Peroxisome Proliferator-activated Receptors Receptors Research Articles

Impact of Phytochemicals on PPAR Receptors: Implications for Disease Treatments

Peroxisome proliferator-activated receptors (PPARs) are members of the ligand-dependent nuclear receptor family. PPARs have attracted wide attention as pharmacologic mediators to manage multiple diseases and their underlying signaling targets. They mediate a broad range of specific biological activities and multiple organ toxicity, including cellular differentiation, metabolic syndrome, cancer, atherosclerosis, neurodegeneration, cardiovascular diseases, and inflammation related to their up/downstream signaling pathways. Consequently, several types of selective PPAR ligands, such as fibrates and thiazolidinediones (TZDs), have been approved as their pharmacological agonists. Despite these advances, the use of PPAR agonists is known to cause adverse effects in various systems. Conversely, some naturally occurring PPAR agonists, including polyunsaturated fatty acids and natural endogenous PPAR agonists curcumin and resveratrol, have been introduced as safe agonists as a result of their clinical evidence or preclinical experiments. This review focuses on research on plant-derived active ingredients (natural phytochemicals) as potential safe and promising PPAR agonists. Moreover, it provides a comprehensive review and critique of the role of phytochemicals in PPARs-related diseases and provides an understanding of phytochemical-mediated PPAR-dependent and -independent cascades. The findings of this research will help to define the functions of phytochemicals as potent PPAR pharmacological agonists in underlying disease mechanisms and their related complications.

Phthalate monoesters act through peroxisome proliferator-activated receptors in the mouse ovary

Widespread use of phthalates as solvents and plasticizers leads to everyday human exposure. The mechanisms by which phthalate metabolites act as ovarian toxicants are not fully understood. Thus, this study tested the hypothesis that the phthalate metabolites monononyl phthalate (MNP), monoisononyl phthalate (MiNP), mono(2-ethylhexyl) phthalate (MEHP), monobenzyl phthalate (MBzP), monobutyl phthalate (MBP), monoisobutyl phthalate (MiBP), and monoethyl phthalate (MEP) act through peroxisome proliferator-activated receptors (PPARs) in mouse granulosa cells. Primary granulosa cells were isolated from CD-1 mice and cultured with vehicle control (dimethyl sulfoxide) or MNP, MiNP, MEHP, MBzP, MBP, MiBP, or MEP (0.4–400 μM) for 24 h. Following culture, qPCR was performed for known PPAR targets, Fabp4 and Cd36. Treatment with the phthalate metabolites led to significant changes in Fabp4 and Cd36 expression relative to control in dose-dependent or nonmonotonic fashion. Primary granulosa cell cultures were also transfected with a DNA plasmid containing luciferase expressed under the control of a consensus PPAR response element. MNP, MiNP, MEHP, and MBzP caused dose-dependent changes in expression of luciferase, indicating the presence of functional endogenous PPAR receptors in the granulosa cells that respond to phthalate metabolites. The effects of phthalate metabolites on PPAR target genes were inhibited in most of the cultures by co-treatment with the PPAR-γ inhibitor, T0070907, or with the PPAR-α inhibitor, GW6471. Collectively, these data suggest that some phthalate metabolites may act through endogenous PPAR nuclear receptors in the ovary and that the differing structures of the phthalates result in different levels of activity.

Potential Therapeutic Effects of PPAR Ligands in Glioblastoma.

Glioblastoma (GB), also known as grade IV astrocytoma, represents the most aggressive form of brain tumor, characterized by extraordinary heterogeneity and high invasiveness and mortality. Thus, a great deal of interest is currently being directed to investigate a new therapeutic strategy and in recent years, the research has focused its attention on the evaluation of the anticancer effects of some drugs already in use for other diseases. This is the case of peroxisome proliferator-activated receptors (PPARs) ligands, which over the years have been revealed to possess anticancer properties. PPARs belong to the nuclear receptor superfamily and are divided into three main subtypes: PPAR-α, PPAR-β/δ, and PPAR-γ. These receptors, once activated by specific natural or synthetic ligands, translocate to the nucleus and dimerize with the retinoid X receptors (RXR), starting the signal transduction of numerous genes involved in many physiological processes. PPARs receptors are activated by specific ligands and participate principally in the preservation of homeostasis and in lipid and glucose metabolism. In fact, synthetic PPAR-α agonists, such as fibrates, are drugs currently in use for the clinical treatment of hypertriglyceridemia, while PPAR-γ agonists, including thiazolidinediones (TZDs), are known as insulin-sensitizing drugs. In this review, we will analyze the role of PPARs receptors in the progression of tumorigenesis and the action of PPARs agonists in promoting, or not, the induction of cell death in GB cells, highlighting the conflicting opinions present in the literature.

STUDY OF POSSIBLE MECHANISMS OF ACTOPROTECTIVE ACTION OF СATEKHIN HYDRATE

A study was carried out to study the possible mechanisms of actoprotective action of catechin hydrate administered at a dosage of 100 mg/kg. The animals were subjected to daily exhausting loads in the forced swimming test with a load of 10% of the animal's weight. After the end of the experiment, the rats were decapitated under chloral hydrate anesthesia (350 mg/kg) and the skeletal muscle was taken to obtain the supernatant. Using the ELISA method, the concentrations of nitric oxide isoforms (eNOS, iNOS, nNOS), PPAR (peroxisome proliferator-activated receptors) and JNK were estimated. It was found that against the background of the introduction of the test substance, an increase in eNOS activity was observed by 48.7% (p <0.05) relative to the group of negative control rats, as well as a decrease in iNOS and JNK — 1.9 times (p <0.05). In comparison with the group receiving Metaprot®, the concentration of endothelial synthase in the group receiving catechin hydrate was 1.3 times higher (p <0.05). The experiment performed suggests that the actoprotective effect of catechin hydrate is likely to be associated with inhibition of pathways mediated by JNK, activation of PPAR receptors, and the effect of these compounds on NO isoforms.

Zerumbone Ameliorates Neuropathic Pain Symptoms via Cannabinoid and PPAR Receptors Using In Vivo and In Silico Models.

Neuropathic pain is a chronic pain condition persisting past the presence of any noxious stimulus or inflammation. Zerumbone, of the Zingiber zerumbet ginger plant, has exhibited anti-allodynic and antihyperalgesic effects in a neuropathic pain animal model, amongst other pharmacological properties. This study was conducted to further elucidate the mechanisms underlying zerumbone’s antineuropathic actions. Research on therapeutic agents involving cannabinoid (CB) and peroxisome proliferator-activated receptors (PPARs) is rising. These receptor systems have shown importance in causing a synergistic effect in suppressing nociceptive processing. Behavioural responses were assessed using the von Frey filament test (mechanical allodynia) and Hargreaves plantar test (thermal hyperalgesia), in chronic constriction injury (CCI) neuropathic pain mice. Antagonists SR141716 (CB1 receptor), SR144528 (CB2 receptor), GW6471 (PPARα receptor) and GW9662 (PPARγ receptor) were pre-administered before the zerumbone treatment. Our findings indicated the involvement of CB1, PPARα and PPARγ in zerumbone’s action against mechanical allodynia, whereas only CB1 and PPARα were involved against thermal hyperalgesia. Molecular docking studies also suggest that zerumbone has a comparable and favourable binding affinity against the respective agonist on the CB and PPAR receptors studied. This finding will contribute to advance our knowledge on zerumbone and its significance in treating neuropathic pain.

Characterization of the Troglitazone Induced Apoptosis in a Human Colon Cancer Cell Line

Troglitazone (TRO), a peroxisome proliferator‐activated receptor (PPAR) agonist, was a drug used as an anti‐inflammatory and anti‐diabetic agent. PPARɣ specifically is a known member of the steroid receptor superfamily and is a ligand‐activated nuclear transcription factor that regulates lipid and glucose homeostasis. As a PPARɣ activator, TRO, a thiazolidinedione, has been shown to have the effect of inducing cell differentiation but also inhibiting cell growth, proliferation, and angiogenesis thereby facilitating apoptosis, making it a potential candidate to study as a cancer chemotherapeutic agent.Through the use of flow cytometry, TRO‐induced apoptosis of tissue culture grown colorectal cancer cells was examined. Apoptosis was quantified by analyzing cells that contain less than the 2N DNA content (one hallmark of apoptosis). A dose response curve was determined for increasing concentrations of TRO vs sub2N DNA content. These studies confirm that TRO was able to induce apoptosis in our cell lines at concentrations greater than 30mM.Next we examined which PPAR receptors subtypes are being activated by TRO. HCT116 cells were exposed to various concentrations of TRO for 24hr then RNA was isolated from these cells. Specific gene targets to each PPAR receptor subtypes were identified and using RT‐PCR, changes in mRNAs expression was examined. Targets for PPARdelta and PPAR gamma were consistently upregulated. We are working to refine these experiments to get better determinations on which receptors are activated by TRO.These experiments confirm that TRO induces apoptosis in HCT116 cells. Additionally, we have identified changes in at least one target of PPAR receptors in response to TRO exposure. Further experiments are needed to exactly determine which PPAR receptors are being activated by TRO, and whether the apoptosis medicated by TRO is a result of PPAR receptor activation.

Metabolički sindrom i poremećaji metabolizma masti - molekularni i biohemijski aspekti

The review highlights the characteristics of adipose tissue as a metabolically active organ, reveals endocrinous functions of adipose tissue and the role of adipose tissue in immune system's functioning. The role of obesity in the development of insulin resistance (IR) and diabetes mellitus type 2 and the effect of dyslipidemia on the development of metabolic syndrome (MS) and IR are given. It is shown that the main function of fatty tissue is energy storage via the maintenance of balance between lipolysis and lipogenesis processes. Inhibition of lipogenesis and enhancement of lipolysis are observed in metabolic disorders, in particular, IR. Adipose tissue's function is regulated by adipokines excreted by it. Inflammation condition is an essential constituent and one of the reasons of IR status. Neutralization of the main inflammatory cytokines does not restore sensitivity to insulin, which is indicative of the fact that inflammation condition is not the only cause of IR. Chronic low-grade inflammation develops as a result of obesity. Pro-inflammatory cytokines affect insulin signaling via stimulation of stress kinases. Functions of signal and immune cells are dependent on phospholipid composition. Unsaturated fatty acids are the substrate for synthesis of bioactive mediators. Allocated peroxisome proliferator-activated receptors (PPARs) are considered to be the main therapeutic target. Synthetic ligands of thiazolidinidones and components of the endogenous cannabinoid system of N-acetylethanolamines, capable of interacting and binding to PPARs receptors, are investigated. N-stearoylethanolamine is of special interest; its positive effect on normalization of lipid profile of different tissues, particularly insulin-sensitive tissues, has already been shown.

PPAR-gamma Signaling in Metabolic Homeostasis

BACKGROUND: Peroxisome proliferator-activated receptor (PPAR)-γ, or also known as nuclear receptor subfamily 1 group C member 3 (NR1C3), is a PPAR which serves as master regulator of adipocytes differentiation, and plays an important role in lipid metabolism or adipogenesis. Recent study showed that PPAR-γ is expressed in most tissue and also has critical impact in many metabolic homeostasis disorders.CONTENT: Dysregulation of PPAR-γ is correlated to the development of obesity, type 2 diabetes, atherosclerosis, cardiovascular disease, acute kidney injury, autoimmune disease, gastrointestinal disease and Alzheimer’s disease. Abundant number of new emerging compounds, with in vitro and in vivo effectiveness as natural and synthetic agonists of PPARs, are investigated, developed and used as the treatment of metabolic disorders of glucose and/or lipid and other diseases.SUMMARY: Based on all studies explanation, targeting PPAR-γ is proven to be a good therapeutic method for reducing negative effect of several metabolic homeostasis disorder. Now, many natural and synthetic agonists of PPARs are used as the treatment of metabolic disorders of glucose and/or lipid or another metabolic homeostasis disorder. Such agonists have different properties and specificities for individual PPARs receptors, different absorption and distribution, and distinctive gene expression profiles, which ultimately lead to different clinical outcomes.KEYWORDS: PPAR-γ, dysregulation, agonist, adipogenesis, metabolic disorder, homeostasis

PPAR-pan activation induces hepatic oxidative stress and lipidomic remodelling

The peroxisome proliferator-activated receptors (PPARs) are ligand activated nuclear receptors that regulate cellular homoeostasis and metabolism. PPARs control the expression of genes involved in fatty-acid and lipid metabolism. Despite evidence showing beneficial effects of their activation in the treatment of metabolic diseases, particularly dyslipidaemias and type 2 diabetes, PPAR agonists have also been associated with a variety of side effects and adverse pathological changes. Agonists have been developed that simultaneously activate the three PPAR receptors (PPARα, γ and δ) in the hope that the beneficial effects can be harnessed while avoiding some of the negative side effects.In this study, the hepatic effects of a discontinued PPAR-pan agonist (a triple agonist of PPAR-α, -γ, and -δ), was investigated after dietary treatment of male Sprague–Dawley (SD) rats. The agonist induced liver enlargement in conjunction with metabolomic and lipidomic remodelling. Increased concentrations of several metabolites related to processes of oxidation, such as oxo-methionine, methyl-cytosine and adenosyl-methionine indicated increased stress and immune status. These changes are reflected in lipidomic changes, and increased energy demands as determined by free fatty acid (decreased 18:3 n−3, 20:5 n−3 and increased ratios of n−6/n−3 fatty acids) triacylglycerol, phospholipid (decreased and increased bulk changes respectively) and eicosanoid content (increases in PGB2 and 15-deoxy PGJ2). We conclude that the investigated PPAR agonist, GW625019, induces liver enlargement, accompanied by lipidomic remodelling, oxidative stress and increases in several pro-inflammatory eicosanoids. This suggests that such pathways should be monitored in the drug development process and also outline how PPAR agonists induce liver proliferation.

PPAR-α agonist fenofibrate protects against the damaging effects of MPTP in a rat model of Parkinson's disease

Parkinson's disease (PD) is a chronic neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The etiology and pathogenesis of PD are still unknown, however, many evidences suggest a prominent role of oxidative stress, inflammation, apoptosis, mitochondrial dysfunction and proteosomal dysfunction. The peroxisome proliferator-activated receptor (PPAR) ligands, a member of the nuclear receptor family, have anti-inflammatory activity over a variety of rodent's models for acute and chronic inflammation. PPAR-α agonists, a subtype of the PPAR receptors, such as fenofibrate, have been shown a major role in the regulation of inflammatory processes. Animal models of PD have shown that neuroinflammation is one of the most important mechanisms involved in dopaminergic cell death. In addition, anti-inflammatory drugs are able to attenuate toxin-induced parkinsonism. In this study we evaluated the effects of oral administration of fenofibrate 100mg/kg 1h after infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the SNpc. First, we assessed the motor behavior in the open field for 24h, 7, 14 and 21 days after MPTP. Twenty-two days after surgery, the animals were tested for two-way active avoidance and forced swimming for evaluation regarding cognitive and depressive parameters, respectively. Twenty-three days after infusion of the toxin, we quantified DA and turnover and evaluated oxidative stress through the measurement of GSH (glutathione peroxidase), SOD (superoxide dismutase) and LOOH (hydroperoxide lipid). The data show that fenofibrate was able to decrease hypolocomotion caused by MPTP 24h after injury, depressive-like behavior 22 days after the toxin infusion, and also protected against decreased level of DA and excessive production of reactive oxygen species (ROS) 23 days after surgery. Thus, fenofibrate has shown a neuroprotective effect in the MPTP model of Parkinson's disease.

Peroxisome Proliferator-Activated Receptor (PPAR) Agonists as Promising New Medications for Drug Addiction: Preclinical Evidence

This review examines the growing literature on the role of peroxisome proliferator-activated receptors (PPARs) in addiction. There are two subtypes of PPAR receptors that have been studied in addiction: PPAR-α and PPAR-γ. The role of each PPAR subtype in common models of addictive behavior, mainly pre-clinical models, is summarized. In particular, studies are reviewed that investigated the effects of PPAR-α agonists on relapse, sensitization, conditioned place preference, withdrawal and drug intake, and effects of PPAR-γ agonists on relapse, withdrawal and drug intake. Finally, studies that investigated the effects of PPAR agonists on neural pathways of addiction are reviewed. Taken together these preclinical data indicate that PPAR agonists are promising new medications for drug addiction treatment.

Scaffold-Based Pan-Agonist Design for the PPARα, PPARβ and PPARγ Receptors

As important members of nuclear receptor superfamily, Peroxisome proliferator-activated receptors (PPAR) play essential roles in regulating cellular differentiation, development, metabolism, and tumorigenesis of higher organisms. The PPAR receptors have 3 identified subtypes: PPARα, PPARβ and PPARγ, all of which have been treated as attractive targets for developing drugs to treat type 2 diabetes. Due to the undesirable side-effects, many PPAR agonists including PPARα/γ and PPARβ/γ dual agonists are stopped by US FDA in the clinical trials. An alternative strategy is to design novel pan-agonist that can simultaneously activate PPARα, PPARβ and PPARγ. Under such an idea, in the current study we adopted the core hopping algorithm and glide docking procedure to generate 7 novel compounds based on a typical PPAR pan-agonist LY465608. It was observed by the docking procedures and molecular dynamics simulations that the compounds generated by the core hopping and glide docking not only possessed the similar functions as the original LY465608 compound to activate PPARα, PPARβ and PPARγ receptors, but also had more favorable conformation for binding to the PPAR receptors. The additional absorption, distribution, metabolism and excretion (ADME) predictions showed that the 7 compounds (especially Cpd#1) hold high potential to be novel lead compounds for the PPAR pan-agonist. Our findings can provide a new strategy or useful insights for designing the effective pan-agonists against the type 2 diabetes.

PPAR agonists for the treatment of cardiovascular disease in patients with diabetes

Diabetes is a complex disease defined by hyperglycaemia; however, strong associations with abdominal obesity, hypertension and dyslipidaemia contribute to the high risk of cardiovascular disease. Although aggressive glycaemic control reduces microvascular complications, the evidence for macrovascular complications is less certain. The theoretical benefits of the mode of action of peroxisome proliferator-activated receptor (PPAR) agonists are clear. In clinical practice, PPAR-α agonists such as fibrates improve dyslipidaemia, while PPAR-γ agonists such as thiazolidinediones improve insulin resistance and diabetes control. However, although these agents are traditionally classed according to their target, they have different and sometimes conflicting clinical benefit and adverse event profiles. It is speculated that this is because of differing properties and specificities for the PPAR receptors (each of which targets specific genes). This is most obvious in the impact on cardiovascular outcomes--in clinical trials pioglitazone appeared to reduce cardiovascular events, whereas rosiglitazone potentially increased the risk of myocardial infarction. The development of a dual PPAR-α/γ agonist may prove beneficial in effectively managing glycaemic control and improving dyslipidaemia in patients with type 2 diabetes. Yet, development of agents such as muraglitazar and tesaglitazar has been hindered by various serious adverse events. Aleglitazar, a balanced dual PPAR-α/γ agonist, is currently the most advanced in clinical development and has shown promising results in phase II clinical trials with beneficial effects on glucose and lipid variables. A phase III study, ALECARDIO, is ongoing and will establish whether improvements in laboratory test profiles translate into an improvement in cardiovascular outcomes.

PPAR- γ Agonist in Treatment of Diabetes: Cardiovascular Safety Considerations

The peroxisome proliferator-activated receptors (PPARs) are nuclear fatty acid receptors, which contain a type II zinc finger DNA binding motif and a hydrophobic ligand binding pocket. These receptors are thought to play an important role in metabolic diseases such as obesity, insulin resistance, and coronary artery disease. Three subtypes of PPAR receptors have been described: PPARα, PPARδ/β, and PPARγ. PPARα is found in the liver, muscle, kidney, and heart. In the liver, its role is to up-regulate genes involved in fatty acid uptake, binding, β-oxidation and electron transport, and oxidative phosphorylation in subcutaneous fat but not in skeletal muscle. PPARδ/β is expressed in many tissues but markedly in brain, adipose tissue, and skin. PPARγ has high expression in fat, low expression in the liver, and very low expression in the muscle. The thiazolidinediones (TZD) are synthetic ligands of PPARγ. By activating a number of genes in tissues, PPARγ increases glucose and lipid uptake, increases glucose oxidation, decreases free fatty acid concentration, and decreases insulin resistance. Although, there is a rationale for the use of TZDs in patients with type 2 diabetes mellitus, clinical studies have produced conflicting data. While currently used TZDs are clearly associated with heart failure (HF) worsening; with regards to cardiovascular outcomes, pioglitazone seems to be related to a trend toward reduction in cardiovascular morbidity and mortality, whereas rosiglitazone may actually increase risk of cardiovascular events. We review the existing literature on TZDs and discuss role and cardiovascular safety of these agents for the contemporary treatment of diabetes. Other side effects of these agents i.e. increase in osteoporosis and possible risk of bladder cancer is also discussed.

NUCLEAR RECEPTORS

NUCLEAR RECEPTORS

Phytochemicals as Modulators of PPARs and RXRs

Welcome to this special issue of PPAR Research on “Phytochemicals as modulators of PPARs and RXRs.” Plants have played a crucial role in the prevention and treatment of human diseases for thousands of years. A significant number of contemporary drugs with high efficacy are derived from herbal origin. These natural phytochemicals, including certain nutrients, are therefore of great medicinal value. Peroxisome proliferator-activated receptors (PPARs) belong to the steroid hormone receptor superfamily that bind to and are activated by fatty acids, eicosanoids, and a group of xenobiotics called peroxisome proliferators. Each of these receptors binds to specific peroxisome proliferator response elements (PPRE) as a heterodimer with a retinoid X receptor (RXR). Binding to these receptors has been proven to control the pathological conditions associated with obesity, aging-related diseases, inflammation, immune disorder, cell cycle regulation as well as cancer. There is a strong mechanistic basis for PPAR and RXR targeting, as these nuclear receptors are transcriptional factors that modulate gene expression relevant to the control of blood glucose and lipids, as well as the processes of inflammation and carcinogenesis. Since PPARs play an important role in lipid metabolism, the search for natural ligands had begun with fatty acids and eicosanoids. In fact, the discovery that many natural dietary compounds, especially phytochemicals, are PPAR activators is of great significance for human health. With metabolic syndrome, diabetes, and chronic systemic inflammatory diseases now reaching pandemic proportions, the importance of the discovery of natural PPAR ligands is self-evident. The special issue begins with a review of terpenoids as modulators of the PPAR family. To date more than 40,000 terpenoids have been described. Also known as isoprenoids, terpenoids constitute one of the largest and most diverse group of phytochemicals. Members of this phytochemical family are well known to us as the flavours of cinnamon, ginger, and cloves and the scents of camphor and eucalyptus. The vitamin A precursors known as carotenoids and psychoactive cannabinoids are also forms of terpenoid. In this issue, T. Goto and colleagues review the biosynthesis, metabolism, and plant origins of various dietary terpenoids. The physiological effects of these compounds on carbohydrate and lipid metabolism are described in terms of their PPARγ and PPARα activating abilities. This is followed by the research article on the kinetic assessment and therapeutic modulation of metabolic and obesity-associated inflammatory profiles by a high-fat diet, whereas the whole process was found to be mediated by PPAR activation. Another research article has proposed glycyrrhizic acid, the bioactive compound extracted from roots of licorice (Glycyrrhiza glabra), as a potent PPARγ agonist. This phytochemical is capable of ameliorating metabolic syndrome by affecting glucose homeostasis, lipid metabolism, and adipogenesis. The focus is then shifted to the findings on verbascoside, a phytochemical that exerts a strong anti-inflammatory activity against the development of experimental inflammatory bowel disease. This work by the S. Cuzzocrea team has proven that verbascoside is a PPARα ligand by using a knock-out animal model. S. N. Lewis and colleagues conclude this special issue with a comprehensive review of computational approaches to the discovery of phytochemical ligands for PPARα and PPARγ. This timely review is an excellent reference document for the existing 3D structures of PPAR receptors cocrystallized with a variety of ligands and available on-line at the RCSB database. Lewis gives an expert description of the potential for in silico screening of phytochemical databases. The challenges of applying computational techniques to the analysis of a flexible ligand binding to a flexible receptor are described. This review is a most helpful exposition of the state-of-the-art computational methods regarding natural PPAR ligand discovery. Joshua K. Ko Susanna S. Lee Harry Martin

Targeting PPAR receptors in the airway for the treatment of inflammatory lung disease

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. PPARgamma regulates several metabolic pathways by binding to sequence-specific PPAR response elements in the promoter region of genes involved in lipid biosynthesis and glucose metabolism. However, more recently PPARgamma, PPARalpha and PPARbeta/delta agonists have been demonstrated to exhibit anti-inflammatory and immunomodulatory properties thus opening up new avenues for research. The actions of PPARgamma and PPARalpha activation are thought to be due to their ability to down regulate pro-inflammatory gene expression and inflammatory cell functions, and as such makes them an attractive target for novel drug intervention. Interestingly, PPARbeta/delta has been shown to be involved in wound healing, angiogenesis, lipid metabolism and thrombosis. In this review we will focus on the data describing the beneficial effects of these ligands in the airway and in the pulmonary vasculature and in vivo in animal models of allergic and occupational asthma, chronic obstructive pulmonary disease and pulmonary fibrosis. A clinical trial is underway to examine the effect of rosiglitazone in asthma patients and the outcome of this trial is awaited with much anticipation. In conclusion, PPARs are novel targets for lung disease and continued work with these ligands may result in a potential new treatment for chronic inflammatory lung diseases.

Antineoplastic effect of iodine in mammary cancer: participation of 6-iodolactone (6-IL) and peroxisome proliferator-activated receptors (PPAR)

IntroductionStudies in mammary cancer demonstrated that moderately high concentrations of molecular iodine (I2) have a antiproliferative and apoptotic effect either in vivo as in vitro, however the cellular intermediated involved in these effects has not been elucidated.MethodsVirgin Sprague-Dawley rats were treated with methyl-nitrosourea (MNU: single dose ip, 50 mg/Kg bw) and the participation of arachidonic acid (AA) and PPAR receptors in the antineoplasic effect of I2 where analyzed.ResultsI2-treated rats for four weeks exhibited a significant reduction in the incidence (62.5 vs. 100%) and size (0.87 ± 0.98 vs 1.96 ± 1.5 cm3) of mammary tumors. HPLC analysis showed that tumoral but not normal mammary tissue contained an elevated basal concentration of AA and significantly more AA-iodinated called 6-iodolactone (6-IL) after chronic I2 treatment. Tumors from I2-treated rats showed fewer cells positive to proliferating cell nuclear antigen, lower blood vessel density, as well as decreases in vascular endothelial growth factor, urokinase-type plasminogen activator, and PPAR type alpha (PPARα). These same tumors showed increases in the cell death markers, TUNEL-positive cells (p < 0.05) and the enzyme caspase-3 (trend), as well as significant induction of PPAR type gamma (PPARγ).ConclusionTogether, these data demonstrate that the antineoplasic effect of iodine involves 6-IL formation and PPARγ induction.

The Role of PPARs in MDR – a lesson from embryonic development

One of the most important features of embryonic cells is their resistence to xenobiotics, which provides a natural protection for embryos against these potentially harmful molecules. In this way, embryo cells resemble cancer cells and thus understanding the basis of this phenomenon may contribute to overcoming the multi-drug-resistance (MDR) of some tumours. Peroxisome proliferator-activated receptors (PPARs) are steroid nuclear receptors that regulate diverse biological processes such as lipid and carbohydrate metabolism, development, differentiation, apoptosis, neoplastic transformation, inflammation and regeneration of tissues. Recently it has been found that they may also regulate the expression of some MDR proteins. In this article we summarise the main known relationships between some MDR pumps and three isoforms of PPAR receptors (PPAR-alpha, PPAR-beta/delta, PPAR-gamma). We hypothesize that regulation of MDR proteins by PPAR ligands in embryos could lead to the improvement of cancer treatment.

PPARγ

Interest in peroxisome proliferator-activated receptors (PPARs) has steadily increased over the past 15 years. The recognition that subclasses of this receptor played critical roles in regulation of metabolism led to...