Histopathological Evaluation of Heart Toxicity of a Novel Selective PPAR-gamma Agonists CKD-501 in db/db Mice

High risk of cardiovascular diseases caused by existing PPAR-gamma agonists such as rosiglitazone and pioglitazone has been recently reported. CKD-501 is a novel selective PPAR-gamma agonist as a potential target to reduce cardiovascular risk in non-insulin dependent diabetes mellitus (NIDDM). In this study, We investigated potential cardiotoxicity of CKD-501 and compared its toxicity with that of rosiglitazone or pioglitazone using db/db mice. After 12-week repeated administration of CKD-501 at doses of 3, 10 and 30 mg/kg/day or rosiglitazone at doses of 10 and 30 mg/kg/day or pioglitazone at doses of 200 and 540 mg/kg/day, animals were sacrificed for investigation of potential toxicities. Diameters of left ventricles and areas of cardiomyocytes were measured. And lipid accumulation and apoptosis in heart muscle were examined by oil red O staining and TUNEL staining, respectively. Diameters of left ventricles were significantly increased in high dose treatment group of pioglitazone compared to control (p CKD-501 > or = rosiglitazone. However, lipid accumulation and apoptotic changes in heart were not observed in all dosing groups. Taken together, the myocardial cell hypertrophy of CKD-501 are relatively lower than that of pioglitazone and similar to rosiglitazone. And it is suggested that the myocardial cell hypertrophy of CKD-501 are less adverse in clinical use for the management of the NIDDM.

IL-10 Mediates Rosiglitazone-Induced Kidney Protection in Cisplatin Nephrotoxicity

Cisplatin, a major anti-neoplastic drug, is known to be nephrotoxic and inflammation-inducing. A peroxisome proliferator-activated receptor gamma agonist, regulating lipid metabolism, has known to have anti-inflammatory effect, but the protection mechanisms in various kidney injuries are not fully understood. The purpose of this study was to examine the reno-protective effect of rosiglitazone on cisplatin nephrotoxicity in mice focusing on inflammation and apoptosis. Male BALB/c mice were pretreated with rosiglitazone (10 mg/kg) or vehicle through daily intraperitoneal injection for 3 days and then were given a single injection of cisplatin (20 mg/kg). Cisplatin induced a significant rise in blood urea nitrogen and creatinine levels, and tubular cell damage with marked tissue inflammation. Tissue cytokines and chemokines measured by a cytometric bead array showed increased TNF-alpha, IL-6, MCP-1, and IFN-gamma levels, while IL-10, an anti-inflammatory cytokine, was significantly decreased by cisplatin treatment. However, rosiglitazone pretreatment substantially reversed the depressed IL-10 level with simultaneous suppression of proinflammatory cytokines and chemokines. This tissue cytokine and chemokine milieu was associated with marked attenuation of kidney injury elicited by cisplatin. These findings suggest that the rosiglitazone-mediated renoprotective effect in cisplatin nephrotoxicity of mice is partially mediated by upregulation of anti-inflammatory IL-10 production.

New Promising Therapeutic Modalities for Thyroid Cancers: Histone Deacetylase Inhibitor, PPAR-gamma Agonist, and Retinoic Acid / 대한내분비외과학회지

Most patients with thyroid cancer have well differentiated tumors that usually respond to conventional therapy including total or near total thyroidectomy, radioiodine ablation and TSH suppression. About 10% of patients, however, have aggressive cancers as a consequence of de-differentiation. During de-differentiation, thyroid cancers not only show more mitosis, fibrosis, and altered cell structure, they also lose thyroid-specific functions (iodine uptake, TSH receptor expression, and thyroglobulin production). These poorly differentiated or undifferentiated tumors mostly fail to take up radioiodine and are responsible for most deaths from thyroid cancer. New therapies need to be developed for patients with these types of tumors. Among the most promising antineoplastic therapies for these poorly differentiated and undifferentiated thyroid cancers are the histone deacetylase inhibitors, the PPAR-gamma agonist and retinoic acids. These drugs have therapeutic effects for thyroid cancers in inhibiting growth and inducing apoptosis and redifferentiation, in vivo and in vitro studies. And, clinical trials in patients with refractory thyroid cancers have been initiated. Further laboratory investigation of these drugs is necessary to understand molecular mechanisms and demonstrate therapeutic efficacy for thyroid cancers.