RESUMEN
Clinical application of the widely used chemotherapeutic agent, doxorubicin (DOX), is limited by its cardiotoxicity. Mitochondrial dysfunction has been revealed as a crucial factor in DOX-induced cardiotoxicity. 7,8,3'-Trihydroxyflavone (THF) is a mimetic brain-derived neurotrophic factor with neuroprotective effects. However, the potential effects of THF on DOX-induced cardiomyocyte damage and mitochondrial disorders remain unclear. H9c2 cardiomyoblasts were exposed to DOX and/or THF at different concentrations. Cardiomyocyte injury was evaluated using lactate dehydrogenase (LDH) assay and Live/Dead cytotoxicity kit. Meanwhile, mitochondrial membrane potential (MMP), morphology, mitochondrial reactive oxygen species (mito-ROS) production, and the oxygen consumption rate of cardiomyocytes were measured. The protein levels of key mitochondria-related factors such as adenosine monophosphate-activated protein kinase (AMPK), mitofusin 2 (Mfn2), dynamin-related protein 1 (Drp1), and optic atrophy protein 1 (OPA1) were examined. We found that THF reduced LDH content and death ratio of DOX-treated cardiomyocytes in a concentration-dependent manner, while increasing MMP without significantly affecting the routine and maximum capacity of mitochondrial respiration. Mechanistically, THF increased the activity of Akt and protein levels of Mfn2 and heme oxygenase 1 (HO-1). Moreover, inhibition of Akt reversed the protective role of THF, increased mito-ROS levels, and repressed Mfn2 and HO-1 expression. Therefore, we conclude, THF relieves DOX-induced cardiotoxicity and improves mitochondrial function by activating Akt-mediated Mfn2 and HO-1 pathways. This finding provides promising therapeutic insights for DOX-induced cardiac dysfunction.
Asunto(s)
Cardiotoxicidad , Proteínas Proto-Oncogénicas c-akt , Humanos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Cardiotoxicidad/metabolismo , Transducción de Señal , Doxorrubicina/toxicidad , Miocitos Cardíacos/metabolismo , Mitocondrias/metabolismo , Apoptosis , Estrés OxidativoRESUMEN
The relationship between mitochondrial dysfunction and cardiovascular disease pathogenesis is well recognized. 7,8-Dihydroxyflavone (7,8-DHF), a mimetic of brain-derived neurotrophic factor, inhibits mitochondrial impairments and improves cardiac function. However, the regulatory role of 7,8-DHF in the mitochondrial function of cardiomyocytes is not fully understood. To investigate the potential mito-protective effects of 7,8-DHF in cardiomyocytes, we treated H9c2 or HL-1 cells with the mitochondrial respiratory complex I inhibitor rotenone (Rot) as an in vitro model of mitochondrial dysfunction. We found that 7,8-DHF effectively eliminated various concentrations of Rot-induced cell death and reduced lactate dehydrogenase release. 7,8-DHF significantly improved mitochondrial membrane potential and inhibited mitochondrial reactive oxygen species. Moreover, 7,8-DHF decreased routine and leak respiration, restored protein levels of mitochondrial complex I-IV, and increased ATP production in Rot-treated H9c2 cells. The protective role of 7,8-DHF in Rot-induced damage was validated in HL-1 cells. Nuclear phosphorylation protein expression of signal transducer and activator of transcription 3 (STAT3) was significantly increased by 7,8-DHF. The present study suggests that 7,8-DHF rescues Rot-induced cytotoxicity by inhibiting mitochondrial dysfunction and promoting nuclear translocation of p-STAT3 in cardiomyocytes, thus nominating 7,8-DHF as a new pharmacological candidate agent against mitochondrial dysfunction in cardiac diseases.
Asunto(s)
Miocitos Cardíacos , Rotenona , Miocitos Cardíacos/metabolismo , Rotenona/farmacología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Mitocondrias/metabolismoRESUMEN
On account of the intralayer and interlayer heterogeneity, high temperature (110 °C), and high salinity (224,919 mg/L) of Tahe channel sand reservoir, single profile control or chemical flooding cannot greatly enhanced oil recovery. The goal of the current research was to optimize a polymer gel formula that was suitable for high-temperature and high-salinity reservoirs, screen an appropriate chemical flooding method, and determine the efficiency of the combination of profile control and chemical flooding. Experimental results indicated that the formed polymer gel could maintain relatively high strength after aging for 30 days. Moreover, the combination of profile control and surfactant flooding could result in an enhanced oil recovery of 17.9%, and the combination of profile control and foam flooding could result in an enhanced oil recovery of 23.0%, which was ascribed to the improvement of sweeping efficiency and displacement efficiency. All the results indicated that the formed polymer gel and the combination of profile control and chemical flooding have great application potential in Tahe high-temperature and high-salinity channel sand reservoir.