Vitamin K Status Based on K1, MK-4, MK-7, and Undercarboxylated Prothrombin Levels in Adolescent and Adult Patients with Cystic Fibrosis: A Cross-Sectional Study.

The available evidence on vitamin K status in cystic fibrosis (CF) is scarce, lacking data on vitamin K2 (menaquinones-MK). Therefore, we assessed vitamin K1, MK-4 and MK-7 concentrations (LC-MS/MS) in 63 pancreatic insufficient and modulator naïve CF patients, and compared to 61 healthy subjects (HS). Vitamin K1 levels did not differ between studied groups. MK-4 concentrations were higher (median <1st-3rd quartile>: 0.778 <0.589-1.086> vs. 0.349 <0.256-0.469>, p < 0.0001) and MK-7 levels lower (0.150 <0.094-0.259> vs. 0.231 <0.191-0.315>, p = 0.0007) in CF patients than in HS. MK-7 concentrations were higher in CF patients receiving K1 and MK-7 supplementation than in those receiving vitamin K1 alone or no supplementation. Moreover, vitamin K1 concentrations depended on the supplementation regime. Based on multivariate logistic regression analysis, we have found that MK-7 supplementation dose has been the only predictive factor for MK-7 levels. In conclusion, vitamin K1 levels in CF are low if not currently supplemented. MK-4 concentrations in CF patients supplemented with large doses of vitamin K1 are higher than in HS. MK-7 levels in CF subjects not receiving MK-7 supplementation, with no regard to vitamin K1 supplementation, are low. There do not seem to be any good clinical predictive factors for vitamin K status.

Post-bariatric pregnancy is associated with vitamin K1 deficiency, a case control study.

BACKGROUND: Maternal obesity is associated with adverse outcome for pregnancy and childbirths. While bariatric surgery may improve fertility and reduce the risk of certain pregnancy-related complications such as hypertension and gestational diabetes mellitus, there is a lack of evidence on the optimal nutritional monitoring and supplementation strategies in pregnancy following bariatric surgery. We aimed to assess the impact of bariatric surgery on micronutrients in post-bariatric pregnancy and possible differences between gastric bypass surgery and sleeve gastrectomy. METHODS: In this prospective case control study, we recruited 204 pregnant women (bariatric surgery n = 59 [gastric bypass surgery n = 26, sleeve gastrectomy n = 31, missing n = 2] and controls n = 145) from Akershus university hospital in Norway. Women with previous bariatric surgery were consecutively invited to study participation at referral to the clinic for morbid obesity and the controls were recruited from the routine ultrasound screening in gestational week 17-20. A clinical questionnaire was completed and blood samples were drawn at mean gestational week 20.4 (SD 4.5). RESULTS: The women with bariatric surgery had a higher pre-pregnant BMI than controls (30.8 [SD 6.0] vs. 25.2 [5.4] kg/m2, p < 0.001). There were no differences between groups regarding maternal weight gain (bariatric surgery 13.3 kg (9.6) vs. control 14.8 kg (6.5), p = 0.228) or development of gestational diabetes (n = 3 [5%] vs. n = 7 [5%], p = 1.000). Mean levels of vitamin K1 was lower after bariatric surgery compared with controls (0.29 [0.35] vs. 0.61 [0.65] ng/mL, p < 0.001). Multiadjusted regression analyses revealed an inverse relationship between bariatric surgery and vitamin K1 (B -0.26 ng/mL [95% CI -0.51, -0.04], p = 0.047) with a fivefold increased risk of vitamin K1 deficiency in post-bariatric pregnancies compared with controls (OR 5.69 [1.05, 30.77] p = 0.044). Compared with sleeve gastrectomy, having a previous gastric bypass surgery was associated with higher risk of vitamin K1 deficiency (OR 17.1 [1.31, 223.3], p = 0.030). CONCLUSION: Post-bariatric pregnancy is negatively associated with vitamin K1 with a higher risk of vitamin K1 deficiency in pregnancies after gastric bypass surgery compared with after sleeve gastrectomy. Vitamin K1 deficiency in post-bariatric pregnancy have potential risk of hypocoaguble state in mother and child and should be explored in future studies.

Observation of the neuroprotective efficacy of vitamin K in a streptozocin-induced diabetes model in chick embryos.

Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia due to insulin deficiency and/or resistance. Vitamin K (VK) is a group of fat-soluble molecules, including naturally occurring vitamin K1 (phylloquinone). vitamin K2 (menaquinone), and synthetic vitamin K3 (menadione). Beyond coagulation, the health benefits of VK have been described to play different roles in both physiological and pathological processes such as inflammation, energy metabolism, neuroprotection, cellular growth, and survival. It was aimed to observe the antioxidant and/or neuroprotective activity of vitamin K1 in our model of chick embryo diabetic neuropathy (DN) induced by streptozotocin (STZ). Ninety White Leghorn, fertile and 0-day-old SPF (specific pathogen-free) eggs (57 ± 4 gr) were used in the study. Chick embryo blood brain tissues were taken for biochemical evaluation. Plasma insulin and glucose levels were measured. In addition, brain tissue total antioxidant level (TAS), total oxidant level (TOS), malondialdehyde (MDA), and vascular endothelial growth factor (VEGF) levels were measured. Plasma glucose levels were higher in the STZ-treated groups and lower in the treatment groups. Plasma insulin levels were observed to be higher in STZ groups in groups treated with high VK. Low TAS, high MDA, TOS, and VEGF levels were recorded in brain tissue STZ groups. Low VEGF, TOS, and MDA levels were recorded in the group treated with the highest VK, while high TAS levels were observed. In our STZ-induced chick embryo diabetic neuropathy model, we observed that VK1 reduced oxidant damage by showing antioxidant properties or by modulating antioxidant enzymes.

Vitamin K1 ameliorates lipopolysaccharide-triggered skeletal muscle damage revealed by faecal bacteria transplantation.

BACKGROUND: Sepsis-associated muscle weakness is common in patients of intensive care units (ICUs), and it is closely associated with poor outcomes. The mechanism of sepsis-induced muscle weakness is unclear. Recent studies have found that gut microbiota and metabolites are involved in the regulation of skeletal muscle mass and metabolism. This study aimed to investigate the effects of gut microbiota and metabolites on sepsis-associated muscle weakness. METHODS: In a lipopolysaccharide (LPS)-induced inflammation mouse model, mice with different sensitivities to LPS-induced inflammation were considered as donor mice for the faecal microbiota transplantation (FMT) assay, and recipient mice were divided into sensitive (Sen) and resistant (Res) groups. Skeletal muscle mass and function, as well as colonic barrier integrity were tested and gut microbiota and metabolite composition were analysed in both groups of mice. The effect of intestinal differential metabolite vitamin K1 on LPS-triggered muscle damage was investigated, and the underlying mechanism was explored. RESULTS: Recipients exhibited varying LPS-triggered muscle damage and intestinal barrier disruption. Tibialis anterior (TA) muscle of Sen exhibited upregulated expression levels of MuRF-1 (0.825 ± 0.063 vs. 0.304 ± 0.293, P = 0.0141) and MAFbx (1.055 ± 0.079 vs. 0.456 ± 0.3, P = 0.0092). Colonic tight junction proteins ZO-1 (0.550 ± 0.087 vs. 0.842 ± 0.094, P = 0.0492) and occludin (0.284 ± 0.057 vs. 0.664 ± 0.191, P = 0.0487) were significantly downregulated in the Sen group. Metabolomic analysis showed significantly higher vitamin K1 in the faeces (P = 0.0195) and serum of the Res group (P = 0.0079) than those of the Sen group. After vitamin K1 intervention, muscle atrophy-related protein expression downregulated (P < 0.05). Meanwhile SIRT1 protein expression were upregulated (0.320 ± 0.035 vs. 0.685 ± 0.081, P = 0.0281) and pNF-κB protein expression were downregulated (0.815 ± 0.295 vs. 0.258 ± 0.130, P = 0.0308). PI3K (0.365 ± 0.142 vs. 0.763 ± 0.013, P = 0.0475), pAKT (0.493 ± 0.159 vs. 1.183 ± 0.344, P = 0.0254) and pmTOR (0.509 ± 0.088 vs. 1.110 ± 0.190, P = 0.0368) protein expression levels were upregulated in TA muscle. Meanwhile, vitamin K1 attenuated serum inflammatory factor levels. CONCLUSIONS: Vitamin K1 might ameliorate LPS-triggered skeletal muscle damage by antagonizing NF-κB-mediated inflammation through upregulation of SIRT1 and regulating the balance between protein synthesis and catabolism.

Dietary Vitamin K1 Intake and Incident Aortic Valve Stenosis.

BACKGROUND: Leaflet calcification contributes to the development and progression of aortic valve stenosis. Vitamin K activates inhibitors of vascular calcification and may modulate inflammation and skeletal bone loss. Therefore, we aimed to determine whether higher dietary intakes of vitamin K1 are associated with a lower incidence of aortic stenosis. METHODS: In the Danish Diet, Cancer and Health study, participants aged 50 to 64 years completed a 192-item food frequency questionnaire at baseline, from which habitual intakes of vitamin K1 were estimated. Participants were prospectively followed using linkage to nationwide registers to determine incident aortic valve stenosis (primary outcome) and aortic stenosis with subsequent complications (aortic valve replacement, heart failure, or cardiovascular disease-related mortality; secondary outcome). RESULTS: In 55 545 participants who were followed for a maximum of 21.5 years, 1085 were diagnosed with aortic stenosis and 615 were identified as having subsequent complications. Participants in the highest quintile of vitamin K1 intake had a 23% lower risk of aortic stenosis (hazard ratio, 0.77 [95% CI, 0.63-0.94]) and a 27% lower risk of aortic stenosis with subsequent complications (hazard ratio, 0.73 [95% CI, 0.56-0.95]), compared with participants in the lowest quintile after adjusting for demographics and cardiovascular risk factors. CONCLUSIONS: In this study, a high intake of vitamin K1-rich foods was associated with a lower incidence of aortic stenosis and a lower risk of aortic stenosis with subsequent complications.

Vitamin K1 Intake and Incident Diabetes in the Danish Diet, Cancer, and Health Study.

CONTEXT: Observational studies have reported lower risks of type 2 diabetes with higher vitamin K1 intake, but these studies overlook effect modification due to known diabetes risk factors. OBJECTIVE: To identify subgroups that might benefit from vitamin K1 intake, we examined associations between vitamin K1 intake and incident diabetes overall and in subpopulations at risk of diabetes. METHODS: Participants from the prospective cohort, the Danish Diet, Cancer, and Health Study, with no history of diabetes were followed up for diabetes incidence. The association between intake of vitamin K1, estimated from a food frequency questionnaire completed at baseline, and incident diabetes was determined using multivariable-adjusted Cox proportional-hazards models. RESULTS: In 54 787 Danish residents with a median (interquartile range) age of 56 (52-60) years at baseline, 6700 individuals were diagnosed with diabetes during 20.8 (17.3-21.6) years of follow-up. Vitamin K1 intake was inversely and linearly associated with incident diabetes (P < .0001). Compared to participants with the lowest vitamin K1 intake (median:57 µg/d), participants with the highest intakes (median:191 µg/d) had a 31% lower risk of diabetes (HR; 95% CI, 0.69; 0.64-0.74) after multivariable adjustments. The inverse association between vitamin K1 intake and incident diabetes was present in all subgroups (namely, men and women, ever and never smokers, low and high physical activity groups, and in participants who were normal to overweight and obese), with differences in absolute risk between subgroups. CONCLUSION: Higher intake of foods rich in vitamin K1 was associated with a lower risk of diabetes. If the associations observed are causal, our results indicate that more cases of diabetes would be prevented in subgroups at higher risk (men, smokers, participants with obesity, and those with low physical activity).

Total Sialic Acid, Antioxidant Enzyme Activities, Trace Elements, and Vitamin Status Before and After Surgery in Women with Uterine Myoma and Endometrial Cancer.

The objective of present study was to examine endometrial tissue Be, As, Cr, Mo, Sr, Ti, Tl, Cu, Co, Se, Zn, Mn, Fe, Cd, Pb, Mg, P, erythrocytes CAT, SOD, GSH-Px, GSH, MDA, serum retinol, cholecalciferol, phylloquinone, TSA, LSA, TOS, and TAS status and to evaluate the relationships between the variables. The study had 110 participants; of these, 50 were women with uterine myoma (UM), 10 were women with endometrial cancer (EC), and 50 were healthy female subjects. In the study, vitamin analyses by HPLC and element analyses were determined using ICP-OES method. It was observed that EC group was significantly lower than healthy group in terms of levels of cholecalciferol (p < 0.05), phylloquinone (p < 0.01), GSH (p < 0.05), Fe (p < 0.05), and had a significant rise in Mg/Fe (p < 0.01) and Zn/Fe (p < 0.05) in preoperative period. UM group had significantly lower retinol (p < 0.05), phylloquinone (p < 0.001), GSH-Px (p < 0.01), GSH (p < 0.01), Cr (p < 0.01), Cu (p < 0.05), Mg (p < 0.01), and Zn (p < 0.01) levels than control group in preoperative period and significantly higher levels of MDA (p < 0.01), TSA (p < 0.01), and LSA (p < 0.01) than control group. It was found that significant associations were observed between Cu-CA 15-3 (r = 0.558, p = 0.016), Mn-CA 15-3 (r = 0.511, p = 0.030), P-CA 15-3(r = - 0.502, p = 0.034) and with UM, also between GSH-CA-125 (r = - 0.825, p = 0.022) and with EC group. The results of correlation analysis observed that concentrations of Cu, Mn, P, and GSH together with CA 15-3 and CA-125 levels might be important for monitoring patients with UM and EC before surgery.

Vitamin K and the Visual System-A Narrative Review.

Vitamin K occupies a unique and often obscured place among its fellow fat-soluble vitamins. Evidence is mounting, however, that vitamin K (VK) may play an important role in the visual system apart from the hepatic carboxylation of hemostatic-related proteins. However, to our knowledge, no review covering the topic has appeared in the medical literature. Recent studies have confirmed that matrix Gla protein (MGP), a vitamin K-dependent protein (VKDP), is essential for the regulation of intraocular pressure in mice. The PREDIMED (Prevención con Dieta Mediterránea) study, a randomized trial involving 5860 adults at risk for cardiovascular disease, demonstrated a 29% reduction in the risk of cataract surgery in participants with the highest tertile of dietary vitamin K1 (PK) intake compared with those with the lowest tertile. However, the specific requirements of the eye and visual system (EVS) for VK, and what might constitute an optimized VK status, is currently unknown and largely unexplored. It is, therefore, the intention of this narrative review to provide an introduction concerning VK and the visual system, review ocular VK biology, and provide some historical context for recent discoveries. Potential opportunities and gaps in current research efforts will be touched upon in the hope of raising awareness and encouraging continued VK-related investigations in this important and highly specialized sensory system.

Effect of phylloquinone on indomethacin-induced gastric ulceration in rats: Role of SIRT-1.

Gastric ulcer is the most common gastrointestinal disorder affecting people globally. Although many drugs are available to treat ulcers, the mortality rate is relatively high, and drugs lack selectivity to treat ulcers without causing side effects. In this study, the potential therapeutic effects of phylloquinone were tested against indomethacin-induced gastric ulcer in rats by giving rats a single oral dose of indomethacin (48 mg/kg), followed by phylloquinone (10 mg/kg) orally, once daily for six consecutive days. Phylloquinone significantly attenuated indomethacin-induced oxidative and inflammatory responses through hindering the inflammatory cascade by decreasing the levels of TNF-α, NF-κB, INOS and COX-2 which counteracts indomethacin effects. Also, it increased NAD+ which enhanced SIRT-1 level. Furthermore, phylloquinone was effective in increasing mucus secretion, decreasing acid secretion, reversing histological effects caused by indomethacin and minimizing ulcer and lesion indices All these findings indicate that phylloquinone may be used in protection and treatment of indomethacin-induced gastric ulcer.

Vitamin K Contribution to DNA Damage-Advantage or Disadvantage? A Human Health Response.

Vitamin K is the common name for a group of compounds recognized as essential for blood clotting. The group comprises phylloquinone (K1)-a 2-methyl-3-phytyl-1,4-naphthoquinone; menaquinone (K2, MK)-a group of compounds with an unsaturated side chain in position 3 of a different number of isoprene units and a 1,4-naphthoquinone group and menadione (K3, MD)-a group of synthetic, water-soluble compounds 2-methyl-1,4-naphthoquinone. However, recent epidemiological studies suggest that vitamin K has various benefits that go beyond blood coagulation processes. A dietary intake of K1 is inversely associated with the risk of pancreatic cancer, K2 has the potential to induce a differentiation in leukemia cells or apoptosis of various types of cancer cells, and K3 has a documented anti-cancer effect. A healthy diet rich in fruit and vegetables ensures an optimal supply of K1 and K2, though consumers often prefer supplements. Interestingly, the synthetic form of vitamin K-menadione-appears in the cell during the metabolism of phylloquinone and is a precursor of MK-4, a form of vitamin K2 inaccessible in food. With this in mind, the purpose of this review is to emphasize the importance of vitamin K as a micronutrient, which not only has a beneficial effect on blood clotting and the skeleton, but also reduces the risk of cancer and other pro-inflammatory diseases. A proper diet should be a basic and common preventive procedure, resulting in a healthier society and reduced burden on healthcare systems.

Changes in the Electron Transfer Symmetry in the Photosystem I Reaction Centers upon Removal of Iron-Sulfur Clusters.

In photosynthetic reaction centers of intact photosystem I (PSI) complexes from cyanobacteria, electron transfer at room temperature occurs along two symmetrical branches of redox cofactors A and B at a ratio of ~3 : 1 in favor of branch A. Previously, this has been indirectly demonstrated using pulsed absorption spectroscopy and more directly by measuring the decay modulation frequencies of electron spin echo signals (electron spin echo envelope modulation, ESEEM), which allows to determine the distance between the separated charges of the primary electron donor P700+ and phylloquinone acceptors A1A- and A1B- in the symmetric redox cofactors branches A and B. In the present work, these distances were determined using ESEEM in PSI complexes lacking three 4Fe-4S clusters, FX, FA, and FB, and the PsaC protein subunit (the so-called P700-A1 core), in which phylloquinone molecules A1A and A1B serve as the terminal electron acceptors. It was shown that in the P700-A1 core preparations, the average distance between the centers of the P700+A1- ion-radical pair at a temperature of 150 K in an aqueous glycerol solution and in a dried trehalose matrix, as well as in a trehalose matrix at 280 K, is ~25.5 Å, which corresponds to the symmetrical electron transfer along the A and B branches of redox cofactors at a ratio of 1 : 1. Possible reasons for the change in the electron transfer symmetry in PSI upon removal of the PsaC subunit and 4Fe-4S clusters FX, FA, and FB are discussed.

Role of Vitamin K in Selected Malignant Neoplasms in Women.

The main function of vitamin K in the human organism is its activity in the blood clotting cascade. Epidemiological studies suggest that reduced intake of vitamin K may contribute to an increased risk of geriatric diseases such as atherosclerosis, dementia, osteoporosis, and osteoarthritis. A growing number of studies also indicate that vitamin K may be involved not only in preventing the development of certain cancers but it may also support classical cancer chemotherapy. This review article summarizes the results of studies on the anticancer effects of vitamin K on selected female malignancies, i.e., breast, cervical, and ovarian cancer, published over the past 20 years. The promising effects of vitamin K on cancer cells observed so far indicate its great potential, but also the need for expansion of our knowledge in this area by conducting extensive research, including clinical trials.

New insights into vitamin K biology with relevance to cancer.

Phylloquinone (vitamin K1) and menaquinones (vitamin K2 family) are essential for post-translational γ-carboxylation of a small number of proteins, including clotting factors. These modified proteins have now been implicated in diverse physiological and pathological processes including cancer. Vitamin K intake has been inversely associated with cancer incidence and mortality in observational studies. Newly discovered functions of vitamin K in cancer cells include activation of the steroid and xenobiotic receptor (SXR) and regulation of oxidative stress, apoptosis, and autophagy. We provide an update of vitamin K biology, non-canonical mechanisms of vitamin K actions, the potential functions of vitamin K-dependent proteins in cancer, and observational trials on vitamin K intake and cancer.

Vitamin K: A novel cancer chemosensitizer.

Cancer incidences are growing rapidly and causing millions of deaths globally. Cancer treatment is one of the most exigent challenges. Drug resistance is a natural phenomenon and is considered one of the major obstacles in the successful treatment of cancer by chemotherapy. Combination therapy by the amalgamation of various anticancer drugs has suggested modulating tumor response by targeting various signaling pathways in a synergistic or additive manner. Vitamin K is an essential nutrient and has recently been investigated as a potential anticancer agent. The combination of vitamin K analogs, such as vitamins K1, K2, K3, and K5, with other chemotherapeutic drugs have demonstrated a safe, cost-effective, and most efficient way to overcome drug resistance and improved the outcomes of prevailing chemotherapy. Published reports have shown that vitamin K in combination therapy improved the efficacy of clinical drugs by promoting apoptosis and cell cycle arrest and overcoming drug resistance by inhibiting P-glycoprotein. In this review, we discuss the mechanism, cellular targets, and possible ways to develop vitamin K subtypes into effective cancer chemosensitizers. Finally, this review will provide a scientific basis for exploiting vitamin K as a potential agent to improve the efficacy of chemotherapeutic drugs.

GGCX-related congenital combined vitamin K-dependent clotting factors deficiency-1: Description of a fetus with chondrodysplasia punctata.

Congenital combined vitamin K-dependent clotting factors deficiency (VKCFD) is a rare autosomal recessive disease resulting in hemorrhagic symptoms usually associated with developmental disorders and bone abnormalities. Pathogenic variants in two genes encoding enzymes of the vitamin K cycle, GGCX and VKORC1, can lead to this disorder. We present the case of a male fetus with a brachytelephalangic chondrodysplasia punctata (CDP), absence of nasal bone, growth restriction, and bilateral ventriculomegaly at 18 weeks of gestation. Pathological examination showed a Binder phenotype, hypoplastic distal phalanges, stippled epiphyses, and brain abnormalities suggestive of a brain hemorrhage. Two GGCX pathogenic variants inherited respectively from the mother and the father were identified. To our knowledge, this is the first prenatal description of VKCFD. Even if it remains a rare etiology, which is mostly described in children or adult patients, VKCFD should be considered in fetuses with CDP.

Vitamin K status, all-cause mortality, and cardiovascular disease in adults with chronic kidney disease: the Chronic Renal Insufficiency Cohort.

BACKGROUND: Vascular calcification contributes to cardiovascular disease (CVD) and mortality in individuals with chronic kidney disease (CKD). Vitamin K-dependent proteins function as calcification inhibitors in vascular tissue. OBJECTIVES: We sought to determine the association of vitamin K status with mortality and CVD events in adults with CKD. METHODS: Plasma dephospho-uncarboxylated matrix gla protein ((dp)ucMGP), which increases when vitamin K status is low, and plasma phylloquinone (vitamin K1), which decreases when vitamin K status is low, were measured in 3066 Chronic Renal Insufficiency Cohort participants (median age = 61 y, 45% female, 41% non-Hispanic black, median estimated glomerular filtration rate [eGFR] = 41 mL/min/1.73m2). The association of vitamin K status biomarkers with all-cause mortality and atherosclerotic-related CVD was determined using multivariable Cox proportional hazards regression. RESULTS: There were 1122 deaths and 599 atherosclerotic CVD events over the median 12.8 follow-up years. All-cause mortality risk was 21-29% lower among participants with plasma (dp)ucMGP <450 pmol/L (n = 2361) compared with those with plasma (dp)ucMGP ≥450 pmol/L (adjusted HRs [95% CIs]: <300 pmol/L = 0.71 [0.61, 0.83], 300-449 pmol/L = 0.77 [0.66, 0.90]) and 16-19% lower among participants with plasma phylloquinone ≥0.50 nmol/L (n = 2421) compared to those with plasma phylloquinone <0.50 nmol/L (adjusted HRs: 0.50, 0.99 nmol/L = 0.84 [0.72, 0.99], ≥1.00 nmol/L = 0.81 [0.70, 0.95]). The risk of atherosclerotic CVD events did not significantly differ across plasma (dp)ucMGP or phylloquinone categories. CONCLUSIONS: Two biomarkers of vitamin K status were associated with a lower all-cause mortality risk but not atherosclerotic CVD events. Additional studies are needed to clarify the mechanism underlying this association and evaluate the impact of improving vitamin K status in people with CKD.

Vitamin K Effects on Gas6 and Soluble Axl Receptors in Intensive Care Patients: An Observational Screening Study.

Growth arrest-specific gene 6 protein (Gas6) is avitamin K-dependent tissue bound protein. Gas6 has been shown to promote growth and therapy resistance among different types of cancer as well as thromboembolism. The aim of this prospective screening study: ClinicalTrials.gov; Identifier: NTC3782025, was to evaluate the effects of intravenously administered vitamin K1 on Gas6 and its soluble (s)Axl receptor plasma levels in intensive care patients. Vitamin K1 was intravenously injected in non-warfarin treated patients with prolonged Owren prothrombin time international normalized ratio (PT-INR) > 1.2 and blood samples were retrieved before and 20-28 h after injection. Citrate plasma samples from 52 intensive care patients were analysed for different vitamin K dependent proteins. There was a significant, but small increase in median Gas6. Only one patient had a large increase in sAxl, but overall, no significant changes in sAxl Gas6 did not correlate to PT-INR, thrombin generation assay, coagulation factors II, VII, IX and X, but to protein S and decarboxylated matrix Gla protein (dp-ucMGP). In conclusion, there was a small increase in Gas6 over 20-28 h. The pathophysiology and clinical importance of this remains to be investigated. To verify a true vitamin K effect, improvement of Gas6 carboxylation defects needs to be studied.

Association between vitamin K1 intake and mortality in the Danish Diet, Cancer, and Health cohort.

Reported associations between vitamin K1 and both all-cause and cause-specific mortality are conflicting. The 56,048 participants from the Danish Diet, Cancer, and Health prospective cohort study, with a median [IQR] age of 56 [52-60] years at entry and of whom 47.6% male, were followed for 23 years, with 14,083 reported deaths. Of these, 5015 deaths were CVD-related, and 6342 deaths were cancer-related. Intake of vitamin K1 (phylloquinone) was estimated from a food-frequency questionnaire (FFQ), and its relationship with mortality outcomes was investigated using Cox proportional hazards models. A moderate to high (87-192 µg/d) intake of vitamin K1 was associated with a lower risk of all-cause [HR (95%CI) for quintile 5 vs quintile 1: 0.76 (0.72, 0.79)], cardiovascular disease (CVD)-related [quintile 5 vs quintile 1: 0.72 (0.66, 0.79)], and cancer-related mortality [quintile 5 vs quintile 1: 0.80 (0.75, 0.86)], after adjusting for demographic and lifestyle confounders. The association between vitamin K1 intake and cardiovascular disease-related mortality was present in all subpopulations (categorised according to sex, smoking status, diabetes status, and hypertension status), while the association with cancer-related mortality was only present in current/former smokers (p for interaction = 0.002). These findings suggest that promoting adequate intakes of foods rich in vitamin K1 may help to reduce all-cause, CVD-related, and cancer-related mortality at the population level.

Vitamin K Intake and Atherosclerotic Cardiovascular Disease in the Danish Diet Cancer and Health Study.

Background Dietary vitamin K (K1 and K2) may reduce atherosclerotic cardiovascular disease (ASCVD) risk via several mechanisms. However, studies linking vitamin K intake with incident ASCVD are limited. We aimed to determine the relationship between dietary vitamin K intake and ASCVD hospitalizations. Methods and Results In this prospective cohort study, participants from the Danish Diet, Cancer, and Health Study, with no prior ASCVD, completed a food-frequency questionnaire at baseline and were followed up for hospital admissions of ASCVD; ischemic heart disease, ischemic stroke, or peripheral artery disease. Intakes of vitamin K1 and vitamin K2 were estimated from the food-frequency questionnaire, and their relationship with ASCVD hospitalizations was determined using Cox proportional hazards models. Among 53 372 Danish citizens with a median (interquartile range) age of 56 (52-60) years, 8726 individuals were hospitalized for any ASCVD during 21 (17-22) years of follow-up. Compared with participants with the lowest vitamin K1 intakes, participants with the highest intakes had a 21% lower risk of an ASCVD-related hospitalization (hazard ratio, 0.79; 95% CI: 0.74-0.84), after multivariable adjustments for relevant demographic covariates. Likewise for vitamin K2, the risk of an ASCVD-related hospitalization for participants with the highest intakes was 14% lower than participants with the lowest vitamin K2 intake (hazard ratio, 0.86; 95% CI, 0.81-0.91). Conclusions Risk of ASCVD was inversely associated with diets high in vitamin K1 or K2. The similar inverse associations with both vitamin K1 and K2, despite very different dietary sources, highlight the potential importance of vitamin K for ASCVD prevention.

Effect of Vitamin K-Mediated PXR Activation on Drug-Metabolizing Gene Expression in Human Intestinal Carcinoma LS180 Cell Line.

The pregnane X receptor (PXR) is the key regulator of our defense mechanism against foreign substances such as drugs, dietary nutrients, or environmental pollutants. Because of increased health consciousness, the use of dietary supplements has gradually increased, and most of them can activate PXR. Therefore, an analysis of the interaction between drugs and nutrients is important because altered levels of drug-metabolizing enzymes or transporters can remarkably affect the efficiency of a co-administered drug. In the present study, we analyzed the effect of vitamin K-mediated PXR activation on drug metabolism-related gene expression in intestine-derived LS180 cells via gene expression studies and western blotting analyses. We demonstrated that menaquinone 4 (MK-4), along with other vitamin Ks, including vitamin K1, has the potential to induce MDR1 and CYP3A4 gene expression. We showed that PXR knockdown reversed MK-4-mediated stimulation of these genes, indicating the involvement of PXR in this effect. In addition, we showed that the expression of MDR1 and CYP3A4 genes increased synergistically after 24 h of rifampicin and MK-4 co-treatment. Our study thus elucidates the importance of drug-nutrient interaction mediated via PXR.