http://www.hindawi.comThe latest articles from Hindawi Publishing Corporation© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/790568Decreased expression of peroxisome proliferator activated receptor-γ (PPARγ) and high levels of the proinflammatory enzyme cyclooxygenase-2 (COX-2) have been observed in many tumor types. Both reduced (PPARγ) expression and elevated COX-2 within the tumor are associated with poor prognosis in lung cancer patients, and recent work has indicated that these signaling pathways may be interrelated. Synthetic (PPARγ) agonists such as the thiazolidinedione (TZD) class of anti-diabetic drugs can decrease COX-2 levels, inhibit growth of non-small-cell lung cancer (NSCLC) cells in vitro, and block tumor progression in xenograft models. TZDs alter the expression of COX-2 and consequent production of the protumorigenic inflammatory molecule prostaglandin E2 (PGE2) through both (PPARγ) dependent and independent mechanisms. Certain TZDs also reduce expression of PGE2 receptors or upregulate the PGE2 catabolic enzyme 15-prostaglandin dehydrogenase. As several COX-2 enzymatic products have antitumor properties and specific COX-2 inhibition has been associated with increased risk of adverse cardiac events, directly reducing the effects or concentration of PGE2 may provide a more safe and effective strategy for lung cancer treatment. Understanding the mechanisms underlying these effects may be helpful for designing anticancer therapies. This article summarizes recent research on the relationship between (PPARγ), TZDs, and the COX-2/PGE2 pathways in lung cancer.Saswati Hazra, Katherine A. Peebles, Sherven Sharma, Jenny T. Mao, and Steven M. Dubinett© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/358052Omega-3 (or n-3) polyunsaturated fatty acids (PUFAs) and their metabolites are natural ligands for peroxisome proliferator receptor activator (PPAR)γ and, due to the effects of PPARγ on cell proliferation, survival, and differentiation, are potential anticancer agents. Dietary intake of omega-3 PUFAs has been associated with a reduced risk of certain cancers in human populations and in animal models. In vitro studies have shown that omega-3 PUFAs inhibit cell proliferation and induce apoptosis in cancer cells through various pathways but one of which involves PPARγ activation. The differential activation of PPARγ and PPARγ-regulated genes by specific dietary fatty acids may be central to their distinct roles in cancer. This review summarizes studies relating PUFAs to PPARγ and cancer and offers a new paradigm relating an n-3 PUFA through PPARγ to the expression of the cell surface proteoglycan, syndecan-1, and to the death of cancer cells.Iris J. Edwards and Joseph T. O'Flaherty© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/936906INT131 (formerly T0903131, T131, AMG131) is a potent non-thiazolidinedione (TZD) selective peroxisome proliferator-activated receptor γ modulator (SPPARM) currently in Phase 2 clinical trials for treatment of type-2 diabetes mellitus (T2DM). This new chemical entity represents a second generation SPPARM approach developed after the first generation PPARγ full agonists to address their inherent limitations. INT131 was specifically and carefully designed using preclinical models to exhibit a biological profile of strong efficacy with de minimis side effects compared to PPARγ full agonists. As a potent PPARγ modulator, INT131 binds to PPARγ with high affinity. In pharmacology models of diabetes and in early clinical studies, it achieved a high level of efficacy in terms of antidiabetic actions such as insulin sensitization and glucose and insulin lowering, but had little activity in terms of other, undesired, effects associated with TZD PPARγ full agonists such as edema and adipogenesis. Ongoing clinical development is directed at translating these findings into establishing a novel and effective treatment for T2DM patients with an improved safety profile in relation to that currently available.Linda S. Higgins and Christos S. Mantzoros© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/520465Peroxisome proliferator-activated receptors (PPARs) play an important role in regulating both glucose and lipid metabolism. Agonists for both PPARγ and PPARγ have been used to treat dyslipidemia and hyperglycemia, respectively. In addition to affecting glucose metabolism, PPARγ agonists also regulate lipid metabolism. In this review, we will focus on the randomized clinical trials that directly compared the lipid effects of the thiazolidinedione class of PPARγ agonists, pioglitazone and rosiglitazone, head-to-head either as monotherapy or in combination with other lipid-altering or glucose-lowering agentsMark A. Deeg and Meng H. Tan© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/651419Exposure to the estrogen receptor alpha (ERα) ligand diethylstilbesterol (DES) between neonatal days 2 to 12 induces penile adipogenesis and adult infertility in rats. The objective of this study was to investigate the in vivo interaction between DES-activated ERα and the proadipogenic transcription factor peroxisome proliferator-activated receptor gamma (PPARγ). Transcripts for PPARs α, β, and γ and γ1a splice variant were detected in Sprague-Dawley normal rat penis with PPARγ predominating. In addition, PPARγ1b and PPARγ2 were newly induced by DES. The PPARγ transcripts were significantly upregulated with DES and reduced by antiestrogen ICI 182, 780. At the cellular level, PPARγ protein was detected in urethral transitional epithelium and stromal, endothelial, neuronal, and smooth muscular cells. Treatment with DES activated ERα and induced adipocyte differentiation in corpus cavernosum penis. Those adipocytes exhibited strong nuclear PPARγ expression. These results suggest a biological overlap between PPARγ and ERα and highlight a mechanism for endocrine disruption.Mahmoud M. Mansour, Hari O. Goyal, Tim D. Braden, John C. Dennis, Dean D. Schwartz, Robert L. Judd, Frank F. Bartol, Elaine S. Coleman, and Edward E. Morrison© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/285842Inflammation has been recognized as an important hallmark of atherosclerosis. The pharmacological activation of PPAR-γ by the thiazolidinediones in diabetes, and of PPAR-α by the fibrates in hyperlipidemia has been shown to help to reduce inflammatory markers in preclinical and clinical studies. PPARs are known to modulate immune pathways through at least three different mechanisms: by direct binding to PPRE of anti-inflammatory cytokines genes; by transrepression of transcription factors like NF-κB and AP-1; or by corepression. The regulation of the inflammatory pathways by PPARs can be achieved on each one of the cells involved in the atherosclerotic process, that is, monocytes, macrophages, T cells, endothelial cells, and smooth muscle cells. Moreover, as each of these cellular components is interconnected with each other, PPAR activation in one cell type could affect the other ones. As activation of PPARs has clear ant-inflammatory benefits, PPARs ligands should be considered as a new therapeutical approach to ameliorate the exacerbated immune response in atherosclerotic diseases.Ana Z. Fernandez© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/250568Induction of differentiation and apoptosis in cancer cells by ligands of PPARγ is a novel therapeutic approach to malignant tumors. Chondrosarcoma (malignant cartilage tumor) and OUMS-27 cells (cell line established from grade III human chondrosarcoma) express PPARγ. PPARγ ligands inhibited cell proliferation in a dose-dependent manner, and induced apoptosis of OUMS-27. The higher-grade chondrosarcoma expressed a higher amount of antiapoptotic Bcl-xL in vivo. The treatment of OUMS-27 by 15d-PGJ2, the most potent endogenous ligand for PPARγ, downregulated expression of Bcl-xL and induced transient upregulation of proapoptotic Bax, which could accelerate cytochrome c release from mitochondria to the cytosol, followed by induction of caspase-dependent apoptosis. 15d-PGJ2 induced the expression of CDK inhibitor p21 protein in human chondrosarcoma cells, which appears to be involved in the mechanism of inhibition of cell proliferation. These findings suggest that targeted therapy with PPARγ ligands could be a novel strategy against chondrosarcoma.K. Nishida, T. Kunisada, Z. N. Shen, Y. Kadota, K. Hashizume, and T. Ozaki© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/204514The peroxisome proliferator-activated receptors (PPARs) are ligand-inducible transcription factors which belong to the superfamily of nuclear hormone receptors. In recent years it turned out that natural as well as synthetic PPAR agonists exhibit profound antineoplastic as well as redifferentiation effects in tumors of the central nervous system (CNS). The molecular understanding of the underlying mechanisms is still emerging, with partially controverse findings reported by a number of studies dealing with the influence of PPARs on treatment of tumor cells in vitro. Remarkably, studies examining the effects of these drugs in vivo are just beginning to emerge. However, the agonists of PPARs, in particular the thiazolidinediones, seem to be promising candidates for new approaches in human CNS tumor therapy.Lars Tatenhorst, Eric Hahnen, and Michael T. Heneka© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/906542Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor family of ligand-activated transcription factors. This subfamily is composed of three members—PPARα, PPARδ, and PPARγ—that differ in their cell and tissue distribution as well as in their target genes. PPARα is abundantly expressed in liver, brown adipose tissue, kidney, intestine, heart, and skeletal muscle; and its ligands have been used to treat diseases such as obesity and diabetes. The recent finding that members of the PPAR family, including the PPARα, are expressed by tumor and endothelial cells together with the observation that PPAR ligands regulate cell growth, survival, migration, and invasion, suggested that PPARs also play a role in cancer. In this review, we focus on the contribution of PPARα to tumor and endothelial cell functions and provide compelling evidence that PPARα can be viewed as a new class of ligand activated tumor “suppressor” gene with antiangiogenic and antitumorigenic activities. Given that PPAR ligands are currently used in medicine as hypolipidemic drugs with excellent tolerance and limited toxicity, PPARα activation might offer a novel and potentially low-toxic approach for the treatment of tumor-associated angiogenesis and cancer.Ambra Pozzi and Jorge H. Capdevila© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/254108Peroxisome 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 and cancer biology, among others. Since then, PPARs have become an exciting target for the development of therapies directed at many disorders including cancer. PPARs are expressed in many tumors including lung cancer, and their function has been linked to the process of carcinogenesis. 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 a member of this family (PPARγ) is believed to affect lung tumor cell biology.Shou Wei Han and Jesse Roman© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/638356Michael K. Racke and Paul D. Drew© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/904041Rosiglitazone (RGZ), a thiazolidinedione ligand of the peroxisome proliferator-activated receptor (PPAR)-γ, has been recently described as possessing antitumoral properties. We investigated RGZ effect on cell proliferation in two cell line models (SW13 and H295R) of human adrenocortical carcinoma (ACC) and its interaction with the signaling pathways of the activated IGF-I receptor (IGF-IR). We demonstrate a high expression of IGF-IR in the two cell lines and in ACC. Cell proliferation is stimulated by IGF-I in a dose- and time-dependent manner and is inhibited by RGZ. The analysis of the main intracellular signaling pathways downstream of the activated IGF-IR, phosphatidyl inositol 3-kinase (PI3K)-Akt, and extracellular signal-regulated kinase (ERK1/2) cascades reveals that RGZ rapidly interferes with the Akt and ERK1/2 phosphorylation/activation which mediates IGF-I stimulated proliferation. In conclusion, our results suggest that RGZ exerts an inhibitory effect on human ACC cell proliferation by interfering with the PI3K/Akt and ERK1/2 signaling pathways downstream of the activated IGF-IR.Cantini Giulia, Lombardi Adriana, Piscitelli Elisabetta, Giada Poli, Ceni Elisabetta, Marchiani Sara, Ercolino Tonino, Galli Andrea, Serio Mario, Mannelli Massimo, and Luconi Michaela© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/658520Central nervous system (CNS) is an immune privileged site, nevertheless inflammation associates with many CNS diseases. Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors that regulate immune and inflammatory responses. Specific ligands for PPARα, γ, and δ isoforms have proven effective in the animal models of multiple sclerosis (MS), Alzheimer's disease, Parkinson's disease, and trauma/stroke, suggesting their use in the treatment of neuroinflammatory diseases. The activation of NF-κB and Jak-Stat signaling pathways and secretion of inflammatory cytokines are critical in the pathogenesis of CNS diseases. Interestingly, PPAR agonists mitigate CNS disease by modulating inflammatory signaling network in immune cells. In this manuscript, we review the current knowledge on how PPARs regulate neuroinflammatory signaling networks in CNS diseases.John J. Bright, Saravanan Kanakasabai, Wanida Chearwae, and Sharmistha Chakraborty© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/542694Proline is metabolized by its own specialized enzymes with their own tissue and subcellular localizations and mechanisms of regulation. The central enzyme in this metabolic system is proline oxidase, a flavin adenine dinucleotide-containing enzyme which is tightly bound to mitochondrial inner membranes. The electrons from proline can be used to generate ATP or can directly reduce oxygen to form superoxide. Although proline may be derived from the diet and biosynthesized endogenously, an important source in the microenvironment is from degradation of extracellular matrix by matrix metalloproteinases. Previous studies showed that proline oxidase is a p53-induced gene and its overexpression can initiate proline-dependent apoptosis by both intrinsic and extrinsic pathways. Another important factor regulating proline oxidase is peroxisome proliferator activated receptor gamma (PPARγ). Importantly, in several cancer cells, proline oxidase may be an important mediator of the PPARγ-stimulated generation of ROS and induction of apoptosis. Knockdown of proline oxidase expression by antisense RNA markedly decreased these PPARγ-stimulated effects. These findings suggest an important role in the proposed antitumor effects of PPARγ. Moreover, it is possible that proline oxidase may contribute to the other metabolic effects of PPARγ.James M. Phang, Jui Pandhare, Olga Zabirnyk, and Yongmin Liu© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/352437A growing body of evidence indicates that PPAR (peroxisome proliferator-activated receptor) α agonists might have therapeutic usefulness in antitumoral therapy by decreasing abnormal cell growth, and reducing tumoral angiogenesis. Most of the anti-inflammatory and antineoplastic properties of PPAR ligands are due to their inhibitory effects on transcription of a variety of genes involved in inflammation, cell growth and angiogenesis. Cyclooxygenase (COX)-2 and vascular endothelial growth factor (VEGF) are crucial agents in inflammatory and angiogenic processes. They also have been significantly associated to cell proliferation, tumor growth, and metastasis, promoting tumor-associated angiogenesis. Aberrant expression of VEGF and COX-2 has been observed in a variety of tumors, pointing to these proteins as important therapeutic targets in the treatment of pathological angiogenesis and tumor growth. This review summarizes the current understanding of the role of PPARα and its ligands in the regulation of COX-2 and VEGF gene expression in the context of tumor progression.Raquel Grau, Manuel D. Díaz-Muñoz, Cristina Cacheiro-Llaguno, Manuel Fresno, and Miguel A. Iñiguez© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/230893Chemically synthesized ligands for nuclear receptors of the PPAR family modulate a number of physiological functions, particularly insulin resistance in the context of energy homeostasis and the metabolic syndrome. Additionally, these compounds may treat or prevent the development of many secondary consequences of the metabolic syndrome. Many PPAR agonists are also known to influence the proliferation and apoptosis of breast carcinoma cells though the experiments were carried out at suprapharmacological doses of PPAR ligands. It is possible that the breast epithelium of diabetics exposed to PPAR agonists will experience perturbation of the corresponding signaling pathway. Consequently, these patients' lifetime breast carcinoma risks could be modified, as their breast lesion incidence or the rates of the conversion of these lesions to carcinomas might vary upward or downward. PPAR activating treatment may also influence the progression of existing, undiagnosed invasive lesions. In this review, we attempt to summarize the possible influence of chemical PPAR ligands on the molecular pathways involved in the initiation and progression of breast carcinoma, with a major emphasis on PPARγ agonists thiazolidinediones (TZDs).Ancha Baranova© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/256251Before the discovery of peroxisome proliferator activated receptors (PPARs), it was well known that certain drugs considered as classical PPAR-alpha agonists induced hepatocarcinoma or peroxisome proliferation in rodents. These drugs were derivatives of fibric acid, and they included clofibrate, bezafibrate, and fenofibrate. However, such toxicity has never been observed in human patients treated with these hypolipidemic drugs. Thiazolidinediones are a new class of PPAR activators showing greater specificity for the γ isoform of PPARs. These drugs are used as insulin sensitizers in the treatment of type II diabetes. In addition, they have been shown to induce cell differentiation or apoptosis in various experimental models of cancer. PPAR-α ligands have also been shown to induce cancer cell differentiation and, paradoxically, PPAR-γ drug activators have been reported to act as carcinogens. The confusing picture that emerges from these data is further complicated by the series of intriguing side effects observed following administration of pharmacological PPAR ligands (rhabdomyolysis, liver and heart toxicity, anemia, leucopenia). These side effects cannot be easily explained by simple interactions between the drug and nuclear receptors. Rather, these side effects seem to indicate that the ligands have biological activity independent of the nuclear receptors. Considering the emerging role of mitochondria in cancer and the potential metabolic connections between this organelle and PPAR physiology, characterization of the reciprocal influences is fundamental not only for a better understanding of cancer biology, but also for more defined pharmacotoxicological profiles of drugs that modulate PPARs.Roberto Scatena, Patrizia Bottoni, and Bruno Giardina© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/546753PPARs are members of the steroid hormone nuclear receptor superfamily and play an important role in the regulation of lipid metabolism, energy balance, artherosclerosis and glucose control. Recent studies suggest that they play an important role in regulating inflammation. This review will focus on PPAR-α regulation of the immune response. We describe how PPAR-α regulates differentiation of T cells by transactivation and/or interaction with other transcription factors. Moreover, PPAR-α agonists have been shown to ameliorate experimental autoimmune encephalomyelitis (EAE) in mice, suggesting that they could provide a therapy for human autoimmune diseases such as multiple sclerosis.Yuhong Yang, Anne R. Gocke, Amy Lovett-Racke, Paul D. Drew, and Michael K. Racke© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/403896Peroxisome proliferator-activated receptors (PPARs) are well studied for their peripheral physiological and pathological impact, but they also play an important role for the pathogenesis of various disorders of the central nervous system (CNS) like multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's, and Parkinson's disease. The observation that PPARs are able to suppress the inflammatory response in peripheral macrophages and in several models of human autoimmune diseases lead to the idea that PPARs might be beneficial for CNS disorders possessing an inflammatory component. The neuroinflammatory response during the course of Alzheimer's disease (AD) is triggered by the neurodegeneration and the deposition of the β-amyloid peptide in extracellular plaques. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been considered to delay the onset and reduce the risk to develop Alzheimer's disease, while they also directly activate PPARγ. This led to the hypothesis that NSAID protection in AD may be partly mediated by PPARγ. Several lines of evidence have supported this hypothesis, using AD-related transgenic cellular and animal models. Stimulation of PPARγ receptors by synthetic agonist (thiazolidinediones) inducing anti-inflammatory, anti-amyloidogenic, and insulin sensitising effects may account for the observed effects. Several clinical trials already revealed promising results using PPAR agonists, therefore PPARs represent an attractive therapeutic target for the treatment of AD.Markus P. Kummer and Michael T. Heneka© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/524671Peroxisome proliferators-activated receptors (PPARs) are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. The three PPAR isoforms (α, γ and β/δ) have been found to play a pleiotropic role in cell fat metabolism. Furthermore, in recent years, evidence has been found regarding the antiproliferative, proapoptotic, and differentiation-promoting activities displayed by PPAR ligands, particularly by PPARγ ligands. PPAR ligands affect the expression of different growth-related genes through both PPAR-dependent and PPAR-independent mechanisms. Moreover, an interaction between PPAR ligands and other molecules which strengthen the effects of PPAR ligands has been described. Here we review the action of PPAR on the control of gene expression with particular regard to the effect of PPAR ligands on the expression of genes involved in the regulation of cell-cycle, differentiation, and apoptosis. Moreover, the interaction between PPAR ligands and 4-hydroxynonenal (HNE), the major product of the lipid peroxidation, has been reviewed.Giuseppina Barrera, Cristina Toaldo, Stefania Pizzimenti, Angelo Cerbone, Piergiorgio Pettazzoni, Mario Umberto Dianzani, and Carlo Ferretti© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/587401Cholangiocarcinoma is a predominantly fatal cancer, which can be difficult to treat. It has been reported that the administration of pioglitazone temporarily improved not only diabetic control, but also bile duct carcinoma-induced cholangiohepatitis. Pioglitazone is considered to have both direct and indirect mechanisms of action on the tumor-related hepatitis. Several molecules induced by thiazolidinedione, including Smad pathway-related molecules, adipokines, and other lipid metabolism-related proteins, may directly or indirectly suppress tumor development and/or tumor-induced cholangiohepatitis. Although the most frequent and critical side effect of thiazolidinedione is drug-induced hepatitis, it can probably be avoided by careful monitoring of serum hepatic enzyme levels. Thiazolidinedione should be considered for management of tumor-induced hepatitis in the presence of diabetes unless severe side effects occur.Satoru Suzuki and Kiyoshi Hashizume© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/148687Although the highest levels of PPARγ expression in the body have been reported in the gastrointestinal epithelium, little is known about the physiological functions of that receptor in the gut. Moreover, there is considerable controversy concerning the effects of thiazolidinedione PPARγ agonists on the two major diseases of the gastrointestinal track: colorectal cancer and inflammatory bowel disease. We will undertake to review both historical and recently published data with a view toward summarizing what is presently known about the roles of PPARγ in both physiological and pathological processes in the gastrointestinal epithelium.Brian M. Necela and E. Aubrey Thompson© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/169414Mononuclear phagocytes often function as control switches of the immune system, securing the balance between pro- and anti-inflammatory reactions. For this purpose and depending on the activating stimuli, these cells can develop into different subsets: proinflammatory classically activated (M1) or anti-inflammatory alternatively activated (M2) macrophages. The expression of the nuclear peroxisome proliferator-activated receptors (PPARs) is regulated by M1- or M2-inducing stimuli, and these receptors are generally considered to counteract inflammatory M1 macrophages, while actively promoting M2 activation. This is of importance in a tumor context, where M1 are important initiators of inflammation-driven cancers. As a consequence, PPAR agonists are potentially usefull for inhibiting the early phases of tumorigenesis through their antagonistic effect on M1. In more established tumors, the macrophage phenotype is more diverse, making it more difficult to predict the outcome of PPAR agonism. Overall, in our view current knowledge provides a sound basis for the clinical evaluation of PPAR ligands as chemopreventive agents in chronic inflammation-associated cancer development, while cautioning against the unthoughtful application of these agents as cancer therapeutics.Jo A. Van Ginderachter, Kiavash Movahedi, Jan Van den Bossche, and Patrick De Baetselier© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/762398Peroxisome proliferator-activated receptor-γ (PPARγ) and retinoic acid X-receptor (RXR) heterodimer, which regulates cell growth and differentiation, represses the TGFβ1 gene that encodes for the protein involved in cancer biology. This review will introduce the novel mechanism associated with the inhibition of the TGFβ1 gene by PPARγ activation, which regulates the dephosphorylation of Zf9 transcription factor. Pharmacological manipulation of TGFβ1 by PPARγ activators can be applied for treating TGFβ1-induced pathophysiologic disorders such as cancer metastasis and fibrosis. In this article, we will discuss the opposing effects of TGFβ on tumor growth and metastasis, and address the signaling pathways regulated by PPARγ for tumor progression and suppression.Chang Ho Lee, Hyung Don Kim, Sang Mi Shin, and Sang Geon Kim© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/704165Peroxisome proliferator-activated receptors (PPARs) are ligand binding transcription factors which function in many physiological roles including lipid metabolism, cell growth, differentiation, and apoptosis. PPARs and their ligands have been shown to play a role in cancer. In particular, PPARγ ligands including endogenous prostaglandins and the synthetic thiazolidinediones (TZDs) can induce apoptosis of cancer cells with antitumor activity. Thus, PPARγ ligands have a potential in both chemoprevention and therapy of several types of cancer either as single agents or in combination with other antitumor agents. Accordingly, the involvement of PPARγ and its ligands in regulation of apoptosis of cancer cells have been extensively studied. Depending on cell types or ligands, induction of apoptosis in cancer cells by PPARγ ligands can be either PPARγ-dependent or -independent. Through increasing our understanding of the mechanisms of PPARγ ligand-induced apoptosis, we can develop better strategies which may include combining other antitumor agents for PPARγ-targeted cancer chemoprevention and therapy. This review will highlight recent research advances on PPARγ and apoptosis in cancer.Heath A. Elrod and Shi-Yong Sun© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/326915In recent years, the study of the peroxisome proliferators activated receptor gamma (PPAR-γ) as a potential target for cancer prevention and therapy has gained a strong interest. However, the overall biological significance of PPAR-γ in cancer development and progression is still controversial. While many reports documented antiproliferative effects in human cancer cell and animal models, several studies demonstrating potential tumor promoting actions of PPAR-γ ligands raised considerable concerns about the role of PPAR-γ in human cancers. Controversy also exists about the role of PPAR-γ in human pancreatic cancers. The current review summarizes the data about PPAR-γ in pancreatic cancer and highlights the biologically relevant interactions between the cyclooxygenase and PPAR system.Guido Eibl© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/349185Accumulation of amyloid-β peptide (Aβ) appears to contribute to the pathogenesis of Alzheimer's disease (AD). Therapeutic hope for the prevention or removal of Aβ deposits has been placed in strategies involving immunization against the Aβ peptide. Initial Aβ immunization studies in animal models of AD showed great promise. However, when this strategy was attempted in human subjects with AD, an unacceptable degree of meningoencephalitis occurred. It is generally believed that this adverse outcome resulted from a T-cell response to Aβ. Specifically, CD4+ Th1 and Th17 cells may contribute to severe CNS inflammation and limit the utility of Aβ immunization in the treatment of AD. Interleukin (IL)-12 and IL-23 play critical roles in the development of Th1 and Th17 cells, respectively. In the present study, Aβ1−42 synergistically elevated the expression of IL-12 and IL-23 triggered by inflammatory activation of microglia, and the peroxisome proliferator-activated receptor (PPAR)-γ agonist 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2) effectively blocked the elevation of these proinflammatory cytokines. Furthermore, 15d-PGJ2 suppressed the Aβ-related synergistic induction of CD14, MyD88, and Toll-like receptor 2, molecules that play critical roles in neuroinflammatory conditions. Collectively, these studies suggest that PPAR-γ agonists may be effective in modulating the development of AD.Jihong Xu, Steven W. Barger, and Paul D. Drew© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/627463The role of peroxisome proliferator-activated receptors (PPARs) in altering lipid and glucose metabolism is well established. More recent studies indicate that PPARs also play critical roles in controlling immune responses. We and others have previously demonstrated that PPAR-γ agonists modulate the development of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). This review will discuss the cellular and molecular mechanisms by which these agonists are believed to modulate disease. The therapeutic potential of PPAR-γ agonists in the treatment of multiple sclerosis will also be considered.Paul D. Drew, Jihong Xu, and Michael K. Racke© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/309469Peroxisome proliferator-activated receptor-gamma (PPARγ) exerts multiple functions in determination of cell fate, tissue metabolism, and host immunity. Two synthetic PPARγ ligands (rosiglitazone and pioglitazone) were approved for the therapy of type-2 diabetes mellitus and are expected to serve as novel cures for inflammatory diseases and cancer. However, PPARγ and its ligands exhibit a janus-face behaviour as tumor modulators in various systems, resulting in either tumor suppression or tumor promotion. This may be in part due to signaling crosstalk to the mitogen-activated protein kinase (MAPK) cascades. The genomic activity of PPARγ is modulated, in addition to ligand binding, by phosphorylation of a serine residue by MAPKs, such as extracellular signal-regulated protein kinases-1/2 (ERK-1/2), or by nucleocytoplasmic compartmentalization through the ERK activators MAPK kinases-1/2 (MEK-1/2). PPARγ ligands themselves activate the ERK cascade through nongenomic and often PPARγ-independent signaling. In the current review, we discuss the molecular mechanisms and physiological implications of the crosstalk of PPARγ with MEK-ERK signaling and its potential as a novel drug target for cancer therapy in patients.Elke Burgermeister and Rony Seger© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/453120Microglia and astrocytes express numerous members of the Toll-like receptor (TLR) family that are pivotal for recognizing conserved microbial motifs expressed by a wide array of pathogens. Despite the critical role for TLRs in pathogen recognition, when dysregulated these pathways can also exacerbate CNS tissue destruction. Therefore, a critical balance must be achieved to elicit sufficient immunity to combat CNS infectious insults and down-regulate these responses to avoid pathological tissue damage. We performed a comprehensive survey on the efficacy of various PPAR-γ agonists to modulate proinflammatory mediator release from primary microglia and astrocytes in response to numerous TLR ligands relevant to CNS infectious diseases. The results demonstrated differential abilities of select PPAR-γ agonists to modulate glial activation. For example, 15d-PGJ2 and pioglitazone were both effective at reducing IL-12 p40 release by TLR ligand-activated glia, whereas CXCL2 expression was either augmented or inhibited by 15d-PGJ2, effects that were dependent on the TLR ligand examined. Pioglitazone and troglitazone demonstrated opposing actions on microglial CCL2 production that were TLR ligand-dependent. Collectively, this information may be exploited to modulate the host immune response during CNS infections to maximize host immunity while minimizing inappropriate bystander tissue damage that is often characteristic of such diseases.Catherine Gurley, Jessica Nichols, Shuliang Liu, Nirmal K. Phulwani, Nilufer Esen, and Tammy Kielian© 2008, Hindawi Publishing Corporation. All rights reserved.