Regulation of Cystathionine γ-Lyase Expression by Lipopolysaccharide in Human Umbilical Vein Endothelial Cells: Involvement of NF-κB Signaling
Main Article Content
Abstract
Hydrogen sulfide (H₂S) acts as a signaling molecule that modulates vascular tone, protects against oxidative stress, and functions as an oxygen sensor. Cystathionine γ‑lyase (CSE) facilitates the production of H₂S, and the CSE/H₂S signaling pathway is implicated in endotoxin‑induced inflammation, such as that induced by lipopolysaccharide (LPS). Therefore, it is essential to examine the expression and regulation of CSE in human umbilical vein endothelial cells (HUVECs) following LPS stimulation. LPS treatment for 6 hours significantly increased CSE mRNA and protein levels in HUVECs. A dual‑luciferase reporter plasmid pGL4.12‑HuCSE710, containing either the wild‑type CSE gene promoter or its mutant variant, was co‑transfected with the pRL‑CMV vector into HEK‑293T cells. This study investigated the effects of nuclear factor‑κB (NF‑κB) transcription factor binding to this promoter on the transcriptional regulation of the CSE gene in HUVECs after LPS treatment. The DNA sequence GGACATTCC within the CSE gene promoter was significantly associated with the transcriptional regulation of CSE in response to LPS treatment. These findings have substantial implications for further research on the regulatory mechanisms of CSE in inflammation and offer promising insights with potential clinical relevance. Therefore, LPS regulates CSE expression in HUVECs primarily through NF‑κB activation, with the NF‑κB binding site on the CSE promoter being critical for LPS‑induced upregulation and subsequent inflammatory response.
Keywords:
hydrogen sulphide (H₂S), cystathionine γ lyase (CSE), lipopolysaccharide (LPS), nuclear factor κB (NF κB), transcription factor
Article Details
How to Cite
WANG, Maoxian.
Regulation of Cystathionine γ-Lyase Expression by Lipopolysaccharide in Human Umbilical Vein Endothelial Cells: Involvement of NF-κB Signaling.
Medical Research Archives, [S.l.], v. 14, n. 4, may 2026.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/7466>. Date accessed: 22 may 2026.
doi: https://doi.org/10.18103/mra.v14i4.7466.
Keywords
hydrogen sulphide (H2S), cystathionine ? lyase (CSE), lipopolysaccharide (LPS), nuclear factor ?B (NF ?B), transcription factor
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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15. He J, Wang L, Chen Y, et al. Mechanistic insights into HOTAIR driven ADAM17/NF κB activation and endothelial dysfunction in LPS challenged HUVECs. Immunol Invest. 2025;54(6):867-893. doi:10.1080/08820139.2025.2485332
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21. Shahid A, Chambers S, Scott Thomas A, Zawari M, Bhatia M. Anti inflammatory effects of alpha lipoic acid modulate cystathionine γ lyase expression in RAW 264.7 macrophages. Int J Mol Sci. 2026;27(8):4123. doi:10.3390/ijms27084123
22. Wang M, Guo Z, Wang S. The binding site for the transcription factor, NF κB, on the cystathionine γ lyase promoter is critical for LPS induced cystathionine γ lyase expression. Int J Mol Med. 2014;34(2):639-645. doi:10.3892/ijmm.2014.1788
23. Li LC, Dahiya R. MethPrimer: designing primers for methylation PCRs. Bioinformatics. 2002;18(11):1427-1431. doi:10.1093/bioinformatics/18.11.1427
24. Heinemeyer T, Wingender E, Reuter I, et al. Databases on transcriptional regulation: TRANSFAC, TRRD and COMPEL. Nucleic Acids Res. 1998;26(1):362-367. doi:10.1093/nar/26.1.362
25. Xu H, Zhang Y, Li W, et al. Material-driven nanoplatforms for precision hydrogen sulfide delivery. Redox Biol. 2025; 87:103909. doi: 10.1016/j.redox.2025.103909
26. Shanker SS, Shankar S, Satheesh G, et al. Protective effect of Triphala mediated by H₂S signaling pathway in LPS induced RAW macrophages. J Pharm Bioallied Sci. 2024;16(Suppl 5): S4511-S4513. doi: 10.4103/jpbs.jpbs_1059_24
27. Li L, Bhatia M, Zhu YZ, et al. Hydrogen sulfide is a novel mediator of lipopolysaccharide induced inflammation in the mouse. FASEB J. 2005;19(9):1196-1198. doi: 10.1096/fj.04-3584fje
28. Whiteman M, Li L, Rose P, Tan CH, Parkinson DB, Moore PK. The effect of hydrogen sulfide donors on lipopolysaccharide induced formation of inflammatory mediators in macrophages. Antioxid Redox Signal. 2010;12(10):1147-1154. doi:10.1089 /ars.2009.2899
29. Szabo C, Coletta C, Chao C, et al. Tumor derived hydrogen sulfide, produced by cystathionine β synthase, stimulates bioenergetic coupling, tumor bioenergetics and angiogenesis. Proc Natl Acad Sci USA. 2013;110(30):12474-12479. doi:10.1073/pnas.1306245110
30. Sen N, Paul BD, Gadalla MM, et al. Hydrogen sulfide linked sulfhydration of NF κB mediates its antiapoptotic actions. Mol Cell. 2012;45(1):13-24. doi: 10.1016/j.molcel.2011.10.021
31. Zhang H, Lin Y, Ma Y, Zhang J, Wang C, Zhang H. Protective effect of hydrogen sulfide on monocrotaline induced pulmonary arterial hypertension via inhibition of the endothelial mesenchymal transition. Int J Mol Med. 2019;44(6):2091-2102. doi:10.3892/ijmm.2019.4378
32. Wang Y, Zhang C, Xu C, et al. H₂S mediates apoptosis in response to inflammation through PI3K/Akt/NF-κB signaling pathway. Biotechnol Lett. 2020;42(3):375-387. doi:10.1007/s10529-019-02787-6
33. Bourque C, Zhang Y, Fu M, et al. H₂S protects lipopolysaccharide induced inflammation by blocking NF κB transactivation in endothelial cells. Toxicol Appl Pharmacol. 2018; 338:20-29. doi: 10.1016/j.taap. 2017.11.008
34. Pan LL, Liu XH, Gong QH, Zhu YZ. Role of cystathionine γ lyase/hydrogen sulfide pathway in cardiovascular disease: a novel therapeutic strategy? Antioxid Redox Signal. 2012;17(1):106-118. doi:10.1089/ars.2011.4349
35. Yang G, Wang R. H₂S and blood vessels: an overview. Handb Exp Pharmacol. 2015; 230:85-110. doi:10.1007/978-3-319-18144-8_4
36. Allosteric activators of cystathionine γ lyase to augment endogenous hydrogen sulfide and inhibit pathologic calcification. bioRxiv. Published online July 26, 2025. doi:10.1101/2025.07.23.654321
37. Dilxat T, Shi Q, Chen X, Liu X. Garlic oil supplementation blocks inflammatory pyroptosis- related acute lung injury by suppressing the NF κB/NLRP3 signaling pathway via H₂S generation. Aging (Albany NY). 2024;16(8):7025-7042. doi:10.18632/aging.205757
38. Yu L, Luo Q, Rao X, Xiao X, Wang P. Unveiling the anti-inflammatory mechanism of exogenous hydrogen sulfide in Kawasaki disease based on network pharmacology and experimental validation. Sci Rep. 2025;15(1):7410. doi:10.1038/s41598-025-91998-7
39. Yang G, Wang R. Anti-atherogenic effect of hydrogen sulfide by over-expression of cystathionine gamma-lyase (CSE) gene. PLoS ONE. 2014;9(11): e113038. doi: 10.1371/journal.pone.0113038
40. Fan J, Zheng F, Li S, et al. Hydrogen sulfide lowers hyperhomocysteinemia dependent on cystathionine γ lyase S‑sulfhydration in ApoE‑knockout atherosclerotic mice. Br J Pharmacol. 2019 ;176(17) :3180-3192. doi :10.1111/bph.14719
41. Bai L, Qi Y, Chen S, et al. Angiotensin II downregulates vascular endothelial cell hydrogen sulfide production by enhancing cystathionine γ‑lyase degradation through ROS-activated ubiquitination pathway. Biochem Biophys Res Commun. 2019;514(3):907-912. doi: 10.1016/j.bbrc.2019.05.044
42. Lo Faro ML, Fox B, Whatmore JL, Winyard PG, Whiteman M. Hydrogen sulfide and nitric oxide interactions in inflammation. Nitric Oxide. 2014; 41:38-47. doi: 10.1016/j.niox.2014.05.014
43. Motterlini R, Otterbein LE. The therapeutic potential of carbon monoxide. Nat Rev Drug Discov. 2010;9(9):728-743. doi:10.1038/nrd3228
2. Kimura H. Signaling by hydrogen sulfide (H₂S) and polysulfides (H₂Sₙ) in the central nervous system. Neurochem Int. 2019; 126:118-125. doi: 10.1016/j.neuint.2019.01.027
3. Zhuang R, Guo L, Wang H, et al. Exogenous hydrogen sulfide inhibits oral mucosal wound induced macrophage activation via the NF κB pathway. Oral Dis. 2018;24(5):793-801. doi:10.1111/odi.12838
4. Zheng Y, Liao J, Zeng T, et al. Lipopolysaccharide regulates biosynthesis of cystathionine gamma lyase and hydrogen sulfide through Toll like receptor 4/p38 and Toll like receptor 4/NF κB pathways in macrophages. In Vitro Cell Dev Biol Anim. 2013;49(9):679-688. doi:10.1007/s11626-013-9653-5
5. Rao CY, Fu LY, Hu CL, et al. H₂S mitigates severe acute pancreatitis through the PI3K/AKT NF κB pathway in vivo. World J Gastroenterol. 2015;21(15):4555-4563. doi:10.3748/wjg. v21.i15.4555
6. Wen YD, Wang H, Zhu YZ. The drug developments of hydrogen sulfide on cardiovascular disease. Oxid Med Cell Longev. 2018; 2018:4010395. doi:10.1155/2018/4010395
7. Wang XL, Pan LL, Long F, et al. Endogenous hydrogen sulfide ameliorates NOX4 induced oxidative stress in LPS stimulated macrophages and mice. Cell Physiol Biochem. 2018;47(2):458-474. doi:10.1159/000489946
8. George L, Ramasamy T, Sirajudeen K, Manickam V. LPS induced apoptosis is partially mediated by hydrogen sulphide in RAW 264.7 murine macrophages. Immunol Invest. 2019;48(5):451-465. doi:10.1080/08820139.2019.1570245
9. Zhang D, Wang X, Chen S, et al. Endogenous hydrogen sulfide sulfhydrates IKKβ at cysteine 179 to control pulmonary artery endothelial cell inflammation. Clin Sci (Lond). 2019;133(20):2045-2059. doi:10.1042/CS20190514
10. Qiu Z, Li J, Zhang Y, et al. Endogenous hydrogen sulphide promotes the ex vivo expansion of haematopoietic stem cells by regulating the activation of the JAK2/STAT3 pathway. Immunology. 2025;175(4):534-543. doi:10.1111/imm.13886
11. Zhu M, Fan X, Zhang N, et al. Endothelial endogenous CSE/H₂S inhibits endothelial pyroptosis by activating sirtuin1 to attenuate LPS induced acute lung injury. FASEB J. 2025;39(5): e70420. doi:10.1096/fj.202402044R
12. Jung T, Kim S, Son EH, Lemaître RN, Krueger MA, Gharib SA. Hydrogen sulfide attenuates PMA induced hypertrophy in human cardiomyocytes by modulating gene expression and reducing sulfide methylation. Biochem Pharmacol. 2026; 245:117666. doi: 10.1016/j.bcp.2025.117666
13. Hu HJ, Jiang ZS, Zhou SH, Liu QM. Hydrogen sulfide suppresses angiotensin II stimulated endothelin 1 generation and subsequent cytotoxicity induced endoplasmic reticulum stress in endothelial cells via NF κB. Mol Med Rep. 2016;14(5):4729-4740. doi:10.3892/mmr.2016.5812
14. Zhu XY, Liu SJ, Liu YJ, Wang S, Ni X. Glucocorticoids suppress cystathionine γ lyase expression and H₂S production in lipopolysaccharide treated macrophages. Cell Mol Life Sci. 2010;67(7):1119-1132. doi:10.1007/s00018-009-0250-5
15. He J, Wang L, Chen Y, et al. Mechanistic insights into HOTAIR driven ADAM17/NF κB activation and endothelial dysfunction in LPS challenged HUVECs. Immunol Invest. 2025;54(6):867-893. doi:10.1080/08820139.2025.2485332
16. Liu MH, Lin XL, Xiao LL. Hydrogen sulfide attenuates TMAO induced macrophage inflammation through increased SIRT1 sulfhydration. Mol Med Rep. 2023;28(1):129. doi:10.3892/mmr.2023.13016
17. Kimura H. The physiological role of hydrogen sulfide and beyond. Nitric Oxide. 2014; 41:4-10. doi: 10.1016/j.niox.2014.05.012
18. Yu H, Fan J, Zhang Y, Zhao Z, Lin Z, Jiang P. Syndecan 3 inhibits lipopolysaccharide induced inflammation of bovine mammary epithelial cells through the NF κB signal transduction pathway. J Dairy Sci. 2024;107(12):11563-11575. doi:10.3168/jds.2024-25239
19. Sun S, Duan X, Wu Q, et al. FABP4 inhibitor alleviates lipopolysaccharide induced HUVEC injury by inactivating NF κB and activating PPARγ. Int Heart J. 2024;65(6):1153-1160. doi:10.1536/ihj.24-293
20. Luo Z, Xu G, Li C, et al. Hijacking the hydrogen sulfide axis: a novel 4 trifluoromethylquinoline derivative suppresses glioblastoma via cystathionine γ lyase suppression. J Med Chem. 2026;69(3):3457-3476. doi: 10.1021/acs.jmedchem.5c02456
21. Shahid A, Chambers S, Scott Thomas A, Zawari M, Bhatia M. Anti inflammatory effects of alpha lipoic acid modulate cystathionine γ lyase expression in RAW 264.7 macrophages. Int J Mol Sci. 2026;27(8):4123. doi:10.3390/ijms27084123
22. Wang M, Guo Z, Wang S. The binding site for the transcription factor, NF κB, on the cystathionine γ lyase promoter is critical for LPS induced cystathionine γ lyase expression. Int J Mol Med. 2014;34(2):639-645. doi:10.3892/ijmm.2014.1788
23. Li LC, Dahiya R. MethPrimer: designing primers for methylation PCRs. Bioinformatics. 2002;18(11):1427-1431. doi:10.1093/bioinformatics/18.11.1427
24. Heinemeyer T, Wingender E, Reuter I, et al. Databases on transcriptional regulation: TRANSFAC, TRRD and COMPEL. Nucleic Acids Res. 1998;26(1):362-367. doi:10.1093/nar/26.1.362
25. Xu H, Zhang Y, Li W, et al. Material-driven nanoplatforms for precision hydrogen sulfide delivery. Redox Biol. 2025; 87:103909. doi: 10.1016/j.redox.2025.103909
26. Shanker SS, Shankar S, Satheesh G, et al. Protective effect of Triphala mediated by H₂S signaling pathway in LPS induced RAW macrophages. J Pharm Bioallied Sci. 2024;16(Suppl 5): S4511-S4513. doi: 10.4103/jpbs.jpbs_1059_24
27. Li L, Bhatia M, Zhu YZ, et al. Hydrogen sulfide is a novel mediator of lipopolysaccharide induced inflammation in the mouse. FASEB J. 2005;19(9):1196-1198. doi: 10.1096/fj.04-3584fje
28. Whiteman M, Li L, Rose P, Tan CH, Parkinson DB, Moore PK. The effect of hydrogen sulfide donors on lipopolysaccharide induced formation of inflammatory mediators in macrophages. Antioxid Redox Signal. 2010;12(10):1147-1154. doi:10.1089 /ars.2009.2899
29. Szabo C, Coletta C, Chao C, et al. Tumor derived hydrogen sulfide, produced by cystathionine β synthase, stimulates bioenergetic coupling, tumor bioenergetics and angiogenesis. Proc Natl Acad Sci USA. 2013;110(30):12474-12479. doi:10.1073/pnas.1306245110
30. Sen N, Paul BD, Gadalla MM, et al. Hydrogen sulfide linked sulfhydration of NF κB mediates its antiapoptotic actions. Mol Cell. 2012;45(1):13-24. doi: 10.1016/j.molcel.2011.10.021
31. Zhang H, Lin Y, Ma Y, Zhang J, Wang C, Zhang H. Protective effect of hydrogen sulfide on monocrotaline induced pulmonary arterial hypertension via inhibition of the endothelial mesenchymal transition. Int J Mol Med. 2019;44(6):2091-2102. doi:10.3892/ijmm.2019.4378
32. Wang Y, Zhang C, Xu C, et al. H₂S mediates apoptosis in response to inflammation through PI3K/Akt/NF-κB signaling pathway. Biotechnol Lett. 2020;42(3):375-387. doi:10.1007/s10529-019-02787-6
33. Bourque C, Zhang Y, Fu M, et al. H₂S protects lipopolysaccharide induced inflammation by blocking NF κB transactivation in endothelial cells. Toxicol Appl Pharmacol. 2018; 338:20-29. doi: 10.1016/j.taap. 2017.11.008
34. Pan LL, Liu XH, Gong QH, Zhu YZ. Role of cystathionine γ lyase/hydrogen sulfide pathway in cardiovascular disease: a novel therapeutic strategy? Antioxid Redox Signal. 2012;17(1):106-118. doi:10.1089/ars.2011.4349
35. Yang G, Wang R. H₂S and blood vessels: an overview. Handb Exp Pharmacol. 2015; 230:85-110. doi:10.1007/978-3-319-18144-8_4
36. Allosteric activators of cystathionine γ lyase to augment endogenous hydrogen sulfide and inhibit pathologic calcification. bioRxiv. Published online July 26, 2025. doi:10.1101/2025.07.23.654321
37. Dilxat T, Shi Q, Chen X, Liu X. Garlic oil supplementation blocks inflammatory pyroptosis- related acute lung injury by suppressing the NF κB/NLRP3 signaling pathway via H₂S generation. Aging (Albany NY). 2024;16(8):7025-7042. doi:10.18632/aging.205757
38. Yu L, Luo Q, Rao X, Xiao X, Wang P. Unveiling the anti-inflammatory mechanism of exogenous hydrogen sulfide in Kawasaki disease based on network pharmacology and experimental validation. Sci Rep. 2025;15(1):7410. doi:10.1038/s41598-025-91998-7
39. Yang G, Wang R. Anti-atherogenic effect of hydrogen sulfide by over-expression of cystathionine gamma-lyase (CSE) gene. PLoS ONE. 2014;9(11): e113038. doi: 10.1371/journal.pone.0113038
40. Fan J, Zheng F, Li S, et al. Hydrogen sulfide lowers hyperhomocysteinemia dependent on cystathionine γ lyase S‑sulfhydration in ApoE‑knockout atherosclerotic mice. Br J Pharmacol. 2019 ;176(17) :3180-3192. doi :10.1111/bph.14719
41. Bai L, Qi Y, Chen S, et al. Angiotensin II downregulates vascular endothelial cell hydrogen sulfide production by enhancing cystathionine γ‑lyase degradation through ROS-activated ubiquitination pathway. Biochem Biophys Res Commun. 2019;514(3):907-912. doi: 10.1016/j.bbrc.2019.05.044
42. Lo Faro ML, Fox B, Whatmore JL, Winyard PG, Whiteman M. Hydrogen sulfide and nitric oxide interactions in inflammation. Nitric Oxide. 2014; 41:38-47. doi: 10.1016/j.niox.2014.05.014
43. Motterlini R, Otterbein LE. The therapeutic potential of carbon monoxide. Nat Rev Drug Discov. 2010;9(9):728-743. doi:10.1038/nrd3228