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Vitamin D and evolution: Pharmacologic implications

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Vitamin D3 is produced non-enzymatically when the cholesterol precursor 7-dehydrocholesterol is exposed to UV-B, i.e., evolutionary the first function of the molecule was that of an UV-B radiation scavenging end product. Vitamin D endocrinology started when some 550 million years ago first species developed a vitamin D receptor (VDR) that binds with high affinity the vitamin D metabolite 1α,25-dihydroxyvitamin D3. VDR evolved from a subfamily of nuclear receptors sensing the levels of cholesterol derivatives, such as bile acids, and controlling metabolic genes supporting cellular processes, such as innate and adaptive immunity. During vertebrate evolution, the skeletal and adaptive immune system showed in part interesting synchronous development although adaptive immunity is evolutionary older. There are bidirectional osteoimmune interactions between the immune system and bone metabolism, the regulation of both is under control of vitamin D. This diversity of physiological functions explains the pleiotropy of vitamin D signaling and opens the potential for various pharmacological applications of vitamin D as well as of its natural and synthetic derivatives. The overall impact of vitamin D on human health is demonstrated by the fact that the need for its efficient synthesis served in European hunter and gatherers as an evolutionary driver for increased 7-dehydrocholesterol levels, while light skin was established far later via populations from Anatolia and the northern Caucasus entering Europe 9000 and 5000 years ago, respectively. The later population settled preferentially in northern Europe and we hypothesize that the introduction of high vitamin D responsiveness was an essential trait for surviving dark winters without suffering from the detrimental consequences of vitamin D deficiency.
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... This reaction is reversible and PreD3 and VitD3 both coexist. From an evolutionary point of view, the observation that VitD3 production is strictly dependent on UVB sheds light on the ancient origin of the hormone, at least 1.2 billion of years ago, when algae began to produce cholesterol [5]. This process has probably developed as a scavenger mechanism to protect from UVB radiation, which is absorbed and dissipated in the rearrangement of double bonds [6]. ...
... This is part of the biochemical pathway first described This reaction is reversible and PreD3 and VitD3 both coexist. From an evolutionary point of view, the observation that VitD3 production is strictly dependent on UVB sheds light on the ancient origin of the hormone, at least 1.2 billion of years ago, when algae began to produce cholesterol [5]. This process has probably developed as a scavenger mechanism to protect from UVB radiation, which is absorbed and dissipated in the rearrangement of double bonds [6]. ...
... Besides the well-known role of vitamin D in calcium and bone metabolism, in the last ten years additional effects have been described, with special regard to the immune system. From an evolutionary point of view, specific investigations and genome-wide association studies demonstrated that the ancient and initial role of vitamin D was likely the regulation of genes involved in energy metabolism [5]. During vertebrate evolution, skeletal and immune systems evolved quite simultaneously and vitamin D was a central driver of the osteo-immune bidirectional interactions [44]. ...
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Vitamin D is a steroid hormone classically involved in the calcium metabolism and bone homeostasis. Recently, new and interesting aspects of vitamin D metabolism has been elucidated, namely the special role of the skin, the metabolic control of liver hydroxylase CYP2R1, the specificity of 1α-hydroxylase in different tissues and cell types and the genomic, non-genomic and epigenomic effects of vitamin D receptor, which will be addressed in the present review. Moreover, in the last decades, several extraskeletal effects which can be attributed to vitamin D have been shown. These beneficial effects will be here summarized, focusing on the immune system and cardiovascular system.
... Vitamin D3 is an essential fat-soluble nutrient involved in a plethora of metabolic pathways [1][2][3][4][5]. When consumed within the dietary reference level limits, vitamin D exerts multiple health benefits [6][7][8]. Apart from food sources, the majority of vitamin D3 is produced non-enzymatically via ultraviolet-B (UVB) exposure of 7-dehydrocholesterol on skin [6,[9][10][11]. Despite the existence of this additional pathway to increase plasma 25-hydroxycholecalciferol (25(OH)D) concentrations, vitamin D deficiency remains an important global challenge [12][13][14] with supplementation being proposed for several conditions including pregnancy [15][16][17][18][19], ageing [20,21], obesity [22][23][24][25], infertility [26,27], skeletal health [28], glycemic control [29] and diabetes [30,31], abnormal lipidemic profile [32], cardiovascular [33,34], autoimmune [35][36][37][38][39] and liver disease [40,41]. ...
... When consumed within the dietary reference level limits, vitamin D exerts multiple health benefits [6][7][8]. Apart from food sources, the majority of vitamin D3 is produced non-enzymatically via ultraviolet-B (UVB) exposure of 7-dehydrocholesterol on skin [6,[9][10][11]. Despite the existence of this additional pathway to increase plasma 25-hydroxycholecalciferol (25(OH)D) concentrations, vitamin D deficiency remains an important global challenge [12][13][14] with supplementation being proposed for several conditions including pregnancy [15][16][17][18][19], ageing [20,21], obesity [22][23][24][25], infertility [26,27], skeletal health [28], glycemic control [29] and diabetes [30,31], abnormal lipidemic profile [32], cardiovascular [33,34], autoimmune [35][36][37][38][39] and liver disease [40,41]. ...
... Two reviewers (M.G.G. and M.P.N.) independently extracted characteristics of the retrieved RCTs and outcomes of interest from full-text articles. Extracted data involved (1) the number of participants at each stage, (2) participant characteristics, (3) study characteristics (registry, design, ethical approval, country, funding), (4) administered dose of vitamin D3 and methods of delivery, (5) intervention duration, (6) washout period (whenever applicable), (7) participant recruitment sites, (8) assays and kits for determining 25(OH)D levels, (9) baseline and post-intervention results (including 25(OH)D, Ca, and parathyroid hormone (PTH) concentrations), (10) recorded adverse events, (11) drop-outs, and (12) analysis performed (intention-to-treat or per protocol). ...
Article
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(1) Background: Vitamin D deficiency is an important public health concern and supplementation is common for this deficiency. Many different modes of delivering supplementation have been proposed in order to enhance absorption and utilization. The present review compared the efficacy of vitamin D3 buccal spray against other forms of supplementation delivery. (2) Methods: The protocol was registered at PROSPERO (CRD42019136146). Medline/PubMed, CENTRAL and clinicaltrials.gov were searched from their inception until September 2019, for randomized controlled trials (RCTs) that compare vitamin D3 delivery via sublingual spray against other delivery methods. Eligible RCTs involved humans, of any age and health status, published in any language that evaluated changes in plasma 25(OH)D concentrations. Three reviewers independently extracted data, assessed risk of bias (RoB) and the quality of the trials. (3) Results: Out of 9759 RCTs, four matched the predefined criteria. Intervention duration ranged from 30 days to 3 months whereas vitamin D3 dosage ranged between 800 and 3000 IU/day. One RCT advocated for the superiority of buccal spray in increasing plasma 25(OH)D concentrations, although several limitations were recorded in that trial. The rest failed to report differences in post-intervention 25(OH)D concentrations between delivery methods. Considerable clinical heterogeneity was observed due to study design, intervention duration and dosage, assays and labs used to perform the assays, population age and health status, not allowing for synthesis of the results. (4) Conclusions: Based on the available evidence, delivery of vitamin D3 via buccal spray does not appear superior to the other modes of delivery. Future RCTs avoiding the existing methodological shortcomings are warranted.
... All rights reserved is now greater appreciation of how the evolution of genetic variants associated with vitamin D metabolism and signaling have evolved in concert with skin pigmentation. As modern populations have dispersed and undergone bottlenecks and admixture, variant genes encoding for proteins responsible for photoconversion of 7-DHC into pre-D (Kuan, Martineau, Griffiths, Hypponen, & Walton, 2013) and governing transport, metabolism and signaling of vitamin D, including DHCR7, GC, CYP2R1 and CYP24A1 (Hanel & Carlberg, 2020a, 2020b, have undergone changes in frequency appeared and become common. Genetic changes affecting vitamin D metabolism rather than skin pigmentation have been particularly important (Hanel & Carlberg, 2020a, 2020b, especially at extreme northern high latitudes where levels of UVB are low and highly seasonal, creating conditions for only short and sporadic cutaneous photosynthesis of vitamin D Jablonski & Chaplin, 2010). ...
... As modern populations have dispersed and undergone bottlenecks and admixture, variant genes encoding for proteins responsible for photoconversion of 7-DHC into pre-D (Kuan, Martineau, Griffiths, Hypponen, & Walton, 2013) and governing transport, metabolism and signaling of vitamin D, including DHCR7, GC, CYP2R1 and CYP24A1 (Hanel & Carlberg, 2020a, 2020b, have undergone changes in frequency appeared and become common. Genetic changes affecting vitamin D metabolism rather than skin pigmentation have been particularly important (Hanel & Carlberg, 2020a, 2020b, especially at extreme northern high latitudes where levels of UVB are low and highly seasonal, creating conditions for only short and sporadic cutaneous photosynthesis of vitamin D Jablonski & Chaplin, 2010). Lastly, the nature of the genetic changes occurring was being mediated by numerous lifestyle variables (including diet, typical body coverings and kinds of shelter, and patterns of daily activity) which affected vitamin D status and would have contributed to individual survival and reproductive success. ...
... The evolutionary trend toward depigmented skin in high-latitude Eurasian populations involved numerous genes affecting skin pigmentation and vitamin D metabolism, and did not result in uniform adaptive strategies across the great expanse of northern Eurasia favoring extreme depigmentation (Hanel & Carlberg, 2020a, 2020b. Rather, what we observe is that skin pigmentation has evolved as part of a larger genetic and cultural package favoring enhanced availability and economical utilization of dietary and cutaneously synthesized vitamin D. ...
Article
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The primary biological role of human skin pigmentation is as a mediator of penetration of ultraviolet radiation (UVR) into the deep layers of skin and the cutaneous circulation. Since the origin of Homo sapiens, dark, protective constitutive pigmentation and strong tanning abilities have been favored under conditions of high UVR, and represent the baseline condition for modern humans. The evolution of partly depigmented skin and variable tanning abilities has occurred multiple times in prehistory, as populations have dispersed into environments with lower and more seasonal UVR regimes, with unique complements of genes and cultural practices. The evolution of extremes of dark pigmentation and depigmentation has been rare and occurred only under conditions of extremely high or low environmental UVR, promoted by positive selection on variant pigmentation genes followed by limited gene flow. Over time, the evolution of human skin pigmentation has been influenced by the nature and course of human dispersals and modifications of cultural practices, which have modified the nature and actions of skin pigmentation genes. Throughout most of prehistory and history, the evolution of human skin pigmentation has been a contingent and non‐deterministic process.
... Antioxidants 2020, 9, 997 2 of 16 a fat-soluble and evolutionally well-conserved in vivo steroid product of almost all creatures on Earth [2]. Vitamin D has skeletal and extraskeletal effects. ...
... Vitamin D makes impact through vitamin D receptor (VDR), which is the member of the nuclear receptor sub-family (NR1H), together with the liver X receptor α and β (LXRα/β), farnesoid X receptor (FXR), pregnane X receptor (PXR), and constitutive androstane receptor (CAR) [2]. The biochemical signal transduction pathway of vitamin D is fairly well-known: activated VDR is bound to the VDR response element (VDRE) site of DNA in cell nucleus and when vitamin D binds to VDR, it heterodimerizes with retinoid X receptor (RXR) and starts to modulate gene transcription. ...
... Alternatively, the reason of this variance is in the possible differences in the estrogen and androgen steroid receptor signal transduction that links to vitamin D physiology? It is known that VDR, PXR, and CAR receptors belong to same nuclear receptor sub-family [2], and estrogen and androgen receptors are also steroid nucleus receptors, and it is possible that there might be some cross-reactions between their ligands and receptors. Another attractive theory is that in the same individual the vitamin D requirement changes during variant life periods and, as a result of illnesses, different metabolic states. ...
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Background: Several reports prove interconnection between vitamin D (VD) deficiency and increased cardiovascular risk. Our aim was to investigate the effects of VD status on biomechanical and oxidative-nitrative (O-N) stress parameters of coronary arterioles in rats. Methods: 4-week-old male Wistar rats were divided into a control group (11 animals) with optimal VD supply (300 IU/kgbw/day) and a VD-deficient group (11 animals, <5 IU/kg/day). After 8 weeks, coronary arteriole segments were prepared. Geometrical, elastic, and biomechanical characteristics were measured by in vitro arteriography. O-N stress markers were investigated by immunohistochemistry. Results: Inner radius decreased; wall thickness and wall-thickness/lumen diameter ratio increased; tangential wall stress and elastic modulus were reduced in VD-deficient group. No difference could be found in wall-cross-sectional area, intima-media area %. While the elastic elements of the vessel wall decreased, the α-smooth muscle actin (α-SMA) immunostaining intensity showed no changes. Significant elevation was found in the lipid peroxidation marker of 4-hidroxy-2-nonenal (HNE), while other O-N stress markers staining intensity (poly(ADP)ribose, 3-nitrotyrosine) did not change. Conclusions: Inward eutrophic remodeling has developed. The potential background of these impairments may involve the initial change in oxidative damage markers (HNE). These mechanisms can contribute to the increased incidence of the cardiovascular diseases in VD deficiency.
... Before regulating the calcium endocrine system, ancient VDR functioned as a xenobiotic receptor mediating the degradation of marine biotoxins 2 . Evolutionary pressures led to the functional repurposing of the receptor with the acquisition of new roles including detoxification of endogeneous compounds, lipid metabolism, immunity and calcium homeostasis [13][14] . In humans, VDR retains the ability to detoxify toxic compounds such as the secondary bile acid, lithocholic acid (LCA) that binds and activate hVDR in the micromolar range 15 . ...
... The jawless fishes whose modern lampreys are descendants were first to diverge after the 1R WGD event and lampreys are considered to be the most basal vertebrates among extant organisms. As revealed by VDR gene repertoire analysis [33][34] , its function has evolved along with more complex animal species from detoxification response in the basal vertebrates to lipid metabolism, immunity and calcium homeostasis in higher vertebrates 14 . ...
... Once produced, vitamin D3 can be released from the epidermal' plasma membranes reaching the circulation system bound to the vitamin D binding protein (VDBP or simply DBP) [19][20][21], a member of the albuminoid superfamily produced in the liver [14,22]. Like albumin, DBP is a constitutive protein, able to transport vitamin D, whether produced in the skin or ingested, to the liver and kidneys [23], where it undergoes two sequential hydroxylation reactions, finally providing the biologically active metabolite. ...
Article
Full-text available
Vitamin D is a fat-soluble steroid hormone playing a pivotal role in calcium and phosphate homeostasis as well as in bone health. Vitamin D levels are not exclusively dependent on food intake. Indeed, the endogenous production—occurring in the skin and dependent on sun exposure—contributes to the majority amount of vitamin D present in the body. Since vitamin D receptors (VDRs) are ubiquitous and drive the expression of hundreds of genes, the interest in vitamin D has tremendously grown and its role in different diseases has been extensively studied. Several investigations indicated that vitamin D action extends far beyond bone health and calcium metabolism, showing broad effects on a variety of critical illnesses, including cancer, infections, cardiovascular and autoimmune diseases. Epidemiological studies indicated that low circulating vitamin D levels inversely correlate with cutaneous manifestations and bone abnormalities, clinical hallmarks of neurofibromatosis type 1 (NF1). NF1 is an autosomal dominant tumour predisposition syndrome causing significant pain and morbidity, for which limited treatment options are available. In this context, vitamin D or its analogues have been used to treat both skin and bone lesions in NF1 patients, alone or combined with other therapeutic agents. Here we provide an overview of vitamin D, its characteristic nutritional properties relevant for health benefits and its role in NF1 disorder. We focus on preclinical and clinical studies that demonstrated the clinical correlation between vitamin D status and NF1 disease, thus providing important insights into disease pathogenesis and new opportunities for targeted therapy.
... There are such diverse functions of vitamin D that it could be potentially beneficial in pharmaceutical applications. [47] Serum variations in the vitamin D status of the individuals could arise because of genetic differences in the vitamin D related enzymes. It could also be varied because of the underlying conditions of the patients especially those suffering with chronic pains. ...
Article
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Background and objective: Despite abundant sunshine, India is a country with high prevalence of vitamin D deficiency. It has been suggested that vitamin D deficiency could be a potential cause of chronic non-specific musculoskeletal pain. The study was conducted to evaluate the effect of supplementation of vitamin D and calcium on patients suffering with chronic non-specific musculoskeletal pain. Methodology: The experimental trial was a pre-post study conducted on 50 hypovitaminosis D patients aged 30-60 years visiting a local orthopedician or physician with complain of chronic non-specific musculoskeletal pain. Oral supplementation with vitamin D and calcium was given for 3 months. Before the intervention trial, pain, physical activity, serum vitamin D, serum calcium, body mass index and waist to hip ratio (WHR) of the respondents were assessed, which was statistically compared with post-intervention data of the same parameters. Assessment of pain was carried out using visual analog scale. Physical activity levels were compared pre and post the intervention. Also, fatigue, mood alteration, and sleep were compared. Results: Ninety percent of the subjects had vitamin D deficiency. Thirty-six percent of the subjects had severe chronic non-specific musculoskeletal pain, whereas 56% had moderate chronic non-specific musculoskeletal pain. The mean pain score prior to intervention was 6.22 which significantly decreased to 3.52. Mean vitamin D levels significantly rose from 17.38 ng/ml to 39.40 ng/ml. Serum vitamin D, serum calcium, and physical activity levels increased, whereas pain, weight, BMI, and WHR decreased significantly post-intervention. Conclusions: Supplementation with vitamin D and calcium decreases chronic non-specific musculoskeletal pain.
... The primary association between vitamin D and immunity is mainly thought to be based on energy metabolism and defense against infections. However, in recent years, vitamin D has been shown to be a multifaceted regulator of the immune system (Hanel and Carlberg, 2020). Vitamin D has been used for the treatment of autoimmune disorders by attenuation of the inflammatory immune response (Dimitrov et al., 2017), and it has also been shown to benefit organ transplant patients by inhibiting autoimmunity (Zhou et al., 2017). ...
Article
Full-text available
Radiotherapy (RT) is a mainstay treatment in several types of cancer and acts by mediating various forms of cancer cell death, although it is still a large challenge to enhance therapy efficacy. Radiation resistance represents the main cause of cancer progression, therefore, overcoming treatment resistance is now the greatest challenge for clinicians. Increasing evidence indicates that immune response plays a role in reprogramming the radiation-induced tumor microenvironment (TME). Intriguingly, radiation-induced immunosuppression possibly overwhelms the ability of immune system to ablate tumor cells. This induces an immune equilibrium, which, we hypothesize, is an opportunity for radiosensitizers to make actions. Vitamin D has been reported to act in synergistic with RT by potentiating antiproliferative effect induced by therapeutics. Additionally, vitamin D can also regulate the TME and may even lead to immunostimulation by blocking immunosuppression following radiation. Previous reviews have focused on vitamin D metabolism and epidemiological trials, however, the synergistic effect of vitamin D and existing therapies remains unknown. This review summarizes vitamin D mediated radiosensitization, radiation immunity, and vitamin D-regulated TME, which may contribute to more successful vitamin D-adjuvant radiotherapy.
... It is a fat-soluble prohormone and a secosteroid produced in the skin after exposure to sunlight. VD deficiency is related to some factors, such as less sunlight exposure, insufficient intake of VD and absorption problems [4,5]. VD deficiency is a common problem all over the world, especially in newborns, the prevention of VD deficiency continues to be the priority of health services [6,7]. ...
Article
Objective: Vitamin D (VD) deficiency is a common problem worldwide, especially in pregnant women and newborns. Regular administration of VD supplements has been recommended worldwide since 2010. Recently, a new formulation providing VD supplementation in the form of a spray which is absorbed through the buccal mucosa has been introduced, but there is very little information in the literature about the effectiveness of it, especially in children. Therefore, in our study, we aim to investigate whether there was a difference in VD levels at one year of age infants who have started oral vitamin D supplements (400 IU/day) as spray or drop form in the neonatal period and have used it regularly during the first year of life. Methods: In our retrospective study, the medical records of 243 healthy infants at one year of age who were followed up regularly in the first year of life in our well-child follow-up clinic were evaluated. The infants who had congenital anomalies, chronic diseases, and those using irregular vitamin D supplements were excluded from this study. Results: The findings showed that the spray form of VD was used in 136 babies (56.0%) in the study group and the drop form was used in 107 (44.0%) of them. VD deficiency (defined as 25 [OH] D level <20 ng/ml) was 33.3% (n=81). VD levels were 24 ng/ml (8-109 ng/ml) and 21 ng/ml (7-65 ng/ml) in the infants using spray and drop form, respectively. The difference between the two forms of VD supplementation regarding 25 (OH) D levels was significant (p=0.010); VD levels were higher in the infants using the spray form. Conclusion: Our study findings suggest that the infants using oral spray form have higher VD levels compared to oral drop form. Concerning VD levels, the spray form may be preferred as a suitable alternative to the drop form, and the spray form may provide regular and easy use in children.
... The functional analysis of the most responsive common vitamin D target genes in PBMCs indicate the regulation of metabolism, cell growth and innate and adaptive immunity as the prominent role of the micronutrient in leukocytes demonstrating that the pleiotropy of vitamin D signaling has an evolutionary origin 56 . Computational pathway analysis additionally highlighted the genes HLA-DRA and HLA-DRB1, which encode for components of the major histocompatibility complex (MHC) II, as common drivers of the functional profile of vitamin D in PBMCs. ...
Article
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Vitamin D is essential for the function of the immune system. In this study, we treated peripheral blood mononuclear cells (PBMCs) of healthy adults with the biologically active form of vitamin D3, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) using two different approaches: single repeats with PBMCs obtained from a cohort of 12 individuals and personalized analysis based on triplicates of five study participants. This identified 877 (cohort approach) and 3951 (personalized approach) genes that significantly (p < 0.05) changed their expression 24 h after 1,25(OH)2D3 stimulation. From these, 333 and 1232 were classified as supertargets, a third of which were identified as novel. Individuals differed largely in their vitamin D response not only by the magnitude of expression change but also by their personal selection of (super)target genes. Functional analysis of the target genes suggested the overarching role of vitamin D in the regulation of metabolism, proliferation and differentiation, but in particular in the control of functions mediated by the innate and adaptive immune system, such as responses to infectious diseases and chronic inflammatory disorders. In conclusion, immune cells are an important target of vitamin D and common genes may serve as biomarkers for personal responses to the micronutrient.
... Once produced, vitamin D 3 can be released from the epidermal' plasma membranes reaching the circulation system bound to the vitamin D binding protein (VDBP or simply DBP) [19][20][21], a member of the albuminoid superfamily produced in the liver [14,22]. Like albumin, DBP is a constitutive protein, able to transport vitamin D, whether produced in the skin or ingested, to the liver and kidneys [23], where it undergoes two sequential hydroxylation reactions, finally providing the biologically active metabolite. ...
Article
Full-text available
Simple Summary: We herein describe the relevance of Vitamin D for human health, with a special focus on its role in Neurofibromatosis type 1 (NF1) disease. Indeed, epidemiological studies revealed that low circulating vitamin D levels inversely correlate with cutaneous manifestations and bone abnormalities, clinical hallmarks of NF1. NF1 is an autosomal dominant syndrome with a severe predisposition in developing tumors and for which limited treatment options are thus far available. In this context, vitamin D or its analogues has been used to treat both skin and bone lesions in NF1 patients, alone or in association with other therapeutic agents. We provide an exhaustive and detailed analysis of the most relevant preclinical and clinical studies aimed at analyzing the correlation between vitamin D deficiency and NF1 lesion progression. This review can add a valuable contribution to the current knowledge of NF1 disease investigating possible therapeutic strategies to ameliorate NF1 conditions. Abstract: Vitamin D is a fat-soluble steroid hormone playing a pivotal role in calcium and phosphate homeostasis as well as in bone health. Vitamin D levels are not exclusively dependent on food intake. Indeed, the endogenous production-occurring in the skin and dependent on sun exposure-contributes to the majority amount of vitamin D present in the body. Since vitamin D receptors (VDRs) are ubiquitous and drive the expression of hundreds of genes, the interest in vitamin D has tremendously grown and its role in different diseases has been extensively studied. Several investigations indicated that vitamin D action extends far beyond bone health and calcium metabolism, showing broad effects on a variety of critical illnesses, including cancer, infections, cardiovascular and autoimmune diseases. Epidemiological studies indicated that low circulating vitamin D levels inversely correlate with cutaneous manifestations and bone abnormalities, clinical hallmarks of neurofibromatosis type 1 (NF1). NF1 is an autosomal dominant tumour predisposition syndrome causing significant pain and morbidity, for which limited treatment options are available. In this context, vitamin D or its analogues have been used to treat both skin and bone lesions in NF1 patients, alone or combined with other therapeutic agents. Here we provide an overview of vitamin D, its characteristic nutritional properties relevant for health benefits and its role in NF1 disorder. We focus on preclinical and clinical studies that demonstrated the clinical correlation between vitamin D status and NF1 disease, thus providing important insights into disease pathogenesis and new opportunities for targeted therapy.
... This indicates that VDR and its five relatives have a common ancestor and that the individual receptor genes developed by whole genome duplications in early vertebrate evolution [28]. Interestingly, the six NRs function as sensors for cholesterol derivatives, such as 1,25(OH) 2 D 3 , oxysterols and bile acids [29]. Moreover, FXR, VDR, CAR and PXR detect toxic secondary bile acids, such as lithocholic acid, and get activated by them [30][31][32][33]. ...
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For at least 1.2 billion years, eukaryotes have been able to synthesize sterols and, therefore, can produce vitamin D when exposed to UV-B. Vitamin D endocrinology was established some 550 million years ago in animals, when the high-affinity nuclear receptor VDR (vitamin D receptor), transport proteins and enzymes for vitamin D metabolism evolved. This enabled vitamin D to regulate, via its target genes, physiological process, the first of which were detoxification and energy metabolism. In this way, vitamin D was enabled to modulate the energy-consuming processes of the innate immune system in its fight against microbes. In the evolving adaptive immune system, vitamin D started to act as a negative regulator of growth, which prevents overboarding reactions of T cells in the context of autoimmune diseases. When, some 400 million years ago, species left the ocean and were exposed to gravitation, vitamin D endocrinology took over the additional role as a major regulator of calcium homeostasis, being important for a stable skeleton. Homo sapiens evolved approximately 300,000 years ago in East Africa and had adapted vitamin D endocrinology to the intensive exposure of the equatorial sun. However, when some 75,000 years ago, when anatomically modern humans started to populate all continents, they also reached regions with seasonally low or no UV-B, i.e., and under these conditions vitamin D became a vitamin.
... In the United States and other countries, the historical strategy of supplementing infants with at least 200 IU (5 μg) of vitamin D per day has successfully reduced the incidence of rickets disease; however, today, the disease is not uncommon [5][6][7][8] . The first evolutionary function of VDR is to control metabolism to strongly support the evolution of the immune system of ancestral vertebrates 9 . Therefore, VDR and its ligands are the first specialised structure to resist bacterial and viral infections and multiple sclerosis [10][11] . ...
Article
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Vitamin D deficiency is associated with an increased risk of many adverse health effects. Vitamin D plays an important role in immunity and its classic effects on calcium and bone homeostasis. Enzymes that metabolize vitamin D and vitamin D receptor (VDR) are present in many cell types, including various immune cells such as antigen presenting cells, T cells, B cells, and monocytes. Vitamin D has the ability to play an autocrine role in the local immune environment. Vitamin D can regulate innate and adaptive immune responses. Vitamin D deficiency is related to decreased autoimmunity and increased susceptibility to infection. The beneficial effects of vitamin D supplementation on individuals lacking autoimmune diseases may exceed its effects on calcium and bone homeostasis. The main concern of the Unani medical system is human health, and its maintenance is the main function of Tabiat (immunity). Tabiat plays role in different stages of disease. If it exceeds time, the disease process will develop. Unani physician offers a variety of natural therapies, and regiminal therapy is one of them. The main purpose of this review article is to explore this ancient holistic pathy and establish a connection with modern theory.
... Phosphorus and vitamin D are intimately related, so that hyperphosphatemia and vitamin D has been associated with tumorigenesis, and reduced phosphorus content and availability in tropical and subtropical soil with reduced cancer risk [118]. Tumuli's and Ignatavicius [119] Page: 68 www.raftpubs.com next reorganization. ...
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The leading cause of illness in aging is a group known as Noncommunicable Diseases. There should be some meeting points that modify the cells homeostasis and impaired the cell physiology developing different diseases. Quantum physics studied the atomic and subatomic particles and revolutionized the reality perception with paradoxical and weird concepts. Heisenberg's uncertainty principle established that it is not possible to determine the two characteristic properties of particles with accuracy. Subatomic particles have a wave-particle duality. Two subatomic particles are entangled, something happening over here can have an instantaneous effect over there, no matter how far away there are. All these concepts have tried to apply to biology and life sciences, quantum biology is behind photosynthesis, mitochondrial respiration, enzyme activity, the sense of smell, animal migration, heredity's fidelity, and consciousness. We can apply all these concepts to diseases pathogeny. So, we describe quantum phenomena in oxidative stress, calcification, signal transduction, vitamin D production and cancer mutations. Aging diseases also could be explained by applying quantum physics concepts. It is a new, hard to believe, and an incredible path to be built, but we need to open the treatment options to our patients with new perspectives. Keywords: Oxidative stress; Calcification; Signal transduction; Vitamin D; Cancer mutations; Quantum phenomena
... The long-term knowledge of the association of vitamin D deficiency with rickets in children and osteomalacia in adults led to the consideration of calcium and phosphate metabolism and bone biology as the main roles of vitamin D in humans. However, during evolution, VDR was probably involved first in energy metabolism and defense against infections, and 1,25(OH) 2 D 3 is today considered an important multifaceted regulator of the immune system [7]. ...
Article
Full-text available
Vitamin D3 is the precursor of 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), a pleiotropic hormone that is a major regulator of the human genome. 1,25(OH)2D3 modulates the phenotype and physiology of many cell types by controlling the expression of hundreds of genes in a tissue- and cell-specific fashion. Vitamin D deficiency is common among cancer patients and numerous studies have reported that 1,25(OH)2D3 promotes the differentiation of a wide panel of cultured carcinoma cells, frequently associated with a reduction in cell proliferation and survival. A major mechanism of this action is inhibition of the epithelial–mesenchymal transition, which in turn is largely based on antagonism of the Wnt/β-catenin, TGF-β and EGF signaling pathways. In addition, 1,25(OH)2D3 controls the gene expression profile and phenotype of cancer-associated fibroblasts (CAFs), which are important players in the tumorigenic process. Moreover, recent data suggest a regulatory role of 1,25(OH)2D3 in the biology of normal and cancer stem cells (CSCs). Here, we revise the current knowledge of the molecular and genetic basis of the regulation by 1,25(OH)2D3 of the differentiation and stemness of human carcinoma cells, CAFs and CSCs. These effects support a homeostatic non-cytotoxic anticancer action of 1,25(OH)2D3 based on reprogramming of the phenotype of several cell types.
... Thus, rather than bone metabolism, the prime function of vitamin D was the regulation of energy metabolism 40 . Since the immune system requires substantial amounts of energy 41 , vitamin D and its receptor obtained via the control of immunometabolism a modulatory impact on immunity 42 . ...
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Homo sapiens evolved in East Africa and had dark skin, hair and eyes, in order to protect against deleterious consequences of intensive UV radiation at equatorial latitudes. Intensive skin pigmentation was thought to bear the risk of inefficient vitamin D3 synthesis in the skin. This initiated the hypothesis that within the past 75,000 years, in which humans migrated to higher latitudes in Asia and Europe, the need for vitamin D3 synthesis served as an evolutionary driver for skin lightening. In this review, we summarize the recent archeogenomic reconstruction of population admixture in Europe and demonstrate that skin lightening happened as late as 5000 years ago through immigration of lighter pigmented populations from western Anatolia and the Russian steppe but not primarily via evolutionary pressure for vitamin D3 synthesis. We show that variations in genes encoding for proteins being responsible for the transport, metabolism and signaling of vitamin D provide alternative mechanisms of adaptation to a life in northern latitudes without suffering from consequences of vitamin D deficiency. This includes hypotheses explaining differences in the vitamin D status and response index of European populations.
... The high-affinity 1,25(OH)2D3-binding VDR protein evolved already some 550 million years ago in a boneless vertebrate [40]. The initial function of VDR was most likely the regulation of energy metabolism [41]. The fact that the innate immune system and the developing adaptive J o u r n a l P r e -p r o o f immunity require substantial amounts of energy [42] seem to have served as a starting point how vitamin D and its receptor got via the control of immunometabolism a modulatory impact on immunity [43]. ...
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A low vitamin D status is associated with an increased risk of various cancers, such as of colon, breast, prostate and hematological cells. The biologically most active vitamin D metabolite 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) is a high affinity ligand of the transcription factor vitamin D receptor (VDR). 1,25(OH)2D3 induces via VDR changes to the epigenome of healthy and neoplastic cells and in this way influences their transcriptome. Ligand-activated VDR binds to more than 10,000 loci within the human genome and affects the transcription of some 1000 target genes in a large proportion of human tissues and cell types. From the evolutionary perspective, the prime role of vitamin D was probably the control of energy metabolism later shifting to modulate innate and adaptive immunity as well as to regulate calcium and bone homeostasis. Since rapidly growing immune and cancer cells both use the same pathways and genes for controlling their proliferation, differentiation and apoptosis, not surprisingly, vitamin D signaling changes these processes also in neoplastic cells. Thus, anti-cancer effects of vitamin D may derive from managing growth and differentiation in immunity. This review provides an update on the molecular basis of vitamin D signaling, i.e., the effects of 1,25(OH)2D3 on the epigenome and transcriptome, and its relationship to cancer prevention and therapy.
... Full 1,25(OH) 2 D 3 -sensitive VDR evolved first some 550 million years ago in a boneless fish [120,121]. In analogy to the evolutionary history of related nuclear receptors [122,123], the prime function of vitamin D and its receptor VDR is assumed to be the control of energy homeostasis. ...
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Fanconi anemia (FA) is a rare disorder with the clinical characteristics of (i) specific malformations at birth, (ii) progressive bone marrow failure already during early childhood and (iii) dramatically increased risk of developing cancer in early age, such as acute myeloid leukemia and squamous cell carcinoma. Patients with FA show DNA fragility due to a defect in the DNA repair machinery based on predominately recessive mutations in 23 genes. Interestingly, patients originating from the same family and sharing an identical mutation, frequently show significant differences in their clinical presentation. This implies that epigenetics plays an important role in the manifestation of the disease. The biologically active form of vitamin D, 1α,25-dihydroxyvitamin D3 controls cellular growth, differentiation and apoptosis via the modulation of the immune system. The nuclear hormone activates the transcription factor vitamin D receptor that affects, via fine-tuning of the epigenome, the transcription of >1000 human genes. In this review, we discuss that changes in the epigenome, in particular in immune cells, may be central for the clinical manifestation of FA. These epigenetic changes can be modulated by vitamin D suggesting that the individual FA patient’s vitamin D status and responsiveness are of critical importance for disease progression.
... Interestingly, a fully potent VDR protein evolved some 550 million years ago in a boneless vertebrate, i.e., at a time when there was no need for calcium homeostasis and bone formation [6][7][8]. VDR's first evolutionary function was the control of metabolism, in order to support the evolving immune system of ancestral vertebrates with energy [9]. Thus, VDR and its ligand first specialized in the modulation of innate and adaptive immunity, such as fighting against bacterial and viral infections [10,11] and preventing autoimmune diseases, such as multiple sclerosis and rheumatoid arthritis [12,13], before they took on the additional task of regulating bone metabolism. ...
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The biologically active form of vitamin D3 , 1α,25-dihydroxyvitamin D 3 (1,25(OH)2 D3), modulates innate and adaptive immunity via genes regulated by the transcription factor vitamin D receptor (VDR). In order to identify the key vitamin D target genes involved in these processes, transcriptome-wide datasets were compared, which were obtained from a human monocytic cell line (THP-1) and peripheral blood mononuclear cells (PBMCs) treated in vitro by 1,25(OH)2 D3 , filtered using different approaches, as well as from PBMCs of individuals supplemented with a vitamin D3 bolus. The led to the genes ACVRL1, CAMP, CD14, CD93, CEBPB, FN1, MAPK13, NINJ1, LILRB4, LRRC25, SEMA6B, SRGN, THBD, THEMIS2 and TREM1. Public epigenome-and transcriptome-wide data from THP-1 cells were used to characterize these genes based on the level of their VDR-driven enhancers as well as the level of the dynamics of their mRNA production. Both types of datasets allowed the categorization of the vitamin D target genes into three groups according to their role in (i) acute response to infection, (ii) infection in general and (iii) autoimmunity. In conclusion, 15 genes were identified as major mediators of the action of vitamin D in innate and adaptive immunity and their individual functions are explained based on different gene regulatory scenarios.
... Interestingly, the nuclear receptor for vitamin D, VDR, evolved some 550 million years ago in a boneless fish, i.e. even before vertebrates developed a stable skeleton for locomotion (Whitfield et al. 2003, Bouillon & Suda 2014. Thus, in analogy to other members of the nuclear receptor superfamily, VDR's evolutionary oldest function was the control of energy metabolism, supporting the evolving immune system of ancestral vertebrates (Hanel & Carlberg 2019). Vitamin D supports the immune system in its fight against infections, such as tuberculosis (Chun et al. 2014), and in parallel prevents autoimmune disorders, such as multiple sclerosis (Lu et al. 2019). ...
Article
The transcription factor vitamin D receptor (VDR) is the exclusive nuclear target of the biologically active form of vitamin D (1,25(OH)2D3). In THP-1 human monocytes we obtained a highly accurate VDR cistrome after 2 and 24 h ligand stimulation comprising more than 11,600 genomic loci, 78% of which were detected exclusively after 24 h. In contrast, a group of 510 persistent VDR sites occurred at all conditions and some 2,100 VDR loci were only transiently occupied. Machine learning and statistical analysis as well as a comparison with the re-analyzed B cell VDR cistrome indicated a subgroup of 339 highly conserved persistent VDR sites that were suited best for describing vitamin D-triggered gene regulatory scenarios. The 1,25(OH)2D3-dependent transcriptome of THP-1 cells comprised 587 genes, 311 of which were primary targets with main functions in the immune system. More than 97% of the latter genes were located within 1,25(OH)2D3-modulated topologically associated domains (TADs). The number of persistent and transient VDR sites was found to be the main discriminator for sorting these TADs into five classes carrying vitamin D target genes involved in distinct biological processes. In conclusion, specific regulation of biological processes by vitamin D depends on differences in time-dependent VDR binding.
... Immune and bone systems are linked at multiple levels and give rise to the concept of osteoimmunity. Bone marrow is basically the origin of all immune cells including B, T, neutrophils, and macrophages [106]. Hence, the low levels of deficiency of vitamin D have been associated with immune suppression and initiation of many diseases. ...
Article
Introduction: Global emergence of coronavirus disease-19 (COVID-19) has clearly shown variable severity, mortality, and frequency between and within populations worldwide. These striking differences have made many biological variables attractive for future investigations. One of these variables, vitamin D, has been implicated in COVID-19 with rapidly growing scientific evidence. Areas covered: The review intended to systematically explore the sources, and immunomodulatory role of vitamin D in COVID-19. Search engines and data sources including Google Scholar, PubMed, NCBI, Scopus, and Web of Science were used for data collection. The search terms used were Vitamin D, COVID-19, immune system, and antiviral mechanism. Overall, 232 sources of information were collected and 188 were included in this review. Expert opinion: Interaction of vitamin D and vitamin D receptor (VDR) triggers the cellular events to modulate the immune system by regulation of many genes. Vitamin D operates as a double-edged sword against COVID-19. First, in macrophages, it promotes the production of antimicrobial and antiviral proteins like β-defensin 2 and cathelicidin, and these proteins inhibit the replication of viral particles and promote the clearance of virus from the cells by autophagy. Second, it suppresses cytokine storm and inflammatory processes in COVID-19.
... Immune and bone systems are linked at multiple levels and give rise to the concept of osteoimmunity. Bone marrow is basically the origin of all immune cells including B, T, neutrophils, and macrophages [106]. Hence, the low levels of deficiency of vitamin D have been associated with immune suppression and initiation of many diseases. ...
Article
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Abstract Introduction: Global emergence of coronavirus disease-19 (COVID-19) has clearly shown variable severity, mortality, and frequency between and within populations worldwide. These striking differences have made many biological variables attractive for future investigations. One of these variables, vitamin D, has been implicated in COVID-19 with rapidly growing scientific evidence. Areas covered: The review intended to systematically explore the sources, and immunomodulatory the role of vitamin D in COVID-19. Search engines and data sources including Google Scholar, PubMed, NCBI, Scopus, and Web of Science were used for data collection. The search terms used were Vitamin D, COVID-19, immune system, antiviral mechanism. Overall, 232 sources of information were collected and 188 were included in this review. Expert opinion: Interaction of vitamin D and vitamin D receptor (VDR), triggers the cellular events to modulate the immune system by regulation of many genes. Vitamin D operates as a double-edged sword against COVID-19. First, in macrophages, it promotes the production of antimicrobial and antiviral proteins like β-defensin 2 and cathelicidin, these proteins inhibit the replication of viral particles and promote the clearance of virus from the cells by autophagy. Second, suppresses cytokine storm and inflammatory processes in COVID-19. Keywords: COVID-19; Vitamin D; immune system; mechanism of action; photosynthesis.
... A.R. Webb et al. indicated that the vitamin D requirements in the human body are mostly met through skin exposure to sunlight [21]. However, an obvious seasonal cycle of serum 25(OH)D concentrations was observed in populations at mid-high latitudes [74][75][76]. A.R. Webb et al. also reported that the average concentration VOLUME XX, 2017 1 was lowest in February and highest in September [77]. The UVB irradiance reaching the surface of the Earth is also related to latitude. ...
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Objectives: Fine particulate matter (PM2.5) is the principal air pollutant and poses a serious threat to public health. This study explored the effects of PM2.5 on the action spectrum of ultraviolet radiation for vitamin D production (UVvitD) received by manikin surfaces. Methods: Multi-inclination angle ultraviolet radiation monitoring was conducted with different concentrations of PM2.5. Combining monitoring data with the PM2.5 concentration, solar elevation angle (SEA), and inclination angle, a UVvitD exposure model for human body multi-inclined surfaces was constructed through a multiple linear regression analysis. A 3D manikin model was used to examine the PM2.5 effects on UVvitD received by the manikin surface. Results: When PM2.5 concentrations ranged from 35 μg/m3 to 100 μg/m3 (average concentration of PM2.5 in this range: 62 μg/m3), the UVvitD received by the whole body was reduced by approximately 8.45% to 19.82% compared with the UVvitD received when PM2.5 concentrations ranged from 6 μg/m3 to 35 μg/m3 (average concentration of PM2.5 in this range: 17 μg/m3) with SEAs between 30° and 50°. Moreover, the UVvitD dose was reduced by 11.82% in the above comparisons. When further comparing PM2.5 concentrations from 100 μg/m3 to 161 μg/m3 (average concentration of PM2.5 in this range: 132 μg/m3) with those from 6 μg/m3 to 35 μg/m3 (average concentration of PM2.5 in this range: 17 μg/m3), the UVvitD received by the whole body was reduced by approximately 21.6% to 50.64% at SEAs between 30° and 50°. The UVvitD dose was reduced by 30.2%. Conclusions: The occurrence of PM2.5 obviously reduced the UVvitD received by the manikin surface.
... Interestingly, the UVB fraction of sunlight is also required for skin formation of vitamin D, and the skin cells also possess fully functional enzymatic machinery to convert vitamin D to its active metabolite-calcitriol [25,[132][133][134]. The skin cells (keratinocytes) also express vitamin D receptor (VDR), and the skin is a very important target for vitamin D metabolite activity [135]. Alternative nuclear receptors for vitamin D metabolites have recently been reported to be expressed in the skin. ...
Article
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Psoriasis is a chronic inflammatory skin disease with systemic manifestation, in which psychological factors play an important role. The etiology of psoriasis is complex and multifactorial, including genetic background and environmental factors such as emotional or physical stress. Psychological stress may also play a role in exacerbation of psoriasis, by dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, sympathetic–adrenal–medullary axis, peripheral nervous system, and immune system. Skin cells also express various neuropeptides and hormones in response to stress, including the fully functional analog of the HPA axis. The deterioration of psoriatic lesions is accompanied by increased production of inflammatory mediators, which could contribute to the imbalance of neurotransmitters and the development of symptoms of depression and anxiety. Therefore, deregulation of the crosstalk between endocrine, paracrine, and autocrine stress signaling pathways contributes to clinical manifestations of psoriasis, which requires multidisciplinary approaches.
... Vitamin D deficiency (VDD) is known as a major health issue and affects the normal functions of many organs (1). It is believed that the effect of VDD is more profound in organs in which vitamin D metabolizing enzymes and vitamin D receptors (VDRs) are present (2,3). Given the presence of VDRs as well as its metabolizing enzymes in male and female reproductive systems, VDD is also likely to affect human fertility (4). ...
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Background: Today, vitamin D deficiency (VDD) is one of the major health issues around the world and VDD is associated with several diseases. This study was conducted to find the relationship between vitamin D status in male's serum with sperm function and clinical outcomes in infertile men candidate for intracytoplasmic sperm injection (ICSI). Materials and methods: In this cohort study, different parameters of male fertility such as sperm parameters, oxidative stress, and sperm chromatin status were evaluated in sperm samples of 30 infertile couples candidate for ICSI. Clinical outcomes like fertilization, embryo quality, and implantation were also assessed. Data were analyzed using SPSS Statistics 25.0 software. Besides, assessment of the correlation between aforementioned parameters with the level of serum vitamin D, in this study, ICSI candidates were divided into three groups [individuals with sufficient vitamin D levels (>30 ng/ml), insufficient vitamin D levels (between 20-29 ng/ml), and VDD (<20 ng/ml)]. The aforementioned parametesr were also compared between these study groups. Results: Analysis of all the data revealed a significant correlation between the level of vitamin D with sperm concentration (P=0.000, r=0.5), sperm count (P=0.03, r=0.31) and sperm reactive oxygen species (ROS) level (P=0.000, r=-0.77). Moreover, comparing clinical outcomes within study groups showed a significant difference in implantation rate between sufficient and other groups (insufficient and deficient) (P=0.02). Conclusion: Considering the association between sperm concentration and level of ROS with vitamin D and, higher implantation rate in individuals with vitamin D sufficient group compared to other two groups, our data call for vitamin D supplementation as part of male infertility treatment. But considering our sample size, further research is needed to verify these findings.
... Vitamin D 3 (cholecalciferol) is produced in the skin when 7-dehydrocholesterol is exposed to solar ultraviolet radiation. In the liver cholecalciferol is converted into calcifediol (25-OH-cholecalciferol or 25(OH)D 3 ) and in the kidneys into calcitriol (1,25(OH) 2 -cholecalciferol or 1α,25-dihydroxyvitamin D 3 or 1,25(OH) 2 D 3 ) which is the high-affinity ligand to the nuclear receptor vitamin D receptor (VDR) [10,11]. The active form of vitamin D 3 , 1,25(OH) 2 D 3 , is endowed with anti-inflammatory and immunomodulatory properties. ...
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Background Glaucoma is an optic neuropathy characterized by loss of function and death of retinal ganglion cells (RGCs), leading to irreversible vision loss. Neuroinflammation is recognized as one of the causes of glaucoma, and currently no treatment is addressing this mechanism. We aimed to investigate the anti-inflammatory and neuroprotective effects of 1,25(OH) 2 D 3 (1α,25-dihydroxyvitamin D 3 , calcitriol), in a genetic model of age-related glaucomatous neurodegeneration (DBA/2J mice). Methods DBA/2J mice were randomized to 1,25(OH) 2 D 3 or vehicle treatment groups. Pattern electroretinogram, flash electroretinogram, and intraocular pressure were recorded weekly. Immunostaining for RBPMS, Iba-1, and GFAP was carried out on retinal flat mounts to assess retinal ganglion cell density and quantify microglial and astrocyte activation, respectively. Molecular biology analyses were carried out to evaluate retinal expression of pro-inflammatory cytokines, pNFκB-p65, and neuroprotective factors. Investigators that analysed the data were blind to experimental groups, which were unveiled after graph design and statistical analysis, that were carried out with GraphPad Prism. Several statistical tests and approaches were used: the generalized estimated equations (GEE) analysis, t -test, and one-way ANOVA. Results DBA/2J mice treated with 1,25(OH) 2 D 3 for 5 weeks showed improved PERG and FERG amplitudes and reduced RGCs death, compared to vehicle-treated age-matched controls. 1,25(OH) 2 D 3 treatment decreased microglial and astrocyte activation, as well as expression of inflammatory cytokines and pNF-κB-p65 ( p < 0.05). Moreover, 1,25(OH) 2 D 3 -treated DBA/2J mice displayed increased mRNA levels of neuroprotective factors ( p < 0.05), such as BDNF. Conclusions 1,25(OH) 2 D 3 protected RGCs preserving retinal function, reducing inflammatory cytokines, and increasing expression of neuroprotective factors. Therefore, 1,25(OH) 2 D 3 could attenuate the retinal damage in glaucomatous patients and warrants further clinical evaluation for the treatment of optic neuropathies.
... A weakness is the lack of data on melanized skin types because photobiological responses are affected by skin type (48)(49)(50)(51). The quantitative impact of melanin on vitamin D synthesis remains controversial with recent studies casting doubt on the need for vitamin D as a driver for the evolution of light skin with Homo sapiens' migration from Africa (52,53). The results from this study only apply to FST I/II, and it will be important to assess the effect of skin melanin on the action spectrum for 25(OH)D 3 . ...
Article
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Action spectra are important biological weighting functions for risk/benefit analyses of ultraviolet (UV) radiation (UVR) exposure. One important human benefit of exposure to terrestrial solar UVB radiation (∼295 to 315 nm) is the cutaneous synthesis of vitamin D 3 that is initiated by the photoconversion of 7-dehydrocholesterol to previtamin D 3 . An action spectrum for this process that is followed by other nonphotochemical steps to achieve biologically active vitamin D 3 has been established from ex vivo data and is widely used, although its validity has been questioned. We tested this action spectrum in vivo by full- or partial-body suberythemal irradiation of 75 healthy young volunteers with five different polychromatic UVR spectra on five serial occasions. Serum 25-hydroxyvitamin D 3 [25(OH)D 3 ] levels, as the most accurate measure of vitamin D 3 status, were assessed before, during, and after the exposures. These were then used to generate linear dose–response curves that were different for each UVR spectrum. It was established that the previtamin D 3 action spectrum was not valid when related to the serum 25(OH)D 3 levels, as weighting the UVR doses with this action spectrum did not result in a common regression line unless it was adjusted by a blue shift, with 5 nm giving the best fit. Such a blue shift is in accord with the published in vitro action spectra for vitamin D 3 synthesis. Thus, calculations regarding the risk (typically erythema) versus the benefit of exposure to solar UVR based on the ex vivo previtamin D 3 action spectrum require revision.
... VDR evolves from a nuclear receptor subfamily, and it can sense the level of sterol derivatives and control metabolic genes that support cellular processes, such as innate immunity and adaptive immunity (Hanel and Carlberg 2020). In the present study, we identified a functional VDR in Pacific abalone with the phylogenetic tree analysis, which showed that the cloned sequence was clustered with the confirmed VDR of gastropod. ...
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Vitamin D3 is believed to be a contributing factor to innate immunity. Vitamin D receptor (VDR) has a positive effect on inhibiting nuclear factor κB (NF-κB)-mediated inflammation. The underlying molecular mechanisms remain unclear, particularly in mollusks. Consequently, this study will investigate the process of vitamin D3/VDR regulating NF-κB pathway and further explore their functions on inflammation, autophagy, and apoptosis in abalone Haliotis discus hannai. Results showed that knockdown of VDR by using siRNA and dsRNA of VDR in vitro and in vivo led to more intense response of NF-κB signaling to lipopolysaccharide and higher level of apoptosis and autophagy. In addition, 1,25(OH)2D3 stimulation after VDR silencing could partially alleviate apoptosis and induce autophagy. Overexpression of VDR restricted the K48-polyubiquitin chain-dependent inhibitor of κB (IκB) ubiquitination and apoptosis-associated speck-like protein containing CARD (ASC) oligomerization. Besides, VDR silencing resulted in increase of ASC speck formation. In further mechanistic studies, we showed that VDR can directly bind to IκB and IKK1 in vitro and in vivo. In the feeding trial, H&E staining, TUNEL, and electron microscope results showed that vitamin D3 deficiency (0 IU/kg) could recruit more basophilic cells and increase more TUNEL-positive apoptotic cells and lipid droplets (LDs) than vitamin D3 supplement (1000 IU/kg and 5000 IU/kg). In summary, abalone VDR plays a negative regulator role in NF-κB-mediated inflammation via interacting with IκB and inhibiting ubiquitin-dependent degradation of IκB. Vitamin D3 in combination with VDR is essential to establish a delicate balance between autophagy and apoptosis in response to inflammation.
... VDR is a nuclear transcription factor that regulates bone metabolism and the inflammatory process by binding with specific ligands (31,32), such as steroid hormone 1alpha,25(OH)2-vitamin D3 (1,25(OH)2-D3) (33,34). VDR gene polymorphsim confers increased risk of AS in Chinese Han population (35,36). ...
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Dysregulated microRNAs (miRNAs or miRs) serve potential roles in inflammatory systemic disease, including ankylosing spondylitis (AS). The aim of the present study was to investigate the potential function of miR-150-5p in osteogenic differentiation of AS fibroblasts and its underlying mechanism. The expression of miR-150-5p and vitamin D receptor (VDR) in AS joint capsules and fibroblasts was detected by reverse transcription-quantitative (RT-q)PCR and western blotting. Following overexpression of miR-150-5p, the alteration in osteogenic gene expression was detected by RT-qPCR, western blotting and alkaline phosphatase activity assay, as well as alizarin red staining. The association between miR-150-5p and VDR was confirmed by luciferase assay and rescue experiments were performed. Patients with AS exhibited decreased expression of miR-150-5p in joint capsules. Treatment with bone morphogenic protein 2 (BMP-2) and transforming growth factor-β1 (TGF-β1) led to downregulation of miR-150-5p in AS fibroblasts. Enforced expression of miR-150-5p attenuated osteogenic differentiation of AS fibroblasts. These results demonstrated that miR-150-5p inhibited osteogenic differentiation of AS fibroblasts by targeting VDR. miR-150-5p overexpression decreased osteogenic transformation of fibroblasts by decreasing VDR expression in AS.
... Its target receptors, i.e., vitamin D receptors (VDRs), are expressed in almost all human tissues [4]. In general, vitamin D can exert endocrine, paracrine, and autocrine effects as part of a complex regulation and interactions of vitamin D metabolism [4,5]. ...
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As a consequence of epidemiological studies showing significant associations of vitamin D deficiency with a variety of adverse extra-skeletal clinical outcomes including cardiovascular diseases, cancer, and mortality, large vitamin D randomized controlled trials (RCTs) have been designed and conducted over the last few years. The vast majority of these trials did not restrict their study populations to individuals with vitamin D deficiency, and some even allowed moderate vitamin D supplementation in the placebo groups. In these RCTs, there were no significant effects on the primary outcomes, including cancer, cardiovascular events, and mortality, but explorative outcome analyses and meta-analyses revealed indications for potential benefits such as reductions in cancer mortality or acute respiratory infections. Importantly, data from RCTs with relatively high doses of vitamin D supplementation did, by the vast majority, not show significant safety issues, except for trials in critically or severely ill patients or in those using very high intermittent vitamin D doses. The recent large vitamin D RCTs did not challenge the beneficial effects of vitamin D regarding rickets and osteomalacia, that therefore continue to provide the scientific basis for nutritional vitamin D guidelines and recommendations. There remains a great need to evaluate the effects of vitamin D treatment in populations with vitamin D deficiency or certain characteristics suggesting a high sensitivity to treatment. Outcomes and limitations of recently published large vitamin D RCTs must inform the design of future vitamin D or nutrition trials that should use more personalized approaches.
Article
Background Type 1 diabetes (T1D) is accompanied by numerous side effects, including renal dysfunction. Mounting evidence suggests that overactivation of nuclear factor ĸB (NF-κB) is one of the key triggers of diabetes-associated chronic kidney disease. Vitamin D3 is considered as a strong modulator of a number of transcription factors, including NF-κB. The purpose of our study was to assess the contribution of NF-κB to type 1 diabetes (T1D)-induced kidney dysfunction and to determine if vitamin D3 supplementation can correct the changes associated with T1D. Methods The following animal groups were used: control, diabetic (induced by single i.p. injection of streptozocin at dose 55 mg/kg b.w.), T1D group treated with vitamin D3 (600 IU/kg b.w.), T1D group treated with NF-κB inhibitor – BAY 11–7082. Results Diabetes led to a decrease in serum 25(OH)D that was accompanied by down-regulation of vitamin D receptor (VDR) expression and up-regulation of hydroxylases CYP24A1 and CYP27B1 synthesis in the kidneys. Diabetes activated the transcription factor NF-κB and increased cleaved (p17) caspase-3 level in renal tissue. Restoration of vitamin D status normalized vitamin D-endocrine system, decreased NF-κB activation and caspase-3 protein level in the kidneys of diabetic animals. BAY 11–7082 partially mimicked the effects of vitamin D3. General significance Vitamin D3 supplementation counteracts diabetes-induced kidney damage, most likely through VDR-mediated inhibition of NF-κB activation.
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This study was designed to investigate the ameliorating effect of methanolic extract of green walnut husk (GWH) in hypercholesterolemic rats. A total of thirty male Albino Wistar rats (Rattus norvegicus domestica) were divided randomly into six equal groups. Group 1, negative control, fed on a standard rat diet whereas groups 2–6, hypercholesterolemic rats, fed a high-fat diet (1% cholesterol in a standard diet). Group 2, positive control, was left untreated, whereas the groups 3–5 treated orally with methanolic extract of GWH at 200, 400, and 800 mg/kg/day BW, respectively. Group 6, treatment control, received atorvastatin intraperitoneally at a dosage rate of 0.8 mg/kg/day. The treatment lasted for 84 days. Lipid profiles, biomarkers for liver and kidney functions, some hematological parameters, and liver histopathological assessment were performed. No significant variation was observed on lipid profile values after 42 days of GWH intake; while after 84 days, there was significant reduction (P
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The leading cause and foremost reason for mortality and morbidity in the world is a group known as Noncommunicable Diseases. The best approach to treat them is to evaluate and control the risk factors. There are shared by all these diseases leading to the existence of some meeting points behind all of them. There should be some key to acquire conditions that modify the cells homeostasis and impaired the cell physiology developing different diseases. Physics try to explain the nature of the phenomena that surround us, at first, at the level of our macroscopic perception. Quantum physics studied the atomic and subatomic particles and revolutionized the reality perception with paradoxical and weird concepts. Heisenberg's uncertainty principle established that it is not possible to determine the two characteristic properties of particles with accuracy; measurement affects the system and change it. Subatomic particles have a wave-particle duality that could be in a coherence statement, also can pass through high-energy barriers. Two subatomic particles are entangled, something happening over here can have an instantaneous effect over there, no matter how far away there are. All these concepts have tried to apply to biology and life sciences, especially when classical physics fails to give an accurate description. Quantum biology is behind photosynthesis, mitochondrial respiration, enzyme activity, the sense of smell, animal migration, heredity's fidelity, and consciousness. We can apply all these concepts to diseases pathogeny. So, we describe quantum phenomena in oxidative stress, calcification, signal transduction, vitamin D production, cancer mutations, and microbiome induced pathology. I want to propose that medicine also can be explained by applying quantum physics concepts. It is a new, hard to believe, and an incredible path to be built, but we need to open the treatment options to our patients with new perspectives.
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Background Vitamin D deficiency is a global phenomenon and causes serious morbidities in people via fluctuation in ions homeostasis, oxidative and inflammatory stress. The fundamental goal of this review was to comprehend the growing awareness, biological impact, fortification and different resources of Vitamin D. Methods The purpose of the present study was to explore the biological impact, fortification and different ethnobotanicals and food resources of Vitamin D. The information was gathered from different published national and international articles, book chapters, etc using Google Scholar, Science Direct, Elsevier, PubMed, Springer, etc databases for a comprehensive understanding and perspective associated with Vitamin D. Result There is a growing awareness of Vitamin D as a requirement for optimal health. Unfortunately, there are very few food sources that naturally contain Vitamin D such as fish, milk, eggs, microalgae, mushrooms, and some ethnomedicines. However, the common population could not get sufficient Vitamin D and results fail to meet the requirements even leads senescence. Increasing awareness about Vitamin D, their rich foods and the fortification of foods can help in getting rid of the serious morbidities associated with Vitamin D deficiency. Conclusion The review elucidates the biological impact and the existing knowledge of natural sources to overtake the optimal requirements Vitamin D found in foods and ethnomedicine. It has been demonstrated that Vitamin D exhibits an essential role in calcium homeostasis and senescence due to oxidative and inflammatory damage. To maintain the biological applicability concerning Vitamin D for calcium homeostasis and senescence, it can be an active area of future research that has the potential to reveal new therapeutic strategies.
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This is a response to the letter "Vitamin D and Covid-19: A Note of Caution" by Rabbitt & Slattery in relation to our paper "Optimisation of Vitamin D Status for Enhanced Immuno-protection against Covid-19" which appeared in the April 2020 issue of the Irish Medical Journal.
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Vitamin D (VD) plays a vital role in various physiological processes in addition to its classic functions on maintaining the balance of calcium and phosphorus metabolism. However, there still are gaps to understand in depth the issues on the precise requirement, metabolic processes, and physiological functions of VD in fish. In this study, we investigated the effects of VD on the growth, intestinal health, host immunity and metabolism in turbot ( Scophthalmus maximus L.), one important commercial carnivorous fish in aquaculture, through the supplementation of different doses of dietary VD 3 (0, 200, 400, 800 and 1600 IU VD 3 /kg diet). According to our results, the optimal VD 3 level in the feed for turbot growth was estimated to be around 400 IU/kg, whereas VD 3 deficiency or overdose in diets induced the intestinal inflammation, lowered the diversity of gut microbiota, and impaired the host resistance to bacterial infection in turbot. Moreover, the level of 1α,25(OH) 2 D 3 , the active metabolite of VD 3 , reached a peak value in the turbot serum in the 400 IU group, although the concentrations of calcium and phosphate in the turbot were stable in all groups. Finally, the deficiency of dietary VD 3 disturbed the nutritional metabolism in turbot, especially the metabolism of lipids and glucose. In conclusion, this study evaluated the optimal dose of dietary VD 3 for turbot, and provided the evidence that VD has a significant impact on intestinal health, host immunity and nutritional metabolism in fish, which deepened our understanding on the physiological functions and metabolism of VD 3 in fish.
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The genomic actions of the vitamin D are mediated via its biologically most potent metabolite 1α,25‐dihydroxyvitamin D3 (1,25(OH)2D3) and the transcription factor vitamin D receptor (VDR). Activation of VDR by 1,25(OH)2D3 leads to change in the expression of more 1000 genes in various human tissues. Based on (epi)genome, transcriptome and crystal structure data the molecular details of this nuclear vitamin D signaling pathway are well understood. Vitamin D is known for its role on calcium homeostasis and bone formation, but it also modulates energy metabolism, innate and adaptive immunity as well as cellular growth, differentiation and apoptosis. The observation of rapid, non‐genomic effects of 1,25(OH)2D3 at cellular membranes and in the cytosol initiated the question, whether there are alternative vitamin D binding proteins in these cellular compartments. So far, the best candidate is the enzyme PDIA3 (protein disulfide isomerase family A member 3), which is found at various subcellular locations. Furthermore, also VDR seems to play a role in membrane‐based responses to vitamin D. In this viewpoint, we will dispute whether these rapid, non‐genomic pathways are a meaningful addition to the genome‐wide effects of vitamin D.
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Uncontrolled overgrowth of cells, such as in cancer, is an unavoidable risk in life that affects nearly every second individual in industrialized countries. However, in part this risk can be controlled through lifestyle adjustments, such as the avoidance of smoking, unhealthy diet, obesity, physical inactivity and other cancer risk factors. A low vitamin D status is a risk in particular for cancers of colon, prostate, breast and leukocytes. Vitamin D3 is produced non-enzymatically, when the cholesterol precursor 7-dehydrocholesterol is exposed to UV-B from sunlight, i.e., all cholesterol synthesizing species, including humans, can make vitamin D3. Vitamin D endocrinology started some 550 million years ago, when the metabolite 1α,25-dihydroxyvitamin D3 and the transcription factor vitamin D receptor teamed up for regulating the expression of hundreds of target genes in a multitude of different tissues and cell types. Initially, these genes were focused on the control of energy homeostasis, which later also involved energy-demanding innate and adaptive immunity. Rapidly growing cells of the immune system as well as those of malignant tumors rely on comparable genes and pathways, some of which are modulated by vitamin D. Accordingly, vitamin D has anti-cancer effects both directly via controling the differentiation, proliferation and apoptosis of neoplastic cells as well as indirectly through regulating immune cells that belong to the microenvironment of malignant tumors. This review discusses effects of vitamin D on the epigenome and transcriptome of stromal and tumor cells, inter-individual variations in vitamin D responsiveness and their relation to the prevention and possible therapy of cancer.
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Vitamin D regulates the pleiotropic effect to maintain cellular homeostasis and epidemiological evidence establishes an association between vitamin D deficiency and various human diseases. Here, the role of autophagy, the cellular self-degradation process, in vitamin D-dependent function is documented in different cellular settings and discussed the molecular aspects for treating chronic inflammatory, infectious diseases, and cancer. Vitamin D activates autophagy through a genomic and non-genomic signaling pathway to influence a wide variety of physiological functions of different body organs along with bone health and calcium metabolism. Moreover, it induces autophagy as a protective mechanism to inhibit oxidative stress and apoptosis to regulate cell proliferation, differentiation, and immune modulation. Furthermore, vitamin D and its receptor regulate autophagy signaling to control inflammation and host immunity by activating antimicrobial defense mechanisms. Vitamin D has been revealed as a potent anticancer agent and induces autophagy to increase the response to radiation and chemotherapeutic drugs for potential cancer therapy. Increasing vitamin D levels in the human body through timely exposure to sunlight or vitamin D supplements could activate autophagy as part of the homeostasis mechanism to prevent multiple human diseases and aging-associated dysfunctions.
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The biological active form of vitamin D3, 1α,25-dehydroxyvitamin D3 [1α,25(OH)2D3], exerts pleiotropic effects including bone mineralization, anti-tumor, as well as immunomodulator. This study aimed to explore the potential impact of 1α,25(OH)2D3 on tumor-associated macrophages (TAMs) infiltration in ovarian cancer. Firstly, human monocytic THP-1 cells were differentiated into macrophages (M0) in the presence of phorbol 12-myristate 13-acetate (PMA). In Vivo, 1α,25(OH)2D3 not only reversed the polarization of M2 macrophages, but also decreased the proliferation and migration abilities of ovarian cancer cells induced by M2 macrophages supernatant. Furthermore, 1α,25(OH)2D3 dramatically decreased the secretion of TGF-β1 and MMP-9 in M2 macrophages. However, no significant effect was observed in 1α,25(OH)2D3 treated M1 macrophages. In Vivo, vitamin D3 had an inhibitive effect of 1α,25(OH)2D3-treated M2 macrophages on tumorigenesis. In addition, we conducted the association of TAMs with the poor prognosis of patients with ovarian cancer by meta-analysis, which suggested the higher proportion of M2 macrophages was related to the poorer prognosis in ovarian cancer. Collectively, these results identified distinct roles of 1α,25(OH)2D3 treated M1 and M2 macrophages on cell proliferation and migration abilities in ovarian cancer.
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A nivel mundial, los productores de aceite de palma crudo (APC) se han visto en la necesidad de adaptarse a las más recientes exigencias de calidad de los distintos mercados, al igual que a los requisitos normativos pedidos por los países en donde se comercializa este tipo de aceite. Ac-tualmente, más y nuevos parámetros de calidad conforman el grupo de requerimientos exigi-dos por los compradores durante las negociaciones del APC, materia prima indispensable para la producción de distintos alimentos. Hoy por hoy, los metales pesados, trazas de hidrocarburos aromáticos y alifáticos, cloropropanoles y compuestos de cloro y fósforo son monitoreados con mayor frecuencia durante la evaluación de las propiedades y características del aceite de palma 65 Baena S. María A.., K. (2021). La calidad del aceite de palma como un nuevo reto para la palmicultura mundial. Palmas, 42(1), 65-80. Palabras clave: Aceite de palma, Calidad, Comercialización, Fitonutrientes, Precursores de contaminantes, Contaminantes del aceite de palma.
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Chronic fluorosis is an endemic disease that severely impairs human health. Studies have proved that the change of various receptors in the body is attributed to excessive fluoride intake. For instance, it will reduce the expression of acetylcholine receptor that affects the release of neurotransmitters and will cause changes of N-methyl-D-aspartic acid receptor that impacts cellular Ca²⁺ influx and of advanced glycation end product receptor, augmenting the inflammatory response of the body, etc. These changes are the key mechanism of multi-system injuries caused by fluorosis. With the increased attention on more and more receptors in recent years, the role they played in the pathogenesis of chronic fluorosis is becoming ever more essential. Therefore, an in-depth study of its mechanism of action is possibly vital to uncover the injury of chronic fluorosis and can also provide a theoretical basis for prevention and clinical treatments.
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The biological role of two key vitamins, folic acid and vitamin D is so fundamental to life processes, it follows that their UV sensitivity, dietary abundance (both key exposomal factors) and variability in dependent genes will modify their functional efficacy, particularly in the context of maintaining the integrity and function of genome and epigenome. This article therefore examines folate and vitamin D-related phenotypic adaptation to environmental factors which vary across the human life cycle as well as over an evolutionary time-scale. Molecular mechanisms, key nutrigenomic factors, phenotypic maladaptation and evolutionary models are discussed.
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Palm oil has been used for centuries as a food source and medicine. The palm oil production chain generates large amounts of byproducts, which contain various residual oils. These residual oils can be used to develop new products because they contain high concentrations of vitamin E, carotenoids, and squalene, which are powerful antioxidants that have been shown to protect cell membranes against damage caused by free radicals and reactive oxygen species. This review provides an overview of the literature on the oil fractions recovered from the by-products generated by the palm oil production chain (OFRB), including the characteristics of the phytonutrients and their concentrations found in various studies. There is an increasing number of studies exploring the potential uses of the by-products, generated by palm oil mills and refineries, after processing them. Thus, the goal of this review is to summarize, in detail, the research on the recovery of residual oil contained in the byproducts generated by the palm oil production chain and the functional, nutritional, and pharmaceutical properties of the phytochemicals contained in OFRB as well as suggest areas that need further research.
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Lip, oral cavity, and pharyngeal cancers (LOCP) constitute a group of rare neoplasms with unfavorable prognosis. So far, not much is known about the role of vitamin D and oxidative stress in the pathogenesis of LOCP in the European population. The aim of the study was to determine the concentrations of vitamin D, osteopontin, melatonin, and malondialdehyde (MDA) as markers of oxidative stress and/or inflammation, as well as the activities of antioxidant enzymes in the course of LOCP. The vitamin D, melatonin, and osteopontin concentrations in blood serum, the MDA levels in erythrocytes and blood plasma, and the activities of superoxide dismutase (SOD-1), catalase (CAT), and glutathione peroxidase (GPx) in erythrocytes were measured in blood samples taken from 25 LOCP patients of middle age (YCG), 20 LOCP elderly patients (OCG), and 25 healthy middle-aged volunteers. In both cancer groups, decreases in vitamin D and CAT, as well as increases in osteopontin and blood plasma MDA, were observed. An increase in GPx activity in YCG and a decrease in melatonin level in OCG were found. The results indicate the vitamin D deficiency and disturbed oxidant-antioxidant homeostasis in LOCP patients. Osteopontin seems to be associated with LOCP carcinogenesis and requires further research.
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This review examines putative, yet likely critical evolutionary pressures contributing to human skin pigmentation and subsequently, depigmentation phenotypes. To achieve this, it provides a synthesis of ideas that frame contemporary thinking, without limiting the narrative to pigmentation genes alone. It examines how geography and hence the quality and quantity of UV exposure, pigmentation genes, diet‐related genes, vitamins, anti‐oxidant nutrients, and cultural practices intersect and interact to facilitate the evolution of human skin color. The article has a strong focus on the vitamin D‐folate evolutionary model, with updates on the latest biophysical research findings to support this paradigm. This model is examined within a broad canvas that takes human expansion out of Africa and genetic architecture into account. A thorough discourse on the biology of melanization is provided (includes relationship to BH4 and DNA damage repair), with the relevance of this to the UV sensitivity of folate and UV photosynthesis of vitamin D explained in detail, including the relevance of these vitamins to reproductive success. It explores whether we might be able to predict vitamin‐related gene polymorphisms that pivot metabolism to the prevailing UVR exposome within the vitamin D‐folate evolutionary hypothesis context. This is discussed in terms of a primary adaptive phenotype (pigmentation/depigmentation), a secondary adaptive phenotype (flexible metabolic phenotype based on vitamin‐related gene polymorphism profile), and a tertiary adaptive strategy (dietary anti‐oxidants to support the secondary adaptive phenotype). Finally, alternative evolutionary models for pigmentation are discussed, as are challenges to future research in this area. Early humans were subjected to two opposing UVR/pigmentation clines; the first (folate driven) involved melanization as one moves closer to the equator (ancestral phenotype). The second (vitamin D driven) involved depigmentation following early human expansion out of Africa and changing cultural practices (agricultural development). This second cline, therefore, drives depigmentation from the equator to the pole.
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Objective To test the “vitamin D-folate hypothesis for the evolution of human skin pigmentation.” Methods Total ozone mapping spectrometer (TOMS) satellite data were used to examine surface UV-irradiance in a large (n = 649) Australian cross-sectional study population. Genetic analysis was used to score vitamin D- and folate-related gene polymorphisms (n = 22), along with two pigmentation gene variants (IRF4-rs12203592/HERC2-rs12913832). Red cell folate and vitamin D3 were measured by immunoassay and HPLC, respectively. Results • Ultraviolet radiation (UVR) and pigmentation genes interact to modify blood vitamin levels; Light skin IRF4-TT genotype has greatest folate loss while light skin HERC2-GG genotype has greatest vitamin D3 synthesis (reflected in both TOMS and seasonal data). • UV-wavelength exhibits a dose–response relationship in folate loss within light skin IRF4-TT genotype (305 > 310 > 324 > 380 nm). Significant vitamin D3 photosynthesis only occurs within light skin HERC2-GG genotype, and is maximal at 305 nm. • Three dietary antioxidants (vitamins C, E, and β-carotene) interact with UVR and pigmentation genes preventing oxidative loss of labile reduced folate vitamers, with greatest benefit in light skin IRF4-TT subjects. The putative photosensitiser, riboflavin, did not sensitize red cell folate to UVR and actually afforded protection. • Four genes (5xSNPs) influenced blood vitamin levels when stratified by pigmentation genotype; MTHFR-rs1801133/rs1801131, TS-rs34489327, CYP24A-rs17216707, and VDR-ApaI-rs7975232. • Lightest IRF4-TT/darkest HERC2-AA genotype combination (greatest folate loss/lowest vitamin D3 synthesis) has 0% occurrence. The opposing, commonest (39%) compound genotype (darkest IRF4-CC/lightest HERC2-GG) permits least folate loss and greatest synthesis of vitamin D3. Conclusion New biophysical evidence supports the vitamin D-folate hypothesis for evolution of skin pigmentation.
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Bal arıları meyve, sebze ve tohum oluşumu için çok önemli hayvanlardır. Arılar, çiçekli bitkilerin erkek yapılarındaki polenleri dişi kısımlarına aktararak bitkilerde meyve ve tohum oluşumunu sağlar. Ayrıca bal yapmaları nedeniyle de tarih boyunca bu böceklere çok önem verilmiştir. Biz insanlar her zaman bal arısına hayran olmuşuzdur. Afrika, Avrupa ve Asya’daki en eski atalarımız, yüz binlerce yıl boyunca, bu arının bal depolama ve balmumu yapma konusundaki şaşırtıcı endüstrisine, çok değerli iki maddeye kesinlikle hayran kaldılar. Daha yakın zamanlarda, son 10.000 yılda, karmaşık arıcılık zanaatını icat ettik ve bal arıları üzerine bilimsel çalışmalarımıza başladık. Örneğin, bu arının «çiçek değişmezliği» uygulamasını ilk kez tanımlayan antik filozof Aristotales’ti: Bir işçi arı, yiyecek toplamanın verimliliğini artırmak için yiyecek arama gezisi boyunca genellikle bir tür çiçeğe yapışır. Bal arısının doğal dünyasında nasıl yaşadığını bilmek, geniş bir bilimsel araştırma yelpazesi gerekmektedir. Bunun nedeni, Apis mellifera’nın biyolojideki, özellikle davranışla ilgili temel soruları araştırmak için model sistemlerden biri haline gelmesidir. Bu arıları ister hayvan bilişindeki, ister davranışsal genetikteki veya sosyal davranışlardaki bazı gizemleri çözmek için çalışıyor olun, birinin deneysel araştırmalarını tasarlamadan önce doğal biyolojilerine aşina olmak kritik derecede önemlidir.
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The term osteoimmunology was coined many years ago to describe the research field that deals with the cross-regulation between bone cells and the immune system. As a matter of fact, many factors that are classically considered immune-related, such as InterLeukins (i.e., IL-6, -11, -17, and -23), Tumor Necrosis Factor (TNF)-α, Receptor-Activator of Nuclear factor Kappa B (RANK), and its Ligand (RANKL), Nuclear Factor of Activated T-cell, cytoplasmatic-1 (NFATc1), and others have all been found to be crucial in osteoclast and osteoblast biology. Conversely, bone cells, which we used to think would only regulate each other and take care of remodeling bone, actually regulate immune cells, by creating the so-called “endosteal niche.” Both osteoblasts and osteoclasts participate to this niche, either by favoring engraftment, or mobilization of Hematopoietic Stem Cells (HSCs). In this review, we will describe the main milestones at the base of the osteoimmunology and present the key cellular players of the bone-immune system cross-talk, including HSCs, osteoblasts, osteoclasts, bone marrow macrophages, osteomacs, T- and B-lymphocytes, dendritic cells, and neutrophils. We will also briefly describe some pathological conditions in which the bone-immune system cross-talk plays a crucial role, with the final aim to portray the state of the art in the mechanisms regulating the bone-immune system interplay, and some of the latest molecular players in the field. This is important to encourage investigation in this field, to identify new targets in the treatment of bone and immune diseases.
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The roles of migration, admixture and acculturation in the European transition to farming have been debated for over 100 years. Genome-wide ancient DNA studies indicate predominantly Aegean ancestry for continental Neolithic farmers, but also variable admixture with local Mesolithic hunter-gatherers. Neolithic cultures first appear in Britain circa 4000 bc, a millennium after they appeared in adjacent areas of continental Europe. The pattern and process of this delayed British Neolithic transition remain unclear. We assembled genome-wide data from 6 Mesolithic and 67 Neolithic individuals found in Britain, dating 8500–2500 bc. Our analyses reveal persistent genetic affinities between Mesolithic British and Western European hunter-gatherers. We find overwhelming support for agriculture being introduced to Britain by incoming continental farmers, with small, geographically structured levels of hunter-gatherer ancestry. Unlike other European Neolithic populations, we detect no resurgence of hunter-gatherer ancestry at any time during the Neolithic in Britain. Genetic affinities with Iberian Neolithic individuals indicate that British Neolithic people were mostly descended from Aegean farmers who followed the Mediterranean route of dispersal. We also infer considerable variation in pigmentation levels in Europe by circa 6000 bc.
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Genetic variation in contemporary South Asian populations follows a northwest to southeast decreasing cline of shared West Eurasian ancestry. A growing body of ancient DNA evidence is being used to build increasingly more realistic models of demographic changes in the last few thousand years. Through high-quality modern genomes, these models can be tested for gene and genome level deviations. Using local ancestry deconvolution and masking, we reconstructed population-specific surrogates of the two main ancestral components for more than 500 samples from 25 South Asian populations and showed our approach to be robust via coalescent simulations. Our f3 and f4 statistics–based estimates reveal that the reconstructed haplotypes are good proxies for the source populations that admixed in the area and point to complex interpopulation relationships within the West Eurasian component, compatible with multiple waves of arrival, as opposed to a simpler one wave scenario. Our approach also provides reliable local haplotypes for future downstream analyses. As one such example, the local ancestry deconvolution in South Asians reveals opposite selective pressures on two pigmentation genes (SLC45A2 and SLC24A5) that are common or fixed in West Eurasians, suggesting post-admixture purifying and positive selection signals, respectively.
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For many individuals, in particular during winter, supplementation with the secosteroid vitamin D3 is essential for the prevention of bone disorders, muscle weakness, autoimmune diseases, and possibly also different types of cancer. Vitamin D3 acts via its metabolite 1α,25-dihydroxyvitamin D3 [1,25(OH) 2 D 3 ] as potent agonist of the transcription factor vitamin D receptor (VDR). Thus, vitamin D directly affects chromatin structure and gene regulation at thousands of genomic loci, i.e., the epigenome and transcriptome of its target tissues. Modifications of 1,25(OH) 2 D 3 at its side-chain, A-ring, triene system, or C-ring, alone and in combination, as well as nonsteroidal mimics provided numerous potent VDR agonists and some antagonists. The nearly 150 crystal structures of VDR's ligand-binding domain with various vitamin D compounds allow a detailed molecular understanding of their action. This review discusses the most important vitamin D analogs presented during the past 10 years and molecular insight derived from new structural information on the VDR protein.
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Tolerogenic dendritic cells (tolDCs) instruct regulatory T cells (Tregs) to dampen autoimmunity. Active vitamin D3 (1α,25-dihydroxyvitamin D3; 1α,25(OH)2D3) imprints human monocyte-derived DCs with tolerogenic properties by reprogramming their glucose metabolism. Here we identify the glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4) as a critical checkpoint and direct transcriptional target of 1α,25(OH)2D3 in determining the tolDC profile. Using tracer metabolomics, we show that PFKFB4 activity is essential for glucose metabolism, especially for glucose oxidation, which is elevated upon 1α,25(OH)2D3 exposure. Pharmacological inhibition of PFKFB4 reversed the 1α,25(OH)2D3-mediated shift in metabolism, DC profile and function, as determined by expression of inhibitory surface markers and secretion of regulatory cytokines and factors. Moreover, PFKFB4 inhibition in 1α,25(OH)2D3-treated DCs blocked their hallmark capacity to induce suppressive Tregs. This work demonstrates that alterations in the bioenergetic metabolism of immune cells are central to the immunomodulatory effects induced by 1α,25(OH)2D3.
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For thousands of years the Eurasian steppes have been a centre of human migrations and cultural change. Here we sequence the genomes of 137 ancient humans (about 1× average coverage), covering a period of 4,000 years, to understand the population history of the Eurasian steppes after the Bronze Age migrations. We find that the genetics of the Scythian groups that dominated the Eurasian steppes throughout the Iron Age were highly structured, with diverse origins comprising Late Bronze Age herders, European farmers and southern Siberian hunter-gatherers. Later, Scythians admixed with the eastern steppe nomads who formed the Xiongnu confederations, and moved westward in about the second or third century bc, forming the Hun traditions in the fourth–fifth century ad, and carrying with them plague that was basal to the Justinian plague. These nomads were further admixed with East Asian groups during several short- term khanates in the Medieval period. These historical events transformed the Eurasian steppes from being inhabited by Indo-European speakers of largely West Eurasian ancestry to the mostly Turkic-speaking groups of the present day, who are primarily of East Asian ancestry.
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Fossil evidence points to an African origin of Homo sapiens from a group called either H. heidelbergensis or H. rhodesiensis. However, the exact place and time of emergence of H. sapiens remain obscure because the fossil record is scarce and the chronological age of many key specimens remains uncertain. In particular, it is unclear whether the present day 'modern' morphology rapidly emerged approximately 200 thousand years ago (ka) among earlier representatives of H. sapiens1 or evolved gradually over the last 400 thousand years2. Here we report newly discovered human fossils from Jebel Irhoud, Morocco, and interpret the affinities of the hominins from this site with other archaic and recent human groups. We identified a mosaic of features including facial, mandibular and dental morphology that aligns the Jebel Irhoud material with early or recent anatomically modern humans and more primitive neurocranial and endocranial morphology. In combination with an age of 315 ± 34 thousand years (as determined by thermoluminescence dating)3, this evidence makes Jebel Irhoud the oldest and richest African Middle Stone Age hominin site that documents early stages of the H. sapiens clade in which key features of modern morphology were established. Furthermore, it shows that the evolutionary processes behind the emergence of H. sapiens involved the whole African continent.
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Farming was first introduced to southeastern Europe in the mid-7th millennium BCE - brought by migrants from Anatolia who settled in the region before spreading throughout Europe. However, the dynamics of the interaction between the first farmers and the indigenous hunter-gatherers remain poorly understood because of the near absence of ancient DNA from the region. We report new genome-wide ancient DNA data from 204 individuals-65 Paleolithic and Mesolithic, 93 Neolithic, and 46 Copper, Bronze and Iron Age-who lived in southeastern Europe and surrounding regions between about 12,000 and 500 BCE. We document that the hunter-gatherer populations of southeastern Europe, the Baltic, and the North Pontic Steppe were distinctive from those of western Europe, with a West-East cline of ancestry. We show that the people who brought farming to Europe were not part of a single population, as early farmers from southern Greece are not descended from the Neolithic population of northwestern Anatolia that was ancest
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The effects of vitamin D3 dietary administration on certain innate immune parameters on the expression of immune-related genes in head-kidney (HK) and gut were investigated in European sea bass Dicentrarchus labrax. Vitamin D3 (vD3) was orally administered to fish in a commercial pellet food supplemented with 0 (control); 3750; 18,750; or 37,500?U?kg(-1). Furthermore, gut histology was considered. This study showed a modulation in the activities examined in fish fed with the addition of vD3. After just 2?weeks of administration, diet supplementation with the vitamin resulted in increased phagocytic ability, while serum peroxidase content was increased in fish fed with all experimental diets after 4?weeks, no significant differences were observed in protease, anti-protease, natural haemolytic complement activities and total IgM level. At gene level, fbl and rbl transcripts were up-regulated in HK in fish fed with the highest concentration of vD3-supplemented diets after 4?weeks, while in the gut, an up-regulation of hep gene was observed in fish fed with the different doses of vD3. These results suggest that vD3 may be of great interest for immunostimulatory purposes in fish farms.
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Vitamin D insufficiency is a worldwide epidemic affecting billions of individuals, including pregnant women and children. Despite its high incidence, the impact of active vitamin D3 (1,25(OH)D3) on embryonic development beyond osteo-regulation remains largely undefined. Here, we demonstrate that 1,25(OH)D3 availability modulates zebrafish hematopoietic stem and progenitor cell (HSPC) production. Loss of Cyp27b1-mediated biosynthesis or vitamin D receptor (VDR) function by gene knockdown resulted in significantly reduced runx1 expression and Flk1+cMyb+ HSPC numbers. Selective modulation in vivo and in vitro in zebrafish indicated that vitamin D3 acts directly on HSPCs, independent of calcium regulation, to increase proliferation. Notably, ex vivo treatment of human HSPCs with 1,25(OH)D3 also enhanced hematopoietic colony numbers, illustrating conservation across species. Finally, gene expression and epistasis analysis indicated that CXCL8 (IL-8) was a functional target of vitamin D3-mediated HSPC regulation. Together, these findings highlight the relevance of developmental 1,25(OH)D3 availability for definitive hematopoiesis and suggest potential therapeutic utility in HSPC expansion.
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Nutritional or classical rickets (here labeled as "rickets") is a worldwide disease involving mostly infants and young children having inadequate sunlight exposure,often associated with a low dietary intake of Vitamin D. Rickets targets all layers of society independently of economic status with historical information spanning more than two millennia. Vitamin D is critical for the absorption of calcium and prevention of rickets in children as well as osteomalacia in adults. The initial and misleading paradigm of the 19th and 20th centuries that rickets may have been the consequence of infection has been,indeed,reversed following the identification of the Vitamin D molecule’s important role in the function of the immune system. Although traditionally considered limited to osteopathology,Vitamin D deficiency is now known to be linked to infection,inflammation,and carcinogenesis. In this review,we consider the key historical (Whistler,pre-Whistler and post-Whistler descriptors) and social facts around rickets; highlight the osteo-pathological features of rickets and the pathology of the upper and lower respiratory tract,stressing the fact that lungs remain the main secondary organ affected by Vitamin D deficiency; and emphasize the public health role in identifying the cases of child neglect or abuse based on the evaluation of the costochondral region.
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The lamprey belongs to the phylogenetically oldest group of vertebrates that diverged from the mammalian evolutionary line 560 million years ago. A comparison between the lamprey and mammalian basal ganglia establishes a detailed similarity regarding its input from cortex/pallium and thalamus, as well as its intrinsic organisation and projections of the output nuclei. This means that the basal ganglia circuits now present in rodents and primates most likely had evolved already at the dawn of vertebrate evolution. This includes the 'direct pathway' with striatal projection neurons (SPNs) expressing dopamine D1 receptors, which act to inhibit the tonically active GABAergic output neurons in globus pallidus interne and substantia nigra pars reticulate that at rest keep the brainstem motor centres under tonic inhibition. The 'indirect pathway' with dopamine D2 receptor-expressing SPNs and intrinsic basal ganglia nuclei is also conserved. The net effect of the direct pathway is to disinhibit brainstem motor centres and release motor programs, while the indirect pathway instead will suppress motor activity. Transmitters, connectivity and membrane properties are virtually identical in lamprey and rodent basal ganglia. We predict that the basal ganglia contains a series of modules each controlling a given pattern of behaviour including locomotion, eye-movements, posture, and chewing that contain both the direct pathway to release a motor program and the indirect pathway to inhibit competing behaviours. The phasic dopamine input serves value-based decisions and motor learning. During vertebrate evolution with a progressively more diverse motor behaviour, the number of modules will have increased progressively. These new modules with a similar design will be used to control newly developed patterns of behaviour a process referred to as exaptation.
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Modern humans arrived in Europe ~45,000 years ago, but little is known about their genetic composition before the start of farming ~8,500 years ago. Here we analyse genome-wide data from 51 Eurasians from ~45,000-7,000 years ago. Over this time, the proportion of Neanderthal DNA decreased from 3-6% to around 2%, consistent with natural selection against Neanderthal variants in modern humans. Whereas there is no evidence of the earliest modern humans in Europe contributing to the genetic composition of present-day Europeans, all individuals between ~37,000 and ~14,000 years ago descended from a single founder population which forms part of the ancestry of present-day Europeans. An ~35,000-year-old individual from northwest Europe represents an early branch of this founder population which was then displaced across a broad region, before reappearing in southwest Europe at the height of the last Ice Age ~19,000 years ago. During the major warming period after ~14,000 years ago, a genetic component related to present-day Near Easterners became widespread in Europe. These results document how population turnover and migration have been recurring themes of European prehistory.
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Vitamin D (VD3) has been linked to immunologic processes, and its supplementation may have a role in treatment or prevention of diseases with underlying autoimmune or proinflammatory states. As initiators of the immune responses, Dendritic Cells (DC) are a potential target of VD3 to dampen autoimmunity and inflammation, but the role of DC in VD3-mediated immunomodulation in vivo is not understood. In addition to being targets of VD3, DC can provide a local source of bioactive VD3 for regulation of T cell responses. Here we review existing studies that describe the tolerogenic potential of VD3 on DC, and discuss them in the context of current understanding of DC development and function. We speculate on mechanisms that might account for the potent but poorly understood tolerogenic activities of VD3 and the role of DC as both targets and sources of this hormone. This article is protected by copyright. All rights reserved.
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Ancient DNA makes it possible to observe natural selection directly by analysing samples from populations before, during and after adaptation events. Here we report a genome-wide scan for selection using ancient DNA, capitalizing on the largest ancient DNA data set yet assembled: 230 West Eurasians who lived between 6500 and 300 bc, including 163 with newly reported data. The new samples include, to our knowledge, the first genome-wide ancient DNA from Anatolian Neolithic farmers, whose genetic material we obtained by extracting from petrous bones, and who we show were members of the population that was the source of Europe's first farmers. We also report a transect of the steppe region in Samara between 5600 and 300 bc, which allows us to identify admixture into the steppe from at least two external sources. We detect selection at loci associated with diet, pigmentation and immunity, and two independent episodes of selection on height.
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