Significance: An abundance of experimental evidence suggests that hydrogen sulfide (H(2)S) plays a prominent role in physiology and pathophysiology. Many targets exist for H(2)S therapy. The molecular targets of H(2)S include proteins, enzymes, transcription factors, and membrane ion channels.
Recent advances: Novel H(2)S precursors are being synthesized and discovered that are capable of releasing H(2)S in a slow and sustained manner. This presents a novel and advantageous approach to H(2)S therapy for treatment of chronic conditions associated with a decline in endogenous H(2)S, such as diabetes and cardiovascular disease.
Critical issues: While H(2)S is cytoprotective at physiological concentrations, it is not universally cytoprotective, as it appears to have pro-apoptotic actions in cancer cells and is well known to be toxic at supraphysiological concentrations. Many of the pleiotropic effects of H(2)S on health are associated with the inhibition of inflammation and upregulation of prosurvival pathways. The powerful anti-inflammatory, cytoprotective, immunomodulating, and trophic effects of H(2)S on the vast majority of normal cells seem to be mediated mainly by its actions as an extremely versatile direct and indirect antioxidant and free radical scavenger. While the overall effects of H(2)S on transformed (i.e., malignant) cells can be characterized as pro-oxidant and pro-apoptotic, they contrast sharply with the cytoprotective effects on most normal cells.
Future directions: H(2)S has become a molecule of great interest, and several slow-releasing H(2)S prodrugs are currently under development. We believe that additional agents regulating H(2)S bioavailability will be developed during the next 10 years.