The antioxidants role in cell response regulation attracted great interest in the last decades and it is undergoing to a profound reconsideration. The mere concept of "biological antioxidant" has been frequently misconceived or misused, possibly leading to the misinterpretation of some experimental observation. Organosulfur compounds in general and α-lipoic acid, a dithiol molecule, can be considered a typical example of the kind. Reduced α-lipoic acid, dehydrolipoic acid has been in fact originally considered a bona fide, reducing, electron donor molecule. A more recent approach, according to stoichiometric and thermodynamic evidences, lead to a reinterpretation of the biochemical role of "antioxidants". The electrophilic nature of oxidized nucleophilic molecules, including α-lipoic acid, renders more plausible a mechanism based on the ability to activate Nrf2/EpRE mediated hormetic response. In this study, we demonstrate that nmolar concentrations of oxidized α-lipoic acid, but not dehydrolipoic acid, protect human umbilical primary endothelial cells (HUVEC) from TNF-α induced dysfunction, inhibit NF-κB activation and block apoptosis following the activation of Nrf2 transcription factor. Our observations corroborate the concept that the major, if not the unique, mechanism by which α-lipoic acid can non-enzymatically exert its reducing activity is related to the electrophilic nature of the oxidized form.
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