CN111870689A - Application of nattokinase in medicine for treating osteoporosis - Google Patents
Application of nattokinase in medicine for treating osteoporosis Download PDFInfo
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- CN111870689A CN111870689A CN202010808557.3A CN202010808557A CN111870689A CN 111870689 A CN111870689 A CN 111870689A CN 202010808557 A CN202010808557 A CN 202010808557A CN 111870689 A CN111870689 A CN 111870689A
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- Prior art keywords
- nattokinase
- bone
- osteoporosis
- treating osteoporosis
- medicine
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- 229940086319 nattokinase Drugs 0.000 title claims abstract description 49
- 108010073682 nattokinase Proteins 0.000 title claims abstract description 49
- 208000001132 Osteoporosis Diseases 0.000 title claims abstract description 36
- 239000003814 drug Substances 0.000 title claims abstract description 25
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/482—Serine endopeptidases (3.4.21)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
- C12Y304/21—Serine endopeptidases (3.4.21)
- C12Y304/21062—Subtilisin (3.4.21.62)
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- Life Sciences & Earth Sciences (AREA)
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- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Rheumatology (AREA)
- Epidemiology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Biochemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- General Engineering & Computer Science (AREA)
- Genetics & Genomics (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention discloses an application of nattokinase in drugs for treating osteoporosis; the nattokinase is prepared by fermenting nattokinase strains; the nattokinase serving as an active component is applied to the medicine for treating the osteoporosis alone or in combination with other medicines. The nattokinase has the effects of well reducing the s-TRAP value, increasing the bone mineral content, increasing the bone density and increasing Calcitonin (CT), osteocalcin (BGP) and estradiol (E2), and can be seen to have the effect of remarkably improving osteoporosis.
Description
Technical Field
The present invention relates to the field of osteoporosis treatment. More specifically, the invention relates to an application of nattokinase in a medicine for treating osteoporosis.
Background
Osteoporosis is a systemic skeletal disease characterized by a decrease in the total bone mass, a destruction of the microstructure of the bone tissue, a decrease in bone density, a decrease in the number of trabeculae, a decrease in bone strength, and an susceptibility to fracture. Osteoporosis was previously thought to be a natural consequence of aging without medical intervention; it is now considered a disease that is prone to fracture and can affect most elderly people, especially elderly women. Severe osteoporosis can result in spontaneous vertebral fractures, increasing the risk of bone loss from fractures, and in severe cases, can affect patient longevity and quality of life.
The main causes of osteoporosis are: estrogen deficiency causes osteoclast proliferation and differentiation, osteoclast activation, and osteoclast apoptosis inhibition, so that the bone resorption rate exceeds the bone formation rate. Resulting in a decrease in bone mass and osteoporosis. On the other hand, estrogen can increase the secretion of calcitonin, inhibit the activity of parathyroid hormone, inhibit the dissolution of bone calcium, promote the absorption of calcium in intestinal tract, promote the synthesis of vitamin D in kidney and promote the reconstruction of bone.
The current main therapeutic drugs for osteoporosis are as follows:
2.1 bone resorption inhibitor
2.1.1 Estrogen replacement therapy
The estrogen is supplemented to menopausal women, so that the absorption of osteoclasts can be inhibited, the number of osteoclasts can be reduced, and the absorption of intestinal calcium can be promoted, but the long-term application of the estrogen can cause adverse reactions such as breast cancer, cardiovascular accidents, thromboembolism and the like.
2.1.2 Selective Estrogen receptor modulators
Can be combined with estrogen receptor, selectively acts on estrogen receptor of different tissues, has estrogen activating effect on bone and cardiovascular system, and has adverse reaction of leg spasm and deep venous thrombosis after long-term use.
Eprafen: isoflavone derivatives, and plant estrogen.
Bisphosphonates: contains calcium crystal compound, and can inhibit osteoclast precursor cell.
Calcitonin: binds to the CT receptor on osteoclasts, inhibiting osteoclast activity.
2.2 bone formation promoter
2.2.1 fluoride: can effectively stimulate mitosis of osteoblasts and can obviously improve bone density after being used.
2.2.2 Parathyroid hormone (PTJ): maintain blood calcium balance, regulate calcium and phosphorus metabolism, and promote bone formation with small intermittent dose.
2.2.3 insulin growth factor (IGF-1): can promote mitosis of various cells, and regulate function and metabolism of bone cells.
2.3 bone mineralization promoters
2.3.1 vitamin D and its active metabolites: can promote calcium absorption;
2.3.2 calcium preparation: supplementing elements necessary for bone formation.
However, the above products on the market have been unable to meet the needs of people, and therefore, it is necessary to develop a product capable of solving the above problems.
Disclosure of Invention
To achieve these objects and other advantages in accordance with the present invention, there is provided a use of nattokinase in a medicament for treating osteoporosis.
According to a preferred embodiment of the invention, the nattokinase is applied to the medicine for treating osteoporosis, and the nattokinase is prepared by fermenting nattokinase strains.
According to a preferred embodiment of the invention, the nattokinase is applied to the medicine for treating osteoporosis, and the nattokinase serving as an active component is applied to the medicine for treating osteoporosis alone or in combination with other medicines.
According to a preferred embodiment of the invention, the natto kinase is used in a drug for treating osteoporosis, and the natto kinase can be mixed with pharmaceutically acceptable auxiliary materials to prepare a liquid medicament, a capsule or a tablet.
According to a preferred embodiment of the invention, the nattokinase is applied to the medicine for treating osteoporosis, the subtilase plasmin is prepared by fermenting Bacillus subtilis QK02 strain which is preserved by China Center for Type Culture Collection (CCTCC) in Wuhan Hubei with the preservation number of CCTCC NO: M203078 and the preservation date of 11 months and 17 days in 2003.
The invention at least comprises the following beneficial effects: the invention applies the nattokinase to an animal model of osteoporosis, researches the treatment effect of the nattokinase to the osteoporosis, and has obvious result.
Additional advantages, objects, and features of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention.
Detailed Description
The present invention is further described in detail below with reference to examples so that those skilled in the art can practice the invention with reference to the description.
The following description is presented to disclose the invention so as to enable any person skilled in the art to practice the invention. The preferred embodiments in the following description are given by way of example only, and other obvious variations will occur to those skilled in the art. The basic principles of the invention, as defined in the following description, may be applied to other embodiments, variations, modifications, equivalents, and other technical solutions without departing from the spirit and scope of the invention.
It is understood that the terms "a" and "an" should be interpreted as meaning "at least one" or "one or more," i.e., that a single element may be present in a single embodiment, but in alternate embodiments, the element may be present in multiple embodiments, and the terms "a" and "an" should not be interpreted as limiting the number.
1. Reagent and animal
180-200g adult male SD rats (purchased from the disease prevention and control center in Hubei province) are raised in a well-ventilated, clean and tidy animal room to provide clean drinking water and words;
bone densitometer (griffonia technologies, ltd., beijing);
tretinoin (Retinoic Acid, Wuhansenjie chemical science and technology Co., Ltd.);
sodium carboxymethylcellulose (CMC-Na, national drug group);
serum alkaline phosphatase kit, tartrate-resistant acid phosphatase kit (Nanjing Biotechnology Co., Ltd.);
calcitonin (CT) quantitative determination kit, osteocalcin (BGP) detection kit, estradiol (E2) determination kit (beijing north biotechnology research institute, ltd);
gushukang (Liaoning kang pharmaceutical Co., Ltd.);
preparing natto kinase powder: preparing a bacillus subtilis fermentation culture medium in a fermentation tank, sterilizing, inoculating bacillus subtilis shake-flask seed liquid, fermenting for 22 hours, centrifuging, performing membrane filtration and membrane concentration on the centrifugate, and performing spray drying on the obtained concentrated solution to obtain the nattokinase dry powder. Wherein the original seeds of the bacillus subtilis Subtilisin-QK original seed batch are separated from fermented soybeans by professor royal trade rich laboratory of Wuhan university, the strain is preserved in the national typical culture preservation center, and the strain number is CCTCCNO: m203078.
2. Animal grouping and modeling
60 rats, randomly divided into 6 groups of 10 rats each;
high dose group: 10 patients are subjected to intragastric administration at 10 am every day from the beginning of the test, retinoic acid is given at 70mg/Kg, then nattokinase liquid medicine with the concentration of 10000IU/Kg is prepared by normal saline from the 16 th day, and the intragastric administration is carried out 1 time a day, 400mL/Kg every time and continuously for 5 weeks;
the medium dose group: 10 patients are subjected to intragastric administration at 10 am every day from the beginning of the test, retinoic acid is given at 70mg/Kg, then nattokinase liquid medicine with the concentration of 10000IU/Kg is prepared by normal saline from the 16 th day, and the intragastric administration is carried out 1 time a day, 200mL/Kg every time and continuously for 5 weeks;
low dose group: 10 patients are subjected to intragastric administration at 10 am every day from the beginning of the test, retinoic acid is given at 70mg/Kg, then nattokinase liquid medicine with the concentration of 10000IU/Kg is prepared by normal saline from the 16 th day, and the intragastric administration is carried out 1 time a day, 100mL/Kg every time and continuously for 5 weeks;
model group: 10 patients, performing intragastric administration at 10 am every day within 15 days from the beginning of the test, administering retinoic acid at 70mg/Kg, and performing intragastric administration with 0.5% CMC-Na solution 1 time a day, 10mL/Kg each time for 5 weeks from the 16 th day;
negative control group: 10 patients, performing intragastric administration at 10 am every day within 15 days from the beginning of the test, administering tretinoin at a dose of 70mg/Kg, and performing intragastric administration with 0.5% CMC-Na solution from 16 days for 5 weeks, 1 time a day, 10mL/Kg each time;
positive control group: performing intragastric administration at 10 am every day within 15 days from the beginning of the test, administering a 0.5% CMC-Na solution at a rate of 10mL/Kg, and performing intragastric administration with Gushukang from 16 days for 1 time every day, 3g/Kg every time, continuously for 5 weeks;
3. test method
After dosing, the rats were sacrificed; and taking 5-10 mL of blood from the abdominal artery, placing the blood in water bath at 37 ℃ for 2h, centrifuging after serum is separated, centrifuging at 2000rpm for 5min, and taking rat serum to store at-20 ℃ for detection.
The rats were dissected from the right femur, weighed rapidly, and then immersed in physiological saline and stored at-20 ℃ for testing.
4. Index measuring method
4.1 serum Biochemical index determination
Alkaline phosphatase in serum is a specific indicator reflecting osteoblast activity and bone formation. Determining contents of bone alkaline phosphatase (b-ALP) and tartrate-resistant acid phosphatase (s-TRAP) by enzymatic reaction colorimetry;
measuring the content of serum calcium (s-Ca) by a methyl thymol colorimetric method;
and (3) determining the content of serum phosphorus (s-P) by a malachite green direct chromogenic method.
4.2 bone mineral content determination
After the right femur is stripped, the right femur is dried in a drying oven at 110 ℃ and the weight of the dry bone is weighed; carbonizing the dried thighbone, putting the carbonized thighbone in a muffle furnace at 800 ℃ for ashing for 6 hours, taking out the carbonized thighbone and weighing the ashes; bone ash is dissolved in 6mol/L HCl, and then the content of Ca and P in the bone is measured.
4.3 bone Density determination (BMD) determination
After the right femur had been stripped, its bone density value (BMD) was scanned with a bone densitometer.
4.4 Calcitonin (CT), osteocalcin (BGP) and estradiol (E2) assays
Blood is taken from rat eyeballs, serum is separated, and the content of calcitonin, osteocalcin and estradiol in the rat serum is measured.
5. Clinical results
5.1 Effect of Nattokinase on serological indices
TABLE 1 serological indices of various groups of animal models with osteoporosis
As can be seen from Table 1, the mechanism of retinoic acid-induced osteoporosis model is that retinoic acid activates osteoclasts to promote bone resorption, and serum tartrate-resistant acid phosphatase (s-TRAP) mainly reflects osteoclast activity and number. As can be seen from Table 1, the b-ALP and s-TRAP of the model group are obviously increased, which indicates that the alkaline phosphatase and the tartrate-resistant phosphatase in the serum of the rat of the model group are obviously increased, and indicates that the retinoic acid-induced osteoporosis model is effective.
Compared with the model group, the s-TRAP of the natto kinase in the low-dose group, the medium-dose group and the high-dose group is reduced, particularly the s-TRAP value of the high-dose group is far lower than that of the model group and that of the positive control group, which shows that the natto kinase can inhibit the activity of osteoclasts or reduce the quantity of the natto kinase, and can well inhibit the loss of bone mass.
Compared with the model group, the contents of Ca and P in the low-dose group, the medium-dose group and the high-dose group of the nattokinase are all increased, which proves that the nattokinase can effectively improve the problem of the reduction of the contents of Ca and P in serum caused by osteoporosis.
5.2 Effect of Nattokinase on bone mineral content
TABLE 2 bone mineral content index for each group of osteoporosis animal models
As can be seen from Table 2, the weight coefficient of bone ash (weight of bone ash/weight of dry bone) of the model group did not change significantly, the contents of calcium and phosphorus in the bone ash were all significantly reduced, and the contents of calcium and phosphorus in the bone ash were significantly increased in the medium and high dose groups after continuous administration of nattokinase for 5 weeks.
The retinoic acid has a certain stimulation effect on gastrointestinal tracts and can influence the absorption of rats to calcium and phosphorus, the contents of blood calcium, bone calcium and bone phosphorus in a model group are obviously reduced, and the contents of blood calcium, bone calcium and bone phosphorus can be obviously improved in a medium-dose group and a high-dose group of nattokinase, so that the nattokinase can improve the absorption of calcium and phosphorus in intestinal tracts, and the osteoporosis problem is solved.
5.3 bone Density determination (BMD) determination
TABLE 3 bone Density indices for various groups of osteoporosis animal models
From the results in table 3, it can be seen that the bone density of the low-dose group, the medium-dose group and the high-dose group of nattokinase is improved to a certain extent compared with the model group, and especially the bone density of the high-dose group is greatly improved, so that the nattokinase of the present invention has a good effect of promoting the bone density improvement, thereby improving the osteoporosis problem.
5.4 Calcitonin (CT), osteocalcin (BGP) and estradiol (E2) assays
TABLE 4 bone Density indices for various groups of animal models with osteoporosis
From the results in table 4, it can be seen that compared with the model group, the low dose group, the medium dose group and the high dose group of nattokinase have greatly improved Calcitonin (CT), osteocalcin (BGP) and estradiol (E2), especially the high dose group has a large improvement range, and it can be seen that the nattokinase of the present invention has a significant effect of improving osteoporosis.
In conclusion, the natto kinase has good effects of reducing the s-TRAP value, increasing the bone mineral content, increasing the bone density and increasing Calcitonin (CT), osteocalcin (BGP) and estradiol (E2), and can be seen to have the obvious effect of improving osteoporosis.
While embodiments of the invention have been disclosed above, it is not limited to the applications listed in the description and the embodiments, which are fully applicable in all kinds of fields of application of the invention, and further modifications may readily be effected by those skilled in the art, so that the invention is not limited to the specific details and embodiments shown and described herein, without departing from the general concept defined by the claims and their equivalents.
Claims (5)
1. Application of nattokinase in preparing medicine for treating osteoporosis is provided.
2. The nattokinase for use in a medicament for treating osteoporosis of claim 1, wherein the nattokinase is prepared by fermentation of a nattokinase strain.
3. The nattokinase for use in a drug for treating osteoporosis according to claim 1, wherein the nattokinase as an active ingredient is used in a drug for treating osteoporosis alone or in combination with other drugs.
4. The nattokinase for use in a medicament for treating osteoporosis of claim 1, wherein the nattokinase may be formulated with pharmaceutically acceptable excipients to form a liquid preparation, a capsule or a tablet.
5. The nattokinase for use in a medicament for treating osteoporosis according to claim 1, wherein the nattokinase is prepared by fermenting Bacillus subtilis QK02 strain which has been preserved in the national culture collection center with the strain number of CCTCCNO: m203078.
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