Dynamic changes and influencing factors of vitamin K levels in neonates / 中国新生儿科杂志

Objective:To study the incidences of vitamin K 1 and K 2 deficiency (VKD) in umbilical cord blood (UBC) of neonates and the dynamic changes and influencing factors of serum vitamin K 1 levels after preventive vitamin K 1 supplementation. Methods:From January 2021 to June 2022, neonates born in the Obstetrics Department of our hospital were prospectively enrolled and the levels of vitamin K 1 and K 2 in UBC and serum vitamin K 1 levels at 14 d and 28 d after vitamin K 1 supplementation were measured. The neonates were assigned into hospitalization group and healthy group and further assigned into early-preterm, late-preterm and full-term groups based on gestational age (GA). The incidences of VKD of different GA were studied. Dynamic changes of vitamin K 1 levels were calculated. Multivariate logistic regression was used to analyze the influencing factors of vitamin K 1 levels in hospitalization group at 28 d. Results:A total of 100 neonates were included. 80 neonates were hospitalized, including 25 early-preterm, 25 late-preterm and 30 full-term. 20 were healthy full-term neonates. No significant differences existed in the incidences of VKD of different GA ( P>0.05), however, the overall incidences were high (82.0% and 84.0%, respectively). After preventive vitamin K 1 supplementation, the levels of vitamin K 1 in full-term and preterm groups at 14 d were higher than at birth and 28 d. The levels of vitamin K 1 in hospitalized full-term neonates at 14 d and 28 d were higher than hospitalized preterm neonates. The levels of vitamin K 1 at 28 d in healthy group was significantly higher than hospitalization group ( P<0.05). Multivariate logistic regression analysis showed that maternal complications during pregnancy ( OR=5.889, 95% CI 1.621-21.399, P=0.007) and neonatal antibiotic use ( OR=5.615, 95% CI 1.833-17.221, P=0.003) were risk factors and formula feeding ( OR=0.389, 95% CI 0.193-0.786, P=0.008) was a protective factor for VKD. Conclusions:VKD is common in neonates. The serum vitamin K 1 level increases significantly after preventive vitamin K 1 supplementation. The vitamin K 1 levels of hospitalized full-term neonates at 14 d and 28 d are higher than hospitalized preterm neonates. The levels of vitamin K 1 at 28 d in hospitalized neonates are influenced by feeding methods, maternal complications during pregnancy and neonatal antibiotic use.

Effect of vitamin K 2 on traumatic brain injury and the relationship with NLRP3 inflammasomes in rats / 中华麻醉学杂志

Objective:To evaluate the effect of vitamin K 2 on traumatic brain injury (TBI) and the relationship with nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasomes in rats. Methods:Thirty-six SPF healthy male Sprague-Dawley rats, weighing 280-300 g, were divided into 3 groups ( n=12 each) by a random number table method: sham operation group (group Sham), group TBI and TBI plus vitamin K 2 group (group TBI+ VK 2). The TBI model was developed using modified Feeney′s method.In TBI+ VK 2 group, vitamin K 2 400 mg/kg (dissolved in dimethyl sulfoxide) was intraperitoneally injected at 30 min after developing TBI model.The equal volume of dimethyl sulfoxide was intraperitoneally injected in group Sham and group TBI.The modified neurological severity score (mNSS) was measured and open field tests were performed at 24 h after development of TBI.The rats were sacrificed after the end of behavioral testing, and brains were obtained for measurement of brain water content (by wet-dry weight method), percentage of brain injury volume (by TTC assay), contents of interleukin-1β (IL-1β), IL-18 and caspase-1 in cortex on the injured side (by enzyme-linked immunosorbent assay) and expression of NLRP3, caspase-1 and IL-18 in cortex on the injured side (by Western blot). Results:Compared with group Sham, the mNSS score was significantly increased, the total distance travelled was reduced, the time spent in the central zone was shortened, the brain water content and percentage of brain injury volume were increased, the contents of IL-1β, IL-18 and caspase-1 in cortex on the injured side were increased, and the expression of NLRP3, caspase-1 and IL-18 was up-regulated in group TBI ( P<0.05 or 0.01). Compared with group TBI, the mNSS score was significantly decreased, the total distance travelled was increased, the time spent in the central zone was prolonged, the brain water content and percentage of brain injury volume were decreased, the contents of IL-1β, IL-18 and caspase-1 in cortex on the injured side were decreased, and the expression of NLRP3, caspase-1 and IL-18 was down-regulated in group TBI+ VK 2 ( P<0.05 or 0.01). Conclusions:Vitamin K 2 can reduce TBI, and the mechanism may be related to inhibition of the activation of NLRP3 inflammasomes in rats.

Increased serum osteocalcin levels and vitamin K status by daily cheese intake

Background:Cheese is a major source of long-chained vitamin K2 variants. How intake of vitamin K2 rich cheese affects vitamin K and osteocalcin has not been studied. The aim was to establish a maximum efficacy dose (MED) after daily intake of vitamin K2-rich cheese (Jarlsberg®) based on increase in ratio between carboxylated and undercarboxylated osteocalcin during a five-week diet.Methods:20 healthy healthy volunteers (HV) were recruited. The daily intake of Jarlsberg®cheese in the study varied from 20 to 152g. Clinical investigation was performed initially and after three, four and five weeks with measurement of vital signs, hematological and biochemical variables, carboxylatedand undercarboxylated osteocalcin and vitamin K. The ratio OR=carboxylated/undercarboxylated osteocalcin was the main variable.Results:The MED decreased with treatment duration and was estimated to 57 g/day (95% CI: 47-67)after five weeks diet, resulting in a mean OR increase of 30% (95% CI: 23.8-36.8). Both OR and serum osteocalcin followed a quadratic dose response curve. For osteocalcin,a maximal increase of 46% was estimated at 59 g/day for five weeks. The serum content of long-chained vitamin K2 increased significantly with increasing cheese dose. The increase were mainly obtained the first three weeks and kept unchanged the following two weeks. The cheese doses close to the MED caused nearly significant reductionsin total cholesterol, LDL-cholesterol, the LDL/HDL ratio and significant reduction in the blood pressures after five weeks diet (p?0.05). Conclusions: MED of Jarlsberg® cheese was estimated to 57g/day. Daily intake of Jarlsberg®cheese increasedthe osteocalcin level, vitamin K2andpositively affected the lipid patterns and blood pressure.

Clinical application of zoledronic acid combined with vitamin K2 in percutaneous vertebroplasty for multi-segment osteoporotic vertebral compression fractures / 中国骨伤

OBJECTIVE@#To explore the clinical effect of zoledronic acid combined with vitamin K2 regimen in percutaneous vertebroplasty for multi-segment osteoporotic vertebral compression fractures(OVCFs).@*METHODS@#This study was a retrospective control study. A total of 364 patients with OVCFs who were admitted to our spinal surgery department from January 2014 to January 2017 were selected as the study subjects. According to whether zoledronic acid combined with vitamin K2 was used to treat osteoporosis after surgery, the patients were divided into control group and experimental group. Among them, 257 patients in the control group were treated with calcium carbonate and vitamin D regimen, while 107 patients in the experimental group were treated with zoledronic acid combined with vitamin K2 regimen on the basis of the control group. Visual analogue scale (VAS) score and Oswestry Disability Index (ODI) were used to evaluate the clinical effect. Pre- and post-operative bone mineral density of lumbar spine and proximal femur, vertebral height ratio of responsible vertebral body and Cobb angle of vertebral body were observed by image data. Serological indicators related to bone metabolism were detected by laboratory. The complications such as fever, dizziness, osteoarthritis, muscular and soft tissue pain and adjacent vertebral re-fracture were compared between two groups.@*RESULTS@#There was no significant difference in general data between the two groups (0.05);VAS score in the experimental group was significantly lower than that in the control group 1 month, 3 months and 1 year after operation(0.05), and at the 24 hours, 3 months, 1 year after operation, the experimental group was significantly lower than the control group (0.05). The vertebral height ratio of the responsible vertebral body in experimental group was significantly higher than that in control group and Cobb angle in experimental group was significantly lower than that in control group at 3 months and 1 year after operation (0.05), but at 3 months and 1 year after operation, the bone mineral density of lumbar spine and proximal femur in experimental group was significantly lower than that in control group (0.05). At 1 year after operation the total type I collagen amino-terminal elongation peptide and β-collagen degradation products in experimental group was significantly lower than that in the control group (<0.05), but the 25-hydroxyvitamin D operation in experimental group was significantly higher than that in control group(<0.05). The incidence of postoperative complications such as fever, dizziness, osteoarthritis, muscle and soft tissue pain and adjacent vertebral re-fracture in experimental group was significantly lower than that in control group (<0.05).@*CONCLUSION@#Zoledronic acid injection combined with vitamin K2 regimen can be used for anti-osteoporosis treatment of OVCFs vertebroplasty. It has a definite curative effect and a high safety factor. It is worth popularizing.

Effects of different hemodialysis methods on vitamin K2 and abdominal aortic calcification / 实用医学杂志

Objective To compare the effects of different hemodialysis methods on vitamin K2and abdomi-nal aortic calcification.Methods From January 2016 to June 2017,collect 60 maintenance hemodialysis(MHD) patients in the First Affiliated Hospital of Shihezi University,including low flux hemodialysis(HD)patients with 30 cases and high flux hemodialysis(HFHD)patients with 30 cases.Selecting 30 cases as healthy group and con-trol group with similar sex and age.Blood biochemical detection of serum calcium,phosphorus,magnesium,albu-min,parathyroid hormone and other indicators were deternmined.Detecting the abdominal aortic calcification score calculation with abdominal lateral X-ray.Detecting serum vitamin K2levels in the three groups with ELISA.Further analyzing the correlation between vitamin K2levels and abdominal aortic calcium integration. Results Firstly, compared with the control group,vitamin K2levels in group HD and group HFHD were decreased(P<0.05).Vi-tamin K2levels in group HD were lower than those in group HFHD(P<0.05).Secondly,the score of abdominal aorta calcification in group HD was higher than that in group HFHD(P<0.05).Thirdly,levels of vitamin K2and abdominal aortic calcification score were negatively correlated(r =-0.319,P < 0.05),and 25(OH)VD3,calci-um,phosphorus,magnesium,calcium and phosphorus product,parathyroid hormone had no correlation(P >0.05). Conclusion In MHD patients,the level of vitamin K2in HFHD group is higher than that in HD group, the abdominal aortic calcification score is lower than that of HD group,and vitamin K2can delay the process of vas-cular calcification.

Synthesis of vitamin K2 by isopentenyl transferase NovA in Pichia pastoris Gpn12 / 生物工程学报

The effect of methanol addition on the heterologous expression of isoprenyl transferase NovQ was studied in Pichia pastoris Gpn12, with menadione and isopentenol as precursors to catalyze vitamin K2 (MK-3) synthesis. The expression of NovQ increased by 36% when 2% methanol was added every 24 h. The influence of initial pH, temperature, methanol addition, precursors (menadione, isopentenol) addition, catalytic time and cetyltrimethyl-ammonium bromide (CTAB) addition were explored in the P. pastoris whole-cell catalytic synthesis process of MK-3 in shaking flask. Three significant factors were then studied by response surface method. The optimal catalytic conditions obtained were as follows: catalytic temperature 31.56 ℃, menadione 295.54 mg/L, catalytic time 15.87 h. Consistent with the response surface prediction results, the optimized yield of MK-3 reached 98.47 mg/L in shaking flask, 35% higher than that of the control group. On this basis, the production in a 30-L fermenter reached 189.67 mg/L when the cell catalyst of 220 g/L (dry weight) was used to catalyze the synthesis for 24 h. This method laid the foundation for the large-scale production of MK-3 by P. pastoris Gpn12.

Optimization Medium Composition for Vitamin K2 by Flavobacterium sp. using Response Surface Methodology and Addition of Arachis hypogaea

ABSTRACT The purpose of this research was to enhance the production of vitamin K2 by fermentation optimization and Arachis hypogaea supplementation in Flavobacterium sp. mutant SP-L-01. Optimized culture condition were as follows: 6-days shake-flask culture at 37oC with initial pH value 7.0 ± 0.2, shaking speed in 120 r/min and medium volume of 30 mL with 2% inoculums. After optimization of fermentation medium by response surface methodology (RSM), optimized medium were maltose 23.8 g/l, glucose 9.69 g/l, beef extract 15 g/l, K2HPO4 4.5 g/l，NaCl 3.0 g/l and MgSO4·7H2O 0.3 g/l. Production of vitamin K2 after optimization reached to 10.97 mg/l, which is 79.25% higher than that before optimization (6.12 mg/l). 3 mg/mL of arachis hypogaea was added into the medium at 72 h of shake-flake cultivation, which improved the production of menaquinone-4 (MK4) up to 371% and menaquinone-6 (MK6) up to 149% higher than those of the original medium. D-(+)-catechin, one of the components of arachis hypogaea, was added alone into the medium, which also improved the vitamin K2 synthesis.

Effect of vitamin K2 on β-glycerophosphate-induced calcification in rat vascular smooth muscle cells and the mechanism / 中华肾脏病杂志

Objective To explore the effect of vitamin K2 on β-glycerophosphate(β-GP)-induced rat vascular smooth muscle cells (VSMCs) calcification and and the mechanism.Methods VSMCs were obtained from rat aortic,and identified by immunocytochemistry,then randomly divided into control group,high phosphorus group,vitamin K2 group (the group was settled three subgroups according to the concentration of vitamin K2 based on the high phosphorus medium,namely 10 μmol/L,25 μmol/L,50 μmol/L) and noggin (bone morphogenetic protein pathway inhibitor) group.Calcification was visualized by Alizarin red staining,calcium load in cells was quantified by o-cresolphthalein complexone method and alkaline phosphatase (ALP) activity was measured after stimulating 14 days,gene expressions of bone morphogenetic protein-2 (BMP-2),SMAD1,SMAD7 and Runx2 mRNA were detected by RT-PCR,Runx2 protein levels was detected by Western blotting after stimulating 3 days.Results Compared with the cells in control group,high phosphorus induced cell calcification,increased ALP activity,up-regulated the expression of BMP-2,SMAD1,Runx2 mRNA (P ＜ 0.05) and down-regulated the expression of SMAD7 (P ＜ 0.01),while compared with high phosphorus group,the calcium deposition,ALP activity and the expression of BMP-2,SMAD1,Runx2 mRNA were remarkably reduced in a dose-dependent manner by treatment with vitamin K2 (P ＜ 0.05) and the expression of SMAD7 was increased (P ＜ 0.01).Compared with high phosphorus group,SMAD1 and Runx2 expression in noggin group were remarkably reduced(P ＜ 0.01).Conclusion Vitamin K2 inhibits β-glycerophosphate-induced VSMCs calcification which correlates with the suppression of the expression of osteoblast markers through the down-regulation of bone morphogenetic protein pathway.

Enhanced Production of Vitamin K2 from Bacillus subtilis (natto) by Mutation and Optimization of the Fermentation Medium

The aim of this study was to enhance the production of vitamin K2 by using N-methyl-N-nitro-N-nitroso-guanidine (NTG) and low energy ion beam implantation and optimizing the fermentation medium. Mutation resulted in 1.66-fold higher production of vitamin K2 than that of the parentl strain. The production by the mutant BN-P15-11-1was increased 55% and reached 3.593±0.107 mg/L by using the Plackett-Burman and Box-Behnken designs to optimize the fermentation medium. The optimal fermentation culture medium was composed of (g/L) glycerol 69.6, sucrose 34.5, K2HPO4 4.0, peptone 20, yeast extract 25 and fermented at 37 °C and 150 rpm for 72 h. The results showed that the NTG and low energy ion beam implantation mutations and optimizing fermentation medium were effective methods to enhance vitamin K2 production.

Therapeutic effects of combined vitamin K2 with arsenic trioxide on proliferation of HL-60 cells / 中国地方病学杂志

Objective To investigate the therapeutic effects of arsenic trioxide(ATO) plus vitamin K2(VK2) on proliferation of HL-60 cells from acute promyelocytic leukemia cell line and explore the possible mechanism.Methods ①HL-60 cells were exposed to ATO(0.0,0.5,1.0,2.0,4.0 μmol/L),VK2(0.0,2.5,5.0,10.0,20.0μmol/L),or both of different concentrations (0.5 μmol/L ATO + 2.5 μmol/L VK2,1.0 μmol/L ATO + 5.0μmol/L VK2,2.0 μmol/L ATO + 10.0 μmol/L VK2,4.0 μmol/L ATO + 20.0 μmol/L VK2) for 24,48 or 72 h,respectively.The method of CCK-8 was used to assess the proliferation of HL-60 cells and the half inhibitory concentration(IC50) of ATO or VK2 was calculated,respectively.②Combination index (CI) was used to evaluate the combinative effect of the two treatments:CI ＜ 1,=1 or ＞ 1 indicated synergistic,additive,or antagonistic effect,respectively.③After HL-60 cells were treated with 1.0 μmol/L ATO or 5.0 μmol/L VK2 individually or simultaneously for 48 h,Annnexin V/PI staining was performed to identify the apoptosis rate of each group.Untreated cells were used as control group.Results ①ATO or VK2 alone inhibited the proliferation of HL-60 cells in a concentration and time dependent manner.The IC50 of ATO or VK2 at time of 24,48,72 h were (22.86 ± 2.44),(6.66 ± 0.34),(4.14 ± 0.41) and (18.40 ± 1.12),(13.48 ± 0.73),(8.95 ± 0.40) μmol/L,respectively; ②The combination of ATO and VK2 illustrated a synergistic effect with CI ＜ 1.③No statistical difference was found among control group [(4.38 ± 0.56)％],1.0 μmol/L ATO group [(5.76 ± 1.63)％] and 5.0 μmol/L VK2 group [(6.38 ± 1.42)％] in the apoptosis rate(all P ＞ 0.05).However,the apoptosis rate of combined group did rise to (44.18 ± 8.42)％,with a significant improvement to that of VK2 or ATO group alone (all P ＜ 0.01).Conclusions The combination of VK2 and ATO exhibits an enhanced synergistical inhibitive effect on proliferation of HL-60 cells,and apoptosis may be involved in this synergy in part.

Synergistic growth inhibition by sorafenib and vitamin K2 in human hepatocellular carcinoma cells

OBJECTIVE: Sorafenib is an oral multikinase inhibitor that has been proven effective as a single-agent therapy in hepatocellular carcinoma, and there is a strong rationale for investigating its use in combination with other agents. Vitamin K2 is nearly non-toxic to humans and has been shown to inhibit the growth of hepatocellular carcinoma. In this study, we evaluated the effects of a combination of sorafenib and vitamin K2 on the growth of hepatocellular carcinoma cells. METHODS: Flow cytometry, 3-(4,5-dimethyl-2-thiazolyl-2,5-diphenyl-2H-tetrazolium bromide) and nude mouse xenograft assays were used to examine the effects of sorafenib and vitamin K2 on the growth of hepatocellular carcinoma cells. Western blotting was used to elucidate the possible mechanisms underlying these effects. RESULTS: Assays for 3-(4,5-dimethyl-2-thiazolyl-2,5-diphenyl-2H-tetrazolium bromide) revealed a strong synergistic growth-inhibitory effect between sorafenib and vitamin K2. Flow cytometry showed an increase in cell cycle arrest and apoptosis after treatment with a combination of these two drugs at low concentrations. Sorafenib-mediated inhibition of extracellular signal-regulated kinase phosphorylation was promoted by vitamin K2, and downregulation of Mcl-1, which is required for sorafenib-induced apoptosis, was observed after combined treatment. Vitamin K2 also attenuated the downregulation of p21 expression induced by sorafenib, which may represent the mechanism by which vitamin K2 promotes the inhibitory effects of sorafenib on cell proliferation. Moreover, the combination of sorafenib and vitamin K2 significantly inhibited the growth of hepatocellular carcinoma xenografts in nude mice. CONCLUSIONS: Our results determined that combined treatment with sorafenib and vitamin K2 can work synergistically to inhibit the growth of hepatocellular carcinoma cells. This finding raises the possibility that this combined treatment strategy might be promising as a new therapy against hepatocellular carcinoma, especially for patients with poor liver tolerance.

Effect of vitamin K2 and benazepril combination therapy on gastric cancer in nude mice / 中国药学杂志

OBJECTIVE: To investigate the effect of vitamin K2 combined with benazepril on human gastric cancer in nude mice. METHODS: SGC-7901 human gastric cancer cells were implanted into BALB/c nude mice to establish the cancer model. Fourteen days after the subcutaneous implantation of cancer cells, 40 nude mice were randomly divided into 4 groups; control group, vitamin K2 therapy group, benazepril therapy group and combination therapy group (vitamin K2 + benazepril). After 14 d, the tumor growth was evaluated, apoptosis indices were examined by TUNEL assay, and VEGF and caspase 3 expression were assessed by immunohisto-chemical staining. RESULTS: Compared to the control group, tumor weights were decreased and apoptosis indexes was significantly increased in the therapy groups (P < 0.05), the protein expression of caspase 3 were up-regulated, and VEGF were decreased in the therapy group (P < 0.05), and all the changes above were more significant in combination therapy group than vitamin K2 or benazepril group (P < 0.05). CONCLUSION: The combination of vitamin K2 and benazepril enhances anti-tumor efficacy possibly through angiogenesis suppression and apoptosis induction. Copyright 2012 by the Chinese Pharmaceutical Association.

Effect of Dietary Vitamin K2 Supplementation on Bone Mineral Density in Ovariectomized Rats

Vitamin K has been suggested to plays a role in bone metabolism. The objective of this study was to determine whether vitamin K2 supplementation is related to bone mineral density, bone formation markers, and bone resorption in ovariectomized (OVX) rats. Forty Sprague-Dawley female rats (body weight, 200 +/- 10 g) were divided into four groups: a sham group fed a control diet, a sham group fed a vitamin K2 supplemented diet, OVX fed a control diet, and OVX fed a vitamin K2 supplemented diet (3.5 mg vitamin K2/kg diet). All rats were fed the experimental diets for 6 weeks, and deionized water was provided ad libitum. Serum alkaline phosphatase activity (ALP), osteocalcin, and urinary deoxypyridinoline crosslink values were measured as markers of bone formation and resorption. Bone mineral density (BMD) and bone mineral content were measured in the spine and femur using PIXImus (GE Lunar Co., Madison, WI, USA). No significant differences in body weight gain, food intake, or food efficiency ratio were observed between the control and experimental groups. Serum ALP, osteocalcin, and urinary crosslink values were not significantly different between the vitamin K2 supplemented groups. No significant differences were observed for any of the variables in the sham group. Spine BMD values were significantly lower in the OVX than those in the sham groups. Spine and femur BMD per weight of vitamin K2 tended to be higher than the control diet group within the OVX group, but no significant differences were observed. In conclusion, dietary vitamin K2 supplementation may have a beneficial effect on spine and femur BMD in OVX rats. Further research is needed to understand the potential benefits of vitamin K2 on bone loss in OVX rats.

Preventive effects of vitamin K2 on tumor recurrence in patients with hepatocellular carcinoma after radical resection / 中华消化外科杂志

Objective To study the preventive effects of vitamin K2 on tumor recurrence in patients with hepatocellalar carcinoma (HCC) after radical resection. Methods The clinical data of 50 patients with HCC who received radical resection from March 2006 to March 2007 in No. 181 Hospital of PLA were analyzed retrospec-tively. All the patients were divided into 2 groups according to the random number table. Twenty-six patients in vitamin K2 group were administered with menatetrenone (45 mg per day), and the rest 24 pateints were in the control group. The accumulative and tumor-free survival rates, differences between the 2 groups, multivariate factors for prognosis were analyzed by Kaplan-Meier curve, Log-rank test and Cox regression model, respectively. Results During a period of 36 month follow-up, 10 patients died and 28 had tunor recurrence. The 1-, 2-, 3-year accumulative survival rates were 96%, 92% and 83% in vitamin K2 group, and 96%, 82% and 63% in control group (χ2 = 3.61, P > 0.05). The 1-, 2-, 3-year tumor-free survival rates were 92%, 60% and 38% in vitamin K2 group, and 75%, 42% and 12% in control group, with significant difference between the 2 groups (χ2 =5.61, P <0.05). Univariate and multivariate Cox proportional hazard analysis showed that without taking menate-trenone, the preoperative level of alpha fetoprotein (AFP) ≥800 μg/L and vascular invasion were the indepen-dent risk factors for tumor recurrence. Conclusions Vitamin K2 has a suppressive effect on tumor recurrence of HCC, while patients with AFP≥800 μg/L before operation or with vascular invasion have poor prognosis.

Comparison of the Effect of Vitamin K2 and Risedronate on Trabecular Bone in Glucocorticoid-Treated Rats: A Bone Histomorphometry Study

PURPOSE: To compare the effect of vitamin K2 and risedronate on trabecular bone in glucocorticoid (GC)-treated rats. MATERIALS AND METHODS: Forty-eight Sprague-Dawley female rats, 3 months of age, were randomized by the stratified weight method into 5 groups according to the following treatment schedule: age-matched control, GC administration, and GC administration with concomitant administration of vitamin K2, risedronate, or vitamin K2 + risedronate. GC (methylprednisolone sodium succinate, 5.0 mg/kg) and risedronate (10 microgram/kg) were administered subcutaneously three and five times a week, respectively. Vitamin K2 (menatetrenone, 30 mg/kg) was administered orally three times a week. At the end of the 8-week experiment, bone histomorphometric analysis was performed on trabecular bone of the tibial proximal metaphysis. RESULTS: GC administration decreased trabecular bone mass compared with age-matched controls because of decreased bone formation (mineralizing surface, mineral apposition rate, and bone formation rate) and increased bone erosion. Vitamin K2 attenuated GC-induced trabecular bone loss by preventing GC-induced decrease in bone formation (mineralizing surface) and subsequently reducing GC-induced increase in bone erosion. Risedronate prevented GC-induced trabecular bone loss by preventing GC-induced increase in bone erosion although it also suppressed bone formation (mineralizing surface, mineral apposition rate, and bone formation rate). Vitamin K2 mildly attenuated suppression of bone formation (mineralizing surface) and bone erosion caused by risedronate without affecting trabecular bone mass when administered in combination. CONCLUSION: The present study showed differential effect of vitamin K2 and risedronate on trabecular bone in GC-treated rats.

Induce apoptosis effect and possible mechanism of Vitamin K_2 on K562 cells / 临床检验杂志

Objective To study the effects and possible mechanism of Vitamin K2(Vit K_2)in the treatment of K562 cells.Method The possible mechanism of the apoptosis of K562 cells induced by Vitamin K2(Vit K_2)were investigated with the transmission electron microscope,flow cytometry(FCM),retrotrans criptase polymerase chain reaction(RT-PCR)and chemiluminescence assay.Results Apoptosis peak on FCM and positive AnnexinV-FITC on cell membrane showed that Vit K_2 induced apoptosis of K562 cells and in a dose-and-time-dependent manner;G0/G1 cell arrested;significantly down-regulated the expression of bcl-2 and survivin,but had no effect on the expression of bax;The activities of caspase-3 were significantly increased.Conclusions Vit K_2 induces apoptosis of K562 cells through activating caspase-3 pathways and the apoptosis-related genes bcl-2、survivin might play an important role in this process.

The Effect of Vitamin K2 in Addition to Risedronate on the Patients with Postmenopausal Osteoporosis

OBJECTIVE: To assess the effect of vitamin K2 in addition to risedronate on postmenopausal osteoporosis METHOD: We enrolled 21 postmenopausal osteoporosis women (age: 65.2+/-7.8 years). Ten subjects received risedronate (35 mg, weekly) and vitamin K2 (45 mg, daily) and eleven subjects only received risedronate. They all received calcium citrate 2,130 mg and vitamin D 600 IU daily. The duration of treatment was 7.7+/-1.4 months. Bone mineral density (BMD) of lumbar spine and both femurs, serum osteocalcin and urine deoxypyridinoline were examined at baseline and after treatment. RESULTS: After treatment, BMD, serum osteocalcin and urine deoxypyridinoline were improved in each group but there was no statistical difference between the groups. CONCLUSION: There was no evidence of the benefit of vitamin K2 in addition to risedronate in bone metabolism on postmenopausal osteoporosis.

Effects of Vitamin K2 on the Development of Osteopenia in Rats as the Models of Osteoporosis

Vitamin K2 is widely used for the treatment of osteoporosis in Japan. To understand the effects of vitamin K2 on bone mass and bone metabolism, we reviewed its effects on the development of osteopenia in rats, which characterizes models of osteoporosis. Vitamin K2 was found to attenuate the increase in bone resorption and/or maintain bone formation, reduce bone loss, protect against the loss of trabecular bone mass and its connectivity, and prevent the decrease in strength of the long bone in ovariectomized rats. However, combined treatment of bisphosphonates and vitamin K2 had an additive effect in preventing the deterioration of the trabecular bone architecture in ovariectomized rats, while the combined treatment of raloxifene and vitamin K2 improved the bone strength of the femoral neck. The use of vitamin K2 alone suppressed the increase in trabecular bone turnover and endocortical bone resorption, which attenuated the development of cancellous and cortical osteopenia in orchidectomized rats. In addition, vitamin K2 inhibited the decrease in bone formation in prednisolone-treated rats, thereby preventing cancellous and cortical osteopenia. In sciatic neurectomized rats, vitamin K2 suppressed endocortical bone resorption and stimulated bone formation, delaying the reduction of the trabecular thickness and retarding the development of cortical osteopenia. Vitamin K2 also prevented the acceleration of bone resorption and the reduction in bone formation in tail-suspended rats, which counteracted cancellous bone loss. Concomitant use of vitamin K2 with a bisphosphonate ameliorated the suppression of bone formation and more effectively prevented cancellous bone loss in tail-suspended rats. Vitamin K2 stimulated renal calcium reabsorption, retarded the increase in serum parathyroid hormone levels, and attenuated cortical bone loss primarily by suppressing bone resorption in calcium-deficient rats while maintaining the strength of the long bone in rats with magnesium deficiency. These findings suggest that vitamin K2 may not only stimulate bone formation, but may also suppress bone resorption. Thus, vitamin K2 could regulate bone metabolism in rats, which represented the various models of osteoporosis. However, the effects of vitamin K2 on bone mass and bone metabolism seem to be modest.

The Therapeutic Effect of Menatetrenone (Vitamin K2) on Posttransplant Osteoporosis in Renal Transplant Recipient / 대한신장학회잡지

BACKGROUND: Posttransplant osteoporosis in renal transplant recipient is frequently observed complications, but therapeutic modalities are not clearly elucidated. Recent studies indicate that vitamin K2 also play a role in bone metabolism. Therefore, we performed prospective study to evaluate the effect of vitamin K2 (Menatetrenone(R)) on posttransplant osteroporosis. METHODS: Our study included total 83 patients (40 male, 43 female; age 36.9+/-5.5 years) who received a renal transplant more than 6 months ago. They underwent dual-energy X-ray absorptiometry (DEXA) at lumbar spine and femoral neck. The patients with osteoporosis were treated with vitamin K2 (glakay 15 mg) (group 1) or vitamin D3 with calcium carbonate (group 2). The patients without osteoporosis was observed without any treatment (group 3). After one year, follow-up BMD was performed in all patients. RESULTS: Of 83 patients, 44 patients (53.0%) had osteoporosis and 39 patients (47.0%) had not. In group 1 (N=28), vitamin K2 treatment significantly increased BMD at femoral neck (-3.2+/-0.4 vs 2.6+/-0.6, p0.05). In group 2 (N=16), there was significant increase in BMD at femoral neck (-3.0+/-0.6 vs -2.5+/-0.8, p0.05). Between group 1 and 2, there was no significant difference in BMD change. In group 3, BMD decreased at femoral neck (-1.3+/-0.2 vs -1.5+/-0.2) and lumbar spine (-0.8+/-0.2 vs -1.0+/-0.2) during follow-up period. CONCLUSION: Vitamin K2 (Menatetrenone(R)) is effective in treating osteoporosis at femoral neck and its effectiveness is s imilar with that of using vitamin D3 with calcium carbonate.

Combined Treatment with Vitamin K2 and Bisphosphonate in Postmenopausal Women with Osteoporosis

Vitamin K2, as well as bisphosphonates, such as etidronate, alendronate, and risedronate, is widely used in the treatment with osteoporosis in Japan. Etidronate increases the lumbar bone mineral density (BMD), and prevents new vertebral fractures, in patients with osteoporosis, while alendronate and risedronate increase the lumbar and femoral neck BMDs, and prevent new vertebral and femoral neck fractures. Vitamin K2 enhances gamma-carboxylation of bone glutamic acid residues and the secretion of osteocalcin, sustains the lumbar BMD, and prevents osteoporotic fractures in patients with osteoporosis. Bisphosphonates, such as alendronate and risedronate, rather than vitamin K2, should be initially chosen for the treatment of osteoporosis, because they are more efficacious than vitamin K2. Available evidence suggest that risedronate prevents deterioration of the connectivity of the trabeculae in ovariectomized rats, whereas vitamin K2 increase the trabecular thickness, and that a combination of risedronate and vitamin K2 has a synergistic effect on preventing the deterioration of trabecular bone architecture induced by estrogen deficiency. Some studies have shown that combined treatment with etidronate and vitamin K2 appears to be more effective than etidronate alone in the prevention of new osteoporotic vertebral fractures. Based on these findings, combined treatment with vitamin K2 and bisphosphonates may be more efficacious in the prevention new vertebral fractures than a single treatment with bisphosphonate in postmenopausal women with osteoporosis. Thus, this combined treatment should be recommended for the treatment of postmenopausal osteoporosis. It is proposed that the role of vitamin K2 should be emphasized, when used in combination with bisphosphonates, especially in patients with vitamin K deficiency.