OBJECTIVE The synthetic triterpenoid 2-cyano-3,12-dioxoolean-1,9(11)-dien-C28-methyl ester(CDDO-Me)is considered a promising anti-tumorigenic compound.In this study,we investigated the anti-cancer effect of CDDO-Me on...OBJECTIVE The synthetic triterpenoid 2-cyano-3,12-dioxoolean-1,9(11)-dien-C28-methyl ester(CDDO-Me)is considered a promising anti-tumorigenic compound.In this study,we investigated the anti-cancer effect of CDDO-Me on breast cancer cells and its underlying mechanisms.METHODS To investigate the effect of CDDO-Me on various breast cancer cells,cell viability assay using calcein-AM and EthD-1 as well as MTT assay was performed.To clarify the origin of CDDO-Me-induced vacuoles,electron microscopy as well as fluorescence microscopy using YFP-ER or YFP-Mito construct was performed.To measure the changes in intracellular Ca2+and ROS levels,flow cytometry using Fluo-3 and H2DCF-DA was performed.RESULTS CDDO-Me treatment induces progressive ER-derived vacuolation and subsequent apoptosis in various breast cancer cells.CDDO-Me-induced increases in intracellular Ca2+ levels,reflecting influx from the extracellular milieu,make a critical contribution to ER-derived vacuolation and subsequent cell death.In parallel with increasing 2+ Calevels,CDDO-Me markedly increases the generation of reactive oxygen species(ROS).Interestingly,we found that there exists a reciprocal positive-regulatory loop between Ca2+ influx and ROS generation that triggers ER stress and ER dilation in response to CDDO-Me.CONCLUSION ER-derived vacuolation via Ca2+ influx and ROS generation is responsible for the potent anticancer effects of CDDOMe on breast cancer cells.展开更多
Sickle cell disease （SCD） is an inherited disorder of hemoglobin in which the abnormal hemoglobin S polymerizes when deoxygenated. This polymerization of hemoglobin S not only results in hemolysis and vaso- occlusio...Sickle cell disease （SCD） is an inherited disorder of hemoglobin in which the abnormal hemoglobin S polymerizes when deoxygenated. This polymerization of hemoglobin S not only results in hemolysis and vaso- occlusion but also precipitates inflammation, oxidative stress and chronic organ dysfunction. Oxidative stress is increasingly recognized as an important intermediate in these pathophysiological processes and is therefore an important target for therapeutic intervention. The transcription factor nuclear erythroid derived- 2 related factor 2 （Nrf2） controls the expression of anti-oxidant enzymes and is emerging as a protein whose function can be exploited with therapeutic intent. This review article is focused on triterpenoids that activate Nrf2, and their potential for reducing oxidative stress in SCD as an approach to prevent organ dysfunction associated with this disease. A brief overview of oxidative stress in the clinical context of SCD is accompanied by a discussion of several pathophysiological mechanisms contributing to oxidative stress. Finally, these mechanisms are then related to current management strategies in SCD that are either utilized currently or under evaluation. The article concludes with a perspective on the potential of the various therapeutic interventions to reduce oxidative stress and morbidity associated with SCD.展开更多
基金The project supported by the National Research Foundation of Korea(NRF)grant funded by the Korean government(MSIP)(2011-0030043)a grant of the Korean Health Technology R&D Progect,Ministry of Health&Welfare(HI14C2230)
文摘OBJECTIVE The synthetic triterpenoid 2-cyano-3,12-dioxoolean-1,9(11)-dien-C28-methyl ester(CDDO-Me)is considered a promising anti-tumorigenic compound.In this study,we investigated the anti-cancer effect of CDDO-Me on breast cancer cells and its underlying mechanisms.METHODS To investigate the effect of CDDO-Me on various breast cancer cells,cell viability assay using calcein-AM and EthD-1 as well as MTT assay was performed.To clarify the origin of CDDO-Me-induced vacuoles,electron microscopy as well as fluorescence microscopy using YFP-ER or YFP-Mito construct was performed.To measure the changes in intracellular Ca2+and ROS levels,flow cytometry using Fluo-3 and H2DCF-DA was performed.RESULTS CDDO-Me treatment induces progressive ER-derived vacuolation and subsequent apoptosis in various breast cancer cells.CDDO-Me-induced increases in intracellular Ca2+ levels,reflecting influx from the extracellular milieu,make a critical contribution to ER-derived vacuolation and subsequent cell death.In parallel with increasing 2+ Calevels,CDDO-Me markedly increases the generation of reactive oxygen species(ROS).Interestingly,we found that there exists a reciprocal positive-regulatory loop between Ca2+ influx and ROS generation that triggers ER stress and ER dilation in response to CDDO-Me.CONCLUSION ER-derived vacuolation via Ca2+ influx and ROS generation is responsible for the potent anticancer effects of CDDOMe on breast cancer cells.
文摘Sickle cell disease （SCD） is an inherited disorder of hemoglobin in which the abnormal hemoglobin S polymerizes when deoxygenated. This polymerization of hemoglobin S not only results in hemolysis and vaso- occlusion but also precipitates inflammation, oxidative stress and chronic organ dysfunction. Oxidative stress is increasingly recognized as an important intermediate in these pathophysiological processes and is therefore an important target for therapeutic intervention. The transcription factor nuclear erythroid derived- 2 related factor 2 （Nrf2） controls the expression of anti-oxidant enzymes and is emerging as a protein whose function can be exploited with therapeutic intent. This review article is focused on triterpenoids that activate Nrf2, and their potential for reducing oxidative stress in SCD as an approach to prevent organ dysfunction associated with this disease. A brief overview of oxidative stress in the clinical context of SCD is accompanied by a discussion of several pathophysiological mechanisms contributing to oxidative stress. Finally, these mechanisms are then related to current management strategies in SCD that are either utilized currently or under evaluation. The article concludes with a perspective on the potential of the various therapeutic interventions to reduce oxidative stress and morbidity associated with SCD.
