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INTRODUCTION: Cisplatin is a life-saving anticancer compound used to treat multiple solid malignant tumors, while it causes permanent hearing loss. There is no known cure, and the FDA has not approved any preventative treatment for cisplatin-based ototoxicity. OBJECTIVES: This study investigated whether the carbon monoxide (CO)-releasing tricarbonyldichlororuthenium (II) dimer, CORM-2, reverses cisplatin-induced hearing impairment and reduces cisplatin accumulation in the mouse inner ear. METHODS: Male 6-week-old BALB/c mice were randomly assigned to one of the following groups: control (saline-treated, i.p.), CORM-2 only (30 mg/kg, i.p., four doses), cisplatin only (20 mg/kg, i.p., one dose), and CORM-2 + cisplatin, to determine whether cisplatin-based hearing impairment was alleviated by CORM-2 treatment. RESULTS: Our results revealed CORM-2 significantly attenuated cisplatin-induced hearing loss in young adult mice. CORM-2 co-treatment significantly decreased platinum accumulation in the inner ear and activated the plasma membrane repair system of the stria vascularis. Moreover, CORM-2 co-treatment significantly decreased cisplatin-induced inflammation, apoptosis, and cochlear necroptosis. Because the stria vascularis is the likely cochlear entry point of cisplatin, we next focused on the microvasculature. Cisplatin induced increased extravasation of a chromatic tracer (fluorescein isothiocyanate [FITC]-dextran, MW 75 kDa) around the cochlear microvessels at 4 days post-treatment; this extravasation was completely inhibited by CORM-2 co-therapy. CORM-2 co-treatment effectively maintained the integrity of stria vascularis components including endothelial cells, pericytes, and perivascular-resident macrophage-type melanocytes. CONCLUSION: CORM-2 co-therapy substantially protects against cisplatin-induced ototoxicity by reducing platinum accumulation and toxic cellular stress responses. These data indicate that CORM-2 co-treatment may be translated into clinical strategy to reduce cisplatin-induced hearing loss.
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OBJECTIVES: To assess the association between altered expression of caveolin-1 and p53/p21, as indicatives of cellular senescence, in preeclamptic placenta. STUDY DESIGN: Placental tissues and serum were collected from rats (Sham and reduced uterine perfusion pressure group) at 18.5 days post coitum and humans (normotensive pregnant and preeclampsia groups). The concentration and expression of caveolin-1 were measured in the collected tissues, and the correlation between p53 and p21 expression was evaluation. MAIN OUTCOME MEASURES: Placental mRNA expression and serum concentration of caveolin-1 were measured using qRT-PCR and ELISA, respectively. Altered expressions of caveolin-1 and p53/p21 were revealed and quantified by immunohistochemistry. The association between these changes was investigated using correlation analysis. RESULTS: Placental mRNA expressions and serum concentrations of caveolin-1 were significantly decreased in reduced uterine perfusion pressure and preeclampsia groups. The expressions of caveolin-1 and p53/ p21 were significantly altered in placenta complicated with preeclampsia. Correlation analysis revealed a significant inverse association between changes in caveolin-1 and p53/p21. Subsequently, these results were obtained by investigating the preeclampsia onset time. CONCLUSION: These results revealed that the expression of caveolin-1 profoundly decreases in the placenta and serum of preeclampsia. These factors contribute to the mechanism of accelerated cellular senescence in placenta, which is one of the various etiologies of preeclampsia.