key: cord-0945499-vwqvfcb2
authors: Merz, Tamara; McCook, Oscar; Brucker, Cosima; Waller, Christiane; Calzia, Enrico; Radermacher, Peter; Datzmann, Thomas
title: H(2)S in Critical Illness—A New Horizon for Sodium Thiosulfate?
date: 2022-04-04
journal: Biomolecules
DOI: 10.3390/biom12040543
sha: 9adb3b5fb0ee4d201dafae9b5e685adad268c92f
doc_id: 945499
cord_uid: vwqvfcb2

Ever since the discovery of endogenous H(2)S and the identification of its cytoprotective properties, efforts have been made to develop strategies to use H(2)S as a therapeutic agent. The ability of H(2)S to regulate vascular tone, inflammation, oxidative stress, and apoptosis might be particularly useful in the therapeutic management of critical illness. However, neither the inhalation of gaseous H(2)S, nor the administration of inorganic H(2)S-releasing salts or slow-releasing H(2)S-donors are feasible for clinical use. Na(2)S(2)O(3) is a clinically approved compound with a good safety profile and is able to release H(2)S, in particular under hypoxic conditions. Pre-clinical studies show promise for Na(2)S(2)O(3) in the acute management of critical illness. A current clinical trial is investigating the therapeutic potential for Na(2)S(2)O(3) in myocardial infarct. Pre-eclampsia and COVID-19 pneumonia might be relevant targets for future clinical trials.

This review summarizes the current evidence for the therapeutic potential of sodium thiosulfate (Na 2 S 2 O 3 ), a clinically approved H 2 S donor with minimal side effects, in critical illness. H 2 S has a variety of biological roles, such as the regulation of vascular tone, as well as anti-oxidant and anti-inflammatory properties, which could exert a potential therapeutic benefit in intensive care. However, to date, the narrow therapeutic window and potential for toxic adverse effects have prevented the application of gaseous inhaled H 2 S in the clinical setting [1] [2] [3] [4] [5] . Other strategies for H 2 S administration, such as H 2 Sreleasing salts (NaHS and Na 2 S) and specifically developed H 2 S slow-releasing donors (such as GYY4137 and AP39) with a better pharmacokinetic profile, have similar limitations for clinical use [5] [6] [7] [8] . Na 2 S 2 O 3 is a detoxifying agent, which is clinically approved as an antidote for cyanide poisoning as well as chronic renal failure-induced calciphylaxis [9] and cisplatin overdose [10] . Na 2 S 2 O 3 can induce metabolic acidosis, but otherwise no major side effects have been reported [11] [12] [13] , thus Na 2 S 2 O 3 is a promising H 2 S donor for clinical use. The thiosulfate anion (S 2 O 3 2− ) is an endogenous oxidation product of H 2 S degradation, and, in turn, can serve as a source of H 2 S [14] . In particular, under hypoxic conditions, 3-mercaptopyruvate sulfurtansferase (3-MST) and rhodanese have been reported to be able to facilitate sulfide release from thiosulfate [14] . Cysteine-aminotransferase uses L-cysteine to form 3-mercapto-pyruvate, which is then used by 3-mercaptopyruvate-sulfurtransferase (MST) for mitochondrial H 2 S release. Sulfide quinone oxidoreductase (SQR) oxidizes H 2 S to persulfides in the mitochondria, and persulfides are further oxidized, which ultimately results in the formation of thiosulfate and sulfate. MST and rhodanese can re-generate H 2 S from thiosulfate, a process which can also happen non-enzymatically. Figure created in BioRender. Adapted from "Electron transport chain", by BioRender.com (2022). Retrieved from https://app.biorender.com/biorender-templates (accessed on 15 March 2022).

Given the tight interplay of O 2 and H 2 S availability, it is not surprising that H 2 S plays a role in mediating many consequences of hypoxia: e.g., regulation of vascular tone, inflammation, oxidative stress, and apoptosis, all of which are affected by critical illness. For example, hemorrhagic shock-induced tissue ischemia and hypoxemia can trigger systemic hyper-inflammation [26] , and reperfusion can cause ischemia/reperfusion injury (I/R), which contributes to systemic inflammation, oxidative stress, and multiple organ failure [27] . Even though the potential vaso-dilatory effects of H 2 S donors could aggravate shock-induced hypotension [7] , other beneficial H 2 S effects might outweigh that risk. Still, the optimal timing and dosing window of H 2 S donors in these conditions must be evaluated carefully. Exogenous H 2 S administration can be facilitated by using inorganic H 2 S-releasing salts (NaSH and Na 2 S), slow-releasing H 2 S donors (GYY4137, AP39), and preexisting clinically approved compounds, which have been recently identified to be able to release H 2 S (ammonium tetrathiomolybdate (ATTM), Na 2 S 2 O 3 ). H 2 S-releasing salts cause rapidly increasing, potentially toxic, peak H 2 S concentrations, which dissipate quickly [28] , can have pro-inflammatory effects [29] , and damage the mitochondria [20, 30] . Even when these peak concentrations are prevented, the therapeutic window for H 2 S-releasing salts is very narrow, which is why they are unsuitable for clinical use [4] [5] [6] 31] . In contrast, slow H 2 S-releasing donors seem to have different effects, in that they rather seem to ameliorate inflammation [29] . However, translationally relevant in vivo results for slow-releasing H 2 S donors also render them unlikely for clinical development, since they have failed to exert organ protection and/or even have adverse effects in these models so far [7, 8] , in spite of many promising pre-clinical studies in non-resuscitated rodents. ATTM showed organ protection in in vivo models of I/R [32, 33] . However, it is not clear if ATTM is superior to standard treatment, because these studies did not include standard ICU measures. Na 2 S 2 O 3 is a clinically available compound with a good safety profile [12] and is reportedly able to release H 2 S, in particular, under hypoxic conditions [14] . Further biochemical effects of STS are summarized in Figure 3 . Its potential to reduce oxidized glutathione and its effects on vascular tone might be of particular importance for therapeutic approaches in critical care. Thus, Na 2 S 2 O 3 is a promising candidate to bring H 2 S therapy in critical illness to the clinic. The following section will explore available literature reports of exogenous Na 2 S 2 O 3 administration in experimental models of critical illness. [34] , mediate vaso-dilation [35] , work as a calcium chelator [36] , and work as an antidote for cyanide [37] . Figure taken from [38] . Copyright 2019 Springer Nature Switzerland AG. Reprinted with permission.

Animal studies investigating the effects of Na 2 S 2 O 3 in models of critical illness are summarized in Table 1 .

In seven different ex vivo studies using the Langendorff rat heart model (i.e., isolated heart with retrograde perfusion with a nutrient-rich oxygenated buffer), with 30 min ischemia followed by 60 min reperfusion, a variety of beneficial effects of different modes of Na 2 S 2 O 3 administration have been reported. Both pre- [39] [40] [41] [42] and post-conditioning [43] or Na 2 S 2 O 3 administration starting with reperfusion [41, 42, 44] were reported to reduce cardiac injury, apoptosis [39, 43] , inflammatory markers [39] , and oxidative stress, [39, [42] [43] [44] and to protect cardiac mitochondria [39, 40, [42] [43] [44] , resulting in improved cardiac contractility [40, 44] in comparison to non-Na 2 S 2 O 3 -treated hearts. The same group of scientists was also able to confirm the beneficial pre-conditioning effects of Na 2 S 2 O 3 in in vivo rat model of myocardial I/R, i.e., left anterior descending artery ligation [39] and isoproterenolinduced myocardial infarction (MI) [45] . The beneficial effects of Na 2 S 2 O 3 in MI were also demonstrated in dogs [46] . In one of the in vivo rat MI studies, an additional beneficial effect on the brain-reduced apoptosis and oxidative stress associated with improved mitochondrial function-was determined [45] . Marutani et al. also reported a benefit of repeated i.p. Na 2 S 2 O 3 administration on the murine brain after cerebral I/R by bilateral common carotid artery occlusion: improved 20-day survival and better neuronal function in the treated animals [47] . 

In rats with 28 days of oral administration of Na 2 S 2 O 3 and adenine-induced vascular calcification, Na 2 S 2 O 3 treatment alleviated the calcification [54] . In this study, hearts from Na 2 S 2 O 3 -treated animals without vascular calcification were also characterized by reduced cardiac injury and diminished oxidative stress after the Langendorff I/R experiments [54] . However, this benefit of Na 2 S 2 O 3 did not extend to calcified hearts after I/R challenge [54] . Mohan et al. reported a beneficial effect of both oral preventative and therapeutic Na 2 S 2 O 3 on adenine-induced renal failure, which also rendered the mitochondria of treated animals more resistant to in vitro I/R [57] . Angiotensin-II (Ang-II)-induced hypertension, cardiac hypertrophy, and cardiac fibrosis was also alleviated by regular i.p. injections of Na 2 S 2 O 3 in rats, which were also associated with a reduction of oxidative stress [58] . In rats with l-NNAadministration, an inhibitor of nitric oxide synthases which causes hypertension and chronic heart disease, two weeks of oral administration of Na 2 S 2 O 3 ameliorated the hypertension, improved cardiac function [35] , and improved glomerular filtration [59] . Interestingly, the authors of these studies did not observe any metabolic acidosis associated with the oral administration of Na 2 S 2 O 3 in their animals, which is an advantage of oral administration over infusion [35] : patients with i.v. administration of Na 2 S 2 O 3 have been reported to develop metabolic acidosis [11, 60] . This begs the question of if oral administration is the preferable route of administration, even though oral Na 2 S 2 O 3 bioavailability seems much more limited when compared to i.v. infusion [12] . However, the effects of oral Na 2 S 2 O 3 on an acute injury in combination with the hypertension were not investigated by these groups. Chronic hypertension as a co-morbidity might worsen the patient's outcome after critical illness, but is, in itself, not a condition that is normally treated in the intensive care unit. These reported "long-term" benefits show promise for Na 2 S 2 O 3 as a therapeutic agent but are not feasible for the acute management of critical illness [35, 59] . However, it is tempting to speculate that "long-term" effects of oral Na 2 S 2 O 3 might still be associated with a benefit for the patient after an acute injury.

In models of endotoxemia, i.p. Na 2 S 2 O 3 post-treatment in mice led to improved survival [48] , attenuated lung inflammation [50] , and ameliorated neuroinflammation [51] . In animals with concomitant acute liver failure and LPS administration, Na 2 S 2 O 3 treatment decreased liver injury associated with anti-oxidant effects and preserved mitochondrial function [49] . In models of polymicrobial sepsis, Na 2 S 2 O 3 also had beneficial effects on the murine lung [50] and colonic and hepatic microcirculation in rats [55] . In contrast, in rabbits with E. coli septicemia and fluid resuscitation, Na 2 S 2 O 3 in combination with other antioxidants did not have a benefit [56] .

To date, the role of endogenous H 2 S-producing enzymes for the beneficial Na 2 S 2 O 3mediated effects is not entirely clear. In a study with mice with arteriovenous fistula (AVF)-induced chronic heart failure, the authors suggest that Na 2 S 2 O 3 exerted a benefit by attenuating the AVF-induced loss of CSE expression and thus enhancing endogenous H 2 S generation [61] . In the Langendorff heart model, a co-treatment with the CSE and CBS inhibitor l-propargylglycine (PAG) attenuated Na 2 S 2 O 3 effects [41] . In P. aeruginosa-induced sepsis, daily s.c. Na 2 S 2 O 3 injections for four days improved survival of wildtype mice, however, there was no survival benefit in CSE −/− mice in the same study [52] . These studies hint towards a critical role for CSE in mediating Na 2 S 2 O 3 effects. In contrast, in resuscitated CSE −/− mice with blunt chest trauma and hemorrhagic shock, Na 2 S 2 O 3 clearly reduced the vasopressor requirements needed to achieve hemodynamic targets, thereby attenuating lactic acidosis and both lung and kidney dysfunction [53] . However, in CSE −/− mice with diabetes type I as a co-morbidity undergoing the same kind of injury, this benefit of Na 2 S 2 O 3 was lost [62] (under review). Wildtype animals were not yet investigated in this context. Furthermore, in a translationally relevant porcine model of hemorrhagic shock with underlying atherosclerosis, Na 2 S 2 O 3 also exerted a benefit [13] . Here, it is important to point out that atherosclerosis is associated with a down-regulation of the endogenous H 2 S enzymes, which worsens the outcome of these animals from critical injury [63] [64] [65] . Even though these animals can be considered a large-animal analog to CSE −/− mice, with respect to their lack of CSE, they have reduced CSE expression and not a global knock out as the CSE −/− , thus the atherosclerotic pigs might still have residual CSE activity. Still, in the atherosclerotic pigs with hemorrhagic shock and subsequent intensive care management, i.v. administration of Na 2 S 2 O 3 during the first 24 h of resuscitation was associated with improved lung function at 48 and 72 h after hemorrhagic shock, which was associated with increased levels of glucocorticoid receptor expression in the lung [13] . Strikingly, the clinical benefit of Na 2 S 2 O 3 on lung function could not be observed in resuscitated cardiovascular healthy pigs after hemorrhagic shock [66] (unpublished data), which, in contrast to some of the results from mouse experiments, suggests a particular benefit from Na 2 S 2 O 3 for subjects with impaired CSE/impaired endogenous H 2 S availability.

Interestingly, in the atherosclerotic pigs, the beneficial effects manifested 24 h after the Na 2 S 2 O 3 had already been stopped, even though elevated sulfide levels were only detected immediately at the end of Na 2 S 2 O 3 administration, but not 24 h after the administration [13] . This begs the question of if the elevation of sulfide levels or the thiosulfate itself actually exerts the therapeutic benefit. In one of the abovementioned studies, the authors added Na 2 S 2 O 3 -treated groups only after observing that H 2 S inhalation in their study elevated plasma sulfide as well as thiosulfate levels [48] . They hypothesized that thiosulfate is the actual beneficial molecule. This is in line with findings from Marutani et al., who detected elevated cerebral thiosulfate, but not sulfide levels, in their murine model of brain I/R [47] . In contrast, Ravindran et al. reported elevated H 2 S levels in the brain after Na 2 S 2 O 3 treatment and do not mention thiosulfate [45] . In murine LPS-and sepsis-induced acute lung injury, Sakaguchi et al. reported that Na 2 S 2 O 3 treatment elevated both plasma and lung tissue thiosulfate and sulfide levels [50] . Shirozu et al. detected elevated plasma and liver thiosulfate levels after Na 2 S 2 O 3 administration in their model, whereas sulfide levels were only elevated in the plasma for 6 h [49] . Thus, they also hypothesized that thiosulfate itself mediated the beneficial effects, in particular, that CSE −/− mice in their study also were characterized by elevated thiosulfate levels and mirrored the beneficial effects of Na 2 S 2 O 3 in wildtype animals [49] . Recent work from Marutani et al. also suggests that H 2 S catabolism, i.e., high SQR activity, which would naturally contribute to elevated thiosulfate levels, can contribute to cerebral hypoxia tolerance [67] . For further information on the potential therapeutic perspective for sulfide catabolism and the sulfide/thiosulfate interplay, the reader is referred to a recent review by Marutani and Ichinose [68] . Further potential downstream cellular signaling pathways for therapeutic effects of Na 2 S 2 O 3 , such as Nrf2 signaling, have been recently reviewed by Zhang et al. [69] . Na 2 S 2 O 3 is an example for a sulfane sulfur-containing compound, which are regarded as a form of H 2 S storage, which can easily release this gasotransmitter in response to biological signals. Both reactive sulfur species (H 2 S and sulfane sulfur) always coexist in a biological system. Toohey has indicated that H 2 S is rather a biodegradation byproduct of sulfane sulfur-containing compounds. The author suggests that the sulfane sulfur compounds, which are present in cells at higher concentrations than H 2 S, are responsible for the observed biological effects attributed to H 2 S [70, 71] , which strengthens the speculation that thiosulfate is "more important" than H 2 S.

Regardless of the underlying mechanism for the cytoprotective effects of Na 2 S 2 O 3 , an open question still exists as to whether there is a future for this clinically available compound in critical care. The pre-clinical results are promising, but have certain limitations: (1) only three out of the 19 studies presented in Table 1 investigated a mixture of male and female animals [13, 46, 52] , in fact most of the studies were limited to male animals;

(2) old age as a complication, which can affect both the expression of the endogenous H 2 S enzymes, as well as H 2 S levels [72] , was not considered in any of the pre-clinical studies presented here; (3) of 12 in vivo studies presented in Table 1 , only 4 studies included basic fluid resuscitation [47] [48] [49] 56] and only 2 studies included resuscitation strategies that are common practice in critical care [13, 53] . Thus, the translational relevance of the other studies remains to be proven.

Already in 1966, Paris et al. were able to achieve an increase in urine output by Na 2 S 2 O 3 treatment in 16 out of 20 patients with severe burn-induced shock, which was even associated with alleviating the shock in these patients [73] . Currently (February 2022), 63 studies are listed on clinicaltrials.gov with the search term "sodium thiosulfate". Most of these trials (34) look at Na 2 S 2 O 3 as an adjuvant in chemotherapy, as an antidote for cisplatin intoxication (see Figure 3 ). Another 20 trials deal with diseases tied into calcium dysregulations (calciphylaxis, vascular calcification, calcinosis cutis), trying to make use of the calcium chelating properties of Na 2 S 2 O 3 (see Figure 3 ). Three trials look at contact dermatitis and three further trials investigate endodontic disease each. One trial investigates the potential of Na 2 S 2 O 3 for kidney transplantation. Only two of the listed trials are directly relevant to critical care: NCT03017963 "Safety and Tolerability of Sodium Thiosulfate in Patients With an Acute Coronary Syndrome (ACS) Undergoing Coronary Angiography Via Trans-radial Approach.", and NCT02899364 "Sodium Thiosulfate to Preserve Cardiac Function in STEMI (GIPS-IV)".

The results of the ACS trial have already been published [74] . A dose-escalation study with i.v. Na 2 S 2 O 3 to a maximum dose of 15 g in two doses has been performed on 18 patients undergoing coronary angiography for ACS. A slight drop in systolic blood pressure was determined 1 h after the administration of the first dose, which could not be observed after the second dose. Two patients experienced brief periods of hypotension, one accompanied by mild nausea. No serious adverse events were observed [74] . The same group will investigate the potential benefit of an intervention with Na 2 S 2 O 3 in a follow-up double-blind, randomized, placebo-controlled, multicenter trial (GIPS-IV), with a planned enrollment of 380 patients with ST-elevation myocardial infarction (STEMI) [75] . Patients will receive 12.5 g Na 2 S 2 O 3 directly after admission and a second dose 6 h later. The primary endpoint is myocardial infarct size after 4 months; secondary endpoints include the effects of Na 2 S 2 O 3 on peak CK-MB (creatine kinase muscle brain type, as an early measure of MI) during admission and left ventricular ejection fraction and NT-proBNP (N terminal pro brain natriuretic peptide, as a measure of heart insufficiency) levels at 4 months follow-up [75] . The group expects first results on the primary endpoint soon ("Q1 2022"), but no updates have been published yet.

Another interesting perspective for the clinical application of Na 2 S 2 O 3 is the treatment of pre-eclampsia. Preliminary results of our own observational study DRKS0001771 ("Role of the oxytocin-receptor and the H 2 S-system in preeclampsia and HELLP-syndrome (NU-HOPE)") confirm the dysregulation of endogenous H 2 S availability in pre-eclampsia, which has also been published previously [76, 77] . Pre-eclampsia is not necessarily a critical illness, but can develop into one, in particular in case of "Hemolysis Elevated Liver Enzymes Low Platelet count (HELLP)" syndrome, thus it is relevant to be considered in the context of this mini review. The interaction between the endogenous H 2 S and oxytocin systems, which has recently been identified, might play a particularly important role in the molecular mechanism of pre-eclampsia and make the perspective of treatment with an H 2 S donor even more relevant. CSE −/− and oxytocin receptor (OTR) −/− mice show a reciprocal loss of other proteins in the heart [78, 79] . Furthermore, resuscitated CSE −/− mice had a particularly pronounced loss of cardiac OTR expression after bunt chest trauma, which could be restored by the administration of an exogenous H 2 S donor (GYY4137) [80] . Preliminary results from our observational trial confirm this interaction and dysregulation of the H 2 Sand OT-systems during pre-eclampsia (see Figure 4A ). Furthermore, psychological trauma might play an important role in this context: a dysregulation and interaction of the H 2 Sand OT-systems has been shown in an animal model of early life stress [78] , and placental CSE expression has been shown to be directly related to the patients' childhood trauma load (see Figure 4B ). Taken together, these results suggest that patients with underlying psychological trauma, in particular, might benefit from treatment with Na 2 S 2 O 3 .

COVID-19 patients might be another group that could profit from Na 2 S 2 O 3 therapy. Na 2 S 2 O 3 is a recognized drug devoid of major side effects, which attenuated murine acute lung injury [50] and cerebral ischemia/reperfusion injury [47] . It was also shown that Na 2 S 2 O 3 significantly attenuated shock-induced impairment of lung mechanics and gas exchange in pigs after hemorrhagic shock [13] . Plasma H 2 S levels of survivors of COVID-19 pneumonia were significantly higher at day 1 and day 7 after admission in comparison to non-survivors [81] . These results suggest that H 2 S might be a valuable biomarker for the severity of COVID-19 infection on the one hand [81] , and that exogenous administration of H 2 S might be a relevant therapeutic approach for these patients on the other hand [82] . Even though several groups have suggested Na 2 S 2 O 3 as a therapeutic adjuvant in the therapy of COVID-19 patients [82, 83] , there currently are no registered clinical trials on the subject. In contrast, clinicaltrials.gov lists 13 clinical trials for the therapeutic potential of N-acetyl-cysteine (NAC) for COVID-19 patients. NAC is an antioxidant molecule, also able to elevate sulfide levels, which might have various benefits for SARS-CoV-2 [84] . 

Sodium thiosulfate (Na 2 S 2 O 3 ) is a clinically approved H 2 S donor with a good safety profile. Pre-clinical experimental studies show that Na 2 S 2 O 3 can mediate cyto-protection in various types of ischemia reperfusion injury, physical trauma, and inflammation. The first clinical trials investigating the effects of Na 2 S 2 O 3 in myocardial infarct in humans are currently ongoing. Extending these clinical trials to other conditions would help uncover the full therapeutic potential for Na 2 S 2 O 3 in critical care. 

Protective and Detrimental Effects of Sodium Sulfide and Hydrogen Sulfide in Murine Ventilator-Induced Lung Injury

Hemodynamic and Metabolic Effects of Hydrogen Sulfide during Porcine Ischemia/Reperfusion Injury

Hydrogen Sulfide Does Not Increase Resuscitability in a Porcine Model of Prolonged Cardiac Arrest

Is Pharmacological, H2S-Induced "suspended Animation" Feasible in the ICU?

H 2 S in Acute Lung Injury: A Therapeutic Dead End(?). Intensive Care Med

Effects of Intravenous Sulfide during Resuscitated Porcine Hemorrhagic Shock

The Mitochondria-Targeted H2S-Donor AP39 in a Murine Model of Combined Hemorrhagic Shock and Blunt Chest Trauma

Metabolic, Cardiac, and Renal Effects of the Slow Hydrogen Sulfide-Releasing Molecule GYY4137 during Resuscitated Septic Shock in Swine with Pre-Existing Coronary Artery Disease

Cisplatin Overdose: Toxicities and Management

Metabolic Acidosis after Sodium Thiosulfate Infusion and the Role of Hydrogen Sulfide

Medical Uses of Sodium Thiosulfate

Effects of Sodium Thiosulfate (Na2S2O3) during Resuscitation from Hemorrhagic Shock in Swine with Preexisting Atherosclerosis

Thiosulfate: A Readily Accessible Source of Hydrogen Sulfide in Oxygen Sensing

Determination of Sulfide in Brain-Tissue by Gas Dialysis Ion Chromatography-Postmortem Studies and 2 Case-Reports

The Possible Role of Hydrogen Sulfide as an Endogenous Neuromodulator

Thioredoxin and Dihydrolipoic Acid Are Required for 3-Mercaptopyruvate Sulfurtransferase to Produce Hydrogen Sulfide

Oxidation of H2S in Mammalian Cells and Mitochondria

Sulfide Oxidation Evidences the Immediate Cellular Response to a Decrease in the Mitochondrial ATP/O 2 Ratio

Regulation of Mitochondrial Bioenergetic Function by Hydrogen Sulfide. Part I. Biochemical and Physiological Mechanisms

Organization of the Human Mitochondrial Hydrogen Sulfide Oxidation Pathway

Enzymology of H2S Biogenesis, Decay and Signaling

The Role of Hemoproteins: Hemoglobin, Myoglobin and Neuroglobin in Endogenous Thiosulfate Production Processes

Hydrogen Sulfide as an Oxygen Sensor

Hydrogen Sulfide as an Oxygen Sensor

Hemorrhagic Shock

Ischemia and Reperfusion-from Mechanism to Translation

H2S during Circulatory Shock: Some Unresolved Questions

Hydrogen Sulfide and Inflammation: The Good, the Bad, the Ugly and the Promising

Sulfide-Inhibition of Mitochondrial Respiration at Very Low Oxygen Concentrations

Regulation of Mitochondrial Bioenergetic Function by Hydrogen Sulfide. Part II Pathophysiological and Therapeutic Aspects

Ammonium Tetrathiomolybdate Following Ischemia/Reperfusion Injury: Chemistry, Pharmacology, and Impact of a New Class of Sulfide Donor in Preclinical Injury Models

Neuroprotective Effects of Ammonium Tetrathiomolybdate, a Slow-Release Sulfide Donor, in a Rodent Model of Regional Stroke

Unraveling the Role of Thiosulfate Sulfurtransferase in Metabolic Diseases

Cardiac Protection by Oral Sodium Thiosulfate in a Rat Model of L-NNA-Induced Heart Disease

Sodium Thiosulfate Treatment for Calcific Uremic Arteriolopathy in Children and Young Adults

Nitrite and Thiosulfate Therapy in Cyanide Poisoning

Sodium Thiosulfate: A New Player for Circulatory Shock and Ischemia/Reperfusion Injury? In Annual Update in Intensive Care

Sodium Thiosulfate Preconditioning Ameliorates Ischemia/Reperfusion Injury in Rat Hearts Via Reduction of Oxidative Stress and Apoptosis. Cardiovasc. Drugs Ther

Preconditioning the Rat Heart with Sodium Thiosulfate Preserved the Mitochondria in Response to Ischemia-Reperfusion Injury

Attenuation of Cardiac Ischemia-Reperfusion Injury by Sodium Thiosulfate Is Partially Dependent on the Effect of Cystathione Beta Synthase in the Myocardium

Inhibition of PI3K/MTOR/KATP Channel Blunts Sodium Thiosulphate Preconditioning Mediated Cardioprotection against Ischemia-Reperfusion Injury

Sodium Thiosulfate Post-Conditioning Protects Rat Hearts against Ischemia Reperfusion Injury via Reduction of Apoptosis and Oxidative Stress

Effect of Sodium Thiosulfate Postconditioning on Ischemia-Reperfusion Injury Induced Mitochondrial Dysfunction in Rat Heart

Beneficial Effect of Sodium Thiosulfate Extends beyond Myocardial Tissue in Isoproterenol Model of Infarction: Implication for Nootropic Effects

Sodium Thiosulfate in the Treatment of Early Postischemic Disorders

Thiosulfate Mediates Cytoprotective Effects of Hydrogen Sulfide against Neuronal Ischemia

Hydrogen Sulfide Prevents Endotoxin-Induced Systemic Inflammation and Improves Survival by Altering Sulfide Metabolism in Mice

Cystathionine γ-Lyase Deficiency Protects Mice from Galactosamine/Lipopolysaccharide-Induced Acute Liver Failure

Sodium Thiosulfate Attenuates Acute Lung Injury in Mice

Sodium Thiosulphate Attenuates Brain Inflammation Induced by Systemic Lipopolysaccharide Administration in C57BL/6J Mice

Host Cystathionine-γ Lyase Derived Hydrogen Sulfide Protects against Pseudomonas Aeruginosa Sepsis

Effects of Sodium Thiosulfate During Resuscitation From Trauma-and-Hemorrhage in Cystathionine Gamma Lyase (CSE) Knockout Mice

Sodium Thiosulfate Mediated Cardioprotection against Myocardial Ischemia-Reperfusion Injury Is Defunct in Rat Heart with Co-Morbidity of Vascular Calcification

Sodium Thiosulfate Improves Intestinal and Hepatic Microcirculation Without Affecting Mitochondrial Function in Experimental Sepsis

Effect of Antioxidants in Experimental Escherichia Coli Septicemia

Renal Mitochondria Can Withstand Hypoxic/Ischemic Injury Secondary to Renal Failure in Uremic Rats Pretreated with Sodium Thiosulfate

Exogenous Administration of Thiosulfate, a Donor of Hydrogen Sulfide, Attenuates Angiotensin II-Induced Hypertensive Heart Disease in Rats

Sodium Thiosulfate Improves Renal Function and Oxygenation in L-NNA-Induced Hypertension in Rats

Successfully Treated Calcific Uremic Arteriolopathy: Two Cases of a High Anion Gap Metabolic Acidosis with Intravenous Sodium Thiosulfate

Cardioprotective Role of Sodium Thiosulfate on Chronic Heart Failure by Modulating Endogenous H2S Generation

Effects of Sodium Thiosulfate during Resuscitation from Trauma-and-Hemorrhage in Cystathionine-γ-Lyase Knockout Mice with Diabetes Type 1

The Role of Glucocorticoid Receptor and Oxytocin Receptor in the Septic Heart in a Clinically Relevant, Resuscitated Porcine Model With Underlying Atherosclerosis

Cystathionine-γ-Lyase Expression Is Associated with Mitochondrial Respiration during Sepsis-Induced Acute Kidney Injury in Swine with Atherosclerosis

Cardiovascular Disease and Resuscitated Septic Shock Lead to the Downregulation of the H2S-Producing Enzyme Cystathionine-γ-Lyase in the Porcine Coronary Artery

The H 2 S Donor Sodium Thiosulfate (Na 2 S 2 O 3 ) Does Not Improve Inflammation and Organ Damage after Hemorrhagic Shock in Cardiovascular Healthy Swine

Sulfide Catabolism Ameliorates Hypoxic Brain Injury

Emerging Pharmacological Tools to Control Hydrogen Sulfide Signaling in Critical Illness

Sodium Thiosulfate: Clinical Applications and Underlying Molecular Mechanisms

Sulphane Sulphur in Biological Systems: A Possible Regulatory Role

Sulfane) Sulfur: New Chemistry and New Regulatory Roles in Biology. Molecules

The Hydrogen Sulfide Signaling System: Changes during Aging and the Benefits of Caloric Restriction

Use of Sodium Thiosulfate in Shock Due to Burns

Safety and Tolerability of Sodium Thiosulfate in Patients with an Acute Coronary Syndrome Undergoing Coronary Angiography: A Dose-Escalation Safety Pilot Study (SAFE-ACS)

Rationale and Design of the Groningen Intervention Study for the Preservation of Cardiac Function with Sodium Thiosulfate after St-Segment Elevation Myocardial Infarction (GIPS-IV)

Dysregulation of Hydrogen Sulfide Producing Enzyme Cystathionine γ-Lyase Contributes to Maternal Hypertension and Placental Abnormalities in Preeclampsia

Hydrogen Sulfide Producing Enzymes in Pregnancy and Preeclampsia

Maternal Separation Induces Long-Term Alterations in the Cardiac Oxytocin Receptor and Cystathionine γ-Lyase Expression in Mice

The Interaction of the Endogenous Hydrogen Sulfide and Oxytocin Systems in Fluid Regulation and the Cardiovascular System

Interaction of the Hydrogen Sulfide System with the Oxytocin System in the Injured Mouse Heart

Serum Hydrogen Sulfide and Outcome Association in Pneumonia by the SARS-CoV-2 Coronavirus

H2S as a Therapeutic Adjuvant Against COVID-19: Why and How? Shock

Possible Application of H2S-Producing Compounds in Therapy of Coronavirus (COVID-19) Infection and Pneumonia

N-Acetylcysteine and Hydrogen Sulfide in Coronavirus Disease

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.