International Journal of Molecular Sciences

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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

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19 pages, 2453 KiB

Open AccessArticle

Selective Hepatic Cbs Knockout Aggravates Liver Damage, Endothelial Dysfunction and ROS Stress in Mice Fed a Western Diet

by Sebastiaan Lambooy, Andries Heida, Christian Joschko, Dalibor Nakladal, Azuwerus van Buiten, Niels Kloosterhuis, Nicolette Huijkman, Albert Gerding, Bart van de Sluis, Robert Henning and Leo Deelman

Int. J. Mol. Sci. 2023, 24(8), 7019; https://doi.org/10.3390/ijms24087019 - 10 Apr 2023

Cited by 2 | Viewed by 1466

Abstract

Cystathionine-β-synthase (CBS) is highly expressed in the liver, and deficiencies in Cbs lead to hyperhomocysteinemia (HHCy) and disturbed production of antioxidants such as hydrogen sulfide. We therefore hypothesized that liver-specific Cbs deficient (LiCKO) mice would be particularly susceptible to the development of non-alcoholic fatty liver disease (NAFLD). NAFLD was induced by a high-fat high-cholesterol (HFC) diet; LiCKO and controls were split into eight groups based on genotype (con, LiCKO), diet (normal diet, HFC), and diet duration (12 weeks, 20 weeks). LiCKO mice displayed intermediate to severe HHCy. Plasma H₂O₂ was increased by HFC, and further aggravated in LiCKO. LiCKO mice fed an HFC diet had heavier livers, increased lipid peroxidation, elevated ALAT, aggravated hepatic steatosis, and inflammation. LiCKO mice showed decreased L-carnitine in the liver, but this did not result in impaired fatty acid oxidation. Moreover, HFC-fed LiCKO mice demonstrated vascular and renal endothelial dysfunction. Liver and endothelial damage correlated significantly with systemic ROS status. In conclusion, this study demonstrates an important role for CBS in the liver in the development of NAFLD, which is most probably mediated through impaired defense against oxidative stress. Full article

(This article belongs to the Special Issue Endogenous Gaseous Signaling Molecules: Their Mechanism(s) of Action and Pharmacological Effects 2.0)

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14 pages, 1957 KiB

Open AccessArticle

Ovariectomy Exacerbates Acute Ethanol-Induced Tachycardia: Role of Nitric Oxide and NMDA Receptors in the Rostral Ventrolateral Medulla

by Jiro Hasegawa Situmorang, Hsun-Hsun Lin, Md Sharyful Islam and Chih-Chia Lai

Int. J. Mol. Sci. 2023, 24(6), 5087; https://doi.org/10.3390/ijms24065087 - 07 Mar 2023

Cited by 2 | Viewed by 1303

Abstract

Ethanol consumption influences cardiovascular functions. In humans, acute consumption of ethanol causes dose-dependent tachycardia. Our previous study showed that ethanol-induced tachycardia might involve decreased nitric oxide (NO) signaling in the brain’s medulla. NMDA receptors, another important target of ethanol, are one of the upstream signals of nitric oxide. Reports showed the modulation of NMDA receptor function by estrogen or estrogen receptors. The present study aims to examine the hypothesis that depletion of estrogen by ovariectomy (OVX) might modulate ethanol-induced tachycardia by regulating NMDA receptor function and NO signaling in the cardiovascular regulatory nucleus of the brain. Ethanol (3.2 g/kg, 40% v/v, 10 mL/kg) or saline (10 mL/kg) was administered by oral gavage in sham or OVX female Sprague-Dawley (SD) rats. The blood pressure (BP) and heart rate (HR) were measured using the tail-cuff method. The levels of phosphoserine 896 of the GluN1 subunit (pGluN1-serine 896) and NMDA GluN1 subunits (GluN1) were determined by immunohistochemistry. The expressions of nitric oxide synthase (NOS) and estrogen receptors in the tissue were measured by Western blotting. Nitric oxide contents were measured as total nitrate-nitrite by colorimetric assay kit. In a 2-h observation, there was no significant change in BP between the saline and ethanol groups. However, compared with saline, ethanol caused an increase in HR (tachycardia) in sham control or OVX rats. Interestingly, ethanol produced more significant tachycardia in the OVX group than in the sham control group. Nitric oxide levels were lower in the area of the rostral ventrolateral medulla (RVLM) 60 min following ethanol administration in OVX compared with sham control, without significant changes in the expression of NOS and estrogen receptors (ERα and ERβ). In addition, a decrease in the immunoreactivity of pGluN1-serine 896, without significant changes in GluN1, was found in neurons of RVLM 40 min following ethanol administration in OVX compared with sham control. Our results suggest that depletion of estradiol (E2) by OVX might exacerbate the tachycardia following ethanol administration, the underlying mechanism of which might be associated with decreased NMDA receptor function and NO level in the RVLM. Full article

(This article belongs to the Special Issue Endogenous Gaseous Signaling Molecules: Their Mechanism(s) of Action and Pharmacological Effects 2.0)

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