A role for taurine in mitochondrial function Hansen, Svend Høime; Andersen, Mogens Larsen; Cornett, Claus ...
Journal of biomedical science,
08/2010, Volume:
17 Suppl 1, Issue:
Suppl 1
Journal Article
Peer reviewed
Open access
The mitochondrial pH gradient across the inner-membrane is stabilised by buffering of the matrix. A low-molecular mass buffer compound has to be localised in the matrix to maintain its alkaline pH ...value. Taurine is found ubiquitously in animal cells with concentrations in the millimolar range and its pKa value is determined to 9.0 (25 degrees C) and 8.6 (37 degrees C), respectively. Localisation of such a low-molecular buffer in the mitochondrial matrix, transforms the matrix into a biochemical reaction chamber for the important matrix-localised enzyme systems. Three acyl-CoA dehydrogenase enzymes, which are pivotal for beta-oxidation of fatty acids, are demonstrated to have optimal activity in a taurine buffer. By application of the model presented, taurine depletion caused by hyperglycemia could provide a link between mitochondrial dysfunction and diabetes.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Summary
Background
Elevated serum bile acids (BA) are harmful to the heart and alterations in the BA composition have been suggested to cause cardiovascular disturbances in cirrhosis.
Aim
To ...investigate any associations between specific groups or individual serum BA and structural and functional cardiac abnormalities in patients with cirrhosis.
Methods
An explorative study in 86 patients with cirrhosis. All participants underwent extensive cardiac assessment, including cardiac MRI with quantification of myocardial extracellular volume (ECV), which is indicative of diffuse myocardial fibrosis. A panel of 15 individual serum BA and C4, a marker of de novo bile acid synthesis, were assessed.
Results
Patients with advanced cirrhosis had higher levels of total BA and conjugated BA, as well as lower C4 levels (p < 0.001). Conjugated BA levels were higher in patients with a high cardiac index (p < 0.001), increased left atrial volume index (LAVI) (p < 0.001), and in those with an abnormal myocardial ECV (p < 0.05). We also found several strong correlations between conjugated BA, both as a group and individually, and parameters of cardiac dysfunction. In a model adjusted for sex, age, BMI and MELD, conjugated BA remained significantly associated with LAVI, septal e′, left ventricular volumes and cardiac index. In addition, taurocholic acid correlated closely with hepatic venous pressure gradient (HVPG) (p = 0.01).
Conclusions
Increased serum concentrations of conjugated BA are associated with several cardiac parameters, indicating a potential role in the development of hyperdynamic circulation and cardiac dysfunction in cirrhosis. Moreover, taurine‐conjugated BA are associated with portal hypertension.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Yersinia pestis, the etiologic agent of plague, is a bacterium associated with wild rodents and their fleas. Historically it was responsible for three pandemics: the Plague of Justinian in the 6th ...century AD, which persisted until the 8th century 1; the renowned Black Death of the 14th century 2, 3, with recurrent outbreaks until the 18th century 4; and the most recent 19th century pandemic, in which Y. pestis spread worldwide 5 and became endemic in several regions 6. The discovery of molecular signatures of Y. pestis in prehistoric Eurasian individuals and two genomes from Southern Siberia suggest that Y. pestis caused some form of disease in humans prior to the first historically documented pandemic 7. Here, we present six new European Y. pestis genomes spanning the Late Neolithic to the Bronze Age (LNBA; 4,800 to 3,700 calibrated years before present). This time period is characterized by major transformative cultural and social changes that led to cross-European networks of contact and exchange 8, 9. We show that all known LNBA strains form a single putatively extinct clade in the Y. pestis phylogeny. Interpreting our data within the context of recent ancient human genomic evidence that suggests an increase in human mobility during the LNBA, we propose a possible scenario for the early spread of Y. pestis: the pathogen may have entered Europe from Central Eurasia following an expansion of people from the steppe, persisted within Europe until the mid-Bronze Age, and moved back toward Central Eurasia in parallel with human populations.
•Six Late Neolithic–Early Bronze Age European Y. pestis genomes were reconstructed•All Late Neolithic and Early Bronze Age Y. pestis form a single phylogenetic branch
Andrades Valtueña et al. present the first six European Y. pestis genomes dating from the Late Neolithic and the Early Bronze Age. These data suggest that Y. pestis entered Europe during a human migration around 4800 BP, persisted in Europe, and traveled back to Central Eurasia.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Taurine, glutathione and bioenergetics Hansen, Svend Høime; Grunnet, Niels
Advances in experimental medicine and biology,
2013, Volume:
776
Journal Article
Peer reviewed
Biochemistry textbook presentations of bioenergetics and mitochondrial function normally focus on the chemiosmotic theory with introduction of the tricarboxylic acid cycle and the electron transport ...chain, the proton and electrical gradients and subsequent oxidative phosphorylation and ATP-production by ATP synthase. The compound glutathione (GSH) is often mentioned in relation to mitochondrial function, primarily for a role as redox scavenger. Here we argue that its role as redox pair with oxidised glutathione (GSSG) is pivotal with regard to controlling the electrical or redox gradient across the mitochondrial inner-membrane. The very high concentration of taurine in oxidative tissue has recently led to discussions on the role of taurine in the mitochondria, e.g. with taurine acting as a pH buffer in the mitochondrial matrix. A very important consequence of the slightly alkaline pH is the fact that the NADH/NAD(+) redox pair can be brought in redox equilibrium with the GSH redox pair GSH/GSSG.An additional consequence of having GSH as redox buffer is the fact that from the pH dependence of its redox potential, it becomes possible to explain that the mitochondrial membrane potential has been observed to be independent of the matrix pH. Finally a simplified model for mitochondrial oxidation is presented with introduction of GSH as redox buffer to stabilise the electrical gradient, and taurine as pH buffer stabilising the pH gradient, but simultaneously establishing the equilibrium between the NADH/NAD(+) redox pair and the redox buffer pair GSH/GSSG.
•Only few 25(OH) D assays comply with requirements in the Vitamin D Standardization Program.•25(OH) assays vary greatly in the categorization of patients in vitamin D ...deficiency/sufficiency.•Standardization has been obtained in some 25(OH)D immunoassays.
Serum total 25-hydroxyvitamin D is a measure of the total circulating 25-hydroxyvitamin D concentration and is the primary measurement for estimating vitamin D status. A number of automated immunoassays are commercially available, and in an attempt to standardize the assays the Vitamin D Standardization Program (VDSP) was established in 2010. Therefore, the aim of the current project is to evaluate the status of the standardization of routinely used 25-hydroxyvitamin D assays.
200 patient serum samples were measured in Spring 2017 on seven different assays for 25-hydroxyvitamin D. Samples were measured in duplicate for the evaluation of precision. A certified standard reference material (SRM972a) from The National Institute of Standardization and Technology (NIST) was measured to evaluate the accuracy of the assays. Finally, the agreement of the assays of clinically categorizing patients into vitamin D deficiency, inadequacy or adequacy was evaluated.
All seven assays achieved precision below the VDSP requirement of CV < 10%. However, only two of the assays achieved an accuracy bias <5% when measuring the SRM972a. When comparing methods using Deming regression, substantial proportional and/or systematic bias was found between many of the assays. Finally, when evaluating the ability of the assays to categorize patients into “vitamin D deficiency” (25-hydroxyvitamin D concentration < 30 nmol/L (<12 ng/mL)), “vitamin D inadequacy” (30–50 nmol/L (12–20 ng/mL)), “vitamin D adequacy” (50–250 nmol/L (20–100 ng/mL)) and “risk of toxicity” (>250 nmol/L (>100 ng/mL)), clinically relevant differences between assays were detected. Especially in the deficiency group, major discrepancies were found as the percentage of patients ranged from 1.5%–14.3% between the assays..
In conclusion, some of the commercially available assays have been standardized with performance as required by the VDSP. However, several of the assays do still not comply with the VDSP requirements even eight years after the program was started. This may have clinical consequences for patients, and manufacturers are therefore encouraged to continue their work on standardizing serum 25-hydroxyvitamin D assays.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A rapid, inexpensive, and simple high‐resolution NMR spectroscopic method is outlined for determining the content of surfactants and other low‐molecular‐weight organic compounds in detergent ...formulations. With simple sample preparation, quantitative results can be obtained from an internal standard and/or the method can be used as a fingerprint analysis of the surfactant composition. The NMR sample is prepared by suspending the detergent sample in deuterated acetic acid and thus dissolving surfactants and other organic compounds. Any content of carbonate will be liberated as CO2, whereas other inorganic materials are removed by centrifugation. From one‐dimensional 1H and two‐dimensional HSQC NMR spectra, the surfactant components and low‐molecular‐weight organic compounds can be identified from reference spectra. Intensities of signature signals in the one‐dimensional 1H NMR spectrum are used for quantification by comparing with an internal standard. Furthermore, it is demonstrated how 31P NMR can be used to identify and quantify phosphonate‐type chelators.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Summary
Background
Bile acid diarrhoea is often missed because gold standard nuclear medicine tauroselcholic 75‐Se acid (SeHCAT) testing has limited availability. Empirical treatment effect has ...unknown diagnostic performance, whereas plasma 7α‐hydroxy‐4‐cholesten‐3‐one (C4) is inexpensive but lacks sensitivity.
Aims
To determine diagnostic characteristics of empirical treatment and explore improvements in diagnostics with potential better availability than SeHCAT.
Methods
This diagnostic accuracy study was part of a randomised, placebo‐controlled trial of colesevelam. Consecutive patients with chronic diarrhoea attending SeHCAT had blood and stool sampled. Key thresholds were C4 > 46 ng/mL and SeHCAT retention ≤10%. A questionnaire recorded patient‐reported empirical treatment effect. We analysed receiver operating characteristics and explored machine learning applied logistic regression and decision tree modelling with internal validation.
Results
Ninety‐six (38%) of 251 patients had SeHCAT retention ≤10%. The effect of empirical treatment assessed with test results for bile acid studies blinded had 63% (95% confidence interval 44%–79%) sensitivity and 65% (47%–80%) specificity; C4 > 46 ng/mL had 47% (37%–57%) and 92% (87%–96%), respectively. A decision tree combining C4 ≥ 31 ng/mL with ≥1.1 daily watery stools (Bristol type 6 and 7) had 70% (51%–85%) sensitivity and 95% (83%–99%) specificity. The logistic regression model, including C4, the sum of measured stool bile acids and daily watery stools, had 77% (58%–90%) sensitivity and 93% (80%–98%) specificity.
Conclusions
Diagnosis of bile acid diarrhoea using empirical treatment was inadequate. Exploration suggested considerable improvements in the sensitivity of C4‐based testing, offering potential widely available diagnostics. Further validation is warranted. ClinicalTrials.gov: NCT03876717.
Diagnostic performance of diagnostic tests for bile acid diarrhoea
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background
The gut‐liver axis and enterohepatic circulation have gained increasing attention lately. Patients with short bowel syndrome (SBS) are, in fact, human knock‐out models that may assist in ...the understanding of bile acid synthesis and regulation.
We evaluated effect of glepaglutide (a long‐acting glucagon‐like peptide‐2 analog) on bile acid synthesis (the enterohepatic circulation of bile acids and liver biochemistry in patients with SBS).
Method
In a single‐center, double‐blinded, dose‐finding, crossover phase 2 trial, 18 patients with SBS were randomly assigned to 2 of 3 treatment arms (0.1, 1, and 10 mg) with daily subcutaneous injections of glepaglutide for 3 weeks. The washout period between the 2 treatment periods was 4–8 weeks. Measurements were performed at baseline and at the end of each treatment period and included postprandial plasma samples for fibroblast growth factor 19 (FGF19), 7α‐hydroxy‐4‐cholesten‐3‐one (C4), total excretion of fecal bile acids, gene expression of farnesoid X receptor (FXR) in intestinal mucosal biopsies, total plasma bile acids, and liver biochemistry.
Results
Compared with baseline, the median (interquartile range) postprandial response (area under the curve 0–2h) of FGF19 increased by 150 h × ng/L (41, 195; P = 0.001) and C4 decreased by 82 h × µg/L (−169, −28; p = 0.010) in the 10‐mg dose. FXR gene expression did not change in any of the groups. Alkaline phosphatase significantly decreased.
Conclusion
Glepaglutide may stimulate the bile acid/FXR/FGF19 axis, leading to increased plasma concentrations of FGF19. Thereby, glepaglutide may ameliorate the accelerated de novo bile acid synthesis and play a role in the prevention and/or treatment of intestinal failure–associated liver disease.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK, VSZLJ
Eleven biconical vessels from the Copper Age sites Pietrele and Blejeşti (Romania) have been investigated using p-XRF. In most cases, traces of lead could be measured on their surfaces. Samples of ...slag-like material from two vessels and the clay of one vessel were investigated using laboratory methods, namely SEM, XRD, LIA and optical microscopy. The vessels were obviously used as a kind of crucible in which slag-like remains and galena ore were detected. It still remains unclear as to what final product was gained by smelting galena in this way. The amount of these such vessels in the Pietrele settlement, their appearance as grave goods in Pietrele and Vărăști (Romania), and their supposed occurrence in a number of other Copper Age settlements in Romania and Bulgaria show the significance of this phenomenon. It must have been a widespread and more or less well known practice, an important part of cultural habit during a particular period in the Lower Danube region and likely even farther afield. For the first time, extensive experimentation with lead ore can be shown in a clear chronological horizon, ca. 4400-4300 BCE in southeastern Europe.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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