Ribavirin is a guanosine analog and has a broad-spectrum antiviral activity against RNA viruses. Based on this, we aimed to show the anti-SARS-CoV-2 activity of this drug molecule via in vitro, in silico and molecular techniques. Ribavirin showed antiviral activity in Vero E6 cells following SARS-CoV-2 infection whereas the drug itself did not show any toxic effect over the concentration range tested. In silico analysis suggested that Ribarivin has a broad-spectrum impact on SARS-CoV-2, acting at different viral proteins. According to the detailed molecular techniques, Ribavirin was shown to decrease the expression of TMPRSS2 both at mRNA and protein levels 48 hours after treatment. The suppressive effect of Ribavirin in ACE2 protein expression was shown to be dependent on cell types. Finally, proteolytic activity assays showed that Ribavirin also showed an inhibitory effect on TMPRSS2 enzyme. Based on these results, we hypothesized that Ribavirin may inhibit the expression of TMPRSS2 by modulating the formation of inhibitory G-quadruplex structures at the TMPRSS2 promoter. As a conclusion, Ribavirin is a potential antiviral drug for the treatment against SARS-CoV-2, and it interferes with the effect of TMPRSS2 and ACE2 expression.

Extracellular vesicles (EVs) play important roles in diabetes mellitus (DM) via connecting the immune cell response to tissue injury, besides stimulation to muscle insulin resistance, while DM is associated with increased risks for major cardiovascular complications. Under DM, chronic hyperglycemia, and subsequent increase in the production of reactive oxygen species (ROS) further lead to cardiac growth remodeling and dysfunction. The purinergic drug ticagrelor is a P2Y12 receptor antagonist. Although it is widely used in cardioprotection, the underlying molecular mechanism of its inhibitory effect on diabetic cardiomyopathy is poorly elucidated. Here, we aimed to understand how ticagrelor exerts its cardio-regulatory effects. For this purpose, we investigated the anti-oxidative and cardioprotective effect of EVs derived from ticagrelor-pretreated cardiomyocytes under DM conditions. To mimic DM in cardiomyocytes, we used high glucose incubated H9c2-cells (HG). HG cells were treated with EVs, which were derived from either ticagrelor-pretreated or untreated H9c2-cells. Our results demonstrated that ticagrelor-pretreated H9c2-derived EVs significantly decreased the hyperglycemia-induced aberrant ROS production, prevented the development of apoptosis and ER stress, and alleviated oxidative stress associated miRNA-expression profile. Importantly, EVs derived from ticagrelor-pretreated H9c2-cells enhanced endothelial cell migration and tube formation, suggesting a modulation of the EV profile in cardiomyocytes. Our data, for the first time, indicate that ticagrelor can exert an important regulatory effect on diabetic cardiomyopathy through extracellular vesicular modulation behind its receptor-inhibition-related effects.

Ribavirin is a guanosine analog and has a broad-spectrum antiviral activity against RNA viruses. Based on this, we aimed to show the anti-SARS-CoV-2 activity of this drug molecule via in vitro, in silico and molecular techniques. Ribavirin showed antiviral activity in Vero E6 cells following SARS-CoV-2 infection. In silico analysis suggested that Ribarivin has a broad-spectrum impact on Vero E6 cells. According to the detailed molecular techniques, Ribavirin was shown to decrease TMPRSS2 expression both at mRNA and protein level 48 hours after treatment. The suppressive effect of Ribavirin in ACE2 protein expression was shown to be dependent on cell types. Finally, proteolytic activity assays showed that Ribavirin also showed an inhibitory effect on TMPRSS2 enzyme. As a conclusion, Ribavirin is a potential antiviral drug for the treatment against SARS-CoV-2, and it interferes with the effect of TMPRSS2 and ACE2 expression.

No abstract

Exosomes play important roles in Diabetes Mellitus (DM) via connecting the immune cell response to tissue injury, besides stimulation to muscle insulin resistance, while DM is associated with increase risks for major cardiovascular complications. Under DM, chronic hyperglycemia and subsequent augmentation of reactive oxygen species (ROS) further lead to cardiac growth remodeling and dysfunction. Although a P2Y12 receptor inhibitor, ticagrelor, is widely used in cardioprotection, its inhibitory effect on diabetic cardiomyopathy is poorly elucidated. Here, we aimed to investigate the anti-oxidative and cardioprotective effect of exosomes, derived from ticagrelor pretreated-cardiomyocytes. To mimic DM in cardiomyocytes, we used high glucose incubated H9c2-cells (HG). HG cells were treated with exosomes, which were derived from either ticagrelor-pretreated or untreated H9c2-cells. Our results demonstrated that exosomes derived from ticagrelor-pretreated H9c2-cells significantly decreased the aberrant ROS production, prevented the development of apoptosis and ER stress under hyperglycemia, and alleviated oxidative stress associated with a miRNA-expression profile. Importantly, exosomes derived from ticagrelor-pretreated H9c2-cells enhanced endothelial cell migration and tube formation, suggesting a modulation of the exosome profile in cardiomyocytes. Our data, for the first time, indicate that ticagrelor can exert an important regulatory effect on diabetic cardiomyopathy through exosomal modulation behind its receptor-inhibitor related action.