Hydrogen sulfide: The hidden player of isothiocyanates pharmacology

Hydrogen sulfide (H 2 S) is an endogenous gasotransmitter that exhibits a plethora of beneficial effects in numerous systems (i.e. cardiovascular system and central nervous system). In particular, H 2 S promotes anti-inflammatory, antioxidant, anti-hypertensive, and cardioprotective properties, thus playing a crucial role in maintaining tissue homeostasis. Accordingly, an impairment in the biosynthesis of H 2 S has been described in the etiopathogenesis of many pathological conditions. Therefore, to ensure a "physiological" balance in the endogenous levels of H 2 S through H 2 S-donors represents an intriguing pharmacological strategy to prevent and/or treat several "H 2 S-poor" pathologies. Among H 2 S-releasing moieties, isothiocyanates (ITCs) have been recently recognized as "smart" H 2 S-donors, as they show a long-lasting and thiol-dependent H 2 S release. Accordingly, both natural and synthetic ITCs promote antioxidant, anti-inflammatory, antiviral, cardioprotective, anticancer, and anti-nociceptive properties. This impressive overlap in the effects exhibited by H 2 S and ITCs also helps for an understanding of their mechanism of action, as they modulate the same intracellular signaling pathways mainly through S-sulfhydration reactions. Finally, both H 2 S and ITCs show a peculiar dualism in their effects, promoting beneficial properties at low concentrations and toxic effects at high doses. This opposite behavior (known as "hormesis") further suggests that H 2 S plays a crucial role in the health-promoting effects of structurally heterogeneous ITCs, "unmasking" the hidden player in the isothiocyanate pharmacology.