Review Reports

Round 1

Reviewer 1 Report

This is a rigorous and comprehensive revew article on a timely topic from lead experts in the field. The manuscript reads well and provide a very nice summary for the intrested reader. It rarely happens to me, but this time I support publication as is.

Author Response

We thank Reviewer 1 for his/her very positive comments and for the time taken to read our manuscript.  

 

Reviewer 2 Report

Due to its role as a physiologic membrane-permeable signal transmitter molecule in mammalian tissues, hydrogen sulfide has received considerable attention in the recent past. This review focuses on the (bio)chemistry of hydrogen sulfide and persulfides. In this respect, this is a well done and comprehensive review. In the style of a chemical compendium, it lists virtually all (bio)chemical parameters of the most relevant (redox) reactions involving hydrogen sulfide and biological relevant reactive species, including reaction schemes, dissociation constants, redox potentials, rate constants, and so on. It further discusses the biological sources of hydrogen sulfide and persulfide, cellular concentrations,  detoxification and the (protein) modifications catalyzed by these molecules. For the expert in the field, this work represents a valuable source for all biochemical parameters and it would indeed be excellent if one could find these data compiled together into a single source of reference.

Due to its focus on biochemistry, the recent findings concerning the physiology and the biological relevance of hydrogen sulfide are treated only briefly and are not explicitly discussed. From this point of view, this review is likely of only limited interest for the general reader of ARS.  Yet, the reference section is comprehensive, balanced and up-to-date so that this review may also serve as an excellent starting point for those readers that are interested more in the physiology of hydrogen sulfide than in its biochemistry.

Author Response

We thank Reviewer 2 for his/her very positive comments and for the time taken to read our manuscript. We appreciate the constructive criticism. We have revised our manuscript to expand the “Physiology and pharmacology of H₂S” section. Since covering general physiological implications of H₂S would be beyond the scope of the manuscript, we have put the focus on antioxidant effects. The new section incorporates four more references and now reads:

3.3. Physiology and pharmacology of H₂S

Although early studies indicated that physiological concentrations of H₂S in different tissues were in the 30-100 µM range, improved detection methods suggest that actual concentrations are in the 4-55 nM range for most tissues [63–66].

Externally added H₂S at higher concentrations has been observed to have different effects. In the cardiovascular system H₂S has multiple nitric oxide-dependent and independent effects that include relaxation of smooth muscle cells and regulation of blood pressure, promotion of angiogenesis and attenuation of myocardial ischemia reperfusion injury [19,67–72]. In the nervous system H₂S is considered to be a neuromodulator. For example, it affects hippocampal long-term potentiation [18]. It has also been shown to inhibit HOCl- and peroxynitrite-mediated toxicity in neuronal cells [21,23]. Moreover, H₂S protects neurons from oxidative stress by increasing γ-glutamylcysteine synthetase activity and cystine transport, which induces the production of reduced glutathione [22]. In the respiratory system H₂S has potential therapeutic uses against fibrosis and chronic obstructive pulmonary disease [73,74]. In the liver, a hepatoprotective effect of H₂S has been observed against ethanol-induced liver injury in mice [75].

H₂S has shown both pro- and anti-inflammatory effects. In sepsis and acute pancreatitis a pro-inflammatory effect of H₂S has been observed [76–78], whereas an anti-inflammatory effect has been reported for intestinal ischemic damage and ethanol-induced gastritis [79–81].

The antioxidant effects cannot be attributed to direct reactions with oxidants since, from a kinetic perspective, H₂S may not be able to trap oxidative species, as rationalized below. The indirect mechanisms underlying the observed antioxidant effects may be various. For example, H₂S was proposed to inhibit oxidative stress through persulfidation of Keap1, which activates Nrf2 signaling and promotes its translocation to the nucleus and the expression of antioxidant pathways [75,82–85].

Reviewer 3 Report

A very informative review that should be useful for all that work in this field. Highly recommended.

Author Response

We thank Reviewer 3 for his/her very positive comments and for the time taken to read our manuscript.