Search Results (6)

Hydrogen sulfide (H₂S) was recognized as a gaseous signaling molecule, similar to nitric oxide (-NO) and carbon monoxide (CO). The aim of this review is to provide an overview of the formation of hydrogen sulfide (H₂S) in the human body. H₂S is synthesized by enzymatic processes involving cysteine and several enzymes, including cystathionine-β-synthase (CBS), cystathionine-γ-lyase (CSE), cysteine aminotransferase (CAT), 3-mercaptopyruvate sulfurtransferase (3MST) and D-amino acid oxidase (DAO). The physiological and pathological effects of hydrogen sulfide (H₂S) on various systems in the human body have led to extensive research efforts to develop appropriate methods to deliver H₂S under conditions that mimic physiological settings and respond to various stimuli. These functions span a wide spectrum, ranging from effects on the endocrine system and cellular lifespan to protection of liver and kidney function. The exact physiological and hazardous thresholds of hydrogen sulfide (H₂S) in the human body are currently not well understood and need to be researched in depth. This article provides an overview of the physiological significance of H₂S in the human body. It highlights the various sources of H₂S production in different situations and examines existing techniques for detecting this gas. Full article

Recently, a CRISPR-Cas9 genome-editing system was developed with introduced sequential ‘driver’ mutations in the WNT, MAPK, TGF-β, TP53 and PI3K pathways into organoids derived from normal human intestinal epithelial cells. Prior studies have demonstrated that isogenic organoids harboring mutations in the tumor suppressor genes APC, SMAD4 and TP53, as well as the oncogene KRAS, assumed more proliferative and invasive properties in vitro and in vivo. A separate body of studies implicates the role of various hydrogen sulfide (H₂S)-producing enzymes in the pathogenesis of colon cancer. The current study was designed to determine if the sequential mutations in the above pathway affect the expression of various H₂S producing enzymes. Western blotting was used to detect the expression of the H₂S-producing enzymes cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST), as well as several key enzymes involved in H₂S degradation such as thiosulfate sulfurtransferase/rhodanese (TST), ethylmalonic encephalopathy 1 protein/persulfide dioxygenase (ETHE1) and sulfide-quinone oxidoreductase (SQR). H₂S levels were detected by live-cell imaging using a fluorescent H₂S probe. Bioenergetic parameters were assessed by Extracellular Flux Analysis; markers of epithelial-mesenchymal transition (EMT) were assessed by Western blotting. The results show that the consecutive mutations produced gradual upregulations in CBS expression—in particular in its truncated (45 kDa) form—as well as in CSE and 3-MST expression. In more advanced organoids, when the upregulation of H₂S-producing enzymes coincided with the downregulation of the H₂S-degrading enzyme SQR, increased H₂S generation was also detected. This effect coincided with the upregulation of cellular bioenergetics (mitochondrial respiration and/or glycolysis) and an upregulation of the Wnt/β-catenin pathway, a key effector of EMT. Thus sequential mutations in colon epithelial cells according to the Vogelstein sequence are associated with a gradual upregulation of multiple H₂S generating pathways, which, in turn, translates into functional changes in cellular bioenergetics and dedifferentiation, producing more aggressive and more invasive colon cancer phenotypes. Full article

The gasotransmitter hydrogen sulfide (H₂S) produced by the transsulfuration pathway (TSP) is an important biological mediator, involved in many physiological and pathological processes in multiple higher organisms, including humans. Cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE) enzymes play a central role in H₂S production and metabolism. Here, we investigated the role of H₂S in learning and memory processes by exploring several Drosophila melanogaster strains with single and double deletions of CBS and CSE developed by the CRISPR/Cas9 technique. We monitored the learning and memory parameters of these strains using the mating rejection courtship paradigm and demonstrated that the deletion of the CBS gene, which is expressed predominantly in the central nervous system, and double deletions completely block short- and long-term memory formation in fruit flies. On the other hand, the flies with CSE deletion preserve short- and long-term memory but fail to exhibit long-term memory retention. Transcriptome profiling of the heads of the males from the strains with deletions in Gene Ontology terms revealed a strong down-regulation of many genes involved in learning and memory, reproductive behavior, cognition, and the oxidation–reduction process in all strains with CBS deletion, indicating an important role of the hydrogen sulfide production in these vital processes. Full article

Hydrogen sulfide (H₂S) was the third gasotransmitter to be recognized as a cytoprotectant. A recent study demonstrated that exogenous supplementation of H₂S ameliorates functional insufficiency in chronic kidney disease (CKD). However, how the H₂S system is impaired by CKD has not been elucidated. The uremic toxin indoxyl sulfate (IS) is known to accumulate in CKD patients and harm the renal tubular cells. This study therefore treated the proximal tubular cells, LLC-PK₁, with IS to see how IS affects H₂S formation. Our results showed that H₂S release from LLC-PK₁ cells was markedly attenuated by IS when compared with control cells. The H₂S donors NaHS and GYY-4137 significantly attenuated IS-induced tubular damage, indicating that IS impairs H₂S formation. Interestingly, IS downregulated the H₂S-producing enzymes cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST), and these effects could be reversed by inhibition of the IS receptor, aryl hydrocarbon receptor (AhR). As transcription factor specificity protein 1 (Sp1) regulates the gene expression of H₂S-producing enzymes, we further showed that IS significantly decreased the DNA binding activity of Sp1 but not its protein expression. Blockade of AhR reversed low Sp1 activity caused by IS. Moreover, exogenous H₂S supplementation attenuated IS-mediated superoxide formation and depletion of the cellular glutathione content. These results clearly indicate that IS activates AhR, which then attenuates Sp1 function through the regulation of H₂S-producing enzyme expression. The attenuation of H₂S formation contributes to the low antioxidant defense of glutathione in uremic toxin-mediated oxidative stress, causing tubular cell damage. Full article

The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing and approximately 25% of the global population may have NAFLD. NAFLD is associated with obesity and metabolic syndrome, but its pathophysiology is complex and only partly understood. The transsulfuration pathway (TSP) is a metabolic pathway regulating homocysteine and cysteine metabolism and is vital in controlling sulfur balance in the organism. Precise control of this pathway is critical for maintenance of optimal cellular function. The TSP is closely linked to other pathways such as the folate and methionine cycles, hydrogen sulfide (H₂S) and glutathione (GSH) production. Impaired activity of the TSP will cause an increase in homocysteine and a decrease in cysteine levels. Homocysteine will also be increased due to impairment of the folate and methionine cycles. The key enzymes of the TSP, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE), are highly expressed in the liver and deficient CBS and CSE expression causes hepatic steatosis, inflammation, and fibrosis in animal models. A causative link between the TSP and NAFLD has not been established. However, dysfunctions in the TSP and related pathways, in terms of enzyme expression and the plasma levels of the metabolites (e.g., homocysteine, cystathionine, and cysteine), have been reported in NAFLD and liver cirrhosis in both animal models and humans. Further investigation of the TSP in relation to NAFLD may reveal mechanisms involved in the development and progression of NAFLD. Full article

Hydrogen sulfide (H₂S) is a Janus-faced molecule. On one hand, several toxic functions have been attributed to H₂S and exposure to high levels of this gas is extremely hazardous to health. On the other hand, H₂S delivery based clinical therapies are being developed to combat inflammation, visceral pain, oxidative stress related tissue injury, thrombosis and cancer. Since its discovery, H₂S has been found to have pleiotropic effects on physiology and health. H₂S is a gasotransmitter that exerts its effect on different systems, such as gastrointestinal, neuronal, cardiovascular, respiratory, renal, and hepatic systems. In the gastrointestinal tract, in addition to H₂S production by mammalian cystathionine-β-synthase (CBS), cystathionine-γ-lyase (CSE), H₂S is also generated by the metabolic activity of resident gut microbes, mainly by colonic Sulfate-Reducing Bacteria (SRB) via a dissimilatory sulfate reduction (DSR) pathway. In the gut, H₂S regulates functions such as inflammation, ischemia/ reperfusion injury and motility. H₂S derived from gut microbes has been found to be associated with gastrointestinal disorders such as ulcerative colitis, Crohn’s disease and irritable bowel syndrome. This underscores the importance of gut microbes and their production of H₂S on host physiology and pathophysiology. Full article