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Endogenous Gaseous Signaling Molecules: Their Mechanism(s) of Action and Pharmacological Effects

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 36014

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Dr. Marcin Magierowski

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Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland
Interests: gaseous mediators; hydrogen sulfide; carbon monoxide; molecular gastroenterology; gastrointestinal pharmacology; Barrett’s esophagus; digestive system pathologies
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Binghe Wang

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Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA
Interests: drug design; organic synthesis; drug delivery; computational chemistry; drug screening; instrument analysis; cell culture; biochemistry; enzyme inhibition; fluorescent sensing; click chemistry
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Endogenously produced gaseous signaling molecules such as hydrogen sulfide (H₂S), nitric oxide (NO) and carbon monoxide (CO) have been shown to exert anti-inflammatory, vasoactive and anti-oxidative effects, among many other properties. Their pleiotropic effects raise an intriguing question about their mechanism(s) of action (MOA(s)). CO is known to affect the synthesis of cyclic guanosine monophosphate (cGMP) via the activation of soluble guanylyl cyclase (sGC), inhibit CBS and cytochrome c oxidase, and affect ion channels. Similarly, NO diffuses from the endothelium to smooth muscle, located in the vascular wall, where it also activates sGC, leading to a rise in cGMP levels. H₂S, on the other hand, is an anti-oxidant and seems to affect ATP-dependent potassium ion channels. These are just examples of their MOAs. Moreover, H₂S-releasing hybrids of non-steroidal anti-inflammatory drugs have been shown to reduce the gastrointestinal side effects and gastrotoxicity characteristic of the parent drugs. Therefore, a variety of CO, H₂S and NO donors have been developed and are now available for preclinical pharmacological assessment. Some of these compounds are currently at the stage of clinical trials. However, there is much more to be done in developing pharmaceutically acceptable donors of these gaseous signaling molecules and in understanding the MOAs for their pleiotropic effects.

This Special Issue of the International Journal of Molecular Sciences aims to gather articles focused on recent developments in the study of H₂S, NO or CO, either produced endogenously or delivered from pharmaceutical donors, in health and disease. Review articles or manuscripts on original research regarding H₂S, CO or NO donors, the cross-talk among these signaling molecules, or their novel mechanisms are within the scope of this Special Issue.

Dr. Marcin Magierowski
Prof. Dr. Binghe Wang
Guest Editors

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Keywords

hydrogen sulfide
carbon monoxide
nitric oxide
molecular pharmacology
donors
prodrugs

Published Papers (10 papers)

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Research

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13 pages, 5740 KiB

Open AccessArticle

Role of Hydrogen Sulfide and Polysulfides in the Regulation of Lipolysis in the Adipose Tissue: Possible Implications for the Pathogenesis of Metabolic Syndrome

by Jerzy Bełtowski and Krzysztof Wiórkowski

Int. J. Mol. Sci. 2022, 23(3), 1346; https://doi.org/10.3390/ijms23031346 - 25 Jan 2022

Cited by 7 | Viewed by 1949

Abstract

Hydrogen sulfide (H₂S) and inorganic polysulfides are important signaling molecules; however, little is known about their role in the adipose tissue. We examined the effect of H₂S and polysulfides on adipose tissue lipolysis. H₂S and polysulfide production by mesenteric adipose tissue explants in rats was measured. The effect of Na₂S and Na₂S₄, the H₂S and polysulfide donors, respectively, on lipolysis markers, plasma non-esterified fatty acids (NEFA) and glycerol, was examined. Na₂S but not Na₂S₄ increased plasma NEFA and glycerol in a time- and dose-dependent manner. Na₂S increased cyclic AMP but not cyclic GMP concentration in the adipose tissue. The effect of Na₂S on NEFA and glycerol was abolished by the specific inhibitor of protein kinase A, KT5720. The effect of Na₂S on lipolysis was not abolished by propranolol, suggesting no involvement of β-adrenergic receptors. In addition, Na₂S had no effect on phosphodiesterase activity in the adipose tissue. Obesity induced by feeding rats a highly palatable diet for 1 month was associated with increased plasma NEFA and glycerol concentrations, as well as greater H₂S production in the adipose tissue. In conclusion, H₂S stimulates lipolysis and may contribute to the enhanced lipolysis associated with obesity. Full article

(This article belongs to the Special Issue Endogenous Gaseous Signaling Molecules: Their Mechanism(s) of Action and Pharmacological Effects)

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16 pages, 3064 KiB

Open AccessArticle

Investigation of H₂S Donor Treatment on Neutrophil Extracellular Traps in Experimental Colitis

by Szilvia Török, Nikoletta Almási, Zsuzsanna Valkusz, Anikó Pósa, Csaba Varga and Krisztina Kupai

Int. J. Mol. Sci. 2021, 22(23), 12729; https://doi.org/10.3390/ijms222312729 - 25 Nov 2021

Cited by 5 | Viewed by 1985

Abstract

Inflammatory bowel diseases (IBD) are chronic, immune-mediated disorders, which affect the gastrointestinal tract with intermittent ulceration. It is increasingly clear that neutrophil extracellular traps (NETs) seem to have a role in IBD; however, the associated pathogenesis is still not known. Furthermore, several conventional therapies are available against IBD, although these might have side effects. Our current study aimed to investigate the effects of hydrogen sulfide (H₂S) treatment on NETs formation and on the expression of inflammatory mediators in experimental rat colitis. To model IBD, 2,4,6-trinitrobenzenesulfonic acid (TNBS) was administered intracolonically (i.c.) to Wistar–Harlan male rats. Animals were treated (2 times/day) with H₂S donor Lawesson’s reagent per os. Our results showed that H₂S treatment significantly decreased the extent of colonic lesions. Furthermore, the expression of members of NETs formation: peptidyl arginine deiminase 4 (PAD4), citrullinated histone H3 (citH3), myeloperoxidase (MPO) and inflammatory regulators, such as nuclear transcription factor-kappa B (NF-κB) and high-mobility group box 1 (HMGB1) were reduced in H₂S treated group compared to TNBS. Additionally, H₂S donor administration elevated the expression of ubiquitin C-terminal hydroxylase L1 (UCHL-1), a potential anti-inflammatory mediator. Taken together, our results showed that H₂S may exert anti-inflammatory effect through the inhibition of NETs formation, which suggests a new therapeutic approach against IBD. Full article

(This article belongs to the Special Issue Endogenous Gaseous Signaling Molecules: Their Mechanism(s) of Action and Pharmacological Effects)

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25 pages, 5135 KiB

Open AccessArticle

The Slow-Releasing and Mitochondria-Targeted Hydrogen Sulfide (H₂S) Delivery Molecule AP39 Induces Brain Tolerance to Ischemia

by Bartosz Pomierny, Weronika Krzyżanowska, Jakub Jurczyk, Alicja Skórkowska, Beata Strach, Małgorzata Szafarz, Katarzyna Przejczowska-Pomierny, Roberta Torregrossa, Matthew Whiteman, Monika Marcinkowska, Joanna Pera and Bogusława Budziszewska

Int. J. Mol. Sci. 2021, 22(15), 7816; https://doi.org/10.3390/ijms22157816 - 22 Jul 2021

Cited by 25 | Viewed by 3848

Abstract

Ischemic stroke is the third leading cause of death in the world, which accounts for almost 12% of the total deaths worldwide. Despite decades of research, the available and effective pharmacotherapy is limited. Some evidence underlines the beneficial properties of hydrogen sulfide (H₂S) donors, such as NaSH, in an animal model of brain ischemia and in in vitro research; however, these data are ambiguous. This study was undertaken to verify the neuroprotective activity of AP39, a slow-releasing mitochondria-targeted H₂S delivery molecule. We administered AP39 for 7 days prior to ischemia onset, and the potential to induce brain tolerance to ischemia was verified. To do this, we used the rat model of 90-min middle cerebral artery occlusion (MCAO) and used LC-MS/MS, RT-PCR, Luminex^TM assays, Western blot and immunofluorescent double-staining to determine the absolute H₂S levels, inflammatory markers, neurotrophic factor signaling pathways and apoptosis marker in the ipsilateral frontal cortex, hippocampus and in the dorsal striatum 24 h after ischemia onset. AP39 (50 nmol/kg) reduced the infarct volume, neurological deficit and reduced the microglia marker (Iba1) expression. AP39 also exerted prominent anti-inflammatory activity in reducing the release of Il-1β, Il-6 and TNFα in brain areas particularly affected by ischemia. Furthermore, AP39 enhanced the pro-survival pathways of neurotrophic factors BDNF-TrkB and NGF-TrkA and reduced the proapoptotic proNGF-p75^NTR-sortilin pathway activity. These changes corresponded with reduced levels of cleaved caspase 3. Altogether, AP39 treatment induced adaptative changes within the brain and, by that, developed brain tolerance to ischemia. Full article

(This article belongs to the Special Issue Endogenous Gaseous Signaling Molecules: Their Mechanism(s) of Action and Pharmacological Effects)

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18 pages, 4315 KiB

Open AccessArticle

Novel Hydrogen Sulfide (H₂S)-Releasing BW-HS-101 and Its Non-H₂S Releasing Derivative in Modulation of Microscopic and Molecular Parameters of Gastric Mucosal Barrier

by Dominik Bakalarz, Edyta Korbut, Zhengnan Yuan, Bingchen Yu, Dagmara Wójcik, Aleksandra Danielak, Katarzyna Magierowska, Slawomir Kwiecień, Tomasz Brzozowski, Monika Marcinkowska, Binghe Wang and Marcin Magierowski

Int. J. Mol. Sci. 2021, 22(10), 5211; https://doi.org/10.3390/ijms22105211 - 14 May 2021

Cited by 8 | Viewed by 3483

Abstract

Hydrogen sulfide (H₂S) is an endogenously produced molecule with anti-inflammatory and cytoprotective properties. We aimed to investigate for the first time if a novel, esterase-sensitive H₂S-prodrug, BW-HS-101 with the ability to release H₂S in a controllable manner, prevents gastric mucosa against acetylsalicylic acid-induced gastropathy on microscopic and molecular levels. Wistar rats were pretreated intragastrically with vehicle, BW-HS-101 (0.5–50 μmol/kg) or its analogue without the ability to release H₂S, BW-iHS-101 prior to ASA administration (125 mg/kg, intragastrically). BW-HS-101 was administered alone or in combination with nitroarginine (L-NNA, 20 mg/kg, intraperitoneally) or zinc protoporphyrin IX (10 mg/kg, intraperitoneally). Gastroprotective effects of BW-HS-101 were additionally evaluated against necrotic damage induced by intragastrical administration of 75% ethanol. Gastric mucosal damage was assessed microscopically, and gastric blood flow was determined by laser flowmetry. Gastric mucosal DNA oxidation and PGE₂ concentration were assessed by ELISA. Serum and/or gastric protein concentrations of IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-13, VEGF, GM-CSF, IFN-γ, TNF-α, and EGF were determined by a microbeads/fluorescent-based multiplex assay. Changes in gastric mucosal iNOS, HMOX-1, SOCS3, IL1-R1, IL1-R2, TNF-R2, COX-1, and COX-2 mRNA were assessed by real-time PCR. BW-HS-101 or BW-iHS-101 applied at a dose of 50 μmol/kg protected gastric mucosa against ASA-induced gastric damage and prevented a decrease in the gastric blood flow level. H₂S prodrug decreased DNA oxidation, systemic and gastric mucosal inflammation with accompanied upregulation of SOCS3, and EGF and HMOX-1 expression. Pharmacological inhibition of nitric oxide (NO) synthase but not carbon monoxide (CO)/heme oxygenase (HMOX) activity by L-NNA or ZnPP, respectively, reversed the gastroprotective effect of BW-HS-101. BW-HS-101 also protected against ethanol-induced gastric injury formation. We conclude that BW-HS-101, due to its ability to release H₂S in a controllable manner, prevents gastric mucosa against drugs-induced gastropathy, inflammation and DNA oxidation, and upregulate gastric microcirculation. Gastroprotective effects of this H₂S prodrug involves endogenous NO but not CO activity and could be mediated by cytoprotective and anti-inflammatory SOCS3 and EGF pathways. Full article

(This article belongs to the Special Issue Endogenous Gaseous Signaling Molecules: Their Mechanism(s) of Action and Pharmacological Effects)

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13 pages, 3295 KiB

Open AccessArticle

Implication of a Key Region of Six Bacillus cereus Genes Involved in Siroheme Synthesis, Nitrite Reductase Production and Iron Cluster Repair in the Bacterial Response to Nitric Oxide Stress

by Constance Porrini, Cyprien Guérin, Seav-Ly Tran, Rozenn Dervyn, Pierre Nicolas and Nalini Ramarao

Int. J. Mol. Sci. 2021, 22(10), 5079; https://doi.org/10.3390/ijms22105079 - 11 May 2021

Cited by 3 | Viewed by 1961

Abstract

Bacterial response to nitric oxide (NO) is of major importance for bacterial survival. NO stress is a main actor of the eukaryotic immune response and several pathogenic bacteria have developed means for detoxification and repair of the damages caused by NO. However, bacterial mechanisms of NO resistance by Gram-positive bacteria are poorly described. In the opportunistic foodborne pathogen Bacillus cereus, genome sequence analyses did not identify homologs to known NO reductases and transcriptional regulators, such as NsrR, which orchestrate the response to NO of other pathogenic or non-pathogenic bacteria. Using a transcriptomic approach, we investigated the adaptation of B. cereus to NO stress. A cluster of 6 genes was identified to be strongly up-regulated in the early phase of the response. This cluster contains an iron-sulfur cluster repair enzyme, a nitrite reductase and three enzymes involved in siroheme biosynthesis. The expression pattern and close genetic localization suggest a functional link between these genes, which may play a pivotal role in the resistance of B. cereus to NO stress during infection. Full article

(This article belongs to the Special Issue Endogenous Gaseous Signaling Molecules: Their Mechanism(s) of Action and Pharmacological Effects)

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17 pages, 3730 KiB

Open AccessArticle

Fructose Intake Impairs the Synergistic Vasomotor Manifestation of Nitric Oxide and Hydrogen Sulfide in Rat Aorta

by Andrea Berenyiova, Samuel Golas, Magdalena Drobna, Martina Cebova and Sona Cacanyiova

Int. J. Mol. Sci. 2021, 22(9), 4749; https://doi.org/10.3390/ijms22094749 - 30 Apr 2021

Cited by 8 | Viewed by 1792

Abstract

In this study, we evaluated the effect of eight weeks of administration of 10% fructose solution to adult Wistar Kyoto (WKY) rats on systolic blood pressure (SBP), plasma and biometric parameters, vasoactive properties of the thoracic aorta (TA), NO synthase (NOS) activity, and the expression of enzymes producing NO and H₂S. Eight weeks of fructose administration did not affect SBP, glycaemia, or the plasma levels of total cholesterol or low-density and high-density lipoprotein; however, it significantly increased the plasma levels of γ-glutamyl transferase and alanine transaminase. Chronic fructose intake deteriorated endothelium-dependent vasorelaxation (EDVR) and increased the sensitivity of adrenergic receptors to noradrenaline. Acute NOS inhibition evoked a reduction in EDVR that was similar between groups; however, it increased adrenergic contraction more in fructose-fed rats. CSE inhibition decreased EDVR in WKY but not in fructose-fed rats. The application of a H₂S scavenger evoked a reduction in the EDVR in WKY rats and normalized the sensitivity of adrenergic receptors in rats treated with fructose. Fructose intake did not change NOS activity but reduced the expression of eNOS and CBS in the TA and CSE and CBS in the left ventricle. Based on our results, we could assume that the impaired vascular function induced by increased fructose intake was probably not directly associated with a decreased production of NO, but rather with impairment of the NO–H₂S interaction and its manifestation in vasoactive responses. Full article

(This article belongs to the Special Issue Endogenous Gaseous Signaling Molecules: Their Mechanism(s) of Action and Pharmacological Effects)

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11 pages, 1512 KiB

Open AccessArticle

Distinct Pharmacological Properties of Gaseous CO and CO-Releasing Molecule in Human Platelets

by Patrycja Kaczara, Kamil Przyborowski, Tasnim Mohaissen and Stefan Chlopicki

Int. J. Mol. Sci. 2021, 22(7), 3584; https://doi.org/10.3390/ijms22073584 - 30 Mar 2021

Cited by 7 | Viewed by 2030

Abstract

Carbon monoxide (CO)—gaseous or released by CO-RMs—both possess antiplatelet properties; however, it remains uncertain whether the mechanisms involved are the same. Here, we characterise the involvement of soluble guanylate cyclase (sGC) in the effects of CO—delivered by gaseous CO–saturated buffer (CO_G) and generated by CORM-A1—on platelet aggregation and energy metabolism, as well as on vasodilatation in aorta, using light transmission aggregometry, Seahorse XFe technique, and wire myography, respectively. ODQ completely prevented the inhibitory effect of CO_G on platelet aggregation, but did not modify antiplatelet effect of CORM-A1. In turn, CO_G did not affect, whereas CORM-A1 substantially inhibited energy metabolism in platelets. Even though activation of sGC by BAY 41-2272 or BAY 58-2667 inhibited significantly platelet aggregation, their effects on energy metabolism in platelets were absent or weak and could not contribute to antiplatelet effects of sGC activation. In contrast, vasodilatation of murine aortic rings, induced either by CO_G or CORM-A1, was dependent on sGC. We conclude that the source (CO_G vs. CORM-A1) and kinetics (rapid vs. slow) of CO delivery represent key determinants of the mechanism of antiplatelet action of CO, involving either impairment of energy metabolism or activation of sGG. Full article

(This article belongs to the Special Issue Endogenous Gaseous Signaling Molecules: Their Mechanism(s) of Action and Pharmacological Effects)

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Review

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19 pages, 1696 KiB

Open AccessReview

Impact of Hydrogen Sulfide on Mitochondrial and Bacterial Bioenergetics

by Vitaliy B. Borisov and Elena Forte

Int. J. Mol. Sci. 2021, 22(23), 12688; https://doi.org/10.3390/ijms222312688 - 24 Nov 2021

Cited by 27 | Viewed by 3866

Abstract

This review focuses on the effects of hydrogen sulfide (H₂S) on the unique bioenergetic molecular machines in mitochondria and bacteria—the protein complexes of electron transport chains and associated enzymes. H₂S, along with nitric oxide and carbon monoxide, belongs to the class of endogenous gaseous signaling molecules. This compound plays critical roles in physiology and pathophysiology. Enzymes implicated in H₂S metabolism and physiological actions are promising targets for novel pharmaceutical agents. The biological effects of H₂S are biphasic, changing from cytoprotection to cytotoxicity through increasing the compound concentration. In mammals, H₂S enhances the activity of F_oF₁-ATP (adenosine triphosphate) synthase and lactate dehydrogenase via their S-sulfhydration, thereby stimulating mitochondrial electron transport. H₂S serves as an electron donor for the mitochondrial respiratory chain via sulfide quinone oxidoreductase and cytochrome c oxidase at low H₂S levels. The latter enzyme is inhibited by high H₂S concentrations, resulting in the reversible inhibition of electron transport and ATP production in mitochondria. In the branched respiratory chain of Escherichia coli, H₂S inhibits the bo₃ terminal oxidase but does not affect the alternative bd-type oxidases. Thus, in E. coli and presumably other bacteria, cytochrome bd permits respiration and cell growth in H₂S-rich environments. A complete picture of the impact of H₂S on bioenergetics is lacking, but this field is fast-moving, and active ongoing research on this topic will likely shed light on additional, yet unknown biological effects. Full article

(This article belongs to the Special Issue Endogenous Gaseous Signaling Molecules: Their Mechanism(s) of Action and Pharmacological Effects)

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13 pages, 1003 KiB

Open AccessReview

Hydrogen Sulfide Metabolite, Sodium Thiosulfate: Clinical Applications and Underlying Molecular Mechanisms

by Max Y. Zhang, George J. Dugbartey, Smriti Juriasingani and Alp Sener

Int. J. Mol. Sci. 2021, 22(12), 6452; https://doi.org/10.3390/ijms22126452 - 16 Jun 2021

Cited by 40 | Viewed by 7364

Abstract

Thiosulfate in the form of sodium thiosulfate (STS) is a major oxidation product of hydrogen sulfide (H₂S), an endogenous signaling molecule and the third member of the gasotransmitter family. STS is currently used in the clinical treatment of acute cyanide poisoning, cisplatin toxicities in cancer therapy, and calciphylaxis in dialysis patients. Burgeoning evidence show that STS has antioxidant and anti-inflammatory properties, making it a potential therapeutic candidate molecule that can target multiple molecular pathways in various diseases and drug-induced toxicities. This review discusses the biochemical and molecular pathways in the generation of STS from H₂S, its clinical usefulness, and potential clinical applications, as well as the molecular mechanisms underlying these clinical applications and a future perspective in kidney transplantation. Full article

(This article belongs to the Special Issue Endogenous Gaseous Signaling Molecules: Their Mechanism(s) of Action and Pharmacological Effects)

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25 pages, 4489 KiB

Open AccessReview

Carbon Monoxide and Nitric Oxide as Examples of the Youngest Class of Transmitters

by Alicja Nowaczyk, Magdalena Kowalska, Jacek Nowaczyk and Grzegorz Grześk

Int. J. Mol. Sci. 2021, 22(11), 6029; https://doi.org/10.3390/ijms22116029 - 2 Jun 2021

Cited by 27 | Viewed by 6262

Abstract

The year 2021 is the 100th anniversary of the confirmation of the neurotransmission phenomenon by Otto Loewi. Over the course of the hundred years, about 100 neurotransmitters belonging to many chemical groups have been discovered. In order to celebrate the 100th anniversary of the confirmation of neurotransmitters, we present an overview of the first two endogenous gaseous transmitters i.e., nitric oxide, and carbon monoxide, which are often termed as gasotransmitters. Full article

(This article belongs to the Special Issue Endogenous Gaseous Signaling Molecules: Their Mechanism(s) of Action and Pharmacological Effects)

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