PMID: 

Vascul Pharmacol. 2019 Nov – Dec;122-123:106581. Epub 2019 Aug 14. PMID: 31421222

Abstract Title: 

Vitamin K-MK-7 improves nitric oxide-dependent endothelial function in ApoE/LDLRmice.

Abstract: 

Although, vitamin Kdisplays vasoprotective effects, it is still not known whether Ktreatment improves endothelial function. In ApoE/LDLRmice at the stage prior to atherosclerosis development, four-week treatment with K-MK-7, given at a low dose (0.05 mg/kg), improved acetylcholine- and flow-induced, endothelium-dependent vasodilation in aorta or in femoral artery, as assessed by MRI in vivo. This effect was associated with an increased NO production, as evidenced by EPR measurements in ex vivo aorta. Treatment with higher doses of K-MK-7 (0.5; 5 mg/kg) resulted in a dose-dependent increase in plasma K-MK-7 and K-MK-4 concentration, without further improvement in endothelial function. In ApoE/LDLRmice with developed atherosclerotic plaques, treatment with a low (0.03 mg/kg) or high (10 mg/kg) dose of K-MK-7 resulted in a similar degree of endothelium-dependent vasodilation improvement and increase in plasma nitrate concentration, what was not associated with changes in thrombin generation as measured by CAT. Both doses of K-MK-7 also reduced media thickness in the brachiocephalic artery, but did not modify atherosclerotic plaque size. In conclusion, K-MK-7 improves NO-dependent endothelial function in ApoE/LDLRmice. This study, identifies the endothelial profile of the pharmacological activity of vitamin K, which has not been previously described.

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PMID: 

Pediatr Int. 2019 Dec ;61(12):1188-1195. Epub 2019 Dec 13. PMID: 31560147

Abstract Title: 

Vitamin Kimmunosuppressive effect on pediatric patients with atopic dermatitis.

Abstract: 

BACKGROUND: Over 20 kinds of steroids, tacrolimus ointments, and cyclosporine capsules are usually recommended for the treatment of atopic dermatitis (AD), depending on the symptoms of patients. However, several side effects sometimes occur with the extensive use of these agents for the treatment of pediatric AD patients. The purpose of this study was to explore whether vitamin Kcould be a new immunosuppressive candidate for pediatric patients with AD.METHODS: The immunosuppressive efficacy of vitamin Kwas evaluated through a cell-culture procedure using mitogen-activated peripheral blood mononuclear cells (PBMCs) obtained from pediatric AD patients.RESULTS: The mean (SD) ICvalue of vitamin Kfor the proliferation of concanavalin A-activated PBMCs was 15.37 (30.05) μmol/L, while the value for tacrolimus was 0.10 (0.28) ng/mL (0.12 (0.35) nmol/L). There was a significant correlation between the ICvalues for vitamin Kand those for tacrolimus (P = 0.0001, r = 0.8871). However, there was no significant correlation between the ICvalues of vitamin Kand those of cyclosporine A or methylprednisolone. A significant correlation between the ICvalues of vitamin Kor tacrolimus and blood eosinophil counts (P = 0.0099, r = 0.7086 and P = 0.0032, r = 0.7722, respectively) was observed.CONCLUSION: Vitamin K-inhibited T-cell mitogen stimulated proliferation of PBMCs from pediatric AD patients in a dose-dependent manner. The PBMCs from pediatric AD patients were more sensitive to the immunosuppressive efficacy of vitamin Kthan the PBMCs from healthy subjects. The individual immunosuppressive pharmacological efficacy of vitamin Kand of tacrolimus could be inferred from the blood eosinophil count of pediatric AD patients.

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PMID: 

Breast Cancer. 2019 Oct 17. Epub 2019 Oct 17. PMID: 31625014

Abstract Title: 

Vitamin Kinduces non-apoptotic cell death along with autophagosome formation in breast cancer cell lines.

Abstract: 

BACKGROUND: Vitamin K(VK2) has been reported to induce apoptosis in many types of cancer cells including leukemia. However, there are no precise reports regarding the breast cancer cells. From the stand point of clinical implications of VK2 including chemoprevention, we investigated the effects of VK2 on breast cancer cell lines.METHODS: Breast cancer cell lines were cultured with VK2, and the cytotoxicity and cell death phenotype were examined. The HL-60 leukemia cells were used as a control for VK2-induced apoptosis.RESULTS: VK2 exhibited the cytotoxic effect, especially in triple negative breast cancer cell lines, namely, MDA-MB-231 and MDA-MB-468. However, in contrast to HL-60 cells, typical features of the cells undergoing apoptosis, such as chromatin condensation, nuclear fragments, and cleavage of caspase-3 were not detected. Transmission electron microscopy exhibited an increased number of autophagosomes/autolysosomes with plasma membrane integrity. An autophagy inhibitor, 3-methyladenine, apparently attenuated VK2-induced cytotoxicity, which indicated the involvement of autophagy-dependent cell death. Interestingly, both VK2-induced non-apoptotic cell death in MDA-MB-231 cells and VK2-induced apoptosis in HL-60 cells were suppressed in the presence of reactive oxygen species (ROS) scavengers. Therefore, ROS production by VK2 seems to be located up-stream in the molecular machinery for both the types of cell death execution.CONCLUSION: The VK2 induced non-apoptotic cell death along with autophagy, in triple negative breast cancer cell lines. Cell death phenotype induced by VK2 appears to differ among the type of cancers. This suggests the possibility of using VK2 for the breast cancer therapy.

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PMID: 

Headache. 2019 Nov 25. Epub 2019 Nov 25. PMID: 31769041

Abstract Title: 

Vitamin K2 Status and Arterial Stiffness Among Untreated Migraine Patients: A Case-Control Study.

Abstract: 

OBJECTIVE: We aimed to examine arterial stiffness and vitamin K2 status in migraine subjects by comparison to controls.BACKGROUND: Migraine is a primary headache disorder that has been associated with an increased risk of cardiovascular events. Mechanisms underlying this increased risk, however, remain unclear. Vitamin K2 deficiency emerged as a cardiovascular risk factor, but vitamin K2 status has never been explored in migraine subjects.DESIGN AND METHODS: This is a case-control, single-center, observational study that includes a cohort of subjects with migraine and their age- and sex-matched controls. Arterial stiffness was measured using carotid-femoral pulse wave velocity (cfPWV). Dephosphorylated-uncarboxylated matrix-Gla-protein (dp-ucMGP) was used as a marker for vitamin K2 status. A propensity-matched scoring method was used.RESULTS: A total of 146 patients (73 matched pairs) were included in this study, of whom 89% were women with a mean age of 31.9 ± 8.4 years. Compared with controls, migraine patients had statistically significantly higher mean cfPWV (7.2 ± 1.1 vs 6.4 ± 0.8 m/s, 95% confidence interval (CI) of mean difference [0.45, 1.08], P 

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PMID: 

Calcif Tissue Int. 2020 Feb 14. Epub 2020 Feb 14. PMID: 32060566

Abstract Title: 

Effect of Low-Dose Vitamin K2 Supplementation on Bone Mineral Density in Middle-Aged and Elderly Chinese: A Randomized Controlled Study.

Abstract: 

Previous studies indicated a positive effect of vitamin K2 (VK2) supplementation on bone turnover biomarkers and bone mineral density (BMD), but the doses varied, and few studies have focused on the difference between VK2 supplementation alone and in combination with calcium and vitamin D. The aim of this study was to explore a low and effective dose of VK2 for improving BMD, and to examine whether the co-supplementation of VK2, calcium and vitamin Dwould bring greater effects. In this trial, a total of 311 community-dwelling men and postmenopausal women aged 50 and 75 years were randomly assigned to four groups, receiving placebo, 50 µg/day, 90 µg/day or co-supplementation with calcium (500 mg/day) and vitamin D(10 µg/day) for 1 year. At the endpoint, the bone loss of femoral neck was significantly lower in postmenopausal women in the two 90 µg groups (treatment × time, p = 0.006) compared with placebo, but no effects in men. Serum biomarkers cOC/ucOC ratio increased in the intervention groups (treatment × time, p 

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PMID: 

Int J Mol Sci. 2019 Jun 13 ;20(12). Epub 2019 Jun 13. PMID: 31200560

Abstract Title: 

Vitamin D Supplementation Reduces Both Oxidative DNA Damage and Insulin Resistance in the Elderly with Metabolic Disorders.

Abstract: 

Research evidence indicates that vitamin D deficiency is involved in the pathogenesis of insulin resistance (IR) and associated metabolic disorders including hyperglycemia and dyslipidemia. It also suggested that vitamin D deficiency is associated with elevated levels of oxidative stress and its complications. Therefore, the aim of our study was to determine the effect of vitamin D supplementation on DNA damage and metabolic parameters in vitamin D deficient individuals aged>45 with metabolic disorders.Of 98 initially screened participants, 92 subjects deficient in vitamin D were included in the study. They were randomly assigned to the following group: with vitamin D supplementation (intervention group,48) and without supplementation (comparative group,44). The patients from both groups were divided into two subgroups according to the presence or absence of type 2 diabetes (T2DM). The intervention group was treated with 2000 International Unit (IU) cholecalciferol/day between October and March for three months. At baseline and after three-month supplementation vitamin D concentration (25-OH)D3 and endogenous and oxidative DNA damage were determined. In addition, fast plasma glucose (FPG), fasting insulin, HbA1c and lipid fraction (total cholesterol (TC), low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), triglyceride (TG)), as well as anthropometric measurements (weight, height) were gathered. The following IR-related parameters were calculated Homeostatic Model Assesment – Insulin Resistance (HOMA-IR) and TG/HDL ratio.Three-month vitamin D supplementation increased the mean vitamin D concentration to generally accepted physiological level independently of T2DM presence. Importantly, vitamin D exposure decreased the level of oxidative DNA damage in lymphocytes of patients of intervention group. Among studied metabolic parameters, vitamin D markedly increased HDL level, decreased HOMA-IR, TG/HDL ratio. Furthermore, we found that HbA1c percentage diminished about 0.5% in T2DM patients supplemented with vitamin D.The current study demonstrated that daily 2000I U intake of vitamin D for three months decreased the level of oxidative DNA damage, a marker of oxidative stress, independently on T2DM presence. Furthermore, vitamin D reduced metabolic parameters connected with IR and improved glucose and lipid metabolism. Therefore, our results support the assertion that vitamin D, by reducing oxidative stress and improving of metabolic profile, may decrease IR and related diseases.

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PMID: 

Clin Lab. 2019 May 1 ;65(5). PMID: 31115227

Abstract Title: 

Pre-Diabetics with Hypovitaminosis D Have Higher Risk for Insulin Resistance.

Abstract: 

BACKGROUND: Various studies have been reported on the relationship between vitamin D, whose deficiency has been identified in a pandemic way, and metabolic-endocrine diseases, including insulin resistance. Insulin resistance is an important public health issue since it is a common cause of death as it transforms into metabolic syndrome and type 2 diabetes mellitus (DM). In this study, the aim is to investigate the relationship between the level of serum 25 hydroxy vitamin D (25(OH)D) and insulin resistance.
METHODS: A retrospective study was carried out including 2,008 patients aged between 18 – 67 chosen from among the patients who had applied to Saglik Bilimleri University Antalya Training and Research Hospital. Patients were divided into three groups as non-diabetic, pre-diabetic, and diabetic according to their blood glucose profile and into three categories according to their 25(OH)D levels. The relationship between serum vitamin D levels and insulin resistance was compared between the groups. Individuals with homeostasis model assessment of insulin re-sistance (HOMA-IR)>2.5 were considered to have insulin resistance.
RESULTS: The study was composed of 2,008 patients, 1,614 were female (80.4%). Of the participants, 216 (10.6%) were diabetics, 849 (42.3%) were pre-diabetics, and 943 (47.1%) were non-diabetics. It was identified that age, fasting blood glucose, HbA1c, triglyceride (Tg), very-low-density lipoprotein cholesterol (VLDL-C), fasting insulin, and HOMA-IR levels were significantly higher in diabetic patients than in pre-diabetic patients (all p<0.001) and similarly higher in pre-diabetics than in non-diabetics. Tg, VLDL, fasting insulin, and HOMA-IR levels were significantly lower in the group with 25(OH)D≥ 30 ng/mL. Especially in pre-diabetic individuals, a significant negative correlation was observed between the 25(OH)D level and HbA1c (p = 0.020), Tg (p = 0.001), VLDL-C (p = 0.001), fasting insulin (p<0.001) and HOMA-IR (p<0.001). While high HOMA-IR was positively associated with fasting blood glucose and total cholesterol values (all p<0.001), it was negatively associated with age (p<0.001), LDL-cholesterol (p<0.001), HDL-cholesterol (p<0.001) and 25(OH)D (p = 0.001).
CONCLUSIONS: Diabetic subjects have lower plasma 25(OH)D levels and pre-diabetics with hypovitaminosis D have higher risk for insulin resistance. Thus, HOMA-IR must be well evaluated in pre-diabetic individuals with vitamin D deficiency/insufficiency, if there is associating abdominal obesity.

PMID: 

Complement Ther Clin Pract. 2019 Feb ;34:294-304. Epub 2018 Dec 19. PMID: 30712741

Abstract Title: 

The effects of vitamin D supplementation on indices of glycemic control in Iranian diabetics: A systematic review and meta-analysis.

Abstract: 

BACKGROUND AND PURPOSE: This systematic review and meta-analysis aimed to assess the effects of vitamin D supplements on indices of glycemic control [homeostatic model assessment-insulin resistance (HOMA-IR), hemoglobin A1C (HbA1C), fasting blood glucose (FBG), and quantitative insulin-sensitivity check index (QUICKI) and lipid profile in diabetic patients.METHODS: Eight databases were searched, for randomized controlled trials (RCTs) or cross-sectional and cohort studies that have been published up to December 2017. We used the comprehensive meta-analysis (CMA) software for all statistical analysis and used the Iindex for assessing heterogeneity. A p value of

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PMID: 

J Endocr Soc. 2018 Jul 1 ;2(7):687-709. Epub 2018 May 25. PMID: 29951596

Abstract Title: 

Vitamin D Supplementation, Glycemic Control, and Insulin Resistance in Prediabetics: A Meta-Analysis.

Abstract: 

Diabetes prevention is a public health priority. Vitamin D supplementation may help prevent the development of diabetes in persons at increased risk. We performed a meta-analysis of controlled clinical trials that assessed glycemic outcome measures among adults at risk for type 2 diabetes, including prediabetes, overweight, or obesity. We searched PUBMED/ MEDLINE, CINAHL, and Google Scholar databases for trials published prior to April 2017. Placebo-controlled clinical trials with random allocation to vitamin D with or without calcium supplementation were selected. Data collection included country, study design, inclusion criteria, sample size, form, and dose of vitamin D, supplementation interval, control group, duration, participant characteristics, comorbidities, baseline and follow-up serum 25-hydroxyvitamin D [25(OH)D] concentration, and available outcome measures [glycosylated hemoglobin (HbA1c), fasting plasma glucose, plasma glucose after 2-hour oral glucose tolerance test, and homeostatic model assessment of insulin resistance (HOMA-IR)]. Data synthesis was conducted using random-effect models (PROSPERO registration no. CRD42017055326). Twenty-eight trials, representing 3848 participants, met the eligibility criteria. Compared with the control group, vitamin D supplementation significantly reduced HbA1c level by -0.48% (95% CI, -0.79 to -0.18), fasting plasma glucose level by -0.46 mmol/L (95% CI, -0.74 to -0.19), and HOMA-IR level by -0.39 (95% CI, -0.68 to -0.11). Subgroup analysis revealed that the effects of vitamin D supplementation on different glycemic measures were influenced by age, calcium coadministration, vitamin D deficiency, serum 25(OH)D level after supplementation, and duration of supplementation. Vitamin D supplementation and improved vitamin D status improved glycemic measures and insulin sensitivity and may be useful as part of a preventive strategy for type 2 diabetes.

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PMID: 

Biofactors. 2020 Jan ;46(1):21-37. Epub 2019 Oct 1. PMID: 31573736

Abstract Title: 

A systematic review on the mechanisms of vitamin K effects on the complications of diabetes and pre-diabetes.

Abstract: 

Diabetes mellitus and pre-diabetes are prevalent endocrine disorders associated with substantial morbidity and premature mortality. Vitamin K is known to have several beneficial effects on complications of diabetes and pre-diabetes. However, systematic consolidation of evidence is required to quantify these effects in order to inform clinical practice and research. A systematic search in PubMed, Scopus, Embase, ProQuest, and Google Scholar databases was undertaken from database inception up to October 2018 to evaluate functional roles of different forms of vitamin K on diabetes and pre-diabetes. From 3,734 identified records, nine articles met the inclusion criteria and were evaluated. Vitamin K supplementation was found to be associated with significant reductions in blood glucose (six studies), increased fasting serum insulin (four studies), reduced hemoglobin A1c (three studies), reduced homeostatic model assessment-insulin resistance index (HOMA-IR) (two studies), and increasedß-cell function (two studies) in diabetic animal studies. Following 2-hour oral glucose tolerance test, vitamin K supplementation was observed to be effective in reducing blood glucose and insulin levels in the pre-diabetic population. However, no evidence of effect was observed for fasting blood sugar, insulin, HOMA-IR, and homeostatic model assessment-β-cell function index (two studies). A statistically significant effect was also noted with vitamin K in improving dyslipidemia (three studies) as well as oxidative stress and inflammatory markers (five studies) in diabetic animals. In conclusion, clinical trials and animal studies confirm that vitamin K supplementation may improve both clinical features and complications of diabetes and pre-diabetes. However, quantification of clinical efficacy in the pre-diabetic population and among individuals with comorbidities requires further investigation.

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