Search

Abstract Heat shock protein 90 (Hsp90) and its co-chaperones promote cancer, and targeting Hsp90 holds promise for cancer treatment. Most of the efforts to harness this potential have focused on targeting the Hsp90 N-terminus ATP binding site. Although newer-generation inhibitors have shown improved efficacy in aggressive cancers, induction of the cellular heat shock response (HSR) by these inhibitors is thought to limit their clinical efficacy. Therefore, Hsp90 inhibitors with novel mechanisms of action and that do not trigger the HSR would be advantageous. Here, we investigated the mechanism by which capsaicin inhibits Hsp90. Through mutagenesis, chemical modifications, and proteomic studies, we show that capsaicin binds to the N-terminus of Hsp90 and inhibits its ATPase activity. Consequently, capsaicin and its analogs inhibit Hsp90 ATPase-dependent progesterone receptor reconstitution in vitro. Capsaicin did not induce the HSR, instead, it promoted the degradation of Hsp70 through the lysosome-autophagy pathway. Remarkably, capsaicin did not induce degradation of the constitutively expressed cognate Hsc70, indicating selectivity for Hsp70. Combined treatments of capsaicin and the Hsp90 inhibitor 17-AAG improved the anti-tumor efficacy of 17-AAG in cell culture and tridimensional tumor spheroid growth assays using breast and prostate cancer models. Consistent with this, in silico docking studies revealed that capsaicin binding to the ATP binding site of Hsp90 was distinct from classical N-terminus Hsp90 inhibitors, indicating a novel mechanism of action. Collectively, these findings support the use of capsaicin as a chemical scaffold to develop novel Hsp90 N-terminus inhibitors as well as its ability to be a potential cancer co-therapeutic.

Abstract Inflammatory diseases including COVID-19 are associated with a cytokine storm characterized by high interleukin-6 (IL-6) titers. In particular, while recent studies examined COVID-19 associated arrhythmic risks from cardiac injury and/or from pharmacotherapy such as the combination of azithromycin (AZM) and hydroxychloroquine (HCQ), the role of IL-6 per se in increasing the arrhythmic risk remains poorly understood. The objective is to elucidate the electrophysiological basis of inflammation-associated arrhythmic risk in the presence of AZM and HCQ. IL-6, AZM and HCQ were concomitantly administered to guinea pigs in-vivo and in-vitro. Electrocardiograms, action potentials and ion-currents were analyzed. IL-6 alone or the combination AZM + HCQ induced mild to moderate reduction in heart rate, PR-interval and corrected QT (QTc) in-vivo and in-vitro. Notably, IL-6 alone was more potent than the combination of the two drugs in reducing heart rate, increasing PR-interval and QTc. In addition, the in-vivo or in-vitro combination of IL-6 + AZM + HCQ caused severe bradycardia, conduction abnormalities, QTc prolongation and asystole. These electrocardiographic abnormalities were attenuated in-vivo by tocilizumab (TCZ), a monoclonal antibody against IL-6 receptor, and are due in part to the prolongation of action potential duration and selective inhibition of Na+, Ca2+ and K+ currents. Inflammation confers greater risk for arrhythmia than the drug combination therapy. As such, in the setting of elevated IL-6 during inflammation caution must be taken when co-administering drugs known to predispose to fatal arrhythmias and TCZ could be an important player as a novel anti-arrhythmic agent. Thus, identifying inflammation as a critical culprit is essential for proper management.

Riparian vegetation is frequently exposed to abiotic stress, which generates reactive oxygen species (ROS) caused by strong differences in a river's hydrological conditions. Among different ROS, hydrogen peroxide (H2O2) is relatively steady and can be measured appropriately. Thus, the quantification of plant H2O2 can be used as a stress indicator for riparian vegetation management. The current study examines the spatial distribution of plants by riparian vegetation communities across the elevation gradient of riparian zones through quantification of environmental stress using foliar H2O2 concentration. The trees Salix spp., Robinia pseudoacacia, Ailanthus altissima with Juglans mandshurica, and the herbs Phragmites australis, Phragmites japonica, and Miscanthus sacchariflorus were selected for this study. Leaf tissues were collected to analyze H2O2 concentration, meanwhile riparian soil was sampled to measure total nitrogen (TN), total phosphorus (TP), and moisture content. The H2O2 concentration of tree species increased with higher soil moisture content, which was negatively correlated for Salix and herb spp., in which H2O2 concentration always decreased with high soil moisture. In this study, we found a unique significant interaction between soil moisture content and H2O2 concentration, both positively or negatively correlated relationships, when compared with other parameters, such as TN or TP concentrations or TN: TP in riparian soil. The species-specific distribution zones can be explained by the H2O2 concentration in the plant for gravelly and sandy channels on a theoretical range of soil moisture. Each species' H2O2 concentration was estimated through derived equations and is directly related to an elevation above the channel. The comparison with the observed distribution of plant elevations in the field indicated that all species showed a spatial distribution that acts as species-specific elevations where H2O2 concentrations stayed below 40 μmol/gFW. Hence, the present study suggests that foliar H2O2 concentration can be a useful benchmark for the distribution potentiality of riparian vegetation. [ABSTRACT FROM AUTHOR]