vitamin-k-semiquinone-radical and Arthritis--Rheumatoid

Rheumatoid arthritis (RA) is an autoimmune disease of multifactorial etiology, characterized by a chronic inflammatory reaction of the joints, but can also affect other tissues. Some environmental factors can trigger an immune system response in genetically susceptible individuals, activating the disease. Lower diversity of gut microbiota, and dysbiosis, have been observed in RA patients. In this regard, approaches to decrease inflammation, and to restore the microbiota, have been suggested. These include oral administration of single probiotics, or probiotic mixtures, on their own, or in combination with drugs. Vitamin K (VitK) is one of the many products of the intestinal microbiota. Lower levels of some forms of VitK have been measured in the serum and stools of RA patients and some studies have found an inverse correlation between VitK levels and the clinical severity of the disease. Additionally, some forms of this vitamin, when given orally, have been shown to exert positive effects in decreasing RA activity, and delaying its onset and progress. This review aims at describing the link between the gut microbiota and RA, focusing on the role of VitK and probiotics as possible adjuvant therapies in this disease.

Topics: Arthritis, Rheumatoid; Gastrointestinal Microbiome; Humans; Inflammation; Probiotics; Rheumatic Fever; Vitamin K; Vitamins

Vitamin K2 [menaquinone-4 (MK-4)] has been reported to induce apoptosis in hepatocellular carcinoma, leukemia, and MDS cell lines. The effects of MK-4 on the development of arthritis have never been addressed so far. In this study, we investigated the effect of MK-4 upon the proliferation of rheumatoid synovial cells and the development of arthritis in collagen-induced arthritis (CIA). We analyzed the effect of MK-4 on the proliferation of fibroblast-like synoviocytes (FLSs) using the 3-(4,5-demethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The proapoptotic effect of MK-4 upon FLS was investigated with annexin V staining and DNA fragmentation and caspase 3/7 assays. Moreover, we analyzed the effect of MK-4 on the development of CIA in female dark agouti rats. Our results indicated that MK-4 inhibited the proliferation of FLS and the development of CIA in a dose-dependent manner. We concluded that MK-4 may represent a new agent for the treatment of RA in the setting of combination therapy with other disease-modifying antirheumatic drugs.

Topics: Animals; Antirheumatic Agents; Apoptosis; Arthritis, Rheumatoid; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Female; Fibroblasts; Humans; Models, Biological; Rats; Reactive Oxygen Species; Tetrazolium Salts; Thiazoles; Vitamin K

Topics: Arthritis, Rheumatoid; Cohort Studies; Fractures, Bone; Glucocorticoids; Glycine max; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Incidence; Prospective Studies; Risk; Risk Factors; Vitamin K

The connective tissues are a complex organisation of tissues, cells and intercellular materials spread throughout the body and are subject to a large number of diseases. Such complexity makes the study of the metabolism of the connective tissues in health and more particularly in disease states difficult if one uses conventional biochemical methodology. Fortunately the techniques of quantitative cytochemistry, as developed in recent years, have made it possible to study the metabolism of even such complex and refractory connective tissues as bone. Using properly validated assays of enzyme activity in unfixed sections from various tissues a number of the diseases of the connective tissues have been studied. For example the synovia from patients with rheumatoid arthritis and related conditions have been studied using these techniques and marked alterations in the metabolism of the synovial lining cell population of this tissue have been demonstrated. These alterations in metabolism are believed to be related to the destruction of cartilage and bone found in such diseases. Investigations of the metabolism of the chondrocytes of articular cartilage in a strain of mice which spontaneously develops osteoarthritis has revealed a lack of certain key enzymes of carbohydrate metabolism in precisely those areas where degradation of the matrix of articular cartilage begins suggesting a causal relationship between these events. These same techniques have been used to study the cellular kinetics and metabolism of the dermis and epidermis in the disfiguring disease, psoriasis. The metabolism of healing bone fractures, the diagnosis and treatment of the mucopolysaccharidoses and the metabolic effects of currently used anti-inflammatory and anti-rheumatic drugs have also been examined. Perhaps the most exciting aspect of these studies has been the development and use of the technique of the cytochemical bioassay (CBA) to study hormonally mediated diseases of the connective tissues. Such studies have recently shed new light on the molecular lesion in pseudohypoparathyroidism. Though still in their relative infancy the studies described in this review show the potential inherent in the use of quantitative cytochemistry for the study of diseases of the connective tissues.

Topics: Animals; Arthritis, Rheumatoid; Cartilage, Articular; Cell Division; Connective Tissue Diseases; Disease Models, Animal; Epidermal Cells; Fractures, Bone; Glucosephosphate Dehydrogenase; Glycolysis; Hexosephosphates; Histocytochemistry; Humans; Lysosomes; Mitochondria; Mucopolysaccharidoses; NADP; Osteoarthritis; Pseudohypoparathyroidism; Psoriasis; Synovial Membrane; Vitamin K; Wound Healing; Zinc

Cases of enhanced anticoagulant effect in response to high-dose vitamin E supplementation have been reported among patients taking oral anticoagulants. Although a vitamin E-vitamin K interaction was proposed to underlie this effect, it has not been systematically investigated in adults with normal baseline coagulation status.. The objective was to study the effect of 12 wk of supplementation with 1000 IU RRR-alpha-tocopherol/d on biochemical measures of vitamin K status in men and women not taking oral anticoagulants.. Vitamin K status, which was assessed with the use of plasma phylloquinone concentrations, the degree of under-gamma-carboxylation of prothrombin (proteins induced by vitamin K absence-factor II, PIVKA-II), and the percentage of undercarboxylated osteocalcin (ucOC), was determined in 38 men and women with rheumatoid arthritis (study A) and in 32 healthy men (study B) participating in 2 independent, 12-wk randomized clinical trials of vitamin E supplementation (1000 IU/d).. Mean (+/- SD) PIVKA-II increased from 1.7 +/- 1.7 to 11.9 +/- 16.1 ng/mL (P < 0.001) in study A and from 1.8 +/- 0.6 to 5.3 +/- 3.9 ng/mL (P < 0.001) in study B in response to 12 wk of vitamin E supplementation. An increase in PIVKA-II is indicative of poor vitamin K status. In contrast, the other measures of vitamin K status (ie, plasma phylloquinone concentration and percentage of ucOC) did not change significantly in response to the supplementation.. High-dose vitamin E supplementation increased PIVKA-II in adults not receiving oral anticoagulant therapy. The clinical significance of these changes warrants further investigation, but high doses of vitamin E may antagonize vitamin K. Whether such an interaction is potentially beneficial or harmful remains to be determined.

Topics: Adult; Aged; Aged, 80 and over; alpha-Tocopherol; Antioxidants; Arthritis, Rheumatoid; Blood Coagulation; Dietary Supplements; Female; Humans; Male; Middle Aged; Nutritional Status; Vitamin E; Vitamin K

Vitamin K is a fat-soluble vitamin involved in blood coagulation and bone metabolism. The detection and monitoring of vitamin K homologues in rheumatoid arthritis (RA) patients is a challenging problem due to the smaller concentrations of vitamin K and the presence of several interfering medications. Therefore, this study aimed to develop a new highly sensitive and selective chemiluminescence (CL) method designated to quantify vitamin K homologues in plasma of RA patients including phylloquinone (PK, vitamin K(1)), menaquinone-4 (MK-4, vitamin K(2)) and menaquinone-7 (MK-7, vitamin K(2)). The method was based on the unique photochemical properties of vitamin K homologues that were exploited for selective luminol CL reaction. The correlation coefficients of 0.998 or more were obtained in the concentration ranges of 0.1-100 ng mL(-1) vitamin K homologues. The detection limits were 0.03-0.1 ng mL(-1) in human plasma for vitamin K homologues. The developed HPLC-CL system was successfully applied for selective determination of vitamin K homologues in plasma of RA patients. The developed method may provide a useful tool for monitoring vitamin K homologues in different clinical studies such as RA, osteoporosis and hepatocellular carcinoma in which vitamin K is intervented.

Topics: Arthritis, Rheumatoid; Carcinoma, Hepatocellular; Drug Interactions; Humans; Limit of Detection; Liver Neoplasms; Luminescent Measurements; Luminol; Methods; Osteoporosis; Vitamin K

Matrix γ-carboxyglutamate (Gla) protein (MGP) is an important local inhibitor of vascular calcification, which can undergo two post-translational modifications: vitamin K-dependent γ-glutamate carboxylation and serine phosphorylation. While carboxylation is thought to have effects upon binding of calcium-ions, phosphorylation is supposed to affect the cellular release of MGP. Since both modifications can be exerted incompletely, various MGP species can be detected in the circulation. MGP levels were measured with two commercially available competitive and two novel sandwich assays in healthy controls, in patients with rheumatic disease, aortic valve disease, and end-stage renal disease, as well as in volunteers after vitamin K supplementation (VKS) and treatment with vitamin K antagonists (VKA). Major differences were found between the MGP assays, including significantly different behaviour with regard to vascular disease and the response to VKA and VKS. The dual-antibody assay measuring non-phosphorylated, non-carboxylated MGP (dp-ucMGP) was particularly sensitive for these changes and would be suited to assess the vascular vitamin K status. We conclude that the different assays for particular circulating MGP species allows the assessment of various aspects of the MGP system.

Topics: Adult; Aged; Antibodies, Monoclonal; Aortic Valve Insufficiency; Arthritis, Rheumatoid; Biomarkers; Calcinosis; Calcium-Binding Proteins; Chondrocalcinosis; Disease Progression; Enzyme-Linked Immunosorbent Assay; Extracellular Matrix Proteins; Feasibility Studies; Humans; Kidney Failure, Chronic; Matrix Gla Protein; Middle Aged; Prognosis; Protein Processing, Post-Translational; Vitamin K

Spinal and peripheral skeletal demineralisation is sometimes observed in rheumatoid arthritis (RA). Numerous studies have shown the role of osteoclasts in its genesis, but few studies have been conducted to demonstrate a functional anomaly of osteoblasts. Synthesized by osteoblasts, osteocalcin enables to approach the osteoblastic activity, through titration of its serum level. In 31 patients suffering from erosive classical RA, we titrated the serum osteocalcin. In 9 cases, we found a definite decrease of the serum osteocalcin levels. There was a statistically significant difference between these 9 patients and the 21 others, in the presence of anomalies of the CD4/CD8 lymphocytic ratio, the presence of extra-articular manifestations, a high level of rheumatoid factors, class IgM, with an immuno-enzymatic technique. On the contrary, there was no difference regarding the mean duration of the RA course, the mean age, calcemia, and alkaline phosphatases level. Thus, in the course of severe clinical and immunological rheumatoid arthritis, an anomaly of cellular immunity was observed associated with abnormal serum osteocalcin levels. The exact mechanism of this decrease remains to be specified. Other prospective studies are necessary to confirm this preliminary research.

Topics: 1-Carboxyglutamic Acid; Arthritis, Rheumatoid; Bone and Bones; Calcium-Binding Proteins; Female; Humans; Immunoglobulin M; Leukocyte Count; Male; Middle Aged; Osteocalcin; Rheumatoid Factor; T-Lymphocytes; Vitamin K

Osteocalcin, a vitamin K dependent protein synthesised by osteoblasts, was measured in serum by radioimmunoassay in patients with rheumatoid arthritis (n = 36) and seronegative spondyloarthropathies (n = 23). The serum osteocalcin levels were decreased in both patient groups compared with the levels measured in age and sex matched healthy controls. We found no relation between serum osteocalcin and the disease duration or inflammatory activity of the patients who were without drug treatment at the first examination. After administration of glucocorticoids (20 mg prednisolone a day) circulating osteocalcin decreased significantly after one week of treatment. During gradual reduction of the steroid dosage osteocalcin returned to pretreatment values. Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) did not influence circulating osteocalcin. During treatment with chloroquine or penicillamine serum osteocalcin increased significantly, concomitant with a reduction of the acute phase reactants. Controversy persists about the abnormality of bone turnover in rheumatic diseases, but our data suggest that the overall bone turnover is decreased in patients with rheumatoid arthritis and other inflammatory arthritides.

Topics: Adrenocorticotropic Hormone; Adult; Aged; Arthritis; Arthritis, Rheumatoid; Azathioprine; Calcium-Binding Proteins; Chloroquine; Cyclophosphamide; Drug Therapy, Combination; Female; Haptoglobins; Humans; Male; Middle Aged; Osteocalcin; Penicillamine; Prednisolone; Vitamin K

Topics: Arthritis, Rheumatoid; Humans; Injections, Intra-Articular; Vitamin K

Topics: Arthritis, Rheumatoid; Greece; Humans; Magnoliopsida; Medicine, Chinese Traditional; Phytotherapy; Vitamin K

Topics: Aged; Anticoagulants; Arthritis, Rheumatoid; Arthroplasty; Aspirin; Blood Coagulation; Blood Platelets; Dextrans; Follow-Up Studies; Heparin; Hip Joint; Humans; Joint Prosthesis; Osteoarthritis; Postoperative Complications; Spondylitis, Ankylosing; Vitamin K; Warfarin

Fourteen cases of ASA induced hypoprothrombinemic bleeding, including three patients reported by the authors, are reviewed. Predisposing factors toward bleeding include malnutrition and malabsorption syndrome. Although the bleeding is usually benign, it may be serious on occasion. The importance of this rarely considered cause of ASA associated bleeding lies in the fact that it is readily corrected with Vitamin K.

Topics: Adult; Aged; Arthritis, Rheumatoid; Aspirin; Epistaxis; Female; Humans; Hypoprothrombinemias; Malabsorption Syndromes; Male; Middle Aged; Nutrition Disorders; Vitamin K

Topics: Arthritis, Rheumatoid; Ascorbic Acid; Culture Techniques; Cytoplasm; Extracellular Space; Humans; Hydrogen-Ion Concentration; Lysosomes; NADP; Oxidation-Reduction; Synovial Membrane; Vitamin K

Topics: Anemia; Arthritis; Arthritis, Rheumatoid; Calcium; Humans; Iron; Vitamin K; Vitamins