Increased circulating desmosine and age-dependent elastinolysis in idiopathic pulmonary fibrosis

Abstract Although chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) seem to be opposite entities from a clinical perspective, common initial pathogenic steps have been suggested in both lung diseases. Emphysema is caused by an elastase/anti-elastase imbalance leading to accelerated elastin degradation. Elastinolysis is however, also accelerated in the IPF patients’ lungs. The amino acids desmosine and isodesmosine (DES) are unique to elastin. During the degradation process, elastases liberate DES from elastin fibers. Blood DES levels consequently reflect the rate of systemic elastinolysis and are increased in COPD. This is the first report describing elevated DES levels in IPF patients. We also demonstrated that the age-related increment of DES concentrations is enhanced in IPF. Our current study suggests that elastinolysis is a shared pathogenic step in both COPD and IPF. Further investigation is required to establish the relevance of accelerated elastin degradation in IPF and to determine whether decelerating this process leads to slower progression of lung fibrosis and better survival for patients with IPF.https://deepblue.lib.umich.edu/bitstream/2027.42/142803/1/12931_2018_Article_747.pd

Higher Serum Vitamin D Concentrations Are Longitudinally Associated with Better Global Quality of Life and Less Fatigue in Colorectal Cancer Survivors up to 2 Years after Treatment

BACKGROUND: Vitamin D status may be an important determinant of health-related quality of life of colorectal cancer survivors. The current study investigated longitudinal associations between serum 25-hydroxyvitamin D3 (25OHD3) concentrations and quality of life in stage I-III colorectal cancer survivors up to 2 years after treatment. METHODS: Patients with colorectal cancer (n = 261) were included upon diagnosis. Home visits (including blood sampling) were performed at diagnosis and at 6 weeks, 6 months, 1 year, and 2 years after treatment. Serum 25OHD3 concentrations were measured using LC/MS-MS and adjusted for season. Validated questionnaires were used to assess global quality of life and cognitive functioning (EORTC-QLQ-C30), fatigue (EORTC-QLQ-C30 and Checklist Individual Strength, CIS), and depression and anxiety (Hospital Anxiety and Depression Scale). Statistical analyses were performed using linear mixed models and adjusted for sex, age, time since diagnosis, therapy, comorbidities, physical activity, and body mass index. RESULTS: At diagnosis, 45% of patients were vitamin D deficient (<50 nmol/L). After treatment, 25OHD3 concentrations increased on average with 3.1 nmol/L every 6 months. In confounder-adjusted models, 20 nmol/L increments in 25OHD3 were longitudinally associated with increased global quality of life [β 2.9; 95% confidence interval (CI), 1.5-4.3] and reduced fatigue (EORTC-QLQ-C30 subscale: β -3.5; 95% CI, -5.3 to -1.8 and CIS: β -2.8; 95% CI, -4.7 to -0.9). Observed associations were present both within and between individuals over time. CONCLUSIONS: Higher concentrations of 25OHD3 were longitudinally associated with better global quality of life and less fatigue in colorectal cancer survivors. IMPACT: This study suggests that higher 25OHD3 concentrations may be beneficial for colorectal cancer survivors. Future intervention studies are needed to corroborate these findings

Adiponectin and vitamin D-binding protein are independently associated at birth in both mothers and neonates

CONTEXT: Adult body fat is associated with birth anthropometry, suggesting a role for metabolic regulators including vitamin D and the adipokines-adiponectin and irisin-which have been reported to interact but, as yet, data remain controversial. OBJECTIVE: To study (i) the relationship between vitamin D, its binding protein (VDBP) and the adipokines, adiponectin, and irisin in mothers and neonates at birth and (ii) their effects on neonate anthropometric outcomes. DESIGN: Cross-sectional study for healthy mothers with full-term and uncomplicated births. SETTING: Primary care. SUBJECTS: Seventy pairs of newly delivered neonates and their mothers. MAIN OUTCOMES FEATURES: Biochemical markers from maternal and cord: VDBP, adiponectin, irisin, calcium, albumin, parathyroid hormone, 25OHD, 1,25(OH)D. Maternal demographic and social characteristics and neonate anthropometric parameters were recorded. RESULTS: Maternal VDBP levels (364.1 ± 11.9 μg/ml) demonstrated a strong positive correlation with maternal adiponectin (4.4 ± 0.4 μg/ml) and irisin (308.8 ± 50.8 ng/ml) concentrations, which remained significant (p &lt; 0.001 and p &lt; 0.041, respectively) after adjustment with multiple parameters, including weeks of gestation, maternal age, and BMI. The finding of a strong association of VDBP (355.3 ± 29.2 μg/ml) and adiponectin (11.9 ± 2.0 μg/ml) but not irisin (174.4 ± 26.0 ng/ml) was also evident in neonates (p = 0.03 and p = 0.94, respectively). No association was observed in both maternal and neonatal vitamin D, adiponectin, and irisin. CONCLUSIONS: The main findings of this study are (i) the perspective of a potential independent interaction of VDBP and adiponectin in both mothers and neonates and (ii) the lack of a causative model effect of both maternal/neonatal vitamin D status and adipokine profile on neonatal anthropometry at birth, as a surrogate marker of future metabolic health of the offspring

Reduced Vitamin K Status as a Potentially Modifiable Risk Factor of Severe Coronavirus Disease 2019

BACKGROUND: Respiratory failure and thromboembolism are frequent in SARS-CoV-2-infected patients. Vitamin K activates both hepatic coagulation factors and extrahepatic endothelial anticoagulant protein S, required for thrombosis prevention. In times of vitamin K insufficiency, hepatic procoagulant factors are preferentially activated over extrahepatic proteins. Vitamin K also activates matrix Gla protein (MGP), which protects against pulmonary and vascular elastic fiber damage. We hypothesized that vitamin K may be implicated in coronavirus disease 2019 (COVID-19), linking pulmonary and thromboembolic disease. METHODS: 135 hospitalized COVID-19 patients were compared with 184 historical controls. Poor outcome was defined as invasive ventilation and/or death. Inactive vitamin K-dependent MGP (dp-ucMGP) and prothrombin (PIVKA-II) were measured, inversely related to extrahepatic and hepatic vitamin K status, respectively. Desmosine was measured to quantify the rate of elastic fiber degradation. Arterial calcification severity was assessed by computed tomography. RESULTS: Dp-ucMGP was elevated in COVID-19 patients compared to controls (p<0.001), with even higher dp-ucMGP in patients with poor outcomes (p<0.001). PIVKA-II was normal in 82.1% of patients. Dp-ucMGP was correlated with desmosine (p<0.001), and coronary artery (p=0.002) and thoracic aortic (p<0.001) calcification scores. CONCLUSIONS: Dp-ucMGP was severely increased in COVID-19 patients, indicating extrahepatic vitamin K insufficiency, which was related to poor outcome while hepatic procoagulant factor II remained unaffected. These data suggest a mechanism of pneumonia-induced extrahepatic vitamin K depletion leading to accelerated elastic fiber damage and thrombosis in severe COVID-19 due to impaired activation of MGP and endothelial protein S, respectively. A clinical trial could assess whether vitamin K administration improves COVID-19 outcomes

Circulating concentrations of vitamin D in relation to pancreatic cancer risk in European populations.

Evidence from in vivo, in vitro and ecological studies are suggestive of a protective effect of vitamin D against pancreatic cancer (PC). However, this has not been confirmed by analytical epidemiological studies. We aimed to examine the association between pre-diagnostic circulating vitamin D concentrations and PC incidence in European populations. We conducted a pooled nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) and the Nord-Trøndelag Health Study's second survey (HUNT2) cohorts. In total, 738 primary incident PC cases (EPIC n = 626; HUNT2 n = 112; median follow-up = 6.9 years) were matched to 738 controls. Vitamin D [25(OH)D2 and 25(OH)D3 combined] concentrations were determined using isotope-dilution liquid chromatography-tandem mass spectrometry. Conditional logistic regression models with adjustments for body mass index and smoking habits were used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (95%CI). Compared with a reference category of >50 to 75 nmol/L vitamin D, the IRRs (95% CIs) were 0.71 (0.42-1.20); 0.94 (0.72-1.22); 1.12 (0.82-1.53) and 1.26 (0.79-2.01) for clinically pre-defined categories of ≤25; >25 to 50; >75 to 100; and >100 nmol/L vitamin D, respectively (p for trend = 0.09). Corresponding analyses by quintiles of season-standardized vitamin D concentrations also did not reveal associations with PC risk (p for trend = 0.23). Although these findings among participants from the largest combination of European cohort studies to date show increasing effect estimates of PC risk with increasing pre-diagnostic concentrations of vitamin D, they are not statistically significant

Circulating concentrations of vitamin D in relation to pancreatic cancer risk in European populations

Evidence from in vivo, in vitro and ecological studies are suggestive of a protective effect of vitamin D against pancreatic cancer (PC). However, this has not been confirmed by analytical epidemiological studies. We aimed to examine the association between pre-diagnostic circulating vitamin D concentrations and PC incidence in European populations. We conducted a pooled nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) and the Nord-Trøndelag Health Study's second survey (HUNT2) cohorts. In total, 738 primary incident PC cases (EPIC n = 626; HUNT2 n = 112; median follow-up = 6.9 years) were matched to 738 controls. Vitamin D [25(OH)D2 and 25(OH)D3 combined] concentrations were determined using isotope-dilution liquid chromatography-tandem mass spectrometry. Conditional logistic regression models with adjustments for body mass index and smoking habits were used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (95%CI). Compared with a reference category of >50 to 75 nmol/L vitamin D, the IRRs (95% CIs) were 0.71 (0.42-1.20); 0.94 (0.72-1.22); 1.12 (0.82-1.53) and 1.26 (0.79-2.01) for clinically pre-defined categories of ≤25; >25 to 50; >75 to 100; and >100 nmol/L vitamin D, respectively (p for trend = 0.09). Corresponding analyses by quintiles of season-standardized vitamin D concentrations also did not reveal associations with PC risk (p for trend = 0.23). Although these findings among participants from the largest combination of European cohort studies to date show increasing effect estimates of PC risk with increasing pre-diagnostic concentrations of vitamin D, they are not statistically significant

Correlation of different cellular assays to analyze T cell-related cytokine profiles in vitamin D-3-supplemented patients with multiple sclerosis

Different laboratory approaches have been exploited to analyze an effect of vitamin D-3 supplements on T cell cytokine profiles in multiple sclerosis, with poorly reproducible results. We assessed the correlation between intra-cellular flowcytometry analysis of CD4 T cell-enriched CD3(+)CD8(-) lymphocytes after PMA/ionomycin stimulation directly ex-vivo or after 72 h pre-stimulation with anti-CD3, and cytokine levels excreted in culture supernatants. Pre-stimulation with anti-CD3 resulted in higher proportions of cells positive for IFN-gamma, IL-17A, IL-4, IL-10 and GM-CSF (all P &lt;0.001), but not TNF-alpha. Positive correlation between approaches was highly variable, but most eminent for IFN-gamma and IL-4 (R = 0.608-0.612 and R = 0.677-0.777, resp., all P &lt;0.001). No effect of 16-weeks vitamin D-3 supplements on any outcome was found except for a decreased TNF-alpha concentration in culture supernatants. Choice of immune-assay is, apparently, a relevant confounder for the reproducibility of individual studies.</p

Vitamin D-3 supplementation and neurofilament light chain in multiple sclerosis

Objectives Low circulating vitamin D levels are associated with an increased risk of active MRI lesions and relapses in several cohorts with relapsing remitting multiple sclerosis (RRMS). Randomized controlled supplementation trials are, however, negative on their primary endpoints, while secondary MRI endpoints suggest anti-inflammatory effects. Circulating levels of neurofilament light chain (NfL) are a biomarker of disease activity in RRMS. We explored whether 48-week high-dose vitamin D-3 supplements were associated with lower circulating NfL levels. Materials & Methods Of N = 40 Dutch interferon beta-treated participants with RRMS of the SOLAR trial, plasma samples at baseline and 48-week follow-up were available. Of these participants, N = 24 were supplemented with 14 000 IU/d vitamin D-3 and N = 16 with placebo. Twenty-five hydroxyvitamin D-3 (25(OH)D-3) levels were measured with LC-MS/MS, and NfL levels were measured in duplicate with Simoa. Results Serum 25(OH)D-3 levels at 48 weeks were increased in the vitamin D-3 when compared to placebo group (median level 281 [IQR 205-330] vs 72 [39-88] nmol/L; P <.01). NfL levels at 48 weeks did not differ between the treatment groups (median level 25.4 [IQR 19.6-32.2] vs 25.3 [17.9-30.1] pg/mL; P = .74). Higher week 48 NfL level showed a trend toward association with a higher risk of combined unique active lesions on the week 48 MRI scan (OR 2.39 [95% CI 0.93-6.12] for each 10 pg/mL increase; P = .07). Conclusions Supplementation of high-dose vitamin D-3 for 48 weeks was not associated with lower NfL levels. This study does not support an effect of vitamin D-3 on this biomarker of neuro-axonal injury

Stress-Axis Regulation by Vitamin D3 in Multiple Sclerosis

Multiple sclerosis (MS) has been associated with both a poor vitamin D status and hyperactivity of the hypothalamus–pituitary–adrenal (HPA) axis. Since nuclear receptor ligands may regulate each other, we explored the association of vitamin D3 supplements with circadian cortisol levels in a double-blind and placebo-controlled supplementation study

Post hoc analysis of a randomised controlled trial: effect of vitamin D supplementation on circulating levels of desmosine in COPD

Background: Vitamin D supplementation lowers exacerbation frequency in severe vitamin D-deficient patients with COPD. Data regarding the effect of vitamin D on elastin degradation are lacking. Based on the vitamin's anti-inflammatory properties, we hypothesised that vitamin D supplementation reduces elastin degradation, particularly in vitamin D-deficient COPD patients. We assessed the effect of vitamin D status and supplementation on elastin degradation by measuring plasma desmosine, a biomarker of elastin degradation. Methods: Desmosine was measured every 4 months in plasma of 142 vitamin D-naïve COPD patients from the Leuven vitamin D intervention trial (100 000 IU vitamin D3 supplementation every 4 weeks for 1 year). Results: No significant association was found between baseline 25-hydroxyvitamin D (25(OH)D) and desmosine levels. No significant difference in desmosine change over time was found between the placebo and intervention group during the course of the trial. In the intervention arm, an unexpected inverse association was found between desmosine change and baseline 25(OH)D levels (p=0.005). Conclusions: Vitamin D supplementation did not have a significant overall effect on elastin degradation compared to placebo. Contrary to our hypothesis, the intervention decelerated elastin degradation in vitamin D-sufficient COPD patients and not in vitamin D-deficient subjects.status: publishe