Hydrogen Sulfide, the Next Potent Preventive and Therapeutic Agent in Aging and Age-Associated Diseases
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Hydrogen sulfide (H2S) is the third endogenous signaling gasotransmitter, following nitric oxide and carbon monoxide. It is physiologically generated by cystathionine-γ-lyase, cystathionine-β-synthase, and 3-mercaptopyruvate sulfurtransferase. H2S has been gaining increasing attention as an important endogenous signaling molecule because of its significant effects on the cardiovascular and nervous systems. Substantial evidence shows that H2S is involved in aging by inhibiting free-radical reactions, activating SIRT1, and probably interacting with the age-related gene Klotho. Moreover, H2S has been shown to have therapeutic potential in age-associated diseases. This article provides an overview of the physiological functions and effects of H2S in aging and age-associated diseases, and proposes the potential health and therapeutic benefits of H2S.Keywords:
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Hydrogen sulfide (H2S) has been recognized as a signaling molecule as well as a cytoprotectant. H2S modulates synaptic activity by enhancing the activity of N-methyl-D-aspartate receptors in neurons and by activating astrocytes that surround the synapse. It protects neurons from oxidative stress by recovering glutathione levels, scavenging ROS and suppressing intracellular Ca2+ concentrations. H2S is known to be produced from L-cysteine by two pyridoxal 5'-phophate (PLP)-dependent enzymes, cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CSE). Recently, 3-mercaptopyruvate sulfurtransferase (3MST) has emerged as the third H2S-producing enzyme. 3MST produces H2S from 3-mercaptopyruvate (3MP), an achiral keto acid, which is generated by PLP-dependent cysteine aminotransferase (CAT) from L-cysteine and alpha-ketoglutarate. In addition to these enzymes, we found an additional pathway to produce H2S from D-cysteine. D-Cysteine is metabolized by D-amino acid oxidase (DAO) to 3MP, which is a substrate for 3MST. Unlike the L-cysteine pathway, this D-cysteine pathway operates predominantly in the cerebellum and the kidney. The activity to produce H2S from D-cysteine is greater than that from L-cysteine. Exploring sources of D-cysteine may lead to a new insight into the physiological role of H2S.
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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.
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Hydrogen sulfide (H2S), a bioactive gasotransmitter, is produced endogenously primarily by three enzymes, cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (MST). This chapter comprehensively reviews the characteristics, mechanisms, and potential regulation of H2S generation by the CSE/CBS/MST system. The production of polysulfide, the predominant form of H2S storage in vivo, is also discussed. In addition, exogenous H2S donors designed for mammalian cells are summarized and classified.
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Hydrogen sulphide (H₂S) is produced endogenously via two enzymes dependent on pyridoxal phosphate (PLP): cystathionine beta-synthase (CBS, EC 4.2.1.22), cystathionase γ-liase (CTH, EC 4.4.1.1), and a third, 3-mercaptopyruvate sulfurtransferase (MPST, EC 2.8.1.2). H₂S strengthens the defence mechanisms of the gastric mucosal barrier, and plays an important role in gastroprotection, including the increased resistance to damage caused by various irritants and non-steroidal anti-inflammatory drugs. The study was conducted to determine the role of H₂S in ulcerated gastric mucosa of rats caused by immobilization in cold water (WRS). The activity and expression of γ-cystathionase, cystathionine β-synthase, 3-mercaptopyruvate sulfurtransferase, and rhodanese was compared with healthy mucosa, together with H₂S generation, and cysteine, glutathione, and cystathionine levels. The results showed that the defence mechanism against stress is associated with stimulation of the production of H₂S in the tissue and confirmed the observed advantageous effect of H₂S on healing of gastric ulcers. In case of animals pretreated with exogenous sources of H₂S and NaHS, and some changes observed in the ulcerated gastric mucosa tend to return to values found in the healthy tissue, a finding that is in accordance with the previously determined gastroprotective properties of H₂S. The results presented in this paper point to the possible role of rhodanese in H₂S production in the gastric mucosa of rats, together with the earlier mentioned three enzymes, which are all active in this tissue.
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