ABSTRACT
Hydropersulfides (RSSH) are oxidized thiol (RSH) derivatives that have been shown to be biologically prevalent with likely important functions (along with other polysulfur compounds). The functional utility of RSSH can be gleaned from their unique chemical properties. That is, RSSH possess chemical reactivity not present in other biologically relevant sulfur species that should allow them to be used in specific ways in biology as effector/signaling molecules. For example, compared to RSH, RSSH are considered to be superior nucleophiles, reductants and metal ligands. Moreover, unlike RSH, RSSH can be either reductants/nucleophiles or oxidants/electrophiles depending on the protonated state. It has also become clear that studies related to the chemical biology and physiology of hydrogen suflide (H2S) must also consider the effects of RSSH (and related polysulfur species) as they are biochemically linked. Herein is a discussion of the relevant chemistry of RSSH that can serve as a basis for understanding how RSSH can be used by cells to, for example, combat stresses and used in signaling. Also, discussed are some current experimental studies regarding the biological activity of RSSH that can be explained by their chemical properties.
Subject(s)
Hydrogen Sulfide , Sulfides , Sulfides/chemistry , Reducing Agents , Oxidation-Reduction , Signal TransductionABSTRACT
Earlier studies revealed the presence of cysteine persulfide (CysSSH) and related polysulfide species in various mammalian tissues. CysSSH has both antioxidant and oxidant properties, modulates redox-dependent signal transduction and has been shown to mitigate oxidative stress. However, its functional relevance in the setting of myocardial ischaemia-reperfusion injury (IRI) remains unknown. The present study was undertaken to (1) study the dynamics of production and consumption of persulfides under normoxic and hypoxic conditions in the heart, and (2) determine whether exogenous administration of the CysSSH donor, cysteine trisulfide (Cys-SSS-Cys) at the onset of reperfusion rescues functional impairment and myocardial damage by interfering with lipid peroxidation. Utilising a well-established ex vivo Langendorff murine model, we here demonstrate that endogenous tissue concentrations of CysSSH are upregulated when oxygen supply is compromised (global myocardial ischaemia) and rapidly restored to baseline levels upon reperfusion, suggestive of active regulation. In a separate set of experiments, exogenous administration of Cys-SSS-Cys for 10 min at the onset of reperfusion was found to decrease malondialdehyde (MDA) concentrations, formation of 4-hydroxynonenal (4-HNE) protein adducts and rescue the heart from injury. Cys-SSS-Cys also restored post-ischaemic cardiac function, improving both coronary flow and left ventricular developed pressure (LVDP). Taken together, these results support the notion that endogenous CysSSH plays an important role as a "redox preconditioning" agent to combat the oxidative insult in myocardial IRI.
Subject(s)
Ischemic Preconditioning, Myocardial , Ischemic Preconditioning , Myocardial Reperfusion Injury , Mice , Animals , Myocardial Reperfusion Injury/prevention & control , Myocardial Reperfusion Injury/metabolism , Lipid Peroxidation , Cysteine/metabolism , Myocardium/metabolism , Mammals/metabolismABSTRACT
It has become apparent that hydrogen sulfide (H2S), hydropersulfides (RSSH) and other polysulfide species are all intimately linked biochemically. Indeed, at least some of the biological activity attributed to hydrogen sulfide (H2S) may actually be due to its conversion to RSSH and derived polysulfur species (and vice-versa). The unique chemistry associated with the hydropersulfide functional group (-SSH) predicts that it possesses possible protective properties that can help a cell contend with oxidative and/or electrophilic stress. However, since RSSH and polysulfides possess chemical properties akin to disulfides (RSSR), they can also be sources of oxidative/electrophilic stress/signaling as well. Herein are discussed the unique chemistry, possible biochemistry and the physiological implications of RSSH (and polysulfides), especially as it pertains to their putative cellular protection properties against a variety of stresses and/or as possible stressors/signaling agents themselves.
ABSTRACT
S-Nitrosothiol (RS-NO) generation/levels have been implicated as being important to numerous physiological and pathophysiological processes. As such, the mechanism(s) of their generation and degradation are important factors in determining their biological activity. Along with the effects on the activity of thiol proteins, RS-NOs have also been reported to be reservoirs or storage forms of nitric oxide (NO). That is, it is hypothesized that NO can be released from RS-NO at opportune times to, for example, regulate vascular tone. However, to date there are few established mechanisms that can account for facile NO release from RS-NO. Recent discovery of the biological formation and prevalence of hydropersulfides (RSSH) and their subsequent reaction with RS-NO species provides a possible route for NO release from RS-NO. Herein, it is found that RSSH is capable of reacting with RS-NO to liberate NO and that the analogous reaction using RSH is not nearly as proficient in generating NO. Moreover, computational results support the prevalence of this reaction over other possible competing processes. Finally, results of biological studies of NO-mediated vasorelaxation are consistent with the idea that RS-NO species can be degraded by RSSH to release NO.
Subject(s)
Nitric Oxide , S-Nitrosothiols , Nitric Oxide/metabolism , Proteins/metabolism , Sulfhydryl CompoundsABSTRACT
S-Nitrosothiol (RS-NO) formation in proteins and peptides have been implicated as factors in the etiology of many diseases and as possible regulators of thiol protein function. They have also been proposed as possible storage forms of nitric oxide (NO). However, despite their proposed functions/roles, there appears to be little consensus regarding the physiological mechanisms of RS-NO formation and degradation. Hydropersulfides (RSSH) have recently been discovered as endogenously generated species with unique reactivity. One important reaction of RSSH is with RS-NO, which leads to the degradation of RS-NO as well as the release of NO. Thus, it can be speculated that RSSH can be a factor in the regulation of steady-state RS-NO levels, and therefore may be important in RS-NO (patho)physiology. Moreover, RSSH-mediated NO release from RS-NO may be a possible mechanism allowing RS-NO to serve as a storage form of NO.
ABSTRACT
Significance: Hydrogen sulfide (H2S) is reported to be an important mediator involved in numerous physiological processes. H2S and hydropersulfides (RSSH) species are intimately linked biochemically. Therefore, interest in the mechanisms of the biological activity of H2S has led to investigations of the chemical biology of RSSH since they are likely to coexist in a biological system. Currently it is hypothesized that RSSH may be responsible for a least part of the observed H2S-mediated biology/physiology. Recent Advances: It has been recently touted that thiols (RSH) and RSSH have some important differences in terms of their chemical biology and that the generation of RSSH from RSH is purposeful to exploit these chemical differences as a response to a physiological or biological stress. This transformation may represent an unappreciated/unrecognized biological mechanism for dealing with cellular stresses. Critical Issues: Although recent studies indicate a diverse and potentially important chemical biology associated with RSSH species, these ideas have their foundations in early studies (some over 60 years old). It is vital to recognize the nature of this early work to fully appreciate the current ideas regarding RSSH biology. Importantly, these early studies were performed before the realization of purposeful H2S biosynthesis (before 1996). Future Directions: Taking clues from the past studies of RSSH chemistry and biology, progress in delineating the chemical biology of RSSH will continue. Determination of the possible relevance of RSSH chemical biology to signaling and cellular physiology will be a primary focus of many future studies. Antioxid. Redox Signal. 36, 244-255.
Subject(s)
Hydrogen Sulfide , Sulfides , Oxidation-Reduction , Signal Transduction , Sulfhydryl CompoundsABSTRACT
Sulfides and persulfides/polysulfides (R-Sn-R', n > 2; R-Sn-H, n > 1) are endogenously produced metabolites that are abundant in mammalian and human cells and tissues. The most typical persulfides that are widely distributed among different organisms include various reactive persulfides-low-molecular-weight thiol compounds such as cysteine hydropersulfide, glutathione hydropersulfide, and glutathione trisulfide as well as protein-bound thiols. These species are generally more redox-active than are other simple thiols and disulfides. Although hydrogen sulfide (H2S) has been suggested for years to be a small signaling molecule, it is intimately linked biochemically to persulfides and may actually be more relevant as a marker of functionally active persulfides. Reactive persulfides can act as powerful antioxidants and redox signaling species and are involved in energy metabolism. Recent evidence revealed that cysteinyl-tRNA synthetases (CARSs) act as the principal cysteine persulfide synthases in mammals and contribute significantly to endogenous persulfide/polysulfide production, in addition to being associated with a battery of enzymes including cystathionine ß-synthase, cystathionine γ-lyase, and 3-mercaptopyruvate sulfurtransferase, which have been described as H2S-producing enzymes. The reactive sulfur metabolites including persulfides/polysulfides derived from CARS2, a mitochondrial isoform of CARS, also mediate not only mitochondrial biogenesis and bioenergetics but also anti-inflammatory and immunomodulatory functions. The physiological roles of persulfides, their biosynthetic pathways, and their pathophysiology in various diseases are not fully understood, however. Developing basic and high precision techniques and methods for the detection, characterization, and quantitation of sulfides and persulfides is therefore of great importance so as to thoroughly understand and clarify the exact functions and roles of these species in cells and in vivo.
Subject(s)
Chemistry Techniques, Analytical/methods , Hydrogen Sulfide/analysis , Sulfides/analysis , Animals , Cell Line , Humans , Hydrogen Sulfide/metabolism , Protein Processing, Post-Translational , Proteins/analysis , Proteins/chemistry , Proteomics/methods , Sulfides/metabolismABSTRACT
The recent report by Fan et al alleged that the ProPerDP method is inadequate for the detection of protein persulfidation. Upon careful evaluation of their work, we conclude that the claim made by Fan et al is not supported by their data, rather founded in methodological shortcomings. It is understood that the ProPerDP method generates a mixture of cysteine-containing and non-cysteine-containing peptides. Instead, Fan et al suggested that the detection of non-cysteine-containing peptides indicates nonspecific alkylation at noncysteine residues. However, if true, then such peptides would not be released by reduction and therefore not appear as products in the reported workflow. Moreover, the authors' biological assessment of ProPerDP using Escherichia coli mutants was based on assumptions that have not been confirmed by other methods. We conclude that Fan et al did not rigorously assess the method and that ProPerDP remains a reliable approach for analyses of protein per/polysulfidation.
ABSTRACT
The hydropersulfide (RSSH) functional group has received significant recent interest due to its unique chemical properties that set it apart from other biological species. The chemistry of RSSH predicts that one possible biological role may be as a protectant against cellular oxidative and electrophilic stress. That is, RSSH has reducing and nucleophilic properties that may combat the potentially destructive biochemistry of toxicologically relevant oxidants and electrophiles. However, there are currently numerous other molecules that have established roles in this regard. For example, ascorbate and tocopherols are potent antioxidants that quench deleterious oxidative reactions and glutathione (GSH) is a well-established and highly prevalent biological protectant against electrophile toxicity. Thus, in order to begin to understand the possible role of RSSH species as protectants against oxidative/electrophilic stress, the inherent chemical properties of RSSH versus these other protectants will be discussed and contrasted.
Subject(s)
Antioxidants/physiology , Oxidative Stress/physiology , Sulfides/metabolism , Animals , Antioxidants/chemistry , Ascorbic Acid/chemistry , Ascorbic Acid/physiology , Glutathione/chemistry , Glutathione/physiology , Humans , Hydrogen Sulfide/chemistry , Hydrogen Sulfide/metabolism , Nitric Oxide/chemistry , Nitric Oxide/physiology , Oxidation-Reduction , Sulfides/chemistryABSTRACT
Hydropersulfides are reported to be good biological reductants, superior to thiols and akin to selenols. As such, they have been previously shown to reduce metalloproteins such as ferric myoglobin and ferric cytochrome c to their ferrous forms under conditions where little or no reduction from corresponding thiols is observed. Not surprisingly, the reduction of ferric myoglobin to ferrous myoglobin under aerobic conditions results in the generation of oxymyoglobin (dioxygen bound ferrous myoglobin). Previous studies have demonstrated that oxymyoglobin can also act as an oxidant with highly reducing species such as hydroxylamine and ascorbate. Considering the reducing properties of hydropersulfides, it is possible that they can also react with oxymyoglobin similarly to hydroxylamine or ascorbate. Herein, this reaction is examined and indeed hydropersulfides are found to react with oxymyoglobin similarly to other reducing species leading to a fleeting ferric myoglobin which is rapidly reduced to the ferrous form also by hydropersulfide.
Subject(s)
Myoglobin/chemistry , Sulfides/chemistry , Animals , Ascorbic Acid/chemistry , Cattle , Horses , Hydroxylamine/chemistry , Models, Chemical , Oxidation-Reduction , Oxygen/chemistry , Penicillamine/analogs & derivativesABSTRACT
Significance: Hydropersulfides (RSSH) and related polysulfide species (RSnR, n > 2, R = alkyl, H) are highly biologically prevalent with likely important physiological functions. Due to their prevalence, many labs have begun to investigate their possible roles, especially with regards to their protective, redox, and signaling properties. Recent Advances: A significant amount of work has been performed while delineating the chemical reactivity/chemical properties of hydropersulfides, and it is clear that their overall chemistry is distinct from all other biologically relevant sulfur species (e.g., thiols, disulfides, sulfenic acids, etc.). Critical Issues: One way to predict and ultimately understand the biological functions of hydropersulfides is to focus on their unique chemistry, which should provide the rationale for why this unique functionality is present. Interestingly, some of the chemical properties of RSSH are strikingly similar to those of selenols (RSeH). Therefore, it may be important to consider the known functions of selenoproteins when speculating about the possible functions of RSSH species. Future Directions: Currently, many of the inherent chemical differences between hydropersulfides and other biological sulfur species have been established. It remains to be determined, however, whether and how these differences are utilized to accomplish specific biochemical/physiological goals. A significant aspect of elucidating the biological utility of hydropersulfides will be to determine the mechanisms of regulation of their formation and/or biosynthesis, that is, based on whether it can be determined under what cellular conditions hydropersulfides are made, more meaningful speculation regarding their functions/roles can be developed.
Subject(s)
Selenium Compounds/chemistry , Sulfides/chemistry , Oxidation-Reduction , Selenium Compounds/metabolism , Signal Transduction , Sulfhydryl Compounds/chemistry , Sulfides/metabolismABSTRACT
Hydropersulfide and polysulfide species have recently been shown to elicit a wide variety of biological and physiological responses. In this study, we examine the effects of cysteine trisulfide (Cys-SSS-Cys; also known as thiocystine) treatment on E. coli. Previous studies in mammalian cells have shown that Cys-SSS-Cys treatment results in protection from the electrophiles. Here, we show that the protective effect of Cys-SSS-Cys treatment against electrophile-induced cell death is conserved in E. coli. This protection correlates with the rapid generation of cysteine hydropersulfide (Cys-SSH) in the culture media. We go on to demonstrate that an exogenous phosphatase expressed in E. coli, containing only a single catalytic cysteine, is protected from electrophile-induced inactivation in the presence of hydropersulfides. These data together demonstrate that E. coli can utilize Cys-SSS-Cys to generate Cys-SSH and that the Cys-SSH can protect cellular thiols from reactivity with the electrophiles.
Subject(s)
Cystine/pharmacology , Escherichia coli/drug effects , Microbial Viability/drug effects , Sulfides/pharmacology , Cystine/analogs & derivatives , Cystine/chemistry , Escherichia coli/cytology , Escherichia coli/metabolism , Sulfides/chemistry , Sulfides/metabolismABSTRACT
Hydrogen sulfide and related/derived persulfides (RSnH, RSSnR, n > 1) have been the subject of recent research interest because of their reported physiological signaling roles. In spite of their described actions, the chemical/biochemical mechanisms of activity have not been established. From a chemical perspective, it is likely that metals and metalloproteins are possible biological targets for the actions of these species. Thus, the chemical biology of hydrogen sulfide and persulfides with metals and metalloproteins will be discussed as a prelude to future speculation regarding their physiological function and utility.
Subject(s)
Hydrogen Sulfide/chemistry , Metalloproteins/chemistry , Metals/chemistry , Sulfides/chemistry , Clostridium , Electron Transport Complex IV/chemistry , Free Radicals/chemistry , Hemeproteins/chemistry , Hydrogen Sulfide/metabolism , Metalloproteins/metabolism , Metals/metabolism , Mitochondria/metabolism , Mitochondria/ultrastructure , Oxidation-Reduction , Protein Binding , Signal Transduction , Sulfhydryl Compounds/chemistry , Sulfides/metabolismABSTRACT
We previously reported that 9,10-phenanthraquinone (9,10-PQ), an atmospheric electron acceptor, undergoes redox cycling with dithiols as electron donors, resulting in the formation of semiquinone radicals and monothiyl radicals; however, monothiols have little reactivity. Because persulfide and polysulfide species are highly reducing, we speculate that 9,10-PQ might undergo one-electron reduction with these reactive sulfides. In the present study, we explored the redox cycling capability of a variety of quinone-related electron acceptors, including 9,10-PQ, during interactions with the hydropersulfide Na2S2 and its related polysulfides. No reaction occurred when 9,10-PQ was incubated with Na2S; however, when 5 µM 9,10-PQ was incubated with either 250 µM Na2S2 or Na2S4, we detected extensive consumption of dissolved oxygen (84 µM). Under these conditions, both the semiquinone radicals of 9,10-PQ and their thiyl radical species were also detected using ESR, suggesting that a redox cycle reaction occurred utilizing one-electron reduction processes. Notably, the perthiyl radicals remained stable even under aerobic conditions. Similar phenomenon has also been observed with other electron acceptors, such as pyrroloquinoline quinone, vitamin K3, and coenzyme Q10. Our experiments with N-methoxycarbonyl penicillamine persulfide (MCPSSH), a precursor for endogenous cysteine persulfide, suggested the possibility of a redox coupling reaction with 9,10-PQ inside cells. Our study indicates that hydropersulfide and its related polysulfides are efficient electron donors that interact with quinones. Redox coupling reactions between quinoid electron acceptors and such highly reactive thiols might occur in biological systems.
Subject(s)
Electrons , Phenanthrenes/metabolism , Sulfides/metabolism , Humans , Molecular Structure , Oxidation-Reduction , Phenanthrenes/chemistry , Sulfides/chemistry , Tumor Cells, CulturedABSTRACT
The physiological importance of reactive sulfur species (RSS) such as cysteine hydropersulfide (CysSSH) has been increasingly recognized in recent years. We have established a reactive sulfur metabolomics analysis by using RSS metabolic profiling, which revealed appreciable amounts of RSS generated endogenously and ubiquitously in both prokaryotic and eukaryotic organisms. The chemical nature of these polysulfides is not fully understood, however, because of their reactive or complicated redox-active properties. In our study here, we determined that tyrosine and a hydroxyphenyl-containing derivative, ß-(4-hydroxyphenyl)ethyl iodoacetamide (HPE-IAM), had potent stabilizing effects on diverse polysulfide residues formed in CysSSH-related low-molecular-weight species, e.g., glutathione polysulfides (oxidized glutathione trisulfide and oxidized glutathione tetrasulfide). The protective effect against degradation was likely caused by the inhibitory activity of hydroxyphenyl residues of tyrosine and HPE-IAM against alkaline hydrolysis of polysulfides. This hydrolysis occurred via heterolytic scission triggered by the hydroxyl anion acting on polysulfides that are cleaved into thiolates and sulfenic acids, with the hydrolysis being enhanced by alkylating reagents (e.g. IAM) and dimedone. Moreover, tyrosine prevented electrophilic degradation occurring in alkaline pH. The polysulfide stabilization induced by tyrosine or the hydroxyphenyl moiety of HPE-IAM will greatly improve our understanding of the chemical properties of polysulfides and may benefit the sulfur metabolomics analysis if it can be applied successfully to any kind of biological samples, including clinical specimens.
Subject(s)
Metabolome , Metabolomics , Sulfides/metabolism , Sulfur/metabolism , Tyrosine/metabolism , Chromatography, Liquid , Glutathione/analogs & derivatives , Glutathione/metabolism , Humans , Metabolomics/methods , Oxidation-Reduction , Reactive Oxygen Species/metabolism , Signal Transduction , Tandem Mass SpectrometryABSTRACT
Hydropersulfides and related polysulfides have recently become topics of significant interest due to their physiological prevalence and proposed biological functions. Currently, examination of the effects of hydropersulfide treatment on cells is difficult due to their lack of inherent stability with respect to disproportionation. Herein, it is reported that the treatment of a variety of cell types with cysteine trisulfide (also known as thiocystine; Cys-SSS-Cys), results in an increase in intracellular hydropersulfide levels (e.g., cysteine hydropersulfide; Cys-SSH, and glutathione hydropersulfide; GSSH). Thus, Cys-SSS-Cys represents a possible pharmacological agent for examining the effects of hydropersulfides on cell function/viability. It has also been found that cells with increased intracellular hydropersulfide levels can export Cys-SSH into the extracellular media. Interestingly, the Cys-SSH is the major hydropersulfide exported by cells, although GSSH is the predominant intracellular species. The possible implications of cellular export are discussed.
Subject(s)
Cysteine/metabolism , Cysteine/toxicity , Sulfides/metabolism , Sulfides/toxicity , 3T3 Cells , Animals , Cell Line , Cell Survival/drug effects , Cysteine/chemistry , Humans , Mice , Molecular Structure , Sulfides/chemistry , Tetrazolium Salts/pharmacologyABSTRACT
BACKGROUND AND PURPOSE: Posttranslational modifications of cysteine residues represent a major aspect of redox biology, and their reliable detection is key in providing mechanistic insights. The metastable character of these modifications and cell lysis-induced artifactual oxidation render current state-of-the-art protocols to rely on alkylation-based stabilization of labile cysteine derivatives before cell/tissue rupture. An untested assumption in these procedures is that for all cysteine derivatives, alkylation rates are faster than their dynamic interchange. However, when the interconversion of cysteine derivatives is not rate limiting, electrophilic labelling is under Curtin-Hammett control; hence, the final alkylated mixture may not represent the speciation that prevailed before alkylation. EXPERIMENTAL APPROACH: Buffered aqueous solutions of inorganic, organic, cysteine, GSH and GAPDH polysulfide species were used. Additional experiments in human plasma and serum revealed that monobromobimane can extract sulfide from the endogenous sulfur pool by shifting speciation equilibria, suggesting caution should be exercised when interpreting experimental results using this tool. KEY RESULTS: In the majority of cases, the speciation of alkylated polysulfide/thiol derivatives depended on the experimental conditions. Alkylation perturbed sulfur speciation in both a concentration- and time-dependent manner and strong alkylating agents cleaved polysulfur chains. Moreover, the labelling of sulfenic acids with dimedone also affected cysteine speciation, suggesting that part of the endogenous pool of products previously believed to represent sulfenic acid species may represent polysulfides. CONCLUSIONS AND IMPLICATIONS: We highlight methodological caveats potentially arising from these pitfalls and conclude that current derivatization strategies often fail to adequately capture physiological speciation of sulfur species. LINKED ARTICLES: This article is part of a themed section on Chemical Biology of Reactive Sulfur Species. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.4/issuetoc.
Subject(s)
Alkylating Agents/chemistry , Sulfur Compounds/chemistry , Adult , Humans , Iodoacetamide/chemistry , Maleimides/chemistry , Methyl Methanesulfonate/analogs & derivatives , Methyl Methanesulfonate/chemistry , Sulfur Compounds/analysis , Sulfur Compounds/bloodABSTRACT
BACKGROUND AND PURPOSE: The signalling associated with hydrogen sulfide (H2 S) remains to be established, and recent studies have alluded to the possibility that H2 S-derived species play important roles. Of particular interest are hydropersulfides (RSSH) and related polysulfides (RSSn R, n > 1). This work elucidates the fundamental chemical relationship between these sulfur species as well as examines their biological effects. EXPERIMENTAL APPROACH: Using standard analytical techniques (1 H-NMR and MS), the equilibrium reactions between H2 S, disulfides (RSSR), RSSH, dialkyltrisulfides (RSSSR) and thiols (RSH) were examined. Their ability to protect cells from electrophilic and/or oxidative stress was also examined using cell culture. KEY RESULTS: H2 S, RSSR, RSSH, RSSSR and RSH are all in a dynamic equilibrium. In a biological system, these species can exist simultaneously, and thus, it is difficult to discern which species is (are) the biological effector(s). Treatment of cells with the dialkyl trisulfide cysteine trisulfide (Cys-SSS-Cys) resulted in high intracellular levels of hydropersulfides and protection from electrophilic stress. CONCLUSIONS AND IMPLICATIONS: In aqueous systems, the reaction between H2 S and RSSR results in the formation of equilibria whereby H2 S, RSH, RSSR, RSSH and RSSSR are present. In a biological system, any of these species can be responsible for the observed biological activity. These equilibrium species can also be generated via the reaction of RSH with RSSSR. Due to these equilibria, Cys-SSS-Cys can be a method for generating any of the other species. Importantly, HEK293T cells treated with Cys-SSS-Cys results in increased levels of hydropersulfides, allowing examination of the biological effects of RSSH. LINKED ARTICLES: This article is part of a themed section on Chemical Biology of Reactive Sulfur Species. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.4/issuetoc.
Subject(s)
Sulfides/chemistry , Cell Survival/drug effects , HEK293 Cells , Humans , Sulfides/pharmacologyABSTRACT
Due to the excitement surrounding the discovery of NO as an endogenously generated signalling molecule, a number of other nitrogen oxides were also investigated as possible physiological mediators. Among these was nitroxyl (HNO). Over the past 25 years or so, a significant amount of work by this laboratory and many others has disclosed that HNO possesses unique chemical properties and important pharmacological utility. Indeed, the pharmacological potential for HNO as a treatment for heart failure, among other uses, has garnered this curious molecule a considerable amount of recent attention. This review summarizes the events that led to this recent attention as well as poses important questions that are still to be answered with regards to understanding the chemistry and biology of HNO. LINKED ARTICLES: This article is part of a themed section on Nitric Oxide 20 Years from the 1998 Nobel Prize. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.2/issuetoc.