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What are the physiological roles of Hydrogen sulfide?


I am thinking why hydrogen sulfide has its effects in the body. For instance, it is one Salmonella's virulence factor. I am not sure if such a balance equations holds

H2O + H2S ←→…

Actually, I miss here some factors because I am not understanding the biochemistry enough to answer this. I think H2S can exists in some sort of ionic form. Hydrogen sulfide reminds me of ammonia. I think it inhibits some systems. By which mechanisms?

It is mentioned in many places the empirical effects: signaling functions similar to NO and CO. But I am interested in how this happens. What is the rate of adhesion of H2S to hemoglobin for instance?

H2S can change to sulfite and thiosulfate in mitochondria which are then excreted into urine. I think most of the biological effects are done before these forms. But in which forms?


$H_2S$ is the end product of sulfur related respirations (like sulfate respiration, sulfur respiration, etc… ).

By aerob (oxygen) respiration the oxygen in $O_2$ has 0 oxidation number, by $CO_2$ the oxygen has -2 oxidation number, so it was reduced while the carbon was oxidized.

By the thiosulfate respiration of Salmonella enterica the following reaction happens by the reduction of thiosulfate: $S_2O_3^{2-} +2H^+ + 2e^- o HS^- + HSO_3^{-}$. In this case the sulfur in $S_2O_3^{2-}$ has +2 oxidation number while the sulfur in $HS^-$ has -2 oxidation number, so the sulfur was reduced, it was an electron acceptor, just like oxygen by aerob respiration.

So in the case of Salmonella enterica $H_2S$ production is a byproduct of anaerob respiration. It makes growth faster.

Sulfate-reducing bacteria are those bacteria that can obtain energy by oxidizing organic compounds or molecular hydrogen (H2) while reducing sulfate (SO2- 4) to hydrogen sulfide (H2S).1 In a sense, these organisms "breathe" sulfate rather than oxygen in a form of anaerobic respiration.

Salmonella typhimurium produces H2S from thiosulfate or sulfite.

  • 1987 - The phs gene and hydrogen sulfide production by Salmonella typhimurium.

  • 2011 - Thiosulfate Reduction in Salmonella enterica Is Driven by the Proton Motive Force

S. enterica uses gut inflammation to enhance its sulfur related respiration to outgrow the resident microbes in the intestinal lumen (microbiota). The inflammation creates tetrathionate $S_4O_6^{2-}$ in which the sulfur has an average oxidation number of +2.5. This tetrathionate is reduced by the tetrathionate reductase into thiosulfate with sulfur having +2 oxidation number. So sulfur related respiration helps to make growth faster in order to colonize the gut.

Here we show that reactive oxygen species generated during inflammation react with endogenous, luminal sulphur compounds (thiosulphate) to form a new respiratory electron acceptor, tetrathionate. The genes conferring the ability to use tetrathionate as an electron acceptor produce a growth advantage for S. Typhimurium over the competing microbiota in the lumen of the inflamed gut. We conclude that S. Typhimurium virulence factors induce host-driven production of a new electron acceptor that allows the pathogen to use respiration to compete with fermenting gut microbes. Thus the ability to trigger intestinal inflammation is crucial for the biology of this diarrhoeal pathogen.

  • 2010 - Gut inflammation provides a respiratory electron acceptor for Salmonella

  • 2001 - The Alternative Electron Acceptor Tetrathionate Supports B12-Dependent Anaerobic Growth of Salmonella enterica Serovar Typhimurium on Ethanolamine or 1,2-Propanediol

Since $H_2S$ is a gasotransmitter in the human body, there can be other mechanisms which help S. enterica.

  • in small amounts $H_2S$ has anti-inflammatory and anti-apoptotic effects
  • in large amounts $H_2S$ has pro-inflammatory and pro-apoptotic effects

So S. enterica can probably cause inflammation due to killing cells with a fast release of $H_2S$ or prevent inflammation and keep infected cells alive with a slow release of $H_2S$. I found many evidence of the pro-inflammatory theory. By the anti-apoptotic theory I wasn't so lucky, I found only a single review about anti-apoptotic strategies of intracellular pathogens, but it did not mention $H_2S$ production as a possible mechanism. So it might not be true, further studies needed…

In the digestive system, H2S exerts potent anti-inflammatory actions, regulates blood flow and smooth muscle tone, modulates epithelial secretion and promotes healing of ulcers [4, 5].

  • 2012 - Hydrogen Sulfide: A Rescue Molecule for Mucosal Defence and Repair

Hydrogen sulfide (H2S) is the most recent endogenous gasotransmitter that has been reported to serve many physiological and pathological functions in different tissues. Studies over the past decade have revealed that H2S can be synthesized through numerous pathways and its bioavailability regulated through its conversion into different biochemical forms. H2S exerts its biological effects in various manners including redox regulation of protein and small molecular weight thiols, polysulfides, thiosulfate/sulfite, iron-sulfur cluster proteins, and anti-oxidant properties that affect multiple cellular and molecular responses.

Understanding precise pathophysiological signaling mechanisms and the metabolism of H2S is a topic of active research. Unraveling H2S interactions within different tissues, with other biochemical molecules and various signaling mediators is becoming ever more complex.

These results demonstrate that H2S donors can down-regulate adhesion molecule and proinflammatory cytokine expression, therefore identifying H2S, its synthesis enzymes, and molecular targets (e.g., KATP channels) as potential targets for novel anti-inflammatory therapies.

Thus, all of the above findings demonstrate that H2S induces cytoprotection by an anti-apoptotic pathway.

  • 2013 - Hydrogen sulfide chemical biology: Pathophysiological roles and detection

A short course of H2S infusion was associated with reduction of lung and kidney injury. Prolonged infusion did not enhance protection. Systemically, infusion of H2S increased both the pro-inflammatory response during endotoxemia, as demonstrated by increased TNF-α levels, as well as the anti-inflammatory response, as demonstrated by increased IL-10 levels. In LPS-stimulated whole blood of healthy volunteers, co-incubation with H2S had solely anti-inflammatory effects, resulting in decreased TNF-α levels and increased IL-10 levels. Co-incubation with a neutralizing IL-10 antibody partly abrogated the decrease in TNF-α levels. In conclusion, a short course of H2S infusion reduced organ injury during endotoxemia, at least in part via upregulation of IL-10.

  • 2012 - A short course of infusion of a hydrogen sulfide-donor attenuates endotoxemia induced organ injury via stimulation of anti-inflammatory pathways, with no additional protection from prolonged infusion

H2S causes apoptosis in HPSCs by activating the mitochondrial pathway. It is suggested that H2S might be one of the factors modifying the pathogenesis of pulpitis by causing loss of viability of HPSCs through apoptosis.

  • 2011 - Hydrogen Sulfide Causes Apoptosis in Human Pulp Stem Cells

The level ofendogenous H2S was increasing along with the infection occurrence and the gradient of infection aggravate. We can presume that endogenous H2S participated in inflammatory reaction of abdominal infection and could be one of the serology index which concerned with the gradient of infection.

  • 2012 - P53 The level changes and clinical significance of endogenous hydrogen sulfide of patients with acute abdominal infection

The evidences showed that H2S has an obvious effect on colon smooth muscle contraction, and can increase the intestinal movements in slow transmit constipation. Our experiment states that H2S has anti-inflammation effect in prophase of acute peritoneal cavity infection.

  • 2014 - P48 Regulation of hydrogen sulfide in digestive stystem

  • 2010 - Hydrogen Sulfide Improves Neutrophil Migration and Survival in Sepsis via K+ATP Channel Activation

  • 2012 - Hydrogen sulfide and resolution of acute inflammation: A comparative study utilizing a novel fluorescent probe

  • 2008 - Staying alive: bacterial inhibition of apoptosis during infection

H2S is believed to have two contradicting roles in inflammation. It acts as both pro- and anti-inflammatory molecule(9). Li et al. reported that the physiological concentration of H2S has anti-inflammatory effects, while higher concentrations of H2S can produce pro-inflammatory effects(10). The H2S inflammatory role was also studied in different systems. In the gastrointestinal tract, the H2S regulating role functions by activating KATP channels in order to promote the inflammation response(57). The similar H2S function was observed in pancreas(7), but the actual mechanisms are largely unknown. In conclusion, H2S pathway is a possible route for targeting the inflammation treatment. However, much work needs to be done for understanding the mechanisms of the contradictory roles of H2S in inflammation.

  • 2012 - The Crosstalk between H2S and NO Signaling Pathways

  • 2013 - Gasotransmitters, poisons, and antimicrobials: it's a gas, gas, gas!

Developing evidence suggests that dysbiosis (abnormal microbial composition or function) can contribute to if not cause chronic intestinal inflammation. 5,7 This inflammation can be caused either by an abnormal composition of entericbacteria with an elevated ratio of aggressive vs protective species, defective production of short-chain fatty acids and other protective microbial products, or enhanced production of hydrogen sulfide and nitrates that block butyrate metabolism and disrupt the mucosal barrier.

  • 2010 - Inflammation and Nutrition in Chronic Disease

  • 2013 - Potential Role of Hydrogen Sulfide in the Pathogenesis of Vascular Dysfunction in Septic Shock

These results showed that physiological concentrations of H2S can induce apoptosis of PDL cells and HGFs in periodontitis, suggesting that H2S may play an important role in periodontal tissue damage in periodontal diseases.

  • 2009 - Hydrogen sulfide induces apoptosis in human periodontium cells

  • 2010 - Bacteria-derived hydrogen sulfide promotes IL-8 production from epithelial cells

We have shown that inactivation of H2S producing enzymes (cystathionine beta-synthase, cystathionine gamma lyase, or 3-mercaptopyruvate sulfurtransferase) and NO-synthase in several Gram (+) and Gram (−) bacteria render them highly sensitive to different classes of antibiotics (Gusarov et al., Science 325 (2009) 1380-1384; Shatalin et al. Science 334 (2011) 986-990). We also presented evidence that Bacillus anthracis-derived NO is critical at the early stage of infection (Shatalin et al. PNAS 105 (2008) 1009-1013). Here we show that: (1) cbs/cse and nos mutations change Bacilli global gene transcription profile; (2) apore formation process in cbs/cse and nos mutants of B. anthracis is affected; (3) virulence of cbs/cse and nos mutants of B. anthracis is diminished. These results demonstrate that bacterial H2S and NO are an important virulence factors, and that enzymes generated these gases may serve as an attractive target for antimicrobial therapy.

  • 2014 - S7-6 Role of H2S and NO in Bacillus anthracis spore formation and virulence

Btw. there is non-hydrogen sulfide producing S. enterica too, which can probably (no study about this yet) cause salmonellosis. So using thiosulfate as electron acceptor and producing $H_2S$ might not be essential by the infection. (There are other non-sulfur electron acceptors e.g. nitrate, fumarate, etc… for the case of anaerob metabolism.)

  • 2013 - Genetic Analysis of Non-Hydrogen Sulfide-Producing Salmonella enterica Serovar Typhimurium and S. enterica Serovar Infantis Isolates in Japan

  • 2011 - Salmonella enterica Serovar Typhimurium Colonizing the Lumen of the Chicken Intestine Grows Slowly and Upregulates a Unique Set of Virulence and Metabolism Genes

  • 2013 - Salmonella Uses Energy Taxis to Benefit from Intestinal Inflammation

  • 2006 - Role of Gluconeogenesis and the Tricarboxylic Acid Cycle in the Virulence of Salmonella enterica Serovar Typhimurium in BALB/c Mice

  • 1981 - Aerotaxis in Salmonella typhimurium: role of electron transport.

  • 2010 - IDENTIFICATION OF NOVEL VIRULENCE GENES OF SALMONELLA ENTERICA

  • 2014 - Increasing prevalence of hydrogen sulfide negative Salmonella in retail meats

Overall hydrogen-sulfide and other gasotransmitters are important virulence factors of many pathogens.


Alan Boyd's answer

Production of hydrogen sulphide is used as a convenient method for detecting the presence of pathogenic Salmonella, there is nothing to link this with virulence.

which I agree with.


Biological functions of hydrogen sulfide

Hydrogen sulfide is produced in small amounts by some cells of the mammalian body and has a number of biological signaling functions. (Only two other such gases are currently known: nitric oxide (NO) and carbon monoxide (CO).)

The gas is produced from cysteine by the enzymes cystathionine beta-synthase and cystathionine gamma-lyase. It acts as a relaxant of smooth muscle and as a vasodilator [1] and is also active in the brain, where it increases the response of the NMDA receptor and facilitates long term potentiation, [2] which is involved in the formation of memory.

Eventually the gas is converted to sulfite in the mitochondria by thiosulfate reductase, and the sulfite is further oxidized to thiosulfate and sulfate by sulfite oxidase. The sulfates are excreted in the urine. [3]

Due to its effects similar to nitric oxide (without its potential to form peroxides by interacting with superoxide), hydrogen sulfide is now recognized as potentially protecting against cardiovascular disease. [1] The cardioprotective role effect of garlic is caused by catabolism of the polysulfide group in allicin to H
2 S , a reaction that could depend on reduction mediated by glutathione. [4]

Though both nitric oxide (NO) and hydrogen sulfide have been shown to relax blood vessels, their mechanisms of action are different: while NO activates the enzyme guanylyl cyclase, H
2 S activates ATP-sensitive potassium channels in smooth muscle cells. Researchers are not clear how the vessel-relaxing responsibilities are shared between nitric oxide and hydrogen sulfide. However, there exists some evidence to suggest that nitric oxide does most of the vessel-relaxing work in large vessels and hydrogen sulfide is responsible for similar action in smaller blood vessels. [5]

Recent findings suggest strong cellular crosstalk of NO and H
2 S , [6] demonstrating that the vasodilatatory effects of these two gases are mutually dependent. Additionally, H
2 S reacts with intracellular S-nitrosothiols to form the smallest S-nitrosothiol (HSNO), and a role of hydrogen sulfide in controlling the intracellular S-nitrosothiol pool has been suggested. [7]

Like nitric oxide, hydrogen sulfide is involved in the relaxation of smooth muscle that causes erection of the penis, presenting possible new therapy opportunities for erectile dysfunction. [8] [9]

Hydrogen sulfide ( H
2 S ) deficiency can be detrimental to the vascular function after an acute myocardial infarction (AMI). [10] AMIs can lead to cardiac dysfunction through two distinct changes increased oxidative stress via free radical accumulation and decreased NO bioavailability. [11] Free radical accumulation occurs due to increased electron transport uncoupling at the active site of endothelial nitric oxide synthase (eNOS), an enzyme involved in converting L-arginine to NO. [10] [11] During an AMI, oxidative degradation of tetrahydrobiopterin (BH4), a cofactor in NO production, limits BH4 availability and limits NO productionby eNOS. [11] Instead, eNOS reacts with oxygen, another cosubstrates involved in NO production. The products of eNOS are reduced to superoxides, increasing free radical production and oxidative stress within the cells. [10] A H
2 S deficiency impairs eNOS activity by limiting Akt activation and inhibiting Akt phosphorylation of the eNOSS1177 activation site. [6] [10] Instead, Akt activity is increased to phosphorylate the eNOST495 inhibition site, downregulating eNOS production of NO. [6] [10]

H
2 S therapy uses a H
2 S donor, such as diallyl trisulfide (DATS), to increase the supply of H
2 S to an AMI patient. H
2 S donors reduce myocardial injury and reperfusion complications. [10] Increased H
2 S levels within the body will react with oxygen to produce sulfane sulfur, a storage intermediate for H
2 S . [10] H
2 S pools in the body attracts oxygen to react with excess H
2 S and eNOS to increase NO production. [10] With increased use of oxygen to produce more NO, less oxygen is available to react with eNOS to produce superoxides during an AMI, ultimately lowering the accumulation of reactive oxygen species (ROS). [10] Furthermore, decreased accumulation of ROS lowers oxidative stress in vascular smooth muscle cells, decreasing oxidative degeneration of BH4. [11] Increased BH4 cofactor contributes to increased production of NO within the body. [11] Higher concentrations of H
2 S directly increase eNOS activity through Akt activation to increase phosphorylation of the eNOSS1177 activation site, and decrease phosphorylation of the eNOST495 inhibition site. [6] [10] This phosphorylation process upregulates eNOS activity, catalyzing more conversion of L-arginine to NO. [6] [10] Increased NO production enables soluble guanylyl cyclase (sGC) activity, leading to an increased conversion of guanosine triphosphate (GTP) to 3’,5’-cyclic guanosine monophosphate (cGMP). [12] In H
2 S therapy immediately following an AMI, increased cGMP triggers an increase in protein kinase G (PKG) activity. [13] PKG reduces intracellular Ca2+ in vascular smooth muscle to increase smooth muscle relaxation and promote blood flow. [13] PKG also limits smooth muscle cell proliferation, reducing intima thickening following AMI injury, ultimately decreasing myocardial infarct size. [10] [12]

In Alzheimer's disease the brain's hydrogen sulfide concentration is severely decreased. [14] In a certain rat model of Parkinson's disease, the brain's hydrogen sulfide concentration was found to be reduced, and administering hydrogen sulfide alleviated the condition. [15] In trisomy 21 (Down syndrome) the body produces an excess of hydrogen sulfide. [3] Hydrogen sulfide is also involved in the disease process of type 1 diabetes. The beta cells of the pancreas in type 1 diabetes produce an excess of the gas, leading to the death of these cells and to a reduced production of insulin by those that remain. [5]

In 2005, it was shown that mice can be put into a state of suspended animation-like hypothermia by applying a low dosage of hydrogen sulfide (81 ppm H
2 S ) in the air. The breathing rate of the animals sank from 120 to 10 breaths per minute and their temperature fell from 37 °C to just 2 °C above ambient temperature (in effect, they had become cold-blooded). The mice survived this procedure for 6 hours and afterwards showed no negative health consequences. [16] In 2006 it was shown that the blood pressure of mice treated in this fashion with hydrogen sulfide did not significantly decrease. [17]

A similar process known as hibernation occurs naturally in many mammals and also in toads, but not in mice. (Mice can fall into a state called clinical torpor when food shortage occurs). If the H
2 S -induced hibernation can be made to work in humans, it could be useful in the emergency management of severely injured patients, and in the conservation of donated organs. In 2008, hypothermia induced by hydrogen sulfide for 48 hours was shown to reduce the extent of brain damage caused by experimental stroke in rats. [18]

As mentioned above, hydrogen sulfide binds to cytochrome oxidase and thereby prevents oxygen from binding, which leads to the dramatic slowdown of metabolism. Animals and humans naturally produce some hydrogen sulfide in their body researchers have proposed that the gas is used to regulate metabolic activity and body temperature, which would explain the above findings. [19]

Two recent studies cast doubt that the effect can be achieved in larger mammals. A 2008 study failed to reproduce the effect in pigs, concluding that the effects seen in mice were not present in larger mammals. [20] Likewise a paper by Haouzi et al. noted that there is no induction of hypometabolism in sheep, either. [21]

At the February 2010 TED conference, Mark Roth announced that hydrogen sulfide induced hypothermia in humans had completed Phase I clinical trials. [22] The clinical trials commissioned by the company he helped found, Ikaria, were however withdrawn or terminated by August 2011. [23] [24]


Hydrogen Sulfide: The Third Gasotransmitter in Biology and Medicine

The last two decades have seen one of the greatest excitements and discoveries in science, gasotransmitters in biology and medicine. Leading the trend by nitric oxide and extending the trudge by carbon monoxide, here comes hydrogen sulfide (H2S) who builds up the momentum as the third gasotransmitter. Being produced by different cells and tissues in our body, H2S, alone or together with the other two gasotransmitters, regulates an array of physiological processes and plays important roles in the pathogenesis of various diseases from neurodegenerative diseases to diabetes or heart failure, to name a few. As a journal dedicated to serve the emergent and challenging field of H2S biology and medicine, Antioxidant and Redox Signaling assembles the most recent discoveries and most provoking ideas from leading scientists in H2S fields, which were communicated in the First International Conference of H2S in Biology and Medicine, and brings them to our readers in two Forum Issues. Through intellectual exchange and intelligent challenge with an open-mind approach, we can reasonably expect that sooner rather than later the exploration of metabolism and function of H2S will provide solutions for many of the biological mysteries of life and pave way for the arrival of many more gasotransmitters. Antioxid. Redox Signal. 12, 000–000.


Physiological Implications of Hydrogen Sulfide in Plants: Pleasant Exploration behind Its Unpleasant Odour

Recently, overwhelming evidence has proven that hydrogen sulfide (H2S), which was identified as a gasotransmitter in animals, plays important roles in diverse physiological processes in plants as well. With the discovery and systematic classification of the enzymes producing H2S in vivo, a better understanding of the mechanisms by which H2S influences plant responses to various stimuli was reached. There are many functions of H2S, including the modulation of defense responses and plant growth and development, as well as the regulation of senescence and maturation. Additionally, mounting evidence indicates that H2S signaling interacts with plant hormones, hydrogen peroxide, nitric oxide, carbon monoxide, and other molecules in signaling pathways.

1. Introduction

Hydrogen sulfide (H2S) is a colorless, flammable gas with the characteristic odor of rotten eggs. It was widely considered to be just a toxic gas for nearly 300 years mostly due to its unpleasant smell. The breakthrough in the effort to link endogenous H2S levels and functional changes came when the possible role of H2S as an endogenous neuromodulator in the brain was reported [1]. The focus on enzymes generating H2S was another breakthrough in 2001 [2]. The initial work concluded that H2S was a physiological vasodilator and regulator of blood pressure, which stimulated research on H2S physiology [3]. In plants, H2S has been revealed as a crucial player in the regulation of normal plant physiological processes, including seed germination, root morphogenesis, photosynthesis, and flower senescence [4–8]. It was also shown to be an important messenger in plant defense signaling against various abiotic stresses at physiological concentrations [9–13]. In this review, we discuss recent progress that increases our understanding of H2S synthesis and signaling functions in plants.

2. H2S Synthesis

In mammalian cells, H2S is physiologically generated by pyridoxal-5′-phosphate-dependent enzymes, including cystathionine beta-synthase, cystathionine gamma-lyase, and 3-mercaptopyruvate sulfurtransferase (3-MST), during cysteine (Cys) metabolism [3, 14]. H2S is generated in plants via both enzymatic and nonenzymatic pathways, although the latter only accounts for a small portion of H2S production. Figure 1, with the enzymes highlighted, demonstrates the production of H2S in Arabidopsis thaliana.

Several candidate Cys-degrading enzymes have been reported to exist in different plant species (shown in Table 1). In the model plant A. thaliana, the enzymes that produce H2S can be roughly divided into two categories. One class of these enzymes is Cys desulfhydrases (CDes), which degrade Cys into H2S, ammonia, and pyruvate in a stoichiometric ratio of 1 : 1 : 1 and require pyridoxal 5′-phosphate as a cofactor [15]. L-Cys desulfhydrase is one of the enzymes that decompose L-Cys and was first discovered in the sulfur metabolism of tobacco cultured cells [16]. D-Cys desulfhydrase 1 specifically uses D-Cys as its substrate, and D-Cys desulfhydrase 2 degrades L/D-Cys simultaneously [17, 18]. The production of H2S by CDes has been confirmed in various areas of biology [9, 11, 14, 15, 19, 20]. CDes are Cys desulfhydrases with singular functions in desulfuration. Their mRNA levels were significantly higher in the stems and cauline leaves than in the roots, rosette leaves, and flowers of A. thaliana [9].

Another class of the enzymes is O-acetyl-L-serine (thiol) lyase (OAS-TL), which is responsible for the incorporation of inorganic S into Cys, and free H2S appears to be released only in a minor reaction [21]. During an incubation period, the enzyme formed about 25 times more Cys than H2S, in a molar ratio, per mg protein [22]. Nine OAS-TL genes have been identified in A. thaliana, which are located in the cytosol, mitochondria, or plastid [23]. Recently, DES1 was reported as a frequent novel L-Cys desulfhydrase, which, based on sequence feature alignments, belongs to the OAS-TL family [24–28]. The Km value for L-Cys in the DES1 reaction is 13-fold lower than that for OAS in the OAS-TL reaction, indicating a much higher affinity of DES1 for L-Cys as a substrate [2]. The biochemical characterization of the T-DNA insertion mutant des1 reveals that the total intracellular Cys concentration increased by approximately 25% [28]. However, as a member of the OAS-TL family, its function in synthesizing H2S has not been clearly studied. In vitro, the reaction of OAS-TL is a net H2S-consuming reaction [22]. Thus, the statement that DES1 is the only enzyme involving in the degradation of Cys is open to question [24, 28, 29].

In addition, Nifs/NFS, with L-Cys desulfhydrase-like activity, is also potentially involved in H2S production [31, 32]. Two genes, At5g26600 and At1g01010, in A. thaliana have been identified that encode proteins with CDes structural features [15], and 3-MST is also related to H2S production in plants [33].

3. Physiological Functions of H2S in Plants

H2S has been reported to play important roles in diverse physiological processes in plants. Research on the endogenous H2S of higher plants can be traced back to 1978, when H2S was observed to be released from leaves of cucumber, corn, and soybean [34]. Leaves of older plants contain higher H2S concentrations than younger plants [35]. A recent study showed that the mRNA levels of CDes were gradually elevated in a developmental stage-dependent manner [9]. The importance of H2S in the regulation of plant growth, development, and senescence has emerged.

The improvement in seed germination rates due to exogenous H2S treatments was confirmed. H2S or HS − , rather than other sulfur-containing components derived from the exogenous H2S donor, NaHS, contributed to the promotion of seed germination [4]. NaHS preferentially affects the activity of endosperm β-amylase and maintains lower levels of malondialdehyde and hydrogen peroxide (H2O2) in germinating seeds [7]. In addition, the application of NaHS to seedling cuttings of sweet potato promoted the number and length of adventitious roots [5]. At the same time, H2S modulates the expression of genes involved in photosynthesis and thiol redox modification to regulate its photosynthesis [36]. It is hypothesized that an increase in the stomatal density also contributes to this process [37]. The osmotic-induced decrease in the chlorophyll concentration could be alleviated by spraying the NaHS solution [6]. H2S was also found to delay flower opening and senescence in cut flowers and branches [8]. These effects occur in a dose-dependent manner. In the cytosol, H2S negatively regulates autophagy and modulates the transcriptional profile of A. thaliana using des1 [38]. H2S strongly affects plant metabolism at most stages of life and causes statistically significant increases in biomass, including higher fruit yields [39].

H2S also plays pivotal roles in plant responses or adaptation under biotic and abiotic stress conditions. Early studies concerning H2S emissions in plants were associated with plant responses to pathogens as part of sulfur-induced resistance [40]. In 2008, H2S was found to be an important cellular signal for the first time, highlighting the protective effect of H2S against copper stress [4]. Thereafter, a stream of publications on various positive effects of H2S and H2S signaling in plants emerged. Soon, H2S was shown to alleviate the effects of aluminum, cadmium, chromium and boron toxicity, drought and osmotic stress, heat stress, hypoxia, and other stresses [9, 11–13, 20, 41–43]. Most of these reports discussed, as analogies with animal systems, how H2S signaling is important for plant protection against stress.

Stomatal movement is very important in plant responses to environmental stimuli, and a key target of H2S signaling in plants is the specialized guard cell. Recent studies have reported that H2S is responsible for drought stress relief by inducing stomatal closure in A. thaliana [9, 20]. These observations are consistent with a previous report in both Vicia faba and Impatiens walleriana [30]. Similarly, H2S was confirmed to be a novel downstream indicator of nitric oxide (NO) during ethylene-induced stomatal closure [44]. However, the effect of H2S on stomatal movement has been a controversial topic. Another research group reported that exogenous H2S induced stomatal opening by reducing the accumulation of NO in guard cells of A. thaliana and a crop plant, Capsicum annuum [45, 46]. The reasons for these different observations are not clear and require further study. The difference may simply be due to the different experimental materials and methods. The purpose of stomatal closure is to reduce the moisture loss under drought stress, and the induction of stomatal opening is to enhance photosynthesis and reduce the photorespiration.

4. Cross-talk of H2S with Other Signals

Plants perceive and respond to H2S, but studies on the mechanisms of H2S functioning in plant responses to stress are very limited. An overview of our current understanding of plant H2S signaling is shown in Figure 2. H2S is particularly active and may interact with and modify numerous other signals. Thus, there may be multiple routes of H2S perception and signaling to be unraveled.

Several lines of evidence point to an interrelationship between H2S and plant hormones in plant defenses. Abscisic acid (ABA) is produced in large amounts in plants under various abiotic stresses. Under drought stress, the expression of CDes was significantly upregulated, and the production rate of H2S from these plants also increased [9]. Subsequently, the relationship between H2S and ABA was reported based on a deficiency of H2S in the lcd mutant that had a weakened ABA induction of stomatal closure, which indicated that the induction of stomatal closure by ABA was partially dependent on H2S. As H2S was also involved in the expression regulation of ion-channel genes, H2S may be a critical component of ABA-induced stomatal closure via ion channels. At the same time, H2S influenced the expression of ABA receptors, and the influence of H2S may have begun upstream of the ABA signaling pathway. Therefore, the above results showed that H2S interacted with ABA in the stomatal regulation responsible for drought stress in A. thaliana [20]. Indole acetic acid (IAA) showed a rapid increase in different plants treated by exogenous H2S [5], and ethylene (Eth) could induce H2S generation [44]. In addition, gibberellic acid (GA) and jasmonic acid (JA) were also involved in the H2S signal transduction process. H2S can alleviate the GA-induced programmed cell death in wheat aleurone cells [47], and H2S may function downstream of H2O2 in JA-induced stomatal closure in V. faba [48].

H2O2 is another signaling molecule in plants, especially in guard cells. Abiotic stress induces synthesis of both H2S and H2O2 yet it is unclear how these two molecules work in concert in the physiological process. H2S may represent a novel downstream component of the H2O2 signaling cascade during JA-induced stomatal movement in V. faba [48]. Pretreatment of H2O2 could improve the germination percentage of Jatropha curcas seeds, and this improvement was mediated by H2S [49]. These results suggest that H2O2 is upstream of H2S. However, there is plenty of evidence to the contrary. H2S inhibited the cadmium influx through the plasma membrane calcium channels, which were activated by H2O2 [50]. H2S can participate in enhancing plant resistance to abiotic stress via the improvement of antioxidant systems, such as heavy metal stress, osmotic stress, heat stress, and hypoxia stress [4–7, 10, 42, 43, 49].

Recent evidence suggests that H2S also plays a role in the NO and carbon monoxide (CO) signaling pathway. In bermudagrass, sodium nitroprusside (SNP, a NO donor) and NaHS combined treatments showed that NO signaling could be blocked by H2S inhibitors and scavengers, indicating that NO-activated H2S was essential for the cadmium stress response [51]. Additional evidence showed that both NaHS and GYY4137 reduced the NO accumulation to a large extent in A. thaliana epidermal cells [45]. In sweet potato seedlings, a rapid increase in endogenous H2S and NO was sequentially observed in shoot tips treated with NaHS. A similar phenomenon in H2S donor-dependent root organogenesis was observed in both excised willow shoots and soybean seedlings. These results indicated that the process of H2S-induced adventitious root formation was likely mediated by IAA and NO and that H2S acts upstream in IAA and NO signaling transduction pathways [5]. Similarly, heme oxygenase 1 functions as a downstream component in H2S-induced adventitious root formation by the modulation of expression of related genes, which suggested that CO was involved in H2S-induced cucumber adventitious root formation [52].

Additionally, growing evidence suggests that H2S signaling interacts with calcium (Ca) signaling pathways. Ca 2+ confers structure and rigidity to the cell wall and regulates plant processes through calmodulin. Li et al. (2013) showed that NaHS pretreatment could improve the entry of extracellular Ca 2+ into tobacco suspension cultured cells mediated by intracellular calmodulin to increase the heat tolerance [41]. At the level of transcription, the expression of Ca 2+ channel coding genes decreased, whereas Ca 2+ -ATPase and Ca 2+ -H + cation antiporters were elevated in the lcd mutant. This was in accordance with stronger Ca 2+ fluorescence in the wild type than in the lcd mutant [20]. These results suggest that Ca signaling plays an important role in the mechanism of H2S.

Numerous studies showed that, during the enhancement of plant resistance, many substances changed simultaneously. H2S plays an ameliorative role in protecting plants by increasing the proline content against aluminum toxicity and heat stress [10, 12, 41]. Aluminum-induced citrate secretion was also significantly enhanced by NaHS pretreatment [10]. During the NaHS preincubation period the grain β-amylase activity increased, improving seed germination [7].

5. Conclusions and Perspectives

The mechanisms by which H2S is generated still remain unresolved, and elucidating how it is made by different plant cells under different conditions is clearly a research priority. H2S is a key factor in the tolerance of cells to the oxidative stress induced by a range of abiotic conditions, including heavy metal toxicity, drought and osmotic stress, hot stress, hypoxia and other stresses. This probably involves the activation of antioxidant defenses, the induction of stomatal closure, and the enhanced expression of genes encoding resistance-associated enzymes. In these processes, plant hormones, H2O2, NO, CO, and Ca signaling participate in H2S signal transduction, resulting in a complex signaling network.

There are numerous unanswered questions and important areas for further research, concentrated in the following areas. (1) Owing to the promiscuous chemical properties of H2S, it is problematic to achieve adequate specificity and selectivity for its measurement. At present, the physiological H2S level was measured by various techniques such as the methylene blue method, monobromobimane, gas chromatography, ion selective electrodes, and fluorescent probes [53]. The diverse detection methods resulted in magnitude differences in measured biological sulfide levels, which will certainly attract increasing attention. (2) The mechanism of H2S functions performed at the protein level. Until now, a great number of studies focused on protein S-sulfhydration, which is impossible to determine directly by chemical analyses. But in mammals, there have been many results indicating that this process might occur by the transition of intermediate links, such as positional changes and interactions with associated proteins. Moreover, if H2S can thiolate proteins, it may have the same effect on DNA. (3) Even though H2S is a short-lived molecule, it is an extremely active one. The mechanisms by which either H2S or other molecules participating in H2S signaling function are also important. Thus, elucidation of the H2S complex signaling network is clearly a research priority.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

Acknowledgments

This work was supported by the National Natural Science Foundation of China (31372085 to Yanxi Pei 31400237 to Zhuping Jin 31300236 to Zhiqiang Liu) and Shanxi Province Science Foundation for Youths (2014021026-2, to Zhuping Jin).

References

  1. K. Abe and H. Kimura, “The possible role of hydrogen sulfide as an endogenous neuromodulator,” The Journal of Neuroscience, vol. 16, no. 3, pp. 1066–1071, 1996. View at: Google Scholar
  2. W. Zhao, J. Zhang, Y. Lu, and R. Wang, “The vasorelaxant effect of H2S as a novel endogenous gaseous KATP channel opener,” The EMBO Journal, vol. 20, no. 21, pp. 6008–6016, 2001. View at: Publisher Site | Google Scholar
  3. G. Yang, L. Wu, B. Jiang et al., “H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine γ-lyase,” Science, vol. 322, no. 5901, pp. 587–590, 2008. View at: Publisher Site | Google Scholar
  4. H. Zhang, L.-Y. Hu, K.-D. Hu, Y.-D. He, S.-H. Wang, and J.-P. Luo, “Hydrogen sulfide promotes wheat seed germination and alleviates oxidative damage against copper stress,” Journal of Integrative Plant Biology, vol. 50, no. 12, pp. 1518–1529, 2008. View at: Publisher Site | Google Scholar
  5. H. Zhang, J. Tang, X.-P. Liu et al., “Hydrogen sulfide promotes root organogenesis in Ipomoea batatas, Salix matsudana and Glycine max,” Journal of Integrative Plant Biology, vol. 51, no. 12, pp. 1086–1094, 2009. View at: Publisher Site | Google Scholar
  6. H. Zhang, Y.-K. Ye, S.-H. Wang, J.-P. Luo, J. Tang, and D.-F. Ma, “Hydrogen sulfide counteracts chlorophyll loss in sweetpotato seedling leaves and alleviates oxidative damage against osmotic stress,” Plant Growth Regulation, vol. 58, no. 3, pp. 243–250, 2009. View at: Publisher Site | Google Scholar
  7. H. Zhang, W. Dou, C.-X. Jiang, Z.-J. Wei, J. Liu, and R. L. Jones, “Hydrogen sulfide stimulates β-amylase activity during early stages of wheat grain germination,” Plant Signaling and Behavior, vol. 5, no. 8, pp. 1031–1033, 2010. View at: Publisher Site | Google Scholar
  8. H. Zhang, S.-L. Hu, Z.-J. Zhang et al., “Hydrogen sulfide acts as a regulator of flower senescence in plants,” Postharvest Biology and Technology, vol. 60, no. 3, pp. 251–257, 2011. View at: Publisher Site | Google Scholar
  9. Z. Jin, J. Shen, Z. Qiao, G. Yang, R. Wang, and Y. Pei, “Hydrogen sulfide improves drought resistance in Arabidopsis thaliana,” Biochemical and Biophysical Research Communications, vol. 414, no. 3, pp. 481–486, 2011. View at: Publisher Site | Google Scholar
  10. J. Chen, W.-H. Wang, F.-H. Wu et al., “Hydrogen sulfide alleviates aluminum toxicity in barley seedlings,” Plant and Soil, vol. 362, no. 1-2, pp. 301–318, 2013. View at: Publisher Site | Google Scholar
  11. Y.-W. Li, Z.-H. Gong, Y. Mu et al., “An Arabidopsis mutant atcsr-2 exhibits high cadmium stress sensitivity involved in the restriction of H2S emission,” Journal of Zhejiang University: Science B, vol. 13, no. 12, pp. 1006–1014, 2012. View at: Publisher Site | Google Scholar
  12. Z.-G. Li, M. Gong, H. Xie, L. Yang, and J. Li, “Hydrogen sulfide donor sodium hydrosulfide-induced heat tolerance in tobacco (Nicotiana tabacum L) suspension cultured cells and involvement of Ca 2+ and calmodulin,” Plant Science, vol. 185-186, pp. 185–189, 2012. View at: Publisher Site | Google Scholar
  13. H. Zhang, L.-Y. Hu, P. Li, K.-D. Hu, C.-X. Jiang, and J.-P. Luo, “Hydrogen sulfide alleviated chromium toxicity in wheat,” Biologia Plantarum, vol. 54, no. 4, pp. 743–747, 2010. View at: Publisher Site | Google Scholar
  14. R. Wang, “Physiological implications of hydrogen sulfide: a whiff exploration that blossomed,” Physiological Reviews, vol. 92, no. 2, pp. 791–896, 2012. View at: Publisher Site | Google Scholar
  15. J. Papenbrock, A. Riemenschneider, A. Kamp, H. N. Schulz-Vogt, and A. Schmidt, “Characterization of cysteine-degrading and H2S-releasing enzymes of higher plants𠅏rom the field to the test tube and back,” Plant Biology, vol. 9, no. 5, pp. 582–588, 2007. View at: Publisher Site | Google Scholar
  16. H. M. Harrington and I. K. Smith, “Cysteine metabolism in cultured tobacco cells,” Plant Physiology, vol. 65, no. 1, pp. 151–155, 1980. View at: Publisher Site | Google Scholar
  17. A. Schmidt, “A cysteine desulfhydrase from spinach leaves specific for D-cysteine,” Zeitschrift für Pflanzenphysiologie, vol. 107, no. 4, pp. 301–312, 1982. View at: Publisher Site | Google Scholar
  18. A. Riemenschneider, E. Bonacina, A. Schmidt, and J. Papenbrock, “Remove from marked Records Isolation and characterization of a second D-cysteine desulfhydrase-like protein from Arabidopsis,” in Proceedings of the 6th International Workshop on Plant Sulfur Metabolism: Sulfur Transport and Assimilation in Plants in the Post Genomic Era, K. Saito, L. J. de Kok, I. Stulen et al., Eds., pp. 103–106, Chiba, Japan, 2005. View at: Google Scholar
  19. J. J. Shen, Z. J. Qiao, T. J. Xing et al., “Cadmium toxicity is alleviated by AtLCD and AtDCD in Escherichia coli,” Journal of Applied Microbiology, vol. 113, no. 5, pp. 1130–1138, 2012. View at: Publisher Site | Google Scholar
  20. Z. Jin, S. Xue, Y. Luo et al., “Hydrogen sulfide interacting with abscisic acid in stomatal regulation responses to drought stress in Arabidopsis,” Plant Physiology and Biochemistry, vol. 62, no. 1, pp. 41–46, 2013. View at: Publisher Site | Google Scholar
  21. C.-H. Tai and P. F. Cook, “O-acetylserine sulfhydrylase,” Advances in Enzymology and Related Areas of Molecular Biology, vol. 74, pp. 185–234, 2000. View at: Google Scholar
  22. P. Burandt, J. Papenbrock, and A. Schmidt, “Genotypical differences in total sulfur contents and cysteine desulfhydrase activities in Brassica napus L.,” Phyton-International Journal of Experimental Botany, vol. 41, no. 1, pp. 75–86, 2001. View at: Google Scholar
  23. C. Álvarez, L. Calo, L. C. Romero, I. Garc໚, and C. Gotor, “An O-Acetylserine(thiol)lyase homolog with l-Cysteine desulfhydrase activity regulates cysteine homeostasis in Arabidopsis,” Plant Physiology, vol. 152, no. 2, pp. 656–669, 2010. View at: Publisher Site | Google Scholar
  24. M. Wirtz, M. Droux, and R. Hell, “O-acetylserine (thiol) lyase: an enigmatic enzyme of plant cysteine biosynthesis revisited in Arabidopsis thaliana,” Journal of Experimental Botany, vol. 55, no. 404, pp. 1785–1798, 2004. View at: Publisher Site | Google Scholar
  25. E. R. Bonner, R. E. Cahoon, S. M. Knapke, and J. M. Jez, “Molecular basis of cysteine biosynthesis in plants: structural and functional analysis of O-acetylserine sulfhydrylase from Arabidopsis thaliana,” The Journal of Biological Chemistry, vol. 280, no. 46, pp. 38803–38813, 2005. View at: Publisher Site | Google Scholar
  26. C. Heeg, C. Kruse, R. Jost et al., “Analysis of the Arabidopsis O-acetylserine(thiol)lyase gene family demonstrates compartment-specific differences in the regulation of cysteine synthesis,” Plant Cell, vol. 20, no. 1, pp. 168–185, 2008. View at: Publisher Site | Google Scholar
  27. J. M. Jez and S. Dey, “The cysteine regulatory complex from plants and microbes: what was old is new again,” Current Opinion in Structural Biology, vol. 23, no. 2, pp. 302–310, 2013. View at: Publisher Site | Google Scholar
  28. L. C. Romero, I. Garc໚, and C. Gotor, “L-cysteine desulfhydrase 1 modulates the generation of the signaling molecule sulfide in plant cytosol,” Plant Signaling & Behavior, vol. 8, no. 5, Article ID e24007, 2013. View at: Publisher Site | Google Scholar
  29. L. C. Romero, M. Á. Aroca, A. M. Laureano-Marín, I. Moreno, I. Garc໚, and C. Gotor, “Cysteine and cysteine-related signaling pathways in Arabidopsis thaliana,” Molecular Plant, vol. 7, no. 2, pp. 264–276, 2014. View at: Publisher Site | Google Scholar
  30. C. Gotor, C. Álvarez, M. Á. Berm﫞z, I. Moreno, I. Garc໚, and L. C. Romero, “Low abundance does not mean less importance in cysteine metabolism,” Plant Signaling and Behavior, vol. 5, no. 8, pp. 1028–1030, 2010. View at: Publisher Site | Google Scholar
  31. S. Kushnir, E. Babiychuk, S. Storozhenko et al., “A mutation of the mitochondrial ABC transporter stat1 leads to dwarfism and chlorosis in the Arabidopsis mutant starik,” Plant Cell, vol. 13, no. 1, pp. 89–100, 2001. View at: Publisher Site | Google Scholar
  32. S. Léon, B. Touraine, J.-F. Briat, and S. Lobrບux, “The AtNFS2 gene from Arabidopsis thaliana encodes a Nifs-like plastidial cysteine desulphurase,” Biochemical Journal, vol. 366, no. 2, pp. 557–564, 2002. View at: Publisher Site | Google Scholar
  33. J. Papenbrock, S. Guretzki, and M. Henne, “Latest news about the sulfurtransferase protein family of higher plants,” Journal of Amino Acids, vol. 41, no. 1, pp. 43–57, 2011. View at: Publisher Site | Google Scholar
  34. L. G. Wilson, R. A. Bressan, and P. Filner, “Light-dependent emission of hydrogen sulfide from plants,” Plant Physiology, vol. 61, no. 2, pp. 184–189, 1978. View at: Publisher Site | Google Scholar
  35. H. Rennenberg and P. Filner, “Developmental changes in the potential for H2S emission in cucurbit plants,” Plant Physiology, vol. 71, no. 2, pp. 269–275, 1983. View at: Publisher Site | Google Scholar
  36. J. Chen, F.-H. Wu, W.-H. Wang et al., “Hydrogen sulphide enhances photosynthesis through promoting chloroplast biogenesis, photosynthetic enzyme expression, and thiol redox modification in Spinacia oleracea seedlings,” Journal of Experimental Botany, vol. 62, no. 13, pp. 4481–4493, 2011. View at: Publisher Site | Google Scholar
  37. B. Duan, Y. Ma, M. Jiang, F. Yang, L. Ni, and W. Lu, “Improvement of photosynthesis in rice (Oryza sativa L.) as a result of an increase in stomatal aperture and density by exogenous hydrogen sulfide treatment,” Plant Growth Regulation, vol. 75, no. 1, pp. 33–44, 2014. View at: Publisher Site | Google Scholar
  38. C. Álvarez, I. Garc໚, I. Moreno et al., “Cysteine-generated sulfide in the cytosol negatively regulates autophagy and modulates the transcriptional profile in Arabidopsis,” The Plant Cell, vol. 24, no. 11, pp. 4621–4634, 2012. View at: Publisher Site | Google Scholar
  39. F. D. Dooley, S. P. Nair, and P. D. Ward, “Increased growth and germination success in plants following hydrogen sulfide administration,” PLoS ONE, vol. 8, no. 4, Article ID e62048, 2013. View at: Publisher Site | Google Scholar
  40. E. Bloem, A. Riemenschneider, J. Volker et al., “Sulphur supply and infection with Pyrenopeziza brassicae influence L-cysteine desulphydrase activity in Brassica napus L.,” Journal of Experimental Botany, vol. 55, no. 406, pp. 2305–2312, 2004. View at: Publisher Site | Google Scholar
  41. Z.-G. Li, X.-J. Ding, and P.-F. Du, “Hydrogen sulfide donor sodium hydrosulfide-improved heat tolerance in maize and involvement of proline,” Journal of Plant Physiology, vol. 170, no. 8, pp. 741–747, 2013. View at: Publisher Site | Google Scholar
  42. W. Cheng, L. Zhang, C. Jiao et al., “Hydrogen sulfide alleviates hypoxia-induced root tip death in Pisum sativum,” Plant Physiology and Biochemistry, vol. 70, pp. 278–286, 2013. View at: Publisher Site | Google Scholar
  43. B.-L. Wang, L. Shi, Y.-X. Li, and W.-H. Zhang, “Boron toxicity is alleviated by hydrogen sulfide in cucumber (Cucumis sativus L.) seedlings,” Planta, vol. 231, no. 6, pp. 1301–1309, 2010. View at: Publisher Site | Google Scholar
  44. J. Liu, L. Hou, G. Liu, X. Liu, and X. Wang, “Hydrogen sulfide induced by nitric oxide mediates ethylene-induced stomatal closure of Arabidopsis thaliana,” Chinese Science Bulletin, vol. 56, no. 33, pp. 3547–3553, 2011. View at: Publisher Site | Google Scholar
  45. M. Lisjak, N. Srivastava, T. Teklic et al., “A novel hydrogen sulfide donor causes stomatal opening and reduces nitric oxide accumulation,” Plant Physiology and Biochemistry, vol. 48, no. 12, pp. 931–935, 2010. View at: Publisher Site | Google Scholar
  46. M. Lisjak, T. Teklić, I. D. Wilson, M. E. Wood, M. Whiteman, and J. T. Hancock, “Hydrogen sulfide effects on stomatal apertures,” Plant Signaling and Behavior, vol. 6, no. 10, pp. 1444–1446, 2011. View at: Google Scholar
  47. Y. Xie, C. Zhang, D. Lai et al., “Hydrogen sulfide delays GA-triggered programmed cell death in wheat aleurone layers by the modulation of glutathione homeostasis and heme oxygenase-1 expression,” Journal of Plant Physiology, vol. 171, no. 2, pp. 53–62, 2014. View at: Google Scholar
  48. Z. Hou, J. Liu, L. Hou, X. Li, and X. Liu, “H2S may function downstream of H2O2 in jasmonic acid-induced stomatal closure in Vicia faba,” Chinese Bulletin of Botany, vol. 46, no. 4, pp. 396–406, 2011. View at: Publisher Site | Google Scholar
  49. Z.-G. Li, M. Gong, and P. Liu, “Hydrogen sulfide is a mediator in H2O2-induced seed germination in Jatropha Curcas,” Acta Physiologiae Plantarum, vol. 34, no. 6, pp. 2207–2213, 2012. View at: Publisher Site | Google Scholar
  50. J. Sun, R. Wang, X. Zhang et al., “Hydrogen sulfide alleviates cadmium toxicity through regulations of cadmium transport across the plasma and vacuolar membranes in Populus euphratica cells,” Plant Physiology and Biochemistry, vol. 65, pp. 67–74, 2013. View at: Publisher Site | Google Scholar
  51. H. Shi, T. Ye, and Z. Chan, “Nitric oxide-activated hydrogen sulfide is essential for cadmium stress response in bermudagrass (Cynodon dactylon (L). Pers.),” Plant Physiology and Biochemistry, vol. 74, pp. 99–107, 2014. View at: Publisher Site | Google Scholar
  52. Y.-T. Lin, M.-Y. Li, W.-T. Cui, W. Lu, and W.-B. Shen, “Haem oxygenase-1 is involved in hydrogen sulfide-induced cucumber adventitious root formation,” Journal of Plant Growth Regulation, vol. 31, no. 4, pp. 519–528, 2012. View at: Publisher Site | Google Scholar
  53. P. Nagy, Z. Pálinkás, A. Nagy, B. Budai, I. Tóth, and A. Vasas, “Chemical aspects of hydrogen sulfide measurements in physiological samples,” Biochimica et Biophysica Acta, vol. 1840, no. 2, pp. 876–891, 2014. View at: Publisher Site | Google Scholar

Copyright

Copyright © 2015 Zhuping Jin and Yanxi Pei. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Overview of Ers

Endoplasmic reticulum (ER) is a reticular organelle composed of tubular structure and flat sac and it is composed of smooth and rough ER. Smooth ER is responsible for the production and synthesis of structural and non-structural fatty acids and phospholipids. In addition, it plays an important role in calcium homeostasis and carbohydrate metabolism. Rough ER is the main site for proteins synthesis, modification, proteins folding and assembly into stable secondary and tertiary structures, as well as the secretion of proteins (Young, 2017). The various stressors including hypoxia, hypoglycemia, stress, calcium deficiency, high-fat diet, and oxidative stress, can disturb the protein folding process, resulting in the accumulation of unfolded and misfolded proteins in the ER, which is called ERS (Mao et al., 2019). The accumulation of unfolded proteins in ER triggers a stable signal network called UPR to reduce the overload caused by unfolded protein. One of the mechanisms of the above effects is that UPR can activate a series of signals to promote the synthesis of new proteins in response to stress, and reduce the synthesis of general proteins. Another is that UPR can promote protein degradation through autophagy and enhance the clearance of unfolded proteins through a process called ER-associated degradation (Iurlaro and Munoz-Pinedo, 2016). If ER function is seriously damaged, ERS can induce apoptosis (Hetz et al., 2015 Chan et al., 2016). The apoptosis induced by ERS is mainly achieved by the following three pathways: the activation of transcription factor C/EBP homologous protein (CHOP)/growth inhibition and DNA damage induced gene 153 (Gadd153), the activation of apoptosis signal-regulating kinase 1(ASK1)/c-Jun N-terminal kinase (JNK) kinase pathway and the activation of caspase 12 (Wu et al., 2018b).

Under ERS, the protein expression level of GRP78, ATF6, phosphor-PERK, and phosphor-IRE1 are increased and considered as the markers of ERS (Su and Li, 2016). ERS is mediated by three ERS sensors: pancreatic endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1) and activating transcription factor 6 (ATF6), which, respectively, mediates one of three parallel signal transduction pathways (Lindahl et al., 2017). Under non-stressful conditions, the binding immunoglobulin (BIP) binds to PERK, IRE1, and ATF6 to stabilize and prevent their activation. The stressors leading to ERS and the unfolded proteins promote the isolation of BIP from PERK, IRE1, and ATF6, thereby activating these three molecules. Subsequently, the autophosphorylated PERK phosphorylates eIF2a to inhibit mRNA translation and global protein synthesize, and increases ATF4 expression. The activated IRE1 cleaves XBP1 mRNA and the isolated ATF6 is cleaved by 1-site protease (SP1) and 2-site protease (SP2) proteins in Golgi complex. At last, the spliced Xbp1, the ATF4 and the spliced ATF6 promote the expression of ER chaperone genes, which are further involved in eliminating unfolded proteins and restoring homeostasis in normal cells (Figure 1 Ji et al., 2019). Recent studies have shown that ERS plays an important role in many diseases including metabolic diseases and inflammatory diseases, which has become a research hotspot (Wang and Kaufman, 2016).

Figure 1. ERS and UPR are mediated by three parallel signal transduction pathways. Binding immunoglobulin (BIP) binds to PERK, IRE1, and ATF6 to stabilize and prevent their activation under non-pressure conditions. The stressors and the unfolded proteins promote the separation of BiP from PERK, IRE1, and ATF6, thus activating these three molecules. Subsequently, the self phosphorylated PERK phosphorylated eIF2a, inhibited mRNA translation and protein synthesis, increased the expression of ATF4. The activated IRE1 cleaved XBP1 mRNA. The isolated ATF6 was cleaved by the 1-site protease (sp1) and 2-site protease (sp2) proteins of Golgi complex. Finally, the cleaved XBP1, ATF4, and spliced ATF6 promote the expression of Er chaperone genes, which are further involved in the elimination of unfolded proteins and the restoration of normal cell homeostasis. PERK, pancreatic endoplasmic reticulum kinase IRE1, inositol-requiring enzyme 1 ATF6, activating transcription factor 6 XBP1, X-box binding protein 1 ERS, endoplasmic reticulum stress UPR, unfolded protein response.


Overview of H2S

For many years, H2S has been considered to be a toxic and odorous gas. However, since the 1990s, many studies have shown that H2S, along with NO and CO, belongs to the category of gasotransmitters (Wang et al., 2020b). Three 𠇌lassic” H2S-producing enzymes have been identified: cystathionine-γ-lyase (CSE), cystathionine-β-synthase (CBS), and 3-mercaptopyruvate thiotransferase (3-MST) (Rose et al., 2017). The expression of H2S-producing enzyme is subcellular and tissue-specific. At the cellular level, CSE occurs strictly in the cytoplasm, while cysteine aminotransferase (CAT) is located in the mitochondria. In terms of tissue specificity, CSE is the most abundant in the cardiovascular system, while CBS is dominant in the nervous system and liver and is expressed in the heart (Kar et al., 2019 Shen et al., 2019). In the process of endogenous H2S production, CBS catalyzes the β-substitution reaction of homocysteine with serine to produce L-cystathionine. L-cystenine is produced by the elimination of α, γ-cysteine of L-cystathionine catalyzed by CSE. L-cystenine then produces H2S via β elimination reaction catalyzed by CSE/CBS. L-cystenine also produces 3-mercaptopyruvate (3-MP) by transferring its amines to α-ketoglutarate catalyzed by CAT. 3-MST catalyzes the sulfur of 3-MP to convert into H2S. In cardiomyocytes that mainly express CSE, H2S is produced with L-cysteine as substrate under the catalysis of CSE (Figure 1) (Behera et al., 2019). In addition, there are some other recognized or assumed sources of H2S, including D-amino acid oxylase (Han et al., 2020) and methionine oxidase (Pol et al., 2018). In biological systems, several non-enzymatic methods can also produce H2S (Yang et al., 2019). In T2DM patients with DCM, endogenous H2S production by CSE is inhibited in cardiomyocytes (Mard et al., 2016). H2S level in plasma is decreased, and the supplement of H2S can reduce the cardiomyopathy dysfunction induced by hyperglycemia (Kar et al., 2019).

Figure 1. In vivo synthesis process and biological function of hydrogen sulfide (H2S). In the process of endogenous H2S production, firstly, cystathionine-β-synthase (CBS) catalyzes the β-substitution reaction of homocysteine with serine to produce L-cystathionine. L-cystenine is produced by the elimination of α, γ-cysteine of L-cystathionine catalyzed by cystathionine-γ-lyase (CSE). L-cystenine then produces hydrogen sulfide (H2S) via β elimination reaction catalyzed by CSE/CBS. L-cystenine also produces 3-mercaptopyruvate (3-MP) by transferring its amines to α-ketoglutarate catalyzed by cysteine aminotransferase (CAT). 3-Mercaptopyruvate thiotransferase (3-MST) catalyzes the sulfur of 3-MP to convert into H2S. In cardiomyocytes that mainly express CSE, H2S is produced with L-cysteine as substrate under the catalysis of CSE. (The part in the figure is marked in red.) H2S plays important roles in many physiological processes, including vasodilation, blood pressure reduction, anti-apoptosis, anti-inflammation, anti-oxidative stress, cell survival/death, cell differentiation, cell proliferation/hypertrophy, mitochondrial bioenergetics/biogenesis, and endoplasmic reticulum stress.

H2S can act as a signal molecule immediately after it is released, and it can also be stored as bound endosulfan, which can release H2S. At physiological pH, nearly two-thirds of H2S is in the form of hydrogen sulfide anion (HS–) (Guo et al., 2016). H2S plays important roles in many physiological processes, including vasodilation, blood pressure reduction (Greaney et al., 2017 Jin et al., 2017), anti-apoptosis (Li et al., 2019b), anti-inflammation (Zhao et al., 2019), anti-oxidative stress (Tocmo and Parkin, 2019), cell survival/death, cell differentiation, cell proliferation/hypertrophy, mitochondrial bioenergetics/biogenesis, and endoplasmic reticulum stress (ERS) (Figure 1) (Zhang D. et al., 2017). Recent studies have shown that H2S ameliorates diabetic complications including endothelial dysfunction (Li et al., 2019a), nephropathy (Karmin and Siow, 2018), retinopathy (Wang P. et al., 2019), and cardiovascular diseases (Citi et al., 2018). Research has reported that in diabetes, intraislet H2S could promote opening of the ATP dependent potassium channel, increase K + efflux to lead to cell membrane hyperpolarization, and then close the L-type voltage-dependent calcium channel, thus inhibiting insulin secretion of pancreatic beta cells. On the contrary, much literature has shown that H2S can promote the release of insulin from β-cells. The reason for the above contradiction has not been fully studied (Szabo, 2012 Piragine and Calderone, 2020). In addition, H2S could also regulate the apoptosis of islet beta cells and increase ERS and apoptosis of pancreatic beta cells by inhibiting the extracellular signal regulated kinase (ERK) and activating p38 mitogen activated protein kinase (p38 MAPK) signal pathway (Yang et al., 2007). Other studies have shown that H2S could inhibit high glucose (HG)–induced apoptosis of pancreatic beta cells through the antioxidant, anti-inflammatory, or protein kinase B (Akt) signaling pathways (Taniguchi et al., 2011). However, the mechanism of H2S in diabetes is not fully understood.


4 H2S AND SKIN DISEASES

4.1 Folk medicine and the early evidence based on protein sulfur

Bathing in natural thermal waters containing sulfur (with H2S concentrations in the range 0.3–8 mM) has been used for centuries as a folk medicine procedure in the search for effective treatment and relief of several conditions including wound healing, acne, rosacea, scabies, atopic dermatitis (AD), psoriasis, and urticaria. Furthermore, over the last two decades, there have been an increasing number of in vitro and in vivo studies providing some insight into the effects of external application of such thermal waters on the skin.

For example, Shani et al. ( 1997 ) report the efficacy of Dead Sea sulfurous therapy in 1,408 AD patients, with reduction of pruritus during the first week of treatment and complete elimination of lesions in 90% of patients after 4 to 6 weeks of therapy. In patients with psoriatic plaques, Mazzulla, Nicoletta, Perrotta, De Stefano, and Sesti ( 2013 ) point out that bathing treatment in the sulfurous waters of Terme Luigiane (Italy) promotes a significant recovery of the mechanical properties of the skin (i.e., increase of the elasticity parameters). Balneotherapy studies in mice with experimental AD induced by the hapten dinitrochlorobenzene report that treatment with mineral water containing high sulfur, calcium, and chlorine concentrations reduces scratching behaviour, decreases the severity of skin lesions, and reduces serum levels of IgE, IL-1, IL-13, and TNF-α in comparison with the controls (Bajgai et al., 2017 ).

Joly, Branka, and Lefeuvre ( 2014 ) showed that the thermal waters from Uriage-les-Bains (TWFULB), with high concentrations of sulfate anion, showed significant protective effects against oxidative stress induced by exposure of human dermal fibroblasts to hypoxanthine/xanthine oxidase, with improved cell viability and reduced lipid peroxidation. TWFULB also showed to have significant SOD-like activity and protective effects on the UVB-stressed DNA in human keratinocytes. In an ex vivo model of human skin explants, TWFULB was able to counterbalance the negative effect of UVB on the intracellular catalase activity and on the cutaneous claudin-6 expression. In the study by Karagülle et al. ( 2018 ), incubation of the human keratinocyte cell line HaCaT with two different thermal waters, thermo-mineral BJ1 (Bursa, Turkey) or oligomineral BG (Bolu, Turkey) for 3 days, significantly reduced expression of IL-1α, TNF-α, and VEGF. However, while the antiangiogenic effects of BG water on HaCaT cells might be due to the sulfur contents, the anti-inflammatory effects of the BJ1 waters were attributed to its silica contents.

From these reports, it is clear that the results obtained with natural waters cannot be solely due to the presence of H2S–sulfur and, mainly in relation to the beneficial effects in humans, other variables such as salt contents, osmolarity, pH, temperature, the presence of other potentially active substances, and even a placebo effect must be considered. However, it is a fact that the inappropriate regulation of H2S production is implicated in several skin pathological conditions. The study of the relative amounts of protein-bound sulfhydryl/thiol and disulfide groups in human epidermis has been the focus of many investigations, particularly since Barrnett and Seligman ( 1954 ) published their specific staining method to demonstrate the presence of sulfhydryl and disulfide groups by histochemistry. The early findings on protein sulfur contents in skin diseases (summarized by Steiner, 1960 ) are strikingly well correlated with our present knowledge in relation to H2S.

4.2 Inflammation, pruritus, and cytoprotection

Several in vitro and in vivo studies have shown the anti-inflammatory effects of H2S as well as its participation in the resolution of inflammation and repair processes (Wallace, Ferraz, & Muscara, 2012 ). For example, Alshorafa et al. ( 2012 ) reported that treatment of HaCaT cells with the spontaneous H2S donor NaHS resulted in significant inhibition of the TNF-α-induced up-regulation of inducible NOS, IL-6, and IL-8 in a dose-dependent manner, via suppression of p38 MAPK, ERK, and NF-κB activation pathways. The study from Shimizu et al. ( 2013 ) showed that in mice with the cutaneous Arthus reaction, the exogenous application of NaHS resulted in attenuated inflammatory reaction, TNF-α and IFN-γ expression, and reduced number of neutrophils recruited to the skin lesions.

H2S also plays an important role on the pruritogenic response. We have previously shown that inhibition of endogenous H2S synthesis with β-cyano- l -alanine (a CSE/CBS inhibitor) results in significant potentiation of the scratching behavior induced by compound 48/80 in mice, along with increased neutrophil recruitment, as measured by myeloperoxidase activity (Rodrigues et al., 2017 ). Moreover, H2S donors can have important therapeutic applications for treatment of both histaminergic and non-histaminergic pruritus in mice (Coavoy-Sánchez et al., 2016 Rodrigues et al., 2017 ). Regarding the histaminergic pathway, the H2S donors sodium sulfide (Na2S) and Lawesson's reagent (Figure 1) significantly reduced the pruritus induced in mice by the intradermal injection of either histamine or the mast cell degranulator compound 48/80, and these effects were, at least in part, mediated by stabilization of mast cells (Rodrigues et al., 2017 ). When histamine-independent pruritus was induced by the activation of PAR2 with the peptide agonist SLIGRL-NH2, the response was effectively reduced by NaHS, via ATP-sensitive potassium channel opening and involving the participation of NO (in a cGMP-independent manner). Furthermore, in this model, TRPA1 cation channels mediate the PAR2-induced pruritus, but H2S does not interfere with this pathway (Coavoy-Sánchez et al., 2016 ).

On the other hand, pro-pruriceptive effects of H2S have also been reported in the literature. The study by Wang et al. ( 2015 ) showed that the spontaneous H2S donors NaHS and Na2S (at doses within the μmol·kg −1 range Figure 1) can induce intense scratching behaviour by the activation of T-type calcium channels in a dose-dependent manner. Again, these apparently contradictory data can be explained not only on the basis of the high doses of the H2S donors used, but also by taking into account the chemical characteristics of these donors. While H2S production in vivo follows a slow kinetic profile, the administration of spontaneous H2S donors will instantaneously yield very high amounts of this mediator, thus more closely resembling a toxic exposure to H2S than its physiological production.

The cytoprotective effects of H2S in the skin have been demonstrated in in vitro experiments with HaCaT cell cultures. In a chemical hypoxia-induced cell injury model, Yang et al. ( 2011 ) showed that the addition of NaHS significantly reduced cell injury and the inflammatory responses, as shown by the increased cell viability and GSH levels, and decreased ROS generation and reduced production of IL-1, IL-6, and IL-8. In addition, NaHS markedly reduced cobalt(II) chloride-induced COX-2 overexpression, PGE2 production, and NF-κB activation. In another study, the same group (Yang et al., 2014 ) showed that NSHD-1 (an N-mercapto-based H2S donor Figure 1) is able to protect HaCaT cells from methylglyoxal-induced injury and dysfunction. The anti-apoptotic effects of H2S were reported an in vitro model of cutaneous tissue transplantation (Henderson et al., 2010 ), where NaHS significantly decreased the apoptosis of 3T3 fibroblast cells in response to ischaemia–reperfusion injury.

4.3 Dermal wound healing and angiogenesis

Dermal wound healing is a physiological process that restores the anatomical structure and function of injured skin. It is a complex process that involves an early inflammatory reaction, angiogenesis, collagen deposition, formation of granulation tissue, re-epithelialization, and tissue remodelling. Several studies have recognized H2S as a molecule that accelerates the dermal wound healing process. For example, Cai et al. ( 2007 ) investigated the role of H2S in angiogenesis in a series of in vitro and in vivo experiments. Treatment of RF/6A endothelial cells with NaHS resulted in increased cell proliferation, migration, scratched wound healing, and tube-like structure formation, the last two processes being dependent on Akt phosphorylation. The effects of H2S on angiogenesis in vivo were assessed using a Matrigel plug assay in mice, as the intraperitoneal injection of 10 μmol·kg −1 ·day −1 NaHS (but not 200 μmol·kg −1 ·day −1 ) caused a significant increase in cellular infiltration, neovascularization, and Hb content, thus characterizing the pro-angiogenic effects of the H2S donor at low doses.

In another study, Papapetropoulos et al. ( 2009 ) conclude that endogenous H2S is a pro-healing factor, as this process was shown to be significantly delayed in CSE −/− mice. In this study, mice had 5% of their total body surface area burned by scalding, and throughout the observation period, wound areas in CSE +/+ mice were consistently smaller than in CSE −/− mice. Moreover, the topical administration of NaHS accelerated the healing process (closure) of rat skin wounds caused by burning. Furthermore, Coletta et al. ( 2015 ) reported that the in vitro treatment of bEnd3 microvascular endothelial cells with 3-mercaptopyruvate (in order to increase 3MST-derived H2S) promoted angiogenesis. In vivo, this substrate also caused a sustained increase in neovascularization and facilitated wound closure in a burn wound model in rats. In a previous study using the same model, Coletta et al. ( 2012 ) reported that the administration of NaHS contributed to microvessel growth and promotes wound healing and that this effect was dependent on eNOS-derived NO.

Using in vitro wound healing-related assays, Saha et al. ( 2016 ) observed that HUVEC in which CBS expression was knocked down demonstrated decreased migratory ability and wound closure rates. Liu et al. ( 2014 ) found that CSE expression was decreased in diabetic foot ulcers and that Type 2 diabetic db/db mice intraperitoneally treated with the H2S donors NaHS and 4-hydroxythiobenzamide (Figure 1) showed significantly improved wound healing via restoration of the endothelial progenitor cell functions and activation of angiopoietin-1. Moreover, the study from Zhao et al. ( 2017 ) shows that in diabetic ob/ob mice, CSE expression and H2S content are significantly reduced in granulation tissues of wounds in comparison with the control animals and that treatment of these animals with intraperitoneal NaHS results in significantly improved wound healing, which was associated with reduced neutrophil and macrophage infiltration and decreased production of TNF-α and IL-6. NaHS treatment also led to decreased MMP-9 and increased collagen deposition and vascular-like structures in the granulation tissues of wounds in ob/ob mice.

A more recent study by Yang et al. ( 2019 ) shows that treatment with the H2S donor Na2S can also improve diabetic wound healing via inhibition of the release of neutrophil extracellular traps (NET a process known as NETosis), both in vivo and in vitro. The delayed wound healing observed in diabetic db/db mice was accelerated by intraperitoneal treatment with Na2S, in parallel with down-regulation of NET release and blockade of ROS-induced MAPK ERK1/2 and p38 activation. Wang et al. ( 2015 ) reported that in rats with streptozotocin-induced diabetes, topical treatment with a 2% NaHS-containing ointment resulted in accelerated wound healing, by promoting angiogenesis in the granulation tissues via augmented VEGF production. In addition, reduced TNF-α expression and leukocyte adhesion, and enhanced antioxidant effects (due to increased SOD activity and decreased lipoperoxidation) were also characterized as mediators of the beneficial effects of H2S on wound healing in diabetes.

Wu et al. ( 2016 ) developed nanofibres able to release H2S in a pH-dependent manner by electrospinning polycaprolactone (PCL) containing JK-1 (a pH-controlled H2S donor Figure 1). These H2S-releasing nanofibres (called “PCL-JK1”) were employed as a wound dressing in a murine model of cutaneous wound healing and found that such dressings enhanced wound repair and regeneration, including enhanced neovessel formation and increased collagen deposition. More recently, Lin et al. ( 2017 ) have produced an H2S-releasing depot formulation (termed “[email protected]”) for treatment of diabetic wounds. The formulation involves a microparticle system that comprises hydrophobic phase-change materials (1-tetradecanol and paraffin wax) that provide an in situ depot for the sustained release of H2S. The topical treatment of wounds in diabetic db/db mice with [email protected] promoted increased proliferation and migration of epidermal keratinocytes (re-epithelialization), as well as increased angiogenesis, by inducing a sustained phosphorylation of ERK1/2 and p38 and thus accelerating the healing of full-thickness wounds. Taken together, all these studies clearly show that H2S contributes to wound healing by attenuating inflammation and increasing angiogenesis.

4.4 Psoriasis

Alshorafa et al. ( 2012 ) showed that patients with psoriasis present with serum H2S levels significantly lower than those found in healthy subjects. In addition, in both primary psoriatic lesions and NCTC 2544 human keratinocytes, the H2S donor NaHS not only reduced basal expression and secretion of IL-8 but also interfered with that induced by IL-17 and IL-22 by reducing ERK phosphorylation levels (Mirandola et al., 2011 ). In line with these findings, we have observed that in a murine model of psoriasis (induced by the topical application of the immunomodulator imiquimod), the topical administration of a microemulsion system containing the slow-release H2S donor GYY-4137 (Figure 1) had beneficial effects by controlling pruritus, reducing neutrophil recruitment to the sites of lesion, and improving the clinical severity index of the disease (Schmidt et al., 2015 ).

4.5 Melanoma

Endogenous H2S has been involved in the regulation of cancer. Working with human melanoma samples, Panza et al. ( 2015 ) have shown that CSE expression is very high in primary tumours, low in metastatic lesions and almost silent in non-lymph node metastases. In fact, the primary role played by CSE was confirmed when it was observed that the overexpression of CSE in human melanoma cells led to spontaneous apoptosis. In this report, it is also shown that diallyl trisulfide (DATS, 100 μM, one of the active components present in garlic oil Figure 1) inhibits cellular proliferation of the human melanoma A375 cells (the most lethal type of skin cancer cells) via suppression of NF-κB activity and inhibition of Akt and ERK pathways. These results are supported by a proof of concept performed in vivo by using an animal melanoma model in which the administration of the CSE substrate l -cysteine (600 mg·kg −1 ) or the H2S donor DATS (50 mg·kg −1 ) significantly inhibited tumour growth in mice.

In an earlier study, Wang, Yang, Hsieh, and Sheen ( 2010 ), also making use of the human melanoma A375 cells as well as basal cell carcinoma cells (the most prevalent form). DATS (25 μM) inhibited growth of both cell types by increasing intracellular ROS generation and cytosolic Ca 2+ mobilization and by decreasing mitochondrial membrane potential without having significant effects on normal keratinocyte HaCaT cell growth. In a more recent study from the same group (Wang, Chu, Hsieh, & Sheen, 2017 ), DATS (at 10 and 25 μM) inhibited the invasion ability of A375 cells, lowered protein expression and activation of the metalloproteinases MMP-2 and MMP-9, and inhibited metastasis via regulation of F-actin aggregation. Moreover, DATS exerts inhibitory effects on A375 cell adhesion parallel to a decrease in protein expression of integrins α4, α5, αv, β1, β3, and β4 and activation of focal adhesion kinase, thus resulting in a non-migratory phenotype that could explain the antimetastatic potential of the H2S donor DATS.

De Cicco et al. ( 2017 ) showed that acetyl deacylasadisulfide (100 μM Figure 1), a natural H2S donor isolated from the latex of the plant Ferula assa-foetida, can induce apoptosis of the human melanoma cell lines PES 43 and A375 via reduction of NF-κB activity, decreased expression of the anti-apoptotic proteins c-FLIP, X-linked inhibitor of apoptosis protein, and Bcl-2, and inhibition of the phosphorylation and activation of both Akt and ERK proteins. In a previous investigation, this group observed that the hybrid compound ATB-346 (100 μM Figure 1), an H2S-releasing naproxen derivative, inhibits human melanoma cell proliferation by inhibiting pro-survival pathways associated with NF-κB and Akt activation. Furthermore, oral administration of ATB-346 (43 μmol·kg −1 ) to mice resulted in significant growth delay of the melanoma tumours (up to 70%), without affecting body weight (De Cicco et al., 2016 ). In a recently published study from the same group, Ercolano et al. ( 2019 ) show that another H2S-releasing naproxen derivative, naproxen-4-hydroxybenzodithioate (naproxen-HBTA at 10 and 30 μM Figure 1), induced caspase 3-mediated apoptosis and inhibited human melanoma cell proliferation, migration, invasion, and colony formation in vitro. In addition, the authors also show the beneficial effects, in vivo, of this H2S-releasing naproxen derivative, as the daily oral treatment of mice with 14.5 mg·kg −1 of naproxen-HBTA resulted in significant suppression of melanoma growth and progression.

Although the antiproliferative effects of increased production of CSE-derived H2S were reported, the study from Leikam et al. ( 2014 ) showed that CSE overexpression in tumour cells had pro-tumorigenic functions and that the blockade of CSE enzymic activity in human melanoma cells not only reduced proliferation rates and enhanced cell sensitivity to H2O2 but also induced senescence. Therefore, the role of CSE-derived H2S on tumour regulation cannot be absolutely defined as this may be related to the actual amounts of H2S produced by this enzyme in the different cell systems studied, bearing in mind the U-shaped pattern of the dose-concentration–response curves that H2S usually shows in many experimental models and systems.


Physiological role of hydrogen sulfide and polysulfide in the central nervous system.

Hydrogen sulfide (H2S) is a well-known toxic gas that has the smell of rotten eggs. This pungent gas was considered as a physiological mediator, after the identification of endogenous sulfides in the mammalian brain. H2S is produced from L-cysteine by enzymes such as cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3MST) along with cysteine aminotransferase (CAT). We recently identified a fourth pathway, where H2S is produced from D-cysteine by the enzyme D-amino acid oxidase (DAO) along with 3MST. We demonstrated that H2S is a neuromodulator that facilitates hippocampal long-term potentiation (LTP) by enhancing the activity of N-methyl-D-aspartate (NMDA) receptors. It also induces Ca(2+) influx in the astrocytes by activating the transient receptor potential ankyrin-1 (TRPA1) channels. In addition to being a signaling molecule, it also functions as a neuroprotective agent by enhancing the production of glutathione, a major intracellular antioxidant that scavenges the reactive oxygen species (ROS) in the mitochondria. H2S regulates the activity of the enzymes by incorporating the bound sulfane sulfur to cysteine residues. This modification is known as sulfhydration or sulfuration. The neuroprotective ubiquitin E3 ligase, parkin, enhances its neuroprotective activity by this modification. This review is focused on the functional role of H2S as a signaling molecule and as a cytoprotectant in the nervous system. In addition, this review shows the recent findings that indicate that the H2S-derived polysulfides found in the brain activate TRPA1 channels more potently than parental H2S.


Hydrogen sulfide helps maintain the drive to breathe

Effective regulation of breathing pattern is essential for many different mammalian processes such as energy production, metabolic regulation and even speech. Researchers have recently discovered that the body's production of hydrogen sulfide is important to generate a normal breathing pattern, potentially leading to new treatments for people suffering from breathing disorders such as central sleep apnea.

This result may seem surprising at first given that exposure to high levels of hydrogen sulfide can be toxic to mammalian health. However, hydrogen sulfide is produced in small quantities in the body by an enzyme called cystathionine β-synthase (CBS) and is believed to act as a bioactive gas to regulate different body functions. CBS is located in both the brain and in peripheral systems including arteries, veins and kidneys.

In a study published this month in Communications Biology, researchers from the University of Tsukuba further investigated the role of hydrogen sulfide as a bioactive gas in the body. First they looked at the effect of inhibiting the activity of the CBS enzyme in rats, thereby inhibiting the production of hydrogen sulfide. They found that this resulted in a change in the breathing patterns of the rats from a normal pattern to a gasping pattern. From this, the researchers concluded that the production of hydrogen sulfide allows the regions of the brain that are responsible for controlling breathing patterns to function normally.

Breathing normally requires cells located throughout the body to sense internal levels of oxygen and carbon dioxide and communicate this information to specific brain regions that control breathing rate and pattern. To determine how the different areas of the body are affected by hydrogen sulfide, researchers used different compounds to selectively block the production of hydrogen sulfide in the brain or in peripheral cells.

"Hydrogen sulfide produced by CBS enables neurons located in the brain regions that regulate breathing to communicate," explains Professor Tadachika Koganezawa, the senior researcher on the study. "Without hydrogen sulfide, the centers of the brain responsible for controlling breathing were not able to maintain the neural network to generate normal breathing pattern." The researchers found that these effects were specific to the brain, as inhibition of hydrogen sulfide in peripheral cells had no effect.

By unraveling the effect of hydrogen sulfide in the brain centers that control breathing, researchers can now begin to explore the potential role of hydrogen sulfide in disorders that affect breathing such as central sleep apnea or hyperventilation.

More information: Minako Okazaki et al. Endogenous hydrogen sulfide maintains eupnea in an in situ arterially perfused preparation of rats, Communications Biology (2020). DOI: 10.1038/s42003-020-01312-6


Rotten Egg Gas May Be Key to Human Longevity

Hydrogen sulfide may have an effect on the age-related gene Klotho to promote longevity. Klotho can improve longevity by inhibiting IIS signaling, inducing FOXO (forkhead box proteins) derepression, and decreasing angiotensin II-induced oxidative stress (Zhang Y et al)

Hydrogen sulfide (H2S) is a colorless, poisonous, flammable gas with the characteristic foul odor of rotten eggs. A few breaths of air containing high levels of this gas can cause death. Lower, longer-term exposure can cause eye irritation, headache, and fatigue.

Human body produces small amounts of hydrogen sulfide and uses it as a signaling molecule.

“Hydrogen sulfide is produced within the human body, and has a variety of important physiological effects. For example, it relaxes the vascular endothelium and smooth muscle cells, which is important to maintaining clean arteries as one ages,” said Dr Zhi-Sheng Jiang of the University of South China’s Institute of Cardiovascular Disease, senior author of the paper published in the journal Molecular and Cellular Biology (full paper).

“H2S has been gaining increasing attention as an important endogenous signaling molecule because of its significant effects on the cardiovascular and nervous systems.”

Dr Jiang said the evidence is mounting that hydrogen sulfide slows aging by inhibiting free-radical reactions, by activating SIRT1, an enzyme believed to be a regulator of lifespan, and probably through its interactions with a gene age-related called Klotho, which appears to have its own market basket of anti-aging activity.

The gene Klotho, which appears to be upregulated by hydrogen sulfide, is thought to extend lifespan via a number of different pathways, some of which promote production of endogenous antioxidants, according to the scientists.

“Produced in the kidneys, it has direct angiotensin-converting enzyme (ACE) inhibiting activity that is, it’s an ACE inhibitor, just like certain drugs that mitigate high blood pressure. Not surprisingly, plasma hydrogen sulfide declines with age, and is lower in spontaneously hypertensive rats than in those with normal blood pressure. More generally, a lack of hydrogen sulfide is implicated in cardiovascular disease.”

A decline in hydrogen sulfide is also thought to undermine neurological health. Endogenous hydrogen sulfide has been found wanting in an animal model of Parkinson’s disease, and is found to be depressed in the brains of patients with Alzheimer’s disease. There are even suggestions, mostly in animal models, but also in human studies, that hydrogen sulfide may be protective against cancer.

“Data available so far strongly suggest that H2S may become the next potent agent for preventing and ameliorating the symptoms of aging and age-associated diseases,” Dr Jiang said. “In the future, people may take H2S via food, or as an anti-aging supplement.”

Bibliographic information: Zhang Y et al. Hydrogen sulfide: the next potent preventive and therapeutic agent in aging and age-associated diseases. Mol. Cell. Bio., published online ahead of print January 07, 2013 doi: 10.1128/MCB.01215-12


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