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Peroxisome proliferator-activated receptor γ and colorectal cancer  [cached]
Yun Dai,Wei-Hong Wang
World Journal of Gastrointestinal Oncology , 2010,
Abstract: Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily and ligand-activated transcription factors. PPARγ plays an important role in adipocyte differentiation, lipid storage and energy dissipation in adipose tissue, and is involved in the control of inflammatory reactions as well as in glucose metabolism through the improvement of insulin sensitivity. Growing evidence has demonstrated that activation of PPARγ has an antineoplastic effect in tumors, including colorectal cancer. High expression of PPARγ is detected in human colon cancer cell lines and adenocarcinoma. This review describes the molecular mechanisms by which PPARγ regulates tumorigenesis in colorectal cancer, and examines current clinical trials evaluating PPARγ agonists as therapeutic agents for colorectal cancer.
Peroxisome Proliferator-Activated Receptors in Lung Cancer  [PDF]
Venkateshwar G. Keshamouni,ShouWei Han,Jesse Roman
PPAR Research , 2007, DOI: 10.1155/2007/90289
Abstract: Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily. Their discovery in the 1990s provided insights into the cellular mechanisms involved in the control of energy homeostasis; the regulation of cell differentiation, proliferation, and apoptosis; and the modulation of important biological and pathological processes related to inflammation, among others. Since then, PPARs have become an exciting therapeutic target for several diseases. PPARs are expressed by many tumors including lung carcinoma cells, and their function has been linked to the process of carcinogenesis in lung. Consequently, intense research is being conducted in this area with the hope of discovering new PPAR-related therapeutic targets for the treatment of lung cancer. This review summarizes the research being conducted in this area and focuses on the mechanisms by which PPARs are believed to affect lung tumor cell biology.
Peroxisome Proliferator-Activated Receptors in Diabetic Nephropathy  [PDF]
Shinji Kume,Takashi Uzu,Keiji Isshiki,Daisuke Koya
PPAR Research , 2008, DOI: 10.1155/2008/879523
Abstract: Diabetic nephropathy is a leading cause of end-stage renal disease, which is increasing in incidence worldwide, despite intensive treatment approaches such as glycemic and blood pressure control in patients with diabetes mellitus. New therapeutic strategies are needed to prevent the onset of diabetic nephropathy. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear transcription factors that play important roles in lipid and glucose homeostases. These agents might prevent the progression of diabetic nephropathy, since PPAR agonists improve dyslipidemia and insulin resistance. Furthermore, data from murine models suggest that PPAR agonists also have independent renoprotective effects by suppressing inflammation, oxidative stress, lipotoxicity, and activation of the renin-angiotensin system. This review summarizes data from clinical and experimental studies regarding the relationship between PPARs and diabetic nephropathy. The therapeutic potential of PPAR agonists in the treatment of diabetic nephropathy is also discussed.
PPAR- Ligands as Potential Therapeutic Agents for Wet Age-Related Macular Degeneration
Marisol del V Cano,Peter L. Gehlbach
PPAR Research , 2008, DOI: 10.1155/2008/821592
Abstract: The peroxisome proliferator-activated receptors (PPAR's) are members of the steroid/thyroid nuclear receptor, superfamily of transcription factors. There are currently three known PPAR subtypes, , , and . The PPARs are now recognized participants in a number of biological pathways some of which are implicated in the pathogenesis of age-related macular degeneration (AMD). These include immune modulation, lipid regulation, and oxidant/antioxidant pathways important to the onset and progression of “dry” AMD, and vascular endothelial growth factor (VEGF) mediated pathways that stimulate choroidal neovascularization (CNV), characteristic of “wet” AMD. PPAR- is found in retina and also on vascular cells important to formation of CNV. At this time, however, relatively little is known about potential contributions of PPAR- to the pathogenesis of dry and wet AMD. This review examines current literature for potential roles of PPAR- in the pathogenesis and potential treatment of AMD with emphasis on prevention and treatment of wet AMD.
Peroxisome Proliferator Activated Receptors and Lipoprotein Metabolism
Sander Kersten
PPAR Research , 2008, DOI: 10.1155/2008/132960
Abstract: Plasma lipoproteins are responsible for carrying triglycerides and cholesterol in the blood and ensuring their delivery to target organs. Regulation of lipoprotein metabolism takes place at numerous levels including via changes in gene transcription. An important group of transcription factors that mediates the effect of dietary fatty acids and certain drugs on plasma lipoproteins are the peroxisome proliferator activated receptors (PPARs). Three PPAR isotypes can be distinguished, all of which have a major role in regulating lipoprotein metabolism. PPAR is the molecular target for the fibrate class of drugs. Activation of PPAR in mice and humans markedly reduces hepatic triglyceride production and promotes plasma triglyceride clearance, leading to a clinically significant reduction in plasma triglyceride levels. In addition, plasma high-density lipoprotein (HDL)-cholesterol levels are increased upon PPAR activation in humans. PPAR is the molecular target for the thiazolidinedione class of drugs. Activation of PPAR in mice and human is generally associated with a modest increase in plasma HDL-cholesterol and a decrease in plasma triglycerides. The latter effect is caused by an increase in lipoprotein lipase-dependent plasma triglyceride clearance. Analogous to PPAR, activation of PPAR/ leads to increased plasma HDL-cholesterol and decreased plasma triglyceride levels. In this paper, a fresh perspective on the relation between PPARs and lipoprotein metabolism is presented. The emphasis is on the physiological role of PPARs and the mechanisms underlying the effect of synthetic PPAR agonists on plasma lipoprotein levels.
The Role of Peroxisome Proliferator-Activated Receptor β/δ on the Inflammatory Basis of Metabolic Disease  [PDF]
Teresa Coll,Emma Barroso,David álvarez-Guardia,Lucía Serrano,Laia Salvadó,Manuel Merlos,Xavier Palomer,Manuel Vázquez-Carrera
PPAR Research , 2010, DOI: 10.1155/2010/368467
Abstract: The pathophysiology underlying several metabolic diseases, such as obesity, type 2 diabetes mellitus, and atherosclerosis, involves a state of chronic low-level inflammation. Evidence is now emerging that the nuclear receptor Peroxisome Proliferator-Activated Receptor (PPAR) ameliorates these pathologies partly through its anti-inflammatory effects. PPAR activation prevents the production of inflammatory cytokines by adipocytes, and it is involved in the acquisition of the anti-inflammatory phenotype of macrophages infiltrated in adipose tissue. Furthermore, PPAR ligands prevent fatty acid-induced inflammation in skeletal muscle cells, avoid the development of cardiac hypertrophy, and suppress macrophage-derived inflammation in atherosclerosis. These data are promising and suggest that PPAR ligands may become a therapeutic option for preventing the inflammatory basis of metabolic diseases. 1. Introduction Over the last decade, an abundance of evidence has shown a close link between a state of chronic low-level inflammation and metabolic dysfunction. In fact, excessive nutrition consumption or storage has the capacity to activate both inflammatory and metabolic signaling networks since they are linked and interdependent [1]. Peroxisome Proliferator-Activated Receptors (PPARs), which are members of the nuclear receptor family, have emerged as important regulators of metabolic and inflammatory signaling, particularly in the context of metabolic disease [2–4]. The ability of these receptors to connect metabolism and inflammation makes them interesting targets for the treatment of metabolic diseases, such as atherosclerosis and diabetes, through modulation of the inflammatory process. Here, we will focus on recent advances in our understanding of the role of one of these PPAR members, the PPAR / , as an integrator of metabolic and inflammatory signaling networks. 2. Peroxisome Proliferator-Activated Receptors (PPARs) PPARs are members of the nuclear receptor superfamily of ligand-activated transcription factors that regulate the expression of genes involved in fatty acid uptake and oxidation, lipid metabolism, and inflammation [2]. To be transcriptionally active, PPARs need to heterodimerize with the 9-cis retinoic acid receptor (RXR) (NR2B) (Figure 1). PPAR-RXR heterodimers bind to DNA-specific sequences called peroxisome proliferator-response elements (PPREs), which consist of an imperfect direct repeat of the consensus binding site for nuclear hormone receptors (AGGTCA), separated by one nucleotide (Direct Repeat 1, DR-1). These sequences have been
Peroxisome Proliferator-Activated Receptor (PPAR): Balance for Survival in Parasitic Infections
Marion M. Chan,Kyle W. Evans,Andrea R. Moore,Dunne Fong
Journal of Biomedicine and Biotechnology , 2010, DOI: 10.1155/2010/828951
Abstract: Parasitic infections induce a magnitude of host responses. At the opposite ends of the spectrum are those that ensure the host's needs to eliminate the invaders and to minimize damage to its own tissues. This review analyzes how parasites would manipulate immunity by activating the immunosuppressive nuclear factor, peroxisome proliferator-activated receptors (PPARs) with type 2 cytokines and free fatty acids from arachidonic acid metabolism. PPARs limit the action of type 1 immunity, in which classically activated macrophages act through the production of proinflammatory signals, to spare the parasites. They also favor the development of alternately activated macrophages which control inflammation so the host would not be destroyed. Possibly, the nuclear factors hold a pivotal role in the establishment of chronic infection by delicately balancing the pro- and anti-inflammatory signaling mechanisms and their ligands may be used as combination therapeutics to limit host pathology.
The Role of Peroxisome Proliferator-Activated Receptors in Pulmonary Vascular Disease  [PDF]
Rachel E. Nisbet,Roy L. Sutliff,C. Michael Hart
PPAR Research , 2007, DOI: 10.1155/2007/18797
Abstract: Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily that regulate diverse physiological processes ranging from lipogenesis to inflammation. Recent evidence has established potential roles of PPARs in both systemic and pulmonary vascular disease and function. Existing treatment strategies for pulmonary hypertension, the most common manifestation of pulmonary vascular disease, are limited by an incomplete understanding of the underlying disease pathogenesis and lack of efficacy indicating an urgent need for new approaches to treat this disorder. Derangements in pulmonary endothelial-derived mediators and endothelial dysfunction have been shown to play a pivotal role in pulmonary hypertension pathogenesis. Therefore, the following review will focus on selected mediators implicated in pulmonary vascular dysfunction and evidence that PPARs, in particular PPARγ, participate in their regulation and may provide a potential novel therapeutic target for the treatment of pulmonary hypertension.
Peroxisome Proliferator-Activated Receptors and Acute Lung Injury  [PDF]
Rosanna Di Paola,Salvatore Cuzzocrea
PPAR Research , 2007, DOI: 10.1155/2007/63745
Abstract: Peroxisome proliferator-activated receptors are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily. PPARs regulate several metabolic pathways by binding to sequence-specific PPAR response elements in the promoter region of target genes, including lipid biosynthesis and glucose metabolism. Recently, PPARs and their respective ligands have been implicated as regulators of cellular inflammatory and immune responses. These molecules are thought to exert anti-inflammatory effects by negatively regulating the expression of proinflammatory genes. Several studies have demonstrated that PPAR ligands possess anti-inflammatory properties and that these properties may prove helpful in the treatment of inflammatory diseases of the lung. This review will outline the anti-inflammatory effects of PPARs and PPAR ligands and discuss their potential therapeutic effects in animal models of inflammatory lung disease.
Peroxisome Proliferator-Activated Receptor Alpha Target Genes  [PDF]
Maryam Rakhshandehroo,Bianca Knoch,Michael Müller,Sander Kersten
PPAR Research , 2010, DOI: 10.1155/2010/612089
Abstract: The peroxisome proliferator-activated receptor alpha (PPAR ) is a ligand-activated transcription factor involved in the regulation of a variety of processes, ranging from inflammation and immunity to nutrient metabolism and energy homeostasis. PPAR serves as a molecular target for hypolipidemic fibrates drugs which bind the receptor with high affinity. Furthermore, PPAR binds and is activated by numerous fatty acids and fatty acid-derived compounds. PPAR governs biological processes by altering the expression of a large number of target genes. Accordingly, the specific role of PPAR is directly related to the biological function of its target genes. Here, we present an overview of the involvement of PPAR in lipid metabolism and other pathways through a detailed analysis of the different known or putative PPAR target genes. The emphasis is on gene regulation by PPAR in liver although many of the results likely apply to other organs and tissues as well. 1. Introduction Nutrient metabolism and energy homeostasis are tightly controlled by numerous regulatory systems involving specific transcription factors. The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the superfamily of nuclear hormone receptors and play an important role in nutrient homeostasis [1–3]. Three different PPAR subtypes are known: and All PPARs share the same molecular mode of action via formation of heterodimers with the nuclear receptor RXR, followed by binding to specific DNA-response elements in target genes known as peroxisome proliferator response elements (PPREs). PPREs are characterized by a common core sequence consisting of a direct repeat of the consensus sequence AGGTCA interspaced by a single nucleotide [1, 4]. Expression of and is found ubiquitously, whereas is mainly expressed in adipose tissue, macrophages, and colon [5, 6]. Activation of transcription by PPARs is dependent on a number of different steps including ligand binding to PPAR, binding of PPAR to the target gene, removal of corepressors and recruitment of coactivators, remodeling of the chromatin structure, and finally facilitation of gene transcription [7]. This paper will focus exclusively on ? was first discovered in the early 1990s and since then has been identified as the master regulator of hepatic lipid metabolism [8]. In addition, has been shown to govern glucose metabolism, lipoprotein metabolism, liver inflammation, amino acid metabolism, and hepatocyte proliferation (specifically in rodents). Synthetic agonists of lower plasma triglycerides
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