PPAR Research https://www.hindawi.com The latest articles from Hindawi © 2017 , Hindawi Limited . All rights reserved. PPAR Agonists for the Prevention and Treatment of Lung Cancer Mon, 20 Feb 2017 00:00:00 +0000 http://www.hindawi.com/journals/ppar/2017/8252796/ Lung cancer is the most common and most fatal of all malignancies worldwide. Furthermore, with more than half of all lung cancer patients presenting with distant metastases at the time of initial diagnosis, the overall prognosis for the disease is poor. There is thus a desperate need for new prevention and treatment strategies. Recently, a family of nuclear hormone receptors, the peroxisome proliferator-activated receptors (PPARs), has attracted significant attention for its role in various malignancies including lung cancer. Three PPARs, PPARα, PPARβ/δ, and PPARγ, display distinct biological activities and varied influences on lung cancer biology. PPARα activation generally inhibits tumorigenesis through its antiangiogenic and anti-inflammatory effects. Activated PPARγ is also antitumorigenic and antimetastatic, regulating several functions of cancer cells and controlling the tumor microenvironment. Unlike PPARα and PPARγ, whether PPARβ/δ activation is anti- or protumorigenic or even inconsequential currently remains an open question that requires additional investigation. This review of current literature emphasizes the multifaceted effects of PPAR agonists in lung cancer and discusses how they may be applied as novel therapeutic strategies for the disease. Sowmya P. Lakshmi, Aravind T. Reddy, Asoka Banno, and Raju C. Reddy Copyright © 2017 Sowmya P. Lakshmi et al. All rights reserved. Interactions between PPAR Gamma and the Canonical Wnt/Beta-Catenin Pathway in Type 2 Diabetes and Colon Cancer Sun, 19 Feb 2017 00:00:00 +0000 http://www.hindawi.com/journals/ppar/2017/5879090/ In both colon cancer and type 2 diabetes, metabolic changes induced by upregulation of the Wnt/beta-catenin signaling and downregulation of peroxisome proliferator-activated receptor gamma (PPAR gamma) may help account for the frequent association of these two diseases. In both diseases, PPAR gamma is downregulated while the canonical Wnt/beta-catenin pathway is upregulated. In colon cancer, upregulation of the canonical Wnt system induces activation of pyruvate dehydrogenase kinase and deactivation of the pyruvate dehydrogenase complex. As a result, a large part of cytosolic pyruvate is converted into lactate through activation of lactate dehydrogenase. Lactate is extruded out of the cell by means of activation of monocarboxylate lactate transporter-1. This phenomenon is called Warburg effect. PPAR gamma agonists induce beta-catenin inhibition, while inhibition of the canonical Wnt/beta-catenin pathway activates PPAR gamma. Yves Lecarpentier, Victor Claes, Alexandre Vallée, and Jean-Louis Hébert Copyright © 2017 Yves Lecarpentier et al. All rights reserved. PPARγ and Its Role in Cardiovascular Diseases Tue, 24 Jan 2017 13:59:48 +0000 http://www.hindawi.com/journals/ppar/2017/6404638/ Peroxisome proliferator-activated receptor Gamma (PPARγ), a ligand-activated transcription factor, has a role in various cellular functions as well as glucose homeostasis, lipid metabolism, and prevention of oxidative stress. The activators of PPARγ are already widely used in the treatment of diabetes mellitus. The cardioprotective effect of PPARγ activation has been studied extensively over the years making them potential therapeutic targets in diseases associated with cardiovascular disorders. However, they are also associated with adverse cardiovascular events such as congestive heart failure and myocardial infarction. This review aims to discuss the role of PPARγ in the various cardiovascular diseases and summarize the current knowledge on PPARγ agonists from multiple clinical trials. Finally, we also review the new PPARγ agonists under development as potential therapeutics with reduced or no adverse effects. Mini Chandra, Sumitra Miriyala, and Manikandan Panchatcharam Copyright © 2017 Mini Chandra et al. All rights reserved. Quercetin and Quercetin-Rich Red Onion Extract Alter Pgc-1α Promoter Methylation and Splice Variant Expression Mon, 16 Jan 2017 05:55:50 +0000 http://www.hindawi.com/journals/ppar/2017/3235693/ Pgc-1α and its various isoforms may play a role in determining skeletal muscle mitochondrial adaptations in response to diet. 8 wks of dietary supplementation with the flavonoid quercetin (Q) or red onion extract (ROE) in a high fat diet (HFD) ameliorates HFD-induced obesity and insulin resistance in C57BL/J mice while upregulating Pgc-1α and increasing skeletal muscle mitochondrial number and function. Here, mice were fed a low fat (LF), high fat (HF), high fat plus quercetin (HF + Q), or high fat plus red onion extract (HF + RO) diet for 9 wks and skeletal muscle Pgc-1α isoform expression and DNA methylation were determined. Quantification of various Pgc-1α isoforms, including isoforms Pgc-1α-a, Pgc-1α-b, Pgc-1α-c, Pgc-1α4, total NT-Pgc-1α, and FL-Pgc-1α, showed that only total NT-Pgc-1α expression was increased in LF, HF + Q, and HF + RO compared to HF. Furthermore, Q supplementation decreased Pgc-1α-a expression compared to LF and HF, and ROE decreased Pgc-1α-a expression compared to LF. FL-Pgc-1α was decreased in HF + Q and HF + RO compared to LF and HF. HF exhibited hypermethylation at the −260 nucleotide (nt) in the Pgc-1α promoter. Q and ROE prevented HFD-induced hypermethylation. −260 nt methylation levels were associated with NT-Pgc-1α expression only. Pgc-1α isoform expression may be epigenetically regulated by Q and ROE through DNA methylation. Prasad P. Devarshi, Aarin D. Jones, Erin M. Taylor, Barbara Stefanska, and Tara M. Henagan Copyright © 2017 Prasad P. Devarshi et al. All rights reserved. Potential Role of ANGPTL4 in the Cross Talk between Metabolism and Cancer through PPAR Signaling Pathway Sun, 15 Jan 2017 00:00:00 +0000 http://www.hindawi.com/journals/ppar/2017/8187235/ The angiopoietin-like 4 (ANGPTL4) protein belongs to a superfamily of secreted proteins structurally related to factors modulating angiogenesis known as angiopoietins. At first, ANGPTL4 has been identified as an adipokine exclusively involved in lipid metabolism, because of its prevalent expression in liver and adipose tissue. This protein regulates lipid metabolism by inhibiting lipoprotein lipase (LPL) activity and stimulating lipolysis of white adipose tissue (WAT), resulting in increased levels of plasma triglycerides (TG) and fatty acids. Subsequently, ANGPTL4 has been shown to be involved in several nonmetabolic and metabolic conditions, both physiological and pathological, including angiogenesis and vascular permeability, cell differentiation, tumorigenesis, glucose homoeostasis, lipid metabolism, energy homeostasis, wound healing, inflammation, and redox regulation. The transcriptional regulation of ANGPTL4 can be modulated by several transcription factors, including PPARα, PPARβ/δ, PPARγ, and HIF-1α, and nutritional and hormonal conditions. Several studies showed that high levels of ANGPTL4 are associated with poor prognosis in patients with various solid tumors, suggesting an important role in cancer onset and progression, metastasis, and anoikis resistance. Here, we have discussed the potential role of ANGPTL4 in mediating the cross talk between metabolic syndromes, such as diabetes and obesity, and cancer through regulation of its expression by PPARs. Laura La Paglia, Angela Listì, Stefano Caruso, Valeria Amodeo, Francesco Passiglia, Viviana Bazan, and Daniele Fanale Copyright © 2017 Laura La Paglia et al. All rights reserved. MicroRNAs-Dependent Regulation of PPARs in Metabolic Diseases and Cancers Thu, 12 Jan 2017 09:10:21 +0000 http://www.hindawi.com/journals/ppar/2017/7058424/ Peroxisome proliferator-activated receptors (PPARs) are a family of ligand-dependent nuclear receptors, which control the transcription of genes involved in energy homeostasis and inflammation and cell proliferation/differentiation. Alterations of PPARs’ expression and/or activity are commonly associated with metabolic disorders occurring with obesity, type 2 diabetes, and fatty liver disease, as well as with inflammation and cancer. Emerging evidence now indicates that microRNAs (miRNAs), a family of small noncoding RNAs, which fine-tune gene expression, play a significant role in the pathophysiological mechanisms regulating the expression and activity of PPARs. Herein, the regulation of PPARs by miRNAs is reviewed in the context of metabolic disorders, inflammation, and cancer. The reciprocal control of miRNAs expression by PPARs, as well as the therapeutic potential of modulating PPAR expression/activity by pharmacological compounds targeting miRNA, is also discussed. Dorothea Portius, Cyril Sobolewski, and Michelangelo Foti Copyright © 2017 Dorothea Portius et al. All rights reserved. Bezafibrate Attenuates Pressure Overload-Induced Cardiac Hypertrophy and Fibrosis Tue, 03 Jan 2017 10:25:26 +0000 http://www.hindawi.com/journals/ppar/2017/5789714/ Background. Peroxisome proliferator-activated receptor-α (PPAR-α) is closely associated with the development of cardiac hypertrophy. Previous studies have indicated that bezafibrate (BZA), a PPAR-α agonist, could attenuate insulin resistance and obesity. This study was designed to determine whether BZA could protect against pressure overload-induced cardiac hypertrophy. Methods. Mice were orally given BZA (100 mg/kg) for 7 weeks beginning 1 week after aortic banding (AB) surgery. Cardiac hypertrophy was assessed based on echocardiographic, histological, and molecular aspects. Moreover, neonatal rat ventricular cardiomyocytes (NRVMs) were used to investigate the effects of BZA on the cardiomyocyte hypertrophic response in vitro. Results. Our study demonstrated that BZA could alleviate cardiac hypertrophy and fibrosis in mice subjected to AB surgery. BZA treatment also reduced the phosphorylation of protein kinase B (AKT)/glycogen synthase kinase-3β (GSK3β) and mitogen-activated protein kinases (MAPKs). BZA suppressed phenylephrine- (PE-) induced hypertrophy of cardiomyocyte in vitro. The protective effects of BZA were abolished by the treatment of the PPAR-α antagonist in vitro. Conclusions. BZA could attenuate pressure overload-induced cardiac hypertrophy and fibrosis. Si-Chi Xu, Zhen-Guo Ma, Wen-Ying Wei, Yu-Pei Yuan, and Qi-Zhu Tang Copyright © 2017 Si-Chi Xu et al. All rights reserved. Peroxisome Proliferator-Activated Receptor Modulation during Metabolic Diseases and Cancers: Master and Minions Wed, 28 Dec 2016 08:43:10 +0000 http://www.hindawi.com/journals/ppar/2016/6517313/ The prevalence of obesity and metabolic diseases (such as type 2 diabetes mellitus, dyslipidaemia, and cardiovascular diseases) has increased in the last decade, in both industrialized and developing countries. This also coincided with our observation of a similar increase in the prevalence of cancers. The aetiology of these diseases is very complex and involves genetic, nutritional, and environmental factors. Much evidence indicates the central role undertaken by peroxisome proliferator-activated receptors (PPARs) in the development of these disorders. Due to the fact that their ligands could become crucial in future target-therapies, PPARs have therefore become the focal point of much research. Based on this evidence, this narrative review was written with the purpose of outlining the effects of PPARs, their actions, and their prospective uses in metabolic diseases and cancers. Salvatore Giovanni Vitale, Antonio Simone Laganà, Angela Nigro, Valentina Lucia La Rosa, Paola Rossetti, Agnese Maria Chiara Rapisarda, Sandro La Vignera, Rosita Angela Condorelli, Francesco Corrado, Massimo Buscema, and Rosario D’Anna Copyright © 2016 Salvatore Giovanni Vitale et al. All rights reserved. PPARs and Mitochondrial Metabolism: From NAFLD to HCC Tue, 27 Dec 2016 12:44:33 +0000 http://www.hindawi.com/journals/ppar/2016/7403230/ Metabolic related diseases, such as type 2 diabetes, metabolic syndrome, and nonalcoholic fatty liver disease (NAFLD), are widespread threats which bring about a significant burden of deaths worldwide, mainly due to cardiovascular events and cancer. The pathogenesis of these diseases is extremely complex, multifactorial, and only partially understood. As the main metabolic organ, the liver is central to maintain whole body energetic homeostasis. At the cellular level, mitochondria are the metabolic hub connecting and integrating all the main biochemical, hormonal, and inflammatory signaling pathways to fulfill the energetic and biosynthetic demand of the cell. In the liver, mitochondria metabolism needs to cope with the energetic regulation of the whole body. The nuclear receptors PPARs orchestrate lipid and glucose metabolism and are involved in a variety of diseases, from metabolic disorders to cancer. In this review, focus is placed on the roles of PPARs in the regulation of liver mitochondrial metabolism in physiology and pathology, from NAFLD to HCC. Tommaso Mello, Maria Materozzi, and Andrea Galli Copyright © 2016 Tommaso Mello et al. All rights reserved. Peroxisome Proliferator-Activated Receptor γ Induces the Expression of Tissue Factor Pathway Inhibitor-1 (TFPI-1) in Human Macrophages Tue, 27 Dec 2016 06:25:30 +0000 http://www.hindawi.com/journals/ppar/2016/2756781/ Tissue factor (TF) is the initiator of the blood coagulation cascade after interaction with the activated factor VII (FVIIa). Moreover, the TF/FVIIa complex also activates intracellular signalling pathways leading to the production of inflammatory cytokines. The TF/FVIIa complex is inhibited by the tissue factor pathway inhibitor-1 (TFPI-1). Peroxisome proliferator-activated receptor gamma (PPARγ) is a transcription factor that, together with PPARα and PPARβ/δ, controls macrophage functions. However, whether PPARγ activation modulates the expression of TFP1-1 in human macrophages is not known. Here we report that PPARγ activation increases the expression of TFPI-1 in human macrophages in vitro as well as in vivo in circulating peripheral blood mononuclear cells. The induction of TFPI-1 expression by PPARγ ligands, an effect shared by the activation of PPARα and PPARβ/δ, occurs also in proinflammatory M1 and in anti-inflammatory M2 polarized macrophages. As a functional consequence, treatment with PPARγ ligands significantly reduces the inflammatory response induced by FVIIa, as measured by variations in the IL-8, MMP-2, and MCP-1 expression. These data identify a novel role for PPARγ in the control of TF the pathway. G. Chinetti-Gbaguidi, C. Copin, B. Derudas, N. Marx, J. Eechkoute, and B. Staels Copyright © 2016 G. Chinetti-Gbaguidi et al. All rights reserved. Natalizumab Treatment Modulates Peroxisome Proliferator-Activated Receptors Expression in Women with Multiple Sclerosis Sun, 18 Dec 2016 12:56:43 +0000 http://www.hindawi.com/journals/ppar/2016/5716415/ Peroxisome Proliferator-Activated Receptors (PPAR) are transcription factors suggested to be involved in inflammatory lesions of autoimmune encephalomyelitis and multiple sclerosis (MS). Our objective was to assess whether Natalizumab (NTZ) therapy is associated with alterations of PPAR expression in MS patients. We analyzed gene expression of PPAR in peripheral blood mononuclear cells (PBMC) as well as blood inflammatory markers in women with MS previously medicated with first-line immunomodulators (baseline) and after NTZ therapy. No differences in PPARα, PPARβ/δ, PPARγ, and CD36 mRNA expression were found in PBMC between patients under baseline and healthy controls. At three months, NTZ increased PPARβ/δ mRNA () in comparison to baseline, while mRNA expression of PPARγ and CD36 (a well-known PPAR target gene) was lower in comparison to healthy controls ( and , resp.). Although these trends of alterations remain after six months of therapy, the results were not statistically significant. Osteopontin levels were elevated in patients () and did not change during the follow-up period of NTZ treatment. These results suggest that PPAR-mediated processes may contribute to the mechanisms of action of NTZ therapy. Véronique Ferret-Sena, Alexandra Maia e Silva, Armando Sena, Inês Cavaleiro, José Vale, Bruno Derudas, Giulia Chinetti-Gbaguidi, and Bart Staels Copyright © 2016 Véronique Ferret-Sena et al. All rights reserved. PPARδ as a Metabolic Initiator of Mammary Neoplasia and Immune Tolerance Sun, 18 Dec 2016 11:53:20 +0000 http://www.hindawi.com/journals/ppar/2016/3082340/ PPARδ is a ligand-activated nuclear receptor that regulates the transcription of genes associated with proliferation, metabolism, inflammation, and immunity. Within this transcription factor family, PPARδ is unique in that it initiates oncogenesis in a metabolic and tissue-specific context, especially in mammary epithelium, and can regulate autoimmunity in some tissues. This review discusses its role in these processes and how it ultimately impacts breast cancer. Robert I. Glazer Copyright © 2016 Robert I. Glazer. All rights reserved. Nutrigenomic Functions of PPARs in Obesogenic Environments Wed, 30 Nov 2016 07:26:16 +0000 http://www.hindawi.com/journals/ppar/2016/4794576/ Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that mediate the effects of several nutrients or drugs through transcriptional regulation of their target genes in obesogenic environments. This review consists of three parts. First, we summarize current knowledge regarding the role of PPARs in governing the development of white and brown/beige adipocytes from uncommitted progenitor cells. Next, we discuss the interactions of dietary bioactive molecules, such as fatty acids and phytochemicals, with PPARs for the modulation of PPAR-dependent transcriptional activities and metabolic consequences. Lastly, the effects of PPAR polymorphism on obesity and metabolic outcomes are discussed. In this review, we aim to highlight the critical role of PPARs in the modulation of adiposity and subsequent metabolic adaptation in response to dietary challenges and genetic modifications. Understanding the changes in obesogenic environments as a consequence of PPARs/nutrient interactions may help expand the field of individualized nutrition to prevent obesity and obesity-associated metabolic comorbidities. Soonkyu Chung, Young Jun Kim, Soo Jin Yang, Yunkyoung Lee, and Myoungsook Lee Copyright © 2016 Soonkyu Chung et al. All rights reserved. Transcriptome-Wide Analysis Reveals the Role of PPARγ Controlling the Lipid Metabolism in Goat Mammary Epithelial Cells Thu, 13 Oct 2016 11:00:37 +0000 http://www.hindawi.com/journals/ppar/2016/9195680/ To explore the large-scale effect of peroxisome proliferator-activated receptor (PPARG) in goat mammary epithelial cells (GMEC), an oligonucleotide microarray platform was used for transcriptome profiling in cells overexpressing PPARG and incubated with or without rosiglitazone (ROSI, a PPARγ agonist). A total of 1143 differentially expressed genes (DEG) due to treatment were detected. The Dynamic Impact Approach (DIA) analysis uncovered the most impacted and induced pathways “fatty acid elongation in mitochondria,” “glycosaminoglycan biosynthesis-keratan sulfate,” and “pentose phosphate pathway.” The data highlights the central role of PPARG in milk fatty acid metabolism via controlling fatty acid elongation, biosynthesis of unsaturated fatty acid, lipid formation, and lipid secretion; furthermore, its role related to carbohydrate metabolism promotes the production of intermediates required for milk fat synthesis. Analysis of upstream regulators indicated that PPARG participates in multiple physiological processes via controlling or cross talking with other key transcription factors such as PPARD and NR1H3 (also known as liver-X-receptor-α). This transcriptome-wide analysis represents the first attempt to better understand the biological relevance of PPARG expression in ruminant mammary cells. Overall, the data underscored the importance of PPARG in mammary lipid metabolism and transcription factor control. Hengbo Shi, Wangsheng Zhao, Changhui Zhang, Khuram Shahzad, Jun Luo, and Juan J. Loor Copyright © 2016 Hengbo Shi et al. All rights reserved. PPAR Gamma in Neuroblastoma: The Translational Perspectives of Hypoglycemic Drugs Wed, 05 Oct 2016 12:31:05 +0000 http://www.hindawi.com/journals/ppar/2016/3038164/ Neuroblastoma (NB) is the most common and aggressive pediatric cancer, characterized by a remarkable phenotypic diversity and high malignancy. The heterogeneous clinical behavior, ranging from spontaneous remission to fatal metastatic disease, is attributable to NB biology and genetics. Despite major advances in therapies, NB is still associated with a high morbidity and mortality. Thus, novel diagnostic, prognostic, and therapeutic approaches are required, mainly to improve treatment outcomes of high-risk NB patients. Among neuroepithelial cancers, NB is the most studied tumor as far as PPAR ligands are concerned. PPAR ligands are endowed with antitumoral effects, mainly acting on cancer stem cells, and constitute a possible add-on therapy to antiblastic drugs, in particular for NB with unfavourable prognosis. While discussing clinical background, this review will provide a synopsis of the major studies about PPAR expression in NB, focusing on the potential beneficial effects of hypoglycemic drugs, thiazolidinediones and metformin, to reduce the occurrence of relapses as well as tumor regrowth in NB patients. Serena Vella, Pier Giulio Conaldi, Tullio Florio, and Aldo Pagano Copyright © 2016 Serena Vella et al. All rights reserved. PPARγ in Bacterial Infections: A Friend or Foe? Wed, 28 Sep 2016 14:17:19 +0000 http://www.hindawi.com/journals/ppar/2016/7963540/ Peroxisome proliferator-activated receptor γ (PPARγ) is now recognized as an important modulator of leukocyte inflammatory responses and function. Its immunoregulatory function has been studied in a variety of contexts, including bacterial infections of the lungs and central nervous system, sepsis, and conditions such as chronic granulomatous disease. Although it is generally believed that PPARγ activation is beneficial for the host during bacterial infections via its anti-inflammatory and antibacterial properties, PPARγ agonists have also been shown to dampen the host immune response and in some cases exacerbate infection by promoting leukocyte apoptosis and interfering with leukocyte migration and infiltration. In this review we discuss the role of PPARγ and its activation during bacterial infections, with focus on the potential of PPARγ agonists and perhaps antagonists as novel therapeutic modalities. We conclude that adjustment in the dosage and timing of PPARγ agonist administration, based on the competence of host antimicrobial defenses and the extent of inflammatory response and tissue injury, is critical for achieving the essential balance between pro- and anti-inflammatory effects on the immune system. Aravind T. Reddy, Sowmya P. Lakshmi, and Raju C. Reddy Copyright © 2016 Aravind T. Reddy et al. All rights reserved. IL-15 Mediates Mitochondrial Activity through a PPARδ-Dependent-PPARα-Independent Mechanism in Skeletal Muscle Cells Wed, 21 Sep 2016 09:44:41 +0000 http://www.hindawi.com/journals/ppar/2016/5465804/ Molecular mediators of metabolic processes, to increase energy expenditure, have become a focus for therapies of obesity. The discovery of cytokines secreted from the skeletal muscle (SKM), termed “myokines,” has garnered attention due to their positive effects on metabolic processes. Interleukin-15 (IL-15) is a myokine that has numerous positive metabolic effects and is linked to the PPAR family of mitochondrial regulators. Here, we aimed to determine the importance of PPARα and/or PPARδ as targets of IL-15 signaling. C2C12 SKM cells were differentiated for 6 days and treated every other day with IL-15 (100 ng/mL), a PPARα inhibitor (GW-6471), a PPARδ inhibitor (GSK-3787), or both IL-15 and the inhibitors. IL-15 increased mitochondrial activity and induced PPARα, PPARδ, PGC1α, PGC1β, UCP2, and Nrf1 expression. There was no effect of inhibiting PPARα, in combination with IL-15, on the aforementioned mRNA levels except for PGC1β and Nrf1. However, with PPARδ inhibition, IL-15 failed to induce the expression levels of PGC1α, PGC1β, UCP2, and Nrf1. Further, inhibition of PPARδ abolished IL-15 induced increases in citrate synthase activity, ATP production, and overall mitochondrial activity. IL-15 had no effects on mitochondrial biogenesis. Our data indicates that PPARδ activity is required for the beneficial metabolic effects of IL-15 signaling in SKM. Shantaé M. Thornton, James E. Krolopp, and Marcia J. Abbott Copyright © 2016 Shantaé M. Thornton et al. All rights reserved. PPARγ as a Novel Therapeutic Target in Lung Cancer Tue, 06 Sep 2016 15:39:40 +0000 http://www.hindawi.com/journals/ppar/2016/8972570/ Lung cancer is the leading cause of cancer-related death, with more than half the patients having advanced-stage disease at the time of initial diagnosis and thus facing a poor prognosis. This dire situation poses a need for new approaches in prevention and treatment. Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated transcription factor belonging to the nuclear hormone receptor superfamily. Its involvement in adipocyte differentiation and glucose and lipid homeostasis is well-recognized, but accumulating evidence now suggests that PPARγ may also function as a tumor suppressor, inhibiting development of primary tumors and metastases in lung cancer and other malignancies. Besides having prodifferentiation, antiproliferative, and proapoptotic effects, PPARγ agonists have been shown to prevent cancer cells from acquiring the migratory and invasive capabilities essential for successful metastasis. Angiogenesis and secretion of certain matrix metalloproteinases and extracellular matrix proteins within the tumor microenvironment are also regulated by PPARγ. This review of the current literature highlights the potential of PPARγ agonists as novel therapeutic modalities in lung cancer, either as monotherapy or in combination with standard cytotoxic chemotherapy. Aravind T. Reddy, Sowmya P. Lakshmi, and Raju C. Reddy Copyright © 2016 Aravind T. Reddy et al. All rights reserved. Commonalities in the Association between PPARG and Vitamin D Related with Obesity and Carcinogenesis Mon, 08 Aug 2016 16:27:04 +0000 http://www.hindawi.com/journals/ppar/2016/2308249/ The PPAR nuclear receptor family has acquired great relevance in the last decade, which is formed by three different isoforms (PPARα, PPAR/δ, and PPAR ϒ). Those nuclear receptors are members of the steroid receptor superfamily which take part in essential metabolic and life-sustaining actions. Specifically, PPARG has been implicated in the regulation of processes concerning metabolism, inflammation, atherosclerosis, cell differentiation, and proliferation. Thus, a considerable amount of literature has emerged in the last ten years linking PPARG signalling with metabolic conditions such as obesity and diabetes, cardiovascular disease, and, more recently, cancer. This review paper, at crossroads of basic sciences, preclinical, and clinical data, intends to analyse the last research concerning PPARG signalling in obesity and cancer. Afterwards, possible links between four interrelated actors will be established: PPARG, the vitamin D/VDR system, obesity, and cancer, opening up the door to further investigation and new hypothesis in this fascinating area of research. Borja Bandera Merchan, Francisco José Tinahones, and Manuel Macías-González Copyright © 2016 Borja Bandera Merchan et al. All rights reserved. PPAR Ligands Function as Suppressors That Target Biological Actions of HMGB1 Tue, 02 Aug 2016 07:14:00 +0000 http://www.hindawi.com/journals/ppar/2016/2612743/ High mobility group box 1 (HMGB1), which has become one of the most intriguing molecules in inflammatory disorders and cancers and with which ligand-activated peroxisome proliferator-activated receptors (PPARs) are highly associated, is considered as a therapeutic target. Of particular interest is the fact that certain PPAR ligands have demonstrated their potent anti-inflammatory activities and potential anticancer effects. In this review article we summarize recent experimental evidence that PPAR ligands function as suppressors that target biological actions of HMGB1, including intracellular expression, receptor signaling cascades, and extracellular secretion of HMGB1 in cell lines and/or animal models. We also propose the possible mechanisms underlying PPAR involvement in inflammatory disorders and discuss the future therapeutic value of PPAR ligands targeting HMGB1 molecule for cancer prevention and treatment. Shibo Ying, Xiang Xiao, Tianhui Chen, and Jianlin Lou Copyright © 2016 Shibo Ying et al. All rights reserved. Peroxisome Proliferator-Activated Receptors in Female Reproduction and Fertility Sun, 31 Jul 2016 09:58:45 +0000 http://www.hindawi.com/journals/ppar/2016/4612306/ Reproductive functions may be altered by the exposure to a multitude of endogenous and exogenous agents, drug or environmental pollutants, which are known to affect gene transcription through the peroxisome proliferator-activated receptors (PPARs) activation. PPARs act as ligand activated transcription factors and regulate metabolic processes such as lipid and glucose metabolism, energy homeostasis, inflammation, and cell proliferation and differentiation. All PPARs isotypes are expressed along the hypothalamic-pituitary-gonadal axis and are strictly involved in reproductive functions. Since female fertility and energy metabolism are tightly interconnected, the research on female infertility points towards the exploration of potential PPARs activating/antagonizing compounds, mainly belonging to the class of thiazolidinediones (TZDs) and fibrates, as useful agents for the maintenance of metabolic homeostasis in women with ovarian dysfunctions. In the present review, we discuss the recent evidence about PPARs expression in the hypothalamic-pituitary-gonadal axis and their involvement in female reproduction. Finally, the therapeutic potential of their manipulation through several drugs is also discussed. Maurizio Vitti, Giovanna Di Emidio, Michela Di Carlo, Gaspare Carta, Andrea Antonosante, Paolo Giovanni Artini, Annamaria Cimini, Carla Tatone, and Elisabetta Benedetti Copyright © 2016 Maurizio Vitti et al. All rights reserved. PPAR in Cardiovascular Disorders Tue, 26 Jul 2016 08:25:21 +0000 http://www.hindawi.com/journals/ppar/2016/6293629/ Alexander N. Orekhov, Nigora Mukhamedova, Ekaterina A. Ivanova, and Manfredi Rizzo Copyright © 2016 Alexander N. Orekhov et al. All rights reserved. HDAC Inhibition Modulates Cardiac PPARs and Fatty Acid Metabolism in Diabetic Cardiomyopathy Thu, 30 Jun 2016 12:26:59 +0000 http://www.hindawi.com/journals/ppar/2016/5938740/ Peroxisome proliferator-activated receptors (PPARs) regulate cardiac glucose and lipid homeostasis. Histone deacetylase (HDAC) inhibitor has anti-inflammatory effects which may play a key role in modulating PPARs and fatty acid metabolism. The aim of this study was to investigate whether HDAC inhibitor, MPT0E014, can modulate myocardial PPARs, inflammation, and fatty acid metabolism in diabetes mellitus (DM) cardiomyopathy. Electrocardiography, echocardiography, and western blotting were used to evaluate the electrophysiological activity, cardiac structure, fatty acid metabolism, inflammation, and PPAR isoform expressions in the control and streptozotocin-nicotinamide-induced DM rats with or without MPT0E014. Compared to control, DM and MPT0E014-treated DM rats had elevated blood glucose levels and lower body weights. However, MPT0E014-treated DM and control rats had smaller left ventricular end-diastolic diameter and shorter QT interval than DM rats. The control and MPT0E014-treated DM rats had greater cardiac PPAR-α and PPAR-δ protein expressions, but less cardiac PPAR-γ than DM rats. Moreover, control and MPT0E014-treated DM rats had lower concentrations of 5′ adenosine monophosphate-activated protein kinase 2α, PPAR-γ coactivator 1α, phosphorylated acetyl CoA carboxylase, cluster of differentiation 36, diacylglycerol acyltransferase 1 (DGAT1), DGAT2, tumor necrosis factor-α, and interleukin-6 protein than DM rats. HDAC inhibition significantly attenuated DM cardiomyopathy through modulation of cardiac PPARS, fatty acid metabolism, and proinflammatory cytokines. Ting-I Lee, Yu-Hsun Kao, Wen-Chin Tsai, Cheng-Chih Chung, Yao-Chang Chen, and Yi-Jen Chen Copyright © 2016 Ting-I Lee et al. All rights reserved. Testosterone Replacement Modulates Cardiac Metabolic Remodeling after Myocardial Infarction by Upregulating PPARα Thu, 16 Jun 2016 08:55:09 +0000 http://www.hindawi.com/journals/ppar/2016/4518754/ Despite the importance of testosterone as a metabolic hormone, its effects on myocardial metabolism in the ischemic heart remain unclear. Myocardial ischemia leads to metabolic remodeling, ultimately resulting in ATP deficiency and cardiac dysfunction. In the present study, the effects of testosterone replacement on the ischemic heart were assessed in a castrated rat myocardial infarction model established by ligating the left anterior descending coronary artery 2 weeks after castration. The results of real-time PCR and Western blot analyses showed that peroxisome proliferator-activated receptor α (PPARα) decreased in the ischemic myocardium of castrated rats, compared with the sham-castration group, and the mRNA expression of genes involved in fatty acid metabolism (the fatty acid translocase CD36, carnitine palmitoyltransferase I, and medium-chain acyl-CoA dehydrogenase) and glucose transporter-4 also decreased. A decline in ATP levels in the castrated rats was accompanied by increased cardiomyocyte apoptosis and fibrosis and impaired cardiac function, compared with the sham-castration group, and these detrimental effects were reversed by testosterone replacement. Taken together, our findings suggest that testosterone can modulate myocardial metabolic remodeling by upregulating PPARα after myocardial infarction, exerting a protective effect on cardiac function. Jing Yang, Fengyue Wang, Weiju Sun, Yanli Dong, Mingyu Li, and Lu Fu Copyright © 2016 Jing Yang et al. All rights reserved. A Citrus bergamia Extract Decreases Adipogenesis and Increases Lipolysis by Modulating PPAR Levels in Mesenchymal Stem Cells from Human Adipose Tissue Wed, 15 Jun 2016 08:35:29 +0000 http://www.hindawi.com/journals/ppar/2016/4563815/ The aim of this research was to assess the impact of a well-characterized extract from Citrus bergamia juice on adipogenesis and/or lipolysis using mesenchymal stem cells from human adipose tissue as a cell model. To evaluate the effects on adipogenesis, some cell cultures were treated with adipogenic medium plus 10 or 100 μg/mL of extract. To determine the properties on lipolysis, additional mesenchymal stem cells were cultured with adipogenic medium for 14 days and after this time added with Citrus bergamia for further 14 days. To verify adipogenic differentiation, oil red O staining at 7, 14, 21, and 28 days was performed. Moreover, the expression of peroxisome proliferator-activated receptor gamma (PPAR-γ), adipocytes fatty acid-binding protein (A-FABP), adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), monoglyceride lipase (MGL), 5′-adenosine monophosphate-activated protein kinase (AMPK)α1/2, and pAMPKα1/2 was evaluated by Western blot analysis and the release of glycerol by colorimetric assay. Citrus bergamia extract suppressed the accumulation of intracellular lipids in mesenchymal stem cells during adipogenic differentiation and promoted lipolysis by repressing the expression of adipogenic genes and activating lipolytic genes. Citrus bergamia extract could be a useful natural product for improving adipose mobilization in obesity-related disorders. Debora Lo Furno, Adriana Carol Eleonora Graziano, Rosanna Avola, Rosario Giuffrida, Vincenzo Perciavalle, Francesco Bonina, Giuliana Mannino, and Venera Cardile Copyright © 2016 Debora Lo Furno et al. All rights reserved. Pioglitazone Attenuates Drug-Eluting Stent-Induced Proinflammatory State in Patients by Blocking Ubiquitination of PPAR Tue, 14 Jun 2016 06:21:51 +0000 http://www.hindawi.com/journals/ppar/2016/7407153/ The inflammatory response after polymer-based drug-eluting stent (DES) placement has recently emerged as a major concern. The biologic roles of peroxisome proliferator-activated receptor- (PPAR-) activators thiazolidinedione (TZD) remain controversial in cardiovascular disease. Herein, we investigated the antiinflammatory effects of pioglitazone (PIO) on circulating peripheral blood mononuclear cells (MNCs) in patients after coronary DES implantation. Methods and Results. Twenty-eight patients with coronary artery disease and who underwent DES implantations were randomly assigned to pioglitazone (30 mg/d; PIO) or placebo (control; Con) treatment in addition to optimal standard therapy. After 12 weeks of treatment, plasma concentrations of high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), tumor necrosis factor- (TNF-), and matrix metalloproteinase-9 (MMP-9) were significantly decreased in PIO group compared to the Con group (, 0.011, 0.008, and 0.012, resp.). DES-induced mRNA expressions of IL-6, TNF-, and MMP-9 in circulating MNC were significantly blocked by PIO (, 0.012, and 0.007, resp.). In addition, PIO markedly inhibited DES-enhanced NF-κB function and DES-blocked PPAR- activity. Mechanically, DES induced PPAR- ubiquitination and degradation in protein level, which can be totally reversed by PIO. Conclusion. PIO treatment attenuated DES-induced PPAR loss, NF-κB activation, and proinflammation, indicating that PIO may have a novel direct protective role in modulating proinflammation in DES era. Zhongxia Wang, Tao Zhang, Lizhe Sun, Ruifeng Li, Yuanyuan Wei, Xiaojuan Fan, Zuyi Yuan, Junhui Liu, and Tao Chen Copyright © 2016 Zhongxia Wang et al. All rights reserved. PPARγ Agonists as an Anti-Inflammatory Treatment Inhibiting Rotavirus Infection of Small Intestinal Villi Mon, 13 Jun 2016 12:09:50 +0000 http://www.hindawi.com/journals/ppar/2016/4049373/ Rotavirus infection has been reported to induce an inflammatory response in the host cell accompanied by the increased expression or activation of some cellular molecules including ROS, NF-κB, and COX-2. PPARγ stimulation and N-acetylcysteine (NAC) treatment have been found to interfere with viral infections including rotavirus infection. Small intestinal villi isolated from in vivo infected mice with rotavirus ECwt were analyzed for the percentage of ECwt-infected cells, the presence of rotavirus antigens, and infectious virion yield following treatment with pioglitazone. Isolated villi were also infected in vitro and treated with PPARγ agonists (PGZ, TZD, RGZ, DHA, and ALA), all-trans retinoic acid (ATRA), and NAC. After treatments, the expression of cellular proteins including PPARγ, NF-κB, PDI, Hsc70, and COX-2 was analyzed using immunochemistry, ELISA, immunofluorescence, and Western blotting. The results showed that rotavirus infection led to an increased accumulation of the cellular proteins studied and ROS. The virus infection-induced accumulation of the cellular proteins studied and ROS was reduced upon pioglitazone treatment, causing also a concomitant reduction of the infectious virion yield. We hypothesized that rotavirus infection is benefiting from the induction of a host cell proinflammatory response and that the interference of the inflammatory pathways involved leads to decreased infection. Dory Gómez, Natalia Muñoz, Rafael Guerrero, Orlando Acosta, and Carlos A. Guerrero Copyright © 2016 Dory Gómez et al. All rights reserved. Pioglitazone Effect on Glioma Stem Cell Lines: Really a Promising Drug Therapy for Glioblastoma? Wed, 25 May 2016 11:26:05 +0000 http://www.hindawi.com/journals/ppar/2016/7175067/ Glioblastoma multiforme (GBM) represents one of the most frequent malignant brain tumors. Current therapies do not provide real solutions to this pathology. Their failure can be ascribed to a cell subpopulation with stem-like properties called glioma stem cells (GSCs). Therefore, new therapeutic strategies GSC-targeted are needed. PPARγ, a nuclear receptor involved in lipid metabolism, has already been indicated as a promising target for antineoplastic therapies. Recent studies have reported that synthetic PPARγ agonists, already in clinical use for the treatment of type II diabetes, exhibit antineoplastic effects in a wide range of malignant tumor cells, including glioma cells. We investigated the effect of the synthetic PPARγ agonist Pioglitazone on viability, proliferation, morphology, and differentiation in six GSC lines isolated from GBM patients. We also analyzed Pioglitazone-induced changes in transcriptional levels of Wnt/β catenin related genes. Results showed that response to Pioglitazone was heterogeneous inducing an evident decrease of cell viability and proliferation only in a subset of GSC lines. We did not find any sign of cell differentiation neither observing cell morphology nor analyzing the expression of stemness and differentiation markers. Moreover, Wnt/β signaling pathway was only mildly affected from a transcriptional point of view after Pioglitazone exposure. Chiara Cilibrasi, Valentina Butta, Gabriele Riva, and Angela Bentivegna Copyright © 2016 Chiara Cilibrasi et al. All rights reserved. Current Advances in the Biochemical and Physiological Aspects of the Treatment of Type 2 Diabetes Mellitus with Thiazolidinediones Mon, 23 May 2016 06:25:28 +0000 http://www.hindawi.com/journals/ppar/2016/7614270/ The present review summarizes the current advances in the biochemical and physiological aspects in the treatment of type 2 diabetes mellitus (DM2) with thiazolidinediones (TZDs). DM2 is a metabolic disorder characterized by hyperglycemia, triggering the abnormal activation of physiological pathways such as glucose autooxidation, polyol’s pathway, formation of advance glycation end (AGE) products, and glycolysis, leading to the overproduction of reactive oxygen species (ROS) and proinflammatory cytokines, which are responsible for the micro- and macrovascular complications of the disease. The treatment of DM2 has been directed toward the reduction of hyperglycemia using different drugs such as insulin sensitizers, as the case of TZDs, which are able to lower blood glucose levels and circulating triglycerides by binding to the nuclear peroxisome proliferator-activated receptor gamma (PPARγ) as full agonists. When TZDs interact with PPARγ, the receptor regulates the transcription of different genes involved in glucose homeostasis, insulin resistance, and adipogenesis. However, TZDs exhibit some adverse effects such as fluid retention, weight gain, hepatotoxicity, plasma-volume expansion, hemodilution, edema, bone fractures, and congestive heart failure, which limits their use in DM2 patients. D. Alemán-González-Duhart, F. Tamay-Cach, S. Álvarez-Almazán, and J. E. Mendieta-Wejebe Copyright © 2016 D. Alemán-González-Duhart et al. All rights reserved. Peroxisome Proliferator-Activated Receptor-γ Is Critical to Cardiac Fibrosis Thu, 12 May 2016 17:12:45 +0000 http://www.hindawi.com/journals/ppar/2016/2198645/ Peroxisome proliferator-activated receptor-γ (PPARγ) is a ligand-activated transcription factor belonging to the nuclear receptor superfamily, which plays a central role in regulating lipid and glucose metabolism. However, accumulating evidence demonstrates that PPARγ agonists have potential to reduce inflammation, influence the balance of immune cells, suppress oxidative stress, and improve endothelial function, which are all involved in the cellular and molecular mechanisms of cardiac fibrosis. Thus, in this review we discuss the role of PPARγ in various cardiovascular conditions associated with cardiac fibrosis, including diabetes mellitus, hypertension, myocardial infarction, heart failure, ischemia/reperfusion injury, atrial fibrillation, and several other cardiovascular disease (CVD) conditions, and summarize the developmental status of PPARγ agonists for the clinical management of CVD. Huang-Jun Liu, Hai-Han Liao, Zheng Yang, and Qi-Zhu Tang Copyright © 2016 Huang-Jun Liu et al. All rights reserved.