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1
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Chakraborty S, Choudhuri A, Mishra A, Sengupta R. The hunt for transnitrosylase. Nitric Oxide 2024; 152:31-47. [PMID: 39299646 DOI: 10.1016/j.niox.2024.09.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 07/04/2024] [Accepted: 09/16/2024] [Indexed: 09/22/2024]
Abstract
The biochemical interplay between antioxidants and pro-oxidants maintains the redox homeostatic balance of the cell, which, when perturbed to moderate or high extents, has been implicated in the onset and/or progression of chronic diseases such as diabetes mellitus, cancer, and neurodegenerative diseases. Thioredoxin, glutaredoxin, and lipoic acid-like thiol oxidoreductase systems constitute a unique ensemble of robust cellular antioxidant defenses, owing to their indispensable roles as S-denitrosylases, S-deglutathionylases, and disulfide reductants in maintaining a reduced free thiol state with biological relevance. Thus, in cells subjected to nitrosative stress, cellular antioxidants will S-denitrosylate their cognate S-nitrosoprotein substrates, rather than participate in trans-S-nitrosylation via protein-protein interactions. Researchers have been at the forefront of vaguely establishing the concept of 'transnitrosylation' and its influence on pathophysiology with experimental evidence from in vitro studies that lack proper biochemical logic. The suggestive and reiterative use of antioxidants as transnitrosylases in the scientific literature leaves us on a cliffhanger with several open-ended questions that prompted us to 'hunt' for scientific logic behind the trans-S-nitrosylation chemistry. Given the gravity of the situation and to look at the bigger picture of 'trans-S-nitrosylation', we aim to present a novel attempt at justifying the hesitance in accepting antioxidants as capable of transnitrosylating their cognate protein partners and reflecting on the need to resolve the controversy that would be crucial from the perspective of understanding therapeutic outcomes involving such cellular antioxidants in disease pathogenesis. Further characterization is required to identify the regulatory mechanisms or conditions where an antioxidant like Trx, Grx, or DJ-1 can act as a cellular transnitrosylase.
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Affiliation(s)
- Surupa Chakraborty
- Amity Institute of Biotechnology Kolkata, Amity University Kolkata, Action Area II, Rajarhat, Newtown, Kolkata, West Bengal, 700135, India
| | - Ankita Choudhuri
- Amity Institute of Biotechnology Kolkata, Amity University Kolkata, Action Area II, Rajarhat, Newtown, Kolkata, West Bengal, 700135, India
| | - Akansha Mishra
- Amity Institute of Biotechnology Kolkata, Amity University Kolkata, Action Area II, Rajarhat, Newtown, Kolkata, West Bengal, 700135, India
| | - Rajib Sengupta
- Amity Institute of Biotechnology Kolkata, Amity University Kolkata, Action Area II, Rajarhat, Newtown, Kolkata, West Bengal, 700135, India.
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2
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Erdos T, Masuda M, Venketaraman V. Glutathione in HIV-Associated Neurocognitive Disorders. Curr Issues Mol Biol 2024; 46:5530-5549. [PMID: 38921002 PMCID: PMC11202908 DOI: 10.3390/cimb46060330] [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: 03/21/2024] [Revised: 05/27/2024] [Accepted: 05/28/2024] [Indexed: 06/27/2024] Open
Abstract
A large portion of patients with Human Immunodeficiency Virus (HIV) have neurologic sequelae. Those with better-controlled HIV via antiretroviral therapies generally have less severe neurologic symptoms. However, for many patients, antiretrovirals do not adequately resolve symptoms. Since much of the pathogenesis of HIV/AIDS (Autoimmune Deficiency Syndrome) involves oxidative stress either directly, through viral interaction, or indirectly, through inflammatory mechanisms, we have reviewed relevant trials of glutathione supplementation in each of the HIV-associated neurocognitive diseases and have found disease-specific results. For diseases for which trials have not been completed, predicted responses to glutathione supplementation are made based on relevant mechanisms seen in the literature. It is not sufficient to conclude that all HIV-associated neurocognitive disorders (HAND) will benefit from the antioxidant effects of glutathione supplementation. The potential effects of glutathione supplementation in patients with HAND are likely to differ based on the specific HIV-associated neurocognitive disease.
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Affiliation(s)
| | | | - Vishwanath Venketaraman
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA; (T.E.); (M.M.)
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3
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Li T, Tan S, Li M, Luo J, Zhang Y, Jiang Z, Deng Y, Han L, Ke H, Shen J, Tang Y, Liu F, Chen H, Yang T. Holographically Activatable Nanoprobe via Glutathione/Albumin-Mediated Exponential Signal Amplification for High-Contrast Tumor Imaging. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2023; 35:e2209603. [PMID: 36524741 DOI: 10.1002/adma.202209603] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 12/11/2022] [Indexed: 06/17/2023]
Abstract
Glutathione (GSH)-activatable probes hold great promise for in vivo cancer imaging, but are restricted by their dependence on non-selective intracellular GSH enrichment and uncontrollable background noise. Here, a holographically activatable nanoprobe caging manganese tetraoxide is shown for tumor-selective contrast enhancement in magnetic resonance imaging (MRI) through cooperative GSH/albumin-mediated cascade signal amplification in tumors and rapid elimination in normal tissues. Once targeting tumors, the endocytosed nanoprobe effectively senses the lysosomal microenvironment to undergo instantaneous decomposition into Mn2+ with threshold GSH concentration of ≈ 0.12 mm for brightening MRI signals, thus achieving high contrast tumor imaging and flexible monitoring of GSH-relevant cisplatin resistance during chemotherapy. Upon efficient up-regulation of extracellular GSH in tumor via exogenous injection, the relaxivity-silent interstitial nanoprobe remarkably evolves into Mn2+ that are further captured/retained and re-activated into ultrahigh-relaxivity-capable complex by stromal albumin in the tumor, and simultaneously allows the renal clearance of off-targeted nanoprobe in the form of Mn2+ via lymphatic vessels for suppressing background noise to distinguish tiny liver metastasis. These findings demonstrate the concept of holographic tumor activation via both tumor GSH/albumin-mediated cascade signal amplification and simultaneous background suppression for precise tumor malignancy detection, surveillance, and surgical guidance.
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Affiliation(s)
- Ting Li
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, and College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
| | - Shuangxiu Tan
- Department of Radiology, Second Affiliated Hospital of Soochow University, Suzhou, 215004, China
| | - Mengjuan Li
- Department of Radiology, Second Affiliated Hospital of Soochow University, Suzhou, 215004, China
| | - Jie Luo
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, and College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
| | - Yueyue Zhang
- Department of Radiology, Second Affiliated Hospital of Soochow University, Suzhou, 215004, China
| | - Zhen Jiang
- Department of Radiology, Second Affiliated Hospital of Soochow University, Suzhou, 215004, China
| | - Yibin Deng
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, and College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
| | - Liang Han
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, and College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
| | - Hengte Ke
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, and College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
| | - Junkang Shen
- Department of Radiology, Second Affiliated Hospital of Soochow University, Suzhou, 215004, China
| | - Yong'an Tang
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, and College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
| | - Fan Liu
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, and College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
| | - Huabing Chen
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, and College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
- Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
- Institute for Interdisciplinary Drug Research and Translational Sciences, Soochow University, Suzhou, 215006, China
- State Key Laboratory of Radiation Medicine and Protection, and School of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, China
| | - Tao Yang
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, and College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
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YILDIZ H. Effects of glutathione on mitochondrial DNA and antioxidant enzyme activities in Drosophila melanogaster. INTERNATIONAL JOURNAL OF SECONDARY METABOLITE 2022. [DOI: 10.21448/ijsm.1084592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
The free radical theory in aging assumes that the accumulation of macromolecular damage induced by toxic reactive oxygen species plays a central role in the aging process. The intake of nutritional antioxidants can prevent this damage by neutralizing reactive oxygen derivatives. Glutathione (GSH; en-L-Glutamyl-L-cysteinyl glycine) is the lowest molecular weight thiol in the cells and as a cofactor of many enzymes and a potent antioxidant plays an important role in maintaining normal cell functions by destroying toxic oxygen radicals. In this study, the effects of GSH on SOD, GST and catalase enzymes and mtDNA damage were investigated at various time intervals by giving reduced glutathione to Drosophila. It was observed that 3-week GSH administration did not have a statistically significant effect on SOD and GST activities whereas GSH application decreased the catalase enzyme activities significantly. Although the decrease in antioxidant capacity with age was observed in SOD and catalase enzymes, such a situation was not observed in GST enzyme activities. There was no statistically significant difference between the control and GSH groups in mtDNA copy number values, while in the GSH group, oxidative mtDNA damage was high. These results may be due to the prooxidant effect of GSH at the dose used in this study.
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Luna-López A, Flores-González GA, Rivera-Ruz IA, Librado-Osorio R, Erosa-De Haro LA, Königsberg M, Alarcón-Aguilar A. Methotrexate Induces an Antioxidant Hormetic Response in Primary Rat Astrocytes. Dose Response 2022; 20:15593258221130752. [PMCID: PMC9619289 DOI: 10.1177/15593258221130752] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Accepted: 09/17/2022] [Indexed: 11/03/2022] Open
Abstract
Neurodegenerative diseases have increased worldwide in recent years. Their relationship with oxidative stress has motivated the research to find therapies and medications capable of suppressing oxidative damage and therefore slowing the progression of these diseases. Glutathione (GSH) is the most important cellular antioxidant in living beings and is responsible for regulating the cellular redox state. However, GSH cannot be administered by any route of administration, so molecules that increase its levels by activating Nrf2-ARE signaling pathway are explored; since Nrf2 regulates the main genes involved in GSH de novo synthesis and recycling. Astrocytes are the most important cell-type in the antioxidant cell response and are responsible for providing GSH and other substrates for neurons to have an efficient antioxidant response. Methotrexate (MTX) is an anti-inflammatory agent that has different cellular effects when administered at low or high concentrations. So in this study, we used MTX different concentrations and exposure times to induce a hormetic antioxidant response in rat primary astrocytes. Our results showed that 20 nM MTX pre-conditioning for 12 h augmented the GSH/GSSG ratio and protected cellular viability against a toxic MTX and H2O2 insult, which was abrogated when Nrf2 was inhibited by brusatol. Hence, MTX subsequent studies as a drug to counteract the progression of some stress-associated neurodegenerative diseases are suggested.
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Affiliation(s)
- Armando Luna-López
- Departamento de Investigación Básica, Instituto Nacional de Geriatría, CDMX, México
| | - Giovanna Adonahi Flores-González
- Laboratorio de Bioenergética y Envejecimiento Celular, Depto. de Ciencias de la Salud, Universidad Autónoma Metropolitana, Unidad Iztapalapa, CDMX, México
| | - Itzel Alejandra Rivera-Ruz
- Laboratorio de Bioenergética y Envejecimiento Celular, Depto. de Ciencias de la Salud, Universidad Autónoma Metropolitana, Unidad Iztapalapa, CDMX, México
| | - Raúl Librado-Osorio
- Departamento de Investigación Básica, Instituto Nacional de Geriatría, CDMX, México
| | | | - Mina Königsberg
- Laboratorio de Bioenergética y Envejecimiento Celular, Depto. de Ciencias de la Salud, Universidad Autónoma Metropolitana, Unidad Iztapalapa, CDMX, México
| | - Adriana Alarcón-Aguilar
- Laboratorio de Bioenergética y Envejecimiento Celular, Depto. de Ciencias de la Salud, Universidad Autónoma Metropolitana, Unidad Iztapalapa, CDMX, México,Adriana Alarcón-Aguilar, Departamento de Ciencias de la Salud, División de Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, A.P. 55-535, México D.F. C.P 09340, México.
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Lavoie JC, Mohamed I, Teixeira V. Dose-Response Effects of Glutathione Supplement in Parenteral Nutrition on Pulmonary Oxidative Stress and Alveolarization in Newborn Guinea Pig. Antioxidants (Basel) 2022; 11:antiox11101956. [PMID: 36290679 PMCID: PMC9598316 DOI: 10.3390/antiox11101956] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 09/17/2022] [Accepted: 09/26/2022] [Indexed: 11/21/2022] Open
Abstract
In premature infants, glutathione deficiency impairs the capacity to detoxify the peroxides resulting from O2 metabolism and those contaminating the parenteral nutrition (PN) leading to increased oxidative stress, which is a major contributor to bronchopulmonary dysplasia (BPD) development. In animals, the supplementation of PN with glutathione prevented the induction of pulmonary oxidative stress and hypoalveolarization (characteristic of BPD). Hypothesis: the dose of glutathione that corrects the plasma glutathione deficiency is sufficient to prevent oxidative stress and preserve pulmonary integrity. Three-day-old guinea pigs received a PN, supplemented or not with GSSG (up to 1300 µg/kg/d), the stable form of glutathione in PN. Animals with no handling other than being orally fed constituted the control group. After 4 days, lungs were removed to determine the GSH, GSSG, redox potential and the alveolarization index. Total plasma glutathione was quantified. The effective dose to improve pulmonary GSH and prevent the loss of alveoli was 330 µg/kg/d. A 750 µg/kg/d dose corrected the low-plasma glutathione, high-pulmonary GSSG and oxidized redox potential. Therefore, the results suggest that, in a clinical setting, the dose that improves low-plasma glutathione could be effective in preventing BPD development.
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Affiliation(s)
- Jean-Claude Lavoie
- Research Center of the CHU Sainte-Justine, Department of Nutrition, Université de Montréal, Montréal, QC H3T 1C5, Canada
- Correspondence:
| | - Ibrahim Mohamed
- Research Center of the CHU Sainte-Justine, Department of Paediatrics, Université de Montréal, Montréal, QC H3T 1C5, Canada
| | - Vitor Teixeira
- Research Center of the CHU Sainte-Justine, Department of Nutrition, Université de Montréal, Montréal, QC H3T 1C5, Canada
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7
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Spraakman NA, Coester AM, Bourgonje AR, Nieuwenhuijs VB, Sanders JSF, Leuvenink HGD, van Goor H, Nieuwenhuijs-Moeke GJ. Systemic and Renal Dynamics of Free Sulfhydryl Groups during Living Donor Kidney Transplantation. Int J Mol Sci 2022; 23:ijms23179789. [PMID: 36077183 PMCID: PMC9455962 DOI: 10.3390/ijms23179789] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 08/12/2022] [Accepted: 08/17/2022] [Indexed: 11/16/2022] Open
Abstract
During ischemia−reperfusion injury (IRI), reactive oxygen species are produced that can be scavenged by free sulfhydryl groups (R-SH, free thiols). In this study, we hypothesized that R-SH levels decrease as a consequence of renal IRI and that R-SH levels reflect post-transplant graft function. Systemic venous, arterial, renal venous, and urinary samples were collected in donors and recipients before, during, and after transplantation. R-SH was measured colorimetrically. Systemic arterial R-SH levels in recipients increased significantly up to 30 sec after reperfusion (p < 0.001). In contrast, renal venous R-SH levels significantly decreased at 5 and 10 min compared to 30 sec after reperfusion (both p < 0.001). This resulted in a significant decrease in delta R-SH (defined as the difference between renal venous and systemic arterial R-SH levels) till 30 sec after reperfusion (p < 0.001), indicating a net decrease in R-SH levels across the transplanted kidney. Overall, these results suggest trans-renal oxidative stress as a consequence of IRI during kidney transplantation, reflected by systemic and renal changes in R-SH levels in transplant recipients.
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Affiliation(s)
- Nora A. Spraakman
- Department of Anesthesiology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
- Correspondence:
| | - Annemieke M. Coester
- Department of Surgery, Amphia Hospital, Molengracht 21, 4818 CK Breda, The Netherlands
| | - Arno R. Bourgonje
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
| | | | - Jan-Stephan F. Sanders
- Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
| | - Henri G. D. Leuvenink
- Department of Surgery, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
| | - Harry van Goor
- Department of Pathology and Medical Biology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
| | - Gertrude J. Nieuwenhuijs-Moeke
- Department of Anesthesiology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
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8
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Garavaglia ML, Giustarini D, Colombo G, Reggiani F, Finazzi S, Calatroni M, Landoni L, Portinaro NM, Milzani A, Badalamenti S, Rossi R, Dalle-Donne I. Blood Thiol Redox State in Chronic Kidney Disease. Int J Mol Sci 2022; 23:ijms23052853. [PMID: 35269995 PMCID: PMC8911004 DOI: 10.3390/ijms23052853] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 02/26/2022] [Accepted: 03/03/2022] [Indexed: 02/05/2023] Open
Abstract
Thiols (sulfhydryl groups) are effective antioxidants that can preserve the correct structure of proteins, and can protect cells and tissues from damage induced by oxidative stress. Abnormal levels of thiols have been measured in the blood of patients with moderate-to-severe chronic kidney disease (CKD) compared to healthy subjects, as well as in end-stage renal disease (ESRD) patients on haemodialysis or peritoneal dialysis. The levels of protein thiols (a measure of the endogenous antioxidant capacity inversely related to protein oxidation) and S-thiolated proteins (mixed disulphides of protein thiols and low molecular mass thiols), and the protein thiolation index (the molar ratio of the S-thiolated proteins to free protein thiols in plasma) have been investigated in the plasma or red blood cells of CKD and ESRD patients as possible biomarkers of oxidative stress. This type of minimally invasive analysis provides valuable information on the redox status of the less-easily accessible tissues and organs, and of the whole organism. This review provides an overview of reversible modifications in protein thiols in the setting of CKD and renal replacement therapy. The evidence suggests that protein thiols, S-thiolated proteins, and the protein thiolation index are promising biomarkers of reversible oxidative stress that could be included in the routine monitoring of CKD and ESRD patients.
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Affiliation(s)
- Maria Lisa Garavaglia
- Department of Biosciences (Department of Excellence 2018–2022), Università degli Studi di Milano, Via Celoria 26, 20133 Milan, Italy; (M.L.G.); (G.C.); (L.L.); (A.M.)
| | - Daniela Giustarini
- Department of Biotechnology, Chemistry and Pharmacy (Department of Excellence 2018–2022), University of Siena, Via A. Moro 2, 53100 Siena, Italy;
| | - Graziano Colombo
- Department of Biosciences (Department of Excellence 2018–2022), Università degli Studi di Milano, Via Celoria 26, 20133 Milan, Italy; (M.L.G.); (G.C.); (L.L.); (A.M.)
| | - Francesco Reggiani
- Nephrology and Dialysis Unit, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy or (F.R.); (S.F.); or (M.C.); (S.B.)
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy
| | - Silvia Finazzi
- Nephrology and Dialysis Unit, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy or (F.R.); (S.F.); or (M.C.); (S.B.)
| | - Marta Calatroni
- Nephrology and Dialysis Unit, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy or (F.R.); (S.F.); or (M.C.); (S.B.)
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy
| | - Lucia Landoni
- Department of Biosciences (Department of Excellence 2018–2022), Università degli Studi di Milano, Via Celoria 26, 20133 Milan, Italy; (M.L.G.); (G.C.); (L.L.); (A.M.)
| | - Nicola Marcello Portinaro
- Department of Medical Biotechnologies and Translational Medicine, Università degli Studi di Milano, 20133 Milan, Italy;
| | - Aldo Milzani
- Department of Biosciences (Department of Excellence 2018–2022), Università degli Studi di Milano, Via Celoria 26, 20133 Milan, Italy; (M.L.G.); (G.C.); (L.L.); (A.M.)
| | - Salvatore Badalamenti
- Nephrology and Dialysis Unit, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy or (F.R.); (S.F.); or (M.C.); (S.B.)
| | - Ranieri Rossi
- Department of Biotechnology, Chemistry and Pharmacy (Department of Excellence 2018–2022), University of Siena, Via A. Moro 2, 53100 Siena, Italy;
- Correspondence: (R.R.); (I.D.-D.)
| | - Isabella Dalle-Donne
- Department of Biosciences (Department of Excellence 2018–2022), Università degli Studi di Milano, Via Celoria 26, 20133 Milan, Italy; (M.L.G.); (G.C.); (L.L.); (A.M.)
- Correspondence: (R.R.); (I.D.-D.)
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Abstract
Glutathione (GSH) is the most abundant non-protein thiol, and plays crucial roles in the antioxidant defense system and the maintenance of redox homeostasis in neurons. GSH depletion in the brain is a common finding in patients with neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, and can cause neurodegeneration prior to disease onset. Excitatory amino acid carrier 1 (EAAC1), a sodium-dependent glutamate/cysteine transporter that is selectively present in neurons, plays a central role in the regulation of neuronal GSH production. The expression of EAAC1 is posttranslationally controlled by the glutamate transporter-associated protein 3–18 (GTRAP3-18) or miR-96-5p in neurons. The regulatory mechanism of neuronal GSH production mediated by EAAC1 may be a new target in therapeutic strategies for these neurodegenerative diseases. This review describes the regulatory mechanism of neuronal GSH production and its potential therapeutic application in the treatment of neurodegenerative diseases.
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Grzych G, Pekar JD, Chevalier-Curt MJ, Decoin R, Vergriete P, Henry H, Odou P, Maboudou P, Brousseau T, Vamecq J. Antioxidants other than vitamin C may be detected by glucose meters: Immediate relevance for patients with disorders targeted by antioxidant therapies. Clin Biochem 2021; 92:71-76. [PMID: 33766514 DOI: 10.1016/j.clinbiochem.2021.03.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 03/11/2021] [Accepted: 03/13/2021] [Indexed: 10/21/2022]
Abstract
Owing to their ease of use, glucose meters are frequently used in research and medicine. However, little is known of whether other non-glucose molecules, besides vitamin C, interfere with glucometry. Therefore, we sought to determine whether other antioxidants might behave like vitamin C in causing falsely elevated blood glucose levels, potentially exposing patients to glycemic mismanagement by being administered harmful doses of glucose-lowering drugs. To determine whether various antioxidants can be detected by seven commercial glucose meters, human blood samples were spiked with various antioxidants ex vivo and their effect on the glucose results were assessed by Parkes error grid analysis. Several of the glucose meters demonstrated a positive bias in the glucose measurement of blood samples spiked with vitamin C, N-acetylcysteine, and glutathione. With the most interference-sensitive glucose meter, non-blood solutions of 1 mmol/L N-acetylcysteine, glutathione, cysteine, vitamin C, dihydrolipoate, and dithiothreitol mimicked the results seen on that glucose meter for 0.7, 1.0, 1.2, 2.6, 3.7 and 5.5 mmol/L glucose solutions, respectively. Glucose meter users should be alerted that some of these devices might produce spurious glucose results not only in patients on vitamin C therapy but also in those being administered other antioxidants. As discussed herein, the clinical relevance of the data is immediate in view of the current use of antioxidant therapies for disorders such as the metabolic syndrome, diabetes, cardiovascular diseases, and coronavirus disease 2019.
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Affiliation(s)
- Guillaume Grzych
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000 Lille, France; CHU Lille, Service d'Hormonologie, Métabolisme, Nutrition, Oncologie, F-59000 Lille, France
| | - Jean-David Pekar
- CHU Lille, Biochemistry Emergency, F-59000 Lille, France; CHU Lille, Service de Biochimie Automatisée Protéines, F-59000 Lille, France
| | | | - Raphaël Decoin
- CHU Lille, Service d'Hormonologie, Métabolisme, Nutrition, Oncologie, F-59000 Lille, France
| | - Pauline Vergriete
- CHU Lille, Service de Biochimie Automatisée Protéines, F-59000 Lille, France
| | - Héloïse Henry
- Univ. Lille, CHU Lille, ULR 7365 - GRITA - Groupe de Recherche sur les formes Injectables et les Technologies Associées, F-59000 Lille, France
| | - Pascal Odou
- Univ. Lille, CHU Lille, ULR 7365 - GRITA - Groupe de Recherche sur les formes Injectables et les Technologies Associées, F-59000 Lille, France
| | - Patrice Maboudou
- CHU Lille, Biochemistry Emergency, F-59000 Lille, France; CHU Lille, Service de Biochimie Automatisée Protéines, F-59000 Lille, France
| | - Thierry Brousseau
- CHU Lille, Service de Biochimie Automatisée Protéines, F-59000 Lille, France
| | - Joseph Vamecq
- Inserm, EA 7364 RADEME, Univ Lille, HMNO, CBP, CHU Lille, 2, Boulevard du Prof. Jules Leclercq, 59037 Lille, France.
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11
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Neri AA, Dontas IA, Iliopoulos DC, Karatzas T. Pathophysiological Changes During Ischemia-reperfusion Injury in Rodent Hepatic Steatosis. In Vivo 2021; 34:953-964. [PMID: 32354880 DOI: 10.21873/invivo.11863] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 02/03/2020] [Accepted: 02/07/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND/AIM Ischemia and reperfusion injuries may produce deleterious effects on hepatic tissue after liver surgery and transplantation. The impact of ischemia-reperfusion injury (IRI) on the liver depends on its substrate, the percentage of liver ischemic tissue subjected to IRI and the ischemia time. The consequences of IRI are more evident in pathologic liver substrates, such as steatotic livers. This review is the result of an extended bibliographic PubMed search focused on the last 20 years. It highlights basic differences encountered during IRI in lean and steatotic livers based on studies using rodent experimental models. CONCLUSION The main difference in cell death between lean and steatotic livers is the prevalence of apoptosis in the former and necrosis in the latter. There are also major changes in the effect of intracellular mediators, such as TNFα and IL-1β. Further experimental studies are needed in order to increase current knowledge of IRI effects and relevant mechanisms in both lean and steatotic livers, so that new preventive and therapeutic strategies maybe developed.
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Affiliation(s)
- Anna-Aikaterini Neri
- Laboratory for Research of the Musculoskeletal System "Th. Garofalidis", KAT Hospital, School of Medicine, National & Kapodistrian University of Athens, Kifissia, Greece
| | - Ismene A Dontas
- Laboratory for Research of the Musculoskeletal System "Th. Garofalidis", KAT Hospital, School of Medicine, National & Kapodistrian University of Athens, Kifissia, Greece
| | - Dimitrios C Iliopoulos
- Laboratory of Experimental Surgery & Surgical Research "N.S. Christeas", School of Medicine, National & Kapodistrian University of Athens, Athens, Greece
| | - Theodore Karatzas
- Laboratory of Experimental Surgery & Surgical Research "N.S. Christeas", School of Medicine, National & Kapodistrian University of Athens, Athens, Greece.,2 Department of Propedeutic Surgery, School of Medicine, National & Kapodistrian University of Athens, Athens, Greece
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Morin G, Guiraut C, Perez Marcogliese M, Mohamed I, Lavoie JC. Glutathione Supplementation of Parenteral Nutrition Prevents Oxidative Stress and Sustains Protein Synthesis in Guinea Pig Model. Nutrients 2019; 11:nu11092063. [PMID: 31484318 PMCID: PMC6770543 DOI: 10.3390/nu11092063] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 08/23/2019] [Accepted: 08/28/2019] [Indexed: 11/30/2022] Open
Abstract
Peroxides contaminating parenteral nutrition (PN) limit the use of methionine as a precursor of cysteine. Thus, PN causes a cysteine deficiency, characterized by low levels of glutathione, the main molecule used in peroxide detoxification, and limited growth in individuals receiving long-term PN compared to the average population. We hypothesize that glutathione supplementation in PN can be used as a pro-cysteine that improves glutathione levels and protein synthesis and reduces oxidative stress caused by PN. One-month-old guinea pigs (7–8 per group) were used to compare glutathione-enriched to a non-enriched PN, animals on enteral nutrition were used as a reference. PN: Dextrose, amino acids (Primene), lipid emulsion (Intralipid), multivitamins, electrolytes; five-day infusion. Glutathione (GSH, GSSG, redox potential) and the incorporation of radioactive leucine into the protein fraction (protein synthesis index) were measured in the blood, lungs, liver, and gastrocnemius muscle. Data were analysed by ANOVA; p < 0.05 was considered significant. The addition of glutathione to PN prevented the PN-induced oxidative stress in the lungs and muscles and supported protein synthesis in liver and muscles. The results potentially support the recommendation to add glutathione to the PN and demonstrate that glutathione could act as a biologically available cysteine precursor.
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Affiliation(s)
- Guillaume Morin
- Department of Nutrition, Université de Montréal, 2405 Chemin de la Côte-Sainte-Catherine, Montréal, QC H3T 1A8, Canada
| | - Clémence Guiraut
- Department of Nutrition, Université de Montréal, 2405 Chemin de la Côte-Sainte-Catherine, Montréal, QC H3T 1A8, Canada
- CHU Sainte-Justine Research Centre, Université de Montréal, 3175 Chemin de la Côte-Sainte-Catherine, Montréal, QC H3T 1C5, Canada
| | - Marisol Perez Marcogliese
- CHU Sainte-Justine Research Centre, Université de Montréal, 3175 Chemin de la Côte-Sainte-Catherine, Montréal, QC H3T 1C5, Canada
| | - Ibrahim Mohamed
- Department of Nutrition, Université de Montréal, 2405 Chemin de la Côte-Sainte-Catherine, Montréal, QC H3T 1A8, Canada
- CHU Sainte-Justine Research Centre, Université de Montréal, 3175 Chemin de la Côte-Sainte-Catherine, Montréal, QC H3T 1C5, Canada
- Department of Pediatrics-Neonatology, CHU Sainte-Justine, Université de Montréal, 3175 Chemin de la Côte-Sainte-Catherine, Montréal, QC H3T 1C5, Canada
| | - Jean-Claude Lavoie
- Department of Nutrition, Université de Montréal, 2405 Chemin de la Côte-Sainte-Catherine, Montréal, QC H3T 1A8, Canada.
- CHU Sainte-Justine Research Centre, Université de Montréal, 3175 Chemin de la Côte-Sainte-Catherine, Montréal, QC H3T 1C5, Canada.
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Implications of plasma thiol redox in disease. Clin Sci (Lond) 2018; 132:1257-1280. [DOI: 10.1042/cs20180157] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Revised: 05/09/2018] [Accepted: 05/22/2018] [Indexed: 12/21/2022]
Abstract
Thiol groups are crucially involved in signaling/homeostasis through oxidation, reduction, and disulphide exchange. The overall thiol pool is the resultant of several individual pools of small compounds (e.g. cysteine), peptides (e.g. glutathione), and thiol proteins (e.g. thioredoxin (Trx)), which are not in equilibrium and present specific oxidized/reduced ratios. This review addresses mechanisms and implications of circulating plasma thiol/disulphide redox pools, which are involved in several physiologic processes and explored as disease biomarkers. Thiol pools are regulated by mechanisms linked to their intrinsic reactivity against oxidants, concentration of antioxidants, thiol-disulphide exchange rates, and their dynamic release/removal from plasma. Major thiol couples determining plasma redox potential (Eh) are reduced cysteine (CyS)/cystine (the disulphide form of cysteine) (CySS), followed by GSH/disulphide-oxidized glutathione (GSSG). Hydrogen peroxide and hypohalous acids are the main plasma oxidants, while water-soluble and lipid-soluble small molecules are the main antioxidants. The thiol proteome and thiol-oxidoreductases are emerging investigative areas given their specific disease-related responses (e.g. protein disulphide isomerases (PDIs) in thrombosis). Plasma cysteine and glutathione redox couples exhibit pro-oxidant changes directly correlated with ageing/age-related diseases. We further discuss changes in thiol-disulphide redox state in specific groups of diseases: cardiovascular, cancer, and neurodegenerative. These results indicate association with the disease states, although not yet clear-cut to yield specific biomarkers. We also highlight mechanisms whereby thiol pools affect atherosclerosis pathophysiology. Overall, it is unlikely that a single measurement provides global assessment of plasma oxidative stress. Rather, assessment of individual thiol pools and thiol-proteins specific to any given condition has more solid and logical perspective to yield novel relevant information on disease risk and prognosis.
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Locatelli MC, D'Antona A, Labianca R, Vinci M, Tedeschi M, Carcione R, Corbo A, Venturino P, Luporini G. A Phase II Study of Combination Chemotherapy in Advanced Ovarian Carcinoma with Cisplatin and Cyclophosphamide plus Reduced Glutathione as Potential Protective Agent against Cisplatin Toxicity. TUMORI JOURNAL 2018; 79:37-9. [PMID: 8497920 DOI: 10.1177/030089169307900108] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Aims and Backgroud The clinical use of cisplatin (CDDP)„ one of the most active agents in advanced ovarian cancer, is limited by nephrotoxicity and cumulative neurotoxicity. In preclinical studies, reduced glutathione (GSH) demonstrated a protective action against CDDP nephrotoxicity. We treated 20 patients with advanced ovarian carcinoma, with polichemotherapy containing CDDP + GSH, to assess the protective action of GSH against CDDP nephrotoxicity. Methods Between January 1988 and December 1989, 20 patients, with advanced ovarian carcinoma (St. III-IV-FIGO), not pretreated received CDDP: 45 mg/m2 i.v., on day 1-2, + cyclophosphamide (CPA): 900 mg/m2 i.v. on day 2 + GSH 2500 mg i.v. in normal saline 100 ml (in 15 min), before CDDP, every 21-28 days. Results A pathologic complete response rate (PCR) of 55 % (11/20) was observed (7/14 patients with bulky disease). Median survival was 26.5 months and 5 patients were still alive and disease free at 35 months. Toxicity was limited, without any case of nephrotoxicity. Conclusions On the basis of our previous experience with the same regimen without GSH, this study suggests that also in the clinical setting, GSH has no negative interference on CDDP activity and that GSH might improve the therapeutic index of CDDP. However, our data need to be confirmed by large randomized clinical studies.
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Affiliation(s)
- M C Locatelli
- Medical Oncology Dept., San Carlo Borromeo Hospital, Milan, Italy
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Truscelli G, Tanzilli G, Viceconte N, Dominici M, Arrivi A, Sommariva L, Granatelli A, Gaudio C, Mangieri E. Glutathione sodium salt as a novel adjunctive treatment for acute myocardial infarction. Med Hypotheses 2017; 102:48-50. [PMID: 28478830 DOI: 10.1016/j.mehy.2017.03.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Accepted: 03/05/2017] [Indexed: 10/20/2022]
Abstract
Timely recanalization of infarct related artery along with effective myocardial cell reperfusion represents a major challenge in the management of STEMI. The reperfusion of coronary arteries can induce further cardiomyocyte death by generating oxidative stress, which itself can mediate myocardial damage through a number of different mechanisms. Based on experimental and clinical studies, interventions to treat reperfusion injury by antioxidants were considered to be an appropriate therapeutic option. We emphasize the hypothesis that glutathione sodium salt, a physiologic antioxidant, may be of value when administered to STEMI patients both at an early stage of myocardial reperfusion by primary angioplasty and for up to three days after the procedure, in addition to standard treatment.
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Affiliation(s)
- G Truscelli
- Department of Heart and Great Vessels "Attilio Reale", "Sapienza" University of Rome, Italy
| | - G Tanzilli
- Department of Heart and Great Vessels "Attilio Reale", "Sapienza" University of Rome, Italy
| | - N Viceconte
- Department of Heart and Great Vessels "Attilio Reale", "Sapienza" University of Rome, Italy
| | | | - A Arrivi
- Ospedale "Santa Maria" Terni, Italy
| | | | - A Granatelli
- Ospedale " San Giovanni Evangelista" Tivoli, Italy
| | - C Gaudio
- Department of Heart and Great Vessels "Attilio Reale", "Sapienza" University of Rome, Italy
| | - E Mangieri
- Department of Heart and Great Vessels "Attilio Reale", "Sapienza" University of Rome, Italy.
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Abstract
Abstract
Background
CW002, a novel nondepolarizing neuromuscular blocking agent of intermediate duration, is degraded in vitro by l-cysteine; CW002-induced neuromuscular blockade (NMB) is antagonized in vivo by exogenous l-cysteine.1 Further, Institutional Animal Care and Use Committee–approved studies of safety and efficacy in eight anesthetized monkeys and six cats are described.
Methods
Mean arterial pressure, heart rate, twitch, and train-of-four were recorded; estimated dose producing 95% twitch inhibition (ED95) for NMB and twitch recovery intervals from 5 to 95% of baseline were derived. Antagonism of 99 to 100% block in monkeys by l-cysteine (50 mg/kg) was tested after bolus doses of approximately 3.75 to 20 × ED95 and after infusions. Vagal and sympathetic autonomic responses were recorded in cats. Dose ratios for [circulatory (ED20) or autonomic (ED50) changes/ED95 (NMB)] were calculated.
Results
ED95s of CW002 in monkeys and cats were 0.040 and 0.035 mg/kg; l-cysteine readily antagonized block in monkeys: 5 to 95% twitch recovery intervals were shortened to 1.8 to 3.6 min after 3.75 to 10 × ED95 or infusions versus 11.5 to 13.5 min during spontaneous recovery. ED for 20% decrease of mean arterial pressure (n = 27) was 1.06 mg/kg in monkeys; ED for 20% increase of HR (n = 27) was 2.16 mg/kg. ED50s for vagal and sympathetic inhibition in cats were 0.59 and >>0.80 mg/kg (n = 14 and 15). Dose ratios for [circulatory or autonomic changes/ED95 (NMB)] were all more than 15 × ED95.
Conclusions
The data further verify the neuromuscular blocking properties of CW002, including rapid reversal by l-cysteine of 100% NMB under several circumstances. A notable lack of autonomic or circulatory effects provided added proof of safety and efficacy.
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Effects of pre-natal alcohol exposure on hippocampal synaptic plasticity: Sex, age and methodological considerations. Neurosci Biobehav Rev 2016; 64:12-34. [PMID: 26906760 DOI: 10.1016/j.neubiorev.2016.02.014] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Revised: 01/14/2016] [Accepted: 02/18/2016] [Indexed: 12/28/2022]
Abstract
The consumption of alcohol during gestation is detrimental to the developing central nervous system (CNS). The severity of structural and functional brain alterations associated with alcohol intake depends on many factors including the timing and duration of alcohol consumption. The hippocampal formation, a brain region implicated in learning and memory, is highly susceptible to the effects of developmental alcohol exposure. Some of the observed effects of alcohol on learning and memory may be due to changes at the synaptic level, as this teratogen has been repeatedly shown to interfere with hippocampal synaptic plasticity. At the molecular level alcohol interferes with receptor proteins and can disrupt hormones that are important for neuronal signaling and synaptic plasticity. In this review we examine the consequences of prenatal and early postnatal alcohol exposure on hippocampal synaptic plasticity and highlight the numerous factors that can modulate the effects of alcohol. We also discuss some potential mechanisms responsible for these changes as well as emerging therapeutic avenues that are beginning to be explored.
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White-Schenk D, Shi R, Leary JF. Nanomedicine strategies for treatment of secondary spinal cord injury. Int J Nanomedicine 2015; 10:923-38. [PMID: 25673988 PMCID: PMC4321603 DOI: 10.2147/ijn.s75686] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Neurological injury, such as spinal cord injury, has a secondary injury associated with it. The secondary injury results from the biological cascade after the primary injury and affects previous uninjured, healthy tissue. Therefore, the mitigation of such a cascade would benefit patients suffering a primary injury and allow the body to recover more quickly. Unfortunately, the delivery of effective therapeutics is quite limited. Due to the inefficient delivery of therapeutic drugs, nanoparticles have become a major field of exploration for medical applications. Based on their material properties, they can help treat disease by delivering drugs to specific tissues, enhancing detection methods, or a mixture of both. Incorporating nanomedicine into the treatment of neuronal injury and disease would likely push nanomedicine into a new light. This review highlights the various pathological issues involved in secondary spinal cord injury, current treatment options, and the improvements that could be made using a nanomedical approach.
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Affiliation(s)
- Désirée White-Schenk
- Interdisciplinary Biomedical Sciences Program, Purdue University, West Lafayette, IN, USA ; Birck Nanotechnology Center, Discovery Park, Purdue University, West Lafayette, IN, USA
| | - Riyi Shi
- Interdisciplinary Biomedical Sciences Program, Purdue University, West Lafayette, IN, USA ; Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA ; Department of Basic Medical Sciences, Lynn School of Veterinary Medicine, Purdue University, West Lafayette, IN, USA
| | - James F Leary
- Interdisciplinary Biomedical Sciences Program, Purdue University, West Lafayette, IN, USA ; Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA ; Department of Basic Medical Sciences, Lynn School of Veterinary Medicine, Purdue University, West Lafayette, IN, USA ; Birck Nanotechnology Center, Discovery Park, Purdue University, West Lafayette, IN, USA
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Turell L, Radi R, Alvarez B. The thiol pool in human plasma: the central contribution of albumin to redox processes. Free Radic Biol Med 2013; 65:244-253. [PMID: 23747983 PMCID: PMC3909715 DOI: 10.1016/j.freeradbiomed.2013.05.050] [Citation(s) in RCA: 485] [Impact Index Per Article: 40.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2012] [Revised: 04/02/2013] [Accepted: 05/31/2013] [Indexed: 12/20/2022]
Abstract
The plasma compartment has particular features regarding the nature and concentration of low and high molecular weight thiols and oxidized derivatives. Plasma is relatively poor in thiol-based antioxidants; thiols are in lower concentrations than in cells and mostly oxidized. The different thiol-disulfide pairs are not in equilibrium and the steady-state concentrations of total thiols as well as reduced versus oxidized ratios are maintained by kinetic barriers, including the rates of reactions and transport processes. The single thiol of human serum albumin (HSA-SH) is the most abundant plasma thiol. It is an important target for oxidants and electrophiles due to its reactivity with a wide variety of species and its relatively high concentration. A relatively stable sulfenic (HSA-SO3H) acid can be formed in albumin exposed to oxidants. Plasma increases in mixed disulfides (HSA-SSR) or in sulfinic (HSA-SO2H) and sulfonic (HSA-SO3H) acids are associated with different pathologies and may constitute biomarkers of the antioxidant role of the albumin thiol. In this work we provide a critical review of the plasma thiol pool with a focus on human serum albumin.
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Affiliation(s)
- Lucía Turell
- Laboratorio de Enzimología, Facultad de Ciencias, Universidad de la República, 11400 Montevideo, Uruguay; Laboratorio de Fisicoquímica Biológica, Facultad de Ciencias, Universidad de la República, 11400 Montevideo, Uruguay; Center for Free Radical and Biomedical Research, Facultad de Medicina, Universidad de la República, 11800 Montevideo, Uruguay
| | - Rafael Radi
- Center for Free Radical and Biomedical Research, Facultad de Medicina, Universidad de la República, 11800 Montevideo, Uruguay; Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, 11800 Montevideo, Uruguay
| | - Beatriz Alvarez
- Laboratorio de Enzimología, Facultad de Ciencias, Universidad de la República, 11400 Montevideo, Uruguay; Center for Free Radical and Biomedical Research, Facultad de Medicina, Universidad de la República, 11800 Montevideo, Uruguay.
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Patten AR, Brocardo PS, Sakiyama C, Wortman RC, Noonan A, Gil-Mohapel J, Christie BR. Impairments in hippocampal synaptic plasticity following prenatal ethanol exposure are dependent on glutathione levels. Hippocampus 2013; 23:1463-75. [PMID: 23996467 DOI: 10.1002/hipo.22199] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/22/2013] [Indexed: 11/09/2022]
Abstract
Previous studies from our laboratory have shown that prenatal ethanol exposure (PNEE) causes a significant deficit in synaptic plasticity, namely long-term potentiation (LTP), in the dentate gyrus (DG) region of the hippocampus of male rats. PNEE has also been shown to induce an increase in oxidative stress and a reduction in antioxidant capacity in the brains of both male and female animals. In this study the interaction between LTP and the major antioxidant in the brain, glutathione (GSH), is examined. We show that depletion of the intracellular reserves of GSH with diethyl maleate (DEM) reduces LTP in control male, but not female animals, mirroring the effects of PNEE. Furthermore, treatment of PNEE animals with N-acetyl cysteine (NAC), a cysteine donor for the synthesis of GSH, increases GSH levels in the hippocampus and completely restores the deficits in LTP in PNEE males. These results indicate that in males GSH plays a major role in regulating LTP, and that PNEE may cause reductions in LTP by reducing the intracellular pool of this endogenous antioxidant.
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Affiliation(s)
- Anna R Patten
- Division of Medical Sciences, Island Medical Program, University of Victoria, Victoria, British Columbia, Canada; Department of Biology, University of Victoria, Victoria, British Columbia, Canada
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Abstract
Dysregulation of glutathione homeostasis and alterations in glutathione-dependent enzyme activities are increasingly implicated in the induction and progression of neurodegenerative diseases, including Alzheimer’s, Parkinson’s and Huntington’s diseases, amyotrophic lateral sclerosis, and Friedreich’s ataxia. In this review background is provided on the steady-state synthesis, regulation, and transport of glutathione, with primary focus on the brain. A brief overview is presented on the distinct but vital roles of glutathione in cellular maintenance and survival, and on the functions of key glutathione-dependent enzymes. Major contributors to initiation and progression of neurodegenerative diseases are considered, including oxidative stress, protein misfolding, and protein aggregation. In each case examples of key regulatory mechanisms are identified that are sensitive to changes in glutathione redox status and/or in the activities of glutathione-dependent enzymes. Mechanisms of dysregulation of glutathione and/or glutathione-dependent enzymes are discussed that are implicated in pathogenesis of each neurodegenerative disease. Limitations in information or interpretation are identified, and possible avenues for further research are described with an aim to elucidating novel targets for therapeutic interventions. The pros and cons of administration of N-acetylcysteine or glutathione as therapeutic agents for neurodegenerative diseases, as well as the potential utility of serum glutathione as a biomarker, are critically evaluated.
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Pratschke S, Bilzer M, Grützner U, Angele M, Tufman A, Jauch KW, Schauer RJ. Tacrolimus Preconditioning of Rat Liver Allografts Impacts Glutathione Homeostasis and Early Reperfusion Injury. J Surg Res 2012; 176:309-16. [DOI: 10.1016/j.jss.2011.07.045] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2011] [Revised: 07/21/2011] [Accepted: 07/29/2011] [Indexed: 12/26/2022]
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Kern JK, Geier DA, Adams JB, Garver CR, Audhya T, Geier MR. A clinical trial of glutathione supplementation in autism spectrum disorders. Med Sci Monit 2012; 17:CR677-82. [PMID: 22129897 PMCID: PMC3628138 DOI: 10.12659/msm.882125] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Background Recent evidence shows that subjects diagnosed with an autism spectrum disorder (ASD) have significantly lower levels of glutathione than typically developing children. The purpose of this study was to examine the use of two commonly used glutathione supplements in subjects diagnosed with an ASD to determine their efficacy in increasing blood glutathione levels in subjects diagnosed with an ASD. Material/Methods The study was an eight-week, open-label trial using oral lipoceutical glutathione (n=13) or transdermal glutathione (n=13) in children, 3–13 years of age, with a diagnosis of an ASD. Subjects underwent pre- and post-treatment lab testing to evaluate plasma reduced glutathione, oxidized glutathione, cysteine, taurine, free and total sulfate, and whole-blood glutathione levels. Results The oral treatment group showed significant increases in plasma reduced glutathione, but not whole-blood glutathione levels following supplementation. Both the oral and transdermal treatment groups showed significant increases in plasma sulfate, cysteine, and taurine following supplementation. Conclusions The results suggest that oral and transdermal glutathione supplementation may have some benefit in improving some of the transsulfuration metabolites. Future studies among subjects diagnosed with an ASD should further explore the pharmacokinetics of glutathione supplementation and evaluate the potential effects of glutathione supplementation upon clinical symptoms.
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Brain oxidative stress: detection and mapping of anti-oxidant marker 'Glutathione' in different brain regions of healthy male/female, MCI and Alzheimer patients using non-invasive magnetic resonance spectroscopy. Biochem Biophys Res Commun 2011; 417:43-8. [PMID: 22120629 DOI: 10.1016/j.bbrc.2011.11.047] [Citation(s) in RCA: 142] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2011] [Accepted: 11/10/2011] [Indexed: 11/23/2022]
Abstract
Glutathione (GSH) serves as an important anti-oxidant in the brain by scavenging harmful reactive oxygen species that are generated during different molecular processes. The GSH level in the brain provides indirect information on oxidative stress of the brain. We report in vivo detection of GSH non-invasively from various brain regions (frontal cortex, parietal cortex, hippocampus and cerebellum) in bilateral hemispheres of healthy male and female subjects and from bi-lateral frontal cortices in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). All AD patients who participated in this study were on medication with cholinesterase inhibitors. Healthy young male (age 26.4±3.0) and healthy young female (age 23.6±2.1) subjects have higher amount of GSH in the parietal cortical region and a specific GSH distribution pattern (parietal cortex>frontal cortex>hippocampus ~ cerebellum) has been found. Overall mean GSH content is higher in healthy young female compared to healthy young male subjects and GSH is distributed differently in two hemispheres among male and female subjects. In both young female and male subjects, statistically significant (p=0.02 for young female and p=0.001 for young male) difference in mean GSH content is found when compared between left frontal cortex (LFC) and right frontal cortex (RFC). In healthy young female subjects, we report statistically significant positive correlation of GSH content between RFC and LFC (r=0.641, p=0.004) as well as right parietal cortex (RPC) and left parietal cortex (LPC) (r=0.797, p=0.000) regions. In healthy young male subjects, statistically significant positive correlation of GSH content was observed between LFC and LPC (r=0.481, p=0.032) regions. This statistical analysis implicates that in case of a high GSH content in LPC of a young male, his LFC region would also contain high GSH and vice versa. The difference in mean of GSH content between healthy young female control and female AD patients in RFC region (p=0.003) and difference in mean of GSH content between healthy young male control and male AD patients (p=0.05) in LFC region is found to be statistically significant. It is the first scientific report correlating alteration (in selective brain regions) of GSH level with clinical status of male and female subjects using non-invasive imaging technique.
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Chen P, Stone J, Sullivan G, Drisko JA, Chen Q. Anti-cancer effect of pharmacologic ascorbate and its interaction with supplementary parenteral glutathione in preclinical cancer models. Free Radic Biol Med 2011; 51:681-7. [PMID: 21672627 DOI: 10.1016/j.freeradbiomed.2011.05.031] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2011] [Revised: 05/20/2011] [Accepted: 05/23/2011] [Indexed: 11/22/2022]
Abstract
Two popular complementary, alternative, and integrative medicine therapies, high-dose intravenous ascorbic acid (AA) and intravenous glutathione (GSH), are often coadministered to cancer patients with unclear efficacy and drug-drug interaction. In this study we provide the first survey evidence for clinical use of iv GSH with iv AA. To address questions of efficacy and drug-drug interaction, we tested 10 cancer cell lines with AA, GSH, and their combination. The results showed that pharmacologic AA induced cytotoxicity in all tested cancer cells, with IC(50) less than 4 mM, a concentration easily achievable in humans. GSH reduced cytotoxicity by 10-95% by attenuating AA-induced H(2)O(2) production. Treatment in mouse pancreatic cancer xenografts showed that intraperitoneal AA at 4 g/kg daily reduced tumor volume by 42%. Addition of intraperitoneal GSH inhibited the AA-induced tumor volume reduction. Although all treatments (AA, GSH, and AA+GSH) improved survival rate, AA+GSH inhibited the cytotoxic effect of AA alone and failed to provide further survival benefit. These data confirm the pro-oxidative anti-cancer mechanism of pharmacologic AA and suggest that AA and GSH administered together provide no additional benefit compared with AA alone. There is an antagonism between ascorbate and glutathione in treating cancer, and therefore iv AA and iv GSH should not be coadministered to cancer patients on the same day.
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Affiliation(s)
- Ping Chen
- Program in Integrative Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
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Saitoh T, Satoh H, Nobuhara M, Machii M, Tanaka T, Ohtani H, Saotome M, Urushida T, Katoh H, Hayashi H. Intravenous glutathione prevents renal oxidative stress after coronary angiography more effectively than oral N-acetylcysteine. Heart Vessels 2010; 26:465-72. [DOI: 10.1007/s00380-010-0078-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2010] [Accepted: 07/23/2010] [Indexed: 10/18/2022]
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Zheng MQ, Tang K, Zimmerman MC, Liu L, Xie B, Rozanski GJ. Role of gamma-glutamyl transpeptidase in redox regulation of K+ channel remodeling in postmyocardial infarction rat hearts. Am J Physiol Cell Physiol 2009; 297:C253-62. [PMID: 19419996 DOI: 10.1152/ajpcell.00634.2008] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
gamma-Glutamyl transpeptidase (gamma-GT) is a key enzyme in GSH metabolism that regulates intracellular GSH levels in response to extracellular GSH (GSH(o)). The objective of this study was to identify the role of gamma-GT in reversing pathogenic K(+) channel remodeling in the diseased heart. Chronic ventricular dysfunction was induced in rats by myocardial infarction (MI), and studies were done after 6-8 wk. Biochemical assays of tissue extracts from post-MI hearts revealed significant increases in gamma-GT activity in left ventricle (47%) and septum (28%) compared with sham hearts, which paralleled increases in protein abundance and mRNA. Voltage-clamp studies of isolated left ventricular myocytes from post-MI hearts showed that downregulation of transient outward K(+) current (I(to)) was reversed after 4-5 h by 10 mmol/l GSH(o) or N-acetylcysteine (NAC(o)), and that the effect of GSH(o) but not NAC(o) was blocked by the gamma-GT inhibitors, acivicin or S-hexyl-GSH. Inhibition of gamma-glutamylcysteine synthetase by buthionine sulfoximine did not prevent upregulation of I(to) by GSH(o), suggesting that intracellular synthesis of GSH was not directly involved. However, pretreatment of post-MI myocytes with an SOD mimetic [manganese (III) tetrapyridylporphyrin] and catalase completely blocked recovery of I(to) by GSH(o). Confocal microscopy using the fluorogenic dye 2',7'-dichlorodihydrofluorescein diacetate confirmed that GSH(o) increased reactive oxygen species (ROS) generation by post-MI myocytes and to a lesser extent in myocytes from sham hearts. Furthermore, GSH(o)-mediated upregulation of I(to) was blocked by inhibitors of tyrosine kinase (genistein, lavendustin A, and AG1024) and thioredoxin reductase (auranofin and 13-cis-retinoic acid). These data suggest that GSH(o) elicits gamma-GT- and ROS-dependent transactivation of tyrosine kinase signaling that upregulates K(+) channel activity or expression via redox-mediated mechanisms. The signaling events stimulated by gamma-GT catalysis of GSH(o) may be a therapeutic target to reverse pathogenic electrical remodeling of the failing heart.
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Affiliation(s)
- Ming-Qi Zheng
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198-5850, USA
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Abstract
The brain is among the major organs generating large amounts of reactive oxygen species and is especially susceptible to oxidative stress. Glutathione (GSH) plays critical roles as an antioxidant, enzyme cofactor, cysteine storage form, the major redox buffer, and a neuromodulator in the central nervous system. GSH deficiency has been implicated in neurodegenerative diseases. GSH is a tripeptide comprised of glutamate, cysteine, and glycine. Cysteine is the rate-limiting substrate for GSH synthesis within neurons. Most neuronal cysteine uptake is mediated by sodium-dependent excitatory amino acid transporter (EAAT) systems, known as excitatory amino acid carrier 1 (EAAC1). Previous studies demonstrated EAAT is vulnerable to oxidative stress, leading to impaired function. A recent study found EAAC1-deficient mice to have decreased brain GSH levels and increased susceptibility to oxidative stress. The function of EAAC1 is also regulated by glutamate transporter associated protein 3-18. This review focuses on the mechanisms underlying GSH synthesis, especially those related to neuronal cysteine transport via EAAC1, as well as on the importance of GSH functions against oxidative stress.
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Affiliation(s)
- Koji Aoyama
- Department of Pharmacology, Teikyo University School of Medicine, Itabashi, Tokyo, Japan
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Hausheer FH, Schilsky RL, Bain S, Berghorn EJ, Lieberman F. Diagnosis, management, and evaluation of chemotherapy-induced peripheral neuropathy. Semin Oncol 2006; 33:15-49. [PMID: 16473643 DOI: 10.1053/j.seminoncol.2005.12.010] [Citation(s) in RCA: 268] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Peripheral neuropathy induced by cancer chemotherapy represents a large unmet need for patients due to the absence of treatment that can prevent or mitigate this common clinical problem. Chemotherapy-induced peripheral neuropathy (CIPN) diagnosis and management is further compounded by the lack of reliable and standardized means to diagnose and monitor patients who are at risk for, or who are symptomatic from, this complication of treatment. The pathogenesis and pathophysiology of CIPN are not fully elucidated, but there is increasing evidence of damage or interference with tubulin function. The diagnosis of CIPN may present a diagnostic dilemma due to the large number of potential toxic etiologies and conditions, which may mimic some of the clinical features; the diagnosis must be approached with care in such patients. The incidence and severity of CIPN is commonly under-reported by physicians as compared with patients. The development of new and reliable methods for the assessment of CIPN as well as safe and effective treatments to prevent this complication of treatment would represent important medical advancements for cancer patients.
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Hong SY, Gil HW, Yang JO, Lee EY, Kim HK, Kim SH, Chung YH, Hwang SK, Lee ZW. Pharmacokinetics of glutathione and its metabolites in normal subjects. J Korean Med Sci 2005; 20:721-6. [PMID: 16224142 PMCID: PMC2779265 DOI: 10.3346/jkms.2005.20.5.721] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
To determine the loading and maintenance dosage of glutathione (GSH) for patients suffering from reactive oxygen species (ROS) injury such as acute paraquat intoxication, a kinetic study of reduced GSH was performed in synchrony with that of cysteine (Cys), cystine (Cys2), and methionine (Met). Human subject's porticipitation was voluntary. The effective dose of Cys, Cys2, and Met against ROS in fibroblast cells generated by paraquat was assessed using laser scanning confocal microscopy. Both Cys and Met suppressed ROS in a dose-dependent manner at concentrations of 1-1,000 microM; the concentration required to suppress ROS by 50% was 10 microM for Cys and 50 microM for Met. Using metabolite kinetics with the assumption that Cys and Met are the metabolites of GSH, expected concentrations of Cys and Met of above 20 and 50 microM were estimated when GSH was administered at 50 mg/kg body weights every 205.4 min for Cys and 427.4 min for Met.
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Affiliation(s)
- Sae-Yong Hong
- Department of Internal Medicine and Clinical Research Institute, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Hyo-Wook Gil
- Department of Internal Medicine and Clinical Research Institute, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Jong-Oh Yang
- Department of Internal Medicine and Clinical Research Institute, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Eun-Young Lee
- Department of Internal Medicine and Clinical Research Institute, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Hyung-Kee Kim
- Department of Clinical Pharmacology, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Soo-Hyun Kim
- Proteome Analysis Team, Korea Basic Science Institute, Daejeon, Korea
| | - Young-Ho Chung
- Proteome Analysis Team, Korea Basic Science Institute, Daejeon, Korea
| | - Soo-Kyung Hwang
- Proteome Analysis Team, Korea Basic Science Institute, Daejeon, Korea
| | - Zee-Won Lee
- Proteome Analysis Team, Korea Basic Science Institute, Daejeon, Korea
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Schauer RJ, Kalmuk S, Gerbes AL, Leiderer R, Meissner H, Schildberg FW, Messmer K, Bilzer M. Intravenous administration of glutathione protects parenchymal and non-parenchymal liver cells against reperfusion injury following rat liver transplantation. World J Gastroenterol 2004; 10:864-70. [PMID: 15040034 PMCID: PMC4726997 DOI: 10.3748/wjg.v10.i6.864] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To investigated the effects of intravenous administration of the antioxidant glutathione (GSH) on reperfusion injury following liver transplantation.
METHODS: Livers of male Lewis rats were transplanted after 24 h of hypothermic preservation in University of Wisconsin solution in a syngeneic setting. During a 2-h reperfusion period either saline (controls, n = 8) or GSH (50 or 100 μmol/(h·kg), n = 5 each) was continuously administered via the jugular vein.
RESULTS: Two hours after starting reperfusion plasma ALT increased to 1 457 ± 281 U/L (mean ± SE) in controls but to only 908 ± 187 U/L (P < 0.05) in animals treated with 100 μmol GSH/(h·kg). No protection was conveyed by 50 μmol GSH/(h·kg). Cytoprotection was confirmed by morphological findings on electron microscopy: GSH treatment prevented detachment of sinusoidal endothelial cells (SEC) as well as loss of microvilli and mitochondrial swelling of hepatocytes. Accordingly, postischemic bile flow increased 2-fold. Intravital fluorescence microscopy revealed a nearly complete restoration of sinusoidal blood flow and a significant reduction of leukocyte adherence to sinusoids and postsinusoidal venules. Following infusion of 50 μmol and 100 μmol GSH/(h·kg), plasma GSH increased to 65 ± 7 mol/L and 97 ± 18 mol/L, but to only 20 ± 3 mol/L in untreated recipients. Furthermore, plasma glutathione disulfide (GSSG) increased to 7.5 ± 1.0 mol/L in animals treated with 100 μmol/(h·kg) GSH but did not raise levels of untreated controls (1.8 ± 0.5 mol/L) following infusion of 50 μmol GSH/(h·kg) (2.2 ± 0.2 mol/L).
CONCLUSION: Plasma GSH levels above a critical level may act as a “sink” for ROS produced in the hepatic vasculature during reperfusion of liver grafts. Therefore, GSH can be considered a candidate antioxidant for the prevention of reperfusion injury after liver transplantation, in particular since it has a low toxicity in humans.
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Affiliation(s)
- Rolf J Schauer
- Surgical Department, University Hospital Klinikum Grosshadern, Marchioninistr. 15, 81377 Munich, Germany.
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Schauer RJ, Gerbes AL, Vonier D, Meissner H, Michl P, Leiderer R, Schildberg FW, Messmer K, Bilzer M. Glutathione protects the rat liver against reperfusion injury after prolonged warm ischemia. Ann Surg 2004; 239:220-31. [PMID: 14745330 PMCID: PMC1356215 DOI: 10.1097/01.sla.0000110321.64275.95] [Citation(s) in RCA: 92] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE To evaluate the potential of postischemic intravenous infusion of the endogenous antioxidant glutathione (GSH) to protect the liver from reperfusion injury following prolonged warm ischemia. BACKGROUND DATA The release of reactive oxygen species (ROS) by activated Kupffer cells (KC) and leukocytes causes reperfusion injury of the liver after warm ischemia. Therefore, safe and cost-effective antioxidant strategies would appear a promising approach to prevent hepatic reperfusion injury during liver resection, but need to be developed. METHODS Livers of male Lewis rats were subjected to 60, 90, or 120 minutes of normothermic ischemia. During a 120 minutes reperfusion period either GSH (50, 100 or 200 micromol/h/kg; n= 6-8) or saline (n= 8) was continuously administered via the jugular vein. RESULTS Postischemic GSH treatment significantly prevented necrotic injury to hepatocytes as indicated by a 50-60% reduction of serum ALT and AST. After 1 hour of ischemia and 2 hours of reperfusion apoptotic hepatocytes were rare (0.50 +/- 0.10%; mean +/- SD) and not different in GSH-treated animals (0.65 +/- 0.20%). GSH (200 micromol GSH/h/kg) improved survival following 2 hours of ischemia (6 of 9 versus 3 of 9 rats; P < 0.05). Intravital fluorescence microscopy revealed a nearly complete restoration of sinusoidal blood flow. This was paralleled by a reduction of leukocyte adherence to sinusoids and postsinusoidal venules. Intravenous GSH administration resulted in a 10- to 40-fold increase of plasma GSH levels, whereas intracellular GSH contents were unaffected. Plasma concentrations of oxidized glutathione (GSSG) increased up to 5-fold in GSH-treated animals suggesting counteraction of the vascular oxidant stress produced by activated KC. CONCLUSIONS Intravenous GSH administration during reperfusion of ischemic livers prevents reperfusion injury in rats. Because GSH is well tolerable also in man, this novel approach could be introduced to human liver surgery.
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Affiliation(s)
- Rolf J Schauer
- Department of Surgery, Klinikum of the University of Munich, Grosshadern, Germany.
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Wardman P, Folkes LK, Bentzen SM, Stratford MR, Hoskin PJ, Phillips H, Jackson S. Influence of plasma glutathione levels on radiation mucositis. Int J Radiat Oncol Biol Phys 2001; 51:460-4. [PMID: 11583019 DOI: 10.1016/s0360-3016(01)01612-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
PURPOSE To test the hypothesis that there is a link between plasma glutathione (GSH) or other antioxidants (uric acid, ascorbate) and the severity of radiation mucositis following radiation treatment of tumors of the head and neck. PATIENTS AND METHODS Patients with carcinomas of the head-and-neck region were treated with the continuous hyperfractionated accelerated radiotherapy (CHART) regimen (54 Gy in 36 fractions over 12 days). Samples of blood plasma were analyzed for GSH, cysteine, urate, and ascorbate by high-pressure liquid chromatography. Patients were graded for dysphagia and requirement for analgesics. The areas under the curves of scores over 2-6 weeks following treatment were computed, and Spearman's rank-correlation coefficient was used to test for an association between plasma GSH levels (or those of other antioxidants) and mucositis. RESULTS The pretreatment plasma GSH level in 18 patients scored in the study was 1.0 +/- 0.7 M. Analysis of these and the dysphagia scores produced a correlation coefficient of 0.22 (confidence interval -0.28, 0.61; p = 0.39). No correlation was seen between mucositis severity and other measures of plasma antioxidants: cysteine (7.6 +/- 1.7 M), cysteine + GSH (8.6 +/- 1.9 M), uric acid (317 +/- 86 M), ascorbate (29 +/- 20 M), or whole-blood GSH concentrations (1,010 +/- 239 M). CONCLUSION The measurements of approximately micromolar levels of plasma GSH, or about 10 M cysteine + GSH (almost all of the total nonprotein thiols), are consistent with most other published data for either healthy adults or cancer patients; however, the values reported in an earlier study, suggesting a link between GSH and mucositis, are much higher. The hypothesis of a possible link between radiation mucositis and plasma-free (nonprotein) thiols was not supported.
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Affiliation(s)
- P Wardman
- Gray Cancer Institute, Mount Vernon Hospital, Northwood, Middlesex, UK.
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Kugiyama K, Miyao Y, Sakamoto T, Kawano H, Soejima H, Miyamoto S, Yoshimura M, Ogawa H, Sugiyama S, Yasue H. Glutathione attenuates coronary constriction to acetylcholine in patients with coronary spastic angina. Am J Physiol Heart Circ Physiol 2001; 280:H264-71. [PMID: 11123241 DOI: 10.1152/ajpheart.2001.280.1.h264] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
This study examined the effect of reduced glutathione (GSH), an important antioxidant that restores intracellular redox imbalance and prevents inactivation of endothelial-derived nitric oxide, on the abnormal vasomotor reactivity in spastic coronary arteries. The responses of epicardial diameter of the left coronary arteries to intracoronary infusion of acetylcholine (ACh; 50 microg/min) were measured by quantitative coronary angiography before and during combined intracoronary infusion of GSH (50 mg/min for 6 min) or saline as a placebo in 24 patients with coronary spastic angina and in 28 control patients. All of the spastic coronary arteries showed constrictor response to ACh, whereas the control coronary arteries as a whole showed only minimal diameter changes to ACh. GSH infusion suppressed constrictor response of epicardial diameter to ACh in patients with coronary spastic angina, whereas it had no significant effect in control subjects. Saline infusion did not have any effects. The results indicate that GSH attenuated the constrictor response to ACh in epicardial coronary arteries of patients with coronary spastic angina. GSH may have an important role in the regulation of coronary vasomotor function in patients with coronary spastic angina.
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Affiliation(s)
- K Kugiyama
- Department of Cardiovascular Medicine, Kumamoto University School of Medicine, Kumamoto, Japan 860-8556.
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35
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Bianchi G, Brizi M, Rossi B, Ronchi M, Grossi G, Marchesini G. Synthesis of glutathione in response to methionine load in control subjects and in patients with cirrhosis. Metabolism 2000; 49:1434-9. [PMID: 11092507 DOI: 10.1053/meta.2000.16554] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
The fasting plasma level of reduced glutathione (GSH), a methionine-derived tripeptide, is reduced in cirrhosis. There is evidence that a reduced activity of S-adenosyl-L-methionine synthetase limiting the flux of methionine along the transmethylation/transsulfuration pathway may contribute to decrease GSH levels. No studies have analyzed plasma GSH in response to a methionine load. In 6 control subjects and in 10 patients with cirrhosis, plasma sulfur amino acid and plasma and erythrocyte GSH levels were measured in response to a L-methionine load (0.1 g/kg). Blood samples were obtained throughout the day after the oral load. Urine was collected for measurement of sulfur excretion. During the study period, all subjects consumed a standard diet of 1,683 kcal containing 2% protein and virtually no methionine. Plasma methionine increased in both groups to a peak level exceeding 20 times the basal value 90 minutes after the load, and declined thereafter. Methionine clearance, calculated on the descending part of the methionine-time curve, was reduced by 50% in cirrhosis (P = .0001). Fasting GSH was higher in controls (mean +/- SD, 3.9 +/- 1.3 v 1.6 +/- 0.7 micromol/L, P = .0004). In response to a methionine load, it peaked at 10.2 +/- 7.2 and 3.2 +/- 1.3 micromol/L, respectively (P = .009). Thereafter, plasma GSH progressively declined, and after 24 hours, it returned to the fasting preinfusion values in both groups. Plasma cysteine and taurine concentrations, as well as the erythrocyte GSH time course, paralleled plasma GSH levels, with less significant differences between groups. Sulfate excretion was delayed. GSH synthesis is stimulated by a methionine load. The reduced flux of methionine along the transmethylation/transsulfuration pathway reduces GSH synthesis in cirrhosis. Defective methionine metabolism also may be responsible for reduced fasting GSH.
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Affiliation(s)
- G Bianchi
- Dipartimento di Medicina Interna, Università di Bologna, Italy
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36
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Abstract
Altered gamma-glutamylcysteinylglycine homeostasis has been implicated in a wide variety of human diseases. The measurement of the rates of synthesis or loss of gamma-glutamylcysteinylglycine is necessary in order to make meaningful inferences about changes in gamma-glutamylcysteinylglycine concentration in these diseased states. In this review, we discuss methods for measuring gamma-glutamylcysteinylglycine concentration in biological samples as well as how improvements in the sensitivity of gas chromatography-mass spectrometric analyses have permitted the development of new and convenient stable isotope tracer methods for the in-vivo measurement of gamma-glutamylcysteinylglycine kinetics.
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Affiliation(s)
- M Reid
- USDA/Agricultural Research Service, Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
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Affiliation(s)
- M Bilzer
- Department of Medicine II, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Germany
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38
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Abstract
Thiol and disulfide forms of glutathione (GSH) and cysteine (Cys) were measured in plasma from 24 healthy individuals aged 25-35 and redox potential values (E(h)) for thiol/disulfide couples were calculated using the Nernst equation. Although the concentration of GSH (2.8 +/- 0.9 microM) was much greater than that of GSSG (0.14 +/- 0.04 microM), the redox potential of the GSSG/2GSH pool (-137 +/- 9 mV) was considerably more oxidized than values for tissues and cultured cells (-185 to -258 mV). This indicates that a rapid oxidation of GSH occurs upon release into plasma. The difference in values between individuals was remarkably small, suggesting that the rates of reduction and oxidation in the plasma are closely balanced to maintain this redox potential. The redox potential for the Cys and cystine (CySS) pool (-80 +/- 9 mV) was 57 mV more oxidized, showing that the GSSG/2GSH and the CySS/2Cys pools are not in redox equilibrium in the plasma. Potentials for thiol/disulfide couples involving CysGly were intermediate between the values for these couples. Regression analyses showed that the redox potentials for the different thiol/disulfide couples within individuals were correlated, with the E(h) for CySS-mono-Gly/(Cys. CysGly) providing the best correlation with other low molecular weight pools as well as protein disulfides of GSH, CysGly and Cys. These results suggest that E(h) values for GSSG/2GSH and CySS-mono-Gly/(Cys. CysGly) may provide useful means to quantitatively express the oxidant/antioxidant balance in clinical and epidemiologic studies.
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Affiliation(s)
- D P Jones
- Department of Biochemistry, Atlanta, GA, USA.
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Metges CC, Yu YM, Cai W, Lu XM, Wong S, Ajami AM, Young VR. Plasma L-5-oxoproline carbon and nitrogen kinetics in healthy young adults. J Nutr 1999; 129:1998-2004. [PMID: 10539775 DOI: 10.1093/jn/129.11.1998] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
L-5-oxoproline (OP), an intermediate of the gamma-glutamyl cycle of glutathione synthesis and degradation, may serve as a probe for the state of glutathione kinetics. We explored the whole-body carbon and nitrogen kinetics of OP in five male healthy subjects (75.2 kg; 181 cm; 26 y) after a 5-d adaptation to an adequate L-amino acid-based diet (160 mg N x kg(-1) x d(-1); 188 kJ x kg(-1) x d(-1)), using a crossover design. On day 6 of the diet period, we carried out an 8-h tracer protocol (3 h fast; 5 h fed; 2/3 of daily nitrogen intake) with intravenous infusion of L-[1-(13)C]oxoproline and L-[3, 3-(2)H]cysteine or, in randomized order, on the second occasion, L-[(15)N]oxoproline and L-[3,3-(2)H]cysteine. Plasma OP was isolated by cation exchange and after addition of internal standards (DL-[(2)H(3)]-5-oxoproline; L-[(15)N, U-(13)C(5)]-5-oxoproline; DL-[(2)H(3)]-glutamic acid) derivatized to form TBDMS esters and measured by gas chromatography/mass spectrometry. Plasma OP concentration did not differ between fed and fasted state (fast: 59. 4 +/- 8.3; fed 59.2 +/- 8.9 nmol/mL). (13)C- and (15)N OP flux during the fasted and fed state were 19 +/- 3.6, 21.2 +/- 3.2, and 22.6 +/- 3.9, 25.8 +/- 4.3 micromol x kg(-1) x 30 min(-1), respectively. OP oxidation was 15.6 +/- 3.6 and 17.9 +/- 3.5 micromol x kg(-1) x 30 min(-1), in fasting and feeding, respectively, (P < 0.05). More than 80% of the plasma flux was oxidized. These findings are compared with the published literature on GSH turnover in plasma of human subjects and underscore the need to define more completely the dynamic aspects of glutathione metabolism and of the intermediates of the gamma-glutamyl cycle.
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Affiliation(s)
- C C Metges
- Laboratory of Human Nutrition, School of Science and Clinical Research Center, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
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Andersson A, Lindgren A, Arnadottir M, Prytz H, Hultberg B. Thiols as a Measure of Plasma Redox Status in Healthy Subjects and in Patients with Renal or Liver Failure. Clin Chem 1999. [DOI: 10.1093/clinchem/45.7.1084] [Citation(s) in RCA: 44] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Affiliation(s)
| | | | | | - Hanne Prytz
- Internal Medicine, University Hospital, S-221 85 Lund, Sweden
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Bilzer M, Paumgartner G, Gerbes AL. Glutathione protects the rat liver against reperfusion injury after hypothermic preservation. Gastroenterology 1999; 117:200-10. [PMID: 10381928 DOI: 10.1016/s0016-5085(99)70568-8] [Citation(s) in RCA: 59] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS The extracellular generation of reactive oxygen species (ROS) by Kupffer cells contributes to reperfusion injury of the liver allograft. The endogenous antioxidant glutathione (GSH) can detoxify these ROS; however, this effect might be limited by the low extracellular concentration of GSH. We therefore investigated whether an increase of extracellular GSH protects the liver against reperfusion injury after cold preservation. METHODS Livers of male Sprague-Dawley rats subjected to 24 hours of cold ischemia in University of Wisconsin solution (4 degrees C) were reperfused for 2 hours in the absence (controls) or presence of 0.5, 1, 2, or 4 mmol/L GSH (n = 4-6 each). RESULTS Two hours after starting reperfusion of control livers, the sinusoidal release of lactate dehydrogenase and purine nucleoside phosphorylase increased to 247 +/- 96 and 27 +/- 13 mU. min(-1). g liver(-1), respectively, but only to 76 +/- 43 and 10 +/- 4 mU. min(-1). g liver(-1) in the presence of 4 mmol/L GSH. This cytoprotective effect was confirmed histologically by a marked reduction of trypan blue staining of hepatocytes. Compared with control livers, postischemic bile flow was significantly enhanced by GSH (0.15 +/- 0.02 vs. 0.41 +/- 0.11 microL. min(-1). g liver(-1)), indicating improved liver function. During reperfusion of control livers, intracellular GSH content declined from 4.5 +/- 0.3 to 2.3 +/- 0.1 micromol/g liver, but only to 3.8 +/- 0.4 micromol/g liver in the presence of 4 mmol/L GSH. Reperfusion of untreated livers was accompanied by a prolonged increase of portal pressure to maximally 12.5 +/- 1.9 cm H2O, which was significantly attenuated by 4 mmol/L GSH (7.2 +/- 1.4 cm H2O). Similar cytoprotective and hemodynamic effects were observed with 2 mmol/L GSH, but not with 0.5 and 1 mmol/L GSH. CONCLUSIONS Treatment of cold-preserved livers with GSH upon reperfusion prevents damage of hepatocytes, deterioration of the hepatic circulation, and loss of intracellular GSH. In view of these protective effects and its low toxicity in humans, GSH should be considered a candidate drug for prevention of ROS-related reperfusion injury of the liver allograft.
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Affiliation(s)
- M Bilzer
- Department of Medicine II, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Munich, Germany
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Hospers GA, Eisenhauer EA, de Vries EG. The sulfhydryl containing compounds WR-2721 and glutathione as radio- and chemoprotective agents. A review, indications for use and prospects. Br J Cancer 1999; 80:629-38. [PMID: 10360638 PMCID: PMC2362304 DOI: 10.1038/sj.bjc.6690404] [Citation(s) in RCA: 79] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Radio- and chemotherapy for the treatment of malignancies are often associated with significant toxicity. One approach to reduce the toxicity is the concomitant treatment with chemoprotective agents. This article reviews two sulfhydryl compounds, namely the agent WR-2721 (amifostine), a compound recently registered for use in human in many countries, and the natural occurring compound glutathione (GSH). GSH is not registered as a chemoprotective agent. WR-2721 is an aminothiol prodrug and has to be converted to the active compound WR-1065 by membrane-bound alkaline phosphatase. WR-1065 and GSH both act as naturally occurring thiols. No protective effect on the tumour has been found when these compounds are administered intravenously. There is even in vitro evidence for an increased anti-tumour effect with mafosfamide after pretreatment with WR-2721, and in vivo after treatment with carboplatin and paclitaxel. Randomized clinical studies have shown that WR-2721 and GSH decrease cisplatin-induced nephrotoxicity and that WR-2721 reduces radiation radiotherapy-induced toxicity. Side-effects associated with WR-2721 are nausea, vomiting and hypotension, GSH has no side-effects. An exact role of WR-2721 and GSH as chemoprotectors is not yet completely clear. Future studies should examine the protective effect of these drugs on mucositis, cardiac toxicity, neuro- and ototoxicity, the development of secondary neoplasms and their effect on quality of life.
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Affiliation(s)
- G A Hospers
- Department of Internal Medicine, University Hospital Groningen, The Netherlands
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Wang S, Bottje WG, Cawthon D, Evenson C, Beers K, McNew R. Hepatic export of glutathione and uptake of constituent amino acids, glutamate and cysteine, in broilers in vivo. Poult Sci 1998; 77:1556-64. [PMID: 9776066 DOI: 10.1093/ps/77.10.1556] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
This study was conducted to document the glutathione (GSH) cycle (interorgan circulation of GSH) in broilers in vivo. Two experiments were conducted on 36 anesthetized male broilers (n = 6 per treatment) implanted with cannulae in the carotid artery, hepatic portal, and hepatic veins. Plasma GSH, glutamate, cysteine, cystine, and cysteinylglycine levels in each vessel were monitored following a bolus injection [Experiment (Exp.) 1] or 30 min continuous infusion (Exp. 2) of GSH, or a gamma-glutamyltranspeptidase inhibitor (AT125) into the hepatic portal vein. Controls received saline alone. The GSH and AT125 treatments were used to determine the effect of increasing the prehepatic GSH load and of inhibiting systemic GSH degradation, respectively, on the GSH cycle. Hepatic export of GSH was clearly evident in all three treatment groups in both experiments (Exp.). The GSH and AT125 treatments raised amino acid levels in some or all of the vessels, whereas cysteinylglycine was elevated by AT125 and depressed by the GSH treatment compared to Controls. Hepatic uptake of glutamate, cysteine, and/or cystine was observed in Controls and GSH-treated birds, but not in birds given AT125 (Exp. 2). Neither hepatic export nor uptake of cysteinylglycine was observed in any treatment group. The results clearly demonstrate the ability of the avian liver to export GSH into the general circulation despite alterations that might arise from changes in extra-hepatic ability to utilize GSH or its constituent amino acids.
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Affiliation(s)
- S Wang
- Department of Poultry Science, Center for Excellence for Poultry Science, University of Arkansas, Fayetteville 72701, USA
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Wang S, Cawthon D, Bottje WG. Age-related changes of plasma glutathione and cysteine in broilers: effect of dithiothreitol reduction vitro on free and bound pools. Poult Sci 1998; 77:1234-40. [PMID: 9706095 DOI: 10.1093/ps/77.8.1234] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
A study was conducted to determine free and protein-bound pools of glutathione and cysteine in the plasma of male broiler chicks. Birds were brooded in battery cages and provided ad libitum access to a starter diet and water. Plasma was treated with a reducing agent, dithiothreitol (DTT), or left untreated, and analyzed by HPLC to determine free and protein bound pools of reduced (GSH) and oxidized (GSSG) glutathione, cysteine (Cys), and cystine (Cyss). With respect to total plasma pools of GSH and Cys, between 0 and 21 d of age; 1) free GSH increased from 30 to 90% with a reciprocal decrease in protein-bound GSH, but GSSG was not detected; and 2) free Cys decreased from 20 to 10%, free Cyss increased from 24 to 45%, and protein-bound Cys decreased from 55 to 44%. The majority of the GSH plasma pool in this study was present in a free, acid-soluble form, whereas most of the total Cys pool was present as Cyss or bound to protein.
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Affiliation(s)
- S Wang
- Department of Poultry Science, Center of Excellence for Poultry Science, University of Arkansas, Fayetteville 72701, USA
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Kugiyama K, Ohgushi M, Motoyama T, Hirashima O, Soejima H, Misumi K, Yoshimura M, Ogawa H, Sugiyama S, Yasue H. Intracoronary infusion of reduced glutathione improves endothelial vasomotor response to acetylcholine in human coronary circulation. Circulation 1998; 97:2299-301. [PMID: 9639372 DOI: 10.1161/01.cir.97.23.2299] [Citation(s) in RCA: 65] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Oxygen free radicals have been shown to cause endothelial vasomotor dysfunction. This study examined the effect of reduced glutathione (GSH), an antioxidant, on human coronary circulation. METHODS AND RESULTS Responses of epicardial diameter and blood flow of the left anterior descending coronary artery to intracoronary infusion of acetylcholine (ACh, 50 microg/min) were measured by quantitative coronary angiography and Doppler flow-wire technique, respectively, before and during combined intracoronary infusion of GSH (50 mg/min) or saline in 26 subjects with no significant coronary stenosis. GSH infusion suppressed the constrictor response of epicardial diameter to ACh and enhanced the increase in blood flow response to ACh. Furthermore, GSH potentiated the coronary dilator effect of nitroglycerin. A beneficial effect of GSH on the epicardial diameter response to ACh was observed in a subgroup of subjects with > or = 1 coronary risk factors but not in a subgroup without risk factors. Saline infusion did not have any effects. CONCLUSIONS The results indicate that GSH improved coronary endothelial vasomotor function, particularly in subjects with coronary risk factors, and it potentiated the vasodilator effect of nitroglycerin in human coronary arteries.
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Affiliation(s)
- K Kugiyama
- Division of Cardiology, Kumamoto University School of Medicine, Kumamoto City, Japan.
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Pietraforte D, Minetti M. Direct ESR detection or peroxynitrite-induced tyrosine-centred protein radicals in human blood plasma. Biochem J 1997; 325 ( Pt 3):675-84. [PMID: 9271088 PMCID: PMC1218611 DOI: 10.1042/bj3250675] [Citation(s) in RCA: 45] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Peroxynitrite, the reaction product of O2.- and .NO, is a toxic compound involved in several oxidative processes that modify proteins. The mechanisms of these oxidative reactions are not completely understood. In this study, using direct ESR at 37 degrees C, we observed that peroxynitrite induced in human blood plasma a long-lived singlet signal at g = 2.004 arising from proteins. This signal was not due to a specific plasma protein, because several purified proteins were able to form a peroxynitrite-induced g = 2.004 signal, but serum albumin and IgG showed the most intense signals. Hydroxyurea, a tyrosyl radical scavenger, strongly inhibited the signal, and horseradish peroxidase/H2O2, a radical-generating system known to induce tyrosyl radicals, induced a similar signal. Furthermore peptides containing a Tyr in the central portion of the molecule were able to form a stable peroxynitrite-dependent g = 2.004 signal, whereas peptides in which Tyr was substituted with Gly, Trp or Phe and peptides with Tyr at the N-terminus or near the C-terminus did not form radicals that were stable at 37 degrees C. We suggest that Tyr residues are at least the major radical sources of the peroxynitrite-dependent g = 2.004 signal at 37 degrees C in plasma or in isolated proteins. Although significantly enhanced by CO2/bicarbonate, the signal was detectable in whole plasma at relatively high peroxynitrite concentrations (>2 mM) but, after removal of ascorbate or urate or in dialysed plasma, it was detectable at lower concentrations (100-1000 microM). Our results suggest that the major role of ascorbate and urate is to reduce or 'repair' the radical(s) centred on Tyr residues and not to scavenge peroxynitrite (or nitrosoperoxycarbonate, the oxidant formed in CO2-containing fluids). This mechanism of inhibition by plasma antioxidants may be a means of preserving the physiological functions of peroxynitrite.
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Affiliation(s)
- D Pietraforte
- Laboratorio di Biologia Cellulare, Istituto Superiore di Sanità, V. Regina Elena 299, 00161 Roma, Italy
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Cerielo A, Motz E, Cavarape A, Lizzio S, Russo A, Quatraro A, Giugliano D. Hyperglycemia counterbalances the antihypertensive effect of glutathione in diabetic patients: evidence linking hypertension and glycemia through the oxidative stress in diabetes mellitus. J Diabetes Complications 1997; 11:250-5. [PMID: 9201603 DOI: 10.1016/s1056-8727(97)00021-4] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Diabetes mellitus is associated with hypertension. An antihypertensive effect of the antioxidant glutathione has been recently demonstrated. It has been suggested that hyperglycemia may contribute to the pathophysiology of hypertension in diabetes by generating an oxidative stress. In this study, three different tests were performed in ten hypertensive and ten nonhypertensive diabetic subjects: (1) an oral glucose tolerance test, (2) glutathione i.v. administration (1 g/m2 bolus + 1 g/m2 in 2 h), and (3) oral glucose tolerance test + glutathione administration. At -15', 0', 30', 60', 90', 120', and 180' systolic and diastolic blood pressure, plasma glucose, and insulin were measured. Variations in plasma glucose and insulin levels were not different during each test in the two groups of patients and in test (1) compared to (3). Glutathione administration reduced systolic and diastolic blood pressure in both hypertensive and nonhypertensive diabetic subjects from 30' to 120'. This phenomenon was abolished as glycemia increased after oral glucose loading. In hypertensive, but not in nonhypertensive diabetic subjects, a significant increase of systolic and diastolic blood pressure was observed at 90' and 120' of the oral glucose tolerance test (p < 0.01). These data show that hyperglycemia can counteract the hypotensive effects of the antioxidant glutathione, suggesting that glucose may impair arterial relaxation by producing free radicals. Also, it appears that hypertension in diabetic patients is aggravated by high glucose plasma levels.
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Affiliation(s)
- A Cerielo
- Department of Clinical and Experimental Medicine and Pathology, University of Udine, Italy
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Smyth JF, Bowman A, Perren T, Wilkinson P, Prescott RJ, Quinn KJ, Tedeschi M. Glutathione reduces the toxicity and improves quality of life of women diagnosed with ovarian cancer treated with cisplatin: results of a double-blind, randomised trial. Ann Oncol 1997; 8:569-73. [PMID: 9261526 DOI: 10.1023/a:1008211226339] [Citation(s) in RCA: 133] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Early clinical trials have suggested that glutathione (GSH) offers protection from the toxic effects of cisplatin. PATIENTS AND METHODS One hundred fifty-one patients with ovarian cancer (stage I-IV) were evaluated in a clinical trial of cisplatin (CDDP) +/- glutathione (GSH). The objective was to determine whether GSH would enhance the feasibility of giving six cycles of CDDP at 100 mg/m2 without dose reduction due to toxicity. RESULTS When considering the proportion of patients receiving six courses of CDDP at any dose, GSH produced a significant advantage over control--58% versus 39%, (P = 0.04). For these patients there was a significant difference between the reduction in creatinine clearance for GSH treated patients compared with control--74% versus 62% (P = 0.006). Quality of life scores demonstrated that for patients receiving GSH there was a statistically significant improvement in depression, emesis, peripheral neurotoxicity, hair loss, shortness of breath and difficulty concentrating. As an indication of overall activity, these patients were statistically significantly more able to undertake housekeeping and shopping. Clinically assessed response to treatment demonstrated a trend towards a better outcome in the GSH group (73% versus 62%) but this was not statistically significant (P = 0.25). CONCLUSIONS The results demonstrate that adding GSH to CDDP allows more cycles of CDDP treatment to be administered because less toxicity is observed and the patient's quality of life is improved.
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Affiliation(s)
- J F Smyth
- ICRF Medical Oncology Unit, Western General Hospital, Edinburgh, UK
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Bianchi G, Bugianesi E, Ronchi M, Fabbri A, Zoli M, Marchesini G. Glutathione kinetics in normal man and in patients with liver cirrhosis. J Hepatol 1997; 26:606-13. [PMID: 9075668 DOI: 10.1016/s0168-8278(97)80426-6] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND/AIMS The dynamics of glutathione in plasma has always been studied by bolus injections. Data are available suggesting that the low plasma levels of cirrhosis are due to decreased production in glutathione-producing tissues, mainly the liver. We aimed to measure the kinetics of glutathione during controlled steady-state conditions, and to determine the reasons for its reduced plasma levels in advanced cirrhosis. METHODS The plasma clearance of glutathione was measured in six control subjects and in ten patients with cirrhosis during a 2-step infusion study, producing steady-state levels approximately 5 and 10 times basal values. The plasma disappearance curve after infusion stop was used to determine the apparent volume of distribution and half-life of glutathione, and the estimated basal appearance rate. RESULTS The clearance of glutathione did not reject 1st-order kinetics, i.e., it was concentration-independent, and was nearly doubled in cirrhosis. The half-life of exogenous glutathione was not different, whereas the volume of distribution was larger in cirrhosis, in the same range as extracellular water. The endogenous basal appearance rate of glutathione was reduced by 50%, and correlated with liver function, measured by routine and dynamic tests. CONCLUSIONS The data confirm that the primary defect responsible for reduced glutathione in liver disease is a reduced production, possibly related to hepatocyte dysfunction and a block along the pathway of methionine metabolism.
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Affiliation(s)
- G Bianchi
- Dipartimento di Medicina Interna, Università di Bologna, Italy
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Scorza G, Pietraforte D, Minetti M. Role of ascorbate and protein thiols in the release of nitric oxide from S-nitroso-albumin and S-nitroso-glutathione in human plasma. Free Radic Biol Med 1997; 22:633-42. [PMID: 9013126 DOI: 10.1016/s0891-5849(96)00378-4] [Citation(s) in RCA: 102] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
In this work we investigated the stability in aerobic plasma of two naturally occurring S-nitrosothiols, the S-nitroso adduct of serum albumin (S-NO-albumin) and the S-nitroso adduct of glutathione (S-NO-glutathione). In contrast to their behavior in physiological buffers, in which they are stable, in plasma these S-nitrosothiols showed a slow but continuous release of .NO. In the presence of red blood cells, the .NO was quantitatively oxidized to NO3- with stoichiometric formation of methemoglobin. In the absence of red blood cells, the principal oxidation product was NO2- with small amounts of NO3- (about 1/5 of the amount of NO2-). The release of .NO was also proven by spin trapping experiments with 2-(4-Carboxyphenyl)4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide which, when added to plasma in the presence of S-NO-glutathione, was transformed into 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl. Both dialysable and nondialysable compounds are involved in the release of .NO from S-nitrosothiols. Ascorbate and the thiol group of serum albumin are the plasma components mainly involved in the release of .NO, while endogenous L-cysteine and glutathione play a minor role due to their relative low concentrations. However, in contrast to the thiol-dependent release that is known to induce the formation of disulfides, the ascorbate-dependent release of .NO from S-NO-glutathione resulted in the formation of free sulfhydryls. Our results suggest that in plasma the .NO release from S-NO-albumin and S-NO-glutathione may be regulated by heterolytic NO+ transfer and reductive activation to .NO, rather than by homolytic decomposition of labile S-nitrosothiols.
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Affiliation(s)
- G Scorza
- Laboratorio di Biologia Cellulare, Istituto Superiore di Sanità, Roma, Italy
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