WO2024067345A1 - Use of nucleotide, nutritional composition, food product, and use thereof - Google Patents
Use of nucleotide, nutritional composition, food product, and use thereof Download PDFInfo
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- WO2024067345A1 WO2024067345A1 PCT/CN2023/120375 CN2023120375W WO2024067345A1 WO 2024067345 A1 WO2024067345 A1 WO 2024067345A1 CN 2023120375 W CN2023120375 W CN 2023120375W WO 2024067345 A1 WO2024067345 A1 WO 2024067345A1
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- WIPO (PCT)
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- mass
- lactoferrin
- parts
- nucleotides
- physiologically acceptable
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- 108010063045 Lactoferrin Proteins 0.000 claims abstract description 72
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- INTPYBRGLGSMRA-WFIJOQBCSA-L disodium cytidine 5'-monophosphate Chemical compound [Na+].[Na+].O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP([O-])([O-])=O)O1 INTPYBRGLGSMRA-WFIJOQBCSA-L 0.000 description 1
- 235000013890 disodium inosinate Nutrition 0.000 description 1
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- 230000004821 effect on bone Effects 0.000 description 1
- 210000001671 embryonic stem cell Anatomy 0.000 description 1
- 230000035194 endochondral ossification Effects 0.000 description 1
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- 230000002496 gastric effect Effects 0.000 description 1
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- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical class O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 1
- 239000004226 guanylic acid Substances 0.000 description 1
- 230000003284 homeostatic effect Effects 0.000 description 1
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- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 210000000933 neural crest Anatomy 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000037360 nucleotide metabolism Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 210000004409 osteocyte Anatomy 0.000 description 1
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- 230000000577 osteoprotective effect Effects 0.000 description 1
- 150000002972 pentoses Chemical class 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
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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
- A23L33/13—Nucleic acids or derivatives thereof
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
- A23C9/00—Milk preparations; Milk powder or milk powder preparations
- A23C9/152—Milk preparations; Milk powder or milk powder preparations containing additives
- A23C9/1526—Amino acids; Peptides; Protein hydrolysates; Nucleic acids; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
- A23C9/00—Milk preparations; Milk powder or milk powder preparations
- A23C9/16—Agglomerating or granulating milk powder; Making instant milk powder; Products obtained thereby
-
- 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
- A23L33/17—Amino acids, peptides or proteins
- A23L33/19—Dairy proteins
-
- 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
Definitions
- the present invention generally relates to the field of food. Specifically, the present invention relates to the use of nucleotides for non-therapeutic purposes in promoting bone growth, development and health in the human or animal body.
- the present invention also relates to a nutritional composition comprising nucleotides and lactoferrin, a food comprising the nutritional composition, and the use of the nutritional composition or food for non-therapeutic purposes in promoting bone growth, development and health in the human or animal body.
- Bone is a highly active connective tissue that can repair its own micro-damage through bone metabolism and bone remodeling, and maintain the homeostatic balance of bone structure, load and calcium content. At the same time, bone also regulates metabolic processes as an endocrine organ and is an important organ for maintaining human life. From the neonatal period, bone mass increases with age until the bone matures and reaches its peak in adolescence. Studies have found that paying attention to increasing bone mass during adolescence can achieve individual peak bone mass in adolescence. Therefore, the growth and development of bones during adolescence is crucial to bone maturation. Studies have pointed out that bone mineral density (BMD) during adolescence determines the peak bone mass and subsequent bone loss rate in adulthood.
- BMD bone mineral density
- Reduced BMD can lead to insufficient bone mass, which in turn causes a series of bone diseases such as rickets and osteomalacia, which seriously affect the bone health of adolescents.
- nutritional supplementation is an important factor affecting the peak bone mass. The intake of nutrients can increase the peak bone mass and promote bone formation.
- Osteoporosis is a systemic bone disease caused by a variety of reasons, which is particularly harmful to the health and quality of life of the elderly. Bone remodeling is a complex biological process. Osteoclasts in bone tissue complete the bone absorption function, and osteoblasts dominate the bone formation function. Once the balance between the two is broken, it will cause bone metabolic diseases such as osteoporosis. At present, drugs for the treatment of osteoporosis mainly slow down bone loss and restore bone metabolism balance by inhibiting bone absorption and stimulating bone formation. Food ingredients without side effects are particularly important in the process of preventing and treating osteoporosis.
- One object of the present invention is to provide non-therapeutic uses of nucleotides in promoting bone growth and health in humans or animals, such as improving bone density.
- Another object of the present invention is to provide a nutritional composition comprising nucleotides and lactoferrin.
- Another object of the present invention is to provide a food product comprising the nutritional composition.
- a further object of the present invention is to provide a non-therapeutic use of the nutritional composition or food in promoting bone growth and health in the human or animal body, such as improving bone density.
- nucleotides for non-therapeutic purposes in promoting bone growth and health in humans or animals, such as improving bone density, wherein the nucleotides include or consist of the following:
- 5'-Adenosine monophosphate 5'-AMP
- physiologically acceptable salt thereof preferably a sodium salt, preferably 5'-Adenosine monophosphate
- 5'-Cytidylic acid or a physiologically acceptable salt thereof, preferably a sodium salt, preferably disodium 5'-cytidylic acid;
- 5'-guanylic acid or a physiologically acceptable salt thereof, preferably a sodium salt, preferably disodium 5'-guanylate;
- 5'-Uridylic acid or a physiologically acceptable salt thereof, preferably a sodium salt, preferably disodium 5'-uridine monophosphate, and
- 5'-inosinic acid 5'-IMP
- a physiologically acceptable salt thereof preferably a sodium salt, preferably disodium 5'-inosinic acid.
- 5'-adenosine (5'-AMP) or a physiologically acceptable salt thereof is 4.0-35.0% by mass, preferably 14.0-22.0% by mass;
- 5'-cytidylic acid (5'-CMP) or a physiologically acceptable salt thereof is 20.0-70.0% by mass, preferably 38.0-46.0% by mass;
- 5'-guanylic acid (5'-GMP) or a physiologically acceptable salt thereof is 3.0-30.0% by mass, preferably 11.0-19.0% by mass;
- 5'-uridine monophosphate (5'-UMP) or a physiologically acceptable salt thereof is 5.0-40.0% by mass, preferably 15.0-23.0% by mass, and
- the content of 5'-inosinic acid (5'-IMP) or a physiologically acceptable salt thereof is 0.1-20.0% by mass, preferably 3.0-9.0% by mass.
- promoting bone growth, development and health comprises one or more of the following: improving osteoporosis, repairing cartilage damage, and repairing osteogenesis damage.
- a nutritional composition comprising nucleotides and lactoferrin, wherein the nucleotides comprise or consist of:
- 5'-Adenosine monophosphate 5'-AMP
- physiologically acceptable salt thereof preferably a sodium salt, preferably 5'-Adenosine monophosphate
- 5'-Cytidylic acid or a physiologically acceptable salt thereof, preferably a sodium salt, preferably disodium 5'-cytidylic acid;
- 5'-guanylic acid or a physiologically acceptable salt thereof, preferably a sodium salt, preferably disodium 5'-guanylate;
- 5'-Uridylic acid or a physiologically acceptable salt thereof, preferably a sodium salt, preferably disodium 5'-uridine monophosphate, and
- 5'-inosinic acid 5'-IMP
- a physiologically acceptable salt thereof preferably a sodium salt, preferably disodium 5'-inosinic acid.
- 5'-adenosine (5'-AMP) or a physiologically acceptable salt thereof is 4.0-35.0% by mass, preferably 14.0-22.0% by mass;
- 5'-cytidylic acid (5'-CMP) or a physiologically acceptable salt thereof is 20.0-70.0% by mass, preferably 38.0-46.0% by mass;
- 5'-guanylic acid (5'-GMP) or a physiologically acceptable salt thereof is 3.0-30.0% by mass, preferably 11.0-19.0% by mass;
- 5'-uridine monophosphate (5'-UMP) or a physiologically acceptable salt thereof is 5.0-40.0% by mass, preferably 15.0-23.0% by mass, and
- the content of 5'-inosinic acid (5'-IMP) or a physiologically acceptable salt thereof is 0.1-20.0% by mass, preferably 3.0-9.0% by mass.
- lactoferrin is derived from Or it can be provided in the following forms: a nutrient rich in lactoferrin, such as concentrated whey protein powder rich in lactoferrin and/or lactoferrin powder, etc., preferably lactoferrin powder.
- the amount of lactoferrin relative to 1 part by mass of the nucleotide is 0.01-20 parts by mass, preferably 0.02-15 parts by mass, preferably 0.05-12 parts by mass, preferably 0.05-10 parts by mass, preferably 0.05-8 parts by mass, preferably 0.05-5 parts by mass, preferably 0.1-2 parts by mass, preferably 0.1-0.3 parts by mass, preferably 0.12-0.25 parts by mass.
- Food comprising the nutritional composition according to any one of items 4 to 8.
- infant formula such as infant formula milk powder, baby food, nutritional or dietary supplement, pregnant woman formula milk powder, or middle-aged and elderly milk powder.
- FIG1 shows a graph of fluorescence intensity of zebrafish vertebrae after different treatments.
- infant refers to a human between 0 and 6 months of age.
- infant refers to persons 6 to 12 months of age.
- young child refers to a person between 12 and 36 months of age.
- infant refers to a human aged 0-36 months.
- child refers to a person aged 3-6 years.
- young refers to persons aged 18-40 years.
- infant formula used herein covers infant formula, follow-on formula and toddler formula.
- infant formula is used as a breast milk substitute from birth
- follow-on formula is used as a breast milk substitute from 6-12 months after the birth of the infant
- toddler formula refers to a breast milk substitute from 12-36 months after the birth of the infant.
- infant formula refers to a liquid or powdered product made from milk and milk protein products or soybeans and soybean protein products as the main raw materials, with appropriate amounts of vitamins, minerals and/or other ingredients added, and produced and processed only by physical methods. It is suitable for normal infants to eat, and its energy and nutrients can meet the normal nutritional needs of infants aged 0-6 months.
- follow-up infant formula refers to a liquid or powdered product made from milk and milk protein products or soy and soy protein products as the main raw materials, with appropriate amounts of vitamins, minerals and/or other ingredients added, and produced and processed only by physical methods. It is suitable for older infants, and its energy and nutritional components can meet part of the nutritional needs of normal older infants aged 6-12 months.
- infant formula food refers to a liquid or powdered product made from milk and milk protein products or soy and soy protein products as the main raw materials, with appropriate amounts of vitamins, minerals and/or other ingredients added, and produced and processed only by physical methods. It is suitable for infants to eat, and its energy and nutritional components can meet part of the nutritional needs of normal infants aged 12-36 months.
- breast milk is to be understood as a mother's breast milk or colostrum.
- exclusive breastfed infant or young child has its usual meaning and refers to an infant who derives a substantial portion of his or her nutrients and/or energy from human breast milk.
- infant formula has its ordinary meaning and refers to infant formula that is primarily produced by physically processing the source of nutrients and/or energy.
- the term “mainly” refers to at least 50%, such as at least 75%, of those nutrients and/or energy.
- composition of the present invention may comprise, consist of, or consist essentially of the following elements: the basic elements and necessary limitations of the present invention described herein, and any other or optional ingredients, components, or limitations described herein or otherwise as required.
- the individual described in the present invention is applicable to normal humans, and can be an infant and/or an older infant, and/or a toddler, and/or a child, and/or a young person, and/or a middle-aged person, and/or an elderly person.
- the present invention relates to the non-therapeutic use of nucleotides in promoting the growth and health of bones in humans or animals, such as improving bone density, a nutritional composition comprising nucleotides and lactoferrin, a food comprising the nutritional composition, and the non-therapeutic use of the nutritional composition or food in promoting the growth and health of bones in humans or animals, such as improving bone density.
- non-therapeutic purpose means nutritional and health purposes, ie, non-medical purposes or purposes of non-medical use, and these terms are used interchangeably.
- the present invention provides the use of nucleotides for non-therapeutic purposes (nutritional and health purposes) in promoting bone growth and health in the human or animal body, such as improving bone density.
- Nucleotides are a class of compounds composed of three substances: purine bases or pyrimidine bases, ribose or deoxyribose, and phosphate. Pentose and organic bases synthesize nucleosides, and nucleosides and phosphates synthesize nucleotides. Four types of nucleotides make up nucleic acids. Nucleotides are mainly involved in the formation of nucleic acids, and many single nucleotides also have a variety of important biological functions, such as adenosine triphosphate (ATP) and dehydrogenases related to energy metabolism. Some nucleotide analogs can interfere with nucleotide metabolism and can be used as anticancer drugs.
- ATP adenosine triphosphate
- nucleotides are divided into two categories: ribonucleotides and deoxynucleotides.
- adenylic acid also called adenine nucleotide, AMP
- guanylic acid also called guanine nucleotide, GMP
- cytidylic acid also called cytosine nucleotide, CMP
- uridylic acid also called uracil nucleotide, UMP
- thymidylic acid also called thymus
- the phosphate in the nucleotide has several forms, such as one molecule, two molecules and three molecules.
- the nucleotide molecule can also be dehydrated and condensed to form a cyclic nucleotide.
- Nucleotides are a type of non-protein nitrogen in breast milk. Nucleotides in dairy products also have specific physiological functions, especially for infants and young children. Adding nucleotides to infant formula powder has certain significance in improving infants' immune function, increasing iron absorption, affecting lipoprotein metabolism, improving intestinal beneficial bacteria, improving intestinal function and liver function, and promoting growth. It is increasingly valued by various countries. In 2008, my country has allowed nucleotides to be added to infant formula. At present, there is no relevant research on its effect on bone development in the existing technology.
- nucleotides also have new functions of promoting bone growth, development and health, such as improving bone density and osteoporosis, thus meeting the market demand for bone-strengthening functions.
- the nucleotide comprises, consists essentially of, is essentially composed of, or is composed of:
- 5'-Adenosine monophosphate 5'-AMP
- a physiologically acceptable salt thereof preferably a sodium salt (e.g., a disodium salt), preferably 5'-Adenosine monophosphate;
- 5'-Cytidylic acid or a physiologically acceptable salt thereof, preferably a sodium salt (e.g., a disodium salt), preferably disodium 5'-cytidylic acid;
- 5'-guanylic acid or a physiologically acceptable salt thereof, preferably a sodium salt (e.g., a disodium salt), preferably disodium 5'-guanylate;
- 5'-Uridine monophosphate (5'-UMP) or a physiologically acceptable salt thereof, preferably a sodium salt (e.g., a disodium salt), preferably disodium 5'-uridine monophosphate, and
- 5'-inosinic acid or a physiologically acceptable salt thereof, preferably a sodium salt (e.g., a disodium salt), preferably disodium 5'-inosinic acid.
- a sodium salt e.g., a disodium salt
- the term "mainly” should be understood to mean 50% by mass or more of the mentioned substance, for example 60% by mass or more, 70% by mass or more, 80% by mass or more, 90% by mass or more, 95% by mass or more.
- the term "substantially” should be understood to mean at least 85% by mass, such as at least 90% by mass, 90%-99.9% by mass of the substance referred to.
- the 5'-adenosine monophosphate (5'-AMP) or a physiologically acceptable salt thereof is 5'-adenosine monophosphate.
- the 5'-cytidylic acid (5'-CMP) or a physiologically acceptable salt thereof is 5'-cytidylic acid disodium.
- the 5'-guanylic acid (5'-GMP) or a physiologically acceptable salt thereof is disodium 5'-guanylate.
- the 5'-uridine monophosphate (5'-UMP) or a physiologically acceptable salt thereof is 5'-uridine monophosphate disodium.
- the 5'-inosinic acid (5'-IMP) or a physiologically acceptable salt thereof is disodium 5'-inosinic acid.
- the nucleotide comprises, consists essentially of, is essentially composed of, or is composed of:
- 5'-adenosine (5'-AMP) or a physiologically acceptable salt thereof is 4.0-35.0% by mass, preferably 14.0-22.0% by mass;
- 5'-cytidylic acid (5'-CMP) or a physiologically acceptable salt thereof is 20.0-70.0% by mass, preferably 38.0-46.0% by mass;
- 5'-guanylic acid (5'-GMP) or a physiologically acceptable salt thereof is 3.0-30.0% by mass, preferably 11.0-19.0% by mass;
- 5'-uridine monophosphate (5'-UMP) or a physiologically acceptable salt thereof is 5.0-40.0% by mass, preferably 15.0-23.0% by mass, and
- the content of 5'-inosinic acid (IMP) or a physiologically acceptable salt thereof is 0.5-20.0% by mass, preferably 3.0-9.0% by mass.
- the amount of 5'-adenosine monophosphate (5'-AMP) or a physiologically acceptable salt thereof, such as 5'-adenosine monophosphate is 4.0-35.0% by weight, preferably 14.0-22.0% by weight, relative to the total weight of the nucleotides, for example, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2 , 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1
- the amount of 5'-cytidylic acid (5'-CMP) or a physiologically acceptable salt thereof, such as 5'-cytidylic acid disodium, relative to the total weight of the nucleotide is 20.0-70.0% by mass, preferably 38.0-46.0% by mass, for example, 20.0, 20.1, 20.2, 20.3, 20.4, 20.5, 20.6, 20.7, 20.8, 20.9, 21.0, 21.1, 21.2, 21.3, 21.4, 21.5, 21.6, 21.7, 21.8, 21.9, 22.0, 22.1, 22.2, 22.3, 22.4, 22.5, 22.6, 22.7, 22.8, 22.9, 23.0, 23.1, 23.2, 23.3, 23.4, 23.5 , 23.6, 23.7, 23.8, 23.9, 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5
- the amount of 5'-guanosine monophosphate (5'-GMP) or a physiologically acceptable salt thereof, such as disodium 5'-guanylate, relative to the total weight of the nucleotide is 3.0-30.0% by weight, preferably 11.0-19.0% by weight, for example, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9 , 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.
- the amount of 5'-uridylic acid (5'-UMP) or a physiologically acceptable salt thereof, such as 5'-uridylic acid disodium is 5.0-40.0% by weight relative to the total weight of the nucleotide.
- 15.0-23.0% by mass for example 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 .9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3, 14.4,
- the 5'-inosinic acid (5'-IMP) or a physiologically acceptable salt thereof, for example 5'-inosinic acid disodium in an amount of 0.1-20% by mass, preferably 3.0-9.0% by mass, for example 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1,
- each nucleotide When the content of each nucleotide is within the above range, the effect on promoting bone growth and development (eg, improving osteoporosis and/or repairing cartilage damage and/or repairing osteogenesis damage) is more significant.
- said promoting bone growth, development and health comprises improving bone density.
- the promotion of bone growth, development and health includes one or more of the following: improving osteoporosis, repairing cartilage damage, and repairing osteoblastic damage.
- the promoting bone growth and development includes: promoting human bone growth, development and health, including promoting bone growth, development and health in infants, children, adolescents and/or middle-aged and elderly people; and/or promoting animal, especially mammal bone growth, development and health.
- an amount of, for example, 0.018g/ day-0.15g/ day can be taken.
- it can significantly play a role in promoting bone growth and development (e.g., improving osteoporosis and/or repairing cartilage damage and/or repairing osteogenic damage).
- the nucleotides can be used alone or in the form of a composition comprising the nucleotides, such as a food, especially a milk powder.
- the food can be an infant formula (e.g., an infant formula, an older infant formula, a toddler formula), such as an infant formula milk powder (e.g., an infant formula milk powder, a toddler formula milk powder), a baby food supplement, a nutrition or dietary supplement, or a formula milk powder for pregnant women, a milk powder for the middle-aged and elderly.
- the nucleotide is used in the form of a food containing the nucleotide.
- the total amount of the nucleotide in the food is 0.0012-0.058% by mass, preferably 0.0025-0.058% by mass, for example, 0.0012, 0.0015, 0.0020, 0.0025, 0.0030, 0.0035, 0.0040, 0.0045, 0.0050, 0.0055, 0.0060, 0.0065, 0.0070, 0.0075, 0.0080, 0.0085, 0.0090, 0.0095, 0.010, 0.011, 0.012, 0.013, 0.014, 0.015, 0.016, 0.017, 0.018, 0.019, 0.020 0.054, 0.055, 0.056, 0.057, 0.058, 0.059, 0.060, 0.061, 0.062, 0.063, 0.064, 0.065, 0.066, 0.067, 0.068, 0.069, 0.070, 0.071, 0.072
- the nucleotides can also be used in combination with lactoferrin.
- lactoferrin When the nucleotides are combined with When lactoferrin is used in combination, its effect in promoting bone growth, development and health, such as improving bone density, can be further enhanced, and there may even be a synergistic effect in this regard.
- the present invention relates to a nutritional composition
- a nutritional composition comprising nucleotides and lactoferrin.
- nucleotides are as described above in the use of nucleotides.
- the nutritional composition comprises nucleotides and lactoferrin, wherein:
- the nucleotides include one or more selected from the following, mainly include one or more selected from the following, basically consist of one or more selected from the following, or consist of one or more selected from the following:
- 5'-Adenosine monophosphate 5'-AMP
- a physiologically acceptable salt thereof preferably a sodium salt (e.g., a disodium salt), preferably 5'-Adenosine monophosphate;
- 5'-Cytidylic acid or a physiologically acceptable salt thereof, preferably a sodium salt (e.g., a disodium salt), preferably disodium 5'-cytidylic acid;
- 5'-guanylic acid or a physiologically acceptable salt thereof, preferably a sodium salt (e.g., a disodium salt), preferably disodium 5'-guanylate;
- 5'-Uridine monophosphate (5'-UMP) or a physiologically acceptable salt thereof, preferably a sodium salt (e.g., a disodium salt), preferably disodium 5'-uridine monophosphate, and
- 5'-inosinic acid or a physiologically acceptable salt thereof, preferably a sodium salt (e.g., a disodium salt), preferably disodium 5'-inosinic acid.
- a sodium salt e.g., a disodium salt
- 5'-adenosine (5'-AMP) or a physiologically acceptable salt thereof is 4.0-35.0% by mass, preferably 14.0-22.0% by mass;
- 5'-cytidylic acid (5'-CMP) or a physiologically acceptable salt thereof is 20.0-70.0% by mass, preferably 38.0-46.0% by mass;
- 5'-guanylic acid (5'-GMP) or a physiologically acceptable salt thereof is 3.0-30.0% by mass, preferably 11.0-19.0% by mass;
- 5'-uridine monophosphate (5'-UMP) or a physiologically acceptable salt thereof is 5.0-40.0% by mass, preferably 15.0-23.0% by mass, and
- the content of 5'-inosinic acid (5'-IMP) or a physiologically acceptable salt thereof is 0.1-20.0% by mass, preferably 3.0-9.0% by mass.
- Lactoferrin is an iron-binding glycoprotein with a molecular weight of about 80 kDa and belongs to the transferrin family. Lactoferrin is found in high levels in colostrum and milk, and in lower levels in mucosal secretions such as tears, saliva, semen, nasal and bronchial secretions, bile and gastrointestinal fluid. In addition, lactoferrin is also a component of neutrophils. Lactoferrin is one of the body's main defense molecules. In addition to helping transport and transfer iron ions and increasing the bioavailability of iron, it also has a variety of biological immune activities, including broad-spectrum antibacterial, antiviral, antioxidant and immune regulatory activities.
- the nutritional composition consists essentially of nucleotides and lactoferrin.
- the nutritional composition consists essentially of nucleotides and lactoferrin.
- the nutritional composition consists of nucleotides and lactoferrin.
- the lactoferrin may be derived from or provided in the following form: a nutrient rich in lactoferrin (LF), such as concentrated whey protein powder rich in lactoferrin and/or lactoferrin powder, etc., preferably lactoferrin powder.
- LF lactoferrin
- the amount of lactoferrin relative to 1 part by mass of nucleotides can be 0.01-20 parts by mass, preferably 0.02-15 parts by mass, preferably 0.05-12 parts by mass, preferably 0.05-10 parts by mass, preferably 0.05-8 parts by mass, preferably 0.05-5 parts by mass, preferably 0.1-2 parts by mass, preferably 0.1-0.3 parts by mass, preferably 0.12-0.25 parts by mass, for example, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18 ⁇ 0.19 ⁇ 0.20 ⁇ 0.21 ⁇ 0.22 ⁇ 0.23 ⁇ 0.24 ⁇ 0.25 ⁇ 0.26 ⁇ 0.27 ⁇ 0.28 ⁇ 0.29 ⁇ 0.30 ⁇ 0.31 ⁇ 0.32 ⁇ 0.33 ⁇ 0.34 ⁇ 0.35 ⁇ 0.36 ⁇ 0.37 ⁇ 0.38 ⁇ 0.39 ⁇ 0.40 ⁇ 0.41 ⁇ 0.42 ⁇ 0.43
- the ratio of nucleotides to lactoferrin is within the above range, the effect on promoting bone growth and health, such as increasing bone density, is more significant.
- the amount of lactoferrin can be 0.1-0.3 parts by mass, preferably 0.12-0.25 parts by mass, or any other value or range within the range as described above relative to 1 part by mass of nucleotides.
- nucleotides and lactoferrin are used in the above ratio range, the effect is more significant, and bone growth and development can be promoted synergistically, and bone density can be increased.
- the present invention also relates to a food product comprising the nutritional composition.
- the food of the present invention may be in powder form or in liquid form.
- the food of the present invention can be infant formula (e.g., infant formula, follow-on formula, toddler formula), such as infant formula milk powder (e.g., infant formula milk powder, toddler formula milk powder), baby food, nutritional or dietary supplement, pregnant woman formula milk powder, or middle-aged and elderly milk powder.
- infant formula milk powder e.g., infant formula milk powder, toddler formula milk powder
- baby food e.g., infant formula milk powder, toddler formula milk powder
- nutritional or dietary supplement e.g., nursing woman formula milk powder, or middle-aged and elderly milk powder.
- the nutritional composition is added in an amount such that the total mass content of the nucleotides is 0.0012-0.058%, preferably 0.0025-0.058%, relative to the total mass of the food.
- the total mass content of the nucleotides may be 0.0012, 0.0015, 0.0020, 0.0025, 0.0030, 0.0035, 0.0040, 0.0045, 0.0050, 0.0055, 0.0060, 0.0065, 0.0070, 0.0075, 0.0080, 0.0085, 0.0090, 0.0095, 0.010, 0.011, 0.012, 0.013, 0.014, 0.015, 0.016, 0.017, 0.018, 0.019, 0.190, 0.191, 0.192, 0.193, 0.194, 0.195, 0.196, 0.197, 0.201 4.
- nucleotide When the nucleotide is used in the above amount, it can significantly play a role in promoting bone growth and development (e.g., improving osteoporosis and/or repairing cartilage damage and/or repairing osteoblastic damage).
- the amount of the nutritional composition added is such that, relative to the total mass of the food, the amount of lactoferrin is 0.002-1.0% by mass, preferably 0.004-0.7% by mass.
- the amount of lactoferrin may be 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.010, 0.015, 0.020, 0.025, 0.030, 0.035, 0.040, 0.045, 0.050, 0.055, 0.060, 0.065, 0.070, 0.075, 0.080 , 0.085, 0.090, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.
- nucleotides and lactoferrin in food When the content of nucleotides and lactoferrin in food is within the above range, it can significantly promote bone growth, development and health (such as improving osteoporosis, repairing cartilage damage, repairing bone damage, etc.), and at the same time it can balance various aspects of nutrition required by the human body or animal body.
- the amount of lactoferrin in the food, relative to 1 mass part of nucleotide, is 0.1-20 mass parts, preferably 0.1-10 mass parts, preferably 0.1-2 mass parts, and even more preferably, the amount of lactoferrin is 0.1-0.3 mass parts, preferably 0.12-0.25 mass parts, or any other value or range within this range as described above, and the content of the nucleotide in the food is 0.0025-0.058 mass%, or any other value or range within this range as described above for the nucleotide, and the content of the lactoferrin is 0.004-0.8 mass%, or any other value or range within this range as described above for the lactoferrin.
- the ratio of nucleotide to lactoferrin and the respective dosage are within the above range or preferred range, the effect is more significant, and the growth and health of bones can be promoted synergistically, especially the improvement of bone density, such as repairing cartilage loss and repairing bone damage, and at the same time, the various aspects of nutrition required by the human or animal body can be balanced.
- the food may also contain other ingredients, such as protein Ingredients often contained in formula foods such as infant formula foods such as milk powder, such as proteins/amino acids, carbohydrates, fats, vitamins, minerals, etc.
- the present invention relates to the use of the above nutritional composition or the above food for non-therapeutic purposes in promoting bone growth and health of the human or animal body, such as improving bone density.
- said promoting bone growth, development and health comprises improving bone density.
- the promotion of bone growth, development and health includes one or more of the following: improving osteoporosis, repairing cartilage damage, and repairing osteoblastic damage.
- the promoting bone growth and development includes: promoting human bone growth, development and health, including promoting bone growth, development and health in infants, children, adolescents and/or middle-aged and elderly people; and/or promoting animal, especially mammal bone growth, development and health.
- the nucleotide can be used in an amount of, for example, 0.0003-0.1 g/day/kg body weight, such as 0.001-0.05 g/day/kg body weight, such as 0.003-0.025 g/day/kg body weight, such as 0.006-0.013 g/day/kg, for example, 0.0003, 0.0004, 0.0005, 0.0006, 0.0007, 0.0008, 0.0009, 0.0010, 0.0015, 0.0020, 0.0025, 0.0030, 0.0035, 0.0040, 0.0045, 0.0050, 0.006 55, 0.0060, 0.0065, 0.0070, 0.0075, 0.0080, 0.0085, 0.0090, 0.0095, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.010, 0.011, 0.012, 0.013, 0.014, 0.015, 0.016, 0.017, 0.018, 0.019, 0.020, 0.021, 0.0
- the nucleotide can be taken in an amount of, for example, 0.018g/day-0.15g/day.
- the amount of lactoferrin used relative to 1 part by mass of nucleotide can be 0.01-20 parts by mass, preferably 0.02-15 parts by mass, preferably 0.05-12 parts by mass, preferably 0.05-10 parts by mass, preferably 0.05-8 parts by mass, preferably 0.05-5 parts by mass, preferably 0.1-2 parts by mass, preferably 0.1-0.3 parts by mass, preferably 0.12-0.25 mass parts, or any other value or range within this range as described above.
- the lactoferrin is used in an amount of 0.1-0.3 mass parts, preferably 0.12-0.25 mass parts, relative to 1 mass part of the nucleotide.
- nucleotides and lactoferrin are used in an amount within the above range, especially within a preferred range, the effect on promoting bone growth and health, such as increasing bone density, is more significant.
- zebrafish In basic and preclinical research, zebrafish has become an important model organism for studying bone development and disease. Since zebrafish are transparent throughout the embryonic and larval stages, their bone formation and osteoblast activity can be monitored more clearly and in detail. Like other vertebrates, zebrafish have a complex ossified skeleton composed of cartilage and bone. The skeleton is formed by the condensation of mesenchymal cells that first produce chondrocytes, then osteocytes and osteoblasts. Based on the evolutionary conservation of vertebrate skeletal genes, zebrafish skeletons contain the same bone cells as mammals, and many skeletal structures have obvious homology in mammals. Therefore, the zebrafish model can be used for the study of osteoporosis, arthritis, and bone development. This method systematically and intuitively evaluates the effects on bone development, which has far-reaching significance for the application of raw materials.
- Lactoferrin Hilmar 1000 lactoferrin from Hilmar, USA, lactoferrin content 97.2% by mass
- Nucleotides and lactoferrin were prepared into 10.0 mg/mL stock solutions with standard dilution water and used immediately after preparation.
- chondroitin sulfate A sodium salt (hereinafter referred to as chondroitin sulfate), white powder, batch number I2003201, Shanghai Aladdin Biochemical Technology Co., Ltd., stored at 4°C away from light. Prepared into 20.0 mg/mL stock solution with ultrapure water, used immediately after preparation.
- Zebrafish were raised in 28°C fish water (water quality: 200 mg instant sea salt was added to 1 L reverse osmosis water, conductivity was 450-550 ⁇ S/cm; pH was 6.5-8.5; hardness was 50-100 mg/L CaCO 3 ), and the experimental animal use license number was SYXK (Zhejiang) 2012-0171.
- the feeding and management complied with the requirements of the international AAALAC certification (certification number: 001458).
- Wild-type AB strain zebrafish were bred in natural pairs. Zebrafish aged 3 days post fertilization (3 dpf) were used for the determination of the maximum detection concentration (MTC) of the anti-osteoporosis efficacy of the samples and their efficacy evaluation.
- MTC maximum detection concentration
- Transgenic cartilage green fluorescent zebrafish Tg (Col2a1a: eGFP) were bred by natural pair mating. Zebrafish aged 2 days post fertilization (2dpf) were used for evaluation of cartilage damage repair efficacy of samples and compositions.
- Transgenic osteogenic green fluorescent zebrafish Tg(OlaSp7:nlsGFP)cy25 were bred by natural pair mating. Zebrafish aged 3 days post fertilization (3dpf) were used for evaluation of the osteoprotective efficacy of samples and compositions.
- zebrafish (mg/L) [human (g/day) ⁇ 1000]/6.
- Dexamethasone (Batch No. L1931006, Shanghai Aladdin Biochemical Technology Co., Ltd., China); 4% tissue cell fixative (batch number 20210828, Solarbio, China); Alizarin Red (batch number C12071107, Shanghai McLean Biochemical Technology Co., Ltd., China); Glycerol (batch number C12219636, Shanghai McLean Biochemical Technology Co., Ltd., China); Potassium hydroxide (batch number T20110104, Sinopharm Chemical Reagent Co., Ltd., China); Anhydrous magnesium chloride (C1809044, Shanghai Aladdin Biochemical Technology Co., Ltd., China); Anhydrous ethanol (batch number 20210514, Sinopharm Chemical Reagent Co., Ltd., China); Hydrogen peroxide (batch number 20210203, Sinopharm Chemical Reagent Co., Ltd., China); Dimethyl sulfoxide (DMSO, batch number BCCD8942, Sigma, Switzerland); Methylcellulose (batch number C200
- 3dpf wild-type AB strain zebrafish were randomly selected in a 6-well plate, with 15 in each well (experimental group). The samples were given water-soluble (concentrations are shown in Table 1), and the positive control alendronate sodium tablets were 2.50 ⁇ g/mL. At the same time, a model control group and a normal control group were set up, with a capacity of 3mL per well. Except for the normal control group, dexamethasone was given water-soluble to establish a zebrafish osteoporosis model in all other experimental groups. The zebrafish were treated at 28°C until 5dpf and the solution was changed. After the solution was changed, the treatment continued until 7dpf.
- 2dpf transgenic cartilage green fluorescent zebrafish were randomly selected in a 6-well plate, and 15 zebrafish were treated in each well (experimental group).
- the samples were given water-soluble (concentrations are shown in Table 1), and the positive control chondroitin sulfate concentration was 1000 ⁇ g/mL.
- a normal control group and a model control group were set up, and the capacity of each well was 3mL.
- the other experimental groups were given water-soluble dexamethasone to establish a zebrafish cartilage injury model. After treatment at 28°C until 5dpf, 8 zebrafish were randomly selected from each experimental group and photographed under a fluorescence microscope.
- NIS-Elements D 3.20 advanced image processing software was used to collect data and analyze the cartilage fluorescence intensity. The statistical analysis results of this indicator were used to evaluate the cartilage injury repair efficacy of each experimental group. The statistical analysis results are expressed as mean ⁇ SE. SPSS26.0 software was used for statistical analysis, p ⁇ 0.05 indicated that the difference was statistically significant.
- 3dpf transgenic teleost green fluorescent zebrafish (cy25) were randomly selected in a 6-well plate, and 15 zebrafish were treated in each well (experimental group).
- the samples were given water-soluble (concentrations are shown in Table 2), and the positive control alendronate sodium tablets were 5.00 ⁇ g/mL.
- a normal control group and a model control group were set up, and the volume of each well was 3mL.
- dexamethasone was given water-soluble to establish a zebrafish osteoblast injury model in all other groups. The medium was changed once at 5dpf. After 4 days of treatment at 28°C, 8 zebrafish were randomly selected from each experimental group and photographed under a fluorescence microscope.
- NIS-Elements D 3.20 advanced image processing software was used to analyze and collect data, and the zebrafish osteoblast fluorescence intensity was analyzed. The statistical analysis results of this indicator were used to evaluate the osteoblast protection efficacy of the samples and compositions. The statistical analysis results are expressed as mean ⁇ SE. SPSS26.0 software was used for statistical analysis, and p ⁇ 0.05 indicated that the difference was statistically significant.
- Osteoporosis is an important public health problem worldwide.
- Existing osteoporosis models are still insufficient in terms of efficiency and speed: on the one hand, the rat model is time-consuming, labor-intensive, inefficient, low-sensitivity, and requires a large amount of compounds; on the other hand, the experimental conditions of in vitro osteoblast and osteoclast primary cell models are harsh, difficult to master and control, and the action links are relatively single, which cannot reflect the comprehensive effects of in vivo experiments.
- zebrafish skeleton has physiological and genetic basis: like mammals, zebrafish skeleton develops from three embryonic stem cell lines, namely neural crest, somatic mesoderm and lateral plate. Studies have shown that zebrafish larvae skeleton contains cells required for bone formation and bone resorption, which is a relatively complete system.
- the bone formation mechanism also includes endochondral ossification and intramembranous ossification, and the process is strictly regulated by a complex mechanism including a series of transcription factors and hormones.
- the key genes involved in the regulation, such as runx2, osteonectin, and osteoprogenin, have a high degree of homology with the relevant genes of mammals. In China, zebrafish are used to establish osteoporosis models.
- This experiment used zebrafish model animals.
- the zebrafish larvae at 4 days post fertilization (4dpf) were exposed to different concentrations of nucleotides (31.2, 62.5, 125 ⁇ g/mL) or 2.5 ⁇ g/mL alendronate sodium tablets (positive control group).
- a normal control group normal zebrafish treated with fish water
- a model control group normal zebrafish treated with dexamethasone
- Tables 1 and 2 show that compared with the normal control group without dexamethasone, The fluorescence intensity of zebrafish vertebrae in the dexamethasone model control group was significantly reduced, indicating that dexamethasone significantly reduced the amount of mineralization and bone density of zebrafish head bones, successfully inducing osteoporosis in zebrafish.
- dexamethasone followed by 62.5 and 125 ⁇ g/mL nucleotide treatment increased the cumulative optical density of zebrafish vertebrae, significantly increased vertebral bone density, improved osteoporosis, and reversed dexamethasone-induced bone loss. This shows that nucleotides can significantly increase vertebral bone density and improve osteoporosis.
- zebrafish model animals were used. Zebrafish larvae at 4 days post-fertilization (4dpf) were exposed to different concentrations of nucleotides (31.2, 62.5, 125 ⁇ g/mL) or 1000 ⁇ g/mL chondroitin sulfate (positive control group). A normal control group (normal zebrafish treated with fish water) and a model control group (normal zebrafish treated with dexamethasone) were set up at the same time. After culturing at 28°C for 5 days, the cartilage was stained with alizarin red, and photos were taken after staining to calculate the cumulative optical density of zebrafish cartilage.
- nucleotides 31.2, 62.5, 125 ⁇ g/mL
- chondroitin sulfate positive control group
- a normal control group normal zebrafish treated with fish water
- a model control group normal zebrafish treated with dexamethasone
- zebrafish model animals were used. Zebrafish larvae at 4 days post fertilization (4dpf) were exposed to different concentrations of nucleotides (31.2, 62.5, 125 ⁇ g/mL) or 5 ⁇ g/mL alendronate sodium (positive control group). A normal control group (normal zebrafish treated with fish water) and a model control group (normal zebrafish treated with dexamethasone) were set up at the same time. After culturing at 28°C for 5 days, the cells were stained with alizarin red, and photos were taken after staining to calculate the cumulative optical density of zebrafish bone formation.
- nucleotides 31.2, 62.5, 125 ⁇ g/mL
- alendronate sodium positive control group
- a normal control group normal zebrafish treated with fish water
- a model control group normal zebrafish treated with dexamethasone
- nucleotides can significantly increase the density of vertebral bones and/or cartilage and/or osteoblasts, improve osteoporosis and/or repair cartilage and/or osteoblast damage.
- zebrafish model animals were used. Zebrafish larvae at 4 days post-fertilization (dpf) were exposed to different concentrations of nucleotides and lactoferrin or 1000 ⁇ g/mL chondroitin sulfate (positive control group). A normal control group (normal zebrafish treated with fish water) and a model control group (normal zebrafish treated with dexamethasone) were set up at the same time. After culturing at 28°C for 5 days, the cartilage was stained with alizarin red, and photos were taken after staining to calculate the cumulative optical density of zebrafish cartilage.
- dpf Zebrafish larvae at 4 days post-fertilization
- a normal control group normal zebrafish treated with fish water
- a model control group normal zebrafish treated with dexamethasone
- the present inventors found that, compared with the model control group, when nucleotides and lactoferrin were used in combination, the fluorescence intensity of cartilage could be significantly increased, dexamethasone-induced cartilage damage could be reversed, and cartilage damage could be improved, and there could be a synergistic effect between nucleotides and lactoferrin.
- Experimental Example 2 is equivalent to the combination of Comparative Examples 1 and 6.
- Comparative Examples 1 and 6 respectively make the cartilage fluorescence stronger.
- the degrees increased by 458514, 153966, and 296322.
- the increment of cartilage fluorescence intensity in Example 2 (458514) is greater than the sum of the increments of Comparative Examples 1 and 6 (450288).
- Experimental Example 5 is equivalent to the combination of Comparative Examples 2 and 6. Compared with the model control group, Example 5, Comparative Examples 2 and 6 increase the cartilage fluorescence intensity by 611209, 226275 and 296322, respectively. The increase in cartilage fluorescence intensity in Example 5 (611209) is greater than the sum of the increases in Comparative Examples 2 and 6 (522597).
- the inventors also found that compared with the model control group, when the two components of nucleotides and lactoferrin were used in combination, the effect was more significant, which could significantly increase the osteogenic fluorescence intensity, reverse dexamethasone-induced osteogenic damage, improve osteogenic damage, and there could be a synergistic effect between nucleotides and lactoferrin.
- Experimental Example 2 is equivalent to the combination of Comparative Examples 1 and 6.
- Example 2 Comparative Examples 1, and 6 increase the cartilage fluorescence intensity by 246660, 62708, and 148487, respectively.
- the increase in cartilage fluorescence intensity in Example 2 (246660) is greater than the sum of the increases in Comparative Examples 1 and 6 (211195).
- the present invention provides research on the efficacy of nucleotides in promoting bone development, and finds that nucleotides can promote bone growth and health, improve bone density, such as improving osteoporosis, and repair cartilage damage and osteogenesis damage. And when nucleotides are used together with lactoferrin, the effect is more significant, and there can be a synergistic effect between the two components. Therefore, nucleotides have broad prospects in improving osteoporosis and promoting bone development in the body, and provide new ideas for the development of functional foods in the future.
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Abstract
The present invention relates to the use of a nucleotide in promoting bone growth development and health in a human body or animal body for non-therapeutic purposes. The present invention further relates to a nutritional composition comprising the nucleotide and lactoferrin, a food product comprising the nutritional composition, and the use of the nutritional composition or food product in promoting bone growth development and health in a human body or animal body for non-therapeutic purposes.
Description
本申请要求于2022年9月26日递交的第202211176665.9号中国专利申请的优先权，在此全文引用上述中国专利申请公开的内容以作为本申请的一部分。This application claims priority to Chinese Patent Application No. 202211176665.9 filed on September 26, 2022. The contents of the above-mentioned Chinese patent application disclosure are hereby cited in their entirety as a part of this application.
本发明总体上涉及食品领域。具体地，本发明涉及核苷酸在促进人体或动物体的骨骼生长发育和健康中的非治疗目的的用途。本发明还涉及包括核苷酸和乳铁蛋白的营养组合物、包括所述营养组合物的食品以及所述营养组合物或食品在促进人体或动物体的骨骼生长发育和健康中的非治疗目的的用途。The present invention generally relates to the field of food. Specifically, the present invention relates to the use of nucleotides for non-therapeutic purposes in promoting bone growth, development and health in the human or animal body. The present invention also relates to a nutritional composition comprising nucleotides and lactoferrin, a food comprising the nutritional composition, and the use of the nutritional composition or food for non-therapeutic purposes in promoting bone growth, development and health in the human or animal body.
骨是一种高活性结缔组织，可以通过骨代谢及骨重塑来修复自身微损伤，保持骨结构、荷载及钙含量的内稳态平衡，同时骨也作为内分泌器官调控代谢过程，是维持人体生命的重要器官。从新生儿时期开始，骨量随年龄的增长而增加，直到青年时期骨发育成熟，骨量达到峰值。研究发现，青少年时期注意提高骨量，能够在青年时期获得个体峰值骨量。因而青少年时期骨的生长发育对骨的成熟至关重要。有研究指出，青少年时期的骨密度(Bonemineral density，BMD)决定了成年后的骨量峰值和随后的骨丢失速率。BMD降低会导致骨量不足，从而引发佝偻病、软骨病等一系列骨疾病，严重影响青少年的骨健康。在这一时期，营养的补充是影响骨量峰值的重要因素，摄入营养物质能够提高骨量峰值，促进骨的形成。Bone is a highly active connective tissue that can repair its own micro-damage through bone metabolism and bone remodeling, and maintain the homeostatic balance of bone structure, load and calcium content. At the same time, bone also regulates metabolic processes as an endocrine organ and is an important organ for maintaining human life. From the neonatal period, bone mass increases with age until the bone matures and reaches its peak in adolescence. Studies have found that paying attention to increasing bone mass during adolescence can achieve individual peak bone mass in adolescence. Therefore, the growth and development of bones during adolescence is crucial to bone maturation. Studies have pointed out that bone mineral density (BMD) during adolescence determines the peak bone mass and subsequent bone loss rate in adulthood. Reduced BMD can lead to insufficient bone mass, which in turn causes a series of bone diseases such as rickets and osteomalacia, which seriously affect the bone health of adolescents. During this period, nutritional supplementation is an important factor affecting the peak bone mass. The intake of nutrients can increase the peak bone mass and promote bone formation.
骨质疏松是多种原因引起的一种全身性骨骼疾病，尤其危害老年人群的健康和生活质量。骨重塑是一个复杂的生物学过程，骨组织中的破骨细胞完成骨的吸收功能，成骨细胞主导骨的形成功能，二者平衡一旦被打破就会引起骨质疏松等骨代谢性疾病。目前，治疗骨质疏松的药物主要通过抑制骨吸收、刺激骨形成来减缓骨量丢失、恢复骨代谢平衡。无副作用的食品原料在防治骨质疏松的过程中显得尤为重要。
Osteoporosis is a systemic bone disease caused by a variety of reasons, which is particularly harmful to the health and quality of life of the elderly. Bone remodeling is a complex biological process. Osteoclasts in bone tissue complete the bone absorption function, and osteoblasts dominate the bone formation function. Once the balance between the two is broken, it will cause bone metabolic diseases such as osteoporosis. At present, drugs for the treatment of osteoporosis mainly slow down bone loss and restore bone metabolism balance by inhibiting bone absorption and stimulating bone formation. Food ingredients without side effects are particularly important in the process of preventing and treating osteoporosis.
因此寻求一种天然的功能性营养物质来提高青少年BMD，增加骨形成，对提高骨量、预防青少年骨折与中老年骨质疏松症等骨疾病以及维持骨健康有着重要意义。Therefore, seeking a natural functional nutrient to improve adolescent BMD and increase bone formation is of great significance for increasing bone mass, preventing adolescent fractures and bone diseases such as osteoporosis in middle-aged and elderly people, and maintaining bone health.
发明内容Summary of the invention
本发明的一个目的是提供核苷酸在促进人体或动物体的骨骼生长发育和健康、例如改善骨密度中的非治疗目的的用途。One object of the present invention is to provide non-therapeutic uses of nucleotides in promoting bone growth and health in humans or animals, such as improving bone density.
本发明的另一目的是提供一种包括核苷酸和乳铁蛋白的营养组合物。Another object of the present invention is to provide a nutritional composition comprising nucleotides and lactoferrin.
本发明的另一目的是提供一种包括所述营养组合物的食品。Another object of the present invention is to provide a food product comprising the nutritional composition.
本发明的进一步目的是提供所述营养组合物或食品在促进人体或动物体的骨骼生长发育和健康、例如改善骨密度中的非治疗目的的用途。A further object of the present invention is to provide a non-therapeutic use of the nutritional composition or food in promoting bone growth and health in the human or animal body, such as improving bone density.
特别地，本发明通过如下实现：In particular, the present invention is achieved by:
1.核苷酸在促进人体或动物体的骨骼生长发育和健康、例如改善骨密度中的非治疗目的的用途，其中，所述核苷酸包括如下、或者由如下组成：1. The use of nucleotides for non-therapeutic purposes in promoting bone growth and health in humans or animals, such as improving bone density, wherein the nucleotides include or consist of the following:
5’-腺苷酸(5’-AMP)或其生理学上可接受的盐、优选钠盐，优选5’-腺苷酸；5'-Adenosine monophosphate (5'-AMP) or a physiologically acceptable salt thereof, preferably a sodium salt, preferably 5'-Adenosine monophosphate;
5’-胞苷酸(5’-CMP)或其生理学上可接受的盐、优选钠盐，优选5’-胞苷酸二钠；5'-Cytidylic acid (5'-CMP) or a physiologically acceptable salt thereof, preferably a sodium salt, preferably disodium 5'-cytidylic acid;
5’-鸟苷酸(5’-GMP)或其生理学上可接受的盐、优选钠盐，优选5’-鸟苷酸二钠；5'-guanylic acid (5'-GMP) or a physiologically acceptable salt thereof, preferably a sodium salt, preferably disodium 5'-guanylate;
5’-尿苷酸(5’-UMP)或其生理学上可接受的盐、优选钠盐，优选5’-尿苷酸二钠，和5'-Uridylic acid (5'-UMP) or a physiologically acceptable salt thereof, preferably a sodium salt, preferably disodium 5'-uridine monophosphate, and
5’-肌苷酸(5’-IMP)或其生理学上可接受的盐、优选钠盐，优选5’-肌苷酸二钠。5'-inosinic acid (5'-IMP) or a physiologically acceptable salt thereof, preferably a sodium salt, preferably disodium 5'-inosinic acid.
2.如条目1所述的用途，其中相对于所述核苷酸的总重量，2. The use according to item 1, wherein relative to the total weight of the nucleotides,
5’-腺苷酸(5’-AMP)或其生理学上可接受的盐为4.0-35.0％质量、优选14.0-22.0％质量；5'-adenosine (5'-AMP) or a physiologically acceptable salt thereof is 4.0-35.0% by mass, preferably 14.0-22.0% by mass;
5’-胞苷酸(5’-CMP)或其生理学上可接受的盐为20.0-70.0％质量、优选38.0-46.0％质量；5'-cytidylic acid (5'-CMP) or a physiologically acceptable salt thereof is 20.0-70.0% by mass, preferably 38.0-46.0% by mass;
5’-鸟苷酸(5’-GMP)或其生理学上可接受的盐为3.0-30.0％质量、优选11.0-19.0％质量；
5'-guanylic acid (5'-GMP) or a physiologically acceptable salt thereof is 3.0-30.0% by mass, preferably 11.0-19.0% by mass;
5’-尿苷酸(5’-UMP)或其生理学上可接受的盐为5.0-40.0％质量、优选15.0-23.0％质量，和5'-uridine monophosphate (5'-UMP) or a physiologically acceptable salt thereof is 5.0-40.0% by mass, preferably 15.0-23.0% by mass, and
5’-肌苷酸(5’-IMP)或其生理学上可接受的盐为0.1-20.0％质量、优选3.0-9.0％质量。The content of 5'-inosinic acid (5'-IMP) or a physiologically acceptable salt thereof is 0.1-20.0% by mass, preferably 3.0-9.0% by mass.
3.如条目1-2任一项所述的用途，其中促进骨骼生长发育和健康包括如下的一种或多种：改善骨质疏松、修复软骨损伤、修复成骨损伤。3. The use according to any one of items 1 to 2, wherein promoting bone growth, development and health comprises one or more of the following: improving osteoporosis, repairing cartilage damage, and repairing osteogenesis damage.
4.营养组合物，其包括核苷酸和乳铁蛋白，其中，所述核苷酸包括如下、或者由如下组成：4. A nutritional composition comprising nucleotides and lactoferrin, wherein the nucleotides comprise or consist of:
5’-腺苷酸(5’-AMP)或其生理学上可接受的盐、优选钠盐，优选5’-腺苷酸；5'-Adenosine monophosphate (5'-AMP) or a physiologically acceptable salt thereof, preferably a sodium salt, preferably 5'-Adenosine monophosphate;
5’-胞苷酸(5’-CMP)或其生理学上可接受的盐、优选钠盐，优选5’-胞苷酸二钠；5'-Cytidylic acid (5'-CMP) or a physiologically acceptable salt thereof, preferably a sodium salt, preferably disodium 5'-cytidylic acid;
5’-鸟苷酸(5’-GMP)或其生理学上可接受的盐、优选钠盐，优选5’-鸟苷酸二钠；5'-guanylic acid (5'-GMP) or a physiologically acceptable salt thereof, preferably a sodium salt, preferably disodium 5'-guanylate;
5’-尿苷酸(5’-UMP)或其生理学上可接受的盐、优选钠盐，优选5’-尿苷酸二钠，和5'-Uridylic acid (5'-UMP) or a physiologically acceptable salt thereof, preferably a sodium salt, preferably disodium 5'-uridine monophosphate, and
5’-肌苷酸(5’-IMP)或其生理学上可接受的盐、优选钠盐，优选5’-肌苷酸二钠。5'-inosinic acid (5'-IMP) or a physiologically acceptable salt thereof, preferably a sodium salt, preferably disodium 5'-inosinic acid.
5.如条目4所述的营养组合物，其中相对于所述核苷酸的总重量，5. The nutritional composition according to item 4, wherein relative to the total weight of the nucleotides,
5’-腺苷酸(5’-AMP)或其生理学上可接受的盐为4.0-35.0％质量、优选14.0-22.0％质量；5'-adenosine (5'-AMP) or a physiologically acceptable salt thereof is 4.0-35.0% by mass, preferably 14.0-22.0% by mass;
5’-胞苷酸(5’-CMP)或其生理学上可接受的盐为20.0-70.0％质量、优选38.0-46.0％质量；5'-cytidylic acid (5'-CMP) or a physiologically acceptable salt thereof is 20.0-70.0% by mass, preferably 38.0-46.0% by mass;
5’-鸟苷酸(5’-GMP)或其生理学上可接受的盐为3.0-30.0％质量、优选11.0-19.0％质量；5'-guanylic acid (5'-GMP) or a physiologically acceptable salt thereof is 3.0-30.0% by mass, preferably 11.0-19.0% by mass;
5’-尿苷酸(5’-UMP)或其生理学上可接受的盐为5.0-40.0％质量、优选15.0-23.0％质量，和5'-uridine monophosphate (5'-UMP) or a physiologically acceptable salt thereof is 5.0-40.0% by mass, preferably 15.0-23.0% by mass, and
5’-肌苷酸(5’-IMP)或其生理学上可接受的盐为0.1-20.0％质量、优选3.0-9.0％质量。The content of 5'-inosinic acid (5'-IMP) or a physiologically acceptable salt thereof is 0.1-20.0% by mass, preferably 3.0-9.0% by mass.
6.如条目4-5任一项所述的营养组合物，其由核苷酸和乳铁蛋白组成。6. The nutritional composition according to any one of items 4-5, consisting of nucleotides and lactoferrin.
7.如条目4-6任一项所述的营养组合物，其中所述乳铁蛋白来源于如下
或者以如下形式提供：富含乳铁蛋白的营养成分，如富含乳铁蛋白浓缩乳清蛋白粉和/或乳铁蛋白粉等，优选乳铁蛋白粉。7. The nutritional composition according to any one of items 4 to 6, wherein the lactoferrin is derived from Or it can be provided in the following forms: a nutrient rich in lactoferrin, such as concentrated whey protein powder rich in lactoferrin and/or lactoferrin powder, etc., preferably lactoferrin powder.
8.如条目4-7任一项所述的营养组合物，其中相对于1质量份的核苷酸，乳铁蛋白的量为0.01-20质量份、优选0.02-15质量份、优选0.05-12质量份、优选0.05-10质量份、优选0.05-8质量份、优选0.05-5质量份、优选0.1-2质量份、优选0.1-0.3质量份、优选0.12-0.25质量份。8. The nutritional composition according to any one of items 4 to 7, wherein the amount of lactoferrin relative to 1 part by mass of the nucleotide is 0.01-20 parts by mass, preferably 0.02-15 parts by mass, preferably 0.05-12 parts by mass, preferably 0.05-10 parts by mass, preferably 0.05-8 parts by mass, preferably 0.05-5 parts by mass, preferably 0.1-2 parts by mass, preferably 0.1-0.3 parts by mass, preferably 0.12-0.25 parts by mass.
9.食品，其包括如条目4-8任一项所述的营养组合物。9. Food comprising the nutritional composition according to any one of items 4 to 8.
10.如条目9所述的食品，其中所述食品是粉末形式或者液体形式。10. The food according to item 9, wherein the food is in powder form or liquid form.
11.如条目9-10任一项所述的食品，其中所述食品是婴幼儿配方食品例如婴幼儿配方奶粉、婴儿辅食、营养或膳食补充剂、孕妇调制奶粉、或中老年奶粉。11. The food according to any one of items 9 to 10, wherein the food is an infant formula such as infant formula milk powder, baby food, nutritional or dietary supplement, pregnant woman formula milk powder, or middle-aged and elderly milk powder.
12.如条目9-11任一项所述的食品，其中所述营养组合物的添加量使得，相对于所述食品的总质量，所述核苷酸的总质量含量为0.0012-0.058％、优选0.0025-0.058％，所述乳铁蛋白的质量含量为0.002-1.0％、优选0.004-0.7％。12. The food according to any one of items 9 to 11, wherein the nutritional composition is added in an amount such that, relative to the total mass of the food, the total mass content of the nucleotides is 0.0012-0.058%, preferably 0.0025-0.058%, and the mass content of the lactoferrin is 0.002-1.0%, preferably 0.004-0.7%.
13.如条目9-12任一项所述的食品，其中相对于1质量份的核苷酸，乳铁蛋白的量为0.1-20质量份、优选0.1-10质量份、优选0.1-2质量份、优选0.1-0.3质量份、优选0.12-0.25质量份，并且所述食品中所述核苷酸的含量为0.0025-0.058％质量，所述乳铁蛋白的含量为0.004-0.7％质量。13. The food according to any one of items 9 to 12, wherein the amount of lactoferrin is 0.1-20 parts by mass, preferably 0.1-10 parts by mass, preferably 0.1-2 parts by mass, preferably 0.1-0.3 parts by mass, preferably 0.12-0.25 parts by mass relative to 1 part by mass of the nucleotide, and the content of the nucleotide in the food is 0.0025-0.058% by mass, and the content of the lactoferrin is 0.004-0.7% by mass.
14.如条目4-8任一项所述的营养组合物或者如条目9-13任一项所述的食品在促进人体或动物体的骨骼生长发育和健康、例如改善骨密度中的非治疗目的的用途。14. Use of the nutritional composition according to any one of items 4 to 8 or the food according to any one of items 9 to 13 for non-therapeutic purposes in promoting bone growth and health in humans or animals, such as improving bone density.
15.如条目14所述的用途，其中所述促进骨骼生长发育和健康包括如下的一种或多种：改善骨质疏松、修复软骨损伤、修复成骨损伤。15. The use according to item 14, wherein the promotion of bone growth, development and health comprises one or more of the following: improving osteoporosis, repairing cartilage damage, and repairing bone damage.
图1显示了采用不同处理后斑马鱼脊椎骨荧光强度的图。FIG1 shows a graph of fluorescence intensity of zebrafish vertebrae after different treatments.
如无特殊说明，本说明书中的科技术语的含义与本领域技术人员一般理解的含义相同，但如有冲突，则以本说明书中的定义为准。Unless otherwise specified, the meanings of the technical terms in this specification are the same as those generally understood by those skilled in the art. However, if there is any conflict, the definitions in this specification shall prevail.
如本文所用，下列术语具有如下含义。
As used herein, the following terms have the following meanings.
术语“婴儿”是指0～6月龄的人。The term "infant" refers to a human between 0 and 6 months of age.
术语“较大婴儿”是指6～12月龄的人。The term "older infant" refers to persons 6 to 12 months of age.
术语“幼儿”是指12～36月龄的人。The term "young child" refers to a person between 12 and 36 months of age.
术语“婴幼儿”是指0-36个月龄的人。The term "infant" refers to a human aged 0-36 months.
术语“儿童”是指3-6岁年龄的人。The term "child" refers to a person aged 3-6 years.
术语“少年”是指7-17岁年龄的人。The term "juvenile" refers to a person aged 7-17 years.
术语“青年人”是指18-40岁年龄的人。The term "youth" refers to persons aged 18-40 years.
术语“青少年”是指7-40岁年龄的人。The term "adolescent" refers to persons aged 7-40 years.
术语“中年人”是指41-65岁年龄的人。The term "middle-aged" refers to persons aged 41-65 years.
术语“老人”或“老年人”指的是65岁年龄以上的人。The term "elderly" or "senior citizen" refers to persons over the age of 65 years.
本文中使用的术语“婴幼儿配方食品”涵盖婴儿配方食品、较大婴儿配方食品和幼儿配方食品。通常，婴儿配方食品从婴儿出生起作为母乳替代品，较大婴儿配方食品是从婴儿出生后的6-12个月作为母乳替代品，幼儿配方食品指从婴儿出生后的12-36个月作为母乳替代品。The term "infant formula" used herein covers infant formula, follow-on formula and toddler formula. Generally, infant formula is used as a breast milk substitute from birth, follow-on formula is used as a breast milk substitute from 6-12 months after the birth of the infant, and toddler formula refers to a breast milk substitute from 12-36 months after the birth of the infant.
术语“婴儿配方食品”是指以乳类及乳蛋白制品或大豆及大豆蛋白制品为主要原料，加入适量维生素、矿物质和/或其它成分，仅用物理方法生产加工制成的液态或粉状产品。适用于正常婴儿食用，其能量和营养成分能够满足0-6个月婴儿的正常营养需要。The term "infant formula" refers to a liquid or powdered product made from milk and milk protein products or soybeans and soybean protein products as the main raw materials, with appropriate amounts of vitamins, minerals and/or other ingredients added, and produced and processed only by physical methods. It is suitable for normal infants to eat, and its energy and nutrients can meet the normal nutritional needs of infants aged 0-6 months.
术语“较大婴儿配方食品”是指以乳类及乳蛋白制品或大豆及大豆蛋白制品为主要原料，加入适量维生素、矿物质和/或其它成分，仅用物理方法生产加工制成的液态或粉状产品。适用于较大婴儿食用，其能量和营养成分能够满足6-12个月正常较大婴儿的部分营养需要。The term "follow-up infant formula" refers to a liquid or powdered product made from milk and milk protein products or soy and soy protein products as the main raw materials, with appropriate amounts of vitamins, minerals and/or other ingredients added, and produced and processed only by physical methods. It is suitable for older infants, and its energy and nutritional components can meet part of the nutritional needs of normal older infants aged 6-12 months.
术语“幼儿配方食品”是指以乳类及乳蛋白制品或大豆及大豆蛋白制品为主要原料，加入适量维生素、矿物质和/或其它成分，仅用物理方法生产加工制成的液态或粉状产品。适用于幼儿食用，其能量和营养成分能够满足12-36个月正常幼儿的部分营养需要。The term "infant formula food" refers to a liquid or powdered product made from milk and milk protein products or soy and soy protein products as the main raw materials, with appropriate amounts of vitamins, minerals and/or other ingredients added, and produced and processed only by physical methods. It is suitable for infants to eat, and its energy and nutritional components can meet part of the nutritional needs of normal infants aged 12-36 months.
术语“母乳”应理解为母亲的母乳或初乳。The term "breast milk" is to be understood as a mother's breast milk or colostrum.
术语“完全用母乳喂养的婴儿或幼儿”具有通常的含义，指绝大部分营养物质和/或能量源于人类母乳的婴儿。The term "exclusively breastfed infant or young child" has its usual meaning and refers to an infant who derives a substantial portion of his or her nutrients and/or energy from human breast milk.
术语“主要用婴幼儿配方食品喂养的婴儿/较大婴儿/幼儿”具有通常的含义，指营养物质和/或能量的营养源主要源于物理方法生产加工制成的婴幼
儿配方食品、较大婴儿乳或成长乳的婴儿或幼儿。术语“主要”是指至少50％、例如至少75％的那些营养物质和/或能量。The term "infants/older infants/young children fed primarily with infant formula" has its ordinary meaning and refers to infant formula that is primarily produced by physically processing the source of nutrients and/or energy. The term "mainly" refers to at least 50%, such as at least 75%, of those nutrients and/or energy.
另外，在本发明的上下文中，术语“包含”或“包括”不排除其它可能的要素。本发明的组合物(包括本文所述的多个实施方式)可包含下列要素、由下列要素组成或基本上由下列要素组成：本文所述的本发明的基本要素和必要限制，以及本文所述的或另外视需求而定的任何其它或任选的成分、组分或限制。In addition, in the context of the present invention, the term "comprising" or "including" does not exclude other possible elements. The composition of the present invention (including the various embodiments described herein) may comprise, consist of, or consist essentially of the following elements: the basic elements and necessary limitations of the present invention described herein, and any other or optional ingredients, components, or limitations described herein or otherwise as required.
本发明所述个体适用于正常人类，可以是婴儿和/或较大婴儿、和/或幼儿、和/或儿童、和/或青年人、和/或中年人、和/或老年人。The individual described in the present invention is applicable to normal humans, and can be an infant and/or an older infant, and/or a toddler, and/or a child, and/or a young person, and/or a middle-aged person, and/or an elderly person.
除非另外指明，否则所有百分比均按质量计。Unless otherwise indicated, all percentages are by mass.
现在开始更详细描述本发明。应当注意，本申请描述的各个方面、特征、实施方式、实施例以及其优点可以相容和/或可以组合在一起。Now the present invention will be described in more detail. It should be noted that the various aspects, features, embodiments, examples and advantages described in the present application may be compatible and/or may be combined together.
本发明涉及核苷酸在促进人体或动物体的骨骼生长发育和健康、例如改善骨密度中的非治疗目的的用途，包括核苷酸和乳铁蛋白的营养组合物，包括所述营养组合物的食品，以及所述营养组合物或食品在促进人体或动物体的骨骼生长发育和健康、例如改善骨密度中的非治疗目的的用途。The present invention relates to the non-therapeutic use of nucleotides in promoting the growth and health of bones in humans or animals, such as improving bone density, a nutritional composition comprising nucleotides and lactoferrin, a food comprising the nutritional composition, and the non-therapeutic use of the nutritional composition or food in promoting the growth and health of bones in humans or animals, such as improving bone density.
在本文中，术语“非治疗目的”意指营养和保健目的，即非医疗目的或者非医疗用途目的，这些术语是可以互换使用的。As used herein, the term "non-therapeutic purpose" means nutritional and health purposes, ie, non-medical purposes or purposes of non-medical use, and these terms are used interchangeably.
以下将对本发明进行具体说明。The present invention will be described in detail below.
核苷酸的用途Uses of Nucleotides
在一个方面中，本发明提供了核苷酸在促进人体或动物体的骨骼生长发育和健康、例如改善骨密度中的非治疗目的(营养和保健目的)的用途。In one aspect, the present invention provides the use of nucleotides for non-therapeutic purposes (nutritional and health purposes) in promoting bone growth and health in the human or animal body, such as improving bone density.
核苷酸是一类由嘌呤碱或嘧啶碱基、核糖或脱氧核糖以及磷酸三种物质组成的化合物。五碳糖与有机碱合成核苷，核苷与磷酸合成核苷酸，4种核苷酸组成核酸。核苷酸主要参与构成核酸，许多单核苷酸也具有多种重要的生物学功能，如与能量代谢有关的三磷酸腺苷(ATP)、脱氢辅酶等。某些核苷酸的类似物能干扰核苷酸代谢，可作为抗癌药物。根据糖的不同，核苷酸有核糖核苷酸及脱氧核苷酸两类。根据碱基的不同，又有腺苷酸(也称作腺嘌呤核苷酸，AMP)、鸟苷酸(也称作鸟嘌呤核苷酸，GMP)、胞苷酸(也称作胞嘧啶核苷酸，CMP)、尿苷酸(也称作尿嘧啶核苷酸，UMP)、胸苷酸(也称作胸腺
嘧啶核苷酸，TMP)及肌苷酸(也称作次黄嘌呤核苷酸，IMP)等。核苷酸中的磷酸又有一分子、两分子及三分子几种形式。此外，核苷酸分子内部还可脱水缩合成为环核苷酸。Nucleotides are a class of compounds composed of three substances: purine bases or pyrimidine bases, ribose or deoxyribose, and phosphate. Pentose and organic bases synthesize nucleosides, and nucleosides and phosphates synthesize nucleotides. Four types of nucleotides make up nucleic acids. Nucleotides are mainly involved in the formation of nucleic acids, and many single nucleotides also have a variety of important biological functions, such as adenosine triphosphate (ATP) and dehydrogenases related to energy metabolism. Some nucleotide analogs can interfere with nucleotide metabolism and can be used as anticancer drugs. Depending on the sugar, nucleotides are divided into two categories: ribonucleotides and deoxynucleotides. Depending on the base, there are adenylic acid (also called adenine nucleotide, AMP), guanylic acid (also called guanine nucleotide, GMP), cytidylic acid (also called cytosine nucleotide, CMP), uridylic acid (also called uracil nucleotide, UMP), thymidylic acid (also called thymus The phosphate in the nucleotide has several forms, such as one molecule, two molecules and three molecules. In addition, the nucleotide molecule can also be dehydrated and condensed to form a cyclic nucleotide.
核苷酸，是母乳非蛋白氮的一种，乳品的核苷酸还具有特定的生理功能,尤其是对婴幼儿。婴儿配方粉中添加核苷酸,对提高婴儿的免疫功能,增加铁的吸收,影响脂蛋白的代谢,改善肠道有益菌群,完善肠道功能和肝功能及促进生长有一定的意义,并越来越为各国所重视。2008年，我国已允许核苷酸添加到婴儿奶粉中。目前现有技术并未有其对骨骼发育的相关研究。Nucleotides are a type of non-protein nitrogen in breast milk. Nucleotides in dairy products also have specific physiological functions, especially for infants and young children. Adding nucleotides to infant formula powder has certain significance in improving infants' immune function, increasing iron absorption, affecting lipoprotein metabolism, improving intestinal beneficial bacteria, improving intestinal function and liver function, and promoting growth. It is increasingly valued by various countries. In 2008, my country has allowed nucleotides to be added to infant formula. At present, there is no relevant research on its effect on bone development in the existing technology.
然而，本发明人研究发现，一些核苷酸还具有促进骨骼生长发育和健康、例如改善骨密度例如改善骨质疏松的新功能，弥补了市场对健骨功能的需求。However, the inventors have discovered that some nucleotides also have new functions of promoting bone growth, development and health, such as improving bone density and osteoporosis, thus meeting the market demand for bone-strengthening functions.
在一种实施方式中，所述核苷酸包括如下、主要包括如下、基本上由如下组成、或者由如下组成：In one embodiment, the nucleotide comprises, consists essentially of, is essentially composed of, or is composed of:
5’-腺苷酸(5’-AMP)或其生理学上可接受的盐、优选钠盐(例如二钠盐)，优选5’-腺苷酸；5'-Adenosine monophosphate (5'-AMP) or a physiologically acceptable salt thereof, preferably a sodium salt (e.g., a disodium salt), preferably 5'-Adenosine monophosphate;
5’-胞苷酸(5’-CMP)或其生理学上可接受的盐、优选钠盐(例如二钠盐)，优选5’-胞苷酸二钠；5'-Cytidylic acid (5'-CMP) or a physiologically acceptable salt thereof, preferably a sodium salt (e.g., a disodium salt), preferably disodium 5'-cytidylic acid;
5’-鸟苷酸(5’-GMP)或其生理学上可接受的盐、优选钠盐(例如二钠盐)，优选5’-鸟苷酸二钠；5'-guanylic acid (5'-GMP) or a physiologically acceptable salt thereof, preferably a sodium salt (e.g., a disodium salt), preferably disodium 5'-guanylate;
5’-尿苷酸(5’-UMP)或其生理学上可接受的盐、优选钠盐(例如二钠盐)，优选5’-尿苷酸二钠，和5'-Uridine monophosphate (5'-UMP) or a physiologically acceptable salt thereof, preferably a sodium salt (e.g., a disodium salt), preferably disodium 5'-uridine monophosphate, and
5’-肌苷酸(5’-IMP)或其生理学上可接受的盐、优选钠盐(例如二钠盐)，优选5’-肌苷酸二钠。5'-inosinic acid (5'-IMP) or a physiologically acceptable salt thereof, preferably a sodium salt (e.g., a disodium salt), preferably disodium 5'-inosinic acid.
在本文中，当未另外说明时，术语“主要”应被理解为意指占所提及物质的50％质量以上，例如60％质量以上、70％质量以上、80％质量以上、90％质量以上、95％质量以上。Herein, when not otherwise specified, the term "mainly" should be understood to mean 50% by mass or more of the mentioned substance, for example 60% by mass or more, 70% by mass or more, 80% by mass or more, 90% by mass or more, 95% by mass or more.
在本文中，当未另外说明时，术语“基本上”应被理解为意指占所提及物质的至少85％质量，例如至少90％质量、90％-99.9％质量。In this document, when not otherwise stated, the term "substantially" should be understood to mean at least 85% by mass, such as at least 90% by mass, 90%-99.9% by mass of the substance referred to.
在一种实施方式中，所述5’-腺苷酸(5’-AMP)或其生理学上可接受的盐为5’-腺苷酸。In one embodiment, the 5'-adenosine monophosphate (5'-AMP) or a physiologically acceptable salt thereof is 5'-adenosine monophosphate.
在一种实施方式中，所述5’-胞苷酸(5’-CMP)或其生理学上可接受的盐为5’-胞苷酸二钠。
In one embodiment, the 5'-cytidylic acid (5'-CMP) or a physiologically acceptable salt thereof is 5'-cytidylic acid disodium.
在一种实施方式中，所述5’-鸟苷酸(5’-GMP)或其生理学上可接受的盐为5’-鸟苷酸二钠。In one embodiment, the 5'-guanylic acid (5'-GMP) or a physiologically acceptable salt thereof is disodium 5'-guanylate.
在一种实施方式中，所述5’-尿苷酸(5’-UMP)或其生理学上可接受的盐为5’-尿苷酸二钠。In one embodiment, the 5'-uridine monophosphate (5'-UMP) or a physiologically acceptable salt thereof is 5'-uridine monophosphate disodium.
在一种实施方式中，所述5’-肌苷酸(5’-IMP)或其生理学上可接受的盐为5’-肌苷酸二钠。In one embodiment, the 5'-inosinic acid (5'-IMP) or a physiologically acceptable salt thereof is disodium 5'-inosinic acid.
在一种实施方式中，所述核苷酸包括如下、主要包括如下、基本上由如下组成、或者由如下组成：In one embodiment, the nucleotide comprises, consists essentially of, is essentially composed of, or is composed of:
5’-腺苷酸；5'-Adenylic acid;
5’-胞苷酸二钠；5'-cytidylate disodium;
5’-鸟苷酸二钠；Disodium 5'-guanylate;
5’-尿苷酸二钠；和5'-Uridine monophosphate disodium; and
5’-肌苷酸二钠。Disodium 5'-inosinate.
在一种实施方式中，相对于所述核苷酸的总重量，In one embodiment, relative to the total weight of the nucleotides,
5’-腺苷酸(5’-AMP)或其生理学上可接受的盐为4.0-35.0％质量、优选14.0-22.0％质量；5'-adenosine (5'-AMP) or a physiologically acceptable salt thereof is 4.0-35.0% by mass, preferably 14.0-22.0% by mass;
5’-胞苷酸(5’-CMP)或其生理学上可接受的盐为20.0-70.0％质量、优选38.0-46.0％质量；5'-cytidylic acid (5'-CMP) or a physiologically acceptable salt thereof is 20.0-70.0% by mass, preferably 38.0-46.0% by mass;
5’-鸟苷酸(5’-GMP)或其生理学上可接受的盐为3.0-30.0％质量、优选11.0-19.0％质量；5'-guanylic acid (5'-GMP) or a physiologically acceptable salt thereof is 3.0-30.0% by mass, preferably 11.0-19.0% by mass;
5’-尿苷酸(5’-UMP)或其生理学上可接受的盐为5.0-40.0％质量、优选15.0-23.0％质量，和5'-uridine monophosphate (5'-UMP) or a physiologically acceptable salt thereof is 5.0-40.0% by mass, preferably 15.0-23.0% by mass, and
5’-肌苷酸(IMP)或其生理学上可接受的盐为0.5-20.0％质量、优选3.0-9.0％质量。The content of 5'-inosinic acid (IMP) or a physiologically acceptable salt thereof is 0.5-20.0% by mass, preferably 3.0-9.0% by mass.
在一种实施方式中，相对于所述核苷酸的总重量，所述5’-腺苷酸(5’-AMP)或其生理学上可接受的盐、例如5’-腺苷酸的量为4.0-35.0％质量、优选14.0-22.0％质量，例如可以为4.0、4.1、4.2、4.3、4.4、4.5、4.6、4.7、4.8、4.9、5.0、5.1、5.2、5.3、5.4、5.5、5.6、5.7、5.8、5.9、6.0、6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9、7.0、7.1、7.2、7.3、7.4、7.5、7.6、7.7、7.8、7.9、8.0、8.1、8.2、8.3、8.4、8.5、8.6、8.7、8.8、8.9、9.0、9.1、9.2、9.3、9.4、9.5、9.6、9.7、9.8、9.9、10.0、10.1、10.2、10.3、10.4、10.5、10.6、
10.7、10.8、10.9、11.0、11.1、11.2、11.3、11.4、11.5、11.6、11.7、11.8、11.9、12.0、12.1、12.2、12.3、12.4、12.5、12.6、12.7、12.8、12.9、13.0、13.1、13.2、13.3、13.4、13.5、13.6、13.7、13.8、13.9、14.0、14.1、14.2、14.3、14.4、14.5、14.6、14.7、14.8、14.9、15.0、15.1、15.2、15.3、15.4、15.5、15.6、15.7、15.8、15.9、16.0、16.1、16.2、16.3、16.4、16.5、16.6、16.7、16.8、16.9、17.0、17.1、17.2、17.3、17.4、17.5、17.6、17.7、17.8、17.9、18.0、18.1、18.2、18.3、18.4、18.5、18.6、18.7、18.8、18.9、19.0、19.1、19.2、19.3、19.4、19.5、19.6、19.7、19.8、19.9、20.0、20.1、20.2、20.3、20.4、20.5、20.6、20.7、20.8、20.9、21.0、21.1、21.2、21.3、21.4、21.5、21.6、21.7、21.8、21.9、22.0、22.1、22.2、22.3、22.4、22.5、22.6、22.7、22.8、22.9、23.0、23.1、23.2、23.3、23.4、23.5、23.6、23.7、23.8、23.9、24.0、24.1、24.2、24.3、24.4、24.5、24.6、24.7、24.8、24.9、25.0、25.1、25.2、25.3、25.4、25.5、25.6、25.7、25.8、25.9、26.0、26.1、26.2、26.3、26.4、26.5、26.6、26.7、26.8、26.9、27.0、27.1、27.2、27.3、27.4、27.5、27.6、27.7、27.8、27.9、28.0、28.1、28.2、28.3、28.4、28.5、28.6、28.7、28.8、28.9、29.0、29.1、29.2、29.3、29.4、29.5、29.6、29.7、29.8、29.9、30.0、30.1、30.2、30.3、30.4、30.5、30.6、30.7、30.8、30.9、31.0、31.1、31.2、31.3、31.4、31.5、31.6、31.7、31.8、31.9、32.0、32.1、32.2、32.3、32.4、32.5、32.6、32.7、32.8、32.9、33.0、33.1、33.2、33.3、33.4、33.5、33.6、33.7、33.8、33.9、34.0、34.1、34.2、34.3、34.4、34.5、34.6、34.7、34.8、34.9、35.0％质量、或者由其任意两者所限定的范围。In one embodiment, the amount of 5'-adenosine monophosphate (5'-AMP) or a physiologically acceptable salt thereof, such as 5'-adenosine monophosphate, is 4.0-35.0% by weight, preferably 14.0-22.0% by weight, relative to the total weight of the nucleotides, for example, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2 , 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7 , 13.8, 13.9, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0, 15.1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9, 16.0, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8 , 16.9, 17.0, 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9, 18.0, 18.1, 18.2, 18.3, 18.4, 18.5, 18.6, 18.7, 18.8, 18.9, 19.0, 19.1, 19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9 , 20.0, 20.1, 20.2, 20.3, 20.4, 20.5, 20.6, 20.7, 20.8, 20.9, 21.0, 21.1, 21.2, 21.3, 21.4, 21.5, 21.6, 21.7, 21.8, 21.9, 22.0, 22.1, 22.2, 22.3, 22.4, 22.5, 22.6, 22.7, 22.8, 22.9, 23.0 , 23.1, 23.2, 23.3, 23.4, 23.5, 23.6, 23.7, 23.8, 23.9, 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.0, 26. 1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, 28.0, 28.1, 28.2, 28.3, 28.4, 28.5, 28.6, 28.7, 28.8, 28.9, 29.0, 29.1, 29. 2, 29.3, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, 30.0, 30.1, 30.2, 30.3, 30.4, 30.5, 30.6, 30.7, 30.8, 30.9, 31.0, 31.1, 31.2, 31.3, 31.4, 31.5, 31.6, 31.7, 31.8, 31.9, 32.0, 32.1, 32.2, 32. 3, 32.4, 32.5, 32.6, 32.7, 32.8, 32.9, 33.0, 33.1, 33.2, 33.3, 33.4, 33.5, 33.6, 33.7, 33.8, 33.9, 34.0, 34.1, 34.2, 34.3, 34.4, 34.5, 34.6, 34.7, 34.8, 34.9, 35.0% by mass, or a range defined by any two of them.
在一种实施方式中，相对于所述核苷酸的总重量，所述5’-胞苷酸(5’-CMP)或其生理学上可接受的盐、例如5’-胞苷酸二钠的量为20.0-70.0％质量、优选38.0-46.0％质量，例如可以为20.0、20.1、20.2、20.3、20.4、20.5、20.6、20.7、20.8、20.9、21.0、21.1、21.2、21.3、21.4、21.5、21.6、21.7、21.8、21.9、22.0、22.1、22.2、22.3、22.4、22.5、22.6、22.7、22.8、22.9、23.0、23.1、23.2、23.3、23.4、23.5、23.6、23.7、23.8、23.9、24.0、24.1、24.2、24.3、24.4、24.5、24.6、24.7、24.8、24.9、25.0、25.1、25.2、25.3、25.4、25.5、25.6、25.7、25.8、25.9、26.0、26.1、26.2、26.3、26.4、26.5、26.6、26.7、26.8、26.9、27.0、27.1、27.2、27.3、27.4、27.5、27.6、27.7、27.8、27.9、28.0、28.1、28.2、28.3、28.4、28.5、28.6、28.7、28.8、28.9、29.0、
29.1、29.2、29.3、29.4、29.5、29.6、29.7、29.8、29.9、30.0、30.1、30.2、30.3、30.4、30.5、30.6、30.7、30.8、30.9、31.0、31.1、31.2、31.3、31.4、31.5、31.6、31.7、31.8、31.9、32.0、32.1、32.2、32.3、32.4、32.5、32.6、32.7、32.8、32.9、33.0、33.1、33.2、33.3、33.4、33.5、33.6、33.7、33.8、33.9、34.0、34.1、34.2、34.3、34.4、34.5、34.6、34.7、34.8、34.9、35.0、35.1、35.2、35.3、35.4、35.5、35.6、35.7、35.8、35.9、36.0、36.1、36.2、36.3、36.4、36.5、36.6、36.7、36.8、36.9、37.0、37.1、37.2、37.3、37.4、37.5、37.6、37.7、37.8、37.9、38.0、38.1、38.2、38.3、38.4、38.5、38.6、38.7、38.8、38.9、39.0、39.1、39.2、39.3、39.4、39.5、39.6、39.7、39.8、39.9、40.0、40.1、40.2、40.3、40.4、40.5、40.6、40.7、40.8、40.9、41.0、41.1、41.2、41.3、41.4、41.5、41.6、41.7、41.8、41.9、42.0、42.1、42.2、42.3、42.4、42.5、42.6、42.7、42.8、42.9、43.0、43.1、43.2、43.3、43.4、43.5、43.6、43.7、43.8、43.9、44.0、44.1、44.2、44.3、44.4、44.5、44.6、44.7、44.8、44.9、45.0、45.1、45.2、45.3、45.4、45.5、45.6、45.7、45.8、45.9、46.0、46.1、46.2、46.3、46.4、46.5、46.6、46.7、46.8、46.9、47.0、47.1、47.2、47.3、47.4、47.5、47.6、47.7、47.8、47.9、48.0、48.1、48.2、48.3、48.4、48.5、48.6、48.7、48.8、48.9、49.0、49.1、49.2、49.3、49.4、49.5、49.6、49.7、49.8、49.9、50.0、50.1、50.2、50.3、50.4、50.5、50.6、50.7、50.8、50.9、51.0、51.1、51.2、51.3、51.4、51.5、51.6、51.7、51.8、51.9、52.0、52.1、52.2、52.3、52.4、52.5、52.6、52.7、52.8、52.9、53.0、53.1、53.2、53.3、53.4、53.5、53.6、53.7、53.8、53.9、54.0、54.1、54.2、54.3、54.4、54.5、54.6、54.7、54.8、54.9、55.0、55.1、55.2、55.3、55.4、55.5、55.6、55.7、55.8、55.9、56.0、56.1、56.2、56.3、56.4、56.5、56.6、56.7、56.8、56.9、57.0、57.1、57.2、57.3、57.4、57.5、57.6、57.7、57.8、57.9、58.0、58.1、58.2、58.3、58.4、58.5、58.6、58.7、58.8、58.9、59.0、59.1、59.2、59.3、59.4、59.5、59.6、59.7、59.8、59.9、60.0、60.1、60.2、60.3、60.4、60.5、60.6、60.7、60.8、60.9、61.0、61.1、61.2、61.3、61.4、61.5、61.6、61.7、61.8、61.9、62.0、62.1、62.2、62.3、62.4、62.5、62.6、62.7、62.8、62.9、63.0、63.1、63.2、63.3、63.4、63.5、63.6、63.7、63.8、63.9、64.0、64.1、64.2、64.3、64.4、64.5、64.6、64.7、64.8、64.9、65.0、65.1、65.2、65.3、65.4、65.5、65.6、65.7、65.8、65.9、66.0、66.1、66.2、
66.3、66.4、66.5、66.6、66.7、66.8、66.9、67.0、67.1、67.2、67.3、67.4、67.5、67.6、67.7、67.8、67.9、68.0、68.1、68.2、68.3、68.4、68.5、68.6、68.7、68.8、68.9、69.0、69.1、69.2、69.3、69.4、69.5、69.6、69.7、69.8、69.9、70.0％质量、或者由其任意两者所限定的范围。In one embodiment, the amount of 5'-cytidylic acid (5'-CMP) or a physiologically acceptable salt thereof, such as 5'-cytidylic acid disodium, relative to the total weight of the nucleotide is 20.0-70.0% by mass, preferably 38.0-46.0% by mass, for example, 20.0, 20.1, 20.2, 20.3, 20.4, 20.5, 20.6, 20.7, 20.8, 20.9, 21.0, 21.1, 21.2, 21.3, 21.4, 21.5, 21.6, 21.7, 21.8, 21.9, 22.0, 22.1, 22.2, 22.3, 22.4, 22.5, 22.6, 22.7, 22.8, 22.9, 23.0, 23.1, 23.2, 23.3, 23.4, 23.5 , 23.6, 23.7, 23.8, 23.9, 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.0, 26.1, 26.2, 26.3 .3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, 28.0, 28.1, 28.2, 28.3, 28.4, 28.5, 28.6, 28.7, 28.8, 28.9, 29.0, 29.1, 29.2, 29.3, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, 30.0, 30.1, 30.2, 30.3, 30.4, 30.5, 30.6, 30.7, 30.8, 30.9, 31.0, 31.1, 31.2, 31.3, 31.4, 31.5, 31.6, 31.7, 31.8, 31.9, 32.0, 32.1, 32.2, 32.3, 32.4, 32.5, 32.6, 32.7, 32.8, 32.9, 33.0, 33.1, 33.2, 33.3, 33.4, 33.5, 33.6, 33 .7, 33.8, 33.9, 34.0, 34.1, 34.2, 34.3, 34.4, 34.5, 34.6, 34.7, 34.8, 34.9, 35.0, 35.1, 35.2, 35.3, 35.4, 35.5, 35.6, 35.7, 35.8, 35.9, 36.0, 36.1, 36.2, 36.3, 36.4, 36.5, 36.6, 36.7, 36.8, 36.9, 37.0, 37.1, 37.2, 37.3, 37.4, 37.5, 37.6, 37.7, 37.8, 37.9, 38.0, 38.1, 38.2, 38.3, 38.4、38.5、38.6、38.7、38.8、38.9、39.0、39.1、39.2、39.3、39.4、39.5、39.6、39.7、39.8、39.9、40.0、40.1、40.2、40.3、40.4、40.5、40.6、40.7、40.8、40.9、41.0、41.1、41.2、41.3、41.4、41.5、41.6、41.7、41.8、41.9、42.0、42.1、42.2、42.3、42.4、42.5、42.6、42.7、42.8、42.9、43 .0, 43.1, 43.2, 43.3, 43.4, 43.5, 43.6, 43.7, 43.8, 43.9, 44.0, 44.1, 44.2, 44.3, 44.4, 44.5, 44.6, 44.7, 44.8, 44.9, 45.0, 45.1, 45.2, 45.3, 45.4, 45.5, 45.6, 45.7, 45.8, 45.9, 46.0, 46.1, 46.2, 46.3, 46.4, 46.5, 46.6, 46.7, 46.8, 46.9, 47.0, 47.1, 47.2, 47.3, 47.4, 47.5, 47.6, 47.7、47.8、47.9、48.0、48.1、48.2、48.3、48.4、48.5、48.6、48.7、48.8、48.9、49.0、49.1、49.2、49.3、49.4、49.5、49.6、49.7、49.8、49.9、50.0、50.1、50.2、50.3、50.4、50.5、50.6、50.7、50.8、50.9、51.0、51.1、51.2、51.3、51.4、51.5、51.6、51.7、51.8、51.9、52.0、52.1、52.2、52 .3, 52.4, 52.5, 52.6, 52.7, 52.8, 52.9, 53.0, 53.1, 53.2, 53.3, 53.4, 53.5, 53.6, 53.7, 53.8, 53.9, 54.0, 54.1, 54.2, 54.3, 54.4, 54.5, 54.6, 54.7, 54.8, 54.9, 55.0, 55.1, 55.2, 55.3, 55.4, 55.5, 55.6, 55.7, 55.8, 55.9, 56.0, 56.1, 56.2, 56.3, 56.4, 56.5, 56.6, 56.7, 56.8, 56.9, 57.0、57.1、57.2、57.3、57.4、57.5、57.6、57.7、57.8、57.9、58.0、58.1、58.2、58.3、58.4、58.5、58.6、58.7、58.8、58.9、59.0、59.1、59.2、59.3、59.4、59.5、59.6、59.7、59.8、59.9、60.0、60.1、60.2、60.3、60.4、60.5、60.6、60.7、60.8、60.9、61.0、61.1、61.2、61.3、61.4、61.5、61 .6, 61.7, 61.8, 61.9, 62.0, 62.1, 62.2, 62.3, 62.4, 62.5, 62.6, 62.7, 62.8, 62.9, 63.0, 63.1, 63.2, 63.3, 63.4, 63.5, 63.6, 63.7, 63.8, 63.9, 64.0, 64.1, 64.2, 64.3, 64.4, 64.5, 64.6, 64.7, 64.8, 64.9, 65.0, 65.1, 65.2, 65.3, 65.4, 65.5, 65.6, 65.7, 65.8, 65.9, 66.0, 66.1, 66.2, 0%, 66.3%, 66.4%, 66.5%, 66.6%, 66.7%, 66.8%, 66.9%, 67.0%, 67.1%, 67.2%, 67.3%, 67.4%, 67.5%, 67.6%, 67.7%, 67.8%, 67.9%, 68.0%, 68.1%, 68.2%, 68.3%, 68.4%, 68.5%, 68.6%, 68.7%, 68.8%, 68.9%, 69.0%, 69.1%, 69.2%, 69.3%, 69.4%, 69.5%, 69.6%, 69.7%, 69.8%, 69.9%, 70.0% by mass, or a range defined by any two of them.
在一种实施方式中，相对于所述核苷酸的总重量，所述5’-鸟苷酸(5’-GMP)或其生理学上可接受的盐、例如5’-鸟苷酸二钠的量为3.0-30.0％质量、优选11.0-19.0％质量，例如可以为3.0、3.1、3.2、3.3、3.4、3.5、3.6、3.7、3.8、3.9、4.0、4.1、4.2、4.3、4.4、4.5、4.6、4.7、4.8、4.9、5.0、5.1、5.2、5.3、5.4、5.5、5.6、5.7、5.8、5.9、6.0、6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9、7.0、7.1、7.2、7.3、7.4、7.5、7.6、7.7、7.8、7.9、8.0、8.1、8.2、8.3、8.4、8.5、8.6、8.7、8.8、8.9、9.0、9.1、9.2、9.3、9.4、9.5、9.6、9.7、9.8、9.9、10.0、10.1、10.2、10.3、10.4、10.5、10.6、10.7、10.8、10.9、11.0、11.1、11.2、11.3、11.4、11.5、11.6、11.7、11.8、11.9、12.0、12.1、12.2、12.3、12.4、12.5、12.6、12.7、12.8、12.9、13.0、13.1、13.2、13.3、13.4、13.5、13.6、13.7、13.8、13.9、14.0、14.1、14.2、14.3、14.4、14.5、14.6、14.7、14.8、14.9、15.0、15.1、15.2、15.3、15.4、15.5、15.6、15.7、15.8、15.9、16.0、16.1、16.2、16.3、16.4、16.5、16.6、16.7、16.8、16.9、17.0、17.1、17.2、17.3、17.4、17.5、17.6、17.7、17.8、17.9、18.0、18.1、18.2、18.3、18.4、18.5、18.6、18.7、18.8、18.9、19.0、19.1、19.2、19.3、19.4、19.5、19.6、19.7、19.8、19.9、20.0、20.1、20.2、20.3、20.4、20.5、20.6、20.7、20.8、20.9、21.0、21.1、21.2、21.3、21.4、21.5、21.6、21.7、21.8、21.9、22.0、22.1、22.2、22.3、22.4、22.5、22.6、22.7、22.8、22.9、23.0、23.1、23.2、23.3、23.4、23.5、23.6、23.7、23.8、23.9、24.0、24.1、24.2、24.3、24.4、24.5、24.6、24.7、24.8、24.9、25.0、25.1、25.2、25.3、25.4、25.5、25.6、25.7、25.8、25.9、26.0、26.1、26.2、26.3、26.4、26.5、26.6、26.7、26.8、26.9、27.0、27.1、27.2、27.3、27.4、27.5、27.6、27.7、27.8、27.9、28.0、28.1、28.2、28.3、28.4、28.5、28.6、28.7、28.8、28.9、29.0、29.1、29.2、29.3、29.4、29.5、29.6、29.7、29.8、29.9、30.0％质量、或者由其任意两者所限定的范围。In one embodiment, the amount of 5'-guanosine monophosphate (5'-GMP) or a physiologically acceptable salt thereof, such as disodium 5'-guanylate, relative to the total weight of the nucleotide is 3.0-30.0% by weight, preferably 11.0-19.0% by weight, for example, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9 , 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9. 3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9 , 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0, 15.1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9, 16.0, 16.1, 16.2, 16.3, 16.4 , 16.5, 16.6, 16.7, 16.8, 16.9, 17.0, 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9, 18.0, 18.1, 18.2, 18.3, 18.4, 18.5, 18.6, 18.7, 18.8, 18.9, 19.0, 19.1, 19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19. 9, 20.0, 20.1, 20.2, 20.3, 20.4, 20.5, 20.6, 20.7, 20.8, 20.9, 21.0, 21.1, 21.2, 21.3, 21.4, 21.5, 21.6, 21.7, 21.8, 21.9, 22.0, 22.1, 22.2, 22.3, 22.4, 22.5, 22.6, 22.7, 22.8, 22.9, 23.0, 23.1, 23.2, 23.3, 23. 4, 23.5, 23.6, 23.7, 23.8, 23.9, 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.0, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26. 9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, 28.0, 28.1, 28.2, 28.3, 28.4, 28.5, 28.6, 28.7, 28.8, 28.9, 29.0, 29.1, 29.2, 29.3, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, 30.0% by mass, or a range defined by any two of them.
在一种实施方式中，相对于所述核苷酸的总重量，所述5’-尿苷酸(5’-UMP)或其生理学上可接受的盐、例如5’-尿苷酸二钠的量为5.0-40.0％质量、
优选15.0-23.0％质量，例如可以为5.0、5.1、5.2、5.3、5.4、5.5、5.6、5.7、5.8、5.9、6.0、6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9、7.0、7.1、7.2、7.3、7.4、7.5、7.6、7.7、7.8、7.9、8.0、8.1、8.2、8.3、8.4、8.5、8.6、8.7、8.8、8.9、9.0、9.1、9.2、9.3、9.4、9.5、9.6、9.7、9.8、9.9、10.0、10.1、10.2、10.3、10.4、10.5、10.6、10.7、10.8、10.9、11.0、11.1、11.2、11.3、11.4、11.5、11.6、11.7、11.8、11.9、12.0、12.1、12.2、12.3、12.4、12.5、12.6、12.7、12.8、12.9、13.0、13.1、13.2、13.3、13.4、13.5、13.6、13.7、13.8、13.9、14.0、14.1、14.2、14.3、14.4、14.5、14.6、14.7、14.8、14.9、15.0、15.1、15.2、15.3、15.4、15.5、15.6、15.7、15.8、15.9、16.0、16.1、16.2、16.3、16.4、16.5、16.6、16.7、16.8、16.9、17.0、17.1、17.2、17.3、17.4、17.5、17.6、17.7、17.8、17.9、18.0、18.1、18.2、18.3、18.4、18.5、18.6、18.7、18.8、18.9、19.0、19.1、19.2、19.3、19.4、19.5、19.6、19.7、19.8、19.9、20.0、20.1、20.2、20.3、20.4、20.5、20.6、20.7、20.8、20.9、21.0、21.1、21.2、21.3、21.4、21.5、21.6、21.7、21.8、21.9、22.0、22.1、22.2、22.3、22.4、22.5、22.6、22.7、22.8、22.9、23.0、23.1、23.2、23.3、23.4、23.5、23.6、23.7、23.8、23.9、24.0、24.1、24.2、24.3、24.4、24.5、24.6、24.7、24.8、24.9、25.0、25.1、25.2、25.3、25.4、25.5、25.6、25.7、25.8、25.9、26.0、26.1、26.2、26.3、26.4、26.5、26.6、26.7、26.8、26.9、27.0、27.1、27.2、27.3、27.4、27.5、27.6、27.7、27.8、27.9、28.0、28.1、28.2、28.3、28.4、28.5、28.6、28.7、28.8、28.9、29.0、29.1、29.2、29.3、29.4、29.5、29.6、29.7、29.8、29.9、30.0、30.1、30.2、30.3、30.4、30.5、30.6、30.7、30.8、30.9、31.0、31.1、31.2、31.3、31.4、31.5、31.6、31.7、31.8、31.9、32.0、32.1、32.2、32.3、32.4、32.5、32.6、32.7、32.8、32.9、33.0、33.1、33.2、33.3、33.4、33.5、33.6、33.7、33.8、33.9、34.0、34.1、34.2、34.3、34.4、34.5、34.6、34.7、34.8、34.9、35.0、35.1、35.2、35.3、35.4、35.5、35.6、35.7、35.8、35.9、36.0、36.1、36.2、36.3、36.4、36.5、36.6、36.7、36.8、36.9、37.0、37.1、37.2、37.3、37.4、37.5、37.6、37.7、37.8、37.9、38.0、38.1、38.2、38.3、38.4、38.5、38.6、38.7、38.8、38.9、39.0、39.1、39.2、39.3、39.4、39.5、39.6、39.7、39.8、39.9、40.0％质量、或者由其任意两者所限定的范围。In one embodiment, the amount of 5'-uridylic acid (5'-UMP) or a physiologically acceptable salt thereof, such as 5'-uridylic acid disodium, is 5.0-40.0% by weight relative to the total weight of the nucleotide. Preferably 15.0-23.0% by mass, for example 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 .9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0, 15.1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9, 16.0, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 17.0, 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9, 18.0, 18.1, 18.2, 18.3, 18.4, 18.5, 18. 6, 18.7, 18.8, 18.9, 19.0, 19.1, 19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9, 20.0, 20.1, 20.2, 20.3, 20.4, 20.5, 20.6, 20.7, 20.8, 20.9, 21.0, 21.1, 21.2, 21.3, 21.4, 21.5, 21.6, 21.7, 21.8, 21.9, 22.0, 22.1, 22.2, 22.3, 22.4, 22.5, 22.6, 22.7, 22.8, 22.9, 2 3.0, 23.1, 23.2, 23.3, 23.4, 23.5, 23.6, 23.7, 23.8, 23.9, 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.0, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3 , 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, 28.0, 28.1, 28.2, 28.3, 28.4, 28.5, 28.6, 28.7, 28.8, 28.9, 29.0, 29.1, 29.2, 29.3, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, 30.0, 30.1, 30.2, 30.3, 30.4, 30.5, 30.6, 30.7, 30.8, 30.9, 31.0, 31.1, 31.2, 31.3, 31.4, 31.5, 31.6, 31 .7, 31.8, 31.9, 32.0, 32.1, 32.2, 32.3, 32.4, 32.5, 32.6, 32.7, 32.8, 32.9, 33.0, 33.1, 33.2, 33.3, 33.4, 33.5, 33.6, 33.7, 33.8, 33.9, 34.0, 34.1, 34.2, 34.3, 34.4, 34.5, 34.6, 34.7, 34.8, 34.9, 35.0, 35.1, 35.2, 35.3, 35.4, 35.5, 35.6, 35.7, 35.8, 35.9, 36.0, 39.0, 39.1, 39.2, 39.3, 39.4, 39.5, 39.6, 39.7, 39.8, 39.9, 40.0% by mass, or a range defined by any two of them.
在一种实施方式中，相对于所述核苷酸的总重量，所述5’-肌苷酸(5’-IMP)
或其生理学上可接受的盐、例如5’-肌苷酸二钠的量为0.1-20％质量、优选3.0-9.0％质量，例如可以为0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9、1.0、1.1、1.2、1.3、1.4、1.5、1.6、1.7、1.8、1.9、2.0、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9、3.0、3.1、3.2、3.3、3.4、3.5、3.6、3.7、3.8、3.9、4.0、4.1、4.2、4.3、4.4、4.5、4.6、4.7、4.8、4.9、5.0、5.1、5.2、5.3、5.4、5.5、5.6、5.7、5.8、5.9、6.0、6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9、7.0、7.1、7.2、7.3、7.4、7.5、7.6、7.7、7.8、7.9、8.0、8.1、8.2、8.3、8.4、8.5、8.6、8.7、8.8、8.9、9.0、9.1、9.2、9.3、9.4、9.5、9.6、9.7、9.8、9.9、10.0、10.1、10.2、10.3、10.4、10.5、10.6、10.7、10.8、10.9、11.0、11.1、11.2、11.3、11.4、11.5、11.6、11.7、11.8、11.9、12.0、12.1、12.2、12.3、12.4、12.5、12.6、12.7、12.8、12.9、13.0、13.1、13.2、13.3、13.4、13.5、13.6、13.7、13.8、13.9、14.0、14.1、14.2、14.3、14.4、14.5、14.6、14.7、14.8、14.9、15.0、15.1、15.2、15.3、15.4、15.5、15.6、15.7、15.8、15.9、16.0、16.1、16.2、16.3、16.4、16.5、16.6、16.7、16.8、16.9、17.0、17.1、17.2、17.3、17.4、17.5、17.6、17.7、17.8、17.9、18.0、18.1、18.2、18.3、18.4、18.5、18.6、18.7、18.8、18.9、19.0、19.1、19.2、19.3、19.4、19.5、19.6、19.7、19.8、19.9、20.0％质量、或者由其任意两者所限定的范围。In one embodiment, relative to the total weight of the nucleotides, the 5'-inosinic acid (5'-IMP) or a physiologically acceptable salt thereof, for example 5'-inosinic acid disodium, in an amount of 0.1-20% by mass, preferably 3.0-9.0% by mass, for example 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0 8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10 .7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0, 15.1, 15.2, 15.3, 15.4, 15.5, 19.0, 19.1, 19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9, 20.0% by mass, or a range defined by any two of them.
当所述各核苷酸的含量在上述范围内时，在促进骨骼生长和发育(例如改善骨质疏松和/或修复软骨损伤和/或修复成骨损伤)方面的作用更显著。When the content of each nucleotide is within the above range, the effect on promoting bone growth and development (eg, improving osteoporosis and/or repairing cartilage damage and/or repairing osteogenesis damage) is more significant.
在一种实施方式中，所述促进骨骼生长发育和健康包括改善骨密度。In one embodiment, said promoting bone growth, development and health comprises improving bone density.
在一种实施方式中，所述促进骨骼生长发育和健康包括如下的一种或多种：改善骨质疏松、修复软骨损伤、修复成骨损伤。In one embodiment, the promotion of bone growth, development and health includes one or more of the following: improving osteoporosis, repairing cartilage damage, and repairing osteoblastic damage.
在一种实施方式中，所述促进骨骼生长发育包括：促进人体骨骼生长发育和健康，包括促进婴幼儿、儿童、青少年和/或中老年人的骨骼生长发育和健康；和/或促进动物体、尤其是哺乳动物骨骼生长发育和健康。In one embodiment, the promoting bone growth and development includes: promoting human bone growth, development and health, including promoting bone growth, development and health in infants, children, adolescents and/or middle-aged and elderly people; and/or promoting animal, especially mammal bone growth, development and health.
在一种实施方式中，所述核苷酸可以例如0.0003-0.1g/天/kg体重、例如0.001-0.05g/天/kg体重、例如0.003-0.025g/天/kg体重、例如0.005-0.013g/天/kg体重的量使用，例如可以0.0003、0.0004、0.0005、0.0006、0.0007、0.0008、0.0009、0.0010、0.0015、0.0020、0.0025、0.0030、0.0035、0.0040、0.0045、0.0050、0.0055、0.0060、0.0065、0.0070、0.0075、0.0080、0.0085、0.0090、0.0095、0.010、0.011、0.012、0.013、0.014、0.015、0.016、0.017、
0.018、0.019、0.020、0.021、0.022、0.023、0.024、0.025、0.026、0.027、0.028、0.029、0.030、0.031、0.032、0.033、0.034、0.035、0.036、0.037、0.038、0.039、0.040、0.041、0.042、0.043、0.044、0.045、0.046、0.047、0.048、0.049、0.050、0.051、0.052、0.053、0.054、0.055、0.056、0.057、0.058、0.059、0.060、0.061、0.062、0.063、0.064、0.065、0.066、0.067、0.068、0.069、0.070、0.071、0.072、0.073、0.074、0.075、0.076、0.077、0.078、0.079、0.080、0.081、0.082、0.083、0.084、0.085、0.086、0.087、0.088、0.089、0.090、0.091、0.092、0.093、0.094、0.095、0.096、0.097、0.098、0.099、0.10g/天/kg体重、或者由其任意两者所限定的范围的量使用。例如，对于体重6kg的婴儿，可以例如0.018g/天-0.15g/天的使用量摄入。当以上述量使用时，能够显著地发挥在促进骨骼生长和发育(例如改善骨质疏松和/或修复软骨损伤和/或修复成骨损伤)方面的作用。In one embodiment, the nucleotide can be used in an amount of, for example, 0.0003-0.1 g/day/kg body weight, such as 0.001-0.05 g/day/kg body weight, such as 0.003-0.025 g/day/kg body weight, such as 0.005-0.013 g/day/kg body weight, for example, 0.0003, 0.0004, 0.0005, 0.0006, 0.0007, 0.0008, 0.0009, 0.0010, 0.0015、0.0020、0.0025、0.0030、0.0035、0.0040、0.0045、0.0050、0.0055、0.0060、0.0065、0.0070、0.0075、0.0080、0.0085、0.0090、0.0095、0.010、0.011、0.012、0.013、0.014、0.015、0.016、0.017、 0.018, 0.019, 0.020, 0.021, 0.022, 0.023, 0.024, 0.025, 0.026, 0.027, 0.028, 0.029, 0.030, 0.031, 0.032, 0.033, 0.034, 0.035, 0.036, 0.037, 0.038, 0.039 , 0.040, 0.041, 0.042, 0.043, 0.044, 0.045, 0.046, 0.047, 0.048, 0.049, 0.050, 0.051, 0.052, 0.053, 0.054, 0.055, 0.056, 0.057, 0.058, 0.059, 0.060, 0.061 1. 0.062, 0.063, 0.064, 0.065, 0.066, 0.067, 0.068, 0.069, 0.070, 0.071, 0.072, 0.073, 0.074, 0.075, 0.076, 0.077, 0.078, 0.079, 0.080, 0.081, 0.082, 0.0 0.083, 0.084, 0.085, 0.086, 0.087, 0.088, 0.089, 0.090, 0.091, 0.092, 0.093, 0.094, 0.095, 0.096, 0.097, 0.098, 0.099, 0.10g/ day/kg body weight or the amount of the range limited by any two thereof. For example, for an infant weighing 6kg, an amount of, for example, 0.018g/ day-0.15g/ day can be taken. When used in the above amounts, it can significantly play a role in promoting bone growth and development (e.g., improving osteoporosis and/or repairing cartilage damage and/or repairing osteogenic damage).
在一种实施方式中，所述核苷酸可以单独地使用、或者以包括其的组合物例如食品、尤其是奶粉的形式使用。所述食品可以是婴幼儿配方食品(例如婴儿配方食品、较大婴儿配方食品、幼儿配方食品)例如婴幼儿配方奶粉(例如婴儿配方奶粉、幼儿配方奶粉)、婴儿辅食、营养或膳食补充剂、或孕妇调制奶粉、中老年奶粉。In one embodiment, the nucleotides can be used alone or in the form of a composition comprising the nucleotides, such as a food, especially a milk powder. The food can be an infant formula (e.g., an infant formula, an older infant formula, a toddler formula), such as an infant formula milk powder (e.g., an infant formula milk powder, a toddler formula milk powder), a baby food supplement, a nutrition or dietary supplement, or a formula milk powder for pregnant women, a milk powder for the middle-aged and elderly.
在一种实施方式中，所述核苷酸以包含其的食品的形式使用。优选地，所述核苷酸在食品中的总量为0.0012-0.058％质量、优选0.0025-0.058％质量，例如可以为0.0012、0.0015、0.0020、0.0025、0.0030、0.0035、0.0040、0.0045、0.0050、0.0055、0.0060、0.0065、0.0070、0.0075、0.0080、0.0085、0.0090、0.0095、0.010、0.011、0.012、0.013、0.014、0.015、0.016、0.017、0.018、0.019、0.020、0.021、0.022、0.023、0.024、0.025、0.026、0.027、0.028、0.029、0.030、0.031、0.032、0.033、0.034、0.035、0.036、0.037、0.038、0.039、0.040、0.041、0.042、0.043、0.044、0.045、0.046、0.047、0.048、0.049、0.050、0.051、0.052、0.053、0.054、0.055、0.056、0.057、0.058％质量、或者由其任意两者所限定的范围。当核苷酸以上述量使用时，能够显著地发挥出核苷酸在促进骨骼生长和发育(例如改善骨质疏松和/或修复软骨损伤和/或修复成骨损伤)方面的作用。In one embodiment, the nucleotide is used in the form of a food containing the nucleotide. Preferably, the total amount of the nucleotide in the food is 0.0012-0.058% by mass, preferably 0.0025-0.058% by mass, for example, 0.0012, 0.0015, 0.0020, 0.0025, 0.0030, 0.0035, 0.0040, 0.0045, 0.0050, 0.0055, 0.0060, 0.0065, 0.0070, 0.0075, 0.0080, 0.0085, 0.0090, 0.0095, 0.010, 0.011, 0.012, 0.013, 0.014, 0.015, 0.016, 0.017, 0.018, 0.019, 0.020 0.054, 0.055, 0.056, 0.057, 0.058, 0.059, 0.060, 0.061, 0.062, 0.063, 0.064, 0.065, 0.066, 0.067, 0.068, 0.069, 0.070, 0.071, 0.072, 0.073, 0.074, 0.075, 0.076, 0.077, 0.078, 0.079, 0.080, 0.081, 0.082, 0.083, 0.084, 0.085, 0.086, 0.087, 0.088, 0.089, 0.010, 0.110, 0.111, 0.112, 0.113, 0.114, 0.115 When nucleotides are used in the above amount, the effects of nucleotides in promoting bone growth and development (eg, improving osteoporosis and/or repairing cartilage damage and/or repairing osteogenic damage) can be significantly exerted.
营养组合物Nutritional composition
所述核苷酸还可以与乳铁蛋白组合使用。本发明人发现，当将核苷酸与
乳铁蛋白组合使用时，可进一步增强在促进骨骼生长发育和健康、例如改善骨密度方面的作用，甚至在此方面可以存在协同作用。The nucleotides can also be used in combination with lactoferrin. The inventors have found that when the nucleotides are combined with When lactoferrin is used in combination, its effect in promoting bone growth, development and health, such as improving bone density, can be further enhanced, and there may even be a synergistic effect in this regard.
因此，在另一方面中，本发明涉及一种营养组合物，其包括核苷酸和乳铁蛋白。Thus, in another aspect, the present invention relates to a nutritional composition comprising nucleotides and lactoferrin.
所述核苷酸如以上在核苷酸的用途中所描述。The nucleotides are as described above in the use of nucleotides.
因此，在一种实施方式中，所述营养组合物包括核苷酸和乳铁蛋白，其中，Therefore, in one embodiment, the nutritional composition comprises nucleotides and lactoferrin, wherein:
所述核苷酸包括选自如下的一种或多种、主要包括选自如下的一种或多种、基本上由选自如下的一种或多种组成、或者由选自如下的一种或多种组成：The nucleotides include one or more selected from the following, mainly include one or more selected from the following, basically consist of one or more selected from the following, or consist of one or more selected from the following:
5’-腺苷酸(5’-AMP)或其生理学上可接受的盐、优选钠盐(例如二钠盐)，优选5’-腺苷酸；5'-Adenosine monophosphate (5'-AMP) or a physiologically acceptable salt thereof, preferably a sodium salt (e.g., a disodium salt), preferably 5'-Adenosine monophosphate;
5’-胞苷酸(5’-CMP)或其生理学上可接受的盐、优选钠盐(例如二钠盐)，优选5’-胞苷酸二钠；5'-Cytidylic acid (5'-CMP) or a physiologically acceptable salt thereof, preferably a sodium salt (e.g., a disodium salt), preferably disodium 5'-cytidylic acid;
5’-鸟苷酸(5’-GMP)或其生理学上可接受的盐、优选钠盐(例如二钠盐)，优选5’-鸟苷酸二钠；5'-guanylic acid (5'-GMP) or a physiologically acceptable salt thereof, preferably a sodium salt (e.g., a disodium salt), preferably disodium 5'-guanylate;
5’-尿苷酸(5’-UMP)或其生理学上可接受的盐、优选钠盐(例如二钠盐)，优选5’-尿苷酸二钠，和5'-Uridine monophosphate (5'-UMP) or a physiologically acceptable salt thereof, preferably a sodium salt (e.g., a disodium salt), preferably disodium 5'-uridine monophosphate, and
5’-肌苷酸(5’-IMP)或其生理学上可接受的盐、优选钠盐(例如二钠盐)，优选5’-肌苷酸二钠。5'-inosinic acid (5'-IMP) or a physiologically acceptable salt thereof, preferably a sodium salt (e.g., a disodium salt), preferably disodium 5'-inosinic acid.
在一种实施方式中，相对于所述核苷酸的总重量，In one embodiment, relative to the total weight of the nucleotides,
5’-腺苷酸(5’-AMP)或其生理学上可接受的盐为4.0-35.0％质量、优选14.0-22.0％质量；5'-adenosine (5'-AMP) or a physiologically acceptable salt thereof is 4.0-35.0% by mass, preferably 14.0-22.0% by mass;
5’-胞苷酸(5’-CMP)或其生理学上可接受的盐为20.0-70.0％质量、优选38.0-46.0％质量；5'-cytidylic acid (5'-CMP) or a physiologically acceptable salt thereof is 20.0-70.0% by mass, preferably 38.0-46.0% by mass;
5’-鸟苷酸(5’-GMP)或其生理学上可接受的盐为3.0-30.0％质量、优选11.0-19.0％质量；5'-guanylic acid (5'-GMP) or a physiologically acceptable salt thereof is 3.0-30.0% by mass, preferably 11.0-19.0% by mass;
5’-尿苷酸(5’-UMP)或其生理学上可接受的盐为5.0-40.0％质量、优选15.0-23.0％质量，和5'-uridine monophosphate (5'-UMP) or a physiologically acceptable salt thereof is 5.0-40.0% by mass, preferably 15.0-23.0% by mass, and
5’-肌苷酸(5’-IMP)或其生理学上可接受的盐为0.1-20.0％质量、优选3.0-9.0％质量。
The content of 5'-inosinic acid (5'-IMP) or a physiologically acceptable salt thereof is 0.1-20.0% by mass, preferably 3.0-9.0% by mass.
以上在核苷酸的用途中关于核苷酸的所有描述也适用于此。All the above descriptions about nucleotides in the uses of nucleotides also apply here.
乳铁蛋白是分子量为80kDa左右的铁结合糖蛋白，属于转铁蛋白家族。乳铁蛋白在初乳和牛奶中含量高，在眼泪、唾液、精液、鼻和支气管分泌物、胆汁和胃肠液等粘膜分泌物中的含量较低。此外，乳铁蛋白也是中性粒细胞的组成成分。乳铁蛋白是机体主要防御分子之一，除了帮助转运传递铁离子，增加铁元素的生物利用率之外，它还具有多种生物免疫活性，包括广谱抗菌性、抗病毒活性、抗氧化活性和调节免疫活性。Lactoferrin is an iron-binding glycoprotein with a molecular weight of about 80 kDa and belongs to the transferrin family. Lactoferrin is found in high levels in colostrum and milk, and in lower levels in mucosal secretions such as tears, saliva, semen, nasal and bronchial secretions, bile and gastrointestinal fluid. In addition, lactoferrin is also a component of neutrophils. Lactoferrin is one of the body's main defense molecules. In addition to helping transport and transfer iron ions and increasing the bioavailability of iron, it also has a variety of biological immune activities, including broad-spectrum antibacterial, antiviral, antioxidant and immune regulatory activities.
在一种实施方式中，所述营养组合物主要包括核苷酸和乳铁蛋白。In one embodiment, the nutritional composition consists essentially of nucleotides and lactoferrin.
在一种实施方式中，所述营养组合物基本上由核苷酸和乳铁蛋白组成。In one embodiment, the nutritional composition consists essentially of nucleotides and lactoferrin.
在一种实施方式中，所述营养组合物由核苷酸和乳铁蛋白组成。In one embodiment, the nutritional composition consists of nucleotides and lactoferrin.
在一种实施方式中，所述乳铁蛋白可以来源于如下或者以如下形式提供：富含乳铁蛋白(LF)的营养成分，如富含乳铁蛋白浓缩乳清蛋白粉和/或乳铁蛋白粉等，优选乳铁蛋白粉。In one embodiment, the lactoferrin may be derived from or provided in the following form: a nutrient rich in lactoferrin (LF), such as concentrated whey protein powder rich in lactoferrin and/or lactoferrin powder, etc., preferably lactoferrin powder.
在一种实施方式中，当将核苷酸与乳铁蛋白组合使用时，相对于1质量份的核苷酸，乳铁蛋白的量可以为0.01-20质量份、优选0.02-15质量份、优选0.05-12质量份、优选0.05-10质量份、优选0.05-8质量份、优选0.05-5质量份、优选0.1-2质量份、优选0.1-0.3质量份、优选0.12-0.25质量份，例如可以为0.01、0.02、0.03、0.04、0.05、0.06、0.07、0.08、0.09、0.10、0.11、0.12、0.13、0.14、0.15、0.16、0.17、0.18、0.19、0.20、0.21、0.22、0.23、0.24、0.25、0.26、0.27、0.28、0.29、0.30、0.31、0.32、0.33、0.34、0.35、0.36、0.37、0.38、0.39、0.40、0.41、0.42、0.43、0.44、0.45、0.46、0.47、0.48、0.49、0.50、0.51、0.52、0.53、0.54、0.55、0.56、0.57、0.58、0.59、0.60、0.61、0.62、0.63、0.64、0.65、0.66、0.67、0.68、0.69、0.70、0.71、0.72、0.73、0.74、0.75、0.76、0.77、0.78、0.79、0.80、0.81、0.82、0.83、0.84、0.85、0.86、0.87、0.88、0.89、0.90、0.91、0.92、0.93、0.94、0.95、0.96、0.97、0.98、0.99、1.0、1.1、1.2、1.3、1.4、1.5、1.6、1.7、1.8、1.9、2.0、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9、3.0、3.1、3.2、3.3、3.4、3.5、3.6、3.7、3.8、3.9、4.0、4.1、4.2、4.3、4.4、4.5、4.6、4.7、4.8、4.9、5.0、5.1、5.2、5.3、5.4、5.5、5.6、5.7、5.8、5.9、6.0、6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9、7.0、7.1、7.2、7.3、7.4、7.5、7.6、7.7、7.8、7.9、8.0、8.1、8.2、8.3、8.4、8.5、8.6、8.7、8.8、8.9、9.0、9.1、9.2、9.3、9.4、
9.5、9.6、9.7、9.8、9.9、10.0、10.1、10.2、10.3、10.4、10.5、10.6、10.7、10.8、10.9、11.0、11.1、11.2、11.3、11.4、11.5、11.6、11.7、11.8、11.9、12.0、12.1、12.2、12.3、12.4、12.5、12.6、12.7、12.8、12.9、13.0、13.1、13.2、13.3、13.4、13.5、13.6、13.7、13.8、13.9、14.0、14.1、14.2、14.3、14.4、14.5、14.6、14.7、14.8、14.9、15.0、15.1、15.2、15.3、15.4、15.5、15.6、15.7、15.8、15.9、16.0、16.1、16.2、16.3、16.4、16.5、16.6、16.7、16.8、16.9、17.0、17.1、17.2、17.3、17.4、17.5、17.6、17.7、17.8、17.9、18.0、18.1、18.2、18.3、18.4、18.5、18.6、18.7、18.8、18.9、19.0、19.1、19.2、19.3、19.4、19.5、19.6、19.7、19.8、19.9、20.0质量份、或者由其任意两者所限定的范围。In one embodiment, when nucleotides and lactoferrin are used in combination, the amount of lactoferrin relative to 1 part by mass of nucleotides can be 0.01-20 parts by mass, preferably 0.02-15 parts by mass, preferably 0.05-12 parts by mass, preferably 0.05-10 parts by mass, preferably 0.05-8 parts by mass, preferably 0.05-5 parts by mass, preferably 0.1-2 parts by mass, preferably 0.1-0.3 parts by mass, preferably 0.12-0.25 parts by mass, for example, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18、0.19、0.20、0.21、0.22、0.23、0.24、0.25、0.26、0.27、0.28、0.29、0.30、0.31、0.32、0.33、0.34、0.35、0.36、0.37、0.38、0.39、0.40、0.41、0.42、 0.43、0.44、0.45、0.46、0.47、0.48、0.49、0.50、0.51、0.52、0.53、0.54、0.55、0.56、0.57、0.58、0.59、0.60、0.61、0.62、0.63、0.64、0.65、0.66、0.67、 0.68、0.69、0.70、0.71、0.72、0.73、0.74、0.75、0.76、0.77、0.78、0.79、0.80、0.81、0.82、0.83、0.84、0.85、0.86、0.87、0.88、0.89、0.90、0.91、0.92、 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3. 2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3 , 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5、9.6、9.7、9.8、9.9、10.0、10.1、10.2、10.3、10.4、10.5、10.6、10.7、10.8、10.9、11.0、11.1、11.2、11.3、11.4、11.5、11.6、11.7、11.8、11.9、12.0、12.1、12.2、 12.3、12.4、12.5、12.6、12.7、12.8、12.9、13.0、13.1、13.2、13.3、13.4、13.5、13.6、13.7、13.8、13.9、14.0、14.1、14.2、14.3、14.4、14.5、14.6、14.7、14.8、14.9、1 5.0, 15.1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9, 16.0, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 17.0, 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17 .7, 17.8, 17.9, 18.0, 18.1, 18.2, 18.3, 18.4, 18.5, 18.6, 18.7, 18.8, 18.9, 19.0, 19.1, 19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9, 20.0 parts by mass, or the range defined by any two of them.
当核苷酸与乳铁蛋白的比率在上述范围内时，在促进骨骼生长发育和健康、例如增加骨密度方面的作用更为显著。When the ratio of nucleotides to lactoferrin is within the above range, the effect on promoting bone growth and health, such as increasing bone density, is more significant.
在一种实施方式中，相对于1质量份的核苷酸，乳铁蛋白的量可以为0.1-0.3质量份、优选0.12-0.25质量份、或者如上所述的在此范围内的任何其它值或范围。当核苷酸和乳铁蛋白以上述比率范围的量使用时效果更加显著，可以协同地促进骨骼生长和发育，增加骨密度。In one embodiment, the amount of lactoferrin can be 0.1-0.3 parts by mass, preferably 0.12-0.25 parts by mass, or any other value or range within the range as described above relative to 1 part by mass of nucleotides. When nucleotides and lactoferrin are used in the above ratio range, the effect is more significant, and bone growth and development can be promoted synergistically, and bone density can be increased.
食品food
在另一方面中，本发明还涉及包括所述营养组合物的食品。In another aspect, the present invention also relates to a food product comprising the nutritional composition.
本发明的食品可以是粉末形式，也可以是液体形式。The food of the present invention may be in powder form or in liquid form.
本发明的食品可以是婴幼儿配方食品(例如婴儿配方食品、较大婴儿配方食品、幼儿配方食品)例如婴幼儿配方奶粉(例如婴儿配方奶粉、幼儿配方奶粉)、婴儿辅食、营养或膳食补充剂、孕妇调制奶粉、或中老年奶粉。The food of the present invention can be infant formula (e.g., infant formula, follow-on formula, toddler formula), such as infant formula milk powder (e.g., infant formula milk powder, toddler formula milk powder), baby food, nutritional or dietary supplement, pregnant woman formula milk powder, or middle-aged and elderly milk powder.
在一种实施方式中，所述营养组合物的添加量使得，相对于所述食品的总质量，所述核苷酸的总质量含量为0.0012-0.058％、优选0.0025-0.058％。例如，相对于所述食品的总质量，核苷酸的总质量含量可以为0.0012、0.0015、0.0020、0.0025、0.0030、0.0035、0.0040、0.0045、0.0050、0.0055、0.0060、0.0065、0.0070、0.0075、0.0080、0.0085、0.0090、0.0095、0.010、0.011、0.012、0.013、0.014、0.015、0.016、0.017、0.018、0.019、0.020、0.021、0.022、0.023、0.024、0.025、0.026、0.027、0.028、0.029、0.030、0.031、0.032、0.033、0.034、0.035、0.036、0.037、0.038、0.039、0.040、0.041、0.042、0.043、0.044、
0.045、0.046、0.047、0.048、0.049、0.050、0.051、0.052、0.053、0.054、0.055、0.056、0.057、0.058％质量、或者由其任意两者所限定的范围。当核苷酸以上述量使用时，能够显著地发挥促进骨骼生长和发育(例如改善骨质疏松和/或修复软骨损伤和/或修复成骨损伤)方面的作用。In one embodiment, the nutritional composition is added in an amount such that the total mass content of the nucleotides is 0.0012-0.058%, preferably 0.0025-0.058%, relative to the total mass of the food. For example, the total mass content of the nucleotides may be 0.0012, 0.0015, 0.0020, 0.0025, 0.0030, 0.0035, 0.0040, 0.0045, 0.0050, 0.0055, 0.0060, 0.0065, 0.0070, 0.0075, 0.0080, 0.0085, 0.0090, 0.0095, 0.010, 0.011, 0.012, 0.013, 0.014, 0.015, 0.016, 0.017, 0.018, 0.019, 0.190, 0.191, 0.192, 0.193, 0.194, 0.195, 0.196, 0.197, 0.201 4. 0.015, 0.016, 0.017, 0.018, 0.019, 0.020, 0.021, 0.022, 0.023, 0.024, 0.025, 0.026, 0.027, 0.028, 0.029, 0.030, 0.031, 0.032, 0.033, 0.034, 0.035, 0.036, 0.037, 0.038, 0.039, 0.040, 0.041, 0.042, 0.043, 0.044, 0.045, 0.046, 0.047, 0.048, 0.049, 0.050, 0.051, 0.052, 0.053, 0.054, 0.055, 0.056, 0.057, 0.058% by mass, or a range defined by any two of them. When the nucleotide is used in the above amount, it can significantly play a role in promoting bone growth and development (e.g., improving osteoporosis and/or repairing cartilage damage and/or repairing osteoblastic damage).
在一种实施方式中，所述营养组合物的添加量使得，相对于所述食品的总质量，所述乳铁蛋白的量为0.002-1.0％质量、优选0.004-0.7％质量。例如，相对于所述食品的总质量，乳铁蛋白的量可以为0.002、0.003、0.004、0.005、0.006、0.007、0.008、0.009、0.010、0.015、0.020、0.025、0.030、0.035、0.040、0.045、0.050、0.055、0.060、0.065、0.070、0.075、0.080、0.085、0.090、0.10、0.11、0.12、0.13、0.14、0.15、0.16、0.17、0.18、0.19、0.20、0.21、0.22、0.23、0.24、0.25、0.26、0.27、0.28、0.29、0.30、0.31、0.32、0.33、0.34、0.35、0.36、0.37、0.38、0.39、0.40、0.41、0.42、0.43、0.44、0.45、0.46、0.47、0.48、0.49、0.50、0.51、0.52、0.53、0.54、0.55、0.56、0.57、0.58、0.59、0.60、0.61、0.62、0.63、0.64、0.65、0.66、0.67、0.68、0.69、0.70、0.71、0.72、0.73、0.74、0.75、0.76、0.77、0.78、0.79、0.80、0.81、0.82、0.83、0.84、0.85、0.86、0.87、0.88、0.89、0.90、0.91、0.92、0.93、0.94、0.95、0.96、0.97、0.98、0.99、1.00％质量、或者由其任意两者限定的范围。In one embodiment, the amount of the nutritional composition added is such that, relative to the total mass of the food, the amount of lactoferrin is 0.002-1.0% by mass, preferably 0.004-0.7% by mass. For example, relative to the total mass of the food, the amount of lactoferrin may be 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.010, 0.015, 0.020, 0.025, 0.030, 0.035, 0.040, 0.045, 0.050, 0.055, 0.060, 0.065, 0.070, 0.075, 0.080 , 0.085, 0.090, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39 , 0.40, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.50, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.60, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.70, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.80, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.90, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1.00% by mass, or a range limited by any two thereof.
当食品中核苷酸和乳铁蛋白的含量在上述范围内时，可以显著地促进骨骼生长发育和健康(例如改善骨质疏松、修复软骨损伤、修复成骨损伤等)，并且同时还能够均衡例如人体或动物体所需要的各方面营养。When the content of nucleotides and lactoferrin in food is within the above range, it can significantly promote bone growth, development and health (such as improving osteoporosis, repairing cartilage damage, repairing bone damage, etc.), and at the same time it can balance various aspects of nutrition required by the human body or animal body.
在一种优选实施方式中，所述食品中，相对于1质量份的核苷酸，乳铁蛋白的量为0.1-20质量份、优选0.1-10质量份、优选0.1-2质量份，甚至更优选地，乳铁蛋白的量为0.1-0.3质量份、优选0.12-0.25质量份，或者如上所述的在此范围内的任何其它值或范围，并且所述食品中所述核苷酸的含量为0.0025-0.058％质量、或者如上对于核苷酸所述的在此范围内的任何其它值或范围，所述乳铁蛋白的含量为0.004-0.8％质量、或者如上对于乳铁蛋白所述的在此范围内的任何其它值或范围。当核苷酸与乳铁蛋白的比例以及各自的用量在上述范围内或优选范围内时效果更加显著，可以协同地促进骨骼生长发育和健康，尤其是改善骨密度，例如修复软骨损失、修复成骨损伤方面，并且同时能够均衡人体或动物体所需的各方面营养。In a preferred embodiment, in the food, relative to 1 mass part of nucleotide, the amount of lactoferrin is 0.1-20 mass parts, preferably 0.1-10 mass parts, preferably 0.1-2 mass parts, and even more preferably, the amount of lactoferrin is 0.1-0.3 mass parts, preferably 0.12-0.25 mass parts, or any other value or range within this range as described above, and the content of the nucleotide in the food is 0.0025-0.058 mass%, or any other value or range within this range as described above for the nucleotide, and the content of the lactoferrin is 0.004-0.8 mass%, or any other value or range within this range as described above for the lactoferrin. When the ratio of nucleotide to lactoferrin and the respective dosage are within the above range or preferred range, the effect is more significant, and the growth and health of bones can be promoted synergistically, especially the improvement of bone density, such as repairing cartilage loss and repairing bone damage, and at the same time, the various aspects of nutrition required by the human or animal body can be balanced.
除了核苷酸和乳铁蛋白之外，所述食品还可以包含其它成分，例如蛋白
质/氨基酸、碳水化合物、脂肪、维生素、矿物质等在配方食品例如婴幼儿配方食品如奶粉中经常含有的成分。In addition to nucleotides and lactoferrin, the food may also contain other ingredients, such as protein Ingredients often contained in formula foods such as infant formula foods such as milk powder, such as proteins/amino acids, carbohydrates, fats, vitamins, minerals, etc.
用途use
在另一方面中，本发明涉及上述营养组合物或者上述食品在促进人体或动物体的骨骼生长发育和健康、例如改善骨密度中的非治疗目的的用途。In another aspect, the present invention relates to the use of the above nutritional composition or the above food for non-therapeutic purposes in promoting bone growth and health of the human or animal body, such as improving bone density.
在一种实施方式中，所述促进骨骼生长发育和健康包括改善骨密度。In one embodiment, said promoting bone growth, development and health comprises improving bone density.
在一种实施方式中，所述促进骨骼生长发育和健康包括如下的一种或多种：改善骨质疏松、修复软骨损伤、修复成骨损伤。In one embodiment, the promotion of bone growth, development and health includes one or more of the following: improving osteoporosis, repairing cartilage damage, and repairing osteoblastic damage.
在一种实施方式中，所述促进骨骼生长发育包括：促进人体骨骼生长发育和健康，包括促进婴幼儿、儿童、青少年和/或中老年人的骨骼生长发育和健康；和/或促进动物体、尤其是哺乳动物骨骼生长发育和健康。In one embodiment, the promoting bone growth and development includes: promoting human bone growth, development and health, including promoting bone growth, development and health in infants, children, adolescents and/or middle-aged and elderly people; and/or promoting animal, especially mammal bone growth, development and health.
在一种实施方式中，所述核苷酸可以例如0.0003-0.1g/天/kg体重、例如0.001-0.05g/天/kg体重、例如0.003-0.025g/天/kg体重、例如0.006-0.013g/天/kg的量使用，例如可以0.0003、0.0004、0.0005、0.0006、0.0007、0.0008、0.0009、0.0010、0.0015、0.0020、0.0025、0.0030、0.0035、0.0040、0.0045、0.0050、0.0055、0.0060、0.0065、0.0070、0.0075、0.0080、0.0085、0.0090、0.0095、0.003、0.004、0.005、0.006、0.007、0.008、0.009、0.010、0.011、0.012、0.013、0.014、0.015、0.016、0.017、0.018、0.019、0.020、0.021、0.022、0.023、0.024、0.025、0.026、0.027、0.028、0.029、0.030、0.031、0.032、0.033、0.034、0.035、0.036、0.037、0.038、0.039、0.040、0.041、0.042、0.043、0.044、0.045、0.046、0.047、0.048、0.049、0.050、0.051、0.052、0.053、0.054、0.055、0.056、0.057、0.058、0.059、0.060、0.061、0.062、0.063、0.064、0.065、0.066、0.067、0.068、0.069、0.070、0.071、0.072、0.073、0.074、0.075、0.076、0.077、0.078、0.079、0.080、0.081、0.082、0.083、0.084、0.085、0.086、0.087、0.088、0.089、0.090、0.091、0.092、0.093、0.094、0.095、0.096、0.097、0.098、0.099、0.10g/天/kg体重、或者由其任意两者所限定的范围的量使用。例如，对于体重6kg的婴儿，所述核苷酸可以例如0.018g/天-0.15g/天的使用量摄入。并且相对于1质量份的核苷酸，乳铁蛋白的使用量可以为0.01-20质量份、优选0.02-15质量份、优选0.05-12质量份、优选0.05-10质量份、优选0.05-8质量份、优选0.05-5质量份、优选0.1-2质量份、优选0.1-0.3质量份、优选
0.12-0.25质量份、或者如上所述的在此范围内的任何其它值或范围。优选地，相对于1质量份的所述核苷酸，所述乳铁蛋白以0.1-0.3质量份、优选0.12-0.25质量份的量使用。当核苷酸和乳铁蛋白以在上述范围、尤其是优选范围内的量使用时，在促进骨骼生长发育和健康、例如增加骨密度方面的作用更为显著。In one embodiment, the nucleotide can be used in an amount of, for example, 0.0003-0.1 g/day/kg body weight, such as 0.001-0.05 g/day/kg body weight, such as 0.003-0.025 g/day/kg body weight, such as 0.006-0.013 g/day/kg, for example, 0.0003, 0.0004, 0.0005, 0.0006, 0.0007, 0.0008, 0.0009, 0.0010, 0.0015, 0.0020, 0.0025, 0.0030, 0.0035, 0.0040, 0.0045, 0.0050, 0.006 55, 0.0060, 0.0065, 0.0070, 0.0075, 0.0080, 0.0085, 0.0090, 0.0095, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.010, 0.011, 0.012, 0.013, 0.014, 0.015, 0.016, 0.017, 0.018, 0.019, 0.020, 0.021, 0.022, 0.023, 0.024, 0.025, 0.026, 0.027, 0.028, 0.029, 0.0 30, 0.031, 0.032, 0.033, 0.034, 0.035, 0.036, 0.037, 0.038, 0.039, 0.040, 0.041, 0.042, 0.043, 0.044, 0.045, 0.046, 0.047, 0.048, 0.049, 0.050, 0.051, 0.052, 0.053, 0.054, 0.055, 0.056, 0.057, 0.058, 0.059, 0.060, 0.061, 0.062, 0.063, 0.064, 0.065, 0.066, 0.067 , 0.068, 0.069, 0.070, 0.071, 0.072, 0.073, 0.074, 0.075, 0.076, 0.077, 0.078, 0.079, 0.080, 0.081, 0.082, 0.083, 0.084, 0.085, 0.086, 0.087, 0.088, 0.089, 0.090, 0.091, 0.092, 0.093, 0.094, 0.095, 0.096, 0.097, 0.098, 0.099, 0.10g/day/kg body weight, or the amount of the range limited by any two thereof. For example, for an infant weighing 6kg, the nucleotide can be taken in an amount of, for example, 0.018g/day-0.15g/day. And the amount of lactoferrin used relative to 1 part by mass of nucleotide can be 0.01-20 parts by mass, preferably 0.02-15 parts by mass, preferably 0.05-12 parts by mass, preferably 0.05-10 parts by mass, preferably 0.05-8 parts by mass, preferably 0.05-5 parts by mass, preferably 0.1-2 parts by mass, preferably 0.1-0.3 parts by mass, preferably 0.12-0.25 mass parts, or any other value or range within this range as described above. Preferably, the lactoferrin is used in an amount of 0.1-0.3 mass parts, preferably 0.12-0.25 mass parts, relative to 1 mass part of the nucleotide. When nucleotides and lactoferrin are used in an amount within the above range, especially within a preferred range, the effect on promoting bone growth and health, such as increasing bone density, is more significant.
实施例Example
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。除非特别说明，本发明采用的试剂、方法和设备为本技术领域常规的试剂、方法和设备。In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with embodiment.It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the art.
动物实验Animal experiment
在基础和临床前研究中，斑马鱼已成为研究骨骼发育和疾病的重要模式生物，由于斑马鱼在胚胎和幼体阶段通体透明，可以更清楚详细地监测其骨生成和成骨细胞的活性。和其他脊椎动物一样，斑马鱼是由软骨和骨骼组成的复杂的骨化骨骼。骨骼是通过先产生软骨细胞，然后是骨细胞和成骨细胞的间充质细胞的凝结而形成的。基于脊椎动物骨骼基因的进化保守性，斑马鱼的骨骼中含有与哺乳动物相同的骨细胞，且许多骨骼结构在哺乳动物中有明显的同源性，因此斑马鱼模型可用于骨质疏松、关节炎、骨骼发育的研究。该方法系统直观的评价了对骨骼发育的影响，对原料的应用具有深远的意义。In basic and preclinical research, zebrafish has become an important model organism for studying bone development and disease. Since zebrafish are transparent throughout the embryonic and larval stages, their bone formation and osteoblast activity can be monitored more clearly and in detail. Like other vertebrates, zebrafish have a complex ossified skeleton composed of cartilage and bone. The skeleton is formed by the condensation of mesenchymal cells that first produce chondrocytes, then osteocytes and osteoblasts. Based on the evolutionary conservation of vertebrate skeletal genes, zebrafish skeletons contain the same bone cells as mammals, and many skeletal structures have obvious homology in mammals. Therefore, the zebrafish model can be used for the study of osteoporosis, arthritis, and bone development. This method systematically and intuitively evaluates the effects on bone development, which has far-reaching significance for the application of raw materials.
1.实验材料1. Experimental Materials
1.1.样品和配制信息1.1. Sample and preparation information
复配核苷酸：大连珍奥生物技术股份有限公司(BV2104001BL批号)，其中包含17.8％质量的5’-AMP、41.6％质量的5’-CMP二钠盐、15.2％质量的5’-GMP二钠盐、18.9％质量的5’-UMP二钠盐、6.0％质量的5’-IMP二钠盐。Complex nucleotides: Dalian Zhenao Biotechnology Co., Ltd. (Batch No. BV2104001BL), which contains 17.8% by mass of 5’-AMP, 41.6% by mass of 5’-CMP disodium salt, 15.2% by mass of 5’-GMP disodium salt, 18.9% by mass of 5’-UMP disodium salt, and 6.0% by mass of 5’-IMP disodium salt.
乳铁蛋白：美国Hilmar公司的Hilmar1000lactoferrin，乳铁蛋白含量97.2％质量Lactoferrin: Hilmar 1000 lactoferrin from Hilmar, USA, lactoferrin content 97.2% by mass
核苷酸、乳铁蛋白用标准稀释水配制成10.0mg/mL母液，现配现用。
Nucleotides and lactoferrin were prepared into 10.0 mg/mL stock solutions with standard dilution water and used immediately after preparation.
阳性对照：阿仑膦酸钠片，白色片剂，批号U006983，Merck Sharp& Dohme B.V，阴凉避光储存。用标准稀释水配制成2.50mg/mL母液，-20℃储存。Positive control: Alendronate sodium tablets, white tablets, batch number U006983, Merck Sharp & Dohme B.V., store in a cool and dark place. Prepare 2.50 mg/mL stock solution with standard dilution water and store at -20℃.
阳性对照：硫酸软骨素A钠盐(以下简称硫酸软骨素)，白色粉末，批号I2003201，上海阿拉丁生化科技股份有限公司，4℃避光储存。用超纯水配制成20.0mg/mL母液，现配现用。Positive control: Chondroitin sulfate A sodium salt (hereinafter referred to as chondroitin sulfate), white powder, batch number I2003201, Shanghai Aladdin Biochemical Technology Co., Ltd., stored at 4°C away from light. Prepared into 20.0 mg/mL stock solution with ultrapure water, used immediately after preparation.
1.2.实验动物1.2. Experimental animals
斑马鱼均饲养于28℃的养鱼用水中(水质：每1L反渗透水中加入200mg速溶海盐，电导率为450～550μS/cm；pH为6.5～8.5；硬度为50～100mg/L CaCO3)，实验动物使用许可证号为：SYXK(浙)2012-0171。饲养管理符合国际AAALAC认证(认证编号：001458)的要求。Zebrafish were raised in 28°C fish water (water quality: 200 mg instant sea salt was added to 1 L reverse osmosis water, conductivity was 450-550 μS/cm; pH was 6.5-8.5; hardness was 50-100 mg/L CaCO 3 ), and the experimental animal use license number was SYXK (Zhejiang) 2012-0171. The feeding and management complied with the requirements of the international AAALAC certification (certification number: 001458).
野生型AB品系斑马鱼，以自然成对交配繁殖方式进行。年龄为受精后3天(3dpf)的斑马鱼用于样品抗骨质疏松功效最大检测浓度(MTC)测定及其功效评价。Wild-type AB strain zebrafish were bred in natural pairs. Zebrafish aged 3 days post fertilization (3 dpf) were used for the determination of the maximum detection concentration (MTC) of the anti-osteoporosis efficacy of the samples and their efficacy evaluation.
转基因软骨绿色荧光斑马鱼Tg(Col2a1a:eGFP)，以自然成对交配繁殖方式进行。年龄为受精后2天(2dpf)的斑马鱼用于样品及组合物软骨损伤修复功效评价。Transgenic cartilage green fluorescent zebrafish Tg (Col2a1a: eGFP) were bred by natural pair mating. Zebrafish aged 2 days post fertilization (2dpf) were used for evaluation of cartilage damage repair efficacy of samples and compositions.
转基因成骨绿色荧光斑马鱼Tg(OlaSp7:nlsGFP)cy25，以自然成对交配繁殖方式进行。年龄为受精后3天(3dpf)的斑马鱼用于样品及组合物成骨保护功效评价。Transgenic osteogenic green fluorescent zebrafish Tg(OlaSp7:nlsGFP)cy25 were bred by natural pair mating. Zebrafish aged 3 days post fertilization (3dpf) were used for evaluation of the osteoprotective efficacy of samples and compositions.
用于功效评价的斑马鱼转换人用剂量的换算方法可参见CN113496071A。具体地，对于体重60kg的人，斑马鱼使用剂量与理论人用剂量可以按照如下关系换算：斑马鱼(mg/L)＝[人(g/天)×1000]/6。The conversion method of zebrafish dosage to human dosage for efficacy evaluation can be found in CN113496071A. Specifically, for a person weighing 60 kg, the zebrafish dosage and the theoretical human dosage can be converted according to the following relationship: zebrafish (mg/L) = [human (g/day) × 1000]/6.
1.3.仪器、耗材与试剂1.3. Instruments, consumables and reagents
解剖显微镜(SZX7，OLYMPUS，Japan)；CCD相机(VertA1，上海土森视觉科技有限公司，China)；电动聚焦连续变倍荧光显微镜(AZ100，Nikon，Japan)；精密电子天平(CP214，OHAUS，USA)；摇摆脱色摇床(2D-9556-A，太仓市华利达实验设备有限公司，China)；6孔板(Nest Biotech，China)。Dissecting microscope (SZX7, OLYMPUS, Japan); CCD camera (VertA1, Shanghai Tusen Vision Technology Co., Ltd., China); electric focus continuous zoom fluorescence microscope (AZ100, Nikon, Japan); precision electronic balance (CP214, OHAUS, USA); rocking decolorization shaker (2D-9556-A, Taicang Hualida Experimental Equipment Co., Ltd., China); 6-well plate (Nest Biotech, China).
地塞米松(批号L1931006，上海阿拉丁生化科技股份有限公司，China)；
4％组织细胞固定液(批号20210828，Solarbio，China)；茜素红(批号C12071107，上海麦克林生化科技有限公司，China)；甘油(批号C12219636，上海麦克林生化科技有限公司，China)；氢氧化钾(批号T20110104，国药集团化学试剂有限公司，China)；无水氯化镁(C1809044，上海阿拉丁生化科技股份有限公司，China)；无水乙醇(批号20210514，国药集团化学试剂有限公司，China)；双氧水(批号20210203，国药集团化学试剂有限公司，China)；二甲基亚砜(DMSO，批号BCCD8942，Sigma，Switzerland)；甲基纤维素(批号C2004046，上海阿拉丁生化科技股份有限公司，China)。Dexamethasone (Batch No. L1931006, Shanghai Aladdin Biochemical Technology Co., Ltd., China); 4% tissue cell fixative (batch number 20210828, Solarbio, China); Alizarin Red (batch number C12071107, Shanghai McLean Biochemical Technology Co., Ltd., China); Glycerol (batch number C12219636, Shanghai McLean Biochemical Technology Co., Ltd., China); Potassium hydroxide (batch number T20110104, Sinopharm Chemical Reagent Co., Ltd., China); Anhydrous magnesium chloride (C1809044, Shanghai Aladdin Biochemical Technology Co., Ltd., China); Anhydrous ethanol (batch number 20210514, Sinopharm Chemical Reagent Co., Ltd., China); Hydrogen peroxide (batch number 20210203, Sinopharm Chemical Reagent Co., Ltd., China); Dimethyl sulfoxide (DMSO, batch number BCCD8942, Sigma, Switzerland); Methylcellulose (batch number C2004046, Shanghai Aladdin Biochemical Technology Co., Ltd., China).
1.4检测方法1.4 Detection Method
1.4.1抗骨质疏松功效检测1.4.1 Anti-osteoporosis efficacy testing
随机选取3dpf野生型AB品系斑马鱼于6孔板中，每孔(实验组)15尾。分别水溶给予样品(浓度见表1)，阳性对照阿仑膦酸钠片2.50μg/mL浓度，同时设置模型对照组和正常对照组，每孔容量为3mL。除正常对照组外，其余各实验组均水溶给予地塞米松建立斑马鱼骨质疏松模型。28℃处理至5dpf换液，换液后继续处理至7dpf。处理结束后对斑马鱼进行固定，用茜素红进行染色，染色后每个实验组随机选取8尾斑马鱼置于荧光显微镜下拍照，用NIS-Elements D 3.20高级图像处理软件分析并采集数据，分析脊椎骨荧光强度。供试品对斑马鱼骨质疏松治疗作用计算公式如下:3dpf wild-type AB strain zebrafish were randomly selected in a 6-well plate, with 15 in each well (experimental group). The samples were given water-soluble (concentrations are shown in Table 1), and the positive control alendronate sodium tablets were 2.50μg/mL. At the same time, a model control group and a normal control group were set up, with a capacity of 3mL per well. Except for the normal control group, dexamethasone was given water-soluble to establish a zebrafish osteoporosis model in all other experimental groups. The zebrafish were treated at 28℃ until 5dpf and the solution was changed. After the solution was changed, the treatment continued until 7dpf. After the treatment, the zebrafish were fixed and stained with alizarin red. After staining, 8 zebrafish were randomly selected from each experimental group and photographed under a fluorescence microscope. The NIS-Elements D 3.20 advanced image processing software was used to analyze and collect data, and the fluorescence intensity of the spine was analyzed. The calculation formula for the therapeutic effect of the test product on zebrafish osteoporosis is as follows:
骨质疏松治疗作用(％)＝S(供试品组)－S(模型对照组)/S(正常对照组)－S(模型对照组)×100％Osteoporosis therapeutic effect (%) = S (test group) - S (model control group) / S (normal control group) - S (model control group) × 100%
1.4.2软骨损伤修复功效检测1.4.2 Cartilage damage repair efficacy test
随机选取2dpf转基因软骨绿色荧光斑马于6孔板中，每孔(实验组)均处理15尾斑马鱼。分别水溶给予样品(浓度见表1)，阳性对照硫酸软骨素1000μg/mL浓度，同时设置正常对照组和模型对照组，每孔容量为3mL。除正常对照组外，其余各实验组均水溶给予地塞米松建立斑马鱼软骨损伤模型。28℃处理至5dpf后，每个实验组随机选取8尾斑马鱼置于荧光显微镜下拍照，使用NIS-Elements D 3.20高级图像处理软件采集数据，分析软骨荧光强度，以该指标的统计学分析结果评价各实验组别软骨损伤修复功效。统计学处理结果采用mean±SE表示。用SPSS26.0软件进行统计学分析，p
<0.05表明差异具有统计学意义。2dpf transgenic cartilage green fluorescent zebrafish were randomly selected in a 6-well plate, and 15 zebrafish were treated in each well (experimental group). The samples were given water-soluble (concentrations are shown in Table 1), and the positive control chondroitin sulfate concentration was 1000μg/mL. At the same time, a normal control group and a model control group were set up, and the capacity of each well was 3mL. Except for the normal control group, the other experimental groups were given water-soluble dexamethasone to establish a zebrafish cartilage injury model. After treatment at 28℃ until 5dpf, 8 zebrafish were randomly selected from each experimental group and photographed under a fluorescence microscope. NIS-Elements D 3.20 advanced image processing software was used to collect data and analyze the cartilage fluorescence intensity. The statistical analysis results of this indicator were used to evaluate the cartilage injury repair efficacy of each experimental group. The statistical analysis results are expressed as mean±SE. SPSS26.0 software was used for statistical analysis, p <0.05 indicated that the difference was statistically significant.
1.4.3成骨损伤修复功效检测1.4.3 Osteogenic injury repair efficacy test
随机挑选3dpf转基因硬骨绿色荧光斑马鱼(cy25)于6孔板中，每孔(实验组)均处理15尾斑马鱼。分别水溶给予样品(浓度见表2)，阳性对照阿仑膦酸钠片5.00μg/mL浓度，同时设置正常对照组和模型对照组，每孔容量为3mL。除正常对照组外，其余各组均水溶给予地塞米松建立斑马鱼成骨损伤模型。5dpf换液一次。28℃处理4天后，每个实验组随机选取8尾斑马鱼置于荧光显微镜下拍照，使用NIS-Elements D 3.20高级图像处理软件分析并采集数据，分析斑马鱼成骨荧光强度，以该指标的统计学分析结果评价样品及组合物成骨保护功效。统计学处理结果采用mean±SE表示。用SPSS26.0软件进行统计学分析，p<0.05表明差异具有统计学意义。3dpf transgenic teleost green fluorescent zebrafish (cy25) were randomly selected in a 6-well plate, and 15 zebrafish were treated in each well (experimental group). The samples were given water-soluble (concentrations are shown in Table 2), and the positive control alendronate sodium tablets were 5.00μg/mL. At the same time, a normal control group and a model control group were set up, and the volume of each well was 3mL. Except for the normal control group, dexamethasone was given water-soluble to establish a zebrafish osteoblast injury model in all other groups. The medium was changed once at 5dpf. After 4 days of treatment at 28℃, 8 zebrafish were randomly selected from each experimental group and photographed under a fluorescence microscope. NIS-Elements D 3.20 advanced image processing software was used to analyze and collect data, and the zebrafish osteoblast fluorescence intensity was analyzed. The statistical analysis results of this indicator were used to evaluate the osteoblast protection efficacy of the samples and compositions. The statistical analysis results are expressed as mean±SE. SPSS26.0 software was used for statistical analysis, and p<0.05 indicated that the difference was statistically significant.
1.5数据分析1.5 Data Analysis
统计学处理结果采用mean±SE表示。用SPSS26.0软件进行统计学分析，p<0.05表明差异具有统计学意义。The statistical results were expressed as mean ± SE. SPSS 26.0 software was used for statistical analysis, and p < 0.05 indicated that the difference was statistically significant.
2.实验结果2. Experimental results
2.1.抗骨质疏松功效评价2.1. Evaluation of anti-osteoporosis efficacy
研究了核苷酸对增强骨密度，改善骨骼健康的功效。结果见表1、2图1。The effects of nucleotides on increasing bone density and improving bone health were studied. The results are shown in Table 1 and Figure 2.
表1.抗骨质疏松功效评价实验结果(n＝8)
与模型对照组比较，*p<0.05，**p<0.01，***p<0.001 Table 1. Anti-osteoporosis efficacy evaluation test results (n=8)
Compared with the model control group, *p<0.05, **p<0.01, ***p<0.001
与模型对照组比较，*p<0.05，**p<0.01，***p<0.001 Table 1. Anti-osteoporosis efficacy evaluation test results (n=8)
Compared with the model control group, *p<0.05, **p<0.01, ***p<0.001
表2.抗骨质疏松治疗作用(n＝8)
与模型对照组比较，*p<0.05，**p<0.01，***p<0.001Table 2. Anti-osteoporosis therapeutic effect (n=8)
Compared with the model control group, *p<0.05, **p<0.01, ***p<0.001
与模型对照组比较，*p<0.05，**p<0.01，***p<0.001Table 2. Anti-osteoporosis therapeutic effect (n=8)
Compared with the model control group, *p<0.05, **p<0.01, ***p<0.001
骨质疏松症(osteoporosis,OP)是世界范围内的一个重要公共健康问题。现有骨质疏松模型在高效、快速方面尚存在不足：一方面在于大鼠模型耗时长、劳动强度高、效率低、灵敏度低且化合物用量大；另一方面体外成骨和破骨原代细胞模型实验条件苛刻，难于掌握和控制，作用环节相对单一，不能体现在体试验的综合效果。Osteoporosis (OP) is an important public health problem worldwide. Existing osteoporosis models are still insufficient in terms of efficiency and speed: on the one hand, the rat model is time-consuming, labor-intensive, inefficient, low-sensitivity, and requires a large amount of compounds; on the other hand, the experimental conditions of in vitro osteoblast and osteoclast primary cell models are harsh, difficult to master and control, and the action links are relatively single, which cannot reflect the comprehensive effects of in vivo experiments.
斑马鱼其在骨骼方面的研究具有生理及遗传学依据：和哺乳动物一样，斑马鱼的骨骼是从3种胚胎干细胞系即神经嵴(neural crest)、体节中胚层(somatic mesoderm)和侧板(lateral plate)发育而来的,已有研究表明斑马鱼幼鱼骨包含骨形成和骨吸收活动所需的细胞,是较完整体系。骨骼形成机制也包括软骨内骨化和膜内骨化，其过程都受到包括一系列转录因子和激素在内的复杂机制的严格调控,参与调控的关键基因如runx2、osteonectin、osteoprogenin等与哺乳动物的相关基因具有高度的同源性。国内将斑马鱼用于骨质疏松模型的建立。The research on zebrafish skeleton has physiological and genetic basis: like mammals, zebrafish skeleton develops from three embryonic stem cell lines, namely neural crest, somatic mesoderm and lateral plate. Studies have shown that zebrafish larvae skeleton contains cells required for bone formation and bone resorption, which is a relatively complete system. The bone formation mechanism also includes endochondral ossification and intramembranous ossification, and the process is strictly regulated by a complex mechanism including a series of transcription factors and hormones. The key genes involved in the regulation, such as runx2, osteonectin, and osteoprogenin, have a high degree of homology with the relevant genes of mammals. In China, zebrafish are used to establish osteoporosis models.
本实验采用斑马鱼模型动物，将受精后4天(4dpf)的斑马鱼幼鱼暴露于不同浓度核苷酸(31.2，62.5，125μg/mL)或2.5μg/mL阿仑膦酸钠片(阳性对照组)中，同时设置正常对照组(养鱼用水处理正常斑马鱼)和模型对照组(地塞米松处理正常斑马鱼)。28℃培养5天后，用茜素红进行染色，染色后进行拍照并统计斑马鱼前三节脊椎骨累积光密度。This experiment used zebrafish model animals. The zebrafish larvae at 4 days post fertilization (4dpf) were exposed to different concentrations of nucleotides (31.2, 62.5, 125μg/mL) or 2.5μg/mL alendronate sodium tablets (positive control group). A normal control group (normal zebrafish treated with fish water) and a model control group (normal zebrafish treated with dexamethasone) were set up at the same time. After culturing at 28℃ for 5 days, the cells were stained with alizarin red, and photos were taken after staining to count the cumulative optical density of the first three vertebrae of the zebrafish.
图1、表1和2显示，与未使用地塞米松的正常对照组相比,使用地塞
米松的模型对照组的斑马脊椎骨荧光强度显著减少，这表明，地塞米松使斑马鱼头骨骼矿化量和骨密度显著降低,成功诱导斑马鱼产生骨质疏松。与使用地塞米松的模型对照组相比，使用地塞米松，之后使用62.5，125μg/mL核苷酸处理能增加斑马鱼脊椎骨累积光密度，显著提高脊椎骨密度，改善骨质疏松，逆转地塞米松诱发的骨丢失。这表明核苷酸能够明显提高脊椎骨密度，改善骨质疏松。Figure 1, Tables 1 and 2 show that compared with the normal control group without dexamethasone, The fluorescence intensity of zebrafish vertebrae in the dexamethasone model control group was significantly reduced, indicating that dexamethasone significantly reduced the amount of mineralization and bone density of zebrafish head bones, successfully inducing osteoporosis in zebrafish. Compared with the dexamethasone model control group, dexamethasone followed by 62.5 and 125 μg/mL nucleotide treatment increased the cumulative optical density of zebrafish vertebrae, significantly increased vertebral bone density, improved osteoporosis, and reversed dexamethasone-induced bone loss. This shows that nucleotides can significantly increase vertebral bone density and improve osteoporosis.
2.2.软骨损伤修复功效评价2.2. Evaluation of cartilage damage repair efficacy
表3.软骨损伤修复功效评价实验结果(n＝8)
与模型对照组比较，*p<0.05，**p<0.01，***p<0.001Table 3. Results of cartilage damage repair efficacy evaluation experiment (n=8)
Compared with the model control group, *p<0.05, **p<0.01, ***p<0.001
与模型对照组比较，*p<0.05，**p<0.01，***p<0.001Table 3. Results of cartilage damage repair efficacy evaluation experiment (n=8)
Compared with the model control group, *p<0.05, **p<0.01, ***p<0.001
本实验采用斑马鱼模型动物，将受精后4天(4dpf)的斑马鱼幼鱼暴露于不同浓度核苷酸(31.2，62.5，125μg/mL)或1000μg/mL硫酸软骨素(阳性对照组)中，同时设置正常对照组(养鱼用水处理正常斑马鱼)和模型对照组(地塞米松处理正常斑马鱼)。28℃培养5天后，用茜素红进行染色，染色后进行拍照并统计斑马鱼软骨累积光密度。In this experiment, zebrafish model animals were used. Zebrafish larvae at 4 days post-fertilization (4dpf) were exposed to different concentrations of nucleotides (31.2, 62.5, 125μg/mL) or 1000μg/mL chondroitin sulfate (positive control group). A normal control group (normal zebrafish treated with fish water) and a model control group (normal zebrafish treated with dexamethasone) were set up at the same time. After culturing at 28℃ for 5 days, the cartilage was stained with alizarin red, and photos were taken after staining to calculate the cumulative optical density of zebrafish cartilage.
表3的结果显示，与未使用地塞米松的正常对照组相比，使用地塞米松的模型对照组的斑马脊椎骨荧光强度显著减少，这表明，地塞米松使斑马鱼头骨骼矿化量和骨密度显著降低,成功诱导斑马鱼软骨损伤。与使用地塞米松的模型对照组相比，使用地塞米松，之后使用31.2，62.5，125μg/mL核苷酸处理能增加斑马鱼软骨累积光密度，显著提高软骨荧光强度，改善软骨损伤，逆转地塞米松诱发的软骨损伤。这表明核苷酸能够明显提高软骨密度，修复软骨损伤。
The results in Table 3 show that compared with the normal control group without dexamethasone, the fluorescence intensity of zebrafish vertebrae in the model control group using dexamethasone was significantly reduced, indicating that dexamethasone significantly reduced the amount of mineralization and bone density of zebrafish head bones, and successfully induced zebrafish cartilage damage. Compared with the model control group using dexamethasone, the use of dexamethasone followed by 31.2, 62.5, and 125 μg/mL nucleotide treatment increased the cumulative optical density of zebrafish cartilage, significantly increased the fluorescence intensity of cartilage, improved cartilage damage, and reversed dexamethasone-induced cartilage damage. This shows that nucleotides can significantly increase cartilage density and repair cartilage damage.
2.3.成骨损伤修复功效评价2.3. Evaluation of osteoblastic injury repair efficacy
表4.成骨损伤修复功效评价实验结果(n＝8)
与模型对照组比较，*p<0.05，**p<0.01，***p<0.001Table 4. Results of osteoblast repair efficacy evaluation experiment (n=8)
Compared with the model control group, *p<0.05, **p<0.01, ***p<0.001
与模型对照组比较，*p<0.05，**p<0.01，***p<0.001Table 4. Results of osteoblast repair efficacy evaluation experiment (n=8)
Compared with the model control group, *p<0.05, **p<0.01, ***p<0.001
本实验采用斑马鱼模型动物，将受精后4天(4dpf)的斑马鱼幼鱼暴露于不同浓度核苷酸(31.2，62.5，125μg/mL)或5μg/mL阿仑膦酸钠(阳性对照组)中，同时设置正常对照组(养鱼用水处理正常斑马鱼)和模型对照组(地塞米松处理正常斑马鱼)。28℃培养5天后，用茜素红进行染色，染色后进行拍照并统计斑马鱼成骨累积光密度。In this experiment, zebrafish model animals were used. Zebrafish larvae at 4 days post fertilization (4dpf) were exposed to different concentrations of nucleotides (31.2, 62.5, 125μg/mL) or 5μg/mL alendronate sodium (positive control group). A normal control group (normal zebrafish treated with fish water) and a model control group (normal zebrafish treated with dexamethasone) were set up at the same time. After culturing at 28℃ for 5 days, the cells were stained with alizarin red, and photos were taken after staining to calculate the cumulative optical density of zebrafish bone formation.
表4的结果显示，与未使用地塞米松的正常对照组相比，使用地塞米松的模型对照组的斑马成骨荧光强度显著减少，这表明，地塞米松使斑马鱼头成骨密度显著降低,成功诱导斑马鱼成骨损伤。与使用地塞米松的模型对照组相比，使用地塞米松，之后使用31.2，62.5，125μg/mL核苷酸处理能增加斑马鱼成骨累积光密度，显著提高成骨密度，改善成骨损伤，逆转地塞米松诱发的成骨损伤。这表明核苷酸能显著提高成骨密度，修复成骨损伤。The results in Table 4 show that compared with the normal control group without dexamethasone, the fluorescence intensity of zebrafish osteoblasts in the model control group using dexamethasone was significantly reduced, indicating that dexamethasone significantly reduced the bone density of zebrafish heads and successfully induced zebrafish osteoblast damage. Compared with the model control group using dexamethasone, the use of dexamethasone followed by 31.2, 62.5, and 125 μg/mL nucleotide treatment increased the cumulative optical density of zebrafish osteoblasts, significantly increased the bone density, improved osteoblast damage, and reversed the dexamethasone-induced osteoblast damage. This shows that nucleotides can significantly increase bone density and repair osteoblast damage.
表2-4的结果一起表明，核苷酸能够显著提高脊椎骨和/或软骨和/或成骨钴密度，改善骨质疏松和/或修复软骨和/或成骨损伤。The results in Tables 2-4 together indicate that nucleotides can significantly increase the density of vertebral bones and/or cartilage and/or osteoblasts, improve osteoporosis and/or repair cartilage and/or osteoblast damage.
2.4.组合物软骨损伤修复功效评价2.4. Evaluation of the efficacy of the composition in repairing cartilage damage
研究了核苷酸和乳铁蛋白的组合物对修复软骨损伤，改善骨骼健康的功效。结果详见表5。The efficacy of the combination of nucleotides and lactoferrin in repairing cartilage damage and improving bone health was studied. The results are shown in Table 5.
表5.软骨损伤修复功效评价实验结果(n＝8)
与模型对照组比较，*p<0.05，**p<0.01，***p<0.001Table 5. Results of cartilage damage repair efficacy evaluation experiment (n=8)
Compared with the model control group, *p<0.05, **p<0.01, ***p<0.001
与模型对照组比较，*p<0.05，**p<0.01，***p<0.001Table 5. Results of cartilage damage repair efficacy evaluation experiment (n=8)
Compared with the model control group, *p<0.05, **p<0.01, ***p<0.001
本实验采用斑马鱼模型动物，将受精后4天(4dpf)的斑马鱼幼鱼暴露于不同浓度核苷酸和乳铁蛋白或1000μg/mL硫酸软骨素(阳性对照组)中，同时设置正常对照组(养鱼用水处理正常斑马鱼)和模型对照组(地塞米松处理正常斑马鱼)。28℃培养5天后，用茜素红进行染色，染色后进行拍照并统计斑马鱼软骨累积光密度。In this experiment, zebrafish model animals were used. Zebrafish larvae at 4 days post-fertilization (dpf) were exposed to different concentrations of nucleotides and lactoferrin or 1000 μg/mL chondroitin sulfate (positive control group). A normal control group (normal zebrafish treated with fish water) and a model control group (normal zebrafish treated with dexamethasone) were set up at the same time. After culturing at 28°C for 5 days, the cartilage was stained with alizarin red, and photos were taken after staining to calculate the cumulative optical density of zebrafish cartilage.
表5的结果显示，与未使用地塞米松的正常对照组相比，使用地塞米松的模型对照组的斑马软骨荧光强度显著减少，这表明，地塞米松使斑马鱼软骨骨密度显著降低,成功诱导斑马鱼软骨损伤。The results in Table 5 show that compared with the normal control group without dexamethasone, the fluorescence intensity of zebrafish cartilage in the model control group using dexamethasone was significantly reduced, indicating that dexamethasone significantly reduced the bone density of zebrafish cartilage and successfully induced zebrafish cartilage damage.
然而，本发明人发现，与模型对照组相比，当将核苷酸和乳铁蛋白组合使用时，能够显著提高软骨荧光强度，逆转地塞米松诱发的软骨损伤，对软骨损伤具有改善作用，并且核苷酸和乳铁蛋白之间可以存在协同作用。However, the present inventors found that, compared with the model control group, when nucleotides and lactoferrin were used in combination, the fluorescence intensity of cartilage could be significantly increased, dexamethasone-induced cartilage damage could be reversed, and cartilage damage could be improved, and there could be a synergistic effect between nucleotides and lactoferrin.
特别地，就使用的组分以及用量而言，实验例2相当于对比例1和6的组合，相对于模型对照组而言，实施例2、对比例1、6分别使得软骨荧光强
度增加了458514、153966、296322，实施例2中软骨荧光强度的增量(458514)大于对比例1和6各自的增量之和(450288)。In particular, in terms of the components and dosages used, Experimental Example 2 is equivalent to the combination of Comparative Examples 1 and 6. Compared with the model control group, Example 2, Comparative Examples 1 and 6 respectively make the cartilage fluorescence stronger. The degrees increased by 458514, 153966, and 296322. The increment of cartilage fluorescence intensity in Example 2 (458514) is greater than the sum of the increments of Comparative Examples 1 and 6 (450288).
实验例5相当于对比例2和6的组合，相对于模型对照组而言，实施例5、对比例2、6分别使得软骨荧光强度增加了611209、226275、296322，实施例5中软骨荧光强度的增量(611209)大于对比例2和6各自的增量之和(522597)。Experimental Example 5 is equivalent to the combination of Comparative Examples 2 and 6. Compared with the model control group, Example 5, Comparative Examples 2 and 6 increase the cartilage fluorescence intensity by 611209, 226275 and 296322, respectively. The increase in cartilage fluorescence intensity in Example 5 (611209) is greater than the sum of the increases in Comparative Examples 2 and 6 (522597).
2.5.组合物成骨损伤修复功效评价2.5. Evaluation of the efficacy of the composition in repairing osteoblastic damage
研究了核苷酸和乳铁蛋白的组合物对修复成骨损伤，改善骨骼健康的功效。结果详见表6。The efficacy of the combination of nucleotides and lactoferrin in repairing osteoblastic damage and improving bone health was studied. The results are shown in Table 6.
表6.成骨损伤修复功效评价实验结果(n＝8)
与模型对照组比较，*p<0.05，**p<0.01，***p<0.001Table 6. Results of osteoblast repair efficacy evaluation experiment (n=8)
Compared with the model control group, *p<0.05, **p<0.01, ***p<0.001
与模型对照组比较，*p<0.05，**p<0.01，***p<0.001Table 6. Results of osteoblast repair efficacy evaluation experiment (n=8)
Compared with the model control group, *p<0.05, **p<0.01, ***p<0.001
表6的结果显示，与未使用地塞米松的正常对照组相比，使用地塞米松的模型对照组的斑马成骨荧光强度显著减少，这表明，地塞米松使斑马鱼成骨密度显著降低,成功诱导斑马鱼成骨损伤。与模型对照组相比，各对比例
均可增加斑马鱼软骨累积光密度，说明核苷酸和乳铁蛋白这两种成分均有助于促进骨骼健康。The results in Table 6 show that compared with the normal control group without dexamethasone, the fluorescence intensity of zebrafish osteoblasts in the model control group using dexamethasone was significantly reduced, indicating that dexamethasone significantly reduced the bone density of zebrafish and successfully induced zebrafish osteoblast damage. Both can increase the cumulative optical density of zebrafish cartilage, indicating that both nucleotides and lactoferrin help promote bone health.
本发明人还发现，与模型对照组相比，当将核苷酸和乳铁蛋白两种成分组合使用时效果更加显著，能够显著提高成骨荧光强度，逆转地塞米松诱发的成骨损伤，对成骨损伤具有改善作用，并且核苷酸和乳铁蛋白之间可以存在协同作用。The inventors also found that compared with the model control group, when the two components of nucleotides and lactoferrin were used in combination, the effect was more significant, which could significantly increase the osteogenic fluorescence intensity, reverse dexamethasone-induced osteogenic damage, improve osteogenic damage, and there could be a synergistic effect between nucleotides and lactoferrin.
特别地，就使用的组分以及用量而言，实验例2相当于对比例1和6的组合，相对于模型对照组而言，实施例2、对比例1、6分别使得软骨荧光强度增加了246660、62708、148487，实施例2中软骨荧光强度的增量(246660)大于对比例1和6各自的增量之和(211195)。In particular, in terms of the components and amounts used, Experimental Example 2 is equivalent to the combination of Comparative Examples 1 and 6. Relative to the model control group, Example 2, Comparative Examples 1, and 6 increase the cartilage fluorescence intensity by 246660, 62708, and 148487, respectively. The increase in cartilage fluorescence intensity in Example 2 (246660) is greater than the sum of the increases in Comparative Examples 1 and 6 (211195).
本发明提供了关于核苷酸在促进骨骼发育的功效方面的研究，发现核苷酸能够促进骨骼生长发育和健康，改善骨密度例如改善骨质疏松，修复软骨损伤和成骨损伤。并且当将核苷酸与乳铁蛋白一起使用时效果更加显著，两种组分之间可以存在协同作用。因此，核苷酸在机体改善骨质疏松和促进骨骼发育方面的前景广阔，为未来功能性食品的开发提供了新思路。The present invention provides research on the efficacy of nucleotides in promoting bone development, and finds that nucleotides can promote bone growth and health, improve bone density, such as improving osteoporosis, and repair cartilage damage and osteogenesis damage. And when nucleotides are used together with lactoferrin, the effect is more significant, and there can be a synergistic effect between the two components. Therefore, nucleotides have broad prospects in improving osteoporosis and promoting bone development in the body, and provide new ideas for the development of functional foods in the future.
以上所述的仅是本发明的示例性实施方式。在此应当指出，对于本领域的普通技术人员来说，在不脱离本发明创造构思的前提下，还可以对本发明做出改进，但这些均属于本发明的保护范围。
The above is only an exemplary embodiment of the present invention. It should be noted that, for those skilled in the art, without departing from the inventive concept of the present invention, improvements can be made to the present invention, but these all belong to the protection scope of the present invention.
Claims (10)
- 核苷酸在促进人体或动物体的骨骼生长发育和健康、例如改善骨密度中的非治疗目的的用途，其中，所述核苷酸包括如下、或者由如下组成：The non-therapeutic use of nucleotides in promoting bone growth and health in humans or animals, such as improving bone density, wherein the nucleotides include or consist of:5’-腺苷酸(5’-AMP)或其生理学上可接受的盐、优选钠盐，优选5’-腺苷酸；5'-Adenosine monophosphate (5'-AMP) or a physiologically acceptable salt thereof, preferably a sodium salt, preferably 5'-Adenosine monophosphate;5’-胞苷酸(5’-CMP)或其生理学上可接受的盐、优选钠盐，优选5’-胞苷酸二钠；5'-Cytidylic acid (5'-CMP) or a physiologically acceptable salt thereof, preferably a sodium salt, preferably disodium 5'-cytidylic acid;5’-鸟苷酸(5’-GMP)或其生理学上可接受的盐、优选钠盐，优选5’-鸟苷酸二钠；5'-guanylic acid (5'-GMP) or a physiologically acceptable salt thereof, preferably a sodium salt, preferably disodium 5'-guanylate;5’-尿苷酸(5’-UMP)或其生理学上可接受的盐、优选钠盐，优选5’-尿苷酸二钠，和5'-Uridylic acid (5'-UMP) or a physiologically acceptable salt thereof, preferably a sodium salt, preferably disodium 5'-uridine monophosphate, and5’-肌苷酸(5’-IMP)或其生理学上可接受的盐、优选钠盐，优选5’-肌苷酸二钠。5'-inosinic acid (5'-IMP) or a physiologically acceptable salt thereof, preferably a sodium salt, preferably disodium 5'-inosinic acid.
- 如权利要求1所述的用途，其中相对于所述核苷酸的总重量，The use according to claim 1, wherein relative to the total weight of the nucleotides,5’-腺苷酸(5’-AMP)或其生理学上可接受的盐为4.0-35.0％质量、优选14.0-22.0％质量；5'-adenosine (5'-AMP) or a physiologically acceptable salt thereof is 4.0-35.0% by mass, preferably 14.0-22.0% by mass;5’-胞苷酸(5’-CMP)或其生理学上可接受的盐为20.0-70.0％质量、优选38.0-46.0％质量；5'-cytidylic acid (5'-CMP) or a physiologically acceptable salt thereof is 20.0-70.0% by mass, preferably 38.0-46.0% by mass;5’-鸟苷酸(5’-GMP)或其生理学上可接受的盐为3.0-30.0％质量、优选11.0-19.0％质量；5'-guanylic acid (5'-GMP) or a physiologically acceptable salt thereof is 3.0-30.0% by mass, preferably 11.0-19.0% by mass;5’-尿苷酸(5’-UMP)或其生理学上可接受的盐为5.0-40.0％质量、优选15.0-23.0％质量，和5'-uridine monophosphate (5'-UMP) or a physiologically acceptable salt thereof is 5.0-40.0% by mass, preferably 15.0-23.0% by mass, and5’-肌苷酸(5’-IMP)或其生理学上可接受的盐为0.1-20.0％质量、优选3.0-9.0％质量。The content of 5'-inosinic acid (5'-IMP) or a physiologically acceptable salt thereof is 0.1-20.0% by mass, preferably 3.0-9.0% by mass.
- 如权利要求1-2任一项所述的用途，其中所述促进骨骼生长发育和健康包括如下的一种或多种：改善骨质疏松、修复软骨损伤、修复成骨损伤。The use according to any one of claims 1 to 2, wherein the promotion of bone growth, development and health comprises one or more of the following: improving osteoporosis, repairing cartilage damage, and repairing osteogenesis damage.
- 营养组合物，其包括核苷酸和乳铁蛋白、优选由核苷酸和乳铁蛋白组成，其中所述核苷酸如权利要求1-2任一项中所定义。A nutritional composition comprising, preferably consisting of, nucleotides and lactoferrin, wherein the nucleotides are as defined in any one of claims 1-2.
- 如权利要求4所述的营养组合物，其中所述乳铁蛋白以如下形式提供：富含乳铁蛋白的营养成分，如富含乳铁蛋白浓缩乳清蛋白粉和/或乳铁蛋 白粉等，优选乳铁蛋白粉。The nutritional composition according to claim 4, wherein the lactoferrin is provided in the form of a lactoferrin-rich nutritional ingredient, such as a lactoferrin-rich whey protein concentrate and/or lactoferrin protein. White powder, etc., preferably lactoferrin powder.
- 如权利要求4-5任一项所述的营养组合物，其中相对于1质量份的核苷酸，乳铁蛋白的量为0.01-20质量份、优选0.02-15质量份、优选0.05-12质量份、优选0.05-10质量份、优选0.05-8质量份、优选0.05-5质量份、优选0.1-2质量份、优选0.1-0.3质量份、优选0.12-0.25质量份。The nutritional composition according to any one of claims 4 to 5, wherein the amount of lactoferrin relative to 1 part by mass of nucleotide is 0.01-20 parts by mass, preferably 0.02-15 parts by mass, preferably 0.05-12 parts by mass, preferably 0.05-10 parts by mass, preferably 0.05-8 parts by mass, preferably 0.05-5 parts by mass, preferably 0.1-2 parts by mass, preferably 0.1-0.3 parts by mass, preferably 0.12-0.25 parts by mass.
- 食品，其包括如权利要求4-6任一项所述的营养组合物，优选地其中所述食品是粉末形式或者液体形式；优选地所述食品是婴幼儿配方食品例如婴幼儿配方奶粉、婴儿辅食、营养或膳食补充剂、孕妇调制奶粉、或中老年奶粉。A food comprising the nutritional composition according to any one of claims 4 to 6, wherein the food is preferably in powder form or liquid form; preferably the food is infant formula such as infant formula milk powder, baby food, nutrition or dietary supplement, pregnant woman formula milk powder, or middle-aged and elderly milk powder.
- 如权利要求7所述的食品，其中所述营养组合物的添加量使得，相对于所述食品的总质量，所述核苷酸的总质量含量为0.0012-0.058％、优选0.0025-0.058％，所述乳铁蛋白的质量含量为0.002-1.0％、优选0.004-0.7％。The food according to claim 7, wherein the added amount of the nutritional composition is such that, relative to the total mass of the food, the total mass content of the nucleotides is 0.0012-0.058%, preferably 0.0025-0.058%, and the mass content of the lactoferrin is 0.002-1.0%, preferably 0.004-0.7%.
- 如权利要求7-8任一项所述的食品，其中相对于1质量份的核苷酸，乳铁蛋白的量为0.1-20质量份、优选0.1-10质量份、优选0.1-2质量份、优选0.1-0.3质量份、优选0.12-0.25质量份，并且所述食品中所述核苷酸的含量为0.0025-0.058％质量，所述乳铁蛋白的含量为0.004-0.7％质量。The food according to any one of claims 7 to 8, wherein the amount of lactoferrin relative to 1 part by mass of nucleotide is 0.1-20 parts by mass, preferably 0.1-10 parts by mass, preferably 0.1-2 parts by mass, preferably 0.1-0.3 parts by mass, preferably 0.12-0.25 parts by mass, and the content of the nucleotide in the food is 0.0025-0.058% by mass, and the content of the lactoferrin is 0.004-0.7% by mass.
- 如权利要求4-6任一项所述的营养组合物或者如权利要求7-9任一项所述的食品在促进人体或动物体的骨骼生长发育和健康、例如改善骨密度中的非治疗目的的用途，优选地所述促进骨骼生长发育和健康包括如下的一种或多种：改善骨质疏松、修复软骨损伤、修复成骨损伤。 The use of the nutritional composition as described in any one of claims 4 to 6 or the food as described in any one of claims 7 to 9 for non-therapeutic purposes in promoting bone growth, development and health in humans or animals, such as improving bone density, preferably, the promotion of bone growth, development and health includes one or more of the following: improving osteoporosis, repairing cartilage damage, and repairing osteogenesis damage.
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