Abstract
Oxidative stress has been implicated in pathophysiology of different human stress- and age-associated disorders, including osteoporosis for which antioxidants could be considered as therapeutic remedies as was suggested recently. The 1,4-dihydropyridine (DHP) derivatives are known for their pleiotropic activity, with some also acting as antioxidants. To find compounds with potential antioxidative activity, a group of 27 structurally diverse DHPs, as well as one pyridine compound, were studied. A group of 11 DHPs with 10-fold higher antioxidative potential than of uric acid, were further tested in cell model of human osteoblast-like cells. Short-term combined effects of DHPs and 50 µM H2O2 (1-h each), revealed better antioxidative potential of DHPs if administered before a stressor. Indirect 24-h effect of DHPs was evaluated in cells further exposed to mild oxidative stress conditions induced either by H2O2 or tert-butyl hydroperoxide (both 50 µM). Cell growth (viability and proliferation), generation of ROS and intracellular glutathione concentration were evaluated. The promotion of cell growth was highly dependent on the concentrations of DHPs used, type of stressor applied and treatment set-up. Thiocarbatone III-1, E2-134-1 III-4, Carbatone II-1, AV-153 IV-1, and Diethone I could be considered as therapeutic agents for osteoporosis although further research is needed to elucidate their bioactivity mechanisms, in particular in respect to signaling pathways involving 4-hydroxynoneal and related second messengers of free radicals.
Highlights
Oxidative stress, defined as an imbalance between pro-oxidants and antioxidants in the favor of the former [1], has been implicated in the pathogenesis of numerous stress- and age-associated diseases, whether as a cause or as a consequence of respective illness progression [2]
The DHPs with pronounced antioxidative capacities were selected for the treatment of human osteoblast-like cells (HOS)
The same stands for the observed differential effects of DHPs in respect to their direct pro- and anti-oxidative capacities (TOC/Total Antioxidative Capacity (TAC) assays based on hydrogen peroxide/peroxidase activity principle) vs. influence of DHPs on intracellular production of reactive oxygen species (ROS), which is dependent on cellular oxidative homeostasis affecting viability and mitochondrial stability of the cells
Summary
Oxidative stress, defined as an imbalance between pro-oxidants and antioxidants in the favor of the former [1], has been implicated in the pathogenesis of numerous stress- and age-associated diseases, whether as a cause or as a consequence of respective illness progression [2]. The consensus among researchers in this field highlights the need of its better understanding as well as balancing oxidative homeostasis to the levels that promote health [3]. Antioxidants 2018, 7, 123 with antioxidative properties are important for reducing the detrimental levels of reactive oxygen species (ROS). The importance of ROS-related redox signaling in normal cellular maintenance should not be neglected, nor the fact that antioxidative and/or pro-oxidative activity are in the background of (un)desirable activities of many drugs and physiologically active compounds [3,4,5]. Studies revealing bioactivities of natural antioxidants are complemented by scientific efforts aiming to synthetize new bioactive substances with antioxidant features that could help maintaining oxidative homeostasis of the living cells.
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