Cardiovascular disease (CVD) is the leading cause of death worldwide, despite tremendous progress being made in the medical and surgical treatment of these diseases [68].

It is known that NO plays an important role in cardioprotection in CVD. It exhibits various biological effects: relaxation of blood vessels, prevention of platelet aggregation, inhibition of leukocyte adhesion, and control of proliferation of vascular smooth muscle cells [69]. NO is produced by resident cardiac cells under stress and in large quantities by activated immune cells that enter the damaged myocardium. A deficiency of eNOS and nNOS exacerbates cardiac injury caused by ischemia/reperfusion or myocardial infarction [70]. NO activates soluble guanylate cyclase (sGC), which leads to an increase in cGMP levels and activation of cGMP-dependent protein kinase (PKG) [71]. In addition, NO induces the opening of mitochondrial K⁺-ATP channels and inhibits Ca²⁺ overload [72]. In addition, a mechanism has recently been described in which NO protects endothelial cells from oxidative stress-induced apoptosis by inhibiting cysteine-dependent superoxide dismutase (SOD1) monomerization and thus blocking its inactivation [73].

The diverse effects of CO are mainly explained by its regulation of general signaling pathways such as stimulation of sGC, opening of Ca²⁺-activated large conductive K⁺ channels (BKCa), and activation of mitogen-activated protein kinase (MAPK) and protein kinase B (Akt). The apoptotic effects of CO are tissue-specific and cell-specific. For example, CO acts as an anti-apoptotic agent in endothelial cells [74] and cardiomyocytes [75], thus preventing cell damage. The anti-apoptotic effects of CO appear to be dependent on p38 activation [43,76], phosphorylation of the protein kinase R-like kinase of the endoplasmic reticulum, and/or via Akt activation [77]. CO has been shown to prevent TNF-α [78] and endoplasmic reticulum (ER) stress-induced apoptosis through a p38 MAPK-dependent mechanism [74].

H₂S may be involved in the occurrence and development of some CVDs through various mechanisms [79]. H₂S has been shown to have a wide range of physiological effects on the cardiovascular system, such as the modulation of blood pressure; effects on angiogenesis, inflammation, and smooth muscle cell growth; apoptosis; antioxidant effects; and cardioprotection [80].

H₂S can activate Nrf2 signaling to suppress oxidative stress, thereby suppressing atherosclerosis [58]. Nrf2 is known to be an important antioxidant stress transcription factor that regulates the expression of many antioxidant and cytoprotective genes. ROS are an important risk factor for CVD and can induce endothelial cell apoptosis by activating NF-κB, increasing the expression of adhesion molecules and cytokines and enhancing monocytic adhesion [81,82].

Exogenous H₂S inhibits endothelial cell autophagy induced by oxidative stress via the Nrf2-ROS-AMPK signaling pathway [83]. The use of H₂S donors can activate Nrf2 signaling in mice with myocardial ischemia and upregulate the antioxidant HO-1 and Trx1, as well as reduce myocardial ischemic injury. It is assumed that exogenous H₂S induces nuclear translocation of Nrf2 in cardiomyocytes during myocardial infarction and increases the expression of Trx1 and HO-1 [84].

Great importance is attached to the epigenetic regulation of H₂S of the cardiovascular system through various mechanisms. Thus, DNA methylation of CSE promoter regions contributes to the development of atherosclerosis or inflammation by reducing CSE transcription and H₂S production in macrophages [85]. Recent studies show that H₂S can regulate miRNA expression in CVD. Inhibition of miR-30 can enhance CSE expression and H₂S production in myocardial ischemia/reperfusion (I/R) rats and counteract myocardial ischemic injury [86]. In neonatal rat cardiomyocytes, NaHS administration can upregulate miR-133a and inhibit cardiomyocyte hypertrophy [87]. Na₂S administration can increase miR-133a levels and inhibit cardiac muscle cell hypertrophy induced by hyperhomocysteinemia [88]. Overexpression of miR-133a protects against I/R-induced endoplasmic reticulum stress and cardiomyocyte apoptosis [89]. It was also shown that miRNAs can regulate CSE expression in pathological conditions. In the human macrophage THP-1 model, miR-186 directly inhibits CSE expression, which increases macrophage lipid accumulation [90], whereas miR-216a can suppress the expression of CSE and ATP-binding cassette transporter A1 (ABCA1), reducing cholesterol efflux from foam cells [91]. miR-21 overexpression in aortic smooth muscle cells inhibits CSE and specific protein 1 (SP-1) expression, inhibits H₂S production, stimulates smooth muscle cell proliferation, assembles genes associated with smooth muscle cell differentiation, and regulates CSE/H₂S-dependent proliferation and differentiation of smooth muscle cells by influencing SP-1 [92]. In a mouse model of myocardial ischemia and inflammation, Na₂S inhibits myocardial cell apoptosis and necrosis by inducing miR-21 expression, inhibits myocardial inflammation, and reduces infarct size after reperfusion myocardial ischemia [93]. miR-1 attenuates the protective effect of H₂S on cardiomyocytes by reducing the expression of Bcl-2 [94]. H₂S increases levels of hypoxia-inducible factor 1-α (HIF1A) via the VEGFR2-mTOR pathway, leading to a decrease in miR-640 levels.

SO₂ acts as an important regulator of many biological processes in normal and pathological conditions associated with CVD. Recently, studies of the effect of SO₂ on cell apoptosis have attracted much attention. SO₂ can regulate the apoptosis of vascular smooth muscle cells, endothelial cells, cardiomyocytes, and a number of other cells that may be involved in the pathogenesis of arterial hypertension (AH) and myocardial damage [95].

ROS play a special role in the regulation of eNOS, which can contribute to the activation of the pro-inflammatory NF-κB-dependent pathway. Under these conditions, NF-κB activation increases the levels of IL-6 and TNF-α cytokines, which can influence tyrosine kinase phosphorylation and decrease NO levels [96]. Hypertension is accompanied by structural changes in blood vessels, such as hypertrophy and hyperplasia of the walls of blood vessels, which contributes to an increase in vascular resistance. Some NO donors, such as LA-419, have a beneficial effect in preventing the progression of maladaptive cardiac hypertrophy [97].

HO-1 is activated by hemodynamic stress in response to elevated blood pressure. At the same time, the level of HO-1, sGC, and cGMP in vascular smooth muscle cells depends on the stage of development of AH [98]. A number of researchers have demonstrated that CO significantly reduced ventricular hypertrophy and aortic hypertrophy, attenuating the development of angiotensin-dependent type II hypertension in mice. These cardioprotective mechanisms of CO were due to a decrease in ROS production due to a decrease in Nox and Akt phosphorylation [99,100].

Numerous studies show that a decrease in the level of H₂S contributes to the onset of hypertension. It has been demonstrated in an experimental model that long-term treatment with NaHS can reduce myocardial thickening, coronary intima thickening, interstitial fibrosis, and ROS levels in spontaneously hypertensive rats [101]. Other authors have shown that CSE−/− mice exhibit a significant reduction in endothelium-dependent vasodilation and AH. At the same time, the level of H₂S in the blood serum, heart, aorta, and other tissues was significantly reduced [102]. Similar results were obtained in children with essential hypertension. Compared with healthy children with normal blood pressure, plasma H₂S levels in children with essential hypertension were significantly reduced, and systolic blood pressure correlated negatively with the plasma H₂S/Hcy ratio [103].

SO₂ can enhance arterial vasorelaxation in spontaneously hypertensive rats by enhancing the vasodilatory response to NO in isolated aortic rings and promoting NO production by aortic cells [104]. Abnormal proliferation of vascular smooth muscle cells induces vascular remodeling and accelerates the development of hypertension. Additionally, SO₂ significantly inhibits serum-stimulated proliferation of vascular smooth muscle cells by preventing the transition of the cell cycle from G1 to S phase and DNA replication. In addition, SO₂ increased cAMP synthesis, which led to PKA activation, c-Raf blocking, and extracellularly regulated protein kinase (Erk)/MAPK signaling. As a result, the proliferation of vascular smooth muscle cells was significantly reduced [105].

NO plays an important role in the pathogenesis of atherosclerosis. NO in the endothelium controls the expression of genes involved in atherogenesis. NO reduces the expression of the chemoattractant protein MCP-1 [106]. NO can also inhibit leukocyte adhesion to the vessel wall by reducing leukocyte adhesion molecules CD11/CD18 to bind to the surface of endothelial cells and downregulating CD11/CD18 expression [107]. Leukocyte adhesion is an early event in the development of atherosclerosis. Endothelial-derived NO prevents endothelial cell apoptosis induced by pro-inflammatory cytokines and pro-atherosclerotic factors, including ROC and angiotensin II. Inhibition of apoptosis may also contribute to the anti-inflammatory and anti-atherosclerotic effect of NO [108]. In addition, NO has been shown to inhibit DNA synthesis, mitogenesis, and proliferation of vascular smooth muscle cells [109]. These antiproliferative effects are likely mediated by cGMP [110]. Inhibition of platelet aggregation and adhesion protects smooth muscle from the effects of platelet-derived growth factors. NO also prevents a later stage of atherogenesis, the formation of fibrous plaque. Based on the combination of these effects, NO produced in endothelial cells can be considered as an anti-atherosclerotic factor [111].

H₂S has a protective effect on the formation of atherosclerosis. In a knockout mouse model of atherosclerosis apolipoprotein-E (ApoE), plasma H₂S levels were significantly reduced. Inhibition of CSE further reduced the level of H₂S and increased the level of intercellular adhesion molecule and plasma-1 (ICAM-1), leading to the progression of aortic lesions. The use of NaHS increased the concentration of H₂S in plasma, reduced the levels of ICAM-1 in the aorta and plasma, and reduced the area of aortic lesions [112].

The role of SO₂ in the development of atherosclerosis was unclear until recently. Plasma and aortic SO₂ concentrations were reduced in combination with a decrease in aortic aspartate aminotransferase (AAT) activity in atherosclerotic rats [113], indicating a key role for SO_2/AAT in the pathogenesis of atherosclerosis. The use of SO₂ donors reduced the size of atherosclerotic plaques in the coronary artery by increasing the level of H₂S, NO, glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) in plasma and decreasing the level of malondialdehyde (MDA). Suppression of the proliferation of vascular smooth muscle cells via the cAMP/PKA-mediated Erk/MAPK signaling pathway contributed to the anti-atherosclerotic effects of SO₂ [105].

Cardiovascular dysfunction leads to a decrease in NO production in the vessels. During myocardial ischemia reperfusion, more severe cardiac dysfunctions have been found in eNOS-deficient mice compared to wild-type mice [70]. NO is an important modulator of left ventricular remodeling after myocardial infarction. Overexpression of eNOS limits left ventricular dysfunction and remodeling after myocardial ischemia [114]. NO stimulated PKG activity and the opening of K⁺-ATP channels to induce ROS generation in cardiomyocytes [115]. NO prevents the progression of hypertrophy and the development of heart failure through cGMP/GS3Kβ signaling [116]. In the coronary arteries of rats with heart failure, the level of NO was reduced. However, in MI rats, NO levels were increased due to activation of the eNOS/nNOS/PI3K/Akt pathway and decreased ROS formation [117].

Numerous studies have shown that H₂S can counteract reperfusion myocardial ischemia. In a CSE−/− mouse model, it was shown that H₂S restores eNOS activity and NO levels in the myocardium, which contributes to the prevention of reperfusion myocardial ischemia [118]. Preliminary use of H₂S donors can significantly counteract ischemic myocardial injury, reduce the area of myocardial infarction, and reduce troponin-I levels and oxidative stress. It has been shown that H₂S can increase Nrf2 nuclear translocation and upregulate PKC and STAT-3 phosphorylation by upregulating the expression of HO-1, thioredoxin 1, and heat shock protein 90 (Hsp90) and reducing the activity of proapoptotic factors [84]. NaHS can also reduce caspase-9 activity in cardiomyocytes, increase Bcl-2 expression, reduce p38 MAPK and JNK phosphorylation, and reduce nuclear translocation of p65 NF-κB subunits, which counteracts myocardial reperfusion ischemia [119].

In rat models, it was shown that under conditions of reperfusion MI, SO₂ preconditioning increased cardiac function and attenuated myocardial cell apoptosis [120]. Ischemic preconditioning-induced endoplasmic reticulum stress (ERS) plays a protective role in ischemic injury. Glucose-regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), and phosphorylation of factor 2 α-subunit (p-eIF2 α) are markers of myocardial ischemia/reperfusion. In addition, SO₂ preconditioning significantly increased Akt and phosphoinositide 3-kinase (PI3K) p85 phosphorylation and attenuated myocardial injury in rats [95]. Simultaneous enhancement of PI3K/AKT signaling, downregulation of the ERK-MAPK pathway, increase in ERS, enhancement of antioxidant capacity, and attenuation of cardiomyocyte apoptosis may be involved in SO₂ mediated cardiac defense mechanisms. Apoptosis of cardiomyocytes is a key pathological change in myocardial injury. It should be noted that the use of SO₂ donors alleviated isoproterenol (ISO⁻)-induced myocardial injury in part by reducing cardiomyocyte apoptosis [67]. The anti-apoptotic function of SO₂ was mediated by stimulation of Bcl-2 expression, downregulation of Bax expression, increased mitochondrial membrane potential, inhibition of mitochondrial MPTP opening, decreased release of cytochrome C from mitochondria into the cytoplasm, and decreased activation of caspase-9 and caspase-3. SO₂ can modulate Ca²⁺ current from L-type channels and voltage-dependent K⁺ channels in rat cardiomyocytes. This indicates that ion channels may also be involved in the action of SO₂ when cardiomyocytes are damaged [121].

In the study of the pathogenesis of rheumatic diseases, the role of gasotransmitters is of considerable interest at present. The most studied common and socially significant diseases of the joints are osteoarthritis (OA) and rheumatoid arthritis (RA) [7].

Thus, it has been shown that NO regulates T-cell function under physiological conditions, however, overproduction of NO can contribute to T-lymphocyte dysfunction. NO-dependent tissue damage has been associated with various rheumatic diseases, most commonly with rheumatoid arthritis [122]. In RA, the main source of NO are fibroblasts, osteoclasts, osteoblasts, endothelial cells, and immune cells such as macrophages and neutrophils. NO can cause dysregulation of the balance of osteoblasts and osteoclasts, and in combination with O₂⁻ can be formed into ONOO⁻, which contributes to the degradation of articular cartilage and induces apoptosis. This leads to an imbalance in bone resorption and formation and damage to the joints [123]. Pro-inflammatory cytokines such as IL-1 and TNF induce the activation of iNOS in bone cells, resulting in overproduction of NO, causing bone loss. These actions of NO are relevant to the pathogenesis of osteoporosis in inflammatory joint diseases. Histomorphometric analysis of the bones of normal animals with bone loss caused by inflammation showed a profound depression of bone formation and signs of osteoblast apoptosis. These changes were not observed in iNOS knockout animals, suggesting that iNOS activation may contribute to the development of inflammatory osteoporosis as well as osteoblast apoptosis [124].

In addition to rheumatoid arthritis, NO is also involved in the pathogenesis of autoinflammatory joint diseases such as psoriatic arthritis (PsA) and systemic lupus erythematosus (SLE). In a mouse model of psoriasis and PsA induced by mannan, elevated levels of NO in the skin and extremities were found before the clinical onset of the disease. The generation of NO by local macrophages results in the release of IL-1α, which then activates IL-C3 to produce IL-17A, leading to increased disease severity [125]. NOS expression was also increased in SLE patients [126]. Another disease in which NO may be involved in the pathogenesis is fibromyalgia, the etiology of which has not yet been fully established and is therefore of considerable interest. NO acts as a vascular smooth muscle relaxant, neurotransmitter, and immune regulator that sensitizes the spinal pain pathway. In fibromyalgia, there is an increase in ROS and a decrease in the antioxidant defense system. As a result, oxidative stress develops, which causes neuropathic pain and stimulates the development of chronic fatigue syndrome [127].

OA is a disease that has long been considered a primary metabolic disease, and mechanical cartilage degeneration has been the main element of pathogenesis. To date, the role of inflammation in the pathogenesis of OA is undoubted. NO also plays a role in osteoarthritis [128]. Analysis of the NO content in the synovial fluid of patients with OA has yielded conflicting results [129]. Unlike synoviocytes, chondrocytes have the ability to self-produce NO, as evidenced by increased levels of iNOS and NO in articular cartilage tissues. However, chondrocytes from patients without OA do not express iNOS, and experimental OA does not develop in iNOS knockout mice [130]. Some experiments have shown that NO by itself is not cytotoxic to cultured chondrocytes. However, excess NO can be detrimental, causing cartilage degradation or inhibiting cartilage matrix synthesis and causing mitochondrial dysfunction. There is a correlation between NO synthesis and the prevalence of apoptotic cells in cartilage in experimentally induced OA in rabbits. NO plays a role in mediating chondrocyte apoptosis, which is a common feature of progressive OA. Moreover, NO also alters the function of mitochondria in chondrocytes in OA, which leads to a decrease in cell survival by suppressing the activity of the mitochondrial respiratory chain and ATP synthesis [131]. The concentration of NO is significantly elevated in the synovial fluid in a model of OA in dogs [132] and humans [133]. However, there is evidence that NO has a beneficial effect on some cell types, including osteoblasts.

To a greater extent, H₂S has a protective effect. It has been established that H₂S has a cytoprotective effect through the modulation of antioxidant, anti-inflammatory, anti-apoptotic, and pro-angiogenic effects under various conditions [7]. The beneficial effect of H₂S appears to be dose-dependent, as various studies have shown conflicting results [134]. In mouse macrophages, low concentration of H₂S inhibited the activation and synthesis of several pro-inflammatory mediators such as TNF-α, NF-κB, IL-6, and IL-1β. However, at higher concentrations, H₂S stimulated the production of pro-inflammatory molecules by human macrophages [135]. In addition, other studies have confirmed that H₂S inhibits NF-κB-dependent expression of pro-inflammatory cytokines (e.g., IL-1β, IL-6, TNF-α) in macrophages, chondrocyte cell lines, and myoblast cell lines [136]. Interestingly, synovial fluid levels in RA were found to be higher than in patients with osteoarthritis, and the levels were positively correlated with disease activity and inflammation [137]. The role of CSE in increased cartilage calcification has been revealed. Indeed, increased cartilage calcification is observed when CSE activity is suppressed, for example, in mouse models of age-related or surgically-induced OA. Calcification levels and histological severity of OA in mice and humans were negatively correlated with CSE expression. In vitro results have shown that CSE deficiency results in decreased cellular H₂S levels and increased calcification in chondrocytes. With a pharmacological increase in the level of H₂S in chondrocytes, a decrease in calcification was observed. These studies show that CSE generated is a regulator of experimental and human cartilage calcification [138,139,140]. H₂S donors have shown significant anti-inflammatory effects in an osteoarthritis model and in rheumatoid arthritis in vitro and in vivo [141]. Increasing chondrocyte H₂S production may represent a potential disease modifier for the treatment of OA. Over the past few years, it has become increasingly clear that H₂S affects bone regeneration by acting on several levels, such as regulation of bone cell activity, reduction of oxidative stress, regulation of calcium consumption by bone cells, and promotion of angiogenesis. CBS and CSE are expressed in both multipotent stem cells and osteoblasts [142]. In particular, CSE is the predominant source of H₂S in osteoblasts [143]. H₂S plays a cytoprotective role in bone cells; it protects osteoblasts from homocysteine-induced mitochondrial toxicity [144] as well as from H₂O₂-induced apoptosis [145].

Only a few studies describe the molecular mechanism of H₂S activity in healthy and diseased skeletal muscle. Bitar et al. [146] focused on evaluating the effect of H₂S treatment on the development of sarcopenia. This loss of skeletal muscle mass and dysfunction has been described as a complication in diabetic patients, so studies were conducted using Goto Kakizaki rat models of diabetes with reduced systemic and muscle H₂S bioavailability. The use of H₂S donors increased muscle mass and reduced myostatistis levels. In animals with diabetes, the level of O₂⁻ and H₂O₂ decreased [146]. In model organisms C. elegans with Duchenne muscular dystrophy, the level of H₂S and the expression of genes necessary for sulfur metabolism are reduced. This decrease may be offset by an increase in the bioavailability of sulfur-containing amino acids, which increases lifespan, primarily by improving calcium regulation, mitochondrial structure, and slowing down muscle cell death [147].

CO mediates many of the biological effects that are attributed to HO, the enzyme responsible for CO production in mammals. The antioxidant and anti-inflammatory activity of HO-1 has been demonstrated in various disease models, including control of immune responses, production of inflammatory mediators, and mitigation of cartilage or bone destruction. Because HO-1 is highly expressed in the tissues of the joints of arthritic patients, it has been suggested that this pathway may play a protective role against degenerative joint diseases [148]. Low concentrations of CO are anti-inflammatory and may reduce bone erosion in an arthritis model. CO reduced RANKL expression in the synovium of arthritis mice. CO suppresses osteoclast differentiation by inhibiting RANKL-induced PPAR-γ activation. Considering the role of the PPAR-γ/cFos (AP-1) pathway in the regulation of the transcription factor NFATc1, a major regulator of osteoclastogenesis, further studies are needed to explore SO in the treatment of inflammatory bone diseases [149]. Experimental RA mice had elevated levels of anti-collagen antibodies, but decreased in the CO group. Histological analysis revealed a reduction in inflammation, erosion, and osteoclast counts only in CO-treated animals [150]. Ruthenium(II) tricarbonylchloro(glycinate) (CORM-3), releasing CO, reduced macroscopic signs of inflammation in the hind legs of OA mice, limited inflammatory cell migration and erosion of cartilage and bone, increased serum osteocalcin levels, and reduced PGD2 levels. In synovial tissues, a significant decrease in the expression of the genes of interleukin-1beta, receptor activator of nuclear factor kappa B ligand (RANKL), matrix metalloproteinase (MMP) 9, and MMP-13 were also revealed [151]. The study aimed to investigate the effect of carbon monoxide-releasing molecule 3 on osteoclastogenic differentiation of RAW264.7 cells and to investigate the possible mechanism underlying the regulatory effect. CORM-3 inhibits osteoclastogenic differentiation of RAW264.7 cells via CO release. The inhibitory effect is partially mediated by HO-1. The results suggest a potential application of CORM-3 in some bone defects [152].

The prevalence of chronic kidney disease (CKD) in the population is increasing. Currently, the number of patients in the world suffering from CKD exceeds 850 million people [153]. The study of molecular mechanisms of kidney damage and the search for potential diagnostic markers as well as promising molecules with cytoprotective properties are of research interest. Of particular interest are such gasotransmitters as H₂S, NO, and CO [154].

In recent decades, special attention has been paid to the study of the molecular role of H₂S in kidney diseases. It has been established that CSE, CBS, and 3-3-MPST are localized in the glomeruli of the kidneys, tubular epithelium, and tubulointerstitium [155]. H₂S regulates the excretory function, the release of renin from juxtaglomerular cells, thus controlling the activity of the renin–angiotensin–aldosterone system and blood pressure. H₂S has a wide research potential. Despite the fact that its toxic properties were shown in earlier works [156], more and more scientific data have recently appeared on the study of its cytoprotective properties realized in various tissues, including the kidneys. The described effect is achieved due to antioxidant, anti-inflammatory, and anti-apoptotic actions [157,158].

Acute kidney injury (AKI) is a rapidly progressive renal dysfunction characterized by a rapid increase in creatinine and decreased urine output lasting from hours to days [159]. The causes of AKI can be various factors, including sepsis, glomerulonephritis, medication (e.g., NSAIDs, cisplatin), liver failure, heart failure, ischemia and reperfusion syndrome, etc. [160]. The latter factor is one of the most frequent in the development of this pathological condition and is associated with the development of fibrosis and inflammation in the kidneys and, as a result, acute impairment of their function [161]. H₂S plays an important role in this process and performs various functions depending on the rate of its formation. So, at a high level, it induces the synthesis of pro-inflammatory mediators (IL-1β, IL-6, TNF-α, prostaglandin E2, and NO), whereas at low concentrations it exhibits cytoprotective properties and inhibits their formation, acting as an antioxidant agent [162]. The anti-inflammatory effect is also supported by the suppression of H₂S activity of NF-κB [163]. At the same time, endogenous H₂S realizes its anti-inflammatory and anti-apoptotic potential through inhibition of Toll-like receptors in the renal tubular epithelium [164]. In an experiment on rats with lipopolysaccharide-induced AKI/sepsis-associated AKI, it was demonstrated that H₂S prevented the development of inflammation and oxidative stress by reducing the expression of TNF-α, IL-1β, MDA, MPO, H₂O₂, and caspase-1, as well as through inhibition of the TLR4/NLRP3 signaling pathway [165].

In patients with chronic kidney disease (CKD), a decrease in H₂S levels was found. In experimental work on nephrectomized rats, NaHS exerted antioxidant, antiapoptotic, and anti-inflammatory effects through Nfr2 activation and downregulation of the mammalian target of rapamycin (mTOR), which generally had a positive effect on kidney function [166]. At the same time, NaHS realizes these effects through MAPK and NF-κB, suppressing inflammation and apoptosis. In mice with adenine-induced CKD, NaHS suppressed the production of TNF-α, IL-6, IL-10, NF-κB, MCP-1, MDA/SOD, GSH-Px, p-MAPK, Bax, cleaved caspase-3, and Bcl-2 [167]. Low levels of H₂S negatively affect kidney function and contribute to the acceleration of the progression of CKD due to increased autophagy, apoptosis, development of oxidative stress, and inflammation. An increase in H₂S levels may have a nephroprotective effect and slow down the discussed processes [168].

The progression of CKD is associated with the development of fibrotic processes in the kidneys. This is observed in diabetes mellitus, arterial hypertension, glomerulonephritis, and other diseases [165]. The accumulation of extracellular matrix leads (ECM) to impaired renal function. It has been demonstrated that administration of H₂S to mice with streptozotocin (SZT)-induced obesity reduced the accumulation of type II collagen, tissue inhibitor of metalloproteinase 2, and hydroxyproline in the kidneys and suppressed the activity of connexins and MMP 1/2 [169]. Administration of NaHS to diabetic mice reduced serum levels of creatinine, urea nitrogen, and pro-inflammatory cytokines and inhibited the activation of the TGF-β1/Smad 3 pathway. The anti-inflammatory effects of H₂S, described above, slow the rate of renal fibrosis and CKD progression [170].

H₂S also plays an integrative role in other pathological conditions. Thus, in obstructive nephropathy, there is a decrease in the expression of CSE, CBS, and 3-MPST, which increases the risk of tubulointerstitial fibrosis [171,172]. In mice with induced hyperhomocysteinemia, there is a decrease in CSE and CBS levels, whereas H₂S reduces the concentration of homocysteine [173]. The latter in turn induces kidney damage. Hydrogen sulphide also has a nephroprotective effect when using nephrotoxic drugs such as cisplatin, paracetamol, gentamicin, etc. [174,175,176]. The main defense mechanisms are the suppression of inflammation, apoptosis, and oxidative stress.

NO, which is considered one of the most studied gasotransmitters, plays a key role in various physiological and pathological processes and implements its effects in the kidneys as well [8]. With glomerulonephritis, immune inflammation develops and damage to the structures of the glomeruli of the kidneys, in particular, mesangial cells and podocytes, occurs. In experimental work on rats during the cultivation of mesangial cells, the introduction of NO donators (spermine, NOC-18, and SNAP) suppressed the expression of profibrogenic genes at the transcriptional level, which confirmed the antifibrotic effect of NO [177]. In another study, it was shown that the use of L-arginine in animals with ATS-glomerulonephritis slows down the process of kidney fibrosis induced by the suppression of TGF-β. At the same time, one of the causes of kidney fibrosis is the excessive formation of ECM. In mesangial cells, NO regulates the production of its components (MMP-9, MMP-13, PAI-1, TIMP-1), reducing renal failure [178,179].

At different concentrations, NO, like H₂S, can exhibit different effects. Thus, an increase in NO levels can inhibit mitochondrial respiration. On the other hand, AKI is characterized by NO deficiency, which contributes to the progression of kidney damage and supports the transformation of AKI into CKD and the development of arterial hypertension [180]. It was found that the NO-donator EDV regulates oxidative stress and lipid peroxidation in the kidney tissue and the inflammatory process by suppressing the activity of IL-1β, IL-18, IL-6, and TNF-α [181].

CO is one of the first gasotransmitters. It is involved in a number of physiological and pathological processes. Thus, in AKI caused by obstructive causes, the use of CO in mice reduced the phenomena of fibrosis and prevented kidney damage. This was associated with a decrease in ECM and downregulation of α-SMA, type I collagen, and fibronectin expression in the kidney [182]. At the same time, the MKK 3 signaling pathway is the main one at the stage of implementation of these effects. CO has several important functions that are indirectly related to the functioning of the kidneys. Among them: participation in angiogenesis, the development of vasodilation, a decrease in platelet aggregation, the induction of an inflammatory process, etc. [167,183]. Despite the known toxic effect of CO at high levels, its low concentrations may have a cytoprotective effect. CO has an anti-inflammatory effect by blocking TNF activity and potentiating the expression of the anti-inflammatory cytokine IL-10 [184,185]. The anti-inflammatory and anti-apoptotic properties of CO are also used in transplantology. CO suppresses oxidative stress, mRNA expression of pro-inflammatory cytokines, inhibits apoptosis of the epithelium of the tubules of the kidney graft, and suppresses interstitial fibrosis. These effects are achieved by the increased expression of phosphatidylinositol-3 kinase and phosphorylation of Akt and mitogen-activated protein kinase p38 [156].

Neurodegenerative diseases (ND) are a serious problem in the global health system. They cause severe disability and death for millions of people around the world. The most striking examples of neurodegenerative diseases (ND) are Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) [186].

Potential molecular targets in NS can be gasotransmitters. Thus, it was shown that NO can be a key molecular player in the pathogenesis of AD, characterized by the loss of synapses and neurons, and as a result, memory impairment, cognitive decline, and a tragic ending—death. Most often, NO was associated with neurotoxic damage in AD, however, as it turned out later, its role is far from being so unambiguous in this pathology. Of course, high concentrations of NO lead to nitrosyl stress, with the formation of an extremely aggressive peroxynitrite radical (ONOO⁻), which has a pronounced cytotoxic effect. The pathway of NO/O₂⁻/ONOO⁻-induced apoptosis of neurons has been demonstrated in various experimental models of AD [187]. However, it should be noted that such a neurotoxic effect of NO most often develops when iNOS is overexpressed, which generates high concentrations of NO. Constitutive forms of NOS, on the contrary, can have cytoprotective effects, in particular, due to the induction of the cGMP pathway, which causes an increase in cerebral blood supply, a decrease in oxidative stress, and Ca²⁺ excitotoxicity in AD [1].

Of great interest is the NO-dependent regulation of the level of the key AD protein, β-amyloid precursor protein (APP), which is responsible for the formation of amyloid plaques and neuronal death. NO can modulate the level of APP through the amyloidogenic pathway of processing depending on its concentration, leading to either its activation or inhibition. The NO-mediated anti-amyloidogenic effect was due to signaling through GC/cGMP/PKG, and the amyloidogenic activity of NO at high concentrations was mediated through mechanisms associated with ONOO⁻ [188]. In addition, nitrosyl stress has been shown to lead to β-amyloid (Aβ)-induced neurotoxicity, which underlies the pathogenesis of AD [189].

NO is involved in the pathophysiological processes associated with PD. High levels of nNOS and iNOS expression were found in the substantia nigra (SN) of patients and animals with PD [2]. It is indicated that nitrosyl stress is one of the main causes of degeneration of dopaminergic neurons in PD. In addition, NO can lead to abnormal dopamine metabolism with the formation of toxic metabolites leading to nerve cell death [190]. Stress of the endoplasmic reticulum and disruption of the ubiquitin-proteasome system is also one of the effects of NO in this pathology [191]. Overproduction of NO leads to neuronal damage by S-nitrosylation or nitration of several important proteins, including S-nitrosylation of parkin, protein disulfide isomerase, mitochondrial complex I, peroxiredoxin-2, and nitration of α-synuclein in PD [192]. Additionally, NO disrupts iron homeostasis in neurons, causing its accumulation through a decrease in APP expression in PD models, which leads to the death of dopaminergic neurons [193].

There is an increase in NO and its metabolites in the cerebrospinal fluid of patients with ALS. NO plays a key role in glutamate-induced neuronal death in ALS [194]. Degenerative neurons of the anterior horns of the spinal cord in ALS showed a high expression of nNOS, which may be associated with their subsequent death [195].

H₂S is also involved in AD. H₂S has been shown to bind to Tau proteins, the main components of neurofibrillary glomeruli, and enhances their catalytic activity. H₂S prevents Tau hyperphosphorylation by sulfhydration of GSK3β. Administration of H₂S donors to AD mice improved motor and cognitive impairments in AD [196]. It should be noted that the level of H₂S was reduced in patients with AD compared with normal, and there was a correlation of a decrease in the concentration of H₂S with the progression of the disease [197]. In addition, H₂S induced the expression of aldehyde dehydrogenase 2 and reduced the formation of lipid peroxidation products in the hippocampus of AD rats [198]. Additionally, H₂S donors reduce the activity of JNK and p38, which play a key role not only in the phosphorylation of Tau, but also in inflammation and apoptosis [199]. This messenger reduces the level of homocysteine, a high level of which increases the risk of developing AD, and is a negative concomitant factor of this pathology [200]. The H₂S donor decreased BACE1 and PS1 levels via the PI3/Akt pathway and also decreased Aβ in APP/PS1 transgenic mice [201].

An equally important role of H₂S is in PD. Studies have shown that parkin sulfhydration decreases in PD, leading to a decrease in its catalytic activity [202]. In a mouse model of PD, H₂S demonstrated a reduction in the loss of dopaminergic neurons and promoted adult neurogenesis by regulating the Akt/GSK-3β/β-catenin cascade [203]. On a cell culture treated with 1-Methyl-4-phenylpyridinium ion (MPP+) used to model PD, it was shown that the use of an H₂S donor led to a decrease in the expression of pro-apoptotic proteins caspase 3, Bax, and products of lipid peroxidation and the inhibition of the NO-ROS pathway [4]. In a 6-hydroxydopamine (6-OHDA)-induced PD rat model, administration of an H₂S donor resulted in the inhibition of microglial activation in the SN, accumulation of pro-inflammatory factors, and a decrease in malondialdehyde [204]. In addition, inhaled H₂S in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice prevented neuronal apoptosis and nigrostriatal gliosis [205].

ALS correlated with high levels of H₂S in the cerebrospinal fluid of patients suffering from this disease. It is known that a high concentration of H₂S can lead to cytotoxic effects. It is assumed that in ALS H₂S is responsible for the death of neurons through the activation of the mechanisms of Ca²⁺ excitotoxicity. Thus, the addition of H₂S to a spinal culture obtained from mice with ALS led to Ca²⁺ overload of cells and their death [206]. However, H₂S can activate the mechanisms of antioxidant and anti-inflammatory protection in ALS [82].

It is reported that CO can protect neurons from apoptosis in AD. HO-1 is known to be highly expressed in patients with Alzheimer’s disease, exerting a neuroprotective effect. HO-1/CO has been shown to protect cells from the toxicity of protofibrillar Aβ_1-42 by inhibiting AMPK activation and possibly also by reducing K⁺ efflux through Kv 2.1 K⁺ channels [207]. CO can interfere with Aβ_1-42-dependent astrocyte death by reducing oxidative stress levels [208].