Search Results (135)

Myocardial ischaemia reperfusion injury (IRI) occurring from acute coronary artery disease or cardiac surgical interventions such as bypass surgery can result in myocardial dysfunction, presenting as, myocardial “stunning”, arrhythmias, infarction, and adverse cardiac remodelling, and may lead to both a systemic and a localised inflammatory response. This localised cardiac inflammatory response is regulated through the nucleotide-binding oligomerisation domain (NACHT), leucine-rich repeat (LRR)-containing protein family pyrin domain (PYD)-3 (NLRP3) inflammasome, a multimeric structure whose components are present within both cardiomyocytes and in cardiac fibroblasts. The NLRP3 inflammasome is activated via numerous danger signals produced by IRI and is central to the resultant innate immune response. Inhibition of this inherent inflammatory response has been shown to protect the myocardium and stop the occurrence of the systemic inflammatory response syndrome following the re-establishment of cardiac circulation. Therapies to prevent NLRP3 inflammasome formation in the clinic are currently lacking, and therefore, new pharmacotherapies are required. This review will highlight the role of the NLRP3 inflammasome within the myocardium during IRI and will examine the therapeutic value of inflammasome inhibition with particular attention to carbon monoxide, nitric oxide, and hydrogen sulphide as potential pharmacological inhibitors of NLRP3 inflammasome activation. Full article

Nitric oxide (NO) is a highly versatile gasotransmitter that has first been shown to regulate cardiovascular function and then to exert tight control over a much broader range of processes, including neurotransmitter release, neuronal excitability, and synaptic plasticity. Endothelial NO synthase (eNOS) is usually far from the mind of synaptic neurophysiologists, who have focused most of their attention on neuronal NO synthase (nNOS) as the primary source of NO at the neurovascular unit (NVU). Nevertheless, the available evidence suggests that eNOS could also contribute to generating the burst of NO that, serving as volume intercellular messenger, is produced in response to neuronal activity in the brain parenchyma. Herein, we review the role of eNOS in both the regulation of cerebral blood flow and of synaptic plasticity and discuss the mechanisms by which cerebrovascular endothelial cells may transduce synaptic inputs into a NO signal. We further suggest that eNOS could play a critical role in vascular-to-neuronal communication by integrating signals converging onto cerebrovascular endothelial cells from both the streaming blood and active neurons. Full article

Hydrogen selenide (H₂Se) is an emerging biomolecule of interest with similar properties to that of other gaseous signaling molecules (i.e., gasotransmitters that include nitric oxide, carbon monoxide, and hydrogen sulfide). H₂Se is enzymatically generated in humans where it serves as a key metabolic intermediate in the production of selenoproteins and other selenium-containing biomolecules. However, beyond its participation in biosynthetic pathways, its involvement in cellular signaling or other biological mechanisms remains unclear. To uncover its true biological significance, H₂Se-specific chemical tools capable of functioning under physiological conditions are required but lacking in comparison to those that exist for other gasotransmitters. Recently, researchers have begun to fill this unmet need by developing new H₂Se-releasing compounds, along with pioneering methods for selenide detection and quantification. In combination, the chemical tools highlighted in this review have the potential to spark groundbreaking explorations into the chemical biology of H₂Se, which may lead to its branding as the fourth official gasotransmitter. Full article

Hydrogen sulfide (H₂S) is a novel gasotransmitter. Sucrose (SUC) is a source of cellular energy and a signaling molecule. Maize is the third most common food crop worldwide. However, the interaction of H₂S and SUC in maize thermotolerance is not widely known. In this study, using maize seedlings as materials, the metabolic and functional interactions of H₂S and SUC in maize thermotolerance were investigated. The data show that under heat stress, the survival rate and tissue viability were increased by exogenous SUC, while the malondialdehyde content and electrolyte leakage were reduced by SUC, indicating SUC could increase maize thermotolerance. Also, SUC-promoted thermotolerance was enhanced by H₂S, while separately weakened by an inhibitor (propargylglycine) and a scavenger (hypotaurine) of H₂S and a SUC-transport inhibitor (N-ethylmaleimide), suggesting the interaction of H₂S and SUC in the development of maize thermotolerance. To establish the underlying mechanism of H₂S–SUC interaction-promoted thermotolerance, redox parameters in mesocotyls of maize seedlings were measured before and after heat stress. The data indicate that the activity and gene expression of H₂S-metabolizing enzymes were up-regulated by SUC, whereas H₂S had no significant effect on the activity and gene expression of SUC-metabolizing enzymes. In addition, the activity and gene expression of catalase, glutathione reductase, ascorbate peroxidase, peroxidase, dehydroascorbate reductase, monodehydroascorbate reductase, and superoxide dismutase were reinforced by H₂S, SUC, and their combination under non-heat and heat conditions to varying degrees. Similarly, the content of ascorbic acid, flavone, carotenoid, and polyphenol was increased by H₂S, SUC, and their combination, whereas the production of superoxide radicals and the hydrogen peroxide level were impaired by these treatments to different extents. These results imply that the metabolic and functional interactions of H₂S and sucrose signaling exist in the formation of maize thermotolerance through redox homeodynamics. This finding lays the theoretical basis for developing climate-resistant maize crops and improving food security. Full article

Irisin is a myokine secreted under the influence of physical activity and exposure to low temperatures and through different exogenous stimuli by the cleavage of its precursor, fibronectin type III domain-containing protein 5 (FNDC5). It is mainly known for maintaining of metabolic homeostasis, promoting the browning of white adipose tissue, the thermogenesis process, and glucose homeostasis. Growing experimental evidence suggests the possible central role of irisin in the regulation of cardiometabolic pathophysiological processes. On the other side, hydrogen sulfide (H₂S) is well recognized as a pleiotropic gasotransmitter that regulates several homeostatic balances and physiological functions and takes part in the pathogenesis of cardiometabolic diseases. Through the S-persulfidation of cysteine protein residues, H₂S is capable of interacting with crucial signaling pathways, exerting beneficial effects in regulating glucose and lipid homeostasis as well. H₂S and irisin seem to be intertwined; indeed, recently, H₂S was found to regulate irisin secretion by activating the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)/FNDC5/irisin signaling pathway, and they share several mechanisms of action. Their involvement in metabolic diseases is confirmed by the detection of their lower circulating levels in obese and diabetic subjects. Along with the importance of metabolic disorders, these modulators exert favorable effects against cardiovascular diseases, preventing incidents of hypertension, atherosclerosis, heart failure, myocardial infarction, and ischemia–reperfusion injury. This review, for the first time, aims to explore the role of H₂S and irisin and their possible crosstalk in cardiovascular diseases, pointing out the main effects exerted through the common molecular pathways involved. Full article

Fibrosis, a pathological alteration of the repair response, involves continuous organ damage, scar formation, and eventual functional failure in various chronic inflammatory disorders. Unfortunately, clinical practice offers limited treatment strategies, leading to high mortality rates in chronic diseases. As part of investigations into gaseous mediators, or gasotransmitters, including nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H₂S), numerous studies have confirmed their beneficial roles in attenuating fibrosis. Their therapeutic mechanisms, which involve inhibiting oxidative stress, inflammation, apoptosis, and proliferation, have been increasingly elucidated. Additionally, novel gasotransmitters like hydrogen (H₂) and sulfur dioxide (SO₂) have emerged as promising options for fibrosis treatment. In this review, we primarily demonstrate and summarize the protective and therapeutic effects of gaseous mediators in the process of fibrosis, with a focus on elucidating the underlying molecular mechanisms involved in combating fibrosis. Full article

Early studies have documented that PM2.5 can not only induce cardiac tissue toxicity, but can adversely affect the performance of the myocardium and deteriorate its tolerance to withstand ischemia-reperfusion (IR) injury. The primary factor that contributes to the adverse impacts of PM2.5 exposure on the heart is subcellular changes, with particular emphasis on mitochondrial dysfunction, inflammation, oxidative stress, and deterioration of pro-survival signaling pathways. Despite the ongoing efforts to uncover the mechanistic changes induced in the heart by PM2.5 exposure, no studies have presented strategies for mitigating PM2.5-induced cardiotoxicity or enhancing the tolerance of the myocardium to withstand IR injury. Considering the potential of hydrogen sulfide, a gasotransmitter known to protect the heart from pathologies linked to oxidative stress and mitochondrial dysfunction, we explored the efficacy of H2S in attenuating PM2.5-associated increased IR injury. Female Wistar rats were exposed to 250 μg/m³ of PM2.5 for 3 h daily for 21 days, after which the hearts were isolated and mounted on an isolated rat heart apparatus. H2S was administered directly to the PM2.5-exposed hearts, after which the hearts were subjected to 30 min of ischemia and 60 min of reperfusion to induce IR injury. Our results revealed that the ability of the PM2.5-exposed myocardium to withstand IR injury had considerably improved. The pivotal mechanism driving these beneficial changes was the preservation of mitochondrial function (improved bioenergetics, respiration) along with quality control mechanisms. The improvement in mitochondrial function was also reflected in terms of reduced oxidative stress and activation of pro-survival signaling pathways. Based on these findings, we concluded that hydrogen sulfide holds promise as a potential therapeutic agent for enhancing the myocardium’s resilience to additional stressors in the form of IR injury. Full article

We highlight the particular aspects of the stable gastric pentadecapeptide BPC 157 pleiotropic beneficial activity (not destroyed in human gastric juice, native and stable in human gastric juice, as a cytoprotection mediator holds a response specifically related to preventing or recovering damage as such) and its possible relations with neurotransmitter activity. We attempt to resolve the shortage of the pleiotropic beneficial effects of BPC 157, given the general standard neurotransmitter criteria, in classic terms. We substitute the lack of direct conclusive evidence (i.e., production within the neuron or present in it as a precursor molecule, released eliciting a response on the receptor on the target cells on neurons and being removed from the site of action once its signaling role is complete). This can be a network of interconnected evidence, previously envisaged in the implementation of the cytoprotection effects, consistent beneficial particular evidence that BPC 157 therapy counteracts dopamine, serotonin, glutamate, GABA, adrenalin/noradrenalin, acetylcholine, and NO-system disturbances. This specifically includes counteraction of those disturbances related to their receptors, both blockade and over-activity, destruction, depletion, tolerance, sensitization, and channel disturbances counteraction. Likewise, BPC 157 activates particular receptors (i.e., VGEF and growth hormone). Furthermore, close BPC 157/NO-system relations with the gasotransmitters crossing the cell membrane and acting directly on molecules inside the cell may envisage particular interactions with receptors on the plasma membrane of their target cells. Finally, there is nerve-muscle relation in various muscle disturbance counteractions, and nerve-nerve relation in various encephalopathies counteraction, which is also exemplified specifically by the BPC 157 therapy application. Full article

Atmospheric stressors include a variety of pollutant gases such as CO₂, nitrous oxide (NOx), and sulfurous compounds which could have a natural origin or be generated by uncontrolled human activity. Nevertheless, other atmospheric elements including high and low temperatures, ozone (O₃), UV-B radiation, or acid rain among others can affect, at different levels, a large number of plant species, particularly those of agronomic interest. Paradoxically, both nitric oxide (NO) and hydrogen sulfide (H₂S), until recently were considered toxic since they are part of the polluting gases; however, at present, these molecules are part of the mechanism of response to multiple stresses since they exert signaling functions which usually have an associated stimulation of the enzymatic and non-enzymatic antioxidant systems. At present, these gasotransmitters are considered essential components of the defense against a wide range of environmental stresses including atmospheric ones. This review aims to provide an updated vision of the endogenous metabolism of NO and H₂S in plant cells and to deepen how the exogenous application of these compounds can contribute to crop resilience, particularly, against atmospheric stressors stimulating antioxidant systems. Full article

Hydrogen sulfide (H₂S) has been recently recognized as an important gasotransmitter with cardioprotections, and iron is vital for various cellular activities. This study explored the regulatory role of H₂S on iron metabolism and mitochondrial functions in cultured rat cardiac cells. Rotenone, a mitochondrial complex I inhibitor, was used for establishing an in vitro model of ischemic cell damage. It was first found that rotenone induced oxidative stress and lipid peroxidation and decreased mitochondrial membrane potential and ATP generation, eventually causing cell death. The supplement of H₂S at a physiologically relevant concentration protected from rotenone-induced ferroptotic cell death by reducing oxidative stress and mitochondrial damage, maintaining GPx4 expression and intracellular iron level. Deferiprone, an iron chelator, would also protect from rotenone-induced ferroptosis. Further studies demonstrated that H₂S inhibited ABCB8-mediated iron efflux from mitochondria to cytosol and promoted NFS1-mediated Fe-S cluster biogenesis. It is also found that rotenone stimulated iron-dependent H₂S generation. These results indicate that H₂S would protect cardiac cells from ischemic damage through preserving mitochondrial functions and intracellular Fe-S cluster homeostasis. Full article

H₂S, a gasotransmitter that can be produced both via the transsulfuration pathway and non-enzymatically, plays a key role in vasodilation and angiogenesis during pregnancy. In fact, the involvement of H₂S production on plasma levels of sFLT1, PGF, and other molecules related to preeclampsia has been demonstrated. Interestingly, we have found that maternal fructose intake (a common component of the Western diet) affects tissular H₂S production. However, its consumption is allowed during pregnancy. Thus, (1) to study whether maternal fructose intake affects placental production of H₂S in the offspring, when pregnant; and (2) to study if fructose consumption during pregnancy can increase the risk of preeclampsia, pregnant rats from fructose-fed mothers (10% w/v) subjected (FF) or not (FC) to a fructose supplementation were studied and compared to pregnant control rats (CC). Placental gene expression, H₂S production, plasma sFLT1, and PGF were determined. Descendants of fructose-fed mothers (FC) presented an increase in H₂S production. However, if they consumed fructose during their own gestation (FF), this effect was reversed so that the increase disappeared. Curiously, placental synthesis of H₂S was mainly non-enzymatic. Related to this, placental expression of Cys dioxygenase, an enzyme involved in Cys catabolism (a molecule required for non-enzymatic H₂S synthesis), was significantly decreased in FC rats. Related to preeclampsia, gene expression of sFLT1 (a molecule with antiangiogenic properties) was augmented in both FF and FC dams, although these differences were not reflected in their plasma levels. Furthermore, placental expression of PGF (a molecule with angiogenic properties) was decreased in both FC and FF dams, becoming significantly diminished in plasma of FC versus control dams. Both fructose consumption and maternal fructose intake induce changes in molecules that contribute to increasing the risk of preeclampsia, and these effects are not always mediated by changes in H₂S production. Full article

Recently, myriad studies have defined the versatile abilities of gasotransmitters and their synthesizing enzymes to play a “Maestro” role in orchestrating several oncological and non-oncological circuits and, thus, nominated them as possible therapeutic targets. Although a significant amount of work has been conducted on the role of nitric oxide (NO) and carbon monoxide (CO) and their inter-relationship in the field of oncology, research about hydrogen sulfide (H₂S) remains in its infancy. Recently, non-coding RNAs (ncRNAs) have been reported to play a dominating role in the regulation of the endogenous machinery system of H₂S in several pathological contexts. A growing list of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are leading the way as upstream regulators for H₂S biosynthesis in different mammalian cells during the development and progression of human diseases; therefore, their targeting can be of great therapeutic benefit. In the current review, the authors shed the light onto the biosynthetic pathways of H₂S and their regulation by miRNAs and lncRNAs in various oncological and non-oncological disorders. Full article

Hydrogen sulfide (H₂S) belongs to the family of gasotransmitters and can modulate a myriad of biological signaling pathways. Among others, its cardioprotective effects, through antioxidant, anti-inflammatory, anti-fibrotic, and proangiogenic activities, are well-documented in experimental studies. Cardiorespiratory failure, predominantly cardiomyopathy, is a life-threatening complication that is the number one cause of death in patients with Duchenne muscular dystrophy (DMD). Although recent data suggest the role of H₂S in ameliorating muscle wasting in murine and Caenorhabditis elegans models of DMD, possible cardioprotective effects have not yet been addressed. In this review, we summarize the current understanding of the role of H₂S in animal models of cardiac dysfunctions and cardiac cells. We highlight that DMD may be amenable to H₂S supplementation, and we suggest H₂S as a possible factor regulating DMD-associated cardiomyopathy. Full article

The organic sulfur-containing compounds glucosinolates (GSLs) and the novel gasotransmitter H₂S are known to have cardioprotective effects. This study investigated the antioxidant effects and H₂S-releasing potential of three GSLs ((3E)-4-(methylsulfanyl)but-3-enyl GSL or glucoraphasatin, 4-hydroxybenzyl GSL or glucosinalbin, and (R_S)-6-(methylsulfinyl)hexyl GSL or glucohesperin) in rat cardiac cells. It was found that all three GSLs had no effect on cardiac cell viability but were able to protect against H₂O₂-induced oxidative stress and cell death. NaHS, a H₂S donor, also protected the cells from H₂O₂-stimulated oxidative stress and cell death. The GSLs alone or mixed with cysteine, N-acetylcysteine, glutathione, H₂O₂, iron and pyridoxal-5′-phosphate, or mouse liver lysates did not induce H₂S release. The addition of GSLs also did not alter endogenous H₂S levels in cardiac cells. H₂O₂ significantly induced cysteine oxidation in the cystathionine gamma-lyase (CSE) protein and inhibited the H₂S production rate. In conclusion, this study found that the three tested GSLs protect cardiomyocytes from oxidative stress and cell death but independently of H₂S signaling. Full article