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      The effect of vitamin D supplementation on plasma non-oxidised PTH in a randomised clinical trial

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          Abstract

          Objective

          PTH can be oxidised in vivo, rendering it biologically inactive. Non-oxidised PTH (n-oxPTH) may therefore give a better image of the hormonal status of the patient. While vitamin D supplementation decreases total PTH (tPTH) concentration, the effect on n-oxPTH concentration is unexplored. We investigated the effect of vitamin D on n-oxPTH concentration in comparison to tPTH and compared the correlations between parameters of calcium, bone and lipid metabolism with n-oxPTH and tPTH.

          Methods

          N-oxPTH was measured in 108 vitamin D-insufficient (25(OH)D <75 nmol/L) hypertensive patients, treated with vitamin D (2800 IE daily) or placebo for 8 weeks in the Styrian Vitamin D Hypertension Trial (NCT02136771). We calculated the treatment effect and performed correlation analyses of n-oxPTH and tPTH with parameters of calcium, bone and lipid metabolism and oxidative stress.

          Results

          After treatment, compared to placebo, 25(OH)D concentrations increased, tPTH decreased by 9% ( P < 0.001), n-oxPTH by 7% ( P = 0.025) and the ratio of n-oxPTH/tPTH increased ( P = 0.027). Changes in phosphate and HDL concentration correlated with changes in n-oxPTH, but not tPTH.

          Conclusions

          tPTH and n-oxPTH decrease upon vitamin D supplementation. Our study suggests that vitamin D supplementation reduces the oxidation of PTH, as we observed a small but significant increase in the non-oxidised proportion of PTH upon treatment. In addition, we found that changes in phosphate and HDL concentration showed a relationship with changes in n-oxPTH, but not tPTH. This may be explained by the biological activity of n-oxPTH. Further research should be carried out to establish the clinical relevance of n-oxPTH.

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          Most cited references29

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          Clinical Relevance of Biomarkers of Oxidative Stress

          Abstract Significance: Oxidative stress is considered to be an important component of various diseases. A vast number of methods have been developed and used in virtually all diseases to measure the extent and nature of oxidative stress, ranging from oxidation of DNA to proteins, lipids, and free amino acids. Recent Advances: An increased understanding of the biology behind diseases and redox biology has led to more specific and sensitive tools to measure oxidative stress markers, which are very diverse and sometimes very low in abundance. Critical Issues: The literature is very heterogeneous. It is often difficult to draw general conclusions on the significance of oxidative stress biomarkers, as only in a limited proportion of diseases have a range of different biomarkers been used, and different biomarkers have been used to study different diseases. In addition, biomarkers are often measured using nonspecific methods, while specific methodologies are often too sophisticated or laborious for routine clinical use. Future Directions: Several markers of oxidative stress still represent a viable biomarker opportunity for clinical use. However, positive findings with currently used biomarkers still need to be validated in larger sample sizes and compared with current clinical standards to establish them as clinical diagnostics. It is important to realize that oxidative stress is a nuanced phenomenon that is difficult to characterize, and one biomarker is not necessarily better than others. The vast diversity in oxidative stress between diseases and conditions has to be taken into account when selecting the most appropriate biomarker. Antioxid. Redox Signal. 23, 1144–1170.
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            Effect of vitamin D deficiency and replacement on endothelial function in asymptomatic subjects.

            Vitamin D receptors are present in many tissues. Hypovitaminosis D is considered to be a risk factor for atherosclerosis. This study explores the effects of vitamin D replacement on insulin sensitivity, endothelial function, inflammation, oxidative stress, and leptin in vitamin D-deficient subjects. Twenty-three asymptomatic vitamin D-deficient subjects with 25-hydroxyvitamin D [25(OH)D] levels below 25 nmol/liter were compared with a control group that had a mean 25(OH)D level of 75 nmol/liter. The vitamin D-deficient group received 300,000 IU im monthly for 3 months. The following parameters were evaluated before and after treatment: vitamin D metabolites, leptin, endothelial function by brachial artery flow mediated dilatation (FMD), insulin sensitivity index based on oral glucose tolerance test, and lipid peroxidation as measures of thiobarbituric acid reactive substances (TBARS). FMD measurements were significantly lower in 25(OH)D-deficient subjects than controls (P = 0.001) and improved after replacement therapy (P = 0.002). Posttreatment values of TBARS were significantly lower than pretreatment levels (P < 0.001). A positive correlation between FMD and 25(OH)D (r = 0.45; P = 0.001) and a negative correlation between FMD and TBARS (r = -0.28; P < 0.05) were observed. There was a significant increase in leptin levels after therapy, and the leptin levels were positively correlated with 25(OH)D levels (r = 0.45; P < 0.05). This study shows that 25(OH)D deficiency is associated with endothelial dysfunction and increased lipid peroxidation. Replacement of vitamin D has favorable effects on endothelial function. Vitamin D deficiency can be seen as an independent risk factor of atherosclerosis. Hypovitaminosis D-associated endothelial dysfunction may predispose to higher rates of cardiovascular disease in the winter.
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              Vitamin D protects human endothelial cells from oxidative stress through the autophagic and survival pathways.

              Recently, vitamin D (VitD) has been recognized as increasingly importance in many cellular functions of several tissues and organs other than bone. In particular, VitD showed important beneficial effects in the cardiovascular system. Although the relationship among VitD, endothelium, and cardiovascular disease is well established, little is known about the antioxidant effect of VitD. Our objective was to study the intracellular pathways activated by VitD in cultured human umbilical vein endothelial cells undergoing oxidative stress. Nitric oxide production, cell viability, reactive oxygen species, the mitochondrial permeability transition pore, membrane potential, and caspase-3 activity were measured during oxidative stress induced by administration of 200 μM hydrogen peroxide for 20 minutes. Experiments were repeated in the presence of specific vitamin D receptor ligand ZK191784. Pretreatment with VitD alone or in combination with ZK191784 is able to reduce the apoptosis-related gene expression, involving both intrinsic and extrinsic pathways. At the same time, it has been shown the activation of pro-autophagic beclin 1 and the phosphorylation of ERK1/2 and Akt, indicating a modulation between apoptosis and autophagy. Moreover, VitD alone or in combination with ZK191784 is able to prevent the loss of mitochondrial potential and the consequent cytochrome C release and caspase activation. The present study shows that VitD may prevent endothelial cell death through modulation of the interplay between apoptosis and autophagy. This effect is obtained by inhibiting superoxide anion generation, maintaining mitochondria function and cell viability, activating survival kinases, and inducing NO production.

                Author and article information

                Journal
                Endocr Connect
                Endocr Connect
                EC
                Endocrine Connections
                Bioscientifica Ltd (Bristol )
                2049-3614
                May 2019
                04 April 2019
                : 8
                : 5
                : 518-527
                Affiliations
                [1 ]Department of Clinical Chemistry , Amsterdam Gastroenterology & Metabolism, Amsterdam UMC, Vrije Universiteit Amsterdam, Endocrine Laboratory, Amsterdam, Netherlands
                [2 ]Division of Endocrinology and Diabetology , Department of Internal Medicine, Endocrinology Lab Platform, Medical University of Graz, Graz, Austria
                [3 ]University Institute for Medical and Chemical Laboratory Diagnostics , Paracelsus Medical University, Salzburg, Austria
                [4 ]Division of Cardiology , Department of Internal Medicine, Medical University of Graz, Graz, Austria
                [5 ]Synlab Academy , Synlab Holding Germany GmbH, München, Germany
                [6 ]Specialist Clinic of Rehabilitation Bad Gleichenberg , Bad Gleichenberg, Austria
                [7 ]Department of Clinical Chemistry , Amsterdam Gastroenterology & Metabolism, Amsterdam UMC, University of Amsterdam, Endocrine Laboratory, Amsterdam, Netherlands
                Author notes
                Correspondence should be addressed to A C Heijboer: a.heijboer@ 123456vumc.nl

                *(S Ursem and V Francic contributed equally to this work)

                Article
                EC-19-0097
                10.1530/EC-19-0097
                6499917
                30959477
                d1710090-2e5b-455e-92b1-f51a0eb52eac
                © 2019 The authors

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

                History
                : 27 March 2019
                : 04 April 2019
                Categories
                Research

                biochemical markers of bone turnover,parathyroid hormone,non-oxidised pth,randomised clinical trial,vitamin d

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