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1
Bearden, Shawn E., Richard S. Beard, and Jean C. Pfau. "Extracellular transsulfuration generates hydrogen sulfide from homocysteine and protects endothelium from redox stress." American Journal of Physiology-Heart and Circulatory Physiology 299, no. 5 (November 2010): H1568—H1576. http://dx.doi.org/10.1152/ajpheart.00555.2010.
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Homocysteine, a cardiovascular and neurocognitive disease risk factor, is converted to hydrogen sulfide, a cardiovascular and neuronal protectant, through the transsulfuration pathway. Given the damaging effects of free homocysteine in the blood and the importance of blood homocysteine concentration as a prognosticator of disease, we tested the hypotheses that the blood itself regulates homocysteine-hydrogen sulfide metabolism through transsulfuration and that transsulfuration capacity and hydrogen sulfide availability protect the endothelium from redox stress. Here we show that the transsulfuration enzymes, cystathionine β-synthase and cystathionine γ-lyase, are secreted by microvascular endothelial cells and hepatocytes, circulate as members of the plasma proteome, and actively produce hydrogen sulfide from homocysteine in human blood. We further demonstrate that extracellular transsulfuration regulates cell function when the endothelium is challenged with homocysteine and that hydrogen sulfide protects the endothelium from serum starvation and from hypoxia-reoxygenation injury. These novel findings uncover a unique set of opportunities to explore innovative clinical diagnostics and therapeutic strategies in the approach to homocysteine-related conditions such as atherosclerosis, thrombosis, and dementia.
2
Berry, Thomas, Eid Abohamza, and Ahmed A. Moustafa. "Treatment-resistant schizophrenia: focus on the transsulfuration pathway." Reviews in the Neurosciences 31, no. 2 (January 28, 2020): 219–32. http://dx.doi.org/10.1515/revneuro-2019-0057.
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AbstractTreatment-resistant schizophrenia (TRS) is a severe form of schizophrenia. The severity of illness is positively related to homocysteine levels, with high homocysteine levels due to the low activity of the transsulfuration pathway, which metabolizes homocysteine in synthesizing L-cysteine. Glutathione levels are low in schizophrenia, which indicates shortages of L-cysteine and low activity of the transsulfuration pathway. Hydrogen sulfide (H2S) levels are low in schizophrenia. H2S is synthesized by cystathionine β-synthase and cystathionine γ-lyase, which are the two enzymes in the transsulfuration pathway. Iron-sulfur proteins obtain sulfur from L-cysteine. The oxidative phosphorylation (OXPHOS) pathway has various iron-sulfur proteins. With low levels of L-cysteine, iron-sulfur cluster formation will be dysregulated leading to deficits in OXPHOS in schizophrenia. Molybdenum cofactor (MoCo) synthesis requires sulfur, which is obtained from L-cysteine. With low levels of MoCo synthesis, molybdenum-dependent sulfite oxidase (SUOX) will not be synthesized at appropriate levels. SUOX detoxifies sulfite from sulfur-containing amino acids. If sulfites are not detoxified, there can be sulfite toxicity. The transsulfuration pathway metabolizes selenomethionine, whereby selenium from selenomethionine can be used for selenoprotein synthesis. The low activity of the transsulfuration pathway decreases selenoprotein synthesis. Glutathione peroxidase (GPX), with various GPXs being selenoprotein, is low in schizophrenia. The dysregulations of selenoproteins would lead to oxidant stress, which would increase the methylation of genes and histones leading to epigenetic changes in TRS. An add-on treatment to mainline antipsychotics is proposed for TRS that targets the dysregulations of the transsulfuration pathway and the dysregulations of other pathways stemming from the transsulfuration pathway being dysregulated.
3
Werge, Mikkel Parsberg, Adrian McCann, Elisabeth Douglas Galsgaard, Dorte Holst, Anne Bugge, Nicolai J. Wewer Albrechtsen, and Lise Lotte Gluud. "The Role of the Transsulfuration Pathway in Non-Alcoholic Fatty Liver Disease." Journal of Clinical Medicine 10, no. 5 (March 5, 2021): 1081. http://dx.doi.org/10.3390/jcm10051081.
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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.
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Zatsepina, Olga G., Lyubov N. Chuvakova, Ekaterina A. Nikitina, Alexander P. Rezvykh, Alexey S. Zakluta, Svetlana V. Sarantseva, Nina V. Surina, et al. "Genes Responsible for H2S Production and Metabolism Are Involved in Learning and Memory in Drosophila melanogaster." Biomolecules 12, no. 6 (May 26, 2022): 751. http://dx.doi.org/10.3390/biom12060751.
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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.
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Xu, Zhibin, Gamika Prathapasinghe, Nan Wu, Sun-Young Hwang, Yaw L. Siow, and Karmin O. "Ischemia-reperfusion reduces cystathionine-β-synthase-mediated hydrogen sulfide generation in the kidney." American Journal of Physiology-Renal Physiology 297, no. 1 (July 2009): F27—F35. http://dx.doi.org/10.1152/ajprenal.00096.2009.
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Cystathionine-β-synthase (CBS) catalyzes the rate-limiting step in the transsulfuration pathway for the metabolism of homocysteine (Hcy) in the kidney. Our recent study demonstrates that ischemia-reperfusion reduces the activity of CBS leading to Hcy accumulation in the kidney, which in turn contributes to renal injury. CBS is also capable of catalyzing the reaction of cysteine with Hcy to produce hydrogen sulfide (H2S), a gaseous molecule that plays an important role in many physiological and pathological processes. The aim of the present study was to examine the effect of ischemia-reperfusion on CBS-mediated H2S production in the kidney and to determine whether changes in the endogenous H2S generation had any impact on renal ischemia-reperfusion injury. The left kidney of Sprague-Dawley rat was subjected to 45-min ischemia followed by 6-h reperfusion. The ischemia-reperfusion caused lipid peroxidation and cell death in the kidney. The CBS-mediated H2S production was decreased, leading to a significant reduction in the renal H2S level. The activity of cystathionine-γ-lyase, another enzyme responsible for endogenous H2S generation, was not significantly altered in the kidney upon ischemia-reperfusion. Partial restoration of CBS activity by intraperitoneal injection of the nitric oxide scavenger, 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide not only increased renal H2S levels but also alleviated ischemia-reperfusion-induced lipid peroxidation and reduced cell damage in the kidney tissue. Furthermore, administration of an exogenous H2S donor, NaHS (100 μg/kg), improved renal function. Taken together, these results suggest that maintenance of tissue H2S level may offer a renal protective effect against ischemia-reperfusion injury.
6
O, Karmin, and Yaw L. Siow. "Metabolic Imbalance of Homocysteine and Hydrogen Sulfide in Kidney Disease." Current Medicinal Chemistry 25, no. 3 (January 30, 2018): 367–77. http://dx.doi.org/10.2174/0929867324666170509145240.
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Homocysteine (Hcy) and hydrogen sulfide (H2S) are important molecules produced during the metabolism of sulfur-containing amino acids. Hcy metabolism is central to the supply of methyl groups that are essential for biological function. Hcy can be either regenerated to methionine or metabolized to cysteine, a precursor for glutathione synthesis. Cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE) play a crucial role in metabolizing Hcy to cysteine through the transsulfuration pathway. These two enzymes are also responsible for H2S generation through desulfuration reactions. H2S, at physiological levels serves as a gaseous mediator and has multifaceted effects. Metabolic imbalance of Hcy and H2S has been implicated in pathological conditions including oxidative stress, inflammation, cardiovascular and cerebral dysfunction, fatty liver disease and ischemiareperfusion injury. Organs such as liver, kidney, gut and pancreas contain all the enzymes that are required for Hcy metabolism. The kidney plays an important role in removing Hcy from the circulation. Hyperhomocysteinemia, a condition of elevated blood Hcy level, is a common clinical finding in patients with chronic kidney disease (CKD) or acute kidney injury (AKI), the latter is often caused by ischemia-reperfusion. This paper reviews exiting literatures regarding (1) the role of kidney in regulating Hcy and H2S metabolism; (2) disruption of sulfur-containing amino acid metabolism during ischemiareperfusion; (3) impact of metabolic imbalance of Hcy and H2S on kidney function. Better understanding of molecular mechanisms that regulate Hcy and H2S metabolism under physiological and pathophysiological conditions will help improve therapeutic strategies for patients with kidney disease or other organ injuries.
7
Hwang, Sun-Young, Lindsei K. Sarna, Yaw L. Siow, and Karmin O. "High-fat diet stimulates hepatic cystathionine β-synthase and cystathionine γ-lyase expression." Canadian Journal of Physiology and Pharmacology 91, no. 11 (November 2013): 913–19. http://dx.doi.org/10.1139/cjpp-2013-0106.
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Cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE) catalyze homocysteine (Hcy) metabolism via the trans-sulfuration pathway. They are also responsible for hydrogen sulfide (H2S) production via desulfuration reactions. The liver contributes significantly to the regulation of Hcy and H2S homeostasis, which might participate in many physiological and pathological processes. The aim of this study was to investigate the effect of a high-fat diet (HFD) on hepatic CBS and CSE expression and its impact on Hcy and H2S metabolism. Mice (C57BL/6) fed a HFD (60% kcal fat) for 5 weeks developed fatty liver. The mRNA and protein levels of CBS and CSE in the liver were significantly elevated in mice fed a HFD. Subsequently the metabolism of Hcy by CBS and CSE was increased in the liver, and its level decreased in the circulation. Increased CBS and CSE expression also caused a significant elevation in H2S production in the liver. The level of lipid peroxides was elevated, indicating oxidative stress, while the level of total glutathione remained unchanged in the liver of HFD-fed mice. Upregulation of the trans-sulfuration pathway might play an adaptive role against oxidative stress by maintaining total glutathione levels in the liver.
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Yadav, Pramod K., Victor Vitvitsky, Hanseong Kim, Andrew White, Uhn-Soo Cho, and Ruma Banerjee. "S-3-Carboxypropyl-l-cysteine specifically inhibits cystathionine γ-lyase–dependent hydrogen sulfide synthesis." Journal of Biological Chemistry 294, no. 28 (June 3, 2019): 11011–22. http://dx.doi.org/10.1074/jbc.ra119.009047.
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Hydrogen sulfide (H2S) is a gaseous signaling molecule, which modulates a wide range of mammalian physiological processes. Cystathionine γ-lyase (CSE) catalyzes H2S synthesis and is a potential target for modulating H2S levels under pathophysiological conditions. CSE is inhibited by propargylglycine (PPG), a widely used mechanism-based inhibitor. In this study, we report that inhibition of H2S synthesis from cysteine, but not the canonical cystathionine cleavage reaction catalyzed by CSE in vitro, is sensitive to preincubation of the enzyme with PPG. In contrast, the efficacy of S-3-carboxpropyl-l-cysteine (CPC) a new inhibitor described herein, was not dependent on the order of substrate/inhibitor addition. We observed that CPC inhibited the γ-elimination reaction of cystathionine and H2S synthesis from cysteine by human CSE with Ki values of 50 ± 3 and 180 ± 15 μm, respectively. We noted that CPC spared the other enzymes involved either directly (cystathionine β-synthase and mercaptopyruvate sulfurtransferase) or indirectly (cysteine aminotransferase) in H2S biogenesis. CPC also targeted CSE in cultured cells, inhibiting transsulfuration flux by 80–90%, as monitored by the transfer of radiolabel from [35S]methionine to GSH. The 2.5 Å resolution crystal structure of human CSE in complex with the CPC-derived aminoacrylate intermediate provided a structural framework for the molecular basis of its inhibitory effect. In summary, our study reveals a previously unknown confounding effect of PPG, widely used to inhibit CSE-dependent H2S synthesis, and reports on an alternative inhibitor, CPC, which could be used as a scaffold to develop more potent H2S biogenesis inhibitors.
9
Kolluru, Gopi K., Xinggui Shen, and Christopher G. Kevil. "Reactive Sulfur Species." Arteriosclerosis, Thrombosis, and Vascular Biology 40, no. 4 (April 2020): 874–84. http://dx.doi.org/10.1161/atvbaha.120.314084.
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Hydrogen sulfide has emerged as an important gaseous signaling molecule and a regulator of critical biological processes. However, the physiological significance of hydrogen sulfide metabolites such as persulfides, polysulfides, and other reactive sulfur species (RSS) has only recently been appreciated. Emerging evidence suggests that these RSS molecules may have similar or divergent regulatory roles compared with hydrogen sulfide in various biological activities. However, the chemical nature of persulfides and polysulfides is complex and remains poorly understood within cardiovascular and other pathophysiological conditions. Recent reports suggest that RSS can be produced endogenously, with different forms having unique chemical properties and biological implications involving diverse cellular responses such as protein biosynthesis, cell-cell barrier functions, and mitochondrial bioenergetics. Enzymes of the transsulfuration pathway, CBS (cystathionine beta-synthase) and CSE (cystathionine gamma-lyase), may also produce RSS metabolites besides hydrogen sulfide. Moreover, CARSs (cysteinyl-tRNA synthetase) are also able to generate protein persulfides via cysteine persulfide (CysSSH) incorporation into nascently formed polypeptides suggesting a new biologically relevant amino acid. This brief review discusses the biochemical nature and potential roles of RSS, associated oxidative stress redox signaling, and future research opportunities in cardiovascular disease.
10
González-García, Pilar, Agustín Hidalgo-Gutiérrez, Cristina Mascaraque, Eliana Barriocanal-Casado, Mohammed Bakkali, Marcello Ziosi, Ussipbek Botagoz Abdihankyzy, et al. "Coenzyme Q10 modulates sulfide metabolism and links the mitochondrial respiratory chain to pathways associated to one carbon metabolism." Human Molecular Genetics 29, no. 19 (September 25, 2020): 3296–311. http://dx.doi.org/10.1093/hmg/ddaa214.
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Abstract Abnormalities of one carbon, glutathione and sulfide metabolisms have recently emerged as novel pathomechanisms in diseases with mitochondrial dysfunction. However, the mechanisms underlying these abnormalities are not clear. Also, we recently showed that sulfide oxidation is impaired in Coenzyme Q10 (CoQ10) deficiency. This finding leads us to hypothesize that the therapeutic effects of CoQ10, frequently administered to patients with primary or secondary mitochondrial dysfunction, might be due to its function as cofactor for sulfide:quinone oxidoreductase (SQOR), the first enzyme in the sulfide oxidation pathway. Here, using biased and unbiased approaches, we show that supraphysiological levels of CoQ10 induces an increase in the expression of SQOR in skin fibroblasts from control subjects and patients with mutations in Complex I subunits genes or CoQ biosynthetic genes. This increase of SQOR induces the downregulation of the cystathionine β-synthase and cystathionine γ-lyase, two enzymes of the transsulfuration pathway, the subsequent downregulation of serine biosynthesis and the adaptation of other sulfide linked pathways, such as folate cycle, nucleotides metabolism and glutathione system. These metabolic changes are independent of the presence of sulfur aminoacids, are confirmed in mouse models, and are recapitulated by overexpression of SQOR, further proving that the metabolic effects of CoQ10 supplementation are mediated by the overexpression of SQOR. Our results contribute to a better understanding of how sulfide metabolism is integrated in one carbon metabolism and may explain some of the benefits of CoQ10 supplementation observed in mitochondrial diseases.
11
Mitidieri, Emma, Annalisa Pecoraro, Erika Esposito, Vincenzo Brancaleone, Carlotta Turnaturi, Luigi Napolitano, Vincenzo Mirone, et al. "β3 Relaxant Effect in Human Bladder Involves Cystathionine γ-Lyase-Derived Urothelial Hydrogen Sulfide." Antioxidants 11, no. 8 (July 28, 2022): 1480. http://dx.doi.org/10.3390/antiox11081480.
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It is now well established that the urothelium does not act as a passive barrier but contributes to bladder homeostasis by releasing several signaling molecules in response to physiological and chemical stimuli. Here, we investigated the potential contribution of the hydrogen sulfide (H2S) pathway in regulating human urothelium function in β3 adrenoceptor-mediated relaxation. The relaxant effect of BRL 37344 (0.1–300 µM), a selective β3 adrenoceptor agonist, was evaluated in isolated human bladder strips in the presence or absence of the urothelium. The relaxant effect of BRL 37344 was significantly reduced by urothelium removal. The inhibition of cystathionine-γ-lyase (CSE), but not cystathionine-β-synthase (CBS), significantly reduced the BRL 37344 relaxing effect to the same extent as that given by urothelium removal, suggesting a role for CSE-derived H2S. β3 adrenoceptor stimulation in the human urothelium or in T24 urothelial cells markedly increased H2S and cAMP levels that were reverted by a blockade of CSE and β3 adrenoceptor antagonism. These findings demonstrate a key role for urothelium CSE-derived H2S in the β3 effect on the human bladder through the modulation of cAMP levels. Therefore, the study establishes the relevance of urothelial β3 adrenoceptors in the regulation of bladder tone, supporting the use of β3 agonists in patients affected by an overactive bladder.
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Fernandes, Dalila G. F., João Nunes, Catarina S. Tomé, Karim Zuhra, João M. F. Costa, Alexandra M. M. Antunes, Alessandro Giuffrè, and João B. Vicente. "Human Cystathionine γ-Lyase Is Inhibited by s-Nitrosation: A New Crosstalk Mechanism between NO and H2S." Antioxidants 10, no. 9 (August 30, 2021): 1391. http://dx.doi.org/10.3390/antiox10091391.
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The ‘gasotransmitters’ hydrogen sulfide (H2S), nitric oxide (NO), and carbon monoxide (CO) act as second messengers in human physiology, mediating signal transduction via interaction with or chemical modification of protein targets, thereby regulating processes such as neurotransmission, blood flow, immunomodulation, or energy metabolism. Due to their broad reactivity and potential toxicity, the biosynthesis and breakdown of H2S, NO, and CO are tightly regulated. Growing evidence highlights the active role of gasotransmitters in their mutual cross-regulation. In human physiology, the transsulfuration enzymes cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE) are prominent H2S enzymatic sources. While CBS is known to be inhibited by NO and CO, little is known about CSE regulation by gasotransmitters. Herein, we investigated the effect of s-nitrosation on CSE catalytic activity. H2S production by recombinant human CSE was found to be inhibited by the physiological nitrosating agent s-nitrosoglutathione (GSNO), while reduced glutathione had no effect. GSNO-induced inhibition was partially reverted by ascorbate and accompanied by the disappearance of one solvent accessible protein thiol. By combining differential derivatization procedures and mass spectrometry-based analysis with functional assays, seven out of the ten protein cysteine residues, namely Cys84, Cys109, Cys137, Cys172, Cys229, Cys307, and Cys310, were identified as targets of s-nitrosation. By generating conservative Cys-to-Ser variants of the identified s-nitrosated cysteines, Cys137 was identified as most significantly contributing to the GSNO-mediated CSE inhibition. These results highlight a new mechanism of crosstalk between gasotransmitters.
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Olson, Kenneth R., Michael J. Healy, Zhaohong Qin, Nini Skovgaard, Branka Vulesevic, Douglas W. Duff, Nathan L. Whitfield, Guangdong Yang, Rui Wang, and Steve F. Perry. "Hydrogen sulfide as an oxygen sensor in trout gill chemoreceptors." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 295, no. 2 (August 2008): R669—R680. http://dx.doi.org/10.1152/ajpregu.00807.2007.
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O2 chemoreceptors elicit cardiorespiratory reflexes in all vertebrates, but consensus on O2-sensing signal transduction mechanism(s) is lacking. We recently proposed that hydrogen sulfide (H2S) metabolism is involved in O2 sensing in vascular smooth muscle. Here, we examined the possibility that H2S is an O2 sensor in trout chemoreceptors where the first pair of gills is a primary site of aquatic O2 sensing and the homolog of the mammalian carotid body. Intrabuccal injection of H2S in unanesthetized trout produced a dose-dependent bradycardia and increased ventilatory frequency and amplitude similar to the hypoxic response. Removal of the first, but not second, pair of gills significantly inhibited H2S-mediated bradycardia, consistent with the loss of aquatic chemoreceptors. mRNA for H2S-synthesizing enzymes, cystathionine β-synthase and cystathionine γ-lyase, was present in branchial tissue. Homogenized gills produced H2S enzymatically, and H2S production was inhibited by O2, whereas mitochondrial H2S consumption was O2 dependent. Ambient hypoxia did not affect plasma H2S in unanesthetized trout, but produced a Po2-dependent increase in a sulfide moiety suggestive of increased H2S production. In isolated zebrafish neuroepithelial cells, the putative chemoreceptive cells of fish, both hypoxia and H2S, produced a similar ∼10-mV depolarization. These studies are consistent with H2S involvement in O2 sensing/signal transduction pathway(s) in chemoreceptive cells, as previously demonstrated in vascular smooth muscle. This novel mechanism, whereby H2S concentration ([H2S]) is governed by the balance between constitutive production and oxidation, tightly couples tissue [H2S] to Po2 and may provide an exquisitely sensitive, yet simple, O2 sensor in a variety of tissues.
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Madden, Jane A., Susan B. Ahlf, Mark W. Dantuma, Kenneth R. Olson, and David L. Roerig. "Precursors and inhibitors of hydrogen sulfide synthesis affect acute hypoxic pulmonary vasoconstriction in the intact lung." Journal of Applied Physiology 112, no. 3 (February 1, 2012): 411–18. http://dx.doi.org/10.1152/japplphysiol.01049.2011.
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The effects of hydrogen sulfide (H2S) and acute hypoxia are similar in isolated pulmonary arteries from various species. However, the involvement of H2S in hypoxic pulmonary vasoconstriction (HPV) has not been studied in the intact lung. The present study used an intact, isolated, perfused rat lung preparation to examine whether adding compounds essential to H2S synthesis or to its inhibition would result in a corresponding increase or decrease in the magnitude of HPV. Western blots performed in lung tissue identified the presence of the H2S-synthesizing enzymes, cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfur transferase (3-MST), but not cystathionine β-synthase (CBS). Adding three H2S synthesis precursors, cysteine and oxidized or reduced glutathione, to the perfusate significantly increased peak arterial pressure during hypoxia compared with control ( P < 0.05). Adding α-ketoglutarate to enhance the 3-MST enzyme pathway also resulted in an increase ( P < 0.05). Both aspartate, which inhibits the 3-MST synthesis pathway, and propargylglycine (PPG), which inhibits the CSE pathway, significantly reduced the increases in arterial pressure during hypoxia. Diethylmaleate (DEM), which conjugates sulfhydryls, also reduced the peak hypoxic arterial pressure at concentrations >2 mM. Finally, H2S concentrations as measured with a specially designed polarographic electrode decreased markedly in lung tissue homogenate and in small pulmonary arteries when air was added to the hypoxic environment of the measurement chamber. The results of this study provide evidence that the rate of H2S synthesis plays a role in the magnitude of acute HPV in the isolated perfused rat lung.
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Agné, Alisa M., Jan-Peter Baldin, Audra R. Benjamin, Maria C. Orogo-Wenn, Lukas Wichmann, Kenneth R. Olson, Dafydd V. Walters, and Mike Althaus. "Hydrogen sulfide decreases β-adrenergic agonist-stimulated lung liquid clearance by inhibiting ENaC-mediated transepithelial sodium absorption." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 308, no. 7 (April 1, 2015): R636—R649. http://dx.doi.org/10.1152/ajpregu.00489.2014.
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In pulmonary epithelia, β-adrenergic agonists regulate the membrane abundance of the epithelial sodium channel (ENaC) and, thereby, control the rate of transepithelial electrolyte absorption. This is a crucial regulatory mechanism for lung liquid clearance at birth and thereafter. This study investigated the influence of the gaseous signaling molecule hydrogen sulfide (H2S) on β-adrenergic agonist-regulated pulmonary sodium and liquid absorption. Application of the H2S-liberating molecule Na2S (50 μM) to the alveolar compartment of rat lungs in situ decreased baseline liquid absorption and abrogated the stimulation of liquid absorption by the β-adrenergic agonist terbutaline. There was no additional effect of Na2S over that of the ENaC inhibitor amiloride. In electrophysiological Ussing chamber experiments with native lung epithelia ( Xenopus laevis), Na2S inhibited the stimulation of amiloride-sensitive current by terbutaline. β-adrenergic agonists generally increase ENaC abundance by cAMP formation and activation of PKA. Activation of this pathway by forskolin and 3-isobutyl-1-methylxanthine increased amiloride-sensitive currents in H441 pulmonary epithelial cells. This effect was inhibited by Na2S in a dose-dependent manner (5–50 μM). Na2S had no effect on cellular ATP concentration, cAMP formation, and activation of PKA. By contrast, Na2S prevented the cAMP-induced increase in ENaC activity in the apical membrane of H441 cells. H441 cells expressed the H2S-generating enzymes cystathionine-β-synthase, cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase, and they produced H2S amounts within the employed concentration range. These data demonstrate that H2S prevents the stimulation of ENaC by cAMP/PKA and, thereby, inhibits the proabsorptive effect of β-adrenergic agonists on lung liquid clearance.
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Kundu, Sourav, Sathnur B. Pushpakumar, Aaron Tyagi, Denise Coley, and Utpal Sen. "Hydrogen sulfide deficiency and diabetic renal remodeling: role of matrix metalloproteinase-9." American Journal of Physiology-Endocrinology and Metabolism 304, no. 12 (June 15, 2013): E1365—E1378. http://dx.doi.org/10.1152/ajpendo.00604.2012.
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Matrix metalloproteinase-9 (MMP-9) causes adverse remodeling, whereas hydrogen sulfide (H2S) rescues organs in vascular diseases. The involvement of MMP-9 and H2S in diabetic renovascular remodeling is, however, not well characterized. We determined whether MMP-9 regulates H2S generation and whether H2S modulates connexin through N-methyl-d-aspartate receptor (NMDA-R)-mediated pathway in the diabetic kidney. Wild-type (WT, C57BL/6J), diabetic (Akita, C57BL/6J- Ins2 Akita), MMP-9−/− (M9KO), double knockout (DKO) of Akita/MMP-9−/− mice and in vitro cell culture were used in our study. Hyperglycemic Akita mice exhibited increased level of MMP-9 and decreased production of H2S. H2S-synthesizing enzymes cystathionine-β-synthase and cystathionine-γ-lyase were also diminished. In addition, increased expressions of NMDA-R1 and connexin-40 and -43 were observed in diabetic kidney. As expected, MMP-9 mRNA was not detected in M9KO kidneys. However, very thin protein expression and activity were detected. No other changes were noticed in M9KO kidney. In DKO mice, all the above molecules showed a trend toward baseline despite hyperglycemia. In vitro, glomerular endothelial cells treated with high glucose showed induction of MMP-9, attenuated H2S production, NMDA-R1 induction, and dysregulated conexin-40 and -43 expressions. Silencing MMP-9 by siRNA or inhibition of NMDA-R1 by MK801 or H2S treatment preserved connexin-40 and -43. We conclude that in diabetic renovascular remodeling MMP-9 plays a major role and that H2S has therapeutic potential to prevent adverse diabetic renal remodeling.
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Nalli, Ancy D., Senthilkumar Rajagopal, Sunila Mahavadi, John R. Grider, and Karnam S. Murthy. "Inhibition of RhoA-dependent pathway and contraction by endogenous hydrogen sulfide in rabbit gastric smooth muscle cells." American Journal of Physiology-Cell Physiology 308, no. 6 (March 15, 2015): C485—C495. http://dx.doi.org/10.1152/ajpcell.00280.2014.
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Inhibitory neurotransmitters, chiefly nitric oxide and vasoactive intestinal peptide, increase cyclic nucleotide levels and inhibit muscle contraction via inhibition of myosin light chain (MLC) kinase and activation of MLC phosphatase (MLCP). H2S produced as an endogenous signaling molecule synthesized mainly from l-cysteine via cystathionine-γ-lyase (CSE) and cystathionine-β-synthase (CBS) regulates muscle contraction. The aim of this study was to analyze the expression of CSE and H2S function in the regulation of MLCP activity, 20-kDa regulatory light chain of myosin II (MLC20) phosphorylation, and contraction in isolated gastric smooth muscle cells. Both mRNA expression and protein expression of CSE, but not CBS, were detected in smooth muscle cells of rabbit, human, and mouse stomach. l-cysteine, an activator of CSE, and NaHS, a donor of H2S, inhibited carbachol-induced Rho kinase and PKC activity, Rho kinase-sensitive phosphorylation of MYPT1, PKC-sensitive phosphorylation of CPI-17, and MLC20 phosphorylation and sustained muscle contraction. The inhibitory effects of l-cysteine, but not NaHS, were blocked upon suppression of CSE expression by siRNA or inhibition of its activity by dl-propargylglycine (PPG) suggesting that the effect of l-cysteine is mediated via activation of CSE. Glibenclamide, an inhibitor of KATP channels, had no effect on the inhibition of contraction by H2S. Both l-cysteine and NaHS had no effect on basal cAMP and cGMP levels but augmented forskolin-induced cAMP and SNP-induced cGMP formation. We conclude that both endogenous and exogenous H2S inhibit muscle contraction, and the mechanism involves inhibition of Rho kinase and PKC activities and stimulation of MLCP activity leading to MLC20 dephosphorylation and inhibition of muscle contraction.
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Kitada, Munehiro, Yoshio Ogura, Itaru Monno, Jing Xu, and Daisuke Koya. "Effect of Methionine Restriction on Aging: Its Relationship to Oxidative Stress." Biomedicines 9, no. 2 (January 29, 2021): 130. http://dx.doi.org/10.3390/biomedicines9020130.
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Enhanced oxidative stress is closely related to aging and impaired metabolic health and is influenced by diet-derived nutrients and energy. Recent studies have shown that methionine restriction (MetR) is related to longevity and metabolic health in organisms from yeast to rodents. The effect of MetR on lifespan extension and metabolic health is mediated partially through a reduction in oxidative stress. Methionine metabolism is involved in the supply of methyl donors such as S-adenosyl-methionine (SAM), glutathione synthesis and polyamine metabolism. SAM, a methionine metabolite, activates mechanistic target of rapamycin complex 1 and suppresses autophagy; therefore, MetR can induce autophagy. In the process of glutathione synthesis in methionine metabolism, hydrogen sulfide (H2S) is produced through cystathionine-β-synthase and cystathionine-γ-lyase; however, MetR can induce increased H2S production through this pathway. Similarly, MetR can increase the production of polyamines such as spermidine, which are involved in autophagy. In addition, MetR decreases oxidative stress by inhibiting reactive oxygen species production in mitochondria. Thus, MetR can attenuate oxidative stress through multiple mechanisms, consequently associating with lifespan extension and metabolic health. In this review, we summarize the current understanding of the effects of MetR on lifespan extension and metabolic health, focusing on the reduction in oxidative stress.
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Liao, Ribin, Liwei Xue, Zhanrong Qiang, Cheng Zhang, and Ying Liu. "Release of endogenous hydrogen sulfide in enteric nerve cells suppresses intestinal motility during severe acute pancreatitis." Acta Biochimica et Biophysica Sinica 52, no. 1 (December 31, 2019): 64–71. http://dx.doi.org/10.1093/abbs/gmz139.
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Abstract Previous studies have shown that during severe acute pancreatitis (SAP) attacks, hydrogen sulfide (H2S) is released in the colon. However, the roles played by H2S in regulating enteric nerves remain unclear. In this study, we examined the association between SAP-induced H2S release and loss of intestinal motility, and also explored the relevant mechanism in enteric nerve cells. A rat SAP model was constructed and enteric nerve cells were prepared. Intestinal mobility was evaluated by measuring the number of bowel movements at indicated time points and by performing intestinal propulsion tests. The production of inflammatory cytokines during a SAP attack was quantified by ELISA, and the levels of cystathionine-γ-lyase (CSE) and cystathionine-β-synthase (CBS) were examined by immunohistochemistry and western blot analysis. In vivo studies showed that PI3K/Akt/Sp1 signaling in enteric nerve cells was blocked, confirming the mechanism of endogenous H2S formation by western blot analysis and immunofluorescence. Our results also showed that rats with SAP symptoms had reduced intestinal motility. Furthermore, PI3K/Akt/Sp1 signaling was triggered and CSE expression was up-regulated, and these changes were associated with H2S formation in the colon. In addition, propargylglycine reduced the levels of inflammatory cytokines and suppressed the release of H2S. Enteric nerve cells that were incubated with LY294002 and transfected with a Sp1-knockdown vector displayed decreased levels of CSE production, which led to a decrease in H2S production. These results suggest that SAP symptoms suppressed the intestinal motility of rats via the release of H2S in enteric nerve cells, which was dependent on the inflammation-induced PI3K/Akt/Sp1 signaling pathway.
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Khan, Nazeer Hussain, Di Wang, Wenkang Wang, Muhammad Shahid, Saadullah Khattak, Ebenezeri Erasto Ngowi, Muhammad Sarfraz, Xin-Ying Ji, Chun-Yang Zhang, and Dong-Dong Wu. "Pharmacological Inhibition of Endogenous Hydrogen Sulfide Attenuates Breast Cancer Progression." Molecules 27, no. 13 (June 23, 2022): 4049. http://dx.doi.org/10.3390/molecules27134049.
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Hydrogen sulfide (H2S), a gaseous signaling molecule, is associated with the development of various malignancies via modulating various cellular signaling cascades. Published research has established the fact that inhibition of endogenous H2S production or exposure of H2S donors is an effective approach against cancer progression. However, the effect of pharmacological inhibition of endogenous H2S-producing enzymes (cystathionine-γ-lyase (CSE), cystathionine-β-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (3-MPST)) on the growth of breast cancer (BC) remains unknown. In the present study, DL-propargylglycine (PAG, inhibitor of CSE), aminooxyacetic acid (AOAA, inhibitor of CBS), and L-aspartic acid (L-Asp, inhibitor of 3-MPST) were used to determine the role of endogenous H2S in the growth of BC by in vitro and in vivo experiments. An in silico study was also performed to confirm the results. Corresponding to each enzyme in separate groups, we treated BC cells (MCF-7 and MDA-MB-231) with 10 mM of PAG, AOAA, and L-Asp for 24 h. Findings reveal that the combined dose (PAG + AOAA + L-Asp) group showed exclusive inhibitory effects on BC cells’ viability, proliferation, migration, and invasion compared to the control group. Further, treated cells exhibited increased apoptosis and a reduced level of phospho (p)-extracellular signal-regulated protein kinases such as p-AKT, p-PI3K, and p-mTOR. Moreover, the combined group exhibited potent inhibitory effects on the growth of BC xenograft tumors in nude mice, without obvious toxicity. The molecular docking results were consistent with the wet lab experiments and enhanced the reliability of the drugs. In conclusion, our results demonstrate that the inhibition of endogenous H2S production can significantly inhibit the growth of human breast cancer cells via the AKT/PI3K/mTOR pathway and suggest that endogenous H2S may act as a promising therapeutic target in human BC cells. Our study also empowers the rationale to design novel H2S-based anti-tumor drugs to cure BC.
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Ascenção, Kelly, Nahzli Dilek, Karim Zuhra, Katalin Módis, Toshiro Sato, and Csaba Szabo. "Sequential Accumulation of ‘Driver’ Pathway Mutations Induces the Upregulation of Hydrogen-Sulfide-Producing Enzymes in Human Colonic Epithelial Cell Organoids." Antioxidants 11, no. 9 (September 15, 2022): 1823. http://dx.doi.org/10.3390/antiox11091823.
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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.
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Berenyiova, Andrea, Martina Cebova, Basak Gunes Aydemir, Samuel Golas, Miroslava Majzunova, and Sona Cacanyiova. "Vasoactive Effects of Chronic Treatment with Fructose and Slow-Releasing H2S Donor GYY-4137 in Spontaneously Hypertensive Rats: The Role of Nitroso and Sulfide Signalization." International Journal of Molecular Sciences 23, no. 16 (August 16, 2022): 9215. http://dx.doi.org/10.3390/ijms23169215.
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Increased fructose consumption induces metabolic-syndrome-like pathologies and modulates vasoactivity and the participation of nitric oxide (NO) and hydrogen sulfide (H2S). We investigated whether a slow-releasing H2S donor, GYY-4137, could exert beneficial activity in these conditions. We examined the effect of eight weeks of fructose intake on the blood pressure, biometric parameters, vasoactive responses, and NO and H2S pathways in fructose-fed spontaneously hypertensive rats with or without three weeks of GYY-4137 i.p. application. GYY-4137 reduced triacylglycerol levels and blood pressure, but not adiposity, and all were increased by fructose intake. Fructose intake generally enhanced endothelium-dependent vasorelaxation, decreased adrenergic contraction, and increased protein expression of interleukin-6 (IL-6), tumor necrosis factor alpha (TNFα), and concentration of conjugated dienes in the left ventricle (LV). Although GYY-4137 administration did not affect vasorelaxant responses, it restored disturbed contractility, LV oxidative damage and decreased protein expression of TNFα in fructose-fed rats. While the participation of endogenous H2S in vasoactive responses was not affected by fructose treatment, the expression of H2S-producing enzyme cystathionine β-synthase in the LV was increased, and the stimulation of the NO signaling pathway improved endothelial function in the mesenteric artery. On the other hand, chronic treatment with GYY-4137 increased the expression of H2S-producing enzyme cystathionine γ-lyase in the LV and stimulated the beneficial pro-relaxant and anti-contractile activity of endogenous H2S in thoracic aorta. Our results suggest that sulfide and nitroso signaling pathways could trigger compensatory vasoactive responses in hypertensive rats with metabolic disorder. A slow H2S-releasing donor could partially amend metabolic-related changes and trigger beneficial activity of endogenous H2S.
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Wang, Wenfu, Qiyu Bo, Jian Du, Xin Yu, Kejia Zhu, Jianfeng Cui, Hongda Zhao, Yong Wang, Benkang Shi, and Yaofeng Zhu. "Endogenous H2S sensitizes PAR4-induced bladder pain." American Journal of Physiology-Renal Physiology 314, no. 6 (June 1, 2018): F1077—F1086. http://dx.doi.org/10.1152/ajprenal.00526.2017.
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Bladder pain is a prominent symptom of interstitial cystitis/painful bladder syndrome. Hydrogen sulfide (H2S) generated by cystathionine β-synthase (CBS) or cystathionine γ-lyase (CSE) facilitates bladder hypersensitivity. We assessed involvement of the H2S pathway in protease-activated receptor 4 (PAR4)-induced bladder pain. A bladder pain model was induced by intravesical instillation of PAR4-activating peptide in mice. The role of H2S in this model was evaluated by intraperitoneal preadministration of d,l-propargylglycine (PAG), aminooxyacetic acid (AOAA), or S-adenosylmethionine or the preintravesical administration of NaHS. SV-HUC-1 cells were treated in similar manners. Assessments of CBS, CSE, and macrophage migration inhibitory factor (MIF) expression, bladder voiding function, bladder inflammation, H2S production, and referred bladder pain were performed. The CSE and CBS pathways existed in both mouse bladders and SV-HUC-1 cells. H2S signaling was upregulated in PAR4-induced bladder pain models, and H2S-generating enzyme activity was upregulated in human bladders, mouse bladders, and SV-HUC-1 cells. Pretreatment with AOAA or NaHS inhibited or promoted PAR4-induced mechanical hyperalgesia, respectively; however, PAG only partially inhibited PAR4-induced bladder pain. Treatment with PAG or AOAA decreased H2S production in both mouse bladders and SV-HUC-1 cells. Pretreatment with AOAA increased MIF protein levels in bladder tissues and cells, whereas pretreatment with NaHS lowered MIF protein levels. Bladder pain triggered by the H2S pathway was not accompanied by inflammation or altered micturition behavior. Thus endogenous H2S generated by CBS or CSE caused referred hyperalgesia mediated through MIF in mice with PAR4-induced bladder pain, without causing bladder injury or altering micturition behavior.
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Chen, Qinghai, Shiliang Yu, Kuo Zhang, Zuobiao Zhang, Chao Li, Bingpeng Gao, Weihua Zhang, and Yan Wang. "Exogenous H2S Inhibits Autophagy in Unilateral Ureteral Obstruction Mouse Renal Tubule Cells by Regulating the ROS-AMPK Signaling Pathway." Cellular Physiology and Biochemistry 49, no. 6 (2018): 2200–2213. http://dx.doi.org/10.1159/000493824.
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Background/Aims: The induction of excessive autophagy by increased levels of oxidative stress is one of the main mechanisms underlying unilateral ureteral obstruction (UUO)-induced vascular endothelial cell dysfunction. Hydrogen sulfide (H2S) has been shown to have an anti-oxidative effect, but its mode of action on excessive autophagy in vascular endothelial cells is unclear. Methods: Surgery was used to induce UUO in male C57BL/6 mice as an in vivo model. Human renal epithelial cells (HK-2) were treated with H2O2 as an in vitro model. NaHS was used as an exogenous H2S donor. Transmission electron microscopy was applied to observe the structure of renal autophagosomes. The expression of proteins related to autophagy and apoptosis was detected by western blot analysis in vivo and in vitro. Flow cytometry (DCFH-DA) was used to examine the levels of intracellular reactive oxygen species (ROS). The terminal deoxynucleotidyl transferase dUTP nick end labeling assay was used to detect cell apoptosis. Compound C was used to analyze the association of AMPK with autophagy. Results: Compared with the sham group, in which the ureter was exposed but not ligated, the cell apoptosis index, number of autophagosomes, protein expression of microtubule-associated protein 1 light-chain 3 (LC3)-II/I, beclin-1, and p-AMPK/AMPK were significantly increased in the UUO group. On the other hand, p62, cystathionine β-synthase, and cystathionine γ-lyase protein expression levels and H2S concentration were significantly decreased (p < 0.05). These alterations were ameliorated by the addition of NaHS (p < 0.05). Similar results were observed in vitro. By using the AMPK inhibitor compound C, it was indicated that AMPK was involved in ROS-induced autophagy. In addition, using tissue from patients with obstructive nephropathy, excessive autophagy was observed by an increased LC3-II/LC3-I ratio. Conclusion: NaHS-treatment may exert a protective effect on mouse kidney against UUO by suppressing the ROS-AMPK pathway. ROS-AMPK-mediated autophagy may represent a promising therapeutic target for obstructive nephropathy.
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Nechyporuk, V. M., N. V. Zaichko, and М. М. Korda. "Вплив тиреоїдних гормонів на процеси реметилування та транссульфування сірковмісних амінокислот в органах щурів." Medical and Clinical Chemistry, no. 1 (April 28, 2017). http://dx.doi.org/10.11603/mcch.2410-681x.2017.v0.i1.7689.
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Introduction. Sulfur-containing amino acids affect the vital processes of cells and methylation processes support the redox potential and integrity of cellular systems, incapacitate toxicants and free radicals. Disorders of sulfur-containing amino acids metabolism is associated with different pathologies, including Alzheimer's disease, malignant tumors, neural tube defects, kidneys diseases. The increase of sulfur-containing amino acid homocysteine in the blood is a serious risk factor of cardiovascular diseases such as atherosclerosis, hypertension, venous thrombosis. Regulation of sulfur-containing amino acids metabolism is carried out at different levels, including thyroid hormones. It was shown that hypothyroidism is an independent factor leading to an increase in the concentration of homocysteine in the blood and the risk of cardiovascular diseases development. However, specific molecular mechanisms of the effect of thyroid hormones on sulfur-containing amino acids metabolism are still unknown.The aim of the study – to investigate experimentally the effect of thyroid hormones on remethylation and transsulfuration pathways in the liver and kidneys, homocysteine, cysteine and hidrogen sulfide contents in the blood serum of experimental animals.Methods of the research. L-thyroxine and Mercazolil were used for the modeling of hyper- and hypothyroidism, which were confirmed by the content of free thyroxine, free triiod othyronine, thyroid-stimulating hormone in serum.Results and Discussion. In the liver and kidneys of animals with hypothyroidism a decrease in the activity of remethylation cycle enzymes (S-adenosylmethionine synthetase, S-adenosylhomocysteine hydrolase and betaine-homocysteine methyltransferase), as well as transsulfuration pathway enzymes (cystathionine β-synthase, cystathionine γ-lyase, cysteine transaminase) was observed. At the same time, introduction of L-thyroxine increased the activity of these enzymes in the liver and kidney tissues. Hyperthyroidism caused the decrease of homocysteine concentration whereas hypothyroidism increased the levels of homocysteine, cysteine and decreased the hydrogen sulpide content in blood.Conclusions. Disorders of remethylation and transsulfuration of sulfur-containing amino acids in organs might be important risk factors of atherosclerosis, endothelial dysfunction, and hypercoagulation development.
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Nechyporuk, V. M., and M. M. Korda. "Метаболізм цистеїну при експериментальному гіпер- та гіпотиреозі в щурів." Medical and Clinical Chemistry, no. 4 (January 11, 2018). http://dx.doi.org/10.11603/mcch.2410-681x.2017.v0.i4.8433.
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Introduction. Sulfur-containing amino acids provide vital processes of the cell, maintain the integrity of the redox potential, neutralize free radicals and toxic agents that provide remethylation cycle and transsulfuration processes. It is known that cysteine is formed in cells from homocysteine, and can be used, depending on the needs of the cell for the synthesis of protein, glutathione, in a desulfuration pathway with the formation of hydrogen sulfide (H2S). Regulation of the metabolism of sulfur-containing amino acids is carried out at different levels, including the endocrine system, in particular, thyroid hormones.Theaim of the study – to investigate experimentally the influence of thyroid gland functional state on the main enzymatic systems of the cysteine cycle in the tissues (liver, kidneys, brain, heart), concentration of cysteine and reduced glutathione and H2S in the blood.Research Methods. 40 male rats weighing 150–180 g were used in the study. To model hyper- and hypothyroidism, animals were daily enterally administered with a solution of L-thyroxine (200 μg / day per 1 kg of weight) or mercazolil (10 mg / day per 1 kg) for the 14th and 21st days. In the brain of animals, the desulfurase activity of cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CGL) enzymes was determined, and cysteine, GC, and H2S content in the blood.Results and Discussion. The rats were administered with L-thyroxine and mercazolil to simulate the states of hyper- and hypothyroidism, which were confirmed by the content of fT3, fT4 and TSH in the blood. In organs of animals with hypothyroidism, a decrease in the activity of CBS, CGL, and CAP was observed. At the same time, the introduction of L-thyroxin led to an increase in the activity of these enzymes in the kidney and brain. Hyperthyroidism was accompanied by a decrease, and hypothyroidism did not affect the concentration of glutathione in the blood and its content in the organs of animals. A significant decrease in the concentration of H2S in the blood with hypothyroidism was established.Conclusions. The disorder of the cardiovascular system in hypothyroidism may be a consequence of the disoders of desulfuration processes in organs and tissues, the administration of L-thyroxin leads to a decrease in the synthesis of glutathione in the serum and animal organs may be one of the causes of the resultformation of oxidative stress in patients with hyperthyroidism.
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Řimnáčová, Hedvika, Jiří Moravec, Miriama Štiavnická, Jiřina Havránková, Ladan Monsef, Petr Hošek, Šárka Prokešová, et al. "Evidence of endogenously produced hydrogen sulfide (H2S) and persulfidation in male reproduction." Scientific Reports 12, no. 1 (July 6, 2022). http://dx.doi.org/10.1038/s41598-022-15360-x.
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AbstractPersulfidation contributes to a group of redox post-translational modifications (PTMs), which arise exclusively on the sulfhydryl group of cysteine as a result of hydrogen sulfide (H2S) action. Redox-active molecules, including H2S, contribute to sperm development; therefore, redox PTMs represent an extremely important signalling pathway in sperm life. In this path, persulfidation prevents protein damage caused by irreversible cysteine hyperoxidation and thus maintains this signalling pathway. In our study, we detected both H2S and its production by all H2S-releasing enzymes (cystathionine γ-lyase (CTH), cystathionine β-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (MPST)) in male reproduction, including spermatozoa. We provided evidence that sperm H2S leads to persulfidation of proteins, such as glyceraldehyde-3-phosphate dehydrogenase, tubulin, and anchor protein A-kinase. Overall, this study suggests that persulfidation, as a part of the redox signalling pathway, is tightly regulated by enzymatic H2S production and is required for sperm viability.
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Billiar, Timothy R., Giuseppe Cirino, David Fulton, Roberto Motterlini, Andreas Papapetropoulos, and Csaba Szabo. "Hydrogen sulphide synthesis (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database." IUPHAR/BPS Guide to Pharmacology CITE 2019, no. 4 (September 16, 2019). http://dx.doi.org/10.2218/gtopdb/f279/2019.4.
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Hydrogen sulfide is a gasotransmitter, with similarities to nitric oxide and carbon monoxide. Although the enzymes indicated below have multiple enzymatic activities, the focus here is the generation of hydrogen sulphide (H2S) and the enzymatic characteristics are described accordingly. Cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE) are pyridoxal phosphate (PLP)-dependent enzymes. 3-mercaptopyruvate sulfurtransferase (3-MPST) functions to generate H2S; only CAT is PLP-dependent, while 3-MPST is not. Thus, this third pathway is sometimes referred to as PLP-independent. CBS and CSE are predominantly cytosolic enzymes, while 3-MPST is found both in the cytosol and the mitochondria. For an authoritative review on the pharmacological modulation of H2S levels, see Szabo and Papapetropoulos, 2017 [4].
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Melnik, A. V., and N. V. Zaichko. "Гендерні особливості впливу гіпергомоцистеїнемії на метаболізм сірковмісних амінокислот та гідроген сульфіду в печінці." Medical and Clinical Chemistry, no. 1 (April 28, 2017). http://dx.doi.org/10.11603/mcch.2410-681x.2017.v0.i1.7352.
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Introduction. Sulfur amino acid disorders are recognized as metabolic risk factors for cardiovascular pathology. However, the question of the involvement of sulfur amino acids in the formation of the gender-defined pathology of cardiovascular system remains unclear.The aim of the study – research the impact of thiolactone hyperhomocysteinemia (HHC) on blood levels of sulfur-containing metabolites and enzymes activity in metabolism of homocysteine, cysteine and hydrogen sulfide in the liver of rats of both sexes.Methods of the research. Experiments were conducted on 40 white laboratory rats of both sexes weighing 220–280 g. Hyperhomocysteinemia was modeled by long-term intragastric administration of thiolactone D,L-homocysteine, dosage 100 mg / kg, in 1 % starch solution once per day for 28 days. The research determines the content of homocysteine, cysteine and hydrogen sulfide in blood serum and activity of enzymes in the liver – cystathionine-γ-lyase, cystathionine-β-synthase, cysteine aminotransferase, methionine adenosyltransferase, cysteine dioxygenase and γ-glutamylcysteine ligase.Results and Discussion. Hyperhomocysteinemia initiates gender-defined changes in the content of sulfur-containing metabolites in the serum of rats: increase homocysteine and cysteine and reduction of hydrogen sulfide is 111; 59.2 and 59.4 % in males (females – 82.4, 38.0 and 47.5 %, p<0.05) respectively compared to the control group.HHC in males has led to a more distinct decreased in liver enzyme activity of homocysteine methylation and transsulfuration (on 20.5–24.8 % in males and on 13.4–15.4 % in females, p <0.05), enzymes of cysteine degradation in oxidative and conjugation ways (in 21.1–22.0 % in males and on 13.4–15.3 % in females, p<0.05) and H2S-synthesizing enzymes (20.6–25.9 % in males and on 13.5–17.5 % in females, p<0.05) compared to the control group.Conclusions. It was shown, thiolactone homocysteine administration is accompanied by the rise of homocysteine, cysteine and the reduced levels of hydrogen sulfide in blood in individuals of both sexes, but more significant changes were observed in males. In addition, gender defined changes in the metabolism of sulfur-containing compounds in the liver were registered: male rats showed significantly greater decrease in liver enzyme activity of homocysteine remethylation and transsulfuration, cysteine degradation enzymes and synthesis of hydrogen sulfide in the liver compared to female rats.
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Nunes, Sofia C., Cristiano Ramos, Inês Santos, Cindy Mendes, Fernanda Silva, João B. Vicente, Sofia A. Pereira, Ana Félix, Luís G. Gonçalves, and Jacinta Serpa. "Cysteine Boosts Fitness Under Hypoxia-Mimicked Conditions in Ovarian Cancer by Metabolic Reprogramming." Frontiers in Cell and Developmental Biology 9 (August 11, 2021). http://dx.doi.org/10.3389/fcell.2021.722412.
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Among gynecologic malignancies, ovarian cancer is the third most prevalent and the most common cause of death, especially due to diagnosis at an advanced stage together with resistance to therapy. As a solid tumor grows, cancer cells in the microenvironment are exposed to regions of hypoxia, a selective pressure prompting tumor progression and chemoresistance. We have previously shown that cysteine contributes to the adaptation to this hypoxic microenvironment, but the mechanisms by which cysteine protects ovarian cancer cells from hypoxia-induced death are still to be unveiled. Herein, we hypothesized that cysteine contribution relies on cellular metabolism reprogramming and energy production, being cysteine itself a metabolic source. Our results strongly supported a role of xCT symporter in energy production that requires cysteine metabolism instead of hydrogen sulfide (H2S) per se. Cysteine degradation depends on the action of the H2S-synthesizing enzymes cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and/or 3-mercaptopyruvate sulfurtransferase (MpST; together with cysteine aminotransferase, CAT). In normoxia, CBS and CSE inhibition had a mild impact on cysteine-sustained ATP production, pointing out the relevance of CAT + MpST pathway. However, in hypoxia, the concomitant inhibition of CBS and CSE had a stronger impact on ATP synthesis, thus also supporting a role of their hydrogen sulfide and/or cysteine persulfide-synthesizing activity in this stressful condition. However, the relative contributions of each of these enzymes (CBS/CSE/MpST) on cysteine-derived ATP synthesis under hypoxia remains unclear, due to the lack of specific inhibitors. Strikingly, NMR analysis strongly supported a role of cysteine in the whole cellular metabolism rewiring under hypoxia. Additionally, the use of cysteine to supply biosynthesis and bioenergetics was reinforced, bringing cysteine to the plateau of a main carbon sources in cancer. Collectively, this work supports that sulfur and carbon metabolism reprogramming underlies the adaptation to hypoxic microenvironment promoted by cysteine in ovarian cancer.
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Yang, Bobo, Changsheng Yin, Yu Zhang, Guangwei Xing, Suhua Wang, Fang Li, Michael Aschner, and Rongzhu Lu. "Differential effects of subchronic acrylonitrile exposure on hydrogen sulfide levels in rat blood, brain, and liver." Toxicology Research, April 5, 2022. http://dx.doi.org/10.1093/toxres/tfac011.
Full textAbstract:
Abstract Background Hydrogen sulfide (H2S), as the third gasotransmitter participates in both cellular physiological and pathological processes, including chemical-induced injuries. We recently reported acute acrylonitrile (AN) treatment inhibited endogenous H2S biosynthesis pathway in rat and astrocyte models. However, there is still no evidence to address the correlation between endogenous H2S and sub-chronic AN exposure. Objectives This study aims to explore the modulatory effects of prolonged AN exposure on endogenous H2S levels and its biosynthetic enzymes in rat blood, brain and liver. Methods A total of 50 male Sprague-Dawley rats were randomly divided into 5 groups, including the control group and AN-treated groups at dosages of 6.25, 12.5, 25 or 50 mg/kg. Rats received one exposure/day, 5 days/week, for 4 consecutive weeks. The rat bodyweight and brain/liver organ coefficient were detected, along with liver cytochrome P450 2E1(CYP2E1) expression. In addition, the H2S contents in rat serum and plasma, and in cerebral cortex and liver tissues were measured by methylene blue method. The expression of H2S-generating enzymes, including cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MPST) was also measured with Western blot both in rat cerebral cortex and liver. Results Subchronic exposure to AN significantly inhibited bodyweight-gain and increased the liver CYP2E1 expression compared with the control. In addition, AN significantly increased H2S levels in rat plasma and serum, but not in liver. The endogenous H2S level in rat cerebral cortex was also significantly increased upon AN treatment, when expression of the major H2S-generating enzymes, CBS and 3-MPST were significantly enhanced. However, hepatic protein levels of CBS and CSE were significantly increased, whereas hepatic levels of 3-MPST were significantly decreased. Conclusion This study showed that sub-chronic AN exposure increased endogenous H2S contents in rat blood and brain tissues, but not liver, which may be resulted from the distinct expression profile of H2S-producing enzymes in response to AN. The blood H2S contents may be applied as a potential novel biomarker for surveillance of chronically AN-exposed populations. Highlights Subchronic intraperitoneal exposure to acrylonitrile increased H2S content in rat blood and cerebral cortex, but not in liver. Distinct tissue expression profiles of H2S-producing enzymes contribute to the acrylonitrile-induced differential effects on the H2S level. Blood H2S level may be a biomarker for subchronic exposure to acrylonitrile.