Emerging pharmacological tools to control hydrogen sulfide signaling in critical illness

Abstract

Hydrogen sulfide (H 2 S) has long been known as a toxic environmental hazard. Discovery of physiological roles of H 2 S as a neurotransmitter by Kimura and colleagues triggered an intensive research in the biological roles of H 2 S in the past decades. Manipulation of H 2 S levels by inhibiting H 2 S synthesis or administration of H 2 S-releasing molecules revealed beneficial as well as harmful effects of H 2 S. As a result, it is now established that H 2 S levels are tightly controlled and too much or too little H 2 S levels cause harm. Nonetheless, translation of sulfide-based therapy to clinical practice has been stymied due to the very low therapeutic index of sulfide and the incomplete understanding of endogenous sulfide metabolism. One potential strategy to circumvent this problem is to use a safe and stable sulfide metabolite that may mediate effects of H 2 S. Alternatively, endogenous sulfide levels may be controlled using specific sulfide scavengers. In this review article, the role of endogenous H 2 S production and catabolism will be briefly reviewed followed by an introduction of thiosulfate and H 2 S scavengers as novel pharmacological tools to control H 2 S-dependent signaling.

Green tea polyphenolic antioxidants oxidize hydrogen sulfide to thiosulfate and polysulfides: A possible new mechanism underpinning their biological action

“…In summary, the experimental results of our current study suggest that green tea consumption is associated with the production of thiosulfate and polysulfides, which - in the presence of oxygen - are formed via catalytic reaction with the ubiquitous cellular signaling molecule H 2 S. Thiosulfate itself has been demonstrated to have cytoprotective effects via modulating sulfide levels in vivo [ 71 , 85 ], whereas persulfides and polysulfides have a variety of unique redox-modulating properties we are just beginning to unravel [ 49 ]. The series of non-enzymatic reactions of green tea catechins with H 2 S described in the current work bears an uncanny resemblance to the oxidative enzymatic removal of H 2 S in mammalian and invertebrate mitochondria, where sulfide:oxidoreductase converts sulfide to persulfides and transfers the electrons to the ubiquinone pool, a sulfur dioxygenase subsequently oxidizes one persulfide to sulfite, and a sulfur transferase facilitates the reaction of the second persulfide with sulfite to form thiosulfate [ 86 ].…”

Importance of antiviral H₂S in treatment protocols for COVID-19

“…Produced in mammalian tissues, H 2 S acts as biological mediator and signals many important physiological processes in humans. Figure 1 streamlines clearly the sulphur redox reactions [9]. They used enzyme blocking, donor H 2 S and knock-out models and they reduced the viral replication and chemokine secretion by modulation of transcription factors nuclear factor (NF)-κB and the interferon regulatory factor (IRF)-3.…”

The Interaction of the Endogenous Hydrogen Sulfide and Oxytocin Systems in Fluid Regulation and the Cardiovascular System

“…Non-enzymatic H 2 S generation can take place during hypoxic events, for example, via thiosulfate utilization. Thiosulfate is an oxidation product of H 2 S, which is part of the stepwise enzymatic sulfide oxidation pathway within the mitochondria and can be reduced, e.g., with glutathione (GSH), to H 2 S [ 8 , 9 ]. Sulfide quinone oxidoreductase (SQR) oxidizes H 2 S to glutathione persulfide (GSSH); that is followed by oxidation of GSSH to sulfite by persulfide dioxygenase (SDO); and finally, sulfite is oxidized to either sulfate by sulfite oxidase (SO) or to thiosulfate by rhodanese.…”