Abstract
Curcumin (C) and resveratrol (R) are two well-known nutraceuticals with strong antioxidant activity that can protect cells from oxidative stress. This study aims to investigate the synergy of CR combinations in protecting human endothelial EAhy926 cells against H2O2-induced oxidative stress and its related mechanisms. C and R as individual compounds as well as CR combinations at different ratios were screened for their protective effects against H2O2 (2.5 mM) induced cell death assessed by cell viability assays. The synergistic interaction was analysed using the combination index model. The effects of optimal CR combinations on caspase-3 activity, ROS level, SOD activity, NAD cellular production, expression of Nrf2 and HO-1, and Nrf2 translocation were determined. CR combinations produced a synergistic protection against that of H2O2-induced changes in cell viability, caspase-3 activity, and ROS production. The strongest effect was observed for CR with the ratio of 8 : 2. Further experiments showed that CR 8 : 2 exhibited significantly greater effects in increasing Nrf2 translocation and expressions of Nrf2 and HO-1 proteins, as well as SOD activity and total cellular NAD production, than that of C or R alone. The findings demonstrate that combination of C and R produced a strong synergy in activity against H2O2-induced oxidative stress in EAhy926 cells. The mechanism of this synergy involves the activation of Nrf2-HO-1 signaling pathway and promotion of antioxidant enzymes. Further studies on CR synergy may help develop a new combination therapy for endothelial dysfunction and other conditions related to oxidative stress.
Highlights
Cardiovascular diseases (CVD) are the leading cause of death worldwide and the incidence remains increasing lately in developing countries [1]
E positive control, gallic acid (GA), dose-dependently (1.625–50 μM) restored the cell viability impaired by H2O2 (2.5 mM), with a substantial increase of cell viability to 72.92 ± 8.54% at 12.5 μM. e pretreatment of C significantly restored cell viability at 25 and 50 μM (p < 0.0001), whereas R did not show any significant effect
Individual C and R have been demonstrated to have a cytoprotective effect against oxidative stress through various mechanisms [30,31,32]
Summary
Cardiovascular diseases (CVD) are the leading cause of death worldwide and the incidence remains increasing lately in developing countries [1]. Oxidative stress is the major and independent risk factor of CVD. It can lead to endothelial dysfunction, which triggers the depletion of endothelial nitric oxide synthase (eNOS) and vascular constriction leading to the development of atherosclerosis. Oxidative stress, manifested as an overproduction of reactive oxygen species (ROS), plays a central role in mediating various signaling pathways contributing to vascular inflammation from the early stage of the accumulation of fatty streaks to ultimate plaque rupture [2]. Other traditional risk factors of CVD such as smoke, aging, and arterial hypertension contribute to the oxidative damage to cellular macromolecules such as DNA, lipids, and proteins and endothelial dysfunction [3]. Us, oxidative stress remains an important therapeutic target for cardiovascular diseases, in the early stage of atherosclerosis. Nutraceuticals that are rich in antioxidant components have been shown to be beneficial to lower the burden of oxidative stress in CVD [4]
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