Metabolomics: An Essential Tool to Understand the Function of Peroxisome Proliferator-Activated Receptor Alpha
1Department of Veterinary and Biomedical Sciences and The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania, USA. Toxicologic Pathology
(Impact Factor: 2.14).
11/2012; 41(2). DOI: 10.1177/0192623312466960
The peroxisome proliferator-activated receptor (PPAR) family of nuclear hormone transcription factors (PPARα, PPARβ/δ, and PPARγ) is regulated by a wide array of ligands including natural and synthetic chemicals. PPARs have important roles in control of energy metabolism and are known to influence inflammation, differentiation, carcinogenesis, and chemical toxicity. As such, PPARs have been targeted as therapy for common disorders such as cancer, metabolic syndrome, obesity, and diabetes. The recent application of metabolomics, or the global, unbiased measurement of small molecules found in biofluids, or extracts from cells, tissues, or organisms, has advanced our understanding of the varied and important roles that the PPARs have in normal physiology as well as in pathophysiological processes. Continued development and refinement of analytical platforms, and the application of new bioinformatics strategies, have accelerated the widespread use of metabolomics and have allowed further integration of small molecules into systems biology. Recent studies using metabolomics to understand PPARα function, as well as to identify PPARα biomarkers associated with drug efficacy/toxicity and drug-induced liver injury, will be discussed.
Available from: Christopher B Umbricht
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ABSTRACT: Thyroid nodules are very common and may be detected in up to half of the population. The vast majority of thyroid tumors are benign, and usually indolent even in the event of a malignant diagnosis. The wide range of molecular approaches that have been developed or are under development is a testament to the critical and heretofore unmet need to complement the standard cytopathological fine needle aspiration assessment of thyroid nodules, particularly nodules with intermediate cytology, which have, depending on case selection, a risk of malignancy between 20% and 30%. Currently available molecular assays can be broadly viewed as falling into two classes. One class, exemplified by mutations such as BRAF, RET/PTC, and PAX8/PPARy, (but not RAS mutations) have a very high specificity and positive predictive value, but insufficient sensitivity on their own. While molecular tests for these specific mutations and translocations may be useful to "rule in" cancer, the opposite is true of classifiers based on gene expression panels. These reach the high levels of sensitivity and negative predictive value necessary for "ruling out" cancer safely, allowing the identification of patients that are good candidates for conservative management. Unfortunately, at the present time, no one test has the necessary sensitivity and specificity to warrant its routine use on its own - this may change as more data becomes available, or if additional molecular markers can be incorporated without rendering the test cost-prohibitive. Finally, there is an urgent need for a reappraisal of how to treat thyroid cancers, given the indolent nature of the majority of these tumors, with more attention on identifying tumors that do or do not have the potential of life-threatening behavior.
Minerva otorinolaringologica 06/2013; 63(2):39-52.
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ABSTRACT: The identification, application, and qualification of safety biomarkers are becoming increasingly critical to successful drug discovery and development as companies are striving to develop drugs for difficult targets and for novel disease indications in a risk-adverse environment. Translational safety biomarkers that are minimally invasive and monitor drug-induced toxicity during human clinical trials are urgently needed to assess whether toxicities observed in preclinical toxicology studies are relevant to humans at therapeutic doses. The interpretation of data during the biomarker qualification phase should include careful consideration of the analytic method used, the biology, pharmacokinetic and pharmacodynamic properties of the biomarker, and the pathophysiology of the process studied. The purpose of this review is to summarize commonly employed technologies in the development of fluid- and tissue-based safety biomarkers in drug discovery and development and to highlight areas of ongoing novel assay development.
Veterinary Pathology 10/2013; 51(1). DOI:10.1177/0300985813505117 · 1.87 Impact Factor
Available from: Daisuke Usuda
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ABSTRACT: Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor superfamily, which is composed of four members encoded by distinct genes (α, β, γ, and δ). The genes undergo transactivation or transrepression under specific mechanisms that lead to the induction or repression of target gene expression. As is the case with other nuclear receptors, all four PPAR isoforms contain five or six structural regions in four functional domains; namely, A/B, C, D, and E/F. PPARs have many functions, particularly functions involving control of vascular tone, inflammation, and energy homeostasis, and are, therefore, important targets for hypertension, obesity, obesity-induced inflammation, and metabolic syndrome in general. Hence, PPARs also represent drug targets, and PPARα and PPARγ agonists are used clinically in the treatment of dyslipidemia and type 2 diabetes mellitus, respectively. Because of their pleiotropic effects, they have been identified as active in a number of diseases and are targets for the development of a broad range of therapies for a variety of diseases. It is likely that the range of PPARγ agonist therapeutic actions will result in novel approaches to lifestyle and other diseases. The combination of PPARs with reagents or with other cardiovascular drugs, such as diuretics and angiotensin II receptor blockers, should be studied. This article provides a review of PPAR isoform characteristics, a discussion of progress in our understanding of the biological actions of PPARs, and a summary of PPAR agonist development for patient management. We also include a summary of the experimental and clinical evidence obtained from animal studies and clinical trials conducted to evaluate the usefulness and effectiveness of PPAR agonists in the treatment of lifestyle-related diseases.
World Journal of Cardiology (WJC) 08/2014; 6(8):744-54. DOI:10.4330/wjc.v6.i8.744 · 2.06 Impact Factor
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