Search Results (25)

Brassinin, a sulfur-containing phytoalexin, exerts anticancer and anti-inflammatory effects. Hydrogen sulfide (H₂S) is an important gasotransmitter with significant cardioprotective properties. The effects of brassinin on H₂S signaling and vascular smooth muscle cell (SMC) functions remain unexplored. This study found that brassinin protected against angiotensin II (Ang II)-induced SMC dysfunctions. These effects included the attenuation of excessive cell proliferation, migration, and oxidative stress; and upregulation of smooth muscle contractile protein expressions; and down-regulation of inflammatory gene expressions. Notably, brassinin did not directly release H₂S under the tested conditions; instead, it stimulated endogenous H₂S synthesis in cultured SMCs by inducing the expression of cystathionine gamma-lyase (CSE), a key H₂S-generating enzyme. Further mechanistic investigations revealed that brassinin may bind to the transcription factor C/EBPβ and enhance its interaction with the CSE promoter, thereby upregulating CSE transcription. In conclusion, our findings demonstrate that brassinin protects against SMC dysfunction, at least in part, by activating H₂S signaling rather than acting as a direct H₂S donor. These results provide new insights into the potential of brassinin as a therapeutic agent for improving vascular health and preventing cardiovascular diseases. Full article

As a rare and functional edible mushroom, the market potential of ready-to-eat fresh-cut Changgen mushrooms (Oudemansiella raphanipes) is booming in developing countries. However, fresh-cut mushrooms preservation is challenging in distribution and consumption. The present study discovered that exogenous L-cysteine (L-Cys) treatment delayed the weight loss, browning degree, nutrition depletion and microbial contamination of fresh-cut Changgen mushrooms at 4 °C. Based on transcriptomic data, exogenous L-Cys significantly activated the metabolism of 17 amino acids, including L-Cys and methionine, a prerequisite for hydrogen sulfide (H₂S) synthesis. Exogenous L-Cys also stimulated the activities and gene expressions of cystathionine beta-synthase and cystathionine gamma-lyase, thereby increasing H₂S levels. Furthermore, exogenous L-Cys enhanced the energy metabolism by improving cytochrome c oxidase, H⁺-ATPase and Ca²⁺-ATPase enzymes activity. Exogenous L-Cys treatment reduced the reactive oxygen species by regulating enzyme activities such as polyphenol oxidase, catalase and superoxide dismutase. This study contributes valuable insights into the physiological function of L-Cys and the role of H₂S on the fresh-cut Changgen mushroom. Full article

Cystathionine gamma-lyase (CSE) and TNF-α are now recognized as key regulators of intestinal homeostasis, inflammation, and wound healing. In colonic epithelial cells, both molecules have been shown to influence a variety of biological processes, but the specific interactions between intracellular signaling pathways regulated by CSE and TNF-α are poorly understood. In the present study, we investigated these interactions in normal colonocytes and an organoid model of the healthy human colon using CSE-specific pharmacological inhibitors and siRNA-mediated transient gene silencing in analytical and functional assays in vitro. We demonstrated that CSE and TNF-α mutually regulated each other’s functions in colonic epithelial cells. TNF-α treatment stimulated CSE activity within minutes and upregulated CSE expression after 24 h, increasing endogenous CSE-derived H₂S production. In turn, CSE activity promoted TNF-α-induced NF-ĸB and ERK1/2 activation but did not affect the p38 MAPK signaling pathway. Inhibition of CSE activity completely abolished the TNF-α-induced increase in transepithelial permeability and wound healing. Our data suggest that CSE activity may be essential for effective TNF-α-mediated intestinal injury response. Furthermore, CSE regulation of TNF-α-controlled intracellular signaling pathways could provide new therapeutic targets in diseases of the colon associated with impaired epithelial wound healing. Full article

Preeclampsia (PE) is a multifactorial pregnancy disorder characterized by hypertension and proteinuria, posing significant risks to both maternal and fetal health. Despite extensive research, its complex pathophysiology remains incompletely understood. This narrative review aims to elucidate the intricate mechanisms contributing to PE, focusing on abnormal placentation, maternal systemic response, oxidative stress, inflammation, and genetic and epigenetic factors. This review synthesizes findings from recent studies, clinical trials, and meta-analyses, highlighting key molecular and cellular pathways involved in PE. The review integrates data on oxidative stress biomarkers, angiogenic factors, immune interactions, and mitochondrial dysfunction. PE is initiated by poor placentation due to inadequate trophoblast invasion and improper spiral artery remodeling, leading to placental hypoxia. This triggers the release of anti-angiogenic factors such as soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), causing widespread endothelial dysfunction and systemic inflammation. Oxidative stress, mitochondrial abnormalities, and immune dysregulation further exacerbate the condition. Genetic and epigenetic modifications, including polymorphisms in the Fms-like tyrosine kinase 1 (FLT1) gene and altered microRNA (miRNA) expression, play critical roles. Emerging therapeutic strategies targeting oxidative stress, inflammation, angiogenesis, and specific molecular pathways like the heme oxygenase-1/carbon monoxide (HO-1/CO) and cystathionine gamma-lyase/hydrogen sulfide (CSE/H2S) pathways show promise in mitigating preeclampsia’s effects. PE is a complex disorder with multifactorial origins involving abnormal placentation, endothelial dysfunction, systemic inflammation, and oxidative stress. Despite advances in understanding its pathophysiology, effective prevention and treatment strategies remain limited. Continued research is essential to develop targeted therapies that can improve outcomes for both mothers and their babies. Full article

Leukemias are cancers of the blood-forming system, representing a significant challenge in medical science. The development of leukemia cells involves substantial disturbances within the cellular machinery, offering hope in the search for effective selective treatments that could improve the 5-year survival rate. Consequently, the pathophysiological processes within leukemia cells are the focus of critical research. Enzymes such as cystathionine beta-synthase and sulfurtransferases like thiosulfate sulfurtransferase, 3-mercaptopyruvate sulfurtransferase, and cystathionine gamma-lyase play a vital role in cellular sulfur metabolism. These enzymes are essential to maintaining cellular homeostasis, providing robust antioxidant defenses, and supporting cell division. Numerous studies have demonstrated that cancerous processes can alter the expression and activity of these enzymes, uncovering potential vulnerabilities or molecular targets for cancer therapy. Recent laboratory research has indicated that certain leukemia cell lines may exhibit significant changes in the expression patterns of these enzymes. Analysis of the scientific literature and online datasets has confirmed variations in sulfur enzyme function in specific leukemic cell lines compared to normal leukocytes. This comprehensive review collects and analyzes available information on sulfur enzymes in normal and leukemic cell lines, providing valuable insights and identifying new research pathways in this field. 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

The saphenous vein is the conduit of choice for bypass grafting. Unfortunately, the hemodynamic stress associated with the arterial environment of the bypass vein graft leads to the development of intimal hyperplasia (IH), an excessive cellular growth and collagen deposition that results in restenosis and secondary graft occlusion. Hydrogen sulfide (H₂S) is a ubiquitous redox-modifying gasotransmitter that inhibits IH. H₂S is produced via the reverse trans-sulfuration pathway by three enzymes: cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (3-MST). However, the expression and regulation of these enzymes in the human vasculature remains unclear. Here, we investigated the expression of CSE, CBS and 3-MST in segments of native human saphenous vein and large arteries. Furthermore, we evaluated the regulation of these enzymes in vein segments cultured under static, venous (7 mmHg pressure) or arterial (100 mmHg pressure) pressure. CSE was expressed in the media, neointima and intima of the vessels and was negatively regulated by arterial shear stress. Adenoviral-mediated CSE overexpression or RNA interference-mediated CSE knock-down revealed that CSE inhibited primary human VSMC migration but not proliferation. We propose that high shear stress in arteriovenous bypass grafts inhibits CSE expression in both the media and endothelium, which may contribute to increased VSMC migration in the context of IH. Full article

Hydrogen sulfide (H₂S), synthesized by cystathionine gamma-lyase (Cth), contributes to the inflammatory response observed in sepsis. This study examines the effect of Cth-derived H₂S in adhesion molecules on endothelial cells of vital organs in mice in a cecal ligation puncture (CLP)-induced model of sepsis, using two different and complementary approaches: Cth gene deletion and pharmacological inhibition. Our findings revealed a decreased level of H₂S-synthesizing activity (via Cth) in both Cth^−/− mice and PAG-treated wild-type (WT) mice following CLP-induced sepsis. Both treatment groups had reduced MPO activity and expression of chemokines (MCP-1 and MIP-2α), adhesion molecules (ICAM-1 and VCAM-1), ERK1/2 phosphorylation, and NF-κB in the liver and lung compared with in CLP-WT mice. Additionally, we found that PAG treatment in Cth^−/− mice had no additional effect on the expression of ERK1/2 phosphorylation, NF-κB, or the production of chemokines and adhesion molecules in the liver and lung compared to Cth^−/− mice following CLP-induced sepsis. The WT group with sepsis had an increased immunoreactivity of adhesion molecules on endothelial cells in the liver and lung than the WT sham-operated control. The Cth^−/−, PAG-treated WT, and Cth^−/− groups of mice showed decreased immunoreactivity of adhesion molecules on endothelial cells in the liver and lung following sepsis. Inhibition of H₂S production via both approaches reduced adhesion molecule expression on endothelial cells and reduced liver and lung injury in mice with sepsis. In conclusion, this study demonstrates that H₂S has an important role in the pathogenesis of sepsis and validates PAG use as a suited tool for investigating the Cth/H₂S-signalling axis in sepsis. Full article

3-mercaptopyruvate sulfurtransferase (3-MST) plays the important role of producing hydrogen sulfide. Conserved from bacteria to Mammalia, this enzyme is localized in mitochondria as well as the cytoplasm. 3-MST mediates the reaction of 3-mercaptopyruvate with dihydrolipoic acid and thioredoxin to produce hydrogen sulfide. Hydrogen sulfide is also produced through cystathionine beta-synthase and cystathionine gamma-lyase, along with 3-MST, and is known to alleviate a variety of illnesses such as cancer, heart disease, and neurological conditions. The importance of cystathionine beta-synthase and cystathionine gamma-lyase in hydrogen sulfide biogenesis is well-described, but documentation of the 3-MST pathway is limited. This account compiles the current state of knowledge about the role of 3-MST in physiology and pathology. Attempts at targeting the 3-MST pathway for therapeutic benefit are discussed, highlighting the potential of 3-MST as a therapeutic target. Full article

Hydrogen sulfide (H₂S) has been shown to act as both anti-inflammatory and pro-inflammatory mediators. Application of H₂S donors generally protects against inflammation; however, experimental results using mice lacking endogenous H₂S-producing enzymes, such as cystathionine γ-lyase (CTH) and mercaptopyruvate sulfurtransferase (MPST), are often contradictory. We herein examined two types of model hapten-induced inflammation models, colitis (an inflammatory bowel disease model of mucosal immunity) and contact dermatitis (a type IV allergic model of systemic immunity), in CTH-deficient (Cth^–/–) and MPST-deficient (Mpst^–/–) mice. Both mice exhibited no significant alteration from wild-type mice in trinitrobenzene sulfonic acid (Th1-type hapten)-induced colitis (a Crohn’s disease model) and oxazolone (Th1/Th2 mix-type; Th2 dominant)-induced colitis (an ulcerative colitis model). However, Cth^–/– (not Mpst^–/–) mice displayed more exacerbated phenotypes in trinitrochlorobenzene (TNCB; Th1-type)-induced contact dermatitis, but not oxazolone, at the delayed phase (24 h post-administration) of inflammation. CTH mRNA expression was upregulated in the TNCB-treated ears of both wild-type and Mpst^–/– mice. Although mRNA expression of pro-inflammatory cytokines (IL-1β and IL-6) was upregulated in both early (2 h) and delayed phases of TNCB-triggered dermatitis in all genotypes, that of Th2 (IL-4) and Treg cytokines (IL-10) was upregulated only in Cth^–/– mice, when that of Th1 cytokines (IFNγ and IL-2) was upregulated in wild-type and Mpst^–/– mice at the delayed phase. These results suggest that (upregulated) CTH or H₂S produced by it helps maintain Th1/Th2 balance to protect against contact dermatitis. Full article

We previously demonstrated that treatment with BemA (bempedoic acid), an inhibitor of ATP citrate lyase, significantly reduces fatty liver in a model of liver steatosis (HFHFr—female Sprague-Dawley rat fed a high-fat high-fructose diet). Since the hepatic production of the gasotransmitter H₂S is impaired in liver disorders, we were interested in determining if the production of H₂S was altered in our HFHFr model and whether the administration of BemA reversed these changes. We used stored liver samples from a previous study to determine the total and enzymatic H₂S production, as well as the expression of CBS (cystathionine β-synthase), CSE (cystathionine γ-lyase), and 3MST (3-mercaptopiruvate sulfurtransferase), and the expression/activity of FXR (farnesoid X receptor), a transcription factor involved in regulating CSE expression. Our data show that the HFHFr diet reduces the total and enzymatic production of liver H₂S, mainly by decreasing the expression of CBS and CSE. Furthermore, BemA treatment restored H₂S production, increasing the expression of CBS and CSE, providing evidence for the involvement of FXR transcriptional activity and the mTORC1 (mammalian target of rapamycin1)/S6K1 (ribosomal protein S6 kinase beta-1)/PGC1α (peroxisome proliferator receptor gamma coactivator1α) pathway. Full article

Atherosclerosis is the greatest contributor to cardiovascular events and is involved in the majority of deaths worldwide. Plaque rapture or erosion precipitates life-threatening thrombi, resulting in the obstruction blood flow to the heart (acute coronary syndrome), brain (ischemic stroke) or low extremities (peripheral vascular diseases). Among these events, major causation dues to the plaque rupture. Although the initiation, procession, and precise time of controlling plaque rupture are unclear, foam cell formation and apoptosis, cell death, extracellular matrix components, protease expression and activity, local inflammation, intraplaque hemorrhage, and calcification contribute to the plaque instability. These alterations tightly associate with the function regulation of intraplaque various cell populations. Hydrogen sulfide (H₂S) is gasotransmitter derived from methionine metabolism and exerts a protective role in the genesis of atherosclerosis. Recent progress also showed H₂S mediated the plaque stability. In this review, we discuss the progress of endogenous H₂S modulation on functions of vascular smooth muscle cells, monocytes/macrophages, and T cells, and the molecular mechanism in plaque stability. Full article

Pinewood nematode, Bursaphelenchus xylophilus, a pine-parasitic nematode, poses a serious threat to pine trees globally, causing pine wilt disease. When dispersal-stage juvenile 4 (dauer, J_IV, a durable stage) of B. xylophilus enters the new pine, it transforms into a propagative adult (dauer moulting) and reproduces quickly. Our previous studies have found that pine-volatile β-pinene promotes dauer moulting of B. xylophilus; however, this mechanism is not clear. Here, this study is attempting to unravel the molecular process underlying dauer moulting of B. xylophilus through signal chemical tests and transcriptome analysis. The results showed that β-pinene could promote dauer moulting of B. xylophilus, while other common dauer moulting signals, such as dafachronic acid (DA), part of the TGF/insulin signal pathway, were inoperative. Moreover, the J_IV soaked in 1% β-pinene for only 6 h could transform into adults at a significant rate. Therefore, the transcriptomes of J_IV soaked in 1% β-pinene for 6 h were sequenced. It was found that 15,556 genes were expressed; however, only 156 genes were expressed differentially and enriched in the metabolism of xenobiotics, peroxisome, fatty acid metabolism, and carbon metabolism, indicating that energy metabolism was active at the early stage of dauer moulting. With a stricter parameter, the number of differential genes fell to 19, including 4 sterol hydroxylase, 5 dehydrogenase, 2 glucuronosyltransferase, 5 nuclear-related factor, 1 calcium-binding protein, 1 nitrogen metabolic regulation protein, and 1 cystathionine gamma-lyase. These results indicated that dauer moulting of B. xylophilus into adults might not be regulated by the TGF-β/insulin signal pathway but by another new signal pathway related to the 19 differential genes which need more exploration. Our results contribute to the understanding of the molecular mechanisms behind dauer moulting and may be useful in reducing pine wilt disease by suppressing this moulting to cut the life cycle of B. xylophilus. Full article

As a potential medicine for the treatment of depression, psilocybin has gradually attracted attention. To elucidate the molecular mechanism regulating psilocybin synthesis in Gymnopilus dilepis, ultra-performance liquid chromatography (UPLC) was used to detect the changes in psilocybin content after S-adenosyl-l-homocysteine (SAH) treatment and the changes of psilocybin content in different parts (stipe and pileus), and RNA-Seq was used to explore the mechanism of psilocybin content changes. In this study, the psilocybin content in G. dilepis mycelia treated with SAH was significantly lower than that in the control group, and the content of psilocybin in the stipe was significantly higher than that in the pileus. Transcriptome analysis revealed that differential expression genes (DEGs) were associated with cysteine and methionine metabolism. In particular, the transcription levels of genes encoding Cystathionine gamma-lyase (CTH) in different treatments and different parts were positively correlated with psilocybin content. In addition, we found that the exogenous addition of CTH activity inhibitor (DL-propargylglycine, PAG) could reduce the content of psilocybin and L-serine, and the content of psilocybin and L-serine returned to normal levels after L-cysteine supplementation, suggesting that psilocybin synthesis may be positively correlated with L-cysteine or CTH, and L-cysteine regulates the synthesis of psilocybin by affecting L-serine and 4-hydroxy-L-tryptophan. In conclusion, this study revealed a new molecular mechanism that affects psilocybin biosynthesis, which can provide a theoretical basis for improving psilocybin synthesis and the possibility for the development of biomedicine. Full article

Cystathionine-y-lyase (CSE) is a critical enzyme for hydrogen sulfide (H₂S) biosynthesis and plays a key role in respiratory syncytial virus (RSV) pathogenesis. The transcription factor NRF2 is the master regulator of cytoprotective and antioxidant gene expression, and is degraded during RSV infection. While some evidence supports the role of NRF2 in CSE gene transcription, its role in CSE expression in airway epithelial cells is not known. Here, we show that RSV infection decreased CSE expression and activity in primary small airway epithelial (SAE) cells, while treatment with tert-butylhydroquinone (tBHQ), an NRF2 inducer, led to an increase of both. Using reporter gene assays, we identified an NRF2 response element required for the NRF2 inducible expression of the CSE promoter. Electrophoretic mobility shift assays demonstrated inducible specific NRF2 binding to the DNA probe corresponding to the putative CSE promoter NRF2 binding sequence. Using chromatin immunoprecipitation assays, we found a 50% reduction in NRF2 binding to the endogenous CSE proximal promoter in SAE cells infected with RSV, and increased binding in cells stimulated with tBHQ. Our results support the hypothesis that NRF2 regulates CSE gene transcription in airway epithelial cells, and that RSV-induced NRF2 degradation likely accounts for the observed reduced CSE expression and activity. Full article