The Impact of Vitamin K2 (Menaquionones) in Children’s Health and Diseases: A Review of the Literature

Vitamin K2 activates vitamin K-dependent proteins that support many biological functions, such as bone mineralization, the inhibition of vascular stiffness, the improvement of endothelial function, the maintenance of strong teeth, brain development, joint health, and optimal body weight. Due to the transformation of food habits in developed countries over the last five decades, vitamin K and, specifically, vitamin K2 intakes among parents and their offspring have decreased significantly, resulting in serious health implications. The therapeutics used in pediatric practice (antibiotics and glucocorticoids) are also to blame for this situation. Low vitamin K status is much more frequent in newborns, due to both endogenous and exogenous insufficiencies. Just after birth vitamin K stores are low, and since human milk is relatively poor in this nutrient, breast-fed infants are at particular risk of a bleeding disorder called vitamin K deficiency bleeding. A pilot study showed that better vitamin K status is associated with lower rate of low-energy fracture incidence. An ongoing clinical trial is intended to address whether vitamin K2 and D3 supplementation might positively impact the biological process of bone healing. Vitamin K2 as menaquinone-7 (MK-7) has a documented history of safe and effective use. The lack of adverse effects of MK-7 makes it the ideal choice for supplementation by pregnant and nursing women and children, both healthy and suffering from various malabsorptions and health disorders, such as dyslipidemia, diabetes, thalassemia major (TM), cystic fibrosis (CF), inflammatory bowel diseases (IBD), and chronic liver diseases. Additionally, worthy of consideration is the use of vitamin K2 in obesity-related health outcomes.

CKD-MBD und sekundärer Hyperparathyreoidismus (Teil 1)

ZUSAMMENFASSUNGDer Begriff CKD-MBD (Chronic Kidney Disease – Mineral Bone Disorder) ist seit einigen Jahren für Störungen des Kalzium-Phosphat-Stoffwechsels und der damit verbundenen Risiken für das Mineral-Knochen- und Herz-Kreislauf-System bei chronischen Nierenerkrankungen bekannt. Die Bezeichnung entstand nach einem Paradigmenwechsel in der Pathophysiologie des sekundären Hyperparathyreoidismus und da neue Akteure wie FGF23 und Klotho gefunden wurden, die eine wichtige Rolle bei der Entstehung der Störungen spielen. Das wachsende Verständnis der Zusammenhänge zwischen den neuen Akteuren und Kalzium, Phosphat, Vitamin D und Vitamin K2 und der Verkalkung von Gefäßen und Weichteilen beeinflusste unweigerlich unsere Therapien. Dieser erste Teil des Beitrags verschafft einen Überblick über die neuesten Erkenntnisse zum Phosphat-Sensing, die Rolle von FGF23 und Klotho und die Besonderheiten des Vitamin-D- und Vitamin-K-Stoffwechsels bei Gesundheit und chronischer Nierenerkrankung.

CKD-MBD und sekundärer Hyperparathyreoidismus (Teil 2)

ZUSAMMENFASSUNGDer Begriff CKD-MBD (Chronic Kidney Disease – Mineral Bone Disorder) ist seit einigen Jahren für Störungen des Kalzium-Phosphat-Stoffwechsels und der damit verbundenen Risiken für das Mineral-Knochen- und Herz-Kreislauf-System bei chronischen Nierenerkrankungen bekannt. Die Bezeichnung entstand nach einem Paradigmenwechsel in der Pathophysiologie des sekundären Hyperparathyreoidismus und da neue Akteure wie FGF23 und Klotho gefunden wurden, die eine wichtige Rolle bei der Entstehung der Störungen spielen. Das wachsende Verständnis der Zusammenhänge zwischen den neuen Akteuren und Kalzium, Phosphat, Vitamin D und Vitamin K2 sowie der Verkalkung von Gefäßen und Weichteilen beeinflusste unweigerlich unsere Therapien. Dieser zweite Teil des Beitrags verschafft einen Überblick über die Implikationen der neuen pathophysiologischen Erkenntnisse, v. a. im Hinblick auf neue Therapeutika für eine optimale Therapie von Patienten mit CKD-MBD.

Physiological roles of short-chain and long-chain menaquinones (vitamin K2) in Lactococcus cremoris

Lactococcus cremoris and L. lactis are well-known for their occurrence and applications in dairy fermentations, but their niche extends to a range of natural and food production environments. L. cremoris and L. lactis produce MKs (vitamin K2), mainly as the long-chain forms represented by MK-9 and MK-8, and a detectable amount of short-chain forms represented by MK-3. The physiological significance of the different MK forms in the lifestyle of these bacterial species has not been investigated extensively. In this study, we used L. cremoris MG1363 to construct mutants producing different MK profiles by deletion of genes encoding (i) a menaquinone-specific isochorismate synthase, (ii) a geranyltranstransferase and (iii) a prenyl diphosphate synthase. These gene deletions resulted in (i) a non-MK producer (ΔmenF), (ii) a presumed MK-1 producer (ΔispA) and (iii) a MK-3 producer (Δllmg_0196), respectively. By examining the phenotypes of the MG1363 wildtype strain and respective mutants, including biomass accumulation, stationary phase survival, oxygen consumption, primary metabolites, azo dye/copper reduction, and proteomes, under aerobic, anaerobic and respiration-permissive conditions, we could infer that short-chain MKs like MK-1 and MK-3 are preferred to mediate extracellular electron transfer and reaction with extracellular oxygen, while the long-chain MKs like MK-9 and MK-8 are more efficient in aerobic respiratory electron transport chain. The different electron transfer routes mediated by short-chain and long-chain MKs likely support growth and survival of L. cremoris in a range of (transiently) anaerobic and aerobic niches including food fermentations, highlighting the physiological significance of diverse MKs in L. cremoris.

Simultaneous Determination of Vitamins D3 (Calcitriol, Cholecalciferol) and K2 (Menaquinone-4 and Menaquinone-7) in Dietary Supplements by UHPLC

The content and composition of dietary supplements is of great interest due to their increasing consumption and variety of available brand offered in the market. Accurate determination of vitamins is important for the improvement of dietary supplement quality and nutrition assessments. In this regard, the simultaneous determination of vitamin D3 (calcitriol—CT and cholecalciferol—CHL) and K2 (menaquinone-4—MK-4 and menaquinone-7—MK-7) in dietary supplements was developed by using ultra-high-pressure liquid chromatography (UHPLC). The overall runtime per sample was above 35 min, with the retention times of 2.40, 6.59, 7.06, and 32.6 min for vitamin D3 (CT and CHL) and vitamin K2 (MK-4 and MK-7), respectively. The limits of detection and limits of quantification for the target nutritional compounds ranged between 0.04–0.05 µg/mL, respectively. The validation results indicated that the method had reasonable linearity (R2 ≥ 0.9990), good recovery (>82%), satisfactory intra-day precision (≤1.9%) and inter-day precision (≤3.5%), and high selectivity and specificity. The validated UHPLC method was demonstrated to be precise, accurate, and robust for the simultaneous determination of vitamins D3 (CT and CHL) and K2 (MK-4 and MK-7) in dietary supplements.

Vitamin K2 Inhibits Hepatocellular Carcinoma Cell Proliferation by Binding to 17β-Hydroxysteroid Dehydrogenase 4

Our previous studies have proved that 17β-hydroxysteroid dehydrogenase 4 (HSD17B4) is a novel proliferation-promoting protein. The overexpression of HSD17B4 promotes hepatocellular carcinoma (HCC) cell proliferation. Vitamin K2 (VK2), a fat-soluble vitamin, has the function of promoting coagulation and can inhibit the progression of liver cancer. A previous study demonstrated that VK2 could bind to HSD17B4 in HepG2 cells. However, the mechanism of VK2 in inhibiting HCC cell proliferation is not clear. In this study, we investigate whether VK2 can inhibit the proliferation of HCC cell induced by HSD17B4 and the possible mechanism. We detected the effect of VK2 on HSD17B4-induced HCC cell proliferation, and the activation of STAT3, AKT, and MEK/ERK signaling pathways. We measured the effect of HSD17B4 on the growth of transplanted tumor and the inhibitory effect of VK2. Our results indicated that VK2 directly binds to HSD17B4, but does not affect the expression of HSD17B4, to inhibit the proliferation of HCC cells by inhibiting the activation of Akt and MEK/ERK signaling pathways, leading to decreased STAT3 activation. VK2 also inhibited the growth of HSD17B4-induced transplanted tumors. These findings provide a theoretical and experimental basis for possible future prevention and treatment of HCC using VK2.