Central sleep apnea and exposure to ambient hydrogen sulfide emissions from massive strandings of decomposing sargassum in the Caribbean.

BACKGROUND: Sargassum invasion of Caribbean and American shorelines is a recurring environmental hazard. Potential health effects of long-term chronic exposure to sargassum gaseous emissions, notably hydrogen sulfide (H2S), are overlooked. H2S plays an important role in neurotransmission and is involved in generating and transmitting respiratory rhythm. Central sleep apnea (CSA) has been attributed to the depression of respiratory centers. OBJECTIVE: Evaluate the effects of exposure to sargassum-H2S on CSA. METHODS: This study, set in the Caribbean, describes the clinical and polysomnographic characteristics of individuals living and/or working in areas impacted by sargassum strandings, in comparison with non-exposed subjects. Environmental exposure was estimated by the closest ground H2S sensor. Multivariate linear regression was applied to analyze CSA changes according to cumulative H2S exposure over time. Effects of air pollution and other sargassum toxic compounds (NH3) on CSA were also controlled. RESULTS: Among the 685 study patients, 27 % were living and/or working in sargassum impacted areas. Compared with non-exposed patients, exposed ones had similar sleep apnea syndrome risk factors, but had increased levels of CSA events (expressed as absolute number or % of total sleep apnea). Multivariate regression retained only male gender and mean H2S concentration over a 6-month exposure period as independent predictors of an increase in CSA events. A minimal exposure length of 1 month generated a significant rise in CSA events, with the latter increasing proportionally with a cumulative increase in H2S concentration over time. CONCLUSION: This pioneer work highlights a potential effect of sargassum-H2S on the central nervous system, notably on the modulation of the activity of the brain's respiratory control center. These observations, jointly with previous studies from our group, constitute a body of evidence strongly supporting a deleterious effect of sargassum-H2S on the health of individuals chronically exposed to low to moderate concentration levels over time.

Respiratory and nervous system effects of a hydrogen sulfide crisis in Carson, California.

BACKGROUND: In October 2021, many residents in Carson, California experienced malodors, headaches, and respiratory symptoms. Hydrogen sulfide (H2S), a toxic odorous gas, was measured in Carson at concentrations up to 7000 parts per billion (ppb) and remained above California's acute air quality standard of 30 ppb for about a month. Research on how low- and medium-level H2S exposure affects the respiratory and nervous systems has yielded conflicting results, and few studies have examined the effects of subacute H2S exposure. METHODS: We calculated daily rates of emergency department (ED) visits with various respiratory and nervous systems diagnosis codes in Carson area ZIP codes (≤6 km from event's epicenter) and in Los Angeles County ZIP codes >15 km from event's epicenter (control area). Using controlled interrupted time series, we compared ED visit rates during the month of the H2S crisis in Carson to the predicted rates had the incident not occurred, based on 2018-2021 ED trends, and controlling for ED visit rate changes in the control area. RESULTS: We observed a 24 % increase in ED visit rate for all respiratory system diseases (rate ratio = 1.24, 95 % CI: 1.16, 1.32), a 38 % increase for asthma (RR = 1.38, 95 % CI: 1.26, 1.50), a 26 % increase for acute upper respiratory infections (RR = 1.26, 95 % CI: 1.13, 1.38), a 21 % increase for dizziness (RR = 1.21, 95 % CI: 1.04, 1.38), and a 25 % increase for migraines and headaches (RR = 1.25, 95 % CI: 1.13, 1.36) in the Carson area during the first month of the H2S event compared to the expected rates. CONCLUSIONS: This H2S crisis was associated with increased ED visit rates for multiple respiratory and nervous system outcomes. Reducing H2S exposure and improving to response during H2S episodes may improve public health.

Selection on standing genetic variation mediates convergent evolution in extremophile fish.

Hydrogen sulfide is a toxic gas that disrupts numerous biological processes, including energy production in the mitochondria, yet fish in the Poecilia mexicana species complex have independently evolved sulfide tolerance several times. Despite clear evidence for convergence at the phenotypic level in these fishes, it is unclear if the repeated evolution of hydrogen sulfide tolerance is the result of similar genomic changes. To address this gap, we used a targeted capture approach to sequence genes associated with sulfide processes and toxicity from five sulfidic and five nonsulfidic populations in the species complex. By comparing sequence variation in candidate genes to a reference set, we identified similar population structure and differentiation, suggesting that patterns of variation in most genes associated with sulfide processes and toxicity are due to demographic history and not selection. But the presence of tree discordance for a subset of genes suggests that several loci are evolving divergently between ecotypes. We identified two differentiation outlier genes that are associated with sulfide detoxification in the mitochondria that have signatures of selection in all five sulfidic populations. Further investigation into these regions identified long, shared haplotypes among sulfidic populations. Together, these results reveal that selection on standing genetic variation in putatively adaptive genes may be driving phenotypic convergence in this species complex.

Low level exposure to hydrogen sulfide: a review of emissions, community exposure, health effects, and exposure guidelines.

Hydrogen sulfide (H2S) is a toxic gas that is well-known for its acute health risks in occupational settings, but less is known about effects of chronic and low-level exposures. This critical review investigates toxicological and experimental studies, exposure sources, standards, and epidemiological studies pertaining to chronic exposure to H2S from both natural and anthropogenic sources. H2S releases, while poorly documented, appear to have increased in recent years from oil and gas and possibly other facilities. Chronic exposures below 10 ppm have long been associated with odor aversion, ocular, nasal, respiratory and neurological effects. However, exposure to much lower levels, below 0.03 ppm (30 ppb), has been associated with increased prevalence of neurological effects, and increments below 0.001 ppm (1 ppb) in H2S concentrations have been associated with ocular, nasal, and respiratory effects. Many of the studies in the epidemiological literature are limited by exposure measurement error, co-pollutant exposures and potential confounding, small sample size, and concerns of representativeness, and studies have yet to consider vulnerable populations. Long-term community-based studies are needed to confirm the low concentration findings and to refine exposure guidelines. Revised guidelines that incorporate both short- and long-term limits are needed to protect communities, especially sensitive populations living near H2S sources.

A highly sensitive and low toxicity cellulose-based fluorescent polymer for H2S detection in cells, zebrafish and food samples.

A cellulose based polymer probe (HC-HS) was prepared for the detection of H2S. HC-HS can be applied to fluorescence imaging of H2S in living cells and zebrafish, and HC-HS was made into test strips to detect H2S produced in the process of food corruption.

Preliminary study on the acute effects of hydrogen sulfide on Amphipoda (Lysianassoidea; Pseudorchomene sp. and Anonyx sp.) collected from deep-sea floors in the Sea of Japan.

To study the environmental impact of the assessment technologies for the development of shallow methane hydrate zones in the Sea of Japan, deep-sea amphipods (Pseudorchomene sp. and Anonyx sp.) were collected from a depth of approximately 1000 m and were tested for H2S toxicity. At 0.57 mg L-1 H2S, all specimens of Pseudorchomene sp. were dead after 96 h, whereas all individuals survived at 0.18 mg L-1. Moreover, Anonyx sp. had a survival rate of 17 % after 96 h at 0.24 mg L-1. A similar toxicity test was conducted with the coastal amphipod Merita sp., a detritivore, and all individuals died within 24 h at 0.15 mg L-1. These results suggested that compared with coastal detritivorous amphipods, deep-sea detritivorous amphipods, which also live near biomats with sediment H2S concentrations exceeding 10 mg L-1, showed a higher tolerance to H2S.

Acute hydrogen sulfide-induced neurochemical and morphological changes in the brainstem.

Hydrogen sulfide (H2S) is a toxin affecting the cardiovascular, respiratory, and central nervous systems. Acute H2S exposure is associated with a high rate of mortality and morbidity. The precise pathophysiology of H2S-induced death is a controversial topic; however, inhibition of the respiratory center in the brainstem is commonly cited as a cause of death. There is a knowledge gap on toxicity and toxic mechanisms of acute H2S poisoning on the brainstem, a brain region responsible for regulating many reflective and vital functions. Serotonin (5-HT), dopamine (DA), and γ-aminobutyric acid (GABA) play a role in maintaining a normal stable respiratory rhythmicity. We hypothesized that the inhibitory respiratory effects of H2S poisoning are mediated by 5-HT in the respiratory center of the brainstem. Male C57BL/6 mice were exposed once to an LCt50 concentration of H2S (1000 ppm). Batches of surviving mice were euthanized at 5 min, 2 h, 12 h, 24 h, 72 h, and on day 7 post-exposure. Pulmonary function, vigilance state, and mortality were monitored during exposure. The brainstem was analyzed for DA, 3,4-dehydroxyphenyl acetic acid (DOPAC), 5-HT, 5-hydroxyindoleatic acid (5-HIAA), norepinephrine (NE), GABA, glutamate, and glycine using HPLC. Enzymatic activities of monoamine oxidases (MAO) were also measured in the brainstem using commercial kits. Neurodegeneration was assessed using immunohistochemistry and magnetic resonance imaging. Results showed that DA and DOPAC were significantly increased at 5 min post H2S exposure. However, by 2 h DA returned to normal. Activities of MAO were significantly increased at 5 min and 2 h post-exposure. In contrast, NE was significantly decreased at 5 min and 2 h post-exposure. Glutamate was overly sensitive to H2S-induced toxicity manifesting a time-dependent concentration reduction throughout the 7 day duration of the study. Remarkably, there were no changes in 5-HT, 5-HIAA, glycine, or GABA concentrations. Cytochrome c oxidase activity was inhibited but recovered by 24 h. Neurodegeneration was observed starting at 72 h post H2S exposure in select brainstem regions. We conclude that acute H2S exposure causes differential effects on brainstem neurotransmitters. H2S also induces neurodegeneration and biochemical changes in the brainstem. Additional work is needed to fully understand the implications of both the short- and long-term effects of acute H2S poisoning on vital functions regulated by the brainstem.

SOD1 is an essential H2S detoxifying enzyme.

Although hydrogen sulfide (H2S) is an endogenous signaling molecule with antioxidant properties, it is also cytotoxic by potently inhibiting cytochrome c oxidase and mitochondrial respiration. Paradoxically, the primary route of H2S detoxification is thought to occur inside the mitochondrial matrix via a series of relatively slow enzymatic reactions that are unlikely to compete with its rapid inhibition of cytochrome c oxidase. Therefore, alternative or complementary cellular mechanisms of H2S detoxification are predicted to exist. Here, superoxide dismutase [Cu-Zn] (SOD1) is shown to be an efficient H2S oxidase that has an essential role in limiting cytotoxicity from endogenous and exogenous sulfide. Decreased SOD1 expression resulted in increased sensitivity to H2S toxicity in yeast and human cells, while increased SOD1 expression enhanced tolerance to H2S. SOD1 rapidly converted H2S to sulfate under conditions of limiting sulfide; however, when sulfide was in molar excess, SOD1 catalyzed the formation of per- and polysulfides, which induce cellular thiol oxidation. Furthermore, in SOD1-deficient cells, elevated levels of reactive oxygen species catalyzed sulfide oxidation to per- and polysulfides. These data reveal that a fundamental function of SOD1 is to regulate H2S and related reactive sulfur species.

A comprehensive review of treatments for hydrogen sulfide poisoning: past, present, and future.

Hydrogen sulfide (H2S) poisoning remains a significant source of occupational fatalities and is the second most common cause of toxic gas-induced deaths. It is a rapidly metabolized systemic toxicant targeting the mitochondria, among other organelles. Intoxication is mostly acute, but chronic or in-between exposure scenarios also occur. Some genetic defects in H2S metabolism lead to lethal chronic H2S poisoning. In acute exposures, the neural, respiratory, and cardiovascular systems are the primary target organs resulting in respiratory distress, convulsions, hypotension, and cardiac irregularities. Some survivors of acute poisoning develop long-term sequelae, particularly in the central nervous system. Currently, treatment for H2S poisoning is primarily supportive care as there are no FDA-approved drugs. Besides hyperbaric oxygen treatment, drugs in current use for the management of H2S poisoning are controversial. Novel potential drugs are under pre-clinical research development, most of which target binding the H2S. However, there is an acute need to discover new drugs to prevent and treat H2S poisoning, including reducing mortality and morbidity, preventing sequalae from acute exposures, and for treating cumulative pathology from chronic exposures. In this paper, we perform a comprehensive review of H2S poisoning including perspectives on past, present, and future.

Treatment of life-threatening H2S intoxication: Lessons from the trapping agent tetranitrocobinamide.

We sought to evaluate the efficacy of trapping free hydrogen sulfide (H2S) following severe H2S intoxication. Sodium hydrosulfide solution (NaHS, 20 mg/kg) was administered intraperitoneally in 69 freely moving rats. In a first group (protocol 1), 40 rats were randomly assigned to receive saline (n = 20) or the cobalt compound tetranitrocobinamide (TNCbi) (n = 20, 75 mg/kg iv), one minute into coma, when free H2S was still present in the blood. A second group of 27 rats received TNCbi or saline, following epinephrine, 5 min into coma, when the concentration of free H2S has drastically decreased in the blood. In protocol 1, TNCbi significantly increased immediate survival (65 vs 20 %, p < 0.01) while in protocol 2, administration of TNCbi led to the same outcome as untreated animals. We hypothesize that the decreased efficacy of TNCbi with time likely reflects the rapid spontaneous disappearance of the pool of free H2S in the blood following H2S exposure.

The participation of nitric oxide in hydrogen sulphide-mediated chromium tolerance in pepper (Capsicum annuum L) plants by modulating subcellular distribution of chromium and the ascorbate-glutathione cycle.

The promising response of chromium-stressed (Cr(VI)-S) plants to hydrogen sulphide (H2S) has been observed, but the participation of nitric oxide (NO) synthesis in H2S-induced Cr(VI)-S tolerance in plants remains to be elucidated. It was aimed to assess the participation of NO in H2S-mediated Cr(VI)-S tolerance by modulating subcellular distribution of Cr and the ascorbate-glutathione (AsA-GSH) cycle in the pepper seedlings. Two weeks following germination, plants were exposed to control (no Cr) or Cr(VI)-S (50 µM K2Cr2O7) for further two weeks. The Cr(VI)-S-plants grown in nutrient solution were supplied with 200 µM sodium hydrosulphide (NaHS, donor of H2S), or NaHS plus 100 µM sodium nitroprusside (SNP, a donor of NO). Chromium stress suppressed plant growth and leaf water status, while elevated proline content, oxidative stress, and the activities of AsA-GSH related enzymes, as well as endogenous H2S and NO contents. The supplementation of NaHS increased Cr accumulation at root cell walls and vacuoles of leaves as soluble fraction to reduce its toxicity. Furthermore it limited oxidative stress, improved plant growth, modulated leaf water status, and the AsA-GSH cycle-associated enzymes' activities, as well as it further improved H2S and NO contents. The positive effect of NaHS was found to be augmented on those parameters in the CrS-plants by the SNP supplementation. However, 0.1 mM cPTIO, the scavenger of NO, inverted the prominent effect of NaHS by decreasing NO content. The supplementation of SNP along with NaHS + cPTIO reinstalled the positive effect of NaHS by restoring NO content, which suggested that NO might have a potential role in H2S-induced tolerance to Cr(VI)-S in pepper plants by stepping up the AsA-GSH cycle.

Methemoglobin-albumin clusters for the treatment of hydrogen sulfide intoxication.

Hydrogen sulfide (H2S) has attracted significant attention as a seed in drug development. However, H2S is toxic and induces lethal acute intoxication. Here, we developed methemoglobin (metHb)-albumin clusters as detoxifying agents for H2S intoxication, which were designed based on the inherent binding property of metHb with H2S. The metHb-albumin clusters comprising an autoxidized ferric Hb center wrapped covalently with an average of three human serum albumins showed a similar H2S binding affinity to that of naked metHb. Owing to the H2S binding capability, metHb-albumin clusters suppressed cell death induced by H2S exposure while maintaining mitochondrial function in H9c2 cells. In addition, lethal H2S intoxication model mice were rescued by a single administration of metHb-albumin clusters, resulting from the recovery of cytochrome c oxidase activity. Furthermore, the metHb-albumin clusters possessed essential characteristics, such as adequate pharmacokinetic properties and biocompatibility, for their use as detoxifying agents against H2S intoxication. In conclusion, the results obtained in this study suggest that metHb-albumin clusters are promising detoxifying agents for H2S intoxication and that harnessing the inherent H2S binding properties of metHb is an innovative approach to develop detoxifying agents for H2S intoxication.

A nitrobenzoxadiazole-based near-infrared fluorescent probe for the specific imaging of H2S in inflammatory and tumor mice.

As a common gaseous signaling molecule, hydrogen sulfide (H2S) plays a vital role in physiology and pathology. The development of fluorescent probes for detecting H2S has attracted widespread attention. However, most of the reported fluorescent probes with nitrobenzoxadiazole (NBD) as the recognition group have been widely used to simultaneously detect biothiols and H2S, instead of specifically detecting H2S. Herein, a novel NBD-based near-infrared (NIR) fluorescent probe named CX-N for the detection of H2S is synthesized. The selectivity of CX-N for H2S is significantly higher than that for biothiols and other potential interferences. After reacting with H2S, CX-N shows a significant increase in NIR fluorescence (75-fold), large Stokes shift (155 nm) and fast response (4 min). And the possible response mechanism of CX-N to H2S is given and confirmed by HPLC and HRMS. Based on the low cytotoxicity of CX-N, it has been used for H2S imaging in live cells and zebrafish. More importantly, CX-N has also been successfully applied for the real-time imaging of H2S in inflammatory and tumor mice based on its NIR emission, which provides a reliable platform for the specific recognition of H2S in complex biological systems.

Hydrogen sulfide manages hexavalent chromium toxicity in wheat and rice seedlings: The role of sulfur assimilation and ascorbate-glutathione cycle.

The role of hydrogen sulfide (H2S) is well known in the regulation of abiotic stress such as toxic heavy metal. However, mechanism(s) lying behind this amelioration are still poorly known. Consequently, the present study was focused on the regulation/mitigation of hexavalent chromium (Cr(VI) toxicity by the application of H2S in wheat and rice seedlings. Cr(VI) induced accumulation of reactive oxygen species and caused protein oxidation which negatively affect the plant growth in both the cereal crops. We noticed that Cr(VI) toxicity reduced length of wheat and rice seedlings by 21% and 19%, respectively. These reductions in length of both the cereal crops were positively related with the down-regulation in the ascorbate-glutathione cycle, and were recovered by the application NaHS (a donor of H2S). Though exposure of Cr(VI) slightly stimulated sulfur assimilation but addition of H2S further caused enhancement in sulfur assimilation, suggesting its role in the H2S-mediated Cr(VI) stress tolerance in studied cereal crops. Overall, the results revealed that H2S renders Cr(VI) stress tolerance in wheat and rice seedlings by stimulating sulfur assimilation and ascorbate-glutathione which collectively reduce protein oxidation and thus, improved growth was observed.

Toxicity of Hydrogen Sulfide on Rat Brain Neurons.

Hydrogen sulfide (H2S) is a toxic compound known as a member of the gasotransmitter family. H2S has the ability to inhibit the cytochrome c oxidase enzyme in the mitochondrial respiratory chain. Mitochondria play an important role in energy production and the brain needs energy for normal function. Mitochondrial dysfunction is associated with neurodegenerative diseases. This study investigated the mechanisms of cytotoxicity induced by H2S in brain neurons. thioacetamide has been used to produce H2S in water solutions. The results of the study showed that thioacetamide at concentrations of 116, 232 and 464 µg/ml was able to increase the level of reactive oxygen species (ROS), collapse in mitochondrial membrane potential (MMP), damage to the lysosomal membrane, increase in the level of oxidized glutathione (GSSG) and decrease in the level of reduced glutathione (GSH) in brain neurons. The results of the study suggested that H2S causes damage to mitochondria and lysosomes in brain neurons that could be associated with neurodegenerative diseases.

A water-soluble near-infrared fluorescent probe for monitoring change of hydrogen sulfide during cell damage and repair process.

As a signal molecule involved in autophagy, hydrogen sulfide (H2S) is considered to be essential in the development and treatment of diseases. In order to clarify the complex role of H2S in organism and the participation of H2S in disease process, it is urgently needed to visualize the dynamics of H2S. In this contribution, a water-soluble near-infrared (695 nm emission) self-immolative fluorescent probe CySO3N3 was constructed for H2S detection. The ability of self-immolative strategy to detect H2S was verified to increase the metabolic capacity and reduce the toxicity of probe. This probe can not only be used to detect H2S in living cell and mice, but also shows great potential in detecting H2S changes to monitor cell self-repair during inflammation and myocardial injury.

Regulating of LncRNA2264/miR-20b-5p/IL17RD axis on hydrogen sulfide exposure-induced inflammation in broiler thymus by activating MYD88/NF-κB pathway.

Hydrogen sulfide (H2S) is an environmental pollutant. Chronic exposure to H2S can damage the immune system of birds, but the detailed mechanisms of H2S-induced thymus toxicity have not been determined. Competitive endogenous RNA (ceRNA) mechanism participates in many pathophysiological processes by regulating gene expression, including environmental pollutant-induced injury. Therefore, we investigate the specific mechanisms of ceRNA in the process of H2S-induced thymic immune damage in broiler chickens. In the current study, 120 one-day-old male Ross 308 broilers were randomly divided into two groups (n = 60 chickens/group), raising in the control chamber (0.5 ± 0.5 ppm) or H2S-exposed chamber (4.0 ± 0.5 ppm at 0-3 weeks of age and 20.0 ± 0.5 ppm at 4-6 weeks of age groups) to replicate the H2S-exposed broilers. NaHS (3 mM or 6 mM) was used to treat chicken macrophages (HD11) to establish an in vitro. Histopathology and ultrastructural changes of thymus were assessed by hematoxylin and eosin (H&E) staining and transmission electron microscopy (TEM). Gene expression profiles were analyzed by using transcriptomics. The underlying mechanisms of thymic injury were further revealed by dual luciferase reporter gene assay, qRT-PCR and Western blotting. Research results showed that H2S exposure induced an inflammatory response in thymus, with the expression of LncRNA2264 was significantly down-regulated. LncRNA2264 could competitively bind to miR-20b-5p and caused downregulation of the IL17RD. H2S could activate inflammatory factors through the LncRNA2264/miR-20b-5p/IL17RD axis. In summary, this study suggested that LncRNA2264 acted as a miR-20b-5p molecular sponge to regulate the expression of IL17RD involved in H2S exposure-induced thymic inflammation, which has positive implications for guiding the prevention and control of H2S gas poisoning in livestock housing and ensuring animal welfare.

Hydrogen sulfide as a potent scavenger of toxicant acrolein.

Acrolein (ACR) is a metabolic byproduct in vivo and a ubiquitous environmental toxicant. It is implicated in the initiation and development of many diseases through multiple mechanisms, including the induction of oxidative stress. Currently, our understanding of the body defense mechanism against ACR toxicity is still limited. Given that hydrogen sulfide (H2S) has strong antioxidative actions and it shares several properties of ACR scavenger glutathione (GSH), we, therefore, tested whether H2S could be involved in ACR detoxification. Taking advantage of two cell lines that produced different levels of endogenous H2S, we found that the severity of ACR toxicity was reversely correlated with H2S-producing ability. In further support of the role of H2S, supplementing cells with exogenous H2S increased cell resistance to ACR, whereas inhibition of endogenous H2S sensitized cells to ACR. In vivo experiments showed that inhibition of endogenous H2S with CSE inhibitor markedly increased mouse susceptibility to the toxicity of cyclophosphamide and ACR, as evidenced by the increased mortality and worsened organ injury. Further analysis revealed that H2S directly reacted with ACR. It promoted ACR clearance and prevented ACR-initiated protein carbonylation. Collectively, this study characterized H2S as a presently unrecognized endogenous scavenger of ACR and suggested that H2S can be exploited to prevent and treat ACR-associated diseases.

Extracellular cysteines C226 and C232 mediate hydrogen sulfide-dependent inhibition of Orai3-mediated store-operated calcium entry.

The gaseous signaling molecule hydrogen sulfide (H2S) physiologically regulates store-operated Ca2+ entry (SOCE). The SOCE machinery consists of the plasma membrane-localized Orai channels (Orai1-3) and endoplasmic reticulum-localized stromal interaction molecule (STIM)1 and STIM2 proteins. H2S inhibits Orai3- but not Orai1- or Orai2-mediated SOCE. The current objective was to define the mechanism by which H2S selectively modifies Orai3. We measured SOCE and STIM1/Orai3 dynamics and interactions in HEK293 cells exogenously expressing fluorescently tagged human STIM1 and Orai3 in the presence and absence of the H2S donor GYY4137. Two cysteines (C226 and C232) are present in Orai3 that are absent in the Orai1 and Orai2. When we mutated either of these cysteines to serine, alone or in combination, SOCE inhibition by H2S was abolished. We also established that inhibition was dependent on an interaction with STIM1. To further define the effects of H2S on STIM1/Orai3 interaction, we performed a series of fluorescence recovery after photobleaching (FRAP), colocalization, and fluorescence resonance energy transfer (FRET) experiments. Treatment with H2S did not affect the mobility of Orai3 in the membrane, nor did it influence STIM1/Orai3 puncta formation or STIM1-Orai3 protein-protein interactions. These data support a model in which H2S modification of Orai3 at cysteines 226 and 232 limits SOCE evoked upon store depletion and STIM1 engagement, by a mechanism independent of the interaction between Orai3 and STIM1.

Quantitative proteomics reveals tissue-specific toxic mechanisms for acute hydrogen sulfide-induced injury of diverse organs in pig.

Hydrogen sulfide (H2S) is a highly toxic gas in many environmental and occupational places. It can induce multiple organ injuries particularly in lung, trachea and liver, but the relevant mechanisms remain poorly understood. In this study, we used a TMT-based discovery proteomics to identify key proteins and correlated molecular pathways involved in the pathogenesis of acute H2S-induced toxicity in porcine lung, trachea and liver tissues. Pigs were subjected to acute inhalation exposure of up to 250 ppm of H2S for 5 h for the first time. Changes in hematology and biochemical indexes, serum inflammatory cytokines and histopathology demonstrated that acute H2S exposure induced organs inflammatory injury and dysfunction in the porcine lung, trachea and liver. The proteomic data showed 51, 99 and 84 proteins that were significantly altered in lung, trachea and liver, respectively. Gene ontology (GO) annotation, KEGG pathway and protein-protein interaction (PPI) network analysis revealed that acute H2S exposure affected the three organs via different mechanisms that were relatively similar between lung and trachea. Further analysis showed that acute H2S exposure caused inflammatory damages in the porcine lung and trachea through activating complement and coagulation cascades, and regulating the hyaluronan metabolic process. Whereas antigen presentation was found in the lung but oxidative stress and cell apoptosis was observed exclusively in the trachea. In the liver, an induced dysfunction was associated with protein processing in the endoplasmic reticulum and lipid metabolism. Further validation of some H2S responsive proteins using western blotting indicated that our proteomics data were highly reliable. Collectively, these findings provide insight into toxic molecular mechanisms that could potentially be targeted for therapeutic intervention for acute H2S intoxication.