Project description:The purpose of the study was to investigate the nongenotoxic carcinogenic effect of Pioglitazone. Pioglitazone is a PPARgamma agonist and is known to cause bladder tumours in male rats and an increase in the incidence of bladder cancer in humans has been observed in patients treated with Pioglitazone. Pioglitazone is not considered genotoxic or carcinogenic in mice and tumours are only observed in male rats suggesting a nongenotoxic mechanism of tumorigenesis. A suggested hypothesis is urinary calculi formation and subsequent irritation, hyperplasia and metaplasia. Rosiglitazone was used as reference compound as this PPARgamma agonist does not cause changes in the bladder but cause lipoma/liposarcoma in rats.
Project description:The purpose of the study was to investigate the nongenotoxic carcinogenic effect of Pioglitazone. Pioglitazone is a PPARgamma agonist and is known to cause bladder tumours in male rats and an increase in the incidence of bladder cancer in humans has been observed in patients treated with Pioglitazone. Pioglitazone is not considered genotoxic or carcinogenic in mice and tumours are only observed in male rats suggesting a nongenotoxic mechanism of tumorigenesis. A suggested hypothesis is urinary calculi formation and subsequent irritation, hyperplasia and metaplasia. Rosiglitazone was used as reference compound as this PPARgamma agonist does not cause changes in the bladder but cause lipoma/liposarcoma in rats.
Project description:Cardiac pathological hypertrophy is associated with a significantly increased risk of coronary heart disease and has been observed in diabetic patients treated with rosiglitazone, whereas most published studies do not suggest a similar increase in risk of cardiovascular events in pioglitazone-treated diabetic subjects. This study sought to understand the pathophysiological mechanisms underlying the disparate cardiovascular effects of rosiglitazone and pioglitazone and yield knowledge as to the causative nature of rosiglitazone-associated cardiac hypertrophy.
Project description:We characterized the insulin sensitivity and multi-tissue gene expression profiles of lean and insulin resistant, obese Zucker rats untreated or treated with one of four PPARγ ligands (pioglitazone, rosiglitazone, troglitazone, and AG035029). We analyzed the transcriptional profiles of adipose tissue, skeletal muscle, and liver from the rats and determined whether ligand insulin-sensitizing potency was related to ligand-induced alteration of functional pathways. Ligand treatments improved insulin sensitivity in obese rats, albeit to varying degrees. Male Zucker fatty (fa/fa) and lean (fa/+) rats (Charles River, Wilmington, MA) were received at 6 weeks of age. Fatty rats were weight-matched upon arrival and randomly divided into one of five experimental groups. The fatty rat groups varied by the type of chow they were fed - normal chow alone or with a PPARγ ligand admixture: normal chow (fatty control, FC), rosiglitazone-treated (Rosi), pioglitazone-treated (Pio), troglitazone-treated (Tro), or AG035029-treated (AG). Lean control (LC) rats were all fed normal chow. Rats groups were maintained on the diets for 21 days. Adipose tissue (epididymal), skeletal muscle (gastrocnemius), and liver were harvested from lean (LC) and insulin resistant, obese Zucker rats untreated (FC) or treated with one of four PPARγ ligands (pioglitazone [Pio], rosiglitazone [Rosi], troglitazone [Tro], and AG035029 [AG]).
Project description:Trancriptional profiling of rat liver after short-term (up tp 14 days) administration of carcinogenic and non-carcinogenic chemicals
Project description:Cardiac pathological hypertrophy is associated with a significantly increased risk of coronary heart disease and has been observed in diabetic patients treated with rosiglitazone, whereas most published studies do not suggest a similar increase in risk of cardiovascular events in pioglitazone-treated diabetic subjects. This study sought to understand the pathophysiological mechanisms underlying the disparate cardiovascular effects of rosiglitazone and pioglitazone and yield knowledge as to the causative nature of rosiglitazone-associated cardiac hypertrophy. Total RNA obtained from mouse Apex from LDLr-/- mice treated with High Fat diet (HF) diet as control (n=6) or HF+Pio (n=5) or HF+Rosi (n=5).
