Attenuation of doxorubicin-induced cardiotoxicity by mdivi-1: a mitochondrial division/mitophagy inhibitor

Doxorubicin is one of the most effective anti-cancer agents. However, its use is associated with adverse cardiac effects, including cardiomyopathy and progressive heart failure. Given the multiple beneficial effects of the mitochondrial division inhibitor (mdivi-1) in a variety of pathological conditions including heart failure and ischaemia and reperfusion injury, we investigated the effects of mdivi-1 on doxorubicin-induced cardiac dysfunction in naïve and stressed conditions using Langendorff perfused heart models and a model of oxidative stress was used to assess the effects of drug treatments on the mitochondrial depolarisation and hypercontracture of cardiac myocytes. Western blot analysis was used to measure the levels of p-Akt and p-Erk 1/2 and flow cytometry analysis was used to measure the levels p-Drp1 and p-p53 upon drug treatment. The HL60 leukaemia cell line was used to evaluate the effects of pharmacological inhibition of mitochondrial division on the cytotoxicity of doxorubicin in a cancer cell line. Doxorubicin caused a significant impairment of cardiac function and increased the infarct size to risk ratio in both naïve conditions and during ischaemia/reperfusion injury. Interestingly, co-treatment of doxorubicin with mdivi-1 attenuated these detrimental effects of doxorubicin. Doxorubicin also caused a reduction in the time taken to depolarisation and hypercontracture of cardiac myocytes, which were reversed with mdivi-1. Finally, doxorubicin caused a significant elevation in the levels of signalling proteins p-Akt, p-Erk 1/2, p-Drp1 and p-p53. Co-incubation of mdivi-1 with doxorubicin did not reduce the cytotoxicity of doxorubicin against HL-60 cells. These data suggest that the inhibition of mitochondrial fission protects the heart against doxorubicin-induced cardiac injury and identify mitochondrial fission as a new therapeutic target in ameliorating doxorubicin-induced cardiotoxicity without affecting its anti-cancer properties

Oxygen reduction reaction features in neutral media on glassy carbon electrode functionalized by chemically prepared gold nanoparticles

Gold nanoparticles (AuNPs) were prepared by chemical route using 4 different protocols by varying reducer, stabilizing agent and solvent mixture. The obtained AuNPs were characterized by transmission electronic microscopy (TEM), UV-Visible and zeta potential measurements. From these latter surface charge densities were calculated to evidence the effect of the solvent mixture on AuNPs stability. The AuNPs were then deposited onto glassy carbon (GC) electrodes by drop-casting and the resulting deposits were characterized by cyclic voltammetry (CV) in H2SO4 and field emission gun scanning electron microscopy (FEG-SEM). The electrochemical kinetic parameters of the 4 different modified electrodes towards oxygen reduction reaction (ORR) in neutral NaCl-NaHCO3 media (0.15 M / 0.028 M, pH 7.4) were evaluated by rotating disk electrode voltammetry and subsequent Koutecky-Levich treatment. Contrary to what we previously obtained with electrodeposited AuNPs [Gotti et al., Electrochim. Acta 2014], the highest cathodic transfer coefficients were not obtained on the smallest particles, highlighting the influence of the stabilizing ligand together with the deposits morphology on the ORR kinetics