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1.
Vitamin D: A Micronutrient Regulating Genes.
Carlberg, C
Current pharmaceutical design. 2019;(15):1740-1746
Abstract
BACKGROUND At sufficient sun exposure, humans can synthesize vitamin D3 endogenously in their skin, but today's lifestyle makes the secosteroid a true vitamin that needs to be taken up by diet or supplementation with pills. The vitamin D3 metabolite 1α,25-dihydroxyvitamin D3 acts as a nuclear hormone activating the transcription factor vitamin D receptor (VDR). METHODS This review discusses the biological effects of micronutrient vitamin D ranging from calcium homeostasis and bone formation to the modulation of innate and adaptive immunity. RESULTS Since normal human diet is sufficient in vitamin D, the need for efficient vitamin D3 synthesis in the skin acts as an evolutionary driver for its lightening during the migration out of Africa towards North. Via activating the VDR, vitamin D has direct effects on the epigenome and the expression of more than 1000 genes in most human tissues and cell types. CONCLUSIONS The pleiotropic action of vitamin D in health and disease prevention is explained through complex gene regulatory events of the transcription factor VDR.
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2.
Molecular basis of vitamin D action in neurodegeneration: the story of a team perspective.
Gezen-Ak, D, Dursun, E
Hormones (Athens, Greece). 2019;(1):17-21
Abstract
Vitamin D, a secosteroid hormone, has, over the years, mainly been known for its classic role in the maintenance of calcium homeostasis of the human body. However, there is increasing understanding that vitamin D contributes to the regulation of Ca2+ homeostasis, especially via voltage-gated calcium channels, in another major organ that uses calcium, the brain. Almost 30 years ago, the role of dysregulation in the aging brain and in Alzheimer's disease (AD) gave rise to the Ca2+ hypothesis of brain aging and dementia. We thus made calcium homeostasis the starting point of our studies, proposing the notion that the consequences of long-term deficiency and/or inefficient utilization of vitamin D may cause the disruption of calcium homeostasis in neurons, this creating a vulnerability of neurons to aging and neurodegeneration. In this mini-review, we aim to describe the potential of vitamin D (cholecalciferol) as a neurosteroid based on our findings and conclusions.
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3.
Nutrigenomics of Vitamin D.
Carlberg, C
Nutrients. 2019;(3)
Abstract
Nutrigenomics studies how environmental factors, such as food intake and lifestyle, influence the expression of the genome. Vitamin D₃ represents a master example of nutrigenomics, since via its metabolite 1α,25-dihydroxyvitamin D₃, which binds with high-affinity to the vitamin D receptor, the secosteroid directly affects the epigenome and transcriptome at thousands of loci within the human genome. Vitamin D is important for both cellular metabolism and immunity, as it controls calcium homeostasis and modulates the response of the innate and adaptive immune system. At sufficient UV-B exposure, humans can synthesize vitamin D₃ endogenously in their skin, but today's lifestyle often makes the molecule a true vitamin and micronutrient that needs to be taken up by diet or supplementation with pills. The individual's molecular response to vitamin D requires personalized supplementation with vitamin D₃, in order to obtain optimized clinical benefits in the prevention of osteoporosis, sarcopenia, autoimmune diseases, and possibly different types of cancer. The importance of endogenous synthesis of vitamin D₃ created an evolutionary pressure for reduced skin pigmentation, when, during the past 50,000 years, modern humans migrated from Africa towards Asia and Europe. This review will discuss different aspects of how vitamin D interacts with the human genome, focusing on nutritional epigenomics in context of immune responses. This should lead to a better understanding of the clinical benefits of vitamin D.
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4.
Vitamin D and health in the Mediterranean countries.
Grant, WB
Hormones (Athens, Greece). 2019;(1):23-35
Abstract
Vitamin D, traditionally well known for its role in maintaining optimal health through its contribution to calcium metabolism and skeletal health, has received increased attention over the past two decades, with considerable focus being placed on its nonskeletal benefits. This paper is a narrative review of the nonskeletal health benefits of vitamin D, of particular interest to inhabitants of Mediterranean countries, namely, autism, cancer, cardiovascular disease, chronic obstructive pulmonary disease, dental caries, diabetes mellitus, erectile dysfunction, hypertension, metabolic syndrome, respiratory tract infections, all-cause mortality, and pregnancy and birth outcomes, because of the relatively high incidence and/or prevalence of these disorders in this region. Currently, the best evidence is coming out of observational studies related to serum 25-hydroxyvitamin D [25(OH)D] concentrations. Vitamin D clinical trials have generally been poorly designed and conducted, usually being based on vitamin D dose rather than 25(OH)D concentration. The optimal 25(OH)D concentration is above 75 nmol/l (30 ng/ml), with even better health outcomes in the range of 100-150 nmol/l. Achieving these concentrations with vitamin D3 supplements will require 1000-4000 IU/day of vitamin D3. Sensible sun exposure should also be encouraged. Countries should also consider fortifying grain and dairy products with vitamin D3.
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5.
Immunological effects of vitamin D and their relations to autoimmunity.
Yamamoto, E, Jørgensen, TN
Journal of autoimmunity. 2019;:7-16
Abstract
Vitamin D deficiency is an established risk factor for many autoimmune diseases and the anti-inflammatory properties of vitamin D underscore its potential therapeutic value for these diseases. However, results of vitamin D3 supplementation clinical trials have been varied. To understand the clinical heterogeneity, we reviewed the pre-clinical data on vitamin D activity in four common autoimmune diseases: multiple sclerosis (MS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and inflammatory bowel disease (IBD), in which patients are commonly maintained on oral vitamin D3 supplementation. In contrast, many pre-clinical studies utilize other methods of manipulation (i.e. genetic, injection). Given the many actions of vitamin D3 and data supporting a vitamin D-independent role of the Vitamin D receptor (VDR), a more detailed mechanistic understanding of vitamin D3 activity is needed to properly translate pre-clinical findings into the clinic. Therefore, we assessed studies based on route of vitamin D3 administration, and identified where discrepancies in results exist and where more research is needed to establish the benefit of vitamin D supplementation.
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6.
Raising awareness on the therapeutic role of cholecalciferol in CKD: a multidisciplinary-based opinion.
Giannini, S, Mazzaferro, S, Minisola, S, De Nicola, L, Rossini, M, Cozzolino, M
Endocrine. 2018;(2):242-259
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Abstract
Vitamin D is recognized to play an essential role in health and disease. In kidney disease, vitamin D analogs have gained recognition for their involvement and potential therapeutic importance. Nephrologists are aware of the use of oral native vitamin D supplementation, however, uncertainty still exists with regard to the use of this treatment option in chronic kidney disease as well as clinical settings related to chronic kidney disease, where vitamin D supplementation may be an appropriate therapeutic choice. Two consecutive meetings were held in Florence in July and November 2016 comprising six experts in kidney disease (N = 3) and bone mineral metabolism (N = 3) to discuss a range of unresolved issues related to the use of cholecalciferol in chronic kidney disease. The panel focused on the following six key areas where issues relating to the use of oral vitamin D remain controversial: (1) vitamin D and parathyroid hormone levels in the general population, (2) cholecalciferol in chronic kidney disease, (3) vitamin D in cardiovascular disease, (4) vitamin D and renal bone disease, (5) vitamin D in rheumatological diseases affecting the kidney, (6) vitamin D and kidney transplantation.
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Dipeptidyl peptidase-4 inhibitors (DPP-4i) combined with vitamin D3: An exploration to treat new-onset type 1 diabetes mellitus and latent autoimmune diabetes in adults in the future.
Pinheiro, MM, Pinheiro, FMM, Trabachin, ML
International immunopharmacology. 2018;:11-17
Abstract
Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease characterized by destruction of pancreatic beta cells through cell injury caused primarily by cytotoxic T lymphocytes (CD8+). The pathophysiological basis of T1DM seems to be an imbalance between a reduced function of T regulatory lymphocytes and an increased inflammatory activity of Th17 lymphocytes caused by increased production of inflammatory cytokines, as IL-1β, IL-6, IL-17 and IFN-gamma due to environmental factors and genetic predisposition. The preservation of the reserve of beta cells in new-onset T1DM and latent autoimmune diabetes in adults (LADA) by immunomodulation in addition to the incretin effect seems to be possible with an association of DPP-4 inhibitors and vitamin D3. In this review, we discuss the effects of both drugs on the immune system and on beta cell function and their eventual additive effects in preserving the residual function of beta cells in new-onset T1DM and LADA.
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Vitamin D for the management of multiple sclerosis.
Jagannath, VA, Filippini, G, Di Pietrantonj, C, Asokan, GV, Robak, EW, Whamond, L, Robinson, SA
The Cochrane database of systematic reviews. 2018;(9):CD008422
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Abstract
BACKGROUND This review is an update of a previously published review, "Vitamin D for the management of multiple sclerosis" (published in the Cochrane Library; 2010, Issue 12). Multiple sclerosis (MS) is characterised by inflammation, demyelination, axonal or neuronal loss, and astrocytic gliosis in the central nervous system (CNS), which can result in varying levels of disability. Some studies have provided evidence showing an association of MS with low levels of vitamin D and benefit derived from its supplementation. OBJECTIVES To evaluate the benefit and safety of vitamin D supplementation for reducing disease activity in people with MS. SEARCH METHODS We searched the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Specialized Register up to 2 October 2017 through contact with the Information Specialist with search terms relevant to this review. We included references identified from comprehensive electronic database searches and from handsearches of relevant journals and abstract books from conferences. SELECTION CRITERIA We included randomised controlled trials (RCTs) and quasi-RCTs that compared vitamin D versus placebo, routine care, or low doses of vitamin D in patients with MS. Vitamin D was administered as monotherapy or in combination with calcium. Concomitant interventions were allowed if they were used equally in all trial intervention groups. DATA COLLECTION AND ANALYSIS Two review authors independently extracted data and assessed the methodological quality of studies, while another review author sorted any disagreements. We expressed treatment effects as mean differences (MDs) for continuous outcomes (Expanded Disability Status Scale and number of magnetic resonance imaging (MRI) gadolinium-enhancing T1 lesions), as standardised MDs for health-related quality of life, as rate differences for annualised relapse rates, and as risk differences (RDs) for serious adverse events and minor adverse events, together with 95% confidence intervals (CIs). MAIN RESULTS We identified 12 RCTs enrolling 933 participants with MS; 464 were randomised to the vitamin D group, and 469 to the comparator group. Eleven trials tested vitamin D₃, and one trial tested vitamin D₂. Vitamin D₃ had no effect on the annualised relapse rate at 52 weeks' follow-up (rate difference -0.05, 95% CI -0.17 to 0.07; I² = 38%; five trials; 417 participants; very low-quality evidence according to the GRADE instrument); on the Expanded Disability Status Scale at 52 weeks' follow-up (MD -0.25, 95% CI -0.61 to 0.10; I² = 35%; five trials; 221 participants; very low-quality evidence according to GRADE); and on MRI gadolinium-enhancing T1 lesions at 52 weeks' follow-up (MD 0.02, 95% CI -0.45 to 0.48; I² = 12%; two trials; 256 participants; very low-quality evidence according to GRADE). Vitamin D₃ did not increase the risk of serious adverse effects within a range of 26 to 52 weeks' follow-up (RD 0.01, 95% CI -0.03 to 0.04; I² = 35%; eight trials; 621 participants; low-quality evidence according to GRADE) or minor adverse effects within a range of 26 to 96 weeks' follow-up (RD 0.02, 95% CI -0.02 to 0.06; I² = 20%; eight trials; 701 participants; low-quality evidence according to GRADE). Three studies reported health-related quality of life (HRQOL) using different HRQOL scales. One study reported that vitamin D improved ratings on the psychological and social components of the HRQOL scale but had no effects on the physical components. The other two studies found no effect of vitamin D on HRQOL. Two studies reported fatigue using different scales. One study (158 participants) reported that vitamin D₃ reduced fatigue compared with placebo at 26 weeks' follow-up. The other study (71 participants) found no effect on fatigue at 96 weeks' follow-up. Seven studies reported on cytokine levels, four on T-lymphocyte proliferation, and one on matrix metalloproteinase levels, with no consistent pattern of change in these immunological outcomes. The randomised trials included in this review provided no data on time to first treated relapse, number of participants requiring hospitalisation owing to progression of the disease, proportion of participants who remained relapse-free, cognitive function, or psychological symptoms. AUTHORS' CONCLUSIONS To date, very low-quality evidence suggests no benefit of vitamin D for patient-important outcomes among people with MS. Vitamin D appears to have no effect on recurrence of relapse, worsening of disability measured by the Expanded Disability Status Scale (EDSS), and MRI lesions. Effects on health-related quality of life and fatigue are unclear. Vitamin D₃ at the doses and treatment durations used in the included trials appears to be safe, although available data are limited. Seven ongoing studies will likely provide further evidence that can be included in a future update of this review.
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The effect of combined resistance exercise training and vitamin D3 supplementation on musculoskeletal health and function in older adults: a systematic review and meta-analysis.
Antoniak, AE, Greig, CA
BMJ open. 2017;(7):e014619
Abstract
OBJECTIVES In older adults, there is a blunted responsiveness to resistance training and reduced muscle hypertrophy compared with younger adults. There is evidence that both exercise training and vitamin D supplementation may benefit musculoskeletal health in older adults, and it is plausible that in combination their effects may be additive. The aim of this systematic review was to evaluate the effectiveness of combined resistance exercise training and vitamin D3 supplementation on musculoskeletal health in older adults. DATA SOURCES A comprehensive search of electronic databases, including Science Direct, Medline, PubMed, Google Scholar and Cochrane Central Register of Controlled Trials (Cochrane CENTRAL accessed by Wiley Science) was conducted. Eligible studies were randomised controlled trials including men and women (aged ≥65 years or mean age ≥65 years); enlisting resistance exercise training and vitamin D3 supplementation; including outcomes of muscle strength, function, muscle power, body composition, serum vitamin D/calcium status or quality of life comparing results with a control group. The review was informed by a preregistered protocol (http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42015020157). RESULTS Seven studies including a total of 792 participants were identified. Studies were categorised into two groups; group 1 compared vitamin D3 supplementation and exercise training versus exercise alone (describing the additive effect of vitamin D3 supplementation when combined with resistance exercise training) and group 2 compared vitamin D3 supplementation and exercise training versus vitamin D3 supplementation alone (describing the additive effect of resistance exercise training when combined with vitamin D3 supplementation).Meta-analyses for group 1 found muscle strength of the lower limb to be significantly improved within the intervention group (0.98, 95% CI 0.73 to 1.24, p<0.001); all other outcomes showed small but non-significant positive effects for the intervention group. The short physical performance battery (SPPB), timed up and go (TUG), muscle strength of the lower limb and femoral neck bone mineral density showed significantly greater improvements in the intervention group for group 2 comparisons. CONCLUSIONS This review provides tentative support for the additive effect of resistance exercise and vitamin D3 supplementation for the improvement of muscle strength in older adults. For other functional variables, such as SPPB and TUG, no additional benefit beyond exercise was shown. Further evidence is required to draw firm conclusions or make explicit recommendations regarding combined exercise and vitamin D3 supplementation.
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10.
Vitamin D supplementation for sickle cell disease.
Soe, HH, Abas, AB, Than, NN, Ni, H, Singh, J, Said, AR, Osunkwo, I
The Cochrane database of systematic reviews. 2017;(1):CD010858
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Abstract
BACKGROUND Sickle cell disease is a genetic chronic haemolytic and pro-inflammatory disorder. The clinical manifestations of sickle cell disease result from the presence of mutations on the beta globin genes that generate an abnormal haemoglobin product (called haemoglobin S) within the red blood cell. Sickle cell disease can lead to many complications such as acute chest syndrome, stroke, acute and chronic bone complications (including painful vaso-occlusive crisis, osteomyelitis, osteonecrosis and osteoporosis). With increased catabolism and deficits in energy and nutrient intake, individuals with sickle cell disease suffer multiple macro- and micro-nutritional deficiencies, including vitamin D deficiency. Since vitamin D maintains calcium homeostasis and is essential for bone mineralisation, its deficiency may worsen musculoskeletal health problems encountered in sickle cell disease. Therefore, there is a need to review the effects and the safety of vitamin D supplementation in sickle cell disease. OBJECTIVES To investigate the hypothesis that vitamin D supplementation increases serum 25-hydroxyvitamin D level in children and adults with sickle cell disease.To determine the effects of vitamin D supplementation on general health such as growth status and health-related quality of life; on musculoskeletal health including bone mineral density, pain crises, bone fracture and muscle health; on respiratory health which includes lung function tests, acute chest syndrome, acute exacerbation of asthma and respiratory infections; and the safety of vitamin D supplementation in children and adults with sickle cell disease. SEARCH METHODS We searched the Cochrane Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched database such as PubMed, clinical trial registries and the reference lists of relevant articles and reviews.Date of last search: 15 December 2016. SELECTION CRITERIA Randomised controlled studies and quasi-randomised controlled studies (controlled clinical studies) comparing oral administration of any form of vitamin D supplementation to another type of vitamin D or placebo or no supplementation at any dose and for any duration, in people with sickle cell disease, of all ages, gender, and phenotypes including sickle cell anaemia, haemoglobin sickle cell disease and sickle beta-thalassaemia diseases. DATA COLLECTION AND ANALYSIS Two authors independently extracted the data and assessed the risk of bias of the included study. They used the GRADE guidelines to assess the quality of the evidence. MAIN RESULTS One double-blind randomised controlled study including 46 people with sickle cell disease (HbSS, HbSC, HbSβ+thal and HbSβ0thal) was eligible for inclusion in this review. Of the 46 enrolled participants, seven withdrew before randomisation leaving 39 participants who were randomised. Only 25 participants completed the full six months of follow up. Participants were randomised to receive oral vitamin D3 (cholecalciferol) (n = 20) or placebo (n = 19) for six weeks and were followed up to six months. Two participants from the treatment group have missing values of baseline serum 25-hydroxyvitamin D, therefore the number of samples analysed was 37 (vitamin D n = 18, placebo n = 19).The included study had a high risk of bias with regards to incomplete outcome data (high dropout rate in the placebo group), but a low risk of bias for other domains such as random sequence generation, allocation concealment, blinding of participants, personnel and outcome assessors, selective outcome reporting; and an unclear risk of other biases.Compared to the placebo group, the vitamin D group had significantly higher serum 25-hydroxyvitamin D (25(OH)D) levels at eight weeks, mean difference 29.79 (95% confidence interval 26.63 to 32.95); at 16 weeks, mean difference 12.67 (95% confidence interval 10.43 to 14.90); and at 24 weeks, mean difference 15.52 (95% confidence interval 13.50 to 17.54). We determined the quality of the evidence for this outcome to be moderate. There was no significant difference of adverse events (tingling of lips or hands) between the vitamin D and placebo groups, risk ratio 3.16 (95% confidence interval 0.14 to 72.84), but the quality of the evidence was low. Regarding the frequency of pain, the vitamin D group had significantly fewer pain days compared to the placebo group, mean difference -10.00 (95% confidence interval -16.47 to -3.53), but again the quality of the evidence was low. Furthermore, the review included physical functioning PedsQL scores which was reported as absolute change from baseline. The vitamin D group had a lower (worse) health-related quality of life score than the placebo group but this was not significant at eight weeks, mean difference -2.02 (95% confidence interval -6.34 to 2.30). However, the difference was significant at both 16 weeks, mean difference -12.56 (95% confidence interval -16.44 to -8.69) and 24 weeks, mean difference -12.59 (95% confidence interval -17.43 to -7.76). We determined the quality of evidence for this outcome to be low. AUTHORS' CONCLUSIONS We included only one low-quality clinical study which had a high risk of bias with regards to incomplete outcome data. Therefore, we consider that the evidence is not of sufficient quality to guide clinical practice. Until further evidence becomes available, clinicians should consider the relevant existing guidelines for vitamin D supplementation (e.g. the Endocrine Society Clinical Practice Guidelines) and dietary reference intakes for calcium and vitamin D (e.g. from the USA Institute of Medicine). Evidence of vitamin D supplementation in sickle cell disease from high quality studies is needed. Well-designed, randomised, placebo-controlled studies of parallel design, are required to determine the effects and the safety of vitamin D supplementation in children and adults with sickle cell disease.