Levels of vitamin D and cardiometabolic disorders: Systematic review and meta-analysis

February 20, 2010 

Cardiometabolic disorders and vitamin D deficiency are becoming increasingly more prevalent across multiple populations. Different studies have suggested a potential association between abnormal vitamin D levels and multiple pathological conditions including cardiovascular diseases and diabetes.

We aimed to evaluate the association between vitamin D levels, using 25-hydroxy vitamin D (25OHD) as an indicator of vitamin D status, and the presence of cardiometabolic disorders including cardiovascular disease, diabetes and metabolic syndrome.

We performed a systematic review of the current literature on vitamin D and cardiometabolic disorders using the PubMed and Web of Knowledge databases in September 2009. Studies in adults looking at the effect of vitamin D levels on outcomes relating to cardiometabolic disorders were selected. We performed a meta-analysis to assess the risk of developing cardiometabolic disorders comparing the highest and lowest groups of serum 25OHD.

From 6130 references we identified 28 studies that met our inclusion criteria, including 99,745 participants. There was moderate variation between the studies in their grouping of 25OHD levels, design and analytical approach. We found that the highest levels of serum 25OHD were associated with a 43% reduction in cardiometabolic disorders [OR 0.57, 95% (CI 0.48–0.68)]. Similar levels were observed, irrespective of the individual cardiometabolic outcome evaluated or study design. High levels of vitamin D among middle-age and elderly populations are associated with a substantial decrease in cardiovascular disease, type 2 diabetes and metabolic syndrome. If the relationship proves to be causal, interventions targeting vitamin D deficiency in adult populations could potentially slow the current epidemics of cardiometabolic disorders.

January 21, 2010

Association of Marine Omega-3 Fatty Acid Levels With Telomeric Aging in Patients With Coronary Heart Disease

         Increased dietary intake of marine omega-3 fatty acids (aka "fish oils") is associated with prolonged survival in patients with coronary heart disease. However, the mechanisms underlying this protective effect are poorly understood.

Objective:  To investigate the association of omega-3 fatty acid blood levels with temporal changes in telomere length, an emerging marker of biological age.

Design, Setting, and Participants:  Prospective cohort study of 608 ambulatory outpatients in California with stable coronary artery disease recruited from the Heart and Soul Study between September 2000 and December 2002 and followed up to January 2009 (median, 6.0 years; range, 5.0-8.1 years).

Main Outcome Measures:  We measured leukocyte telomere length at baseline and again after 5 years of follow-up. Multivariable linear and logistic regression models were used to investigate the association of baseline levels of omega-3 fatty acids (docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]) with subsequent change in telomere length.

Results:  Individuals in the lowest quartile of DHA+EPA experienced the fastest rate of telomere shortening (0.13 telomere-to-single-copy gene ratio [T/S] units over 5 years; 95% confidence interval [CI], 0.09-0.17), whereas those in the highest quartile experienced the slowest rate of telomere shortening (0.05 T/S units over 5 years; 95% CI, 0.02-0.08; P < .001 for linear trend across quartiles). Levels of DHA+EPA were associated with less telomere shortening before (unadjusted ß coefficient x 10^–3 = 0.06; 95% CI, 0.02-0.10) and after (adjusted ß coefficient x 10^–3 = 0.05; 95% CI, 0.01-0.08) sequential adjustment for established risk factors and potential confounders. Each 1-SD increase in DHA+EPA levels was associated with a 32% reduction in the odds of telomere shortening (adjusted odds ratio, 0.68; 95% CI, 0.47-0.98).

Conclusion:  Among this cohort of patients with coronary artery disease, there was an inverse relationship between baseline blood levels of marine omega-3 fatty acids and the rate of telomere shortening over 5 years.

Elderberry flavonoids bind to and prevent H1N1 infection in vitro.

December 23, 2009

    A ionization technique in mass spectrometry called Direct Analysis in Real Time Mass Spectrometry (DART TOF-MS) coupled with a Direct Binding Assay was used to identify and characterize anti-viral components of an elderberry fruit (Sambucus nigra L.) extract without either derivatization or separation by standard chromatographic techniques.
    The elderberry extract inhibited Human Influenza A (H1N1) infection in vitro with an IC(50) value of 252+/-34 microg/mL. The Direct Binding Assay established that flavonoids from the elderberry extract bind to H1N1 virions and, when bound, block the ability of the viruses to infect host cells.  Two compounds were identified, 5,7,3',4'-tetra-O-methylquercetin (1) and 5,7-dihydroxy-4-oxo-2-(3,4,5-trihydroxyphenyl)chroman-3-yl-3,4,5-trihydroxycyclohexanecarboxylate (2), as H1N1-bound chemical species. Compound 1 and dihydromyricetin (3), the corresponding 3-hydroxyflavonone of 2, were synthesized and shown to inhibit H1N1 infection in vitro by binding to H1N1 virions, blocking host cell entry and/or recognition.
    Compound 1 gave an IC(50) of 0.13 microg/mL (0.36 microM) for H1N1 infection inhibition, while dihydromyricetin (3) achieved an IC(50) of 2.8 microg/mL (8.7 microM). The H1N1 inhibition activities of the elderberry flavonoids compare favorably to the known anti-influenza activities of Oseltamivir (Tamiflu; 0.32 microM) and Amantadine (27 microM).

 

Vitamin D - Summary of Research

December 3, 2009

Vitamin D’s role in calcium absorption and bone health is well known. However research over the past twenty years has suggested that vitamin D is also important for reducing the risk of multiple sclerosis^1,2, breast, prostate and colon cancers^3-5, type 1 diabetes and depression⁶. Vitamin D deficiency is not rare; on the contrary it has a very high prevalence and is even recognized as a major health problem for older adults^7-10.

In a recent study on outpatients, 41% of healthy adults, 49 to 83 years of age were found to be vitamin D deficient throughout the year⁷. Students and young adults are also at risk for vitamin D deficiency, especially those who work inside or who always wear sun protection. In a study conducted at the Boston Medical Center, it was observed that 32% of students and doctors 18 to 29 years of age were vitamin D deficient at the end of the winter¹¹. Surprisingly, nowadays even teenagers and young children are at risk. Sullivan et al.¹² observed that 48% of Caucasian girls aged 9 to 13 years were vitamin D deficient at the end of winter and 17% were still vitamin D deficient at the end of summer due to sunscreen and sun protection.

Sources and metabolism of vitamin D 
Sunlight is the primary source of vitamin D^{26, 27}. Exposure of the skin to UVB from sunlight leads to cutaneous synthesis of cholecalciferol (vitamin D) from its precursors²⁸. A very small number of foods naturally contain vitamin D: oily fish such as salmon, mackerel, and sardines, irradiated mushrooms, egg yolks (although they are high in cholesterol and the amounts are low and highly variable), cod liver oil and fortified foods such as milk (100 IU per 8-ounce serving), orange juice (100 IU per 8-ounce serving) and some breads and cereals^{20, 30}.

There are two naturally occurring forms of vitamin D: cholecalciferol (vitamin D3) from animal sources and ergocalciferol (vitamin D2) from plant sources³¹. Recent studies in humans have provided evidence that vitamin D3 is more efficient than vitamin D2 in increasing serum 25-hydroxyvitamin D [25(OH)D], the precursor of the biologically active form of vitamin D, 1,25(OH)D32. The pro-hormone vitamin D, in the form of vitamin D2 or D3, is first metabolized to 25(OH)D in the liver and then further metabolized to 1,25 dihydroxyvitamin D [1,25(OH)2D] by 1-a-hydroxylase in the kidneys and other target tissues³³.

Populations at risk
Individuals who have darkly pigmented skin, those who are obese and the elderly have an increased risk of vitamin D deficiency. Skin pigmentation (melanin) evolved over time as an effective natural sunscreen because it efficiently absorbs UVB photons. It follows that people with increased skin melanin pigmentation require longer exposures to sunlight to make the same amount of vitamin D3. Thus it is very likely that individuals with darkly pigmented skin are vitamin D deficient.

Those who are obese are also much more likely to be vitamin D deficient. Vitamin D is irreversibly sequestered in the fat pool, especially if body mass index exceeds 30. Obese persons also do very little outdoor activity meaning they acquire very little vitamin D from the sun¹³.

Elderly persons metabolize vitamin D less efficiently and also on average spend less time outdoors^14-16. A person 70 years of age makes less than 25% vitamin D3 when exposed to the same amount of sunlight as a 20 year old.

Bone health and development
One of the primary roles of vitamin D is the regulation of calcium/phosphorus absorption and metabolism for bone health. This role becomes more important during pregnancy and lactation as bones are developing rapidly during this period. Furthermore, insufficient vitamin D intake during infancy can result in biochemical disturbances, reduced bone mineralization, slower growth, bone deformities, and increased risk of fracture, all of which make up the symptoms of rickets³⁴. Studies also suggest that vitamin D deficiency could also lead to low birth weight³⁵.

Adult bone metabolism
In adults, vitamin D maintains bone mineral density and prevents osteoporosis³⁶. Vitamin D also maintains muscle strength and a deficiency in vitamin D can lead to osteomalacia, associated with muscle and bone pain^{37, 38}.

Vitamin D is involved in calcium and phosphorus metabolism and maintains serum calcium concentrations within the physiologically acceptable range, by increasing intestinal calcium absorption. In a vitamin D deficient state, the intestine absorbs 10-15% of dietary calcium^{39, 29} where as when there is a sufficient level of vitamin D, 30% of calcium is absorbed from the diet.

In addition to increasing the efficiency of calcium and phosphorus absorption from the intestine and increasing renal re-absorption, vitamin D also plays an important regulatory role in skeletal metabolism. When intestinal calcium absorption decreases, there is a subsequent decrease in ionized calcium in the blood. Calcium sensors in the parathyroid glands respond to low levels of calcium by increasing the production of parathyroid hormone (PTH)⁴⁰. PTH then induces the conversion of pre-osteoclasts into mature osteoclasts and these mature osteoclasts dissolve bone matrix to release calcium into the extracellular space.

Bone is the largest source of calcium used for maintaining serum levels, thus with low levels of vitamin D, more bone is needed for adequate calcium levels and there is therefore an increased risk for fracture, lower bone mineral density and osteoporosis⁴¹. Vitamin D levels are also involved in the treatment of postmenopausal osteoporosis. The effect of vitamin D repletion on the prevention of bone re-absorption was assessed in 1515 postmenopausal women who were being treated with anti-resorbing medication. When tested at a later date, women who remained vitamin D deficient had a significantly lower change in annualized spine and hip/bone mineral density (BMD) when compared to women whose vitamin D levels had been repleted. It was concluded that optimal vitamin D repletion seems to be necessary to maximize the response to anti-resorbers in terms of both BMD changes and anti-fracture efficacy. ⁴²

Vitamin D and muscle strength
Vitamin D appears to have a direct effect on muscle strength and is thought to maintain function of type II muscle fibers¹⁷. Treatment with the active metabolite 1-alpha-hydroxyvitamin D for three months directly increases both the relative number and size of type II muscle fibers¹⁸.

 

 

 

 

 

These physiologic changes may lead to improvements in muscular functioning and therefore could reduce risk of falling and fractures in the elderly. Vitamin D’s protection against fracture risk in the elderly has been attributed to changes in bone mineral density, however; vitamin D may also directly improve muscle strength thereby reducing fracture risk through fall prevention¹⁹. Falls are the single most common cause of injury mortality in the elderly and account for 40% of all nursing home admissions²⁰. A recent meta-analysis reviewed the effect of vitamin D on elderly individuals (mean age 70) for two months to three years. Vitamin D and number of falls showed consistency of effect^21-25 and corrected pooled results indicated that vitamin D treatment reduced the risk of falling by 22% compared with placebo or calcium treatment alone.

Anticarinogenic properties
Vitamin D levels have been linked with the prevention of several forms of cancer. Studies have shown that vitamin D helps prevent breast, colorectal, ovarian and prostate cancers^43-46. Experimental studies have shown that 1,25(OH)2D can inhibit the growth and expansion of cancer cells proliferation, induces cancer cell death, and inhibits the transfer from dormant to malignant tumor cells^47-50.

Studies have shown that an inverse correlation exists between breast cancer mortality and sun exposure/dietary vitamin D intake. In a recent study, two vitamin D receptor (VDR) gene single nucleotide polymorphisms were associated with breast cancer risk lending support the idea that vitamin D, through its signaling pathway, can affect breast cancer risk51. In clinical studies an impaired vitamin D status is associated with a 20 to 30% increase in breast cancer incidence and a 10 to 20% increase in mortality⁵². In another study, the association between vitamin D intake and breast cancer risk among women in a large prospective cohort was assessed. This study, known as the Iowa Women’s health study assessed questionnaire results about diet and supplements use in 34,321 postmenopausal women. Subsequently, information regarding breast cancer incidence from 1986 to 2004 was gathered. Adjusted relative risks for breast cancer were calculated for dietary, supplemental and total vitamin D intake among all women. They found that a vitamin D intake of greater than 800 IU per day was associated with a decrease in risk of breast cancer among postmenopausal women⁵³. Individuals with serum 25(OH)D levels of approximately 52 ng/mL (4000 IU vitamin D per day) had a 50% lower risk of breast cancer than those with serum levels less than 13 ng/mL⁵⁴.

Vitamin D has also been linked to prostate cancer prevention. In a recent study, 14,916 men initially free of diagnosed cancer were re-assessed 18 years later. One thousand and sixty-six men were identified with incident prostate cancer and the relationship between pre-diagnostic plasma levels of 25(OH)D and 1,25(OH)2D with total and aggressive disease was explored. Nearly 13% (summer/fall) to 36% (winter/spring) of the control participants were deficient in 25(OH)D (less than 20 ng/mL) and 51% (summer/fall) and 77% (winter/spring) had insufficient plasma 25(OH)D levels (less than 32 ng/mL). Men whose levels for both 25(OH)D and 1,25(OH)2D were below the median level had a significantly increased risk of aggressive prostate cancer⁵⁵. 

It has also been proposed that vitamin D provides protection against colon cancer. Genetic variation at the VDR locus, in particular Cdx-2 and FokI SNPs, may influence colon cancer risk⁵⁶. This hypothesis is strengthened by inspection of the geographic distribution of colon cancer deaths in the USA. Analysis reveals that colon cancer mortality rates are highest in places where populations were exposed to the least amounts of natural light (major cities and rural areas at high latitudes)⁵⁷.

Finally, vitamin D has also been shown to reduce the risk of ovarian cancer. A north to south gradient in mortality rates of ovarian cancer exists in the USA (after age adjustments). The highest rates of death occur in the Northeast areas and the lowest mortality rates are in the South through Southwest areas of the United States. This lends to the hypothesis that lower levels of solar radiation are associated with a higher risk of ovarian cancer. Indeed, a recent study which looked at the association of solar ultraviolet B and incidence of ovarian cancer in 175 countries found that solar UVB irradiance is inversely associated with incidence rates of ovarian cancer⁵⁸.

Protection from diabetes
In a recent meta-analysis, done to assess the role of vitamin D in type 2 diabetes, several observational studies showed a relatively consistent association between low vitamin D status, calcium or dairy intake, and prevalence of type 2 diabetes or metabolic syndrome. There was also an inverse association with incidence of type 2 diabetes or metabolic syndrome with intake of vitamin D. Regular doses of vitamin D daily early in life have been projected to reduce diabetes incidence by 80% over the next 30 years⁵⁹ and clinical trials with vitamin D and/or calcium supplementation have suggested that vitamin D and calcium have a role in the prevention of type 2 diabetes in populations at high risk. Vitamin D and calcium insufficiency may negatively influence glycemia, whereas combined supplementation with both nutrients may be beneficial in optimizing glucose metabolism for the prevention of diabetes⁶⁰. The active metabolite of vitamin D, 1,25-Dihydroxyvitamin D, is a potent immunomodulator that enhances the production and secretion of several hormones, including insulin. Furthermore, glycemic control and insulin resistance are improved when vitamin D deficiency is corrected⁶¹. A longitudinal study that began in 1966 administered 2000 IU of vitamin D to children and revealed there was an 80% reduction in the development of type 1 diabetes throughout the following thirty years in those children given vitamin D⁶². In another study, increasing vitamin D levels from 25 to 75 nmol/l led to a 60% improvement in insulin sensitivity^63,64. Finally, low vitamin D levels have been shown to have a negative effect on beta cell function⁶⁵.

Improved immune system and protection from influenza
Vitamin D plays an important role in the regulation of immune system function and limits the over-production of lymphocytes and the cytokine cascades⁶⁶. Over activity of T-helper cell mobilization can lead to an attack of the body’s own cells. Vitamin D suppresses T-helper cell over activity, and therefore plays an important role in the prevention of autoimmune diseases such as type 1 diabetes, rheumatoid arthritis, scleroderma and graft rejection^67,68. However, perhaps of even greater importance, is vitamin D’s dramatic ability to stimulate the expression of potent anti-microbial peptides. Vitamin D stimulates the anti-microbes which exist in neutrophils, monocytes, natural killer cells and in epithelial cells lining the respiratory system. Thus, vitamin D plays a major role in protecting the lung from infection.

Influenza is one of several respiratory viruses that show a distinct increase in infection during winter months. Influenza in North America and Europe, for example generally reaches epidemic peaks during December to March⁶⁹. These are the months during which the UVB irradiance and serum levels of 25-hydroxyvitamin D3 are lowest in the population. A recent randomized controlled trial presented evidence that vitamin D provides a dramatic preventative effect against influenza and colds⁷⁰. In a post-hoc analysis of their original three-year study, it was discovered that 104 post-menopausal African American women given vitamin D were three times less likely to report cold and flu symptoms than 104 placebo controls. A low dose (800 IU per day) reduced reported incidence of cold or flu, and abolished the seasonality of cold and flu reports. A higher dose (2000 IU per day), given during the last year of the trial, eliminated all reports of colds or flu.

Vitamin D has been deemed the "antibiotic vitamin"⁷¹ due primarily to its robust effects on innate immunity, the part of the immune system that responds rapidly to microorganisms using a genetically encoded effector that is ready to attack an antigen before the body has ever encountered that particular antigen. Furthermore, vitamin D appears to enhance the local capacity of the epithelium to produce endogenous antibiotics while it dampens parts of the adaptive immune response, like the signs and symptoms of acute inflammation⁷².

Cardiovascular disease
Vitamin D was shown to inhibit vascular smooth-muscle proliferation, suppress vascular calcification, down-regulate pro-inflammatory cytokines and up-regulate anti-inflammatory cytokines. Vitamin D acts as a negative endocrine regulator of the renin-angiotensin system⁷⁶ and researchers now believe that vitamin D deficiency could contribute to congestive heart failure^77,78.

Calcium and vitamin D supplementation result in a 9.3% decrease in systolic blood pressure, a 5.4% decrease in heart rate⁷⁹ and substantially reduces C-reactive protein levels in critically ill patients⁸⁰. The dose necessary to prevent cardiovascular ailments is unknown, but 2000 - 4000 IU of vitamin D3 has been suggested⁸¹. Research also suggests that plasma 25[OH]D concentrations are associated with risk of coronary heart disease. In a recent study, men deficient in 25(OH)D were at increased risk for myocardial infarction compared with those considered to be sufficient in 25(OH)D. Low levels of 25(OH)D were associated with a higher risk of myocardial infarction even after controlling for factors known to be associated with coronary artery disease⁸².

Disorders of the brain and cognition
Vitamin D receptors can be found all throughout the body and are also present in the brain which suggests they are involved in neural behavior. Indeed, a retrospective review of older adults found a positive correlation between score on the mini-mental state examination and serum vitamin D levels which suggests that vitamin D promotes cognitive abilities in the elderly⁸³. In another study vitamin D deficiency was associated with low mood and with impairment on two of four measures of cognitive performance.

Multiple sclerosis
There is evidence of correlation between frequency of multiple sclerosis (MS) lesions, seasonality^84,85 and geographic latitude^86,87. Studies also suggest that there is a latitude gradient for risk of developing MS. For example, in Australia, the risk of MS in temperate Tasmania is fivefold that of the much sunnier Queensland^88,89. Living at a latitude higher than 37 degrees, where there is less UV exposure increases the risk of developing multiple sclerosis by more than 100%.

Studies also suggest that month of birth and risk of MS is clearly associated, more so in familial cases, implying an interaction exists between genes and environment which is related to latitude⁹⁰. In light of these discoveries, it was hypothesized that vitamin D provides a protective effect and reduces ones risk of MS. Kraght et al., 2008 found that high serum levels of vitamin D decreased the risk of MS⁹¹. An inverse relationship exists between serum vitamin D and MS clinical activity⁹² and high serum levels of vitamin D decrease the relapse rate in MS diseased patients⁹³. Taking a multivitamin with 400 IU of vitamin D is able to reduce the risk of MS by as much as 40%^74,75.

The risk of osteoporosis is high in patients with MS and vitamin D supplementation is often recommended in the early stages of the disease⁹⁴.

Mood and well-being
Vitamin D levels are related to positive mood and well-being and serum concentrations of vitamin D have been shown to be significantly lower in patients with unipolar and bipolar depression⁹⁵. In a randomized study, eight subjects with seasonal affective disorder received vitamin D supplementation and seven subjects received phototherapy. Vitamin D, but not phototherapy was associated with improvement in depression measures⁹⁶. Four-hundred and forty-one subjects were given the Beck Depression Inventory (BDI) and scores were related to vitamin D levels. Subjects with serum 25(OH)D levels <40 nmol/l scored significantly higher (more depressive traits) than those with serum 25(OH)D levels > or = 40 nmol/l; vitamin D supplementation for a year significantly improvement depression scores⁹⁷. Finally, Lansdowne and Provost⁹⁸ randomized 44 healthy subjects to vitamin D3 supplementation over five days in late winter, and reported that vitamin D3 was associated with improved positive effect, in conjunction with reduced negative effect.

Autism
The research suggesting autism could be linked to vitamin D is not direct but rather is inferred and circumstantial. An increase in autism over the last two decades corresponds with advice to avoid the sun. In rats, severe vitamin D deficiency during gestation leads to abnormalities similar to those found in autism such enlarged ventricles⁹⁹. Children with rickets (from very low vitamin D) are likely to be hypotonic, display decreased activity, and have developmental motor delays before treatment¹⁰⁰. Hypotonia is also common in children with autism¹⁰¹, as is decreased activity¹⁰² and developmental motor delays¹⁰³. Children with vitamin D deficiency have several autistic markers¹⁰⁴, autism is more common in areas where the population receives lower doses of UVB¹⁰⁵, and autism is more common in dark-skinned persons¹⁰⁶.

Chronic pain
A number of studies have suggested a link between low levels of vitamin D and higher incidence of chronic pain^107-109. The relationship between latitude/season of the year and pain offer circumstantial evidence that vitamin D could be involved. Vitamin D has been associated with several types of pain: headaches, abdominal pain, knee pain and back pain; but the evidence is not yet entirely convincing^110-112. Six selected cases have demonstrated improvement/resolution of chronic back pain after vitamin D repletion in a Canadian family practice setting¹¹³.

Grove et al.¹¹⁴ assessed backache in postmenopausal women. When 50,000 IU of the vitamin D metabolite calciferol was administered twice weekly there was a signi?cantly better improvement in ‘pain-mobility score’ compared to placebo. Al Faraj and Al Mutairi¹¹⁵ published a case series that assessed chronic low back pain without obvious cause in 360 people. Vitamin D (5000 10,000 IU per day) led to a disappearance of low back pain in 341 of the 360 participants. Goth et al.¹¹⁶ looked at unusual pain resistant to analgesics but in only five people. Pain was resolved five to seven days after supplementation. Unfortunately there is a striking contrast in treatment effects between randomized, double blind trials and those with open designs making it difficult to conclude whether vitamin D is or is not beneficial to pain.

Asthma
As mentioned, vitamin D is important in host defenses against respiratory tract pathogens and studies suggest that vitamin D deficiency increases the risk of respiratory infections. New research suggests that this increased risk may contribute to incident wheezing and illness and may cause asthma exacerbations in both children and adults. Although unproven, the increased risk of respiratory infection could contribute to some cases of asthma. Vitamin D also modulates regulatory T-cell function and interleukin-10 production. This could increase the therapeutic response to glucocorticoids in steroid-resistant asthma¹¹⁷. Furthermore, Brehm et al 2009¹¹⁸ found that vitamin D insufficiency is frequent in asthmatic children and that lower vitamin D levels are associated with increased markers of allergy and asthma severity.

Obesity and body fat
Several studies have shown adult obesity to be inversely correlated with 25OHD levels^119-125 and it has been suggested that adipogenesis may be inhibited by 1,25 dihydroxyvitamin D¹²⁶. Vitamin D insufficiency is associated with increased body fat and decreased height in 90 adolescents females (age 16-22)¹²⁷.

Skin health
Vitamin D has been shown to be beneficial in wound healing, atopic dermatitis (AD) and psoriasis. Cathelicidins were among the ?rst families of antimicrobial peptide (AMPs) discovered on the skin. Cathelicidins have direct antimicrobial activity and will initiate a host cellular response resulting in cytokine release, in?ammation and angiogenesis^128,129. Dysfunction of cathelicidin is relevant in the pathogenesis of several cutaneous diseases and could provide new treatment modalities in the management of infectious and in?ammatory skin diseases including atopic dermatitis (where cathelicidin induction is suppressed) and psoriasis, where a cathelicidin peptide can convert self-DNA to a potent stimulus of an autoin?ammatory cascade¹³⁰. Recent work has identi?ed vitamin D as a major factor involved in the regulation of cathelicidin expression¹³¹. To follow, when patients with atopic dermatitis were given 4000 IU per day oral vitamin D for 21 days, AD lesional skin showed a statistically signi?cant increase in cathelicidin expression¹³². Providing further support to vitamin D’s modulation of AD; atopic dermatitis is more common at higher latitudes, places where vitamin D would be diminished¹³³.

Oral vitamin D has also been assessed in psoriasis. When oral calcitriol was given to 85 psoriasis patients; 88% had some improvement in their disease and 26.5,36.2 & 25.3 had complete, moderate and slight improvement in their disease, respectively. The mean baseline psoriasis area severity index score (PASI) was reduced after oral calcitriol therapy¹³⁴.

Vitamin D3 was evaluated for its actions on dermal wound healing in Wistar rats. Intraperitonial injectons of cholecalciferol at 5, 10, 15 IU/g body weight doses produced increases in wound breaking strength and promoted epithelization¹³⁵. Furthermore in an in vitro study, 0.5 mM of 1,25(OH)2D3, the active metabolite of vitamin D modulated keratinocyte proliferation & increased wound healing¹³⁶.  

The optimal dose of vitamin D
The current recommended daily allowance for vitamin D is 200 IU for children and adults under 50 years of age, 400 IU for adults aged 51 to 70 and 600 IU for those older than 70 years¹³⁷. Recent evidence related to osteoporosis, as presented above, however, suggests that the current RDA is too low to maintain optimal vitamin D status. Vitamin D has a very low degree of toxicity. Hypercalcemia, the main toxic effect does not usually develop until serum 25-OH vitamin D levels are over 500 nmol/l (200 ng/mL) and is more common above 750 nmol/l (300 ng/mL)¹³⁸. Single doses of vitamin D3 as high as 600 000 IU have been administered without producing hypercalcemia139,140. The current tolerable upper intake level (UL) for vitamin D is 50 mcg/d (2000 IU per day) in North America and Europe¹⁴¹ and in the United Kingdom a guidance level exists for vitamin D of 1000 IU per day¹⁴². However sun exposure to the skin safely provides vitamin D in an amount equivalent to an oral dose of 250 mcg/^d143-144. Unfortunately, low and inappropriate upper intake values have hindered objective clinical research on vitamin D nutrition and have thus diminished our understanding of its role in disease prevention.

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Quercetin reduces systolic blood pressure and plasma oxidised low-density lipoprotein concentrations in overweight subjects with a high-cardiovascular disease risk phenotype: a double-blinded, placebo-controlled cross-over study

October 5, 2009

Regular consumption of flavonoids may reduce the risk for CVD. However, the effects of individual flavonoids, for example, quercetin, remain unclear. The present study was undertaken to examine the effects of quercetin supplementation on blood pressure, lipid metabolism, markers of oxidative stress, inflammation, and body composition in an at-risk population of ninety-three overweight or obese subjects aged 25–65 years with metabolic syndrome traits. Subjects were randomised to receive 150 mg quercetin/d in a double-blinded, placebo-controlled cross-over trial with 6-week treatment periods separated by a 5-week washout period. Mean fasting plasma quercetin concentrations increased from 71 to 269 nmol/l (P < 0·001) during quercetin treatment. In contrast to placebo, quercetin decreased systolic blood pressure (SBP) by 2·6 mmHg (P < 0·01) in the entire study group, by 2·9 mmHg (P < 0·01) in the subgroup of hypertensive subjects and by 3·7 mmHg (P < 0·001) in the subgroup of younger adults aged 25–50 years. Quercetin decreased serum HDL-cholesterol concentrations (P < 0·001), while total cholesterol, TAG and the LDL:HDL-cholesterol and TAG:HDL-cholesterol ratios were unaltered. Quercetin significantly decreased plasma concentrations of atherogenic oxidised LDL, but did not affect TNF-a and C-reactive protein when compared with placebo. Quercetin supplementation had no effects on nutritional status. Blood parameters of liver and kidney function, haematology and serum electrolytes did not reveal any adverse effects of quercetin. In conclusion, quercetin reduced SBP and plasma oxidised LDL concentrations in overweight subjects with a high-CVD risk phenotype. Our findings provide further evidence that quercetin may provide protection against CVD.

 

Omega-3 Dietary Supplements and the Risk of Cardiovascular Events: A Systematic Review

Paul E. Marik, MD, FACP, FCCP, FCCM 1 *, Joseph Varon, MD, FACP, FCCP, FCCM 2

1Division of Pulmonary and Critical Care Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 2The University of Texas Health Science Center at Houston, Houston, Texas

Abstract

Background

Epidemiologic data suggest that omega-3 fatty acids derived from fish oil reduce cardiovascular disease. The clinical benefit of dietary fish oil supplementation in preventing cardiovascular events in both high and low risk patients is unclear.

Objective

To assess whether dietary supplements of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) decrease cardiovascular events across a spectrum of patients.

Data Sources

MEDLINE, Embase, the Cochrane Database of Systematic Reviews, and citation review of relevant primary and review articles.

Study Selection

Prospective, randomized, placebo-controlled clinical trials that evaluated clinical cardiovascular end points (cardiovascular death, sudden death, and nonfatal cardiovascular events) and all-cause mortality in patients randomized to EPA/DHA or placebo. We only included studies that used dietary supplements of EPA/DHA which were administered for at least 1 year.

Data Extraction

Data were abstracted on study design, study size, type and dose of omega-3 supplement, cardiovascular events, all-cause mortality, and duration of follow-up. Studies were grouped according to the risk of cardiovascular events (high risk and moderate risk). Meta-analytic techniques were used to analyze the data.

Data Synthesis

We identified 11 studies that included a total of 39 044 patients. The studies included patients after recent myocardial infarction, those with an implanted cardioverter defibrillator, and patients with heart failure, peripheral vascular disease, and hypercholesterolemia. The average dose of EPA/DHA was 1.8 ± 1.2 g/day and the mean duration of follow-up was 2.2 ± 1.2 years. Dietary supplementation with omega-3 fatty acids significantly reduced the risk of cardiovascular deaths (odds ratio [OR]: 0.87, 95% confidence interval [CI]: 0.79-0.95, p = 0.002), sudden cardiac death (OR: 0.87, 95% CI: 0.76-0.99, p = 0.04), all-cause mortality (OR: 0.92, 95% CI: 0.85-0.99, p = 0.02), and nonfatal cardiovascular events (OR: 0.92, 95% CI: 0.85-0.99, p = 0.02). The mortality benefit was largely due to the studies which enrolled high risk patients, while the reduction in nonfatal cardiovascular events was noted in the moderate risk patients (secondary prevention only). Meta-regression failed to demonstrate a relationship between the daily dose of omega-3 fatty acid and clinical outcome.

Conclusions

Dietary supplementation with omega-3 fatty acids should be considered in the secondary prevention of cardiovascular events.

             


A SYNOPSIS OF THE EPIC POTSDAM STUDY

 

 

 

 

 

 

 

 

 

 

Our findings build and expand on those from other prospective studies that have examined the relationships between the number of healthy lifestyle factors and various end points. Of the 84 129 participants of the Nurses' Health Study,  1128 of whom developed a coronary event during 14 years of follow-up, those who were at low risk had a relative risk of developing Coronary Heart Disease (CHD) of 0.17 (95% Confidence Interval (CI), 0.07-0.41). The lifestyle factors considered were not currently smoking, a Body Mass Index (BMI, calculated as weight in kilograms divided by height in meters squared) lower than 25, alcohol consumption of at least 0.5 drinks per day, at least 0.5 hours of moderate to vigorous physical activity per day, and adhering to several dietary elements (increased intake of cereal fiber, marine omega-3 fatty acids, and folic acid; increased ratio of polyunsaturated fats to saturated fats; and low trans fat intake and glycemic load). Another analysis of this same cohort showed that women who were at low risk as evidenced by practicing a healthy lifestyle had a substantially reduced risk of developing diabetes (3300 events during 16 years of follow-up) (relative risk, 0.09; 95% CI, 0.05-0.17). The behaviors of interest were similarly specified, but the dietary variable was modified.

Among 2539 participants of the Healthy Aging: a Longitudinal Study in Europe, the adjusted hazard ratio (aHR) was 0.35 (95% CI, 0.28-0.44) for those with all four factors of interest (Mediterranean diet, moderate alcohol use, physical activity, and not smoking) compared with those not engaging in any of these factors.

In an analysis of data from 37 636 participants aged 45 years or older from the Women's Health Study, 450 of whom developed a stroke during a mean 10 years of follow-up, the aHRs for participants who scored higher on an index of lifestyle factors than those who scored lower were 0.45 (95% CI, 0.24-0.83) for total stroke, 0.29 (95% CI, 0.14-0.63) for ischemic stroke, and 1.27 (95% CI, 0.37-4.29) for hemorrhagic stroke. Lifestyle factors considered in this study were smoking, alcohol use, exercise, BMI, and diet.

In the Health Professionals Follow-up Study, 42 847 men aged 40 to 75 years were followed up over 16 years, and 2183 developed a coronary event. Compared with men with no healthy lifestyle factors, those with all five factors had a large reduction in the risk of developing CHD (HR, 0.13; 95% CI, 0.09-0.19). The lifestyle factors in this study were characterized in much the same way as in the previous studies.

In an analysis of 15 708 participants in the Atherosclerosis Risk in Communities Study, those who adopted a healthy lifestyle experienced a lower risk of all-cause mortality (odds ratio, 0.60; 95% CI, 0.39-0.92) and CVD (odds ratio, 0.65; 95% CI, 0.39-0.92) during four years of follow-up. The four healthy lifestyles considered were eating 5 or more fruits and vegetables per day, exercising 2.5 h/wk or more, having a BMI between 18.5 and 30.0, and not smoking.

Among 20 244 participants in the EPIC-Norfolk study, sizeable reductions in all-cause mortality were demonstrated with increasing numbers of health factors. Participants with all four factors (current not smoking, not physically inactive, moderate alcohol use, and plasma vitamin C level greater than 0.88 mg/dL [to convert to micromoles per liter, multiply by 56.78] as a surrogate for fruit and vegetable consumption) had an advantage of approximately 14 years in chronological age over those without one of the four factors.

Finally, analyses of data from 43 685 participants in the Health Professionals Follow-up Study (994 strokes) and 71 243 participants in the Nurses' Health Study (1559 strokes) showed substantial reductions in the risk of developing an incident stroke among men (relative risk, 0.31; 95% CI, 0.19-0.53) and women (relative risk, 0.21; 95% CI, 0.12-0.36) who practiced a low-risk lifestyle compared with those who did not.  Men were followed up from 1984 to 2004, and women were followed up from 1986 to 2004. The lifestyle factors considered were not currently smoking, at least 30 minutes of moderate to vigorous physical activity per day, a diet score in the top 40%, alcohol consumption of 5 to 15 g/d for women and 5 to 30 g/d for men, and a BMI lower than 25.

We showed that each lifestyle factor was associated with a reduction in risk and that the reduction in risk from combinations of factors followed the multiplicative model. This finding implies that each factor contributes to risk reduction independently of the other factors in the estimated magnitude. The only exception was the combination of diet index above the median and physical exercise, which showed a larger risk reduction as estimated from the relative risk of the single factors. The favorable effect on the risk of developing chronic disease of these two factors was likely partially mediated through BMI. The previous prospective studies that examined the effect of healthy factors on adverse outcomes did not examine the effects of different combinations of lifestyle factors on outcomes. Because our findings may have occurred by chance, the results of other studies investigating the effects of healthy lifestyle on incident chronic disease will be valuable in gauging the significance of this result.

In contrast to some of these studies, we elected not to include moderate use of alcohol as a potentially beneficial behavior. Because of the well-documented harms caused by alcohol abuse,  a great deal of reluctance exists in the public health community to recommend drinking moderately for fear that the message will be misinterpreted and viewed as endorsing unfettered alcohol use. Although moderate alcohol consumption may add to the risk reduction generated by the other four behaviors, any recommendations regarding moderate use of alcohol will require a thoughtful evaluation of whether potential benefits outweigh the clear harms of alcohol abuse.

STUDY LIMITATIONS

Our results should be considered in the light of several limitations. The assessment of end points was based on self-reported information with physician confirmation. Thus, some proportion of incident end points remained undetected. If the association between the exposures and the end points was similar for detected and undetected end points, our HRs should be unbiased.  Second, information about the lifestyle factors except BMI was self-reported and thus is subject to information bias and misclassification. If the misclassification were random, our HRs would have been attenuated. Third, we used a few simple concepts to define adherence to good dietary principles. However, other approaches to characterizing good dietary practices exist and could generate different results. Finally, the results of this study are generalizable to the German population where the study was conducted. Additional studies in other populations will be needed to evaluate how much of chronic disease morbidity and mortality is potentially preventable in other populations.

CONCLUSIONS

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The data from the EPIC-Potsdam study show the unfulfilled potential of preventing chronic diseases. Adhering to recommendations for the four lifestyle factors considered in our analyses can potentially yield enormous reductions in the onset of major chronic diseases such as CVD, diabetes, and cancer. For those with none of the factors, achieving even one promises to increase the time free of the four chronic conditions, and further gains accrue as the number of such factors increases. However, our findings also illustrate the heterogeneity in potential risk reduction that exists among the various combinations of healthy factors, a finding that expands on the previous literature concerning the relationships between healthy lifestyle factors and the incidence of chronic disease. Our results and those of others emphasize the importance and urgency of continuing vigorous efforts to convince people to adopt healthy lifestyles. Because the roots of these factors often originate during the formative stages of life, it is especially important to start early in teaching the important lessons concerning healthy living.

Curcumin Synergizes With Resveratrol to Inhibit Colon Cancer

Authors: Adhip P. N. Majumdar ^abc;  Sanjeev Banerjee ^b;  Jyoti Nautiyal ^b;  Bhaumik B. Patel ^ab;  Vaishali Patel ^c;  Jianhua Du ^c;  Yingjie Yu ^c;  Althea A. Elliott ^a;  Edi Levi ^ac; Fazlul H. Sarkar ^bc

Affiliations:	a John D. Dingell VA Medical Center, Detroit, Michigan, USA
	b Karmanos Cancer Center, Detroit, Michigan, USA
	c Wayne State University, Detroit, Michigan, USA

 

Abstract Development and progression of many malignancies, including colorectal cancer, are associated with activation of multiple signaling pathways. Therefore, inhibition of these signaling pathways with noncytotoxic natural products represents a logical preventive and/or therapeutic approach for colon cancer. Curcumin and resveratrol, both of which inhibit the growth of transformed cells and colon carcinogenesis, were selected to examine whether combining them would be an effective preventive and/or therapeutic strategy for colon cancer. Indeed, the combination of curcumin and resveratrol was found to be more effective in inhibiting growth of p53-positive (wt) and p53-negative colon cancer HCT-116 cells in vitro and in vivo in SCID xenografts of colon cancer HCT-116 (wt) cells than either agent alone. Analysis by Calcusyn software showed synergism between curcumin and resveratrol. The inhibition of tumors in response to curcumin and/or resveratrol was associated with the reduction in proliferation and stimulation of apoptosis accompanied by attenuation of NF-?B activity. In vitro studies have further demonstrated that the combinatorial treatment caused a greater inhibition of constitutive activation of EGFR and its family members as well as IGF-1R. Our current data suggest that the combination of curcumin and resveratrol could be an effective preventive/therapeutic strategy for colon cancer.