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Rapid free thiol rebound is a physiological response following cold-induced vasoconstriction in healthy humans, primary Raynaud and systemic sclerosis.
Abdulle, AE, van Roon, AM, Smit, AJ, Pasch, A, van Meurs, M, Bootsma, H, Bakker, SJL, Said, MY, Fernandez, BO, Feelisch, M, et al
Physiological reports. 2019;(6):e14017
Abstract
Raynaud's phenomenon (RP) is often the first sign of systemic sclerosis (SSc). Molecular mechanisms involved are incompletely understood, but reactive oxygen, nitrogen, and sulfur species are thought to play an important role in the pathogenesis of SSc. Free thiol groups play a protective role against oxidative stress and may represent an attractive therapeutic target. We aimed to investigate the effects of hypothermia-induced vasoconstriction on the responsiveness of redox-related markers. Thirty participants (n = 10/group [SSc, primary Raynaud's phenomenon (PRP), healthy controls (HC)]) were included in this study. Fingertip photoelectric plethysmography was performed during a standardized cooling and recovery experiment. Venous blood was collected at four predetermined time points. Free thiols, NO-derived species (nitros(yl)ated species, nitrite, nitrate), sulfate and endothelin-1 were measured. Lower baseline concentrations of free thiols were observed in PRP and SSc patients (HC: 5.87 [5.41-5.99] μmol/g; PRP: 5.17 [4.74-5.61]; SSc 5.28 [4.75-5.80], P = 0.04). Redox-related markers remained unchanged during cooling. However, an unexpected increase in systemic free thiol concentrations was observed in all groups during the recovery phase. The response of this marker differed between groups, with a higher increase found in SSc patients (HC Δ = 1.30 [1.48-1.17]; PRP Δ = 1.04 [1.06-1.03]; SSc Δ = 1.72 [1.13-1.49], P = 0.04). NO-derived species, sulfate and endothelin-1 levels remained unchanged throughout the recovery phase. This exploratory study sheds light on the rapid responsiveness of systemic free thiol concentrations following reperfusion, which may reflect overall redox balance. The robust response to reperfusion in SSc patients suggests that reductive systems involved in this response are functionally intact in these patients.
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Effect of dalcetrapib plus pravastatin on lipoprotein metabolism and high-density lipoprotein composition and function in dyslipidemic patients: results of a phase IIb dose-ranging study.
Ballantyne, CM, Miller, M, Niesor, EJ, Burgess, T, Kallend, D, Stein, EA
American heart journal. 2012;(3):515-21, 521.e1-3
Abstract
BACKGROUND Cholesteryl ester transfer protein (CETP) is involved in high-density lipoprotein (HDL) remodeling and transfer of lipids between HDL particles and other lipoproteins. Epidemiologic studies show that both elevated HDL-cholesterol (HDL-C) and reduced CETP activity attenuate cardiovascular risk, making inhibition or modulation of CETP a potential therapeutic target. This study analyzed the effect of dalcetrapib on lipoprotein profile, CETP activity, and cellular cholesterol efflux when co-administered with pravastatin in patients with low or average HDL-C. METHODS Patients were randomized in a double-blind fashion to receive placebo or dalcetrapib 300, 600, or 900 mg once daily for 12 weeks. All patients were concomitantly treated to their low-density lipoprotein cholesterol target with pravastatin. Lipoprotein profile was analyzed by nuclear magnetic resonance spectroscopy and polyacrylamide gradient gel electrophoresis. Composition of the HDL fraction was assessed after polyethylene glycol precipitation. Contribution of this fraction to cholesterol efflux was assessed using radiolabeled donor cells. RESULTS Co-administration of dalcetrapib with pravastatin increased HDL-C, apolipoproteins (apo) A-I and A-II, and CETP mass, and decreased CETP activity. A relative increase in large HDL and low-density lipoprotein subparticle fractions was observed. High-density lipoprotein composition showed increased association of esterified cholesterol, free cholesterol, phospholipids, apo A-I, and apo E. Adenosine 5'-triphosphate-binding cassette A1- and scavenger receptor type BI-mediated cholesterol efflux increased. CONCLUSIONS Dalcetrapib up to 600 mg, combined with pravastatin, increased HDL-C and altered lipoprotein profile, HDL composition, and HDL function, with little further change at a 900-mg dose. The impact on cardiovascular events in dyslipidemic patients is being evaluated.
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Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial.
Fayad, ZA, Mani, V, Woodward, M, Kallend, D, Abt, M, Burgess, T, Fuster, V, Ballantyne, CM, Stein, EA, Tardif, JC, et al
Lancet (London, England). 2011;(9802):1547-59
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Abstract
BACKGROUND Dalcetrapib modulates cholesteryl ester transfer protein (CETP) activity to raise high-density lipoprotein cholesterol (HDL-C). After the failure of torcetrapib it was unknown if HDL produced by interaction with CETP had pro-atherogenic or pro-inflammatory properties. dal-PLAQUE is the first multicentre study using novel non-invasive multimodality imaging to assess structural and inflammatory indices of atherosclerosis as primary endpoints. METHODS In this phase 2b, double-blind, multicentre trial, patients (aged 18-75 years) with, or with high risk of, coronary heart disease were randomly assigned (1:1) to dalcetrapib 600 mg/day or placebo for 24 months. Randomisation was done with a computer-generated randomisation code and was stratified by centre. Patients and investigators were masked to treatment. Coprimary endpoints were MRI-assessed indices (total vessel area, wall area, wall thickness, and normalised wall index [average carotid]) after 24 months and (18)F-fluorodeoxyglucose ((18)F-FDG) PET/CT assessment of arterial inflammation within an index vessel (right carotid, left carotid, or ascending thoracic aorta) after 6 months, with no-harm boundaries established before unblinding of the trial. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00655473. FINDINGS 189 patients were screened and 130 randomly assigned to placebo (66 patients) or dalcetrapib (64 patients). For the coprimary MRI and PET/CT endpoints, CIs were below the no-harm boundary or the adverse change was numerically lower in the dalcetrapib group than in the placebo group. MRI-derived change in total vessel area was reduced in patients given dalcetrapib compared with those given placebo after 24 months; absolute change from baseline relative to placebo was -4·01 mm(2) (90% CI -7·23 to -0·80; nominal p=0·04). The PET/CT measure of index vessel most-diseased-segment target-to-background ratio (TBR) was not different between groups, but carotid artery analysis showed a 7% reduction in most-diseased-segment TBR in the dalcetrapib group compared with the placebo group (-7·3 [90% CI -13·5 to -0·8]; nominal p=0·07). Dalcetrapib did not increase office blood pressure and the frequency of adverse events was similar between groups. INTERPRETATION Dalcetrapib showed no evidence of a pathological effect related to the arterial wall over 24 months. Moreover, this trial suggests possible beneficial vascular effects of dalcetrapib, including the reduction in total vessel enlargement over 24 months, but long-term safety and clinical outcomes efficacy of dalcetrapib need to be analysed. FUNDING F Hoffmann-La Roche Ltd.
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Comparison of the thiol-dependent antioxidant systems in the ectomycorrhizal Laccaria bicolor and the saprotrophic Phanerochaete chrysosporium.
Morel, M, Kohler, A, Martin, F, Gelhaye, E, Rouhier, N
The New phytologist. 2008;(2):391-407
Abstract
Sequencing of the Laccaria bicolor and Phanerochaete chrysosporium genomes, together with the availability of many fungal genomes, allow careful comparison to be made of these two basidiomycetes, which possess a different way of life (either symbiotic or saprophytic), with other fungi. Central to the antioxidant systems are superoxide dismutases, catalases and thiol-dependent peroxidases (Tpx). The two reducing systems (thioredoxin (Trx) and glutathione/glutaredoxin (Grx)) are of particular importance against oxidative insults, both for detoxification, through the regeneration of thiol-peroxidases, and for developmental, physiological and signalling processes. Among those thiol-dependent antioxidant systems, special emphasis is given to the redoxin and methionine sulfoxide reductase (Msr) multigenic families. The genes coding for these enzymes were identified in the L. bicolor and P. chrysosporium genomes, were correctly annotated, and the gene content, organization and distribution were compared with other fungi. Expression of the Laccaria genes was also compiled from microarray data. A complete classification, based essentially on gene structure, on phylogenetic and sequence analysis, and on existing experimental data, was proposed. Comparison of the gene content of fungi from all phyla did not show huge differences for multigenic families in the reactive oxygen species (ROS) detoxification network, although some protein subgroups were absent in some fungi.
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Development of a novel process for the biological conversion of H2S and methanethiol to elemental sulfur.
Sipma, J, Janssen, AJ, Pol, LW, Lettinga, G
Biotechnology and bioengineering. 2003;(1):1-11
Abstract
The feasibility of anaerobic treatment of wastewater containing methanethiol (MT), an extremely volatile and malodorous sulfur compound, was investigated in lab-scale bioreactors. Inoculum biomass originating from full-scale anaerobic wastewater treatment facilities was used. Several sludges, tested for their ability to degrade MT, revealed the presence of organisms capable of metabolizing MT as their sole source of energy. Furthermore, batch tests were executed to gain a better understanding of the inhibition potential of MT. It was found that increasing MT concentrations affected acetotrophic organisms more dramatically than methylotrophic organisms. Continuous reactor experiments, using two lab-scale upflow anaerobic sludge bed (UASB) reactors (R1 and R2), aimed to determine the maximal MT load and the effect of elevated sulfide concentrations on MT conversion. Both reactors were operated at a hydraulic retention time (HRT) of about 7 hours, a temperature of 30 degrees C, and a pH of between 7.3 and 7.6. At the highest influent MT concentration applied, 14 mM in R1, corresponding to a volumetric loading rate of about 50 mM MT per day, 87% of the organic sulfur was recovered as hydrogen sulfide (12.2 mM) and the remainder as volatile organic sulfur compounds (VOSCs). Upon decreasing the HRT to 3.5 to 4.0 h at a constant MT loading rate, the sulfide concentration in the reactor decreased to 8 mM and MT conversion efficiency increased to values near 100%. MT conversion was apparently inhibited by the high sulfide concentrations in the reactor. The specific MT degradation rate, as determined after 120 days of operation in R1, was 2.83 +/- 0.27 mmol MT g VSS(-1) day(-1). During biological desulfurization of liquid hydrocarbon phases, such as with liquefied petroleum gas (LPG), the combined removal of hydrogen sulfide and MT is desired. In R2, the simultaneous addition of sodium sulfide and MT was therefore studied and the effect of elevated sulfide concentrations was investigated. The addition of sodium sulfide resulted in enhanced disintegration of sludge granules, causing significant washout of biomass. Additional acetate, added to stimulate growth of methanogenic bacteria to promote granulation, was hardly converted at the termination of the experimental period.