CN112438967A - Application of vitamin K in preparation of medicine and health-care product for preventing and treating urinary calculus - Google Patents
Application of vitamin K in preparation of medicine and health-care product for preventing and treating urinary calculus Download PDFInfo
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- CN112438967A CN112438967A CN201910786840.8A CN201910786840A CN112438967A CN 112438967 A CN112438967 A CN 112438967A CN 201910786840 A CN201910786840 A CN 201910786840A CN 112438967 A CN112438967 A CN 112438967A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/04—Drugs for disorders of the urinary system for urolithiasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Urology & Nephrology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an application of vitamin K (vitamin K) in preparing a medicine and a health product for preventing and treating urinary calculus. In the research of novel urinary calculus prevention and treatment medicines, the inventor of the invention finds that vitamin K can play a role in preventing and treating urinary calculus, and belongs to new application of old medicines. The invention shows that vitamin K can not only protect renal tubular epithelial cells from apoptosis and damage at the cellular level and reduce crystallization and cell adhesion, but also play a role in reducing and delaying the formation of renal crystallization and reducing renal fibrosis and inflammation in a rat model of an animal experiment. Therefore, the vitamin K has important application value and significance in the aspect of preventing and treating urinary calculus.
Description
Technical Field
The invention relates to the field of application of medicines and health-care products, in particular to a new application of an old medicine vitamin K in medicines and health-care products for treating and preventing urinary calculus.
Background
Urinary calculus is a complex disease caused by environmental dietary factors and genetic factors, and is clinically manifested by urinary obstruction and kidney function damage, with the incidence rate exceeding 6-12%. Urinary system stones including kidney stones, ureteral stones, vesical stones and urethral stones mostly originate from the kidney, and the kidney maintains and regulates the water and salt metabolism balance of a human body, discharges waste products, and simultaneously easily forms a salt supersaturation state between a renal tubule and a renal interstitium to cause the calcification of the kidney. Kidney calcification is a crystalloid abnormal deposit of renal tubules or renal interstitium, and is different from vascular calcification, and the formation mechanism is complex. One main characteristic of urinary calculus is recurrence, 50% of patients can recur within 5 years, and can recur for many times, and renal insufficiency of patients can be caused by long-term illness, so that prevention of recurrence is the key point for prevention and treatment of urinary calculus. With global warming and living habits changing, the urinary calculus suffering rate is increasing every year, and it is conjectured that at least tens of millions of people in China will suffer from urinary calculus diseases in life, and the treatment economic cost is also quite staggering. However, the mechanism of calculus formation is still unclear, so that the current clinical lack of effective treatment and recurrence prevention measures, generally, after calculus formation, the symptoms of patients are temporarily relieved by lithotripsy, operation and the like, and the effective drug inhibition and recurrence prevention of calculus formation on the pathogenesis of kidney calcification cannot be realized.
Vitamin K is a fat-soluble vitamin, including naturally occurring vitamin K1 and vitamin K2 as well as synthetic vitamin K3 and vitamin K4. Vitamin K1 is synthesized by plants and vegetables, while vitamin K2 can be produced in animals or synthesized by intestinal bacteria. Vitamin K1 can be converted to vitamin K2 and accumulated in extrahepatic tissues. Vitamin K in human body has limited storage capacity, which easily causes vitamin K deficiency. Warfarin acts as a vitamin K antagonist by blocking the vitamin K cycle, resulting in functional vitamin K deficiency. There is evidence that vitamin K deficiency leads to vascular calcification, while high vitamin K intake can ameliorate vascular calcification diseases.
Meanwhile, the old medicine is screened and used for a new purpose, and the development efficiency can be greatly improved. The new application of the old medicine refers to the new indication or the new application development of the medicine on the market. The development of a brand-new medicine generally needs more than 10 years from establishment of projects to marketing, the cost is extremely high, and the power is less than 10%. The new use of old medicine can greatly reduce the risk of research and development. Because the safety and the pharmacokinetic data of the old medicine are perfect, the safety of the old medicine is greatly guaranteed. The development of the new application can greatly shorten the research and development period, reduce the research and development cost and save manpower and material resources. Therefore, the new application of old medicine becomes one of the most effective and the most rapid means in the current new medicine development.
Vitamin K1(vitamin K1), phyllo menadione (2-methyl-3-phytyl-1, 4-naphthoquinone, phyllo quinone for short), belongs to a polycyclic aromatic ketone, the skeleton is based on 2-methyl-1, 4-naphthoquinone, and a phytane substituent is arranged at the third position. Molecular formula C31H46O2, molecular weight 450.71, CAS: 84-80-0. It is widely found in natural green plants. Vitamin K1 belongs to vitamin medicine, and is essential for liver to synthesize factors II, VII, IX and X. The vitamin K1 injection is a 2009 edition national basic drug catalogue variety and is mainly used for treating hemorrhagic diseases caused by various vitamin K deficiencies.
Vitamin K2(vitamin K2), molecular formula C41H56O2, molecular weight 580.88, CAS: 84-81-1, the English name is 2- [ (2E,6E,10E,14E,18E) -3,7,11,15,19, 23-hemamexyl-2, 6,10,14,18,22-tetracosahexaen-1-yl ] -3-methyl-1, 4-naphthalene dione.
Vitamin K3(vitamin K3), molecular formula C11H9NaO 5S.3h2O, CAS: 58-27-5. Chinese alias: menadione; menadione sodium bisulfite; 2-methyl-1, 4-naphthoquinone; menadione Sodium Bisulfite (MSB), menadione dimethylpyrimidinol sulfite (naproxen MPB); nicotinamide-naphthoquinone sulfite (MNB); menadione Sodium Bisulfite Complex (MSBC); anti-bleeding vitamins.
Vitamin K4(vitamin K4), molecular formula C15H14O4Molecular weight 258.2693, CAS: 573-20-6. Chinese alias: 2-methyl-1, 4-naphthalenediol diacetate.
Disclosure of Invention
The invention provides a new application of vitamin K in treating and preventing urinary calculus. In the research of vitamin K, the inventor finds that the vitamin K has the effects of protecting renal tubular epithelial cells from apoptosis and injury, reducing crystallization and cell adhesion, reducing renal fibrosis and inflammation, increasing renal MGP protein expression and reducing and delaying renal calcification.
The invention is realized by the following technical scheme:
the vitamin K is used singly or in combination with other medicines in the aspect of preparing the medicines for treating and preventing the urinary calculus and the health-care products for preventing and treating the urinary calculus.
Preferably, the application is the application of the vitamin K in preparing the medicines and health care products for treating and preventing urinary calculus, including renal calculus, renal pelvis calculus, ureteral calculus, vesical calculus and urethral calculus, singly or in combination with other medicines or health care products.
Preferably, the application is the application of vitamin K including naturally-occurring vitamin K1 and K2 and synthetic vitamin K3 and K4 in preparing medicines and health products for treating and preventing urinary calculus.
Preferably, in the above application, vitamin K can reduce apoptosis and damage of renal tubular epithelial cells by reducing adhesion of crystals to the renal tubular epithelial cells, reduce renal fibrosis and inflammation, and increase MGP protein expression of the renal tubular epithelial cells and renal tissues to treat and prevent urinary calculus.
The invention has the beneficial effects that:
1. the invention finds that vitamin K can protect renal tubular epithelial cells from apoptosis and damage, reduce crystallization and cell adhesion and play a role in reducing and delaying kidney calcification in the research of urinary calculus forming mechanism. Therefore, the vitamin K can be used as an effective medicine for treating and preventing the kidney calcification, is used for treating and preventing the urinary calculus, belongs to a new application of old medicines, and has important application value and significance in the aspect of reducing the kidney calcification. In specific application, the vitamin K can be directly used as a therapeutic drug for treating and preventing urinary calculus.
2. The invention shows that vitamin K can reduce kidney fibrosis and inflammation, reduce kidney injury, increase kidney MGP protein expression and play a significant role in kidney protection in the research of urinary calculus forming mechanism. Therefore, the medicine has important application value and significance in the aspects of protecting the kidney and reducing the calcification of the kidney.
3. The invention performs a drug experiment on the function of preventing and treating the kidney calcification by new application of old drugs, and provides an experimental basis for research and development of new drugs for preventing and treating the urinary calculus.
Drawings
FIG. 1A shows the detection of the concentration of whole blood VK1 using an ELISA kit. P <0.05, P < 0.01.
FIG. 1B the concentration of VK1 in kidney tissue was measured using an enzyme-linked immunosorbent assay kit. P <0.05, P < 0.01.
FIG. 1C shows the formation of crystals of rat kidney from day 0 to week 8 by HE staining.
The control group was administered 0.75% ethylene glycol and the VK group was co-administered 0.75% ethylene glycol and VK 1. Black arrows point to the crystals formed. Magnification: x 200.
FIG. 2A is a graph showing the effect of VK on cell-to-crystal adhesion using atomic absorption.
FIG. 2B is a graph of the effect of VK on cell viability studied by MTT.
The control group was treated with 100. mu.g/ml calcium oxalate crystals, the warfarin group with 100. mu.g/ml calcium oxalate crystals and 1M warfarin, and the warfarin + VK1 group with 100. mu.g/ml calcium oxalate crystals, 100 μ M VK1 and 1M warfarin. On the contrary, P is less than 0.05 vs; p <0.001vs. (-) -; #, P <0.05vs. warfarin (A). P <0.01vs. control; #, P <0.01vs. warfarin.
FIG. 3A is a study of the effect of VK1 on apoptosis using DAPI staining. Apoptotic nuclei are irregularly shaped.
Figure 3B is a calculation of DAPI staining percentage of apoptotic cells.
FIG. 3C is a study of the effect of VK1 on apoptosis using the TUNEL method. The viable cell nuclei are oval or circular. Green fluorescence represents apoptotic cells.
FIG. 3D is a graph of the percentage of apoptotic cells calculated by the TUNEL method. P <0.01, p < 0.001.
FIG. 4A shows that VK1 can increase MGP expression at the cellular level by Western blot. P <0.05, p <0.01, p <0.001 compared to 0 h.
FIG. 4B shows that VK1 can increase MGP expression in rat kidney tissue by Western blot. P <0.05 compared to EG group.
FIG. 5A shows the protective effect of VK1 on kidney inflammation using semi-quantitative Polymerase Chain Reaction (PCR). The lengths of the MCP-1 products are 412bp respectively.
FIG. 5B shows the protective effect of VK1 on kidney fibrosis using semi-quantitative Polymerase Chain Reaction (PCR). The product length of type I collagen is 123 bp. P <0.005, P <0.01, P <0.0001vs.
FIG. 6 is a graph comparing the rate of renal crystal formation in rats in the vitamin K group and the control group.
FIG. 7 is a graph comparing the area of renal crystal formation in rats in the vitamin K group and the control group.
Detailed Description
Example 1 inhibitory Effect of vitamin K on Kidney calcification in rats
(I) determination of vitamin K concentration in rat blood and kidney tissue
Rats were divided into three groups, with control group given 0.9% saline, EG group given 0.75% ethylene glycol, VK1+ EG group given 0.75% ethylene glycol and 0.77mg/100g VK 1. The administration mode is intraperitoneal injection. Each group was dissected at weeks 0, 2, 4, 6, 8 and whole blood was collected using sterile tubes containing anticoagulant. Kidneys were taken and 1g of kidney tissue was homogenized well with 9g of PBS and centrifuged for 20 minutes (3000 rpm). The supernatant was carefully collected and stored at-80 ℃. The level of VK1 was measured with rat VK1 enzyme-linked immunoassay kit (Chinese enzyme immunoassay, MM-0525R1) and shown in FIG. 1A and FIG. 1B.
As seen from FIG. 1A, the concentration of vitamin K1 in blood was significantly higher from week 2 to week 8 than in the control group and EG group. As can be seen from FIG. 1B, from week 2 to week 8, the concentration of vitamin K1 in rat kidney tissue was significantly higher than that in the control group and EG group, and the molding requirement was met.
(II) determination of degree of calcification of kidney in rat kidney tissue
Rats were divided into three groups, with control group given 0.75% ethylene glycol, VK1 group given 0.75% ethylene glycol and 0.77mg/100g VK 1. The administration mode is intraperitoneal injection. The groups were dissected at weeks 0, 2, 4, 6, and 8, kidneys were removed, fixed in 4% paraformaldehyde, sectioned, HE stained, and crystal formation was observed under a polarization microscope, as shown in fig. 1C, 6, and 7.
As can be seen from FIGS. 1C and 6, from the time of crystal formation, crystal formation occurred in the second week of the control group, and crystal formation did not occur until week 6 in the VK group. As can be seen from fig. 1C and 7, the kidney of the control group was significantly more calcified than the VK group at weeks 6 and 8 from the amount of crystal formation (P < 0.05).
This result indicates that vitamin K can delay and reduce the formation of renal calcification, and has an inhibitory effect on renal calcification.
Example 2 effects of vitamin K on reducing crystallization and tubular epithelial cell adhesion
The adhesion of the crystal to the cell is a key step in the formation of calculus, and the adhesion of the calcium oxalate crystal to the cell is measured by adopting an atomic absorption method. Warfarin is widely used as a vitamin K antagonist, blocking the vitamin K cycle, resulting in functional vitamin K deficiency. After 48 hours of treatment of HK2 cells with warfarin or warfarin and VK1, the calcium oxalate crystals were sonicated for 15 minutes to obtain a uniform crystal composition and suspended in DMEM solution, and HK2 cells were exposed to 100 μ g/ml calcium oxalate crystals for 5 minutes. The plate was rapidly washed three times with PBS solution to remove non-adherent crystals. COM crystals adhered to the cells were dissolved with 5ml 6mM HCl for 24 hours and harvested completely. The calcium concentration in the supernatant was determined by atomic absorption and normalized quantitative analysis was performed on calcium oxalate crystals on the cell surface, the results are shown in FIG. 2A.
As can be seen from FIG. 2A, there was a significant increase in the number of crystals adhered to the cells after warfarin treatment, as compared to the control group. Treatment with VK1 reversed the effects of warfarin, significantly reducing crystal deposition in cells (p <0.05)
This result indicates that vitamin K can reduce crystallization and cell adhesion, thereby reducing the chance of crystals sticking to renal tubular epithelial cells to form crystalline nuclei.
Example 3 vitamin K increases cellular Activity and decreases cellular injury
The experiment groups are divided into a control group, a warfarin group and a warfarin + VK1 group, and the apoptosis and damage conditions are detected by a DAPI and TUNEL analysis method. DAPI is a fluorescent staining method that allows the visualization of nuclear DNA in living cells and is used to determine condensed chromosomes to assess apoptosis. The TUNEL assay relies on the presence of a nick in DNA, recognized by terminal deoxynucleotidyl transferase. The results are shown in FIGS. 3 and 2B.
As can be seen from fig. 3A, 3B, 3C and 3D, warfarin treatment significantly increased the number of apoptosis of HK2 compared to the control group. While VK1 treatment significantly reversed the effects of warfarin, reducing the number of apoptotic cells.
As can be seen in fig. 2B, warfarin treatment significantly reduced cell viability and VK1 treatment significantly reversed the effects of warfarin, increasing cell viability compared to the control group.
These results indicate that vitamin K protects cells from apoptosis and damage caused by exposure to calcium oxalate crystals.
Example 4 vitamin K protection of the kidney reduces inflammation and fibrosis
We used a semi-quantitative real-time PCR method to examine the effects of MCP-1 and collagen I on inflammation activation and fibrosis under crystal load. MCP-1 is an agonist of mononuclear leukocytes, which recruit monocytes to sites of inflammation under a variety of pathological conditions. Collagen i is the most abundant collagen in the human body, and it forms large eosinophilic fibers. Total RNA was extracted from 50 mg rat kidney tissue and the RNA concentration was determined spectrophotometrically. cDNA was synthesized by reverse transcription using Hiscript II Q RT Supermix kit (cat. R222-01, Vazyme, China). The primers are as follows: monocyte chemoattractant protein-1 (MCP-1) sense: 5'-GTTGTTCACAGTTGCTGCCT-3', MCP-1antisense 5'-CTCTGTCATACT GGTCACT TCTAC-3', col1 gen I sense: 5'-GGGTCTAGACATGTTCAGCTTTGTG-3', col1 gen I antisense: 5'-ACCCTTAGGCCATTGTGTATGC-3', GAPDH sense:5 ' -TGCTGAGTATGTCG TGGAGTCTA, GAPDH antisense: 5'-AGTGGGAGTTGCTGTTGAAATC-3'. The results are shown in FIG. 5.
As can be seen in FIG. 5A, MCP-1 expression at week 8 was significantly lower in the VK1 group than in the EG group. As can be seen in fig. 5B, collagen I expression was significantly lower in the VK1 group at weeks 2,6, and 8 than in the EG group (P < 0.01).
These results indicate that treatment with vitamin K protects the kidney from the effects of inflammation and fibrosis.
Example 5 vitamin K increases MGP protein expression
MGP protein expression was examined at the cellular and animal level by the western Blot method. VK1 is a cofactor for gamma carboxylation of glutamic acid residues in a part of proteins, including MGP, osteocalcin, gla-rich proteins, etc. Among these proteins, MGP is an important protein affecting the calcification of the extracellular matrix and has been found to be involved in the formation of kidney stones. We extracted total protein separately from cultured cells and kidney tissue at different time points, and the lysates (50. mu.g) were separated on 10% SDS-PAGE gels and then transferred to membranes (MiLople, Billerica, USA). Blocking with 5% skim milk for 60 minutes, incubating overnight at 4 ℃, diluting the primary antibody at 1: 500-1000, washing, treating the membrane with peroxidase-labeled secondary antibody (1: 2000; abclonal, cat. AS014) for one hour, washing again, and observing the band. The results are shown in FIG. 4.
As can be seen in fig. 4A, VK1 induces time-dependent up-regulation of MGP expression in cells. As can be seen in fig. 4B, at 6 and 8 weeks, the VK treatment resulted in a significant increase in MGP expression compared to the EG (ethylene glycol) group.
These results indicate that treatment with vitamin K results in increased MGP protein expression in tubular epithelial cells and kidney tissue.
Claims (4)
1. The vitamin K is used singly or in combination with other medicines in the aspect of preparing the medicine and the health care product for preventing and treating the urinary calculus.
2. The use according to claim 1, wherein vitamin K is used alone or in combination with other drugs or health products for the manufacture of a medicament or health product for the treatment and prevention of urinary stones, including kidney stones, renal pelvis stones, ureteral stones, bladder stones and urinary stones.
3. The use as claimed in claim 1, wherein the vitamin K comprises the naturally occurring vitamins K1 and K2 and the synthetic vitamins K3 and K4 for the preparation of medicaments and health products for the treatment and prevention of urolithiasis.
4. The use of claim 1, wherein vitamin K treats and prevents urolithiasis by reducing crystalline adhesion to tubular epithelial cells, protecting tubular epithelial cells from apoptosis and damage, reducing kidney fibrosis and inflammation, and increasing expression of MGP protein by tubular epithelial cells and kidney tissue.
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Citations (3)
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| JP2001299279A (en) * | 2000-04-21 | 2001-10-30 | Okuzen:Kk | Bone constituting components containing calcium and magnesium and capsuled nutrient supplement using the same |
| CN105963317A (en) * | 2016-05-05 | 2016-09-28 | 南京素德问医药科技有限公司 | Pharmaceutical composition having function of improving bone density |
| WO2017210467A1 (en) * | 2016-06-02 | 2017-12-07 | Ana Pharmaceuticals, Inc. | Methods and compositions for treatment of hypercalciuria and nephrolithiasis |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001299279A (en) * | 2000-04-21 | 2001-10-30 | Okuzen:Kk | Bone constituting components containing calcium and magnesium and capsuled nutrient supplement using the same |
| CN105963317A (en) * | 2016-05-05 | 2016-09-28 | 南京素德问医药科技有限公司 | Pharmaceutical composition having function of improving bone density |
| WO2017210467A1 (en) * | 2016-06-02 | 2017-12-07 | Ana Pharmaceuticals, Inc. | Methods and compositions for treatment of hypercalciuria and nephrolithiasis |
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| 王跃春等: "维生素K、D、C 和B6对泌尿系草酸钙结石的影响（讲座）" * |
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