ArticleLiterature Review

Vitamin K, an emerging nutrient in brain function

Authors:
To read the full-text of this research, you can request a copy directly from the author.

Abstract

Historically discovered for its role in blood coagulation, there is now convincing evidence that vitamin K has important actions in the nervous system. As a unique cofactor to the γ-glutamyl carboxylase enzyme, vitamin K contributes to the biological activation of proteins Gas6 and protein S, ligands for the receptor tyrosine kinases of the TAM family (Tyro3, Axl, and Mer). Functionally, Gas6 has been involved in a wide range of cellular processes that include cell growth, survival, and apoptosis. In brain, vitamin K also participates in the synthesis of sphingolipids, an important class of lipids present in high concentrations in brain cell membranes. In addition to their structural role, sphingolipids are now known to partake in important cellular events such as proliferation, differentiation, senescence and cell-cell interactions. In recent years, studies have linked alterations in sphingolipid metabolism to age-related cognitive decline and neurodegenerative diseases such as Alzheimer's disease (AD). Emerging data also point to unique actions of the K vitamer menaquinone-4 (MK-4) against oxidative stress and inflammation. Finally, there is now data to suggest that vitamin K has the potential to influence psychomotor behavior and cognition. This review presents an overview of what is known of the role of vitamin K in brain function.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the author.

... Vitamin K antagonists (VKAs) are the drugs most commonly used in the prophylaxis and treatment of thromboembolic disease in older adults [1,2]. In addition to a role in blood coagulation, vitamin K participates in brain health and function [3] by regulating the synthesis of sphingolipids (a constituent of myelin sheaths and neuronal membranes) [4], and through biological activation of ...
... Basic research supports a role for vitamin K in the brain. It regulates the biological activation of two VKDPs, namely Gas6 (growth arrest-specific gene 6) and protein S [3,4]. Gas6 is involved in chemotaxis, mitogenesis, cell growth, and myelination, and has further been shown to rescue cortical neurons from amyloid-β-induced apoptosis, a hallmark of Alzheimer's disease (AD) [22]. ...
... Protein S offers neuronal protection during ischemic/hypoxic injury [23]. Additionally, vitamin K regulates the metabolism of sphingolipids, which are key players in neuronal proliferation, differentiation, senescence, cell-cell interaction, and transformation [3,4]. Alterations in sphingolipid metabolism may also be involved in neurodegenerative disorders such as AD [4]. ...
Article
Full-text available
Vitamin K participates in brain physiology. This study aimed to determine whether using vitamin K antagonists (VKAs), which interfere with the vitamin K cycle, were (i) cross-sectionally associated with altered cognitive performance, and (ii) independent predictors of cognitive changes in older adults over 24 months. Information was collected on the use of VKAs (i.e., warfarin, acenocoumarol, and fluindione) among 378 geriatric outpatients (mean, 82.3 ± 5.6 years; 60.1% female). Global cognitive performance and executive functions were assessed with Mini-Mental State Examination (MMSE) and Frontal Assessment Battery (FAB) scores, respectively, at baseline and after 12 and 24 months of follow-up. Age, gender, body mass index, mean arterial pressure, disability, gait speed, comorbidities, atrial fibrillation, stroke, carotid artery stenosis, leukoaraiosis grade on computed tomography (CT) scan, psychoactive drugs, antidementia drugs, blood-thinning drugs (i.e., anticoagulants other than VKAs, antiplatelet medications), serum creatinine levels, and vitamin B12 concentrations were considered as potential confounders. Using VKAs was associated with lower (i.e., worse) FAB score at baseline (adjusted β = −2.1, p = 0.026), and with a decrease in FAB score after 24 months (adjusted β = −203.6%, p = 0.010), but not after 12 months (p = 0.659). Using VKAs was not associated with any change in MMSE score at baseline (p = 0.655), after 12 months (p = 0.603), or after 24 months (p = 0.201). In conclusion, we found more severe executive dysfunction at baseline and incident executive decline over 24 months among geriatric patients using VKAs, when compared with their counterparts.
... Today, VK is known to be involved in skeletogenesis [6] and redox homeostasis [7,8]. Additional evidence has also suggested that VK is involved in sphingolipid [9] and glucose metabolism [10], brain development and cognitive capacities [9,11,12], pathological calcification and inflammation [13][14][15], angiogenesis [16], and reproduction [10,17,18]. Regarding reproduction, while the transactivation of PXR in Leydig cells increased the expression of several genes involved in steroidogenesis [19], rats fed VK deficient diets showed decreased expression of genes related with the biosynthesis of cholesterol and steroid hormones, as well as reduced concentration of testosterone in plasma and testis [20]. ...
... Today, VK is known to be involved in skeletogenesis [6] and redox homeostasis [7,8]. Additional evidence has also suggested that VK is involved in sphingolipid [9] and glucose metabolism [10], brain development and cognitive capacities [9,11,12], pathological calcification and inflammation [13][14][15], angiogenesis [16], and reproduction [10,17,18]. Regarding reproduction, while the transactivation of PXR in Leydig cells increased the expression of several genes involved in steroidogenesis [19], rats fed VK deficient diets showed decreased expression of genes related with the biosynthesis of cholesterol and steroid hormones, as well as reduced concentration of testosterone in plasma and testis [20]. ...
... Genes targeted by piR-74614 were found to be related to development and signaling of the central nervous system (slc6a16a, six6b, timp2a, slc6a2, atxn1a, pcdh2ab8, elavl4, trim46a and Lrfn2b), and blood coagulation (gata2a and f2rl2). While the role of VK in blood coagulation has been largely reported [3], several articles have recently suggested that VK has an impact on angiogenesis [16,28], brain development and cognitive capacities [9,34], and regulates lipid metabolism, particularly that of sphingolipids [9]. As phospholipid and cholesterol composition determines the fluidity of the plasma membrane, their modulation has a direct impact on sperm physiology and functionality [76]. ...
Article
Background: Vitamin K (VK) is a fat-soluble vitamin known for its essential role in blood coagulation, but also on other biological processes (e.g. reproduction, brain and bone development) have been recently suggested. Nevertheless, the molecular mechanisms behind its particular function on reproduction are not yet fully understood. Methods: The potential role of VK on reproduction through nutritional supplementation in Senegalese sole (Solea senegalensis) was assessed by gonadal maturation and 11-ketosterone, testosterone and estriol plasma levels when fed with control or VK supplemented (1250 mg kg-1 of VK1) diets along a six month trial. At the end, sperm production and quality (viability and DNA fragmentation) were evaluated. Circulating small non-coding RNAs (sncRNAs) in blood plasma from males were also studied through RNA-Seq. Results: Fish fed with dietary VK supplementation had increased testosterone levels and lower sperm DNA fragmentation. SncRNAs from blood plasma were found differentially expressed when nutritional and sperm quality conditions were compared. PiR-675//676//4794//5462 and piR-74,614 were found up-regulated in males fed with dietary VK supplementation. Let-7 g, let-7e(18 nt), let-7a-1, let-7a-3//7a-2//7a-1, let-7e(23 nt) and piR-675//676//4794//5462 were found to be up-regulated and miR-146a and miR-146a-1//146a-2//146a-3 down-regulated when fish with low and high sperm DNA fragmentation were compared. Bioinformatic analyses of predicted mRNAs targeted by sncRNAs revealed the potential underlying pathways. Conclusions: VK supplementation improve fish gonad maturation and sperm quality and suggest an unexpected and complex regulation of the nutritional status and reproductive performance through circulating sncRNAs. General significance: The use of circulating sncRNAs as reliable and less-invasive physiological biomarkers in fish nutrition and reproduction has been unveiled.
... Vitamin K includes a group of lipid-soluble molecules based on a common 2-methyl-1,4-naphtoquinone ring but with a different side chain at the 3-position [1][2][3]. Phylloquinone (2-methyl-3-phytyl-1,4-naphtoquinone), or vitamin K1, is mainly found in vegetables [1,2]. A second class of vitamers is the menaquinones (MK). ...
... A second class of vitamers is the menaquinones (MK). MKs are produced by bacteria as provitamins and present unsaturated 5-carbon (prenyl) side chains at the 3-position [1][2][3]. One of the menaquinones, MK-4, is not commonly produced by bacteria, but synthesised from vitamin K1 [2,3]. ...
... MKs are produced by bacteria as provitamins and present unsaturated 5-carbon (prenyl) side chains at the 3-position [1][2][3]. One of the menaquinones, MK-4, is not commonly produced by bacteria, but synthesised from vitamin K1 [2,3]. Vitamin K has a key role in the carboxylation of glutamate residues in proteins leading to gamma-carboxyglutamate (Gla) residues. ...
Article
Full-text available
Objectives: Recent studies have suggested that vitamin K may exert significant effects on the central nervous system. The present study investigates the relationship between vitamin K plasmatic levels and cognitive functions in elderly patients on oral anticoagulant therapy (OAT). Design: At the Thrombosis Centre of Haematology, "Sapienza" University of Rome, 85 patients on OAT, aged between 75 and 92, were randomly enrolled in the study. Patients were on OAT with vitamin K antagonists (VKAs). Vitamin K1 concentrations were determined using standardized High-Performance Liquid Chromatography (HPLC). Cognitive functions were assessed using the Milan Overall Dementia Assessment (MODA). Results: MODA scores are positively correlated to vitamin K1 concentration. Patients with vitamin K1 below 0.100 μg/L and between 0.100 and 0.400 μg/L and between 0.100 and 0.400 μg/L and between 0.100 and 0.400 p < 0.001). Even long-term OAT (>10 years) does not affect MODA scores. Education seems to exert a greater role on the cognitive status in comparison with aging. Conclusions: The study shows a positive association between vitamin K1 concentration and cognitive status in elderly patients (≥75 years) on OAT. The relationship between vitamin K1 concentration and MODA scores is described by a linear model. Cognitive status is not influenced by the duration of OAT but by the years of education.
... Vitamin K (VK) is an essential micronutrient that vertebrates do not synthesize, thus they depend on dietary sources to obtain the required daily amounts. Nowadays, VK is known to be required for blood coagulation [49,50], skeletal tissue [21] and redox [23,51] homeostasis, sphingolipid [52] and glucose metabolism [53], neural development and cognitive capacities [52,[54][55][56], pathological calcification and inflammation [57][58][59], angiogenesis [60], and reproduction [61][62][63]. Studies in fish also suggest that VK is required for blood coagulation [16,64], skeletal development and skeletal tissues homeostasis [15,17,18], redox homeostasis [18], sphingolipid metabolism [14], brain development and cognitive capacities [19], pathological calcification and inflammation [16], and reproduction [14,16,65], reinforcing the idea of a well conserved function of VK throughout vertebrate evolution [26,66]. ...
... Vitamin K (VK) is an essential micronutrient that vertebrates do not synthesize, thus they depend on dietary sources to obtain the required daily amounts. Nowadays, VK is known to be required for blood coagulation [49,50], skeletal tissue [21] and redox [23,51] homeostasis, sphingolipid [52] and glucose metabolism [53], neural development and cognitive capacities [52,[54][55][56], pathological calcification and inflammation [57][58][59], angiogenesis [60], and reproduction [61][62][63]. Studies in fish also suggest that VK is required for blood coagulation [16,64], skeletal development and skeletal tissues homeostasis [15,17,18], redox homeostasis [18], sphingolipid metabolism [14], brain development and cognitive capacities [19], pathological calcification and inflammation [16], and reproduction [14,16,65], reinforcing the idea of a well conserved function of VK throughout vertebrate evolution [26,66]. ...
... In line with this, ssvkorc1 and ssvkorc1l1 were here found to be expressed in both tissues (liver and vertebra). High expression of ssvkorc1l1 in brain is in agreement with previous reports, showing high expression in fish and rodent brains [24,65,81], and the proposed role of VK in brain development and homeostasis [19,52]. High expression of ssvkorc1l1 observed in ovary further supports a central role of VK in reproduction [14,82], and is in agreement with the VK nutritional requirement proposed for offspring development [83]. ...
Article
Full-text available
Vitamin K (VK) is a key nutrient for several biological processes (e.g., blood clotting and bone metabolism). To fulfill VK nutritional requirements, VK action as an activator of pregnane X receptor (Pxr) signaling pathway, and as a co-factor of γ-glutamyl carboxylase enzyme, should be considered. In this regard, VK recycling through vitamin K epoxide reductases (Vkors) is essential and should be better understood. Here, the expression patterns of vitamin K epoxide reductase complex subunit 1 (vkorc1) and vkorc1 like 1 (vkorc1l1) were determined during the larval ontogeny of Senegalese sole (Solea senegalensis), and in early juveniles cultured under different physiological conditions. Full-length transcripts for ssvkorc1 and ssvkorc1l1 were determined and peptide sequences were found to be evolutionarily conserved. During larval development, expression of ssvkorc1 showed a slight increase during absence or low feed intake. Expression of ssvkorc1l1 continuously decreased until 24 h post-fertilization, and remained constant afterwards. Both ssvkors were ubiquitously expressed in adult tissues, and highest expression was found in liver for ssvkorc1, and ovary and brain for ssvkorc1l1. Expression of ssvkorc1 and ssvkorc1l1 was differentially regulated under physiological conditions related to fasting and re-feeding, but also under VK dietary supplementation and induced deficiency. The present work provides new and basic molecular clues evidencing how VK metabolism in marine fish is sensitive to nutritional and environmental conditions.
... In older individuals, both dietary and serum VK1 were significant and independent predictors of cognitive function [17]. Lifetime consumption of a low VK1 diet resulted in cognitive deficits in rats [18,19]. Another study found a low intake of VK1 in nine of 31 elderly individuals who had early AD Commonly referred to as phylloquinone, VK1 is the plant form of vitamin K, and it is primarily found in green, leafy vegetables. ...
... In older individuals, both dietary and serum VK1 were significant and independent predictors of cognitive function [17]. Lifetime consumption of a low VK1 diet resulted in cognitive deficits in rats [18,19]. Another study found a low intake of VK1 in nine of 31 elderly individuals who had early AD [20]. ...
... Both VK1 and VK2 have roles in brain health via the regulation of sphingolipid metabolism [19,31,32]. Sphingolipids are complex lipids that possess important biological functions in the development and survival of neurons. ...
Article
Full-text available
Recent studies have highlighted the importance of vitamin K2 (VK2) in human health. However, there have been no clinical studies investigating the role of VK2 in the prevention or treatment of Alzheimer’s disease (AD), a debilitating disease for which currently there is no cure. In reviewing basic science research and clinical studies that have connected VK2 to factors involved in AD pathogenesis, we have found a growing body of evidence demonstrating that VK2 has the potential to slow the progression of AD and contribute to its prevention. In our review, we consider the antiapoptotic and antioxidant effects of VK2 and its impact on neuroinflammation, mitochondrial dysfunction, cognition, cardiovascular health, and comorbidities in AD. We also examine the link between dysbiosis and VK2 in the context of the microbiome’s role in AD pathogenesis. Our review is the first to consider the physiological roles of VK2 in the context of AD, and, given the recent shift in AD research toward nonpharmacological interventions, our findings emphasize the timeliness and need for clinical studies involving VK2.
... As a fat-soluble nutrient, vitamin K (VK) can regulate the synthesis of sphingolipids (8). As a main component of the myelin sheath and neuron membrane, sphingolipids participate in the proliferation and differentiation of neurons (9). The current studies find that VK has an important role in the nervous system (10, 11). ...
... VK participated in the synthesis of sphingolipids, which were the main components of myelin sheaths and were involved in the proliferation and differentiation of neurons (33). Studies showed that two VKdependent proteins, named growth arrest-specific 6 (Gas6) and S protein, might affect the cognitive process (9). In addition, VK had anti-inflammatory activity and provided antioxidant stress protection (11). ...
Article
Full-text available
Several previous studies discussed the association between vitamin K (VK) status and cognition. But the association between dietary VK consumption and cognitive performance in the elderly was not well understood. Therefore, we investigated the correlation between dietary VK intake and the cognition of the elderly. Our research used the data of the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2014. The dietary intake of VK was assessed by two 24-h dietary recalls. The cognitive function was measured in the survey of NHANES, including the Consortium to Establish a Registry for Alzheimer’s disease Word Learning subtest (CERAD W-L), Animal Fluency Test (AFT), and Digit Symbol Substitution Test (DSST). Logistic regression and restricted cubic spline models were applied to assess the relationship between dietary VK intake and cognition. Compared with the lowest dietary VK intake group, the multivariate-adjusted odds ratio (OR) [95% confidence interval (95% CI)] of low CERAD W-L score for the highest intake group was 0.39 (0.26–0.60), the multivariate-adjusted OR (95% CI) of low AFT score was 0.59 (0.38–0.92), and the multivariate-adjusted OR (95% CI) of low DSST score was 0.44 (0.29–0.65), respectively. There was an L-shaped dose–response relationship between dietary VK intake and low CERAD W-L score. There was a linear dose–response relationship between dietary VK intake and low AFT score, and there was also a linear dose–response relationship for the low DSST score. In addition, we also found a negative association between VK from vegetables and the risk of low CERAD W-L scores. Dietary VK intake and VK intake from vegetables were inversely related to the risk of low cognitive performance of the elderly.
... Nowadays, VK is quite well known in vertebrates to be required for blood coagulation [35][36][37], skeletal and joint tissues [19,[38][39][40][41][42], and pathological calcification and inflammation [37,[43][44][45]. There are some reports on their potential role on redox homeostasis [41,46,47], sphingolipid [48,49] and glucose metabolism [50], neural development and cognitive capacities [20,48,51,52], as well as angiogenesis [53]. Furthermore, some evidences have been presented regarding the potential role of VK on the reproduction of mammalian [54,55] and fish species [37,49,55]. ...
... Nowadays, VK is quite well known in vertebrates to be required for blood coagulation [35][36][37], skeletal and joint tissues [19,[38][39][40][41][42], and pathological calcification and inflammation [37,[43][44][45]. There are some reports on their potential role on redox homeostasis [41,46,47], sphingolipid [48,49] and glucose metabolism [50], neural development and cognitive capacities [20,48,51,52], as well as angiogenesis [53]. Furthermore, some evidences have been presented regarding the potential role of VK on the reproduction of mammalian [54,55] and fish species [37,49,55]. ...
Article
Full-text available
Vitamin K (VK) is a fat-soluble vitamin that vertebrates have to acquire from the diet, since they are not able to de novo synthesize it. VK has been historically known to be required for the control of blood coagulation, and more recently, bone development and homeostasis. Our understanding of the VK metabolism and the VK-related molecular pathways has been also increased, and the two main VK-related pathways-the pregnane X receptor (PXR) transactivation and the co-factor role on the γ-glutamyl carboxylation of the VK dependent proteins-have been thoroughly investigated during the last decades. Although several studies evidenced how VK may have a broader VK biological function than previously thought, including the reproduction, little is known about the specific molecular pathways. In vertebrates, sex differentiation and gametogenesis are tightly regulated processes through a highly complex molecular, cellular and tissue crosstalk. Here, VK metabolism and related pathways, as well as how gametogenesis might be impacted by VK nutritional status, will be reviewed. Critical knowledge gaps and future perspectives on how the different VK-related pathways come into play on vertebrate's reproduction will be identified and proposed. The present review will pave the research progress to warrant a successful reproductive status through VK nutritional interventions as well as towards the establishment of reliable biomarkers for determining proper nutritional VK status in vertebrates.
... It acts as a cofactor for the enzyme that allows the activation of vitamin K-dependent factors (II, VII, IX, X, protein C, and protein S). A recent review collected studies that show its involvement in the metabolism of the central nervous system (CNS), suggesting the possibility that a vitamin K deficiency might be related to the onset of cognitive impairment (1). ...
... Furthermore, vitamin K is known to be an inductor of sphingolipids synthesis. These polar lipids are an essential part of CNS cell membrane and are linked to neuronal proliferation and differentiation (1). Several studies are also investigating the correlation between cognitive impairment and the use of vitamin K antagonists (VKAs, i.e., warfarin, acenocoumarol, and fluindion) as oral anticoagulants. ...
Article
Full-text available
Vitamin K is a fat-soluble nutrient discovered in 1935 and its role in blood coagulation has been thoroughly explored. In recent years, studies conducted in vitro and on animals highlighted vitamin K involvement in brain cells development and survival. In particular, vitamin K seems to have an antiapoptotic and anti-inflammatory effect mediated by the activation of Growth Arrest Specific Gene 6 and Protein S. Moreover, this vitamin is involved in sphingolipids metabolism, a class of lipids that participate in the proliferation, differentiation, and survival of brain cells. An altered expression in sphingolipids profile has been related to neuroinflammation and neurodegeneration. This review stems from a growing interest in the role of vitamin K in brain functions, especially in cognition, also in view of an expected increase of prevalence of Alzheimer's disease and other forms of dementia. It collects recent researches that show interesting, even though not definitive, evidence of a direct correlation between vitamin K levels and cognitive performance. Moreover, vitamin K antagonists, used worldwide as oral anticoagulants, according to recent studies may have a negative influence on cognitive domains such as visual memory, verbal fluency and brain volume. The aim of this review is to analyze the evidence of clinical studies carried out up to date on the relationship between vitamin K intake and cognitive performances. The involvement of vitamin K antagonists (VKAs) in declining cognitive performances is also addressed separately.
... The major source of vitamin K1 is green vegetables, cabbage, spinach, kiwi, avocado, grapes, and plant chlorophylls, while vitamin K2 main source is fermented food, meat, and dairy products (Dismore et al. 2003;Tarento et al. 2019). Vitamin K essential role is reported in the synthesis of sphingolipid and protein Gas6 in the peripheral and central nervous system (Ferland 2012). Vitamin K has an essential role in the pathogenesis of Alzheimer's disease as it improves the cognitive function by regulating the sulfotransferase activity, growth factors, and tyrosine kinase receptor activity in the brain (Presse et al. 2008;Ferland 2012;Presse 2013). ...
... Vitamin K essential role is reported in the synthesis of sphingolipid and protein Gas6 in the peripheral and central nervous system (Ferland 2012). Vitamin K has an essential role in the pathogenesis of Alzheimer's disease as it improves the cognitive function by regulating the sulfotransferase activity, growth factors, and tyrosine kinase receptor activity in the brain (Presse et al. 2008;Ferland 2012;Presse 2013). Intake of vitamin K also suppresses growth and invasion of human hepatocellular carcinoma via protein kinase A activation, which results in moderate suppression of tumor recurrence (Yoshida et al. 2008). ...
Chapter
Full-text available
Vitamins are either fat-soluble (vitamin A, D, E, and K) or water-soluble (vitamin B and C) and required in small amounts for maintaining the healthy growth and normal function of the human body. Vitamin deficiency is a major public health issue worldwide. More than two billion people have found vitamin deficient and are mostly belong to developing countries. Vitamin A deficiency is of severe health concern under the age of 5 years children in several South-East Asian and African countries. Similarly, vitamin D and vitamin B12 deficiencies are the other major growing health concern. The global community must prioritize their action to eradicate hunger as well as vitamin deficiency in low- and middle-income countries. Various vitamin supplementation, food fortification, biofortification, and health policy programs are needed to improve the scenario of vitamin deficiency. Nutrition policy should transit from a simple reductionist method to multifaceted solutions and also work in the synergy of the scientific community to improve the health quality of large population. This chapter is mainly focused on vitamin types and their roles in human health, the global scenario of vitamin deficiency, and a significant source of vitamins to eradicate their deficiency.
... The important role of vit K in the nervous system is the regulation of the activity of key enzymes involved in the synthesis and metabolism pathway of sphingolipid. Sphingolipid is involved in many cellular events, including proliferation, differentiation, aging, cellular communication, and alteration [4]. ...
... Vit K2 deficiency increases the risk of developing diseases such as osteoporosis, atherosclerosis, prostate cancer, liver cancer, diabetes, dental caries, kidney diseases, and some neurodegenerative disease such as Alzheimer and Parkinson's disease. In addition, vit K2 has significant antioxidant effects [5], which strengthens neuritis in PC12D cells in the presence of neural growth factor also prevents against glutathione-dependent oxidative deficiency (as a function of free radical accumulation) and cell death in embryonic cortical neurons [4]. ...
Article
Full-text available
Neuroprotection using compounds with dual functions of anti-apoptotic and antioxidant effects fight against neurodegeneration. Vitamin K2 acts as a cofactor in many biochemical pathways, including sphingolipid synthesis in the nervous system, which is involved in many cellular events, including proliferation, differentiation, cellular communication, and alteration. This study aimed to investigate the protective effects of vitamin K2 in PC12 cells as an in vitro model of Parkinson’s disease. The protective effects of vitamin K2 against 6-OHDA-induced apoptosis in PC12 cells were assessed using resazurin for viability, DCF-DA for ROS level, DTNB for glutathione level, flow cytometry for sub G1, and western blot analysis for detecting bax and pro-caspase-3 expression level. The results showed that 6-OHDA significantly decreased cell viability, glutathione and pro-caspase-3 levels, and increased ROS, the amount of bax in PC12 cells, while the pretreatment with 5 μM vitamin K2 significantly decreased the cell death induced by 6-OHDA. Generally, the results may present a new insight about the potential protective action of vitamin K2 against the progression of Parkinson’s disease. Further studies may warrant the use of vitamin K2 as an antioxidant and anti-apoptotic agent in slowing nerve injury in neurodegenerative disease, particularly in Parkinson’s disease.
... Vitamin K modulates the synthesis and metabolism of sphingolipids, which are major constituents of the myelin sheath and neuronal cell membranes, and also key players in neuronal proliferation, differentiation, senescence, cell-cell interaction, and transformation. (50) Additionally, two vitamin K-dependent proteins (VKDPs), growth arrest-specific gene 6 (Gas6) and protein S, are also closely associated with the central nervous system (CNS) health and function. (46,50) Gas6 is involved in chemotaxis, mitogenesis, cell growth, and myelination, and has further been shown to rescue cortical neurons from amyloid β-induced apoptosis which is a specific marker of Alzheimer's disease (AD). ...
... (50) Additionally, two vitamin K-dependent proteins (VKDPs), growth arrest-specific gene 6 (Gas6) and protein S, are also closely associated with the central nervous system (CNS) health and function. (46,50) Gas6 is involved in chemotaxis, mitogenesis, cell growth, and myelination, and has further been shown to rescue cortical neurons from amyloid β-induced apoptosis which is a specific marker of Alzheimer's disease (AD). (51) Since protein S offers neuronal protection during ischemic/hypoxic injury, both in vivo and in vitro, (52) it is plausible that protein S protects neurons from N-methyl-daspartate induced toxicity and apoptosis. ...
Article
The most fundamental function of vitamin K is to activate the blood coagulation factors in the liver. Despite the recent recognition of its extra-hepatic actions, the current Dietary Reference Intakes for vitamin K is based on the amount necessary for maintaining the normal blood coagulation in many countries. To define the Dietary Reference Intake for vitamin K, appropriate biomarkers well-reflecting the vitamin K status are essential. Unfortunately, however, no markers are currently available with properties enabling us to properly define the vitamin K status; i.g., no interference by other factors and the presence of widely approved cut-off values. Thus, Adequate Intake is determined, which is an index based on the representative dietary intake data from healthy individuals. Recently, epidemiological studies have been reported regarding the relationship between vitamin K and noncommunicable diseases including osteoporotic fracture. Furthermore, studies focusing on the relationship between vitamin K intake and metabolic syndrome, physical function, depression, cognition, and all-cause mortality have become available, although limited in number. This review summarizes the recent findings in favor of the novel functions of vitamin K. More epidemiological studies are needed to define the appropriate vitamin K intake value based on the prevention of various disorders.
... Vitamin K is a fat-soluble vitamin. The vitamin K family contains a 2-methyl-1,4-naphthoquinone ring, but their structure at the 3-position is not the same (1). According to the structure of the 3-position, vitamin K exists in two forms. ...
... According to the structure of the 3-position, vitamin K exists in two forms. Vitamin K1 is phylloquinone (2-methyl-3-phytyl-1,4-naphthoquinone) (PK), which is synthesized in plants and is the main source of dietary vitamin K (1). Vitamin K2 is the menaquinones. ...
Article
Full-text available
Objective: The vitamin K family has a wide range of effects in the body, including the central nervous system. Menaquinone-4 (MK-4), a form of vitamin K2, is converted from phylloquinone (PK), which is the main source of dietary vitamin K and is the main form of vitamin K in the brain. We conducted this study to investigate the serum concentration of MK-4 and the correlations between MK-4 and developmental quotients in children with autism spectrum disorder (ASD). Methods: We selected 731 children with ASD who were diagnosed for the first time. During the same period, 332 neurotypical children who underwent regular physical examinations in our outpatient department were selected as the TD group. We investigated the general situation of children, including gender and age. Children in ASD group were assessed for autistic symptoms and development quotients, including Autism Behavior Checklist (ABC), Childhood Autism Rating Scale (CARS), ADOS-2, and Griffiths Development Scales-Chinese Language Edition (GDS-C). Both groups of children were tested for serum menaquinone-4. We compared serum menaquinone-4 levels of ASD group and TD group. We then conducted a correlation analysis between the level of menaquinone-4 and the developmental quotient of children with ASD. Results: The results of this study indicate that the serum concentration of MK-4 in children with ASD is lower than that in children with typical development ( t = −2.702, P = 0.007). The serum concentration of MK-4 is related to the developmental quotients of several subscales in ASD children, and this correlation is more obvious in males. Conclusion: we conclude that MK-4 is present in lower concentrations in children with ASD, which may affect cognition and developmental quotients. The role of MK-4 in ASD needs to be further explored.
... Moreover, vitamin K might be related to reducing risk of CVD by preventing vascular calcification [22][23][24][25]. Vitamin K is also related to brain health since it is a cofactor for the activation of two proteins, Gas6 and protein S, that are related to the cognitive process in the brain [26]. Moreover, vitamin K affects the metabolism of sphingolipids which are associated with cellular events in the brain [26]. ...
... Vitamin K is also related to brain health since it is a cofactor for the activation of two proteins, Gas6 and protein S, that are related to the cognitive process in the brain [26]. Moreover, vitamin K affects the metabolism of sphingolipids which are associated with cellular events in the brain [26]. A reduced form of vitamin K (KH 2 ) directly protects phospholipid membranes from peroxidation by reactive oxygen species (ROS), suggesting its antioxidant activity [27]. ...
Article
Full-text available
Vitamin K is a fat-soluble vitamin that mainly exists as phylloquinone or menaquinone in nature. Vitamin K plays an important role in blood clotting and bone health in humans. For use as a nutraceutical, vitamin K is produced by natural extraction, chemical synthesis, and microbial fermentation. Natural extraction and chemical synthesis methods for vitamin K production have limitations, such as low yield of products and environmental concerns. Microbial fermentation is a more sustainable process for industrial production of natural vitamin K than two other methods. Recent advanced genetic technology facilitates industrial production of vitamin K by increasing the yield and productivity of microbial host strains. This review covers (i) general information about vitamin K and microbial host, (ii) current titers of vitamin K produced by wild-type microorganisms, and (iii) vitamin K production by engineered microorganisms, including the details of strain engineering strategies. Finally, current limitations and future directions for microbial production of vitamin K are also discussed.
... In addition to its role as enzymatic cofactor in the carboxylation reaction, there is evidence to support other specific actions for VK notably, the K 1 and MK-4 vitamers. Specifically, both vitamers have been involved in the synthesis of sphingolipids, a group of complex lipids present in brain cell membranes and which possess important cell signaling properties [11]. Recent studies also point to protective roles for K 1 and MK-4 against oxidative stress and inflammatory processes. ...
... In addition, there is increasing evidence that K 1 and MK-4 have additional actions outside their role as enzymatic cofactor, e.g., inflammation, oxidative stress. In recent years, VK has been associated with a number of age-related conditions such as osteoporosis [1], the calcification process [3], insulin resistance [4,38], cancer [39], and cognitive decline [11]. This report aimed to investigate the influence of lifetime dietary VK exposure on the tissue content and distribution of the K 1 and MK-4 vitamers at different life stages in male and female rats fed different diets since weaning, or subjected to caloric restriction, a life-prolonging model. ...
Article
Full-text available
Whether through the vitamin K-dependent proteins or the individual K vitamers, vitamin K (VK) is associated with a number of age-related conditions (e.g., osteoporosis, atherosclerosis, insulin resistance, cognitive decline). In light of this, we investigated the influence of lifetime dietary VK exposure on the tissue distribution of phylloquinone (K₁) and menaquinone-4 (MK-4) vitamers in 3-, 12- and 22-month-old male and female rats fed different K₁ diets since weaning or subjected to a 40% calorie restricted diet (CR) since adulthood. Dietary K₁ intakes around the minimal amount required for normal blood coagulation had no significant influence on body weights of both male and female rats at different life stages. Tissue contents of the K vitamers differed according to organs, were generally higher in females than in males, and increased with K₁ intake. The MK-4/total VK ratios tended to be increased in old age possibly reflecting an increased physiological demand for MK-4 during aging. Our study also confirmed the greater susceptibility of male rats to low VK containing diet, notably at a younger age. Despite lifelong higher K₁ intakes per unit body weight, tissue K₁ and MK-4 contents at 20 months were generally lower in CR rats compared to their ad libitum (AL) counterparts. Whether the lower tissue MK-4 content is the result of lower synthesis from K₁ or greater tissue utilization remains to be determined. However, the more youthful coagulation profile observed in old CR rats (vs. AL rats) tends to support the notion that CR is associated with greater utilization of the K vitamers to sustain physiological functions.
... VK2 has been found to play a neuroprotective role in nervous system diseases, but there are few studies on the relationship between VK2 and PD. Recent studies have found that natural vitamin K can improve mental activity and cognition by participating in the synthesis of sphingolipids to nourish brain cells [17]. The elderly AGING people who take vitamin k every day are shown to have better cognition and behavior [18]. ...
Article
Although it is known that inflammation is involved in Parkinson's disease (PD) pathogenesis and vitamin K2 (VK2) has anti-inflammatory effects, to date few studies have been reported on the relationship between VK2 and PD development. Herein we presented a case-control study involving 93 PD patients and 95 healthy controls. Overall, the serum VK2 level of PD patients (3.49 ± 1.68 ng/ml) was significantly lower than that of healthy controls (5.77 ± 2.71 ng/ml). When the PD patients were stratified by disease progression, we observed that the serum VK2 level of late stage patients was further decreased to 3.15 ± 1.18 ng/ml while the serum VK2 level of early stage patients was 3.92 ± 2.09 ng/ml. Furthermore, the curve analysis showed that the serum VK2 level decreased gradually with the increment of PD Hoehn-Yahr (H-Y) stage. We also confirmed the dysregulated inflammatory responses and coagulation cascades in PD patients by public dataset, which are associated to the decreased VK2 level. In summary, we found the serum VK2 level in PD patients is lower than that in healthy controls. The decrease of VK2 level may be related to the occurrence and progression of PD by loosening the regulation of inflammatory responses and coagulation cascades signal.
... During the last decade, some studies have evidenced the potential role of VK on lipid metabolism and synthesis (Moreau et al., 2007;Sui et al., 2011;Ferland, 2012). Its nuclear receptor, the Pxr, regulates lipid metabolism through the transcription of several enzymes involved in lipid synthesis (Bitter et al., 2015). ...
Article
Warfarin is the most worldwide used anticoagulant drug and rodenticide. Since it crosses placental barrier it can induce warfarin embryopathy (WE), a fetal mortality in neonates characterized by skeletal deformities in addition to brain hemorrhages. Although the effects of warfarin exposure in aquatic off target species were already described, the particular molecular toxicological mechanisms during early development are still unclear. Here, we used zebrafish (Danio rerio) to describe and compare the developmental effects of warfarin exposure (0, 15.13, 75.68 and 378.43 mM) on two distinct early developmental phases (embryos and eleuthero-embryos). Although exposure to both developmental phases induced fish mortality, only embryos exposed to the highest warfarin level exhibited features mimicking mammalian WE, e.g. high mortality, higher incidence of hemorrhages and altered skeletal development, among other effects. To gain insights into the toxic mechanisms underlying warfarin exposure, the transcriptome of embryos exposed to warfarin was explored through RNA-Seq and compared to that of control embryos. 766 differentially expressed (564 up- and 202 down-regulated) genes were identified. Gene Ontology analysis revealed particular cellular components (cytoplasm, extracellular matrix, lysosome and vacuole), biological processes (mainly amino acid and lipid metabolism and response to stimulus) and pathways (oxidative stress response and apoptosis signaling pathways) being significantly overrepresented in zebrafish embryos upon warfarin exposure. Protein-protein interaction further evidenced an altered redox system, blood coagulation and vasculogenesis, visual phototransduction and collagen formation upon warfarin exposure. The present study not only describes for the first time the WE in zebrafish, it provides new insights for a better risk assessment, and highlights the need for programming the rat eradication actions outside the fish spawning season to avoid an impact on off target fish community. The urge for the development of more species-specific anticoagulants for rodent pest control is also highlighted.
... Adequate intakes of fat-soluble vitamins during pregnancy are critically important to the development of regulatory systems in the brain. For example, vitamin A is needed for cellular differentiation [6,7], vitamin A and D attach to their receptors on specific sites of the genome to affect gene expression [8,9], vitamin E is vital for cell signaling [10], and vitamin K plays an essential role in cell signaling as well as in the synthesis of lipids in the brain [11][12][13][14][15][16]. Very few reports have examined the effects of maternal vitamins A and K on offspring brain development and function [17,18]. ...
Article
Recent research shows a link between vitamin intake during pregnancy and offspring health. Inadequate intakes of water soluble vitamins during pregnancy lead to obesity and characteristics of the metabolic syndrome, concurrent with altered developments in food intake regulatory pathways. Few studies, however, have reported on the effects of fat-soluble vitamins (A, D, E and K) on the development of food intake regulatory pathways. The majority of studies to date have focused on associations between inadequate and high intakes of folic acid and vitamin D and neurocognitive development of the offspring. Hence, the objective of this review is to present an evaluation of the role of maternal vitamins A, D, E and K in brain development and function of neural pathways that regulate feeding behaviors. PubMed and Google Scholar were searched from 1975 through September, 2016. The majority of studies supporting a role for fat-soluble vitamins in regulating brain development and associated behaviors have been conducted in animal and cell models, leaving uncertain their relevance to neurocognitive development and function in humans. Nevertheless, although current research on defining the role of maternal fat-soluble vitamins in offspring's brain development is limited, it is sufficient to warrant further investigations on their impact when intake amounts during pregnancy are not only inadequate but also exceed requirements.
... Epidemiological and experimental evidence links vitamin K with potential for anticancer effects (3). In brain this vitamin is possibly exerting neuro-protective activity (4). Ultimately, vitamin K has been implicated in prevention of metabolic disorders (5). ...
Article
Full-text available
PURPOSE: Recently new roles for vitamin K, different from that in coagulation, have been proposed, including prevention of cardiometabolic diseases. It was the aim of the present work to evaluate the impact of vitamin K treatment on the changes in liver and pancreas of rats with experimentally induced metabolic syndrome. METHODS: Four groups of rats were used, as follows: one control group fed regular rat chow; one group fed high fat, high fructose (HFHF) diet for 12 weeks to induce a metabolic syndrome (MS) and two groups with MS treated with vitamin K1 and K2 respectively. At the end of the experiment, liver tissue and pancreatic were dissected out for morphological examination. RESULTS: All groups of rats fed HFHF diet expressed liver histological changes consistent with steatosis. These alterations were more pronounced in the groups treated with vitamin K2 and K1. The pancreatic tissue of the HFHF fed animals showed similar degree of lipomatosis irrespective of treatment. CONCLUSIONS: In rats with diet-induced MS, treatment with vitamin K1 and K2 did not produce the expected morphological evidence of improvement, even tended to aggravate the liver changes. These results disagreed with other effects of vitamin K that were established.
... Por último, un número limitado de estudios centrados en la relación entre la vitamina K, el estado nutricional, el comportamiento y la adquisición del conocimiento sugieren que la ingesta dietaria de vitamina K y el tratamiento con warfarina pueden modular la cognición. Las funciones de la vitamina K en el sistema nervioso han sido revisadas recientemente (85,86). ...
... Insofar as dairy foods are concerned, there may be differences within the category since OCS was less with flavored milk and greater with cheese; since all dairy products were treated together in the YHEI-TW, this may have accounted for non-significant associations on multiple linear regression for dairy. There is evidence that vitamin K-2 as found in cheese may play a role in brain function [45][46][47]. Of particular interest, regular breakfast, in its own right, is associated with better school performance, suggesting a role for diurnal dietary pattern in brain function [8,17]. ...
Article
Full-text available
Background: Child school performance during puberty may be at increased risk through emotional disturbance. It is hypothesized that this may be mitigated by dietary quality. Methods: In a nationally representative sample (Nutrition and Health Survey in Taiwan, NAHSIT), 1371 Taiwanese aged 11-16 years, overall competence at school, (OCS) and emotional status have been assessed by teachers with the SAED (Scale for Assessing Emotional Disturbance). Parents provided family socio-demographics and students completed a behavioral and dietary questionnaire (Youth Healthy Eating Index - Taiwan, YHEI-TW). Associations between emotional disturbance (ED), OCS and dietary quality (YHEI-TW) were assessed in multiple linear regression models with adjustments for covariates including parental characteristics, personal behaviors, body fatness and puberty. Results: Boys or girls with ED had a less favorable OCS (p < 0.001), minimally dependent on YHEI-TW. On multivariable analysis there was a more positive association between OCS and YHEI-TW among boys (β = 0.05, p < 0.01) and girls (β = 0.07, p < 0.001). Poor dietary quality was associated with ED, especially in girls (β = - 0.06, p < 0.001). Additionally, parental characteristics, body fatness, and personal behaviors are associated with OCS. Puberty is associated with ED and may be indirectly linked to OCS. Conclusions: Unsatisfactory food intake is associated with the link between emotional disturbance and impaired school performance, as assessed by OCS, especially among girls. For both genders, socio-economic and behavioral factors including parenteral income, reading, screen viewing and smoking are modulators of this association. Puberty was a modifying factor in girls. Dietary quality is a relevant factor for health (ED) as well as education (OCS) during early adolescence.
... Vitamin K in brain contributes to sphingolipid synthesis, which is involved in cell proliferation, differentiation and cellto-cell interactions. Deterioration of sphingolipid metabolism causes cognitive decline and neurodegenerative diseases, such as Alzheimer's disease [21]. Furthermore, development of mitochondrial dysfunction was reduced by vitamin K2, which can serve as an electron carrier helping to maintain normal adenosine triphosphate (ATP) production in the mitochondria [22,23]. ...
Article
Full-text available
Background: Vitamin K2 (VK2) belongs to the vitamin K family and comprises a number of subtypes differing in length of side chains consisting of isoprenoid groups (menaquinone-n, MK-n). It is essential for a number of physiological functions although the full spectrum of activity has not yet been elucidated. Due to its role in protection of mitochondrial damage, VK2 could be relevant in preventing disease progress in multiple sclerosis (MS). Methods: We measured VK2 serum levels by the double antibody sandwich Enzyme-linked Immunosorbent Assay (ELISA) technique in MS patients and age and sex matched controls, both under vitamin D supplementation, and related it to disease characteristics and treatment. Results: Overall, 45 MS patients (31 females and 39 of the relapsing-remitting type) and 29 healthy controls (19 females) were included in the analysis. The MS patients had vastly lower VK2 blood levels than controls (235 ± 100 ng/ml vs. 812 ± 154 ng/ml, respectively). Female patients had significantly lower VK2 levels than males and a decrease with age by approximately 10% per decade was found. The VK2 levels were lower with increasing numbers of attacks per year and were higher in patients with optic nerve lesions. No consistent relationship with medications was detected. Conclusion: The substantially lower levels of VK2 in MS patients could be due to depletion, lower production in the gut, diminished absorption or, less likely, reduced intake of precursor vitamin K1. The role of VK2 in MS development and progress deserves further study.
... Phylloquinones and menaquinones are not toxic in animal studies but it is not recommended to use menadione (vitamin K3) therapeutically (Marcus & Coulston, 2001). Vitamin K is expressed at high concentrations in brain cell membranes where it participates in the synthesis of sphingolipids, an important class of lipids essential for myelination (Ferland, 2012). Vitamin K is essential for the activation of the TAM kinase ligands ProS1 and Gas6, which are the major vitamin-K dependent proteins in the nervous system (Tsou et al., 2014). ...
Article
Tyro3, Axl, and Mertk, referred to as the TAM family of receptor tyrosine kinases, are instrumental in maintaining cell survival and homeostasis in mammals. TAM receptors interact with multiple signaling molecules to regulate cell migration, survival, phagocytosis and clearance of metabolic products and cell debris called efferocytosis. The TAMs also function as rheostats to reduce the expression of proinflammatory molecules and prevent autoimmunity. All three TAM receptors are activated in a concentration-dependent manner by the vitamin K-dependent growth arrest-specific protein 6 (Gas6). Gas6 and the TAM are abundantly expressed in the nervous system. Gas6, secreted by neurons and endothelial cells, is the sole ligand for Axl. ProteinS1 (ProS1), another vitamin K-dependent protein functions mainly as an anti-coagulant, and independent of this function can activate Tyro3 and Mertk, but not Axl. This review will focus on the role of the TAM receptors and their ligands in the nervous system. We highlight studies that explore the function of TAM signaling in myelination, the visual cortex, neural cancers, and multiple sclerosis (MS) using Gas6-/-and TAM mutant mice models.
... Notably, the essential vitamin K, menaquinones are synthesized by Bacteroides, Prevotella, Enterobacter, Veillonella, and Eubacterium lentum, in the human gut and some menaquinones are produced by conversion of vitamin K1 into K2 (Aydin, 2017;Karl et al., 2017). Recent studies have documented that vitamin K deficiency has a positive relationship with depression and AD, and further, their supplementation has a beneficial effect in treating these diseases and improves cognitive function (Allison, 2001;Bolzetta et al., 2019;Ferland, 2012). Even though, vitamin K is known to exhibit anti-inflammatory properties and correlates with some brain disorders, yet, the question persists concerning the exact role of K in the intestinal microbial metabolism and how it affects the composition of gut microbiota and brain function. ...
Article
Existing outcomes from clinical trials reveal the unmet therapeutic need in the treatment of psychiatric and central nervous system (CNS) disorders. A rudimentary understanding of the disease pathogenesis and the complex nature of target mechanisms pose a challenge in slowing the severity of brain diseases. Beyond the current therapies, use of natural products “nutraceuticals” and live biotherapeutics “probiotics” as putative alternative therapies have received more clinical attention in recent years. Following the emergence of “gut-brain-immune axis” concept and its importance in mental illnesses and neurological disorders, upcoming treatments are targeted towards this regimen. Even though substantial progress has been made understanding the critical roles of this axis with preclinical studies, only limited information is available, translating it to humans. Here, we review the aspect of “gut-brain-immune axis” as a substantial target following the treatment approaches with potential nutraceuticals- “vitamins and fish oils (omega-3 polyunsaturated fatty acids)”, and probiotics directly influencing pathobiology of brain disorders with limitation to clinical studies. We would highlight the claims of these supplements on microbiota-gut-brain-immune axis in the treatment of psychiatric and neurological disorders and explore a wide range of outstanding critical questions.
... Vitamin K2 is necessary to activate VKDPs in the brain, such as growth arrest-specific gene 6 protein (Gas6) and protein S, which are connected to cognitive processes. Gas6 and protein S influence different procedures in the brain, such as apoptosis, cell growth, and myelination [21]. Moreover, protein S is anticoagulant factor with direct cellular activities. ...
Article
Full-text available
Abstract: 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 outcome
... Previously known for its role in blood coagulation and bone metabolism, vitamin K was also recognized as a cofactor for the γ-glutamyl carboxylase enzyme. [14]. Naturally, vitamin K is found in two major forms including phylloquinone (vitamin K 1 ), which is mostly present in plant-based products, and menaquinone (vitamin K 2 ), which is produced by microorganisms including intestinal bacteria [15]. ...
Article
Full-text available
The overactivation of microglia is known to trigger inflammatory reactions in the central nervous system, which ultimately induce neuroinflammatory disorders including Alzheimer’s disease. However, increasing evidence has shown that menaquinone-4 (MK-4), a subtype of vitamin K2, can attenuate inflammation in the peripheral system. Whereas it was also observed at high levels within the brain, its function in this organ has not been well characterized. Therefore, we investigated the effect of MK-4 on microglial activation and clarified the underlying mechanism. Mouse microglia-derived MG6 cells were exposed to lipopolysaccharide (LPS) either with or without MK-4 pretreatment. Cell responses with respect to inflammatory cytokines (Il-1β, Tnf-α, and Il-6) were measured by qRT-PCR. We further analyzed the phosphorylation of TAK1, IKKα/β, and p65 of the NF-κB subunit by Western blotting. We observed that in LPS-induced MG6 cells, MK-4 dose-dependently suppressed the upregulation of inflammatory cytokines at the mRNA level. It also significantly decreased the phosphorylation of p65, but did not affect that TAK1 and IKKα/β. Furthermore, the nuclear translocation of NF-κB in LPS-induced MG6 cells was inhibited by MK-4. These results indicate that MK-4 attenuates microglial inflammation by inhibiting NF-κB signaling.
... This biological process is inhibited by warfarin ( Figure 2). In addition to the well-known biological function of blood coagulation and bone metabolism, emerging studies support VK involved in multiple cellular and physiological processes such as oxidative stress (3,4), immune response and anti-inflammation (5,6), and cancer progression (7,8) and associated with protective and promoting roles in diverse organs or tissues, such as testis (9), brain (10)(11)(12)(13)(14), intestine (15)(16)(17), muscle (18,19), bone (20)(21)(22), liver (7,23), kidney (24,25), pancreas (26,27), fat tissues (28)(29)(30), and cardiovascular system (31)(32)(33)(34) (Figure 3). ...
Article
Full-text available
Intestinal diseases, such as inflammatory bowel diseases (IBDs) and colorectal cancer (CRC) generally characterized by clinical symptoms, including malabsorption, intestinal dysfunction, injury, and microbiome imbalance, as well as certain secondary intestinal disease complications, continue to be serious public health problems worldwide. The role of vitamin K (VK) on intestinal health has drawn growing interest in recent years. In addition to its role in blood coagulation and bone health, several investigations continue to explore the role of VK as an emerging novel biological compound with the potential function of improving intestinal health. This study aims to present a thorough review on the bacterial sources, intestinal absorption, uptake of VK, and VK deficiency in patients with intestinal diseases, with emphasis on the effect of VK supplementation on immunity, anti-inflammation, intestinal microbes and its metabolites, antioxidation, and coagulation, and promoting epithelial development. Besides, VK-dependent proteins (VKDPs) are another crucial mechanism for VK to exert a gastroprotection role for their functions of anti-inflammation, immunomodulation, and anti-tumorigenesis. In summary, published studies preliminarily show that VK presents a beneficial effect on intestinal health and may be used as a therapeutic drug to prevent/treat intestinal diseases, but the specific mechanism of VK in intestinal health has yet to be elucidated.
... In the brain, Vit K is a central player in the synthesis and metabolism of sphingolipid which regulates cognitive function via involvement in various neuronal processes, such as proliferation, differentiation, cellular communication, and aging [17,18]. Additionally, Vit K participates in the enzymatic activation of two proteins whose activity contributes to the maintenance of cerebral homeostasis, namely growth-arrest specific 6 protein (Gas-6) which possesses anti-apoptotic, mitogenic and myelinating activity, and protein S which shows neuronal protective efficacy and ability to maintain blood brain barrier integrity [19]. ...
Article
Aging is a naturally occurring process inevitably affecting each living human. The brain is adversely affected by aging with increased risks of developing various neurological disorders. Thus, it is essential to investigate practical approaches that can counteract the impact of aging on the brain. Vitamin K2 (Vit. K2) is a naturally occurring vitamin with reported valuable therapeutic effects. The current study highlights the role of Vit. K2 administration in counteracting age-related changes in the brain using naturally aging rats. Three-month-old rats were assigned to two groups: an ageing control group receiving a drug vehicle and an ageing group orally gavaged with Vit. K2 (30 mg/kg, once daily 5 days per week). Treatment was continued for 17 months. Ten three-month-old rats were used as the adult control. Vit. K2 improved functional performance, reduced social anxiety, depressive-like behavior, and enhanced memory performance with concomitant preservation of hippocampal and cerebral cortex tyrosine hydroxylase expression. Biochemically, Vit. K2 administration restored oxidative-anti-oxidative homeostasis in the brain. Vit. K2 modulated inflammatory signaling, as evidenced by suppression in the brain of NLRP3, caspase-1, Il-1β, TNFα, IL-6, and CD68 expression. Concomitantly, histopathological examination revealed consistent hippocampal and cerebral cortex improvement. Thus, it can be inferred that Vit K2 can slow down age-related changes in the brain associated with modulation of NLRP3/caspase-1/Nrf-2 signaling.
... Vitamin K2 is involved in the synthesis of sphingolipids and the biological activation of vitamin K-dependent proteins. Insufficient levels may cause dysfunction in the CNS [50]. Lastly, bioactive peptides have been shown to exert various activities affecting the cardiovascular, digestive, immune, and nervous systems [51]. ...
Article
Full-text available
Various dairy nutrients have been associated with cognitive performance. Several observational studies have explored associations between the intake of total dairy or some dairy subgroups and cognitive performance. However, studies on the potential impact of a broad variety of dairy subclasses are scarce. We examined cross-sectional associations between a wide assortment of dairy products and cognitive performance. A total of 619 Dutch community-dwelling adults aged ≥65 years completed a semi-quantitative Food Frequency Questionnaire. Cognitive performance was assessed with an extensive neuropsychological test battery; the tests were clustered into cognitive domains using z-scores. Linear and logistic regression analyses, adjusted for age, sex, BMI, education, smoking, alcohol consumption, habitual physical activity, total energy intake, and dietary factors, were performed to quantify the associations. The Benjamini–Hochberg method was used to correct for multiple testing. After full adjustment, higher skimmed dairy (β ± SD: 0.05 ± 0.02, p = 0.06), fermented dairy (0.04 ± 0.02, p = 0.09), and buttermilk (0.08 ± 0.03, p = 0.19) consumption were associated with better executive functioning. Logistic regression analyses indicated that a 30 g increase in Dutch cheese intake was associated with a 33% lower probability of poor information processing speed (PR = 0.67, 95% CI 0.47–0.97). No associations were observed between dairy consumption and attention and working memory or episodic memory.
... Vitamins K was discovered in 1929 as a substance essential for blood coagulation and was named the "coagulation vitamin." Today, it is well known that "vitamins K" encompasses a group of fat-soluble 2-methyl-1,4 naphthoquinone derivatives with isopropyl side chains, including phylloquinone (vitamin K 1 ), menaquinones (vitamin K 2 ) and menadione (vitamin K 3 ) [1]. The mechanism of activity of vitamins K is attributed to the reduced form of vitamins K (KH 2 ) that activates blood coagulation factors (prothrombin, factor VII, IX, X) through post-translational modification of vitamins K-dependent proteins (VKDPs) by γ-glutamyl carboxylase (GGCX), which converts glutamate (Glu) residues to γ-carboxyglutamate (Gla). ...
Article
Full-text available
Vitamins K exert a range of activities that extend far beyond coagulation and include anti-inflammatory effects, but the mechanisms involved in anti-inflammatory action remain unclear. In the present study, we showed that various forms of exogenous vitamins—K1, K3, K2 (MK-4, MK-5, MK-6 and MK-7)—regulated a wide scope of inflammatory pathways in murine macrophages in vitro, including NOS-2, COX-2, cytokines and MMPs. Moreover, we demonstrated for the first time that macrophages are able to synthesise endogenous MK-4 on their own. Vitamins with shorter isoprenoid chains—K1, K3 and MK-5—exhibited stronger anti-inflammatory potential than vitamins with longer isoprenoid chains (MK-6 and MK-7) and simultaneously were preferably used as a substrate for MK-4 endogenous production. Most interesting, atorvastatin pretreatment inhibited endogenous MK-4 production but had no impact on the anti-inflammatory activity of vitamin K. In summary, our results demonstrate that macrophages are able to synthesise endogenous MK-4 using exogenous vitamin K, and statin inhibits this process. However, the anti-inflammatory effect of exogenous vitamin K was independent of endogenous MK-4 synthesis.
... Growing evidence advocates that MK-4 has a number of biological functions, including promoting growth factor of neuron-like cells, mediating apoptosis in several cancer cells, controlling glucose homeostasis [29]. In the central nervous system (CNS), MK-4 controls the activity of proteins involved in tissue renewal and cell growth control, myelination, mitogenesis, chemotaxis, neuroprotection [30]. The medium and long side-chain MKs were recovered mostly in the liver samples [31]. ...
Article
Full-text available
As human life expectancy is rising, the incidence of age-associated diseases will also increase. Scientific evidence has revealed that healthy diets, including good fats, vitamins, minerals, or polyphenolics, could have antioxidant and anti-inflammatory activities, with antiaging effects. Recent studies demonstrated that vitamin K is a vital cofactor in activating several proteins, which act against age-related syndromes. Thus, vitamin K can carboxylate osteocalcin (a protein capable of transporting and fixing calcium in bone), activate matrix Gla protein (an inhibitor of vascular calcification and cardiovascular events) and carboxylate Gas6 protein (involved in brain physiology and a cognitive decline and neurodegenerative disease inhibitor). By improving insulin sensitivity, vitamin K lowers diabetes risk. It also exerts antiproliferative, proapoptotic, autophagic effects and has been associated with a reduced risk of cancer. Recent research shows that protein S, another vitamin K-dependent protein, can prevent the cytokine storm observed in COVID-19 cases. The reduced activation of protein S due to the pneumonia-induced vitamin K depletion was correlated with higher thrombogenicity and possibly fatal outcomes in COVID-19 patients. Our review aimed to present the latest scientific evidence about vitamin K and its role in preventing age-associated diseases and/or improving the effectiveness of medical treatments in mature adults ˃50 years old.
... In recent years, studies have linked alterations in sphingolipid metabolism to age-related cognitive decline and neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. [10][11][12] ...
... [16][17][18] Vitamin K has been shown to have anti-inflammatory properties in both in vitro and in vivo studies [19][20][21] and its protective effect in maintaining cognitive integrity is thought to be mediated, in part, through this mechanism. 22 However despite this apparent link, direct studies measuring cognitive function, vitamin K status and inflammation are lacking. ...
Article
Full-text available
Studies have shown associations between reduced vitamin K status and poor cognitive function. However, despite this apparent link, direct studies measuring cognitive function, vitamin K status and inflammation are lacking. In the current study, The ELDERMET cohort was investigated to identify associations between cognition, vitamin K status and inflammation. The primary aim of the ELDERMET study was to investigate the relationship between gut bacteria, diet, lifestyle and health in 500 older Irish adults. Significant differences in serum phylloquinone, dietary phylloquinone and inflammatory markers were found across varying levels of cognitive function, after controlling for sex, age, body mass index (BMI), triglycerides and blood pressure. In addition, significantly higher levels of dietary phylloquinone were found in those with better cognition compared to those with the poorest function. Higher levels of inflammatory were also associated with poor cognition. Furthermore, both dietary and serum phylloquinone were significant independent predictors of good cognitive function, after controlling for confounders. This study highlights the importance of dietary vitamin K as a potentially protective cognitive factor; it also provides evidence for the correlation between cognition and inflammation. Strategies should be devised by which elderly populations can access rich dietary sources of phylloquinone to maintain cognition.
... Factor II (Prothrombin) Pro-coagulant [7] S [51]. Although the association between vitamin K deficiency and cognitive impairment is still not definitively established, several works have shown a direct correlation between low levels of vitamin K and deterioration of cognitive and behavioural performances (recently reviewed in Reference [47]). ...
Article
Full-text available
Vitamin K health benefits have been recently widely shown to extend beyond blood homeostasis and implicated in chronic low-grade inflammatory diseases such as cardiovascular disease, osteoarthritis, dementia, cognitive impairment, mobility disability, and frailty. Novel and more efficient nutritional and therapeutic options are urgently needed to lower the burden and the associated health care costs of these age-related diseases. Naturally occurring vitamin K comprise the phylloquinone (vitamin K1), and a series of menaquinones broadly designated as vitamin K2 that differ in source, absorption rates, tissue distribution, bioavailability, and target activity. Although vitamin K1 and K2 sources are mainly dietary, consumer preference for diet supplements is growing, especially when derived from marine resources. The aim of this review is to update the reader regarding the specific contribution and effect of each K1 and K2 vitamers in human health, identify potential methods for its sustainable and cost-efficient production, and novel natural sources of vitamin K and formulations to improve absorption and bioavailability. This new information will contribute to foster the use of vitamin K as a health-promoting supplement, which meets the increasing consumer demand. Simultaneously, relevant information on the clinical context and direct health consequences of vitamin K deficiency focusing in aging and age-related diseases will be discussed.
Chapter
Fat-soluble vitamins play essential roles in vertebrate’s development and homeostasis, and thus, an optimal, efficient and sustainable fish farming deeply depends on the optimization of their dietary levels provided. Subsequently, nutritional imbalances are considered one of the major causative factors of vertebrate’s abnormal development. Although approaches such as nutritional-dose-response trials, gene knock-down and over-expression studies, have provided valuable knowledge on its metabolism and dietary requirements; this knowledge is still mostly based on studies with mammalian species. Even though nutritional approaches involving different (i) research tools (i.e. NGS, RT-qPCR, proteomics, histology, immunohistochemistry, in situ hybridization, etc.), (ii) experimental approaches (in vivo and in vitro), and (iii) developmental stages (larval, juvenile and adult stages), have been applied to different fish species, the biological roles, underlying mechanisms and nutritional requirements in farmed fish are not fully understood yet. Here, knowledge gained during the last decade for each of the fat-soluble vitamins is compiled, reviewed from a holistic point of view, and the potential points of convergence of fat-soluble vitamins signaling pathways at molecular, cellular and tissue levels identified for the proper development of nutritionally balanced diets, based on integrative, multifactorial and multidisciplinary nutritional studies to be conducted in the nearest future.
Chapter
Heavy ethanol consumption leads to brain alterations. The most common forms are frontal atrophy, cerebellar atrophy, and thiamine deficiency-associated syndrome of Wernicke-Korsakoff. Atrophy includes both reduced gray matter and white matter. Regarding gray matter, there is decreased neuronogenesis and increased neurodegeneration. Neuron bodies affectation leads to axonal degeneration; myelin synthesis is also impaired. Neuroinflammation, with increased lipid peroxidation and oxidative damage, underlies most of the pathological changes observed. Therefore, it is important to analyze the behavior of antioxidant vitamins in the pathogenesis of brain alterations in alcoholics. In general, a marked deficiency of most of them is observed. Although vitamin supplementation to experimental animals seems effective, clinical trials yield poor results. Ethanol withdrawal is the best therapeutic approach because it has been shown that brain atrophy recovers after abstinence.
Chapter
Vitamins are classified as lipid- and water-soluble compounds. Although not directly involved in enzymatic reactions needed for biological processes, they participate in the modulation of many genes through nuclear transcription factors as well as nuclear and membrane receptors. Their deficiency leads to impairment of health status. This chapter reviews the physiological function, the effect of deficiency or excess (in rare cases) of each vitamin, the methods for their measurements, and their reference values.
Article
Transthyretin-associated forms of cardiac amyloidosis are fatal protein misfolding diseases that can be inherited (ATTRm) or acquired (ATTRwt). Precise biomarkers for ATTR disease identification and monitoring are undiscovered, disease-specific therapeutic options are needed, and the current understanding of ATTR molecular pathogenesis is limited. The aim of this study was to investigate and compare the serum proteomes in ATTRm and ATTRwt cardiac amyloidosis to identify differentially expressed blood proteins that were disease-specific. Using multiple-reaction monitoring mass spectrometry (MRM-MS), the concentrations of 160 proteins were analyzed in serum samples from ATTRm and ATTRwt patients, and a healthy control group. Patient and control sera were matched to age (≥ 60 years), gender (male), and race (Caucasian). The circulating concentrations of 123/160 proteins were significantly different in patient vs. control sera; TTR and retinol-binding protein (RBP4) levels were significantly decreased (p < 0.03) in ATTRm compared to controls. In ATTRm, 14/123 proteins were identified as unique to that group and found generally to be lower than controls; moreover, the concentrations of RBP4 and 6 other proteins in this group were significantly different (p < 0.04) compared to ATTRwt. Predicted interactions among the 14 proteins unique to ATTRm were categorized as reaction and binding associations. Alternatively, twenty-seven proteins were found to be unique to ATTRwt with associated interactions defined as activation, catalysis, and inhibition, in addition to reaction and binding. This study demonstrates significant proteomic differences between ATTR patient and control sera, and disease-associated variations in circulating levels of several proteins including TTR and RBP4.
Article
Background: Vitamins and minerals play multiple functions within the central nervous system which may help to maintain brain health and optimal cognitive functioning. Supplementation of the diet with various vitamins and minerals has been suggested as a means of maintaining cognitive function, or even of preventing dementia, in later life. Objectives: To evaluate the effects of vitamin and mineral supplementation on cognitive function in cognitively healthy people aged 40 years or more. Search methods: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group's (CDCIG) specialised register, as well as MEDLINE, Embase, PsycINFO, CINAHL, ClinicalTrials.gov and the WHO Portal/ICTRP from inception to 26th January 2018. Selection criteria: We included randomised controlled trials that evaluated the cognitive effects on people aged 40 years or more of any vitamin or mineral supplements taken by mouth for at least three months. Data collection and analysis: Study selection, data extraction, and quality assessments were done in duplicate. Vitamins were considered broadly in the categories of B vitamins, antioxidant vitamins, and combinations of both. Minerals were considered separately, where possible. If interventions and outcomes were considered sufficiently similar, then data were pooled. In order to separate short-term cognitive effects from possible longer-term effects on the trajectory of cognitive decline, data were pooled for various treatment durations from 3 months to 12 months and up to 10 years or more. Main results: In total, we included 28 studies with more than 83,000 participants. There were some general limitations of the evidence. Most participants were enrolled in studies which were not designed primarily to assess cognition. These studies often had no baseline cognitive assessment and used only brief cognitive assessments at follow-up. Very few studies assessed the incidence of dementia. Most study reports did not mention adverse events or made only very general statements about them. Only 10 studies had a mean follow-up > 5 years. Only two studies had participants whose mean age was < 60 years at baseline. The risk of bias in the included studies was generally low, other than a risk of attrition bias for longer-term outcomes. We considered the certainty of the evidence behind almost all results to be moderate or low.We included 14 studies with 27,882 participants which compared folic acid, vitamin B12, vitamin B6, or a combination of these to placebo. The majority of participants were aged over 60 years and had a history of cardio- or cerebrovascular disease. We found that giving B vitamin supplements to cognitively healthy adults, mainly in their 60s and 70s, probably has little or no effect on global cognitive function at any time point up to 5 years (SMD values from -0.03 to 0.06) and may also have no effect at 5-10 years (SMD -0.01). There were very sparse data on adverse effects or on incidence of cognitive impairment or dementia.We included 8 studies with 47,840 participants in which the active intervention was one or more of the antioxidant vitamins: ß-carotene, vitamin C or vitamin E. Results were mixed. For overall cognitive function, there was low-certainty evidence of benefit associated with ß-carotene after a mean of 18 years of treatment (MD 0.18 TICS points, 95% CI 0.01 to 0.35) and of vitamin C after 5 years to 10 years (MD 0.46 TICS points, 95% CI 0.14 to 0.78), but not at earlier time points. From two studies which reported on dementia incidence, there was low-certainty evidence of no effect of an antioxidant vitamin combination or of vitamin E, either alone or combined with selenium. One of the included studies had been designed to look for effects on the incidence of prostate cancer; it found a statistically significant increase in prostate cancer diagnoses among men taking vitamin E.One trial with 4143 participants compared vitamin D3 (400 IU/day) and calcium supplements to placebo. We found low- to moderate-certainty evidence of no effect of vitamin D3 and calcium supplements at any time-point up to 10 years on overall cognitive function (MD after a mean of 7.8 years -0.1 MMSE points, 95% CI -0.81 to 0.61) or the incidence of dementia (HR 0.94, 95% CI 0.72 to 1.24). A pilot study with 60 participants used a higher dose of vitamin D3 (4000 IU on alternate days) and found preliminary evidence that this dose probably has no effect on cognitive function over six months.We included data from one trial of zinc and copper supplementation with 1072 participants. There was moderate-certainty evidence of little or no effect on overall cognitive function (MD 0.6 MMSE points, 95% CI -0.19 to 1.39) or on the incidence of cognitive impairment after 5 years to 10 years. A second smaller trial provided no usable data, but reported no cognitive effects of six months of supplementation with zinc gluconate.From one study with 3711 participants, there was low-certainty evidence of no effect of approximately five years of selenium supplementation on the incidence of dementia (HR 0.83, 95% CI 0.61 to 1.13).Finally, we included three trials of complex supplements (combinations of B vitamins, antioxidant vitamins, and minerals) with 6306 participants. From the one trial which assessed overall cognitive function, there was low-certainty evidence of little or no effect on the TICS (MD after a mean of 8.5 years 0.12, 95% CI -0.14 to 0.38). Authors' conclusions: We did not find evidence that any vitamin or mineral supplementation strategy for cognitively healthy adults in mid or late life has a meaningful effect on cognitive decline or dementia, although the evidence does not permit definitive conclusions. There were very few data on supplementation starting in midlife (< 60 years); studies designed to assess cognitive outcomes tended to be too short to assess maintenance of cognitive function; longer studies often had other primary outcomes and used cognitive measures which may have lacked sensitivity. The only positive signals of effect came from studies of long-term supplementation with antioxidant vitamins. These may be the most promising for further research.
Article
Full-text available
Background: Emerging evidence suggests novel roles for bacterially derived vitamin K forms known as menaquinones in health and disease, which may be attributable in part to anti-inflammatory effects. However, the relevance of menaquinones produced by gut bacteria to vitamin K requirements and inflammation is undetermined.Objective: This study aimed to quantify fecal menaquinone concentrations and identify associations between fecal menaquinone concentrations and serum vitamin K concentrations, gut microbiota composition, and inflammation.Design: Fecal and serum menaquinone concentrations, fecal microbiota composition, and plasma and fecal cytokine concentrations were measured in 80 men and postmenopausal women (48 men, 32 women, age 40-65 y) enrolled in a randomized, parallel-arm, provided-food trial. After consuming a run-in diet for 2 wk, participants were randomly assigned to consume a whole grain-rich (WG) or a refined grain-based (RG) diet for 6 wk. Outcomes were measured at weeks 2 and 8.Results: The median total daily excretion of menaquinones in feces was 850 nmol/d but was highly variable (range: 64-5358 nmol/d). The total median (IQR) fecal concentrations of menaquinones decreased in the WG diet compared with the RG diet [-6.8 nmol/g (13.0 nmol/g) dry weight for WG compared with 1.8 nmol/g (12.3 nmol/g) dry weight for RG; P < 0.01)]. However, interindividual variability in fecal menaquinone concentrations partitioned individuals into 2 distinct groups based on interindividual differences in concentrations of different menaquinone forms rather than the diet group or the time point. The relative abundances of several gut bacteria taxa, Bacteroides and Prevotella in particular, differed between these groups, and 42% of identified genera were associated with ≥1 menaquinone form. Menaquinones were not detected in serum, and neither fecal concentrations of individual menaquinones nor the menaquinone group was associated with any marker of inflammation.Conclusion: Menaquinone concentrations in the human gut appear highly variable and are associated with gut microbiota composition. However, the health implications remain unclear. This trial was registered at clinicaltrials.gov as NCT01902394.
Poster
Full-text available
Hypoxic-Ischaemic Encephalopathy (HIE) accounts for a significant proportion of neonatal deaths in resource limited settings. Moderate hypothermia started within the first 6 hours after birth is known to improve survival and outcome at 18 months. Although now considered standard care in developed countries, controlled therapeutic hypothermia requires close monitoring and advanced care, which are not yet feasible in MSF settings...
Article
Full-text available
Background: Vitamins and minerals have many functions in the nervous system which are important for brain health. It has been suggested that various different vitamin and mineral supplements might be useful in maintaining cognitive function and delaying the onset of dementia. In this review, we sought to examine the evidence for this in people who already had mild cognitive impairment (MCI). Objectives: To evaluate the effects of vitamin and mineral supplementation on cognitive function and the incidence of dementia in people with mild cognitive impairment. Search methods: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group's (CDCIG) specialised register, as well as MEDLINE, Embase, PsycINFO, CENTRAL, CINAHL, LILACs, Web of Science Core Collection, ClinicalTrials.gov, and the WHO Portal/ICTRP, from inception to 25 January 2018. Selection criteria: We included randomised or quasi-randomised, placebo-controlled trials which evaluated orally administered vitamin or mineral supplements in participants with a diagnosis of mild cognitive impairment and which assessed the incidence of dementia or cognitive outcomes, or both. We were interested in studies applicable to the general population of older people and therefore excluded studies in which participants had severe vitamin or mineral deficiencies. Data collection and analysis: We sought data on our primary outcomes of dementia incidence and overall cognitive function and on secondary outcomes of episodic memory, executive function, speed of processing, quality of life, functional performance, clinical global impression, adverse events, and mortality. We conducted data collection and analysis according to standard Cochrane systematic review methods. We assessed the risk of bias of included studies using the Cochrane 'Risk of bias' assessment tool. We grouped vitamins and minerals according to their putative mechanism of action and, where we considered it to be clinically appropriate, we pooled data using random-effects methods. We used GRADE methods to assess the overall quality of evidence for each comparison and outcome. Main results: We included five trials with 879 participants which investigated B vitamin supplements. In four trials, the intervention was a combination of vitamins B6, B12, and folic acid; in one, it was folic acid only. Doses varied. We considered there to be some risks of performance and attrition bias and of selective outcome reporting among these trials. Our primary efficacy outcomes were the incidence of dementia and scores on measures of overall cognitive function. None of the trials reported the incidence of dementia and the evidence on overall cognitive function was of very low-quality. There was probably little or no effect of B vitamins taken for six to 24 months on episodic memory, executive function, speed of processing, or quality of life. The evidence on our other secondary clinical outcomes, including harms, was very sparse or very low-quality. There was evidence from one study that there may be a slower rate of brain atrophy over two years in participants taking B vitamins. The same study reported subgroup analyses based on the level of serum homocysteine (tHcy) at baseline and found evidence that B vitamins may improve episodic memory in those with tHcy above the median at baseline.We included one trial (n = 516) of vitamin E supplementation. Vitamin E was given as 1000 IU of alpha-tocopherol twice daily. We considered this trial to be at risk of attrition and selective reporting bias. There was probably no effect of vitamin E on the probability of progression from MCI to Alzheimer's dementia over three years (HR 1.02; 95% CI 0.74 to 1.41; n = 516; 1 study, moderate-quality evidence). There was also no evidence of an effect at intermediate time points. The available data did not allow us to conduct analyses, but the authors reported no significant effect of three years of supplementation with vitamin E on overall cognitive function, episodic memory, speed of processing, clinical global impression, functional performance, adverse events, or mortality (five deaths in each group). We considered this to be low-quality evidence.We included one trial (n = 256) of combined vitamin E and vitamin C supplementation and one trial (n = 26) of supplementation with chromium picolinate. In both cases, there was a single eligible cognitive outcome, but we considered the evidence to be very low-quality and so could not be sure of any effects. Authors' conclusions: The evidence on vitamin and mineral supplements as treatments for MCI is very limited. Three years of treatment with high-dose vitamin E probably does not reduce the risk of progression to dementia, but we have no data on this outcome for other supplements. Only B vitamins have been assessed in more than one RCT. There is no evidence for beneficial effects on cognition of supplementation with B vitamins for six to 24 months. Evidence from a single study of a reduced rate of brain atrophy in participants taking vitamin B and a beneficial effect of vitamin B on episodic memory in those with higher tHcy at baseline warrants attempted replication.
Article
Vitamin K1 and vitamin K2 play very important biological roles acting as members of chains of electron transport as antioxidants in membranes and as cofactors for the posttranslational modification of proteins that participate in a number of physiological functions such as coagulation. The interaction of these vitamins with dimyristoyl. phosphatidylcholine (DMPC) model membranes has been studied by using a biophysical approach. It was observed by using differential scanning calorimetry that both vitamins have a very limited miscibility with DMPC and they form domains rich in the vitamins at high concentrations. Experiments using X-ray diffraction also showed the formation of different phases as a consequence of the inclusion of either vitamin K at temperatures below the phase transition. However, in the fluid state a homogenous phase was detected and a decrease of the thickness of the membrane accompanied by an increase in the water layer thickness. 2H-NMR spectroscopy showed that both vitamins K induced a decrease in the onset of the phase transition which was bigger for vitamin K1 and both vitamins decreased the order of the membrane as seen through the first moment, (M1). 1H NOESY MAS-NMR showed that protons located at the rings or at the beginning of the lateral chain of both vitamins K interacted with a clear preference with protons located in the polar part of DMPC. On the other hand, protons located on the lateral chain have a nearer proximity with the methyl end of the myristoyl chains of DMPC. In agreement with the 2H-NMR, ATR-FTIR indicated that both vitamins decreased the order parameters of DMPC. It was additionally deduced that the lateral chains of both vitamins were oriented almost in parallel to the myristoyl chains of the phospholipid.
Article
Background: Vitamin K antagonists (VKAs) are commonly used for their role in haemostasis by interfering with the vitamin K cycle. Since vitamin K also participates in brain physiology, this voxel-based morphometric study aimed to determine whether the duration of exposure to VKAs correlated with focal brain volume reduction in older adults. Methods: In this exposed/unexposed (1: 2) study nested within the GAIT (Gait and Alzheimer Interactions Tracking) cohort, 18 participants exposed to VKA (mean age 75 ± 5 years; 33.3% female; mean exposure 2,122 ± 1,799 days) and 36 matched participants using no VKA (mean age 75 ± 5 years; 33.3% female) underwent MRI scanning of the brain. Cortical grey and white matter volumes were automatically segmented using statistical parametric mapping. Age, gender, educational level, history of atrial fibrillation, type of MRI, and total intracranial volume were included as covariables. Results: The duration of exposure to VKA correlated inversely across the whole brain with the subvolumes of two clusters in the grey matter (right frontal inferior operculum and right precuneus) and one cluster in the white matter (left middle frontal gyrus). In contrast, the grade of white matter hyperintensities did not differ according to the use of VKA. Conclusion: We found focal atrophies in older adults exposed to VKA. These findings provide new insights elucidating the effects of VKAs on brain health and function in older adults.
Article
Nutritional deficiencies often precede the diagnosis of cystic fibrosis (CF) in infants, and occur at a stage where the rapidly developing brain is more vulnerable to insult. We aim to compare fat-soluble nutrient status of newly diagnosed non-screened infants with CF to that of healthy infants, and explore the association with neurodevelopment evaluated by electroencephalography (EEG). Our results show that CF infants had lower levels of all fat-soluble vitamins and docosahexaenoic acid (DHA) compared to controls. The auditory evoked potential responses were higher in CF compared to controls whereas the visual components did not differ between groups. DHA levels were correlated with auditory evoked potential responses. Although resting state frequency power was similar between groups, we observed a negative correlation between DHA levels and low frequencies. This study emphasizes the need for long-term neurodevelopmental follow-up of CF infants and pursuing intervention strategies in the future.
Article
The fat-soluble vitamins are vitamins A, D, E, and K. Each vitamin has unique characteristics and contributes to the overall health of an individual. These vitamins have complex absorption, metabolism, and distribution elements that provide protection to the cells in the body as well as many organs. Fat-soluble vitamins, once ingested and processed, are stored in the body for use. Most fat-soluble vitamins are obtained from fruits, vegetables, nuts, and animals.
Article
Background: Febrile seizure (FS) is the most common neurological disorder of childhood. The exact pathophysiology of FS is unknown. Recent studies showed that the role of vitamin K in non-hematological and inflammatory disorders. The present study aimed to investigate serum vitamin K levels in children with FS. Aim: To evaluate the vitamin K levels in children with febrile seizure. Study design: Prospective case-control study Methods: This multicenter study examined representative populations in eight different cities in Turkey between April 1, 2018 and April 1, 2019. Blood samples were taken from all children at presentation. Vitamin K 1, Vitamin K2, tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), and interleukin 6 (IL-6) levels searched by enzyme-linked immuno-sorbent assay. Results: The study was conducted with 155 children: 84 children with FS and 71 children in febrile control group. Serum vitamin K1 and vitamin K2 were also higher in FS group than the controls. The results of statistical analysis showed that vitamin K1 and K2 levels were correlated with TNF-α, IL-1β and IL-6 levels. The median vitamin K1 and vitamin K2 levels of children experiencing their first FS were higher than children with recurrent FS. The type of FS has no effect on serum vitamin K1 and vitamin K2 levels. Conclusion: This study demonstrates that the vitamin K levels in children with febrile seizure was higher than control group. These new findings may contribute to clarifying the etiopathogenesis of FS.
Article
Full-text available
Background: Alzheimer's disease (AD) is the most common cause of dementia, with a multifactorial etiology, in which the person has great difficulty identifying feelings of hunger, satiety, and feeding, which may affect their nutritional status. Pathologically, it is associated with neurodegeneration of synapses followed by neuronal loss, accompanied by glial proliferation surrounded by neurofibrillary tangles, beta-amyloid peptide (Aβ) deposition, inflammation and cerebrovascular injury hindering the ability to perform activities of daily living. This study aimed to analyze quantitatively the differences between an elderly group with AD and a control group, in terms of macro and micronutrient consumption evaluation. Methods: the study involved 69 participants who were assessed via collection of anthropometric measurements (weight, height and body mass index) with nutritional status being assessed by 24-hour food recall and three-day food record. Cognitive assessments were performed using the Mini-Mental State Examination (MMSE) and Clinical Dementia Ranting (CDR). Results: The intake of lipids in patients with severe dementia, was lower (p <0.05). The consumption of proteins showed a decrease with demential advance. For vitamins, there was a significant difference (p <0.05) in the amount of thiamine, niacin, vitamin D, E and K and calcium, chromium and iodine minerals, which were significantly reduced in AD patients (p <0.05). Conclusions: Decreases in macronutrient and micronutrient consumption may result in a consequent impairment of nutritional status, dementia progression, and decreased quality and life expectancy of elderly patients with AD.
Chapter
Full-text available
panjang sangat ditentukan oleh kualitas pertumbuhan dan perkembangan otak selama periode kritis di awal kehidupan anak. Pada 1 dekade terakhir ini, berkembang keilmuan baru yang mengaitkan antara pembentukan struktur dan fungsi otak dengan sistem gastrointestinal, dengan istilah yang dikenal sebagai konsep “Gut-Brain-Axis”. Secara fungsional, keterkaitan antara sistem saluran cerna dengan otak, diperankan oleh mikrobiota di dalam saluran cerna. Sehingga para ahli juga menggunakan istilah konsep “Microbiota-Gut-Brain-Axis” (Yarandi, 2016).
Article
We gathered some theoretic and practical concepts related to the importance of nutrition in the prevention and management of Alzheimer disease (AD). Besides the role of nutrients in brain development and functioning, some nutrients exert special control in the development of AD, due to their participation in neurotransmitter synthesis, their modulation in epigenetics mechanisms, and as antioxidants. In addition, some non-nutrient food–derived substances have shown potential in the control of neuroinflammation and consequently in the prevention of AD. Finally, it is important to be aware of the nutritional status and food intake patterns of the patient with AD.
Chapter
Full-text available
Amyotrophic Lateral Sclerosis (ALS) is considered a fatal motor neuron disease of unknown origin without a cure or efficacious treatment. ALS exhibits multiple pathways and systems of deterioration, such as muscle wasting, weight loss, hyper-metabolism, altered substrate utilization, impaired detoxification, oxidative stress, inflammation, immune dysfunction, mitochondrial damage, hormonal imbalance, glutamate excitotoxicity, blood-brain barrier breakdown, gastrointestinal, pulmonary, and hepatic dysfunction, and other metabolic changes. Persons with ALS (pALS) and healthcare practitioners are increasingly interested in how nutrition might help address this disease, as there is scientific documentation of ALS reversals. The conventional medical nutrition therapy (MNT) guidelines do not adequately address the individualized nutritional status of pALS, as they are primarily designed to prevent weight loss and address feeding difficulties. The problem is that standard MNT includes many toxic, processed, and high-sugar foods which may significantly worsen metabolic status and neuroinflammation. The metabolic dysregulation of pALS alters their caloric and nutrient requirements which might be therapeutically modified by targeted dietary and supplement protocols using Integrative and Functional Medical Nutrition Therapy (IFMNT). Dietary interventions are reviewed, including the Deanna Protocol, the ketogenic diet, and others. Specific nutritional supplements are reviewed, such as vitamins, minerals, amino acids, fatty acids, herbs, and other nutritional factors that may offer a targeted approach to metabolic dysregulation. This chapter explores the metabolic and nutritional consequences of ALS and reviews dietary and supplement approaches that might optimize ALS management or potentially support reversal through personalized nutritional assessment and the application of IFMNT.
Article
Full-text available
In a previous report, we showed vitamin K to preferentially accumulate in brain regions rich in white matter and to positively correlate with certain sphingolipids. In rodents, pharmacological vitamin K deficiency has resulted in behavioral perturbations. To gain insight on the role of vitamin K status on brain function, we investigated learning abilities (Morris water maze), motor activity (open field), and anxiety (elevated plus maze) in distinct groups of 6-, 12-, and 20-mo-old female Sprague-Dawley rats that had been fed diets containing low (L; ~80 μg/kg diet), adequate (A; ~500 μg/kg diet), or high (H; ~2000 μg/kg diet) levels of phylloquinone (μg/kg diet; n = 9-12/diet) since weaning. In 20-mo-old rats, sphingolipids (cerebroside, sulfatide, sphingomyelin, ceramide, and gangliosides), phylloquinone, and menaquinone-4 were also assessed in cerebellum, midbrain, pons medulla, striatum, and hippocampus. Lifetime consumption of a low-vitamin K diet resulted in cognitive deficits in the 20-mo-old rats, with those in the L group having longer latencies than those in the H group (P < 0.05); this was associated with higher concentrations of ceramides in the hippocampus (P < 0.05) and lower gangliosides in the pons medulla and midbrain (P < 0.05). The low-vitamin K diet did not affect cognition at 6 and 12 mo of age, nor did it affect motor activity or anxiety at any age. Although much remains to be elucidated about the mechanism of action of vitamin K in cognition, this report points to vitamin K as an important nutritional factor contributing to cognitive health during aging.
Article
Full-text available
Multiple sclerosis (MS) is a complex demyelinating disease of the central nervous system. Current research has shown that at least in some cases, the primary insult in MS could be directed at the oligodendrocyte, and that the earliest immune responses are primarily via innate immune cells. We have identified a family of receptor protein tyrosine kinases, known as the TAM receptors (Tyro3, Axl and Mertk), as potentially important in regulating both the oligodendrocyte and immune responses. We have previously shown that Gas6, a ligand for the TAM receptors, can affect the severity of demyelination in mice, with a loss of signalling via Gas6 leading to decreased oligodendrocyte survival and increased microglial activation during cuprizone-induced demyelination. We hypothesised TAM receptor signalling would also influence the extent of recovery in mice following demyelination. A significant effect of the absence of Gas6 was detected upon remyelination, with a lower level of myelination after 4 weeks of recovery in comparison with wild-type mice. The delay in remyelination was accompanied by a reduction in oligodendrocyte numbers. To understand the molecular mechanisms that drive the observed effects, we also examined the effect of exogenous Gas6 in in vitro myelination assays. We found that Gas6 significantly increased myelination in a dose-dependent manner, suggesting that TAM receptor signalling could be directly involved in myelination by oligodendrocytes. The reduced rate of remyelination in the absence of Gas6 could thus result from a lack of Gas6 at a critical time during myelin production after injury. These findings establish Gas6 as an important regulator of both CNS demyelination and remyelination.
Article
Full-text available
Growth arrest-specific protein 6 (gas6) activities are mediated through the Tyro3, Axl, and Mer family of receptor tyrosine kinases. Gas6 is expressed and secreted by a wide variety of cell types, including cells of the central nervous system (CNS). In this study, we tested the hypothesis that administration of recombinant human Gas6 (rhGas6) protein into the CNS improves recovery following cuprizone withdrawal. After a 4-week cuprizone diet, cuprizone was removed and PBS or rhGas6 (400 ng/ml, 4 µg/ml and 40 µg/ml) was delivered by osmotic mini-pump into the corpus callosum of C57Bl6 mice for 14 days. Nine of 11 (82%) PBS-treated mice had abundant lipid-associated debris in the corpus callosum by Oil-Red-O staining while only 4 of 19 (21%) mice treated with rhGas6 had low Oil-Red-O positive droplets. In rhGas6-treated mice, SMI32-positive axonal spheroids and APP-positive deposits were reduced in number relative to PBS-treated mice. Compared to PBS, rhGas6 enhanced remyelination as revealed by MBP immunostaining and electron microscopy. The rhGas6-treated mice had more oligodendrocytes expressing Olig1 in the cytoplasm, indicative of oligodendrocyte progenitor cell maturation. Relative to PBS-treated mice, rhGas6-treated mice had fewer activated microglia in the corpus callosum by Iba1 immunostaining. The data show that rhGas6 treatment resulted in more efficient repair following cuprizone-induced injury.
Article
Full-text available
The anticoagulant factor protein S (PS) protects neurons from hypoxic/ischemic injury. However, molecular mechanisms mediating PS protection in injured neurons remain unknown. Here, we show mouse recombinant PS protects dose-dependently mouse cortical neurons from excitotoxic NMDA-mediated neuritic bead formation and apoptosis by activating the phosphatidylinositol 3-kinase (PI3K)-Akt pathway (EC(50) = 26 ± 4 nm). PS stimulated phosphorylation of Bad and Mdm2, two downstream targets of Akt, which in neurons subjected to pathological overstimulation of NMDA receptors (NMDARs) increased the antiapoptotic Bcl-2 and Bcl-X(L) levels and reduced the proapoptotic p53 and Bax levels. Adenoviral transduction with a kinase-deficient Akt mutant (Ad.Akt(K179A)) resulted in loss of PS-mediated neuronal protection, Akt activation, and Bad and Mdm2 phosphorylation. Using the TAM receptors tyrosine kinases Tyro3-, Axl-, and Mer-deficient neurons, we showed that PS protected neurons lacking Axl and Mer, but not Tyro3, suggesting a requirement of Tyro3 for PS-mediated protection. Consistent with these results, PS dose-dependently phosphorylated Tyro3 on neurons (EC(50) = 25 ± 3 nm). In an in vivo model of NMDA-induced excitotoxic lesions in the striatum, PS dose-dependently reduced the lesion volume in control mice (EC(50) = 22 ± 2 nm) and protected Axl(-/-) and Mer(-/-) transgenic mice, but not Tyro3(-/-) transgenic mice. Using different structural PS analogs, we demonstrated that the C terminus sex hormone-binding globulin-like (SHBG) domain of PS is critical for neuronal protection in vitro and in vivo. Thus, our data show that PS protects neurons by activating the Tyro3-PI3K-Akt pathway via its SHGB domain, suggesting potentially a novel neuroprotective approach for acute brain injury and chronic neurodegenerative disorders associated with excessive activation of NMDARs.
Article
Full-text available
Vitamin K occurs in the natural world in several forms, including a plant form, phylloquinone (PK), and a bacterial form, menaquinones (MKs). In many species, including humans, PK is a minor constituent of hepatic vitamin K content, with most hepatic vitamin K content comprising long-chain MKs. Menaquinone-4 (MK-4) is ubiquitously present in extrahepatic tissues, with particularly high concentrations in the brain, kidney and pancreas of humans and rats. It has consistently been shown that PK is endogenously converted to MK-4 (refs 4-8). This occurs either directly within certain tissues or by interconversion to menadione (K(3)), followed by prenylation to MK-4 (refs 9-12). No previous study has sought to identify the human enzyme responsible for MK-4 biosynthesis. Previously we provided evidence for the conversion of PK and K(3) into MK-4 in mouse cerebra. However, the molecular mechanisms for these conversion reactions are unclear. Here we identify a human MK-4 biosynthetic enzyme. We screened the human genome database for prenylation enzymes and found UbiA prenyltransferase containing 1 (UBIAD1), a human homologue of Escherichia coli prenyltransferase menA. We found that short interfering RNA against the UBIAD1 gene inhibited the conversion of deuterium-labelled vitamin K derivatives into deuterium-labelled-MK-4 (MK-4-d(7)) in human cells. We confirmed that the UBIAD1 gene encodes an MK-4 biosynthetic enzyme through its expression and conversion of deuterium-labelled vitamin K derivatives into MK-4-d(7) in insect cells infected with UBIAD1 baculovirus. Converted MK-4-d(7) was chemically identified by (2)H-NMR analysis. MK-4 biosynthesis by UBIAD1 was not affected by the vitamin K antagonist warfarin. UBIAD1 was localized in endoplasmic reticulum and ubiquitously expressed in several tissues of mice. Our results show that UBIAD1 is a human MK-4 biosynthetic enzyme; this identification will permit more effective decisions to be made about vitamin K intake and bone health.
Article
Full-text available
During the past century, treatments for the diseases of youth and middle age have helped raise life expectancy significantly. However, cognitive decline has emerged as one of the greatest health threats of old age, with nearly 50% of adults over the age of 85 afflicted with Alzheimer's disease. Developing therapeutic interventions for such conditions demands a greater understanding of the processes underlying normal and pathological brain ageing. Recent advances in the biology of ageing in model organisms, together with molecular and systems-level studies of the brain, are beginning to shed light on these mechanisms and their potential roles in cognitive decline.
Article
Full-text available
Gangliosides are considered to be essential in the maintenance and repair of nervous tissues; however, the mechanisms for neurodegeneration caused by ganglioside defects are unknown. We examined gene expression profiles in double knockout (DKO) mice of GM2/GD2 synthase and GD3 synthase genes and showed that the majority of complement genes and their receptors were up-regulated in cerebellum in DKO mice. Inflammatory reactions were demonstrated in those tissues by measuring up-regulated inflammatory cytokines, indicating the presence of complement activation and inflammation as reported in Alzheimer's disease. Immunoblotting of fractionated membrane extracts by sucrose density gradient revealed that complement-regulatory molecules such as decay-accelerating factor and CD59 were dispersed from glycolipid-enriched microdomain/rafts in DKO cerebellum. Immunohistostaining of these molecules showed disordered membrane localization. These results suggested that dysfunction of complement-regulatory molecules may be due to abnormal glycolipid-enriched microdomain/rafts that triggered complement activation, subsequent inflammation, and neurodegeneration in DKO mice. Generation of the triple KO mice lacking complement activity in addition to the two glycosyltransferases suggested that complement activation is involved in the inflammatory reactions and neurodegeneration caused by the ganglioside deficiency.
Article
Full-text available
Most molecular and cellular studies of cognitive function have focused on either normal or pathological states, but recent research with transgenic mice has started to address the mechanisms of enhanced cognition. These results point to key synaptic and nuclear signalling events that can be manipulated to facilitate the induction or increase the stability of synaptic plasticity, and therefore enhance the acquisition or retention of information. Here, we review these surprising findings and explore their implications to both mechanisms of learning and memory and to ongoing efforts to develop treatments for cognitive disorders. These findings represent the beginning of a fundamental new approach in the study of enhanced cognition.
Article
Full-text available
Sphingolipids (SLs) are essential constituents of eukaryotic cells. Besides playing structural roles in cellular membranes, some metabolites, including ceramide, sphingosine, and sphingosine-1-phosphate, have drawn attention as bioactive signaling molecules involved in the regulation of cell growth, differentiation, senescence, and apoptosis. Understanding the many cell regulatory functions of SL metabolites requires an advanced knowledge of how and where in the cell they are generated, converted, or degraded. This review will provide a short overview of the metabolism, localization, and compartmentalization of SLs. Also, a discussion on bioactive members of the SL family and inducers of SL enzymes that lead to ceramide generation will be presented.
Article
Full-text available
The present review explores the role of ceramides in neuronal apoptosis, as well as the recent discovery of the signaling pathways involved in this process placing particular emphasis on the correlation between cellular metabolism and neuronal death. Endogenous levels of ceramides are increased following various pro-apoptotic stimuli which have been identified as potential causes of chronic and acute neurodegenerative diseases. Ceramides induce changes in multiple enzymes and cell signaling components. The early inhibition of the neuronal survival pathway regulated by phosphatidil-inositol-3-kinase/protein kinase B or AKT mediated by ceramide may be a relevant early event in the decision of neuronal survival/death. It may perturb several molecular and metabolic functions. In particular it might decrease glycolysis through rapid modulation of hexokinase activity. This would in turn generate limited amounts of mitochondrial substrates leading to mitochondrial dysfunction and neuronal apoptosis. Subtle and early metabolic alterations caused by inhibition of the PI3K/AKT pathway mediated by ceramide may potentially work with genes associated with neurodegenerative diseases such as Parkinson's and Alzheimer's disease. Together they may be determinant steps in downstream events leading to neuronal apoptosis. Therefore, reinforcement of the PI3K/AKT pathway could constitute an important neuroprotective strategy.
Article
Full-text available
Vitamin K modulates cytokines involved in bone turnover, including interleukin-6 (IL-6) and osteoprotegerin in vitro. The objective of this study was to assess 1) associations between measures of vitamin K status [plasma phylloquinone and serum percentage of undercarboxylated osteocalcin (%ucOC)] and IL-6, osteoprotegerin, and C-reactive protein (CRP) concentrations and 2) the effect of daily 500 mug phylloquinone supplementation for 3 y on cytokine concentrations. Concentrations of IL-6, osteoprotegerin, and CRP and bone mineral density (BMD) were measured at baseline and after 3 y of follow-up in 379 healthy men and women (60-81 y; 58.5% women) participating in a randomized trial that studied the effect of vitamin K supplementation on bone loss. Cross-sectionally, plasma phylloquinone was inversely associated with IL-6 and CRP, whereas serum %ucOC was inversely associated with IL-6. Osteoprotegerin was associated positively with plasma phylloquinone and inversely with %ucOC. No differences were observed in the 3-y change in IL-6, osteoprotegerin, and CRP concentrations between participants who received phylloquinone supplementation and those who did not. Overall, no association was observed between the 3-y changes in circulating cytokines and BMD. Poor vitamin K status was associated with high concentrations of cytokines involved in bone turnover, but vitamin K supplementation did not confer a decrease in cytokine concentrations. The healthy status of this cohort may explain a lack of effect of vitamin K supplementation on cytokine concentrations. This trial was registered with www.clinicaltrials.gov as NCT00183001.
Article
Full-text available
The modulation of phosphosphingolipid synthesis by vitamin K depletion has been observed in the vitamin K-dependent microorganism, Bacteriodes levii. When cultured briefly without the vitamin, a reduction occurred in the activity of the first enzyme of the sphingolipid pathway, 3-ketodihydrosphingosine synthase. In this report, 16-day-old mice were treated with the vitamin K antagonist, warfarin. Brain microsomes from these animals showed a 19% reduction in synthase activity. Mice treated with warfarin for 2 weeks showed a major reduction in sulfatide level (42%), with a lesser degree or no reduction in levels of gangliosides and cerebrosides. In further experiments, mice were treated with warfarin for 2 weeks and a group was then injected with vitamin K1 (aquamephyton) for 3 days. Enzyme activity returned to a normal level within 2-3 days. Sulfatide levels had increased 33% in the vitamin K-injected group and ganglioside levels also increased, where levels of cerebrosides and sphingomyelin declined. Sulfatide synthesis determined by [35S] sulfate incorporation, showed a 52% increase in incorporation following administration of vitamin K for 3 days. These results suggest a role for vitamin K in the biosynthesis of sulfatides and other sphingolipids in brain. This putative role could be by post-translational protein modification analogous to the role of vitamin K in other systems.
Article
Full-text available
Bacteroides melaninogenicus requires vitamin K for normal growth. Cells incubated in a vitamin K-free medium form defective cell envelopes. Studies with vitamin K-grown “K(+)” and vitamin K-depleted “K(–)” cells showed that [¹⁴C]choline and [¹⁴C]glycerol were not taken up, but several amino acids and acetate were incorporated to the same degree by both types of cultures. However, K(–) cells incorporated succinate to a greater degree than did K(+) cultures. The relative incorporation of succinate into ceramide phosphorylethanolamine and ceramide phosphorylglycerol was depressed compared with incorporation into phosphatidylethanolamine in K(–) cultures. B. melaninogenicus can be grown in serial subculture in the absence of vitamin K in the presence of 2.5 mg/ml of succinate. Under these conditions the relative incorporation of [2,3-¹⁴C]succinate and ³²P into ceramide phosphorylethanolamine and ceramide phosphorylglycerol is markedly depressed. Stimulation of phosphosphingolipid synthesis by vitamin K was shown by comparing the uptake of ³²P and lipid phosphorus levels of a succinate-grown, vitamin K-depleted culture supplemented with ³²P plus 0.1 μg/ml vitamin K1 with a similar culture supplemented with ³²P only. The phosphosphingolipids from the vitamin K-supplemented cells incorporated greater amounts of ³²P and had higher levels of phosphorus than did the ceramide phosphorylethanolamine and ceramide phosphorylglycerol of the culture without added vitamin K. It was further shown that vitamin K added to a vitamin K-depleted culture stimulated synthesis of ceramide phosphorylethanolamine and ceramide phosphorylglycerol 38 min and 60 min, respectively, following the addition of the vitamin; incorporation of ³²P into other phospholipids was unaffected.
Article
Full-text available
A set of growth arrest-specific genes (gas) whose expression is negatively regulated after serum induction has previously been described (C. Schneider, R. M. King, and L. Philipson, Cell 54:787-793, 1988). The detailed analysis of one of them, gas6, is reported here, gas6 mRNA (2.6 kb) is abundantly expressed in serum-starved (48 h in 0.5% fetal calf serum) NIH 3T3 cells but decreases dramatically after fetal calf serum or basic fibroblast growth factor stimulation. The human homolog of gas6 was also cloned and sequenced, revealing a high degree of homology and a similar pattern of expression in IMR90 human fibroblasts. Computer analysis of the protein encoded by murine and human gas6 cDNAs showed significant homology (43 and 44% amino acid identity, respectively) to human protein S, a negative coregulator in the blood coagulation pathway. By using an anti-human Gas6 monospecific affinity-purified antibody, we show that the biosynthetic level of human Gas6 fully reflects mRNA expression in IMR90 human fibroblasts. This finding thus defines a new member of vitamin K-dependent proteins that is expressed in many human and mouse tissues and may be involved in the regulation of a protease cascade relevant in growth regulation.
Article
Full-text available
We identified Ark, the mouse homolog of the receptor tyrosine kinase Axl (Ufo, Tyro7), in a screen for novel factors involved in GnRH neuronal migration by using differential-display PCR on cell lines derived at two windows during GnRH neuronal development. Ark is expressed in Gn10 GnRH cells, developed from a tumor in the olfactory area when GnRH neurons are migrating, but not in GT1-7 cells, derived from a tumor in the forebrain when GnRH neurons are postmigratory. Since Ark (Ax1) signaling protects from programmed cell death in fibroblasts, we hypothesized that it may play an antiapoptotic role in GnRH neurons. Gn10 (Ark positive) GnRH cells were more resistant to serum withdrawal-induced apoptosis than GT1-7 (Ark negative) cells, and this effect was augmented with the addition of Gas6, the Ark (Ax1) ligand. Gas6/Ark stimulated the extracellular signal-regulated kinase, ERK, and the serine-threonine kinase, Akt, a downstream component of the phosphoinositide 3-kinase (PI3-K) pathway. To determine whether ERK or Akt activation is required for the antiapoptotic effects of Gas6/Ark in GnRH neurons, cells were serum starved in the absence or presence of Gas6, with or without inhibitors of ERK and PI3-K signaling cascades. Gas6 rescued Gn10 cells from apoptosis, and this effect was blocked by coincubation of the cells with the mitogen-activated protein/ERK kinase (MEK) inhibitor, PD98059, or wortmannin (but not rapamycin). These data support an important role for Gas6/Ark signaling via the ERK and PI3-K (via Akt) pathways in the protection of GnRH neurons from programmed cell death across neuronal migration.
Book
Vitamin K: Past, Present, Future Essential for normal blood coagulation, possible roles in bone, vascular, and tumor metabolism, and a nutrient critical to the health of the newborn infant -- these are just some of the many health-promoting aspects of Vitamin K. Vitamin K in Health and Disease navigates the exciting research venues that have opened in the past few years surrounding this micro nutrient, particularly its role in skeletal and cardiovascular health. It also provides the historical timeline of vitamin K research and discovery that began in the 1930s. Comprehensive in scope, this book offers complete coverage of the chemistry of Vitamin K; deficiency signs and nutritional assessment; metabolism and biochemistry; and pharmacology. It also presents up-to-date scientific studies on the nutritional, metabolic, and medical aspects along with a review of current dietary requirements and the difficulty involved in establishing an appropriate dietary reference intake for Vitamin K. Extensive References, More than 45 Illustrations, Numerous Tables Based on John Suttie’s 35 years of experience directing a broad vitamin K research program, this work discusses plasma and non-plasma Vitamin K-dependent proteins. It also includes helpful tables on food sources, population intake of Vitamin K, and the impact of diet on the circulating levels of the vitamin – highlighting the role of vitamin K in health and disease. Vitamin K in Health and Disease provides a foundation for future innovations in research and in determining the best ways to implement current knowledge.
Article
Neuronal apoptosis has been implicated as an important mechanism of cell death in acute and chronic neurodegenerative disorders. Ceramide is a product of sphingolipid metabolism which induces neuronal apoptosis in culture, and ceramide levels increase in neurons during various conditions associated with cell death. In this study we investigate the mechanism of ceramide-induced apoptosis in primary cortical neuronal cells. We show that ceramide treatment initiates a cascade of biochemical alterations associated with cell death: earliest signal transduction changes involve Akt dephosphorylation and inactivation followed by dephosphorylation of proapoptotic regulators such as BAD (proapoptotic Bcl-2 family member), Forkhead family transcription factors, glycogen synthase kinase 3-beta, mitochondrial depolarization and permeabilization, release of cytochrome c into the cytosol, and caspase-3 activation. Bongkrekic acid, an agent that inhibits mitochondrial depolarization, significantly reduces ceramide-induced cell death and correlated caspase-3 activation. Together, these data demonstrate the importance of the mitochondrial-dependent intrinsic pathway of caspase activation for ceramide-induced neuronal apoptosis.
Article
THE Axl receptor tyrosine kinase was identified as a protein encoded by a transforming gene from primary human myeloid leukaemia cells by DNA-mediated transformation of NIH 3T3 cells1-3. Axl is the founding member of a family of related receptors that includes Eyk4, encoded by a chicken proto-oncogene originally described as a retroviral transforming gene, and c-Mer5, encoded by a human protooncogene expressed in neoplastic B- and T-cell lines. The transforming activity of Axl demonstrates that the receptor can drive cellular proliferation. The function of Axl in non-transformed cells and tissues is unknown, but may involve the stimulation of cell proliferation in response to an appropriate signal, namely a ligand that activates the receptor. We report here the purification of an Axl stimulatory factor, and its identification as the product of growth-arrest-specific gene 6 (ref. 6). This is, to our knowledge, the first description of a ligand for the Axl family of receptors.
Article
Gas6, a product of the growth-arrest-specific gene 6, protects neurons from serum deprivation-induced apoptosis. Neuronal apoptosis is also caused by amyloid β protein (Aβ), whose accumulation in the brain is a characteristic feature of Alzheimer’s disease. Aβ induces Ca2+ influx via L-type voltage-dependent calcium channels (L-VSCCs), leading to its neurotoxicity. In the present study, we investigated effects of Gas6 on Aβ-induced cell death in primary cultures of rat cortical neurons. Aβ caused neuronal cell death in a concentration- and time-dependent manner. Gas6 significantly prevented neurons from Aβ-induced cell death. Gas6 ameliorated Aβ-induced apoptotic features such as the condensation of chromatin and the fragmentation of DNA. Prior to cell death, Aβ increased influx of Ca2+ into neurons through L-VSCCs. Gas6 significantly inhibited the Aβ-induced Ca2+ influx. The inhibitor of L-VSCCs also suppressed Aβ-induced neuronal cell death. The present cortical cultures contained few non-neuronal cells, indicating that Gas6 affected the survival of neurons directly, but not indirectly via non-neuronal cells. In conclusion, we demonstrate that Gas6 rescues cortical neurons from Aβ-induced apoptosis. Furthermore, the present study indicates that inhibition of L-VSCC contributes to the neuroprotective effect of Gas6.
Article
Gas6 is the newest member of the family of vitamin K-dependent proteins that acts as a ligand for the Axl family of RTK with homology to neural cell adhesion molecules. Gas6-Axl interactions have been implicated in anti-apoptotic activity. Here we report the first identification of Gas6 in the rat brain synaptosomes from three brain regions: striatum, hippocampus and frontal cortex. Furthermore, we discovered age-related and area-specific declines in the levels of Gas6 in the synaptosomes. The age effects on Gas6 levels were observed in all brain areas. Frontal cortex demonstrated the most dramatic decrease in Gas6 with aging (over 84% decline in old animals, as compared with young) (p<0.001). Gas6 levels in synaptosomes derived from striatum and hippocampus of the old animals were over 55% lower than those of the young (p<0.01). Phospholipid analysis of synaptosomes showed that in the cortex, decreases in Gas6 levels may be explained by age-related decrease in membrane phosphatidylserine composition. The brain area-specific decreases in Gas6 may in turn affect the RTK-regulated cell cycle, resulting in changes in distinct neuronal population viability. Thus, our findings suggest for the first time a role for Gas6 in brain aging.
Article
Gas6 (growth arrest specific gene-6) is a ligand for members of the Axl subfamily of receptor protein-tyrosine kinases. One of these receptors, Tyro-3, is widely expressed in the central nervous system. We have used biochemical and histological techniques, including in situ hybridization, to determine the expression patterns of Gas6 mRNA and protein during development. Gas6 is widely expressed in the rat central nervous system (CNS) beginning at late embryonic stages and its levels remain high in the adult. Gas6 is detected as a single 85 kDa protein, which is encoded by a single 2.5 kb mRNA species. At embryonic day 14 it is detected in the heart, blood vessels, testes, choroid plexus, and in the ventral spinal cord. In the adult, Gas6 is expressed in the cerebral cortex, (predominantly in layer V), the piriform cortex, and the hippocampus (areas CA1, CA3 and the dentate gyrus). It is also expressed in thalamic and hypothalamic structures, the midbrain, and in a subset of motor and trigeminal nuclei. In the cerebellum, it is expressed in Purkinje neurons and deep cerebellar nuclei. Protein S, a protein related to Gas6, is only detected at low levels in the CNS. The spatial and temporal profiles of Gas6 expression suggest that it could potentially serve as the physiologically relevant ligand for Tyro-3 in the postnatal rat nervous system.
Article
Two forms of vitamin K [phylloquinone (K1) and menaquinone-4 (MK-4)] were added to vitamin K-deficient rat food in varying amounts. These diets were given as the sole source of nutrition to rats for one week. The minimal dietary requirements (MDR) to attain maximal prothrombin synthesis were determined to be 0.6 and 6–10 μg/g of food for K1 and MK-4, respectively. The difference between both vitamers could be explained by the limited hepatic accumulation of MK-4. Next, vitamin K was offered to rats at concentrations ranging between 0.6 and 3000 μg/g of food, and the tissue distribution of vitamin K was investigated after one week of administration. Accumulation of K1 and MK-4 was found in all tissues investigated, but both the absolute tissue concentration and the ratio between K1 and MK-4 were tissue-dependent. Highest values were found in liver and in heart, but since the heart contains no γ-glutamylcarboxylase, the function of vitamin K in this tissue remains obscure. High tissue concentrations of MK-4 were also found in pancreas and testis after a diet containing K1 exclusively. The data indicate that this conversion is tissue-specific, but neither the reason nor its mechanism are known.
Article
Vitamin K (VK) has a protective effect on neural cells. Methylmercury is a neurotoxicant that directly induces neuronal death in vivo and in vitro. Therefore, in the present study, we hypothesized that VK inhibits the neurotoxicity of methylmercury. To prove our hypothesis in vitro, we investigated the protective effects of VKs (phylloquinone, vitamin K(1); menaquinone-4, vitamin K(2) ) on methylmercury-induced death in primary cultured neurons from the cerebella of rat pups. As expected, VKs inhibited the death of the primary cultured neurons. It has been reported that the mechanisms underlying methylmercury toxicity involve a decrement of intracellular glutathione (GSH). Actually, treatment with GSH and a GSH inducer, N-acetyl cysteine, inhibited methylmercury-induced neuronal death in the present study. Thus, we investigated whether VKs also have protective effects against GSH-depletion-induced cell death by employing two GSH reducers, L-buthionine sulfoximine (BSO) and diethyl maleate (DEM), in primary cultured neurons and human neuroblastoma IMR-32 cells. Treatment with VKs affected BSO- and DEM-induced cell death in both cultures. On the other hand, the intracellular GSH assay showed that VK(2), menaquinone-4, did not restore the reduced GSH amount induced by methylmercury or BSO treatments. These results indicate that VKs have the potential to protect neurons against the cytotoxicity of methylmercury and agents that deplete GSH, without increasing intracellular GSH levels. The protective effect of VKs may lead to the development of treatments for neural diseases involving GSH depletion.
Article
Vitamin K is essential for blood coagulation and bone metabolism in mammals. This vitamin functions as a cofactor in the posttranslational synthesis of γ-carboxyglutamic acid (Gla) from glutamic acid residues. However, other functions of vitamin K have been reported recently. We previously found that vitamin K suppresses the inflammatory reaction induced by lipopolysaccharide (LPS) in rats and human macrophage-like THP-1 cells. In this study, we further investigated the mechanism underlying the anti-inflammatory effect of vitamin K by using cultures of LPS-treated human- and mouse-derived cells. All the vitamin K analogues analyzed in our study exhibited varied levels of anti-inflammatory activity. The isoprenyl side chain structures, except geranylgeraniol, of these analogues did not show such activity; warfarin did not interfere with this activity. The results of our study suggest that the 2-methyl-1,4-naphtoquinone ring structure contributes to express the anti-inflammatory activity, which is independent of the Gla formation activity of vitamin K. Furthermore, menaquinone-4, a form of vitamin K₂, reduced the activation of nuclear factor κB (NFκB) and inhibited the phosphorylation of IKKα/β after treatment of cells with LPS. These results clearly show that the anti-inflammatory activity of vitamin K is mediated via the inactivation of the NFκB signaling pathway.
Article
Dysregulation of myelin sulfatides is a risk factor for cognitive decline with age. Vitamin K is present in high concentrations in the brain and has been implicated in the regulation of sulfatide metabolism. Our objective was to investigate the age-related interrelation between dietary vitamin K and sulfatides in myelin fractions isolated from the brain regions of Fischer 344 male rats fed one of two dietary forms of vitamin K: phylloquinone or its hydrogenated form, 2',3'-dihydrophylloquinone (dK), for 28 days. Both dietary forms of vitamin K were converted to menaquinone-4 (MK-4) in the brain. The efficiency of dietary dK conversion to MK-4 compared to dietary phylloquinone was lower in the striatum and cortex, and was similar to that in the hippocampus. There were significant positive correlations between sulfatides and MK-4 in the hippocampus (phylloquinone-supplemented diet, 12 and 24 months; dK-supplemented diet, 12 months) and cortex (phylloquinone-supplemented diet, 12 and 24 months). No significant correlations were observed in the striatum. Furthermore, sulfatides in the hippocampus were significantly positively correlated with MK-4 in serum. This is the first attempt to establish and characterize a novel animal model that exploits the inability of dietary dK to convert to brain MK-4 to study the dietary effects of vitamin K on brain sulfatide in brain regions controlling motor and cognitive functions. Our findings suggest that this animal model may be useful for investigation of the effect of the dietary vitamin K on sulfatide metabolism, myelin structure and behavior functions.
Article
Simple sphingolipids such as ceramide and sphingomyelin (SM) as well as more complex glycosphingolipids play very important roles in cell function under physiological conditions and during disease development and progression. Sphingolipids are particularly abundant in the nervous system. Due to their amphiphilic nature they localize to cellular membranes and many of their roles in health and disease result from membrane reorganization and from lipid interaction with protein