Association Between Circulating 25-Hydroxy Vitamin D Receptor and Molecular Response in Multiple Myeloma.

<b>Background and Objective:</b> Vitamin D Receptor (VDR) regulate several body processes related to metabolism, immunological function and oncogenesis. Low vitamin D levels are recognized as associated with a higher incidence of hematologic malignancies and poor outcomes. This study aims to determine whether vitamin D levels and VDR contribute to multiple myeloma (MM). <b>Materials and Methods:</b> This study enrolled twenty-five patients diagnosed with MM. Ages and gender were matched between patients and healthy groups. Serum Protein Electrophoresis (SPEP) was detected for all patients. Also, serum 25-hydroxy vitamin D levels were recorded. The PCR products were submitted to Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) and Sanger sequencing to detect VDR gene polymorphism including (FokI, ApaI and Tru9I). <b>Results:</b> This study revealed that an M spike was detected in five patients newly diagnosed with MM. According to vitamin D levels 84% of patients had a vitamin D deficiency. In the RFLP technique, FokI CT, ApaI AA and Tru9I GG genotypes were highly distributed in patients. Additionally, the MM group had a significant frequency of the T allele in the FokI (44.0%), the A allele in the ApaI (68.0%) and the A allele in the Tru9I (30.0%). <b>Conclusion:</b> The SPEP is an easy-to-perform laboratory test that can be used to detect and quantify monoclonal proteins. Low vitamin D level of less than 20 ng mL¹ is associated with an increased prevalence of MM and a worse response to treatment. In addition, VDR gene polymorphisms may be a molecular marker of MM risk.

Association between the genetic variant in the vitamin D pathway (rs2282679), circulating 25-hydroxyvitamin D levels, insulin resistance and metabolic syndrome criteria.

Introduction: Background and aims: some studies have reported links between 25-hydroxyvitamin D levels and the presence of metabolic syndrome. The aim of the present study was to evaluate whether an association exists among 25-hydroxyvitamin D, rs2282679 of the GC gene and metabolic syndrome (MS). Methods: the study involved a population of 134 postmenopausal obese females. Measurements of anthropometric parameters, blood pressure, bone turnover markers, fasting blood glucose, insulin resistance (HOMA-IR), lipid profile, C-reactive protein and prevalence of MS were recorded. Genotype of CG gene polymorphism (rs2282679) was evaluated. Results: insulin (delta: 4.6 ± 0.9 mUI/l; p = 0.02), triglycerides (delta: 21.6 ± 2.9 mg/dl; p = 0.04) and HOMA-IR (delta: 1.1 ± 0.9 unit; p = 0.02) were lower in TT subjects than TG + GG patients. The percentages of individuals who had MS (OR = 2.80, 95 % CI = 1.39-5.65; p = 0.02), hypertriglyceridemia (OR = 2.39, 95 % CI = 1.44-5.96; p = 0.01), and hyperglycemia (OR = 2.72, 95 % CI = 1.23-6.00; p = 0.43) were higher in G allele carriers. Logistic regression analysis showed an increased risk of MS in G allele carriers (OR = 2.36, 95 % CI = 1.11-5.91, p = 0.02) and an increased risk of 25-hydroxyvitamin D deficiency (< 20 ng/ml) (OR = 2.43, 95 % CI = 1.13-6.69, p = 0.02), too. Conclusions: a negative association among G allele and insulin resistance, hypertriglyceridemia, deficiency of 25 hydroxyvitamin D levels and MS was reported in this population.

Introducción: Antecedentes y objetivos: algunos estudios han demostrado una relación entre los niveles de 25-hidroxivitamina D y la presencia del síndrome metabólico. El objetivo de este estudio fue evaluar si existe una asociación entre la 25-hidroxivitamina D, la variante rs2282679 del gen GC y el síndrome metabólico (SM). Métodos: el estudio involucró a una población de 134 mujeres obesas posmenopáusicas. Se registraron parámetros antropométricos, presión arterial, marcadores de recambio óseo, glucemia en ayunas, resistencia a la insulina (HOMA-IR), perfil lipídico, proteína C reactiva y prevalencia de SM. Se evaluó el genotipo del polimorfismo del gen CG (rs2282679). Resultados: los niveles de insulina (delta: 4,6 ± 0,9 mUI/l; p = 0.02), triglicéridos (delta: 21,6 ± 2,9 mg/dl; p = 0,04) y HOMA-IR (delta: 1,1 ± 0,9 unidades; p = 0,02) fueron menores en los sujetos TT que en los pacientes TG + GG. Los porcentajes de individuos que tenían SM (OR = 2,80, IC 95 % = 1,39-5,65; p = 0,02), hipertrigliceridemia (OR = 2,39, IC 95 % = 1,44-5,96; p = 0,01) e hiperglucemia (OR = 2,72, IC 95 % = 1,23-6,00; p = 0,43) fueron mayores en los portadores del alelo G. El análisis de regresión logística mostró un mayor riesgo de SM en los portadores del alelo G (OR = 2,36, IC 95 % = 1,11-5,91; p = 0,02) y un mayor riesgo de deficiencia de 25-hidroxivitamina D (< 20 ng/ml) (OR = 2,43, IC 95 % = 1,13-6,69; p = 0,02). Conclusiones: en esta población hemos detectado una asociación negativa entre el alelo G y la resistencia a la insulina, hipertrigliceridemia, deficiencia niveles de 25-hidroxivitamina D y SM.

Rational Design of Trident Aptamer Scaffold for Rapid and Accurate Monitoring of 25-Hydroxyvitamin D3 Metabolism in Living Cells.

The level of 25-hydroxyvitamin D3 [25(OH)VD3] in human blood is considered as the best indicator of vitamin D status, and its deficiency or excess can lead to various health problems. Current methods for monitoring 25(OH)VD3 metabolism in living cells have limitations in terms of sensitivity and specificity and are often expensive and time-consuming. To address these issues, an innovative trident scaffold-assisted aptasensor (TSA) system has been developed for the online quantitative monitoring of 25(OH)VD3 in complex biological environments. Through the computer-aided design, the TSA system includes an aptamer molecule recognition layer that is uniformly oriented, maximizing binding site availability, and enhancing sensitivity. The TSA system achieved the direct, highly sensitive, and selective detection of 25(OH)VD3 over a wide concentration range (17.4-12,800 nM), with a limit of detection of 17.4 nM. Moreover, we evaluated the efficacy of the system in monitoring the biotransformation of 25(OH)VD3 in human liver cancer cells (HepG2) and normal liver cells (L-02), demonstrating its potential as a platform for drug-drug interaction studies and candidate drug screening.

Vitamin D and inflammatory cytokines association in mild cognitive impaired subjects.

BACKGROUND: Mild cognitive impairment (MCI) is a prodromal stage of Alzheimer's disease (AD). The association of low Vitamin D and chronic inflammation in the onset of cognitive decline in the elderly population has been established but the variable population-based study is still lacking. METHODOLOGY: The present study aims to investigate the level of plasma Vitamin D, pro-inflammatory cytokines IL-1ß, IL-6, TNF-α, cognitive performance, and white matter changes in the elderly population in the North-Eastern part of Uttar Pradesh, India. RESULTS: 70 participants with (Mean age- 75.14 ± 1.24, Male/Female- 50/20) with an Mini Mental State Examination (MMSE) score of (24.82 ± 1.82) and Montreal Cognitive Assessment Test (MOCA) score (21.83 ± 1.75), were cognitive decline, against the 70 healthy controls (Mean Age-73.18 ± 1.43; Male/Female- 50/20) with MMSE score (28.1 ± 1.5) and MOCA (28.5 ± 1.65), White matter variable Fractional Anisotropy (FA) and Apparent Diffusion Coefficient (ADC) values in MCI subject was found significantly altered in Right temporal lobe, Corpus Callosum (Right) and Hippocampus body (Right), Hippocampus body (left), Hippocampus head (Right) and Hippocampus head (Left)as compared with healthy controls. The level of cytokines IL-1ß, IL-6, TNF-α, was significantly high in MCI subjects as compared with controls. Further lower Vitamin D level in plasma was detected in MCI as compared with healthy controls. CONCLUSION: The result from the present study depicts that chronic inflammation and lower Vitamin D level influences neurodegeneration and decline in cognitive performance in the elderly population. These variables can be used as biomarkers for early identification of AD and interventional strategies can be designed for prevention at the prodromal stage of AD.

Evaluation of interleukins 37 and 38 and vitamin D status in the serum of women with Graves' disease.

BACKGROUND: Graves' disease (GD) is an autoimmune thyroid disorder and recent studies have proposed a role for interleukin (IL)-37, IL-38, and vitamin D (VitD) in the pathophysiology of disease. Therefore, this study investigated the expression of IL-37, IL-38, and VitD in the serum of GD patients and correlations of their levels with some demographic and clinical characteristics. METHODS: Serum IL-37, IL-38, and VitD levels were evaluated in 90 women with GD and 93 control women using enzyme-linked immunosorbent assay kits. Depending on therapy, six patients were newly diagnosed (ND; untreated), and 50 patients were receiving only carbimazole (CMZ), while 34 patients were also on CMZ but also received one (31 patients), two (one patient), or three (two patients) doses of radioactive iodine (RAI). RESULTS: IL-37 levels were significantly higher in GD patients than in controls, while IL-38 and VitD levels were significantly decreased. As indicated by the area under the curve (AUC), receiver operating characteristic curve analysis demonstrated the potential of IL-37, IL-38, and VitD as biomarkers to distinguish GD patients from controls (AUC = 0.953, 0.959, and 0.793, respectively). Multinomial logistic regression analysis showed that altered levels of IL-37, IL-38, and VitD were most likely associated with the pathogenesis of GD. IL-37 was negatively correlated with IL-38 and VitD, while IL-38 and VitD were positively correlated. CONCLUSION: Serum Il-37 levels were upregulated in women with GD, while IL-38 and VitD levels showed downregulated levels. The latter two were positively correlated while they showed a negative correlation with IL-37.

Vitamin D Inhibits the Early Aggregation of α-Synuclein and Modulates Exocytosis Revealed by Electrochemical Measurements.

Alpha-synuclein (α-Syn) localizes at presynaptic terminal and modulates synaptic functions. Increasing evidence demonstrate that α-Syn oligomers, forming at the early of aggregation, are cytotoxic and is thus related to brain neurodegenerative diseases. Herein, we find that vitamin D (VD) can reduce neurocytotoxicity. The reduced neurocytotoxicity might be attributed to the less amount of large-sized α-Syn oligomers inhibited by VD, measured by electrochemical collision at single particle level, which are not observable with traditionally ensembled method. Single-cell amperometry (SCA) results show that VD can recover the amount of neurotransmitter release during exocytosis induced by α-Syn oligomers, further verifying the neuroprotection of VD. Our study reveals the neuroprotective role of VD through inhibiting α-Syn aggregation, which is envisioned to be of great importance in treatment and prevention of the neurodegenerative diseases.

Ultrasound-Assisted Microencapsulation of Soybean Oil and Vitamin D Using Bare Glycogen Nanoparticles.

Ultrasonically synthesized core-shell microcapsules can be made of synthetic polymers or natural biopolymers, such as proteins and polysaccharides, and have found applications in food, drug delivery and cosmetics. This study reports on the ultrasonic synthesis of microcapsules using unmodified (natural) and biodegradable glycogen nanoparticles derived from various sources, such as rabbit and bovine liver, oyster and sweet corn, for the encapsulation of soybean oil and vitamin D. Depending on their source, glycogen nanoparticles exhibited differences in size and 'bound' proteins. We optimized various synthetic parameters, such as ultrasonic power, time and concentration of glycogens and the oil phase to obtain stable core-shell microcapsules. Particularly, under ultrasound-induced emulsification conditions (sonication time 45 s and sonication power 160 W), native glycogens formed microcapsules with diameter between 0.3 µm and 8 µm. It was found that the size of glycogen as well as the protein component play an important role in stabilizing the Pickering emulsion and the microcapsules shell. This study highlights that native glycogen nanoparticles without any further tedious chemical modification steps can be successfully used for the encapsulation of nutrients.

Identification of kinase inhibitors that rule out the CYP27B1-mediated activation of vitamin D: an integrated machine learning and structure-based drug designing approach.

CYP27B1, a cytochrome P450-containing hydroxylase enzyme, converts vitamin D precursor calcidiol (25-hydroxycholecalciferol) to its active form calcitriol (1α,25(OH)2D3). Tyrosine kinase inhibitor such as imatinib is reported to interfere with the activation of vitamin D3 by inhibiting CYP27B1 enzyme. Consequently, there is a decrease in the serum levels of active vitamin D that in turn may increase the relapse risk among the cancer patients treated with imatinib. Within this framework, the current study focuses on identifying other possible kinase inhibitors that may affect the calcitriol level in the body by inhibiting CYP27B1. To achieve this, we explored multiple machine learning approaches including support vector machine (SVM), random forest (RF), and artificial neural network (ANN) to identify possible CYP27B1 inhibitors from a pool of kinase inhibitors database. The most reliable classification model was obtained from the SVM approach with Matthews correlation coefficient of 0.82 for the external test set. This model was further employed for the virtual screening of kinase inhibitors from the binding database (DB), which tend to interfere with the CYP27B1-mediated activation of vitamin D. This screening yielded around 4646 kinase inhibitors that were further subjected to structure-based analyses using the homology model of CYP27B1, as the 3D structure of CYP27B1 complexed with heme was not available. Overall, five kinase inhibitors including two well-known drugs, i.e., AT7867 (Compound-2) and amitriptyline N-oxide (Compound-3), were found to interact with CYP27B1 in such a way that may preclude the conversion of vitamin D to its active form and hence testify the impairment of vitamin D activation pathway.

Mapping the effect of drugs on ACE2 as a novel target site for COVID-19 therapy.

Angiotensin converting enzyme 2 (ACE2) has potentially conflicting roles in health and disease. COVID-19 coronavirus binds to human cells via ACE2 receptor, which is expressed on almost all body organs. Boosting the ACE2 receptor levels on heart and lung cells may provide more cellular enter to virus thereby worsening the infection. Therefore, among the drug targets, ACE2 is suggested as a vital target of COVID-19 therapy. This hypothesis is based on the protective role of the drugs acting on ACE2. Therefore, this review discusses the impact and challenges of using ACE2 as a target in the current therapy of COVID-19.

Bioaccessibility of oil-soluble vitamins (A, D, E) in plant-based emulsions: impact of oil droplet size.

We systematically investigated the impact of oil droplet diameter (≈0.15, 1.6, and 11 µm) on the bioaccessibility of three oil-soluble vitamins (vitamin A palmitate, vitamin D, and vitamin E acetate) encapsulated within soybean oil-in-water emulsions stabilized by quillaja saponin. Lipid digestion kinetics decreased with increasing droplet size due to the reduction in oil-water interfacial area. Vitamin bioaccessibility decreased with increasing droplet size from 0.15 to 11 µm: 87 to 39% for vitamin A; 76 to 44% for vitamin D; 77 to 21% for vitamin E. Vitamin bioaccessibility also decreased as their hydrophobicity and molecular weight increased, probably because their tendency to remain inside the oil droplets and/or be poorly solubilized by the mixed micelles increased. Hydrolysis of the esterified vitamins also occurred under gastrointestinal conditions: vitamin A palmitate (∼90%) and vitamin E acetate (∼3%). Consequently, the composition and structure of emulsion-based delivery systems should be carefully designed when creating vitamin-fortified functional food products.

Non-Musculoskeletal Benefits of Vitamin D beyond the Musculoskeletal System.

Vitamin D, a fat-soluble prohormone, is endogenously synthesized in response to sunlight or taken from dietary supplements. Since vitamin D receptors are present in most tissues and cells in the body, the mounting understanding of the role of vitamin D in humans indicates that it does not only play an important role in the musculoskeletal system, but has beneficial effects elsewhere as well. This review summarizes the metabolism of vitamin D, the research regarding the possible risk factors leading to vitamin D deficiency, and the relationships between vitamin D deficiency and numerous illnesses, including rickets, osteoporosis and osteomalacia, muscle weakness and falls, autoimmune disorders, infectious diseases, cardiovascular diseases (CVDs), cancers, and neurological disorders. The system-wide effects of vitamin D and the mechanisms of the diseases are also discussed. Although accumulating evidence supports associations of vitamin D deficiency with physical and mental disorders and beneficial effects of vitamin D with health maintenance and disease prevention, there continue to be controversies over the beneficial effects of vitamin D. Thus, more well-designed and statistically powered trials are required to enable the assessment of vitamin D's role in optimizing health and preventing disease.

An oligopeptide/aptamer-conjugated dendrimer-based nanocarrier for dual-targeting delivery to bone.

Bone targeting is one of the most potentially valuable therapeutic methods for medically treating bone diseases, such as osteoarthritis, osteoporosis, nonunion bone defects, bone cancer, and myeloma-related bone disease, but its efficacy remains a challenge due to unfavorable bone biodistribution, off-target effects, and the lack of cell specificity. To address these problems, we synthesized a new dual-targeting nanocarrier for delivery to bone by covalently modifying the G4.0 PAMAM dendrimer with the C11 peptide and the CH6 aptamer (CH6-PAMAM-C11). The molecular structure was confirmed using 1H-NMR and FT-IR spectroscopy. CLSM results showed that the novel nanocarrier could successfully accumulate in the targeted cells, mineralized areas and tissues. DLS and TEM demonstrated that CH6-PAMAM-C11 was approximately 40-50 nm in diameter. In vitro targeting experiments confirmed that the C11 ligand had a high affinity for HAP, while the CH6 aptamer had a high affinity for osteoblasts. The in vivo biodistribution analysis showed that CH6-PAMAM-C11 could rapidly accumulate in bone within 4 h and 12 h and then deliver drugs to sites of osteoblast activity. The components of CH6-PAMAM-C11 were well excreted via the kidneys. The accumulation of many more CH6-PAMAM-C11 dual-targeting nanocarriers than single-targeting nanocarriers was observed in the periosteal layer of the rat skull, along with aggregation at sites of osteoblast activity. All of these results indicate that CH6-PAMAM-C11 may be a promising nanocarrier for the delivery of drugs to bone, particularly for the treatment of osteoporosis, and our research strategy may serve as a reference for research in targeted drug, small molecule drug and nucleic acid delivery.

Non-pharmacologic approaches for hidradenitis suppurativa - a systematic review.

Importance: Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition presenting with painful nodules and sinus tracts primarily in intertriginous regions. The persistent nature of HS and challenges in symptom management lead many patients to seek non-pharmacologic approaches due to the paucity and limited efficacy of conventional HS therapeutic options.Objective: To evaluate the existing evidence for non-pharmacologic modalities in treatment of HS.Findings: Discussed in this review are non-pharmacologic modalities with evidence of efficacy in HS treatment, including weight loss, vitamin B12, vitamin D and zinc supplementation, and dietary avoidance of brewer's yeast. Limitations of the available data on non-pharmacologic therapies in HS include the predominance of pilot and single-armed studies, as well as heterogeneity in study design, subject disease severity, concomitant treatment and comorbid conditions.Conclusions and relevance: HS patients are becoming increasingly interested in the use of non-pharmacologic approaches to augment conventional treatments. Strength of evidence for non-pharmacologic therapies in HS is limited by small study size and lack of randomized controlled trials. Future large-scale investigations should be pursued to better establish efficacy and dosing regimens for the use of non-pharmacologic treatments in HS.

Protection from Ultraviolet Damage and Photocarcinogenesis by Vitamin D Compounds.

Exposure of skin cells to UV radiation results in DNA damage, which if inadequately repaired, may cause mutations. UV-induced DNA damage and reactive oxygen and nitrogen species also cause local and systemic suppression of the adaptive immune system. Together, these changes underpin the development of skin tumours. The hormone derived from vitamin D, calcitriol (1,25-dihydroxyvitamin D3) and other related compounds, working via the vitamin D receptor and at least in part through endoplasmic reticulum protein 57 (ERp57), reduce cyclobutane pyrimidine dimers and oxidative DNA damage in keratinocytes and other skin cell types after UV. Calcitriol and related compounds enhance DNA repair in keratinocytes, in part through decreased reactive oxygen species, increased p53 expression and/or activation, increased repair proteins and increased energy availability in the cell when calcitriol is present after UV exposure. There is mitochondrial damage in keratinocytes after UV. In the presence of calcitriol, but not vehicle, glycolysis is increased after UV, along with increased energy-conserving autophagy and changes consistent with enhanced mitophagy. Reduced DNA damage and reduced ROS/RNS should help reduce UV-induced immune suppression. Reduced UV immune suppression is observed after topical treatment with calcitriol and related compounds in hairless mice. These protective effects of calcitriol and related compounds presumably contribute to the observed reduction in skin tumour formation in mice after chronic exposure to UV followed by topical post-irradiation treatment with calcitriol and some, though not all, related compounds.

The Role of Classical and Novel Forms of Vitamin D in the Pathogenesis and Progression of Nonmelanoma Skin Cancers.

Nonmelanoma skin cancers including basal and squamous cell carcinomas (SCC and BCC) represent a significant clinical problem due to their relatively high incidence, imposing an economic burden to healthcare systems around the world. It is accepted that ultraviolet radiation (UVR: λ = 290-400 nm) plays a crucial role in the initiation and promotion of BCC and SCC with UVB (λ = 290-320 nm) having a central role in this process. On the other hand, UVB is required for vitamin D3 (D3) production in the skin, which supplies >90% of the body's requirement for this prohormone. Prolonged exposure to UVB can also generate tachysterol and lumisterol. Vitamin D3 itself and its canonical (1,25(OH)2D3) and noncanonical (CYP11A1-intitated) D3 hydroxyderivatives show photoprotective functions in the skin. These include regulation of keratinocyte proliferation and differentiation, induction of anti-oxidative responses, inhibition of DNA damage and induction of DNA repair mechanisms, and anti-inflammatory activities. Studies in animals have demonstrated that D3 hydroxyderivatives can attenuate UVB or chemically induced epidermal cancerogenesis and inhibit growth of SCC and BCC. Genomic and non-genomic mechanisms of action have been suggested. In addition, vitamin D3 itself inhibits hedgehog signaling pathways which have been implicated in many cancers. Silencing of the vitamin D receptor leads to increased propensity to develop UVB or chemically induced epidermal cancers. Other targets for vitamin D compounds include 1,25D3-MARRS, retinoic orphan receptors α and γ, aryl hydrocarbon receptor, and Wnt signaling. Most recently, photoprotective effects of lumisterol hydroxyderivatives have been identified. Clinical trials demonstrated a beneficial role of vitamin D compounds in the treatment of actinic keratosis. In summary, recent advances in vitamin D biology and pharmacology open new exciting opportunities in chemoprevention and treatment of skin cancers.

Vitamin D and its analogs as anticancer and anti-inflammatory agents.

Vitamin D3 is the precursor of the steroid hormone calcitriol (1α,25-dihydroxyvitamin D3), a potent agonist of the transcription factor vitamin D receptor (VDR). Calcitriol has received large appreciation due to the impact not only on mineral homeostasis, but also on metabolic diseases, immunological disorders, and cancer. A supraphysiological dose of calcitriol is required to reduce the proliferation of cancer cells. However, the dose will lead to calcemic side effects such as hypercalcemia and hypercalciuria. Although several analogs of 1α,25(OH)2D3 have shown potent anticancer or anti-inflammatory activity on cell cultures or in animal models, few vitamin D analogs have been successfully applied in the treatment of cancer or inflammatory diseases. This review will present and discuss vitamin D analogs that have the potential to be used as anticancer or anti-inflammatory agents.

Vitamin D as a Potential Therapeutic Option in Cancer Treatment: Is There a Role for Chemoprevention?

BACKGROUND: Vitamin D (Vit D) serves as a precursor to the potent steroid hormone calcitriol, which regulates numerous genes that control homeostasis, epithelial cell differentiation, proliferation, and apoptosis. Low level of Vit D is implicated in the development and progression of several diseases including bone fractures, cardiovascular disease, diabetes mellitus, and cancers. The present review highlights the role of vitamin D in cancer with a particular emphasis on genetic variants related to Vit D metabolism as well as clinical trials of Vit D supplementation as a potential therapeutic option in the treatment of cancer patients. METHODS: Data were collected following an electronic search in the Web of Science, Medline, PubMed, and Scopus databases by using some keywords such as "cancer", "tumor", "malignancy", "vitamin D", "cholecalciferol" and "calcitriol". RESULTS: The collected evidence from the studies revealed a consistent and strong association between Vit D status and cancer risk and survival. The associations between Vit D-related genetic variants and cancer survival support the hypothesis that Vit D may affect cancer outcomes. The mechanisms whereby Vit D reduces cancer risk and increases survival are regulation of cellular differentiation, proliferation and apoptosis as well as decreased angiogenesis in tumor microenvironment and inhibition of metastasis. CONCLUSION: There is a paucity of evidence-based recommendations for the optimal 25(OH)D levels in patients with cancer and the role of Vit D supplementation for primary or secondary prevention of cancer. Well-designed and sufficiently powered randomized clinical trials are necessary to assess the clinical application of Vit D in enhancing the clinical efficacy of standard and adjuvant chemotherapy regimens.

Clinical factors correlated with vitamin D deficiency in patients with obesity scheduled for bariatric surgery: A single center experience.

We aim to assess the prevalence of vitamin D deficiency (VDD) in patients scheduled for bariatric surgery (BS), and to identify factors that might be associated with VDD. We conducted a cross-sectional observational study involving all consecutive patients scheduled for BS from 2017 to 2019. The exclusion criteria were missing data for vitamin D levels, intake of vitamin D supplements in the 3 months prior to serum vitamin D determination, and renal insufficiency. A total of 206 patients (mean age and body mass index [BMI] of 34.9 ± 10.7 years, and 44.3 ± 6.99 kg/m2, respectively) met the inclusion criteria and were enrolled for data analysis. VDD (<19.9 ng/mL), severe VDD (<10 ng/mL), and vitamin D insufficiency (20-29.9 ng/mL) were present in 68.8 %, 12.5 %, and 31.2 % of patients, respectively. A significant inverse correlation was found between vitamin D levels and initial BMI, parathyroid hormone, and homeostatic model assessment of insulin resistance (r = -0.280, p < 0.05; r = -0.407, p = 0.038; r = -0.445, p = 0.005), respectively. VDD was significantly more prevalent in patients with higher BMI [-0.413 ± 0.12, CI95 % (-0.659; -0.167), p = 0.006], whereas no significant association between hypertension [-1.005 ± 1.65, CI95 % (-4.338; 2.326), p = 0.001], and diabetes type 2 (T2D) [-0.44 ± 2.20, CI95 % (-4.876; 3.986), p = 0.841] was found. We observed significant association between female sex and levels of vitamin D [6.69 ± 2.31, CI95 % (2.06; 11.33), p = 0.006]. The present study shows that in patients scheduled for BS, VDD deficiency is common and was associated with higher BMI, and female sex.

Vitamin D - Deglycosylated Vitamin D Binding Protein Dimer: Positive Synergistic Effects on Recognition, Activation, Phagocytosis and Oxidative Stress on Macrophages.

BACKGROUND: We have recently shown positive effects in the quality of life in autism and amyloid lateral sclerosis patients using a newly developed 25-OH vitamin D deglycosylated vitamin D binding protein complex (VitD~dgVDBP) by reducing oxidative stress. The question arises whether this reduction of oxidative stress was due to a synergistic effect of the dimer in the recognition and activation of phagocytosis on macrophages combined with a lower oxidative burst compared to the VitD free proteins, namely vitamin D binding protein (VDBP: Gc Protein) and deglycosylated dgVDBP (GcMAF). METHODS: VDBP sandwich ELISA of equal protein concentration of VDBP, dgVDBP, and VitD~dgVDBP (1 µg/ mL by BCA protein technique) was used to identify immune affinity to polyclonal antibodies raised against human VDBP. The 25(OH) vitamin D levels of VDBP, dgVDBP and VitD~dgVDBP were estimated by a competitive immune assay using a monoclonal antibody. Macrophage phagocytosis and oxidative burst in absence or presence of 400 pg/mL VDBP, 400 pg/mL dgVDBP, and 400 pg/mL VitD~dgVDBP was measured. RESULTS: The recognition of the antibody against VDBP protein was significantly more than 4-fold higher for VitD~dgVDBP (769.2 +/- 35.1%) compared to dgVDBP (186.5 +/- 16.8 %; p < 0.01) and 7-fold higher to VDBP (100 +/- 11.4 %; p < 0.001). 25(OH) vitamin D levels of VDBP (20.7 nmol/mg; p < 0.001) and dgVDBP (28.8 +/- 3.9 nmol/mL; p < 0.001) was significantly lower than of VitD~dgVDBP (324.0 +/- 12.8 nmol/mL). The calculated VitD/ protein ratio showed significantly higher results in favor of VitD~dgVDBP (1.01 +/- 0.12) compared to dgVDBP (0.06 +/- 0.03; p < 0.001) and VDBP (0.05 +/- 0.01; p < 0.001). The estimation of macrophage phagocytosis rate of VitD~dgVDBP (5,864.3 +/- 742.2 cps) was significantly higher compared to dgVDBP (2,789.6 +/- 102.7 cps; p < 0.01) and VDBP (1,134.3 +/- 135.9 cps) whereas the production of macrophage superoxide anion radicals showed significantly higher levels of dgVDBP (255.3 +/- 14.5 cps) in comparison to VDBP (148.6 +/- 24.7 cps, p < 0.01) and VitD~dgVDBP (142.3 +/- 20.0 cps; p < 0.001). Linear regression between VDBP antibody affinity and macrophage phagocytosis of VDBP, dgVDBP and VitD~dgVDBP resulted in a correlation coefficient of r = 0.95 in favor of VitD~dgVDBP. CONCLUSIONS: VitD~dgVDBP (Il-42) showed higher macrophage activation and lower oxidative burst than VitD free dgVDBP (GcMaf) and VDBP (Gc) which may result from a synergistic effect by presenting protein bound Vitamin D better to macrophages.

Synthesis, CYP24A1-Dependent Metabolism and Antiproliferative Potential against Colorectal Cancer Cells of 1,25-Dihydroxyvitamin D2 Derivatives Modified at the Side Chain and the A-Ring.

Experimental data indicate that low-calcemic vitamin D derivatives (VDDs) exhibit anticancer properties, both in vitro and in vivo. In our search for a vitamin D analog as potential anticancer agent, we investigated the influence of chirality in the side chain of the derivatives of 1,25-dihydroxyergocalciferol (1,25D2) on their activities. In this study, we synthesized modified analogs at the side chain and the A-ring, which differed from one another in their absolute configuration at C-24, namely (24S)- and (24R)-1,25-dihydroxy-19-nor-20a-homo-ergocalciferols (PRI-5105 and PRI-5106, respectively), and evaluated their activity. Unexpectedly, despite introducing double-point modifications, both analogs served as very good substrates for the vitamin D-hydroxylating enzyme. Irrespective of their absolute C-24 configuration, PRI-5105 and PRI-5106 showed relatively low resistance to CYP24A1-dependent metabolic deactivation. Additionally, both VDDs revealed a similar antiproliferative activity against HT-29 colorectal cancer cells which was higher than that of 1,25D3, the major biologically active metabolite of vitamin D. Furthermore, PRI-5105 and PRI-5106 significantly enhanced the cell growth-inhibitory activity of 5-fluorouracil on HT-29 cell line. In conclusion, although the two derivatives showed a relatively high anticancer potential, they exhibited undesired high metabolic conversion.