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Song D, He J, Cheng T, Jin L, Li S, Chen B, Li Y, Liao C. Cystathionine γ-lyase contributes to exacerbation of periodontal destruction in experimental periodontitis under hyperglycemia. J Periodontol 2025; 96:255-267. [PMID: 38937859 DOI: 10.1002/jper.23-0811] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 05/19/2024] [Accepted: 05/20/2024] [Indexed: 06/29/2024]
Abstract
BACKGROUND Diabetes is one of the major inflammatory comorbidities of periodontitis via 2-way interactions. Cystathionine γ-lyase (CTH) is a pivotal endogenous enzyme synthesizing hydrogen sulfide (H2S), and CTH/H2S is crucially implicated in modulating inflammation in various diseases. This study aimed to explore the potential role of CTH in experimental periodontitis under a hyperglycemic condition. METHODS CTH-silenced and normal human periodontal ligament cells (hPDLCs) were cultured in a high glucose and Porphyromonas gingivalis lipopolysaccharide (P.g-LPS) condition. The effects of CTH on hPDLCs were assessed by Cell Counting Kit 8 (CCK8), real-time quantitative polymerase chain reaction (RT-qPCR), and enzyme-linked immunosorbent assay (ELISA). The model of experimental periodontitis under hyperglycemia was established on both Cth-/- and wild-type (WT) mice, and the extent of periodontal destruction was assessed by micro-CT, histology, RNA-Seq, Western blot, tartrate-resistant acid phosphatase (TRAP) staining and immunostaining. RESULTS CTH mRNA expression increased in hPDLCs in response to increasing concentration of P.g-LPS stimulation in a high glucose medium. With reference to WT mice, Cth-/- mice with experimental periodontitis under hyperglycemia exhibited reduced bone loss, decreased leukocyte infiltration and hindered osteoclast formation, along with reduced expression of proinflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) in periodontal tissue. RNA-seq-enriched altered NF-κB pathway signaling in healthy murine gingiva with experimental periodontitis mice under hyperglycemia. Accordingly, phosphorylation of p65 (P-p65) was alleviated in CTH-silenced hPDLCs, leading to decreased expression of IL6 and TNF. CTH knockdown inhibited activation of nuclear factor kappa-B (NF-κB) pathway and decreased production of proinflammatory cytokines under high glucose and P.g-LPS treatment. CONCLUSION The present findings suggest the potential of CTH as a therapeutic target for tackling periodontitis in diabetic patients.
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Affiliation(s)
- Danni Song
- Shanghai Engineering Research Center of Tooth Restoration and Regeneration & Tongji Research Institute of Stomatology & Department of Orthodontics, Stomatological Hospital and Dental School, Tongji University, Shanghai, China
| | - Jiangfeng He
- Shanghai Engineering Research Center of Tooth Restoration and Regeneration & Tongji Research Institute of Stomatology & Department of Orthodontics, Stomatological Hospital and Dental School, Tongji University, Shanghai, China
| | - Tianfan Cheng
- Division of Periodontology & Implant Dentistry, Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, Hong Kong
| | - Lijian Jin
- Division of Periodontology & Implant Dentistry, Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, Hong Kong
| | - Sijin Li
- Shanghai Engineering Research Center of Tooth Restoration and Regeneration & Tongji Research Institute of Stomatology & Department of Orthodontics, Stomatological Hospital and Dental School, Tongji University, Shanghai, China
| | - Beibei Chen
- Shanghai Engineering Research Center of Tooth Restoration and Regeneration & Tongji Research Institute of Stomatology & Department of Orthodontics, Stomatological Hospital and Dental School, Tongji University, Shanghai, China
| | - Yongming Li
- Shanghai Engineering Research Center of Tooth Restoration and Regeneration & Tongji Research Institute of Stomatology & Department of Orthodontics, Stomatological Hospital and Dental School, Tongji University, Shanghai, China
| | - Chongshan Liao
- Shanghai Engineering Research Center of Tooth Restoration and Regeneration & Tongji Research Institute of Stomatology & Department of Orthodontics, Stomatological Hospital and Dental School, Tongji University, Shanghai, China
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Shahid A, Bhatia M. Hydrogen Sulfide: A Versatile Molecule and Therapeutic Target in Health and Diseases. Biomolecules 2024; 14:1145. [PMID: 39334911 PMCID: PMC11430449 DOI: 10.3390/biom14091145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 09/04/2024] [Accepted: 09/06/2024] [Indexed: 09/30/2024] Open
Abstract
In recent years, research has unveiled the significant role of hydrogen sulfide (H2S) in many physiological and pathological processes. The role of endogenous H2S, H2S donors, and inhibitors has been the subject of studies that have aimed to investigate this intriguing molecule. The mechanisms by which H2S contributes to different diseases, including inflammatory conditions, cardiovascular disease, viral infections, and neurological disorders, are complex. Despite noteworthy progress, several questions remain unanswered. H2S donors and inhibitors have shown significant therapeutic potential for various diseases. This review summarizes our current understanding of H2S-based therapeutics in inflammatory conditions, cardiovascular diseases, viral infections, and neurological disorders.
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Affiliation(s)
| | - Madhav Bhatia
- Department of Pathology and Biomedical Science, University of Otago, Christchurch 8140, New Zealand;
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Li S, Hua Y, Liao C. Weakening of M1 macrophage and bone resorption in periodontitis cystathionine γ-lyase-deficient mice. Oral Dis 2024; 30:769-779. [PMID: 36097830 DOI: 10.1111/odi.14374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 08/23/2022] [Accepted: 09/02/2022] [Indexed: 11/26/2022]
Abstract
OBJECTIVES Cystathionine-γ-lyase (CTH) has been proved to involve in inflammation and bone remolding, implying its potential role in the progression of periodontitis. This study was aimed to investigate the function of CTH and its relation to the macrophage polarization in periodontitis. MATERIALS AND METHODS Bone marrow-derived macrophages (BMDMs) from wild-type (WT) and Cth knockout (Cth-/- ) mice were stimulated with lipopolysaccharide (LPS) in vitro and pro-inflammatory cytokines were analyzed by qRT-PCR. Ligature-induced periodontitis was established on WT and Cth-/- mice. Histological analysis, tartrate-resistant acid phosphatase staining, immunostaining, and Western blot were performed to analyze the periodontium destruction and M1 macrophage polarization. RESULTS Cth expression in BMDMs was upregulated upon increasing LPS stimulation. Deletion of Cth suppressed BMDMs inflammatory response with decreased Il1b, Il6, and Tnf mRNA. Cth-/- mice with periodontitis showed attenuated bone loss and impaired osteoclast differentiation compared with WT. Moreover, Cth knockout hindered M1 macrophage polarization, reduced the expression of IL-1β, IL-6, and TNF-α in periodontally diseased tissue. CONCLUSION This study demonstrated that CTH played an important role in regulating the inflammatory responses and periodontitis tissue destruction. Importantly, Cth knockout suppressed M1 macrophages polarization in periodontitis.
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Affiliation(s)
- Sijin Li
- Department of Orthodontics, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
| | - Yongmei Hua
- Department of Orthodontics, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
| | - Chongshan Liao
- Department of Orthodontics, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
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Manandhar S, Chambers S, Miller A, Ishii I, Bhatia M. Pharmacological Inhibition and Genetic Deletion of Cystathionine Gamma-Lyase in Mice Protects against Organ Injury in Sepsis: A Key Role of Adhesion Molecules on Endothelial Cells. Int J Mol Sci 2023; 24:13650. [PMID: 37686458 PMCID: PMC10487872 DOI: 10.3390/ijms241713650] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 08/29/2023] [Accepted: 08/30/2023] [Indexed: 09/10/2023] Open
Abstract
Hydrogen sulfide (H2S), synthesized by cystathionine gamma-lyase (Cth), contributes to the inflammatory response observed in sepsis. This study examines the effect of Cth-derived H2S in adhesion molecules on endothelial cells of vital organs in mice in a cecal ligation puncture (CLP)-induced model of sepsis, using two different and complementary approaches: Cth gene deletion and pharmacological inhibition. Our findings revealed a decreased level of H2S-synthesizing activity (via Cth) in both Cth-/- mice and PAG-treated wild-type (WT) mice following CLP-induced sepsis. Both treatment groups had reduced MPO activity and expression of chemokines (MCP-1 and MIP-2α), adhesion molecules (ICAM-1 and VCAM-1), ERK1/2 phosphorylation, and NF-κB in the liver and lung compared with in CLP-WT mice. Additionally, we found that PAG treatment in Cth-/- mice had no additional effect on the expression of ERK1/2 phosphorylation, NF-κB, or the production of chemokines and adhesion molecules in the liver and lung compared to Cth-/- mice following CLP-induced sepsis. The WT group with sepsis had an increased immunoreactivity of adhesion molecules on endothelial cells in the liver and lung than the WT sham-operated control. The Cth-/-, PAG-treated WT, and Cth-/- groups of mice showed decreased immunoreactivity of adhesion molecules on endothelial cells in the liver and lung following sepsis. Inhibition of H2S production via both approaches reduced adhesion molecule expression on endothelial cells and reduced liver and lung injury in mice with sepsis. In conclusion, this study demonstrates that H2S has an important role in the pathogenesis of sepsis and validates PAG use as a suited tool for investigating the Cth/H2S-signalling axis in sepsis.
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Affiliation(s)
- Sumeet Manandhar
- Department of Pathology and Biomedical Science, University of Otago, Christchurch 8140, New Zealand; (S.M.); (S.C.); (A.M.)
| | - Stephen Chambers
- Department of Pathology and Biomedical Science, University of Otago, Christchurch 8140, New Zealand; (S.M.); (S.C.); (A.M.)
| | - Andrew Miller
- Department of Pathology and Biomedical Science, University of Otago, Christchurch 8140, New Zealand; (S.M.); (S.C.); (A.M.)
| | - Isao Ishii
- Department of Health Chemistry, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan;
| | - Madhav Bhatia
- Department of Pathology and Biomedical Science, University of Otago, Christchurch 8140, New Zealand; (S.M.); (S.C.); (A.M.)
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Akahoshi N, Hasegawa R, Yamamoto S, Takemoto R, Yoshizawa T, Kamichatani W, Ishii I. Differential Roles of Cystathionine Gamma-Lyase and Mercaptopyruvate Sulfurtransferase in Hapten-Induced Colitis and Contact Dermatitis in Mice. Int J Mol Sci 2023; 24:ijms24032659. [PMID: 36768979 PMCID: PMC9916491 DOI: 10.3390/ijms24032659] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 01/27/2023] [Accepted: 01/29/2023] [Indexed: 02/01/2023] Open
Abstract
Hydrogen sulfide (H2S) has been shown to act as both anti-inflammatory and pro-inflammatory mediators. Application of H2S donors generally protects against inflammation; however, experimental results using mice lacking endogenous H2S-producing enzymes, such as cystathionine γ-lyase (CTH) and mercaptopyruvate sulfurtransferase (MPST), are often contradictory. We herein examined two types of model hapten-induced inflammation models, colitis (an inflammatory bowel disease model of mucosal immunity) and contact dermatitis (a type IV allergic model of systemic immunity), in CTH-deficient (Cth-/-) and MPST-deficient (Mpst-/-) mice. Both mice exhibited no significant alteration from wild-type mice in trinitrobenzene sulfonic acid (Th1-type hapten)-induced colitis (a Crohn's disease model) and oxazolone (Th1/Th2 mix-type; Th2 dominant)-induced colitis (an ulcerative colitis model). However, Cth-/- (not Mpst-/-) mice displayed more exacerbated phenotypes in trinitrochlorobenzene (TNCB; Th1-type)-induced contact dermatitis, but not oxazolone, at the delayed phase (24 h post-administration) of inflammation. CTH mRNA expression was upregulated in the TNCB-treated ears of both wild-type and Mpst-/- mice. Although mRNA expression of pro-inflammatory cytokines (IL-1β and IL-6) was upregulated in both early (2 h) and delayed phases of TNCB-triggered dermatitis in all genotypes, that of Th2 (IL-4) and Treg cytokines (IL-10) was upregulated only in Cth-/- mice, when that of Th1 cytokines (IFNγ and IL-2) was upregulated in wild-type and Mpst-/- mice at the delayed phase. These results suggest that (upregulated) CTH or H2S produced by it helps maintain Th1/Th2 balance to protect against contact dermatitis.
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Cirino G, Szabo C, Papapetropoulos A. Physiological roles of hydrogen sulfide in mammalian cells, tissues and organs. Physiol Rev 2022; 103:31-276. [DOI: 10.1152/physrev.00028.2021] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
H2S belongs to the class of molecules known as gasotransmitters, which also includes nitric oxide (NO) and carbon monoxide (CO). Three enzymes are recognized as endogenous sources of H2S in various cells and tissues: cystathionine g-lyase (CSE), cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (3-MST). The current article reviews the regulation of these enzymes as well as the pathways of their enzymatic and non-enzymatic degradation and elimination. The multiple interactions of H2S with other labile endogenous molecules (e.g. NO) and reactive oxygen species are also outlined. The various biological targets and signaling pathways are discussed, with special reference to H2S and oxidative posttranscriptional modification of proteins, the effect of H2S on channels and intracellular second messenger pathways, the regulation of gene transcription and translation and the regulation of cellular bioenergetics and metabolism. The pharmacological and molecular tools currently available to study H2S physiology are also reviewed, including their utility and limitations. In subsequent sections, the role of H2S in the regulation of various physiological and cellular functions is reviewed. The physiological role of H2S in various cell types and organ systems are overviewed. Finally, the role of H2S in the regulation of various organ functions is discussed as well as the characteristic bell-shaped biphasic effects of H2S. In addition, key pathophysiological aspects, debated areas, and future research and translational areas are identified A wide array of significant roles of H2S in the physiological regulation of all organ functions emerges from this review.
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Affiliation(s)
- Giuseppe Cirino
- Department of Pharmacy, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Csaba Szabo
- Chair of Pharmacology, Section of Medicine, University of Fribourg, Switzerland
| | - Andreas Papapetropoulos
- Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece & Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation of the Academy of Athens, Greece
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Shaposhnikov MV, Zakluta AS, Zemskaya NV, Guvatova ZG, Shilova VY, Yakovleva DV, Gorbunova AA, Koval LA, Ulyasheva NS, Evgen'ev MB, Zatsepina OG, Moskalev AA. Deletions of the cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE) genes, involved in the control of hydrogen sulfide biosynthesis, significantly affect lifespan and fitness components of Drosophila melanogaster. Mech Ageing Dev 2022; 203:111656. [PMID: 35247392 DOI: 10.1016/j.mad.2022.111656] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 02/02/2022] [Accepted: 02/28/2022] [Indexed: 12/14/2022]
Abstract
The gasotransmitter hydrogen sulfide (H2S) is an important biological mediator, playing an essential role in many physiological and pathological processes. It is produced by transsulfuration - an evolutionarily highly conserved pathway for the metabolism of sulfur-containing amino acids methionine and cysteine. Cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE) enzymes play a central role in cysteine metabolism and H2S production. Here we investigated the fitness components (longevity, stress resistance, viability of preimaginal stages, and reproductive function parameters) in D. melanogaster lines containing deletions of the CBS and CSE genes. Surprisingly, in most tests, CSE deletion improved, and CBS worsened the fitness. Lines with deletion of both CBS and CSE demonstrated better stress resistance and longevity than lines with single CBS deletion. At the same time, deletion of both CBS and CSE genes causes more serious disturbances of reproductive function parameters than single CBS deletion. Thus, a complex interaction of H2S-producing pathways and cellular stress response in determining the lifespan and fitness components of the whole organism was revealed.
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Affiliation(s)
- Mikhail V Shaposhnikov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russian Federation; Institute of Biology of Komi Scientific Centre of the Ural Branch of the Russian Academy of Sciences, Syktyvkar, Russian Federation.
| | - Alexey S Zakluta
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russian Federation.
| | - Nadezhda V Zemskaya
- Institute of Biology of Komi Scientific Centre of the Ural Branch of the Russian Academy of Sciences, Syktyvkar, Russian Federation.
| | - Zulfiya G Guvatova
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russian Federation.
| | - Victoria Y Shilova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russian Federation.
| | - Daria V Yakovleva
- Institute of Biology of Komi Scientific Centre of the Ural Branch of the Russian Academy of Sciences, Syktyvkar, Russian Federation.
| | - Anastasia A Gorbunova
- Institute of Biology of Komi Scientific Centre of the Ural Branch of the Russian Academy of Sciences, Syktyvkar, Russian Federation.
| | - Liubov A Koval
- Institute of Biology of Komi Scientific Centre of the Ural Branch of the Russian Academy of Sciences, Syktyvkar, Russian Federation.
| | - Natalia S Ulyasheva
- Institute of Biology of Komi Scientific Centre of the Ural Branch of the Russian Academy of Sciences, Syktyvkar, Russian Federation.
| | - Mikhail B Evgen'ev
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russian Federation.
| | - Olga G Zatsepina
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russian Federation.
| | - Alexey A Moskalev
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russian Federation; Institute of Biology of Komi Scientific Centre of the Ural Branch of the Russian Academy of Sciences, Syktyvkar, Russian Federation; Center for Precision Genome Editing and Genetic Technologies for Biomedicine Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russian Federation.
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Diallyl Disulfide Attenuates STAT3 and NF-κB Pathway Through PPAR-γ Activation in Cerulein-Induced Acute Pancreatitis and Associated Lung Injury in Mice. Inflammation 2022; 45:45-58. [DOI: 10.1007/s10753-021-01527-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 06/24/2021] [Accepted: 07/26/2021] [Indexed: 12/16/2022]
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Kumar A, Bhatia M. Role of Hydrogen Sulfide, Substance P and Adhesion Molecules in Acute Pancreatitis. Int J Mol Sci 2021; 22:12136. [PMID: 34830018 PMCID: PMC8622943 DOI: 10.3390/ijms222212136] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 11/03/2021] [Accepted: 11/05/2021] [Indexed: 01/02/2023] Open
Abstract
Inflammation is a natural response to tissue injury. Uncontrolled inflammatory response leads to inflammatory disease. Acute pancreatitis is one of the main reasons for hospitalization amongst gastrointestinal disorders worldwide. It has been demonstrated that endogenous hydrogen sulfide (H2S), a gasotransmitter and substance P, a neuropeptide, are involved in the inflammatory process in acute pancreatitis. Cell adhesion molecules (CAM) are key players in inflammatory disease. Immunoglobulin (Ig) gene superfamily, selectins, and integrins are involved at different steps of leukocyte migration from blood to the site of injury. When the endothelial cells get activated, the CAMs are upregulated which leads to them interacting with leukocytes. This review summarizes our current understanding of the roles H2S, substance P and adhesion molecules play in acute pancreatitis.
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Affiliation(s)
| | - Madhav Bhatia
- Department of Pathology and Biomedical Science, University of Otago, Christchurch 8140, New Zealand;
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10
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Abstract
Significance: Inflammation is a normal response to injury, but uncontrolled inflammation can lead to several diseases. In recent years, research has shown endogenously synthesized hydrogen sulfide (H2S) to be a novel mediator of inflammation. This review summarizes the current understanding and recent advances of H2S role with respect to inflammation in different diseases. Recent Advances: Promising early results from clinical studies suggest an important role of H2S in human inflammatory disease. Critical Issues: Defining the precise mechanism by which H2S contributes to inflammation is a complex challenge, and there is active ongoing research that is focused on addressing this question. Most of this work has been conducted on animal models of human disease and isolated/cultured cells, and its translation to the clinic is another challenge in the area of H2S research. Future Directions: Defining the mechanism by which H2S acts as an inflammatory mediator will help us better understand different inflammatory diseases and help develop novel therapeutic approaches for these diseases.
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Affiliation(s)
- Madhav Bhatia
- Department of Pathology and Biomedical Science, University of Otago, Christchurch, Christchurch, New Zealand
| | - Ravinder Reddy Gaddam
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
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Manandhar S, Sinha P, Ejiwale G, Bhatia M. Hydrogen Sulfide and its Interaction with Other Players in Inflammation. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1315:129-159. [PMID: 34302691 DOI: 10.1007/978-981-16-0991-6_6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hydrogen sulfide (H2S) plays a vital role in human physiology and in the pathophysiology of several diseases. In addition, a substantial role of H2S in inflammation has emerged. This chapter will discuss the involvement of H2S in various inflammatory diseases. Furthermore, the contribution of reactive oxygen species (ROS), adhesion molecules, and leukocyte recruitment in H2S-mediated inflammation will be discussed. The interrelationship of H2S with other gasotransmitters in inflammation will also be examined. There is mixed literature on the contribution of H2S to inflammation due to studies reporting both pro- and anti-inflammatory actions. These apparent discrepancies in the literature could be resolved with further studies.
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Affiliation(s)
- Sumeet Manandhar
- Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand
| | - Priyanka Sinha
- Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand
| | - Grace Ejiwale
- Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand
| | - Madhav Bhatia
- Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand.
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12
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Reply to Radermacher et al. on "Serum Hydrogen Sulfide and Outcome Association in Pneumonia by the SARS-CoV-2 Coronavirus". Shock 2020; 55:139-140. [PMID: 32590691 PMCID: PMC7737862 DOI: 10.1097/shk.0000000000001603] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Abstract
This review addresses the plausibility of hydrogen sulfide (H2S) therapy for acute lung injury (ALI) and circulatory shock, by contrasting the promising preclinical results to the present clinical reality. The review discusses how the narrow therapeutic window and width, and potentially toxic effects, the route, dosing, and timing of administration all have to be balanced out very carefully. The development of standardized methods to determine in vitro and in vivo H2S concentrations, and the pharmacokinetics and pharmacodynamics of H2S-releasing compounds is a necessity to facilitate the safety of H2S-based therapies. We suggest the potential of exploiting already clinically approved compounds, which are known or unknown H2S donors, as a surrogate strategy.
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Ellmers LJ, Templeton EM, Pilbrow AP, Frampton C, Ishii I, Moore PK, Bhatia M, Richards AM, Cameron VA. Hydrogen Sulfide Treatment Improves Post-Infarct Remodeling and Long-Term Cardiac Function in CSE Knockout and Wild-Type Mice. Int J Mol Sci 2020; 21:4284. [PMID: 32560137 PMCID: PMC7352717 DOI: 10.3390/ijms21124284] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 06/10/2020] [Accepted: 06/12/2020] [Indexed: 12/14/2022] Open
Abstract
Hydrogen sulfide (H2S) is recognized as an endogenous gaseous signaling molecule generated by cystathionine γ-lyase (CSE) in cardiovascular tissues. H2S up-regulation has been shown to reduce ischemic injury, and H2S donors are cardioprotective in rodent models when administered concurrent with myocardial ischemia. We evaluated the potential utility of H2S therapy in ameliorating cardiac remodeling with administration delayed until 2 h post-infarction in mice with or without cystathionine γ-lyase gene deletion (CSE-/-). The slow-release H2S donor, GYY4137, was administered from 2 h after surgery and daily for 28 days following myocardial infarction (MI) induced by coronary artery ligation, comparing responses in CSE-/- with wild-type (WT) mice (n = 5-10/group/genotype). Measures of cardiac function and expression of key genes associated with cardiac hypertrophy, fibrosis, and apoptosis were documented in atria, ventricle, and kidney tissues. Post-MI GYY4137 administration reduced infarct area and restored cardiac function, accompanied by reduction of the elevated ventricular expression of genes mediating cardiac remodeling to near-normal levels. Few differences between WT and CSE-/- mice were observed, except CSE-/- mice had higher blood pressures, and higher atrial Mir21a expression across all treatment groups. These findings suggest endogenous CSE gene deletion does not substantially exacerbate the long-term response to MI. Moreover, the H2S donor GYY4137 administered after onset of MI preserves cardiac function and protects against adverse cardiac remodeling in both WT and CSE-deficient mice.
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Affiliation(s)
- Leigh J. Ellmers
- Christchurch Heart Institute, Department of Medicine, University of Otago, Christchurch 8140, New Zealand; (L.J.E.); (E.M.T.); (A.P.P.); (C.F.); (A.M.R.)
| | - Evelyn M. Templeton
- Christchurch Heart Institute, Department of Medicine, University of Otago, Christchurch 8140, New Zealand; (L.J.E.); (E.M.T.); (A.P.P.); (C.F.); (A.M.R.)
| | - Anna P. Pilbrow
- Christchurch Heart Institute, Department of Medicine, University of Otago, Christchurch 8140, New Zealand; (L.J.E.); (E.M.T.); (A.P.P.); (C.F.); (A.M.R.)
| | - Chris Frampton
- Christchurch Heart Institute, Department of Medicine, University of Otago, Christchurch 8140, New Zealand; (L.J.E.); (E.M.T.); (A.P.P.); (C.F.); (A.M.R.)
| | - Isao Ishii
- Laboratory of Health Chemistry, Showa Pharmaceutical University, Tokyo 194-8543, Japan;
| | - Philip K. Moore
- Department of Pharmacology, National University of Singapore, Singapore 119228, Singapore;
| | - Madhav Bhatia
- Inflammation Research Group, Department of Pathology and Biomedical Science, University of Otago, Christchurch 8140, New Zealand;
| | - A. Mark Richards
- Christchurch Heart Institute, Department of Medicine, University of Otago, Christchurch 8140, New Zealand; (L.J.E.); (E.M.T.); (A.P.P.); (C.F.); (A.M.R.)
- Cardiovascular Research Institute, National University of Singapore, Singapore 119228, Singapore
| | - Vicky A. Cameron
- Christchurch Heart Institute, Department of Medicine, University of Otago, Christchurch 8140, New Zealand; (L.J.E.); (E.M.T.); (A.P.P.); (C.F.); (A.M.R.)
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Comparing the preventive effect of sodium hydrosulfide, leptin, and curcumin against L-arginine induced acute pancreatitis in rats: role of corticosterone and inducible nitric oxide synthase. Endocr Regul 2020; 53:221-230. [PMID: 31734652 DOI: 10.2478/enr-2019-0022] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
OBJECTIVES Acute pancreatitis (AP) is a life-threatening condition. Using antioxidants in AP is insufficient and conflicting. Therefore, this study compared the effect of hydrogen sulfide (H2S) donor, sodium hydrosulfide (NaHS), leptin or curcumin pretreatment on AP induced by L-arginine. METHODS Forty adult male rats were used and classified into: 1) control; 2) AP group [each rat was intraperitoneally (i.p.) injected with 2 doses of L-arginine of 250 mg/100 g body weight (b.w.) with an interval of 1 h]; 3) NaHS+AP group (each rat was i.p. injected with 10 mg/kg b.w. of NaHS 1 h before induction of AP); 4) leptin+AP group (each rat was pretreated with 10 μg/kg b.w. of leptin 30 min before induction of AP; and 5) curcumin+AP group (in which rats were i.p. injected with 150 mg/kg b.w. of curcumin 30 min before induction of AP). Serum amylase, lipase, nitric oxide (NO), tumor necrosis factor alpha (TNF-α), and corticosterone (CORT) levels were assayed. In addition, pancreatic tissues were obtained for histopathological examination and malondialde-hyde (MDA), total antioxidant capacity (TAC), and inducible nitric oxide synthase (iNOS) levels were measured. RESULTS All AP treated groups showed significant decrease in serum levels of pancreatic enzymes, NO, and TNF-α, and pancreatic MDA and iNOS levels, while TAC levels were significantly increased. NaHS caused more limitation of inflammation than leptin and curcumin by affecting iNOS. Leptin was more potent than curcumin due to the stimulatory effect of leptin on glucocorticoid release to counteract inflammation. CONCLUSIONS NaHS was more effective in AP amelioration than the leptin and curcumin.
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Protective effect of diallyl disulfide against cerulein-induced acute pancreatitis and associated lung injury in mice. Int Immunopharmacol 2020; 80:106136. [PMID: 31991372 DOI: 10.1016/j.intimp.2019.106136] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 12/17/2019] [Accepted: 12/17/2019] [Indexed: 02/07/2023]
Abstract
Garlic (Allium sativum) - derived organosulfur compound diallyl disulfide (DADS) possesses antioxidant, anti-inflammatory and anti-cancer effects. This study was aimed to investigate the anti-inflammatory role and the underlying molecular mechanisms of DADS in cerulein-induced acute pancreatitis (AP) and associated lung injury. Administration of DADS significantly attenuated the severity of pancreatic and pulmonary inflammation by inhibiting cerulein induced serum amylase, myeloperoxidase activity (MPO) and histological changes in pancreas and lung. Furthermore, the anti-inflammatory effect of DADS was associated with the decrease in tumor necrosis factor (TNF)-α,cystathionine-γ-lyase (CSE), preprotachykinin A (PPTA), neurokinin-1-receptor (NK1R) expression and hydrogen sulfide (H2S) production in both pancreas and lung. In addition, DADS reduced caerulein-induced I-κB degradation and subsequent translocation of NF-κB in the pancreas and lung. These results show for the first time that in AP, DADS exhibits an anti-inflammatory effect by inhibiting CSE/H2S and SP/NK1R signaling and NF-кB pathway.
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17
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Cystathionine-γ-lyase (CSE) deficiency increases erythropoiesis and promotes mitochondrial electron transport via the upregulation of coproporphyrinogen III oxidase and consequent stimulation of heme biosynthesis. Biochem Pharmacol 2019; 169:113604. [PMID: 31421132 DOI: 10.1016/j.bcp.2019.08.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Accepted: 08/09/2019] [Indexed: 12/21/2022]
Abstract
BACKGROUND Hydrogen sulfide (H2S) is an endogenous gasotransmitter produced by mammalian cells. The current study investigated the potential role of H2S in the regulation of heme biosynthesis using mice deficient in cystathionine gamma-lyase (CSE), one of the three major mammalian H2S-producing enzymes. METHODS Wild-type and global CSE-/- mice, as well as mitochondria prepared from their liver were used. In vivo, arterial and venous blood gases were measured, and survival of the mice to severe global hypoxia was monitored. Ex vivo, expression of various heme biosynthetic enzymes including coproporphyrinogen oxidase (CPOX) was measured, and mitochondrial function was evaluated using Extracellular Flux Analysis. Urine samples were collected to measure the oxidized porphyrinogen intermediates. The in vivo/ex vivo studies were complemented with mitochondrial bioenergetic studies in hepatocytes in vitro. Moreover, the potential effect of H2S on the CPOX promoter was studied in cells expressing a CPOX promoter construct system. RESULTS The main findings are as follows: (1) CSE-/- mice exhibit elevated red blood cell counts and red blood cell mean corpuscular volumes compared to wild-type mice; (2) these changes are associated with elevated plasma and liver heme levels and (3) these alterations are likely due to an induction of CPOX (the sixth enzyme involved in heme biosynthesis) in CSE-/- mice. (4) Based on in vitro promoter data the promoter activation of CPOX is directly influenced by H2S, the product of CSE. With respect to the potential functional relevance of these findings, (5) the increased circulating red blood cell numbers do not correspond to any detectable alterations in blood gas parameters under resting conditions, (6) nor do they affect the hypoxia tolerance of the animals in an acute severe hypoxia model. However, there may be a functional interaction between the CSE system and the CPOX system in terms of mitochondrial bioenergetics: (7) CSE-/- hepatocytes and mitochondria isolated from them exhibit increased oxidative phosphorylation parameters, and (8) this increase is partially blunted after CPOX silencing. Although heme is essential for the biosynthesis of mitochondrial electron chain complexes, and CPOX is required for heme biosynthesis, (9) the observed functional mitochondrial alterations are not associated with detectable changes in mitochondrial electron transport chain protein expression. CONCLUSIONS The CSE system regulates the expression of CPOX and consequent heme synthesis. These effects in turn, do not influence global oxygen transport parameters, but may regulate mitochondrial electron transport.
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Lange M, Ok K, Shimberg GD, Bursac B, Markó L, Ivanović-Burmazović I, Michel SLJ, Filipovic MR. Direct Zinc Finger Protein Persulfidation by H 2 S Is Facilitated by Zn 2. Angew Chem Int Ed Engl 2019; 58:7997-8001. [PMID: 30924279 DOI: 10.1002/anie.201900823] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Indexed: 12/21/2022]
Abstract
H2 S is a gaseous signaling molecule that modifies cysteine residues in proteins to form persulfides (P-SSH). One family of proteins modified by H2 S are zinc finger (ZF) proteins, which contain multiple zinc-coordinating cysteine residues. Herein, we report the reactivity of H2 S with a ZF protein called tristetraprolin (TTP). Rapid persulfidation leading to complete thiol oxidation of TTP mediated by H2 S was observed by low-temperature ESI-MS and fluorescence spectroscopy. Persulfidation of TTP required O2 , which reacts with H2 S to form superoxide, as detected by ESI-MS, a hydroethidine fluorescence assay, and EPR spin trapping. H2 S was observed to inhibit TTP function (binding to TNFα mRNA) by an in vitro fluorescence anisotropy assay and to modulate TNFα in vivo. H2 S was unreactive towards TTP when the protein was bound to RNA, thus suggesting a protective effect of RNA.
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Affiliation(s)
- Mike Lange
- Department of Chemistry and Pharmacy, University of Erlangen-Nürnberg, 91058, Erlangen, Germany.,Current address: Center for Biotechnology and Biomedicine, Institute of Bioanalytical Chemistry, Faculty of Chemistry and Mineralogy, University of Leipzig, 04103, Leipzig, Germany
| | - Kiwon Ok
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD, 21201, USA
| | - Geoffrey D Shimberg
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD, 21201, USA
| | - Biljana Bursac
- CNRS, Institut de Biochimie et Génétique Cellulaires-UMR5095, University of Bordeaux, 33077, Bordeaux, France
| | - Lajos Markó
- Experimental and Clinical Research Center, Charité Medical Faculty and Max Delbrück Center (MDC) for Molecular Medicine, Berlin, Germany
| | | | - Sarah L J Michel
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD, 21201, USA
| | - Milos R Filipovic
- Department of Chemistry and Pharmacy, University of Erlangen-Nürnberg, 91058, Erlangen, Germany.,CNRS, Institut de Biochimie et Génétique Cellulaires-UMR5095, University of Bordeaux, 33077, Bordeaux, France
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Lange M, Ok K, Shimberg GD, Bursac B, Markó L, Ivanović‐Burmazović I, Michel SLJ, Filipovic MR. Direct Zinc Finger Protein Persulfidation by H
2
S Is Facilitated by Zn
2+. Angew Chem Int Ed Engl 2019. [DOI: 10.1002/ange.201900823] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Affiliation(s)
- Mike Lange
- Department of Chemistry and Pharmacy University of Erlangen-Nürnberg 91058 Erlangen Germany
- Current address: Center for Biotechnology and Biomedicine Institute of Bioanalytical Chemistry Faculty of Chemistry and Mineralogy University of Leipzig 04103 Leipzig Germany
| | - Kiwon Ok
- Department of Pharmaceutical Sciences University of Maryland School of Pharmacy 20 Penn Street Baltimore MD 21201 USA
| | - Geoffrey D. Shimberg
- Department of Pharmaceutical Sciences University of Maryland School of Pharmacy 20 Penn Street Baltimore MD 21201 USA
| | - Biljana Bursac
- CNRS, Institut de Biochimie et Génétique Cellulaires—UMR5095 University of Bordeaux 33077 Bordeaux France
| | - Lajos Markó
- Experimental and Clinical Research Center Charité Medical Faculty and Max Delbrück Center (MDC) for Molecular Medicine Berlin Germany
| | | | - Sarah L. J. Michel
- Department of Pharmaceutical Sciences University of Maryland School of Pharmacy 20 Penn Street Baltimore MD 21201 USA
| | - Milos R. Filipovic
- Department of Chemistry and Pharmacy University of Erlangen-Nürnberg 91058 Erlangen Germany
- CNRS, Institut de Biochimie et Génétique Cellulaires—UMR5095 University of Bordeaux 33077 Bordeaux France
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Benchoam D, Cuevasanta E, Möller MN, Alvarez B. Hydrogen Sulfide and Persulfides Oxidation by Biologically Relevant Oxidizing Species. Antioxidants (Basel) 2019; 8:antiox8020048. [PMID: 30813248 PMCID: PMC6406583 DOI: 10.3390/antiox8020048] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Revised: 02/15/2019] [Accepted: 02/19/2019] [Indexed: 12/12/2022] Open
Abstract
Hydrogen sulfide (H2S/HS–) can be formed in mammalian tissues and exert physiological effects. It can react with metal centers and oxidized thiol products such as disulfides (RSSR) and sulfenic acids (RSOH). Reactions with oxidized thiol products form persulfides (RSSH/RSS–). Persulfides have been proposed to transduce the signaling effects of H2S through the modification of critical cysteines. They are more nucleophilic and acidic than thiols and, contrary to thiols, also possess electrophilic character. In this review, we summarize the biochemistry of hydrogen sulfide and persulfides, focusing on redox aspects. We describe biologically relevant one- and two-electron oxidants and their reactions with H2S and persulfides, as well as the fates of the oxidation products. The biological implications are discussed.
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Affiliation(s)
- Dayana Benchoam
- Laboratorio de Enzimología, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay.
- Center for Free Radical and Biomedical Research, Universidad de la República, Montevideo 11800, Uruguay.
| | - Ernesto Cuevasanta
- Laboratorio de Enzimología, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay.
- Center for Free Radical and Biomedical Research, Universidad de la República, Montevideo 11800, Uruguay.
- Unidad de Bioquímica Analítica, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay.
| | - Matías N Möller
- Center for Free Radical and Biomedical Research, Universidad de la República, Montevideo 11800, Uruguay.
- Laboratorio de Fisicoquímica Biológica, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay.
| | - Beatriz Alvarez
- Laboratorio de Enzimología, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay.
- Center for Free Radical and Biomedical Research, Universidad de la República, Montevideo 11800, Uruguay.
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Fagone P, Mazzon E, Bramanti P, Bendtzen K, Nicoletti F. Gasotransmitters and the immune system: Mode of action and novel therapeutic targets. Eur J Pharmacol 2018; 834:92-102. [PMID: 30016662 DOI: 10.1016/j.ejphar.2018.07.026] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Revised: 06/29/2018] [Accepted: 07/13/2018] [Indexed: 12/12/2022]
Abstract
Gasotransmitters are a group of gaseous molecules, with pleiotropic biological functions. These molecules include nitric oxide (NO), hydrogen sulfide (H2S), and carbon monoxide (CO). Abnormal production and metabolism of these molecules have been observed in several pathological conditions. The understanding of the role of gasotransmitters in the immune system has grown significantly in the past years, and independent studies have shed light on the effect of exogenous and endogenous gasotransmitters on immune responses. Moreover, encouraging results come from the efficacy of NO-, CO- and H2S -donors in preclinical animal models of autoimmune, acute and chronic inflammatory diseases. To date, data on the influence of gasotransmitters in immunity and immunopathology are often scattered and partial, and the scarcity of clinical trials using NO-, CO- and H2S -donors, reveals that more effort is warranted. This review focuses on the role of gasotransmitters in the immune system and covers the evidences on the possible use of gasotransmitters for the treatment of inflammatory conditions.
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Affiliation(s)
- Paolo Fagone
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Emanuela Mazzon
- IRCCS Centro Neurolesi Bonino Pulejo, Stada Statale 113, C.da Casazza, 98124 Messina, Italy
| | - Placido Bramanti
- IRCCS Centro Neurolesi Bonino Pulejo, Stada Statale 113, C.da Casazza, 98124 Messina, Italy
| | - Klaus Bendtzen
- Institute for Inflammation Research, Rigshospitalet, Copenhagen, Denmark
| | - Ferdinando Nicoletti
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
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Patel D, Rathinam M, Jarvis C, Mahimainathan L, Henderson G, Narasimhan M. Role for Cystathionine γ Lyase (CSE) in an Ethanol (E)-Induced Lesion in Fetal Brain GSH Homeostasis. Int J Mol Sci 2018; 19:ijms19051537. [PMID: 29786653 PMCID: PMC5983808 DOI: 10.3390/ijms19051537] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Revised: 05/19/2018] [Accepted: 05/19/2018] [Indexed: 02/06/2023] Open
Abstract
Earlier, we reported that gestational ethanol (E) can dysregulate neuron glutathione (GSH) homeostasis partially via impairing the EAAC1-mediated inward transport of Cysteine (Cys) and this can affect fetal brain development. In this study, we investigated if there is a role for the transulfuration pathway (TSP), a critical bio-synthetic point to supply Cys in E-induced dysregulation of GSH homeostasis. These studies utilized an in utero E binge model where the pregnant Sprague⁻Dawley (SD) rat dams received five doses of E at 3.5 g/kg by gastric intubation beginning embryonic day (ED) 17 until ED19 separated by 12 h. The postnatal day 7 (PN7) alcohol model employed an oral dosing of 4 g/kg body weight split into 2 feedings at 2 h interval and an iso-caloric and iso-volumic equivalent maltose-dextrin milk solution served as controls. The in vitro model consisted of cerebral cortical neuron cultures from embryonic day (ED) 16⁻17 fetus from SD rats and differentiated neurons from ED18 rat cerebral cortical neuroblasts. E concentrations were 4 mg/mL. E induced an accumulation of cystathionine in primary cortical neurons (PCNs), 2nd trimester equivalent in utero binge, and 3rd trimester equivalent PN7 model suggesting that breakdown of cystathionine, a required process for Cys supply is impaired. This was associated with a significant reduction in cystathionine γ-lyase (CSE) protein expression in PCN (p < 0.05) and in fetal cerebral cortex in utero (53%, p < 0.05) without a change in the expression of cystathionine β-synthase (CBS). Concomitantly, E decreased Cse mRNA expression in PCNs (by 32% within 6 h of exposure, p < 0.05) and in fetal brain (33%, p < 0.05). In parallel, knock down of CSE in differentiated rat cortical neuroblasts exaggerated the E-induced ROS, GSH loss with a pronounced caspase-3 activation and cell death. These studies illustrate the importance of TSP in CSE-related maintenance of GSH and the downstream events via Cys synthesis in neurons and fetal brain.
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Affiliation(s)
- Dhyanesh Patel
- Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, TX 79430, USA.
| | - Marylatha Rathinam
- Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, TX 79430, USA.
| | - Courtney Jarvis
- Department of Microbiology and Immunology, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, TX 79430, USA.
| | - Lenin Mahimainathan
- Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, TX 79430, USA.
| | - George Henderson
- Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, TX 79430, USA.
| | - Madhusudhanan Narasimhan
- Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, TX 79430, USA.
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Santos BM, Garattini EG, Branco LG, Leite-Panissi CR, Nascimento GC. The therapeutic potential of cystathionine gamma-lyase in temporomandibular inflammation-induced orofacial hypernociception. Physiol Behav 2018; 188:128-133. [DOI: 10.1016/j.physbeh.2018.02.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Revised: 01/30/2018] [Accepted: 02/03/2018] [Indexed: 10/18/2022]
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Filipovic MR, Zivanovic J, Alvarez B, Banerjee R. Chemical Biology of H 2S Signaling through Persulfidation. Chem Rev 2018; 118:1253-1337. [PMID: 29112440 PMCID: PMC6029264 DOI: 10.1021/acs.chemrev.7b00205] [Citation(s) in RCA: 691] [Impact Index Per Article: 98.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Signaling by H2S is proposed to occur via persulfidation, a posttranslational modification of cysteine residues (RSH) to persulfides (RSSH). Persulfidation provides a framework for understanding the physiological and pharmacological effects of H2S. Due to the inherent instability of persulfides, their chemistry is understudied. In this review, we discuss the biologically relevant chemistry of H2S and the enzymatic routes for its production and oxidation. We cover the chemical biology of persulfides and the chemical probes for detecting them. We conclude by discussing the roles ascribed to protein persulfidation in cell signaling pathways.
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Affiliation(s)
- Milos R. Filipovic
- Univeristy of Bordeaux, IBGC, UMR 5095, F-33077 Bordeaux, France
- CNRS, IBGC, UMR 5095, F-33077 Bordeaux, France
| | - Jasmina Zivanovic
- Univeristy of Bordeaux, IBGC, UMR 5095, F-33077 Bordeaux, France
- CNRS, IBGC, UMR 5095, F-33077 Bordeaux, France
| | - Beatriz Alvarez
- Laboratorio de Enzimología, Facultad de Ciencias and Center for Free Radical and Biomedical Research, Universidad de la Republica, 11400 Montevideo, Uruguay
| | - Ruma Banerjee
- Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109-0600, United States
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Zimmermann KK, Spassov SG, Strosing KM, Ihle PM, Engelstaedter H, Hoetzel A, Faller S. Hydrogen Sulfide Exerts Anti-oxidative and Anti-inflammatory Effects in Acute Lung Injury. Inflammation 2018; 41:249-259. [PMID: 29098482 DOI: 10.1007/s10753-017-0684-4] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Acute lung injury (ALI) caused by septic stimuli is still a major problem in critical care patients. We have shown previously that hydrogen sulfide (H2S) mediates anti-inflammatory and lung protective effects. In the present study, we aimed to investigate the underlying mechanisms. C57BL/6N mice were instilled with lipopolysaccharide (LPS) intranasally in the absence or presence of inhaled H2S for 6 h. LPS instillation led to alveolar wall thickening, an elevated ALI score, increased neutrophil transmigration, and elevated interleukin-1β cytokine release into the bronchoalveolar lavage fluid. In contrast, H2S inhalation prevented lung injury and inflammation despite LPS treatment. Moreover, H2S inhalation significantly inhibited protein expression of cystathionine-β-synthetase, heat shock protein 70, phosphorylated p38 MAP kinase, NADPH oxidase 2, and the formation of reactive oxygen species (ROS) in LPS-challenged animals. In conclusion, H2S prevents LPS-induced ALI by inhibition of pro-inflammatory and oxidative responses via the concerted attenuation of stress protein, MAP kinase, and ROS signaling pathways.
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Affiliation(s)
- Kornelia K Zimmermann
- Department of Anesthesiology and Critical Care Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany
| | - Sashko G Spassov
- Department of Anesthesiology and Critical Care Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany
| | - Karl M Strosing
- Department of Anesthesiology and Critical Care Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany
| | - Paul M Ihle
- Department of Anesthesiology and Critical Care Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany
| | - Helen Engelstaedter
- Department of Anesthesiology and Critical Care Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany
| | - Alexander Hoetzel
- Department of Anesthesiology and Critical Care Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany
| | - Simone Faller
- Department of Anesthesiology and Critical Care Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany.
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Szabo C, Papapetropoulos A. International Union of Basic and Clinical Pharmacology. CII: Pharmacological Modulation of H 2S Levels: H 2S Donors and H 2S Biosynthesis Inhibitors. Pharmacol Rev 2017; 69:497-564. [PMID: 28978633 PMCID: PMC5629631 DOI: 10.1124/pr.117.014050] [Citation(s) in RCA: 304] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Over the last decade, hydrogen sulfide (H2S) has emerged as an important endogenous gasotransmitter in mammalian cells and tissues. Similar to the previously characterized gasotransmitters nitric oxide and carbon monoxide, H2S is produced by various enzymatic reactions and regulates a host of physiologic and pathophysiological processes in various cells and tissues. H2S levels are decreased in a number of conditions (e.g., diabetes mellitus, ischemia, and aging) and are increased in other states (e.g., inflammation, critical illness, and cancer). Over the last decades, multiple approaches have been identified for the therapeutic exploitation of H2S, either based on H2S donation or inhibition of H2S biosynthesis. H2S donation can be achieved through the inhalation of H2S gas and/or the parenteral or enteral administration of so-called fast-releasing H2S donors (salts of H2S such as NaHS and Na2S) or slow-releasing H2S donors (GYY4137 being the prototypical compound used in hundreds of studies in vitro and in vivo). Recent work also identifies various donors with regulated H2S release profiles, including oxidant-triggered donors, pH-dependent donors, esterase-activated donors, and organelle-targeted (e.g., mitochondrial) compounds. There are also approaches where existing, clinically approved drugs of various classes (e.g., nonsteroidal anti-inflammatories) are coupled with H2S-donating groups (the most advanced compound in clinical trials is ATB-346, an H2S-donating derivative of the non-steroidal anti-inflammatory compound naproxen). For pharmacological inhibition of H2S synthesis, there are now several small molecule compounds targeting each of the three H2S-producing enzymes cystathionine-β-synthase (CBS), cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase. Although many of these compounds have their limitations (potency, selectivity), these molecules, especially in combination with genetic approaches, can be instrumental for the delineation of the biologic processes involving endogenous H2S production. Moreover, some of these compounds (e.g., cell-permeable prodrugs of the CBS inhibitor aminooxyacetate, or benserazide, a potentially repurposable CBS inhibitor) may serve as starting points for future clinical translation. The present article overviews the currently known H2S donors and H2S biosynthesis inhibitors, delineates their mode of action, and offers examples for their biologic effects and potential therapeutic utility.
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Affiliation(s)
- Csaba Szabo
- Department of Anesthesiology, The University of Texas Medical Branch, Galveston, Texas (C.S.); Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Zografou, Greece (A.P.); and Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece (A.P.)
| | - Andreas Papapetropoulos
- Department of Anesthesiology, The University of Texas Medical Branch, Galveston, Texas (C.S.); Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Zografou, Greece (A.P.); and Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece (A.P.)
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Cystathionine-gamma-lyase deficient mice are protected against the development of multiorgan failure and exhibit reduced inflammatory response during burn. Burns 2017; 43:1021-1033. [PMID: 28318752 DOI: 10.1016/j.burns.2017.02.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Revised: 02/07/2017] [Accepted: 02/19/2017] [Indexed: 01/08/2023]
Abstract
Considering the role of H2S in critical illness, the aim of this study was to compare the outcome of burn in wild-type mice and in mice deficient in CSE, one of the principal mammalian H2S-generating enzymes. Animals were subjected to scald burn. Outcome variables included indices of organ injury, clinical chemistry parameters and plasma levels of inflammatory mediators. Plasma levels of H2S significantly increased in response to burn in wild-type mice, but remained unchanged in CSE-/- mice. Expression of the three H2S-producing enzymes (CSE, CBS and 3-MST) in the lung and liver, and the capacity of tissue homogenates to produce H2S, however, was not affected by burn. In CSE deficient mice there was a significant amelioration of burn-induced accumulation of myeloperoxidase levels in heart, lung, liver and kidney and significantly lower degree of malon dialdehyde accumulation in the heart, lung and kidney than in wild-type mice. CSE deficient mice, compared to wild-type mice, showed a significant attenuation of the burn-induced elevation in circulating alkaline aminotransferase and blood urea nitrogen and creatinine levels, indicative of protective effects of CSE deficiency against burn-induced hepatic, and renal functional impairment. Multiple burn-induced inflammatory mediators (TNF-α, IL-1β, IL-4, IL-6, IL-10 and IL-12) were significantly lower in the plasma of CSE-/- animals after burn than in the plasma of wild-type controls subjected to burns. In conclusion, CSE deficiency improves organ function and attenuates the inflammatory response in a murine model of burn.
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Muniraj N, Stamp LK, Badiei A, Hegde A, Cameron V, Bhatia M. Hydrogen sulfide acts as a pro-inflammatory mediator in rheumatic disease. Int J Rheum Dis 2017; 20:182-189. [PMID: 25196086 DOI: 10.1111/1756-185x.12472] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
OBJECTIVE Hydrogen sulfide (H2 S) is a gaseous mediator produced in the body. In experimental models, endogenously produced H2 S has been shown to have pro-inflammatory effects. The aim of this study was to investigate whether H2 S is present in three common rheumatic diseases, rheumatoid arthritis (RA), gout and osteoarthritis (OA) and to determine if H2 S levels correlate with disease activity. METHODS Patients with RA, gout, OA, and healthy controls (n = 30 each) were recruited. Plasma and where possible, synovial fluid (SF), were obtained. Levels of H2 S and interleukin-6 (IL-6) (a known inflammatory marker as a positive control) were determined and assessed for their relationship with disease activity. RESULTS SF-H2 S levels were significantly elevated in both RA and gout when compared to respective plasma levels. Plasma levels of H2 S were not different from those in healthy controls in patients with either RA or gout. In OA, plasma levels of H2 S were significantly elevated compared to healthy controls. In RA, SF-H2 S levels correlated with Disease Activity Score (DAS)-28 and tender joint count. CONCLUSION H2 S is present in the joint and acts as a pro-inflammatory mediator in rheumatic diseases. H2 S may be a novel therapeutic target for these conditions.
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Affiliation(s)
- Nethaji Muniraj
- Department of Pathology, University of Otago, Christchurch, New Zealand
| | - Lisa K Stamp
- Department of Medicine, University of Otago, Christchurch, New Zealand
| | - Alireza Badiei
- Department of Pathology, University of Otago, Christchurch, New Zealand
| | - Akhil Hegde
- Department of Pathology, University of Otago, Christchurch, New Zealand
| | - Vicky Cameron
- Department of Medicine, University of Otago, Christchurch, New Zealand
| | - Madhav Bhatia
- Department of Pathology, University of Otago, Christchurch, New Zealand
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Rose P, Moore PK, Zhu YZ. H 2S biosynthesis and catabolism: new insights from molecular studies. Cell Mol Life Sci 2016; 74:1391-1412. [PMID: 27844098 PMCID: PMC5357297 DOI: 10.1007/s00018-016-2406-8] [Citation(s) in RCA: 103] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Revised: 10/07/2016] [Accepted: 11/01/2016] [Indexed: 02/06/2023]
Abstract
Hydrogen sulfide (H2S) has profound biological effects within living organisms and is now increasingly being considered alongside other gaseous signalling molecules, such as nitric oxide (NO) and carbon monoxide (CO). Conventional use of pharmacological and molecular approaches has spawned a rapidly growing research field that has identified H2S as playing a functional role in cell-signalling and post-translational modifications. Recently, a number of laboratories have reported the use of siRNA methodologies and genetic mouse models to mimic the loss of function of genes involved in the biosynthesis and degradation of H2S within tissues. Studies utilising these systems are revealing new insights into the biology of H2S within the cardiovascular system, inflammatory disease, and in cell signalling. In light of this work, the current review will describe recent advances in H2S research made possible by the use of molecular approaches and genetic mouse models with perturbed capacities to generate or detoxify physiological levels of H2S gas within tissues.
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Affiliation(s)
- Peter Rose
- School of Life Science, University of Lincoln, Brayford Pool, Lincoln, Lincolnshire, LN6 7TS, UK. .,State Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy, Macau University of Science and Technology, Macau, China.
| | - Philip K Moore
- Department of Pharmacology, National University of Singapore, Lee Kong Chian Wing, UHL #05-02R, 21 Lower Kent Ridge Road, Singapore, 119077, Singapore
| | - Yi Zhun Zhu
- State Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy, Macau University of Science and Technology, Macau, China
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Ji L, Li L, Qu F, Zhang G, Wang Y, Bai X, Pan S, Xue D, Wang G, Sun B. Hydrogen sulphide exacerbates acute pancreatitis by over-activating autophagy via AMPK/mTOR pathway. J Cell Mol Med 2016; 20:2349-2361. [PMID: 27419805 PMCID: PMC5134374 DOI: 10.1111/jcmm.12928] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2016] [Accepted: 06/12/2016] [Indexed: 01/14/2023] Open
Abstract
Previously, we have shown that hydrogen sulphide (H2 S) might be pro-inflammatory during acute pancreatitis (AP) through inhibiting apoptosis and subsequently favouring a predominance of necrosis over apoptosis. In this study, we sought to investigate the detrimental effects of H2 S during AP specifically with regard to its regulation on the impaired autophagy. The incubated levels of H2 S were artificially intervened by an administration of sodium hydrosulphide (NaHS) or DL-propargylglycine (PAG) after AP induction. Accumulation of autophagic vacuoles and pre-mature activation of trypsinogen within acini, which indicate the impairment of autophagy during AP, were both exacerbated by treatment with NaHS but attenuated by treatment with PAG. The regulation that H2 S exerted on the impaired autophagy during AP was further attributed to over-activation of autophagy rather than hampered autophagosome-lysosome fusion. To elucidate the molecular mechanism that underlies H2 S-mediated over-activation of autophagy during AP, we evaluated phosphorylations of AMP-activated protein kinase (AMPK), AKT and mammalian target of rapamycin (mTOR). Furthermore, Compound C (CC) was introduced to determine the involvement of mTOR signalling by evaluating phosphorylations of downstream effecters including p70 S6 kinase (P70S6k) and UNC-51-Like kinase 1 (ULK1). Our findings suggested that H2 S exacerbated taurocholate-induced AP by over-activating autophagy via activation of AMPK and subsequently, inhibition of mTOR. Thus, an active suppression of H2 S to restore over-activated autophagy might be a promising therapeutic approach against AP-related injuries.
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Affiliation(s)
- Liang Ji
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Le Li
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Fengzhi Qu
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Guangquan Zhang
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yongwei Wang
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xuewei Bai
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Shangha Pan
- Central Laboratory, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Dongbo Xue
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Gang Wang
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Bei Sun
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
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Role of Cystathionine Gamma-Lyase in Immediate Renal Impairment and Inflammatory Response in Acute Ischemic Kidney Injury. Sci Rep 2016; 6:27517. [PMID: 27273292 PMCID: PMC4897642 DOI: 10.1038/srep27517] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Accepted: 05/20/2016] [Indexed: 12/12/2022] Open
Abstract
Hydrogen sulfide (H2S) is known to act protectively during renal ischemia/reperfusion injury (IRI). However, the role of the endogenous H2S in acute kidney injury (AKI) is largely unclear. Here, we analyzed the role of cystathionine gamma-lyase (CTH) in acute renal IRI using CTH-deficient (Cth−/−) mice whose renal H2S levels were approximately 50% of control (wild-type) mice. Although levels of serum creatinine and renal expression of AKI marker proteins were equivalent between Cth−/− and control mice, histological analysis revealed that IRI caused less renal tubular damage in Cth−/− mice. Flow cytometric analysis revealed that renal population of infiltrated granulocytes/macrophages was equivalent in these mice. However, renal expression levels of certain inflammatory cytokines/adhesion molecules believed to play a role in IRI were found to be lower after IRI only in Cth−/− mice. Our results indicate that the systemic CTH loss does not deteriorate but rather ameliorates the immediate AKI outcome probably due to reduced inflammatory responses in the kidney. The renal expression of CTH and other H2S-producing enzymes was markedly suppressed after IRI, which could be an integrated adaptive response for renal cell protection.
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Korean red ginseng ameliorated experimental pancreatitis through the inhibition of hydrogen sulfide in mice. Pancreatology 2016; 16:326-36. [PMID: 26992849 DOI: 10.1016/j.pan.2016.02.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2015] [Revised: 02/25/2016] [Accepted: 02/26/2016] [Indexed: 02/08/2023]
Abstract
AIM Effective therapy to treat acute pancreatitis (AP) or to prevent its recurrence/complication is still not available. Based on previous results that suggest that: i) hydrogen sulfide (H2S) levels were significantly increased in pancreatitis and gastritis and ii) Korean red ginseng (KRG) efficiently attenuated Helicobacter pylori-associated gastritis through the suppressive actions of H2S, we hypothesized that KRG can ameliorate experimental pancreatitis through suppression of H2S generation. METHODS C57BL/6 mice were pre-administered KRG and then subjected to cerulein injection or pancreatic duct ligation (PDL) to induce pancreatitis. Blood and pancreas tissues were collected and processed to measure serum levels of amylase, lipase and myeloperoxidase and the concentration of H2S and the levels of various inflammatory cytokine in pancreatic tissues of mice with induced AP. RESULTS KRG significantly inhibited NaHS-induced COX-2 and TNF-α mRNA in pancreatic cells, but dl-propargylglycine did not. KRG ameliorated cerulein-induced edematous pancreatitis accompanied with significant inactivation of NF-κB and JNK in pancreatic tissues of C57BL/6 mice (p < 0.001) and also significantly ameliorated PDL-induced necrotizing pancreatitis (p<0.01); in both conditions, the significant suppression of H2S resulting from KRG pretreatment afforded rescuing outcomes. Along with suppressed levels of H2S consequent to depressed expressions of CBS and CSE mRNA, KRG administration efficiently decreased the serum level of amylase, lipase, and myeloperoxidase and the expression of inflammatory cytokines in animal models of mild or severe AP. CONCLUSIONS These results provide evidence for the preventive and therapeutic roles of KRG against AP mediated by H2S suppression.
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Badiei A, Chambers ST, Gaddam RR, Bhatia M. Cystathionine-γ-lyase gene silencing with siRNA in monocytes/ macrophages attenuates inflammation in cecal ligation and puncture-induced sepsis in the mouse. J Biosci 2016; 41:87-95. [PMID: 26949091 DOI: 10.1007/s12038-016-9598-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Hydrogen sulphide is an endogenous inflammatory mediator produced by cystathionine-γ-lyase (CSE) in macrophages. To determine the role of H2S and macrophages in sepsis, we used small interference RNA (siRNA) to target the CSE gene and investigated its effect in a mouse model of sepsis. Cecal ligation puncture (CLP)-induced sepsis is characterized by increased levels of myeloperoxidase (MPO) activity, morphological changes in liver and pro-inflammatory cytokines and chemokines in the liver and lung. SiRNA treatment attenuated inflammation in the liver and lungs of mice following CLP-induced sepsis. Liver MPO activity increased in CLP-induced sepsis and treatment with siRNA significantly reduced this. Similarly, lung MPO activity increased following induction of sepsis with CLP while siRNA treatment significantly reduced MPO activity. Liver and lung cytokine and chemokine levels in CLP-induced sepsis reduced following treatment with siRNA. These findings show a crucial pro-inflammatory role for H2S synthesized by CSE in macrophages in sepsis and suggest CSE gene silencing with siRNA as a potential therapeutic approach for this condition.
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Affiliation(s)
- A Badiei
- Department of Pathology, University of Otago, Christchurch, New Zealand
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Hydrogen Sulfide and Cellular Redox Homeostasis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2016; 2016:6043038. [PMID: 26881033 PMCID: PMC4736422 DOI: 10.1155/2016/6043038] [Citation(s) in RCA: 162] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/26/2015] [Revised: 11/23/2015] [Accepted: 12/01/2015] [Indexed: 01/06/2023]
Abstract
Intracellular redox imbalance is mainly caused by overproduction of reactive oxygen species (ROS) or weakness of the natural antioxidant defense system. It is involved in the pathophysiology of a wide array of human diseases. Hydrogen sulfide (H2S) is now recognized as the third “gasotransmitters” and proved to exert a wide range of physiological and cytoprotective functions in the biological systems. Among these functions, the role of H2S in oxidative stress has been one of the main focuses over years. However, the underlying mechanisms for the antioxidant effect of H2S are still poorly comprehended. This review presents an overview of the current understanding of H2S specially focusing on the new understanding and mechanisms of the antioxidant effects of H2S based on recent reports. Both inhibition of ROS generation and stimulation of antioxidants are discussed. H2S-induced S-sulfhydration of key proteins (e.g., p66Shc and Keap1) is also one of the focuses of this review.
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Badiei A, Chambers ST, Gaddam RR, Fraser R, Bhatia M. Cystathionine-gamma-lyase gene silencing with siRNA in monocytes/macrophages protects mice against acute pancreatitis. Appl Microbiol Biotechnol 2016; 100:337-346. [PMID: 26411454 DOI: 10.1007/s00253-015-6989-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2015] [Revised: 08/24/2015] [Accepted: 09/04/2015] [Indexed: 12/29/2022]
Abstract
Hydrogen sulphide (H2S) is an endogenous inflammatory mediator produced by cystathionine-γ-lyase (CSE) in monocytes/macrophages. To determine the role of H2S and macrophages in inflammation, we used small interference RNA (siRNA) to target the CSE gene and investigated its effect in a mouse model of acute pancreatitis. Acute pancreatitis is characterised by increased levels of plasma amylase, myeloperoxidase (MPO) activity and pro-inflammatory cytokines and chemokines in the pancreas and lung. SiRNA treatment attenuated inflammation in the pancreas and lungs of mice following caerulein-induced acute pancreatitis. MPO activity increased in caerulein-induced acute pancreatitis (16.21 ± 3.571 SD fold increase over control) and treatment with siRNA significantly reduced this (mean 3.555 ± 2.522 SD fold increase over control) (p < 0.0001). Similarly, lung MPO activity increased following treatment with caerulein (3.56 ± 0.941 SD fold increase over control) while siRNA treatment significantly reduced MPO activity (0.8243 ± 0.4353 SD fold increase over control) (p < 0.0001). Caerulein treatment increased plasma amylase activity (7094 ± 207 U/l) and this significantly decreased following siRNA administration (5895 ± 115 U/l) (p < 0.0001). Cytokine and chemokine levels in caerulein-induced acute pancreatitis reduced following treatment with siRNA. For example, siRNA treatment significantly decreased pancreatic and lung monocyte chemoattractant protein (MCP)-1 (169.8 ± 59.75 SD; 90.01 ± 46.97 SD pg/ml, respectively) compared to caerulein-treated mice (324.7 ± 103.9 SD; 222.8 ± 85.37 SD pg/ml, pancreas and lun,g respectively) (p < 0.0001). These findings show a crucial pro-inflammatory role for H2S synthesised by CSE in macrophages in acute pancreatitis and suggest CSE gene silencing with siRNA as a potential therapeutic approach for this condition.
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Affiliation(s)
- A Badiei
- Inflammation Research Group, Department of Pathology, University of Otago, 2 Riccarton Avenue, P.O. Box 4345, Christchurch, 8140, New Zealand
| | - S T Chambers
- Infection Research Group, Department of Pathology, University of Otago, Christchurch, New Zealand
| | - R R Gaddam
- Inflammation Research Group, Department of Pathology, University of Otago, 2 Riccarton Avenue, P.O. Box 4345, Christchurch, 8140, New Zealand
| | - R Fraser
- Inflammation Research Group, Department of Pathology, University of Otago, 2 Riccarton Avenue, P.O. Box 4345, Christchurch, 8140, New Zealand
| | - M Bhatia
- Inflammation Research Group, Department of Pathology, University of Otago, 2 Riccarton Avenue, P.O. Box 4345, Christchurch, 8140, New Zealand.
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Abstract
Inflammation is a response to traumatic, infectious, post-ischemic, toxic, or autoimmune injury. However, uncontrolled inflammation can lead to disease, and inflammation is now believed to be responsible for several disease conditions. Research in our laboratory has shown that hydrogen sulfide (H2S) acts as a novel mediator of inflammation. At present, work in several research groups worldwide is focused on determining the role of H2S in inflammation. H2S has been implicated in different inflammatory conditions. Most of this research involved working with animal models of disease and in vitro systems. Recent research, however, points to a role of H2S in clinical inflammatory disease as well. This chapter describes our current understanding of the role of H2S in inflammation.
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Affiliation(s)
- Madhav Bhatia
- Department of Pathology, University of Otago, Christchurch, 2 Riccarton Avenue, 4345, Christchurch, 8140, New Zealand,
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Gaddam RR, Ang AD, Badiei A, Chambers ST, Bhatia M. Alteration of the renin-angiotensin system in caerulein induced acute pancreatitis in the mouse. Pancreatology 2015; 15:647-653. [PMID: 26444748 DOI: 10.1016/j.pan.2015.09.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2015] [Revised: 08/28/2015] [Accepted: 09/15/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND The objective of this study was to determine if RAS bioactive enzymes and peptides are perturbed in acute pancreatitis and associated lung injury. METHODS The intervention group of mice were treated with ten hourly intraperitoneal (i.p.) injections of caerulein (50 μg/kg) to induce acute pancreatitis. Animals were euthanized, samples of pancreas, lung and blood were collected, and plasma was prepared and stored for subsequent analysis. ACE and ACE2 activities were determined by spectrofluorometric assay. ACE, ACE2, Ang II and Ang-(1-7) levels were quantified by ELISA. RESULTS There was a significant decrease in ACE2 enzymatic activity in pancreatic and lung tissues of mice with acute pancreatitis. In contrast, there were no significant changes in measured levels of ACE and ACE2 in the pancreas, and lung or activity of ACE in pancreatic and lung tissue following acute pancreatitis. There were no significant differences in the activities and levels of circulating ACE and ACE2 following acute pancreatitis. The ACE to ACE2 activity ratio was markedly increased in pancreatic and lung tissues of mice with acute pancreatitis. No significant changes were observed in the levels of Ang II except for a decrease in lung tissue. No changes were observed in Ang-(1-7) levels in pancreas, lung and plasma between the groups. The Ang II to Ang-(1-7) ratio was increased in the pancreas but was decreased in the lung following caerulein treatment. CONCLUSION These data suggest dysregulation of RAS in acute pancreatitis as evidenced by altered Ang II/Ang-(1-7) levels induced by the imbalance of ACE/ACE2 activity.
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Affiliation(s)
| | - Abel Damien Ang
- Department of Pathology, University of Otago, Christchurch, New Zealand
| | - Alireza Badiei
- Department of Pathology, University of Otago, Christchurch, New Zealand
| | | | - Madhav Bhatia
- Department of Pathology, University of Otago, Christchurch, New Zealand.
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Hydrogen sulfide in pharmacology and medicine – An update. Pharmacol Rep 2015; 67:647-58. [DOI: 10.1016/j.pharep.2015.01.005] [Citation(s) in RCA: 105] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2014] [Accepted: 01/05/2015] [Indexed: 12/17/2022]
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Huang S, Li H, Ge J. A cardioprotective insight of the cystathionine γ-lyase/hydrogen sulfide pathway. IJC HEART & VASCULATURE 2015; 7:51-57. [PMID: 28785645 PMCID: PMC5497180 DOI: 10.1016/j.ijcha.2015.01.010] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2014] [Revised: 11/29/2014] [Accepted: 01/20/2015] [Indexed: 11/29/2022]
Abstract
Traditionally, hydrogen sulfide (H2S) was simply considered as a toxic and foul smelling gas, but recently H2S been brought into the spot light of cardiovascular research and development. Since the 1990s, H2S has been mounting evidence of physiological properties such as immune modification, vascular relaxation, attenuation of oxidative stress, inflammatory mitigation, and angiogenesis. H2S has since been recognized as the third physiological gaseous signaling molecule, along with CO and NO [65,66]. H2S is produced endogenously through several key enzymes, including cystathionine β-lyase (CBE), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (MST)/cysteine aminotransferase (CAT). These specific enzymes are expressed accordingly in various organ systems and CSE is the predominant H2S-producing enzyme in the cardiovascular system. The cystathionine γ-lyase (CSE)/H2S pathway has demonstrated various cardioprotective effects, including anti-atherosclerosis, anti-hypertension, pro-angiogenesis, and attenuation of myocardial ischemia-reperfusion injury. CSE exhibits its anti-atherosclerotic effect through 3 mechanisms, namely reduction of chemotactic factor inter cellular adhesion molecule-1 (ICAM-1) and CX3CR1, inhibition of macrophage lipid uptake, and induction of smooth muscle cell apoptosis via MAPK pathway. The CSE/H2S pathway's anti-hypertensive properties are demonstrated via aortic vasodilation through several mechanisms, including the direct stimulation of KATP channels of vascular smooth muscle cells (VSMCs), induction of MAPK pathway, and reduction of homocysteine buildup. Also, CSE/H2S pathway plays an important role in angiogenesis, particularly in increased endothelial cell growth and migration, and in increased vascular network length. In myocardial ischemia-reperfusion injuries, CSE/H2S pathway has shown a clear cardioprotective effect by preserving mitochondria function, increasing antioxidant production, and decreasing infarction injury size. However, CSE/H2S pathway's role in inflammation mitigation is still clouded, due to both pro and anti-inflammatory results presented in the literature, depending on the concentration and form of H2S used in specific experiment models.
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Key Words
- Akt, protein kinase B
- Angiogenesis
- Atherosclerosis
- BCA, brachiocephalic artery
- CAM, chorioallantoic membrane
- CAT, cysteine aminotransferase
- CBS, cystathionine β-lyase
- CLP, cecal ligation and puncture
- CSE KO, CSE knock out
- CSE, cystathionine γ-lyase
- CTO, chronic total occlusion
- CX3CL1, chemokine (C-X3-C Motif) ligand 1
- CX3CR1, CX3C chemokine receptor 1
- Cystathionine γ-lyase
- EC, endothelial cell
- ERK, extracellular signal-regulated kinase
- GAPDH, glyceraldehyde 3-phosphate dehydrogenase
- GSH-Px, glutathione peroxidase
- GYY4137, morpholin-4-Ium-4-methoxyphenyl(morpholino) phosphinodithioate
- H2S, hydrogen sulfide
- HUVECs, human umbilical vein endothelial cells
- Hydrogen sulfide
- ICAM-1, inter cellular adhesion molecule-1
- IMT, intima–media complex thickness
- Ischemia–reperfusion injury
- LPS, lipopolysaccharide
- MAPK, mitogen-activated protein kinase
- MPO, myeloperoxidase
- MST, 3-mercaptopyruvate sulfurtransferase
- NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells
- Nrf2, nuclear factor erythroid 2-related factor 2
- PAG, DL-propagylglycine
- PPAR-γ, peroxisome proliferator-activated receptor
- PTPN1, protein tyrosine phosphatase, non-receptor type 1
- ROS, reactive oxygen species
- S-diclofenac, 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid 4-(3H-1,2-dithiole-3-thione-5-Yl)-phenyl ester
- SAH, S-adenosylhomocysteine
- SAM, S-adenosylmethionine
- SMCs, smooth muscle cells
- SOD, superoxide dismutase
- VEGF, vascular endothelial growth factor
- VSMCs, vascular smooth muscle cells
- Vasorelaxation
- l-NAME, NG-nitro-l-arginine methyl ester
- oxLDL, oxidized low density lipoprotein
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Affiliation(s)
- Steve Huang
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Hua Li
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Departments of Physiology and Medicine/CVRL, UCLA School of Medicine, Los Angeles, CA 90095, USA
| | - Junbo Ge
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
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Identification of key transcription factors in caerulein-induced pancreatitis through expression profiling data. Mol Med Rep 2015; 12:2570-6. [PMID: 25975747 PMCID: PMC4464163 DOI: 10.3892/mmr.2015.3773] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2014] [Accepted: 11/07/2014] [Indexed: 11/16/2022] Open
Abstract
The current study aimed to isolate key transcription factors (TFs) in caerulein-induced pancreatitis, and to identify the difference between wild type and Mist1 knockout (KO) mice, in order to elucidate the contribution of Mist1 to pancreatitis. The gene profile of GSE3644 was downloaded from the Gene Expression Omnibus database then analyzed using the t-test. The isolated differentially expressed genes (DEGs) were mapped into a transcriptional regulatory network derived from the Integrated Transcription Factor Platform database and in the network, the interaction pairs involving at least one DEG were screened. Fisher’s exact test was used to analyze the functional enrichment of the target genes. A total of 1,555 and 3,057 DEGs were identified in the wild type and Mist1KO mice treated with caerulein, respectively. DEGs screened in Mist1KO mice were predominantly enriched in apoptosis, mitogen-activated protein kinase signaling and other cancer-associated pathways. A total of 188 and 51 TFs associated with pathopoiesis were isolated in Mist1KO and wild type mice, respectively. Out of the top 10 TFs (ranked by P-value), 7 TFs, including S-phase kinase-associated protein 2 (Skp2); minichromosome maintenance complex component 3 (Mcm3); cell division cycle 6 (Cdc6); cyclin B1 (Ccnb1); mutS homolog 6 (Msh6); cyclin A2 (Ccna2); and cyclin B2 (Ccnb2), were expressed in the two types of mouse. These TFs were predominantly involved in phosphorylation, DNA replication, cell division and DNA mismatch repair. In addition, specific TFs, including minichromosome maintenance complex component 7 (Mcm7); lymphoid-specific helicase (Hells); and minichromosome maintenance complex component 6 (Mcm6), that function in the unwinding of DNA were identified to participate in Mist1KO pancreatitis. The DEGs, including Cdc6, Mcm6, Msh6 and Wdr1 are closely associated with the regulation of caerulein-induced pancreatitis. Furthermore, other identified TFs were also involved in this type of regulation.
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Abstract
Pharmacological concentrations of H2S donors inhibit some T cell functions by inhibiting mitochondrial function, but evidence is also emerging that H2S at physiological concentrations produced via chemical sources and endogenously is a positive physiological mediator of T cell function. Expression of the H2S biosynthetic enzymes cystathionine γ-lyase (CSE) and cystathionine β-synthase (CBS) is induced in response to T cell receptor signaling. Inhibiting the induction of these enzymes limits T cell activation and proliferation, which can be overcome by exposure to exogenous H2S at submicromolar concentrations. Exogenous H2S at physiological concentrations increases the ability of T cells to form an immunological synapse by altering cytoskeletal actin dynamics and increasing the reorientation of the microtubule-organizing center. Downstream, H2S enhances T cell receptor-dependent induction of CD69, CD25, and Interleukin-2 (IL-2) gene expression. The T cell stimulatory activity of H2S is enhanced under hypoxic conditions that limit its oxidative metabolism by mitochondrial and nonenzymatic processes. Studies of the receptor CD47 have revealed the first endogenous inhibitory signaling pathway that regulates H2S signaling in T cells. Binding of the secreted protein thrombospondin-1 to CD47 elicits signals that block the stimulatory activity of exogenous H2S on T cell activation and limit the induction of CSE and CBS gene expression. CD47 signaling thereby inhibits T cell receptor-mediated T cell activation.
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Du Q, Wang C, Zhang N, Li G, Zhang M, Li L, Zhang Q, Zhang J. In vivo study of the effects of exogenous hydrogen sulfide on lung mitochondria in acute lung injury in rats. BMC Anesthesiol 2014; 14:117. [PMID: 25550681 PMCID: PMC4279795 DOI: 10.1186/1471-2253-14-117] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Accepted: 12/11/2014] [Indexed: 01/11/2023] Open
Abstract
Background Acute lung injury (ALI) is a serious disease with high incidence in ICU, and impaired mitochondria function plays a significant role in ALI. In this study, we examined the possible roles of exogenous hydrogen sulfide (H2S) in lung mitochondria regulation in ALI rats. Methods The rat ALI model was induced by an intra-tongue vein Lipopolysaccharide (LPS) injection. We used sodium hydrosulphide (NaHS) as the H2S donor. We randomly divided 40 Sprague–Dawley rats into five groups: control, LPS injury, LPS + low-dose NaHS (0.78 mg•kg-1), LPS + middle-dose NaHS (1.56 mg•kg-1), and LPS + high-dose NaHS (3.12 mg•kg-1). Rats were killed 3 h after NaHS administration. We calculated a semi-quantitative histological index of lung injury assessments and measured the lung wet-to-dry weight ratio. We further analyzed serum for interleukin-1β levels using enzyme-linked immunosorbent assays. We observed lung mitochondria ultrastructures with an electron microscope. We examined oxidative stress markers in lung mitochondria and the mitochondrial swelling and activity. We analyzed lung mitochondria and cytosol Cyt-c protein expression using Western blotting. Results Compared to the control group, the quantitative assessment score index, wet-to-dry weight ratios, and interleukin-1β content in the LPS injury group were significantly increased and the mitochondrial ultrastructure damaged. Furthermore, mitochondrial activity, adenosine triphosphatease, superoxide dismutase, glutathione peroxidase, and mitochondrial Cyt-c protein expression were significantly decreased, and malondialdehyde content, mitochondrial swelling, and cytosol Cyt-c protein expression were significantly increased in the LPS injury group compared to the control group. These effects were lessened by NaHS. Conclusion Exogenous H2S provided a protective effect against ALI by decreasing the mitochondrial lipid peroxidation level and protecting the cell structure in the LPS-induced rat models. Its regulatory effect on lung mitochondria is positively correlated with the dosage.
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Affiliation(s)
- Quansheng Du
- Department of Pharmacology, Hebei Medical University, 361 Zhongshan Eastern Road, Shijiazhuang, 050017 China ; Intensive Care Unit, Hebei General Hospital, 348 Heping Western Road, Shijiazhuang, 050051 China
| | - Chao Wang
- Clinical research center, Hebei General Hospital, 348 Heping Western Road, Shijiazhuang, 050051 China
| | - Nan Zhang
- Department of Pharmacology, Children's Hospital of Hebei Province, 133 Jianhua Southern Avenue, Shijiazhuang, 050031 China
| | - Guofeng Li
- Department of Pharmacology, Hebei Centers for Disease Control and Prevention, 97 Huaian Eastern Road, Shijiazhuang, 050021 China
| | - Meng Zhang
- Department of chest surgery, Third Hospital of Hebei Medical University, 139 Ziqiang Road, Shijiazhuang, 050051 China
| | - Liping Li
- Department of Pharmacology, Hebei Centers for Disease Control and Prevention, 97 Huaian Eastern Road, Shijiazhuang, 050021 China
| | - Qingzeng Zhang
- Department of Pharmacology, Hebei Centers for Disease Control and Prevention, 97 Huaian Eastern Road, Shijiazhuang, 050021 China
| | - Jianxin Zhang
- Department of Pharmacology, Hebei Medical University, 361 Zhongshan Eastern Road, Shijiazhuang, 050017 China
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Yu XH, Cui LB, Wu K, Zheng XL, Cayabyab FS, Chen ZW, Tang CK. Hydrogen sulfide as a potent cardiovascular protective agent. Clin Chim Acta 2014; 437:78-87. [DOI: 10.1016/j.cca.2014.07.012] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2014] [Revised: 07/07/2014] [Accepted: 07/10/2014] [Indexed: 11/28/2022]
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