New PPARγ partial agonist improves obesity-induced metabolic alterations and atherosclerosis in LDLr−/− mice

Silva, Jacqueline C.; César, Fernanda Andrade de; Oliveira, Edson Mendes de; Turato, Walter Miguel; Tripodi, Gustavo Luis; Castilho, Gabriela; Machado-Lima, Adriana; Heras, Beatriz de las; Rabello, Marcelo Montenegro; Hernandes, Marcelo Zaldini; Pitta, M. G. R.; Pitta, Ivan R.; Passarelli, Marisa; Rudnicki, Martina; Abdalla, Dulcinéia Saes Parra

doi:10.1016/j.phrs.2015.12.010

Cited by 26 publications

(21 citation statements)

References 56 publications

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“…Based on the crucial role of thiazolidinediones in the treatment of diabetes, and given the risk associated with the use of the available drugs of this class (AlSalman et al, 2000;Maeda, 2001;Scheen, 2001;Scheen, 2003;Marcy et al, 2004;Alemán-González-Duhart et al, 2016), the development of new safer thiazolidinediones is of current interest (Cesar et al, 2015;Rudnicki et al, 2016;Silva et al, 2016;Naim et al, 2017;Thangavel et al, 2017). Since glitazones do not cause liver damage in laboratory animals, comparing these to new thiazolidinediones in order to research the mechanism of toxicity can be misleading (Patel et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…Mourão et al (2005) published a study on the synthesis of 5-benzylidene and 5-acridinylidene derivatives, both of which were N-3 substituted; these compounds showed hypoglycemic activity in mice. Many other authors have used similar approaches with promising outcomes (da Costa Leite et al, 2007;Barros et al, 2010;Araújo et al, 2011;Amato et al, DMD # 79012 5 2012;Santin et al, 2013a;Santin et al, 2013b;Cesar et al, 2015;Rudnicki et al, 2016;Silva et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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New Pioglitazone Metabolites and Absence of Opened-Ring Metabolites in New N-Substituted Thiazolidinedione

et al. 2018

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Number of references: 55Number of words in the Abstract: 241 Number of words in the Introduction: 750Number of words in the Discussion: 828Nonstandard abbreviations: ADME, absorption, distribution, metabolism, and excretion; CL h , hepatic clearance; CL int , intrinsic clearance; ESI, electrospray ionization; GQ-11, 5-(indol-3-ylmethylene)-3-(4-methylbenzyl)-thiazolidine-2,4-dione; HLM, human liver microsome; LC-HRMS, liquid chromatography coupled to high resolution mass spectrometry; LC-MS/MS, liquid chromatography-tandem mass spectrometry; MRM, multiple reaction monitoring; PPARγ, peroxisome proliferatoractivated receptor gamma; RLM, rat liver microsome; t 1/2 , half-life; TZD, thiazolidinedione;This article has not been copyedited and formatted. The final version may differ from this version. AbstractThiazolidinediones are drugs used to treat type 2 diabetes mellitus; however, there remain several safety concerns regarding the available drugs in this class. Therefore, the search for new thiazolidinedione candidates is still ongoing; metabolism studies play a crucial step in the development of new candidates. Pioglitazone, which is one of the most commonly used thiazolidinediones, and GQ-11, a new N-substituted thiazolidinedione, were investigated in terms of their metabolic activity in rat and human liver microsomes, in order to assess their metabolic stability and to investigate their metabolites. Methods for preparation of samples were based on liquid-liquid extraction and protein precipitation. Quantitation was performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the metabolite investigation was performed using Ultra-Performance Liquid Chromatography (UPLC) coupled to a hybrid quadrupole-time of flight (Q-Tof) mass spectrometer. The predicted intrinsic clearance of GQ-11 was 70.3 and 46.1 mL/kg/min for rats and humans, respectively. The predicted intrinsic clearance of pioglitazone was 24.1 and 15.9 mL/kg/min for rats and humans, respectively. The pioglitazone metabolite investigation revealed two unpublished metabolites (M-D and M-A). M-A is a hydration product, which may be related to the mechanism of ring opening, and the toxicity of pioglitazone. The metabolites of GQ-11 are products of oxidation; no ring opening metabolite was observed for GQ-11. In conclusion, in the same experimental conditions, a ring opening metabolite was observed only for pioglitazone. The resistance of GQ-11 to ring opening is probably related to N-substitution in the thiazolidinedione ring.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

New Pioglitazone Metabolites and Absence of Opened-Ring Metabolites in New N-Substituted Thiazolidinedione

et al. 2018

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“…The PPARγ/RXR heterodimer undergoes conformational changes which alter co‐activator/co‐repressor dynamics and binds further to PPRE in the promoter region of the target genes. Thus, transcription initiation of the target genes takes place . The latter is a non‐canonical mechanism; namely, activated PPARγ/RXR heterodimer interacts physically with NFκB and impedes NFκB to bind with the promoter region of the target genes encoding inflammation factors such as TNFα, IL‐6, sICAM‐1 and sVCAM‐1 and therefore plays anti‐inflammation …”

Section: Discussionmentioning

confidence: 99%

Trans‐repression ofNFκB pathway mediated byPPARγ improves vascular endothelium insulin resistance

Kong

Gao

Lan

et al. 2018

J Cellular Molecular Medi

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Previous study has shown that thiazolidinediones (TZDs) improved endothelium insulin resistance (IR) induced by high glucose concentration (HG)/hyperglycaemia through a PPARγ‐dependent‐NFκB trans‐repression mechanism. However, it is unclear, whether changes in PPARγ expression affect the endothelium IR and what the underlying mechanism is. In the present study, we aimed to address this issue. HG‐treated human umbilical vascular endothelial cells (HUVEC) were transfected by either PPARγ‐overexpressing (Ad‐PPARγ) or PPARγ‐shRNA‐containing (Ad‐PPARγ‐shRNA) adenoviral vectors. Likewise, the rats fed by high‐fat diet (HFD) were infected by intravenous administration of Ad‐PPARγ or Ad‐PPARγ‐shRNA. The levels of nitric oxide (NO), endothelin‐1 (ET‐1) and cytokines (TNFα, IL‐6, sICAM‐1 and sVCAM‐1) and the expression levels of PPARγ, eNOS, AKT, p‐AKT, IKKα/β and p‐IKKα/β and IκBα were examined; and the interaction between PPARγ and NFκB‐P65 as well as vascular function were evaluated. Our present results showed that overexpression of PPARγ notably increased the levels of NO, eNOS, p‐AKT and IκBα as well as the interaction of PPARγ and NFκB‐P65, and decreased the levels of ET‐1, p‐IKKα/β, TNFα, IL‐6, sICAM‐1 and sVCAM‐1. In contrast, down‐expression of PPARγ displayed the opposite effects. The results demonstrate that the overexpression of PPARγ improves while the down‐expression worsens the endothelium IR via a PPARγ‐mediated NFκB trans‐repression dependent manner. The findings suggest PPARγ is a potential therapeutic target for diabetic vascular complications.

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“…Another potent modulator is a new thiazolidinedione, GQ-177, which has shown a therapeutic potential on diet-induced obesity and atherosclerosis. This molecule was identified as a partial and selective PPARγ agonist, which improved insulin sensitivity and lipid profile without affecting body weight, fat accumulation or bone density in LDLr-/- mice fed with high-fat diet [118]. …”

Section: Testing Of Novel Pparγ Modulators In Micementioning

confidence: 99%

Is the Mouse a Good Model of Human PPARγ-Related Metabolic Diseases?

Pap

Cuaranta-Monroy

Peloquin

et al. 2016

IJMS

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With the increasing number of patients affected with metabolic diseases such as type 2 diabetes, obesity, atherosclerosis and insulin resistance, academic researchers and pharmaceutical companies are eager to better understand metabolic syndrome and develop new drugs for its treatment. Many studies have focused on the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ), which plays a crucial role in adipogenesis and lipid metabolism. These studies have been able to connect this transcription factor to several human metabolic diseases. Due to obvious limitations concerning experimentation in humans, animal models—mainly mouse models—have been generated to investigate the role of PPARγ in different tissues. This review focuses on the metabolic features of human and mouse PPARγ-related diseases and the utility of the mouse as a model.

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New PPARγ partial agonist improves obesity-induced metabolic alterations and atherosclerosis in LDLr−/− mice

Cited by 26 publications

References 56 publications

New Pioglitazone Metabolites and Absence of Opened-Ring Metabolites in New N-Substituted Thiazolidinedione

New Pioglitazone Metabolites and Absence of Opened-Ring Metabolites in New N-Substituted Thiazolidinedione

Trans‐repression ofNFκB pathway mediated byPPARγ improves vascular endothelium insulin resistance

Is the Mouse a Good Model of Human PPARγ-Related Metabolic Diseases?

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