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Vitamin K, an emerging nutrient in brain function
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.
... In microsomal fractions, MK2 and MK3 were shown to have much higher activities than K1 [33], while a partially purified enzymatic system showed similar activities for MK2-6 compared to K1. MKs with seven or more isoprenoid units were not as active [34]. Vitamin K2 has been found to play a role in protection against oxidative stress and inflammation in mammals [35], and improved locomotion defects in mutant fruit flies [36], suggesting that it might benefit human patients suffering mitochondrial pathologies. Mounting evidence suggests that MK-4 is an important component of sphingolipid biosynthesis and can inhibit the proliferation of several cancer cell lines [37]. ...
... This modification allows for the high-affinity binding of calcium ions, which in turn mediates a conformational change necessary for proper folding of the protein. Gla-containing proteins play important roles in the venom of snakes and the toxins of cone snails [38], and they have numerous functions in humans including bone development, calcification, and sphingolipid metabolism [35,39]. The cell-signaling activities of the vitamin K-dependent proteins Gas6 and protein S may also be crucial to cognitive processes [35]. ...
... Gla-containing proteins play important roles in the venom of snakes and the toxins of cone snails [38], and they have numerous functions in humans including bone development, calcification, and sphingolipid metabolism [35,39]. The cell-signaling activities of the vitamin K-dependent proteins Gas6 and protein S may also be crucial to cognitive processes [35]. Among the Gla-containing proteins, however, those involved in blood coagulation have received the most attention. ...
... Doğal formunun stereokimyası 2´-trans, 7´R, 11´R olan trans izomeri olan filokinon, bitkilerin yeşil kısımlarındaki kloroplastların kotiledonlarında yüksek oranda bulunması, fotosentetik organizmaların elektron taşıma sisteminin yapısal bir elemanı olarak görülmesine neden olmuştur. Fakat yapılan farklı çalışmalar filokinonun sadece kotiledonlarında değil aynı zamanda plazma membranlarında ve peroksizomlarda da bulunduğunun tespit edilmesi, bu bileşiğin bitkilerde sadece enerji üretim mekanizmasında değil insan ve hayvanlarda olduğu gibi birçok metabolik süreçte fonksiyonel olarak görev aldığını düşündürmektedir (Kijewski ve ark., 2020;Shearer & Newman, 2008;Ferland, 2012). ...
... K vitaminin nörodejeneratif hastalıklardaki rolü ile ilgili yapılan çalışmalar sonucunda sfingolipid biyosentezinin ilk basamağında yer alan bir enzim olan 3-ketodihidrosfingozin sentazın ve sülfatid sentezinden sorumlu sülfotransferazın K vitamini tarafından aktive edildiği gösterilmiştir (Lev & Milford, 1973). Ayrıca sinir sistemi ve beyindeki koruyucu işlevleri ile ilgili olarak mitogenez, kemotaksis, miyelinleşme, hücre büyümesi, anti-trombotik ve nöroprotektif sinyalde önemli bir rol oynayan Gas6 ve protein S gibi sinir sitemiyle güçlü bağlantısı olan yapıların da K vitaminiyle ilişkili proteinler olduğu saptanmıştır (Ferland, 2012). Sfingolipid metabolizmasındaki değişikliklerin Alzheimer, yaşlanma, Parkinson gibi nörodejeneratif patolojilerle ilişkili olduğu göz önüne alındığında K vitaminin sinir sistemi üzerindeki rolü daha iyi anlaşılacaktır (Ferland, 2013). ...
... Vitamin K is important in regulating inflammation and its potential antioxidant properties may influence inflammatory processes, alleviate inflammation and promote overall metabolic health. Inadequate levels of vitamin K can result in neurological disorders [7][8][9][10][11]. Moreover, recent research has investigated the direct anticonvulsant effects of vitamin K analogs in animal models. ...
... The PHQ-9 was also used to calculate depression score, which ranged from 0 to 27. Depression was rated as "none or minimal" (0-4), "mild" (5-9), "moderate" (10)(11)(12)(13)(14), "moderately severe" (15)(16)(17)(18)(19), or "severe" (20)(21)(22)(23)(24)(25)(26)(27). The importance of drug interactions should be highlight, especially in the case of Vitamin K1 and warfarin. ...
Objective
Information regarding the relationship between epilepsy and vitamin K1 remains unclear. We aimed to assess the association between dietary vitamin K1 intake and epilepsy.
Methods
Data was obtained from the National Health and Nutrition Examination Survey (NHANES) conducted from 2013 to 2018. The study enrolled participants aged ≥ 18 years that provided complete information on their dietary vitamin K1 intake and epilepsy status. Weighted multivariable regression and subgroup analyses were performed to detect the association between dietary vitamin K1 intake and epilepsy.
Results
In total, 10 137 participants (mean age, 48 years) were enrolled. Among them, 84 (0.83%) participants were identified as having epilepsy, whereas 10 053 (99.17%) were included in the non-epilepsy group, with an average dietary vitamin K1 intake of 67.2 ± 6.9 and 105.5 ± 1.5 µg/d, respectively. Each unit (10 µg/d) increase in vitamin K1 intake was associated with a 7% decrease in the odds of epilepsy (odds ratio = 0.93, 95% confidence interval: 0.88–0.98, p = 0.011). Multivariate logistic regression analysis revealed that participants in the higher quartile had lower odds of epilepsy than those in the first quartile of vitamin K1 intake. Subgroup analysis showed a stable and consistent inverse association between dietary vitamin K1 intake and epilepsy.
Conclusion
Higher dietary vitamin K1 intake was associated with lower incidence of epilepsy. Our study did not establish a cause-and-effect relationship. Further large-scale prospective studies and randomized trials are warranted to confirm our findings.
... Our analysis of a large sample of more than 10,000 individuals may help clarify the inconsistent literature on whether vitamin C intake can decrease risk of PD (15)(16)(17)(18)(19). For example, a large Swedish cohort study that followed participants for 17 years linked higher dietary intake of vitamins E and C to lower risk of PD (16), but the Singapore Chinese Health Study found no correlation between dietary intake of carotenoids, as well as vitamins A, C, or E, and the risk of PD (17). ...
... Our analysis of a large sample of more than 10,000 individuals may help clarify the inconsistent literature on whether vitamin C intake can decrease risk of PD (15)(16)(17)(18)(19). For example, a large Swedish cohort study that followed participants for 17 years linked higher dietary intake of vitamins E and C to lower risk of PD (16), but the Singapore Chinese Health Study found no correlation between dietary intake of carotenoids, as well as vitamins A, C, or E, and the risk of PD (17). Our results suggest that deficiency in vitamin C can increase risk of the disease, perhaps because the body cannot buffer oxidative stress (20). ...
Background
While dietary factors have shown an association with Parkinson’s disease (PD), the available data remains a subject of ongoing debate and controversy.
Aim
We sought to evaluate potential relationships between dietary consumption of nutrients and micronutrients and risk of PD in a large sample.
Methods
Cross-sectional data were retrospectively analyzed for 10,651 adults aged 40–80 years that had been collected in the US between 2007 and 2016 as a component of the nationwide National Health and Nutrition Examination Survey. Aspects of dietary intake were compared between those who reported having specific PD medication regimens or not when they completed the survey, and potential associations between diet and risk of PD were explored using binomial logistic regression. We employed Propensity Score Matching (PSM) to minimize the impact of potential confounding factors, thus enhancing the reliability of the results. Additionally, subgroup analysis based on gender and age was conducted to investigate these relationships.
Results
Higher dietary intake of iron was linked to greater PD risk [odds ratio (OR) 1.065, 95% confidence interval (CI) 1.019–1.114, p = 0.006], whereas risk decreased with higher intake of vitamin K (OR 0.999, 95% CI 0.998–1.000, p = 0.024) or vitamin C (OR 0.998, 95% CI 0.996–0.999, p = 0.039). Even after applying PSM, the connection between dietary iron intake and dietary vitamin C intake with PD risk remained substantial. Subgroup analysis results revealed a significant positive association between dietary intake of iron from food and the PD risk, which was evident among individuals under 60 years of age and among males.
Conclusion
The intake of micronutrients can influence risk of PD, which should be verified and explored further in prospective samples with other dietary habits and ethnic backgrounds.
... VKAs can interfere with the vitamin K cycle and reduce the availability of the active form of vitamin K (hydroquinone) in the brain [34]. It regulates the biological activation of two types of VKDP, namely Gas6 (growth arrest speci c gene 6) and protein S [32,33]. Gas6 participates in chemotaxis, mitosis, cell growth, and differentiation. ...
... Protein S provides neuronal protection during ischemia/hypoxia injury [35]. In addition, vitamin K regulates the metabolism of sphingolipids, which are key participants in neuronal proliferation, differentiation, aging, cell-cell interactions, and transformation [32,33]. The changes in sphingolipids metabolism may also be related to neurodegenerative diseases such as AD. ...
Objective
Atrial fibrillation (AF) is one of the most common arrhythmias. At present, the treatment for patients with atrial fibrillation mainly includes oral anticoagulants (OACs). Studies have shown that OACs are associated with cognitive decline in patients with atrial fibrillation, but there is a lack of relevant evidence. This study used Bayesian network meta-analysis to investigate the effects of different oral anticoagulants on cognitive decline in patients with atrial fibrillation.
Method
We systematically searched the clinical studies of oral anticoagulants on patients with atrial fibrillation included in PubMed, Web of Science, Embase, and Cochrane library as of July 3, 2023. Use Cochrane's randomized controlled trial bias risk assessment tool and Newcastle Ottawa Scale (NOS) to assess the bias risk of the included studies. The main outcome measure was a decrease in cognitive function.
Result
A total of 10 studies were included, including two RCTs and seven RCSs, including 882847 patients with atrial fibrillation. Including 8 oral anticoagulants: VKAs, Warfarin, Aspirin, Clopidogrel, Dabigatran, Edoxaban, Rivaroxaban, and Apixaban. The results of the mesh meta-analysis showed that VKAs were superior in reducing the risk of cognitive decline in patients with atrial fibrillation compared to warfarin (OR=-1.19, 95% CI (-2.35, -0.06), P < 0.05) (Table 4). The top three in terms of probability of reducing the incidence of cognitive impairment in patients with atrial fibrillation with different oral anticoagulants are VKAs (87%), Rivaroxaban (62.2%), and Dabigatran (60.8%).
Conclusion
Based on the results of this study, VKAs may be the potential best intervention measures that can reduce the risk of cognitive decline in patients with atrial fibrillation. Due to the limitations of this study, more high-quality randomized controlled trials with large samples and multiple centers are needed in the future to provide more evidence.
... Vitamin K is present predominantly as menaquinone-4 (MK-4) in the brain. It was recently confirmed that MK-4 makes up 98% of the total vitamin K in the brains of 6-month-old and 21-month-old rats (23). MK-4 is unique among the menaquinones since it is not synthesized by bacteria (24). ...
... Guylaine had pointed out that MK-4 protects against oxidative stress (23). Hence, we further speculate that the effect of vitamin K on depressive symptoms might be due to the action of MK-4. ...
Background
The relationship between vitamin intake and depression has attracted increasing attention. However, several studies examining such relationship among populations at different age groups have produced inconsistent findings. This study was aimed to investigate the cross-sectional association between vitamin K intake and depressive symptoms in US adults.
Methods
We used the data from a nationally representative sample of 11,687 adults from the 2013 to 2018 National Health and Nutrition Examination Survey (NHANES). Vitamin K intake was assessed by the 24-h dietary recall at the first day. Depressive symptoms were assessed using the 9-item Patient Health Questionnaire (PHQ-9). Logistic regression and generalized additive model were used to examine the association between vitamin K intake and depressive symptoms.
Results
The weighted prevalence of depressive symptoms was 10.2% (8.0% in men and 12.0% in women). We observed a significant inverse linear relationship between vitamin K intake and depressive symptoms in models adjusted for age, sex, race/ethnicity, marital status, educational status, family poverty income ratio (PIR), home status, body mass index (BMI), smoking status, physical activity, sleep disorders, hypertension, hyperlipidemia, and diabetes. The odds ratios (OR) (95% CI) for the highest compared with the lowest quartile of vitamin K intake was 0.68 (95% CI: 0.52, 0.89, p-trend < 0.05). The association was similar in subgroups stratified by age, sex, race/ethnicity, marital status, educational status, PIR, home status, BMI, smoking status, physical activity, sleep disorders, hypertension, hyperlipidemia, and diabetes.
Conclusion
Vitamin K intake was inversely and independently associated with the odds of depressive symptoms in the US adults. Prospective studies are warranted to confirm our findings.
... cognitive impairment as a result of aging and neurodegenerative disorders like AD. Furthermore, increasing evidence shows the impact of Vitamin K on psychomotor activity and cognition, and the distinct antioxidant and antiinflammatory properties of K vitamer menaquinone-4 (MK-4) are worth mentioning [9,10]. Although there are many studies on the mechanism and possible treatment methods of neurodegenerative diseases, especially PD and AD disease, studies on the link between vitamin K and neurodegenerative diseases belong to the last decade [9][10][11][12][13]. ...
... Furthermore, increasing evidence shows the impact of Vitamin K on psychomotor activity and cognition, and the distinct antioxidant and antiinflammatory properties of K vitamer menaquinone-4 (MK-4) are worth mentioning [9,10]. Although there are many studies on the mechanism and possible treatment methods of neurodegenerative diseases, especially PD and AD disease, studies on the link between vitamin K and neurodegenerative diseases belong to the last decade [9][10][11][12][13]. ...
Neurodegenerative disease refers to a group of disorders that predominantly damage the neurons in the brain. Despite significant progress in the knowledge of neurodegenerative diseases, there is currently no disease-modifying drug available. Vitamin K was first established for its involvement in blood clotting, but there is now compelling evidence indicating its role in the neurological system. In particular, the results of recent studies on the effects of vitamin K2 on preventing apoptosis, oxidative stress, and microglial activation in neuron cells through its role in electron transport are very promising against Alzheimer’s disease. In addition to its protective effect on cognitive functions, its inhibitory effects on inflammation and α-synuclein fibrillization in Parkinson’s disease, which has been revealed in recent years, are remarkable. Although there are many studies on the mechanism and possible treatment methods of neurodegenerative diseases, especially Parkinson’s and Alzheimer’s disease, studies on the relationship between vitamin K and neurodegenerative diseases are very limited, yet have promising findings. Vitamin K has also been proposed for therapeutic use in multiple sclerosis patients to lower the intensity or to slow down the progression of the disease. Accordingly, the aim of this study is to review the current evidence for the use of vitamin K supplementation in neurodegenerative diseases, in particular Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis.
... 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). ...
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.
... 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]. ...
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.
... VK2 is essential for sphingolipid synthesis and is the primary active form of VK in the brain [1]. Its protective effects, particularly against inflammation and oxidative stress, are well-documented [50,51]. Research indicates that VK2 may offer therapeutic benefits for neurological disorders associated with VK2 deficiency, including Alzheimer's disease, stroke, and Parkinson's disease [52,53]. ...
... Similarly, our findings indicate that vitamin K is associated with higher global cognitive function in elderly individuals in the United States in single-and multiple-vitamin models. Although the exact mechanism by which vitamin K affects cognitive function is not yet clear, several potential mechanisms have been proposed to account for the protective effect of vitamin K on cognitive function, including participation in sphingolipid metabolism (38), antiinflammation (39), anti-oxidative stress (40), and the activation of vitamin K-dependent proteins such as growth-arrest specific 6 (Gas6) and protein S (41). ...
Background
Vitamins are essential micronutrients for the prevention and treatment of neurodegenerative diseases. The objectives of the present study were to evaluate the association between dietary vitamin intake and cognitive function in elderly adults and to explore the potential impact of serum neurofilament light chain (NfL) concentration.
Methods
Data from 468 elderly individuals, including information on the dietary consumption of 10 vitamins, were used. Cognitive performance was assessed according to a composite Z-score of the Animal Fluency Test (AFT), Consortium to Establish a Registry for Alzheimer’s Disease (CERAD), and Digit Symbol Substitution Test (DSST). Serum NfL levels were measured using a highly sensitive immunoassay. Bayesian kernel machine regression (BKMR) models were used to estimate the combined effects of vitamin mixtures on cognitive function.
Results
In both single- and multiple-vitamin models, individuals with a higher intake of dietary vitamin K exhibited greater global cognitive function, compared to those with a lower vitamin intake. BKMR revealed positive associations between vitamin mixtures and global cognitive function, AFT Z-scores, and DSST Z-scores. Individuals in the third vitamin K intake tertile exhibited lower serum NfL levels than those in the first tertile (regression coefficient, β = −0.16 [95% confidence interval −0.29 to −0.02]; p = 0.023). Serum NfL levels mediated the association between higher vitamin K intake and global cognitive function (8.73%).
Conclusion
Vitamin mixtures were positively associated with global cognitive function in elderly participants. The association between vitamin K intake and cognitive function may be mediated by serum NfL concentration.
... While vitamin K1 is primarily involved in blood clotting, it also plays a role in bone health. 13 However, its impact on dental health is less pronounced compared to vitamin K2. Ensuring sufficient intake of both forms of vitamin K is important for overall health, including the prevention of dental caries. ...
Dental caries is one of the most prevalent chronic diseases, affecting over half of the global population. The incidence and prevalence of caries have significantly increased in modern times. Various theories have been proposed to explain the etiopathogenesis of dental caries, but many questions remain unanswered despite their popularity. A healthy tooth is well-designed to withstand a harsh oral environment, as it cleanses itself from the inside out. Dental caries indicate that the tooth's fluid flow has been halted or reversed, compromising its defenses. The local process of enamel demineralization by bacterial acid is significantly influenced by nutrition, especially refined carbohydrates like sugar. However, the vulnerability of the tooth begins in the hypothalamus, where changes are initiated in the dentinal fluid flow. Therefore, nutrition plays a crucial role in both the systemic and local aspects of this process. The systemic concept of dental caries recognizes that the process is multifactorial. While reducing sugar intake and oral bacteria counts is important, enhancing the body's defenses with an antioxidant-rich diet, including fruits, vegetables, and vitamin K2, may be even more vital in reducing vulnerability to caries. This systemic approach represents a significant paradigm shift from the traditional 'acid theory' of dental caries, which focused primarily on the local effects of bacterial acid on tooth enamel. Acknowledging the multifactorial nature of dental caries has important implications for future prevention efforts. Instead of solely focusing on reducing sugar consumption and bacterial counts, promoting a diet rich in antioxidants and essential nutrients can strengthen the body's defenses against caries. This holistic approach could lead to more effective strategies for preventing dental caries and improving overall oral health.
... In the present study, there were prospective effects of healthy eating habits, insomnia, and Internet addiction on resilience. Firstly, consistent with the findings of a previous crosssectional study [21], the mechanism of healthy eating as a predictor of enhanced resilience can be explained by the premise that individuals who keep a healthy diet generally intake abundant fruits and vegetables, and that various phytochemicals (e.g., carotenoids and polyphenols) possess biological functions that can promote the development of pressure resilience; specifically, phytochemicals and vitamins may play a key role in enhancing psychosocial stress coping and resilience through their effects of preventing oxidative stress and inflammation in the brain [21,44,45]. Moreover, as another kind of healthy eating habit, regular breakfast consumption can prevent the dysfunction of brain-derived neurotrophic factors and reduce the risk of depression, which can enhance mental resilience [46,47]. ...
This study aimed to explore the longitudinal associations between healthy eating habits, resilience, insomnia, and Internet addiction by using a cross-lagged panel analysis of Chinese college students. Overall, 807 Chinese college students completed questionnaires on healthy eating habits, resilience, insomnia, and Internet addiction from August 2020 (time 1, T1) to November 2020 (time 2, T2), and were selected for the data analyses. Healthy eating habits (T1) had significant effects on resilience (T2; β = 0.064, p < 0.05) and insomnia (T2; β = −0.064, p < 0.05), but not Internet addiction (T2; β = −0.028, p > 0.05). Insomnia (T1) negatively predicted resilience (T2; β = −0.098, p < 0.01). Insomnia was bidirectionally associated with Internet addiction (Internet addiction at T1 to insomnia at T2: β = 0.085, p < 0.01; insomnia at T1 to Internet addiction at T2: β = 0.070, p < 0.05). Additionally, Internet addiction (T1) significantly predicted resilience (T2; β = −0.075, p < 0.05). This study further expanded the understanding of the longitudinal associations between healthy eating habits, resilience, insomnia, and Internet addiction, which provided higher-level evidence and important implications for the interventions for reducing college students’ Internet addiction, developing healthy eating habits, and improving resilience and sleep health.
... However, the L-shaped association observed between log2 VK and depression risk may be attributed to the synergistic effects of VK's mitigation of NF-kB signaling and potential saturation of MAO activity. Finally, Gas-6 is a vitamin K-dependent protein extensively expressed in the nervous system, exerting anti-inflammatory effects, promoting the survival of hippocampal neurons, and regulating microglial survival (29,36). Gas-6 induced neuronal pathways therapy holds promise for clinical significance in treating depression (37). ...
Background
Growing evidence suggests a link between vitamin K (VK) intake and depression, although the underlying mechanisms remain unclear. We aimed to investigate whether oxidative balance scores (OBS) mediate the association between VK intake and depression in participants from the National Health and Nutrition Examination Survey (NHANES) 2007–2018.
Methods
We analyzed data from 30,408 individuals. Dietary VK intake served as the independent variable, depression symptoms as the outcome variable, and OBS as the mediator. Multivariable logistic regression and restricted cubic splines assessed the associations. Mediation analysis was conducted to evaluate the potential mediating role of OBS.
Results
Higher dietary VK intake was associated with lower depression risk in the multivariate model. Compared to the lowest log2 VK quartile, those in the higher quartiles had significantly lower depression odds (Q3: OR 0.66, 95% CI 0.55–0.78; Q4: OR 0.64, 95% CI 0.52–0.78). Additionally, a 1-unit increase in log2 VK intake was associated with a 15% decrease in depression odds (OR 0.85, 95% CI 0.81–0.90). Restricted cubic splines revealed a non-linear relationship between log2 VK and depression (p for non-linearity <0.001). Notably, OBS mediated 26.09% (p < 0.001) of the association between log2 VK and depression.
Conclusion
Higher VK intake is associated with reduced depression risk, potentially mediated by oxidative balance. Further research is warranted to confirm causality and elucidate the underlying mechanisms.
... behavior and prevalent in brain tissue. 7 Moreover, the protective effect of vitamin K in maintaining cognitive integrity is thought to be mediated, in part, via its anti-inflammatory properties, 8 ...
Background
Hypovitaminosis K has been linked to depression and suicide, but epidemiological research is scarce. This study aimed to explore the association among vitamin K with depression and suicidal attempts.
Methods
This was a retrospective cross-sectional study involving 146 cases with a history of suicidal attempts and 149 subjects without a lifetime history of suicidal attempts. The levels of thyroid hormones, lipid profile, inflammatory cytokines, and vitamins were measured.
Results
Subjects who had suicidal attempts presented with a significant decrease in FT4, TC, vitamin D, and vitamin K but increased CRP levels. In these variables, vitamin K has a better diagnostic value for suicidal attempts in depressed patients, with a sensitivity of 0.842 and a specificity of 0.715. Correlation analysis suggested that vitamin K was significantly and positively related to FT4, TC, LDL, and sdLDL. Multivariate analysis showed that serum vitamin K level predicts suicidal attempts in depressive patients (OR = 0.614, P = 0.004, 95% CI 0.153–0.904). Moreover, a negative correlation between vitamin K and suicidal attempts was also noted for partial FT4, CRP, and vitamin D strata analysis.
Conclusion
Our study suggests that low vitamin K levels were correlated with suicidal attempts in patients with depression, indicating that vitamin K deficiency might be a biological risk factor for depression.
... In addition, vitamin K 2 rescued mitochondrial dysfunction by acting as an electron transporter in mitochondria and maintaining efficient adenosine triphosphate (ATP) production [73]. The neuroprotective effects exhibited by vitamin K are further supported by its ability to (i) regulate the mitochondrial membrane potential and (ii) inhibit dopamine neuron damage caused by 6-hydroxydopamine [74] and activate the GAS6 protein, fundamental for cellular growth, survival, and death [75]. Finally, in vitro experiments have shown that vitamin K can reduce α-synuclein (αSyn) fibrillization at a substoichiometric concentration as shown by ThT fluorescence and AFM experiments [76]. ...
Metal ions are fundamental to guarantee the regular physiological activity of the human organism. Similarly, vitamins play a key role in many biological functions of the metabolism, among which are coenzymes, redox mediators, and antioxidants. Due to their importance in the human organism, both metals and vitamins have been extensively studied for their involvement in neurodegenerative diseases (NDs). However, the full potential of the interaction between vitamins and metal ions has not been fully explored by researchers yet, and further investigation on this topic is needed. The aim of this review is to provide an overview of the scientific literature on the implications of vitamins and selected metal ions in two of the most common neurodegenerative diseases, Alzheimer’s and Parkinson’s disease. Furthermore, vitamin–metal ion interactions are discussed in detail focusing on their bioinorganic chemistry, with the perspective of arousing more interest in this fascinating bioinorganic field.
... Menaquinone-7, a form of vitamin K2 found in natto, plays a crucial role in the brain by influencing the synthesis and metabolism of sphingolipids. These sphingolipids are responsible for regulating cognitive function through their involvement in various neuronal processes, including proliferation, differentiation, cellular communication, and aging [83]. Moreover, it is involved in the enzymatic activation of two important proteins that contribute to maintaining cerebral homeostasis. ...
The socioeconomic burden of Alzheimer’s Disease (AD) stems from its characteristic multifactorial etiology and, implicitly, the difficulties associated with its treatment. With the increase in life expectancy and health awareness, nutraceuticals and functional foods are filling in the gaps left by the limitation of classical medical treatment in chronic conditions associated with lifestyle factors, such as neurological disorders. Processes, such as fermentation that enhance food phytochemical content are garnering increased attention due to their functional and health-related properties. This systematic review aims to provide an overview of the evidence of phytochemicals from fermented food sources inducing therapeutic outcomes and cognitive benefits from in vivo experimental models of Alzheimer’s Disease. The present systematic review was conducted in accordance with PRISMA guidelines. Searches were performed in the following databases: MEDLINE, Embase, Cochrane, Scopus, Google Scholar, and Science Citation Index Expanded (Web of Science) by two independent reviewers. Titles and abstracts yielded by the search were screened for eligibility against the inclusion criteria. The search strategy yielded 1899 titles, encompassing studies from 1948 to 2022. After the removal of duplicates, and screening of titles, abstracts, and full texts, thirty three studies obtained from the original search strategy and seven studies from references satisfied the inclusion criteria and were included in the present systematic review. Several studies have emphasized the potential of fermentation to yield small-molecule phytochemicals that are not present in raw products. When these phytochemicals are combined, their collective strength has demonstrated the ability to exceed the antioxidant, anti-inflammatory, and neuroprotective benefits of individual phytochemicals when given in their pure form. Among the various fermented foods that have been studied, soy isoflavones obtained through fermentation have shown the most substantial evidence of altering phytochemical content and improving outcomes in animal models of AD. While promising in initial results, other fermented foods and traditional medicines require more detailed research in order to establish their effectiveness and proper utilization. As is, many of the experimental designs lacked phytochemical analysis of the used fermented product or comparison with the non-fermented counterpart. This, coupled with proper reporting in animal studies, will significantly raise the quality of performed studies as well as the weight of obtained results.
... Vitamin K is a fat-soluble vitamin that regulates the synthesis of sphingolipids, which are important for cellular events such as proliferation, differentiation, senescence, and cell-cell interactions (Ferland, 2012). In nature, vitamin K exists in two forms, K 1 (phylloquinone) and K 2 (menaquinone) (Booth, 2009). ...
Kimchi cabbage is widely consumed in Korea, with the popularity of this pickled vegetable dish growing internationally due to its health benefits. In this study, the physical (size, color), functional (antioxidant activity, total polyphenol, and flavonoid content), and nutritional (water- and fat-soluble vitamins) characteristics of two new kimchi cabbage varieties, namely red and gold kimchi cabbages (RKC and GKC, respectively), were analyzed and compared with those of the common kimchi cabbage (CKC). There were no significant differences in the thickness or length of the three kimchi cabbages, although RKC had the narrowest outer leaves among the three varieties (11.94 cm). Regarding chromaticity, yellowness was highest in GKC (29.86), whereas redness was highest in RKC (9.31). Furthermore, RKC had the highest recorded vitamin B6 and B9 (1,288.5 μg/100 g and 776.7 μg dietary folate equivalent/100 g, respectively). On the other hand, the fat-soluble vitamins vitamin A (β-carotene) and K (Phylloquinone) were both highest in GKC (907.1 μg/100 g and 712.2 μg/100 g, respectively). Generally, all kimchi cabbage samples contained high levels of vitamin E (1.8-4.9 mg α-tocopherol equivalent/100 g). RKC attained the highest antioxidant activity and total polyphenol and total flavonoid contents among the three kimchi cabbages. These results show that gold and red kimchi cabbage can be used as raw materials in the food-processing industry.
... Vitamins are well known for their anti-inflammatory and antioxidant properties. Mounting evidence has shed light on how a deficiency of various vitamins increases the risk of PD onset [7,[17][18][19][20]. Since depletion in antioxidant enzymes and enhanced oxidative stress leads to the onset and progression of PD pathogenesis, vitamin supplementation can be valuable in the therapeutic strategy against PD. ...
Parkinson’s disease (PD) is the second most common progressive neurodegenerative disorder after Alzheimer’s disease. Pathophysiologically, it is characterized by intracytoplasmic aggregates of α-synuclein protein in the Lewy body and loss of dopaminergic neurons from substantia nigra pars compacta and striatum regions of the brain. Although the exact mechanism of neurodegeneration is not fully elucidated, it has been reported that environmental toxins such as MPTP, rotenone, paraquat, and MPP+ induce oxidative stress, which is one of the causative factors for it. To date, there is no complete cure. However, the indispensable role of oxidative stress in mediating PD indicates that antioxidant therapy could be a possible therapeutic strategy against the disease. The deficiency of vitamins has been extensively co-related to PD. Dietary supplementation of vitamins with antioxidant, anti-inflammatory, anti-apoptotic, and free radical scavenging properties could be the potential neuroprotective therapeutic strategy. This review summarizes the studies that evaluated the role of vitamins (A, B, C, D, E, and K) in PD. It will guide future studies in understanding the potential therapeutic role of vitamins in disease pathophysiology and may provide a framework for designing treatment strategies against the disease.
... In the nervous system, vitamin K plays a vital role in regulating the activity of certain enzymes involved in sphingolipid metabolism and synthesis. This substance is known to play a role in various cellular events, such as the formation of new cells and the maintenance of cellular communication (52). Studies show that to gain a more substantial anti-ferroptosis effect, fully reduced forms of vitamin K, which include phylloquinone and menaquinone, confer this benefit (Figure 2). ...
It has been proven that vitamins play an essential role in preventing certain diseases since ancient times. It is thus fruitless to approach the roles of vitamins without making reference to the techniques used in evaluating the effects of these micronutrients. Therefore, the aim of this paper was to summarize the immunological effects of E, K, B5, B6, and B9 vitamins evaluated by flow cytometry. Some of these significant effects were presented and discussed: (a) The role of vitamins E in the prevention and treatment of different types of cancer. (b) The properties of K vitamins in the development and maintenance of pheochromocytoma Cell Line 12 (PC12) cells in Parkinson’s disease; (c) The improvement effect of vitamin B5 on the loss of bone mass in low estrogen conditions; (d) The anticancer role of vitamins B6. (e) The role of Vitamin B9 in the regulation of Treg cells. As such, the flow cytometry technique used to assess these properties is essential to evaluate the immunomodulatory effects of certain vitamins. The technique undergoes constant improvement which makes it possible to determine several parameters with a role in the modulation of the immune function and at the same time increase the accuracy of the methods that highlight them.
... 비타민 K는 지용성 비타민의 한 종류로서 일반적으로 glutamic acid를 carboxylation 하여 α-carboxyglutamic acid로 전환하는 과정에서 필수적인 보조인자로 작용하여 응고단백질을 합성하는 데 관여한다 (Koivu-Tikkanen 등, 2000). 또한 신경세포의 증식, 분화, 노화, 형질 전환 및 세 포 간 상호작용과 관련된 sphingolipid의 합성을 조절한다 (Ferland, 2012). 비타민 K는 자연에 비타민 K1(phylloquinone)과 비타민 K2(menaquinone) 2가지 형태로 존재하며, phylloquinone은 식물에 의해 합성되고 menaquinone은 미 생물에 의해 생성된다 (Booth, 2009). ...
... Prematüre bebekler, olası bir kanama nedeni olarak α-tokoferol takviyesine karşı savunmasız görünmektedir (46). (47). Bir biyokimyacı olan Dam, tavuklarda diyet ve metabolizma üzerine yaptığı çalışmalarla K vitaminini keşfetmiştir (48). ...
... In the brain, vitamin K has been suggested to influence psychomotor behavior and cognition by preventing oxidative stress and inflammation from affecting important cellular events, such as proliferation, differentiation, senescence, and cell-cell interactions [44]. Epidemiological studies on middle-aged North Americans [27] and elderly Japanese [23] reported a negative correlation between depression and vitamin K intake. ...
Epidemiological studies reported that resilience, generally regarded as the ability to manage stress in the face of adversity, correlates with mental health in middle-aged and older adults. Currently, there is limited information on eating habits that affect resilience. Therefore, this cross-sectional study investigated the relationship between vitamin intake and resilience based on sex in community-dwelling middle-aged and older individuals in Shika town, Ishikawa Prefecture, Japan. A total of 221 participants (106 men and 115 women) aged 40 years or older were included in the analysis. We assessed vitamin intake and resilience using a brief-type self-administered diet history questionnaire (BDHQ) and the resilience scale (RS), respectively. A two-way analysis of covariance (ANCOVA) revealed that higher intakes of β-carotene and vitamin K were associated with higher RS in women, but not in men. Furthermore, a multiple logistic regression analysis stratified by sex showed that β-carotene and vitamin K were significant independent variables for RS only in women. The present study suggests that higher intakes of β-carotene and vitamin K were associated with higher resilience among middle-aged and older women. The results obtained demonstrate that β-carotene and vitamin K intakes may enhance resilience by strengthening stress tolerance.
... A growing body of evidence indicates that vitamin K plays a role in maintaining a healthy skeleton, brain and blood vessels [29,30], and that anticoagulants acting as vitamin K antagonists increase the risk of vascular, skeletal, and neurodegenerative diseases [31,32]. Vitamin K deficiency is associated with a higher risk of chronic diseases involving chronic inflammation. ...
Vitamin K is the common name for a group of compounds recognized as essential for blood clotting. The group comprises phylloquinone (K1)—a 2-methyl-3-phytyl-1,4-naphthoquinone; menaquinone (K2, MK)—a group of compounds with an unsaturated side chain in position 3 of a different number of isoprene units and a 1,4-naphthoquinone group and menadione (K3, MD)—a group of synthetic, water-soluble compounds 2-methyl-1,4-naphthoquinone. However, recent epidemiological studies suggest that vitamin K has various benefits that go beyond blood coagulation processes. A dietary intake of K1 is inversely associated with the risk of pancreatic cancer, K2 has the potential to induce a differentiation in leukemia cells or apoptosis of various types of cancer cells, and K3 has a documented anti-cancer effect. A healthy diet rich in fruit and vegetables ensures an optimal supply of K1 and K2, though consumers often prefer supplements. Interestingly, the synthetic form of vitamin K—menadione—appears in the cell during the metabolism of phylloquinone and is a precursor of MK-4, a form of vitamin K2 inaccessible in food. With this in mind, the purpose of this review is to emphasize the importance of vitamin K as a micronutrient, which not only has a beneficial effect on blood clotting and the skeleton, but also reduces the risk of cancer and other pro-inflammatory diseases. A proper diet should be a basic and common preventive procedure, resulting in a healthier society and reduced burden on healthcare systems.
... It is equally well-documented that vitamin K plays a vital role as an antioxidant [9,61]. The antioxidant effects of vitamin K are related to its protective action against oxidative damage by an increase in nuclear factor erythroid 2-related factor 2 (Nrf2) expression with Fig. 1 Canonical vitamin K cycle. ...
Purpose of Review
This narrative review aimed to summarize the current evidence on the connection between dysbiosis and vitamin K deficiency in patients with chronic kidney disease (CKD). The presence of dysbiosis (perturbations in the composition of the microbiota) has been described in several non-communicable diseases, including chronic kidney disease, and it has been hypothesized that dysbiosis may cause vitamin K deficiency. Patients with CKD present both vitamin K deficiency and gut dysbiosis; however, the relationship between gut dysbiosis and vitamin K deficiency remains to be addressed.
Recent Findings
Recently, few studies in animals have demonstrated that a dysbiotic environment is associated with low production of vitamin K by the gut microbiota.
Summary
Vitamin K plays a vital role in blood coagulation as well as in the cardiovascular and bone systems. It serves as a cofactor for γ-glutamyl carboxylases and thus is essential for the post-translational modification and activation of vitamin K-dependent calcification regulators, such as osteocalcin, matrix Gla protein, Gla-rich protein, and proteins C and S. Additionally, vitamin K executes essential antioxidant and anti-inflammatory functions. Dietary intake is the main source of vitamin K; however, it also can be produced by gut microbiota. This review discusses the effects of uremia on the imbalance in gut microbiota, vitamin K-producing bacteria, and vitamin K deficiency in CKD patients, leading to a better understanding and raising hypothesis for future clinical studies.
... 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]. ...
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.
... 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]. ...
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.
BACKGROUND
Malnutrition and epilepsy share a complex bidirectional relationship, with malnutrition serving as a potential risk factor for epilepsy development, while epilepsy, in turn, often exerts profound effects on nutritional status. Nutritional interventions have emerged as a critical adjunctive approach in epilepsy management.
AIM
To explore the multifaceted associations between malnutrition and epilepsy, structured into three primary sections: (1) Elucidating the impact of malnutrition as a risk factor for epilepsy onset; (2) Examining the reciprocal influence of epilepsy on nutritional status, and (3) Evaluating diverse nutritional interventions in the management of epilepsy.
METHODS
A systematic search was conducted across PubMed, Scopus, and Web of Science databases utilizing defined keywords related to malnutrition, epilepsy, and nutritional interventions. Inclusion criteria encompassed various study types, including clinical trials, animal models, cohort studies, case reports, meta-analyses, systematic reviews, guidelines, editorials, and review articles. Four hundred sixteen pertinent references were identified, with 198 review articles, 153 research studies, 21 case reports, 24 meta-analyses, 14 systematic reviews, 4 guidelines, and 2 editorials meeting the predefined criteria.
RESULTS
The review revealed the intricate interplay between malnutrition and epilepsy, highlighting malnutrition as a potential risk factor in epilepsy development and elucidating how epilepsy often leads to nutritional deficiencies. Findings underscored the importance of nutritional interventions in managing epilepsy, showing their impact on seizure frequency, neuronal function, and overall brain health.
CONCLUSION
This systematic review emphasizes the bidirectional relationship between malnutrition and epilepsy while emphasizing the critical role of nutritional management in epilepsy treatment. The multifaceted insights underscore the need for a holistic approach to addressing nutritional aspects alongside conventional epilepsy management strategies
Adequate vitamin K is crucial for optimal health. Although vitamin K detection methods have been established using liquid chromatography–tandem mass spectrometry (LC–MS/MS), some limitations remain. Therefore, we aimed to establish a stable and rapid LC–MS/MS method that can quantify phylloquinone (VK1), menaquinones‐4 (MK‐4), and menaquinones‐7 (MK‐7) in serum and cerebrospinal fluid and explore its clinical applications. We developed an LC–MS/MS method with atmospheric pressure chemical ionization to quantify and validate its performance according to Clinical Laboratory and Standard Institution standards (C62‐Ed2). Serums from 50 healthy individuals and cerebrospinal fluid from 15 patients were collected for clinical application. Sample preparation involved lipase incubation, protein precipitation with ethanol, and liquid–liquid extraction with hexane/ethyl; optimization was performed for sample preparation and LC separation. Linearity was 50–10 000 pg/mL for VK1, MK‐4, and MK‐7. The total coefficient of variation (%) for VK1, MK‐4, and MK‐7 ranged from 8.5% to 10.4%, 8.0% to 10.4%, and 7.0% to 11.1%, respectively. Recovery of VK1, MK‐4, and MK‐7 was 82.3%–110.6%, 92.3%–110.6%, and 89.5%–117.8%, respectively. VK1 and MK‐7 were detected in the serum of all 50 healthy subjects, whereas MK‐4 was detected in only 13 (26%) subjects. Approximately 53.3% (8/15) had no detectable vitamin K in their cerebrospinal fluid. The developed method exhibited satisfactory performance and was applicable for detecting VK1, MK‐4, and MK‐7 in serum and cerebrospinal fluid.
Alzheimer's disease (AD) is the most prevalent progressive neurodegenerative disease often characterized by memory loss, cognitive decline, and behavioral changes. The actual pathophysiology of AD remains unclear, but several factors including genetic, environmental, and lifestyle contribute significantly to the pathogenesis of AD. Even after over two decades of combined efforts to create novel interventions that can retard the progress of the disease, researchers still only have a small number of alternate medicines with poor efficacy. There is a recent growth of interest in the role of nutrients in brain health as we learn more about what nutrients are and how they impact hormonal and neurological processes that can result in a variety of neurological and psychiatric conditions. Additionally, deficiency of vitamins also gained attention for their pivotal roles in cognitive health. Vitamins, a crucial dietary supplement, regulate various physiological functions and maintain neuronal health, energy metabolism, and antioxidant defence. Vitamin B, such as B1, B6, and B12, are chief constituents for the metabolism of homocysteine and the release of neurotransmitters, a decrease in vitamin E and D may result in increased oxidative damage, which further contributes to neuronal loss. Vitamin deficiencies may make AD degenerative processes more severe as increased amyloid-beta (Aβ) plaque development and tau protein phosphorylation, are two characteristics of AD. This review explores a comprehensive summary of the most widely used vitamins and discusses the findings of recent research on the relationship between these vital micronutrients and AD.
Menatetrenone (MK-4), a potent form of vitamin K2, has gained significant attention for its diverse therapeutic potential, particularly in bone health, cardiovascular protection, and metabolic disorders. This manuscript explores the origins and chemical structure of menatetrenone, highlighting its synthesis from dietary sources and its enzymatic conversion in the body. The review examines the extensive therapeutic applications of MK-4, focusing on its role in treating osteoporosis, diabetes, and cardiovascular diseases, along with emerging evidence of its anticancer and neuroprotective effects. Furthermore, the manuscript discusses innovative delivery systems, such as nanostructured lipid carriers and other advanced formulations, designed to enhance the bioavailability and therapeutic efficacy of menatetrenone. By addressing the challenges associated with its pharmacokinetics and exploring novel drug delivery strategies, this review provides a comprehensive overview of menatetrenone's therapeutic promise and outlines future directions for its clinical use.
Vitamin K (VK) is an essential micronutrient impacting many systems in the body. This lipid-soluble vitamin is found in various plant and animal products and is absorbed via the lymphatic system. This biomolecule’s importance to human health includes but is not limited to its promotion of brain, cardiovascular, bone, and immune functions. These biological properties are also necessary for maintaining domesticated animal health. The synergistic impact of both VK and vitamin D (VD) maximizes these health benefits, specifically for the circulatory and skeletal systems. This manuscript reviews VK’s properties, molecular structures, nutrikinetics, mechanisms of action, daily requirements, safety in supplemental form, biomarkers used for its detection, and impacts on various organs. The purpose of synthesizing this information is to evaluate the potential uses of VK for the treatment or prevention of diseases.
Recent research has been exploring the link between vitamin deficiencies and the pathogenesis of neurodegenerative ailments such as cognition impairment, dementia, and Alzheimer’s disease (AD). Lipophilic vitamins A, D, E and K, offer a range of health benefits, including antioxidant, anti-inflammatory, and neuroprotective characteristics, which are crucial for sustaining nerve myelination and neurotransmission in different brain functions. The neuroprotective role of lipophilic vitamins has been demonstrated by a number of preclinical and clinical studies, with a special focus on early-detection of AD. Such experimental and clinical investigations offer an important cost-effective strategy for the management of neurodegenerative disorders with different dietary supplements and nutraceuticals containing lipophilic vitamins. While the aetiology of AD is still elusive, experimental studies and histopathology of human brain has suggested a reduction in brain volume, oligomerisation and subsequent stabilisation of Aβ fibrils, coupled with phagocyte elimination, as the primary mechanism involved in the reduction of oxidative stress. This,in turn, slows the progression of cognitive decline. However, the underlying mechanisms of action of lipophilic vitamins are complex, and further studies are needed to bridge the gap in our knowledge. This book chapter offers an overview of the pathogenesis of AD and proposed usage of lipophilic vitamins, as well as the distribution these agents in nature. The physiological functions of each vitamin have been discussed in detail, supplemented with information to their biologically active metabolites and purported mechanisms of action. Finally, keeping in mind the novel delivery systems and advancements in the delivery of drugs into the brain, a section on nanotechnological interventions, as well as key challenges and future perspectives have also been addressed.
Background
Atrial fibrillation (AF) is 1 of the most common types of arrhythmias. At present, the treatment for patients with AF mainly includes oral anticoagulants (OACs). Studies have shown that OACs are associated with cognitive decline in patients with atrial fibrillation; however, there is a lack of relevant evidence. This study used Bayesian network meta-analysis (NMA) to investigate the effects of different oral anticoagulants on cognitive decline in patients with AF.
Methods
We systematically searched for clinical studies on oral anticoagulants in patients with AF in PubMed, Web of Science, Embase, and the Cochrane Library as of July 3, 2023. Cochrane’s randomized controlled trial bias risk assessment tool and the Newcastle–Ottawa Scale were used to assess the bias risk of the included studies. The main outcome measure was decreased cognitive functioning.
Results
Ten studies were included, including 2 RCTs and 7 RCSs, including 882,847 patients with AF. Five oral anticoagulants and 2 anticoagulants were included: VKAs (especially warfarin), Dabigatran, Edoxaban, Rivaroxaban, Apixaban, and Aspirin, Clopidogrel. The results of the mesh meta-analysis showed that VKAs were superior to warfarin in reducing the risk of cognitive decline in patients with AF (OR = −1.19, 95% CI (−2.35, −0.06), P < .05) (Table 5). The top 3 drugs in terms of the probability of reducing the incidence of cognitive impairment in patients with AF with different oral anticoagulants were VKAs (87%), rivaroxaban (62.2%), and dabigatran (60.8%).
Conclusion
Based on the results of this study, VKAs may be the best intervention measure for reducing the risk of cognitive decline in patients with AF. Owing to the limitations of this study, more high-quality randomized controlled trials with large sample sizes and multiple centers are required to provide more evidence.
Besides its role in coagulation, vitamin K seems to be involved in various other mechanisms, including inflammation and age-related diseases, also at the level of gene expression. This work examined the roles of two vitamin K2 (menaquinones) vitamers, namely, menaquinone-4 (MK4) and reduced menaquinone-7 (MK7R), as gene modulator compounds, as well as their potential role in the epigenetic regulation of genes involved in amyloidogenesis and neuroinflammation. The SK-N-BE human neuroblastoma cells provided a “first-line” model for screening the neuroinflammatory and neurodegenerative molecular pathways. MK7R, being a new vitamin K form, was first tested in terms of solubilization, uptake and cell viability, together with MK4 as an endogenous control. We assessed the expression of key factors in amyloidogenesis and neuroinflammation, observing that the MK7R treatment was associated with the downregulation of neurodegeneration- (PSEN1 and BACE1) and neuroinflammation- (IL-1β and IL-6) associated genes, whereas genes retaining protective roles toward amiloidogenesis were upregulated (ADAM10 and ADAM17). By profiling the DNA methylation patterns of genes known to be epigenetically regulated, we observed a correlation between hypermethylation and the downregulation of PSEN1, IL-1β and IL-6. These results suggest a possible role of MK7R in the treatment of cognitive impairment, giving a possible base for further preclinical experiments in animal models of neurodegenerative disease.
Alzheimer’s disease (AD) is a severe neurodegenerative ailment of the brain, affecting millions of elderly people globally. It has also created a great health concern in the future. Several acquired disease conditions and some other factors enhance the chance of developing AD. No treatment can completely cure AD. Scientific literature has established that vitamins have a number of targets in the aetiology of AD through which they act to prevent the neuronal dysfunction in the disease. Thus, by understanding the role of vitamins, we are able to state that vitamins can be a good choice to overcome the detrimental effects of AD. Antioxidant vitamins play a major role because they act by reducing the degree of oxidative stress in the brain. The categories of vitamins having promising effects in declining the course of AD and its symptoms are reviewed. Low vitamin intake can increase the chances of acquiring AD. Fortunately, these significant vitamins that protect the brain can be acquired through various fruits and vegetables that are discussed here.
Alzheimer's disease (AD) is a progressive, age-related neurodegenerative disorder that affects a large proportion of the elderly population. It currently lacks effective treatments, placing a heavy burden on patients, families, healthcare systems, and society. This is mainly due to our limited comprehension of the pathophysiology of AD progression, as well as the lack of effective drug targets and intervention timing to address the underlying pathology. AD is a multifactorial condition, and emerging evidence suggests that abnormalities in the gut microbiota play a significant role as environmental and multifaceted contributors to AD, although the exact mechanisms are yet to be fully explored. Changes in the composition of microbiota influence host neuronal health through their metabolites. These metabolites regulate intestinal epithelia, blood-brain barrier (BBB) permeability and neuroinflammation by impacting mitochondrial function. The decline in the proportion of beneficial microbes and their essential metabolites during aging and AD is directly linked to poor mitochondrial function, although the specific mechanisms remain unclear. In this review, we discuss recent developments in understanding the impact of the microbiome and its metabolites on various cell types, their influence on the integrity of the gut and BBB barriers, systemic and brain inflammation, and cell-specific effects in AD pathology. This information is expected to pave the way for a new understanding of the interactions between microbiota and mitochondria in AD, providing a foundation for the development of novel treatments for AD.
The TAM receptors may help delay the progression of Alzheimer's disease (AD). AD is the most common neurodegenerative disease associated with human aging. The TAM receptors, derived from the first letter of its three constituents -Tyro3, Axl, and Mertk, are associated with immune responses, cellular differentiation and migration, and clearance of apoptotic cells and debris, with the two canonical ligands, Growth Arrest Specific 6 (Gas6) and ProS1. Several kinds of research have indicated the participation of the TAM system in AD pathology. Also, the TAMs regulate multiple features of microglia, the significant sensors of disorder in the central nervous system (CNS). In this review, we describe the biology of the TAM receptors and ligands in the CNS. Then, we discuss the relationship between the TAM system and AD, specially focusing on its functional expression in the microglia. Finally, we also summarize some agents that could interfere with the TAM signaling pathways and discuss potential difficulties and strategies for drug development.
Everybody eats, and what we eat – or do not – affects the brain and mind. There is significant general, applied, academic, and industry interest about nutrition and the brain, yet there is much misinformation and no single reliable guide. Diet Impacts on Brain and Mind provides a comprehensive account of this emerging multi-disciplinary science, exploring the acute and chronic impacts of human diet on the brain and mind. It has a primarily human focus and is broad in scope, covering wide-ranging topics like brain development, whole diets, specific nutrients, research methodology, and food as a drug. It is written in an accessible format and is of interest to undergraduate and graduate students studying nutritional neuroscience and related disciplines, healthcare professionals with an applied interest, industry researchers seeking topic overviews, and interested general readers.
Çocuk psikoloji ve sosyolojisi
O livro enfatiza fatores que regem a vida humana do início ao fim e que podem ser muito diferentes entre indivíduos e populações: 1) caracteres genéticos herdados diretamente de nossos pais e indiretamente de nossos ancestrais, os quais permanecem relativamente estáveis ao longo da vida; 2) fatores ambientais (alimentação, condição e estilo de vida) até certo ponto controláveis, sendo a alimentação o mais importante. A primeira parte do livro trata da definição e da conceituação do processo de envelhecimento e seus efeitos na saúde. Seguem-se a apresentação e a discussão de mecanismos que promovem degradação molecular e celular responsáveis por distúrbios metabólicos que podem resultar em doenças crônico-degenerativas. A maior parte do texto é dedicada à apresentação de alimentos e compostos bioativos que agem combatendo o envelhecimento precoce e retardando doenças da idade. Por fim, faz-se uma discussão sobre conceitos de dietas saudáveis com sugestões para pesquisas, visando melhorar o perfil alimentar do brasileiro.
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.
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.
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.
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.
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.
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.
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.
Oxidative mechanisms of injury are important in many neurological disorders. Developing oligodendrocytes (pre-OLs) are particularly sensitive to oxidative stress-mediated injury. We previously demonstrated a novel function of phylloquinone (vitamin K(1)) and menaquinone 4 (MK-4; a major form of vitamin K2) in protecting pre-OLs and immature neurons against glutathione depletion-induced oxidative damage (Li et al. [ 2003] J. Neurosci. 23:5816-5826). Here we report that vitamin K at nanomolar concentrations prevents arachidonic acid-induced oxidative injury to pre-OLs through blocking the activation of 12-lipoxygenase (12-LOX). Arachidonic acid metabolism is a potential source for reactive oxygen species (ROS) generation during ischemia and reperfusion. Exposure of pre-OLs to arachidonic acid resulted in oxidative cell death in a concentration-dependent manner. Administration of vitamin K (K(1) and MK-4) completely prevented the toxicity. Consistent with our previous findings, inhibitors of 12-LOX abolished ROS production and cell death, indicating that activation of 12-LOX is a key event in arachidonic acid-induced pre-OL death. Vitamin K(1) and MK-4 significantly blocked 12-LOX activation and prevented ROS accumulation in pre-OLs challenged with arachidonic acid. However, vitamin K itself did not directly inhibit 12-LOX enzymatic activity when assayed with purified 12-LOX in vitro. These results suggest that vitamin K, or likely its metabolites, acts upstream of activation of 12-LOX in pre-OLs. In summary, our data indicate that vitamin K prevents oxidative cell death by blocking activation of 12-LOX and ROS generation.
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.
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.
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.
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.
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.
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.
We report the identification of ligands for Tyro 3 (alternatively called Sky, rse, brt, or tif) and Axl (alternatively, Ark or UFO), members of a previously orphan family of receptor-like tyrosine kinases. These ligands correspond to protein S, a protease regulator that is a potent anticoagulant, and Gas6, a protein related to protein S but lacking any known function. Our results are reminiscent of recent findings that the procoagulant thrombin, a protease that drives clot formation by cleaving fibrinogen to form fibrin, also binds and activates intracellular signaling via a G protein-coupled cell surface receptor. Proteases and protease regulators that also activate specific cell surface receptors may serve to integrate coagulation with associated cellular responses required for tissue repair and growth, as well as to coordinate protease cascades and associated cellular responses in other systems, such as those involved in growth and remodeling of the nervous system.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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 proteins within cellular membranes. In this review we discuss some of the functions of sphingolipids in processes that entail cellular membranes and their role in neurodegenerative diseases, with an emphasis on SM, ceramide and gangliosides.
Evidence suggests that a group of phytochemicals known as flavonoids are highly effective in reversing age-related declines in neuro-cognitive performance through their ability to interact with the cellular and molecular architecture of the brain responsible for memory and by reducing neuronal loss due to neurodegenerative processes. In particular, they may increase the number of, and strength of, connections between neurons, via their specific interactions with the ERK and Akt signalling pathways, leading to an increase in neurotrophins such as BDNF. Concurrently, their effects on the peripheral and cerebral vascular system may also lead to enhancements in cognitive performance through increased brain blood flow and an ability to initiate neurogenesis in the hippocampus. Finally, they have also been shown to reduce neuronal damage and losses induced by various neurotoxic species and neuroinflammation. Together, these processes act to maintain the number and quality of synaptic connections in the brain, a factor known to be essential for efficient LTP, synaptic plasticity and ultimately the efficient working of memory.
Neurodegenerative disorders are marked by extensive neuronal apoptosis and gliosis. Although several apoptosis-inducing agents have been described, understanding of the regulatory mechanisms underlying modes of cell death is incomplete. A major breakthrough in delineation of the mechanism of cell death came from elucidation of the sphingomyelin (SM)-ceramide pathway that has received worldwide attention in recent years. The SM pathway induces apoptosis, differentiation, proliferation, and growth arrest depending upon cell and receptor types, and on downstream targets. Sphingomyelin, a plasma membrane constituent, is abundant in mammalian nervous system, and ceramide, its primary catabolic product released by activation of either neutral or acidic sphingomyelinase, serves as a potential lipid second messenger or mediator molecule modulating diverse cellular signaling pathways. Neutral sphingomyelinase (NSMase) is a key enzyme in the regulated activation of the SM cycle and is particularly sensitive to oxidative stress. In a context of increasing clarification of the mechanisms of neurodegeneration, we thought that it would be useful to review details of recent findings that we and others have made concerning different pro-apoptotic neurotoxins including proinflammatory cytokines, hypoxia-induced SM hydrolysis and ceramide production that induce cell death in human primary neurons and primary oligodendrocytes: redox sensitive events. What has and is emerging is a vista of therapeutically important ceramide regulation affecting a variety of different neurodegenerative and neuroinflammatory disorders.
An increasing body of evidence points to a role for vitamin K in brain physiology through its participation in sphingolipid metabolism and biological activation of the vitamin K-dependent protein Gas6. One hypothesis is that vitamin K may also play a role in the pathogenesis of Alzheimer's disease. A recent study found that patients with early-stage Alzheimer's disease consumed less vitamin K than did cognitively intact control subjects. To learn more about the dietary intakes and food sources of vitamin K in these patients, a detailed analysis was conducted. Dietary vitamin K intakes were assessed from 5 nonconsecutive days of food records collected from 31 community-dwelling patients with early-stage Alzheimer's disease and in 31 age- and sex-matched cognitively intact control subjects. Mean vitamin K intake on a person-day basis was 63+/-90 microg/day in patients and 139+/-233 microg/day in control subjects. Vitamin K intakes were significantly less in participants with Alzheimer's disease (P<0.0001), even after adjusting for energy intakes (P=0.0003). Vegetables, fats, and fruits contributed more than 70% of total vitamin K intake in both groups. The main source of vitamin K was green vegetables, which contributed 33% and 49% to total intakes in patients and control subjects, respectively. This lower consumption of green vegetables in participants with Alzheimer's disease explained their lower vitamin K intakes overall. Despite their limitations, results are in line with the most recent research in both vitamin K and Alzheimer's disease and suggest a need to consider vitamin K in future investigations on the role of diet in Alzheimer's disease.
We have shown previously that the administration of warfarin to 16-day-old mice results in a significant reduction in levels of sulfatides, and to a lesser degree a reduction of other sphingolipids in brain. Vitamin K stimulates biosynthesis of sulfatides in warfarin-treated mice. We now report that warfarin inhibits brain sulfotransferase activity. This inhibition is reversed by vitamin K. The treatment of normal mice with vitamin K stimulates the activities of sulfotransferase and arylsulfatase and the turnover rate of brain sulfatides. The ability of vitamin K to influence the activity of biosynthetic and catabolic enzymes and the turnover of sulfatides suggests a possible regulatory role for vitamin K in the maturing brain.
Anecdotal observations of the behavior of rats with a vitamin K-deficiency suggested that this deficiency was associated with hypoactivity, general malaise, and a lack of exploratory behavior. These observations were pursued by assessing locomotor activity in a circular photocell-monitored track, open-field activity, and radial-arm maze performance in rats rendered vitamin K-deficient by dietary depletion or by warfarin treatment. There was a significant reduction (approximately 25% at the median) in the locomotor activity of dietary vitamin K-deficient rats compared with rats fed a control diet. In the open-field, warfarin administration was associated with a significant shift from more exploratory behaviors to less exploratory behaviors. Consistent with these findings, radial-arm maze assessment showed a comparative reduction in locomotor activity in the dietary vitamin K-deficient rats with no alteration in performance, i.e., short-term memory. These animal behavioral studies suggest that sub-clinical and clinical vitamin K-deficiency may contribute to physical and psychiatric symptomatology.
An enzyme present in cell-free extracts of B. melaninogenicus grown with vitamin K is described which catalyzes the synthesis of 3-ketodihydrosphingosine from palmitoyl CoA and l-serine. Activity of the 3-ketodihydrosphingosine synthetase was measured as a function of time, palmitoyl CoA concentration, and serine concentration. The Bacteroides synthetase differs from corresponding enzymes from brain microsomes and from yeast in that it is present in the 100,000g supernatant of sonicated cells and is not associated with any particulate fraction.Extracts prepared from cells depleted of vitamin K showed only slight 3-ketodihydrosphingosine synthetase activity. Neither vitamin K1, menadione, nor pyridoxal phosphate were effective in enhancing the activity in cell-free extracts of vitamin K-depleted B. melaninogenicus. However, induction of the enzyme activity in intact cells was demonstrated by the addition of vitamin K to a vitamin K-depleted culture. Synthetase activity was found to be increased 15 min following the addition of the vitamin, reached a maximum at 75 min, and thereafter remained constant. Both puromycin and rifampcin inhibit induction of the enzyme by vitamin K1 suggesting that vitamin K induces de novo synthesis of the synthetase.
The addition of vitamin K to a culture of grown in a vitamin K free medium stimulated synthesis of the phosphosphingolipids but not other phospholipids such as phosphatidylethanolamine and phosphatidylserine. This stimulation of synthesis of the phosphosphingolipids occurs soon after the addition of the vitamin to the culture and before an increase in general cell metabolism as indicated by an increase in growth rate of the vitamin K supplemented culture.
Review of published cases of pregnancies in which coumarin derivatives or heparin were administered demonstrates that use of either class of anticoagulant carries substantial risks. Of 418 reported pregnancies in which coumarin derivatives were used, one-sixth resulted in abnormal liveborn infants, one-sixth in abortion or stillbirth and, at most, two-thirds in apparently normal infants. In addition to the expected hemorrhagic complications, fetal effects of coumarin derivative administration include a specific embryopathy and central nervous system abnormalities. All available cases (including unpublished ones) of warfarin embryopathy and central nervous system abnormalities following gestational exposure to coumarin derivatives are reviewed, various complications are tabulated, critical periods of teratogenesis are discussed and possible mechanisms proposed. The use of heparin during gestation does not result in a significantly better outcome of pregnancy. In 135 published cases, the infants in one-eighth were stillborn, in one-fifth premature (a third of whom died) and, again at most, in two-thirds apparently normal. Because of the substantial risks of both clases of anticoagulants, and the inherent risks of pregnancy complicated by the indications for anticoagulation, prevention of pregnancy is usually indicated. If pregnancy occurs, a relatively normal outcome can be anticipated in about two-thirds of the pregnancies regardless of the anticoagulant used. Heparin does not appear to be a clearly superior alternative to coumarin derivatives.
Naphthoquinone vitamins (vitamins K) are widely recognized for their role in the gamma-carboxylation of specific glutamyl residues in coagulation, anti-coagulation and extra-hepatic proteins. Recently, however, there have been reports that these compounds can exert actions other than those normally associated with protein gamma-carboxylation. These observations suggest that naphthoquinones may have effects on the production of inflammatory mediators including cytokines. Fibroblasts are now recognized as a rich source of cytokines and we have examined the effect of various naphthoquinones on the production of interleukin 6 (IL-6) by lipopolysaccharide-stimulated human gingival fibroblasts. Compounds examined in this study include: phylloquinone (K1), menaquinone-4 (K2), menadione (K3), 2,3-dimethoxy-1,4-naphthoquinone (DMK) and a synthetic product of vitamin K catabolism, 2-methyl, 3-(2'methyl)-hexanoic acid-1,4-naphthoquinone (KCAT). All of these compounds are capable of inhibiting IL-6 production with a rank order of potency: KCAT > K3 > DMK > K2 > K1. The most potent compound, KCAT, inhibited IL-6 production with an IC50 of 3 x 10(-7)M. The mechanism of action of these naphthoquinones on fibroblast IL-6 production is unknown. Given that K3 and KCAT are inactive in the gamma-carboxylation reaction, we suggest that this activity is not essential for the inhibition of IL-6 production and that activity may be related to the redox capacity of these naphthoquinones.
The present study was undertaken to determine whether there is selective tissue distribution of vitamin K in the rat and whether this distribution mirrors the distribution of tissue vitamin K metabolism. The effects of feeding a vitamin K-free diet followed by resupplementation with phylloquinone (K1) were studied. K1 was recovered in all tissues. In K1-supplemented rats, most tissues accumulated K1 relative to plasma K1 with the highest levels in liver, heart, bone, and cartilaginous tissue (sternum). Low K1 levels were found in the brain. In the K1-free rats, relatively high K1 levels were still found in heart, pancreas, bone and sternum. Surprisingly, menaquinone-4 (MK-4) was detected in all tissues, with low levels in plasma and liver, and much higher levels in pancreas, salivary gland and sternum. MK-4 levels exceeded K1 levels in brain, pancreas, salivary gland and sternum. Supplementation with K1, orally and by intravenous infusion, caused MK-4 levels to rise. Some accumulation of K1 and MK-4 in the mitochondrial fraction was found for kidney, pancreas and salivary gland. In the liver the higher menaquinones (MK-6-9) accumulated in the mitochondria. The results indicate that: (1) there is selective tissue distribution of K1 and MK-4, (2) dietary K1 is a source of MK-4. The results also suggest there may be an as yet unrecognized physiological function for vitamin K (MK-4).
Prostaglandin (PG) E2, a potent bone-resorbing agent, is synthesized in osteoblast-like cells. Since vitamin K reportedly plays an important role in bone metabolism, we investigated the effects of vitamin K2 (menatetrenone) on PGE2 production by human osteoblast-like periosteal cells. In cells incubated with menatetrenone (1 microgram/mL = 2.25 x 10(-6) M) for 2 days, PGE2 production was reduced to 50% of that in untreated control cells. This inhibition was dose and time dependent for up to 10 micrograms/mL and 20 days, respectively, and involved two major steps. In one of these menatetrenone at doses of 0.5-10 micrograms/mL dose dependently inhibited the calcium ionophore A23187-induced release of arachidonic acid (AA) from membrane phospholipids, and in the other the conversion of AA to PG was inhibited, as evidenced by the PG-synthesizing activity in the homogenates of menatetrenone-treated cells with AA being lower than that in untreated cells. The inhibitory effect was almost identical to that for PG production. The PG synthesizing activity in cell homogenates was inhibited only by a high concentration of menatetrenone (10 micrograms/mL) when this was added directly. Menatetrenone (1 microgram/mL) also inhibited 52% of the purified PGH synthase activity from a ram seminal vesicle. This study shows that menatetrenone inhibited PGE2 release from cells by inhibiting both PG production steps, AA release from the membrane and PG synthesizing activity with AA. Inhibition of PGE2 production by menatetrenone might be important in improving bone metabolism.
Neurons from the central nervous system (CNS) of rat embryos die within several days when seeded at a low density of 10(4) cells/cm2 and cultured in a serum-free defined medium. Using these culture systems, we searched for agents to promote the survival of these neurons. As a consequence, a fat-soluble vitamin, vitamin K1, was found to possess such kind of activity: more than 50% of the cortical neurons from 19-day-old rat embryos could survive for 4 days in the presence of vitamin K1, whereas almost all neurons died in its absence. The survival-promoting effect of vitamin K1 was found on neurons from not only cortex, but also hippocampus, striatum, and septum. In addition to vitamin K1, vitamin K2 and K3 also showed the same effect on cortical neurons. The effect of vitamins K1 and K2 was observed at concentrations from 10(-8) to 10(-6) M, and that of vitamin K3 was slightly detected at 10(-6) M. Furthermore, we examined the effect on the neurons from 16- and 21-day-old embryos, too. The activity of vitamin K1 was weaker toward the neurons from 21-day-old embryos compared with that toward 19-day-old ones, and was not recognized toward 16-day-old ones. These results suggest the potential role of the K vitamins on the maintenance of the survival of CNS neurons during the later stages of embryogenesis in vivo.
Molecules with vitamin K activity are important for optimal bone health. The major compound of this group in bone is vitamin K1 (phylloquinone), which is derived exclusively from plant foods in the diet. Vitamin K1 is absorbed along with dietary fat from the small intestine and transported by chylomicrons in blood. In serum obtained after an overnight fast from healthy men more than half of the vitamin K1 was recovered from the density fraction that contains chylomicrons and chylomicron remnants (CR), and only a quarter was associated with the major lipoprotein in serum, low density lipoprotein. The concentration of vitamin K1 in serum is closely related to the triglyceride concentration. Another determinant of vitamin K1 concentration in serum is the presence of specific variants of apolipoprotein E (apoE). ApoE is a small protein through which the vitamin K-rich CR bind to lipoprotein receptors. The three most common variants of apoE promote CR clearance from circulation with very different efficiency, in the order E2>E3>E4. The variant that promotes CR clearance best is associated with low vitamin K1 concentration in serum and increased response to vitamin K antagonists. Vitamin K1 concentration in serum is linked to vitamin K status of bone. The bone protein osteocalcin tends to be less completely carboxylated in people with low vitamin K concentrations in serum. Many hemodialysis patients with a history of bone fractures have indications of poor vitamin K status. The same patients also appear to have a greatly increased prospective bone fracture risk.
Ceramide, produced through either the induction of SM hydrolysis or synthesized de novo transduces signals mediating differentiation, growth, growth arrest, apoptosis, cytokine biosynthesis and secretion, and a variety of other cellular functions. A generalized ceramide signal transduction scheme is shown in Fig. 2 in which ceramide is generated through the activation of distinct SMases residing in separate subcellular compartments in response to specific stimuli. Clearly, specificity of cellular responses to ceramide depends upon many factors which include the nature of the stimulus, co-stimulatory signals and the cell type involved. Ceramide derived from neutral SMase activation is thought to be involved in modulating CAPK and MAP kinases, PLA2 (arachidonic acid mobilization), and CAPP while ceramide generated through acid SMase activation appears to be primarily involved in NF-kappa B activation. While there is no apparent cross-talk between these two ceramide-mediated signalling pathways, there is likely to be significant cross-talk between ceramide signalling and other signal transduction pathways (e.g., the PKC and MAP kinase pathways). Other downstream targets for ceramide action include Cox, IL-6 and IL-2 gene expression, PKC zeta, Vav, Rb, c-Myc, c-Fos, c-Jun and other transcriptional regulators. Many, if not all, of these ceramide-mediated signalling events have been identified in the various cells comprising the immune system and are integral to the optimal functioning of the immune system. Although the role of the SM pathway and the generation of ceramide in T and B lymphocytes have only recently been recognized, it is clear from these studies that signal transduction through SM and ceramide can strongly affect the immune response, either directly through cell signalling events, or indirectly through cytokines produced by other cells as the result of signalling through the SM pathway. An overview of the signalling mechanisms coupling ceramide to the modulation of the immune response is depicted in Fig. 3 and shows how ceramide may play pivotal roles in regulating a number of complex processes. The SM pathway represents a potentially valuable focal point for therapeutic control of immune responses, perhaps for either enhancement of the activity of T cells in the elimination of tumors, or the down-regulation of lymphocyte function in instances of autoimmune disease. The recent explosion of knowledge regarding ceramide signalling notwithstanding, a number of critical questions need to be answered before a comprehensive, mechanistic understanding can be formulated relative to the incredibly varied effects of ceramide on cell function. For example, (i) how is a structurally simple molecule like ceramide able to mediate so many different, and sometimes paradoxical, physiological responses ranging from cell proliferation and differentiation to inhibition of cell growth and apoptosis, (ii) what are the molecular identities and modes of activation of the various SMase isoforms, (iii) what determines the distribution of the unique isoforms of SMase in cells of different lineages or at different stages of differentiation, (iv) what is the relative contribution of ceramide generated through SM hydrolysis versus de novo synthesis, and (v) by what means does ceramide interact with specific intracellular targets? Although a number of ceramide-activatable kinases, phosphatases, and their protein substrates have been identified, a more extensive search for additional cellular targets will be indispensable in determining the phosphorylation cascades linking the activation of the SM pathway to the regulation of nuclear events. Clearly, cross-talk between ceramide-induced signal transduction cascades and other signalling pathways adds to the inherent difficulty in distinguishing the specific effects of complex, intertwining signalling pathways.
The established role of vitamin K in nutrition is as a cofactor in the post-translational conversion of specific glutamyl to gamma-carboxyglutamyl (Gla) residues in a limited number of proteins. Administration of the vitamin K antagonist warfarin has previously been shown to decrease brain sulfatide concentrations and decrease brain galactocerebroside sulfotransferase (GST) activity in young mice. A dietary deficiency of vitamin K has now been shown to decrease (P < 0.01) brain sulfatide concentrations of 30-d-old mice significantly (by 21%). Male 21-d-old rats fed an excess of vitamin K for 7 or 14 d had 26 and 31% (P < 0.05) greater GST activity and 15 and 18% (P < 0.05) greater brain sulfatide concentrations, respectively, than controls fed a vitamin K-deficient diet. Male 21-d-old rats fed a diet containing 500 mg of phylloquinone/kg diet had an intermediate response and were vitamin K sufficient by normal criteria. The vitamin K response was observed when either phylloquinone or menaquinone-4 was fed as a source of the vitamin. These data suggest that in addition to its recognized role in Gla synthesis, vitamin K status is important in the maintenance of normal complex lipid sulfatide metabolism in young rats and mice.
Activation of circulating polymorphonuclear leukocytes (PMN) is a characteristic of systemic inflammation and may contribute to organ malfunction. Continuous arteriovenous hemofiltration (CAVH) has been reported to improve organ malfunction during severe systemic inflammation. This study postulates that the CAVH effects may be linked to alterations in PMN activation.
Sixteen pigs that underwent cecal ligation and rupture were randomized to receive CAVH or no CAVH for 24 hours. The PMN phagocytosis of Candida was measured prior to the insult and at 24, 48, and 72 hours. Temperature, total leukocyte count (WBC), hemodynamic, blood gas, microbiologic, and ionized calcium data were also collected.
All animals developed increased temperature, heart rate, and WBC, and positive blood and peritoneal cultures. Hemodynamic, pulmonary, and ionized calcium changes were not different between the CAVH and no CAVH groups. Phagocytosis of PMN increased in the no CAVH group at 24 hours, but not in the CAVH group. After discontinuing CAVH, phagocytosis increased to the no CAVH rate at 48 and 72 hours.
Continuous arteriovenous hemofiltration attenuates the upregulation of PMN phagocytosis of Candida; this effect disappears after CAVH is discontinued. Hemofiltration does not affect many other manifestations of sepsis, which implies that these manifestations may not be related to PMN phagocytosis capacity.
The current daily recommended dietary allowance for vitamin K is 1 microg/kg. Reliable measurements of vitamin K content in foods are now available, and data from 11 studies of vitamin K intake indicate that the mean intake of young adults is approximately 80 microg phylloquinone/d and that older adults consume approximately 150 microg/d. The vitamin K concentration in most foods is very low (<10 microg/100 g), and the majority of the vitamin is obtained from a few leafy green vegetables and four vegetable oils (soybean, cottonseed, canola and olive) that contain high amounts. Limited data indicate that absorption of phylloquinone from a food matrix is poor. Hydrogenated oils also contain appreciable amounts of 2', 3'-dihydrophylloquinone of unknown physiological importance. Menaquinones absorbed from the diet or the gut appear to provide only a minor portion of the human daily requirement. Measures of the extent to which plasma prothrombin or serum osteocalcin lack essential gamma-carboxyglutamic acid residues formed by vitamin K action, or the urinary excretion of this amino acid, provide more sensitive measures of vitamin K status than measures of plasma phylloquinone or insensitive clotting assays.
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.