Quantitative structure-activity relationship models with receptor-dependent descriptors for predicting peroxisome proliferator-activated receptor activities of thiazolidinedione and oxazolidinedione derivatives

A quantitative structure–activity relationship study has been carried out, in which the relationship between the peroxisome proliferator-activated receptor a and the peroxisome proliferator activated receptor c agonistic activities of thiazo lidinedione and oxazolidinedione derivatives and quantitative descriptors, Vsite calculated in a receptor-dependent manner is modeled. These descriptors quantify the volume occupied by the optimized ligands in regions that are either com mon or specific to the superimposed binding sites of the targets under consideration. The quantita tive structure–activity relationship models were built by forward stepwise linear regression model ing for a training set of 27 compounds and vali dated for a test set of seven compounds, resulting in a squared correlation coefficient value of 0.90 for peroxisome proliferator-activated receptor a and of 0.89 for peroxisome proliferator-activated receptor c. The leave-one-out cross-validation and test set predictability squared correlation coeffi cient values for these models were 0.85 and 0.62 for peroxisome proliferator-activated receptor a and 0.89 and 0.50 for peroxisome proliferator-acti vated receptor c respectively. A dual peroxisome proliferator-activated receptor model has also been developed, and it indicates the structural features required for the design of ligands with dual peroxisome proliferator-activated receptor activity. These quantitative structure–activity relationship models show the importance of the descriptors here introduced in the prediction and interpretation of the compounds affinity and selectivity.info:eu-repo/semantics/publishedVersio

PPARγ contributes to PKM2 and HK2 expression in fatty liver

Rapidly proliferating cells promote glycolysis in aerobic conditions, to increase growth rate. Expression of specific glycolytic enzymes, namely pyruvate kinase M2 and hexokinase 2, concurs to this metabolic adaptation, as their kinetics and intracellular localization favour biosynthetic processes required for cell proliferation. Intracellular factors regulating their selective expression remain largely unknown. Here we show that the peroxisome proliferator-activated receptor gamma transcription factor and nuclear hormone receptor contributes to selective pyruvate kinase M2 and hexokinase 2 gene expression in PTEN-null fatty liver. Peroxisome proliferator-activated receptor gamma expression, liver steatosis, shift to aerobic glycolysis and tumorigenesis are under the control of the Akt2 kinase in PTEN-null mouse livers. Peroxisome proliferator-activated receptor gamma binds to hexokinase 2 and pyruvate kinase M promoters to activate transcription. In vivo rescue of peroxisome proliferator-activated receptor gamma activity causes liver steatosis, hypertrophy and hyperplasia. Our data suggest that therapies with the insulin-sensitizing agents and peroxisome proliferator-activated receptor gamma agonists, thiazolidinediones, may have opposite outcomes depending on the nutritional or genetic origins of liver steatosis

Proposed Mechanism of CLA on Muscle Metabolism

Diagram AMPK, AMP-activated protein kinase; SIRT1, Silent information regulator two protein 1; PGC-1α, peroxisome proliferator activated receptor gamma coactivator 1α; PPAR-d, peroxisome proliferator activated receptor delta; CLA, conjugated linoleic acid Copyright Yeonhwa Park, orcid.org/0000-0001-9727-089

The pathophysiological function of peroxisome proliferator-activated receptor-γ in lung-related diseases

Research into respiratory diseases has reached a critical stage and the introduction of novel therapies is essential in combating these debilitating conditions. With the discovery of the peroxisome proliferator-activated receptor and its involvement in inflammatory responses of cardiovascular disease and diabetes, attention has turned to lung diseases and whether knowledge of this receptor can be applied to therapy of the human airways. In this article, we explore the prospect of peroxisome proliferator-activated receptor-γ as a marker and treatment focal point of lung diseases such as asthma, chronic obstructive pulmonary disorder, lung cancer and cystic fibrosis. It is anticipated that peroxisome proliferator-activated receptor-γ ligands will provide not only useful mechanistic pathway information but also a possible new wave of therapies for sufferers of chronic respiratory diseases

Effects of the interaction of diabetes and iron supplementation on hepatic and pancreatic tissues, oxidative stress markers, and liver peroxisome proliferator-activated receptor-α expression

This study evaluated the effects of the interaction of diabetes and a carbonyl iron supplemented on hepatic and pancreatic tissues, oxidative stress markers and liver peroxisome proliferator-activated receptor-α expressions. Hamsters were divided: Control which received a standard AIN 93 diet; Control Iron, composed of control animals that received a diet with 0.83% carbonyl iron; Diabetic, composed of animals that received a injection of streptozotocin (50 mg/kg, intraperitoneal) on day 35; and Diabetic Iron composed of streptozotocin treated animals that received a diet supplemented with carbonyl iron. Diabetes increased the glucose level and reduced triglycerides. Diabetic Iron group showed higher levels of glucose and serum triglycerides as compared to the Diabetic group. Diabetes decreased mRNA levels of peroxisome proliferator-activated receptor-α. Iron attenuated the diabetes induced down regulation of peroxisome proliferator-activated receptor-α mRNA. Moreover, diabetes increased carbonyl protein and decreased glutathione levels and catalase activity, while iron attenuated the increase in levels of carbonyl protein and attenuated the decrease in those of glutathione level and catalase activity. Histological analysis shows that supplementation iron caused an increase in the size of the islets in Control Iron. The results show that iron does not aggravated liver oxidant/antioxidant status and peroxisome proliferator-activated receptor-α expression in diabetic hamsters

Linking Induction and Transrepression of PPARβ/δ with Cellular Function

The copyrights of all papers published in this journal are retained by the respective authors as per the 'Creative Commons Attribution License' (http://creativecommons.org/licenses/by/3.0/).Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors and members of the nuclear hormone receptor superfamily. PPARβ/δ is ubiquitously expressed and has a central role in homeostasis, and has been suggested as a therapeutic target for a number of metabolic and cardiovascular disorders. This important nuclear receptor controls transcription under different modes of molecular activity which directly control the cellular function and fate of tissues. This complex activity of induction and transrepression of gene expression (with and without exogenous ligands) is poorly understood and yet understanding this molecular control through novel drug development would led to control over a key molecular switch in all cells. This review outlines the main molecular mechanisms of PPARβ/δ, and links the modes of activity to the signalling pathways in inflammation, proliferation and senescence, with the goal to understand how this will translate into novel drug design to control the PPARβ/δ molecular switch.Peer reviewe