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A Phase 1 dose-escalation study of disulfiram and copper gluconate in patients with advanced solid tumors involving the liver using S-glutathionylation as a biomarker.
Kelley, KC, Grossman, KF, Brittain-Blankenship, M, Thorne, KM, Akerley, WL, Terrazas, MC, Kosak, KM, Boucher, KM, Buys, SS, McGregor, KA, et al
BMC cancer. 2021;(1):510
Abstract
BACKGROUND Disulfiram and metals inactivate key oncoproteins resulting in anti-neoplastic activity. The goal of this study was to determine the maximum tolerated dose of copper when administered with disulfiram in patients with advanced solid tumors and liver involvement. METHODS Disulfiram 250 mg was administered daily in 28-day cycles. Four doses of copper gluconate were tested (2, 4, 6, and 8 mg of elemental copper) in a standard 3 + 3 dose escalation design. Patients were evaluated for dose limiting toxicities and response. Protein S-glutathionylation was evaluated as a pharmacodynamic marker. RESULTS Twenty-one patients were enrolled and 16 patients were evaluable for dose limiting toxicities. Among the 21 patients, there was a median of 4 lines of prior chemotherapy. Five Grade 3 toxicities were observed (anorexia, elevated aspartate aminotransferase or AST, elevated alkaline phosphatase, fever, and fatigue). Response data was available for 15 patients. Four patients had stable disease with the longest duration of disease control being 116 days. The median duration of treatment for evaluable patients was 55 days (range 28-124). Reasons for discontinuation included functional decline, disease progression, and disease-associated death. Increased S-glutathionylation of serum proteins was observed with treatment. CONCLUSION Disulfiram 250 mg daily with copper gluconate (8 mg of elemental copper) was well-tolerated in patients with solid tumors involving the liver and was not associated with dose limiting toxicities. While temporary disease stabilization was noted in some patients, no objective responses were observed. Treatment was associated with an increase in S-glutathionylation suggesting that this combination could exert a suppressive effect on cellular growth and protein function. TRIAL REGISTRATION NCT00742911 , first posted 28/08/2008.
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Effects of acute N-acetylcysteine challenge on cortical glutathione and glutamate in schizophrenia: A pilot in vivo proton magnetic resonance spectroscopy study.
Girgis, RR, Baker, S, Mao, X, Gil, R, Javitt, DC, Kantrowitz, JT, Gu, M, Spielman, DM, Ojeil, N, Xu, X, et al
Psychiatry research. 2019;:78-85
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Abstract
Findings from in vivo brain proton magnetic resonance spectroscopy (1H MRS) and preclinical studies have suggested region- and medication status-dependent increases in glutamate (Glu) levels and deficiencies in glutathione (GSH) levels in schizophrenia. N-acetylcysteine (NAC), a GSH synthesis precursor, has demonstrated modest clinical benefit in schizophrenia. The objective of this study was to examine the effects of acute administration of NAC on GSH and Glu levels measured with 1H MRS in 19 patients with schizophrenia and 20 healthy control subjects. Levels of GSH were acquired in dorsal anterior cingulate cortex (dACC), and those of Glu in dACC and medial prefrontal cortex (mPFC), at baseline and 60 min following acute oral administration of 2400 mg of NAC. No differences in the levels of GSH or Glu were found at baseline or following NAC administration between patients with schizophrenia and control subjects in either of the targeted brain regions. Future studies measuring GSH levels in brain regions previously found to exhibit glutamatergic abnormalities or using genetic polymorphisms, while controlling for the age and medication status of the cohorts, are warranted to better identify groups of patients more likely to respond to NAC and its mode of action and mechanisms.
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Vitamin D deficiency is associated with an oxidized plasma cysteine redox potential in critically Ill children.
Alvarez, JA, Grunwell, JR, Gillespie, SE, Tangpricha, V, Hebbar, KB
The Journal of steroid biochemistry and molecular biology. 2018;:164-169
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Abstract
Critically ill populations incur high levels of oxidative stress and commonly present with vitamin D deficiency. This study aimed to investigate the relationship between vitamin D status and plasma markers of glutathione (GSH) and cysteine (Cys) redox and immunity in critically ill children. This was a cross-sectional study of n=50 PICU patients. Subjects were categorized according to their plasma 25-hydroxyvitamin D [25(OH)D] concentrations: (<20, 20-30, and ≥30ng/dL). Plasma GSH, glutathione disulfide (GSSG), Cys, and cystine (CySS) were measured with high-performance liquid chromatography, and their associated redox potentials determined (EhGSSG and EhCySS, respectively). Plasma LL-37, an indicator of innate immune function, was assayed with ELISA. Data were analyzed using general linear regression before and after adjustment for age, sex, and race. Results showed that EhCySS was more reduced in subjects with plasma 25(OH)D concentrations ≥30ng/mL compared to those with 25(OH)D concentrations <20ng/mL (P=0.009). Plasma GSH, GSSG, and total GSH decreased with increasing 25(OH)D category (P=0.06, 0.03, and 0.01, respectively), and plasma glutamine levels were lowest in subjects with plasma 25(OH)D concentrations ≥30ng/mL (P=0.004). Plasma LL-37 concentrations did not significantly differ by vitamin D status (P=0.08). In conclusion, vitamin D sufficiency was associated with more reduced plasma EhCySS, indicative of lower oxidative stress in critically ill children. Plasma GSH, GSSG, and glutamine, however, were lower in the vitamin D sufficient group. The role of vitamin D in maintaining redox status during pediatric critical illness requires further study.
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Eryptosis and oxidative damage in hypertensive and dyslipidemic patients.
Pinzón-Díaz, CE, Calderón-Salinas, JV, Rosas-Flores, MM, Hernández, G, López-Betancourt, A, Quintanar-Escorza, MA
Molecular and cellular biochemistry. 2018;(1-2):105-113
Abstract
Arterial hypertension is a disease that often coexists with dyslipidemia. Both disorders can produce oxidative stress. Studies in vivo and in vitro have proven that oxidative stress can induce an increment of the erythrocyte apoptosis (eryptosis), through the rise of free intracellular calcium concentration ([Ca2+]i). Higher levels of eryptosis have not been described in patients with hypertension, dyslipidemia, or both combined. This study involved 81 men between 26 and 50 years old, assorted into four groups: normotensive with and without dyslipidemia, and hypertensive with and without dyslipidemia. Hypertensive and/or dyslipidemic patients had double mean lipid peroxidation and 30% less mean GSH concentration than the normotensive non-dyslipidemic patients. Mean [Ca2+]i in hypertensive patients was 100 and 200% higher, in patients without and with dyslipidemia, respectively, compared to normotensive patients. Dyslipidemic normotensive patients had three times higher mean PS externalization than the normotensive non-dyslipidemic patients, and the hypertension condition doubled this difference. Hypertensive patients had higher eryptosis associated with higher levels of [Ca2+]i and oxidative stress, suggesting that eryptosis participates in the pathophysiological mechanisms of hypertension. The quantitative analysis, when the dyslipidemic factor is included, shows that oxidative stress-[Ca2+]i-eryptosis do not follow a unique pattern in the different groups and suggests the existence of mechanisms of induction and molecular pathways alternative or additional to oxidative stress and [Ca2+]i, respectively.
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N-Acetylcysteine rapidly replenishes central nervous system glutathione measured via magnetic resonance spectroscopy in human neonates with hypoxic-ischemic encephalopathy.
Moss, HG, Brown, TR, Wiest, DB, Jenkins, DD
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2018;(6):950-958
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Persistent oxidative stress depletes reduced glutathione (GSH), an intracellular antioxidant and an important determinant of CNS injury after hypoxia ischemia. We used standard, short echo time Stimulated Echo Acquisition Mode (STEAM) to detect GSH by magnetic resonance spectroscopy (MRS) in 24 term neonates with hypoxic-ischemic encephalopathy (HIE), on day of life 5-6, after rewarming from therapeutic hypothermia. MRS demonstrated reliable, consistent GSH of 1·64 ± 0·20 mM in the basal ganglia immediately before intravenous infusion of N-acetylcysteine. N-acetylcysteine resulted in a rapid and significant GSH increase to 1·93 ± 0.23 mM within 12-30 min after completion of infusion ( n = 21, p < 0.0001, paired t-test), compared with those who did not receive N-acetylcysteine ( n = 3, GSH = 1.66 ± 0.06 mM and 1.64 ± 0.09 mM). In one perinatal stroke patient, GSH in the diffusion-restricted stroke area was 1.0 mM, indicating significant compromise of intracellular redox potential, which also improved after N-acetylcysteine. For comparison, GSH in healthy term neonates has been reported at 2.5 ± 0.9 mM in the thalamus. This is the first report to show persistent oxidative stress reflected in GSH during the subacute phase in neonates with HIE and rapid response to N-acetylcysteine, using a short echo MRS sequence that is available on all clinical scanners without spectral editing.
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Comparative effects of acute-methionine loading on the plasma sulfur-amino acids in NAC-supplemented HIV+ patients and healthy controls.
Burini, RC, Borges-Santos, MD, Moreto, F, Yu, YM
Amino acids. 2018;(5):569-576
Abstract
In this study, an acute overloading of methionine (MetLo) was used to investigate the trassulfuration pathway response comparing healthy controls and HIV+ patients under their usual diet and dietary N-acetyl-L-cysteine (NAC) supplementation. MetLo (0.1 g Met/kg mass weight) was given after overnight fasting to 20 non-HIV+ control subjects (Co) and 12 HIV+ HAART-treated patients. Blood samples were taken before and after the MetLo in two different 7-day dietary situations, with NAC (1 g/day) or with their usual diet (UD). The amino acids (Met, Hcy, Cys, Tau, Ser, Glu and Gln) and GSH were determined by HPLC and their inflow rate into circulation (plasma) was estimated by the area under the curve (AUC). Under UD, the HIV+ had lower plasma GSH and amino acids (excepting Hcy) and higher oxidative stress (GSSG/GSH ratio), similar remethylation (RM: Me/Hcy + Ser ratio), transmethylation (TM; Hcy/Met ratio) and glutaminogenesis (Glu/Gln ratio), lower transsulfuration (TS: Cys/Hcy + Ser ratio) and Cys/Met ratio and, higher synthetic rates of glutathione (GG: GSH/Cys ratio) and Tau (TG: Tau/Cys ratio). NAC supplementation changed the HIV pattern by increasing RM above control, normalizing plasma Met and TS and, increasing plasma GSH and GG above controls. However, plasma Cys was kept always below controls probably, associatively to its higher consumption in GG (more GSSG than GSH) and TG. The failure of restoring normal Cys by MetLo, in addition to NAC, in HIV+ patients seems to be related to increased flux of Cys into GSH and Tau pathways, probably strengthening the cell-antioxidant capacity against the HIV progression (registered at http://www.clinicaltrials.gov , NCT00910442).
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The Status of Biochemical and Molecular Markers of Oxidative Stress in Preeclamptic Saudi Patients.
Al-Sheikh, YA, Al-Zahrani, KY
Current molecular medicine. 2018;(7):475-485
Abstract
PURPOSE In the light of contradictory results and paucity of information, this comprehensive study examines the activities and levels of key antioxidants and oxidants/pro-oxidants in preeclamptic patients. METHODS Antioxidants including glutathione peroxidase, glutathione reductase, glutathione-S-transferase, superoxide dismutase, catalase, reduced glutathione, selenium, zinc, copper and manganese, as well as marker oxidants/pro-oxidants including hydrogen peroxide, superoxide anions, malondialdehyde, protein carbonyls and oxidized glutathione were determined in plasma and placental tissues of nonpregnant, healthy pregnant and preeclamptic subjects. RESULTS Data indicated that all plasma antioxidants underwent moderate but significant decreases (p< 0.05) in healthy pregnant women, , and much more significant ones (p< 0.0001) in preeclamptic patients, when both were compared to non-pregnant subjects. Furthermore, whereas all plasma antioxidants underwent significant decreases (p< 0.001) in preeclamptic patients compared to healthy pregnant subjects, their placental activities and levels were very significantly decreased (p< 0.0001). However, copper plasma and placental levels were unchanged in all study groups. In contrast, there were increases similar in magnitude and significance of all plasma and placental oxidants/prooxidants compared among the three study groups leading to equally significant decreases in the reduced/oxidized glutathione ratios. In addition, gene transcripts of all antioxidant enzymes underwent marked downregulation (p< 0.0001) in placental tissue of preeclamptic patients compared to healthy pregnant subjects. CONCLUSION Data indicated a metabolic shift in favor of oxidative stress more pronounced in placental tissue of preeclamptic patients compared to healthy pregnant/non-pregnant subjects. We postulate that selenium, zinc and manganese supplements could be beneficial for alleviation of the noted oxidative stress in preeclamptic patients.
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Efficacy of glutathione for the treatment of nonalcoholic fatty liver disease: an open-label, single-arm, multicenter, pilot study.
Honda, Y, Kessoku, T, Sumida, Y, Kobayashi, T, Kato, T, Ogawa, Y, Tomeno, W, Imajo, K, Fujita, K, Yoneda, M, et al
BMC gastroenterology. 2017;(1):96
Abstract
BACKGROUND Glutathione plays crucial roles in the detoxification and antioxidant systems of cells and has been used to treat acute poisoning and chronic liver diseases by intravenous injection. This is a first study examining the therapeutic effects of oral administration of glutathione in patients with nonalcoholic fatty liver disease (NAFLD). METHODS The study was an open label, single arm, multicenter, pilot trial. Thirty-four NAFLD patients diagnosed using ultrasonography were prospectively evaluated. All patients first underwent intervention to improve their lifestyle habits (diet and exercise) for 3 months, followed by treatment with glutathione (300 mg/day) for 4 months. We evaluated their clinical parameters before and after glutathione treatment. We also quantified liver fat and fibrosis using vibration-controlled transient elastography. The primary outcome of the study was the change in alanine aminotransferase (ALT) levels. RESULTS Twenty-nine patients finished the protocol. ALT levels significantly decreased following treatment with glutathione for 4 months. In addition, triglycerides, non-esterified fatty acids, and ferritin levels also decreased with glutathione treatment. Following dichotomization of ALT responders based on a median 12.9% decrease from baseline, we found that ALT responders were younger in age and did not have severe diabetes compared with ALT non-responders. The controlled attenuation parameter also decreased in ALT responders. CONCLUSIONS This pilot study demonstrates the potential therapeutic effects of oral administration of glutathione in practical dose for patients with NAFLD. Large-scale clinical trials are needed to verify its efficacy. TRIAL REGISTRATION UMIN000011118 (date of registration: July 4, 2013).
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The development of lung biochemical monitoring can play a key role in the early prediction of bronchopulmonary dysplasia.
Fabiano, A, Gavilanes, AW, Zimmermann, LJ, Kramer, BW, Paolillo, P, Livolti, G, Picone, S, Bressan, K, Gazzolo, D
Acta paediatrica (Oslo, Norway : 1992). 2016;(5):535-41
Abstract
AIM: Despite advances in perinatal management, there is a flat trend in incidences of respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD) in preterm infants. The main feature of BPD development in preterm infants is an imbalance between increased exposure to free radicals and inadequate antioxidant defences. We investigated the associations between BPD and lipid hydro-peroxide (LOOH) and glutathione (GSH) concentrations in bronchoalveolar lavage fluid (BALF). METHODS In this prospective study, BALF samples were collected from 44 preterm infants with RDS and oxidative stress markers were measured in 11 with BPD and 33 controls without BPD. RESULTS LOOH levels were significantly higher (p < 0.01) in the BPD group (median 16.35; 25th-75th centile 13.75-17.05 nmol/mL) than in the no BPD group (median 13.18; 25th-75th centile 12.92-13.63 nmol/mL). Conversely, GSH levels were significantly lower in the BPD group (p < 0.01) (median 11.52; 25th-75th centile 6.95-13.85 μmol/mg) than the no BPD group (median: 18.69; 25th-75th centile: 13.89-23.64 μmol/mg). Multiple regression analysis showed significant correlations between BPD and mechanical ventilation time (p < 0.01) and LOOH levels (p < 0.05). CONCLUSION Early LOOH level increases in preterm infants developing BPD suggest that lung biochemical monitoring of sick infants might be possible and BPD could be predicted early by evaluating biomarkers.
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Oxidative stress markers at birth: Analyses of a neonatal population.
Giuffrè, M, Rizzo, M, Scaturro, G, Pitruzzella, A, Marino Gammazza, A, Cappello, F, Corsello, G, Li Volti, G
Acta histochemica. 2015;(4-5):486-91
Abstract
In order to further understand neonatal stress and, thus, control it efficaciously, there is a need for more information on the manifestations of stress at the molecular level in the newborn, with particular regard to oxidants, and anti-oxidant and anti-stress mechanisms, including mitochondrial heat shock protein-chaperones such as Hsp60. We investigated patterns of anti-oxidants, biomarkers of oxidative stress, and Hsp60 levels in sera from newborns and found significant associations between glutathione (GSH) levels and gestational age, delivery modality, and lipid hydroperoxydes (LOOH) level. LOOH levels and spontaneous (vaginal) delivery were independently associated with increased GSH levels when these were above the median. Hsp60 and LOOH levels were positively correlated whereas Hsp60 and GSH levels were inversely correlated in spontaneously delivered newborns; in contrast, Hsp60 and GSH levels were positively correlated in newborns delivered by cesarea. Our results point to new directions in the search for definite patterns of GSH, LOOH, and Hsp60 in the newborn's serum that might have functional and diagnostic significance and that could help in the monitoring of newborn health during and after delivery. In addition, the data provide a starting basis for investigating the precise roles and interplay of GSH and Hsp60 in the maintenance of an optimal redox balance at birth to cope with the stress inherent to delivery, and also for investigating the predictive value of any given pattern of GSH, LOOH, and Hsp60 at birth with regard to health status and risk of disease in adult life.