Reactive sulfur species and their significance in health and disease.

Reactive sulfur species (RSS) have been recognized in the last two decades as very important molecules in redox regulation. They are involved in metabolic processes and, in this way, they are responsible for maintenance of health. This review summarizes current information about the essential biological RSS, including H2S, low molecular weight persulfides, protein persulfides as well as organic and inorganic polysulfides, their synthesis, catabolism and chemical reactivity. Moreover, the role of RSS disturbances in various pathologies including vascular diseases, chronic kidney diseases, diabetes mellitus Type 2, neurological diseases, obesity, chronic obstructive pulmonary disease and in the most current problem of COVID-19 is presented. The significance of RSS in aging is also mentioned. Finally, the possibilities of using the precursors of various forms of RSS for therapeutic purposes are discussed.

H2S Donors and Their Use in Medicinal Chemistry.

Hydrogen sulfide (H2S) is a ubiquitous gaseous signaling molecule that has an important role in many physiological and pathological processes in mammalian tissues, with the same importance as two others endogenous gasotransmitters such as NO (nitric oxide) and CO (carbon monoxide). Endogenous H2S is involved in a broad gamut of processes in mammalian tissues including inflammation, vascular tone, hypertension, gastric mucosal integrity, neuromodulation, and defense mechanisms against viral infections as well as SARS-CoV-2 infection. These results suggest that the modulation of H2S levels has a potential therapeutic value. Consequently, synthetic H2S-releasing agents represent not only important research tools, but also potent therapeutic agents. This review has been designed in order to summarize the currently available H2S donors; furthermore, herein we discuss their preparation, the H2S-releasing mechanisms, and their -biological applications.

Inhibitors of bacterial H2S biogenesis targeting antibiotic resistance and tolerance.

Emergent resistance to all clinical antibiotics calls for the next generation of therapeutics. Here we report an effective antimicrobial strategy targeting the bacterial hydrogen sulfide (H2S)-mediated defense system. We identified cystathionine γ-lyase (CSE) as the primary generator of H2S in two major human pathogens, Staphylococcus aureus and Pseudomonas aeruginosa, and discovered small molecules that inhibit bacterial CSE. These inhibitors potentiate bactericidal antibiotics against both pathogens in vitro and in mouse models of infection. CSE inhibitors also suppress bacterial tolerance, disrupting biofilm formation and substantially reducing the number of persister bacteria that survive antibiotic treatment. Our results establish bacterial H2S as a multifunctional defense factor and CSE as a drug target for versatile antibiotic enhancers.

N-Acetylcysteine and Hydrogen Sulfide in Coronavirus Disease 2019.

Significance: Hydrogen sulfide (H2S) is one of the three main gasotransmitters that are endogenously produced in humans and are protective against oxidative stress. Recent findings from studies focusing on coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), shifted our attention to a potentially modulatory role of H2S in this viral respiratory disease. Recent Advances: H2S levels at hospital admission may be of importance since this gasotransmitter has been shown to be protective against lung damage through its antiviral, antioxidant, and anti-inflammatory actions. Furthermore, many COVID-19 cases have been described demonstrating remarkable clinical improvement upon administration of high doses of N-acetylcysteine (NAC). NAC is a renowned pharmacological antioxidant substance acting as a source of cysteine, thereby promoting endogenous glutathione (GSH) biosynthesis as well as generation of sulfane sulfur species when desulfurated to H2S. Critical Issues: Combining H2S physiology and currently available knowledge of COVID-19, H2S is hypothesized to target three main vulnerabilities of SARS-CoV-2: (i) cell entry through interfering with functional host receptors, (ii) viral replication through acting on RNA-dependent RNA polymerase (RdRp), and (iii) the escalation of inflammation to a potentially lethal hyperinflammatory cytokine storm (toll-like receptor 4 [TLR4] pathway and NLR family pyrin domain containing 3 [NLRP3] inflammasome). Future Directions: Dissecting the breakdown of NAC reveals the possibility of increasing endogenous H2S levels, which may provide a convenient rationale for the application of H2S-targeted therapeutics. Further randomized-controlled trials are warranted to investigate its definitive role.

Potential benefits of using hydrogen sulfide, vitamin E and necrostatin-1 to counteract acetaminophen­induced hepatotoxicity in rats.

BACKGROUND: The use of acetaminophen (APAP) is increasing recently, especially with COVID-19 outbreaks. APAP is safe at therapeutic levels, however, an overdose can cause severe liver injury. This study aims to explore possible mechanisms involved in APAP­induced hepatotoxicity and compare different hepatoprotective agents, namely vitamin E, hydrogen sulfide (H2S) and necrostatin-1 (NEC-1). METHODS: Adult male albino rats were divided into groups: Control group, APAP­induced hepatotoxicity group, Vitamin E­treated group, H2S­treated group and NEC-1­treated group. Serum levels for aspartate aminotransferase (AST), alanine aminotransferase (ALT), interleukin-33 (IL-33), tumor necrosis factor alpha (TNF-α), reduced glutathione (GSH) and lipid profile were measured. Histopathological examinations of liver tissue with H(et)E stain and immunohistochemistry for activated caspase-3 were also done. RESULTS: APAP­treated group showed elevated liver transaminases, hyperlipidemia, and deficient liver anti-oxidative response together with disturbed hepatic architecture and increased immune-expression of activated caspase-3 in hepatic tissue. Pretreatment with vitamin E, H2S or NEC-1 reversed the affected parameters. Vitamin E and H2S showed greater improvement when compared to NEC-1. CONCLUSION: Vitamin E, H2S and NEC-1 showed protective effects against APAP-induced hepatotoxicity, thus they may be used as an adjuvant therapy when APAP is indicated for long periods as is the case in COVID-19 patients (Tab. 2, Fig. 2, Ref. 45). Text in PDF www.elis.sk Keywords: acetaminophen, hepatotoxicity, apoptosis, necrostatin-1, vitamin E, H2S.

Anti-inflammatory and antiviral roles of hydrogen sulfide: Rationale for considering H2 S donors in COVID-19 therapy.

The COVID-19 pandemic caused by SARS-Cov-2 demands rapid, safe and effective therapeutic options. In the last decades, the endogenous gasotransmitter hydrogen sulfide (H2 S) has emerged as modulator of several biological functions and its deficiency has been associated with different disorders. Therefore, many H2 S-releasing agents have been developed as potential therapeutic tools for diseases related with impaired H2 S production and/or activity. Some of these compounds are in advanced clinical trials. Presently, the pivotal role of H2 S in modulating the inflammatory response and pro-inflammatory cytokine cascade is well recognized, and the usefulness of some H2 S-donors for the treatment of acute lung inflammation has been reported. Recent data is elucidating several mechanisms of action, which may account for antiviral effects of H2 S. Noteworthy, some preliminary clinical results suggest an inverse relationship between endogenous H2 S levels and severity of COVID-19. Therefore, repurposing of H2 S-releasing drugs may be a potential therapeutic opportunity for treatment of COVID-19. LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc.

H2S as a potential defense against COVID-19?

The outbreak of COVID-19 pneumonia caused by a new coronavirus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) is posing a global health emergency and has led to more than 380,000 deaths worldwide. The cell entry of SARS-CoV-2 depends on two host proteins angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2). There is currently no vaccine available and also no effective drug for the treatment of COVID-19. Hydrogen sulfide (H2S) as a novel gasotransmitter has been shown to protect against lung damage via its anti-inflammation, antioxidative stress, antiviral, prosurvival, and antiaging effects. In light of the research advances on H2S signaling in biology and medicine, this review proposed H2S as a potential defense against COVID-19. It is suggested that H2S may block SARS-CoV-2 entry into host cells by interfering with ACE2 and TMPRSS2, inhibit SARS-CoV-2 replication by attenuating virus assembly/release, and protect SARS-CoV-2-induced lung damage by suppressing immune response and inflammation development. Preclinical studies and clinical trials with slow-releasing H2S donor(s) or the activators of endogenous H2S-generating enzymes should be considered as a preventative treatment or therapy for COVID-19.

The role of host defences in Covid 19 and treatments thereof.

Hydrogen sulfide (H2S) is a natural defence against the infections from enveloped RNA viruses and is likely involved also in Covid 19. It was already shown to inhibit growth and pathogenic mechanisms of a variety of enveloped RNA viruses and it was now found that circulating H2S is higher in Covid 19 survivors compared to fatal cases. H2S release is triggered by carbon monoxide (CO) from the catabolism of heme by inducible heme oxygenase (HO-1) and heme proteins possess catalytic activity necessary for the H2S signalling by protein persulfidation. Subjects with a long promoter for the HMOX1 gene, coding for HO-1, are predicted for lower efficiency of this mechanism. SARS-cov-2 exerts ability to attack the heme of hemoglobin and other heme-proteins thus hampering both release and signalling of H2S. Lack of H2S-induced persulfidation of the KATP channels of leucocytes causes adhesion and release of the inflammatory cytokines, lung infiltration and systemic endothelial damage with hyper-coagulability. These events largely explain the sex and age distribution, clinical manifestations and co-morbidities of Covid-19. The understanding of this mechanism may be of guidance in re-evaluating the ongoing therapeutic strategies, with special attention to the interaction with mechanical ventilation, paracetamol and chloroquine use, and in the individuation of genetic traits causing increased susceptibility to the disruption of these physiologic processes and to a critical Covid 19. Finally, an array of therapeutic interventions with the potential to clinically modulate the HO-1/CO/H2S axis is already available or under development. These include CO donors and H2S donors and a boost to the endogenous production of H2S is also possible.