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1.
The gut microbiome drives inter- and intra-individual differences in metabolism of bioactive small molecules.
Kerimi, A, Kraut, NU, da Encarnacao, JA, Williamson, G
Scientific reports. 2020;(1):19590
Abstract
The origin of inter-individual variability in the action of bioactive small molecules from the diet is poorly understood and poses a substantial obstacle to harnessing their potential for attenuating disease risk. Epidemiological studies show that coffee lowers the risk of developing type 2 diabetes, independently of caffeine, but since coffee is a complex matrix, consumption gives rise to different classes of metabolites in vivo which in turn can affect multiple related pathways in disease development. We quantified key urinary coffee phenolic acid metabolites repeated three times in 36 volunteers, and observed the highest inter- and intra-individual variation for metabolites produced by the colonic microbiome. Notably, a urinary phenolic metabolite not requiring the action of the microbiota was positively correlated with fasting plasma insulin. These data highlight the role of the gut microbiota as the main driver of both intra- and inter-individual variation in metabolism of dietary bioactive small molecules.
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2.
Dynamic thiol/disulphide homeostasis in acute pancreatitis.
Köseoğlu, H, Alışık, M, Başaran, M, Tayfur Yürekli, Ö, Solakoğlu, T, Tahtacı, M, Ersoy, O, Erel, Ö
The Turkish journal of gastroenterology : the official journal of Turkish Society of Gastroenterology. 2018;(3):348-353
Abstract
BACKGROUND/AIMS: The dynamic thiol/disulfide homeostasis plays pivotal roles in many physiological mechanisms in an organism. We aimed to investigate whether dynamic thiol/disulfide homeostasis changes among patients with acute pancreatitis. MATERIALS AND METHODS This prospective trial contained 45 patients with acute pancreatitis and 45 sex-and age-matched healthy volunteers as control group. Thiol/disulfide homeostasis parameters were measured by a novel and automated assay, and detected results were compared between the two groups. RESULTS Disulfide/total thiol percent ratio and disulfide/native thiol percent ratios were significantly higher in acute pancreatitis group; besides the native thiol, total thiol levels and native thiol/total thiol percent ratios were significantly lower (for all p < 0.001). CONCLUSION The thiol/disulfide homeostasis is impaired in acute pancreatitis with a shift toward the oxidative status, and this deficiency might be a pathogenic factor in acute pancreatitis. The correction of this thiol/disulfide imbalance may be a new target in the management of acute pancreatitis.
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3.
An alternative method for measuring oxidative stress in intrahepatic cholestasis of pregnancy: thiol/disulphide homeostasis.
Sanhal, CY, Daglar, K, Kara, O, Yılmaz, ZV, Turkmen, GG, Erel, O, Uygur, D, Yucel, A
The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians. 2018;(11):1477-1482
Abstract
PURPOSE The aim of our study was to evaluate the oxidative stress (OS) in pregnant women with intrahepatic cholestasis of pregnancy (ICP) by evaluating thiol/disulphide homeostasis using an alternative technique. METHODS A total of 57 pregnant women with ICP were compared with 50 gestational age and body mass index matched controls. A recently defined method was used for the measurement of plasma native-total thiol and disulphide levels. The independent two-sample t test, Mann-Whitney-U test, Chi-square test, binary logistic regression with backward elimination and receiver operating characteristic (ROC) curve was performed for statistical analyses. RESULTS Pregnant women with ICP (n = 57) versus controls (n = 50) had significantly lower serum levels of native thiol (233.8 ± 47.4 μmol/L vs. 308.5 ± 51.7 μmol/L, p < .001), total thiol (258.4 ± 46.5 μmol/L vs. 328.0 ± 52.0 μmol/L, p < .001) and higher levels of disulphide (12.3 ± 3.6 μmol/L vs. 9.7 ± 3.4 μmol/L, p < .001). Binary logistic regression showed that the most important variables related to ICP were native thiol and total thiol. According to the ROC curve, the optimal cut-off level for native thiol was 280.0 μmol/L (sensitivity: 86%, specificity: 84.2%, area under the curve (AUC):0.896, 95% CI: 0.831-0.962, p < .001), and the optimal cut-off level for total thiol was 300.0 μmol/L (sensitivity: 86%, specificity: 80.7%, AUC: 0.883, 95% CI: 0.815-0.951, p < .001). CONCLUSIONS To our knowledge, this is the first study in the literature exploring thiol/disulphide balance in ICP. We found that thiol/disulphide balance indicate OS in pregnant woman with ICP.
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4.
Vitamin D supplementation does not improve plasma thiol/disulfide homeostasis.
Mertoglu, C, Siranli, G, Topal, I, Gok, G, Erel, O
Pediatrics international : official journal of the Japan Pediatric Society. 2018;(11):1008-1013
Abstract
BACKGROUND Impairment of thiol/disulfide homeostasis, as well as vitamin D deficiency, are responsible for the pathophysiology of many acute and chronic diseases. This study examined the relationship between thiol/disulfide homeostasis and vitamin D level and supplementation. METHODS A total of 203 healthy children were included in the study. The participants were divided into four groups according to 25-hydroxyvitamin D (25(OH)D) level: group 1, severe deficiency (<10 ng/mL); group 2, deficiency (10-20 ng/mL); group 3, insufficiency (20-30 ng/mL); and group 4, sufficiency (≥30 ng/mL). Furthermore, group 5 was defined as being on vitamin D supplementation. RESULT Native thiol was lower in group 5 than in groups 2-4 (P = 0.003). Disulfide was higher in groups 1, 4 and 5 than groups 2 and 3 (P < 0.001). Total thiol was lower in group 5 than in group 4 (P = 0.032). The ratio of native thiol/total thiol was lower in groups 1 and 5 compared with groups 2 and 3, and in group 4 compared with group 3 (P < 0.001). The ratios of disulfide/total thiol and disulfide/native thiol were higher in groups 1 and 5 than in groups 2 and 3 whereas only the disulfide/total thiol ratio was higher in group 4 than in group 3 (P < 0.001). CONCLUSIONS In healthy children, severe deficiency of vitamin D causes impairment of thiol/disulfide homeostasis and increases protein oxidation, which cannot be reversed by external vitamin D supplementation.
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5.
Effects of Hemodialysis on Thiol-Disulphide Homeostasis in Critically Ill Pediatric Patients with Acute Kidney Injury.
Ayar, G, Sahin, S, Yazici, MU, Neselioglu, S, Erel, O, Bayrakcı, US
BioMed research international. 2018;:1898671
Abstract
AIM: To evaluate thiol/disulphide homeostasis as a new indicator of oxidative stress in AKI patients and to determine the effect of HD on antioxidant balance and oxidative stress through plasma thiols. METHODS This study was performed in patients aged between 12 months and 18 years prospectively who underwent hemodialysis due to AKI and were followed up for a year in a 22-bed tertiary pediatric intensive care unit. 20 patients and 39 controls were included. RESULTS No difference was present between the groups in terms of age and gender. Median values of plasma native thiol, total thiol, and percent thiol were significantly lower in AKI group both before and after dialysis when compared to control group. The median dynamic disulphide values were significantly lower in the AKI group of predialysis compared to the controls. When pre- and postdialysis values were compared, disulphide values were statistically higher after dialysis. When pre- and postdialysis native thiol, dynamic disulphide, total thiol, and percent thiol median values were compared, postdialysis values were significantly higher than the predialysis values. There was a positive correlation between albumin, total thiol, and native thiol values before dialysis in the patient group. CONCLUSION AKI patients have low levels of thiol species showing the presence of oxidative stress and hemodialysis has a positive effect on thiol/disulphide balance. This new method may be an inexpensive and simple tool suitable for clinical studies and can be used in routine screening as a useful indicator to show oxidative stress.
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6.
Effect of Oral Zinc Supplementation on the Thiol Oxido-Reductive Index and Thiol-Related Enzymes in Seminal Plasma and Spermatozoa of Iraqi Asthenospermic Patients.
Alsalman, ARS, Almashhedy, LA, Hadwan, MH
Biological trace element research. 2018;(2):340-349
Abstract
A thiol group plays an essential role in sperm metabolism and the antioxidative defense state. Zinc is the second most abundant element in the human body, following iron. The present study was conducted to study the effect of zinc supplementation on the characteristics of semen along with thiol and thiol-related enzymes in semen of asthenospermic patients. Semen samples were obtained from 60 fertile and 60 asthenospermic men, from couples who had consulted the infertility clinic of Babil Hospital (Hillah city, Iraq). The subfertile group was treated with zinc; every participant took two 220 mg capsules of zinc sulfate per day for 3 months. Semen samples were obtained (before and after zinc supplementation). The levels of reduced thiol, oxidized thiol, thiol oxido-reductive index, and thiol-related enzymes activities were determined in spermatozoa and seminal plasma of patients and healthy groups. Oxidized thiol levels were significantly higher in the infertile patients compared to that in the fertile group. Conversely, reduced thiol level, sulfhydryl oxidase activity, and glutathione peroxidase activity significantly decreased in the infertile patients compared to that in the fertile group. Oxidized thiol levels, reduced thiol levels, and thiol-related enzymes activities of the infertile patients were restored to normal values after treatment with zinc. However, reduced and oxidized thiol levels in spermatozoa did not change significantly in the group treated with zinc. The quantitative values for RSH/RSSR and thiol-related enzymes may provide useful means to qualitatively express the oxidant/antioxidant balance in clinical and epidemiologic studies. ClinicalTrials.gov Identifier: NCT02985905.
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7.
Thiol/disulfide homeostasis in predicting adverse perinatal outcomes at 24-28 weeks of pregnancy in gestational diabetes.
Ozler, S, Oztas, E, Caglar, AT, Uygur, D, Ergin, M, Erel, O, Danisman, N
The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians. 2016;(22):3699-704
Abstract
OBJECTIVE The main aim of this study was to investigate thiol/disulfide homeostasis at 24-28 weeks of pregnancy and to evaluate whether it is predictive for adverse perinatal outcomes or not in gestational diabetes mellitus (GDM). METHODS A total of 110 pregnant women at 24-28 weeks of pregnancy (74 GDM patients and 36 age- and BMI-matched healthy pregnant women) were enrolled in this prospective case-control study. Thiol/disulfide homeostasis was evaluated with a novel spectrophotometric method to determine if there is an association with adverse perinatal outcomes in GDM, by using logistic regression analysis. RESULTS GDM patients, with decreased native thiol levels at 24-28 weeks (OR: 4.890, 95% CI: 1.355-5.764, p = 0.015) and with higher pre-pregnancy BMI (OR: 1.280, 95% CI: 1.072-1.528, p = 0.006), were found to be at increased risk of adverse perinatal outcomes in GDM. There were no statistically significant differences in thiol/disulfide homeostasis between diet- and insulin-treated GDM subgroups. Additionally, 1-h and 2-h glucose levels on 100 g OGTT were found to be predictive for the insulin need in achieving good glycemic control in GDM (OR: 1.022, 95% CI: 1.005-1.038, p = 0.010 and OR: 1.019, 95% CI: 1.004-1.035, p = 0.015). CONCLUSIONS GDM patients, with decreased native thiol levels at 24-28 weeks of pregnancy and with higher pre-pregnancy BMI, have an increased risk of possible adverse perinatal outcomes. Also, increased 1-h and 2-h glucose levels on 100 g OGTT can predict the need for insulin treatment for GDM.
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8.
Pharmacogenomic determinants of the cardiovascular effects of dalcetrapib.
Tardif, JC, Rhéaume, E, Lemieux Perreault, LP, Grégoire, JC, Feroz Zada, Y, Asselin, G, Provost, S, Barhdadi, A, Rhainds, D, L'Allier, PL, et al
Circulation. Cardiovascular genetics. 2015;(2):372-82
Abstract
BACKGROUND Dalcetrapib did not improve clinical outcomes, despite increasing high-density lipoprotein cholesterol by 30%. These results differ from other evidence supporting high-density lipoprotein as a therapeutic target. Responses to dalcetrapib may vary according to patients' genetic profile. METHODS AND RESULTS We conducted a pharmacogenomic evaluation using a genome-wide approach in the dal-OUTCOMES study (discovery cohort, n=5749) and a targeted genotyping panel in the dal-PLAQUE-2 imaging trial (support cohort, n=386). The primary endpoint for the discovery cohort was a composite of cardiovascular events. The change from baseline in carotid intima-media thickness on ultrasonography at 6 and 12 months was evaluated as supporting evidence. A single-nucleotide polymorphism was found to be associated with cardiovascular events in the dalcetrapib arm, identifying the ADCY9 gene on chromosome 16 (rs1967309; P=2.41×10(-8)), with 8 polymorphisms providing P<10(-6) in this gene. Considering patients with genotype AA at rs1967309, there was a 39% reduction in the composite cardiovascular endpoint with dalcetrapib compared with placebo (hazard ratio, 0.61; 95% confidence interval, 0.41-0.92). In patients with genotype GG, there was a 27% increase in events with dalcetrapib versus placebo. Ten single-nucleotide polymorphism in the ADCY9 gene, the majority in linkage disequilibrium with rs1967309, were associated with the effect of dalcetrapib on intima-media thickness (P<0.05). Marker rs2238448 in ADCY9, in linkage disequilibrium with rs1967309 (r(2)=0.8), was associated with both the effects of dalcetrapib on intima-media thickness in dal-PLAQUE-2 (P=0.009) and events in dal-OUTCOMES (P=8.88×10(-8); hazard ratio, 0.67; 95% confidence interval, 0.58-0.78). CONCLUSIONS The effects of dalcetrapib on atherosclerotic outcomes are determined by correlated polymorphisms in the ADCY9 gene. CLINICAL TRIAL INFORMATION URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00658515 and NCT01059682.
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9.
The effect of cholesteryl ester transfer protein inhibition on lipids, lipoproteins, and markers of HDL function after an acute coronary syndrome: the dal-ACUTE randomized trial.
Ray, KK, Ditmarsch, M, Kallend, D, Niesor, EJ, Suchankova, G, Upmanyu, R, Anzures-Cabrera, J, Lehnert, V, Pauly-Evers, M, Holme, I, et al
European heart journal. 2014;(27):1792-800
Abstract
AIMS: The effects of cholesteryl ester transfer protein (CETP) inhibition on lipids, inflammation, and markers of high-density lipoprotein (HDL) function, following an acute coronary syndrome (ACS), are unknown. METHODS AND RESULTS The dal-ACUTE study randomized 300 patients (1 : 1) to dalcetrapib 600 mg/day or placebo within 1 week of an ACS. The primary endpoint was per cent change in HDL-cholesterol (HDL-C) after 4 weeks. Secondary endpoints included apolipoprotein levels, markers of HDL function, and inflammation. Dalcetrapib treatment increased HDL-C and apolipoprotein A1 by 33.7 and 11.8%, respectively (both P < 0.001) and total cholesterol efflux by 9.5% (P = 0.003) after 4 weeks, principally via an increase in non-ATP-binding cassette transporter (ABC) A1-mediated efflux, without statistically significant changes in pre-β1-HDL levels. The increase in total efflux with dalcetrapib correlated most strongly with increases in apolipoprotein A1 and HDL-C (r = 0.46 and 0.43, respectively) rather than the increase in pre-β1-HDL (r = 0.32). Baseline and on-treatment ABCA1-mediated efflux correlated most strongly with pre-β1-HDL levels; in contrast, non-ABCA1-mediated efflux correlated better with apolipoprotein A1 and HDL-C levels. CONCLUSIONS High-density lipoprotein raised through CETP inhibition with dalcetrapib improves cholesterol efflux, principally via a non-ABCA1-mediated pathway. While HDL-C was increased by one-third, apolipoprotein A1 and total efflux were increased only by one-tenth, supporting the concept of dissociation between improvements in HDL function and HDL-C levels, which may be of relevance to ongoing trials and the development of therapeutic interventions targeting HDL.
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10.
Antioxidant and inflammatory response following high-fat meal consumption in overweight subjects.
Miglio, C, Peluso, I, Raguzzini, A, Villaño, DV, Cesqui, E, Catasta, G, Toti, E, Serafini, M
European journal of nutrition. 2013;(3):1107-14
Abstract
PURPOSE Postprandial metabolic stress as a consequence of ingestion of high-energy meals is recognized as an important risk factor for cardiovascular disease. The objective of this study was to evaluate the inflammatory and antioxidant response of the body to the acute ingestion of a high-fat meal (HFM). METHODS Fifteen healthy overweight subjects were recruited for the study. After HFM consumption, plasma glucose, insulin, uric acid (UA), triglycerides (TG), total cholesterol (TC), thiols (SH), inflammatory cytokines (IL-6 and TNF-α) and dietary antioxidants were measured at 0, 0, 5, 1, 2, 4, 6 and 8 h points from ingestion. RESULTS The ingestion of HFM induced significant increases in both TG and TC, with peaks at 4 h (p < 0.001) and 8 h (p < 0.01), respectively. IL-6 and TNF-α significantly increased postprandially, reaching maximum concentrations 8 h after meal consumption (p < 0.001). Whereas plasma concentrations of vitamins and carotenoids were not changed by HFM, SH and UA increased, peaking 2-4 h postingestion (p < 0.001 and 0.01, respectively). Increments of SH and UA were positively correlated with AUC for TG (Pearson coefficient 0.888, p < 0.001 and 0.923, p < 0.001, respectively). CONCLUSIONS Present results indicate that as a consequence of an excess of dietary fat, the body responds through an inflammatory reaction, which is accompanied by an increment of endogenous antioxidant defenses, mediated by UA and SH, but not by vitamins C and E and carotenoids. Although further studies are needed, results of the current investigation represent novel findings on endogenous strategies of redox defense from fat overloads.