Vitamin K Research Articles

Undetected and undiagnosed comorbidity in patients with obesity undergoing bariatric surgery-Results from the Berlin Bariatric Cohort study.

The quality of general obesity management before bariatric surgery (BS) is rarely investigated. Inadequate information regarding undetected and undiagnosed comorbidities (UUCs) in individuals with obesity may influence the penetration, risks, and outcomes of BS. We conducted a cohort study involving a pre-specified medical check-up in a cooperation between a BS department and an outpatient medical centre. A total of 1068 patients (74.4% women) were enrolled in the study. The mean age was 42.1 years (standard deviation [SD] 11.9) and the mean body mass index (BMI) was 46.1 (SD 6.91). The onset of obesity occurred in 11.4% of patients during childhood, 47.2% during schooltime/adolescence, 41.4% in adulthood. Gender differences were observed: men had higher BMI, systolic blood pressure, and impaired metabolic state (including diabetes, dyslipidemia, and liver disease with p-values <.001 for all). Women had lower haemoglobin levels, impaired iron status, lower albumin levels (p < .001), and increased C-reactive protein levels (p < .05). The prevalence of UUC conditions (percentage of cases) was as follows: arterial hypertension, 53%; decreased cystatin C clearance, 57%; dyslipidemia, 41%; fatty liver, 40%; iron deficiency, 37%; diabetes mellitus, 34%; vitamin D deficiency, 32%; chronic pain syndrome, 23%; liver fibrosis, 12%; obstructive sleep apnea, 10%; and vitamin deficiencies (vitamin B12, folic acid, vitamin K1) <10%. Undiagnosed hypertension was more prevalent in younger women, and nutritional deficits were associated with high BMI in both genders. Older age and high BMI were associated with undiagnosed diabetes and decreased glomerular filtration rate in both genders, and with liver fibrosis in men. UUC are highly prevalent in individuals undergoing BS. A refined assessment is recommended to improve health conditions and outcome in these candidates.

Protective Role of Vitamin K2 in Vascular Microcalcification: Clinical Implications

Protective Role of Vitamin K2 in Vascular Microcalcification: Clinical Implications

Association of dietary vitamin K1 intake with epilepsy in adults in US: a cross-sectional study of National Health and Nutrition Examination Survey 2013-2018.

Information regarding the relationship between epilepsy and vitamin K1 remains unclear. We aimed to assess the association between dietary vitamin K1 intake and epilepsy. 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. 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 ± 1.5µg/d, respectively. Each unit (10µg/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. 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.

An analysis of vitamin K status in Chinese healthy children aged 0–18 years

BackgroundVitamin K (VK), an essential fat-soluble nutrient, exists in two primary forms, vitamin K1 (VK1), and vitamin K2 (VK2). VK1 plays an essential role in blood coagulation, while VK2 plays a crucial role in managing bone calcification, supporting bone strength and health. However, comprehensive epidemiological data on VK remains sparse, particularly in children. This study aims to evaluate the levels and characteristics of VK in children of Wenzhou area, China.MethodsA total of 3,342 children undergoing routine physical examinations in the outpatient department from December 2020 to August 2022 were recruited. The levels of VK (including VK1 and menaquinones (MK-4), a major form of VK2) and 25-hydroxy vitamin D (25(OH)D) in fasting serum samples from these children were measured using high-performance liquid chromatography-tandem mass spectrometry. The study analyzed the levels and distribution of VK and 25(OH)D across different sex, age, and weight groups, and explored their potential related factors.ResultsThe median serum levels of MK-4 and VK1 were 0.12 (0.07, 0.21) ng/ml and 0.33 (0.18, 0.57) ng/ml, respectively. The reference ranges of MK-4 and VK1 were 0.01–0.58 ng/ml and 0.03–1.48 ng/ml, respectively. The median serum 25(OH)D level was 21.26 (17.30, 25.35) ng/ml. Moreover, there were no significant variations in the levels of MK-4 and VK1 across different age and sex groups. The level of MK-4 in the underweight group was significantly higher than that in the normal weight group. MK-4 level reached its peak in summer, while the VK1 concentration was at its lowest. Furthermore, a very weak positive correlation was revealed between MK-4 and VK1 levels.ConclusionIn this study, we defined the median values and reference ranges of MK-4 and VK1 in a sample of Chinese children aged 0–18 years. MK-4 levels were higher in underweight children. Both MK-4 and VK1 levels exhibited seasonal variations. Further research is needed to explore the factors affecting MK-4 and VK1 levels.

Nannochloropsis oceanica as a Source of Bioactive Compounds: Mapping the Effects of Cultivation Conditions on Biomass Productivity and Composition Using Response Surface Methodology

Microalga Nannochloropsis oceanica presents a promising source of high-value food ingredients such as protein, omega-3 fatty acids, and vitamins. To fully unlock its potential, a thorough understanding of how cultivation conditions affect both growth and the nutritional composition is required. Hence, this study aimed to test and model the effects of temperature, light intensity, and salinity on biomass productivity and the final contents of protein, eicosapentaenoic acid (EPA), and vitamin K2 using response surface methodology (RSM). The RSM experiment revealed that the highest temperature and light intensity tested favored biomass productivity and protein content. According to the generated models, the two responses peaked with 0.135 g DM·L−1·day−1 and 0.559 g·g−1 DM, respectively, at 27 °C and 300–350 µmol·m−2·s−1. In contrast, the contents of both EPA and menaquinone-4 (MK-4), the only detected K vitamer, were stimulated at the lowest tested temperature. Based on the generated models, the two responses peaked with 0.037 g·g−1 DM and 89.3 µg·g−1 DM, respectively, at 19 °C combined with 3.0% salinity (EPA) or 120 µmol·m−2·s−1 (MK-4). Although additional optima may exist beyond the tested conditions, these findings provide valuable information on N. oceanica’s cellular response to changes in key cultivation conditions. Furthermore, it shows that two-stage cultivation may be needed to fully unlock the potential of this microalga as a future source of valuable lipid ingredients.

Association Between Circulating Vitamin K Levels, Gut Microbiome, and Type 1 Diabetes: A Mendelian Randomization Study

Background/Objectives: Nutritional deficiencies have been proposed as possible etiological causes for autoimmune diseases, among which type 1 diabetes (T1D). Vitamin K (VK) has potentially positive effects on type 2 diabetes, but its role on T1D in humans remains largely unknown. We aimed to examine the presence of a causal association between VK and T1D using a Mendelian randomization (MR) approach. Methods: Genetic variants from a genome-wide association study (GWAS) for VK (N = 2138 Europeans) were used as instruments in our two-sample MR study to investigate whether circulating VK levels are causally associated with the risk of T1D in a large European T1D GWAS cohort (18,942 cases/520,580 controls). Through a multivariable MR (MVMR), the effects of both VK and specific gut microbiota on T1D were investigated given that the gut microbiome synthesizes VK. Results: We found that changes in levels of circulating VK did not affect T1D risk in our univariate two-sample MR, but this study had limited power to detect small effects of VK (OR for T1D of less than 0.8). However, our MVMR indicated a suggestive association of VK with the risk of T1D adjusting for two different gut microbiome populations. Conclusions: In conclusion, VK levels are unlikely to significantly affect the risk of T1D, but small effects cannot be excluded, and the role of gut microbiome in this association should be further investigated.

Vitamin K2 Protects Against SARS-CoV-2 Envelope Protein-Induced Cytotoxicity in Chronic Myeloid Leukemia Cells and Enhances Imatinib Activity.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by excessive proliferation of myeloid cells. The COVID-19 pandemic has raised concerns regarding the impact of SARS-CoV-2 on patients with malignancies, particularly those with CML. This study aimed to investigate the effects of SARS-CoV-2 proteins on CML cell viability and the protective role of vitamin K2 (VK2) in conjunction with imatinib. Experiments conducted on K562 CML cells demonstrated that the SARS-CoV-2 envelope protein induces cytotoxicity and activates caspase 3/7, which are key markers of apoptosis. VK2 mitigated these cytotoxic effects and decreased cytokine production while inhibiting colony formation. Furthermore, the combination of VK2 with imatinib significantly reduced cellular proliferation, diminished mitochondrial membrane potential, and markedly suppressed colony formation. These findings suggest that VK2 protects CML cells from SARS-CoV-2-induced cytotoxicity and enhances the therapeutic efficacy of imatinib, presenting a potential strategy to improve CML treatment during the COVID-19 pandemic.

Circulating Phylloquinone and the Risk of Four Female-Specific Cancers: A Mendelian Randomization Study.

Observational studies have linked vitamin K and cancer, but the causality of this association remains unknown. This Mendelian randomization (MR) study aims to investigate the association between circulating phylloquinone (vitamin K1) levels and four female-specific cancers. We used four single-nucleotide polymorphisms (SNPs) to instrument phylloquinone, with the reported F-statistic 16.00-28.44 for all variants. SNP-outcome associations were obtained from consortia meta-analyses, UK Biobank, and the FinnGen database (up to 145,257/419,675, 27,446/362,324, 15,181/591,477, and 2211/320,454 cases/controls for breast, ovarian, endometrial, and cervical cancer, respectively). Analyses were conducted using five complementary MR methods including pleiotropy robust approaches. The MR Egger intercept test, MR PRESSO global test and leave-one-out analyses were used to test for and identify pleiotropic variants. The relevance of the instrument was validated by positive control analyses on coagulation factor IX (p = 0.01). However, the main MR analysis and all sensitivity analyses were consistently supportive of a null association between phylloquinone and all four cancers (p > 0.05 for all analyses, across all methods). MR-PRESSO did not detect outlying variants, and there was no evidence of horizontal pleiotropy relating to any cancer outcome (pintercept > 0.26 for all). We found no evidence for an association between genetically predicted circulating phylloquinone levels and the risk of four female-specific cancers.

Vitamin K2 in Managing Nocturnal Leg Cramps

Currently, there are no treatments for nocturnal leg cramps (NLCs) that have been proven to be both safe and effective. Seeking safe and effective approaches for managing NLCs is of crucial importance. To determine whether vitamin K2 is better than placebo in managing NLCs. This multicenter, double-blind, placebo-controlled randomized clinical trial was conducted in China between September 2022 and December 2023. This study used a volunteer sample comprising community-dwelling individuals 65 years and older with 2 or more documented episodes of NLCs during 2 weeks of screening. Researchers performed a history and physical screening of candidates recruited from the community through advertisements, and eligible participants were randomized in a 1:1 ratio to receive vitamin K2 or a placebo for 8 weeks. Patients orally took capsules containing either vitamin K2 (menaquinone 7), 180 μg, or a similar-looking placebo every day for 8 weeks. The study products were custom manufactured to have identical packaging and for the capsules to have matching appearance and identical excipients that shared similar taste and weight. The primary outcome was the mean number of NLCs per week between the vitamin K2 and the placebo group. Secondary outcomes included the duration of muscle cramps measured in minutes and the severity of muscle cramps assessed using an analog scale ranging from 1 to 10. Among the 310 participants, 111 participants were excluded. Of the 199 enrolled individuals, 108 (54.3%) were female, and the mean (SD) age was 72.3 (5.5) years. A total of 103 patients (51.8%) were randomly assigned to receive vitamin K2 and 96 (48.2%) were assigned to placebo. The mean (SD) baseline weekly frequency of cramps was comparable in both the vitamin K2 group (2.60 [0.81]) and the placebo group (2.71 [0.80]). During the 8-week intervention, the vitamin K2 group experienced a reduction in the mean (SD) weekly frequency of cramps to 0.96 (1.41). Meanwhile, the placebo group maintained mean (SD) weekly frequency of cramps at 3.63 (2.20). The between-group difference was statistically significant (difference, -2.67; 95% CI, -2.86 to -2.49; P < .001). The vitamin K2 group had a more significant mean (SD) reduction in NLC severity (-2.55 [2.12] points) compared with the placebo group (-1.24 [1.16] points). The vitamin K2 group exhibited a more pronounced mean (SD) decrease in the duration of NLCs (-0.90 [0.88] minutes) than the placebo group (-0.32 [0.78] minutes). No adverse events related to vitamin K2 use were identified. This randomized clinical trial showed that vitamin K2 supplementation significantly reduced the frequency, intensity, and duration of NLCs in an older population with good safety. ClinicalTrials.gov Identifier: NCT05547750.

Vitamin K2 Ameliorates Diabetes-Associated Cognitive Decline by Reducing Oxidative Stress and Neuroinflammation.

Diabetes, a chronic metabolic disease, affects approximately 422million people and leads to 1.5million deaths every year, It is found that 45% of individuals with diabetes eventually develop cognitive impairment. Here we study effects of Vitamin K2 on diabetes-associated cognitive decline (DACD) and its underlying mechanism. Diabetes was induced in adult Swiss albino mice with high-fat diet and a low dose (35mg/kg) of streptozotocin and measured by fasting glucose and HbA1c levels. After one week of development of diabetes, one group of animals received Vitamin K2 (100µg/kg) via oral gavage for 21 days. Then different behavioural studies, including the elevated plus maze, Morris water maze, passive avoidance test and novel object recognition test were performed followed by biochemical tests including AchE, different oxidative stress parameters (SOD, GSH, MDA, catalase, SIRT1, NRF2), inflammatory markers (TNFα, IL1β, MCP1, NFκB), apoptosis marker (Caspase 3). Hippocampal neuronal density was measured using histopathology. Vitamin K2 treatment in diabetic animals led to reduced fasting glucose and HbA1c, It could partially reverse DACD as shown by behavioural studies. Vitamin K2 adminstration reduced corticohippocampal AchE level and neuroinflammation (TNFα, IL1β, MCP1, NFκB, SIRT1). It reduced oxidative stress by increasing antioxidant enzymes (SOD, GSH, catalase), transcription factor NRF2 while reducing caspase 3. This eventually increased CA1 and CA3 neuronal density in diabetic animals. Vitamin K2 partially reverses DACD by increasing ACh while reducing the oxidative stress via Nrf2/ARE pathway and neuroinflammation, thus protecting the hippocampal neurons from diabetes associated damage.

Vitamin K2 and the Vitamin-K-Cycle-Enzyme VKORC1L1 improve endothelial regeneration by inhibiting endothelial-mesenchymal transition, inflammatory cell activation and ferroptosis

Abstract Introduction Vascular inflammation is a crucial contributor to atherosclerosis, in which oxidative stress, endoplasmic reticulum (ER) stress and transition of endothelial to mesenchymal cells (EndMT) are of critical importance. Vitamin-K-antagonists (VKA) promote vascular dysfunction, while dietary vitamin K intake was proposed to reduce incidence of coronary artery disease, but the mechanisms remain unresolved. Key enzyme for regeneration of vitamin K is the Vitamin K epoxide reductase complex subunit 1 (VKORC1), which also represents the pharmacological target of VKA. VKOR-like1 (VKORC1L1) is an isoenzyme of VKORC1, which resides at the ER-membrane, exerts antioxidative properties and is involved in vitamin K maintenance. Aim of this study was to investigate the role of Vitamin K2 and the VKOR-enzymes in endothelial cell inflammation. Methods and Results In human coronary artery endothelial cells (HCAEC), Vitamin K2 improves endothelial regeneration by increasing proliferation and cell viability and by reducing both apoptosis and ferroptosis (relative viability: RSL3 0.11 ± 0.01 vs 0.32 ± 0.05 RSL3+K2-1µM vs. 0.44 ± 0.11 RSL3+K2-10µM, p&amp;lt;0.001). Moreover, Vitamin K2-supplementation inhibits EndMT by reducing expression of mesenchymal markers (Calponin, SM22; Fig.1). In silico analyses of the proteome of human coronary atherosclerosis revealed increased expression of VKORC1L1, but not of VKORC1. In vitro induction of oxidative stress and ER-Stress promoted time- and dose-dependent enhanced expression of VKORC1L1, without altering VKORC1 expression (H2O2: 2.3-fold vs. 0.8-fold after 40 minutes, p=0.04; tunicamycin: 1 μg/ml: 1.43-fold vs. 0.8-fold, p&amp;lt;0.01). Likewise, siRNA-mediated VKORC1L1 knockdown induces an inflammatory gene signature with upregulation of NFkB-signalling and endoplasmic reticulum stress (NF-κB: 1.95-fold ± 0.13, GRP78: 1.32-fold ± 0.04 vs. control, p&amp;lt;0.01). Furthermore, VKORC1L1 downregulation increased formation of reactive oxygen species (ROS) and reduced proliferation (EdU signal: 0.56 ± 0.02 vs. control, p &amp;lt; 0.01). In contrast, VKORC1-knockdown does not impair endothelial regeneration and function (Fig.2). Vitamin K2 reduces vascular inflammation and endoplasmic reticulum stress in the case of VKORC1-, but not VKORC1L1-knockdown. In addition, inducing EndMT resulted in a reduction of VKORC1L1, but not of VKORC1, while VKORC1L1-knockdown aggravates EndMT. Conclusion VKORC1 and its isoenzyme VKORC1L1 exhibit divergent effects on endothelial cell inflammation. Further studies are warranted to shed light on the regulation of the enzymes to improve our understanding regarding vascular side effects of VKA treatment and beneficial effects of vitamin K supplementation.

Role of vitamin K2 and vitamin K cycle enzymes in aortic valvular interstitial cell calcification

Abstract Introduction Calcific aortic valve disease (CAVD) is the most common valve disease. Currently, there is no medical treatment available for CAVD. Vitamin K antagonists promote CAVD while population-based studies suggest that dietary intake of vitamin K reduces the incidence of CAVD in adults. However, randomized trials have so far not proven a clear benefit of vitamin K supplementation on the progression of AVS. Consequently, there is a need for a deeper understanding of the role of vitamin K in valvular calcification. This study aims to further investigate mechanisms of action of vitamin K during valvular calcification. Methods and Results Aortic valve samples were obtained from patients undergoing surgical aortic valve replacement for CAVD and valvular interstitial cells (VIC) were isolated by collagenase II digestion (Fig. 1). VIC expressed typical markers like Vimentin and α-SMA and were cultured in a control medium (CM) or further calcified in a pro-calcifying medium (PCM) containing sodium dihydrogen phosphate and ascorbic acid. PCM led to upregulation of Runt-related transcription factor 2 (RUNX2), alkaline phosphatase (ALP) expression, and ALP-activity after 7 and 21 days of culture. Moreover, alizarin red staining visualized significant calcium mineral deposition after 21 days of culture (Fig. 2). The addition of the most potent vitamin K2 derivative (Menaquinone-7, MK-7) improved cell viability under both control and calcifying conditions (Fig. 3). Moreover, MK-7 protected VIC from ferroptotic cell death (Fig. 4) and increased expression of the vitamin K-dependent Matrix-Gla-protein (MGP), a major inhibitor of ectopic calcification (Fig. 5). To fulfill its function as an activator of vitamin K-dependent proteins like MGP, vitamin K needs to be reduced to vitamin K hydroquinone by the vitamin K epoxide reductase enzymes VKORC1 and VKORC1L1. In VIC, using our calcification protocol, treatment with PCM led to the downregulation of VKORC1, but not of VKORC1L1, an enzyme with known anti-oxidative properties (Fig. 6). We next performed siRNA-mediated knockdown of VKORC1 and VKORC1L1 in VIC and observed calcification after 7 and 21 days of culture by measuring expression of ALP, RUNX2, quantifying ALP activity, and staining for calcium minerals (alizarin red). Intriguingly, VKORC1L1-knockdown sharply increased the expression of ALP. To further elucidate these findings, we will perform overexpression experiments to analyze, if VKORC1L1 can alleviate PCM-induced calcification Conclusion: Vitamin K2 inhibits in vitro calcification of valvular interstitial cells and upregulates the calcification inhibitor Matrix-Gla-Protein. Our results suggest the involvement of the vitamin K cycle enzyme VKORC1L1, which is known to exhibit anti-oxidative and cytoprotective effects. Further studies are warranted to shed light on the regulation of the enzymes to improve our understanding.

Evaluation of MENAQUINONE‐7 and fat‐soluble vitamin production by starter cultures during fermentation in dairy products using RPLC method

AbstractVitamin K2, also known as menaquinone, has become a significant research focus, particularly in fermented products. This study aims to investigate the content of menaquinone‐7 (MK‐7), an essential form of vitamin K, and other fat‐soluble vitamins (A, D, E) during the fermentation of various fermented milk products. The vitamin contents of six fermented milk products were analyzed: two yogurt samples (produced with commercial starter and probiotic starter), two kefir samples (produced with commercial starter and kefir grain), and milk fermented with Lactobacillus acidophilus or Bifidobacterium bifidum. Throughout the fermentation process, continuous pH monitoring was conducted, and fermentation was terminated based on pH levels. Fat‐soluble vitamins and vitamins K1, K2 were extracted from samples taken at specific fermentation periods and quantitatively determined using the reverse phase liquid chromatography (RPLC) method. The developed method was validated according to ICH guidelines. Simultaneously, the microbial content of the samples was analyzed. Among the fermented dairy products analyzed, the highest MK‐7 content (4.82 μg/100 g) was found in the kefir sample produced with kefir grain (KG). The diverse microorganisms in kefir grains necessitated detailed research to explain their role in this complex mechanism. In yogurt samples, the presence of L. acidophilus in the YB sample suggests that this bacterium may be responsible for the observed differences. This is supported by the LA sample, where production with L. acidophilus strain showed an increase from 0.97 to 1.70 at the 20th hour of fermentation. It was noted that the concentration of menaquinone‐7 increased throughout the fermentation period. Given the critical health effects of essential fat‐soluble vitamins and MKs, determining their content in commonly consumed fermented dairy products and understanding the influence of starter cultures, which are potential probiotics, on vitamin production underscores the importance of this research. It is important to highlight the potential of fermented products in nutritional recommendations.

Tranexamic acid with vitamin K mixture decreases bleeding of total hip arthroplasty in a Jordanian population

Background: Bleeding of total hip arthroplasty has severe consequences on postoperative recovery. 75–90% of early bleeding after surgery and during surgery is caused by operative technical issues. tranexamic acid decreases bleeding of arthroplasty. vitamin k has late and dose sensitive effect in clotting. Methods: This retrospective investigation included subjects of middle age and of both genders scheduled for primary hip replacement at Queen Alia hospital, Jordanian Royal medical services, between March 2022 and June 2023. Subjects were classified into two groups. Group I subject were administered intravenous mixture of Tranexamic acid 10 mg/kg with vitamin K1 of 10 mg 5 min pre-skin incision followed by an infusion of Tranexamic acid 1 mg/kg/h and vitamin K1 0.2 mg/kg/h, until skin closure. Group II subjects were administered only intravenous vitamin K1 of 10 mg, 5 min pre- skin incision followed by infusion of 0.2 mg/kg/h until skin closure. Hemoglobin, packed cell volume, platelet count, prothrombin time, partial thromboplastin time and fibrinogen were tested. Bleeding and blood transfusion were remarked. Results: Group I demonstrated a remarkable less modifications in blood tests and less bleeding than group II. Group II demonstrated less bleeding after surgery. The average Hb in group I demonstrated a remarkable less reduction after surgery compared to group II. (p&lt;0.005). No blood transfusion after surgery was needed in group I. Nine (15%) patients in group II needed one unit of blood transfusion during surgery. Conclusion: Intravenous administration of Tranexamic acid with vitamin K mixture in total hip arthroplasty decreased bleeding during and after surgery and decreased the requirement for blood transfusion.

Поздняя витамин-K-зависимая коагулопатия у пациента с гемофилией A: описание клинического наблюдения

Late-onset Vitamin K deficiency bleeding is a rare disease that develops as a manifestation of Vitamin K deficiency in children from 8 days to 6 months of age with an incidence of 4.4 to 72 cases per 100,000 newborns in countries where prophylaxis with Vitamin K1 preparations is not carried out and of 0 to 3 cases per 100,000 in countries where prophylaxis is carried out. In Russia the prophylaxis is carried out using menadione sodium bisulfite, a Vitamin K3 preparation, the effectiveness of which is questionable. One of the specific manifestations of the late-onset Vitamin K deficiency bleeding is intracranial hemorrhage (ICH), which occurs in more than half of all cases of the disease. This disease has not been described in patients with hemophilia A until now. Authors represent a clinical case report of the development of the late-onset Vitamin K deficiency bleeding by a massive ICH in a patient with hemophilia A.

Ubiquitous genome streamlined Acidobacteriota in freshwater environments.

Acidobacteriota are abundant in soil, peatlands, and sediments, but their ecology in freshwater environments remains understudied. UBA12189, an Acidobacteriota genus, is an uncultivated, genome-streamlined lineage with a small genome size found in aquatic environments where detailed genomic analyses are lacking. Here, we analyzed 66 MAGs of UBA12189 (including one complete genome) from freshwater lakes and rivers in Europe, North America, and Asia. UBA12189 has small genome sizes (<1.4 Mbp), low GC content, and a highly diverse pangenome. In freshwater lakes, this bacterial lineage is abundant from the surface waters (epilimnion) down to a 300-m depth (hypolimnion). UBA12189 appears to be free-living from CARD-FISH analysis. When compared to other genome-streamlined bacteria such as Nanopelagicales and Methylopumilus, genome reduction has caused UBA12189 to have a more limited metabolic repertoire in carbon, sulfur, and nitrogen metabolisms, limited numbers of membrane transporters, as well as a higher degree of auxotrophy for various amino acids, vitamins, and reduced sulfur. Despite having reduced genomes, UBA12189 encodes proteorhodopsin, complete biosynthesis pathways for heme and vitamin K2, cbb3-type cytochrome c oxidases, and heme-requiring enzymes. These genes may give a selective advantage during the genome streamlining process. We propose the new genus Acidiparvus, with two new species named "A. lacustris" and "A. fluvialis". Acidiparvus is the first described genome-streamlined lineage under the phylum Acidobacteriota, which is a free-living, slow-growing scavenger in freshwater environments.

HaVTE1 confers ABA insensitivity by blocking the ABA signaling pathway in sunflowers (Helianthus annuus L.)

Sunflower (Helianthus annuus) is the fourth major oilseed crop in the world, with remarkable tolerance in saline-alkali soils. The VTE1 gene encodes tocopherol cyclase (TC), an enzyme pivotal in the biosynthesis of both vitamin E and vitamin K1. Despite its integral role in the synthesis of these crucial vitamins, the functional analysis of VTE1 under abiotic stress in sunflowers remains scant. In the present investigation, a structural analysis of the VTE1 protein across 155 diverse species revealed a highly conserved evolutionary trace. The expression profiling of HaVTE1 depicted that the HaVTE1 was responsive to the ABA pathway. Transgenic results confirmed that overexpression of HaVTE1 in Arabidopsis and sunflower showed decreased sensitivity to ABA while knocking-down in sunflower exhibited the opposite phenotype. Furthermore, biochemical experiments displayed that HaVTE1 decreases ABA sensitivity by scavenging superoxide contents. Concurrently, the transcriptome analysis revealed that HaVTE1 blocked the upstream of the ABA signaling cascade, which was further confirmed by luciferase assay, resulting in reduced sensitivity to ABA of HaVTE1 overexpression plants. The findings shed light on a theoretical basis for the sunflower responses to ABA signaling and abiotic stresses.

Vitamin K - content in food and dietary intake among the Danes

Insufficient information on the content of vitamin K2 in our foods hinder estimation of the dietary intake. We aimed to establish content of eight vitamin K vitamers, vitamin K1 (phylloquinone; PK) and vitamin K2 (menaquinones; MK-4 to MK-10) in 88 composite food samples representing dairy, eggs, meat, fish, cereals, and plant-based alternatives to dairy. Combined with PK data for other foods, the dietary intake among Danes was estimated. The unit’PKeq’ is used to compensate for the difference in molecular weight for MK-4 at 445 g/mol up to MK-10 at 853 g/mol. The highest content was found in chicken thigh with skin at 53 μg PKeq/100 g followed by 49 μg PKeq/100 g in Danablue (blue cheese). The daily intake of vitamin K is 139 μg to 160 μg PKeq for adults. The highest percentage comes from PK (64 %), 27 % from MK-4, 4.6 % from MK-9, and 2.4 % from MK-8.

Metagenomic analysis during capecitabine therapy reveals microbial chemoprotective mechanisms and predicts drug toxicity in colorectal cancer patients.

Unpredictable chemotherapy side effects are a major barrier to successful treatment. Cell culture and mouse experiments indicate that the gut microbiota is influenced by and influences anti-cancer drugs. However, metagenomic data from patients paired to careful side effect monitoring remains limited. Herein, we focus on the oral fluoropyrimidine capecitabine (CAP). We investigate CAP-microbiome interactions through metagenomic sequencing of longitudinal stool sampling from a cohort of advanced colorectal cancer (CRC) patients. We established a prospective cohort study including 56 patients with advanced CRC treated with CAP monotherapy across 4 centers in the Netherlands. Stool samples and clinical questionnaires were collected at baseline, during cycle 3, and post-treatment. Metagenomic sequencing to assess microbial community structure and gene abundance was paired with transposon mutagenesis, targeted gene deletion, and media supplementation experiments. An independent US cohort was used for model validation. CAP treatment significantly altered gut microbial composition and pathway abundance, enriching for menaquinol (vitamin K2) biosynthesis genes. Transposon library screens, targeted gene deletions, and media supplementation confirmed that menaquinol biosynthesis protects Escherichia coli from drug toxicity. Microbial menaquinol biosynthesis genes were associated with decreased peripheral sensory neuropathy. Machine learning models trained in this cohort predicted hand-foot syndrome and dose reductions in an independent cohort. These results suggest treatment-associated increases in microbial vitamin biosynthesis serve a chemoprotective role for bacterial and host cells, with implications for toxicities outside the gastrointestinal tract. We provide a proof-of-concept for the use of microbiome profiling and machine learning to predict drug toxicities across independent cohorts. These observations provide a foundation for future human intervention studies, more in-depth mechanistic dissection in preclinical models, and extension to other cancer treatments.

Increasing Vitamin K2 Synthesis in Bacillus subtilis by Controlling the Expression of MenD and Stabilizing MenA.

As an indispensable member of the family of lipid vitamins, vitamin K2 (MK-7) plays an important role in blood coagulation, cardiovascular health, and kidney health. Microbial fermentation is favored due to its high utilization rate of raw materials, simple operation, and moderate conditions. However, the biosynthesis pathway of vitamin K2 in microorganisms is highly complex, which hinders its industrial production in microbial cell factories. One of the major challenges is the stable expression and deregulation of key enzymes in the vitamin K2 biosynthesis pathway, which remains unclear and has undergone little investigation. In this study, 2-succinyl-5-enolpyruvyl-6-hydroxy-3-cyclohexene-1-carboxylic-acid synthase (MenD) and 1,4-dihydroxy-2-naphthoate polyprenyltransferase (MenA) were identified as pivotal enzymes in the biosynthesis of vitamin K2. To investigate the catalytic efficiency of MenD in the biosynthesis pathway of vitamin K2, structure-based mutation design and site-directed mutagenesis were performed. Three mutation sites were identified in MenD: A115Y, R96 M, and R323M, which improve the expression level and protein stability. Meanwhile, the MenA mutant T290M, which exhibits improved protein stability, was obtained by modifying its hydrophobic stacking structure. Finally, an engineered strain noted ZQ13 that combinatorially overexpressed MenD (A115Y) and MenA (T290M) mutants was constructed and achieved 338.37 mg/L vitamin K2 production in a 3-L fermenter.