Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0851184 (thinning)
 11,252 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The carcinogenic potential of muraglitazar, a dual human peroxisome proliferator-activated receptor alpha/gamma agonist, was evaluated in 2-year studies in mice (1, 5, 20, and 40 mg/kg) and rats (1, 5, 30, and 50 mg/kg). Benign gallbladder adenomas occurred at low incidences in male mice at 20 and 40 mg/kg (area under the curve [AUC] exposures > or = 62 times human exposure at 5 mg/day) and were considered drug related due to an increased incidence of gallbladder mucosal hyperplasia at these doses. There was a dose-related increased incidence of transitional cell papilloma and carcinoma of the urinary bladder in male rats at 5, 30, and 50 mg/kg (AUC exposures > or = 8 times human exposure at 5 mg/day). At 30 and 50 mg/kg, the urinary bladder tumors were accompanied by evidence of increased urine solids. Subsequent investigative studies established that the urinary bladder carcinogenic effect was mediated by urolithiasis rather than a direct pharmacologic effect on urothelium. Incidences of subcutaneous liposarcoma in male rats and subcutaneous lipoma in female rats were increased at 50 mg/kg (AUC exposures > or = 48 times human exposure at 5 mg/day) and attributed, in part, to persistent pharmacologic stimulation of preadipocytes. Toxicologically relevant nonneoplastic changes in target tissues included thinning of cortical bone in mice and hyperplastic and metaplastic adipocyte changes in mice and rats. Considering that muraglitazar is nongenotoxic, the observed tumorigenic effects in mice and rats have no established clinical relevance since they occurred at either clinically nonrelevant exposures (gallbladder and adipose tumors) or by a species-specific mechanism (urinary bladder tumors).
 ...
PMID:Rodent carcinogenicity profile of the antidiabetic dual PPAR alpha and gamma agonist muraglitazar. 1742 6

Perfluorooctanoic acid (PFOA) is a persistent organic pollutant. This study established an in ovo peroxisome proliferator-activated receptor alpha (PPAR alpha) silencing model in chicken embryo heart, and investigated the role of PPAR alpha in PFOA induced developmental cardiotoxicity. The in ovo silencing was achieved by introducing lentivirus expressing PPAR alpha siRNA into ED2 chicken embryo via microinjection (0.05ul/g egg weight). Transfection efficacy was confirmed by fluorescent microscopy and western blotting. To assess the developmental cardiotoxicity, cardiac function (heart rate) and morphology (right ventricular wall thickness) were measured in D1 hatchling chickens. 2mg/kg (egg weight) PFOA exposure at ED0 induced significant elevation of heart rate and thinning of right ventricular wall thickness in D1 hatchling chickens. PPAR alpha silencing did not prevent PFOA-induced elevation of heart rate; however, it did significantly increase the right ventricular wall thickness as compared to PFOA exposed animals. Meanwhile, PPAR alpha silencing did not abolish the protective effects exerted by exposure to 100mg/kg (egg weight) l-carnitine. In conclusion, PFOA-induced heart rate elevation is likely PPAR alpha independent, while the right ventricular wall thinning seems to be PPAR alpha dependent. The protective effects of l-carnitine do not require PPAR alpha.
 ...
PMID:The role of PPAR alpha in perfluorooctanoic acid induced developmental cardiotoxicity and l-carnitine mediated protection-Results of in ovo gene silencing. 2893 91