Transcript The Sunshine Vitamin in Health and Disease

The Sunshine Vitamin in Health and Disease
© BioSoft Publishing 2009
Oh, thou life giving celestial
body, welcome to the new day –
Anonymous
UV rays and their biological action on skin cells
UVB causes sunburns (longer exposure)
UVA produces tanning without burning.
Longer exposure causes sunburns.
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 take place in several steps:
1.
Initial redness and swelling – dilation of blood capillaries in the dermis
2.
An inflammatory response is triggered – synthesis of cytokines, prostaglandins, heat shock proteins
3.
Inflammatory cells (lymphocytes, macrophages) move to the interstitial space. Dark red skin, heat and pain
sensation
4.
After 72 hours massive skin peeling off takes place.
Damage to DNA strands caused by UVB radiation
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.
Site of vitamin D synthesis in the skin
 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 295-300 nm. Generation of pre-vitamin D3 depends on the
intensity and wavelength of UV radiation. Under normal circumstances some 25-50 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 photoisomerization reaction because melanin can also absorb UVB radiation.
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 .
Generation of vitamin D3 and its involvement in calcium metabolism
Biological functions of vitamin D3
Well known for a long time:
Recently added to the list:
 Regulation of calcium
absorption in the gut
 Role in cancer prevention
 Regulation of calcium
uptake by the bone tissue
 Regulation of calcium
metabolism in muscle
 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
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
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).
Vitamin D and cancer
Regulation of prostate cell growth by 1,25(OH)2 D3
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%.
The interplay between the enzymes that synthesize and inactivate 1,25(OH)2D3 , respectively
Modulation of prostaglandin gene expression by vitamin D3
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
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.
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.
Vitamin D and the immune function
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.
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:
1. 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.
2. 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(OH) D3 and innate immunity
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.
Vitamin D and the cognitive function
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.
1,25(OH)2 D3 target genes in the brain*
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 antiinflammatory 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.
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.
Relationship between vitamin D, pro-inflammatory cytokines and cognitive dysfunction
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.
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!
Credits:

sunburn-UV.jpg: http://www.rd.com/advice-and-know-how/how-sunburn-works/article76374.html
 Badger-spf-30-chart.gif: http://earthturns.com/ProductDetails.asp?ProductCode=B-SPF30_TUBE
 uvin.jpg: http://coolshade.tamu.edu/burn1.htm
 UV_SkinLayer.jpg: http://www.skinstore.com/store/category.asp?catID=7368
 250px-skinlayers.jpg: http://en.wikipedia.org/wiki/Vitamin_D
 SOD enzyme on music: http://whozoo.org/mac/Music/index.htm (Dr. M.A. Clark,
Texas Wesleyan University)
 DNA_UV_mutation.jpg http://en.wikipedia.org/wiki/Ultraviolet
 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)
80-90 (2008)
 VitD&Cognitive Function: Reproduced from FASEB Journal 22, 982-1001 (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 superoxide dismutase is singing!
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:
http://www.youtube.com/watch?v=VRDHBA8w1f0&feature=PlayList&p=CEB
7B6B207992634&playnext=1&playnext_from=PL&index=4
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