Thiazolidinedione safety

Kung, Jacqueline; Henry, Robert R.

doi:10.1517/14740338.2012.691963

Cited by 182 publications

(153 citation statements)

References 88 publications

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“…We used pioglitazone and rosiglitazone at the doses that are effective in animal models of diabetes [26,27]. These PPAR-c ligands have systemic side-effects when administered orally, such as cardiac failure [32]. COPD patients often suffer with cardiovascular comorbidities [33], making the use of oral PPAR-c agonists in such patients difficult.…”

Section: Discussionmentioning

confidence: 99%

The effect of peroxisome proliferator-activated receptor- ligands on in vitro and in vivo models of COPD

Lea

Plumb

Metcalfe

et al. 2013

European Respiratory Journal

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Peroxisome proliferator-activated receptor (PPAR)-c is expressed in alveolar macrophages. The anti-inflammatory potential of the PPAR-c ligands rosiglitazone and pioglitazone were investigated using in vitro alveolar macrophage models and in vivo animal models relevant to chronic obstructive pulmonary disease (COPD).PPAR-c protein and gene expression in COPD alveolar macrophages was compared with control smokers and never-smokers. COPD macrophages were used to investigate the effects of PPAR-c ligands and corticosteroids on lipopolysaccharide-induced cytokine production, alternative macrophage activation (M2) gene expression and efferocytosis. The effects of PPAR-c ligands in a subchronic tobacco smoke model in mice were investigated.PPAR-c protein expression was similar in COPD patients compared to controls, although increased gene expression levels were observed in COPD patients and control smokers compared to never-smokers. PPAR-c ligands reduced tumour necrosis factor-a and CC chemokine ligand-5, but not CXC chemokine ligand-8, in COPD alveolar macrophages; these effects were generally less than those of the corticosteroid dexamethasone. Rosiglitazone increased M2 gene expression and enhanced efferocytosis of apoptotic neutrophils. Rosiglitazone and pioglitazone attenuated airway neutrophilia in a corticosteroid-resistant mouse model of pulmonary inflammation.We show biological actions of PPAR-c agonists on corticosteroid-resistant disease, tobacco smokeinduced pulmonary inflammation, skewing of macrophage phenotype and clearance of apoptotic neutrophils.@ERSpublications Biological actions of a PPAR-c agonist shown in COPD-relevant models may affect progression and side-effects in patients

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Section: Discussionmentioning

confidence: 99%

The effect of peroxisome proliferator-activated receptor- ligands on in vitro and in vivo models of COPD

Lea

Plumb

Metcalfe

et al. 2013

European Respiratory Journal

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“…For example, TZDs induce insulin-sensitizing factors adiponectin (Maeda et al 2001) and FGF-21 (Moyers et al 2007) while suppressing the expression of genes promoting insulin resistance, including TNFa (Hofmann et al 1994), resistin (Steppan et al 2001), and retinol-binding protein 4 (Yang et al 2005). The most potent TZD in the clinic is rosiglitazone (rosi) (Lehmann et al 1995), which has durable anti-diabetic effects but, unfortunately, has toxicities that limit its widespread use (Kung and Henry 2012;Ahmadian et al 2013). Because PPARg expression in adipose tissue is required for the in vivo systemic insulin-sensitizing effects of TZDs (Chao et al 2000;He et al 2003), it is critical to understand how rosi binding to PPARg modulates gene expression.…”

mentioning

confidence: 99%

Anti-diabetic rosiglitazone remodels the adipocyte transcriptome by redistributing transcription to PPARγ-driven enhancers

et al. 2014

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Rosiglitazone (rosi) is a powerful insulin sensitizer, but serious toxicities have curtailed its widespread clinical use. Rosi functions as a high-affinity ligand for peroxisome proliferator-activated receptor g (PPARg), the adipocytepredominant nuclear receptor (NR). The classic model, involving binding of ligand to the NR on DNA, explains positive regulation of gene expression, but ligand-dependent repression is not well understood. We addressed this issue by studying the direct effects of rosi on gene transcription using global run-on sequencing (GRO-seq). Rosiinduced changes in gene body transcription were pronounced after 10 min and correlated with steady-state mRNA levels as well as with transcription at nearby enhancers (enhancer RNAs [eRNAs]). Up-regulated eRNAs occurred almost exclusively at PPARg-binding sites, to which rosi treatment recruited coactivators, including MED1, p300, and CBP. In contrast, transcriptional repression by rosi involved a loss of coactivators from eRNA sites devoid of PPARg and enriched for other transcription factors, including AP-1 factors and C/EBPs. Thus, rosi activates and represses transcription by fundamentally different mechanisms that could inform the future development of antidiabetic drugs.

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“…This improvement in insulin sensitivity by TZDs leads to the reduction of blood glucose levels and hemoglobin A1c levels, suppresses inflammation, lowers blood pressure, and decreases urinary proteins (102,103). The PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events) study failed to prove that pioglitazone had a beneficial effect on the primary endpoint, i.e., the reduction of coronary and peripheral events.…”

Section: Diabetes Mellitus (Dm)mentioning

confidence: 99%