H2S Deficiency Research Articles

Recent Developments On Activatable Turn-On Fluorogenic Donors of Hydrogen Sulfide (H2S).

Hydrogen sulfide (H2S) is considered the third member of the gasotransmitter family, along with nitric oxide (NO) and carbon monoxide (CO). Besides its role in physiological and pathophysiological conditions, the promising therapeutic potential of this small-molecule makes it advantageous for various pharmaceutical applications. The endogenous production of H2S at a lower concentration is crucial in maintaining redox balance and cellular homeostasis, and the dysregulation leads to various disease states. In the event of H2S deficiency, the exogenous donation of H2S could help maintain the optimal cellular concentration of H2S and cellular homeostasis. Over the last several years, researchers have developed numerous small-molecule non-fluorogenic organosulfur compounds as H2S donors and investigated their pharmacological potentials. However, reports on stimuli-responsive turn-on fluorogenic donors of H2S have appeared recently. Interestingly, the fluorogenic H2S donors offer additional advantages with the non-invasive real-time monitoring of the H2S release utilizing the simultaneous turn-on fluorogenic processes. The review summarizes the recent developments in turn-on fluorogenic donors of H2S and the potential biological applications that have developed over the years.

Enigmatic mixture of magnetite magnetofossils and diagenetic greigite as the magnetic carriers of the Early Miocene lacustrine sediments from the Most Basin in Central Europe

The Early Miocene lacustrine sediments of the Most Basin in the Czech Republic preserve a European continental paleoenvironmental archive. A number of paleoenvironmental and magnetostratigraphic studies have been carried out on sediment cores from boreholes due to ongoing coal mining in the basin. However, the magnetic carriers of the studied sediments have not been identified clearly. Here, we present a detailed paleo-rock magnetic study from the Burdigalian sediments near the Bilina mining area, Most Basin. The studied clay sediments cover the period of local lakes and a basin-wide lake above the main coal seam. Our results suggest that the magnetic carriers of the studied section in the Most Basin are mixtures of authigenic greigite and magnetite magnetofossils with overlapping magnetic signatures. Greigite is formed by migration of pore water through the sediment column, where iron from siderite grains reacts with these fluids with limited H2S, which then favors greigite precipitation. The co-existence of greigite and magnetite indicates a partial dissolution of magnetofossils due to H2S deficiency. Diagenetic greigite has been problematic in paleomagnetic studies due to an unknown time lag between the depositional remanence and the chemical remanent magnetization (CRM). A ghost polarity interval reveals that greigite acquired at least ∼45 kyr delayed CRM. The revealed timing of remanence acquisition brings a new perspective to the chronostratigraphic structure of the Most Basin.

Endothelial H2S-AMPK dysfunction upregulates the angiocrine factor PAI-1 and contributes to lung fibrosis

Dysfunction of the vascular angiocrine system is critically involved in regenerative defects and fibrosis of injured organs. Previous studies have identified various angiocrine factors and found that risk factors such as aging and metabolic disorders can disturb the vascular angiocrine system in fibrotic organs. One existing key gap is what sense the fibrotic risk to modulate the vascular angiocrine system in organ fibrosis. Here, using human and mouse data, we discovered that the metabolic pathway hydrogen sulfide (H2S)-AMP-activated protein kinase (AMPK) is a sensor of fibrotic stress and serves as a key mechanism upregulating the angiocrine factor plasminogen activator inhibitor-1 (PAI-1) in endothelial cells to participate in lung fibrosis. Activation of the metabolic sensor AMPK was inhibited in endothelial cells of fibrotic lungs, and AMPK inactivation was correlated with enriched fibrotic signature and reduced lung functions in humans. The inactivation of endothelial AMPK accelerated lung fibrosis in mice, while the activation of endothelial AMPK with metformin alleviated lung fibrosis. In fibrotic lungs, endothelial AMPK inactivation led to YAP activation and overexpression of the angiocrine factor PAI-1, which was positively correlated with the fibrotic signature in human fibrotic lungs and inhibition of PAI-1 with Tiplaxtinin mitigated lung fibrosis. Further study identified that the deficiency of the antioxidative gas metabolite H2S accounted for the inactivation of AMPK and activation of YAP-PAI-1 signaling in endothelial cells of fibrotic lungs. H2S deficiency was involved in human lung fibrosis and H2S supplement reversed mouse lung fibrosis in an endothelial AMPK-dependent manner. These findings provide new insight into the mechanism underlying the deregulation of the vascular angiocrine system in fibrotic organs.

Roles of Hydrogen Sulfide in Hypertension Development and Its Complications: What, So What, Now What.

Hypertension is a multicause health challenge, and hydrogen sulfide (H2S) is a multifunctional gasotransmitter. A critical pathologic role of endogenous H2S deficiency in the development of hypertension was established 15 years ago based on animal studies, setting the stage for examining the wide spectrum of cardiovascular effects and the underlying molecular and cellular mechanisms of H2S. We are also starting to gain a better understanding of the role of altered H2S metabolism in human hypertension. The purpose of this article is to examine our current understanding of the roles played by H2S in the development of hypertension in both animals and humans. Additionally, H2S-based antihypertension therapeutic strategies are reviewed. Is H2S at the root of hypertension and one of the solutions for the same? The probability is very high.

Hydrogen sulfide as an anti-calcification stratagem in human aortic valve: Altered biogenesis and mitochondrial metabolism of H2S lead to H2S deficiency in calcific aortic valve disease

Hydrogen sulfide (H2S) was previously revealed to inhibit osteoblastic differentiation of valvular interstitial cells (VICs), a pathological feature in calcific aortic valve disease (CAVD). This study aimed to explore the metabolic control of H2S levels in human aortic valves.Lower levels of bioavailable H2S and higher levels of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) were detected in aortic valves of CAVD patients compared to healthy individuals, accompanied by higher expression of cystathionine γ-lyase (CSE) and same expression of cystathionine β-synthase (CBS). Increased biogenesis of H2S by CSE was found in the aortic valves of CAVD patients which is supported by increased production of lanthionine. In accordance, healthy human aortic VICs mimic human pathology under calcifying conditions, as elevated CSE expression is associated with low levels of H2S. The expression of mitochondrial enzymes involved in H2S catabolism including sulfide quinone oxidoreductase (SQR), the key enzyme in mitochondrial H2S oxidation, persulfide dioxygenase (ETHE1), sulfite oxidase (SO) and thiosulfate sulfurtransferase (TST) were up-regulated in calcific aortic valve tissues, and a similar expression pattern was observed in response to high phosphate levels in VICs. AP39, a mitochondria-targeting H2S donor, rescued VICs from an osteoblastic phenotype switch and reduced the expression of IL-1β and TNF-α in VICs. Both pro-inflammatory cytokines aggravated calcification and osteoblastic differentiation of VICs derived from the calcific aortic valves. In contrast, IL-1β and TNF-α provided an early and transient inhibition of VICs calcification and osteoblastic differentiation in healthy cells and that effect was lost as H2S levels decreased. The benefit was mediated via CSE induction and H2S generation.We conclude that decreased levels of bioavailable H2S in human calcific aortic valves result from an increased H2S metabolism that facilitates the development of CAVD. CSE/H2S represent a pathway that reverses the action of calcifying stimuli.

The level of hydrogen sulfide and morphological changes in the aorta of rats under the influence of vitamin D under the conditions of modulation of the H2S / cystathionine-γ-lyase system

Annotation. Vitamin D and hydrogen sulfide (H2S) belong to pleitropic regulators, which are involved in the control of many cellular functions and biochemical processes, determine the adaptive potential of the cardiovascular system. The relationship between vitamin D and the H2S system is not fully investigated. The aim of the study was to evaluate the effect of the active form of vitamin D - calcitriol (1,25 (OH)2D3) on the morphological state of the thoracic aorta of rats and the level of it’s saturation with hydrogen sulfide under the conditions of the H2S / cystathionine-γ-lyase system modulation. The experiments were performed on 90 white male laboratory rats in accordance with the principles of bioethics (Strasbourg, 1986). 1,25(OH)2D3 was administered in doses of 0.1 μg/kg and 1 μg/kg for 4 weeks. Propargylglycine (50 mg/kg) and NaHS (1 mg/kg) were used to modulate the state of the H2S/cystathionine-γ-lyase system. The content of H2S was determined in the thoracic aorta and morphological changes were evaluated. Statistical calculations were performed in IBM Statistics SPSS 26, differences were evaluated in the Mann-Whitney test at the significance level of p<0.05. It was established that 1,25 (OH)2D3 in a dose of 1.0 μg/kg leads to the formation of H2S deficiency and a complex of morphological changes in the aorta, which are manifested by damage of epithelial cells and stromal elements, and the formation of calcifications. Modulation of the H2S / cystathionine-γ-lyase system is a factor that modifies the effect of high doses of 1,25 (OH)2D3 on vessels: H2S deficiency increases damage of the vascular wall, while increasing tissue H2S saturation has the opposite effect. 1,25 (OH)2D3 in a dose of 0.1 μg/kg shows the ability to increase the level of endogenous H2S and reduces the development of pathological changes in blood vessels under the conditions of long-term inhibition of the H2S / cystathionine-γ-lyase system.

Hydrogen sulfide alleviates uremic cardiomyopathy by regulating PI3K/PKB/mTOR-mediated overactive autophagy in 5/6 nephrectomy mice.

The gasotransmitter hydrogen sulfide (H2S) plays important physiological and pathological roles in the cardiovascular system. However, the involvement of H2S in recovery from uremic cardiomyopathy (UCM) remains unclear. This study aimed to determine the therapeutic efficacy and elucidate the underlying mechanisms of H2S in UCM. A UCM model was established by 5/6 nephrectomy in 10-week-old C57BL/6 mice. Mice were treated with sodium hydrosulfide (NaHS, H2S donor), L-cysteine [L-Cys, cystathionine gamma-lyase (CSE) substrate], and propargylglycine (PPG, CSE inhibitor). Treatment of H9C2 cardiomyocytes utilized different concentrations of uremic serum, NaHS, PPG, and PI3K inhibitors (LY294002). Mouse heart function was assessed by echocardiography. Pathological changes in mouse myocardial tissue were identified using hematoxylin and eosin and Masson's trichrome staining. Cell viability was assessed using the Cell Counting Kit-8. The protein expressions of CSE, p-PI3K, PI3K, p-PKB, PKB, p-mTOR, mTOR, and autophagy-related markers (Beclin-1, P62, and LC3) were detected using Western blotting. We found that NaHS and L-Cys treatment attenuated myocardial disarray, fibrosis, and left ventricular dysfunction in UCM mice. These abnormalities were further aggravated by PPG supplementation. Enhanced autophagy and decreased phosphorylation of PI3K, PKB, and mTOR protein expression by UCM were altered by NaHS and L-Cys treatment. In vitro, uremic serum increased overactive autophagy and decreased the phosphorylation levels of PI3K, PKB, and mTOR in cardiomyocytes, which was substantially exacerbated by endogenous H2S deficiency and attenuated by pre-treatment with 100µm NaHS. However, the protective effects of NaHS were completely inhibited by LY294002. These findings support a protective effect of H2S exerted against UCM by reducing overactive autophagy through activation of the PI3K/PKB/mTOR pathway.

Hydrogen Sulfide Regulates Irisin and Glucose Metabolism in Myotubes and Muscle of HFD-Fed Diabetic Mice.

Irisin, a novel myokine, is secreted by the muscle following proteolytic cleavage of fibronectin type III domain containing 5 (FNDC5) and is considered a novel regulator of glucose homeostasis. Cystathionine γ-lyase (CSE) produces hydrogen sulfide (H2S) and is involved in glucose homeostasis. We examined the hypothesis that H2S deficiency leads to decreased FNDC5 and irisin secretion, and thereby alters glucose metabolism. High-fat diet-fed mice exhibited elevated blood glucose and significantly reduced levels of CSE, H2S, and PGC-1α, with decreased FNDC5/irisin levels and increased oxidative stress in the muscle compared with those of normal diet-fed mice (control). High glucose or palmitate decreases CSE/PGC-1α/FNDC5 levels and glucose uptake in myotubes. Inhibitors (propargylglycine and aminooxyacetate) of H2S producing enzymes or CSE siRNA significantly decreased levels of H2S and FNDC5 along with PGC-1α; similar H2S-deficient conditions also resulted in decreased GLUT4 and glucose uptake. The levels of H2S, PGC-1α, and FNDC5 and glucose uptake were significantly upregulated after treatment with l-cysteine or an H2S donor. Myoblast differentiation showed upregulation of PGC-1α and FNDC5, which was consistent with the increased expression of CSE/H2S. These findings suggest that the upregulation of H2S levels can have beneficial effects on glucose homeostasis via activation of the PGC-1α/FNDC5/irisin signaling pathway.

Inhibition of the 3-mercaptopyruvate sulfurtransferase—hydrogen sulfide system promotes cellular lipid accumulation

H2S is generated in the adipose tissue by cystathionine γ-lyase, cystathionine β-synthase, and 3-mercaptopyruvate sulfurtransferase (3-MST). H2S plays multiple roles in the regulation of various metabolic processes, including insulin resistance. H2S biosynthesis also occurs in adipocytes. Aging is known to be associated with a decline in H2S. Therefore, the question arises whether endogenous H2S deficiency may affect the process of adipocyte maturation and lipid accumulation. Among the three H2S-generating enzymes, the role of 3-MST is the least understood in adipocytes. Here we tested the effect of the 3-MST inhibitor 2-[(4-hydroxy-6-methylpyrimidin-2-yl)sulfanyl]-1-(naphthalen-1-yl)ethan-1-one (HMPSNE) and the H2S donor (GYY4137) on the differentiation and adipogenesis of the adipocyte-like cells 3T3-L1 in vitro. 3T3-L1 cells were differentiated into mature adipocytes in the presence of GYY4137 or HMPSNE. HMPSNE significantly enhanced lipid accumulation into the maturing adipocytes. On the other hand, suppressed lipid accumulation was observed in cells treated with the H2S donor. 3-MST inhibition increased, while H2S donation suppressed the expression of various H2S-producing enzymes during adipocyte differentiation. 3-MST knockdown also facilitated adipocytic differentiation and lipid uptake. The underlying mechanisms may involve impairment of oxidative phosphorylation and fatty acid oxidation as well as the activation of various differentiation-associated transcription factors. Thus, the 3-MST/H2S system plays a tonic role in suppressing lipid accumulation and limiting the differentiation of adipocytes. Stimulation of 3-MST activity or supplementation of H2S—which has been recently linked to various experimental therapeutic approaches during aging—may be a potential experimental approach to counteract adipogenesis.

The effect of the long-term inhibition of hydrogen sulfide production on the reactivity of the cardiovascular system in Wistar rats.

In this study, we investigated the blood pressure responses of the peripheral bed invivo after chronic hydrogen sulfide (H2S) inhibition combined with acute nitric oxide (NO) deficiency. We also evaluated the role of endogenously produced H2S in the vasoactive responses of large- and medium-sized arteries invitro. Changes in integrated blood pressure responses were measured after chronic inhibition of cystathionine-γ-lyase, an enzyme involved in H2S synthesis, with DL-propargylglycine (PPG), and acute inhibition of NO-synthase with nonspecific L-NG-nitro arginine methyl ester (L-NAME), and vasoactive responses of the thoracic aorta (TA) and mesenteric artery (MA) were investigated after acute incubation with PPG. We confirmed that chronic H2S deficiency had no effect on blood pressure, heart trophycity, noradrenaline, and H2S donor vasoactive responses but induced renal hypertrophy and a decrease in acetylcholine-induced hypotensive and L-NAME-induced hypertensive responses. Acute H2S deficiency led to an increase in basal tone (MA) or active tone (TA), whereas endothelium-dependent vasorelaxation remained unaffected. Long-term administration of PPG revealed a role of endogenous H2S in the bioavailability of endothelial NO in peripheral arteries. When both H2S and NO were lacking, the activation of H2S-independent compensatory mechanisms plays an important role in maintaining the vasodilator responses of the cardiovascular system.

Protective role of hydrogen sulfide against diabetic cardiomyopathy via alleviating necroptosis

Diabetic cardiomyopathy lacks effective and novel methods. Hydrogen sulfide (H2S) as the third gasotransmitter plays an important role in the cardiovascular system. Our study was to elucidate the protective effect and possible mechanism of H2S on diabetic cardiomyopathy from the perspective of necroptosis. Leptin receptor deficiency (db/db) mice and streptozotocin (STZ)-induced diabetic cystathionine-γ-lyase (CSE) knockout (KO) mice were investigated. In addition, cardiomyocytes were stimulated with high glucose. We found that plasma H2S level, myocardial H2S production and CSE mRNA expression was impaired in the diabetic mice. CSE deficiency exacerbated diabetic cardiomyopathy, and promoted myocardial oxidative stress, necroptosis and inflammasome in STZ-induced mice. CSE inhibitor dl-propargylglycine (PAG) aggravated cell damage and oxidative stress, deteriorated necroptosis and inflammasome in cardiomyocytes with high glucose stimulation. H2S donor sodium hydrosulfide (NaHS) improved diabetic cardiomyopathy, attenuated myocardial oxidative stress, necroptosis and the NLR family pyrin domain-containing protein 3 (NLRP3) in db/db mice. NaHS also alleviated cell damage, oxidative stress, necroptosis and inflammasome in cardiomyocytes with high glucose stimulation. In Conclusion, H2S deficiency aggravated mitochondrial damage, increased reactive oxygen species accumulation, promoted necroptosis, activated NLRP3 inflammasome, and finally exacerbated diabetic cardiomyopathy. Exogenous H2S supplementation alleviated necroptosis to suppress NLRP3 inflammasome activation and attenuate diabetic cardiomyopathy via mitochondrial dysfunction improvement and oxidative stress inhibition. Our study provides the first evidence and a new mechanism that necroptosis inhibition by a pharmacological manner of H2S administration protected against diabetic cardiomyopathy. It is beneficial to provide a novel strategy for the prevention and treatment of diabetic cardiomyopathy.

Hydrogen sulphide protects mice against the mutual aggravation of cerebral ischaemia/reperfusion injury and colitis

This study was undertaken to determine whether ischaemia/reperfusion (I/R)-induced brain injury and dextran sulfate sodium (DSS)-induced colitis in mice are related. A cerebral I/R model of mice was established by blocking the bilateral common carotid arteries; 3% DSS in drinking water was administered to mice for 7 days to induce colitis; mice with cerebral I/R and colitis were administered DSS for 7 days from the third day onwards after acute cerebral I/R. Brain damage and intestinal inflammation were also tested. The results revealed that cerebral I/R induced brain damage and a marked increase in glial fibrillary acidic protein (GFAP) expression and upregulation of Rho-associated coiled coil-forming protein kinase (RhoA/ROCK) pathway in mouse hippocampal tissues. However, in the colon tissues of mice with colitis, we found a reduction in GFAP. In addition, the expression of endogenous hydrogen sulphide (H2S) synthase reduced in mice brain tissues with cerebral I/R injury, as well.as in mouse colon tissues with colitis. Interestingly, the cerebral I/R-induced pathological changes in mouse brain tissues were aggravated by colitis, colitis mediated colon inflammation, and pathological changes in intestinal tissues had deteriorated when the mice suffered cerebral I/R 2 days before DSS administration. However, brain injury and colon inflammation in mice suffering from both cerebral I/R and colitis were ameliorated by NaHS, an exogenous H2S donor. Furthermore, we found that NaHS promoted the transformation of astrocytes from “A1” to “A2” type. These findings reveal that cerebral I/R injury and colitis are related, the mechanism is correlated with endogenous H2S deficiency.

Hydrogen Sulfide Attenuated Sepsis-Induced Myocardial Dysfunction Through TLR4 Pathway and Endoplasmic Reticulum Stress.

Aims: We examined the change in endogenous hydrogen sulfide (H2S) production and its role in sepsis-induced myocardial dysfunction (SIMD).Results: Significant elevations in plasma cardiac troponin I (cTnI), creatine kinase (CK), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) were noted in SIMD patients, whereas left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), and plasma H2S were significantly decreased relative to those in the controls. Plasma H2S was linearly related to LVEF and LVFS. Subsequently, an SIMD model was developed in mice by injecting lipopolysaccharide (LPS), and NaHS, an H2S donor, was used to elucidate the pathophysiological role of H2S. The mice showed decreased ventricular function and increased levels of TNF-α, IL-1β, cTnI, and CK after LPS injections. Toll-like receptor (TLR) 4 protein and endoplasmic reticulum stress (ERS) proteins were over expressed in the SIMD mice. All of the parameters above showed more noticeable variations in cystathionine γ-lyase knockout mice relative to those in wild type mice. The administration of NaHS could improve ventricular function and attenuate inflammation and ERS in the heart.Conclusion: Overall, these findings indicated that endogenous H2S deficiency contributed to SIMD and exogenous H2S ameliorated sepsis-induced myocardial dysfunction by suppressing inflammation and ERS via inhibition of the TLR4 pathway.

Abnormal nitration and S-sulfhydration modification of Sp1-CSE-H2S pathway trap the progress of hyperhomocysteinemia into a vicious cycle

Sp1-CSE-H2S pathway plays an important role in homocysteine-metabolism, whose disorder can result in hyperhomocysteinemia. H2S deficiency in hyperhomocysteinemia has been reported, while the underlying mechanism and whether it in turn affects the progress of hyperhomocysteinemia are unclear. This study focused on the post-translational modification of Sp1/CSE and revealed four major findings: (1) Homocysteine-accumulation augmented CSE's nitration, inhibited its bio-activity, thus caused H2S deficiency. (2) H2S deficiency inhibited the S-sulfhydration of Sp1, down-regulated CSE and decreased H2S further, which in turn weakened CSE's own S-sulfhydration. (3) CSE was S-sulfhydrated at Cys84, Cys109, Cys172, Cys229, Cys252, Cys307 and Cys310, among which the S-sulfhydration of Cys172 and Cys310 didn't affect its enzymatic activity, while the S-sulfhydration of Cys84, Cys109, Cys229, Cys252 and Cys307 was necessary for its bio-activity. (4) H2S deficiency trapped homocysteine-metabolism into a vicious cycle, which could be broken by either blocking nitration or restoring S-sulfhydration. This study detected a new mechanism that caused severe hyperhomocysteinemia, thereby provided new therapeutic strategies for hyperhomocysteinemia.

Hydrogen Sulfide Restored the Diurnal Variation in Cardiac Function of Aging Mice.

The present study was performed to investigate whether H2S could restore the diurnal variation in cardiac function of aging mice and explore the potential mechanisms. We found that ejection fraction (EF) and fractional shortening (FS) in 3-month-old mice exhibited diurnal variations over a 24-hour period. However, the diurnal variations were disrupted in 18-month-old mice, and there was a decline in EF and FS. In addition, the plasma malondialdehyde (MDA) levels were increased, and H2S concentrations and superoxide dismutase (SOD) activities were decreased in 18-month-old mice. Then, CSE KO mice were used to determine if there was a relationship between endogenous H2S and diurnal variations in EF and FS. There was no difference in 12-hour averaged EF and FS between dark and light periods in CSE KO mice accompanying increased MDA levels and decreased SOD activities in plasma, indicating that deficiency of endogenous H2S blunted diurnal variations of cardiac function. To determine whether oxidative stress disrupted the diurnal variations in cardiac function, D-galactose-induced subacute aging mice were employed. After 3-month D-gal treatment, both 12-hour averaged EF and FS in dark or light periods were decreased; meanwhile, there was no difference in 12-hour averaged EF and FS between dark and light periods. After 3-month NaHS treatment in the D-gal group, the plasma MDA levels were decreased and SOD activities were increased. The EF and FS were lower during the 12-hour light period than those during the 12-hour dark period which was fit to sine curves in the D-gal+NaHS group. Identical findings were also observed in 18-month-old mice. In conclusion, our studies revealed that the disrupted diurnal variation in cardiac function was associated with increased oxidative stress and decreased H2S levels in aging mice. H2S could restore the diurnal variation in cardiac function of aging mice by reducing oxidative stress.

Evaluation of the effect of excess and deficiency of serum hydrogen sulfide on the condition of the vaginal wall of intact rats

Various pathological conditions can be characterized not only by a decrease or increase in basal levels of hydrogen sulfide in the serum, but also the levels of hydrogen sulfide can modulate the course of the pathological process. The impact of serum hydrogen sulfide on the condition of the intact vaginal wall of rats was evaluated in this study. The aim of the study was to evaluate the effect of excess and deficiency of serum hydrogen sulfide on the condition of the vaginal wall of intact rats. The study was performed on 75 female Wistar rats under 1 year of age and weighing 160.0 to 200.0 grams. All animals were divided into 6 groups: control (intact rats); experimental 1 (H2S excess); experimental 2 (H2S deficiency); experimental 3 (intravaginal administration of suppositories with clindamycin); experimental 4 (H2S excess + suppositories with clindamycin); experimental 5 (H2S deficiency + suppositories with clindamycin). The levels of serum hydrogen sulfide were studied, as well as microscopic examination of the structure of the vaginal wall and determination of the levels of TNF-α and IL-1β in tissue homogenate were performed. In experimental groups 3, 4 and 5 all studies were performed in dynamics – 10 minutes, 4, 8 and 24 hours after a single intravaginal administration of clindamycin phosphate. The data were processed using the statistical software package SPSS 20.0 for Windows. Under conditions of both hydrogen sulfide deficiency and excess, no statistically significant changes in TNF-α and IL-1β levels in the vaginal wall of intact rats were observed. Also, no changes in the histological structure of the wall were found. Similar data were demonstrated in experimental groups 3, 4 and 5. This picture is explained by the fact that hydrogen sulfide affects various parts of the inflammatory process, while reducing the production of inflammatory mediators. In intact tissues, in the absence of an inflammatory process, there is no point of application of hydrogen sulfide, and therefore no significant changes are observed. Thus, both excess and deficiency of serum hydrogen sulfide do not affect the condition of the vaginal wall of intact rats.

Endogenous hydrogen sulfide improves vascular remodeling through PPARδ/SOCS3 signaling

IntroductionMounting evidences demonstrated the deficiency of hydrogen sulfide (H2S) facilitated the progression of cardiovascular diseases. However, the exact effects of H2S on vascular remodeling are not consistent. ObjectivesThis study aimed to investigate the beneficial role of endogenous H2S on vascular remodeling. MethodsCSE inhibitor, DL-propargylglycine (PPG) was used to treat mice and vascular smooth muscle cells (VSMCs). Sodium hydrosulfide (NaHS) was given to provide hydrogen sulfide. Vascular tension, H&E staining, masson trichrome staining, western blot and CCK8 were used to determine the vascular remodeling, expressions of inflammatory molecules and proliferation of VSMCs. ResultsThe deficiency of endogenous H2S generated vascular remodeling with aggravated active and passive contraction, thicken aortic walls, collagen deposition, increased phosphorylation of STAT3, decreased production of PPARδ and SOCS3 in aortas, which were reversed by NaHS. PPG inhibited expression of PPARδ and SOCS3, stimulated the phosphorylation of STAT3, increased inflammatory molecules production and proliferation rate of VSMCs which could all be corrected by NaHS supply. PPARδ agonist GW501516 offered protections similar to NaHS in PPG treated VSMCs. Aggravated active and passive contraction in PPG mice aortas, upregulated p-STAT3 and inflammatory molecules, downregulated SOCS3 and phenotype transformation in PPG treated VSMCs could be corrected by PPARδ agonist GW501516 treatment. On the contrary, PPARδ antagonist GSK0660 exhibited opposite effects on vascular contraction in aortas, expressions of p-STAT3 and SOCS3 in VSMCs compared with GW501516. ConclusionIn a word, endogenous H2S protected against vascular remodeling through preserving PPARδ/SOCS3 anti-inflammatory signaling pathway. Deficiency of endogenous H2S should be considered as a risk factor for VSMCs dysfunction

Endogenous hydrogen sulfide improves vascular remodeling through PPARδ/SOCS3 signaling

Mounting evidences demonstrated the deficiency of hydrogen sulfide (H2S) implicated the progression of cardiovascular diseases. This study aimed to investigate the beneficial role of endogenous H2S on vascular remodeling in CSE inhibitor, DL‐propargylglycine (PPG), treated mice. The deficiency of endogenous H2S exhibited aggravated active and passive contraction, coupled with thicken aortic walls, vascular remodeling with collagen deposition, increased phosphorylation of STAT3 and decreased PPARδ, SOCS3, which were reversed by sodium hydrosulfide chronic treatment for 4 weeks. Aggravated active and passive contraction, upregulated p‐STAT3, downregulated SOCS3 in PPG mice aortas could be corrected by PPARδ agonist GW501516. On the contrary, PPARδ antagonist GSK0660 exhibited opposite effects on vascular contraction, expressions of p‐STAT3, SOCS3 in aortas. PPG inhibited expression of PPARδ and SOCS3, stimulated the phosphorylation of STAT3, inflammatory molecules production in vascular smooth muscle cells (VSMCs). PPARδ agonist normalized the phenotype transformation from contractile to synthetic in both PPG mice aortas and PPG treated VSMCs. NaHS offered similar functions with PPARδ agonist. In a word, endogenous H2S benefits against vascular remodeling through preserving PPARδ/SOCS3 inflammatory signaling pathway. Deficiency of endogenous H2S should be considered as a risk factor for VSMCs dysfunction.Support or Funding InformationThis study was supported by the National Natural Science Foundation of China (Grant 31671185, 31871154, 91849120), the Natural Science Foundation of Hebei Province of China (H2017206269), the Hebei Province for Innovation Talents Support Plan (Grant LJRC017), and the Research Foundation for Higher Education of Hebei Province (GCC2014032, ZD2019027).The loss of endogenous H2S aggravated LPS‐induced myocardial dysfunction.Figure 1

Homocysteine and psoriasis.

Psoriasis is caused by a complex interplay among the immune system, genetic background, autoantigens, and environmental factors. Recent studies have demonstrated that patients with psoriasis have a significantly higher serum homocysteine (Hcy) level and a higher prevalence of hyperhomocysteinaemia (HHcy). Insufficiency of folic acid and vitamin B12 can be a cause of HHcy in psoriasis. Hcy may promote the immuno-inflammatory process in the pathogenesis of psoriasis by activating Th1 and Th17 cells and neutrophils, while suppressing regulatory T cells. Moreover, Hcy can drive the immuno-inflammatory process by enhancing the production of the pro-inflammatory cytokines in related to psoriasis. Hcy can induce nuclear factor kappa B activation, which is critical in the immunopathogenesis of psoriasis. There may be a link between the oxidative stress state in psoriasis and the effect of HHcy. Hydrogen sulfide (H2S) may play a protective role in the pathogenesis of psoriasis and the deficiency of H2S in psoriasis may be caused by HHcy. As the role of Hcy in the pathogenesis of psoriasis is most likely established, Hcy can be a potential therapeutic target for the treatment of psoriasis. Systemic folinate calcium, a folic acid derivative, and topical vitamin B12 have found to be effective in treating psoriasis.

Probiotics Ameliorate Gut‐Microbial Dysbiosis, Intestinal Permeability, Systemic Inflammation, and Skeletal Muscle Dysfunction in Cystathionine‐β‐synthase‐Deficient Mice

Recent studies have reported that dietary supplementation of probiotics is a novel approach for enhancing skeletal development and metabolism in both humans and animals. However, the precise role of probiotics in regulating skeletal muscle mass at the cellular and molecular levels in mice still needs to be clarified. Here we show that altered gut‐microbiota eubiosis, systemic inflammation and skeletal muscle dysfunction caused by hydrogen sulfide deficiency and whether the intragastric administration of probiotics (GSL#5) could retard H2S deficiency‐related skeletal muscle defects. To test this hypothesis, we employed 8‐week‐old female wild‐type (WT), cystathionine‐beta‐synthase heterozygote knockout (CBS+/−), and CBS+/− mice supplemented with probiotics (GSL#5) at the dosage of 1×109 CFU every other day through oral gavage for 6 weeks. In the murine model, H2S deficiency (CBS+/− mice) increased gut permeability, and upregulated the inflammatory cytokines TNFα (TNF), and IL‐17 in the blood and the skeletal muscle. Further, the gut microbiota is significantly altered in CBS‐deficient mice as assessed by the Denaturing gradient gel electrophoresis (DGGE) analysis. We documented that long non‐coding RNA‐PVT1 (lncRNA‐PVT1) is, indeed, upregulated in the soleus muscles of CBS‐deficient mice (4.2 fold), as assessed by RT2 lncRNA qPCR Assay. The mechanistic study shows that depressed H2S signaling stimulates the transcription factor C/EBP‐α binding to the promoter of lncRNA‐PVT1 and promotes the expression of lncRNA‐PVT1. Using an electrophoretic mobility shift assay and chromatin immunoprecipitations, we identified that lncRNA‐PVT1 interacts with TNFAIP3 interacting protein 1, TNIP1, leading to the acetylation of NF‐κB (P65 subunit) activity in the soleus muscle of CBS‐deficient mice. Further, activation of P65 region of NF‐κB transcriptionally upregulates atrogin‐1, MuRF‐1 expression. Overexpression of lncRNA‐PVT1 in cultured C2C12 muscle cell lines stimulates an increase in MuRF‐1 (2.3‐fold) and atrogin‐1 (3.7‐fold) expression. In addition, systemic delivery of synthetic lncRNA‐PVT1 in control mice causes the myofibers to undergo atrophy. Gene knockout of lncRNA‐PVT1 in CBS‐deficient mice attenuates atrophy of the myofibers and muscle wasting. Overall, administration of probiotics in CBS‐deficient mice reverses the gut‐microbiota dysbiosis and preserves skeletal muscle mass. In conclusion, our findings provide novel evidence that the administration of probiotics could balance the gut‐microbiota homeostasis as well as skeletal muscle function by modulating systemic inflammation in H2S‐deficient miceSupport or Funding InformationThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.