Vitamin K Abstracts 7

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Serum markers variation consistent with autoschizis induced by ascorbic acid-menadione in patients with prostate cancer.
            (Lasalvia-Prisco et al., 2003) Download
In vitro exposure of malignant prostate cell lines to ascorbic acid-menadione showed that tumor cells were killed through a mechanism named autoschizis. Experimental animal studies showed that autoschizis is also evident when ascorbic acid-menadione is administered to nude mice with implanted human prostate tumors. Prostate-specific antigen (PSA) is a known serum marker of prostate tumor cells specific activity. Recently, total serum homocysteine has been identified as a marker of tumor cell numbers with sensitivity for early detection of tumor cell death induced by treatments. A clinical trial with prostate cancer patients submitted to the association of ascorbic acid-menadione was performed and PSA/homocysteine was assessed in the follow- up. The early response in serum PSA and homocysteine levels was reported. The results showed that ascorbic acid-menadione produced an immediate drop in tumor cell numbers as assessed by homocysteine levels. Serum PSA levels showed an early rise and later dropped. These results suggest that autoschizis can also be induced by this pharmacological association at the clinical level in prostate cancer patients. Further studies are being performed in order to research if these results can be found with other primary tumors as it was shown in in vitro and experimental models. Ascorbic acid-menadione could be emerging as a new antitumoral chemotherapy.

Beneficial role of vitamin K supplementation on insulin sensitivity, glucose metabolism, and the reduced risk of type 2 diabetes: A review.
            (Manna and Kalita, 2016) Download
Micronutrients are gaining acceptance as an important nutritional therapy for the prevention and/or management of diabetes and its associated health risks. Although a very small quantity of micronutrients are required for specific functions in our bodies, moderate deficiencies can lead to serious health issues. Impaired insulin sensitivity and glucose intolerance play a major role in the development of diabetic pathophysiology. Vitamin K is well known for its function in blood coagulation. Moreover, several human studies reported the beneficial role of vitamin K supplementation in improving insulin sensitivity and glucose tolerance, preventing insulin resistance, and reducing the risk of type 2 diabetes (T2 D). Both animal and human studies have suggested that vitamin K-dependent protein (osteocalcin [OC]), regulation of adipokine levels, antiinflammatory properties, and lipid-lowering effects may mediate the beneficial function of vitamin K in insulin sensitivity and glucose tolerance. This review for the first time provides an overview of the currently available preclinical and clinical evidences on the effect of vitamin K supplementation in the management of insulin sensitivity and glucose tolerance. The outcome of this review will increase understanding for the development of a novel adjuvant therapy to achieve better control of glycemia and improve the lives of diabetic patients.

Serum undercarboxylated osteocalcin as biomarker of vitamin K intake and risk of prostate cancer: a nested case-control study in the Heidelberg cohort of the European prospective investigation into cancer and nutrition.
            (Nimptsch et al., 2009) Download
From cell studies, Vitamin K is known to exert anticancer effects on a variety of cancer cell lines, including prostate cancer cells. Recently, we reported an inverse association between dietary intake of menaquinones (vitamin K(2)), but not phylloquinone (vitamin K(1)), and risk of prostate cancer. In this nested case-control study including 250 prostate cancer cases and 494 matched controls, we aimed to confirm this cancer-protective effect using serum undercarboxylated osteocalcin (ucOC), a biomarker of vitamin K status inversely associated with vitamin K intake. In addition, effect modification by a functionally relevant polymorphism in the vitamin K epoxide reductase gene (VKORC1) was assessed. Serum ucOC and intact total osteocalcin (iOC) were analyzed with the use of ELISA tests. Serum ucOC was expressed relative to iOC (i.e., as ucOC/iOC ratio). Conditional logistic regression was used to calculate multivariate adjusted odds ratios (OR) and 95% confidence intervals (95% CI). Serum ucOC/iOC ratio was positively associated with advanced-stage (OR per 0.1 increment, 1.38; 95% CI, 1.03-1.86) and high-grade prostate cancer (OR, 1.21; 95% CI, 1.00-1.46) but not with total prostate cancer. The significant association with advanced-stage prostate cancer was confirmed when serum ucOC/iOC ratio was jointly modeled with menaquinone intake data. There was indication of a lower prostate cancer risk in carriers of the A allele (compared with GG carriers) of the +2255 VKORC1 polymorphism with increasing menaquinone intake (P(interaction) = 0.14) whereas no distinct effect modification was observed for the ucOC/iOC ratio (P(interaction) = 0.37). The increased risks of advanced-stage and high-grade prostate cancer with higher serum ucOC/iOC ratio strengthen the findings for dietary menaquinone intake.


 

Dietary vitamin K intake in relation to cancer incidence and mortality: results from the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Heidelberg).
            (Nimptsch et al., 2010) Download
BACKGROUND:  Anticarcinogenic activities of vitamin K have been observed in animal and cell studies. OBJECTIVE:  On the basis of the growth inhibitory effects of vitamin K as observed in a variety of cancer cell lines, we hypothesized that dietary intake of phylloquinone (vitamin K(1)) and menaquinones (vitamin K(2)) may be associated with overall cancer incidence and mortality. DESIGN:  In the prospective EPIC-Heidelberg (European Prospective Investigation into Cancer and Nutrition-Heidelberg) cohort study, 24,340 participants aged 35-64 y and free of cancer at enrollment (1994-1998) were actively followed up for cancer incidence and mortality through 2008. Dietary vitamin K intake was estimated from food-frequency questionnaires completed at baseline by using HPLC-based food-composition data. Multivariate-adjusted hazard ratios (HRs) and 95% CIs were estimated by using Cox proportional hazards models. RESULTS:  During a median follow-up time of >10 y, 1755 incident cancer cases occurred, of which 458 were fatal. Dietary intake of menaquinones was nonsignificantly inversely associated with overall cancer incidence (HR for the highest compared with the lowest quartile: 0.86; 95% CI: 0.73, 1.01; P for trend = 0.08), and the association was stronger for cancer mortality (HR: 0.72; 95% CI: 0.53, 0.98; P for trend = 0.03). Cancer risk reduction with increasing intake of menaquinones was more pronounced in men than in women, mainly driven by significant inverse associations with prostate (P for trend = 0.03) and lung (P for trend = 0.002) cancer. We found no association with phylloquinone intake. CONCLUSION:  These findings suggest that dietary intake of menaquinones, which is highly determined by the consumption of cheese, is associated with a reduced risk of incident and fatal cancer.

Vitamins K2, K3 and K5 exert antitumor effects on established colorectal cancer in mice by inducing apoptotic death of tumor cells.
            (Ogawa et al., 2007) Download
Although a number of studies have shown that vitamin K possesses antitumor activities on various neoplastic cell lines, there are few reports demonstrating in vivo antitumor effects of vitamin K, and the antitumor effect on colorectal cancer (CRC) remains to be examined. Therefore, antitumor effects of vitamin K on CRC were examined both in vitro and in vivo. Vitamins K2, K3 and K5 suppressed the proliferation of colon 26 cells in a dose-dependent manner, while vitamin K1 did not. On flow cytometry, induction of apoptosis by vitamins K2, K3 and K5 was suggested by population in sub-G1 phase of the cell cycle. Hoechst 33342 staining and a two-color flow cytometric assay using fluorescein isothiocyanate-conjugated annexin V and propidium iodide confirmed that vitamins K2, K3 and K5 induced apoptotic death of colon 26 cells. Enzymatic activity of caspase-3 in colon 26 cells was significantly up-regulated by vitamins K2, K3 and K5. The pan-caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, substantially prevented vitamin K-mediated apoptosis. In vivo study using syngeneic mice with subcutaneously established colon 26 tumors demonstrated that intravenous administration of vitamins K2, K3 and K5 significantly suppressed the tumor growth. The number of apoptotic tumor cells was significantly larger in the vitamin K-treated groups than in the control group. These results suggest that vitamins K2, K3 and K5 exerted effective antitumor effects on CRC in vitro and in vivo by inducing caspase-dependent apoptotic death of tumor cells, suggesting that these K vitamins may be promising agents for the treatment of patients with CRC.

Dietary phylloquinone intakes and metabolic syndrome in US young adults.
            (Pan and Jackson, 2009) Download
OBJECTIVE:  The relationship between dietary intake of vitamin K and metabolic syndrome (MetS) has not been investigated previously. The aim of this study was to examine whether and to what extent vitamin K intake measured as phylloquinone is related to MetS. DESIGN:  We performed a cross-sectional analysis on data from 5800 adults aged 20 to 45 years who participated in the National Health and Nutrition Examination Survey (NHANES) 1999-2004. MetS was defined according to Adult Treatment Panel III criteria. Dietary phylloquinone intakes were obtained from 24-hour dietary recall. Prevalence and odds ratios (OR) of MetS and its components were assessed by quartiles of dietary phylloquinone intake. RESULTS:  The lowest prevalence of MetS and its 5 components was observed in individuals with the highest phylloquinone intake. The prevalence of low high-density lipoprotein cholesterol (HDL) and elevated blood pressure progressively decreased with increasing phylloquinone intake (p < 0.05 for trend). HDL and C-reactive protein (CRP) levels improved gradually with increasing dietary phylloquinone intake (p < 0.05 for trend). In general, participants who had MetS or its element consumed less phylloquinone from diet compared those who did not. In comparison with the lowest phylloquinone intake quartile, the highest quartile of intake was associated with significantly reduced risks of low HDL level, hypertriglyceridemia, and hyperglycemia after adjustment was made for various nondietary confounding factors (OR, 0.73, 95% confidence interval [CI], 0.45-0.98; OR, 0.51, 95% CI, 0.25-0.97; and OR, 0.18, 95% CI, 0.05-0.73, respectively). Only the association between hyperglycemia and phylloquinone intake remained significant after further adjustment for dietary confounders (OR, 0.18, 95% CI, 0.05-0.73). CONCLUSIONS:  Mean reported dietary phylloquinone intakes suggested that most US young adults consume an insufficient amount of vitamin K from their diet. A high intake of phylloquinone may favorably affect MetS or its components, probably through an overall more heart-healthy dietary pattern. The pathogenesis of MetS is profoundly complex and may involve other factors and/or mechanisms, in addition to vitamin K nutriture. Although our data suggest a potential role of vitamin K in MetS, the biological mechanisms underlying the observed associations must be elucidated.

Warfarin causes rapid calcification of the elastic lamellae in rat arteries and heart valves.
            (Price et al., 1998) Download
High doses of warfarin cause focal calcification of the elastic lamellae in the media of major arteries and in aortic heart valves in the rat. Aortic calcification was first seen after 2 weeks of warfarin treatment and progressively increased in density at 3, 4, and 5 weeks of treatment. By 5 weeks, the highly focal calcification of major arteries could be seen on radiographs and by visual inspection of the artery. The calcification of arteries induced by warfarin is similar to that seen in the matrix Gla protein (MGP)-deficient mouse, which suggests that warfarin induces artery calcification by inhibiting gamma-carboxylation of MGP and thereby inactivating the putative calcification-inhibitory activity of the protein. Warfarin treatment markedly increased the levels of MGP mRNA and protein in calcifying arteries and decreased the level of MGP in serum. Warfarin treatment did not affect bone growth, overall weight gain, or serum calcium and phosphorus levels, and, because of the concurrent administration of vitamin K, prothrombin times and hematocrits were normal. The results indicate that the improved warfarin plus vitamin K treatment protocol developed in this study should provide a useful model to investigate the role of MGP in preventing calcification of arteries and heart valves.

Vitamin k2, a naturally occurring menaquinone, exerts therapeutic effects on both hormone-dependent and hormone-independent prostate cancer cells.
            (Samykutty et al., 2013) Download
In recent years, several studies have shown that vitamin k2 (VK2) has anticancer activity in a variety of cancer cells. The antitumor effects of VK2 in prostate cancer are currently not known. In the present study, we sought to characterize the anticancer potential of VK2 in both androgen-dependent and -independent prostate cancer cells. Our investigations show that VK2 is able to suppress viability of androgen-dependent and androgen-independent prostate cancer cells via caspase-3 and -8 dependent apoptosis. We also show that VK2 treatment reduces androgen receptor expression and PSA secretion in androgen-dependent prostate cancer cells. Our results also implicate VK2 as a potential anti-inflammatory agent, as several inflammatory genes are downregulated in prostate cancer cells following treatment with VK2. Additionally, AKT and NF-kB levels in prostate cancer cells are reduced significantly when treated with VK2. These findings correlated with the results of the Boyden chamber and angiogenesis assay, as VK2 treatment reduced cell migration and angiogenesis potential of prostate cancer cells. Finally, in a nude mice model, VK2 administration resulted in significant inhibition of both androgen-dependent and androgen-independent tumor growth. Overall, our results suggest that VK2 may be a potential therapeutic agent in the treatment of prostate cancer.

Vitamin K status and vascular calcification: evidence from observational and clinical studies.
            (Shea and Holden, 2012) Download
Vascular calcification occurs when calcium accumulates in the intima (associated with atherosclerosis) and/or media layers of the vessel wall. Coronary artery calcification (CAC) reflects the calcium burden within the intima and media of the coronary arteries. In population-based studies, CAC independently predicts cardiovascular disease (CVD) and mortality. A preventive role for vitamin K in vascular calcification has been proposed based on its role in activating matrix Gla protein (MGP), a calcification inhibitor that is expressed in vascular tissue. Although animal and in vitro data support this role of vitamin K, overall data from human studies are inconsistent. The majority of population-based studies have relied on vitamin K intake to measure status. Phylloquinone is the primary dietary form of vitamin K and available supplementation trials, albeit limited, suggest phylloquinone supplementation is relevant to CAC. Yet observational studies have found higher dietary menaquinone, but not phylloquinone, to be associated with less calcification. Vascular calcification is highly prevalent in certain patient populations, especially in those with chronic kidney disease (CKD), and it is plausible vitamin K may contribute to reducing vascular calcification in patients at higher risk. Subclinical vitamin K deficiency has been reported in CKD patients, but studies linking vitamin K status to calcification outcomes in CKD are needed to clarify whether or not improving vitamin K status is associated with improved vascular health in CKD. This review summarizes the available evidence of vitamin K and vascular calcification in population-based studies and clinic-based studies, with a specific focus on CKD patients.

Vitamin K, osteoporosis and degenerative diseases of ageing.
            (Vermeer and Theuwissen, 2011) Download
The function of vitamin K is to serve as a co-factor during the post-translational carboxylation of glutamate (Glu) residues into γ-carboxyglutamate (Gla) residues. The vital importance of the Gla-proteins essential for normal haemostasis is well recognized. During recent years, new Gla-containing proteins have been discovered and the vitamin K-dependent carboxylation is also essential for their function. It seems, however, that our dietary vitamin K intake is too low to support the carboxylation of at least some of these Gla-proteins. According to the triage theory, long-term vitamin K inadequacy is an independent, but modifiable risk factor for the development of degenerative diseases of ageing including osteoporosis and atherosclerosis.


 

Effect of vitamin K in bone metabolism and vascular calcification: a review of mechanisms of action and evidences.
            (Villa et al., 2016) Download
Osteoporosis is a public health concern associated with an increased risk of bone fractures and vascular calcification. Vitamin K presents unique benefits on these issues, although understudied. The two main forms of vitamin K are phylloquinone (vitamin K1) and menaquinone (vitamin K2). In this study, it was especially investigated the action of vitamin K2 in bones and vessels. Vitamin K2 has shown to stimulate bone formation by promoting osteoblast differentiation and carboxylation of osteocalcin, and increasing alkaline phosphatase, insulin-like growth factor-1, growth differentiation factor-15, and stanniocalcin 2 levels. Furthermore, vitamin K2 reduces the pro-apoptotic proteins Fas and Bax in osteoblasts, and decreases osteoclast differentiation by increasing osteoprotegerin and reducing the receptor activator of nuclear factor kappa-B ligand. In blood vessels, vitamin K2 reduces the formation of hydroxyapatite, through the carboxylation of matrix Gla protein and Gla rich protein, inhibits the apoptosis of vascular smooth muscle cells, by increasing growth arrest-specific gene 6, and reduces the transdifferentiation of vascular smooth muscle cells to osteoblasts. The commonly used dosage of vitamin K2 in human studies is 45 mg/day and its application can be an interesting strategy in benefitting bone and vascular health, especially to osteoporotic post-menopausal women.

Effects of the blood coagulation vitamin K as an inhibitor of arterial calcification.
            (Wallin et al., 2008) Download
INTRODUCTION:  The transformation of smooth muscle cells (VSMCs) in the vessel wall to osteoblast like cells is known to precede arterial calcification which may cause bleeding complications. The vitamin K-dependent protein MGP has been identified as an inhibitor of this process by binding BMP-2, a growth factor known to trigger the transformation. In this study, we determined if the vitamin K-dependent Gla region in MGP by itself can inhibit the growth factor activity of BMP-2 and if menaquinone-4 (MK4) regulates gene expression in VSMCs. MATERIALS AND METHODS:  A synthetic gamma-carboxyglutamic acid (Gla) containing peptide covering the Gla region in human MGP was used to test its ability to inhibit BMP-2 induced transformation of mouse pro-myoblast C2C12 cells into osteoblasts. MK4 was tested by microarray analysis as a gene regulatory molecule in VSMCs. RESULTS AND CONCLUSIONS:  The results show that the Gla - but not the Glu-peptide inhibited the transformation which provide evidence that the Gla region in MGP is directly involved in the BMP-2/MGP interaction and emphasizes the importance of the vitamin K-dependent modification of MGP. From the data obtained from the microarray analysis, we focused on two quantitatively altered cDNAs representing proteins known to be associated with vessel wall calcification. DT-diaphorase of the vitamin K-cycle, showed increased gene expression with a 4.8-fold higher specific activity in MK4 treated cells. Osteoprotegrin gene expression was down regulated and osteoprotegrin protein secretion from the MK4 treated cells was lowered to 1.8-fold. These findings suggest that MK4 acts as an anti-calcification component in the vessel wall.

Insights into how calcium forms plaques in arteries pave the way for new treatments for heart disease.
            (Weaver, 2013) Download
Heart disease is the leading cause of death in the United States, and its primary cause is hardening of the arteries, or atherosclerosis. As people grow older, fat, cholesterol, and calcium build up in the walls of arteries and form hard structures called plaques. The process of calcium accumulation in blood vessels resembles bone formation and involves maintaining a balance between bone-forming cells called osteoblasts and bone-destroying cells called osteoclasts. The resulting plaques cause arteries to become narrow and stiff and can obstruct blood flow. As a consequence, oxygen-starved tissue can become damaged or die, leading to heart attack and stroke. Although many risk factors for atherosclerosis have been iden- tified, the cause is not known and there is currently no way to reverse it once it sets in.

The realm of vitamin K dependent proteins: shifting from coagulation toward calcification.
            (Willems et al., 2014) Download
In the past few decades vitamin K has emerged from a single-function "haemostasis vitamin" to a "multi-function vitamin." The use of vitamin K antagonists (VKA) inevitably showed that the inhibition was not restricted to vitamin K dependent coagulation factors but also synthesis of functional extrahepatic vitamin K dependent proteins (VKDPs), thereby eliciting undesired side effects. Vascular calcification is one of the recently revealed detrimental effects of VKA. The discovery that VKDPs are involved in vascular calcification has propelled our mechanistic understanding of this process and has opened novel avenues for diagnosis and treatment. This review addresses mechanisms of VKDPs and their significance for physiological and pathological calcification.

Effect of vitamin K supplementation on insulin resistance in older men and women.
            (Yoshida et al., 2008b) Download
OBJECTIVE:  Vitamin K has a potentially beneficial role in insulin resistance, but evidence is limited in humans. We tested the hypothesis that vitamin K supplementation for 36 months will improve insulin resistance in older men and women. RESEARCH DESIGN AND METHODS:  This was an ancillary study of a 36-month, randomized, double-blind, controlled trial designed to assess the impact of supplementation with 500 microg/day phylloquinone on bone loss. Study participants were older nondiabetic men and women (n = 355; aged 60-80 years; 60% women). The primary outcome of this study was insulin resistance as measured by homeostasis model assessment (HOMA-IR) at 36 months. Fasting plasma insulin and glucose were examined as the secondary outcomes. RESULTS:  The effect of 36-month vitamin K supplementation on HOMA-IR differed by sex (sex x treatment interaction P = 0.02). HOMA-IR was statistically significantly lower at the 36-month visit among men in the supplement group versus the men in the control group (P = 0.01) after adjustment for baseline HOMA-IR, BMI, and body weight change. There were no statistically significant differences in outcome measures between intervention groups in women. CONCLUSIONS:  Vitamin K supplementation for 36 months at doses attainable in the diet may reduce progression of insulin resistance in older men.

Phylloquinone intake, insulin sensitivity, and glycemic status in men and women.
            (Yoshida et al., 2008a) Download
BACKGROUND:  Limited evidence suggests that vitamin K may have a beneficial role in glucose homeostasis. No observational data exist on the associations between vitamin K intake and insulin sensitivity. OBJECTIVE:  We aimed to examine associations between vitamin K intake and measures of insulin sensitivity and glycemic status in men and women aged 26-81 y. DESIGN:  We assessed the cross-sectional associations of self-reported phylloquinone (vitamin K(1)) intake with insulin sensitivity and glycemic status in the Framingham Offspring Cohort. Dietary and supplemental phylloquinone intakes were assessed by using a food-frequency questionnaire. Insulin sensitivity was measured by fasting and 2-h post-oral-glucose-tolerance test (OGTT) insulin, the homeostasis model assessment of insulin resistance (HOMA-IR), and the insulin sensitivity index (ISI(0,120)). Glycemic status was assessed by fasting and 2-h post-OGTT glucose and glycated hemoglobin (HbA(1c)). RESULTS:  Higher phylloquinone intake was associated with greater insulin sensitivity and glycemic status, as measured by 2-h post-OGTT insulin and glucose and ISI(0,120), after adjustment for age, sex, waist circumference, lifestyle characteristics, and diet quality [2-h post-OGTT insulin: lowest and highest quintile, 81.0 and 72.7 microU/mL, respectively (P for trend = 0.003); 2-h post-OGTT glucose: 106.3 and 101.9 mg/dL, respectively (P for trend = 0.009); ISI(0,120): 26.3 and 27.3 mg L(2)/mmol mU min (P for trend = 0.009)]. Phylloquinone intake was not associated with fasting insulin and glucose concentrations, HOMA-IR, or HbA(1c). CONCLUSION:  Our findings support a potential beneficial role for phylloquinone in glucose homeostasis in men and women.

 


References

Lasalvia-Prisco, E, et al. (2003), ‘Serum markers variation consistent with autoschizis induced by ascorbic acid-menadione in patients with prostate cancer.’, Med Oncol, 20 (1), 45-52. PubMed: 12665684
Manna, P and J Kalita (2016), ‘Beneficial role of vitamin K supplementation on insulin sensitivity, glucose metabolism, and the reduced risk of type 2 diabetes: A review.’, Nutrition, 32 (7-8), 732-39. PubMed: 27133809
Nimptsch, K, et al. (2009), ‘Serum undercarboxylated osteocalcin as biomarker of vitamin K intake and risk of prostate cancer: a nested case-control study in the Heidelberg cohort of the European prospective investigation into cancer and nutrition.’, Cancer Epidemiol Biomarkers Prev, 18 (1), 49-56. PubMed: 19124480
Nimptsch, K, et al. (2010), ‘Dietary vitamin K intake in relation to cancer incidence and mortality: results from the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Heidelberg).’, Am J Clin Nutr, 91 (5), 1348-58. PubMed: 20335553
Ogawa, M, et al. (2007), ‘Vitamins K2, K3 and K5 exert antitumor effects on established colorectal cancer in mice by inducing apoptotic death of tumor cells.’, Int J Oncol, 31 (2), 323-31. PubMed: 17611688
Pan, Y and RT Jackson (2009), ‘Dietary phylloquinone intakes and metabolic syndrome in US young adults.’, J Am Coll Nutr, 28 (4), 369-79. PubMed: 20368375
Price, PA, SA Faus, and MK Williamson (1998), ‘Warfarin causes rapid calcification of the elastic lamellae in rat arteries and heart valves.’, Arterioscler Thromb Vasc Biol, 18 (9), 1400-7. PubMed: 9743228
Samykutty, A, et al. (2013), ‘Vitamin k2, a naturally occurring menaquinone, exerts therapeutic effects on both hormone-dependent and hormone-independent prostate cancer cells.’, Evid Based Complement Alternat Med, 2013 287358. PubMed: 24062781
Shea, MK and RM Holden (2012), ‘Vitamin K status and vascular calcification: evidence from observational and clinical studies.’, Adv Nutr, 3 (2), 158-65. PubMed: 22516723
Vermeer, C and E Theuwissen (2011), ‘Vitamin K, osteoporosis and degenerative diseases of ageing.’, Menopause Int, 17 (1), 19-23. PubMed: 21427421
Villa, JK, et al. (2016), ‘Effect of vitamin K in bone metabolism and vascular calcification: a review of mechanisms of action and evidences.’, Crit Rev Food Sci Nutr, 0. PubMed: 27437760
Wallin, R, L Schurgers, and N Wajih (2008), ‘Effects of the blood coagulation vitamin K as an inhibitor of arterial calcification.’, Thromb Res, 122 (3), 411-17. PubMed: 18234293
Weaver, J (2013), ‘Insights into how calcium forms plaques in arteries pave the way for new treatments for heart disease.’, PLoS Biol, 11 (4), e1001533. PubMed: 23585734
Willems, BA, et al. (2014), ‘The realm of vitamin K dependent proteins: shifting from coagulation toward calcification.’, Mol Nutr Food Res, 58 (8), 1620-35. PubMed: 24668744
Yoshida, M, et al. (2008a), ‘Phylloquinone intake, insulin sensitivity, and glycemic status in men and women.’, Am J Clin Nutr, 88 (1), 210-15. PubMed: 18614743
Yoshida, M, et al. (2008b), ‘Effect of vitamin K supplementation on insulin resistance in older men and women.’, Diabetes Care, 31 (11), 2092-96. PubMed: 18697901