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Zhou M, Lu D, Jiang A, Zhao C, Lu Y, Zheng B, Miao L, Huang Y, Qu C, Gao Y. Hydrogen sulphide alleviates platelet dysfunction in patients with type 2 diabetes. J Thromb Thrombolysis 2025; 58:433-442. [PMID: 39920555 DOI: 10.1007/s11239-025-03071-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/17/2024] [Indexed: 02/09/2025]
Abstract
Hyperglycaemia stimulate platelet activation by reducing platelet H2S concentrations, potentially leading to cardiovascular events. Exogenous supplementation with H2S reversed this abnormal platelet activation under hyperglycaemia.
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Affiliation(s)
- Minqi Zhou
- Department of Endocrinology, Peking University First Hospital, No.8 Xi Shi Ku Street, Xi Cheng District, Beijing, 100034, China
| | - Difei Lu
- Department of Endocrinology, Peking University First Hospital, No.8 Xi Shi Ku Street, Xi Cheng District, Beijing, 100034, China
| | - Anna Jiang
- Department of Clinical Laboratory, Peking University First Hospital, No.8 Xi Shi Ku Street, Xi Cheng District, Beijing, 100034, China
| | - Chenxu Zhao
- Department of Endocrinology, Peking University First Hospital, No.8 Xi Shi Ku Street, Xi Cheng District, Beijing, 100034, China
| | - Yao Lu
- Department of Clinical Laboratory, Peking University First Hospital, No.8 Xi Shi Ku Street, Xi Cheng District, Beijing, 100034, China
| | - Bo Zheng
- Department of Cardiology, Peking University First Hospital, Beijing, China
| | - Linzi Miao
- Department of Clinical Laboratory, Peking University First Hospital, No.8 Xi Shi Ku Street, Xi Cheng District, Beijing, 100034, China
| | - Youyuan Huang
- Department of Endocrinology, Peking University First Hospital, No.8 Xi Shi Ku Street, Xi Cheng District, Beijing, 100034, China
| | - Chenxue Qu
- Department of Clinical Laboratory, Peking University First Hospital, No.8 Xi Shi Ku Street, Xi Cheng District, Beijing, 100034, China.
| | - Ying Gao
- Department of Endocrinology, Peking University First Hospital, No.8 Xi Shi Ku Street, Xi Cheng District, Beijing, 100034, China.
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Liu H, Negoita F, Brook M, Sakamoto K, Morton NM. Quantification of persulfidation on specific proteins: are we nearly there yet? Essays Biochem 2024; 68:467-478. [PMID: 39290133 PMCID: PMC11625863 DOI: 10.1042/ebc20230095] [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: 04/19/2024] [Revised: 07/18/2024] [Accepted: 08/09/2024] [Indexed: 09/19/2024]
Abstract
Hydrogen sulfide (H2S) played a pivotal role in the early evolution of life on Earth before the predominance of atmospheric oxygen. The legacy of a persistent role for H2S in life's processes recently emerged through its discovery in modern biochemistry as an endogenous cellular signalling modulator involved in numerous biological processes. One major mechanism through which H2S signals is protein cysteine persulfidation, an oxidative post-translational modification. In recent years, chemoproteomic technologies have been developed to allow the global scanning of protein persulfidation targets in mammalian cells and tissues, providing a powerful tool to elucidate the broader impact of altered H2S in organismal physiological health and human disease states. While hundreds of proteins were confirmed to be persulfidated by global persulfidome methodologies, the targeting of specific proteins of interest and the investigation of further mechanistic studies are still underdeveloped due to a lack of stringent specificity of the methods and the inherent instability of persulfides. This review provides an overview of the processes of endogenous H2S production, oxidation, and signalling and highlights the application and limitations of current persulfidation labelling approaches for investigation of this important evolutionarily conserved biological switch for protein function.
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Affiliation(s)
- Hongling Liu
- Molecular Metabolism Group, University/BHF Centre for Cardiovascular Sciences, Queens Medical Research Institute, University of Edinburgh, U.K
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen 2200, Denmark
| | - Florentina Negoita
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen 2200, Denmark
| | - Matthew Brook
- Molecular Metabolism Group, University/BHF Centre for Cardiovascular Sciences, Queens Medical Research Institute, University of Edinburgh, U.K
| | - Kei Sakamoto
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen 2200, Denmark
| | - Nicholas M Morton
- Molecular Metabolism Group, University/BHF Centre for Cardiovascular Sciences, Queens Medical Research Institute, University of Edinburgh, U.K
- Centre for Systems Health and Integrated Metabolic Research, Department of Biosciences, School of Science and Technology, Nottingham Trent University, NG11 8NS, U.K
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Gomez CB, Sánchez-López A, Carvajal K, Centurión D. Effect of Hydrogen Sulfide on Sympathoinhibition in Obese Pithed Rats and Participation of K + Channel. Int J Hypertens 2024; 2024:5848352. [PMID: 39530003 PMCID: PMC11554415 DOI: 10.1155/2024/5848352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 09/26/2024] [Accepted: 10/12/2024] [Indexed: 11/16/2024] Open
Abstract
Elevated blood pressure is the leading metabolic risk factor in attributable deaths, and hydrogen sulfide (H2S) regulates vascular tone and blood pressure. Thus, this study aims to evaluate the mechanism by which NaHS (H2S donor) produces inhibition of the vasopressor sympathetic outflow in obese rats. For that purpose, animals were fed a high-fat diet (HFD) (60% calories from fat) for 12 weeks. They were anesthetized, pithed, and cannulated to evaluate the role of the potassium channel on NaHS-induced sympathoinhibition. Animals received selective electrical stimulation of the vasopressor sympathetic outflow, an intravenous (i.v.) administration of (1) tetraethylammonium (TEA, non-selective K+ channel blocker, 16.5 mg/kg), (2) 4-aminopyridine (4-AP, KV channel blocker, 5 mg/kg), (3) barium chloride (BaCl2, KIR channel blocker, 65 μg/kg), (4) saline solution (vehicle of TEA, 4-AP, and BaCl2, 1 mL/kg), (5) glibenclamide (KATP channel blocker, 10 mg/kg), and (6) glibenclamide vehicle (DMSO + glucose 10% + NaOH, 1 mL/kg), and then a 310 μg/kg·min NaHS i.v. continuous infusion. We observed that (1) NaHS produced inhibition of the vasopressor sympathetic outflow and (2) the sympathoinhibitory effect by NaHS was reversed by the KIR channel blocker, BaCl2, in obese rats. The above data suggest that the potassium channel could be involved in the sympathoinhibition induced by NaHS.
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Affiliation(s)
- Carolina B. Gomez
- Departamento de Farmacobiología, Cinvestav-Coapa, Czda. de Los Tenorios 235, Col. Granjas-Coapa, Alc. Tlalpan, C.P. 14330, Ciudad de México, Mexico
| | - Araceli Sánchez-López
- Departamento de Farmacobiología, Cinvestav-Coapa, Czda. de Los Tenorios 235, Col. Granjas-Coapa, Alc. Tlalpan, C.P. 14330, Ciudad de México, Mexico
| | - Karla Carvajal
- Laboratorio de Nutrición Experimental, Instituto Nacional de Pediatría, Insurgentes Sur 3700 Letra C, Alc. Coyoacán, C.P. 04530, Ciudad de México, Mexico
| | - David Centurión
- Departamento de Farmacobiología, Cinvestav-Coapa, Czda. de Los Tenorios 235, Col. Granjas-Coapa, Alc. Tlalpan, C.P. 14330, Ciudad de México, Mexico
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Stachowicz A, Czepiel K, Wiśniewska A, Stachyra K, Ulatowska-Białas M, Kuśnierz-Cabala B, Surmiak M, Majka G, Kuś K, Wood ME, Torregrossa R, Whiteman M, Olszanecki R. Mitochondria-targeted hydrogen sulfide donor reduces fatty liver and obesity in mice fed a high fat diet by inhibiting de novo lipogenesis and inflammation via mTOR/SREBP-1 and NF-κB signaling pathways. Pharmacol Res 2024; 209:107428. [PMID: 39303773 DOI: 10.1016/j.phrs.2024.107428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 09/09/2024] [Accepted: 09/17/2024] [Indexed: 09/22/2024]
Abstract
Metabolic diseases that include obesity and metabolic-associated fatty liver disease (MAFLD) are a rapidly growing worldwide public health problem. The pathogenesis of MAFLD includes abnormally increased lipogenesis, chronic inflammation, and mitochondrial dysfunction. Mounting evidence suggests that hydrogen sulfide (H2S) is an important player in the liver, regulating lipid metabolism and mitochondrial function. However, direct delivery of H2S to mitochondria has not been investigated as a therapeutic strategy in obesity-related metabolic disorders. Therefore, our aim was to comprehensively evaluate the influence of prolonged treatment with a mitochondria sulfide delivery molecule (AP39) on the development of fatty liver and obesity in a high fat diet (HFD) fed mice. Our results demonstrated that AP39 reduced hepatic steatosis in HFD-fed mice, which was corresponded with decreased triglyceride content. Furthermore, treatment with AP39 downregulated pathways related to biosynthesis of unsaturated fatty acids, lipoprotein assembly and PPAR signaling. It also led to a decrease in hepatic de novo lipogenesis by downregulating mTOR/SREBP-1/SCD1 pathway. Moreover, AP39 administration alleviated obesity in HFD-fed mice, which was reflected by reduced weight of mice and adipose tissue, decreased leptin levels in the plasma and upregulated expression of adipose triglyceride lipase in epididymal white adipose tissue (eWAT). Finally, AP39 reduced inflammation in the liver and eWAT measured as the expression of proinflammatory markers (Il1b, Il6, Tnf, Mcp1), which was due to downregulated mTOR/NF-κB pathway. Taken together, mitochondria-targeted sulfide delivery molecules could potentially provide a novel therapeutic approach to the treatment/prevention of obesity-related metabolic disorders.
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Affiliation(s)
- Aneta Stachowicz
- Department of Pharmacology, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland.
| | - Klaudia Czepiel
- Department of Pharmacology, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland
| | - Anna Wiśniewska
- Department of Pharmacology, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland
| | - Kamila Stachyra
- Department of Pharmacology, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland
| | - Magdalena Ulatowska-Białas
- Department of Pathomorphology, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland
| | - Beata Kuśnierz-Cabala
- Department of Medical Biochemistry, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland
| | - Marcin Surmiak
- II Department of Internal Medicine, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland
| | - Grzegorz Majka
- Department of Immunology, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland
| | - Katarzyna Kuś
- Department of Pharmacology, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland
| | - Mark E Wood
- School of Biosciences, University of Exeter, Exeter, UK
| | | | | | - Rafał Olszanecki
- Department of Pharmacology, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland
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Giacolone J, Osofsky R, Matheson B, Perales G, Shekarriz R, Kanagy N, Clark RM. H 2S-Eluting Hydrogels Promote In Vitro Angiogenesis and Augment In Vivo Ischemic Wound Revascularization. Biomolecules 2024; 14:1350. [PMID: 39595527 PMCID: PMC11591623 DOI: 10.3390/biom14111350] [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: 08/30/2024] [Revised: 10/15/2024] [Accepted: 10/16/2024] [Indexed: 11/28/2024] Open
Abstract
Ischemic wounds are frequently encountered in clinical practice and may be related to ischemia secondary to diabetes, peripheral artery disease and other chronic conditions. Angiogenesis is critical to the resolution of ischemia. Hydrogen sulfide (H2S) is now recognized as an important factor in this process. H2S donors NaHS and GYY4137 were incorporated into the photosensitive polymer hydrogel gelatin methacrylate and evaluated. Human umbilical vein endothelial cell (HUVEC) culture was used to quantify toxicity and angiogenesis. Sprague Dawley rats were subjected to ischemic myocutaneous flap wound creation with and without application of H2S-eluting hydrogels. Tissue perfusion during wound healing was quantified using laser speckle contrast imaging, and gene and protein expression for VEGF were evaluated. Vascular density was assessed by CD31 immunohistochemistry. Successful incorporation of sulfide compounds was confirmed by scanning electron microscopy with energy-dispersive X-ray analysis, and under physiologic conditions, detectable H2S was present for up to 14 days by high-performance liquid chromatography. HUVECs exposed to hydrogels did not demonstrate excess cytotoxicity or apoptosis. A two-fold increase in angiogenic tube formation was observed in HUVECs exposed to H2S-eluting hydrogels. Rat ischemic flap wounds demonstrated greater perfusion at 14 days, and there was greater vascularity of healed wounds compared to untreated animals. A nearly two-fold increase in VEGF mRNA and a four-fold increase in VEGF protein expression were present in wounds from treated animals. Local-regional administration of H2S represents a novel potential therapeutic strategy to promote angiogenesis and improve wound healing after tissue injury or as a result of ischemic disease.
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Affiliation(s)
- Joseph Giacolone
- Department of Surgery, University of New Mexico, Albuquerque, NM 87131, USA; (J.G.); (R.O.)
| | - Robin Osofsky
- Department of Surgery, University of New Mexico, Albuquerque, NM 87131, USA; (J.G.); (R.O.)
| | - Benjamin Matheson
- Department of Cell Biology and Physiology, University of New Mexico, Albuquerque, NM 87131, USA; (B.M.); (N.K.)
| | - Gabriela Perales
- Department of Cell Biology and Physiology, University of New Mexico, Albuquerque, NM 87131, USA; (B.M.); (N.K.)
| | | | - Nancy Kanagy
- Department of Cell Biology and Physiology, University of New Mexico, Albuquerque, NM 87131, USA; (B.M.); (N.K.)
| | - Ross M. Clark
- Department of Surgery, University of New Mexico, Albuquerque, NM 87131, USA; (J.G.); (R.O.)
- Department of Cell Biology and Physiology, University of New Mexico, Albuquerque, NM 87131, USA; (B.M.); (N.K.)
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Sun HJ, Lu QB, Zhu XX, Ni ZR, Su JB, Fu X, Chen G, Zheng GL, Nie XW, Bian JS. Pharmacology of Hydrogen Sulfide and Its Donors in Cardiometabolic Diseases. Pharmacol Rev 2024; 76:846-895. [PMID: 38866561 DOI: 10.1124/pharmrev.123.000928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 04/13/2024] [Accepted: 06/10/2024] [Indexed: 06/14/2024] Open
Abstract
Cardiometabolic diseases (CMDs) are major contributors to global mortality, emphasizing the critical need for novel therapeutic interventions. Hydrogen sulfide (H2S) has garnered enormous attention as a significant gasotransmitter with various physiological, pathophysiological, and pharmacological impacts within mammalian cardiometabolic systems. In addition to its roles in attenuating oxidative stress and inflammatory response, burgeoning research emphasizes the significance of H2S in regulating proteins via persulfidation, a well known modification intricately associated with the pathogenesis of CMDs. This review seeks to investigate recent updates on the physiological actions of endogenous H2S and the pharmacological roles of various H2S donors in addressing diverse aspects of CMDs across cellular, animal, and clinical studies. Of note, advanced methodologies, including multiomics, intestinal microflora analysis, organoid, and single-cell sequencing techniques, are gaining traction due to their ability to offer comprehensive insights into biomedical research. These emerging approaches hold promise in characterizing the pharmacological roles of H2S in health and diseases. We will critically assess the current literature to clarify the roles of H2S in diseases while also delineating the opportunities and challenges they present in H2S-based pharmacotherapy for CMDs. SIGNIFICANCE STATEMENT: This comprehensive review covers recent developments in H2S biology and pharmacology in cardiometabolic diseases CMDs. Endogenous H2S and its donors show great promise for the management of CMDs by regulating numerous proteins and signaling pathways. The emergence of new technologies will considerably advance the pharmacological research and clinical translation of H2S.
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Affiliation(s)
- Hai-Jian Sun
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China (H.-J.S., X.-X.Z., Z.-R.N., J.-B.S., X.F., G.C., G.-L.Z.); Department of Endocrinology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, Jiangsu, China (Q.-B.L.); Shenzhen Key Laboratory of Respiratory Diseases, Shenzhen People's Hospital, Shenzhen, Guangdong, China (X.-W.N.); and Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China (J.-S.B.)
| | - Qing-Bo Lu
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China (H.-J.S., X.-X.Z., Z.-R.N., J.-B.S., X.F., G.C., G.-L.Z.); Department of Endocrinology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, Jiangsu, China (Q.-B.L.); Shenzhen Key Laboratory of Respiratory Diseases, Shenzhen People's Hospital, Shenzhen, Guangdong, China (X.-W.N.); and Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China (J.-S.B.)
| | - Xue-Xue Zhu
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China (H.-J.S., X.-X.Z., Z.-R.N., J.-B.S., X.F., G.C., G.-L.Z.); Department of Endocrinology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, Jiangsu, China (Q.-B.L.); Shenzhen Key Laboratory of Respiratory Diseases, Shenzhen People's Hospital, Shenzhen, Guangdong, China (X.-W.N.); and Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China (J.-S.B.)
| | - Zhang-Rong Ni
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China (H.-J.S., X.-X.Z., Z.-R.N., J.-B.S., X.F., G.C., G.-L.Z.); Department of Endocrinology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, Jiangsu, China (Q.-B.L.); Shenzhen Key Laboratory of Respiratory Diseases, Shenzhen People's Hospital, Shenzhen, Guangdong, China (X.-W.N.); and Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China (J.-S.B.)
| | - Jia-Bao Su
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China (H.-J.S., X.-X.Z., Z.-R.N., J.-B.S., X.F., G.C., G.-L.Z.); Department of Endocrinology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, Jiangsu, China (Q.-B.L.); Shenzhen Key Laboratory of Respiratory Diseases, Shenzhen People's Hospital, Shenzhen, Guangdong, China (X.-W.N.); and Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China (J.-S.B.)
| | - Xiao Fu
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China (H.-J.S., X.-X.Z., Z.-R.N., J.-B.S., X.F., G.C., G.-L.Z.); Department of Endocrinology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, Jiangsu, China (Q.-B.L.); Shenzhen Key Laboratory of Respiratory Diseases, Shenzhen People's Hospital, Shenzhen, Guangdong, China (X.-W.N.); and Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China (J.-S.B.)
| | - Guo Chen
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China (H.-J.S., X.-X.Z., Z.-R.N., J.-B.S., X.F., G.C., G.-L.Z.); Department of Endocrinology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, Jiangsu, China (Q.-B.L.); Shenzhen Key Laboratory of Respiratory Diseases, Shenzhen People's Hospital, Shenzhen, Guangdong, China (X.-W.N.); and Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China (J.-S.B.)
| | - Guan-Li Zheng
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China (H.-J.S., X.-X.Z., Z.-R.N., J.-B.S., X.F., G.C., G.-L.Z.); Department of Endocrinology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, Jiangsu, China (Q.-B.L.); Shenzhen Key Laboratory of Respiratory Diseases, Shenzhen People's Hospital, Shenzhen, Guangdong, China (X.-W.N.); and Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China (J.-S.B.)
| | - Xiao-Wei Nie
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China (H.-J.S., X.-X.Z., Z.-R.N., J.-B.S., X.F., G.C., G.-L.Z.); Department of Endocrinology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, Jiangsu, China (Q.-B.L.); Shenzhen Key Laboratory of Respiratory Diseases, Shenzhen People's Hospital, Shenzhen, Guangdong, China (X.-W.N.); and Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China (J.-S.B.)
| | - Jin-Song Bian
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China (H.-J.S., X.-X.Z., Z.-R.N., J.-B.S., X.F., G.C., G.-L.Z.); Department of Endocrinology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, Jiangsu, China (Q.-B.L.); Shenzhen Key Laboratory of Respiratory Diseases, Shenzhen People's Hospital, Shenzhen, Guangdong, China (X.-W.N.); and Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China (J.-S.B.)
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Mao TH, Huang HQ, Zhang CH. Clinical characteristics and treatment compounds of obesity-related kidney injury. World J Diabetes 2024; 15:1091-1110. [PMID: 38983811 PMCID: PMC11229974 DOI: 10.4239/wjd.v15.i6.1091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 12/22/2023] [Accepted: 04/08/2024] [Indexed: 06/11/2024] Open
Abstract
Disorders in energy homeostasis can lead to various metabolic diseases, particularly obesity. The obesity epidemic has led to an increased incidence of obesity-related nephropathy (ORN), a distinct entity characterized by proteinuria, glomerulomegaly, progressive glomerulosclerosis, and renal function decline. Obesity and its associated renal damage are common in clinical practice, and their incidence is increasing and attracting great attention. There is a great need to identify safe and effective therapeutic modalities, and therapeutics using chemical compounds and natural products are receiving increasing attention. However, the summary is lacking about the specific effects and mechanisms of action of compounds in the treatment of ORN. In this review, we summarize the important clinical features and compound treatment strategies for obesity and obesity-induced kidney injury. We also summarize the pathologic and clinical features of ORN as well as its pathogenesis and potential therapeutics targeting renal inflammation, oxidative stress, insulin resistance, fibrosis, kidney lipid accumulation, and dysregulated autophagy. In addition, detailed information on natural and synthetic compounds used for the treatment of obesity-related kidney disease is summarized. The synthesis of detailed information aims to contribute to a deeper understanding of the clinical treatment modalities for obesity-related kidney diseases, fostering the anticipation of novel insights in this domain.
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Affiliation(s)
- Tuo-Hua Mao
- Department of Endocrinology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Han-Qi Huang
- Department of Endocrinology, Hubei No. 3 People’s Hospital of Jianghan University, Wuhan 430033, Hubei Province, China
| | - Chuan-Hai Zhang
- Department of Physiology, UT Southwestern Medical Center, Dallas, TX 75390, United States
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Spezzini J, Piragine E, Flori L, Calderone V, Martelli A. Natural H 2S-donors: A new pharmacological opportunity for the management of overweight and obesity. Phytother Res 2024; 38:2388-2405. [PMID: 38430052 DOI: 10.1002/ptr.8181] [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: 11/14/2023] [Revised: 01/31/2024] [Accepted: 02/19/2024] [Indexed: 03/03/2024]
Abstract
The prevalence of overweight and obesity has progressively increased in the last few years, becoming a real threat to healthcare systems. To date, the clinical management of body weight gain is an unmet medical need, as there are few approved anti-obesity drugs and most require an extensive monitoring and vigilance due to risk of adverse effects and poor patient adherence/persistence. Growing evidence has shown that the gasotransmitter hydrogen sulfide (H2S) and, therefore, H2S-donors could have a central role in the prevention and treatment of overweight/obesity. The main natural sources of H2S-donors are plants from the Alliaceae (garlic and onion), Brassicaceae (e.g., broccoli, cabbage, and wasabi), and Moringaceae botanical families. In particular, polysulfides and isothiocyanates, which slowly release H2S, derive from the hydrolysis of alliin from Alliaceae and glucosinolates from Brassicaceae/Moringaceae, respectively. In this review, we describe the emerging role of endogenous H2S in regulating adipose tissue function and the potential efficacy of natural H2S-donors in animal models of overweight/obesity, with a final focus on the preliminary results from clinical trials. We conclude that organosulfur-containing plants and their extracts could be used before or in combination with conventional anti-obesity agents to improve treatment efficacy and reduce inflammation in obesogenic conditions. However, further high-quality studies are needed to firmly establish their clinical efficacy.
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Affiliation(s)
| | | | - Lorenzo Flori
- Department of Pharmacy, University of Pisa, Pisa, Italy
| | - Vincenzo Calderone
- Department of Pharmacy, University of Pisa, Pisa, Italy
- Interdepartmental Research Center "Nutraceuticals and Food for Health (NUTRAFOOD)", University of Pisa, Pisa, Italy
- Interdepartmental Research Center "Biology and Pathology of Ageing", University of Pisa, Pisa, Italy
| | - Alma Martelli
- Department of Pharmacy, University of Pisa, Pisa, Italy
- Interdepartmental Research Center "Nutraceuticals and Food for Health (NUTRAFOOD)", University of Pisa, Pisa, Italy
- Interdepartmental Research Center "Biology and Pathology of Ageing", University of Pisa, Pisa, Italy
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9
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Youness RA, Habashy DA, Khater N, Elsayed K, Dawoud A, Hakim S, Nafea H, Bourquin C, Abdel-Kader RM, Gad MZ. Role of Hydrogen Sulfide in Oncological and Non-Oncological Disorders and Its Regulation by Non-Coding RNAs: A Comprehensive Review. Noncoding RNA 2024; 10:7. [PMID: 38250807 PMCID: PMC10801522 DOI: 10.3390/ncrna10010007] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Revised: 01/07/2024] [Accepted: 01/08/2024] [Indexed: 01/23/2024] Open
Abstract
Recently, myriad studies have defined the versatile abilities of gasotransmitters and their synthesizing enzymes to play a "Maestro" role in orchestrating several oncological and non-oncological circuits and, thus, nominated them as possible therapeutic targets. Although a significant amount of work has been conducted on the role of nitric oxide (NO) and carbon monoxide (CO) and their inter-relationship in the field of oncology, research about hydrogen sulfide (H2S) remains in its infancy. Recently, non-coding RNAs (ncRNAs) have been reported to play a dominating role in the regulation of the endogenous machinery system of H2S in several pathological contexts. A growing list of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are leading the way as upstream regulators for H2S biosynthesis in different mammalian cells during the development and progression of human diseases; therefore, their targeting can be of great therapeutic benefit. In the current review, the authors shed the light onto the biosynthetic pathways of H2S and their regulation by miRNAs and lncRNAs in various oncological and non-oncological disorders.
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Affiliation(s)
- Rana A. Youness
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC), Cairo 11835, Egypt
- Biology and Biochemistry Department, Faculty of Biotechnology, German International University (GIU), New Administrative Capital, Cairo 11835, Egypt
| | - Danira Ashraf Habashy
- Pharmacology and Toxicology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC), Cairo 11835, Egypt
- Clinical Pharmacy Department, Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC), Cairo 11835, Egypt
| | - Nour Khater
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC), Cairo 11835, Egypt
| | - Kareem Elsayed
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC), Cairo 11835, Egypt
| | - Alyaa Dawoud
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC), Cairo 11835, Egypt
| | - Sousanna Hakim
- Pharmacology and Toxicology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC), Cairo 11835, Egypt
| | - Heba Nafea
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC), Cairo 11835, Egypt
| | - Carole Bourquin
- School of Pharmaceutical Sciences, Institute of Pharmaceutical Sciences of Western Switzerland, Department of Anaesthesiology, Pharmacology, Intensive Care and Emergency Medicine, University of Geneva, 1211 Geneva, Switzerland;
| | - Reham M. Abdel-Kader
- Pharmacology and Toxicology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC), Cairo 11835, Egypt
| | - Mohamed Z. Gad
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC), Cairo 11835, Egypt
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10
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Nguyen TTP, Nguyen PL, Park SH, Jung CH, Jeon TI. Hydrogen Sulfide and Liver Health: Insights into Liver Diseases. Antioxid Redox Signal 2024; 40:122-144. [PMID: 37917113 DOI: 10.1089/ars.2023.0404] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/03/2023]
Abstract
Significance: Hydrogen sulfide (H2S) is a recently recognized gasotransmitter involved in physiological and pathological conditions in mammals. It protects organs from oxidative stress, inflammation, hypertension, and cell death. With abundant expression of H2S-production enzymes, the liver is closely linked to H2S signaling. Recent Advances: Hepatic H2S comes from various sources, including gut microbiota, exogenous sulfur salts, and endogenous production. Recent studies highlight the importance of hepatic H2S in liver diseases such as nonalcoholic fatty liver disease (NAFLD), liver injury, and cancer, particularly at advanced stages. Endogenous H2S production deficiency is associated with severe liver disease, while exogenous H2S donors protect against liver dysfunction. Critical Issues: However, the roles of H2S in NAFLD, liver injury, and liver cancer are still debated, and its effects depend on donor type, dosage, treatment duration, and cell type, suggesting a multifaceted role. This review aimed to critically evaluate H2S production, metabolism, mode of action, and roles in liver function and disease. Future Direction: Understanding H2S's precise roles and mechanisms in liver health will advance potential therapeutic applications in preclinical and clinical research. Targeting H2S-producing enzymes and exogenous H2S sources, alone or in combination with other drugs, could be explored. Quantifying endogenous H2S levels may aid in diagnosing and managing liver diseases. Antioxid. Redox Signal. 40, 122-144.
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Affiliation(s)
- Thuy T P Nguyen
- Department of Animal Science, College of Agriculture and Life Science, Chonnam National University, Gwangju, Republic of Korea
- Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Phuc L Nguyen
- Department of Animal Science, College of Agriculture and Life Science, Chonnam National University, Gwangju, Republic of Korea
| | - So-Hyun Park
- Aging and Metabolism Research Group, Korea Food Research Institute, Wanju-gun, Republic of Korea
| | - Chang Hwa Jung
- Aging and Metabolism Research Group, Korea Food Research Institute, Wanju-gun, Republic of Korea
| | - Tae-Il Jeon
- Department of Animal Science, College of Agriculture and Life Science, Chonnam National University, Gwangju, Republic of Korea
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11
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Iciek M, Bilska-Wilkosz A, Kozdrowicki M, Górny M. Reactive Sulfur Species in Human Diseases. Antioxid Redox Signal 2023; 39:1000-1023. [PMID: 37440317 DOI: 10.1089/ars.2023.0261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/15/2023]
Abstract
Significance: Reactive sulfur species (RSS) have been recently recognized as redox molecules no less important than reactive oxygen species or reactive nitrogen species. They possess regulatory and protective properties and are involved in various metabolic processes, thereby contributing to the maintenance of human health. It has been documented that many disorders, including neurological, cardiovascular, and respiratory diseases, diabetes mellitus (DM), and cancer, are related to the disruption of RSS homeostasis. Recent Advances: There is still a growing interest in the role of RSS in human diseases. Since a decrease in hydrogen sulfide or other RSS has been reported in many disorders, safe and efficient RSS donors have been developed and tested under in vitro conditions or on animal models. Critical Issues: Cardiovascular diseases and DM are currently the most common chronic diseases worldwide due to stressful and unhealthy lifestyles. In addition, because of high prevalence and aging of the population, neurological disorders including Parkinson's disease and Alzheimer's disease as well as respiratory diseases are a formidable challenge for health care systems. From this point of view, the knowledge of the role of RSS in these disorders and RSS modulation options are important and could be useful in therapeutic strategies. Future Directions: Improvement and standardization of analytical methods used for RSS estimation are crucial for the use of RSS as diagnostic biomarkers. Finding good, safe RSS donors applicable for therapeutic purposes could be useful as primary or adjunctive therapy in many common diseases. Antioxid. Redox Signal. 39, 1000-1023.
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Affiliation(s)
- Małgorzata Iciek
- Faculty of Medicine, Jagiellonian University Medical College, Kraków, Poland
| | - Anna Bilska-Wilkosz
- Faculty of Medicine, Jagiellonian University Medical College, Kraków, Poland
| | - Michał Kozdrowicki
- Faculty of Medicine, Jagiellonian University Medical College, Kraków, Poland
| | - Magdalena Górny
- Faculty of Medicine, Jagiellonian University Medical College, Kraków, Poland
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12
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Piragine E, Malanima MA, Lucenteforte E, Martelli A, Calderone V. Circulating Levels of Hydrogen Sulfide (H 2S) in Patients with Age-Related Diseases: A Systematic Review and Meta-Analysis. Biomolecules 2023; 13:1023. [PMID: 37509058 PMCID: PMC10376967 DOI: 10.3390/biom13071023] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 06/14/2023] [Accepted: 06/15/2023] [Indexed: 07/30/2023] Open
Abstract
Hydrogen sulfide (H2S) is an endogenous gasotransmitter that promotes multiple biological effects in many organs and tissues. An imbalanced biosynthesis of H2S has been observed in animal models of age-related pathological conditions. However, the results from human studies are inconsistent. We performed a systematic review with meta-analysis of studies searched in Medline, Embase, Scopus, and CENTRAL databases. We included observational studies on patients with age-related diseases showing levels of H2S in blood, plasma, or serum. All the analyses were carried out with R software. 31 studies were included in the systematic review and 21 in the meta-analysis. The circulating levels of H2S were significantly reduced in patients with progressive, chronic, and degenerative diseases compared with healthy people (standardized mean difference, SMD: -1.25; 95% confidence interval, CI: -1.98; -0.52). When we stratified results by type of disorder, we observed a significant reduction in circulating levels of H2S in patients with vascular disease (e.g., hypertension) (SMD: -1.32; 95% CI: -2.43; -0.22) or kidney disease (SMD: -2.24; 95% CI: -4.40; -0.08) compared with the control group. These results could support the potential use of compounds targeting the "H2S system" to slow down the progression of many diseases in the elderly.
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Affiliation(s)
| | - Marco Andrea Malanima
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
| | - Ersilia Lucenteforte
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
| | - Alma Martelli
- Department of Pharmacy, University of Pisa, 56126 Pisa, Italy
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13
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Wu X, Xu M, Geng M, Chen S, Little PJ, Xu S, Weng J. Targeting protein modifications in metabolic diseases: molecular mechanisms and targeted therapies. Signal Transduct Target Ther 2023; 8:220. [PMID: 37244925 PMCID: PMC10224996 DOI: 10.1038/s41392-023-01439-y] [Citation(s) in RCA: 91] [Impact Index Per Article: 45.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 03/01/2023] [Accepted: 04/06/2023] [Indexed: 05/29/2023] Open
Abstract
The ever-increasing prevalence of noncommunicable diseases (NCDs) represents a major public health burden worldwide. The most common form of NCD is metabolic diseases, which affect people of all ages and usually manifest their pathobiology through life-threatening cardiovascular complications. A comprehensive understanding of the pathobiology of metabolic diseases will generate novel targets for improved therapies across the common metabolic spectrum. Protein posttranslational modification (PTM) is an important term that refers to biochemical modification of specific amino acid residues in target proteins, which immensely increases the functional diversity of the proteome. The range of PTMs includes phosphorylation, acetylation, methylation, ubiquitination, SUMOylation, neddylation, glycosylation, palmitoylation, myristoylation, prenylation, cholesterylation, glutathionylation, S-nitrosylation, sulfhydration, citrullination, ADP ribosylation, and several novel PTMs. Here, we offer a comprehensive review of PTMs and their roles in common metabolic diseases and pathological consequences, including diabetes, obesity, fatty liver diseases, hyperlipidemia, and atherosclerosis. Building upon this framework, we afford a through description of proteins and pathways involved in metabolic diseases by focusing on PTM-based protein modifications, showcase the pharmaceutical intervention of PTMs in preclinical studies and clinical trials, and offer future perspectives. Fundamental research defining the mechanisms whereby PTMs of proteins regulate metabolic diseases will open new avenues for therapeutic intervention.
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Affiliation(s)
- Xiumei Wu
- Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, Anhui, 230001, China
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-sen University, 510000, Guangzhou, China
| | - Mengyun Xu
- Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Mengya Geng
- Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Shuo Chen
- Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Peter J Little
- School of Pharmacy, University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba, QLD, 4102, Australia
- Sunshine Coast Health Institute and School of Health and Behavioural Sciences, University of the Sunshine Coast, Birtinya, QLD, 4575, Australia
| | - Suowen Xu
- Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Jianping Weng
- Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, Anhui, 230001, China.
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-sen University, 510000, Guangzhou, China.
- Bengbu Medical College, Bengbu, 233000, China.
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14
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Juin SK, Ouseph R, Gondim DD, Jala VR, Sen U. Diabetic Nephropathy and Gaseous Modulators. Antioxidants (Basel) 2023; 12:antiox12051088. [PMID: 37237955 DOI: 10.3390/antiox12051088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 05/05/2023] [Accepted: 05/08/2023] [Indexed: 05/28/2023] Open
Abstract
Diabetic nephropathy (DN) remains the leading cause of vascular morbidity and mortality in diabetes patients. Despite the progress in understanding the diabetic disease process and advanced management of nephropathy, a number of patients still progress to end-stage renal disease (ESRD). The underlying mechanism still needs to be clarified. Gaseous signaling molecules, so-called gasotransmitters, such as nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S), have been shown to play an essential role in the development, progression, and ramification of DN depending on their availability and physiological actions. Although the studies on gasotransmitter regulations of DN are still emerging, the evidence revealed an aberrant level of gasotransmitters in patients with diabetes. In studies, different gasotransmitter donors have been implicated in ameliorating diabetic renal dysfunction. In this perspective, we summarized an overview of the recent advances in the physiological relevance of the gaseous molecules and their multifaceted interaction with other potential factors, such as extracellular matrix (ECM), in the severity modulation of DN. Moreover, the perspective of the present review highlights the possible therapeutic interventions of gasotransmitters in ameliorating this dreaded disease.
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Affiliation(s)
- Subir Kumar Juin
- Department of Physiology, University of Louisville School of Medicine, Louisville, KY 40202, USA
- Department of Microbiology & Immunology, Brown Cancer Center, Center for Microbiomics, Inflammation and Pathogenicity, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Rosemary Ouseph
- Division of Nephrology & Hypertension, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Dibson Dibe Gondim
- Department of Pathology, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Venkatakrishna Rao Jala
- Department of Microbiology & Immunology, Brown Cancer Center, Center for Microbiomics, Inflammation and Pathogenicity, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Utpal Sen
- Department of Physiology, University of Louisville School of Medicine, Louisville, KY 40202, USA
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15
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Alsaeedi A, Welham S, Rose P, Zhu YZ. The Impact of Drugs on Hydrogen Sulfide Homeostasis in Mammals. Antioxidants (Basel) 2023; 12:antiox12040908. [PMID: 37107283 PMCID: PMC10135325 DOI: 10.3390/antiox12040908] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 04/04/2023] [Accepted: 04/09/2023] [Indexed: 04/29/2023] Open
Abstract
Mammalian cells and tissues have the capacity to generate hydrogen sulfide gas (H2S) via catabolic routes involving cysteine metabolism. H2S acts on cell signaling cascades that are necessary in many biochemical and physiological roles important in the heart, brain, liver, kidney, urogenital tract, and cardiovascular and immune systems of mammals. Diminished levels of this molecule are observed in several pathophysiological conditions including heart disease, diabetes, obesity, and immune function. Interestingly, in the last two decades, it has become apparent that some commonly prescribed pharmacological drugs can impact the expression and activities of enzymes responsible for hydrogen sulfide production in cells and tissues. Therefore, the current review provides an overview of the studies that catalogue key drugs and their impact on hydrogen sulfide production in mammals.
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Affiliation(s)
- Asrar Alsaeedi
- School of Biosciences, University of Nottingham, Loughborough, Leicestershire LE12 5RD, UK
| | - Simon Welham
- School of Biosciences, University of Nottingham, Loughborough, Leicestershire LE12 5RD, UK
| | - Peter Rose
- School of Biosciences, University of Nottingham, Loughborough, Leicestershire LE12 5RD, UK
- State Key Laboratory of Quality Research in Chinese Medicine, School of Pharmacy, Macau University of Science and Technology, Macau, China
| | - Yi-Zhun Zhu
- State Key Laboratory of Quality Research in Chinese Medicine, School of Pharmacy, Macau University of Science and Technology, Macau, China
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16
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Jia TT, Zhang Y, Hou JT, Niu H, Wang S. H 2S-based fluorescent imaging for pathophysiological processes. Front Chem 2023; 11:1126309. [PMID: 36778034 PMCID: PMC9911449 DOI: 10.3389/fchem.2023.1126309] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Accepted: 01/16/2023] [Indexed: 01/28/2023] Open
Abstract
Hydrogen sulfide (H2S), as an important endogenous signaling molecule, plays a vital role in many physiological processes. The abnormal behaviors of hydrogen sulfide in organisms may lead to various pathophysiological processes. Monitoring the changes in hydrogen sulfide is helpful for pre-warning and treating these pathophysiological processes. Fluorescence imaging techniques can be used to observe changes in the concentration of analytes in organisms in real-time. Therefore, employing fluorescent probes imaging to investigate the behaviors of hydrogen sulfide in pathophysiological processes is vital. This paper reviews the design strategy and sensing mechanisms of hydrogen sulfide-based fluorescent probes, focusing on imaging applications in various pathophysiological processes, including neurodegenerative diseases, inflammation, apoptosis, oxidative stress, organ injury, and diabetes. This review not only demonstrates the specific value of hydrogen sulfide fluorescent probes in preclinical studies but also illuminates the potential application in clinical diagnostics.
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Affiliation(s)
- Tong-Tong Jia
- College of Chemistry and Chemical Engineering, Luoyang Normal University, Luoyang, China
| | - Yuanyuan Zhang
- College of Food and Bioengineering, Henan University of Science and Technology, Luoyang, China
| | - Ji-Ting Hou
- National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, China
| | - Huawei Niu
- College of Food and Bioengineering, Henan University of Science and Technology, Luoyang, China
| | - Shan Wang
- Key Laboratory of Intelligent Treatment and Life Support for Critical Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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17
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Weng RX, Wei YX, Li YC, Xu X, Zhuang JB, Xu GY, Li R. Folic acid attenuates chronic visceral pain by reducing clostridiales abundance and hydrogen sulfide production. Mol Pain 2023; 19:17448069221149834. [PMID: 36550612 PMCID: PMC9830571 DOI: 10.1177/17448069221149834] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Irritable bowel syndrome (IBS) related chronic visceral pain affects 20% of people worldwide. The treatment options are very limited. Although the scholarly reviews have appraised the potential effects of the intestinal microbiota on intestinal motility and sensation, the exact mechanism of intestinal microbiota in IBS-like chronic visceral pain remains largely unclear. The purpose of this study is to investigate whether Folic Acid (FA) attenuated visceral pain and its possible mechanisms. Chronic visceral hyperalgesia was induced in rats by neonatal colonic inflammation (NCI). 16S rDNA analysis of fecal samples from human subjects and rats was performed. Patch clamp recording was used to determine synaptic transmission of colonic-related spinal dorsal horn. Alpha diversity of intestinal flora was increased in patients with IBS, as well as the obviously increased abundance of Clostridiales order (a main bacteria producing hydrogen sulfide). The hydrogen sulfide content was positive correlation with visceral pain score in patients with IBS. Consistently, NCI increased Clostridiales frequency and hydrogen sulfide content in feces of adult rats. Notably, the concentration of FA was markedly decreased in peripheral blood of IBS patients compared with non-IBS human subjects. FA supplement alleviated chronic visceral pain and normalized the Clostridiales frequency in NCI rats. In addition, FA supplement significantly reduced the frequency of sEPSCs of neurons in the spinal dorsal horn of NCI rats. Folic Acid treatment attenuated chronic visceral pain of NCI rats through reducing hydrogen sulfide production from Clostridiales in intestine.
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Affiliation(s)
- Rui-Xia Weng
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, P. R. China,Institute of Neuroscience, Soochow University, Suzhou, P. R. China,Department of Gastroenterology, The People’s Hospital of Suzhou New District, Suzhou, P. R. China
| | - Ying-Xue Wei
- Institute of Neuroscience, Soochow University, Suzhou, P. R. China
| | - Yong-Chang Li
- Institute of Neuroscience, Soochow University, Suzhou, P. R. China
| | - Xue Xu
- Department of Gastroenterology, The People’s Hospital of Suzhou New District, Suzhou, P. R. China
| | - Jian-Bo Zhuang
- Department of Gastroenterology, The People’s Hospital of Suzhou New District, Suzhou, P. R. China
| | - Guang-Yin Xu
- Institute of Neuroscience, Soochow University, Suzhou, P. R. China,Guang-Yin Xu, Center for Translational Pain Medicine, Institute of Neuroscience, Soochow University, 199 Renai Rd, Suzhou 215123, P. R. China.
| | - Rui Li
- Guang-Yin Xu, Center for Translational Pain Medicine, Institute of Neuroscience, Soochow University, 199 Renai Rd, Suzhou 215123, P. R. China.
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18
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Sun HJ, Xiong SP, Wang ZC, Nie XW, Bian JS. Hydrogen Sulfide in Diabetic Complications Revisited: The State of the Art, Challenges, and Future Directions. Antioxid Redox Signal 2023; 38:18-44. [PMID: 36310428 DOI: 10.1089/ars.2022.0028] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Significance: Diabetes and its related complications are becoming an increasing public health problem that affects hundreds of millions of people globally. Increased disability and mortality rate of diabetic individuals are closely associated with various life-threatening complications, such as atherosclerosis, nephropathy, retinopathy, and cardiomyopathy. Recent Advances: Conventional treatments for diabetes are still limited because of undesirable side effects, including obesity, hypoglycemia, and hepatic and renal toxicity. Studies have shown that hydrogen sulfide (H2S) plays a critical role in the modulation of glycolipid metabolism, pancreatic β cell functions, and diabetic complications. Critical Issues: Preservation of endogenous H2S systems and supplementation of H2S donors are effective in attenuating diabetes-induced complications, thus representing a new avenue to treat diabetes and its associated complications. Future Directions: This review systematically recapitulates and discusses the most recent updates regarding the therapeutic effects of H2S on diabetes and its various complications, with an emphasis on the molecular mechanisms that underlie H2S-mediated protection against diabetic complications. Furthermore, current clinical trials of H2S in diabetic populations are highlighted, and the challenges and solutions to the clinical transformation of H2S-derived therapies in diabetes are proposed. Finally, future research directions of the pharmacological actions of H2S in diabetes and its related complications are summarized. Antioxid. Redox Signal. 38, 18-44.
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Affiliation(s)
- Hai-Jian Sun
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Si-Ping Xiong
- Department of Pathology, The Eighth Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Zi-Chao Wang
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Xiao-Wei Nie
- Shenzhen Key Laboratory of Respiratory Diseases, Shenzhen People's Hospital (The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China
| | - Jin-Song Bian
- Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, China
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19
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Zhang Y, Jelleschitz J, Grune T, Chen W, Zhao Y, Jia M, Wang Y, Liu Z, Höhn A. Methionine restriction - Association with redox homeostasis and implications on aging and diseases. Redox Biol 2022; 57:102464. [PMID: 36152485 PMCID: PMC9508608 DOI: 10.1016/j.redox.2022.102464] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 08/26/2022] [Accepted: 08/30/2022] [Indexed: 10/31/2022] Open
Abstract
Methionine is an essential amino acid, involved in the promotion of growth, immunity, and regulation of energy metabolism. Over the decades, research has long focused on the beneficial effects of methionine supplementation, while data on positive effects of methionine restriction (MR) were first published in 1993. MR is a low-methionine dietary intervention that has been reported to ameliorate aging and aging-related health concomitants and diseases, such as obesity, type 2 diabetes, and cognitive disorders. In addition, MR seems to be an approach to prolong lifespan which has been validated extensively in various animal models, such as Caenorhabditis elegans, Drosophila, yeast, and murine models. MR appears to be associated with a reduction in oxidative stress via so far mainly undiscovered mechanisms, and these changes in redox status appear to be one of the underlying mechanisms for lifespan extension and beneficial health effects. In the present review, the association of methionine metabolism pathways with redox homeostasis is described. In addition, the effects of MR on lifespan, age-related implications, comorbidities, and diseases are discussed.
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Affiliation(s)
- Yuyu Zhang
- Laboratory of Functional Chemistry and Nutrition of Food, College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Julia Jelleschitz
- German Institute of Human Nutrition (DIfE) Potsdam-Rehbruecke, Department of Molecular Toxicology, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany
| | - Tilman Grune
- German Institute of Human Nutrition (DIfE) Potsdam-Rehbruecke, Department of Molecular Toxicology, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany; German Center for Diabetes Research (DZD), 85764, Muenchen-Neuherberg, Germany; NutriAct-Competence Cluster Nutrition Research Berlin-Potsdam, Nuthetal, Germany; German Center for Cardiovascular Research (DZHK), Berlin, Germany; Institute of Nutrition, University of Potsdam, Nuthetal, 14558, Germany
| | - Weixuan Chen
- Laboratory of Functional Chemistry and Nutrition of Food, College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Yihang Zhao
- Laboratory of Functional Chemistry and Nutrition of Food, College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Mengzhen Jia
- Laboratory of Functional Chemistry and Nutrition of Food, College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Yajie Wang
- Laboratory of Functional Chemistry and Nutrition of Food, College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Zhigang Liu
- Laboratory of Functional Chemistry and Nutrition of Food, College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China; German Institute of Human Nutrition (DIfE) Potsdam-Rehbruecke, Department of Molecular Toxicology, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany.
| | - Annika Höhn
- German Institute of Human Nutrition (DIfE) Potsdam-Rehbruecke, Department of Molecular Toxicology, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany; German Center for Diabetes Research (DZD), 85764, Muenchen-Neuherberg, Germany.
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Hydrogen Sulfide Attenuates High-Fat Diet-Induced Obesity: Involvement of mTOR/IKK/NF-κB Signaling Pathway. Mol Neurobiol 2022; 59:6903-6917. [PMID: 36053437 DOI: 10.1007/s12035-022-03004-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 08/16/2022] [Indexed: 10/14/2022]
Abstract
Obesity has become a public health epidemic worldwide and is associated with many diseases with high mortality including hypertension, diabetes, and heart disease. High-fat diet (HFD)-induced energy imbalance is one of the primary causes of obesity, but the underlying mechanisms are not fully elucidated. Our study showed that HFD reduced the level of hydrogen sulfide (H2S) and its catalytic enzyme cystathionine β-synthase (CBS) in mouse hypothalamus and plasma. We found that HFD activated mTOR, IKK/NF-κB, the main pathway regulating inflammation. Activation of inflammatory pathway promoted the production of pro-inflammatory cytokines including IL-6, IL-1β, and TNF-α, which caused cell damage and loss in the hypothalamus. The disturbance of the hypothalamic neuron circuits resulted in body weight gain in HFD-induced mice. Importantly, we also showed that restoration of H2S level with NaHS or activation of CBS with SAMe attenuated HFD-induced activation of mTOR, IKK/NF-κB signaling, which reduced the inflammation and the neuronal cell loss in the hypothalamus, and also inhibited body weight gain in mice. The same effects were obtained by inhibiting mTOR or NF-κB, which suggested that mTOR and NF-κB were the critical molecular factors involved in hypothalamic inflammation. Taken together, this study identified that HFD-induced hypothalamus inflammation plays a critical role in the development of obesity. Moreover, the inhibition of hypothalamic inflammation by regaining H2S level could be a potential therapeutic to prevent the development of obesity.
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Reactive sulfur species and their significance in health and disease. Biosci Rep 2022; 42:231692. [PMID: 36039860 PMCID: PMC9484011 DOI: 10.1042/bsr20221006] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 08/23/2022] [Accepted: 08/25/2022] [Indexed: 11/23/2022] Open
Abstract
Reactive sulfur species (RSS) have been recognized in the last two decades as very important molecules in redox regulation. They are involved in metabolic processes and, in this way, they are responsible for maintenance of health. This review summarizes current information about the essential biological RSS, including H2S, low molecular weight persulfides, protein persulfides as well as organic and inorganic polysulfides, their synthesis, catabolism and chemical reactivity. Moreover, the role of RSS disturbances in various pathologies including vascular diseases, chronic kidney diseases, diabetes mellitus Type 2, neurological diseases, obesity, chronic obstructive pulmonary disease and in the most current problem of COVID-19 is presented. The significance of RSS in aging is also mentioned. Finally, the possibilities of using the precursors of various forms of RSS for therapeutic purposes are discussed.
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Xue W, Zhang Q, Chen Y, Zhu Y. Hydrogen Sulfide Improves Angiogenesis by Regulating the Transcription of pri-miR-126 in Diabetic Endothelial Cells. Cells 2022; 11:cells11172651. [PMID: 36078059 PMCID: PMC9455028 DOI: 10.3390/cells11172651] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/16/2022] [Accepted: 08/23/2022] [Indexed: 01/19/2023] Open
Abstract
Introduction: Diabetes mellitus results in high rates of cardiovascular disease, such as microcirculation disorder of the lower limbs, with angiogenesis impairment being the main factor. The endothelium functions as a barrier between blood and the vessel wall. Vascular endothelial cell dysfunction caused by hyperglycemia is the main factor leading to angiogenesis impairment. Hydrogen sulfide (H2S) and miR-126-3p are known for their pro-angiogenesis effects; however, little is known about how H2S regulates miR-126-3p to promote angiogenesis under high-glucose conditions. Objectives: The main objective of this research was to explore how H2S regulates the miR-126-3p levels under high-glucose conditions. Methods: We evaluated the pro-angiogenesis effects of H2S in the diabetic hindlimb of an ischemia mice model and in vivo Matrigel plugs. Two microRNA datasets were used to screen microRNAs regulated by both diabetes and H2S. The mRNA and protein levels were detected through real-time PCR and Western blot, respectively. Immunofluorescent staining was also used to assess the capillary density and to evaluate the protein levels in vascular endothelial cells. Human umbilical vein endothelial cells (HUVECs) were used in in vitro experiments. A scratch wound-healing assay was applied to detect the migration ability of endothelial cells. Methylated DNA immunoprecipitation combined with real-time PCR was chosen to identify the DNA methylation level in the HUVECs. Results: Exogenous H2S improved angiogenesis in diabetic mice. miR-126-3p was regulated by both diabetes and H2S. Exogenous H2S up-regulated the miR-126-3p level and recovered the migration rate of endothelial cells via down-regulating the DNMT1 protein level, which was increased by high glucose. Furthermore, DNMT1 upregulation in the HUVECs increased the methylation levels of the gene sequences upstream of miR-126-3p and then inhibited the transcription of primary-miR-126, thus decreasing the miR-126-3p level. CSE overexpression in the HUVECs rescued the miR-126-3p level, by decreasing the methylation level to improve migration. Conclusion: H2S increases the miR-126-3p level through down-regulating the methylation level, by decreasing the DNMT1 protein level induced by high glucose, thus improving the angiogenesis originally impaired by high glucose.
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Affiliation(s)
- Wenlong Xue
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
- Shanghai Key Laboratory of Bioactive Small Molecules, Fudan University, Shanghai 200032, China
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Fudan University, Shanghai 200032, China
| | - Qingqing Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
- Shanghai Key Laboratory of Bioactive Small Molecules, Fudan University, Shanghai 200032, China
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Fudan University, Shanghai 200032, China
| | - Ying Chen
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
- Shanghai Key Laboratory of Bioactive Small Molecules, Fudan University, Shanghai 200032, China
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Fudan University, Shanghai 200032, China
| | - Yichun Zhu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
- Shanghai Key Laboratory of Bioactive Small Molecules, Fudan University, Shanghai 200032, China
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Fudan University, Shanghai 200032, China
- Correspondence: ; Tel./Fax: +86-21-5423-7098
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Hydrogen Sulfide Regulates Irisin and Glucose Metabolism in Myotubes and Muscle of HFD-Fed Diabetic Mice. Antioxidants (Basel) 2022; 11:antiox11071369. [PMID: 35883859 PMCID: PMC9311985 DOI: 10.3390/antiox11071369] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 07/04/2022] [Accepted: 07/13/2022] [Indexed: 12/26/2022] Open
Abstract
Irisin, a novel myokine, is secreted by the muscle following proteolytic cleavage of fibronectin type III domain containing 5 (FNDC5) and is considered a novel regulator of glucose homeostasis. Cystathionine γ-lyase (CSE) produces hydrogen sulfide (H2S) and is involved in glucose homeostasis. We examined the hypothesis that H2S deficiency leads to decreased FNDC5 and irisin secretion, and thereby alters glucose metabolism. High-fat diet-fed mice exhibited elevated blood glucose and significantly reduced levels of CSE, H2S, and PGC-1α, with decreased FNDC5/irisin levels and increased oxidative stress in the muscle compared with those of normal diet-fed mice (control). High glucose or palmitate decreases CSE/PGC-1α/FNDC5 levels and glucose uptake in myotubes. Inhibitors (propargylglycine and aminooxyacetate) of H2S producing enzymes or CSE siRNA significantly decreased levels of H2S and FNDC5 along with PGC-1α; similar H2S-deficient conditions also resulted in decreased GLUT4 and glucose uptake. The levels of H2S, PGC-1α, and FNDC5 and glucose uptake were significantly upregulated after treatment with l-cysteine or an H2S donor. Myoblast differentiation showed upregulation of PGC-1α and FNDC5, which was consistent with the increased expression of CSE/H2S. These findings suggest that the upregulation of H2S levels can have beneficial effects on glucose homeostasis via activation of the PGC-1α/FNDC5/irisin signaling pathway.
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Kasuno K, Yodoi J, Iwano M. Urinary Thioredoxin as a Biomarker of Renal Redox Dysregulation and a Companion Diagnostic to Identify Responders to Redox-Modulating Therapeutics. Antioxid Redox Signal 2022; 36:1051-1065. [PMID: 34541903 DOI: 10.1089/ars.2021.0194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Significance: The development and progression of renal diseases, including acute kidney injury (AKI) and chronic kidney disease (CKD), are the result of heterogeneous pathophysiology that reflects a range of environmental factors and, in a lesser extent, genetic mutations. The pathophysiology specific to most kidney diseases is not currently identified; therefore, these diseases are diagnosed based on non-pathological factors. For that reason, pathophysiology-based companion diagnostics for selection of pathophysiology-targeted treatments have not been available, which impedes personalized medicine in kidney disease. Recent Advances: Pathophysiology-targeted therapeutic agents are now being developed for the treatment of redox dysregulation. Redox modulation therapeutics, including bardoxolone methyl, suppresses the onset and progression of AKI and CKD. On the other hand, pathophysiology-targeted diagnostics for renal redox dysregulation are also being developed. Urinary thioredoxin (TXN) is a biomarker that can be used to diagnose tubular redox dysregulation. AKI causes oxidation and urinary excretion of TXN, which depletes TXN from the tubules, resulting in tubular redox dysregulation. Urinary TXN is selectively elevated at the onset of AKI and correlates with the progression of CKD in diabetic nephropathy. Critical Issues: Diagnostic methods should provide information about molecular mechanisms that aid in the selection of appropriate therapies to improve the prognosis of kidney disease. Future Directions: A specific diagnostic method enabling detection of redox dysregulation based on pathological molecular mechanisms is much needed and could provide the first step toward personalized medicine in kidney disease. Urinary TXN is a candidate for a companion diagnostic method to identify responders to redox-modulating therapeutics. Antioxid. Redox Signal. 36, 1051-1065.
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Affiliation(s)
- Kenji Kasuno
- Department of Nephrology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.,Life Science Innovation Center, University of Fukui, Fukui, Japan
| | - Junji Yodoi
- Institute for Virus Research, Kyoto University, Kyoto, Japan.,Japan Biostress Research Promotion Alliance (JBPA), Kyoto, Japan
| | - Masayuki Iwano
- Department of Nephrology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
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25
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Wang Y, Li S, Zhu X, Shi X, Liu X, Zhang H. A novel H2O2 activated NIR fluorescent probe for accurately visualizing H2S fluctuation during oxidative stress. Anal Chim Acta 2022; 1202:339670. [DOI: 10.1016/j.aca.2022.339670] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 02/27/2022] [Accepted: 02/28/2022] [Indexed: 01/22/2023]
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Liu J, Zhao W, Gao ZW, Liu N, Zhang WH, Ling H. Effects of Exogenous Hydrogen Sulfide on Diabetic Metabolic Disorders in db/db Mice Are Associated With Gut Bacterial and Fungal Microbiota. Front Cell Infect Microbiol 2022; 12:801331. [PMID: 35425717 PMCID: PMC9001961 DOI: 10.3389/fcimb.2022.801331] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 03/02/2022] [Indexed: 01/15/2023] Open
Abstract
The effects of hydrogen sulfide (H2S) on diabetic metabolic disorders are still controversial, and the mechanisms underlying these effects remain largely unknown. This study was conducted to investigate the potential relationship between the gut microbiota and the improvement of diabetic metabolic disorders by exogenous H2S in obese db/db mice. The db/db mice were treated with sodium hydrosulfide (NaHS) (80 μmol/kg), or vehicle for 16 weeks, respectively. We measured the serum H2S, obesity parameters, glucose homeostasis, and triglyceride. The sequencing of bacterial 16S rRNA gene and fungal internal transcribed spacer (ITS) in the cecal contents of NaHS-treated mice was performed to evaluate the gut microbial communities. We found that supplying exogenous H2S for 16 weeks significantly inhibited the increase of serum triglyceride, blood glucose, and insulin levels and altered specifically the gut bacterial microbiota structure in db/db mice. The relative abundance of some bacterial genera was correlated with the H2S or blood glucose level. Indeed, exogenous H2S increased Firmicutes and decreased Bacteroidetes at the phylum level along with changes of abundance of multifarious genera. Among them, Unclassified_Enterobacteriaceae, Prevotella, and Lactobacillus decreased and Unclassified_Ruminococcaceae, Oscillospira, Ruminococcus, Sutterella, and Desulfovibrio increased. For fungi, exogenous H2S decreased the abundance of Candida and Aspergillus. Here we demonstrated that, in diabetes, microbial dysbiosis may not be just limited to bacteria due to the inter-linked metabolic interactions among bacteria and fungi in the gut. The beneficial effects of exogenous H2S on diabetic metabolic disorders are likely associated with the alterations of specific microbiota.
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Affiliation(s)
- Jian Liu
- Department of Microbiology, Harbin Medical University, Harbin, China
| | - Wei Zhao
- Department of Microbiology, Harbin Medical University, Harbin, China
| | - Zi-Wei Gao
- Department of Microbiology, Harbin Medical University, Harbin, China
| | - Ning Liu
- Department of Pathophysiology, Harbin Medical University, Harbin, China
| | - Wei-Hua Zhang
- Department of Pathophysiology, Harbin Medical University, Harbin, China
- *Correspondence: Hong Ling, ; Wei-Hua Zhang,
| | - Hong Ling
- Department of Microbiology, Harbin Medical University, Harbin, China
- Wu Lien-Teh Institute, Harbin Medical University, Harbin, China
- Heilongjiang Provincial Key Laboratory of Infection and Immunity, Harbin, China
- Key Laboratory of Pathogen Biology, Harbin, China
- *Correspondence: Hong Ling, ; Wei-Hua Zhang,
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Bahadoran Z, Jeddi S, Mirmiran P, Kashfi K, Azizi F, Ghasemi A. Association between serum hydrogen sulfide concentrations and dysglycemia: a population-based study. BMC Endocr Disord 2022; 22:79. [PMID: 35351094 PMCID: PMC8962595 DOI: 10.1186/s12902-022-00995-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 03/21/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND AND AIM Hydrogen sulfide (H2S), a signaling gasotransmitter, is involved in carbohydrate metabolism. Here, we aimed to assess the potential association between serum H2S and dysglycemia in the framework of a population-based study. METHODS Adults men and women with completed data (n = 798), who participated in the Tehran Lipid and Glucose Study (2014-2017) were included in the study. Medians of fasting serum H2S concentration were compared across the glycemic status of the participants, defined as type 2 diabetes mellitus (T2DM), isolated impaired fasting glucose (IIFG), isolated impaired glucose tolerance (IIGT), combined IFG-IGT, and normal glycemia [i.e., those with both normal fasting glucose (NFG) and normal glucose tolerance (NGT)]. Multinomial logistic regression was used to assess potential associations between serum H2S and the defined glycemic status. RESULTS Mean age of the participants was 45.1 ± 14.0 y, and 48.1% were men. Prevalence of T2DM, IIFG, IIGT, and combined IFG-IGT was 13.9, 9.1, 8.1, and 4.8% respectively. No significant difference was observed in serum H2S concentrations between the groups. Lower serum H2S (< 39.6 µmol/L) was associated with an increased chance of having IIGT (OR = 1.96, 95% CI = 1.15-3.34) in the adjusted model. CONCLUSION Reduced serum H2S level may be associated with impaired glucose tolerance.
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Affiliation(s)
- Zahra Bahadoran
- Nutrition and Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sajad Jeddi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, No. 24, Sahid-Erabi St, Yemen St, Chamran Exp, P.O.Box: 19395-4763, Tehran, Iran
| | - Parvin Mirmiran
- Department of Clinical Nutrition and Human Dietetics, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Khosrow Kashfi
- Department of Molecular, Cellular, and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY, 10031, USA
| | - Fereidoun Azizi
- Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Asghar Ghasemi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, No. 24, Sahid-Erabi St, Yemen St, Chamran Exp, P.O.Box: 19395-4763, Tehran, Iran.
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Reduced Levels of H2S in Diabetes-Associated Osteoarthritis Are Linked to Hyperglycaemia, Nrf-2/HO-1 Signalling Downregulation and Chondrocyte Dysfunction. Antioxidants (Basel) 2022; 11:antiox11040628. [PMID: 35453313 PMCID: PMC9024787 DOI: 10.3390/antiox11040628] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 03/21/2022] [Accepted: 03/23/2022] [Indexed: 12/26/2022] Open
Abstract
Different findings indicate that type 2 diabetes is an independent risk factor for osteoarthritis (OA). However, the mechanisms underlying the connection between both diseases remain unclear. Changes in the balance of hydrogen sulphide (H2S) are thought to play an important role in the pathogenesis of diabetes and its complications, although its role is still controversial. In this study, we examined the modulation of H2S levels in serum and chondrocytes from OA diabetic (DB) and non-diabetic (non-DB) patients and in cells under glucose stress, in order to elucidate whether impairment in H2S-mediated signalling could participate in the onset of DB-related OA. Here, we identified a reduction in H2S synthesis in the cartilage from OA-DB patients and in cells under glucose stress, which is associated with hyperglycaemia-mediated dysregulation of chondrocyte metabolism. In addition, our results indicate that H2S is an inductor of the Nrf-2/HO-1 signalling pathway in cartilage, but is also a downstream target of Nrf-2 transcriptional activity. Thereby, impairment of the H2S/Nrf-2 axis under glucose stress or DB triggers chondrocyte catabolic responses, favouring the disruption of cartilage homeostasis that characterizes OA pathology. Finally, our findings highlight the benefits of the use of exogeneous sources of H2S in the treatment of DB-OA patients, and warrant future clinical studies.
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Mateus I, Prip-Buus C. Hydrogen sulphide in liver glucose/lipid metabolism and non-alcoholic fatty liver disease. Eur J Clin Invest 2022; 52:e13680. [PMID: 34519030 PMCID: PMC9285505 DOI: 10.1111/eci.13680] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 08/24/2021] [Accepted: 09/10/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND For a long time, hydrogen sulphide (H2 S) was considered only as a toxic gas, inhibiting mitochondrial respiration at the level of cytochrome c oxidase, and an environmental pollutant. Nowadays, H2 S is recognized as the third mammalian gasotransmitter, playing an important role in inflammation, septic shock, ischaemia reperfusion events, cardiovascular disease and more recently in liver physiology and chronic liver diseases such as non-alcoholic fatty liver disease (NAFLD). METHODS This narrative review is based on literature search using PubMed. RESULTS From a bioenergetic perspective, H2 S is a very unique molecule, serving as a mitochondrial poison at high concentrations or as an inorganic mitochondrial substrate at low concentrations. By using transgenic animal models to specifically modulate liver H2 S biosynthesis or exogenous compounds that release H2 S, several studies demonstrated that H2 S is a key player in liver glucose and lipid metabolism. Liver H2 S content and biosynthesis were also altered in NAFLD animal models with the in vivo administration of H2 S-releasing molecules preventing the further escalation into non-alcoholic-steatohepatitis. Liver steady-state levels of H2 S, and hence its cell signalling properties, are controlled by a tight balance between its biosynthesis, mainly through the transsulphuration pathway, and its mitochondrial oxidation via the sulphide oxidizing unit. However, studies investigating mitochondrial H2 S oxidation in liver dysfunction still remain scarce. CONCLUSIONS Since H2 S emerges as a key regulator of liver metabolism and metabolic flexibility, further understanding the physiological relevance of mitochondrial H2 S oxidation in liver energy homeostasis and its potential implication in chronic liver diseases are of great interest.
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Affiliation(s)
- Inês Mateus
- Institut Cochin, INSERM, CNRS, Université de Paris, Paris, France
| | - Carina Prip-Buus
- Institut Cochin, INSERM, CNRS, Université de Paris, Paris, France
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30
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Role of Hydrogen Sulfide and Polysulfides in the Regulation of Lipolysis in the Adipose Tissue: Possible Implications for the Pathogenesis of Metabolic Syndrome. Int J Mol Sci 2022; 23:ijms23031346. [PMID: 35163277 PMCID: PMC8836184 DOI: 10.3390/ijms23031346] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 01/21/2022] [Accepted: 01/24/2022] [Indexed: 02/04/2023] Open
Abstract
Hydrogen sulfide (H2S) and inorganic polysulfides are important signaling molecules; however, little is known about their role in the adipose tissue. We examined the effect of H2S and polysulfides on adipose tissue lipolysis. H2S and polysulfide production by mesenteric adipose tissue explants in rats was measured. The effect of Na2S and Na2S4, the H2S and polysulfide donors, respectively, on lipolysis markers, plasma non-esterified fatty acids (NEFA) and glycerol, was examined. Na2S but not Na2S4 increased plasma NEFA and glycerol in a time- and dose-dependent manner. Na2S increased cyclic AMP but not cyclic GMP concentration in the adipose tissue. The effect of Na2S on NEFA and glycerol was abolished by the specific inhibitor of protein kinase A, KT5720. The effect of Na2S on lipolysis was not abolished by propranolol, suggesting no involvement of β-adrenergic receptors. In addition, Na2S had no effect on phosphodiesterase activity in the adipose tissue. Obesity induced by feeding rats a highly palatable diet for 1 month was associated with increased plasma NEFA and glycerol concentrations, as well as greater H2S production in the adipose tissue. In conclusion, H2S stimulates lipolysis and may contribute to the enhanced lipolysis associated with obesity.
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31
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Pavão ML, Ferin R, Lima A, Baptista J. Cysteine and related aminothiols in cardiovascular disease, obesity and insulin resistance. Adv Clin Chem 2022; 109:75-127. [DOI: 10.1016/bs.acc.2022.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Bourgonje AR, Offringa AK, van Eijk LE, Abdulle AE, Hillebrands JL, van der Voort PHJ, van Goor H, van Hezik EJ. N-Acetylcysteine and Hydrogen Sulfide in Coronavirus Disease 2019. Antioxid Redox Signal 2021; 35:1207-1225. [PMID: 33607929 DOI: 10.1089/ars.2020.8247] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Significance: Hydrogen sulfide (H2S) is one of the three main gasotransmitters that are endogenously produced in humans and are protective against oxidative stress. Recent findings from studies focusing on coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), shifted our attention to a potentially modulatory role of H2S in this viral respiratory disease. Recent Advances: H2S levels at hospital admission may be of importance since this gasotransmitter has been shown to be protective against lung damage through its antiviral, antioxidant, and anti-inflammatory actions. Furthermore, many COVID-19 cases have been described demonstrating remarkable clinical improvement upon administration of high doses of N-acetylcysteine (NAC). NAC is a renowned pharmacological antioxidant substance acting as a source of cysteine, thereby promoting endogenous glutathione (GSH) biosynthesis as well as generation of sulfane sulfur species when desulfurated to H2S. Critical Issues: Combining H2S physiology and currently available knowledge of COVID-19, H2S is hypothesized to target three main vulnerabilities of SARS-CoV-2: (i) cell entry through interfering with functional host receptors, (ii) viral replication through acting on RNA-dependent RNA polymerase (RdRp), and (iii) the escalation of inflammation to a potentially lethal hyperinflammatory cytokine storm (toll-like receptor 4 [TLR4] pathway and NLR family pyrin domain containing 3 [NLRP3] inflammasome). Future Directions: Dissecting the breakdown of NAC reveals the possibility of increasing endogenous H2S levels, which may provide a convenient rationale for the application of H2S-targeted therapeutics. Further randomized-controlled trials are warranted to investigate its definitive role.
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Affiliation(s)
- Arno R Bourgonje
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Annette K Offringa
- Microbiology and System Biology, Netherlands Organisation for Applied Scientific Research, Zeist, the Netherlands
| | - Larissa E van Eijk
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Amaal E Abdulle
- Division of Vascular Medicine, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Jan-Luuk Hillebrands
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Peter H J van der Voort
- Department of Critical Care Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Harry van Goor
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Ed J van Hezik
- Visiting Consultant Chest Physician, formerly Walcheren Hospital, Vlissingen, the Netherlands
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Kamat V, Robbings BM, Jung SR, Kelly J, Hurley JB, Bube KP, Sweet IR. Fluidics system for resolving concentration-dependent effects of dissolved gases on tissue metabolism. eLife 2021; 10:e66716. [PMID: 34734803 PMCID: PMC8660022 DOI: 10.7554/elife.66716] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Accepted: 11/01/2021] [Indexed: 12/15/2022] Open
Abstract
Oxygen (O2) and other dissolved gases such as the gasotransmitters H2S, CO, and NO affect cell metabolism and function. To evaluate effects of dissolved gases on processes in tissue, we developed a fluidics system that controls dissolved gases while simultaneously measuring parameters of electron transport, metabolism, and secretory function. We use pancreatic islets, retina, and liver from rodents to highlight its ability to assess effects of O2 and H2S. Protocols aimed at emulating hypoxia-reperfusion conditions resolved a previously unrecognized transient spike in O2 consumption rate (OCR) following replenishment of O2, and tissue-specific recovery of OCR following hypoxia. The system revealed both inhibitory and stimulatory effects of H2S on insulin secretion rate from isolated islets. The unique ability of this new system to quantify metabolic state and cell function in response to precise changes in dissolved gases provides a powerful platform for cell physiologists to study a wide range of disease states.
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Affiliation(s)
- Varun Kamat
- University of Washington Medicine Diabetes Institute, University of WashingtonSeattleUnited States
| | - Brian M Robbings
- University of Washington Medicine Diabetes Institute, University of WashingtonSeattleUnited States
- Department of Biochemistry, University of WashingtonSeattleUnited States
| | - Seung-Ryoung Jung
- University of Washington Medicine Diabetes Institute, University of WashingtonSeattleUnited States
| | | | - James B Hurley
- Department of Biochemistry, University of WashingtonSeattleUnited States
| | - Kenneth P Bube
- Department of Mathematics, University of WashingtonSeattleUnited States
| | - Ian R Sweet
- University of Washington Medicine Diabetes Institute, University of WashingtonSeattleUnited States
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Fan D, Huang H, Wang X, Liu J, Liu B, Yin F. Inverse association of plasma hydrogen sulfide levels with visceral fat area among Chinese young men: a cross-sectional study. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2021; 65:269-276. [PMID: 33740335 PMCID: PMC10065337 DOI: 10.20945/2359-3997000000339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Objective To investigate the association between plasma Hydrogen Sulfide (H2S) levels and visceral fat area (VFA) among Chinese young men. Methods This cross-sectional study involved 156 Chinese male subjects, aged 18-45 years, who visited the First Hospital of Qinhuangdao (Hebei, China) in 2014 for annual health check-up. Participants were categorized into: low (VFA < 75.57 cm2), medium (75.57 cm2 ≤ VFA<100.37 cm2), and high (VFA ≥ 100.37 cm2) (n = 52/group). We estimated VFA and plasma H2S levels by using bioelectrical impedance analysis and a fluorescence probe-based approach, respectively. The associations of H2S with VFA and obesity anthropometric measures were assessed. Results In the high VFA group, the body mass index (BMI, 30.4 ± 2.45 kg/m2), total body fat (TBF, 27.9 ± 3.23 kg), plasma H2S (3.5 µmol/L), free fatty acid (FFA, 0.6 ± 0.24 mmol/L), triglyceride (TG, 2.0 mmol/L), and total cholesterol (TC, 5.5 ± 1.02 mmol/L) levels were significantly higher than that of those of the low and medium VFA groups, respectively (P < 0.05). Plasma H2S levels were found to be inversely correlated with VFA, TBF, waist circumference, BMI, FFA, LnFINS, LnHOMA-IR, LnTG, TC, and LDL-C (P < 0.05). Multiple backward stepwise regression analysis revealed an inverse correlation of plasma H2S levels with FFA (β = -0.214, P = 0.005) and VFA (β = -0.429, P < 0.001), independent of adiposity measures and other confounding factors. Conclusion VFA was independently and inversely associated with plasma H2S levels among Chinese young men. Therefore, determining plasma H2S levels could aid in the assessment of abnormal VAT distribution.
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Affiliation(s)
- Dongmei Fan
- Department of Endocrinology, The First Hospital of Qinhuangdao, Qinhuangdao, China
| | - Huiyan Huang
- Department of Endocrinology, Dalian Hospital affiliated to Shengjing Hospital of China Medical University, Shenyang, China
| | - Xing Wang
- Department of Endocrinology, The First Hospital of Qinhuangdao, Qinhuangdao, China
| | - Junru Liu
- Department of Endocrinology, The First Hospital of Qinhuangdao, Qinhuangdao, China
| | - Bowei Liu
- Department of Endocrinology, The First Hospital of Qinhuangdao, Qinhuangdao, China
| | - Fuzai Yin
- Department of Endocrinology, The First Hospital of Qinhuangdao, Qinhuangdao, China,
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The Role of Obesity-Induced Perivascular Adipose Tissue (PVAT) Dysfunction in Vascular Homeostasis. Nutrients 2021; 13:nu13113843. [PMID: 34836100 PMCID: PMC8621306 DOI: 10.3390/nu13113843] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Revised: 10/23/2021] [Accepted: 10/26/2021] [Indexed: 12/17/2022] Open
Abstract
Perivascular adipose tissue (PVAT) is an additional special type of adipose tissue surrounding blood vessels. Under physiological conditions, PVAT plays a significant role in regulation of vascular tone, intravascular thermoregulation, and vascular smooth muscle cell (VSMC) proliferation. PVAT is responsible for releasing adipocytes-derived relaxing factors (ADRF) and perivascular-derived relaxing factors (PDRF), which have anticontractile properties. Obesity induces increased oxidative stress, an inflammatory state, and hypoxia, which contribute to PVAT dysfunction. The exact mechanism of vascular dysfunction in obesity is still not well clarified; however, there are some pathways such as renin-angiotensin-aldosterone system (RAAS) disorders and PVAT-derived factor dysregulation, which are involved in hypertension and endothelial dysfunction development. Physical activity has a beneficial effect on PVAT function among obese patients by reducing the oxidative stress and inflammatory state. Diet, which is the second most beneficial non-invasive strategy in obesity treatment, may have a positive impact on PVAT-derived factors and may restore the balance in their concentration.
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36
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Juin SK, Pushpakumar S, Sen U. GYY4137 Regulates Extracellular Matrix Turnover in the Diabetic Kidney by Modulating Retinoid X Receptor Signaling. Biomolecules 2021; 11:biom11101477. [PMID: 34680110 PMCID: PMC8533431 DOI: 10.3390/biom11101477] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 09/21/2021] [Accepted: 10/04/2021] [Indexed: 12/20/2022] Open
Abstract
Diabetic kidney is associated with an accumulation of extracellular matrix (ECM) leading to renal fibrosis. Dysregulation of retinoic acid metabolism involving retinoic acid receptors (RARs) and retinoid X receptors (RXRs) has been shown to play a crucial role in diabetic nephropathy (DN). Furthermore, RARs and peroxisome proliferator-activated receptor γ (PPARγ) are known to control the RXR-mediated transcriptional regulation of several target genes involved in DN. Recently, RAR and RXR have been shown to upregulate plasminogen activator inhibitor-1 (PAI-1), a major player involved in ECM accumulation and renal fibrosis during DN. Interestingly, hydrogen sulfide (H2S) has been shown to ameliorate adverse renal remodeling in DN. We investigated the role of RXR signaling in the ECM turnover in diabetic kidney, and whether H2S can mitigate ECM accumulation by modulating PPAR/RAR-mediated RXR signaling. We used wild-type (C57BL/6J), diabetic (C57BL/6-Ins2Akita/J) mice and mouse mesangial cells (MCs) as experimental models. GYY4137 was used as a H2S donor. Results showed that in diabetic kidney, the expression of PPARγ was decreased, whereas upregulations of RXRα, RXRβ, and RARγ1 expression were observed. The changes were associated with elevated PAI-1, MMP-9 and MMP-13. In addition, the expressions of collagen IV, fibronectin and laminin were increased, whereas elastin expression was decreased in the diabetic kidney. Excessive collagen deposition was observed predominantly in the peri-glomerular and glomerular regions of the diabetic kidney. Immunohistochemical localization revealed elevated expression of fibronectin and laminin in the glomeruli of the diabetic kidney. GYY4137 reversed the pathological changes. Similar results were observed in in vitro experiments. In conclusion, our data suggest that RXR signaling plays a significant role in ECM turnover, and GYY4137 modulates PPAR/RAR-mediated RXR signaling to ameliorate PAI-1-dependent adverse ECM turnover in DN.
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Affiliation(s)
| | | | - Utpal Sen
- Correspondence: ; Tel.: +1-502-852-2030; Fax: +1-502-852-6239
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37
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Sun Y, Zhang L, Lu B, Wen J, Wang M, Zhang S, Li Q, Shu F, Lu F, Liu N, Peng S, Zhao Y, Dong S, Lu F, Zhang W, Wang Y. Hydrogen sulphide reduced the accumulation of lipid droplets in cardiac tissues of db/db mice via Hrd1 S-sulfhydration. J Cell Mol Med 2021; 25:9154-9167. [PMID: 34562065 PMCID: PMC8500968 DOI: 10.1111/jcmm.16781] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 06/18/2021] [Accepted: 06/24/2021] [Indexed: 12/19/2022] Open
Abstract
Accumulation of lipid droplets (LDs) induces cardiac dysfunctions in type 2 diabetes patients. Recent studies have shown that hydrogen sulphide (H2 S) ameliorates cardiac functions in db/db mice, but its regulation on the formation of LDs in cardiac tissues is unclear. Db/db mice were injected with NaHS (40 μmol·kg-1 ) for twelve weeks. H9c2 cells were treated with high glucose (40 mmol/L), oleate (200 µmol/L), palmitate (200 µmol/L) and NaHS (100 µmol/L) for 48 hours. Plasmids for the overexpression of wild-type Hrd1 and Hrd1 mutated at Cys115 were constructed. The interaction between Hrd1 and DGAT1 and DGAT2, the ubiquitylation level of DGAT1 and 2, the S-sulfhydration of Hrd1 were measured. Exogenous H2 S ameliorated the cardiac functions, decreased ER stress and reduced the number of LDs in db/db mice. Exogenous H2 S could elevate the ubiquitination level of DGAT 1 and 2 and increased the expression of Hrd1 in cardiac tissues of db/db mice. The S-sulfhydration of Hrd1 by NaHS enhanced the interaction between Hrd1 and DGAT1 and 2 to inhibit the formation of LD. Our findings suggested that H2 S modified Hrd1 S-sulfhydration at Cys115 to reduce the accumulation of LDs in cardiac tissues of db/db mice.
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Affiliation(s)
- Yu Sun
- Department of Pathophysiology, Harbin Medical University, Harbin, China
| | - Linxue Zhang
- Department of Pathophysiology, Harbin Medical University, Harbin, China
| | - Baoling Lu
- Department of Infectious, The Fourth Hospital of Harbin Medical University, Harbin, China
| | - Jingchen Wen
- Department of Pathophysiology, Harbin Medical University, Harbin, China
| | - Mengyi Wang
- Department of Pathophysiology, Harbin Medical University, Harbin, China
| | - Shiwu Zhang
- Department of Pathophysiology, Harbin Medical University, Harbin, China
| | - Qianzhu Li
- Department of Pathophysiology, Harbin Medical University, Harbin, China
| | - Feng Shu
- Department of Pathophysiology, Harbin Medical University, Harbin, China
| | - Fangping Lu
- Department of Pathophysiology, Harbin Medical University, Harbin, China
| | - Ning Liu
- Department of Pathophysiology, Harbin Medical University, Harbin, China
| | - Shuo Peng
- Department of Pathophysiology, Harbin Medical University, Harbin, China
| | - Yajun Zhao
- Department of Pathophysiology, Harbin Medical University, Harbin, China
| | - Shiyun Dong
- Department of Pathophysiology, Harbin Medical University, Harbin, China
| | - Fanghao Lu
- Department of Pathophysiology, Harbin Medical University, Harbin, China
| | - Weihua Zhang
- Department of Pathophysiology, Harbin Medical University, Harbin, China
| | - Yan Wang
- Department of Urologic Surgery, First Affiliated Hospital of Harbin Medical University, Harbin, China
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38
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Allen CL, Wolanska K, Malhi NK, Benest AV, Wood ME, Amoaku W, Torregrossa R, Whiteman M, Bates DO, Whatmore JL. Hydrogen Sulfide Is a Novel Protector of the Retinal Glycocalyx and Endothelial Permeability Barrier. Front Cell Dev Biol 2021; 9:724905. [PMID: 34557493 PMCID: PMC8452977 DOI: 10.3389/fcell.2021.724905] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 07/29/2021] [Indexed: 12/27/2022] Open
Abstract
Significantly reduced levels of the anti-inflammatory gaseous transmitter hydrogen sulfide (H2S) are observed in diabetic patients and correlate with microvascular dysfunction. H2S may protect the microvasculature by preventing loss of the endothelial glycocalyx. We tested the hypothesis that H2S could prevent or treat retinal microvascular endothelial dysfunction in diabetes. Bovine retinal endothelial cells (BRECs) were exposed to normal (NG, 5.5 mmol/L) or high glucose (HG, 25 mmol/L) ± the slow-release H2S donor NaGYY4137 in vitro. Glycocalyx coverage (stained with WGA-FITC) and calcein-labeled monocyte adherence were measured. In vivo, fundus fluorescein angiography (FFA) was performed in normal and streptozotocin-induced (STZ) diabetic rats. Animals received intraocular injection of NaGYY4137 (1 μM) or the mitochondrial-targeted H2S donor AP39 (100 nM) simultaneously with STZ (prevention) or on day 6 after STZ (treatment), and the ratio of interstitial to vascular fluorescence was used to estimate apparent permeability. NaGYY4137 prevented HG-induced loss of BREC glycocalyx, increased monocyte binding to BRECs (p ≤ 0.001), and increased overall glycocalyx coverage (p ≤ 0.001). In rats, the STZ-induced increase in apparent retinal vascular permeability (p ≤ 0.01) was significantly prevented by pre-treatment with NaGYY4137 and AP39 (p < 0.05) and stabilized by their post-STZ administration. NaGYY4137 also reduced the number of acellular capillaries (collagen IV + /IB4-) in the diabetic retina in both groups (p ≤ 0.05). We conclude that NaGYY4137 and AP39 protected the retinal glycocalyx and endothelial permeability barrier from diabetes-associated loss of integrity and reduced the progression of diabetic retinopathy (DR). Hydrogen sulfide donors that target the glycocalyx may therefore be a therapeutic candidate for DR.
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Affiliation(s)
- Claire L Allen
- Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | - Katarzyna Wolanska
- The Institute of Biomedical and Clinical Science, University of Exeter Medical School, St. Luke's Campus, University of Exeter, Exeter, United Kingdom
| | - Naseeb K Malhi
- Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | - Andrew V Benest
- Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | - Mark E Wood
- Biosciences, College of Life and Environmental Science, University of Exeter, Exeter, United Kingdom
| | - Winfried Amoaku
- Academic Ophthalmology, Division of Clinical Neuroscience, School of Medicine, University of Nottingham, Nottingham, United Kingdom
| | - Roberta Torregrossa
- The Institute of Biomedical and Clinical Science, University of Exeter Medical School, St. Luke's Campus, University of Exeter, Exeter, United Kingdom
| | - Matthew Whiteman
- The Institute of Biomedical and Clinical Science, University of Exeter Medical School, St. Luke's Campus, University of Exeter, Exeter, United Kingdom
| | - David O Bates
- Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | - Jacqueline L Whatmore
- The Institute of Biomedical and Clinical Science, University of Exeter Medical School, St. Luke's Campus, University of Exeter, Exeter, United Kingdom
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39
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Pacitti D, Scotton CJ, Kumar V, Khan H, Wark PAB, Torregrossa R, Hansbro PM, Whiteman M. Gasping for Sulfide: A Critical Appraisal of Hydrogen Sulfide in Lung Disease and Accelerated Aging. Antioxid Redox Signal 2021; 35:551-579. [PMID: 33736455 DOI: 10.1089/ars.2021.0039] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Hydrogen sulfide (H2S) is a gaseous signaling molecule involved in a plethora of physiological and pathological processes. It is primarily synthesized by cystathionine-β-synthase, cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase as a metabolite of the transsulfuration pathway. H2S has been shown to exert beneficial roles in lung disease acting as an anti-inflammatory and antiviral and to ameliorate cell metabolism and protect from oxidative stress. H2S interacts with transcription factors, ion channels, and a multitude of proteins via post-translational modifications through S-persulfidation ("sulfhydration"). Perturbation of endogenous H2S synthesis and/or levels have been implicated in the development of accelerated lung aging and diseases, including asthma, chronic obstructive pulmonary disease, and fibrosis. Furthermore, evidence indicates that persulfidation is decreased with aging. Here, we review the use of H2S as a biomarker of lung pathologies and discuss the potential of using H2S-generating molecules and synthesis inhibitors to treat respiratory diseases. Furthermore, we provide a critical appraisal of methods of detection used to quantify H2S concentration in biological samples and discuss the challenges of characterizing physiological and pathological levels. Considerations and caveats of using H2S delivery molecules, the choice of generating molecules, and concentrations are also reviewed. Antioxid. Redox Signal. 35, 551-579.
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Affiliation(s)
- Dario Pacitti
- Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, University of Exeter, Exeter, United Kingdom
| | - Chris J Scotton
- Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, University of Exeter, Exeter, United Kingdom
| | - Vinod Kumar
- Priority Research Centre for Healthy Lungs and Hunter Medical Research Institute, The University of Newcastle, Newcastle, Australia
| | - Haroon Khan
- Priority Research Centre for Healthy Lungs and Hunter Medical Research Institute, The University of Newcastle, Newcastle, Australia
| | - Peter A B Wark
- Priority Research Centre for Healthy Lungs and Hunter Medical Research Institute, The University of Newcastle, Newcastle, Australia
| | - Roberta Torregrossa
- Priority Research Centre for Healthy Lungs and Hunter Medical Research Institute, The University of Newcastle, Newcastle, Australia
| | - Philip M Hansbro
- Faculty of Science, Centre for Inflammation, Centenary Institute, University of Technology Sydney, Sydney, Australia
| | - Matthew Whiteman
- Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, University of Exeter, Exeter, United Kingdom
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40
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Comas F, Latorre J, Ortega F, Arnoriaga Rodríguez M, Kern M, Lluch A, Ricart W, Blüher M, Gotor C, Romero LC, Fernández-Real JM, Moreno-Navarrete JM. Activation of Endogenous H 2S Biosynthesis or Supplementation with Exogenous H 2S Enhances Adipose Tissue Adipogenesis and Preserves Adipocyte Physiology in Humans. Antioxid Redox Signal 2021; 35:319-340. [PMID: 33554726 DOI: 10.1089/ars.2020.8206] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Aims: To investigate the impact of exogenous hydrogen sulfide (H2S) and its endogenous biosynthesis on human adipocytes and adipose tissue in the context of obesity and insulin resistance. Results: Experiments in human adipose tissue explants and in isolated preadipocytes demonstrated that exogenous H2S or the activation of endogenous H2S biosynthesis resulted in increased adipogenesis, insulin action, sirtuin deacetylase, and PPARγ transcriptional activity, whereas chemical inhibition and gene knockdown of each enzyme generating H2S (CTH, CBS, MPST) led to altered adipocyte differentiation, cellular senescence, and increased inflammation. In agreement with these experimental data, visceral and subcutaneous adipose tissue expression of H2S-synthesising enzymes was significantly reduced in morbidly obese subjects in association with attenuated adipogenesis and increased markers of adipose tissue inflammation and senescence. Interestingly, weight-loss interventions (including bariatric surgery or diet/exercise) improved the expression of H2S biosynthesis-related genes. In human preadipocytes, the expression of CTH, CBS, and MPST genes and H2S production were dramatically increased during adipocyte differentiation. More importantly, the adipocyte proteome exhibiting persulfidation was characterized, disclosing that different proteins involved in fatty acid and lipid metabolism, the citrate cycle, insulin signaling, several adipokines, and PPAR, experienced the most dramatic persulfidation (85-98%). Innovation: No previous studies investigated the impact of H2S on human adipose tissue. This study suggests that the potentiation of adipose tissue H2S biosynthesis is a possible therapeutic approach to improve adipose tissue dysfunction in patients with obesity and insulin resistance. Conclusion: Altogether, these data supported the relevance of H2S biosynthesis in the modulation of human adipocyte physiology. Antioxid. Redox Signal. 35, 319-340.
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Affiliation(s)
- Ferran Comas
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain
| | - Jèssica Latorre
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain
| | - Francisco Ortega
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain
| | - María Arnoriaga Rodríguez
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain
| | - Matthias Kern
- Department of Medicine, University of Leipzig, Leipzig, Germany
| | - Aina Lluch
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain
| | - Wifredo Ricart
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain
| | - Matthias Blüher
- Department of Medicine, University of Leipzig, Leipzig, Germany
| | - Cecilia Gotor
- Instituto de Bioquímica Vegetal y Fotosíntesis, Consejo Superior de Investigaciones Científicas and Universidad de Sevilla, Seville, Spain
| | - Luis C Romero
- Instituto de Bioquímica Vegetal y Fotosíntesis, Consejo Superior de Investigaciones Científicas and Universidad de Sevilla, Seville, Spain
| | - José Manuel Fernández-Real
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain.,Department of Medical Sciences, Universitat de Girona, Girona, Spain
| | - José María Moreno-Navarrete
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain.,Department of Medical Sciences, Universitat de Girona, Girona, Spain
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Kim J, Oh J, Han MS. A ratiometric fluorescence probe for the selective detection of H 2S in serum using a pyrene-DPA-Cd 2+ complex. RSC Adv 2021; 11:24410-24415. [PMID: 35479021 PMCID: PMC9036711 DOI: 10.1039/d1ra04277g] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 07/05/2021] [Indexed: 11/29/2022] Open
Abstract
A ratiometric and selective hydrogen sulfide (H2S) detection probe was proposed based on the pyrene-DPA–Cd2+ complex through the metal ion displacement approach (MDA) mechanism. While most MDA-based fluorescence probes with paramagnetic Cu2+ have focused on the development of a simple turn-on sensor using the broad spectral range of fluorescence enhancement, this ratiometric probe exhibited unchanged monomer emission as a built-in internal reference with an increase in excimer emission with added H2S. The demonstrated probe showed a rapid response (within 1 min) and a high sensitivity, with 70 nM as the limit of detection. The selectivity for H2S over cysteine, homocysteine and glutathione was confirmed, and reliable fluorescence enhancement, which could be monitored by the naked eye, was observed upon irradiation with handheld UV light. In addition, this detection system was successfully applied to detect H2S in human serum without interference from biological molecules. The pyrene-DPA–Cd2+ complex is demonstrated as a ratiometric fluorescence probe for selective hydrogen sulfide detection in serum based on a metal displacement approach.![]()
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Affiliation(s)
- Jihoon Kim
- Department of Chemistry, Gwangju Institute of Science and Technology (GIST) 123 Cheomdangwagi-ro, Buk-gu Gwangju 61005 Republic of Korea
| | - Jinyoung Oh
- Department of Chemistry, Gwangju Institute of Science and Technology (GIST) 123 Cheomdangwagi-ro, Buk-gu Gwangju 61005 Republic of Korea
| | - Min Su Han
- Department of Chemistry, Gwangju Institute of Science and Technology (GIST) 123 Cheomdangwagi-ro, Buk-gu Gwangju 61005 Republic of Korea
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42
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Rose P, Moore PK, Whiteman M, Kirk C, Zhu YZ. Diet and Hydrogen Sulfide Production in Mammals. Antioxid Redox Signal 2021; 34:1378-1393. [PMID: 33372834 DOI: 10.1089/ars.2020.8217] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Significance: In recent times, it has emerged that some dietary sulfur compounds can act on mammalian cell signaling systems via their propensity to release hydrogen sulfide (H2S). H2S plays important biochemical and physiological roles in the heart, gastrointestinal tract, brain, kidney, and immune systems of mammals. Reduced levels of H2S in cells and tissues correlate with a spectrum of pathophysiological conditions, including heart disease, diabetes, obesity, and altered immune function. Recent Advances: In the last decade, researchers have now begun to explore the mechanisms by which dietary-derived sulfur compounds, in addition to cysteine, can act as sources of H2S. This research has led to the identified several compounds, organic sulfides, isothiocyanates, and inorganic sulfur species including sulfate that can act as potential sources of H2S in mammalian cells and tissues. Critical Issues: We have summarised progress made in the identification of dietary factors that can impact on endogenous H2S levels in mammals. We also describe current research focused on how some sulfur molecules present in dietary plants, and associated chemical analogues, act as sources of H2S, and discuss the biological properties of these molecules as studied in a range of in vitro and in vivo systems. Future Directions: The identification of sulfur compounds in edible plants that can act as novel H2S releasing molecules is intriguing. Research in this area could inform future studies exploring the impact of diet on H2S levels in mammalian systems. Despite recent progress, additional work is needed to determine the mechanisms by which H2S is released from these molecules following ingestions of dietary plants in humans, whether the amounts of H2S produced is of physiological significance following the metabolism of these compounds in vivo, and if diet could be used to manipulated H2S levels in humans. Importantly, this will lead to a better understanding of the biological significance of H2S generated from dietary sources, and this information could be used in the development of plant breeding initiatives to increase the levels of H2S releasing sulfur compounds in crops, or inform dietary intervention strategies that could be used to alter the levels of H2S in humans.
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Affiliation(s)
- Peter Rose
- School of Biosciences, University of Nottingham, Loughborough, Leicestershire, United Kingdom.,State Key Laboratory of Quality Research in Chinese Medicine, School of Pharmacy, Macau University of Science and Technology, Macau, China
| | - Philip Keith Moore
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Matthew Whiteman
- College of Medicine and Health, University of Exeter Medical School, Exeter, United Kingdom
| | - Charlotte Kirk
- School of Biosciences, University of Nottingham, Loughborough, Leicestershire, United Kingdom
| | - Yi-Zhun Zhu
- State Key Laboratory of Quality Research in Chinese Medicine, School of Pharmacy, Macau University of Science and Technology, Macau, China
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43
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Dorofeyeva NA, Korkach IP, Kutsyk OE, Sagach VF. Modulation of hydrogen sulfide synthesis improves heart function and endothelium-dependent vasorelaxation in diabetes. Can J Physiol Pharmacol 2021; 99:549-555. [PMID: 33064964 DOI: 10.1139/cjpp-2020-0302] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Diabetes dramatically increases the risk of cardiovascular complications. The endothelial dysfunction and diastolic heart dysfunction are associated with a decreasing level of hydrogen sulfide (H2S) and inhibition of the activity of endothelial nitric oxide synthase (NOS) in diabetes. The aim of this study is to investigate the effect of modulation of H2S synthesis on heart functions and vasorelaxation in diabetes. The dl-propargylglycine and l-cysteine were administered intraperitoneally. H2S content in the heart tissue, markers of oxidative stress, inducible NOS and constitutive NOS (cNOS) activities, endothelium-dependent vasorelaxation of the aortic rings, and heart function were studied. We demonstrate that our combination increased H2S synthesis 13 times and cNOS activity 5 times in the heart tissue of diabetic rats. Increasing NO and H2S production caused improvement and restoration of endothelium-dependent relaxation of aorta, effective arterial elastance, and diastolic heart function in diabetic rats. The endothelium-dependent relaxation increased 2.4 times; effective arterial elastance decreased by 47%. The end-diastolic myocardial stiffness decreased 2.2 times. Thus, modulation of H2S synthesis leads to increased cNOS activity by up to 5 times in the cardiovascular system. Increasing NO and H2S production restored endothelium-dependent relaxation of aorta and improved heart function in diabetes.
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Affiliation(s)
- N A Dorofeyeva
- Department of Blood Circulation, Bogomoletz Institute of Physiology, National Academy of Sciences of Ukraine, Kyiv, Ukraine
- Department of Blood Circulation, Bogomoletz Institute of Physiology, National Academy of Sciences of Ukraine, Kyiv, Ukraine
| | - I P Korkach
- Department of Blood Circulation, Bogomoletz Institute of Physiology, National Academy of Sciences of Ukraine, Kyiv, Ukraine
- Department of Blood Circulation, Bogomoletz Institute of Physiology, National Academy of Sciences of Ukraine, Kyiv, Ukraine
| | - O E Kutsyk
- Department of Blood Circulation, Bogomoletz Institute of Physiology, National Academy of Sciences of Ukraine, Kyiv, Ukraine
- Department of Blood Circulation, Bogomoletz Institute of Physiology, National Academy of Sciences of Ukraine, Kyiv, Ukraine
| | - V F Sagach
- Department of Blood Circulation, Bogomoletz Institute of Physiology, National Academy of Sciences of Ukraine, Kyiv, Ukraine
- Department of Blood Circulation, Bogomoletz Institute of Physiology, National Academy of Sciences of Ukraine, Kyiv, Ukraine
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44
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Comas F, Moreno-Navarrete JM. The Impact of H 2S on Obesity-Associated Metabolic Disturbances. Antioxidants (Basel) 2021; 10:antiox10050633. [PMID: 33919190 PMCID: PMC8143163 DOI: 10.3390/antiox10050633] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/18/2021] [Accepted: 04/19/2021] [Indexed: 12/20/2022] Open
Abstract
Over the last several decades, hydrogen sulfide (H2S) has gained attention as a new signaling molecule, with extensive physiological and pathophysiological roles in human disorders affecting vascular biology, immune functions, cellular survival, metabolism, longevity, development, and stress resistance. Apart from its known functions in oxidative stress and inflammation, new evidence has emerged revealing that H2S carries out physiological functions by targeting proteins, enzymes, and transcription factors through a post-translational modification known as persulfidation. This review article provides a critical overview of the current state of the literature addressing the role of H2S in obesity-associated metabolic disturbances, with particular emphasis on its mechanisms of action in obesity, diabetes, non-alcoholic fatty liver disease (NAFLD), and cardiovascular diseases.
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Affiliation(s)
- Ferran Comas
- Department of Diabetes, Endocrinology and Nutrition, Institut d’Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), 17007 Girona, Spain;
| | - José María Moreno-Navarrete
- Department of Diabetes, Endocrinology and Nutrition, Institut d’Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), 17007 Girona, Spain;
- Department of Medical Sciences, Universitat de Girona, 17003 Girona, Spain
- Correspondence: ; Tel.: +(34)-872-98-70-87
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The Role of the Transsulfuration Pathway in Non-Alcoholic Fatty Liver Disease. J Clin Med 2021; 10:jcm10051081. [PMID: 33807699 PMCID: PMC7961611 DOI: 10.3390/jcm10051081] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 02/21/2021] [Accepted: 03/01/2021] [Indexed: 02/07/2023] Open
Abstract
The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing and approximately 25% of the global population may have NAFLD. NAFLD is associated with obesity and metabolic syndrome, but its pathophysiology is complex and only partly understood. The transsulfuration pathway (TSP) is a metabolic pathway regulating homocysteine and cysteine metabolism and is vital in controlling sulfur balance in the organism. Precise control of this pathway is critical for maintenance of optimal cellular function. The TSP is closely linked to other pathways such as the folate and methionine cycles, hydrogen sulfide (H2S) and glutathione (GSH) production. Impaired activity of the TSP will cause an increase in homocysteine and a decrease in cysteine levels. Homocysteine will also be increased due to impairment of the folate and methionine cycles. The key enzymes of the TSP, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE), are highly expressed in the liver and deficient CBS and CSE expression causes hepatic steatosis, inflammation, and fibrosis in animal models. A causative link between the TSP and NAFLD has not been established. However, dysfunctions in the TSP and related pathways, in terms of enzyme expression and the plasma levels of the metabolites (e.g., homocysteine, cystathionine, and cysteine), have been reported in NAFLD and liver cirrhosis in both animal models and humans. Further investigation of the TSP in relation to NAFLD may reveal mechanisms involved in the development and progression of NAFLD.
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46
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Casin KM, Calvert JW. Harnessing the Benefits of Endogenous Hydrogen Sulfide to Reduce Cardiovascular Disease. Antioxidants (Basel) 2021; 10:antiox10030383. [PMID: 33806545 PMCID: PMC8000539 DOI: 10.3390/antiox10030383] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 02/26/2021] [Accepted: 03/01/2021] [Indexed: 02/02/2023] Open
Abstract
Cardiovascular disease is the leading cause of death in the U.S. While various studies have shown the beneficial impact of exogenous hydrogen sulfide (H2S)-releasing drugs, few have demonstrated the influence of endogenous H2S production. Modulating the predominant enzymatic sources of H2S-cystathionine-β-synthase, cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase-is an emerging and promising research area. This review frames the discussion of harnessing endogenous H2S within the context of a non-ischemic form of cardiomyopathy, termed diabetic cardiomyopathy, and heart failure. Also, we examine the current literature around therapeutic interventions, such as intermittent fasting and exercise, that stimulate H2S production.
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Randi EB, Casili G, Jacquemai S, Szabo C. Selenium-Binding Protein 1 (SELENBP1) Supports Hydrogen Sulfide Biosynthesis and Adipogenesis. Antioxidants (Basel) 2021; 10:antiox10030361. [PMID: 33673622 PMCID: PMC7997437 DOI: 10.3390/antiox10030361] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 02/19/2021] [Accepted: 02/24/2021] [Indexed: 12/12/2022] Open
Abstract
Hydrogen sulfide (H2S), a mammalian gasotransmitter, is involved in the regulation of a variety of fundamental processes including intracellular signaling, cellular bioenergetics, cell proliferation, and cell differentiation. Cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (3-MST) are currently considered the three principal mammalian H2S-generating enzymes. However, recently, a fourth H2S-producing enzyme, selenium-binding-protein 1 (SELENBP1), has also been identified. The cellular regulatory role(s) of SELENBP1 are incompletely understood. The current study investigated whether SELENBP1 plays a role in the regulation of adipocyte differentiation in vitro. 3T3-L1 preadipocytes with or without SELENBP1 knock-down were subjected to differentiation-inducing conditions, and H2S production, cellular lipid accumulation, cell proliferation, and mitochondrial activity were quantified. Adipocyte differentiation was associated with an upregulation of H2S biosynthesis. SELENBP1 silencing decreased cellular H2S levels, suppressed the expression of the three “classical” H2S-producing enzymes (CBS, CSE, and 3-MST) and significantly suppressed adipocyte differentiation. Treatment of SELENBP1 knock-down cells with the H2S donor GYY4137 partially restored lipid accumulation, increased cellular H2S levels, and exerted a bell-shaped effect on cellular bioenergetics (enhancement at 1 and 3 mM, and inhibition at 6 mM). We conclude that SELENBP1 in adipocytes (1) contributes to H2S biosynthesis and (2) acts as an endogenous stimulator of adipocyte differentiation.
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Citi V, Martelli A, Gorica E, Brogi S, Testai L, Calderone V. Role of hydrogen sulfide in endothelial dysfunction: Pathophysiology and therapeutic approaches. J Adv Res 2021; 27:99-113. [PMID: 33318870 PMCID: PMC7728589 DOI: 10.1016/j.jare.2020.05.015] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Revised: 05/12/2020] [Accepted: 05/13/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND The vascular endothelium represents a fundamental mechanical and biological barrier for the maintenance of vascular homeostasis along the entire vascular tree. Changes in its integrity are associated to several cardiovascular diseases, including hypertension, atherosclerosis, hyperhomocysteinemia, diabetes, all linked to the peculiar condition named endothelial dysfunction, which is referred to the loss of endothelial physiological functions, comprehending the regulation of vascular relaxation and/or cell redox balance, the inhibition of leukocyte infiltration and the production of NO. Among the endothelium-released vasoactive factors, in the last years hydrogen sulfide has been viewed as one of the main characters involved in the regulation of endothelium functionality, and many studies demonstrated that H2S behaves as a vasoprotective gasotransmitter in those cardiovascular diseases where endothelial dysfunction seems to be the central issue. AIM The role of hydrogen sulfide in endothelial dysfunction-related cardiovascular diseases is discussed in this review. KEY SCIENTIFIC CONCEPTS Possible therapeutic approaches using molecules able to release H2S.
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Affiliation(s)
- Valentina Citi
- Department of Pharmacy, University of Pisa, via Bonanno n.6, 56125 Pisa, Italy
| | - Alma Martelli
- Department of Pharmacy, University of Pisa, via Bonanno n.6, 56125 Pisa, Italy
| | - Era Gorica
- Department of Pharmacy, University of Pisa, via Bonanno n.6, 56125 Pisa, Italy
| | - Simone Brogi
- Department of Pharmacy, University of Pisa, via Bonanno n.6, 56125 Pisa, Italy
| | - Lara Testai
- Department of Pharmacy, University of Pisa, via Bonanno n.6, 56125 Pisa, Italy
| | - Vincenzo Calderone
- Department of Pharmacy, University of Pisa, via Bonanno n.6, 56125 Pisa, Italy
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49
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Sun HJ, Wu ZY, Nie XW, Bian JS. The Role of H 2S in the Metabolism of Glucose and Lipids. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1315:51-66. [PMID: 34302688 DOI: 10.1007/978-981-16-0991-6_3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Glucose and lipids are essential elements for maintaining the body's homeostasis, and their dysfunction may participate in the pathologies of various diseases, particularly diabetes, obesity, metabolic syndrome, cardiovascular ailments, and cancers. Among numerous endogenous mediators, the gasotransmitter hydrogen sulfide (H2S) plays a central role in the maintenance of glucose and lipid homeostasis. Current evidence from both pharmacological studies and transgenic animal models suggest a complex relationship between H2S and metabolic dysregulation, especially in diabetes and obesity. This notion is achieved through tissue-specific expressions and actions of H2S on target metabolic and hormone organs including the pancreas, skeletal muscle, livers, and adipose. In this chapter, we will summarize the roles and mechanisms of H2S in several metabolic organs/tissues that are necessary for glucose and lipid metabolic homeostasis. In addition, future research directions and valuable therapeutic avenues around the pharmacological regulation of H2S in glycolipid metabolism disorder will be also discussed.
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Affiliation(s)
- Hai-Jian Sun
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Zhi-Yuan Wu
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Xiao-Wei Nie
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Center of Clinical Research, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Jin-Song Bian
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. .,National University of Singapore (Suzhou) Research Institute, Suzhou, China.
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50
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Ali A, Wang Y, Wu L, Yang G. Gasotransmitter signaling in energy homeostasis and metabolic disorders. Free Radic Res 2020; 55:83-105. [PMID: 33297784 DOI: 10.1080/10715762.2020.1862827] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Gasotransmitters are small molecules of gases, including nitric oxide (NO), hydrogen sulfide (H2S), and carbon monoxide (CO). These three gasotransmitters can be endogenously produced and regulate a wide range of pathophysiological processes by interacting with specific targets upon diffusion in the biological media. By redox and epigenetic regulation of various physiological functions, NO, H2S, and CO are critical for the maintenance of intracellular energy homeostasis. Accumulated evidence has shown that these three gasotransmitters control ATP generation, mitochondrial biogenesis, glucose metabolism, insulin sensitivity, lipid metabolism, and thermogenesis, etc. Abnormal generation and metabolism of NO, H2S, and/or CO are involved in various abnormal metabolic diseases, including obesity, diabetes, and dyslipidemia. In this review, we summarized the roles of NO, H2S, and CO in the regulation of energy homeostasis as well as their involvements in the metabolism of dysfunction-related diseases. Understanding the interaction among these gasotransmitters and their specific molecular targets are very important for therapeutic applications.
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Affiliation(s)
- Amr Ali
- Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Canada.,Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada
| | - Yuehong Wang
- Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Canada.,Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada
| | - Lingyun Wu
- Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada.,School of Human Kinetics, Laurentian University, Sudbury, Canada.,Health Science North Research Institute, Sudbury, Canada
| | - Guangdong Yang
- Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Canada.,Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada
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