Thymoquinone and Melatonin Boost Both Sirt1 and Nrf2 Activities in a Complementary Way – A Strategy for Controlling Oxidative Stress and Inflammation

Abstract

The oil of black cumin seed (Nigella sativa) has been employed therapeutically in Asian traditional medicine, and rodent studies with it or its most prominent and intriguing component, thymoquinone, suggest that it may indeed have the potential to provide benefit in a wide range of pathologies. There is reason to suspect that thymoquinone’s versatile utility may reflect, in large part, its ability to boost the activity of the sirtuin 1 (Sirt1) deacetylase while concurrently activating the Nrf2 transcription factor. Increased Sirt1 activity promotes autophagy, mitochondrial biogenesis, and FOXO-mediated expression of antioxidant enzymes, while suppressing NF-kappaB-mediated inflammatory signaling; Nrf2 promotes expression of a wide range of antioxidant enzymes, as well as the enzyme rate limiting for glutathione synthesis. Thymoquinone is a substrate for NAD(P)H quinone oxidoreductase 1 (NQO1); this reaction gives rise to NAD+ - obligate substrate for Sirt1 activity – while generating thymohydroquinone, a potent scavenging antioxidant. Thymoquinone, which is electrophilic, promotes Nrf2 activation through covalent reaction with its functional inhibitor Keap1. We suggest that supplemental melatonin may be an ideal complement to thymoquinone, as it can promote increased expression of both Sirt1and Nrf2 – likely via activation of the “clock” transcription factor Bmal1 – whereas thymoquinone boosts the biological activities of the pre-formed proteins.