Vitamin D and Platelets: A Menacing Duo in COVID-19 and Potential Relation to Bone Remodeling

Global data correlate severe vitamin D deficiency with COVID-19-associated coagulopathy, further suggesting the presence of a hypercoagulable state in severe COVID-19 patients, which could promote thrombosis in the lungs and in other organs. The feedback loop between COVID-19-associated coagulopathy and vitamin D also involves platelets (PLTs), since vitamin D deficiency stimulates PLT activation and aggregation and increases fibrinolysis and thrombosis. Vitamin D and PLTs share and play specific roles not only in coagulation and thrombosis but also during inflammation, endothelial dysfunction, and immune response. Additionally, another ‘fil rouge’ between vitamin D and PLTs is represented by their role in mineral metabolism and bone health, since vitamin D deficiency, low PLT count, and altered PLT-related parameters are linked to abnormal bone remodeling in certain pathological conditions, such as osteoporosis (OP). Hence, it is possible to speculate that severe COVID-19 patients are characterized by the presence of several predisposing factors to bone fragility and OP that may be monitored to avoid potential complications. Here, we hypothesize different pervasive actions of vitamin D and PLT association in COVID-19, also allowing for potential preliminary information on bone health status during COVID-19 infection.     

Interactions Via α2β1 Cell Integrin May Protect against the Progression of Airway Structural Changes in Asthma

Increased airway wall thickness and remodeling of bronchial mucosa are characteristic of asthma and may arise from altered integrin signaling on airway cells. Here, we analyzed the expression of β₁-subfamily integrins on blood and airway cells (flow cytometry), inflammatory biomarkers in serum and bronchoalveolar lavage, reticular basement membrane (RBM) thickness and collagen deposits in the mucosa (histology), and airway geometry (CT-imaging) in 92 asthma patients (persistent airflow limitation subtype: n = 47) and 36 controls. Persistent airflow limitation was associated with type-2 inflammation, elevated soluble α₂ integrin chain, and changes in the bronchial wall geometry. Both subtypes of asthma showed thicker RBM than control, but collagen deposition and epithelial α₁ and α₂ integrins staining were similar. Type-I collagen accumulation and RBM thickness were inversely related to the epithelial expression of the α₂ integrin chain. Expression of α₂β₁ integrin on T-cells and eosinophils was not altered in asthma. Collagen I deposits were, however, more abundant in patients with lower α₂β₁ integrin on blood and airway CD8⁺ T-cells. Thicker airway walls in CT were associated with lower α₂ integrin chain on blood CD4⁺ T-cells and airway eosinophils. Our data suggest that α₂β₁ integrin on inflammatory and epithelial cells may protect against airway remodeling advancement in asthma.     

Measurement of particle concentration in powder coating process using capacitance computed tomography and wavelet analysis

Capacitance computed tomography techniques were used to visualize particles movement in the draft tube of a spouted fluidized bed for the coating process of drug production. A total of 512 frames images of the particle concentration distribution were obtained at 10-millisecond intervals over a coating time of 5 min using a capacitance computed tomography system. The three-dimensional capacitance CT images (time and two-dimensional space images) were decomposed to wavelet time and space levels to extract the dominant particle distribution feature using three-dimensional discrete wavelet multiresolution at different coating times. As a result, the time and space dominant particle distribution with a specific frequency level can be visualized.     

Review: Influence of 25(OH)D Blood Concentration and Supplementation during Pregnancy on Preeclampsia Development and Neonatal Outcomes

Briefly, 25-hydroxyvitamin D (25(OH)D) plays an essential role in embryogenesis and the course of intra- and postnatal periods and is crucially involved in the functioning of the mother–placenta–fetus system. The low quantity of 25(OH)D during pregnancy can lead to an elevated risk for preeclampsia occurrence. Despite the numerous studies on the association of 25(OH)D deficiency and preeclampsia development, the current research on this theme is contradictory. In this review, we summarize and analyze study data on the effects of 25(OH)D deficiency and supplementation on pregnancy, labor, and fetal and neonatal outcomes.     

Influence of Umbelliferone on the Anticonvulsant and Neuroprotective Activity of Selected Antiepileptic Drugs: An In Vivo and In Vitro Study

Umbelliferone (7-hydroxycoumarin; UMB) is a coumarin with many biological properties, including antiepileptic activity. This study evaluated the effect of UMB on the ability of classical and novel antiepileptic drugs (e.g., lacosamide (LCM), levetiracetam (LEV), phenobarbital (PB) and valproate (VPA)) to prevent seizures evoked by the 6-Hz corneal-stimulation-induced seizure model. The study also evaluated the influence of this coumarin on the neuroprotective properties of these drugs in two in vitro models of neurodegeneration, including trophic stress and excitotoxicity. The results indicate that UMB (100 mg/kg, i.p.) significantly enhanced the anticonvulsant action of PB (p < 0.01) and VPA (p < 0.05), but not that of LCM orLEV, in the 6-Hz test. Whether alone or in combination with other anticonvulsant drugs (at their ED₅₀ values from the 6-Hz test), UMB (100 mg/kg) did not affect motor coordination; skeletal muscular strength and long-term memory, as determined in the chimney; grip strength; or passive avoidance tests, respectively. Pharmacokinetic characterization revealed that UMB had no impact on total brain concentrations of PB or VPA in mice. The in vitro study indicated that UMB has neuroprotective properties. Administration of UMB (1 µg/mL), together with antiepileptic drugs, mitigated their negative impact on neuronal viability. Under trophic stress (serum deprivation) conditions, UMB enhanced the neurotrophic abilities of all the drugs used. Moreover, this coumarin statistically enhanced the neuroprotective effects of PB (p < 0.05) and VPA (p < 0.001) in the excitotoxicity model of neurodegeneration. The obtained results clearly indicate a positive effect of UMB on the anticonvulsant and neuroprotective properties of the selected drugs.     

Flow Field Simulation and Measurement in Packed Beds Based on 4D-X-Ray Computed Tomography

X-ray computed tomography (XCT) combined with computational fluid dynamics (CFD) simulations have proved to be a powerful and versatile tool to describe fluids flow through packed bed systems. In this contribution, two examples of the application of XCT experiments to track the fluid flow and fluid penetration in packed bed systems are shown. The first one shows how geometrical information extracted from XCT measurements can be coupled to CFD simulations to assess fluid flows reliably. Here the example of a packed bed of three-dimensional (3D) printed cylindrical-shaped particles is considered. Finally, a short case study on the monitoring of the progress of the water penetration front in a packed bed composed of glass spheres using four-dimensional (4D) XCT imaging data is presented.     

3D characterization of cubic boron nitride (CBN) composites used as tool material for high precision abrasive machining processes

Cubic boron nitride (CBN) composites are widely used as cutting tool materials for high precision abrasive machining processes. They are composed of super hard CBN abrasives and a softer binder. CBN abrasives are one of the hardest materials. They are embedded in the binder which can be metallic, polymeric or ceramic. The binder supports the abrasives and offers suitable toughness. The two components are consolidated by sintering processes under high pressure and temperature. Hence, abrasive particles exhibit an irregular spatial distribution in terms of size, location and orientation. In this work, X-ray computed tomography (CT scan) is used to investigate the geometrical properties of CBN abrasives in the volume regarding quantity, dimension and shape. A three-dimensional (3D) model is generated and the CBN abrasives are correspondingly characterized. The contribution includes both detailed explanation of CT scan and 3D modeling implementation, as well as quantification analysis of the key microstructural features for CBN composites.     

基于三维XCT对碳化引起水泥砂浆内部缺陷改变的测试和分析

为了揭示碳化反应对水泥砂浆内部缺陷分布的影响规律,采用三维XCT(X-ray computed tomography)对碳化前后的水泥砂浆的三维内部缺陷体积分数和缺陷尺度分布进行了定量分析.通过XCT的配套软件VG Studio MAX 2.0对水泥砂浆内部缺陷的投影进行三维重构.并通过配套的三维缺陷分析模块软件从三维...     

Influence of Vitamin D on the Vasoactive Effect of Estradiol in a Rat Model of Polycystic Ovary Syndrome

We examined the vasoactive effect of estradiol in a rat model of early PCOS and the influence of vitamin D deficiency (VDD). We created a model of chronic hyperandrogenism and VDD in adolescent female Wistar rats (N = 46) with four experimental groups: vitamin D supplemented (T-D+), VDD (T-D-), hyperandrogenic and vitamin D supplemented (T+D+), and hyperandrogenic and VDD (T+D-). T+ groups received an 8-week-long transdermal Androgel treatment, D-animals were on vitamin D-reduced diet and D+ rats were supplemented orally with vitamin D3. Estrogen-induced vasorelaxation of thoracic aorta segments were measured with a wire myograph system with or without the inhibition of endothelial nitric oxide synthase (eNOS) or cyclooxygenase-2 (COX-2). The distribution of estrogen receptor (ER), eNOS and COX-2 in the aortic wall was assessed by immunohistochemistry. VDD aortas showed significantly lower estradiol-induced relaxation independently of androgenic status that was further decreased by COX-2 inhibition. COX-2 inhibition failed to alter vessel function in D+ rats. Inhibition of eNOS abolished the estradiol-induced relaxation in all groups. Changes in vascular function in VDD were accompanied by significantly decreased ER and eNOS staining. Short-term chronic hyperandrogenism failed to, but VDD induced vascular dysfunction, compromised estrogen-dependent vasodilatation and changes in ER and eNOS immunostaining.     

Influence of Single-Nucleotide Polymorphisms on Vitamin D Receptor Expression in Periodontal Ligament Fibroblasts as a Response to Orthodontic Compression

This study aimed to evaluate if single-nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) gene are associated with gene expression in human periodontal ligament (hPDL) fibroblasts under simulated orthodontic compressive force. hPDL samples from 57 patients were used. A physiological compressive strain was performed to simulate orthodontic tooth movement in pressure areas under cell culture conditions. The RNA from hPDL fibroblasts was isolated to determine the relative gene expression (mRNA) of the VDR. The DNA was also isolated for the genotyping analysis of five SNPs in the VDR gene: BglI (rs739837, G/T), BsmI (rs1544410, T/C), ApaI (rs7975232, A/C), FokI (rs2228570, A/G), and TaqI (rs731236, A/G). Real-time polymerase chain reaction was used for both analyses. Kruskal–Wallis tests were used to compare VDR expression among genotypes of each SNP. A linear regression analysis was performed to evaluate SNP–SNP interaction. An established alpha of 5% was used. The relative mRNA VDR expression according to the genotypes in the SNPs BglI, BsmI, ApaI, FokI, and TaqI was not statistically significantly different (p > 0.05). The SNP–SNP interaction evaluated by regression analysis did not demonstrate any statistically significant association. No association was observed (p > 0.05). In conclusion, the SNPs BglI (rs739837), BsmI (rs1544410), ApaI (rs7975232), FokI (rs2228570), and TaqI (rs731236) did not show an impact on VDR gene expression in hPDL fibroblasts under simulated orthodontic compressive force.     

Vitamin D: Link between Osteoporosis,Obesity, and Diabetes?

Vitamin D (1,25(OH)₂D₃) is a steroid hormone that has a range of physiological functions in skeletal and nonskeletal tissues, and can contribute to prevent and/or treat osteoporosis, obesity, and Type 2 diabetes mellitus (T2DM). In bone metabolism, vitamin D increases the plasma levels of calcium and phosphorus, regulates osteoblast and osteoclast the activity, and combats PTH hypersecretion, promoting bone formation and preventing/treating osteoporosis. This evidence is supported by most clinical studies, especially those that have included calcium and assessed the effects of vitamin D doses (≥800 IU/day) on bone mineral density. However, annual megadoses should be avoided as they impair bone health. Recent findings suggest that low serum vitamin D is the consequence (not the cause) of obesity and the results from randomized double-blind clinical trials are still scarce and inconclusive to establish the relationship between vitamin D, obesity, and T2DM. Nevertheless, there is evidence that vitamin D inhibits fat accumulation, increases insulin synthesis and preserves pancreatic islet cells, decreases insulin resistance and reduces hunger, favoring obesity and T2DM control. To date, there is not enough scientific evidence to support the use of vitamin D as a pathway to prevent and/or treat obesity and T2DM.     

A 3D,Compartmental Tumor-Stromal Microenvironment Model of Patient-Derived Bone Metastasis

Bone is a frequent site of tumor metastasis. The bone–tumor microenvironment is heterogeneous and complex in nature. Such complexity is compounded by relations between metastatic and bone cells influencing their sensitivity/resistance to chemotherapeutics. Standard chemotherapeutics may not show efficacy for every patient, and new therapeutics are slow to emerge, owing to the limitations of existing 2D/3D models. We previously developed a 3D interface model for personalized therapeutic screening, consisting of an electrospun poly lactic acid mesh activated with plasma species and seeded with stromal cells. Tumor cells embedded in an alginate-gelatin hydrogel are overlaid to create a physiologic 3D interface. Here, we applied our 3D model as a migration assay tool to verify the migratory behavior of different patient-derived bone metastasized cells. We assessed the impact of two different chemotherapeutics, Doxorubicin and Cisplatin, on migration of patient cells and their immortalized cell line counterparts. We observed different migratory behaviors and cellular metabolic activities blocked with both Doxorubicin and Cisplatin treatment; however, higher efficiency or lower IC50 was observed with Doxorubicin. Gene expression analysis of MDA-MB231 that migrated through our 3D hybrid model verified epithelial–mesenchymal transition through increased expression of mesenchymal markers involved in the metastasis process. Our findings indicate that we can model tumor migration in vivo, in line with different cell characteristics and it may be a suitable drug screening tool for personalized medicine approaches in metastatic cancer treatment.     

Rufinamide,a Triazole-Derived Antiepileptic Drug,Stimulates Ca2+-Activated K+ Currents While Inhibiting Voltage-Gated Na+ Currents

Rufinamide (RFM) is a clinically utilized antiepileptic drug that, as a triazole derivative, has a unique structure. The extent to which this drug affects membrane ionic currents remains incompletely understood. With the aid of patch clamp technology, we investigated the effects of RFM on the amplitude, gating, and hysteresis of ionic currents from pituitary GH₃ lactotrophs. RFM increased the amplitude of Ca²⁺-activated K⁺ currents (I_K(Ca)) in pituitary GH₃ lactotrophs, and the increase was attenuated by the further addition of iberiotoxin or paxilline. The addition of RFM to the cytosolic surface of the detached patch of membrane resulted in the enhanced activity of large-conductance Ca²⁺-activated K⁺ channels (BK_Ca channels), and paxilline reversed this activity. RFM increased the strength of the hysteresis exhibited by the BK_Ca channels and induced by an inverted isosceles-triangular ramp pulse. The peak and late voltage-gated Na⁺ current (I_Na) evoked by rapid step depolarizations were differentially suppressed by RFM. The molecular docking approach suggested that RFM bound to the intracellular domain of K_Ca1.1 channels with amino acid residues, thereby functionally affecting BK_Ca channels’ activity. This study is the first to present evidence that, in addition to inhibiting the I_Na, RFM effectively modifies the I_K(Ca), which suggests that it has an impact on neuronal function and excitability.     

The Gestational Effects of Maternal Bone Marker Molecules on Fetal Growth,Metabolism and Long-Term Metabolic Health: A Systematic Review

Fetal exposure in adverse environmental factors during intrauterine life can lead to various biological adjustments, affecting not only in utero development of the conceptus, but also its later metabolic and endocrine wellbeing. During human gestation, maternal bone turnover increases, as reflected by molecules involved in bone metabolism, such as vitamin D, osteocalcin, sclerostin, sRANKL, and osteoprotegerin; however, recent studies support their emerging role in endocrine functions and glucose homeostasis regulation. Herein, we sought to systematically review current knowledge on the effects of aforementioned maternal bone biomarkers during pregnancy on fetal intrauterine growth and metabolism, neonatal anthropometric measures at birth, as well as on future endocrine and metabolic wellbeing of the offspring. A growing body of literature converges on the view that maternal bone turnover is likely implicated in fetal growth, and at least to some extent, in neonatal and childhood body composition and metabolic wellbeing. Maternal sclerostin and sRANKL are positively linked with fetal abdominal circumference and subcutaneous fat deposition, contributing to greater birthweights. Vitamin D deficiency correlates with lower birthweights, while research is still needed on intrauterine fetal metabolism, as well as on vitamin D dosing supplementation during pregnancy, to diminish the risks of low birthweight or SGA neonates in high-risk populations.     

Effect of High-Dose Vitamin D3 Intake on Ambulation, Muscular Pain and Bone Mineral Density in a Woman with Multiple Sclerosis: A 10-Year Longitudinal Case Report

Mounting evidence correlate vitamin D3 (cholecalciferol) supplementation or higher serum levels of vitamin D (25(OH)D) with a lower risk of developing multiple sclerosis (MS), reduced relapse rate, slower progression or fewer new brain lesions. We present here the case of a woman who was diagnosed with MS in 1990. From 1980 to 2000, her ability to walk decreased from ~20 to 1 km per day. Since January 2001, a vitamin D3 supplement was ingested daily. The starting dose was 20 mcg (800 IU)/day and escalated to 100 mcg (4000 IU)/day in September 2004 and then to 150 mcg (6000 IU)/day in December 2005. Vitamin D3 intake reduced muscular pain and improved ambulation from 1 (February 2000) to 14 km/day (February 2008). Vitamin D intake over 10 years caused no adverse effects: no hypercalcaemia, nephrolithiasis or hypercalciuria were observed. Bowel problems in MS may need to be addressed as they can cause malabsorption including calcium, which may increase serum PTH and 1,25(OH)2D levels, as well as bone loss. We suggest that periodic assessment of vitamin D3, calcium and magnesium intake, bowel problems and the measurement of serum 25(OH)D, PTH, Ca levels, UCa/Cr and bone health become part of the integral management of persons with MS.     

rs7041 and rs4588 Polymorphisms in Vitamin D Binding Protein Gene (VDBP) and the Risk of Diseases

The purpose of the study was to investigate the role of vitamin D binding protein (VDBP, DBP) and its polymorphism in the vitamin D pathway and human health. This narrative review shows the latest literature on the most popular diseases that have previously been linked to VDBP. Vitamin D plays a crucial role in human metabolism, controlling phosphorus and calcium homeostasis. Vitamin D binding protein bonds vitamin D and its metabolites and transports them to target tissues. The most common polymorphisms in the VDBP gene are rs4588 and rs7041, which are located in exon 11 in domain III of the VDBP gene. rs4588 and rs7041 may be correlated with differences not only in vitamin D status in serum but also with vitamin D metabolites. This review supports the role of single nucleotide polymorphisms (SNPs) in the VDBP gene and presents the latest data showing correlations between VDBP variants with important human diseases such as obesity, diabetes mellitus, tuberculosis, chronic obstructive pulmonary disease, and others. In this review, we aim to systematize the knowledge regarding the occurrence of diseases and their relationship with vitamin D deficiencies, which may be caused by polymorphisms in the VDBP gene. Further research is required on the possible influence of SNPs, modifications in the structure of the binding protein, and their influence on the organism. It is also important to mention that most studies do not have a specific time of year to measure accurate vitamin D metabolite levels, which can be misleading in conclusions due to the seasonal nature of vitamin D.     

Parkinson’s Disease Etiology: Insights and Associations with Phosphate Toxicity

The present paper investigated the association of Parkinson’s disease etiology with phosphate toxicity, a pathophysiological condition in which dysregulated phosphate metabolism causes excessive inorganic phosphate sequestration in body tissue that damages organ systems. Excessive phosphate is proposed to reduce Complex I function of the mitochondrial electron transport chain in Parkinson’s disease and is linked to opening of the mitochondrial permeability transition pore, resulting in increased reactive oxygen species, inflammation, DNA damage, mitochondrial membrane depolarization, and ATP depletion causing cell death. Parkinson’s disease is associated with α-synuclein and Lewy body dementia, a secondary tauopathy related to hyperphosphorylation of tau protein, and tauopathy is among several pathophysiological pathways shared between Parkinson’s disease and diabetes. Excessive phosphate is also associated with ectopic calcification, bone mineral disorders, and low levels of serum vitamin D in patients with Parkinson’s disease. Sarcopenia and cancer in Parkinson’s disease patients are also associated with phosphate toxicity. Additionally, Parkinson’s disease benefits are related to low dietary phosphate intake. More studies are needed to investigate the potential mediating role of phosphate toxicity in the etiology of Parkinson’s disease.     

3D Printed Poly(𝜀-caprolactone)/Hydroxyapatite Scaffolds for Bone Tissue Engineering: A Comparative Study on a Composite Preparation by Melt Blending or Solvent Casting Techniques and the Influence of Bioceramic Content on Scaffold Properties

Bone tissue engineering has been developed in the past decades, with the engineering of bone substitutes on the vanguard of this regenerative approach. Polycaprolactone-based scaffolds are fairly applied for bone regeneration, and several composites have been incorporated so as to improve the scaffolds’ mechanical properties and tissue in-growth. In this study, hydroxyapatite is incorporated on polycaprolactone-based scaffolds at two different proportions, 80:20 and 60:40. Scaffolds are produced with two different blending methods, solvent casting and melt blending. The prepared composites are 3D printed through an extrusion-based technique and further investigated with regard to their chemical, thermal, morphological, and mechanical characteristics. In vitro cytocompatibility and osteogenic differentiation was also assessed with human dental pulp stem/stromal cells. The results show the melt-blending-derived scaffolds to present more promising mechanical properties, along with the incorporation of hydroxyapatite. The latter is also related to an increase in osteogenic activity and promotion. Overall, this study suggests polycaprolactone/hydroxyapatite scaffolds to be promising candidates for bone tissue engineering, particularly when produced by the MB method.     

Controlled accommodation of metal nanostructures within the matrices of polymer architectures through solution-based synthetic strategies

Controlled accommodation of metal nanostructures (MNSs) into the matrix of a well-defined polymer architecture offers an effective approach to achieve hierarchically structured nanocomposites with tunable synergistic properties to broaden application potentials in the emerging fields of energy, environmental science, and medicine. This review focuses on the recently developed zero-dimensional and one-dimensional MNSs@polymer hybrid nanostructures obtained by solution-based synthetic strategies. Progress in the controlled synthesis of those hybrid nanostructures in terms of the number (e.g., monomer, dimer and trimer), organization manner (e.g., linear alignment or confined assembly in certain domains), and spatial arrangement (e.g., in the core and shell) of the MNSs within the distinct polymer matrices are detailed. The synergistic properties and potential applications of those MNSs@polymer hybrids associated with their compositions and morphologies are also reviewed.