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The Sunshine Vitamin in Health and Disease

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1 The Sunshine Vitamin in Health and Disease
© BioSoft Publishing 2009

2 Oh, thou life giving celestial body, welcome to the new day – Anonymous

3 UV rays and their biological action on skin cells
UVB causes sunburns (longer exposure) UVA produces tanning without burning. Longer exposure causes sunburns.

4 The mechanism of sunburns
An overexposure to UV radiation (typical summer day) can cause sunburn and in the long run some form of skin cancer. The most deadly form – malignant melanoma is mostly caused by indirect DNA damage, through oxidative stress due to reactive oxygen species. Sunburns differ significantly from thermal burns, which result from infrared radiation. Although infrared radiation gives sunlight its warmth, it is not the heat of the sun that burns skin. A sunburn manifested by cutaneous redness, swelling and pain is an acute toxic reaction caused by exposure to the sun's ultraviolet radiation. Although the precise mechanism by which a sunburn occurs has not been clearly identified, complex chemical reactions and pathways take place that most likely result in the clinical symptoms. The energy from ultraviolet radiation can damage molecules in the skin, most importantly DNA. One consequence of this is the synthesis of different proteins and enzymes, including heat shock proteins. The effects of prostaglandins and cytokines, lead to dilation of the blood vessels in the dermis and recruitment of inflammatory cells. This, in turn, produces a sunburn's characteristic redness, swelling and pain. Once the signal of excessive radiation exposure is initiated, it generally takes four to six hours for these proteins to be synthesized. Sunburn symptoms thus don't appear until well after exposure. (DNA damage can also result in the destruction of the involved skin cell. This is one of the reasons why skin peels after a bad sunburn.) The body does have mechanisms to repair damaged DNA after ultraviolet exposure. But as the frequency of sunlight exposure increases, so, too, does the probability that some of that damage will escape repair. This mutated DNA may eventually lead to skin cancer. The warmth of a sunburn generally stems from increased blood flow to the exposed site. Even though the burned skin seems much warmer, it would still be close to 37 degrees. Any slight elevation in temperature would be a result of the inflammatory response generated from the chemical processes induced by ultraviolet radiation. Sunburns take place in several steps: Initial redness and swelling – dilation of blood capillaries in the dermis An inflammatory response is triggered – synthesis of cytokines, prostaglandins, heat shock proteins Inflammatory cells (lymphocytes, macrophages) move to the interstitial space. Dark red skin, heat and pain sensation After 72 hours massive skin peeling off takes place.

5 Damage to DNA strands caused by UVB radiation
UV radiation can also damage collagen fibers thus weakening the firmness of the skin tissue. This leads to wrinkles and faster skin aging. UVA and UVB inactivate vitamin A, which may cause further damage to the skin. UVB can damage DNA directly by causing the formation of a cyclobutane thymine dimer involving two adjacent thymine bases. A bulge appears in one of the strands and as a result DNA replication is impaired.

6 Site of vitamin D synthesis in the skin
Individuals with higher skin melanin content will simply require more time in sunlight to produce the same amount of vitamin D as individuals with lower melanin content. The amount of time an individual requires to produce a given amount of vitamin D may also depend upon the person's distance from the equator and on the season of the year. UVB radiation causes the photo-isomerization of 7-dehydrocholesterol in the plasma membrane of stratum spinosum and stratum basale cells of the epidermal layer of the skin. UVB rays are most effective in a narrow range, between nm. Generation of pre-vitamin D3 depends on the intensity and wavelength of UV radiation. Under normal circumstances some micrograms of 7-dehydrocholesterol/cm2 of skin are available for vitamin D3 synthesis. Following a moderate exposure to sunlight UVB rays trigger the synthesis of melanin by the melanocytes in the lower strata of epidermis. The pigment can be a limiting factor in the photo- isomerization reaction because melanin can also absorb UVB radiation.


8 Synthesis of1, 25(OH)2 vitamin D3
It has been shown recently that human macrophages treated with a mycobacterium lipoprotein showed increased expression of 25OH D-1alpha hydroxylase and vitamin D receptor as well as the induction of cathelicidin (a class of antimicrobial peptides called defensins) in response to 25(OH) vitamin D3 .



11 Generation of vitamin D3 and its involvement in calcium metabolism
The physiologically active form of vitamin D mediates its biological effects by binding to the vitamin D receptor (VDR), which is located mainly in the nuclei of target cells. The binding of calcitriol to the VDR allows the VDR to act as a transcription factor that modulates the gene expression of transport proteins (such as TRPV6 and calbindin), which are involved in calcium absorption in the intestine. The Vitamin D receptor belongs to the nuclear receptor superfamily of steroid/thyroid hormone receptors, and VDR are expressed by cells in most organs, including the brain, heart, skin, gonads, prostate, and breast. VDR activation in the intestine, bone, kidney, and parathyroid gland cells leads to the maintenance of calcium and phosphorus levels in the blood (with the assistance of parathyroid hormone and calcitonin) and to the maintenance of bone content. Thus, 1,25(OH)2 D3 maintains calcium homeostasis by increasing the efficiency of intestinal calcium absorption and mobilizing stores from the skeleton. The VDR is known to be involved in cell proliferation and differentiation. Vitamin D also affects the immune system, and VDR are expressed in several white blood cells including monocytes and activated T and B cells.

12 Biological functions of vitamin D3
Well known for a long time: Regulation of calcium absorption in the gut Regulation of calcium uptake by the bone tissue Regulation of calcium metabolism in muscle Recently added to the list: Role in cancer prevention Role in the regulation of immune function and autoimmune disorder prevention Role in hypertension and CVD prevention Role in the regulation of insulin production Possible involvement in the modulation of cognitive function The classical hormonal function of vitamin D is to control blood levels of calcium by regulating the expression of genes involved in its intestinal absorption, renal excretion and movement in and out of skeleton. Calcitriol also binds to cell membrane receptors, initiating rapid non-genomic signaling, including rapid Ca2+ translocation through voltage-gated ion channels, and up-regulation of the mitogen-activated protein kinase (MAPK) cascade via a protein kinase C signaling pathway. A membrane receptor distinct from the VDR has been described, but the VDR may also be involved. Many other so-called non-calcemic functions of calcitriol have been identified, which include regulation of proliferative and apoptotic activity, immunomodulatory and prodifferentiation activity, and interaction with the rennin-angiotensin system (involved in the regulation of blood pressure), insulin secretion, and neuroprotective functions.

13 Vitamin D deficiency (hypovitaminosis) can be caused by:
Inadequate intake from foods coupled with inadequate sunlight (UVB) exposure Disorders that limit its absorption such as Crohn’ disease, cystic fibrosis and Sprue Liver or kidney disorders that impair the conversion of cholecalciferol to its biologically active 1,25(OH)2 vitamin D3 Aging, increased skin pigmentation and obesity

14 Vitamin D deficiency has been linked to:
Increased susceptibility to high blood pressure and arteriosclerosis Autoimmune disorders including type 1 diabetes Cancer Periodontal disease Multiple sclerosis Chronic pain Depression Poor physical performance in older adults and cognitive impairment Behavioral dysfunction (there is some evidence pointing to an association of schizophrenia with winter births and higher latitude).

15 Vitamin D and cancer

16 Regulation of prostate cell growth by 1,25(OH)2 D3
Extrarenal 1,25(OH)2D synthesis influences local cell proliferation and differentiation and depends on serum 25(OH)D concentrations. Moreover, parathyroid hormone does not regulate the expression of colonic 1-alpha- hydroxylase or CYP27B1, and regulation by calcium is in the opposite direction of that reported for renal hydroxylases. Therefore, sufficiency of 25(OH)D as the precursor is the major known limiting factor for extrarenal synthesis of 1,25(OH)2D. By binding to its nuclear receptor (VDR) vitamin D3 alters the gene expression that regulates cell-cycle arrest, apoptosis and differentiation. Augmented levels of circulating 25(OH)D3 lead to increased synthesis of 1,25()H)2 D3 in extrarenal cells and that helps control growth and maturation, thus decreasing the risk of malignancy. It appears that a 25(OH)D3 blood plasma concentration of at least 20 ng /ml may reduce the risk of developing colon, prostate and breast cancer by 30 to 50%.

17 The interplay between the enzymes that synthesize and inactivate 1,25(OH)2D3 , respectively

18 Modulation of prostaglandin gene expression by vitamin D3

19 Effect of nutrients on vitamin D metabolism
Low serum Ca2+ concentration stimulates renal synthesis of 1,25(OH)2 D3 synthesis Soy genistein inhibits CYP 24 activity Dietary folate inhibits CYP 24 activity by increasing methylation status of the promoter region and by down-regulating expression of the gene for this enzyme

20 Vitamin D receptor (VDR) and diet in relation to cancer risk
Vitamin D receptor gene expression is crucial to vitamin D anticancer activity. Experimental animals that lack VDR have shown increased number of chemically-induced tumors in mammary, skin, prostate and colon organ but not in ovary, liver, lung and uterus organs. Rodents (that usually do not develop colon cancer) fed a diet high in saturated fats and phosphorus and low in calcium, fiber, choline, methionine, folate and vitamin D develop spontaneous colon cancer in some 25% of the cases.

21 Future research trends related to vitamin D and cancer
There is a clear need to: Develop predictive, validated and sensitive biomarkers to evaluate intake or exposure to vitamin D that also includes measuring dietary and supplemental vitamin D intake. At present, the most used biomarker of vitamin D status is 25(OH) D3 but there are no standardized methods for the assay of this metabolite. Better understanding of susceptibility biomarkers where polymorphism plays a major role. polymorphism in VDR was linked to cancer risk. relationship between polymorphisms in other genes in the vitamin D metabolic pathway such as CYP 24 and CYP 27B1, vitamin D status and cancer risk. Better understanding of molecular targets for vitamin D.

22 Vitamin D and the immune function

23 Background Research carried out in the 1980s and 1990s has indicated that: Elevated serum levels of 1,25(OH)2 D3 are frequently recorded in sarcoidosis patients where the disease-associated macrophages expressed CYP 24B1 activity. 1,25(OH)2 D3 inhibited the proliferation of cells expressing the VDR. Despite its long-standing association with rickets and osteoporosis, vitamin D has become increasing ly recognized as a pluripotent regulator of biological functions above and beyond its classical effects on bone and calcium homeostasis. Initial evidence for this arose from studies in the early 1980s demonstrating non-classical effects of the active form of vitamin D—1,25(OH)2D (1,25-dihydroxyvitamin D).

24 Vitamin D and innate immunity
Key points: Screening the human genome for potential vitamin D target genes revealed a 1,25(OH)2 D3 response element in the promoter gene for cathelicidin (antimicrobial peptide called defensin) expressed in cells such as epithelial cells, keratinocytes and some myeloid cell lines. Cathelicidin was also induced by 25(OH)D in cells that express the CYP 27B1. 1,25(OH)2 D3 can induce other factors associated with bacterial killing, e.g. NO synthase. Vitamin D mediated immune response has two important benefits for the host: Macrophage-generated 1,25(OH)2 D3 supports local immunity by enhancing the expression of defensins. Some bacterial species ‘fight back’ by inhibiting the expression of defensins. 1,25(OH)2 D3 also downregulates expression of pathogen recognition receptors and in so doing it acts to limit inflammatory T lymphocyte responses that would otherwise promote autoimmunity mediated by T helper1 lymphocytes.

25 25(OH) D3 and innate immunity
As of late, this perception of non classical functions of vitamin D has changed significantly, with emerging data demonstrating functional responses to the ‘inactive’ form of vitamin D—25OHD—that more closely reflect classical vitamin D physiology. This finding, coupled with increasing awareness of the global variability of vitamin D (i.e. 25OHD) status, has further emphasized the importance of vitamin D sufficiency as a key target in human health. Activation of macrophage TLR (e.g. TLR2) signaling by pathogens such as Mycobacterium tuberculosis results in the transcriptional induction of VDR and CP27B expression (blue arrows). Circulating 25OHD (red circles) bound to plasma DBP enters macrophages (red arrows) and is converted to 1,25(OH)2D (blue circles) by mitochondrial CP27B, and can bind to the VDR in the cell. Once bound to VDR, 1,25(OH)2D is able to act as a transcriptional factor leading to the induction of cathelicidin expression (solid purple arrow). Incorporation into phagosomes containing internalized pathogen enables cathelicidin to function as an antibacterial agent. As well as upregulating cathelicidin expression, macrophage synthesis of 1,25(OH)2D can also facilitate negative autoregulation (dashed purple arrows), firstly via increased expression of the feedback enzyme CP24A and its decoy CP24A-SV, and secondly via downregulation of TLR expression. In parallel with autocrine effects on innate antibacterial function, macrophage CP27B might also induce paracrine responses in monocytes, and T or B lymphocytes as a consequence of 1,25(OH)2D secretion. Abbreviations: 1,25(OH)2D, 1,25-dihydroxyvitamin D; 25OHD, 25-hydroxyvitamin D; CP24A, 1,25(OH)2D 24-hydroxylase; CP24A-SV, 1,25(OH)2D 24-hydroxylase splice variant; CP27B, 25OHD-1α hydroxylase; DBP, vitamin-D-binding protein; TLR, Toll-like receptor 2; VDR, vitamin D receptor.

26 Important points to remember:
Immune responses involve local metabolism of vitamin D as shown by the way 25(OH) D3 influences innate immunity. The presence of VDR in human activated T & B lymphocytes provided evidence for the involvement of vitamin D in processes other than calcium homeostasis and indicated a functional role for this vitamin as a mediator of the acquired (adaptive) immunity. 1,25(OH)2 D3 was found to exert direct effects on B lymphocyte homeostasis by inhibiting its differentiation to plasma cells and class-switched memory cells. This finding suggested a possible role for vitamin D in B lymphocyte-related disorders such as systemic lupus erythematosus. Tissue specific synthesis of 1,25(OH)2 D3 from 25(OH) D3 is crucial to both adaptive and innate immune systems. Vitamin D deficiency is associated with compromised immunity, which means an increased risk for infectious diseases such as tuberculosis and an increased susceptibility to type 1 diabetes.

27 Vitamin D and the cognitive function
There is ample biological evidence to suggest an important role for vitamin D in brain development and function. However, direct effects of vitamin D inadequacy on cognition/behavior in human or rodent systems appear to be subtle, and the current experimental evidence base does not yet fully satisfy causal criteria.

28 There has been growing evidence in the past 20 years or so that micronutrient inadequacy may adversely affect brain function. If a causal relationship between micronutrient deficiencies and the underperforming brain could be demonstrated, that would have major public health implications in terms of enormous savings in medical treatment and care. In the next few slides some of the evidence suggesting such a causal relationship with regard to vitamin D involvement in brain development and cognitive/behavioral function will be presented.

29 1,25(OH)2 D3 target genes in the brain*
Calcitriol acts as a prodifferentiation hormone in many tissues. With reference to the brain, it is of interest that the increase in apoptotic cells and decrease in mitosis in the developing rat brain correlates with the appearance of VDR. Both VDR and 1-alpha hydroxylase (the enzyme that catalyze the synthesis of calcitriol) are present in the fetal and adult brain tissue. Some morphological and biochemical changes were observed in the brains of newborn Sprague-Dawley rats whose serum 25OHD3 levels were >90% lower than controls after dams were restricted for dietary vitamin D and UV radiation 6 wk prior to and during pregnancy.

30 Pro-inflammatory cytokine-induced cognitive/behavioral dysfunction and the possible role of vitamin D3 (calcitriol) There is ample evidence to support the notion that depression is associated with increased concentrations of inflammatory cytokines. Calcitriol modulates the enhanced cellular immune response pathway (Th 1) and autoimmune response. The regulatory mechanism involves the decrease of production of pro-inflammatory cytokines and the increase in the synthesis of anti-inflammatory cytokines. This effect was observed in monocytes, microglia, keratinocytes, endothelial cells and human benign prostate hyperplastic cells. Although there is a large body of evidence showing that poor 25(OH) D3 status is clearly associated with many human diseases in which depression is also a factor, the possible involvement of calcitriol in depression-associated diseases has only been suggested in anxiety and depression fibromyalgia subjects. Elevated levels of pro-inflammatory cytokines in the brain can play a causal role in depression. Cytokines are small proteins synthesized by cells directly involved in immune function, such as macrophages and their counterparts in the brain, microglia, and also by many other nucleated cells in the body. Among a range of functions cytokines play a key role in the inflammatory process. Most cytokines can be classified as either pro-inflammatory or anti-inflammatory. Evidence from a variety of systems supports the pro-inflammatory cytokine theory of depression, first proposed some 25 years ago. In humans, support is provided from studies of clinical depression, sickness behavior resulting from infection, illnesses accompanied by inflammation (e.g., autoimmune diseases, heart disease, osteoporosis), chemotherapy, or experimental treatments with endotoxin.

31 Key points: Evidence that calcitriol is involved in both brain development and function is very strong. Evidence regarding the effect of calcitriol on cognitive/behavioral brain functions is rather suggestive and not so clear-cut. Studies in humans and rodents that directly examined effects of vitamin D deficiency or supplementation on cognitive/behavioral performance suggest subtle changes of those brain functions and several other factors besides vitamin D may come into play. Also, the evidence base does not appear to be solid enough to indicate that there is a direct causal relationship.

32 Relationship between vitamin D, pro-inflammatory cytokines and cognitive dysfunction
The inconclusiveness of the human studies regarding the effect of vitamin D status on the cognitive /behavioral functions of the brain is not particularly surprising, given their small number and the many difficulties involved in conducting human trials. However, it is curious that results of rodent studies are not stronger and more consistent, since rodents afford the opportunity for more flexibility in design and ability to control experimental variables than can be achieved in human studies. If calcitriol plays an important role in brain development and function, one might have predicted that performance deficits would be more obvious, particularly in the studies using a severe dietary restriction model or VDR-KO mice. Several observations suggest that additional research may help to explain this apparent paradox. First, a relatively small number of cognitive/behavioral tests have been conducted. If individual neural systems are affected by vitamin D inadequacy, tests specifically targeted at those systems may be required to achieve sufficient sensitivity to detect an effect. Second, it is possible, given the importance of vitamin D in so many aspects of mammalian biology, that there are homeostatic and/or back-up mechanisms that protect vital organs, such as the brain, from loss of calcitriol-regulated functions. This may be particularly true in rodents, who are covered with fur and primarily nocturnal. In this regard, the recent observation that lithocholic acid can substitute for vitamin D under deficiency conditions in rodents is potentially relevant. Third, effects observed in all in vivo rodent studies that demonstrated effects of calcitriol treatment on gene expression in the brain used relatively high doses of calcitriol; some of these studies injected calcitriol directly into the brain. The only study that used vitamin D3 instead of calcitriol treated animals by gastric cannulation with 20,000 IU/kg/day for 4 mo. It is possible that effects resulting from these high-dose treatments do not occur under physiological conditions. However, calcitriol is believed to exert its effects in an autocrine or paracrine manner, even within tiny "nano-domains" within the cell. Hence, the classical concept of "concentration" may not apply, and very high concentrations of calcitriol may be delivered subcellularly under normal physiological conditions. Fourth, there are very few studies that examined effects of vitamin D deficiency on gene expression. And, we are also not aware of any studies in rodents that examined effects of calcitriol treatment on cognitive or behavioral performance. These experiments seem important to do. And fifth, with respect to use of VDR-KO strains, some critical vitamin D-regulated functions during fetal and neonatal brain development could involve non-VDR-mediated mechanisms. Also, other VDR knockout strains are available, as are 1,alpha-hydroxylase-knockout strains, which might be productive to explore as alternative models.

33 Checking the vitamin D status
The best indication of one’s vitamin D status is the blood level of 1,25(OH)2 D3 . The precursor to calcitriol is a better marker of overall vitamin D status than calcitriol itself. Sun exposure is the best way to get vitamin D synthesized in the skin. It is important to get the optimal sun exposure as opposed to lots of sun exposure. Enough exposure is considered when the skin turns slightly pink. Beyond that is sunburn and skin damage. When using oral vitamin D supplementation it is recommended to check with a health care professional.

34 Good nutrition enhances the quality of life and helps you prevent disease.
The best source of quality micronutrients is in fresh fruit and vegetables. Don’t forget: five servings per day!

35 Credits: sunburn-UV.jpg: Badger-spf-30-chart.gif: uvin.jpg: UV_SkinLayer.jpg: 250px-skinlayers.jpg: SOD enzyme on music: (Dr. M.A. Clark, Texas Wesleyan University) DNA_UV_mutation.jpg VitD&Prostate Cell: Reproduced from J.Nutr. 135, 2739S-2748S (2005) 25(OH)D3&innate immunity: Reproduced from Nat.Clin.Pract.Endocrinol.Metab. 4(2) (2008) VitD&Cognitive Function: Reproduced from FASEB Journal 22, (2008) DNA and proteins can “sing” and that’s part of the metabolic symphony that cells play nonstop. As you can hear there is harmony in the melody that super-oxide dismutase is singing!

36 For the inquisitive mind:
An exciting and provocative book by Bruce Lipton (The Biology of Belief – Hay House, 2008) will certainly challenge the way we look at ourselves and the world around us. Dr. Lipton discusses The Four Myth perceptions of the Apocalypse on YouTube: The four myth perceptions, according to Dr. Lipton are: You live in a mechanical universe Your genes control your life Life is based on survival of the fittest Life evolved as a random process

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