CN111357990A - Health food composition for increasing bone mass and application thereof - Google Patents
Health food composition for increasing bone mass and application thereof Download PDFInfo
- Publication number
- CN111357990A CN111357990A CN201911362277.8A CN201911362277A CN111357990A CN 111357990 A CN111357990 A CN 111357990A CN 201911362277 A CN201911362277 A CN 201911362277A CN 111357990 A CN111357990 A CN 111357990A
- Authority
- CN
- China
- Prior art keywords
- health food
- food composition
- bone
- phenolic acids
- bone mass
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 235000013402 health food Nutrition 0.000 title claims abstract description 20
- 239000000203 mixture Substances 0.000 title claims abstract description 18
- 210000000988 bone and bone Anatomy 0.000 title abstract description 13
- 240000000851 Vaccinium corymbosum Species 0.000 claims abstract description 19
- 235000003095 Vaccinium corymbosum Nutrition 0.000 claims abstract description 19
- 235000017537 Vaccinium myrtillus Nutrition 0.000 claims abstract description 19
- 235000021014 blueberries Nutrition 0.000 claims abstract description 19
- 210000000963 osteoblast Anatomy 0.000 claims abstract description 12
- 210000002966 serum Anatomy 0.000 claims abstract description 12
- 241001465754 Metazoa Species 0.000 claims abstract description 6
- 230000014509 gene expression Effects 0.000 claims abstract description 6
- 230000001737 promoting effect Effects 0.000 claims abstract description 5
- 230000002188 osteogenic effect Effects 0.000 claims abstract 3
- 108090000623 proteins and genes Proteins 0.000 claims abstract 2
- -1 phenolic acid compounds Chemical class 0.000 claims description 7
- 230000004069 differentiation Effects 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 150000007513 acids Chemical class 0.000 claims description 4
- 235000013305 food Nutrition 0.000 claims description 3
- 239000000284 extract Substances 0.000 claims description 2
- 239000000463 material Substances 0.000 claims 1
- 150000007965 phenolic acids Chemical class 0.000 abstract description 23
- 235000009048 phenolic acids Nutrition 0.000 abstract description 20
- 230000004072 osteoblast differentiation Effects 0.000 abstract description 5
- 241000700159 Rattus Species 0.000 description 12
- 235000005911 diet Nutrition 0.000 description 12
- 230000037213 diet Effects 0.000 description 12
- 208000001132 Osteoporosis Diseases 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 5
- 208000001164 Osteoporotic Fractures Diseases 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 206010065687 Bone loss Diseases 0.000 description 3
- 238000009825 accumulation Methods 0.000 description 3
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 3
- 230000011164 ossification Effects 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- 208000006386 Bone Resorption Diseases 0.000 description 2
- 102000015775 Core Binding Factor Alpha 1 Subunit Human genes 0.000 description 2
- 108010024682 Core Binding Factor Alpha 1 Subunit Proteins 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000024279 bone resorption Effects 0.000 description 2
- 239000005018 casein Substances 0.000 description 2
- 235000021240 caseins Nutrition 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- SVWLIIFHXFGESG-UHFFFAOYSA-N formic acid;methanol Chemical compound OC.OC=O SVWLIIFHXFGESG-UHFFFAOYSA-N 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- 208000035896 Twin-reversed arterial perfusion sequence Diseases 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000002805 bone matrix Anatomy 0.000 description 1
- 230000010072 bone remodeling Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000005802 health problem Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 230000001582 osteoblastic effect Effects 0.000 description 1
- 210000002997 osteoclast Anatomy 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 150000008442 polyphenolic compounds Chemical class 0.000 description 1
- 235000013824 polyphenols Nutrition 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 238000003753 real-time PCR Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/45—Ericaceae or Vacciniaceae (Heath or Blueberry family), e.g. blueberry, cranberry or bilberry
-
- 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
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Physical Education & Sports Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Rheumatology (AREA)
- Pharmacology & Pharmacy (AREA)
- Mycology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Polymers & Plastics (AREA)
- Epidemiology (AREA)
- Microbiology (AREA)
- Medical Informatics (AREA)
- Botany (AREA)
- Biotechnology (AREA)
- Alternative & Traditional Medicine (AREA)
- Food Science & Technology (AREA)
- Nutrition Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
Abstract
The invention discloses a bone-increasing health food composition for promoting osteoblast differentiation and development, which comprises the effective components of 7 phenolic acids extracted from serum after animals eat blueberries. Research shows that the dosage of the 7 Phenolic acids in the health food is determined, and the Phenolic acids can promote the expression of osteogenic genes, promote the development of osteoblasts and increase the bone mass.
Description
Technical Field
The patent belongs to the field of health-care food, and particularly relates to a health-care food composition for increasing bone mass and application thereof.
Background
With the aging of the social population, the incidence of osteoporosis and osteoporotic fracture is increasing. Research shows that the prevalence rate of osteoporosis of old people aged over 60 years in 2016 China is 36%, wherein the prevalence rate of osteoporosis of men is 23% and the prevalence rate of osteoporosis of women is 49%, which indicates that osteoporosis becomes an important public health problem facing China. The most serious consequence of osteoporosis is osteoporotic fracture, which in turn causes a series of health problems such as difficulty in life, death, etc. According to the prediction of an authority, the number of patients suffering from osteoporosis fracture in China reaches 599 thousands and the corresponding medical expense reaches 1745 million yuan by 2050. The problem of preventing and treating osteoporosis in early stage is not easy.
It is well known that bone formation is dependent on osteoblast activity and differentiation, and osteoclast resorption of an existing mineralized bone matrix is a necessary condition for bone remodeling. In young, rapidly growing animals, bone formation often exceeds bone resorption, leading to bone accumulation. With age or other factors, bone resorption exceeds bone accumulation, resulting in bone loss, leading to osteoporosis. Although there are definite genetic factors that affect an individual's susceptibility to the disease, many of the risk factors that cause osteoporosis are non-genetic in nature. It is recognized that the accumulation of bone mineral in childhood, adolescence, is a major factor in determining the risk of osteoporosis later in life. There is increasing research evidence that unidentified factors found in daily consumption of fruits or vegetables may play a role in establishing an optimal bone mass peak to prevent the occurrence of osteoporosis. Recent studies have shown that a supplemented diet of blueberry (BB) has been shown to increase bone mass and alleviate bone loss due to attenuated steroid deficiency. However, the actual effect of the blueberry is not ideal because the blueberry is directly eaten and the content of the active ingredients is low.
Disclosure of Invention
To explore the effect of blueberry diet on bone formation, the inventors measured the active ingredient in serum of rats fed with blueberry diet or casein diet (control) using LC/MS, and characterized and identified 7 phenolic acids (phenolicacids) with free form concentrations 6 to 10 times higher than the control group (table 1). These 7 play important roles in increasing osteoblast activity, increasing bone mass, and inhibiting bone loss.
TABLE 1 concentration of monomeric form in the blood circulation of rats
The invention provides a bone-increasing health food composition for promoting osteoblast differentiation and development. The bone-increasing health food takes seven kinds of phenoxy acids as main components and has the function of promoting the proliferation of osteoblast cells.
The technical scheme of the invention is as follows:
a bone-increasing health food composition for promoting differentiation and development of osteoblast comprises adjuvants and effective components, wherein the effective components are phenolic acid compounds.
Preferably, the phenolic acid compounds are seven kinds of phenoolic acids, and the seven kinds of phenoolic acids are related extracts in animal serum after the blueberry is eaten by animals.
Preferably, the structures of the seven phenolic acids are shown below:
preferably, the seven phenolic acids are used as effective components of health food, and the effective dosage of the seven phenolic acids in adults and children is as follows:
preferably, the 7 phenolic acids promote osteoblast markers, osteoblastic gene expression.
Preferably, the 7 phenolic acids promote osteoblast differentiation and development and increase bone mass.
Compared with the prior art, the invention has the beneficial effects that:
the invention adopts phenolic acid compounds as the main effective components of the health food, and the prepared health food can promote osteoblast gene expression, promote differentiation and development of osteoblasts and increase bone mass.
Drawings
FIG. 1 shows polyphenols in rat serum fed with a blueberry (BB) or casein (Cas) diet characterized by LC/MS.
FIG. 2 shows the effect of an artificial mixture of seven phenolic acids on the expression of the osteoblast formation markers ALP, OCN, Runx2 and b-catenin mRNA in ST2 cells, which mixture mimics the concentration of seven phenolic acids in serum of rats fed either a Cas or BB diet. ST2 cells were treated with a mixture of phenolic acids at different concentrations for 3 days, depending on their morphology in serum of rats fed Cas or BB diets, and detected using real-time PCR.
FIG. 3 shows the effect of stimulating osteoblast differentiation in rats fed with artificial mixed phenolic acids at 7 different concentrations by ALP staining, which was cultured in ST2 cells for 10 days, in a manner similar to the serum concentration of rats fed with Cas or BB diets.
Detailed Description
Example 1
Control or 10% BB fed rat sera were treated with sepp-pak C18 SPE (Waters, Pittsburgh, Pa., USA) volumetric tubes, which were washed with 3mL of methanol and equilibrated with 3mL of 0.2% aqueous formic acid. Serum (500mL) was loaded into volumetric tubes. The volumetric tube was flushed with 3ml of 0.2% formic acid solution and the total phenolic acids were recovered with 0.2% formic acid-methanol mixture. Methanol solution in N2Dried under the conditions of (1), and then dissolved in 200mL of 0.2% formic acid-methanol solution for phenolic acid analysis. Phenolic acids were characterized and quantified using an Agilent 1100 high performance liquid chromatography system (Agilent Technologies, Santa Clara, Calif., USA) and a 4000Q TRAP mass spectrometer (Applied Biosystems) as described previously. The study found 7 phenolic acids, the concentration of which in free form was 6 to 10 times higher than in the blueberry diet compared to the control group.
Example 2
ST2 cells were treated with an artificial mixture of these phenolic acids at the same concentrations as their serum concentrations in rats on the same diet as BB. Compared with the rat cells of the control group, the osteoblast formation markers ALP and OCN gene expressions containing the same concentration of phenolic acid mixture in serum are obviously up-regulated, and Runx2 and b-catenin mRNA are also obviously up-regulated after mixing (p is less than 0.05) (figure 2). Both ST2 and neonatal rat cranial cell cultures, phenolic acids stimulated osteoblast differentiation (p <0.05) (fig. 3). Taken together, the high bone mass of rats fed the BB diet is likely due, at least to some extent, to high serum phenolic acid concentrations. These phenolic acids are derived from the polyphenolic fraction of BB diets and are produced either by the metabolic action of intestinal bacteria or during the first metabolic processes of the intestinal mucosa or liver.
Claims (6)
1. The bone-increasing health-care food composition for promoting differentiation and development of osteoblasts is characterized by comprising auxiliary materials and effective components, wherein the effective components are phenolic acid compounds.
2. The use of the health food composition as defined in claim 1 in the preparation of health food, wherein the phenolic acid compound is an extract from the serum of an animal after the animal eats the blueberry.
5. the use of the health food composition of claim 1 for preparing health food, wherein 7 phenoolic acids promote expression of osteogenic markers, osteogenic genes.
6. Use of the health food composition according to claim 3 for preparing health food, wherein 7 phenoolic acids promote differentiation and development of osteoblasts.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201911362277.8A CN111357990A (en) | 2019-12-26 | 2019-12-26 | Health food composition for increasing bone mass and application thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201911362277.8A CN111357990A (en) | 2019-12-26 | 2019-12-26 | Health food composition for increasing bone mass and application thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
CN111357990A true CN111357990A (en) | 2020-07-03 |
Family
ID=71198215
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201911362277.8A Pending CN111357990A (en) | 2019-12-26 | 2019-12-26 | Health food composition for increasing bone mass and application thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN111357990A (en) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101023982A (en) * | 2006-02-21 | 2007-08-29 | 江苏省药物研究所 | Medicine composition for treating osteoporosis |
CN104250633A (en) * | 2008-01-11 | 2014-12-31 | 骨治疗公司 | Osteogenic differentiation of bone marrow stem cells and mesenchymal stem cells using a combination of growth factors |
CN105055398A (en) * | 2015-09-02 | 2015-11-18 | 广东医学院 | Application of salvianolic acid capsules to promotion of bone repairing and prevention of osteoarthritis and osteoporosis |
CN109432075A (en) * | 2018-09-25 | 2019-03-08 | 浙江欧谱生物科技有限公司 | Between hydroxy phenylpropionic acid preparing the application in anti-osteoporosis agents |
-
2019
- 2019-12-26 CN CN201911362277.8A patent/CN111357990A/en active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101023982A (en) * | 2006-02-21 | 2007-08-29 | 江苏省药物研究所 | Medicine composition for treating osteoporosis |
CN104250633A (en) * | 2008-01-11 | 2014-12-31 | 骨治疗公司 | Osteogenic differentiation of bone marrow stem cells and mesenchymal stem cells using a combination of growth factors |
CN105055398A (en) * | 2015-09-02 | 2015-11-18 | 广东医学院 | Application of salvianolic acid capsules to promotion of bone repairing and prevention of osteoarthritis and osteoporosis |
CN109432075A (en) * | 2018-09-25 | 2019-03-08 | 浙江欧谱生物科技有限公司 | Between hydroxy phenylpropionic acid preparing the application in anti-osteoporosis agents |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Wilson et al. | Short-chain fatty acids promote the migration of colonic epithelial cells in vitro | |
Robison et al. | Sexual dimorphism in hepatic gene expression and the response to dietary carbohydrate manipulation in the zebrafish (Danio rerio) | |
Qi et al. | Zinc supplementation increased bone mineral density, improves bone histomorphology, and prevents bone loss in diabetic rat | |
Shahnazari et al. | Dietary dried plum increases bone mass, suppresses proinflammatory cytokines and promotes attainment of peak bone mass in male mice | |
Macías-Cruz et al. | Effects of dietary ferulic acid on reproductive function and metabolism of pre-pubertal hairbreed ewes during the anestrous season | |
CN110840882A (en) | Composition for treating osteoporosis | |
Han et al. | Effects of high-fructose corn syrup on bone health and gastrointestinal microbiota in growing male mice | |
Tiidus | Influence of estrogen on muscle plasticity | |
US7311919B2 (en) | Agents for treating osteoporosis and inhibiting osteoclast formation | |
CN111357990A (en) | Health food composition for increasing bone mass and application thereof | |
Nanees et al. | Role of irisin administration in modulating testicular function in adult obese albino rats | |
Sakamoto et al. | The effect of vitamin K 2 on bone metabolism in aged female rats | |
Al-Zamely et al. | Role of hydroxytyrosol in ameliorating effects of high fat diet on male rats CNS | |
Zhou et al. | Wogonin ameliorated obesity-induced lipid metabolism disorders and cardiac injury via suppressing pyroptosis and deactivating IL-17 signaling pathway | |
CN112891333B (en) | Application of all-trans retinoic acid in preparation of anti-transmissible gastroenteritis virus medicine | |
US11414663B2 (en) | Micro-RNA profiling, compositions, and methods of treating diseases | |
Moustafa et al. | The possible role of L-carnitine on the skeletal muscle of ovariectomized rats | |
Dong et al. | Ethanol extract of Fructus ligustri lucidi increased circulating 1, 25 (OH) 2D3 levels, but did not improve calcium balance in mature ovariectomized rats | |
Victoria et al. | Effect of Rambutan Fruit Peel Extract on Total Sperm Counts of Wistar Rats Induced with High-Fat Feed | |
US10744151B1 (en) | Micro-RNA profiling, compositions, and methods of treating diseases | |
HERTZ et al. | Elevation of biotin activity in the serum of estrogen treated chicks; relationship to hormone-induced avidin formation in the oviduct | |
Wang et al. | Ovary metabolome and cecal microbiota changes in aged laying hens supplemented with vitamin E | |
Murphy | Citrate metabolism in the osteopetrotic bone of the grey-lethal mouse | |
US11925671B2 (en) | Process and compositions for enhancing energy expenditure | |
US20230040823A1 (en) | Micro-rna profiling, compositions, and methods of treating diseases |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
RJ01 | Rejection of invention patent application after publication | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20200703 |