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1.
Biochemistry (Mosc) ; 89(Suppl 1): S57-S70, 2024 Jan.
Article En | MEDLINE | ID: mdl-38621744

Neurodegenerative diseases are a growing global health problem with enormous consequences for individuals and society. The most common neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, can be caused by both genetic factors (mutations) and epigenetic changes caused by the environment, in particular, oxidative stress. One of the factors contributing to the development of oxidative stress that has an important effect on the nervous system is vitamin K, which is involved in redox processes. However, its role in cells is ambiguous: accumulation of high concentrations of vitamin K increases the content of reactive oxygen species increases, while small amounts of vitamin K have a protective effect and activate the antioxidant defense systems. The main function of vitamin K is its involvement in the gamma carboxylation of the so-called Gla proteins. Some Gla proteins are expressed in the nervous system and participate in its development. Vitamin K deficiency can lead to a decrease or loss of function of Gla proteins in the nervous system. It is assumed that the level of vitamin K in the body is associated with specific changes involved in the development of dementia and cognitive abilities. Vitamin K also influences the sphingolipid profile in the brain, which also affects cognitive function. The role of vitamin K in the regulation of biochemical processes at the cellular and whole-organism levels has been studied insufficiently. Further research can lead to the discovery of new targets for vitamin K and development of personalized diets and therapies.


Neurodegenerative Diseases , Vitamin K , Humans , Vitamin K/metabolism , Neurodegenerative Diseases/metabolism , Antioxidants/metabolism , Oxidative Stress , Reactive Oxygen Species/metabolism
2.
Cells ; 13(8)2024 Apr 14.
Article En | MEDLINE | ID: mdl-38667296

This review explores the likely clinical impact of Pregnane X Receptor (PXR) activation by vitamin K on human health. PXR, initially recognized as a master regulator of xenobiotic metabolism in liver, emerges as a key regulator influencing intestinal homeostasis, inflammation, oxidative stress, and autophagy. The activation of PXR by vitamin K highlights its role as a potent endogenous and local agonist with diverse clinical implications. Recent research suggests that the vitamin K-mediated activation of PXR highlights this vitamin's potential in addressing pathophysiological conditions by promoting hepatic detoxification, fortifying gut barrier integrity, and controlling pro-inflammatory and apoptotic pathways. PXR activation by vitamin K provides an intricate association with cancer cell survival, particularly in colorectal and liver cancers, to provide new insights into potential novel therapeutic strategies. Understanding the clinical implications of PXR activation by vitamin K bridges molecular mechanisms with health outcomes, further offering personalized therapeutic approaches for complex diseases.


Pregnane X Receptor , Signal Transduction , Vitamin K , Humans , Clinical Relevance , Health , Pregnane X Receptor/metabolism , Vitamin K/metabolism
3.
Vopr Pitan ; 93(1): 92-102, 2024.
Article Ru | MEDLINE | ID: mdl-38555613

The influence of a stress factor, widespread in modern conditions, on the vitamin status has not been studied enough. At the same time, the negative stress impact can be aggravated against the background of unhealthy nutrition, which in turn affects the vitamin status of the organism. In this regard, the goal of the research was to evaluate the effect of chronic restrict stress on the vitamin supply in rats fed a diet with adequate and increased content of fat, sugar and cholesterol. Material and methods. The experiment was carried out on 37 growing male Wistar rats (initial body weight of 45±5 g) divided into 4 groups. Animals of the 1st (control) and the 2nd groups received a complete semi-synthetic diet (CSSD) (20% protein, 10% fat, 58% carbohydrates in the form of starch, 384 kcal/100 g) for 92 days. The levels of all vitamins and mineral elements in the rats' diets were adequate for growing rats. Rats of the 3rd and the 4th groups were fed a high-calorie, high-fat high-carbohydrate diet (HFHCD) (20% protein, 28% fat, 2% cholesterol, 18% carbohydrates in the form of starch, 20% sucrose, 511 kcal/100 g). Animals of groups 2 and 4 were subjected to daily 90-minute immobilization. The concentration of vitamins A (retinol and retinol palmitate) and E (α-tocopherol) in the blood serum and liver were determined by high-performance liquid chromatography, vitamins B1 and B2 in the liver and urine, as well as riboflavin in the blood serum and 4-pyridoxic acid (4-PA) in urine were determined by fluorimetric methods. Biochemical parameters of blood serum were determined on a biochemical analyzer; the total content of fat, triglycerides (TG) and cholesterol (CH) was determined in the liver. Results. Replacing CSSD with HFHCD, both under restraint stress and without, was accompanied by an increase in liver weight by 1.8-2.0 fold, in its fat content by 2.6-3.3 fold, cholesterol by 32.6-35.3 fold and TG - by 33.0-57.6 fold (p=<0.001). An increase in alanine aminotransferase (ALT) activity by 1.7-2.0 fold (p=<0.01), in low-density lipoprotein (LDL) cholesterol level by 5.4 fold (p=<0.05) and the atherogenic coefficient by 2.5 fold (p<0.01) as well as a decrease in creatinine and urea level (p=<0.05) in blood serum were revealed. Immobilization was accompanied by a decrease in body weight, liver and liver fat in rats fed both CSSD and HFHCD (p<0.05), but didn't affect the blood serum biochemical parameters, with the exception of an increase in ALT activity. If the activity of alkaline phosphatase (ALP) did not change during immobilization of rats fed the CSSD, then in animals fed the high-calorie diet it decreased by 37.5% (p=<0.05 from the control) under its increase against the background of restrict stress by 78.7% (p=<0.01) compared to the indicator of rats of the 3rd group. Immobilization of rats treated with CSSD was accompanied by an increase in both absolute serum α-tocopherol level and concentration correlated with the level of cholesterol and triglycerides by 26.0-57.5% (p<0.05), with a simultaneous decrease in its content in the liver per 1 g of wet tissue by 22.1% (p=0.041) relative to the indicators of intact animals. Immobilization reduced the level of retinol palmitate in the liver by 2.3 times (p<0.01), but did not affect retinol level in the blood serum. At the same time, indicators of B vitamin status (the content of vitamins B1 and B2 in the liver per 1 g of wet tissue and per organ, blood serum riboflavin level, urinary excretion of riboflavin and 4-PA) did not change, with the exception of thiamine urinary excretion, which reduced compared to the control by 38.8%. In rats fed HFHCD, immobilization had no additional effect on the supply with vitamins A and E. The content of vitamins B1 and B2 in the liver in terms of the whole organ was reduced by 14.0-26.7% relative to the indicator in animals of the 3rd group, not subjected to chronic stress, only due to differences in liver weight in animals of these groups. Conclusion. The data obtained indicate that chronic stress has a negative effect on the vitamin status of the body, worsening the supply with vitamins A, E and B1, and substantiate the feasibility of studying the mechanisms of this effect in order to develop effective vitamin complexes for the treatment and prevention of diseases caused by long-term stress.


Diterpenes , Retinyl Esters , Vitamin A , Vitamin B Complex , Rats , Male , Animals , alpha-Tocopherol , Rats, Wistar , Thiamine , Riboflavin , Vitamin B Complex/metabolism , Triglycerides/metabolism , Liver/metabolism , Vitamin K/metabolism , Diet , Cholesterol , Carbohydrates , Body Weight , Starch/metabolism
4.
Int J Mol Sci ; 25(4)2024 Feb 07.
Article En | MEDLINE | ID: mdl-38396721

The human Vitamin K Epoxide Reductase Complex (hVKORC1), a key enzyme transforming vitamin K into the form necessary for blood clotting, requires for its activation the reducing equivalents delivered by its redox partner through thiol-disulfide exchange reactions. The luminal loop (L-loop) is the principal mediator of hVKORC1 activation, and it is a region frequently harbouring numerous missense mutations. Four L-loop hVKORC1 mutants, suggested in vitro as either resistant (A41S, H68Y) or completely inactive (S52W, W59R), were studied in the oxidised state by numerical approaches (in silico). The DYNASOME and POCKETOME of each mutant were characterised and compared to the native protein, recently described as a modular protein composed of the structurally stable transmembrane domain (TMD) and the intrinsically disordered L-loop, exhibiting quasi-independent dynamics. The DYNASOME of mutants revealed that L-loop missense point mutations impact not only its folding and dynamics, but also those of the TMD, highlighting a strong mutation-specific interdependence between these domains. Another consequence of the mutation-induced effects manifests in the global changes (geometric, topological, and probabilistic) of the newly detected cryptic pockets and the alternation of the recognition properties of the L-loop with its redox protein. Based on our results, we postulate that (i) intra-protein allosteric regulation and (ii) the inherent allosteric regulation and cryptic pockets of each mutant depend on its DYNASOME; and (iii) the recognition of the redox protein by hVKORC1 (INTERACTOME) depend on their DYNASOME. This multifaceted description of proteins produces "omics" data sets, crucial for understanding the physiological processes of proteins and the pathologies caused by alteration of the protein properties at various "omics" levels. Additionally, such characterisation opens novel perspectives for the development of "allo-network drugs" essential for the treatment of blood disorders.


Mutation, Missense , Vitamin K Epoxide Reductases , Humans , Mutation , Oxidation-Reduction , Vitamin K/metabolism , Vitamin K Epoxide Reductases/genetics , Vitamin K Epoxide Reductases/metabolism
5.
Biochem Biophys Res Commun ; 702: 149635, 2024 Apr 02.
Article En | MEDLINE | ID: mdl-38335702

Dietary vitamin K1 (phylloquinone: PK) and menaquinone (MK-n) are converted to menadione (MD) in the small intestine and then translocated to various tissues where they are converted to vitamin K2 (menaquinone-4: MK-4) by UbiA prenyltransferase domain containing protein 1 (UBIAD1). MK-4 is effective in bone formation and is used to treat osteoporosis in Japan. UBIAD1 is expressed in bone and osteoblasts and shows conversion to MK-4, but the role of UBIAD1 in osteogenesis is unknown. In this study, we investigated the function of UBIAD1 in osteogenesis using a tamoxifen-dependent UBIAD1-deficient mouse model. When UBIAD1 deficiency was induced from the first week of life, the femur was significantly shortened, and bone mineral density (BMD) was reduced. In addition, the expression of bone and chondrocyte matrix proteins and chondrocyte differentiation factors was significantly decreased. In primary cultured chondrocytes, chondrocyte differentiation was significantly reduced by UBIAD1 deficiency. These results suggest that UBIAD1 is an important factor for the regulation of chondrocyte proliferation and differentiation during osteogenesis.


Dimethylallyltranstransferase , Vitamin K , Animals , Mice , Vitamin K/metabolism , Osteogenesis , Chondrogenesis , Dimethylallyltranstransferase/genetics , Dimethylallyltranstransferase/metabolism , Vitamin K 1/pharmacology
6.
Int J Mol Med ; 53(1)2024 Jan.
Article En | MEDLINE | ID: mdl-37997858

Vitamin K (VK), a fat­soluble vitamin, is well known as an anticoagulant in the clinic. It is essential for the post­translational activation of VK­dependent proteins (VKDPs) because hydroquinone VK is a cofactor of glutamine carboxylase. At present, 17 VKDPs are known, which are mainly involved in coagulation and calcification. When Glu residues are carboxylated to Gla residues, these proteins gain a higher calcium­binding ability, which explains why VK has an important role in blood coagulation and biomineralization. However, the current view on the role of VK and several VKDPs in biomineralization remains inconsistent. For instance, conflicting results have been reported regarding the effect of osteocalcin gene knockout on the bone of mice; matrix Gla protein (MGP) promotes osteoblasts mineralization but inhibits vascular smooth muscle cell mineralization. The present review aimed to summarize the existing evidence that several VKDPs, including osteocalcin, MGP, Gla­rich protein and growth arrest specific 6 are closely related to calcification, including bone health, vascular calcification and lithiasis. The current review discussed these controversies and provided suggestions for future studies on VKDPs, i.e. taking into account dietary habits, geographical environments and genetic backgrounds.


Vascular Calcification , Vitamin K , Mice , Animals , Vitamin K/metabolism , Osteocalcin/genetics , Osteocalcin/metabolism , Biomineralization , Calcium-Binding Proteins/genetics , Calcium-Binding Proteins/metabolism , Extracellular Matrix Proteins/genetics , Extracellular Matrix Proteins/metabolism , Vascular Calcification/genetics , Bone and Bones/metabolism
7.
Sci Rep ; 13(1): 22102, 2023 12 13.
Article En | MEDLINE | ID: mdl-38092882

Epidermal growth factor receptor (EGFR) inhibitors frequently cause severe skin rash as a side effect, which is a critical burden for patients who continuously receive drug treatments. Several recent clinical trials have shown that vitamin K is effective against these side effects; however, the underlying mechanisms remain unclear. EGFR inhibitors induce C-C motif chemokine ligand 5 (CCL5) in dermopathy. We hypothesized that menahydroquinone-4 (MKH), the active form of menaquinone-4 (MK-4, vitamin K2(20)), supplied by biosynthesis or external delivery, is essential for the suppressive effect on CCL5. The aim of this study was to explore the underlying mechanisms governing the relieving effects of MKH against skin rashes caused by EGFR inhibitors. The responses generated by EGFR inhibitors and the effect of MKH derivatives (two ester derivatives and MK-4) on them were evaluated using human skin cell lines (HaCaT and HSC-1). EGFR inhibitors downregulated UbiA prenyltransferase domain-containing protein-1 (UBIAD1, MKH synthetase) expression and MKH biosynthesis. Knockdown of UBIAD1 or γ-glutamyl carboxylase and treatment with warfarin upregulated CCL5 expression. MKH derivatives suppressed the CCL5 expression induced by EGFR inhibitors. Our data strongly suggest that MKH is involved in suppressing CCL5 expression and alleviating the skin damage caused by EGFR inhibitors.


Chemokines , Vitamin K , Humans , Ligands , Vitamin K/metabolism , ErbB Receptors , Chemokine CCL5
8.
Anal Chim Acta ; 1284: 341972, 2023 Dec 15.
Article En | MEDLINE | ID: mdl-37996163

Gamma (γ) carboxylation is an essential post-translational modification in vitamin K-dependent proteins (VKDPs), involved in maintaining critical biological homeostasis. Alterations in the abundance or activity of these proteins have pharmacological and pathological consequences. Importantly, low levels of fully γ-carboxylated clotting factors increase plasma des-γ-carboxy precursors resulting in little or no biological activity. Therefore, it is important to characterize the levels of γ-carboxylation that reflect the active state of these proteins. The conventional enzyme-linked immunosorbent assay for protein induced by vitamin K absence or antagonist II (PIVKA-II) quantification uses an antibody that is not applicable to distinguish different γ-carboxylation states. Liquid chromatography-mass spectrometry (LC-MS) approaches have been utilized to distinguish different γ-carboxylated proteoforms, however, these attempts were impeded by poor sensitivity due to spontaneous neutral loss of CO2 and simultaneous cleavage of the backbone bond in the collision cell. In this study, we utilized an alkaline mobile phase in combination with polarity switching (positive and negative ionization modes) to simultaneously identify and quantify γ-carboxylated VKDPs. The method was applied to compare Gla proteomics of prothrombin (FII) in 10 µL plasma samples of healthy control and warfarin-treated adults. We also identified surrogate non-Gla peptides for seven other VKDPs to quantify total (active plus inactive) protein levels. The total protein approach (TPA) was used to quantify absolute levels of the VKDPs in human plasma.


Prothrombin , Vitamin K , Adult , Humans , Prothrombin/chemistry , Prothrombin/genetics , Prothrombin/metabolism , Vitamin K/metabolism , Vitamin K/pharmacology , Protein Processing, Post-Translational , Warfarin , Peptides/metabolism
9.
Trends Endocrinol Metab ; 34(11): 683-684, 2023 11.
Article En | MEDLINE | ID: mdl-37648560

Ferroptosis holds promise for cancer therapy. A recent study by Yang et al. in Cell Metabolism reveals that VKORC1L1-mediated reduction of vitamin K inhibits ferroptosis and establishes a direct p53-VKORC1L1 link in its regulation. As warfarin can inhibit VKORC1L1, the study further underscores this drug's potential as a cancer therapy.


Ferroptosis , Neoplasms , Humans , Warfarin/therapeutic use , Warfarin/pharmacology , Vitamin K Epoxide Reductases/metabolism , Neoplasms/drug therapy , Vitamin K/metabolism , Tumor Suppressor Protein p53
10.
Cell Metab ; 35(8): 1474-1490.e8, 2023 08 08.
Article En | MEDLINE | ID: mdl-37467745

Here, we identified vitamin K epoxide reductase complex subunit 1 like 1 (VKORC1L1) as a potent ferroptosis repressor. VKORC1L1 protects cells from ferroptosis by generating the reduced form of vitamin K, a potent radical-trapping antioxidant, to counteract phospholipid peroxides independent of the canonical GSH/GPX4 mechanism. Notably, we found that VKORC1L1 is also a direct transcriptional target of p53. Activation of p53 induces downregulation of VKORC1L1 expression, thus sensitizing cells to ferroptosis for tumor suppression. Interestingly, a small molecular inhibitor of VKORC1L1, warfarin, is widely prescribed as an FDA-approved anticoagulant drug. Moreover, warfarin represses tumor growth by promoting ferroptosis in both immunodeficient and immunocompetent mouse models. Thus, by downregulating VKORC1L1, p53 executes the tumor suppression function by activating an important ferroptosis pathway involved in vitamin K metabolism. Our study also reveals that warfarin is a potential repurposing drug in cancer therapy, particularly for tumors with high levels of VKORC1L1 expression.


Tumor Suppressor Protein p53 , Warfarin , Animals , Mice , Anticoagulants/pharmacology , Anticoagulants/therapeutic use , Vitamin K/metabolism , Vitamin K Epoxide Reductases/genetics , Vitamin K Epoxide Reductases/metabolism , Warfarin/pharmacology , Warfarin/therapeutic use
11.
Life Sci ; 329: 121955, 2023 Sep 15.
Article En | MEDLINE | ID: mdl-37473801

AIMS: This histological study focuses on the impact of electronic cigarette liquid (EC) on lingual papillae, especially taste buds, compare it to nicotine, and investigates the potential of vitamins in reversing these unwanted changes. MAIN METHODS: 40 adult male rats were allocated into 5 groups. Control injected saline intraperitoneally, electronic cigarettes group injected EC-liquid containing nicotine of dose (0.75 mg/kg), electronic cigarette group injected EC-liquid then supplemented orally with vitamins C and E, nicotine group injected pure nicotine of dose (0.75 mg/kg) and lastly nicotine group injected with pure nicotine of dose (0.75 mg/kg) then supplemented orally with vitamins C and E. Keratin surface area and the ratio between taste buds and its epithelial covering surface areas in fungiform papillae were measured. KEY FINDINGS: Histological examination of EC group revealed abnormal epithelial stratification and mitotic figs. EC plus V group showed intact basal cell layer. N group showed better histological stratification than EC group. Fungiform and circumvallate papillae in EC and N groups showed distorted appearance of taste buds. Histomorphometry analysis showed a significant decrease in taste buds to epithelium surface areas in EC, nicotine, and EC plus V groups, p-value (<0.05). There was no significant difference between control and N plus V groups. SIGNIFICANCE: Administration of vitamins C and E showed preservation of normal histological features of the lingual mucous membrane. EC caused striking damage to taste buds even after the administration of vitamins. The negative effects of electronic cigarettes are not confined only to the presence of nicotine.


Electronic Nicotine Delivery Systems , Taste Buds , Male , Rats , Animals , Taste Buds/metabolism , Ascorbic Acid/pharmacology , Nicotine/pharmacology , Nicotine/metabolism , Tongue , Vitamin A , Vitamin K/metabolism , Dietary Supplements , Vitamins
12.
Nat Metab ; 5(6): 924-932, 2023 06.
Article En | MEDLINE | ID: mdl-37337123

Vitamin K is essential for several physiological processes, such as blood coagulation, in which it serves as a cofactor for the conversion of peptide-bound glutamate to γ-carboxyglutamate in vitamin K-dependent proteins. This process is driven by the vitamin K cycle facilitated by γ-carboxyglutamyl carboxylase, vitamin K epoxide reductase and ferroptosis suppressor protein-1, the latter of which was recently identified as the long-sought-after warfarin-resistant vitamin K reductase. In addition, vitamin K has carboxylation-independent functions. Akin to ubiquinone, vitamin K acts as an electron carrier for ATP production in some organisms and prevents ferroptosis, a type of cell death hallmarked by lipid peroxidation. In this Perspective, we provide an overview of the diverse functions of vitamin K in physiology and metabolism and, at the same time, offer a perspective on its role in ferroptosis together with ferroptosis suppressor protein-1. A comparison between vitamin K and ubiquinone, from an evolutionary perspective, may offer further insights into the manifold roles of vitamin K in biology.


Ferroptosis , Vitamin K , Vitamin K/metabolism , Ubiquinone , Vitamin K Epoxide Reductases/genetics , Vitamin K Epoxide Reductases/metabolism , Blood Coagulation
13.
Nature ; 619(7969): 371-377, 2023 Jul.
Article En | MEDLINE | ID: mdl-37380771

Ferroptosis is evolving as a highly promising approach to combat difficult-to-treat tumour entities including therapy-refractory and dedifferentiating cancers1-3. Recently, ferroptosis suppressor protein-1 (FSP1), along with extramitochondrial ubiquinone or exogenous vitamin K and NAD(P)H/H+ as an electron donor, has been identified as the second ferroptosis-suppressing system, which efficiently prevents lipid peroxidation independently of the cyst(e)ine-glutathione (GSH)-glutathione peroxidase 4 (GPX4) axis4-6. To develop FSP1 inhibitors as next-generation therapeutic ferroptosis inducers, here we performed a small molecule library screen and identified the compound class of 3-phenylquinazolinones (represented by icFSP1) as potent FSP1 inhibitors. We show that icFSP1, unlike iFSP1, the first described on-target FSP1 inhibitor5, does not competitively inhibit FSP1 enzyme activity, but instead triggers subcellular relocalization of FSP1 from the membrane and FSP1 condensation before ferroptosis induction, in synergism with GPX4 inhibition. icFSP1-induced FSP1 condensates show droplet-like properties consistent with phase separation, an emerging and widespread mechanism to modulate biological activity7. N-terminal myristoylation, distinct amino acid residues and intrinsically disordered, low-complexity regions in FSP1 were identified to be essential for FSP1-dependent phase separation in cells and in vitro. We further demonstrate that icFSP1 impairs tumour growth and induces FSP1 condensates in tumours in vivo. Hence, our results suggest that icFSP1 exhibits a unique mechanism of action and synergizes with ferroptosis-inducing agents to potentiate the ferroptotic cell death response, thus providing a rationale for targeting FSP1-dependent phase separation as an efficient anti-cancer therapy.


Apoptosis Regulatory Proteins , Ferroptosis , Mitochondrial Proteins , Humans , Amino Acids/metabolism , Cysteine/metabolism , Ferroptosis/drug effects , Glutathione/metabolism , NAD/metabolism , NADP/metabolism , Neoplasms/drug therapy , Quinazolines/pharmacology , Small Molecule Libraries , Ubiquinone/metabolism , Vitamin K/metabolism , Apoptosis Regulatory Proteins/antagonists & inhibitors , Apoptosis Regulatory Proteins/metabolism , Mitochondrial Proteins/antagonists & inhibitors , Mitochondrial Proteins/metabolism
14.
Nutrients ; 15(8)2023 Apr 18.
Article En | MEDLINE | ID: mdl-37111170

Vitamin K occupies a unique and often obscured place among its fellow fat-soluble vitamins. Evidence is mounting, however, that vitamin K (VK) may play an important role in the visual system apart from the hepatic carboxylation of hemostatic-related proteins. However, to our knowledge, no review covering the topic has appeared in the medical literature. Recent studies have confirmed that matrix Gla protein (MGP), a vitamin K-dependent protein (VKDP), is essential for the regulation of intraocular pressure in mice. The PREDIMED (Prevención con Dieta Mediterránea) study, a randomized trial involving 5860 adults at risk for cardiovascular disease, demonstrated a 29% reduction in the risk of cataract surgery in participants with the highest tertile of dietary vitamin K1 (PK) intake compared with those with the lowest tertile. However, the specific requirements of the eye and visual system (EVS) for VK, and what might constitute an optimized VK status, is currently unknown and largely unexplored. It is, therefore, the intention of this narrative review to provide an introduction concerning VK and the visual system, review ocular VK biology, and provide some historical context for recent discoveries. Potential opportunities and gaps in current research efforts will be touched upon in the hope of raising awareness and encouraging continued VK-related investigations in this important and highly specialized sensory system.


Vitamin K Deficiency , Vitamin K , Mice , Animals , Vitamin K/metabolism , Vitamin K 1 , Vitamins , Sense Organs/metabolism , Vitamin K 2/metabolism
15.
Anticancer Res ; 43(5): 1959-1965, 2023 May.
Article En | MEDLINE | ID: mdl-37097656

BACKGROUND/AIM: Unique cartilage matrix-associated protein (UCMA), a recently discovered vitamin K-dependent protein (VKDP) with a large number of γ-carboxyglutamic acid (Gla) residues, is associated with ectopic calcifications. Although the function of VKDPs is related to their γ-carboxylation status, the carboxylation status of UCMA in breast cancer is still unknown. Here, we investigated the inhibitory effect of UCMA with differing γ-carboxylation status on breast cancer cell lines, such as MDA-MB-231, 4T1, and E0771 cells. MATERIALS AND METHODS: Undercarboxylated UCMA (ucUCMA) was generated by mutating the γ-glutamyl carboxylase (GGCX) recognition sites. The ucUCMA and carboxylated UCMA (cUCMA) proteins were collected from culture media of HEK293-FT cells that had been transfected with mutated GGCX and wild-type UCMA expression plasmids, respectively. Boyden Transwell and colony formation assays were performed to evaluate cancer cell migration, invasion, and proliferation. RESULTS: Culture medium containing cUCMA protein inhibited the migration, invasion, and colony formation of MDA-MB-231 and 4T1 cells to a greater degree than medium containing ucUCMA protein. Significant reductions in the migration, invasion, and colony formation were also observed in cUCMA-treated E0771 cells compared to those in ucUCMA-treated cells. CONCLUSION: The inhibitory role of UCMA in breast cancer is closely related to its γ-carboxylation status. The results of this study may be a basis for the development of UCMA-based anti-cancer drugs.


Breast Neoplasms , Humans , Female , Matrilin Proteins , HEK293 Cells , Proteins/metabolism , Vitamin K/metabolism , Cartilage
16.
Nat Commun ; 14(1): 828, 2023 02 14.
Article En | MEDLINE | ID: mdl-36788244

Vitamin K is a vital micronutrient implicated in a variety of human diseases. Warfarin, a vitamin K antagonist, is the most commonly prescribed oral anticoagulant. Patients overdosed on warfarin can be rescued by administering high doses of vitamin K because of the existence of a warfarin-resistant vitamin K reductase. Despite the functional discovery of vitamin K reductase over eight decades ago, its identity remained elusive. Here, we report the identification of warfarin-resistant vitamin K reductase using a genome-wide CRISPR-Cas9 knockout screen with a vitamin K-dependent apoptotic reporter cell line. We find that ferroptosis suppressor protein 1 (FSP1), a ubiquinone oxidoreductase, is the enzyme responsible for vitamin K reduction in a warfarin-resistant manner, consistent with a recent discovery by Mishima et al. FSP1 inhibitor that inhibited ubiquinone reduction and thus triggered cancer cell ferroptosis, displays strong inhibition of vitamin K-dependent carboxylation. Intriguingly, dihydroorotate dehydrogenase, another ubiquinone-associated ferroptosis suppressor protein parallel to the function of FSP1, does not support vitamin K-dependent carboxylation. These findings provide new insights into selectively controlling the physiological and pathological processes involving electron transfers mediated by vitamin K and ubiquinone.


Apoptosis Regulatory Proteins , NAD(P)H Dehydrogenase (Quinone) , Warfarin , Humans , Anticoagulants/pharmacology , CRISPR-Cas Systems , NAD(P)H Dehydrogenase (Quinone)/metabolism , Ubiquinone/pharmacology , Ubiquinone/metabolism , Vitamin K/metabolism , Vitamin K Epoxide Reductases/genetics , Vitamin K Epoxide Reductases/metabolism , Warfarin/pharmacology , Apoptosis Regulatory Proteins/genetics
17.
ACS Chem Neurosci ; 14(4): 657-666, 2023 02 15.
Article En | MEDLINE | ID: mdl-36728544

Alzheimer's disease is characterized by the presence in the brain of amyloid plaques formed by the aberrant deposition of the amyloid-ß peptide (Aß). Since many vitamins are dysregulated in this disease, we explored whether these molecules contribute to the protein homeostasis system by modulating Aß aggregation. By screening 18 fat-soluble and water-soluble vitamin metabolites, we found that retinoic acid and α-tocopherol, two metabolites of vitamin A and vitamin E, respectively, affect Aß aggregation both in vitro and in a Caenorhabditis elegans model of Aß toxicity. We then show that the effects of these two vitamin metabolites in specific combinations cancel each other out, consistent with the "resilience in complexity" hypothesis, according to which the complex composition of the cellular environment could have an overall protective role against protein aggregation through the simultaneous presence of aggregation promoters and inhibitors. Taken together, these results indicate that vitamins can be added to the list of components of the protein homeostasis system that regulate protein aggregation.


Alzheimer Disease , Vitamin A , Animals , Vitamin E/pharmacology , Vitamin E/metabolism , Protein Aggregates , Amyloid beta-Peptides/metabolism , Alzheimer Disease/metabolism , Vitamins/pharmacology , Vitamins/metabolism , Vitamin K/metabolism , Caenorhabditis elegans
18.
Theriogenology ; 198: 183-193, 2023 Mar 01.
Article En | MEDLINE | ID: mdl-36592516

The effect of vitamin K on bovine endometrial epithelial cells has not been thoroughly investigated. The objective of this study was to examine the effect of the biologically active form of vitamin K, menaquinone-4, on gene expression in bovine endometrial epithelial cells. First, we examined the mRNA and protein expression levels of UBIAD1, a menaquinone-4 biosynthetic enzyme. Second, we screened for potential target genes of menaquinone-4 in bovine endometrial epithelial cells using RNA-sequencing. We found 50 differentially expressed genes; 42 were upregulated, and 8 were downregulated. Among them, a dose-dependent response to menaquinone-4 was observed for the top three upregulated (TRIB3, IL6, and TNFAIP3) and downregulated (CDC6, ORC1, and RRM2) genes. It has been suggested that these genes play important roles in reproductive events. In addition, GDF15 and VEGFA, which are important for cellular functions as they are commonly involved in pathways, such as positive regulation of cell communication, cell differentiation, and positive regulation of MAPK cascade, were upregulated in endometrial epithelial cells by menaquinone-4 treatment. To the best of our knowledge, this is the first study showing the expression of UBIAD1 in the bovine uterus. Moreover, the study determined menaquinone-4 target genes in bovine endometrial epithelial cells, which may positively affect pregnancy with alteration of gene expression in cattle uterus.


Endometrium , Vitamin K , Female , Cattle , Animals , Vitamin K 2/metabolism , Vitamin K 2/pharmacology , Vitamin K/metabolism , Endometrium/metabolism , Epithelial Cells/metabolism
19.
Poult Sci ; 102(3): 102482, 2023 Mar.
Article En | MEDLINE | ID: mdl-36706663

Sodium dehydroacetate (S-DHA) is used widely as a preservative in several products, including poultry feed. The anticoagulation effect of 200 mg/kg S-DHA in rats has been reported to accompany a reduction in hepatic expression of vitamin K epoxide reductase complex 1 (VKORC1). Poultry and mammals have different physiology and coagulation systems, and species differences in VKORC1 expression have been found. The effect of S-DHA on blood clotting of poultry has not been studies deeply. S-DHA was given to yellow-plumage broilers (YBs) as single and multiple administrations. Vitamin K3 (VK3) was injected into YBs 2 wk after S-DHA administration. Then, the prothrombin time (PT), partial activated prothrombin time (APTT), plasma levels of vitamin K (VK), factor IX (FIX), and S-DHA, and hepatic expression of VKORC1 were obtained. Chicken hepatocellular carcinoma (LMH) cells were also exposed to S-DHA, and the cell activity, VK level, and FIX level were measured. S-DHA prolonged the PT or APTT significantly, decreased levels of VK and FIX in blood, and inhibited hepatic expression of VKORC1. The maximum changes were 1.15-fold in the PT, 1.42-fold in the APTT, 0.8-fold in the VK level, 0.7-fold in the FIX level, and 0.35-fold in VKORC1 expression compared with controls. The cell activity, VK level, FIX level, and VKORC1/VKORC1L1 expression of LMH cells were reduced significantly at S-DHA doses of 2.0 to 10.0 mM. Prolongation of the PT/APTT and lower levels of VK/FIX in YBs or the lower cell activity and VK/FIX levels in LMH cells induced by S-DHA therapy were resisted significantly by VK3 treatment. We demonstrated that S-DHA could induce a disorder in coagulation function in YBs or in LMH cells via reduction of VKORC1/VKORC1L1 expression, and that VK could resist this anticoagulation effect.


Blood Coagulation Disorders , Chickens , Vitamin K , Animals , Rats , Anticoagulants/pharmacology , Blood Coagulation/drug effects , Chickens/metabolism , Mammals/metabolism , Vitamin K/metabolism , Vitamin K/pharmacology , Vitamin K/therapeutic use , Vitamin K Epoxide Reductases/genetics , Vitamin K Epoxide Reductases/metabolism , Blood Coagulation Disorders/chemically induced , Blood Coagulation Disorders/drug therapy , Blood Coagulation Disorders/veterinary
20.
Toxicol In Vitro ; 87: 105518, 2023 Mar.
Article En | MEDLINE | ID: mdl-36403723

Sodium dehydroacetate (Na-DHA) is widely used as an antibacterial and preservative additive in food and cosmetics. Previously, we reported that repeated oral administration of Na-DHA induces coagulation disorders, and inhibited liver vitamin K epoxide reductase complex subunit 1 (VKORC1) and VKORC1-like protein 1 (VKORC1L1) in rats. However, the effects of Na-DHA on coagulation factors in rat hepatocytes and the mechanism of VKORC1 and VKORC1L1 signaling in that process are unclear. Here, we constructed stable Vkorc1 and Vkorc1l1 overexpressing cell lines using lentiviruses and transfected small interfering RNAs into buffalo rat liver BRL3A cells for Vkorc1 and Vkorc1l1 overexpression and silencing, respectively. After treatment with 5 mmol/L Na-DHA for 24 h, VKORC1 and VKORC1L1 expression levels were detected by real-time PCR and western blotting. Vitamin K (VK) and factor IX (FIX) contents were detected using enzyme linked immunosorbent assays. We observed that Na-DHA inhibited VKORC1 and VKORC1L1 expression levels and reduced VK and FIX levels in rat hepatocytes. Overexpression or silencing of Vkorc1 and Vkorc1l1 increased or decreased, respectively, the production and secretion of VK and FIX in rat hepatocytes, and alleviated or aggravated the inhibitory effects of Na-DHA on VKORC1 and VKORC1L1 expression levels. Taken together, the results indicated that both VKORC1 and VKORC1L1 signaling play regulatory roles in the effects of Na-DHA on coagulation factors in rat hepatocytes.


Hepatocytes , Vitamin K , Rats , Animals , Vitamin K Epoxide Reductases/genetics , Vitamin K Epoxide Reductases/metabolism , Vitamin K/metabolism , Hepatocytes/metabolism , Blood Coagulation Factors
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