1.Diagnosis and treatment of warfarin resistance.
Shenglan TAN ; Xinmin ZHOU ; Zhi LI ; Wei ZHANG ; Zhaoqian LIU ; Honghao ZHOU
Journal of Central South University(Medical Sciences) 2013;38(3):313-317
Warfarin resistance is a phenomenon that patients need to take much higher than normally prescribed dosage of warfarin to maintain the target therapeutic international normalized ratio (INR) range, or even fail to reach the target INR. Warfarin resistance can be categorized in etiologic terms as hereditary vs acquired, or in pharmacologic terms as pharmacokinetic vs pharmacodynamic. Once warfarin resistance is diagnosed, the type of resistance should be determined as soon as possible so that treatment could be oriented toward the causes. Poor compliance, genetic mutations, concurrent medications that could decrease the absorption or increase the clearance of warfarin, and consumption of diet rich in vitamin K are the major reasons for warfarin resistance. Educating patients, increasing warfarin dosage and switching to other anticoagulants would be effective for warfarin resistance.
Anticoagulants
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pharmacology
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Drug Monitoring
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methods
;
Female
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Humans
;
International Normalized Ratio
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Male
;
Metabolism, Inborn Errors
;
diagnosis
;
etiology
;
genetics
;
Vitamin K
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administration & dosage
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Vitamin K Epoxide Reductases
;
genetics
2.Experiment research of nifedipine and vitamin K3 on ureteral action potential and urine flow in rabbits.
Ming-Jiang WANG ; Xin-Jun WANG ; Gui-Xiang FENG
Chinese Journal of Applied Physiology 2007;23(1):50-65
Action Potentials
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Animals
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Female
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Male
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Nifedipine
;
pharmacology
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Rabbits
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Ureter
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drug effects
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physiology
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Urination
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drug effects
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Vitamin K 3
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pharmacology
3.Effects of newborn bull serum and vitamins on cryopreservation of mouse seminiferous epithelial cells.
Lian-Jun LI ; De-Xue LI ; Xue-Ming ZHANG ; Zhan-Peng YUE ; Xing-Hao WEN ; Bing-Kun LUO
National Journal of Andrology 2002;8(4):244-246
OBJECTIVESTo investigate the effects of newborn bull serum(NBS), vitamin C and vitamin E on cryopreservation of mouse seminiferous epithelial cells.
METHODSThe seminiferous epithelial cells from 7-day-old mice were cryopreserved in different freezing solutions. The cell recoveries were examined by Trypan blue exclusive staining after thawing. The freezing solutions composed of DMEM, 10% dimethylsulphoxide(DMSO), and 0, 5%, 10%, or 20% NBS, respectively, or composed of DMEM, 10% DMSO, 10% NBS, and 150 micrograms/ml vitamin C or 50 micrograms/ml vitamin E, respectively.
RESULTSThe cell recoveries in freezing solution containing 0, 5%, 10%, or 20% NBS were 83.4%, 84.7%, 85.7% and 83.6%, respectively. There were no significant differences between them. The cell recoveries in freezing solution containing vitamin C or vitamin E were 88.0% and 82.9%, respectively. There was no significant differences compared with that in freezing solution containing 10% DMSO and 10% NBS.
CONCLUSIONSNBS, vitamin C and vitamin E have no significant protecting effects on mouse seminiferous epithelial cells, and can not significantly improve the cell recoveries.
Animals ; Ascorbic Acid ; pharmacology ; Cattle ; Cryopreservation ; Epithelial Cells ; physiology ; Fetal Blood ; physiology ; Male ; Mice ; Seminiferous Epithelium ; cytology ; Vitamin K ; pharmacology
4.Comparison of the Effect of Vitamin K2 and Risedronate on Trabecular Bone in Glucocorticoid-Treated Rats: A Bone Histomorphometry Study.
Jun IWAMOTO ; Hideo MATSUMOTO ; Tsuyoshi TADEDA ; Yoshihiro SATO ; James K YEH
Yonsei Medical Journal 2009;50(2):189-194
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.
Animals
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Bone Density/drug effects
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Bone and Bones/anatomy & histology/*drug effects/metabolism
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Etidronic Acid/*analogs & derivatives/pharmacology
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Female
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Glucocorticoids/*pharmacology
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Random Allocation
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Rats
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Vitamin K/*pharmacology
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Vitamins/*pharmacology
5.Differential Effect of Vitamin K and Vitamin D Supplementation on Bone Mass in Young Rats Fed Normal or Low Calcium Diet.
Jun IWAMOTO ; Tsuyoshi TAKEDA ; Shoichi ICHIMURA ; Yoshihiro SATO ; James K YEH
Yonsei Medical Journal 2004;45(2):314-324
The purpose of this study was to clarify the differential effect of vitamin K and vitamin D supplementation on bone mass in young rats fed a normal or low calcium diet. Ninety female Sprague-Dawley rats, 6 weeks of age, were randomized by stratified weight method into nine groups with 10 rats in each group: baseline control, and 0.5% (normal) or 0.1% (low) calcium diet, either alone, or with vitamin K (30 mg/100g, food intake), vitamin D (25microgram/100 g, food intake), or vitamin K + vitamin D. After 10 weeks of feeding, bone histomorphometric analyses were performed on cortical bone of the tibial shaft and cancellous bone of the proximal tibia. Vitamin K supplementation increased the maturation-related cancellous bone gain and retarded the reduction in the maturation-related cortical bone gain in rats fed a low calcium diet, and increased the maturation-related cortical bone gain in rats fed a normal calcium diet. Vitamin D supplementation reduced the maturation-related cancellous bone gain, prevented the reduction in periosteal bone gain, and enhanced the enlargement of the marrow cavity, with no significant effect on the reduction in the maturation-related cortical bone gain in rats fed a low calcium diet, and increased the maturation- related cancellous and cortical bone gains with increased periosteal bone gain in rats fed a normal calcium diet. An additive effect of vitamin K and vitamin D on the maturation- related cortical bone gain was found in rats fed a normal calcium diet. This study shows the differential effects of vitamin K and vitamin D supplementation on cancellous and cortical bone mass in young rats fed a normal or low calcium diet, as well as the additive effect on cortical bone under calcium sufficient condition.
Age Factors
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Animals
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Antifibrinolytic Agents/*pharmacology
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Bone Density/*drug effects
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Bone Development/*drug effects
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Calcium, Dietary/*pharmacology
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Dietary Supplements
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Female
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Rats
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Rats, Sprague-Dawley
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Vitamin D/*pharmacology
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Vitamin K/*pharmacology
6.Vitamin K and osteoporosis.
Acta Academiae Medicinae Sinicae 2003;25(3):346-349
There is a closely relationship between vitamin K and osteoporosis. As a cofactor for carboxylase activity, vitamin K can facilitate the conversion of glutamyl to gamma-carboxyglutamyl residues and influence the synthesis and excretion of gamma-carboxylation of osteocalcin to increase the formation of bone. Vitamin K can also effectively inhibit the absorption of bone mass. Besides, there are increasing evidences that vitamin K can effect the synthesis and excretion of nephrocalcin and interlukin-1,6 that can regulate calcium balance and bone metabolism. Meanwhile, there is a consistent line of evidence in human epidemiologic and intervention studies that clearly demonstrate that vitamin K can not only increase bone mineral density in osteoporotic people, but also reduce fracture rates to improve bony health. However more researches are required before vitamin K is widely applied in prevention and treatment of osteoporosis. The American Medical Association recently has increased the dietary reference intakes of vitamin K to 90 mg/d for females and 120 mg/d for males.
Animals
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Bone Density
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drug effects
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Humans
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Nutritional Requirements
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Osteocalcin
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metabolism
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Osteoporosis
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drug therapy
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etiology
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prevention & control
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Vitamin K
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antagonists & inhibitors
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pharmacology
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therapeutic use
7.Population pharmacokinetic/pharmacodynamic modeling of warfarin by nonlinear mixed effects model.
Rong-fang LIN ; Wei-wei LIN ; Chang-lian WANG ; Pin-fang HUANG ; Su-jun FANG
Acta Pharmaceutica Sinica 2015;50(10):1280-1284
The study aimed to establish a population pharmacokinetic/pharmacodynamic (PPK/PD) model of warfarin. PCR-RFLP technique was used to genotype the CYP2C9 and VKORC1 polymorphisms of 73 patients. RP-HPLC-UV method was used to determine the 190 plasma concentrations of warfarin. Application of NONMEM, the clinical information and 263 international normalized ratio (INR) monitoring data were used to investigate the effect of genetic, physiological, pathological factors, other medication on clearance and anticoagulant response. The final model of warfarin PPK/PD was described as follows: CL = θCL · (WT/60)θWT · θCYP · eηCL (if CYP2C9*1/*1, θCYP = 1; if *1/*3, θCYP = 0.708); EC50 = θEC50 · θVKOR · eηEC50 (if VKORC1- 1639AA, θVKOR = 1; if GA, θVKOR = 2.01; V = θV; K(E0) = θK(E0); Emax = θEmax; E0 = θE0 · eηE0. Among them, the body weight (WT), CYP2C9 and VKORC1 genotype had conspicuous effect on warfarin PK/PD parameters. The goodness diagnosis, Bootstrap, NPDE verification showed that the final model was stable, effective and predictable. It may provide a reference for opitimizing the dose regimen of warfarin.
Anticoagulants
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pharmacology
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Body Weight
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Cytochrome P-450 CYP2C9
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genetics
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Genotype
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Humans
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International Normalized Ratio
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Nonlinear Dynamics
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Polymorphism, Genetic
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Vitamin K Epoxide Reductases
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genetics
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Warfarin
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pharmacokinetics
8.Possible mechanism underlying apoptotic induction effect of vitamin K2 on human MDS cell line MUTZ-1.
Bao-An CHEN ; Ze-Ye SHAO ; Guo-Hua XIA ; Xin XU ; Jia-Hua DING ; Chong GAO ; Yun-Yu SUN ; Xue-Zhi GAO
Journal of Experimental Hematology 2007;15(1):91-94
The study was aimed to investigate the possible mechanism of vitamin K(2) (VK(2)) on myelodysplastic syndrome (MDS) cell line MUTZ-1 in vitro. The flow cytometry was used to analyze apoptosis rate and the change of cell cycle. The expression of apoptosis-related genes bcl-2, survivin and bax were detected by reverse transcription-polymerase chain reaction (RT-PCR). The activity of caspase-3 was detected by chemiluminescence assay. The results indicated that the apoptosis peak on FCM and positive Annexin-V FITC on cell membrane showed that VK(2) induced apoptosis of MUTZ-1 cells in a dose-and-time-dependent manner, S and G(2) cell decrement, G(0)/G(1) cell arrest, VK(2) significantly down-regulated the expression of bcl-2 and survivin, but had no effect on the expression of bax, the activity of caspase-3 was significantly increased. It is concluded that VK(2) induces apoptosis of MUTZ-1 cells through activating caspase-3 pathways and the apoptosis-related genes bcl-2 and survivin may play important roles in the process of apoptosis induction.
Antineoplastic Agents
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pharmacology
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Apoptosis
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drug effects
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Caspase 3
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metabolism
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Cell Line, Tumor
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Humans
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Inhibitor of Apoptosis Proteins
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Microtubule-Associated Proteins
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biosynthesis
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genetics
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Myelodysplastic Syndromes
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drug therapy
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pathology
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Neoplasm Proteins
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biosynthesis
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genetics
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Proto-Oncogene Proteins c-bcl-2
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biosynthesis
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genetics
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RNA, Messenger
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biosynthesis
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genetics
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Vitamin K 2
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pharmacology
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bcl-2-Associated X Protein
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biosynthesis
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genetics
9.Effects of Vitamin K2 on the Development of Osteopenia in Rats as the Models of Osteoporosis.
Jun IWAMOTO ; Tsuyoshi TAKEDA ; Yoshihiro SATO
Yonsei Medical Journal 2006;47(2):157-166
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.
Vitamin K 2/chemistry/metabolism/*pharmacology
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Tomography, X-Ray Computed
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Tibia/pathology
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Rats
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Osteoporosis/*drug therapy/*prevention & control
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Male
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Magnesium Deficiency/diagnosis
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Magnesium/metabolism
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Homeostasis
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Female
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*Disease Models, Animal
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Diphosphonates
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Calcium/metabolism
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Bone and Bones/*drug effects/metabolism
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Bone Resorption
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Bone Diseases, Metabolic/*metabolism
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Animals
10.Involvement of VKORC1 in the inhibition of calcium oxalate crystal formation in HK-2 cells.
Bo HU ; Hao-ran WU ; Zhi-yong MA ; Zhuan-chang WU ; Ying-mei LU ; Guo-wei SHI
Journal of Huazhong University of Science and Technology (Medical Sciences) 2014;34(3):376-381
The vitamin K epoxide reductase complex subunit 1 (VKORC1), the rate-limiting enzyme for vitamin K recycling, is significantly down-regulated in the kidneys of urolithiasis patients. This study searched for direct evidence to define the inhibitory activity of VKORC1 against calcium oxalate (CaOx) crystal formation. In the experiment of VKORC1 overexpression, HK-2 cells were transfected with the pFLAG-CMV-7.1-VKORC1 plasmid as a pFLAG-CMV-7.1-VKORC1 transfection group or the pFLAG-CMV-7.1 plasmid as a pFLAG-CMV-7.1 control group. In the experiment of VKORC1 knockdown, HK-2 cells were transfected with the PGPU6/GFP/Neo-VKORC1shRNA-2 as a PGPU6/GFP/Neo-VKORC1shRNA-2 transfection group or the PGPU6/GFP/Neo-shRNA-NC plasmid as a PGPU6/GFP/Neo-shRNA-NC control group. The expression of VKORC1 in HK-2 cells was detected by real-time quantitative PCR and Western blotting. The CaOx crystal formation was observed under the laser-scanning confocal microscope. It was found that the expression levels of VKORC1 mRNA and protein were significantly higher in the pFLAG-CMV-7.1-VKORC1 transfection group than in the pFLAG-CMV-7.1 control group (P<0.01). The number of CaOx crystals in HK-2 cells incubated in fluorescently labeled CaOx monohydrate (COM) crystal medium for 48 h was 14±4 per field (100×) in the pFLAG-CMV-7.1-VKORC1 transfection group and 26±5 per field (100×) in the pFLAG-CMV-7.1 control group respectively under the laser-scanning confocal microscope. The amount of CaOx crystal aggregation and formation in the pFLAG-CMV-7.1-VKORC1 transfection group was significantly reduced as compared with the pFLAG-CMV-7.1 control group (P<0.05). The expression levels of VKORC1 mRNA and protein were significantly lower in the PGPU6/GFP/Neo-VKORC1shRNA-2 transfection group than in the PGPU6/GFP/Neo-shRNA-NC control group (P<0.05). The number of CaOx crystals in HK-2 cells incubated in fluorescently labeled COM crystal medium was 65±11 per field (100×) in the PGPU6/GFP/Neo-VKORC1shRNA-2 transfection group and 24±6 per field (100×) in the PGPU6/GFP/Neo-shRNA-NC control group respectively under the laser-scanning confocal microscope. The amount of CaOx crystal aggregation and formation in the PGPU6/GFP/Neo-VKORC1shRNA-2 transfection group was significantly increased as compared with the PGPU6/GFP/Neo-shRNA-NC control group (P<0.05). These findings suggested that the VKORC1 protein could inhibit CaOx salt crystallization, adhesion and aggregation. This research would help us to understand the mechanisms involving the interaction between crystallization and epithelial cells and the formation of CaOx.
Apoptosis
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drug effects
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Blotting, Western
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Calcium Oxalate
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chemistry
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metabolism
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pharmacology
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Cell Line
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Crystallization
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Dose-Response Relationship, Drug
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Flow Cytometry
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Gene Expression
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Green Fluorescent Proteins
;
genetics
;
metabolism
;
Humans
;
Microscopy, Confocal
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RNA Interference
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Reverse Transcriptase Polymerase Chain Reaction
;
Time Factors
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Transfection
;
Vitamin K Epoxide Reductases
;
genetics
;
metabolism