RESUMEN
Urotoxicity is a troublesome complication associated with cyclophosphamide (CP) and L-buthionine-SR-sulfoximine (BSO) treatment in chemotherapy. With this concern in mind, the present study investigated the potential effects of a hydroxytyrosol extract from olive mill waste (OMW) on urotoxicity induced by acute CP and BSO doses using a Swiss albino mouse model. Toxicity modulation was evaluated by measuring lipid peroxidation (LPO) and antioxidants in urinary bladder. The findings revealed that the hydroxytyrosol extract exerted a protective effect not only on LPO but also on enzymatic antioxidants. When compared to the controls, the CP-treated animals underwent significant decreases in the glutathione S-transferase (GST), glutathione reductase (GR), glutathione peroxidase (GP), and catalase (CAT) activities. The level of glutathione (GSH) was also reduced with increased doses of LPO in the CP-treated animals. L-Buthionine-SR-sulfoximine treatment exerted an additive toxic effect on the CP-treated animals. Interestingly, pretreatment with the hydroxytyrosol extract restored the activities of all enzymes back to normal levels and exhibited an overall protective effect on the CP- and BSO-induced toxicities in urinary bladder. The restoration of GSH through the treatment with the hydroxytyrosol extract can play an important role in reversing CP-induced apoptosis and free radical-mediated LPO.
Asunto(s)
Antioxidantes/farmacología , Butionina Sulfoximina/toxicidad , Ciclofosfamida/toxicidad , Alcohol Feniletílico/análogos & derivados , Extractos Vegetales/farmacología , Enfermedades de la Vejiga Urinaria/prevención & control , Animales , Catalasa/metabolismo , Cromatografía de Gases , Cromatografía Líquida de Alta Presión , Modelos Animales de Enfermedad , Glutatión/análisis , Glutatión Peroxidasa/metabolismo , Glutatión Reductasa/metabolismo , Glutatión Transferasa/metabolismo , Residuos Industriales/análisis , Peroxidación de Lípido/efectos de los fármacos , Masculino , Espectrometría de Masas , Ratones , Olea/química , Alcohol Feniletílico/farmacología , Vejiga Urinaria/efectos de los fármacos , Enfermedades de la Vejiga Urinaria/inducido químicamenteRESUMEN
Thyroid hormone receptor (TR) and peroxisome proliferator-activated receptor gamma (PPARgamma) co-regulate numerous peripheral metabolic responses. To examine potential crosstalk between PPARgamma and TRbeta in the hypothalamus, thyrotropin-releasing hormone (Trh) regulation in the newborn mouse hypothalamus was followed. QPCR showed PPARgamma to be expressed in the hypothalamus at this developmental stage. Intracerebral injection of PPARgamma agonists modified transcription from a TRH-luc construct introduced into the hypothalamus and increased serum thyroxine levels. Furthermore, shRNA-based in vivo PPARgamma knockdown amplified T(3)-independent transcription and PPARgamma overexpression dose-dependently abrogated T(3)-dependent Trh repression. Overexpression of retinoid X receptor-alpha (RXRalpha), the common heterodimeric partner of PPARgamma and TRbeta, rescued PPARgamma abrogation of T(3)-dependent repression. Thus, competition for RXR could represent one mechanism underlying this hypothalamic crosstalk between PPARgamma and TRbeta. These demonstrations of PPARgamma effects on hypothalamic Trh transcription in vivo consolidate the role of the TRH neuron as a central integrator of energy homeostasis.