PMID: 

Future Microbiol. 2009 Nov ;4(9):1151-65. PMID: 19895218

Abstract Title: 

The vitamin D-antimicrobial peptide pathway and its role in protection against infection.

Abstract: 

Vitamin D deficiency has been correlated with increased rates of infection. Since the early 19th century, both environmental (i.e., sunlight) and dietary sources (cod liver) of vitamin D have been identified as treatments for TB. The recent discovery that vitamin D induces antimicrobial peptide gene expression explains, in part, the 'antibiotic' effect of vitamin D and has greatly renewed interest in the ability of vitamin D to improve immune function. Subsequent work indicates that this regulation is biologically important for the response of the innate immune system to wounds and infection and that deficiency may lead to suboptimal responses toward bacterial and viral infections. The regulation of the cathelicidin antimicrobial peptide gene is a human/primate-specific adaptation and is not conserved in other mammals. The capacity of the vitamin D receptor to act as a high-affinity receptor for vitamin D and a low-affinity receptor for secondary bile acids and potentially other novel nutritional compounds suggests that the evolutionary selection to place the cathelicidin gene under control of the vitamin D receptor allows for its regulation under both endocrine and xenobiotic response systems. Future studies in both humans and humanized mouse models will elucidate the importance of this regulation and lead to the development of potential therapeutic applications.

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PMID: 

Proc Nutr Soc. 2010 Aug ;69(3):286-9. Epub 2010 Jun 2. PMID: 20515520

Abstract Title: 

Mechanisms underlying the effect of vitamin D on the immune system.

Abstract: 

Vitamin D and the vitamin D receptor (VDR) have been shown to be important regulators of the immune system. In particular, vitamin D and VDR deficiency exacerbates experimental autoimmune diseases such as inflammatory bowel disease (IBD). IBD develops due to an immune-mediated attack by pathogenic T-cells that overproduce IL-17 and IFN-gamma and a few regulatory cells. VDR knockout mice have twice as many T-cells making IL-17 and IFN-gamma than wild-type mice. In addition, vitamin D and the VDR are required for normal numbers of regulatory T-cells (iNKT and CD8alphaalpha) that have been shown to suppress experimental IBD. In the absence of vitamin D and the VDR, autoimmunity occurs in the gastrointestinal tract due to increased numbers of IL-17 and IFN-gamma secreting T-cells and a concomitant reduction in regulatory T-cells.

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PMID: 

Rev Med Chir Soc Med Nat Iasi. 2013 Oct-Dec;117(4):965-73. PMID: 24502077

Abstract Title: 

Current status in vitamin D and regulatory T cells–immunological implications.

Abstract: 

There has been a continuous effort to understand possible non-Ca metabolism roles of vitamin D, including its role in the immune system and, in particular, in T cell-medicated immunity. Vitamin D receptor is found in significant concentrations in the T lymphocyte and macrophage populations, when we refer to immune system, and pretty much in any human tissue and cells. Until the eighties, no one had imagined that vitamin D might play a role in the functioning of the immune system. Today we accepted that the normal immune system harbors a regulatory T cell (Treg) population specialized for immune suppression. Currently, the most commonly known regulatory T-cell lineage is called CD4+ CD25high FoxP3+ regulatory T cells. Several autoimmune disorders have been linked to a deficiency in vitamin D3. In some autoimmune diseases, including multiple sclerosis (MS), a compromised Treg function is believed to be critically involved in the disease process. Vitamin D insufficiency has ramifications not only for bone health, but also in other non-skeletal areas of vitamin D function, such as immune cells, muscle cells and, perhaps, adipocytes. As a final conclusion, further researches in the field of vitamin D, Tregs, immunity (inflammatory processes, rejection, autoimmune diseases, etc.), either in vitro on cell cultures or in vivo using lab animals or volunteers are still necessary.

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PMID: 

Virus Res. 2020 Mar 28 ;282:197936. Epub 2020 Mar 28. PMID: 32234325

Abstract Title: 

Analysis of influenza virus-induced perturbation in autophagic flux and its modulation during Vitamin D3 mediated anti-apoptotic signaling.

Abstract: 

Vitamin D3/Calcitriol supplementation in humans is associated with reduced incidence and severity during influenza A virus (IAV) infection. Apoptosis in response to IAV infection is a major contributor to host cell death and tissue damage; however, its modulation by Vitamin D3 remains unclear. In this study, we demonstrate the efficacy of Vitamin D3 in preventing apoptosis induction by pandemic influenza A (H1N1)pdm09 virus in human alveolar cells (A549). Human alveolar epithelial cell line A549 was used to assess the cytotoxic effects of IAV infection. Immunoblotting and fluorescence microscopy were used to study apoptosis and autophagy. The results of the present study demonstrate that IAV induces apoptosis by subversion of host autophagy via down-regulating components of autophagic machinery involved in autophagosome-lysosome fusion and lysosomal activity. Vitamin D3 restores the autophagic flux inhibited by IAV by upregulating the expression of Syntaxin-17 (STX17) and V-type proton ATPase subunit (ATP6V0A2) thereby causing a concomitant decrease in cellular apoptosis via a Vitamin D3 receptor (VDR) dependent mechanism. The present study suggests that Vitamin D3 is a potentially useful agent for limiting IAV-induced cellular injury via its pro-autophagic action.

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PMID: 

Int J Mol Sci. 2020 Mar 27 ;21(7). Epub 2020 Mar 27. PMID: 32230936

Abstract Title: 

Vitamin D Suppresses Ovarian Cancer Growth and Invasion by Targeting Long Non-Coding RNA CCAT2.

Abstract: 

Ovarian cancer is the most deadly gynecologic cancer among women worldwide. Poor response to current treatment makes it necessary to discover new diagnostic biomarkers to detect the cancer early and develop new and effective prevention strategies. Calcitriol, the active metabolite of vitamin D, protects against multiple cancers through unelucidated mechanisms. The oncogenic long non-coding RNA (lncRNA) CCAT2 (colon cancer associated transcript 2) is overexpressed in ovarian cancer. Here, we foundd that calcitriol inhibited CCAT2 expression in ovarian cancer cell lines. Treatment with calcitriol inhibited ovarian cancer cell proliferation, migration, and invasion. As a result of CCAT2 inhibition, calcitriol decreased the binding of transcription factor TCF7L2 (TCF4) to thepromoter, resulting in the repression of c-Myc protein expression. Our results suggest a novel anti-cancer mechanism of vitamin D by targeting CCAT2 in ovarian cancer. The findings may help develop vitamin D as a practical and inexpensive nutraceutical for ovarian cancer prevention.

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PMID: 

Kobe J Med Sci. 2020 Mar 27 ;65(5):E153-E163. Epub 2020 Mar 27. PMID: 32249272

Abstract Title: 

Calcitriol Ameliorates Kidney Injury Through Reducing Podocytopathy, Tubular Injury, Inflammation and Fibrosis in 5/6 Subtotal Nephrectomy Model in Rats.

Abstract: 

Chronic kidney diseases (CKDs) lead to end-stage renal diseases (ESRD) which are characterized by glomerulosclerosis, tubular injury, anemia, inflammation, and interstitial fibrosis. Vitamin D is known to have renal protective effects. However, its effects relate to low and high doses of Vitamin D in CKD model is still unknown. CKD was performed using 5/6 subtotal nephrectomy procedure in male Sprague Dawley rats (3 months old, 200-300 grams, SN group; n=6), then rats were sacrificed on day 14 after operation. Sham operation was used for control (SO group; n=6). Calcitriol was administered in two doses : 0.01µg/mL/100 gramsBW/day (SND1 group; n=6) and 0.05 µg/mL/100 gramsBW/day (SND2 group; n=6) intraperitoneally for 14 days. Glomerulosclerosis and tubular injury score were examined using PAS staining, meanwhile, interstitial fibrosis area fraction was assessed with Sirius Red staining. RT-PCR was performed for assessing nephrin, podocin, IL-6, CD68, Collagen-1, and TGF-β1 mRNA expressions. Immunostaining (IHC) was carried out to observe macrophage (CD68) and myofibroblast (α-SMA). SN demonstrated CKD condition with higher tubular injury, glomerulosclerosis, interstitial fibrosis, and inflammation compared to SO. Calcitriol-treated group (especially SND2) demonstrated significant lower tubular injury, glomerulosclerosis, and interstitial fibrosis compared to SN. SND2 group showed not only significantly lower CD68, IL-6, Collagen-1, and TGF-β1 mRNA expressions, but also higher mRNA expressions of nephrin and podocin. SND2 group also demonstrated reduction of macrophages infiltration and myofibroblasts expansion based on its histopathological appearance. Vitamin D may have a renoprotective effect on 5/6 subtotal nephrectomy model by attenuating podocytopathy, tubular injury, inflammation and interstitial fibrosis.

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PMID: 

Proc Nutr Soc. 2012 Feb ;71(1):90-7. Epub 2011 Nov 25. PMID: 22115013

Abstract Title: 

Vitamin D and respiratory infection in adults.

Abstract: 

Vitamin D insufficiency is a global issue that has significant implications for health. The classical role of vitamin D in bone mineralisation is well known; vitamin D deficiency leads to rickets, osteomalacia or osteoporosis. The role of vitamin D in an immune system is less known. Vitamin D is not an actual vitamin but a secosteroid hormone produced in the skin from 7-dehydrocholesterol after exposure to sunlight UVB radiation. Nutrition and supplements are main sources of vitamin D in wintertime in northern countries as sunlight exposure is inadequate for the production. For activation vitamin D needs to be hydroxylated in liver to form 25-hydroxyvitamin D and in kidney to 1,25-dihydroxyvitamin D, the most active hormone in Ca absorption in the gut. For determination of vitamin D status serum 25-hydroxyvitamin D level, the major circulating form of the hormone is to be measured. Vitamin D regulates gene expression through binding with vitamin D receptors, which dimerises with retinoid X receptor. This complex binds to vitamin D-responsive elements inside the promoter regions of vitamin D-responsive genes. Vitamin D has a key role in innate immunity activation; the production of antimicrobial peptides (cathelicidin and defensins) following Toll-like receptor stimulation by pathogen lipopeptides is dependent on sufficient level of 25-hydroxyvitamin D. Clinically, there is evidence of the association of vitamin D insufficiency and respiratory tract infections. There is also some evidence of the prevention of infections by vitamin D supplementation. Randomised controlled trials are warranted to explore this preventive effect.

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PMID: 

Autoimmun Rev. 2011 Dec ;11(2):84-7. Epub 2011 Aug 16. PMID: 21864722

Abstract Title: 

Vitamin D endocrine system involvement in autoimmune rheumatic diseases.

Abstract: 

Vitamin D is synthesized from cholesterol in the skin (80-90%) under the sunlight and then metabolized into an active D hormone in liver, kidney and peripheral immune/inflammatory cells. These endocrine-immune effects include also the coordinated activities of the vitamin D-activating enzyme, 1alpha-hydroxylase (CYP27B1), and the vitamin D receptor (VDR) on cells of the immune system in mediating intracrine and paracrine actions. Vitamin D is implicated in prevention and protection from chronic infections (i.e. tubercolosis), cancer (i.e. breast cancer) and autoimmune rheumatic diseases since regulates both innate and adaptive immunity potentiating the innate response (monocytes/macrophages with antimicrobial activity and antigen presentation), but suppressing the adaptive immunity (T and B lymphocyte functions). Vitamin D has modulatory effects on B lymphocytes and Ig production and recent reports have demonstrated that 1,25(OH)2D3 does indeed exert direct effects on B cell homeostasis. A circannual rhythm of trough vitamin D levels in winter and peaks in summer time showed negative correlation with clinical status at least in rheumatoid arthritis and systemic lupus erythematosus. Recently, the onset of symptoms of early arthritis during winter or spring have been associated with greater radiographic evidence of disease progression at 12 months possibly are also related to seasonal lower vitamin D serum levels.

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PMID: 

Thorax. 2012 Nov ;67(11):1018-20. Epub 2012 Aug 30. PMID: 22935474

Abstract Title: 

Vitamin D and lung disease.

Abstract: 

The classic role of vitamin D in the regulation of calcium and phosphate metabolism, and its effects on bone health, are well established. More recently a critical role in immunity and respiratory health has been proposed. This arises from evidence for the capacity to generate the active metabolite, 1α,25-dihydroxyvitamin D3 (1,25(OH)D3), locally in many tissues beyond the kidney; expression of the vitamin D receptor (VDR) in immune and structural cells not involved in calcium-phosphate homeostasis; and control by 1,25(OH)D3 of the transcription of genes associated with numerous different biological processes through its nuclear VDR. Abnormalities in the vitamin D axis, including a high prevalence of vitamin D insufficiency worldwide, now appear important in a wide range of pulmonary diseases including viral and bacterial respiratory infection, asthma, chronic obstructive pulmonary disease, and cancer. Actions of vitamin D on innate immune responses, for example, production of antimicrobial peptides and autophagy, and on adaptive immune responses, for example, promoting regulatory lymphocytes, are believed to underpin these associations.

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PMID: 

Immunol Lett. 2019 06 ;210:10-19. Epub 2019 Mar 29. PMID: 30935876

Abstract Title: 

The molecular and clinical evidence of vitamin D signaling as a modulator of the immune system: Role in Behçet's disease.

Abstract: 

Various tissues and cell types are the targets of vitamin D. However, the major targets of vitamin D in the immune system are monocytes/macrophages, dendritic cells (DCs), as well as B and T cells. Vitamin D plays an important role in the immune system modulation via regulating the expression of genes that generate pro-inflammatory mediators and inhibiting the proliferation of pro-inflammatory cells, both of which have been implicated in the pathophysiology of the inflammatory diseases. Recent studies have revealed the important relations between vitamin D and Behçet's disease (BD). Vitamin D function and its deficiency have been linked to a wide range of metabolic disorders including malignant, cardiovascular, infectious, neuromuscular, and autoimmune diseases. Here, we provide a brief analysis of the recent literature regarding immune-regulatory effects as well as clinical evidence of vitamin D influence on the molecular level in BD.

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