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Improved cholecalciferol nutrition in rats is noncalcemic, suppresses parathyroid hormone and increases responsiveness to 1, 25-dihydroxycholecalciferol. Vieth R, Milojevic S, Peltekova V. J Nutr. 2000 Mar;130(3):578-84. PMID: 10702588 We conclude suppression of 1,25(OH)(2)D and PTH, and higher renal VDR mRNA and 24-hydroxylase did not involve higher free 1,25(OH)(2)D concentration or a first pass effect at the gut. Thus, 25(OH)D or a metabolite other than 1,25(OH)(2)D is a physiological, transcriptionally and biochemically active, noncalcemic vitamin D metabolite. When viewed from a perspective that starts with higher vitamin D nutrition, the results indicate that low vitamin D nutrition may bring about a form of resistance to 1,25(OH)2D. This situation would explain why, in humans, nutritional rickets and osteomalacia are commonly associated with normal or increased levels of 1,25(OH)2D (Chesney et al. 1981Citation , Eastwood et al. 1979Citation , Garabedian et al. 1983Citation ,Rasmussen et al. 1980Citation )-these are not like the low hormone levels associated with any other endocrine-deficiency disorder. A connection between lower vitamin D nutrition and vitamin D resistance helps to explain why the supposedly inactive compound 25(OH)D is more relevant in diagnosing nutritional rickets than is the active hormone 1,25(OH)2D. If the features of improved vitamin D nutrition shown here were demonstrated for any newly synthesized compound, the compound would be classified as a noncalcemic 1,25(OH)2D analogue (Brown et al. 1989Citation , Finch et al. 1999Citation , Goff et al. 1993Citation , Koshizuka et al. 1999Citation ). Thus, we contend that 25(OH)D or a metabolite of it other than 1,25(OH)2D exists as a physiological and biologically-active noncalcemic vitamin D metabolite whose effects require further examination, particularly in relationship to studies involving the synthetic analogs of 1,25(OH)2D.

Vitamin D metabolites as clinical markers in autoimmune and chronic disease. Blaney GP, Albert PJ, Proal AD. Ann N Y Acad Sci. 2009 Sep;1173:384-90. PMID: 19758177 DOI: 10.1111/j.1749-6632.2009.04875.x

Essential fatty acids and their metabolites could function as endogenous HMG-CoA reductase and ACE enzyme inhibitors, anti-arrhythmic, anti-hypertensive, anti-atherosclerotic, anti-inflammatory, cytoprotective, and cardioprotective molecules.\nDas UN.\nLipids Health Dis. 2008 Oct 15;7:37. Review.\nPMID: 18922179 \ndoi:10.1186/1476-511X-7-37

Vitamin D and breast cancer. Bertone-Johnson ER. Ann Epidemiol. 2009 Jul;19(7):462-7. Epub 2009 Feb 20. Review. PMID: 19230714 Though the relationship between vitamin D and breast cancer remains unclear, a growing body of evidence suggests that vitamin D may modestly reduce risk. A large number of in vitro studies indicate that vitamin D can inhibit cell proliferation and promote apoptosis and cell differentiation in breast tumor tissue. Results from analytic studies of sunlight exposure and dietary intake have been inconsistent but together generally support a modestly protective role of vitamin D, at least in some population subgroups. Studies using blood vitamin D metabolites to assess vitamin D status may be less prone to misclassification than those of diet and sunlight exposure. Overall, the two prospective and four case-control studies of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D tend to support a protective effect in older women. The relationship between common vitamin D receptor polymorphisms and risk remains unclear. Many questions about this relationship clearly remain, including the utility of assessing vitamin D through diet and sunlight exposure, the relationship between plasma metabolites, and the potential modifying effects of age, menopausal status and tumor characteristics. Given that vitamin D status is modifiable, additional prospective studies are necessary to determine if vitamin D may have important potential for breast cancer prevention.

Li H, Stampfer MJ, Hollis JBW, Mucci LA, Gaziano JM, et al. (2007) A Prospective Study of Plasma Vitamin D Metabolites, Vitamin D Receptor Polymorphisms, and Prostate Cancer. PLoS Med 4(3): e103 doi:10.1371/journal.pmed.0040103

Barger-Lux MJ, Heaney RP, Dowell S, Chen TC, Holick MF. Vitamin D and its major metabolites: serum levels after graded oral dosing in healthy men.Osteoporos Int. 1998;8(3):222-30.PMID: 9797906 [PubMed - indexed for MEDLINE]

Serum levels of vitamin D metabolites and breast cancer risk in the prostate, lung, colorectal, and ovarian cancer screening trial. Freedman DM, Chang SC, Falk RT, Purdue MP, Huang WY, McCarty CA, Hollis BW, Graubard BI, Berg CD, Ziegler RG. Cancer Epidemiol Biomarkers Prev. 2008 Apr;17(4):889-94. Epub 2008 Apr 1. PMID: 18381472 doi: 10.1158/1055-9965.EPI-07-2594 In this prospective study of postmenopausal women, we did not observe an inverse association between circulating 25(OH)D or 1,25(OH)2D and breast cancer risk, although we cannot exclude an association in younger women or with long-term or earlier exposure

Association study on two vitamin D receptor gene polymorphisms and vitamin D metabolites in multiple sclerosis. Smolders J, Damoiseaux J, Menheere P, Tervaert JW, Hupperts R. Ann N Y Acad Sci. 2009 Sep;1173:515-20. PMID: 19758194 DOI: 10.1111/j.1749-6632.2009.04656.x Discussion: We found no association of the Apal and Taql VDR gene SNPs with MS or with vitamin D metabolism in our population. Further research should assess the complex interaction between vitamin D, the VDR, and susceptibility to MS.

Vitamin D and its major metabolites: serum levels after graded oral dosing in healthy men. Barger-Lux MJ, Heaney RP, Dowell S, Chen TC, Holick MF. Osteoporos Int. 1998;8(3):222-30. PMID: 9797906

Vitamin D in preventive medicine: are we ignoring the evidence? Zittermann A. Br J Nutr. 2003 May;89(5):552-72. Review. PMID: 12720576 Vitamin D is metabolised by a hepatic 25-hydroxylase into 25-hydroxyvitamin D (25(OH)D) and by a renal 1alpha-hydroxylase into the vitamin D hormone calcitriol. Calcitriol receptors are present in more than thirty different tissues. Apart from the kidney, several tissues also possess the enzyme 1alpha-hydroxylase, which is able to use circulating 25(OH)D as a substrate. Serum levels of 25(OH)D are the best indicator to assess vitamin D deficiency, insufficiency, hypovitaminosis, adequacy, and toxicity. European children and young adults often have circulating 25(OH)D levels in the insufficiency range during wintertime. Elderly subjects have mean 25(OH)D levels in the insufficiency range throughout the year. In institutionalized subjects 25(OH)D levels are often in the deficiency range. There is now general agreement that a low vitamin D status is involved in the pathogenesis of osteoporosis. Moreover, vitamin D insufficiency can lead to a disturbed muscle function. Epidemiological data also indicate a low vitamin D status in tuberculosis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases, hypertension, and specific types of cancer. Some intervention trials have demonstrated that supplementation with vitamin D or its metabolites is able: (i) to reduce blood pressure in hypertensive patients; (ii) to improve blood glucose levels in diabetics; (iii) to improve symptoms of rheumatoid arthritis and multiple sclerosis. The oral dose necessary to achieve adequate serum 25(OH)D levels is probably much higher than the current recommendations of 5-15 microg/d.

Vitamin D may suppress infections which lead to development of Multiple Sclerosis Steven R Brenner, None (16 August 2007) J Neurol Neurosurg Psychiatry 2008 I read the article with reference to the inverse relationship between multiple sclerosis clinical activity and deficiency of vitamin D by Soilu-Hannienen (1) with interest, and was considering what mechanism could be in play to cause such a relationship. 25-hydroxylated metabolites of vitamin D act as intracellular regulators of the synthesis and action of defensin (2) molecules against bacterial antigens, defensin being an endogenously synthesized antimicrobial substance (2). Human cathelicidin antimicrobial peptide gene is a target of vitamin D receptor and is strongly up-regulated by 1,25-dihydroxyvitamin D3, indicating vitamin D receptor and the 1,25-dihydroxyvitaminD3 regulate primate innate immunity (3)

Thromboxane B2 is an inactive metabolite/product of thromboxane A2. It is almost completely cleared in the urine. It itself is not involved in platelet activation and aggregation in case of a wound, but its precursor, thromboxane A2, is. Thromboxane A2 synthesis is the target of the drug aspirin, which inhibits the COX-1 enzyme (the source of thromboxane A2 in platelets).

Vitamin D is a group of fat-soluble prohormones, the two major forms of which are vitamin D2 (or ergocalciferol) and vitamin D3 (or cholecalciferol).[1] The term vitamin D also refers to metabolites and other analogues of these substances. Vitamin D3 is produced in skin exposed to sunlight, specifically ultraviolet B radiation.\nVitamin D plays an important role in the maintenance of organ systems

Benefits of Vitamin D Supplementation Joel M. Kauffman, Ph.D. Journal of American Physicians and Surgeons Volume 14 Number 2 - Summer 2009 Clinical trials show that vitamin D supplementation at higher levels than previously recommended is beneficial for many conditions. It decreases the frequency of falls and fractures, helps prevent cardiovascular disease, and reduces symptoms of colds or influenza. Benefits are also seen in diabetes mellitus, multiple sclerosis, Crohn disease, pain, depression, and possibly autism. Sunlight does not cause an overdose of vitamin D production, and toxicity from supplementation is rare. Dose recommendations are increasing, but appear to be lagging the favorable trial results. A number of common drugs deplete vitamin D levels, and others may limit its biosynthesis from sunlight. People with adequate levels from sun exposure will not benefit from supplementation. While dietary intake is helpful, supplementation is better able to raise serum 25-hydroxyvitamin D , the major circulating metabolite, to the level now thought adequate, 30-50 ng/mL. Where there is inadequate daily sun exposure, oral doses of 1,000-2,000 IU/d are now considered routine, with much higher doses (up to 50,000 IU) for rapid repletion now considered safe.

Are omega-3 fatty acids options for prevention and treatment of cognitive decline and dementia? Cederholm T, Palmblad J. Curr Opin Clin Nutr Metab Care. 2009 Dec 16. [Epub ahead of print] PMID: 20019606 PURPOSE OF REVIEW: To report recent data on the potential role of omega-3 fatty acids (n-3 FA) found in oily fish, especially docosahexaenoic acid (DHA), to prevent and treat cognitive decline and Alzheimer's disease. RECENT FINDINGS: Observational studies still provide conflicting results, in which the majority indicate beneficial effects on cognition, both when assessed as a continuous variable or as incident dementia, mainly Alzheimer's disease. Experimental studies have demonstrated potentially ameliorating effects of eicosapentaenoic acid (EPA) and DHA on amyloid fragment formation, signal transduction including upregulation of the apolipoprotein receptor SorLA, as well as on angiogenesis. The role of EPA and DHA metabolites on Alzheimer's disease pathology is under investigation. Recently, three randomized intervention studies, with duration up to 6 months have been reported. In contrast to a small study from Taiwan, no positive overall effects were reported from the Swedish OmegAD Study or from a Dutch study, although post hoc analyses indicate that selected individuals with mild forms of Alzheimer's disease or cognitive decline may respond to treatment. SUMMARY: No firm conclusions can be drawn. Based on epidemiological data, fish including oily fish could be advised as part of a balanced diet for public health purpose, although the evidence for better cognition is only fairly consistent. It is unlikely that n-3 FA will emerge as a treatment option in general for improving cognitive function in patients with Alzheimer's disease. n-3 FA, especially DHA, may turn out as an adjuvant therapy in selected cases. Further long-term intervention studies on individuals with mild cognitive reductions are awaite"

The effect of select nutrients on serum high-density lipoprotein cholesterol and apolipoprotein A-I levels. Mooradian AD, Haas MJ, Wong NC. Endocr Rev. 2006 Feb;27(1):2-16. Epub 2005 Oct 21. Review. PMID: 16243964 One of the factors contributing to the increased risk of developing premature atherosclerosis is low plasma concentrations of high-density lipoprotein (HDL) cholesterol (HDLc). Multiple potential mechanisms account for the cardioprotective effects of HDL and its main protein apolipoprotein A-I (apo A-I). The low plasma concentrations of HDL could be the result of increased fractional clearance and reduced expression of apo A-I. To this end, nutrients play an important role in modulating the fractional clearance rate, as well as the rate of apo A-I gene expression. Because medical nutrition therapy constitutes the cornerstone of management of dyslipidemias, it is essential to understand the mechanisms underlying the changes in HDL level in response to alterations in dietary intake. In this review, we will discuss the effect of select nutrients on serum HDLc and apo A-I levels. Specifically, we will review the literature on the effect of carbohydrates, fatty acids, and ketones, as well as some of the nutrient-related metabolites, such as glucosamine and the prostanoids, on apo A-I gene expression. Because there are multiple mechanisms involved in the regulation of serum HDLc levels, changes in gene transcription do not necessarily correlate with clinical observations on serum levels of HDLc.

Vitamin D, nervous system and aging. P. Tuohimaa, T. Keisala, A. Minasyan, J. Cachat and A. Kalueff. . Psychoneuroendocrinology, Volume 34, Supplement 1, December 2009, Pages S278-S286 NEUROACTIVE STEROIDS: EFFECTS AND MECHANISMS OF ACTION doi:10.1016/j.psyneuen.2009.07.003 This is a mini-review of vitamin D3, its active metabolites and their functioning in the central nervous system (CNS), especially in relation to nervous system pathologies and aging. The vitamin D3 endocrine system consists of 3 active calcipherol hormones: calcidiol (25OHD3), 1α-calcitriol (1α,25(OH)2D3) and 24-calcitriol (24,25(OH)2D3). The impact of the calcipherol hormone system on aging, health and disease is discussed. Low serum calcidiol concentrations are associated with an increased risk of several chronic diseases including osteoporosis, cancer, diabetes, autoimmune disorders, hypertension, atherosclerosis and muscle weakness all of which can be considered aging-related diseases. The relationship of many of these diseases and aging-related changes in physiology show a U-shaped response curve to serum calcidiol concentrations. Clinical data suggest that vitamin D3 insufficiency is associated with an increased risk of several CNS diseases, including multiple sclerosis, Alzheimer's and Parkinson's disease, seasonal affective disorder and schizophrenia. In line with this, recent animal and human studies suggest that vitamin D insufficiency is associated with abnormal development and functioning of the CNS. Overall, imbalances in the calcipherol system appear to cause abnormal function, including premature aging, of the CNS.

"Hi! This is Amy Proal. I wrote the article referenced at the start of the thread about vitamin D. Dr. Marshall is not concerned with vitamin D toxicity. Rather his molecular modeling research has clarified the actions of the two vitamin D metabolites 25-D and 1,25-D. The Vitamin D Receptor (VDR) is a fundamental receptor of the body - it controls the expression thousands of genes, as well as the activity of the innate immune system and the antimicrobial peptides. If you think of the VDR as a switch, 25-D (which is a corticosteroid) turns it off (inactivates it) and 1,25-D turn it on (activates it). What is commonly believed among vitamin D researchers is that if people supplement with extra vitamin D it will be converted into 1,25-D and activate the VDR. Unfortunately, Marshall's work revealed that the type of vitamin D derived from supplements and sun remains, for the most part, in it's precursor form 25-D. This means that the extra vitamin D we get from fortified food products and supplements is turning the VDR off, not on. That causes a decrease in immune function and gene transcription."

"We are aware of substantial scientific evidence supporting the role of vitamin D in prevention of cancer. It has been reasonably established that adequate serum vitamin D metabolite levels are associated with substantially lower incidence rates of several types of cancer, including those of the breast, colon, and ovary, and other sites. We have concluded that the vitamin D status of most individuals in North America will need to be greatly improved for substantial reduction in incidence of cancer. Epidemiological studies have shown that higher vitamin D levels are also associated with lower risk of Type I diabetes in children and of multiple sclerosis. Several studies have found that markers of higher vitamin D levels are associated with lower incidence and severity of influenza and several other infectious diseases."

"Vitamin D-dependent calcium binding proteins were discovered in the cytosolic fractions of chicken intestine, and later in mammalian intestine and kidney, by workers including Robert Wasserman of Cornell University. They bound calcium in the micromolar range and were greatly reduced in vitamin D-deficient animals. Expression could be induced by treating these animals with vitamin D metabolites such as calcitriol. They were found to exist in two distant sizes with a molecular weight of approximately 9 kDa and 28 kDa. They were renamed calbindin; calbindin-D9k is found in mammalian intestine and calbindin-D28k in avain intestine and in kidney."