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Heart (British Cardiac Society) Jun 2019Vascular stiffness (VS) and vascular calcification (VC) are surrogate markers of vascular health associated with cardiovascular events. Vitamin K-dependent proteins... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
Vascular stiffness (VS) and vascular calcification (VC) are surrogate markers of vascular health associated with cardiovascular events. Vitamin K-dependent proteins (VKDP) are associated with VS and VC and require vitamin K for activity. We conducted a systematic review and meta-analysis of: (1) the effect of vitamin K supplementation on VS and VC and (2) association of inactive VKDP levels with incident cardiovascular disease and mortality.
METHODS
Two authors searched MEDLINE and Embase databases and Cochrane and ISRCTN registries for studies of vitamin K clinical trials that measured effects on VC, VS or VKDP and longitudinal studies assessing effect of VKDP on incident CVD or mortality. Random effects meta-analyses were performed.
RESULTS
Thirteen controlled clinical trials (n=2162) and 14 longitudinal studies (n=10 726) met prespecified inclusion criteria. Vitamin K supplementation was associated with significant reduction in VC (-9.1% (95% CI -17.7 to -0.5); p=0.04) and VKDP (desphospho-uncarboxylated matrix Gla protein; -44.7% (95% CI -65.1 to -24.3), p<0.0001) and uncarboxylated osteocalcin; -12.0% (95% CI -16.7 to -7.2), p<0.0001) compared with control, with a non-significant improvement in VS. In longitudinal studies with median follow-up of 7.8 (IQR 4.9-11.3) years, VKDP levels were associated with a combined endpoint of CVD or mortality (HR 0.45 (95% CI 0.07 to 0.83), p=0.02).
CONCLUSIONS
Supplementation with vitamin K significantly reduced VC, but not VS, compared with control. The conclusions drawn are limited by small numbers of studies with substantial heterogeneity. VKDP was associated with combined endpoint of CVD or mortality. Larger clinical trials of effect of vitamin K supplementation to improve VC, VS and long-term cardiovascular health are warranted.
TRIAL REGISTRATION NUMBER
CRD42017060344.
Topics: Biomarkers; Dietary Supplements; Humans; Vascular Calcification; Vascular Diseases; Vitamin K; Vitamins
PubMed: 30514729
DOI: 10.1136/heartjnl-2018-313955 -
International Journal of Molecular... Aug 2019Vitamin K is a multifunctional micronutrient implicated in age-related diseases such as cardiovascular diseases, osteoarthritis and osteoporosis. Although vitamin... (Review)
Review
Vitamin K is a multifunctional micronutrient implicated in age-related diseases such as cardiovascular diseases, osteoarthritis and osteoporosis. Although vitamin K-dependent proteins (VKDPs) are described to have a crucial role in the pathogenesis of these diseases, novel roles have emerged for vitamin K, independently of its role in VKDPs carboxylation. Vitamin K has been shown to act as an anti-inflammatory by suppressing nuclear factor κB (NF-κB) signal transduction and to exert a protective effect against oxidative stress by blocking the generation of reactive oxygen species. Available clinical evidences indicate that a high vitamin K status can exert a protective role in the inflammatory and mineralization processes associated with the onset and progression of age-related diseases. Also, vitamin K involvement as a protective super-micronutrient in aging and 'inflammaging' is arising, highlighting its future use in clinical practice. In this review we summarize current knowledge regarding clinical data on vitamin K in skeletal and cardiovascular health, and discuss the potential of vitamin K supplementation as a health benefit. We describe the clinical evidence and explore molecular aspects of vitamin K protective role in aging and age-related diseases, and its involvement as a modulator in the interplay between pathological calcification and inflammation processes.
Topics: Age Factors; Aging; Animals; Biomarkers; Disease Susceptibility; Humans; Micronutrients; Vitamin K
PubMed: 31450694
DOI: 10.3390/ijms20174150 -
IUBMB Life Jun 2008Vitamin K2 [menaquinone-4 (MK-4)] has been reported to induce apoptosis in hepatocellular carcinoma, leukemia, and MDS cell lines. The effects of MK-4 on the development... (Review)
Review
Vitamin K2 [menaquinone-4 (MK-4)] has been reported to induce apoptosis in hepatocellular carcinoma, leukemia, and MDS cell lines. The effects of MK-4 on the development of arthritis have never been addressed so far. In this study, we investigated the effect of MK-4 upon the proliferation of rheumatoid synovial cells and the development of arthritis in collagen-induced arthritis (CIA). We analyzed the effect of MK-4 on the proliferation of fibroblast-like synoviocytes (FLSs) using the 3-(4,5-demethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The proapoptotic effect of MK-4 upon FLS was investigated with annexin V staining and DNA fragmentation and caspase 3/7 assays. Moreover, we analyzed the effect of MK-4 on the development of CIA in female dark agouti rats. Our results indicated that MK-4 inhibited the proliferation of FLS and the development of CIA in a dose-dependent manner. We concluded that MK-4 may represent a new agent for the treatment of RA in the setting of combination therapy with other disease-modifying antirheumatic drugs.
Topics: Animals; Antirheumatic Agents; Apoptosis; Arthritis, Rheumatoid; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Female; Fibroblasts; Humans; Models, Biological; Rats; Reactive Oxygen Species; Tetrazolium Salts; Thiazoles; Vitamin K
PubMed: 18484089
DOI: 10.1002/iub.41 -
Nutrients Aug 2020Type 2 diabetes mellitus is a chronic disease that is characterized by hyperglycemia, insulin resistance, and dysfunctional insulin secretion. Glycemic control remains a... (Review)
Review
Type 2 diabetes mellitus is a chronic disease that is characterized by hyperglycemia, insulin resistance, and dysfunctional insulin secretion. Glycemic control remains a crucial contributor to the progression of type 2 diabetes mellitus as well as the prevention or delay in the onset of diabetes-related complications. Vitamin K is a fat-soluble vitamin that plays an important role in the regulation of the glycemic status. Supplementation of vitamin K may reduce the risk of diabetes mellitus and improve insulin sensitivity. This mini-review summarizes the recent insights into the beneficial effects of vitamin K and its possible mechanism of action on insulin sensitivity and glycemic status, thereby suppressing the progression of diabetes mellitus.
Topics: Adult; Aged; Diabetes Complications; Diabetes Mellitus, Type 2; Dietary Supplements; Disease Progression; Female; Glycemic Control; Humans; Insulin Resistance; Male; Middle Aged; Nutritional Status; Vitamin K; Young Adult
PubMed: 32824773
DOI: 10.3390/nu12082485 -
Basic & Clinical Pharmacology &... Jan 2018Atherosclerosis is a pathological process underpinning many cardiovascular diseases; it is the main cause of global mortality. Atherosclerosis is characterized by an... (Review)
Review
Atherosclerosis is a pathological process underpinning many cardiovascular diseases; it is the main cause of global mortality. Atherosclerosis is characterized by an invasion of inflammatory cells, accumulation of lipids and the formation of fatty streaks (plaques) which subsequently allow accumulation of calcium and other minerals leading to a disturbance in the vascular endothelium and its regulatory role in arterial function. Vascular calcification is a different process, stringently regulated mainly by local factors, in which osteoblast-like cells accumulate in the muscular layer of arteries ultimately taking on the physiological appearance of bone. The elevated stiffness of the arteries leads to severe vascular complications in brain, heart and kidneys. Recently, evidence from animal experiments as well as clinical and epidemiological results suggests that long-term treatment with warfarin, but not with the novel direct anticoagulants, can increase the risk or even induce vascular calcification in some individuals. Gamma-carboxylation is an enzymatic process not only needed for activation of vitamin K but also other proteins which participate in bone formation and vascular calcification. Thus, reduced expression of the vitamin K-dependent proteins which physiologically inhibit calcification of cellular matrix could be postulated to lead to vascular calcification. Published clinical data, describing at present a few thousand patients, need to be supplemented with controlled studies to confirm this interesting hypothesis.
Topics: Animals; Anticoagulants; Arteries; Atherosclerosis; Dietary Supplements; Disease Models, Animal; Humans; Time Factors; Vascular Calcification; Vascular Stiffness; Vitamin K; Warfarin
PubMed: 28639365
DOI: 10.1111/bcpt.12834 -
Synthesis of Naphthoquinone Derivatives: Menaquinones, Lipoquinones and Other Vitamin K Derivatives.Molecules (Basel, Switzerland) Sep 2020Menaquinones are a class of isoprenoid molecules that have important roles in human biology and bacterial electron transport, and multiple methods have been developed... (Review)
Review
Menaquinones are a class of isoprenoid molecules that have important roles in human biology and bacterial electron transport, and multiple methods have been developed for their synthesis. These compounds consist of a methylnaphthoquinone (MK) unit and an isoprene side chain, such as found in vitamin K (phylloquinone), K, and other lipoquinones. The most common naturally occurring menaquinones contain multiple isoprene units and are very hydrophobic, rendering it difficult to evaluate the biological activity of these compounds in aqueous assays. One way to overcome this challenge has been the application of truncated MK-derivatives for their moderate solubility in water. The synthesis of such derivatives has been dominated by Friedel-Crafts alkylation with BF∙OEt. This attractive method occurs over two steps from commercially available starting materials, but it generally produces low yields and a mixture of isomers. In this review, we summarize reported syntheses of both truncated and naturally occurring MK-derivatives that encompass five different synthetic strategies: Nucleophilic ring methods, metal-mediated reactions, electrophilic ring methods, pericyclic reactions, and homologation and side chain extensions. The advantages and disadvantages of each method are discussed, identifying methods with a focus on high yields, regioselectivity, and stereochemistry leading to a detailed overview of the reported chemistry available for preparation of these compounds.
Topics: Alkylation; Catalysis; Naphthoquinones; Oxidation-Reduction; Vitamin K; Vitamin K 2
PubMed: 33003459
DOI: 10.3390/molecules25194477 -
Anesthesiology Dec 2018Vitamin K antagonist therapy is associated with an increased bleeding risk, and clinicians often reverse anticoagulation in patients who require emergency surgical... (Review)
Review
Vitamin K antagonist therapy is associated with an increased bleeding risk, and clinicians often reverse anticoagulation in patients who require emergency surgical procedures. Current guidelines for rapid anticoagulation reversal for emergency surgery recommend four-factor prothrombin complex concentrate and vitamin K coadministration. The authors reviewed the current evidence on prothrombin complex concentrate treatment for vitamin K antagonist reversal in the perioperative setting, focusing on comparative studies and in the context of intracranial hemorrhage and cardiac surgery. The authors searched Cochrane Library and PubMed between January 2008 and December 2017 and retrieved 423 English-language papers, which they then screened for relevance to the perioperative setting; they identified 36 papers to include in this review. Prothrombin complex concentrate therapy was consistently shown to reduce international normalized ratio rapidly and control bleeding effectively. In comparative studies with plasma, prothrombin complex concentrate use was associated with a greater proportion of patients achieving target international normalized ratios rapidly, with improved hemostasis. No differences in thromboembolic event rates were seen between prothrombin complex concentrate and plasma, with prothrombin complex concentrate also demonstrating a lower risk of fluid overload events. Overall, the studies the authors reviewed support current recommendations favoring prothrombin complex concentrate therapy in patients requiring vitamin K antagonist reversal before emergency surgery.
Topics: Anticoagulants; Blood Coagulation Factors; Emergency Medical Services; Humans; International Normalized Ratio; Vitamin K
PubMed: 30157037
DOI: 10.1097/ALN.0000000000002399 -
Archives of Disease in Childhood. Fetal... Mar 2003Policies for giving babies vitamin K prophylactically at birth have been dictated, over the last 60 years, more by what manufacturers decided on commercial grounds to... (Review)
Review
Policies for giving babies vitamin K prophylactically at birth have been dictated, over the last 60 years, more by what manufacturers decided on commercial grounds to put on the market, than by any informed understanding of what babies actually need, or how it can most easily be given. By a pure fluke a 1 mg IM dose, designed to prevent early vitamin deficiency bleeding ("haemorrhagic disease of the newborn") has been found to protect against late deficiency bleeding-a condition unrecognised at the time this policy took hold. Alternative strategies for oral prophylaxis are now opening up (see pp 109 and 113), but these are also, at the moment, dictated more by what the manufacturers choose to provide than by what would make for ease of delivery either in poor countries, or in the developed world.
Topics: Antifibrinolytic Agents; Humans; Infant, Newborn; Neoplasms; Vitamin K; Vitamin K Deficiency Bleeding
PubMed: 12598491
DOI: 10.1136/fn.88.2.f80 -
Nutrients May 2022The aim of the study was to estimate the content of K1, K2 (MK-n) as well as total K vitamins and their sources in the diets of 1985 PURE Poland study participants based...
The aim of the study was to estimate the content of K1, K2 (MK-n) as well as total K vitamins and their sources in the diets of 1985 PURE Poland study participants based on the FFQ questionnaire. Due to the pleiotropic effect of K vitamins, it is important to know their food sources depending on different eating habits. Total vitamin K in the diets amounted to 331.1 ± 151.5 µg/d and 358.6 ± 181.0 µg/d for men and women, respectively. Dietary patterns (DPs) were identified in the study group, and the relationship between them and vitamin K intake was assessed. The proportion of dominant products as sources of vitamin K in the fourth quartile of each of the three identified DPs did not change significantly compared to the proportion of these products as sources of vitamin K in all subjects. In the fourth quartile of individual DPs, vitamin K1 came mainly from vegetables (56.5-76.8%); K2 mainly from processed meat and high-fat cheese and cream (70.1-77.6%); and total K mainly from vegetables and processed meat (57.6-67.8%). Intakes of K vitamins were high and similar in terms of predominant vitamin K provider products, in groups of subjects whose diets were most consistent with the particular DP. In the absence of global findings on the most appropriate dietary content of MK-n vitamins other than phylloquinone, the estimated high content of these vitamins in the diets of the subjects compared with other nations suggests that their level in diets was satisfactory. Future studies should aim to determine the need for MK-n vitamins in terms of fulfilling all their functions in the body.
Topics: Diet; Female; Humans; Male; Poland; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamins
PubMed: 35565883
DOI: 10.3390/nu14091917 -
Applied and Environmental Microbiology Nov 2020Enterohemorrhagic (EHEC) causes serious foodborne disease worldwide. It produces the very potent Shiga toxin 2 (Stx2). The Stx2-encoding genes are located on a...
Enterohemorrhagic (EHEC) causes serious foodborne disease worldwide. It produces the very potent Shiga toxin 2 (Stx2). The Stx2-encoding genes are located on a prophage, and production of the toxin is linked to the synthesis of Stx phages. There is, currently, no good treatment for EHEC infections, as antibiotics may trigger lytic cycle activation of the phages and increased Stx production. This study addresses how four analogs of vitamin K, phylloquinone (K1), menaquinone (K2), menadione (K3), and menadione sodium bisulfite (MSB), influence growth, Stx2-converting phage synthesis, and Stx2 production by the EHEC O157:H7 strain EDL933. Menadione and MSB conferred a concentration-dependent negative effect on bacterial growth, while phylloquinone or menaquinone had little and no effect on bacterial growth, respectively. All four vitamin K analogs affected Stx2 phage production negatively in uninduced cultures and in cultures induced with either hydrogen peroxide (HO), ciprofloxacin, or mitomycin C. Menadione and MSB reduced Stx2 production in cultures induced with either HO or ciprofloxacin. MSB also had a negative effect on Stx2 production in two other EHEC isolates tested. Phylloquinone and menaquinone had, on the other hand, variable and concentration-dependent effects on Stx2 production. MSB, which conferred the strongest inhibitory effect on both Stx2 phage and Stx2 production, improved the growth of EHEC in the presence of HO and ciprofloxacin, which could be explained by the reduced uptake of ciprofloxacin into the bacterial cell. Together, the data suggest that vitamin K analogs have a growth- and potential virulence-reducing effect on EHEC, which could be of therapeutic interest. Enterohemorrhagic (EHEC) can cause serious illness and deaths in humans by producing toxins that can severely damage our intestines and kidneys. There is currently no optimal treatment for EHEC infections, as antibiotics can worsen disease development. Consequently, the need for new treatment options is urgent. Environmental factors in our intestines can affect the virulence of EHEC and help our bodies fight EHEC infections. The ruminant intestine, the main reservoir for EHEC, contains high levels of vitamin K, but the levels are variable in humans. This study shows that vitamin K analogs can inhibit the growth of EHEC and/or production of its main virulence factor, the Shiga toxin. They may also inhibit the spreading of the Shiga toxin encoding bacteriophage. Our findings indicate that vitamin K analogs have the potential to suppress the development of serious disease caused by EHEC.
Topics: Anti-Bacterial Agents; Coliphages; Escherichia coli O157; Shiga Toxin 2; Virulence; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K 3; Vitamins
PubMed: 32769190
DOI: 10.1128/AEM.00583-20