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 ...

Background Peroxisome proliferator-activated receptors (PPARs) are ligand activated transcription factors belonging to the nuclear receptor superfamily. PPARs activation has a profound impact on the local immune response with consequences affecting the progression of chronic inflammatory diseases. Relatively little is known on the role of PPAR-β/δ in the regulation of inflammatory responses. The aim of the present study was to evaluate the influence of PPAR-β/δ receptor in a model of edematous pancreatitis induced in mice by administration of cerulein at supramaximal doses, as well as in necrohemorrhagic model induced by intraductal administration of sodium taurocholate (STC). Measurements Mice were treated with cerulein (50 μg/kg) or STC (5%). GW0742 (0.3 mg/kg) was intraperitoneally administered 1 and 6 hours after cerulein injection or was injected 2 hours before STC infusion. The pancreas and exopancreatic organs were carefully removed for microscopic examination. Pancreatic weight, ...

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 ...

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

OA was surgically induced in dogs by sectioning of the anterior cruciate ligament. The dogs were then randomly divided into 3 treatment groups in which they were administered either placebo, 15 mg/day pioglitazone, or 30 mg/day pioglitazone orally for 8 weeks. Following treatment, the severity of cartilage lesions was scored. Cartilage specimens were processed for histologic and immunohistochemical evaluations; specific antibodies were used to study the levels of matrix metalloproteinase 1 (MMP-1), ADAMTS-5, and inducible nitric oxide synthase (iNOS), as well as phosphorylated MAPKs ERK-1/2, p38, JNK, and NF-κB p65. ...

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2F4B: Indol-1-yl Acetic Acids as Peroxisome Proliferator-Activated Receptor Agonists: Design, Synthesis, Structural Biology, and Molecular Docking Studies

The major findings of the present study were: (1) PPARγ ligands suppressed the growth response of colon cancer cells whereas ligands for PPARα and PPARδ did not. (2) PPARγ ligand induced apoptosis in HT-29 cells was associated with downregulation of c-myc expression and upregulation of c-jun and gadd153 expression. (3) PPARγ ligand induced apoptosis in HT-29 cells was antagonised by signalling mediated through PI3-kinase.. Induction of apoptosis by PPARγ ligands has been reported in several cell types, including macrophages,15 endothelial cells,16 breast cancer cells,17 and choriocarcinoma cells.18 In the present study, we showed that PPARγ ligands induced apoptosis in HT-29 cells and that cell death induced by PPARγ ligands was antagonised when serum was present in the culture medium. Bishop-Bailey16 observed the protective effects of serum against PPARγ ligand induced apoptosis in endothelial cells. This may be explained by the presence of polypeptide growth factors and other cell ...

Obesity-related cardiovascular risk, end points, and mortality are strongly related to arterial stiffening. Current therapeutic approaches for arterial stiffening are not focused on direct targeting within the vessel. Perivascular adipose tissue (PVAT) surrounding the artery has been shown to modulate vascular function and inflammation. Peroxisome proliferator-activated receptor γ (PPARγ) activation significantly decreases arterial stiffness and inflammation in diabetic patients with coronary artery disease. Thus, we hypothesized that PPARγ activation alters the PVAT microenvironment, thereby creating a favorable environment for the attenuation of arterial stiffening in obesity. Obese ob/ob mice were used to investigate the effect of PPARγ activation on the attenuation of arterial stiffening. Various cell types, including macrophages, fibroblasts, adipocytes, and vascular smooth muscle cells, were used to test the inhibitory effect of pioglitazone, a PPARγ agonist, on the expression of elastolytic

In the present study, the EBI was aggravated at 24 hours after SAH in rats. Higher mortality and more severe neurological deficits were observed in SAH-operated animals when BBB permeability, brain water content, and apoptotic cells increased. The above trend of mortality, neurological deficits, brain injury, and neuronal apoptosis were further aggravated by PPARβ/δ silenced, whereas NF-κB and MMP-9 expression were enhanced obviously. However, when we used PPARβ/δ adenovirus to upregulate its expression with suppression of NF-κB and MMP-9 expression, the poor outcome of EBI included neuronal apoptosis after SAH was improved dramatically. In addition, the administration of GW0742 improved neurological deficits and BBB injury at 24 hours after SAH.. PPARs are ligand-activated transcription factors that belong to the nuclear hormone receptor family. Three isotypes are named by PPARα, PPARβ/δ, and PPARγ. It is reported recently that PPARγ protects against the development of aneurismal ...

In adult, bone remodeling is a permanent process, reaching an annual turnover of about 10% of the skeleton. Bone remodeling requires the sequential and coordinated actions of the hematopoietic origin osteoclasts, to remove bone and the mesenchymal origin osteoblasts to replace it. An increased level of bone resorption is the primary cause of age-related bone loss often resulting in osteopenia, and is the major cause of osteoporosis.¦Peroxisome proliferator-activated receptors (PPARs), which are expressed in three isotypes, PPARa, PPARp and PPARy, are ligand-activated transcription factors that control many cellular and metabolic processes, more particularly linked to lipid metabolism. In bone, previous works has shown that PPARy inhibits osteogenesis by favoring adipogenesis from common mesenchymal progenitors. In addition, the pro-osteoclastogenesis activity of PPARy results in an increased bone resorption. Accordingly, treatment with PPARy agonist such as the anti-diabetic drug TZD c

Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors that have begun to receive considerable attention in studies of vascular biology.28,29 There are 3 subtypes of PPARs (PPARα, PPARβ/δ, and PPARγ) that regulate gene expression by binding to PPAR-response elements in target genes. Emerging evidence, based on work with vascular cells in culture and in extracranial blood vessels, suggests that these transcription factors may exhibit multiple protective effects within the vessel wall, including antiinflammatory, antiatherogenic, and antihypertensive effects. For example, although initially thought to be restricted to adipose tissue, PPARγ is now known to be expressed in both endothelium and vascular muscle. Activation of PPARγ reduces the secretion of endothelin, decreases activation of nuclear factor-κB and expression of adhesion molecules, and reduces expression of NAD(P)H oxidase (a major source of superoxide in vascular cells) and receptors for ...

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, ...

ABCA1 is a rate-limiting step for HDL assembly, and regulation of its function is important for the control of the plasma HDL level.33 Expression of the ABCA1 gene is regulated primarily by the liver X receptor (LXR)/retinoid X receptor (RXR) system.92-95 A physiological ligand for LXR is oxysterol, and this ligand may increase in proportion to the cellular cholesterol level. ABCA1 is indeed upregulated by loading cells with cholesterol or inhibiting its intracellular esterification and downregulated by depleting cholesterol (Figure 1).96-98 Agonists of both receptors have also been shown to upregulate the ABCA1 gene, increase the cellular ABCA1 level, and enhance the release of cellular lipid by apoA-I.99 Thus, ABCA1 is likely to function for cholesterol homeostasis to reduce cellular cholesterol when it is overloaded.. The ABCA1 gene is upregulated also by other factors. Peroxidase proliferator-activated receptor α agonists and fibric acids increase its transcription in an LXR-dependent ...

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 ...

PPARγ is constitutively expressed in several cell types, including adipocytes, endothelial cells, smooth muscle cells, epithelial cells, macrophages, and related cells of the immune system (6, 11, 21). In our study we observed that during polymicrobial sepsis, the expression of PPARγ is altered in the lung and in the vasculature. We demonstrated that PPARγ expression was down-regulated in the bronchial epithelium and in smooth muscle and endothelial cells of the thoracic aorta. Interestingly, the expression of PPARγ decreased in a time-dependent fashion during sepsis. This temporal decrease correlated well with the occurrence of hypotension and the severity of the inflammatory response. Treatment with the PPARγ ligands caused up-regulation of PPARγ to normal constitutive expression. Previous studies have also suggested that PPARγ expression may be altered in an inflammatory process. In adipose tissue, mRNA and protein expression decreased after mice were challenged in vivo with endotoxin ...

Oxidative stress is one of the major pathogenesis of chronic obstructive pulmonary disease (COPD). -Glutamylcysteine synthetase (-GCS) is one of the paramount antioxidant enzymes in COPD. Peroxisome proliferator-activated receptor-gamma (PPAR) is a ligand-activated transcription factor, which is activated by specific ligands such as rosiglitazone (RGZ), exerting multiple biological effects. PPAR coactivator-1 (PGC-1) is a PPAR coactivator, which binds to PPAR by induction of PPAR ligands, co-activating PPAR target genes. Growing evidence has suggested that PPAR/PGC-1 can regulate multiple antioxidant genes. However, the effect of PPAR/PGC-1 on -GCS during the development of COPD remains unclear. Here, we measured the expression levels of PPAR, PGC-1 and -GCS, -GCS activity and reactive oxygen species (ROS) contents in lungs of rats treated by cigarette smoke (CS) + lipopolysaccharide (LPS) and CS + LPS + RGZ, as well as lungs of patients suffered from COPD. Compared with lungs from CS + ...

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.

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 ...

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.

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

Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that are activated by fatty acids and their derivatives. PPAR has three subtypes (PPARalpha, beta/delta, and gamma) showing different expression patterns in vertebrates. Each of them is encoded in a separate gene and binds fatty acids and eicosanoids. PPARalpha plays a role in the clearance of circulating or cellular lipids via the regulation of gene expression involved in lipid metabolism in liver and skeletal muscle. PPARbeta/delta is involved in lipid oxidation and cell proliferation. PPARgamma promotes adipocyte differentiation to enhance blood glucose uptake ...

Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that are activated by fatty acids and their derivatives. PPAR has three subtypes (PPARalpha, beta/delta, and gamma) showing different expression patterns in vertebrates. Each of them is encoded in a separate gene and binds fatty acids and eicosanoids. PPARalpha plays a role in the clearance of circulating or cellular lipids via the regulation of gene expression involved in lipid metabolism in liver and skeletal muscle. PPARbeta/delta is involved in lipid oxidation and cell proliferation. PPARgamma promotes adipocyte differentiation to enhance blood glucose uptake ...

Supplementary Materialsawz288_Supplementary_Data. analysis. Specifically, we discovered that A2AR overexpression in THY-Tau22 mice resulted in the hippocampal upregulation of C1q go with proteinalso seen in individuals with frontotemporal lobar degenerationand correlated with the increased loss of glutamatergic synapses, most likely underlying the noticed memory space deficits. These data reveal an integral effect of overactive neuronal A2AR in the starting point of synaptic reduction in tauopathies, paving the true method for new therapeutic approaches. gene coding tau (Hutton P301L mutation. Promoting neuronal A2AR upregulation inside a tauopathy mouse model (THY-Tau22) resulted in a hippocampal upregulation of C1q go with protein connected with a lack of glutamatergic synapses and a potentiation of spatial memory space deficits, suggesting an instrumental role of neuronal A2AR dysregulation towards tau pathology-induced cognitive alterations. Materials and methods Post-mortem brain samples ...

The expression of PPARγ and the effects of dietary PPARγ ligands, such as fish oil, on cell growth have been extensively studied in many carcinoma cell types, including lung cancer (3, 7). However, the exact mechanisms mediating the effects of dietary PPARγ ligands on cell growth inhibition are not fully understood. Fish oil, which is an activator of PPARγ, contains PUFAs of the ω3 and ω6 family and is believed to have anticancer properties (4-6). In this study, we show that fish oil inhibits human lung carcinoma cell growth through suppression of ILK gene expression, suggesting that ILK represents a target for PPARγ ligands. Interestingly, fish oil had little effect on the growth of normal cells and this seems to correlate with the relative lower PPARγ protein levels found in normal cells.. The concentrations of fish oil used in this study are similar or even lower than those reported by others showing inhibition of cell growth and invasion (22, 23). One study found that fish oil at a ...

Prof. Michalik, could you briefly explain: what are PPARs?. LM: PPARs are transcription factors of the nuclear hormone receptor family, discovered around the early 90´s, that form part of a cellular sensing system. As such, they are capable of reading molecular signals - more specifically: fatty acids and derivatives, which function as agonists - and provoking an all-encompassing transcriptional response, allowing cells to adapt to the environment. In mammals, there are four PPAR proteins - PPARα, PPARβ and PPARγ1 and PPARγ2, referred together as PPARγ - which play essential roles in the regulation of cellular differentiation, development, metabolism and tumorigenesis of higher organisms. For example, PPARα is involved in energy homeostasis and cholesterol metabolism, and plays a role during the inflammatory response; PPARβ is also involved in energy homeostasis, apart from its role in regulating the activity of heart and skeletal muscles; and PPARγ is a major actor in adipose ...

The fasting-induced adipose factor (FIAF, ANGPTL4, PGAR, HFARP) was previously identified as a novel adipocytokine that was up-regulated by fasting, by peroxisome proliferator-activated receptor agonists, and by hypoxia. To further characterize FIAF, we studied regulation of FIAF mRNA and protein in liver and adipose cell lines as well as in human and mouse plasma. Expression of FIAF mRNA was up-regulated by peroxisome proliferator-activated receptor α (PPARα) and PPARβ/δ agonists in rat and human hepatoma cell lines and by PPARγ and PPARβ/δ agonists in mouse and human adipocytes. Transactivation, chromatin immunoprecipitation, and gel shift experiments identified a functional PPAR response element within intron 3 of the FIAF gene. At the protein level, in human and mouse blood plasma, FIAF was found to be present both as the native protein and in a truncated form. Differentiation of mouse 3T3-L1 adipocytes was associated with the production of truncated FIAF, whereas in human white ...

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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, ...

PPAR expression and its association with SOD and NF-?B in rats with obstructive jaundice, Peng Gong, Haibo Xu, Jianing Zhang, Zhongyu Wang

Estrogens are necessary for ovarian differentiation during critical developmental windows in most vertebrates and promote the growth and differentiation of the adult female reproductive system. Estrogen actions are largely mediated through the estrogen receptors (ERs), which are ligand-activated transcription factors. To understand the molecular evolution of sex steroid hormone receptors, we isolated cDNAs encoding two steroid receptors from Japanese amphioxus, Branchiostoma belcheri: an ER ortholog and a ketosteroid receptor (SR) ortholog. Reporter gene assays revealed that the SR ortholog has molecular functions similar to those of the vertebrate ER. Surprisingly, the ER ortholog is an estrogen-insensitive repressor of SR-mediated transcription. Furthermore, we found that the SR ortholog can bind to both estrogen-responsive elements (EREs) and androgen-responsive elements (AREs) and mediates transcriptional activation by estrogens through both types of elements. Our findings suggest that the ...

Fingerprint Dive into the research topics of Bile acid-regulated peroxisome proliferator-activated receptor-α (PPARα) activity underlies circadian expression of intestinal peptide absorption transporter PepT1/Slc15a1. Together they form a unique fingerprint. ...

TY - JOUR. T1 - Selective modulation of PPARγ activity can lower plasma glucose without typical thiazolidinedione side-effects in patients with Type 2 diabetes. AU - Dunn, Fredrick L.. AU - Higgins, Linda S.. AU - Fredrickson, Jill. AU - Depaoli, Alex M.. PY - 2011/5. Y1 - 2011/5. N2 - Objective: INT131 besylate is a potent non-thiazolidinedione selective peroxisome proliferator-activated receptor γ (PPARγ) modulator (SPPARM) designed to improve insulin sensitivity and glucose metabolism while minimizing the side effects of full agonist thiazolidinediones. This study was conducted to determine short-term efficacy and safety of INT131 besylate in patients with Type 2 diabetes mellitus (T2DM). Research Design and Methods: This was a 4-week randomized, double-blind, placebo-controlled multi-center study with 1 or 10mg INT131 besylate or placebo daily in subjects with T2DM not receiving pharmacotherapy for their hyperglycemia. The primary efficacy analysis was the comparison of treatment groups ...

Nuclear receptors are transcription factors that are activated upon binding to its ligands. Initially, they had been classified as classic endocrine nuclear hormone receptors and orphan receptors. However, further studies have led to the identification of lipid ligands for some of these adopted orphan receptors, which are responsible for lipid metabolism, storage or elimination. One of the characteristics of these receptors is that they act by forming heterodimers with retinoid X receptor (RXR). The receptors include peroxisome proliferators-Activated receptors (PPARs) for fatty acids, liver X receptor (LCR) for oxysterols, Farnesoid X receptors (FXR) for bile acids and steroid xenobiotic receptor/X receptor (SXR/PXR or Nsil2) for xenobiotics. Other orphan receptors also require RXR for its functions are vitamin D receptor (VDR) for vitamin D and retinoic acid receptor (RAR) for retinoid acids, although these receptors are not involved in lipid metabolism. Upon binding to various ligands, three ...

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.

To study the effects of acquired cardiac ATGL deficiency on cardiac PPARα activity, function, and metabolism, we generated adult mice with tamoxifen-inducible cardiomyocyte-specific ATGL deficiency (icAtglKO). Within 4-6 weeks following ATGL ablation, icAtglKO mice had markedly increased myocardial TAG accumulation, fibrotic remodelling, and pathological hypertrophy. Echocardiographic analysis of hearts in vivo revealed that contractile function was moderately reduced in icAtglKO mice. Analysis of energy metabolism in ex vivo perfused working hearts showed diminished FAO rates which was not paralleled by markedly impaired PPARα target gene expression.. ...

Among the gene expressions tested in this study, only c-myb and cyclin D2 gene expression were inhibited by both PPARα and PPARγ ligands. However, the effective concentrations are higher for PPARα ligands with respect to PPARγ ligands, according to that observed on cell growth inhibition and cell differentiation induction.. Cell cycle analysis indicates that an increase of G0/G1 cells occurs in the culture treated with PPAR ligands, and in particular with 15d-PGJ2, according to data reported by others (Scatena et al., 1999; Kawakami et al., 2002). 15d-PGJ2 also increases the sub-G0/G1 population 2 and 3 days after the treatment.. The down-regulations of c-myb and cyclin D2 expression represent the first evidence of the inhibitory effect exerted by PPAR ligands on these genes. The myb gene family (whose members are A-myb, B-myb, and c-myb) encodes nuclear protein that functions as a transcriptional transactivator (Oh and Reddy, 1999). Expression of these genes is cell cycle-regulated, and ...

PPAR agonists are drugs which act upon the peroxisome proliferator-activated receptor. They are used for the treatment of symptoms of the metabolic syndrome, mainly for lowering triglycerides and blood sugar. PPAR-alpha and PPAR-gamma are the molecular targets of a number of marketed drugs. The main classes of PPAR agonists are: PPARα (alpha) is the main target of fibrate drugs, a class of amphipathic carboxylic acids (clofibrate, gemfibrozil, ciprofibrate, bezafibrate, and fenofibrate). They were originally indicated for cholesterol disorders and more recently for disorders that feature high triglycerides. PPARγ (gamma) is the main target of the drug class of thiazolidinediones (TZDs), used in diabetes mellitus and other diseases that feature insulin resistance. It is also mildly activated by certain NSAIDs (such as ibuprofen) and indoles, as well as from a number of natural compounds. Known inhibitors include the experimental agent GW-9662. They are also used in treating hyperlipidaemia in ...

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, … ...

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 ...

The aims of this study were to investigate the relative distribution of PPAR-γs in SAT and VAT of a large population of obese women and to evaluate their possible pathophysiological implication in human obesity. The two major observations of our study are that 1) PPAR-γ2 is more abundant than PPAR-γ1 in SAT and VAT and 2) PPAR-γ1 is differentially regulated, being expressed at higher levels in SAT than VAT. In addition, both VAT and SAT levels of PPAR-γ1 are major determinants of the variability of waist circumference, and stepwise regression analysis indicates that PPAR-γ1 in SAT may be implicated in the determination of plasma insulin levels. Given the number of patients included as well as their wide range of anthropometric and biochemical characteristics, these results can probably be extrapolated to individual obese women. However, whether they can also be extrapolated to male patients remains an open question.. The chain of events, from biopsy to measurement of PPAR expression, was ...

In this study we report the behavior of two PPAR enantiomeric ligands (R-1 and S-1). Cell-based reporter assays indicate that both enantiomers are dual PPAR/ ligands, being R-1 a full agonist of PPAR and and S-1 a partial agonist of PPAR. 3D-structure analysis of the PPAR ligand binding domain in the complex with the two ligands shows that the suboptimal conformation of helix 12 in the PPAR/S-1 complex is the consequence of a steric hindrance between the ethyl group of the ligand and the Q286 in helix 3. Site-directed mutagenesis confirms that Q286 is a key residue in determining the activity of different ligands. By using FRET assays, we found that the coactivators SRC-1, PGC-1, RIP140, TIF-2 are recruited by R-1, S-1 and rosiglitazone with similar EC50, whereas CBP affinity is higher in the presence of rosiglitazone. Conversely, only S-1 allows the association of the corepressor N-CoR to PPAR as opposed to rosiglitazone and R-1, providing a functional explanation to the partial agonist ...

Free Online Library: Peroxisome Proliferator-Activated Receptor Modulation during Metabolic Diseases and Cancers: Master and Minions.(Report) by PPAR Research; Biological sciences Antilipemic agents B cells Development and progression Physiological aspects Cardiovascular diseases Developing countries Mediation Metabolic diseases Nuclear receptors Obesity Type 2 diabetes

Tomkinson, Nicholas C. O. and Sefler, Andrea M. and Plunket, Kelli D. and Blanchard, Steven G. and Parks, Derek J. and Willson, Timothy M. (1997) Solid-phase synthesis of hybrid thiazolidinedione-fatty acid PPARγ ligands. Bioorganic and Medicinal Chemistry Letters, 7 (19). pp. 2491-2496. ISSN 0960-894X Full text not available in this repository.Request a copy from the Strathclyde author ...

Identification of PPARγ ligands with One-dimensional Drug Profile Matching Diána Kovács,1 Zoltán Simon,2,3 Péter Hári,2,3 András Málnási-Csizmadia,2,4,5 Csaba Hegedus,6 László Drimba,1 József Németh,1 Réka Sári,1 Zoltán Szilvássy,1 Barna Peitl,11Department of Pharmacology and Pharmacotherapy, University of Debrecen, Debrecen, Hungary; 2Drugmotif, Ltd, Veresegyház, Hungary; 3Printnet, Ltd, Budapest, Hungary; 4Department of Biochemistry, Institute of Biology, Eötvös Loránd University, Budapest, Hungary; 5Molecular Biophysics Research Group, Hungarian Academy of Sciences - Eötvös Loránd University, Budapest, Hungary; 6Cera-Med Ltd, Debrecen-Józsa, HungaryIntroduction: Computational molecular database screening helps to decrease the time and resources needed for drug development. Reintroduction of generic drugs by second medical use patents also contributes to cheaper and faster drug development processes. We screened, in silico, the Food and Drug Administration-approved generic

Hepatocellular carcinoma (HCC) is the leading cause of death in male cancer patients in Asia. PPARγ exhibited an inhibitory role in hepatocarcinogenesis in vitro and in vivo. Recently, it was found that honokiol functions not only as a RXR agonist but also a PPARγ agonist, and is capable of potentiating the activation of PPARγ in the presence of PPARγ agonist rosiglitazone in HLE human hepatoma cells. It also has been reported that honokiol exerts inhibitory effects on the growth and migration in hepatoma cells. However, whether PPARγ overexpression modulates the honokiol-induced growth inhibition in hepatoma cells is not known. Firstly, we examined the expression of PPARγ in tumor samples from 83 HCC patients by immunohistochemical staining. Our results showed that 53 samples had no PPARγ and the clinical parameters including tumor number, stages, and macroscopic vascular invasion (MVI) showed significant negative correlation with PPARγ expression. However, the expression of PPARγ was ...

We all examined the neural correlates of sitting cardiac vagal activity within a sample of 432 members (206 guy; 61 Dark-colored; mean their age 42 years). cardiac vagal activity. review of HF-HRV and all desapasionado blood flow attitudes were first of all computed allowing for an accurate calculations of standardised (β) regression weights (Friedrich 1982 First-order terms had been entered into you need to of the version (zHF-HRV and sex/race) NSC697923 and the multiplicative conditions were added in the second step (i. e. zHF-HRV * contest zHF-HRV 5. sex; Aiken & Western world 1991 Significant interaction conditions indicated the fact that the relationship among HF-HRV and cerebral the flow of blood differed by simply sex/race and were ultimately probed simply by computing basic slopes meant for the particular groups (men women; Western european Americans Africa Americans). As well as the ROIs defined in Desk 2 educational whole mind analyses were conducted using the same regression approach ...

PPAR (peroxisome proliferator-activated receptor) family members are among the most widely studied transcription factors. These nuclear receptor proteins exert transcription factor activities and influence multiple cellular events at the molecular level including cell differentiation and development, metabolism and carcinogenesis. This broad spectrum highlights that PPARs are key players of numerous physiological and pathological events. Amongst the PPAR family members, PPARgamma (known to exist in three variant forms) is of particular interest as it is broadly expressed in the mammalian body including all adipose tissue subtypes (white, brown, beige) and also in the intestine, kidneys, pancreas, muscles, placenta, spleen and thymus. As suggested by its expression pattern PPARgamma is indispensable for adipose tissue development, but has also multiple other, context-dependent functions.PPARgamma expression has been reported in several cell types and tissues directly related to immune function (i.e.

Full agonists to the peroxisome proliferator-activated receptor (PPAR)γ, such as Rosiglitazone, have been associated with a series of undesired side effects, such as weight gain, fluid retention, cardiac hypertrophy, and hepatotoxicity. Nevertheless, PPARγ is involved in the expression of genes that control glucose and lipid metabolism and is an important target for drugs against type 2 diabetes, dyslipidemia, atherosclerosis, and cardiovascular disease. In an effort to identify novel PPARγ ligands with an improved pharmacological profile, emphasis has shifted to selective ligands with partial agonist binding properties. Toward this end we applied an integrated in silico/in vitro workflow, based on pharmacophore- and structure-based virtual screening of the ZINC library, coupled with competitive binding and transactivation assays, and adipocyte differentiation and gene expression studies. Hit compound 9 was identified as the most potent ligand (IC50 = 0.3 μM) and a relatively poor inducer of ...

Flavopiridol in patients undergoing PCI overlap substantially, making it difficult to determine optimal treatment.3 While subgroup analyses have been helpful in determining groups with larger absolute benefits from continuing therapy (e.g. patients presenting with MI) 4,5, there remain patients within these broad categories who may also experience serious bleeding events. Most data estimating ischemia and bleeding risk following PCI have focused on early risks, including periprocedural events. 6,7 It remains unclear which patients are at high risk for late ischemic events and may thus benefit most from longer term dual antiplatelet therapy versus those who are high risk for late bleeding events and may thus be harmed. The goal of this study was to identify factors predicting whether the expected benefit of reduced ischemia would outweigh the expected increase in.. ...

Abstract PPARs are transcription factors belonging to the superfamily of nuclear receptors. PPAR-alpha is involved in the regulation of fatty acid (FA) uptake and oxidation, inflam..

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We profiled a large set of PPARγ full agonists and SPPARγMs in multiple batches of experiments, both in vitro and in vivo. In 3T3-L1 adipocyte profiling studies, we did not find robust consistent gene signatures that were oppositely regulated by PPARγ full agonists versus multiple SPPARγMs. Similar findings were obtained in in vivo profiling studies using db/db mice and SD rats. Instead, we found that saturating concentrations of SPPARγMs produced largely similar but attenuated adipocyte gene signatures, compared with PPARγ full agonists. This attenuation was characterized by fewer significantly regulated genes and an overall smaller magnitude of regulation of genes that demonstrated significantly altered expression.. The gene expression profiles we observed could be summarized by a single score, the GAI, which was used to quantify and to rank the maximal gene-regulatory activity of PPARγ ligands. When GAI scores for a group of ligands were compared with results obtained from two other ...