice were injected with radiolabeled Stx2 (125I-Stx2) 4 hours after administration of 5C12, 5H8, or phosphate buffered saline (PBS) and the sites of localization of labeled Stx2, were investigated 3, 24 and 48 hours later. The liver recorded statistically much higher concentrations of labeled Stx2 for groups receiving 5C12 and 5H8 antibodies after 3, 24 and 48?hours, as compared with the PBS group. In contrast, highest levels of labeled Stx2 were detected in the kidneys of the PBS group at all 3 sampling occasions. Mice receiving either of the two HuMAbs were fully guarded against the lethal effect of Stx2, as compared with the fatal outcome of the control group. Conclusions The ...