CA3183855A1 - Nutrient composition, food including the same and use of the nutrient composition - Google Patents
Nutrient composition, food including the same and use of the nutrient compositionInfo
- Publication number
- CA3183855A1 CA3183855A1 CA3183855A CA3183855A CA3183855A1 CA 3183855 A1 CA3183855 A1 CA 3183855A1 CA 3183855 A CA3183855 A CA 3183855A CA 3183855 A CA3183855 A CA 3183855A CA 3183855 A1 CA3183855 A1 CA 3183855A1
- Authority
- CA
- Canada
- Prior art keywords
- milk
- taurine
- milk fat
- fat globule
- globule membrane
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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Classifications
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- 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
- A23C9/20—Dietetic milk products not covered by groups A23C9/12 - A23C9/18
- A23C9/203—Dietetic milk products not covered by groups A23C9/12 - A23C9/18 containing bifidus-active substances, e.g. lactulose; containing oligosaccharides
-
- 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
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- 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
- A23C9/1528—Fatty acids; Mono- or diglycerides; Petroleum jelly; Paraffine; Phospholipids; Derivatives thereof
-
- 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
- A23L33/115—Fatty acids or derivatives thereof; Fats or oils
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- 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
- A23L33/125—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives containing carbohydrate syrups; containing sugars; containing sugar alcohols; containing starch hydrolysates
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- 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
- A23L33/175—Amino acids
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- 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
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Abstract
The invention relates to a nutrient composition, a food including the same and use of the nutrient composition. The nutrition composition includes: human milk oligosaccharide, preferably neutral fucosylated human milk oligosaccharide, which is preferably one or more selected from the group consisting of. 2'-fucosyl lactose, 3'-fucosyl lactose, lacto-N-fucopentaose I, lacto-N-difucohexaose I , lacto-N-difucohexaose II, preferably 2'-fucosyl lactose (2'-FL); milk fat globule membrane;
and taurine. The nutritional composition can improve the brain development and intelligence of babies, infants and young children, especially promote neurodevelopment such as neuron maturation, synaptogenesis and myelination.
and taurine. The nutritional composition can improve the brain development and intelligence of babies, infants and young children, especially promote neurodevelopment such as neuron maturation, synaptogenesis and myelination.
Description
NUTRIENT COMPOSITION, FOOD INCLUDING THE SAME AND USE
OF THE NUTRIENT COMPOSITION
Field of the Invention The present invention generally relates to the field of food. Specifically, the present invention relates to a nutrient composition for improving the brain development and intelligence of infants and young children, especially promoting neurodevelopment such as neuron maturation, synaptogenesis and myelination etc., a food containing the nutrient composition, and use of the nutrient composition. More specifically, the present invention relates to a nutrient composition comprising human milk oligosaccharide (for example neurtral fucosylated human milk oligosaccharide (HMO) selected from the group consisting of 2'-fucosyl lactose (2'-FL), 3'-fucosyl lactose (3'-FL), lacto-N-fucopentaose I (LNFP I), lacto-N-difucohexaose I
(LNDFH
I), and lacto-N-difucohexaose II (LNDFH II), for example 2'-fucosyl lactose (2'-FL)), milk fat globule membrane, and taurine; food comprising the nutrient composition, and the use of said nutrient composition for non-curing purposes (i.e., non-medical purpose) of improving the brain development and intelligence of infants and young children, especially promoting the neurodevelopment of infants and young children.
Background of the Invention Oligodendrocyte precursor cells (OPCs) were first discovered by Raff, and Miller et al. in 1993, and have been intensively studied. Central nervous systems, both under development and mature, contain oligodendroglia precursor cells. Myelin formed cells in the central nervous system originates from oligodendroglia precursor cells.
The types of mylin protein expressed by oligodendrocytes, such as myelin-associated glycopeptides (MAGs) and myelin binding proteins (MBPs), correlate to their phase of maturation. Myelinating OLs express MAG, with the expression of MAG gradually increasing during the maturation of OLs. MAG is a sialic acid binding immunoglobulin-like lectin. Although MAG represents only a small Date Regue/Date Received 2022-12-12 proportion of the total protein content of myelin sheaths, it is expressed mainly in the periaxonal regions of the myelin sheaths. It seems to play an important role in oligodendrocyte- axon interaction and mediates bidirectional signalling axons and OLs, in order to support the formation of the myelin sheaths. MBP is strongly expressed in mature myelinating OLs, and is one of the major components of myelin sheaths. MBP seems to have an active role in the formation and compaction of myelin sheaths. Indeed, MBP is polymerizing and forming a cohesive mesh-like protein network, which is essential for saltatory current.
Brain development is influenced by genetic and environmental factors. Amongst the latter, maternal and early-life nutrition play a key role in the process of neurodevelopment such as neuron maturation, synaptogenesis and myelination.
Myelination is the process by which the oligodendrocyte (OL) in the central nervous system (CNS) form a myelin sheath around axons, which is critical for proper brain connectivity. In humans, myelination starts at mid-gestation, peaks during the first years of life. Environmental factors might influence myelination during human brain development. Specifically, different nutients exhibit different influence on myelination, suggesting that early-life nutrition might be of importance for the regulation of myelination.
During development of central nervous system, oligodendrocyte precursor cells (OPCs) migrate from within the cortex, and will generate the adult population of oligodendrocytes (OLs). After mitosis, OPCs differentiate into myelinating OLs.
These OLs extend numberous processes to establish contacts with axons from different neurons to initiate myelination, which process enhances neuronal connectivity and supports the maturation of emerging cognitive function.
In the central nervous system, each step during myelination, including proliferation of OPCs, differentiation and maturation of OPCs into myelinating OLs, as well as myelin sheath formation is highly regulated by extrinsic and intrinsic factors.
OF THE NUTRIENT COMPOSITION
Field of the Invention The present invention generally relates to the field of food. Specifically, the present invention relates to a nutrient composition for improving the brain development and intelligence of infants and young children, especially promoting neurodevelopment such as neuron maturation, synaptogenesis and myelination etc., a food containing the nutrient composition, and use of the nutrient composition. More specifically, the present invention relates to a nutrient composition comprising human milk oligosaccharide (for example neurtral fucosylated human milk oligosaccharide (HMO) selected from the group consisting of 2'-fucosyl lactose (2'-FL), 3'-fucosyl lactose (3'-FL), lacto-N-fucopentaose I (LNFP I), lacto-N-difucohexaose I
(LNDFH
I), and lacto-N-difucohexaose II (LNDFH II), for example 2'-fucosyl lactose (2'-FL)), milk fat globule membrane, and taurine; food comprising the nutrient composition, and the use of said nutrient composition for non-curing purposes (i.e., non-medical purpose) of improving the brain development and intelligence of infants and young children, especially promoting the neurodevelopment of infants and young children.
Background of the Invention Oligodendrocyte precursor cells (OPCs) were first discovered by Raff, and Miller et al. in 1993, and have been intensively studied. Central nervous systems, both under development and mature, contain oligodendroglia precursor cells. Myelin formed cells in the central nervous system originates from oligodendroglia precursor cells.
The types of mylin protein expressed by oligodendrocytes, such as myelin-associated glycopeptides (MAGs) and myelin binding proteins (MBPs), correlate to their phase of maturation. Myelinating OLs express MAG, with the expression of MAG gradually increasing during the maturation of OLs. MAG is a sialic acid binding immunoglobulin-like lectin. Although MAG represents only a small Date Regue/Date Received 2022-12-12 proportion of the total protein content of myelin sheaths, it is expressed mainly in the periaxonal regions of the myelin sheaths. It seems to play an important role in oligodendrocyte- axon interaction and mediates bidirectional signalling axons and OLs, in order to support the formation of the myelin sheaths. MBP is strongly expressed in mature myelinating OLs, and is one of the major components of myelin sheaths. MBP seems to have an active role in the formation and compaction of myelin sheaths. Indeed, MBP is polymerizing and forming a cohesive mesh-like protein network, which is essential for saltatory current.
Brain development is influenced by genetic and environmental factors. Amongst the latter, maternal and early-life nutrition play a key role in the process of neurodevelopment such as neuron maturation, synaptogenesis and myelination.
Myelination is the process by which the oligodendrocyte (OL) in the central nervous system (CNS) form a myelin sheath around axons, which is critical for proper brain connectivity. In humans, myelination starts at mid-gestation, peaks during the first years of life. Environmental factors might influence myelination during human brain development. Specifically, different nutients exhibit different influence on myelination, suggesting that early-life nutrition might be of importance for the regulation of myelination.
During development of central nervous system, oligodendrocyte precursor cells (OPCs) migrate from within the cortex, and will generate the adult population of oligodendrocytes (OLs). After mitosis, OPCs differentiate into myelinating OLs.
These OLs extend numberous processes to establish contacts with axons from different neurons to initiate myelination, which process enhances neuronal connectivity and supports the maturation of emerging cognitive function.
In the central nervous system, each step during myelination, including proliferation of OPCs, differentiation and maturation of OPCs into myelinating OLs, as well as myelin sheath formation is highly regulated by extrinsic and intrinsic factors.
2 Date Regue/Date Received 2022-12-12 Particularly, various nutrients show different influences on myelination, suggesting that early-life nutrition might be of importance for the regulation of myelination.
Therefore, identification of myelination-supporting early-life nutrition factors is of critical importance for optimal brain and cognition development.
There is a need for providing a composition which enables improving the brain development and intelligence of infants and young children, especially promoting neurodevelopment such as neuron maturation, synaptogenesis and myelination.
Summary of the Invention One object of the present incention is to provide a composition which enables improving the brain development and intelligence of infants and young children, especially promoting neurodevelopment such as neuron maturation, synaptogenesis and myelination.
Another object of the present invention is to provide a food containing the nutrient composition.
Another object of the present invention is to provide a use of said nutrient composition or food for non-curing purposes (i.e., non-medical purpose) of improving the brain development and intelligence of infants and young children, especially promoting neurodevelopment such as neuron maturation, synaptogenesis and myelination, in particular promoting the oligodendrocyte precursor cell proliferation, maturation, and differentiation into oligodendrocytes and/or myelination of oligodendrocytes.
The inventors have conducted studies and discovered that neurodevelopment such as neuron maturation, synaptogenesis and myelination can be significantly promoted and brain development and intelligence can be improved, by the use of human milk oligosaccharide (for example neurtral fucosylated human milk oligosaccharide
Therefore, identification of myelination-supporting early-life nutrition factors is of critical importance for optimal brain and cognition development.
There is a need for providing a composition which enables improving the brain development and intelligence of infants and young children, especially promoting neurodevelopment such as neuron maturation, synaptogenesis and myelination.
Summary of the Invention One object of the present incention is to provide a composition which enables improving the brain development and intelligence of infants and young children, especially promoting neurodevelopment such as neuron maturation, synaptogenesis and myelination.
Another object of the present invention is to provide a food containing the nutrient composition.
Another object of the present invention is to provide a use of said nutrient composition or food for non-curing purposes (i.e., non-medical purpose) of improving the brain development and intelligence of infants and young children, especially promoting neurodevelopment such as neuron maturation, synaptogenesis and myelination, in particular promoting the oligodendrocyte precursor cell proliferation, maturation, and differentiation into oligodendrocytes and/or myelination of oligodendrocytes.
The inventors have conducted studies and discovered that neurodevelopment such as neuron maturation, synaptogenesis and myelination can be significantly promoted and brain development and intelligence can be improved, by the use of human milk oligosaccharide (for example neurtral fucosylated human milk oligosaccharide
3 Date Regue/Date Received 2022-12-12 (HMO) selected from the group consisting of 2'-fucosyl lactose (2'-FL), 3'-fucosyl lactose (3'-FL), lacto-N-fucopentaose I (LNFP I), lacto-N-difucohexaose I
(LNDFH
I), and lacto-N-difucohexaose II (LNDFH II), for example 2'-fucosyl lactose (2'-FL)), milk fat globule membrane, and taurine in combination. Particularly, the inventors have discovered that human milk oligosaccharide (for example neurtral fucosylated human milk oligosaccharide (HMO) selected from the group consisting of 2'-fucosyl lactose (2'-FL), 3'-fucosyl lactose (3'-FL), lacto-N-fucopentaose I
(LNFP I), lacto-N-difucohexaose I (LNDFH I), and lacto-N-difucohexaose II
(LNDFH II), for example 2'-fucosyl lactose (2'-FL)), milk fat globule membrane, and taurine can synergistically promote neurodevelopment such as neuron maturation, synaptogenesis and myelination, in particular can synergistically promote OPC proliferation, maturation and differentiation into mature OL, and/or OL myelination characteristics, and synergistically promote brain development of organics and improvement in memorization.
Particularly, the present invention is realized by:
1. A nutrient composition comprising:
- human milk oligosaccharide (HMO), preferably neurtral fucosylated human milk oligosaccharide (HMO), preferably one or more selected from the group consisting of 2'-fucosyl lactose (2'-FL), 3'-fucosyl lactose (3'-FL), lacto-N-fucopentaose I
(LNFP I), lacto-N-difucohexaose I (LNDFH I), and lacto-N-difucohexaose II
(LNDFH II), preferably 2'-fucosyl lactose;
- milk fat globule membrane; and - taurine.
2. The nutrient composition of item 1, consisting of the human milk oligosaccharide, the milk fat globule membrane, and the taurine.
3. The nutrient composition of either of items 1 and 2, wherein the human milk oligosaccharide is provided in a form of natural origin, and/or synthetic origin,
(LNDFH
I), and lacto-N-difucohexaose II (LNDFH II), for example 2'-fucosyl lactose (2'-FL)), milk fat globule membrane, and taurine in combination. Particularly, the inventors have discovered that human milk oligosaccharide (for example neurtral fucosylated human milk oligosaccharide (HMO) selected from the group consisting of 2'-fucosyl lactose (2'-FL), 3'-fucosyl lactose (3'-FL), lacto-N-fucopentaose I
(LNFP I), lacto-N-difucohexaose I (LNDFH I), and lacto-N-difucohexaose II
(LNDFH II), for example 2'-fucosyl lactose (2'-FL)), milk fat globule membrane, and taurine can synergistically promote neurodevelopment such as neuron maturation, synaptogenesis and myelination, in particular can synergistically promote OPC proliferation, maturation and differentiation into mature OL, and/or OL myelination characteristics, and synergistically promote brain development of organics and improvement in memorization.
Particularly, the present invention is realized by:
1. A nutrient composition comprising:
- human milk oligosaccharide (HMO), preferably neurtral fucosylated human milk oligosaccharide (HMO), preferably one or more selected from the group consisting of 2'-fucosyl lactose (2'-FL), 3'-fucosyl lactose (3'-FL), lacto-N-fucopentaose I
(LNFP I), lacto-N-difucohexaose I (LNDFH I), and lacto-N-difucohexaose II
(LNDFH II), preferably 2'-fucosyl lactose;
- milk fat globule membrane; and - taurine.
2. The nutrient composition of item 1, consisting of the human milk oligosaccharide, the milk fat globule membrane, and the taurine.
3. The nutrient composition of either of items 1 and 2, wherein the human milk oligosaccharide is provided in a form of natural origin, and/or synthetic origin,
4 Date Regue/Date Received 2022-12-12 and/or bacterial fermentation origin.
4. The nutrient composition of any one of items 1 to 3, wherein:
the milk fat globule membrane is cow and/or sheep milk-origin phospholipid;
and/or the milk fat globule membrane is provided in the form of a protein powder containing milk fat globule membrane, said protein powder containing milk fat globule membrane preferably having a milk fat globule membrane content of 6-25%
by weight; and/or of a cow milk-origin phospholipid, said cow milk-origin phospholipid preferably having a milk fat globule membrane content of 9-60% by weight; and/or the milk fat globule membrane at least contains sphingophospholipid and phosphatidylcholine, and optionally further contains phosphatidylserine and/or phosphatidylethanolamine, wherein the sphingophospholipid represents 10% by weight or more of the total milk fat globule membrane, and the phosphatidylcholine represents 15% by weight or more of the total milk fat globule membrane.
4. The nutrient composition of any one of items 1 to 3, wherein:
the milk fat globule membrane is cow and/or sheep milk-origin phospholipid;
and/or the milk fat globule membrane is provided in the form of a protein powder containing milk fat globule membrane, said protein powder containing milk fat globule membrane preferably having a milk fat globule membrane content of 6-25%
by weight; and/or of a cow milk-origin phospholipid, said cow milk-origin phospholipid preferably having a milk fat globule membrane content of 9-60% by weight; and/or the milk fat globule membrane at least contains sphingophospholipid and phosphatidylcholine, and optionally further contains phosphatidylserine and/or phosphatidylethanolamine, wherein the sphingophospholipid represents 10% by weight or more of the total milk fat globule membrane, and the phosphatidylcholine represents 15% by weight or more of the total milk fat globule membrane.
5. The nutrient composition of any one of items 1 to 4, wherein the taurine is provided in the form of monomeric taurine.
6. The nutrient composition of any one of items 1 to 5, wherein:
the weight ratio of the human milk oligosaccharide to the milk fat globule membrane is 1:0.01-500, preferably 1:0.02-100, preferably 1:0.05-50, preferably 1:0.1-10, preferably 1:0.15-6; and the weight ratio of the human milk oligosaccharide to the taurine is 1:0.0005-10, preferably 1:0.001-5, preferably 1: 0.005-1, preferably 1:0.01-0.5;
preferably, the weight ratio of the human milk oligosaccharide to the milk fat globule membrane to the taurine is 1:0.01-500:0.0005-10, preferably 1:0.02-100:0.0005-10, preferably 1:0.05-50:0.001-5, preferably 1:0.1-10:0.005-1, preferably 1:0.15-6:0.01-0.5.
Date Regue/Date Received 2022-12-12
the weight ratio of the human milk oligosaccharide to the milk fat globule membrane is 1:0.01-500, preferably 1:0.02-100, preferably 1:0.05-50, preferably 1:0.1-10, preferably 1:0.15-6; and the weight ratio of the human milk oligosaccharide to the taurine is 1:0.0005-10, preferably 1:0.001-5, preferably 1: 0.005-1, preferably 1:0.01-0.5;
preferably, the weight ratio of the human milk oligosaccharide to the milk fat globule membrane to the taurine is 1:0.01-500:0.0005-10, preferably 1:0.02-100:0.0005-10, preferably 1:0.05-50:0.001-5, preferably 1:0.1-10:0.005-1, preferably 1:0.15-6:0.01-0.5.
Date Regue/Date Received 2022-12-12
7. Food comprising the nutrient composition of any one of items 1 to 6.
8. The food of item 7, wherein said food is in the form of powder or liquid.
9. The food of any one of items 7 to 8, which is a formula food for infants and young children, for example a formula food for infants, a formula food for more grown-up infants, a formula food for young children, for example a formula milk powder for infants and young children, for example a foimula milk powder for infants, and a formula milk powder for young children; a complementary food for infants;
nutritional or dietary supplements; or a formulated milk powder for pregnant women.
nutritional or dietary supplements; or a formulated milk powder for pregnant women.
10. The food of any one of items 7 to 9, wherein the amount of said nutrient composition added, relative to the total weight of said food, is such that:
the human milk oligosaccharide is at a content by weight of at least 0.01%, preferably at least 0.05%, preferably at least 0.1% and at most 10.0%, preferably at most 5.0%, preferably at most 1.0%, the milk fat globule membrane is at a content by weight of at least 0.01%, preferably at least 0.05%, preferably at least 0.1% and at most 5.0%, preferably at most 1.0%, preferably at most 0.6%, and the taurine is at a content by weight of at least 0.001%, preferably at least 0.005%, preferably at least 0.01% and at most 1.0%, preferably at most 0.5%, preferably at most 0.1%.
the human milk oligosaccharide is at a content by weight of at least 0.01%, preferably at least 0.05%, preferably at least 0.1% and at most 10.0%, preferably at most 5.0%, preferably at most 1.0%, the milk fat globule membrane is at a content by weight of at least 0.01%, preferably at least 0.05%, preferably at least 0.1% and at most 5.0%, preferably at most 1.0%, preferably at most 0.6%, and the taurine is at a content by weight of at least 0.001%, preferably at least 0.005%, preferably at least 0.01% and at most 1.0%, preferably at most 0.5%, preferably at most 0.1%.
11. Use of the nutrient composition of any one of items 1 to 6 or the food of any one of items 7 to 10 for non-curing purposes of improving the brain development and intelligence of infants and young children, especially promoting neurodevelopment such as neuron maturation, synaptogenesis and myelination, in particular promoting the the oligodendrocyte precursor cell proliferation, maturation, and differentiation into oligodendrocytes and/or myelination of oligodendrocytes.
Date Recue/Date Received 2022-12-12 Detailed Description of the Invention Unless otherwise specified, the scientific and technical terms in the present description have the same meaning as that generally understood by those skilled in the art. However, in case of conflict, the definition in the present description prevail.
As used herein, the following terms have the meaning below.
The term "infant" refers to a 0-6 month-aged person.
The term "more grown-up infant" refers to a 6-12 month-aged person.
The term "young children" refers to a 12-36 month-aged person.
The term "infant and young child" refers to a 0-36 month-aged person.
The term "formula food for infants and young children" used herein encompasses formula food for infants, formula food for more grown-up infants, and formula food for young children. Generally, formula food for infants serves as an alternative for human milk from a birth of an infant, formula food for more grown-up infants serves as an alternative for human milk from 6 to 12 months after the birth of an infant, and formula food for young children serves as an alternative for human milk from
Date Recue/Date Received 2022-12-12 Detailed Description of the Invention Unless otherwise specified, the scientific and technical terms in the present description have the same meaning as that generally understood by those skilled in the art. However, in case of conflict, the definition in the present description prevail.
As used herein, the following terms have the meaning below.
The term "infant" refers to a 0-6 month-aged person.
The term "more grown-up infant" refers to a 6-12 month-aged person.
The term "young children" refers to a 12-36 month-aged person.
The term "infant and young child" refers to a 0-36 month-aged person.
The term "formula food for infants and young children" used herein encompasses formula food for infants, formula food for more grown-up infants, and formula food for young children. Generally, formula food for infants serves as an alternative for human milk from a birth of an infant, formula food for more grown-up infants serves as an alternative for human milk from 6 to 12 months after the birth of an infant, and formula food for young children serves as an alternative for human milk from
12 to 36 months after the birth of an infant.
The term "formula food for infants" refers to a liquid-state or powder-like product produced, processed and made only via physical methods, with milk and lactoprotein (milk protein) products or soybean and soybean protein products as major raw materials, and with addition of a proper amount of vitamin(s), minerals, and/or other constituent(s). It is suitable for ordinary infants, with its energy and nutrients being Date Recue/Date Received 2022-12-12 able to meet an ordinary (normal) nutritional requirement for a 0-6 month-aged infant.
The term "formula food for more grown-up infants" refers to a liquid-state or powder-like product produced, processed and made only via physical methods, with milk and lactoprotein (milk protein) products or soybean and soybean protein products as major raw materials, and with addition of a proper amount of vitamin(s), minerals, and/or other constituent(s). It is suitable for more grown-up infants, with its energy and nutrients being able to meet part of a nutritional requirement for a 6-.. 12 month-age ordinary (normal) more grown-up infants.
The term "formula food for young children" refers to a liquid-state or powder-like product produced, processed and made only via physical methods, with milk and lactoprotein (milk protein) products or soybean and soybean protein products as major raw materials, and with addition of a proper amount of vitamin(s), minerals, and/or other constituent(s). It is suitable for young children, with its energy and nutrients being able to meet part of a nutritional requirement for a 12-36 month-age ordinary (normal) young children.
The term "human milk" should be understood as mother's human milk or colostrum.
The term "infants or young children fed entirely with human milk" has common meaning and refers to an infant whose majority of nutrition and/or energy originates from human milk.
The term "infants/more grown-up infants/young children fed mainly with formula food for infants and young children" has common meaning and refers to an infant or young children whose nutritional source of nutrition and/or energy mainly originates from formula food for infants and young children and milk or growing up milk for more grown-up infants, which are produced, processed and made only via physical Date Regue/Date Received 2022-12-12 methods. The term "mainly / majority of' refers to at least 50%, for example at least 75% of those nutrition and/or energy.
In addition, in the context of the present invention, the term "contain(s) /
containing / contained", "include(s) / including / included" or "comprise(s) / comprising /
comprised" do not exclude other elements possible. The composition of the present invention (including embodiments described herein) may comprise, consist of, or consist essentially of the following elements: the basic elements and necessary restraints of the present invention described herein, and any other or optional constituents, components or restraints described herein or as may be desired.
Individuals described in the present invention applies to ordinary human beings, and may be infants and/or more grown-up infants, and/or young children, and/or children, and/or adolescents (the youth/young people), and/or middle-aged people, and/or old people, more preferably, human infants and young children fed with formula food.
All percentages are percentages by weight, unless indicated otherwise.
The present incention will now be described in greater detail. It should be noted that various aspects, features, embodiments, examples and anvantages thereof described in the present application are compatible and/or can be combined together.
The present invention relates to a composition for improving the brain development and intelligence of infants and young children, especially promoting neurodevelopment such as neuron maturation, synaptogenesis and myelination, a food containing the nutrient composition, as well as a use of said nutrient composition for non-curing purposes of improving the brain development and intelligence of infants and young children, especially promoting neurodevelopment such as neuron maturation, synaptogenesis and myelination, in particular promoting oligodendrocyte precursor cell proliferation, maturation, and differentiation into Date Regue/Date Received 2022-12-12 oligodendrocytes and/or myelination of oligodendrocytes.
The present invention will be described in detail hereinbelow.
Nutrient Composition In one aspect, the present invention provides a nutrient composition comprising:
- human milk oligosaccharide (HMO), preferably neurtral fucosylated human milk oligosaccharide (HMO), preferably one or more selected from the group consisting of 2'-fucosyl lactose (2'-FL), 3'-fucosyl lactose (3'-FL), lacto-N-fucopentaose I
(LNFP I), lacto-N-difucohexaose I (LNDFH I), and lacto-N-difucohexaose II
(LNDFH II), preferably 2'-fucosyl lactose;
- milk fat globule membrane; and - taurine.
Human milk oligosaccharide HMO is a general term for oligosaccharides with a degree of polymerization of >3 naturally present in human milk . It is based on a lactose molecule with its ends being modified with 5 classes of monoers, i.e.
glucose (Glc), galactose (Gal), N-acetyl glucasamine (G1cNAc), fucose (Fuc), and N-acetyl neuraminic acid (Neu5Ac). HMO comprises 3 to 32 monosaccharides per molecule, these monosaccharides being connected by various glycosidic bonds, constituting the versatility and complexity of HMO. Based on its core structure, HMO may be classified into three types, i.e. neutral fucosylated HMO (containing fucose at its end), neutral non-fucosylated HMO (containing N-acetyl glucasamine at its end), and acidic or salylated HMO (containing sialic acid at its end), representing a proportion of 35-50%, 42-55%, and 12-14% in human milk oligosaccharide, respectively.
2'-fucosyl lactose (2'-FL) is a neutral trisaccharide consisting of an L-fucose, a D-galactose and a D-glucose unit, wherein the monosaccharide L-fucose is connected to the disaccharide D-lactose via an a(1¨>2) bond. It has a molecular fomula of Date Regue/Date Received 2022-12-12 C181431015, a molecular weight of 488.439 g/mol, and a molecular structure of ______________________________________ 0 1 HO
OH OH
_______________________________________ H OH
H) OH \
OH
3'-fucosyl lactose (3'-FL) is a neutral trisaccharide consisting of an L-fucose, a D-galactose and a D-glucose unit, wherein the monosaccharide L-fucose is connected to the disaccharide D-glucose via an a(1¨>3) bond. It has a molecular formula of C181-132015, a molecular weight of 488.44 g/mol, and a molecular structure of .3 0 OH
OH
______________________________________ 0 J __ 0 HO
OH
OH
OH OH
Lacto-N-fucopentaose I (LNFP I) is a neutral pentaose consisting of an L-fucose, a D-glucose, 2 molecules of D-galactose, and an N-acetyl glucasamine unit, wherein the monosaccharide L-fucose is connected to the D-glucose via an a(1¨>3) bond.
It has a molecular formula of C32H55N025, a molecular weight of 853.77 g/mol, and a molecular structure of OH ai Date Recue/Date Received 2022-12-12 Lacto-N-difucohexaose I (LNDFH I) is a neutral hexaose consisting of 2 molecules of L-fucose, a D-glucose, a D-galactose, and an N-acetyl glucasamine unit, wherein the monosaccharide L-fucose is connected to the D-galactose and the N-acetyl glucasamine via an a(1¨>2) bond and an a(1¨>4) bond, respectively. It has a molecular formula of C381-165N029, a molecular weight of 999.91 g/mol, and a molecular structure of HONõ
OH
"pH
1404,0,61 OH
''.9'seLe'L'410 HO
'.51 OH
Lacto-N-difucohexaose II (LNDFH II) is a neutral hexaose consisting of 2 molecules 10 of L-fucose, a D-glucose, a D-galactose, and an N-acetyl glucasamine unit, wherein the monosaccharide L-fucose is connected to the D-glucose and the N-acetyl glucasamine via an a(1¨>3) bond and an a(1¨>4) bond, respectively. It has a molecular formula of C38H65N029, a molecular weight of 999.91 g/mol, and a molecular structure of HO
OH
AH
H
OH
fle.C?Nd' OH
NOV
HO
Date Recue/Date Received 2022-12-12 Sphingophospholipid, a sphingolipid constituted by attaching choline phosphate (or ethanolamine phosphate) on a C-1 hydroxyl of ceramide, has a molecular structure of:
H, OH 0 s II
''''s= e 01.-0.....N.,--NH H 0' 1 N' Phosphatidylethanolamine, 1,2- dip almitoyl- SN-glycerol-3 -pho sphoryl ethanolamine, has a molecular structure of:
0 112"i R24Ø...1H Rt. Re tidy add residue 114:40-CH2CHINH2 ' Taurine, i.e. 2-amino ethanesulfonic acid, has a molecular formula of C2H7NO3S, and a molecular weight of 125.15.
The inventors have surprisingly discovered that when human milk oligosaccharide (HMO) (preferably a neurtral fucosylated human milk oligosaccharide selected from the group consisting of 2'-fucosyl lactose (2'-FL), 3 '-fucosyl lactose (3' -FL), lacto-N-fucopentaose I (LNFP I), lacto-N-difucohexaose I (LNDFH I), and lacto-N-difucohexaose II (LNDFH II), preferably 2'-fucosyl lactose (2'-FL)), milk fat globule membrane, and taurine are used in combination, they can synergistically promote neurodevelopment such as neuron maturation, synaptogenesis and myelination, in particular they can synergistically promote OPC proliferation, maturation and differentiation into mature OL, and/or OL myelination characteristics.
In one embodiment, said nutrient composition consists of: the human milk oligosaccharide (HMO), preferably neurtral fucosylated human milk oligosaccharide (HMO), preferably one or more selected from the group consisting
The term "formula food for infants" refers to a liquid-state or powder-like product produced, processed and made only via physical methods, with milk and lactoprotein (milk protein) products or soybean and soybean protein products as major raw materials, and with addition of a proper amount of vitamin(s), minerals, and/or other constituent(s). It is suitable for ordinary infants, with its energy and nutrients being Date Recue/Date Received 2022-12-12 able to meet an ordinary (normal) nutritional requirement for a 0-6 month-aged infant.
The term "formula food for more grown-up infants" refers to a liquid-state or powder-like product produced, processed and made only via physical methods, with milk and lactoprotein (milk protein) products or soybean and soybean protein products as major raw materials, and with addition of a proper amount of vitamin(s), minerals, and/or other constituent(s). It is suitable for more grown-up infants, with its energy and nutrients being able to meet part of a nutritional requirement for a 6-.. 12 month-age ordinary (normal) more grown-up infants.
The term "formula food for young children" refers to a liquid-state or powder-like product produced, processed and made only via physical methods, with milk and lactoprotein (milk protein) products or soybean and soybean protein products as major raw materials, and with addition of a proper amount of vitamin(s), minerals, and/or other constituent(s). It is suitable for young children, with its energy and nutrients being able to meet part of a nutritional requirement for a 12-36 month-age ordinary (normal) young children.
The term "human milk" should be understood as mother's human milk or colostrum.
The term "infants or young children fed entirely with human milk" has common meaning and refers to an infant whose majority of nutrition and/or energy originates from human milk.
The term "infants/more grown-up infants/young children fed mainly with formula food for infants and young children" has common meaning and refers to an infant or young children whose nutritional source of nutrition and/or energy mainly originates from formula food for infants and young children and milk or growing up milk for more grown-up infants, which are produced, processed and made only via physical Date Regue/Date Received 2022-12-12 methods. The term "mainly / majority of' refers to at least 50%, for example at least 75% of those nutrition and/or energy.
In addition, in the context of the present invention, the term "contain(s) /
containing / contained", "include(s) / including / included" or "comprise(s) / comprising /
comprised" do not exclude other elements possible. The composition of the present invention (including embodiments described herein) may comprise, consist of, or consist essentially of the following elements: the basic elements and necessary restraints of the present invention described herein, and any other or optional constituents, components or restraints described herein or as may be desired.
Individuals described in the present invention applies to ordinary human beings, and may be infants and/or more grown-up infants, and/or young children, and/or children, and/or adolescents (the youth/young people), and/or middle-aged people, and/or old people, more preferably, human infants and young children fed with formula food.
All percentages are percentages by weight, unless indicated otherwise.
The present incention will now be described in greater detail. It should be noted that various aspects, features, embodiments, examples and anvantages thereof described in the present application are compatible and/or can be combined together.
The present invention relates to a composition for improving the brain development and intelligence of infants and young children, especially promoting neurodevelopment such as neuron maturation, synaptogenesis and myelination, a food containing the nutrient composition, as well as a use of said nutrient composition for non-curing purposes of improving the brain development and intelligence of infants and young children, especially promoting neurodevelopment such as neuron maturation, synaptogenesis and myelination, in particular promoting oligodendrocyte precursor cell proliferation, maturation, and differentiation into Date Regue/Date Received 2022-12-12 oligodendrocytes and/or myelination of oligodendrocytes.
The present invention will be described in detail hereinbelow.
Nutrient Composition In one aspect, the present invention provides a nutrient composition comprising:
- human milk oligosaccharide (HMO), preferably neurtral fucosylated human milk oligosaccharide (HMO), preferably one or more selected from the group consisting of 2'-fucosyl lactose (2'-FL), 3'-fucosyl lactose (3'-FL), lacto-N-fucopentaose I
(LNFP I), lacto-N-difucohexaose I (LNDFH I), and lacto-N-difucohexaose II
(LNDFH II), preferably 2'-fucosyl lactose;
- milk fat globule membrane; and - taurine.
Human milk oligosaccharide HMO is a general term for oligosaccharides with a degree of polymerization of >3 naturally present in human milk . It is based on a lactose molecule with its ends being modified with 5 classes of monoers, i.e.
glucose (Glc), galactose (Gal), N-acetyl glucasamine (G1cNAc), fucose (Fuc), and N-acetyl neuraminic acid (Neu5Ac). HMO comprises 3 to 32 monosaccharides per molecule, these monosaccharides being connected by various glycosidic bonds, constituting the versatility and complexity of HMO. Based on its core structure, HMO may be classified into three types, i.e. neutral fucosylated HMO (containing fucose at its end), neutral non-fucosylated HMO (containing N-acetyl glucasamine at its end), and acidic or salylated HMO (containing sialic acid at its end), representing a proportion of 35-50%, 42-55%, and 12-14% in human milk oligosaccharide, respectively.
2'-fucosyl lactose (2'-FL) is a neutral trisaccharide consisting of an L-fucose, a D-galactose and a D-glucose unit, wherein the monosaccharide L-fucose is connected to the disaccharide D-lactose via an a(1¨>2) bond. It has a molecular fomula of Date Regue/Date Received 2022-12-12 C181431015, a molecular weight of 488.439 g/mol, and a molecular structure of ______________________________________ 0 1 HO
OH OH
_______________________________________ H OH
H) OH \
OH
3'-fucosyl lactose (3'-FL) is a neutral trisaccharide consisting of an L-fucose, a D-galactose and a D-glucose unit, wherein the monosaccharide L-fucose is connected to the disaccharide D-glucose via an a(1¨>3) bond. It has a molecular formula of C181-132015, a molecular weight of 488.44 g/mol, and a molecular structure of .3 0 OH
OH
______________________________________ 0 J __ 0 HO
OH
OH
OH OH
Lacto-N-fucopentaose I (LNFP I) is a neutral pentaose consisting of an L-fucose, a D-glucose, 2 molecules of D-galactose, and an N-acetyl glucasamine unit, wherein the monosaccharide L-fucose is connected to the D-glucose via an a(1¨>3) bond.
It has a molecular formula of C32H55N025, a molecular weight of 853.77 g/mol, and a molecular structure of OH ai Date Recue/Date Received 2022-12-12 Lacto-N-difucohexaose I (LNDFH I) is a neutral hexaose consisting of 2 molecules of L-fucose, a D-glucose, a D-galactose, and an N-acetyl glucasamine unit, wherein the monosaccharide L-fucose is connected to the D-galactose and the N-acetyl glucasamine via an a(1¨>2) bond and an a(1¨>4) bond, respectively. It has a molecular formula of C381-165N029, a molecular weight of 999.91 g/mol, and a molecular structure of HONõ
OH
"pH
1404,0,61 OH
''.9'seLe'L'410 HO
'.51 OH
Lacto-N-difucohexaose II (LNDFH II) is a neutral hexaose consisting of 2 molecules 10 of L-fucose, a D-glucose, a D-galactose, and an N-acetyl glucasamine unit, wherein the monosaccharide L-fucose is connected to the D-glucose and the N-acetyl glucasamine via an a(1¨>3) bond and an a(1¨>4) bond, respectively. It has a molecular formula of C38H65N029, a molecular weight of 999.91 g/mol, and a molecular structure of HO
OH
AH
H
OH
fle.C?Nd' OH
NOV
HO
Date Recue/Date Received 2022-12-12 Sphingophospholipid, a sphingolipid constituted by attaching choline phosphate (or ethanolamine phosphate) on a C-1 hydroxyl of ceramide, has a molecular structure of:
H, OH 0 s II
''''s= e 01.-0.....N.,--NH H 0' 1 N' Phosphatidylethanolamine, 1,2- dip almitoyl- SN-glycerol-3 -pho sphoryl ethanolamine, has a molecular structure of:
0 112"i R24Ø...1H Rt. Re tidy add residue 114:40-CH2CHINH2 ' Taurine, i.e. 2-amino ethanesulfonic acid, has a molecular formula of C2H7NO3S, and a molecular weight of 125.15.
The inventors have surprisingly discovered that when human milk oligosaccharide (HMO) (preferably a neurtral fucosylated human milk oligosaccharide selected from the group consisting of 2'-fucosyl lactose (2'-FL), 3 '-fucosyl lactose (3' -FL), lacto-N-fucopentaose I (LNFP I), lacto-N-difucohexaose I (LNDFH I), and lacto-N-difucohexaose II (LNDFH II), preferably 2'-fucosyl lactose (2'-FL)), milk fat globule membrane, and taurine are used in combination, they can synergistically promote neurodevelopment such as neuron maturation, synaptogenesis and myelination, in particular they can synergistically promote OPC proliferation, maturation and differentiation into mature OL, and/or OL myelination characteristics.
In one embodiment, said nutrient composition consists of: the human milk oligosaccharide (HMO), preferably neurtral fucosylated human milk oligosaccharide (HMO), preferably one or more selected from the group consisting
13 Date Recue/Date Received 2022-12-12 of 2'-fucosyl lactose (2'-FL), 3'-fucosyl lactose (3'-FL), lacto-N-fucopentaose I
(LNFP I), lacto-N-difucohexaose I (LNDFH I), and lacto-N-difucohexaose II
(LNDFH II), preferably 2'-fucosyl lactose (2'-FL); the milk fat globule membrane;
and the taurine.
In one embodiment, said human milk oligosaccharide is a neurtral fucosylated human milk oligosaccharide (HMO), preferably one or more neurtral fucosylated human milk oligosaccharides (HMO) selected from the group consisting of 2'-fucosyl lactose (2'-FL), 3'-fucosyl lactose (3'-FL), lacto-N-fucopentaose I
(LNFP
I), lacto-N-difucohexaose I (LNDFH I), and lacto-N-difucohexaose II (LNDFH
II).
In one embodiment, said human milk oligosaccharide is 2'-fucosyl lactose (2'-FL).
In one embodiment, said human milk oligosaccharide (HM0)(for example neurtral fucosylated human milk oligosaccharide (HMO) selected from the group consisting of 2'-fucosyl lactose (2'-FL), 3'-fucosyl lactose (3'-FL), lacto-N-fucopentaose I
(LNFP I), lacto-N-difucohexaose I (LNDFH I), and lacto-N-difucohexaose II
(LNDFH II), for example 2'-fucosyl lactose (2'-FL)) can be provided in the form of the following origins: natural origin, and/or synthetic origin, and/or bacterial fermentation origin. For example, for 2'-fucosyl lactose, 2'-fucosyl lactose can generally be at a content of 60-99.9% in various sources thereof.
In one embodiment, the milk fat globule membrane may be cow and/or sheep milk-origin phospholipid.
In one embodiment, the milk fat globule membrane may be provided in the form of, or may originate from: protein powder containing milk fat globule membrane, and/or cow milk-origin phospholipid. The protein powder containing milk fat globule membrane may commonly have a milk fat globule membrane content of 6-25% by weight, for example 7-15% by weight. The cow milk-origin phospholipid may
(LNFP I), lacto-N-difucohexaose I (LNDFH I), and lacto-N-difucohexaose II
(LNDFH II), preferably 2'-fucosyl lactose (2'-FL); the milk fat globule membrane;
and the taurine.
In one embodiment, said human milk oligosaccharide is a neurtral fucosylated human milk oligosaccharide (HMO), preferably one or more neurtral fucosylated human milk oligosaccharides (HMO) selected from the group consisting of 2'-fucosyl lactose (2'-FL), 3'-fucosyl lactose (3'-FL), lacto-N-fucopentaose I
(LNFP
I), lacto-N-difucohexaose I (LNDFH I), and lacto-N-difucohexaose II (LNDFH
II).
In one embodiment, said human milk oligosaccharide is 2'-fucosyl lactose (2'-FL).
In one embodiment, said human milk oligosaccharide (HM0)(for example neurtral fucosylated human milk oligosaccharide (HMO) selected from the group consisting of 2'-fucosyl lactose (2'-FL), 3'-fucosyl lactose (3'-FL), lacto-N-fucopentaose I
(LNFP I), lacto-N-difucohexaose I (LNDFH I), and lacto-N-difucohexaose II
(LNDFH II), for example 2'-fucosyl lactose (2'-FL)) can be provided in the form of the following origins: natural origin, and/or synthetic origin, and/or bacterial fermentation origin. For example, for 2'-fucosyl lactose, 2'-fucosyl lactose can generally be at a content of 60-99.9% in various sources thereof.
In one embodiment, the milk fat globule membrane may be cow and/or sheep milk-origin phospholipid.
In one embodiment, the milk fat globule membrane may be provided in the form of, or may originate from: protein powder containing milk fat globule membrane, and/or cow milk-origin phospholipid. The protein powder containing milk fat globule membrane may commonly have a milk fat globule membrane content of 6-25% by weight, for example 7-15% by weight. The cow milk-origin phospholipid may
14 Date Regue/Date Received 2022-12-12 commonly have a milk fat globule membrane content of 9-60% by weight. The milk fat globule membrane at least contains sphingophospholipid and phosphatidylcholine, and optionally further contains phosphatidylserine and/or phosphatidylethanolamine, wherein the sphingophospholipid represents a ratio of 10% by weight or more of the total milk fat globule membrane, and the phosphatidylcholine represents a ratio of 15% by weight or more of the total milk fat globule membrane. In one embodiment, the phospholipid constituents in the milk fat globule membrane represent the following ratio of the total phospholipid:
sphingophospholipid (SM) 15-36 %, phosphatidylcholine (PC) 20-40 %, phosphatidylethanolamine (PE) 20-38 %, phosphatidylserine (PS) 5-18 %, and phosphatidylinositol (PI) 3-11 %.
In one embodiment, the taurine may be provided in the form of, or originate from monomeric taurine. The monomeric taurine may commonly have a taurine amount of 98.9-100% by weight.
In one embodiment, the mass ratio of the human milk oligosaccharide (for example neurtral fucosylated human milk oligosaccharide (HMO) selected from the group consisting of 2'-fucosyl lactose (2'-FL), 3'-fucosyl lactose (3'-FL), lacto-N-fucopentaose I (LNFP I), lacto-N-difucohexaose I (LNDFH I), lacto-N-difucohexaose II (LNDFH II), for example 2'-fucosyl lactose (2'-FL)) to the milk fat globule membrane in said nutrient composition may be 1:0.01-500, preferably 1:0.02-100, preferably 1:0.05-50, preferably 1:0.1-10, preferably 1:0.15-6, for example may be 1:0.01, 1:0.015, 1:0.02, 1:0.025, 1:0.03, 1:0.04, 1:0.05, 1:0.06, 1:0.07, 1:0.08, 1:0.09, 1:0.1, 1:0.15, 1:0.2, 1:0.25, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1.0, 1:1.5, 1: 2.0, 1:2.5, 1:3.0, 1:3.5, 1:4.0, 1:4.5, 1:5.0, 1:5.5, 1:6.0, 1:7.0, 1:8.0, 1:9.0, 1:10.0, 1:11.0, 1:12.0, 1:13.0, 1:14.0, 1:15.0, 1:16.0, 1:17.0, 1:18.0, 1:19.0, 1:20.0, 1:21.0, 1:22.0, 1:23.0, 1:24.0, 1:25.0, 1:26.0, 1:27.0, 1:28.0, 1:29.0, 1:30.0, 1:31.0, 1:32.0, 1:33.0, 1:34.0, 1:35.0, 1:36.0, 1:37.0, 1:38.0, 1:39.0, 1:40.0, 1:41.0, 1:42.0, 1:43.0, 1:44.0, 1:45.0, 1:46.0, 1:47.0, 1:48.0, 1:49.0, 1:50.0, Date Recue/Date Received 2022-12-12 1:51.0, 1:52.0, 1:53.0, 1:54.0, 1:55.0, 1:56.0, 1:57.0, 1:58.0, 1:59.0, 1:60.0, 1:61.0, 1:62.0, 1:63.0, 1:64.0, 1:65.0, 1:66.0, 1:67.0, 1:68.0, 1:69.0, 1:70.0, 1:71.0, 1:72.0, 1:73.0, 1:74.0, 1:75.0, 1:76.0, 1:77.0, 1:78.0, 1:79.0, 1:80.0, 1:81.0, 1:82.0, 1:83.0, 1:84.0, 1:85.0, 1:86.0, 1:87.0, 1:88.0, 1:89.0, 1:90.0, 1:91.0, 1:92.0, 1:93.0, 1:94.0, 1:95.0,1:96.0, 1:97.0, 1:98.0, 1:99.0, 1:100,1:110, 1:120,1:130, 1:140, 1:150, 1:160, 1:170, 1:180, 1:190, 1:200, 1:210, 1:220, 1:230, 1:240, 1:250, 1:260, 1:270, 1:280, 1:290, 1:300, 1:310, 1:320, 1:330, 1:340, 1:350, 1:360, 1:370, 1:380, 1:390, 1:400, 1:410, 1:420, 1:430, 1:440, 1:450, 1:460, 1:470, 1:480, 1:490, 1:500, or a range defined by any two thereof and any value and subrange contained within the range.
In one embodiment, the mass ratio of the human milk oligosaccharide (for example neurtral fucosylated human milk oligosaccharide (HMO) selected from the group consisting of 2'-fucosyl lactose (2'-FL), 3'-fucosyl lactose (3'-FL), lacto-N-fucopentaose I (LNFP I), lacto-N-difucohexaose I (LNDFH I), lacto-N-difucohexaose II (LNDFH II), for example 2'-fucosyl lactose (2'-FL)) to the taurine in said nutrient composition may be 1:0.0005-10, preferably 1:0.001-5, preferably 1:0.005-1, preferably 1:0.01-0.5, for example may be 1:0.0005, 1:0.0006, 1:0.0007, 1:0.0008, 1:0.0009, 1:0.001, 1:0.0015, 1:0.002, 1:0.0025, 1:0.003, 1:0.0035, 1:0.004, 1:0.0045, 1:0.005, 1:0.0055, 1:0.006, 1:0.0065, 1:0.007, 1:0.0075, 1:0.008, 1:0.0085, 1:0.009, 1:0.0095, 1:0.01, 1:0.015, 1:0.02, 1:0.025, 1:0.03, 1:0.035, 1:0.04, 1:0.045, 1:0.05, 1:0.055, 1:0.06, 1:0.065, 1:0.07, 1:0.075, 1:0.08, 1:0.085, 1:0.09, 1:0.095, 1:0.1, 1:0.15, 1:0.2, 1:0.25, 1:0.3, 1:0.35, 1:0.4, 1:0.45, 1:0.5, 1:0.55, 1:0.6, 1:0.65, 1:0.7, 1:0.75, 1:0.8, 1:0.85, 1:0.9, 1:0.95, 1:1.0, 1:1.5, 1:2.0, 1:2.5, 1:3.0, 1:3.5, 1:4.0, 1:4.5, 1:5.0, 1:6.0, 1:7.0, 1:8.0, 1:9.0, 1:10.0, or a range defined by any two thereof and any value and subrange contained within the range.
In one embodiment, said nutrient composition may have a mass ratio of the human milk oligosaccharide (for example neurtral fucosylated human milk oligosaccharide (HMO) selected from the group consisting of 2'-fucosyl lactose (2'-FL), 3'-fucosyl lactose (3'-FL), lacto-N-fucopentaose I (LNFP I), lacto-N-difucohexaose I
(LNDFH
Date Recue/Date Received 2022-12-12 I), lacto-N-difucohexaose II (LNDFH II), for example 2'-fucosyl lactose (2'-FL)) to the milk fat globule membrane to the taurine of 1:0.01-500:0.0005-10, preferably 1:0.02-100:0.0005-10, preferably 1:0.05-50:0.001-5, preferably 1:0.1-10:0.005-1, preferably 1:0.15-6:0.01-0.5, or a mass ratio obtained by any combination of the .. ratios described for the mass ratio of the human milk oligosaccharide (for example neurtral fucosylated human milk oligosaccharide (HMO) selected from the group consisting of 2'-fucosyl lactose (2'-FL), 3'-fucosyl lactose (3'-FL), lacto-N-fucopentaose I (LNFP I), lacto-N-difucohexaose I (LNDFH I), lacto-N-difucohexaose II (LNDFH II), for example 2'-fucosyl lactose (2'-FL)) to the milk .. fat globule membrane with the ratios described for the mass ratio of the human milk oligosaccharide (for example neurtral fucosylated human milk oligosaccharide (HMO) selected from the group consisting of 2'-fucosyl lactose (2'-FL), 3'-fucosyl lactose (3'-FL), lacto-N-fucopentaose I (LNFP I), lacto-N-difucohexaose I
(LNDFH
I), lacto-N-difucohexaose II (LNDFH II), for example 2'-fucosyl lactose (2'-FL)) to the taurine.
When the mass ratio of the human milk oligosaccharide (for example neurtral fucosylated human milk oligosaccharide (HMO) selected from the group consisting of 2'-fucosyl lactose (2'-FL), 3'-fucosyl lactose (3'-FL), lacto-N-fucopentaose I
(LNFP I), lacto-N-difucohexaose I (LNDFH I), lacto-N-difucohexaose II (LNDFH
II), for example 2'-fucosyl lactose (2'-FL)) to the milk fat globule membraneto the taurine in the nutrient composition falls within the above-mentioned ranges, more significant promotion in terms of neurodevelopment such as neuron maturation, synaptogenesis and myelination, in particular promotion in terms of OPC
proliferation, maturation and differentiation into OL and/or of OL myelination characteristics, can be realized, and there is more significant synergistic action among various components in terms of these aspects.
Food In another aspect, the present invention also relates to a food containing said nutrient Date Regue/Date Received 2022-12-12 composition.
The food of the present invention may be in a form of powder, and it may also be in a form of liquid.
The food of the present invention may be a formula food for infants and young children (e.g. a formula food for infants, a formula food for more grown-up infants, and a formula food for young children), for example a formula milk powder for infants and young children (e.g. a formula milk powder for infants, and a formula milk powder for young children), a complementary food for infants, nutritional or dietary supplements, or a formulated milk powder for pregnant women.
In one embodiment, said nutrient composition is added in an amount such that the human milk oligosaccharide (e.g. neurtral fucosylated human milk oligosaccharide (HMO) selected from the group consisting of 2'-fucosyl lactose (2'-FL), 3'-fucosyl lactose (3'-FL), lacto-N-fucopentaose I (LNFP I), lacto-N-difucohexaose I
(LNDFH
I), lacto-N-difucohexaose II (LNDFH II), for example 2'-fucosyl lactose (2'-FL)) is at a content by weight of at least 0.01%, preferably at least 0.05%, preferably at least 0.1% and at most 10.0%, preferably at most 5.0%, preferably at most 1.0%, relative to the total weight of said food. For example, 2'-fucosyl lactose (2'-FL) may be at a content by weight, relative to the total weight of said food, of 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 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%, Date Recue/Date Received 2022-12-12 9.7%, 9.8%, 9.9%, 10.0%, or a range defined by any two thereof and any value and subrange contained within the range.
In one embodiment, said nutrient composition is added in an amount such that the milk fat globule membrane is at a content by weight, relative to the total weight of said food, of at least 0.01%, preferably at least 0.05%, preferably at least 0.1% and at most 5.0%, preferably at most 1.0%, preferably at most 0.6%. For example, the milk fat globule membrane may be at a content by weight, relative to the total weight of said food, of 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, .. 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%, or a range defined by any two thereof and any value and subrange contained within the range.
In one embodiment, said nutrient composition is added in an amount such that the taurine is at a content by weigh, relative to the total weight of said food, of at least 0.001%, preferably at least 0.005%, preferably at least 0.01% and at most 1.0%, preferably at most 0.5%, preferably at most 0.1%. For example, the taurine may be at a content by weight, relative to the total weight of said food, of 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%, 0.015%, 0.02%, 0.025%, 0.03%, 0.035%, 0.04%, 0.045%, 0.05%, 0.055%, 0.06%, 0.065%, 0.07%, 0.075%, 0.08%, 0.085%, 0.09%, 0.095%, 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%, Date Recue/Date Received 2022-12-12 0.91%, 0.92%, 0.93%, 0.94%, 0.95%, 0.96%, 0.97%, 0.98%, 0.99%, 1.0%, or a range defined by any two thereof and any value and subrange contained within the range.
In addition the constituents described above for said nutrient composition, said food may have other constituents, for example other proteins, carbohydrates, fat, vitamins, minerals and the like, which are commonly contained in formula food, for example formula food like milk powder for infants and young children.
Use In another aspect, the present invention relates to use of the nutrient composition or food described above for non-curing purposes (i.e., non-medical purpose) of improving the brain development and intelligence of infants and young children, especially promoting neurodevelopment (for example neuron maturation, synaptogenesis and myelination, for example promoting OPC proliferation, maturation, and differentiation into oligodendrocytes (OLs) and/or myelination of oligodendrocytes (OLs)).
Example The present invention will be described in greater detail hereinbelow in combination with the examples, such that the objects, technical solutions and advantages of the present invention will be more apparent. It should be understood that the specific examples described herein is only for explanation of the present invention rather than limination of the present invention. The reagents, methods and devices employed in the present invention are ordinary reagents, methods and devices in the art, unless specifically indicated.
Raw materials The following raw materials are used in the example section which follows, unless indicated otherwise.
Date Regue/Date Received 2022-12-12 2'-fucosyl lactose (2'-FL): GlyCareTM 2'-FL 9000, 2'-fucosyl lactose content 96.0 % by mass Milk fat globule membrane: Tatua of New Zealand PLC1, phospholipid content 12.3% by mass, protein 49.6% by mass;
Taurine: taurine form Beijing Jinkangpu Food Technology Co., Ltd, taurine content 99%.
In the following section, unless indicated otherwise, when a part by mass and ratio of the constituents in the nutrient composition are mentioned, the part by mass refers to the part by mass of 2'-fucosyl lactose (2'-FL), milk fat globule membrane, and taurine, which are active constituents, and the ratio refers to the mass ratio among 2'-fucosyl lactose (2'-FL), milk fat globule membrane, and taurine, which are active constituents.
Several nutrient compositions are formulated by mixing the raw materials 2'-fucosyl lactose (2'-FL), milk fat globule membrane, and taurine according to the ratios shown in the following examples, the composition of which are shown in table 1.
Table 1. Composition of the nutrient compositions No. Part by mass Part by mass of milk fat Part by mass of 2'-FL globule membrane of taurine Example 1 1 2.75 0.05 Example 2 1 0.275 0.5 Example 3 1 0.275 0.01 Example 4 1 2.75 0.5 Comparative 0 0 1 Example 1 Comparative 1 0 0 Example 2 Date Regue/Date Received 2022-12-12 Comparative 0 1 0 Example 3 Comparative 1 0 0.5 Example 4 Comparative 1 0.275 0 Example 5 Comparative 0 0.55 1 Example 6 Cell Experiment Example Current studies on brain development are limited to studies on passive memory using animal experiments. There is no discussion on the development of neuron cells, nor is there exploration on the effect of specific dosage of the composition on early brain development. The present invention uses an in vitro model of culture of primary cell containing neurons and OPC to evaluate the effect of a nutrient mixture on myelination and neurons. Through experimental research on the effects of components containing 2'-FL, milk fat globle membrane and taurine in varying proportions on the brain neurve cell development, this method systematically and intuitively evaluated the effects on early brain development, which is of profound significance in terms of guiding the application of the composition.
1. Materials and methods 1.1 Apparatus and reagent consumables Cell incubator; Laser confocal fluorescence microscope; Centrifuge; Electronic balance; Vortexer, water bath, tissue homogenizer.
Nerve cell culture medium; A2B5, MAG, MBP and other antibodies.
1.2 Experimental Method 1.2.1 Acquisition of nerve primary cells All experiments were approved by ethics, and the primary mixed culture of neurons Date Regue/Date Received 2022-12-12 and OL were carried out according to the following steps. Briefly, the forebrain of newborn rats and mice were dissociated with trypsin (Trypsin EDTA 1X, PAN
BIOTECH) at 37 C for 20 minutes. After addition of Dulbecco modified Eagle medium (DMEM, PAN BIOTECH) containing DNAase I Grade 11 (0.1 mg/ml, PAN
BIOTECH) and 10% fetal bovine serum (FCS, GIBCO), the reaction was stopped.
The cells were mechanically separated three times through a 10 ml pipette, and then centrifuged at 4 C under 515g for 10 minutes.
Living cells were inoculated in 96-well plates (20000/well), which were pre-coated with poly-L-lysine (BD Falcon) and laminin (Sigma). The culture medium consists of Neurobasal (GIBCO) added with 2% B27 (GIBCO), 2 mM L-glutamine (L Glu, PAN BIOTECH), 2% P/S solution (PAN BIOTECH), 1% FCS and 10 ng/ml platelet-derived growth factor (PDGF-AA, PAN BIOTECH). The 96-well plates are stored in a humidified incubator at a temperature of 37 C and with an environment of air (95%) - CO2 (5%).
1.2.2 Nerve cell culture A same number of cells were placed on 48-well plates, and then incubated for 12, 18 or 30 DIVs. Half of the medium were replaced every other day. A mixture or separate nutrition were added to the fresh medium (the nutrient composition prepared above, containing 2'-FL, taurine and/or milk fat global membrane).
1.2.3 Immunohistochemical experiment After 12, 18 and 30 DIVs, the cells were fixed with a cold mixture of 95%
ethanol and acetic acid (5%) for 5 minutes. The non-specific sites were then blocked for 15 minutes at room temperature with a phosphate buffered saline (PBS) solution containing 0.1% saponin (Sigma) and 1% FCS (GIBCO).
At 12 DIVs, nerve cells were co-incubated with mouse monoclonal antibody A2B5 (dilution: 1/200, Millipore, MAB312RX) at room temperature for 2h, and then co-Date Recue/Date Received 2022-12-12 incubated with neurofilament antibody (dilution: 1/500, Sigma, N4142) at room temperature for 2h. Finally, a secondary goat anti-rabbit antibody (diluted 1/400, SIGMA, 5AB460084) was used to co-incubate at room temperature for 1 h.
At 18 DIVs, nerve cells were co-incubated with mouse monoclonal antibody MAG
(dilution: 1/400, Millipore, MAB1567) and neurofilament protein antibody (dilution:
1/500, Sigma, N4142) for 2h. Then a secondary goat anti-rabbit antibody (dilution:
1/400, Sigma, 5AB4600042) and a secondary goat anti-rabbit antibody (dilution:
1/400, SIGMA, 5AB4600084) were used to co-incubate at room temperature for lh.
At 30 DIVs, nerve cells were co-incubated with mouse monoclonal antibody MBP
(dilution: 1/1000, Novus, NBP1-05204) and neurofilament protein antibody (dilution: 1/500, Sigma, N4142) for 2 hours. Then a secondary goat anti-mouse antibody (dilution: 1/800, Sigma, 5AB4600042) and a secondary goat anti-rabbit antibody (dilution: 1/400, SIGMA, 5AB4600084) were used to co-incubate at room temperature for lh.
1.2.4 Microscrope imaging ImageXpress equipped with LED lights (360/480/565 for excitation and 460/535/620 for emission) is used for 20x amplification. All images are acquired using the same settings.
Under the condition of 12 DIVs, the number of OPC was calculated by quantifying the number of A2B5 expressing cells, and the result was expressed as the average number of A2B5 expressing cells per image and per well.
The differentiation of OPC into OL was evaluated by counting the number of MAG
positive cells in cell culture. The results were expressed as the average number of cells per image and per well. The morphological maturity of MAG positive cells were assessed by measuring the average surface area of MAG positive cells in Date Recue/Date Received 2022-12-12 DIV wells ( M/image/well).
At 30 DIVs, the maturity of OL was estimated by calculating the number of MBP
positive cells (average number of cells per imge, per well) and the average surface area of MBP positive cells at 30 DIVs ( M, per image, per well).
1.3 cell experiment grouping Cells were inoculated on a 96-well plate and cultured for a certain period of time.
Half of the culture medium was replaced every other day. Varying concentrations of mixed or separate 2'-FL mixtures were added to the special culture medium for fresh primary cells (added on day 12, 18 and 30, respectively). 6 replicas for each sample.
Oleoxime (300 nM, proved to accelerate OL maturation and myelination in vitro and in vivo) was taken as the positive control. The blank control group, positive control group and sample intervention group were compared, respectively. The effects of milk fat global membrane, 2'-FL and taurine, alone or in mixture, on OPC
population, OL maturation and differentiation, myelin formation and neurite growth was determined by immunohistochemistry (MBP, NF, A2B5). See Table 2 below for specific experimental dosage.
Table 2. Dosage for Cell Experiments milk fat Cell Corresponding 2'-FL globule taurine Experiment Dosage group Example (mg/ml) membrane (mg/ml) Example (mg/ml) 1 Control blank control group positive control group 2 positive control Olesoxime Comparative 3 2'-FL (low dosage) 0.2 Example 2 Comparative 4 2'-FL (medium dosage) 2 Example 2 Date Regue/Date Received 2022-12-12 Comparative 2'-FL (high dosage) 20 Example 2 Comparative milk fat globule 6 0.55 Example 3 membrane (low dosage) milk fat globule Comparative 7 membrane (medium 5.5 Example 3 dosage) Comparative milk fat globule Example 3 membrane (high dosage) Comparative 9 taurine (low dosage 1) 0.02 Example 1 Comparative taurine (low dosage 2) 0.01 Example 1 Comparative 11 taurine (medium dosage) 0.1 Example 1 Comparative 12 taurine (high dosage) 1 Example 1 Comparative 13 2'-FL+taurine 2 1 Example 4 Comparative 2'-FL+milk fat globule 14 2 0.55 Example 5 membrane Comparative milk fat globule 0.55 1 Example 6 membrane +taurine 2'-FL (low dosage)+milk fat globule 16 Example 1 membrane (low 0.2 0.55 0.01 dosage)+taurine (low dosage) 2'-FL (medium dosage)+milk fat globule 17 Example 1 membrane (medium 2 5.5 0.1 dosage)+taurine (medium dosage) 18 Example 1 2'-FL (high 20 55 1 Date Regue/Date Received 2022-12-12 dosage)+milk fat globule membrane (high dosage)+taurine (high dosage) 2'-FL (low to medium dosage)+milk fat globule 19 Example 1 membrane (low to 1 2.75 0.05 medium dosage)+taurine (low to medium dosage) 2'-FL (medium to high dosage)+milk fat globule 20 Example 1 membrane (medium to 4 11 0.2 high dosage)+taurine (medium to high dosage) 2'-FL+milk fat globule 21 Example 2 2 0.55 1 membrane +taurine 2'-FL+milk fat globule 22 Example 3 2 0.55 0.02 membrane +taurine 2'-FL+milk fat globule 23 Example 4 2 5.5 1 membrane +taurine 1.4 Statistics analysis The results were expressed as mean standard error. SPSS software was used for T-test and one-way ANOVA test. When p<0.05, it was judged that there was a significant difference 2. Experimental Results 2.1 Effect of various samples on nerve cells In order to measure the effect of mixed nutrition or single nutrition treatment on OPC, we evaluated the number of positive cells labeled A2B5 after 12 DIVs to estimate the number of OPCs. The average number of A2B5 positive cells per well measured is shown in Table 3.
Date Regue/Date Received 2022-12-12 Table 3. Effect of different nutrient composition samples comprising 2'-FL, milk fat global membrane and/or taurine on the number ofA2B5 positive cells number of A2B5 Cell positive cells Experiment dosage group (mean standard Example deviation) 1 blank control group 116.67 3.79 2 positive control group Olesoxime 171.33 3.51**
3 2'-FL (low) 151.33 4.73**
4 2'-FL(medium) 156.00 5.57**
2'-FL (high) 135.00 6.08**
6 milk fat globule membrane (low) 168.00 5.29**
7 milk fat globule membrane (medium) 131.33 6.11**
8 milk fat globule membrane (high) 106.33 8.74*
9 taurine (low 1) 124.06 8.269**
taurine (low 2) 114.00 5.29 11 taurine (medium) 135.00 5.00**
12 taurine (high) 175.67 4.04 **
13 2'-FL+taurine 145.50 8.469**
14 2'-FL+milk fat globule membrane 140.67 11.354**
milk fat globule membrane +taurine 143.50 8.386**
2'-FL (low dosage)+milk fat globule 16 membrane (low dosage)+taurine (low 182.67 5.69 **
dosage) 2'-FL (medium dosage)+milk fat 17 globule membrane (medium 178.67 5.13 **
dosage)+taurine (medium dosage) 2'-FL (high dosage)+milk fat globule 18 258.00 7.00 **
membrane (high dosage)+taurine Date Regue/Date Received 2022-12-12 (high dosage) 2'-FL (low to medium dosage)+milk fat globule membrane (low to 19 214.67 5.51**
medium dosage)+taurine (low to medium dosage) 2'-FL (medium to high dosage)+milk fat globule membrane (medium to 20 137.00 3.61**
high dosage)+taurine (medium to high dosage) 2'-FL+milk fat globule membrane 263.14 12.71**
+taurine 2'-FL+milk fat globule membrane 246.21 10.79**
+taurine 2'-FL+milk fat globule membrane 255.22 9.03**
+taurine N.B.: * p < 0.05, in comparison with the blank control group, ** p < 0.01, in comparison with the blank control group The results of sample treatment showed that 2'- FL, milk fat global membrane and taurine could increase the number of A2B5 positive cells when used alone, relative to the blank control group (cell experiment example 1), which indicates that these three constituents help the proliferation of oligodendrocyte precursor cell when used alone.
However, the inventors discovered that when any two of the three components were used in combination, there was a strong antagonism.
In particular, it can be seen according to cell experiment examples 13-15 that:
- In terms of components used and the amount of the components used, cell Date Regue/Date Received 2022-12-12 experiment example 13 is equivalent to the combination of cell experiment examples 4 and 12. Relative to the blank control group (cell experiment example 1), cell experiment examples 4 and 12 increase the number of A2B5 positive cells by 39.33 and 59 respectively, while cell experiment example 13 increases the number of A2B5 positive cells by 28.83, which is not only far less than the sum of the former two (98.33) (the difference from the sum of the former two being A1=69.5), but also less than either one of the former two.
- Cell experiment example 14 is equivalent to the combination of cell experiment examples 4 and 6. However, relative to the blank control group (cell experiment example 1), cell experiment examples 4 and 6 increase the number of A2B5 positive cells by 39.33 and 51.33 respectively, while cell experiment example 14 increases the number of A2B5 positive cells by 24, which is not only far less than the sum of the former two (90.66) (the difference from the sum of the former two being A2=66.66), but also less than either one of the former two.
- Cell experiment example 15 is equivalent to the combination of cell experiment examples 6 and 12. However, relative to the blank control group (cell experiment example 1), cell experiment examples 6 and 12 increase the number of A2B5 positive cells by 51.33 and 59 respectively, while cell experiment example 15 increases the number of A2B5 positive cells by 26.83, which is not only far less than the sum of the former two (110.33) (the difference from the sum of the former two being A3=83.5), but also less than either one of the former two.
This indicates that when any two of 2'-FL, milk fat global membrane and taurine are used in combination, there is a strong antagonism in terms of the number of positive cells and thus the proliferation of oligodendrocyte precursor cells, and the effect of their use in combination is less than that of any one of the components when it is used alone.
Moreover, the inventors found that when the three of 2'-FL, milk fat global membrane and taurine are used in combination, a significant reduction in inter-Date Regue/Date Received 2022-12-12 component antagonism, and a synergistic increase in the number of A2B5 positive cells and thus the proliferation of oligodendrocyte precursor cells are enabled.
In particular, cell experiment example 18 is equivalent to the combination of cell experiment examples 5, 8 and 12 in terms of the components used and the amount of components used. With respect to cell experiment example 1, cell experiment examples 5, 8, 12 and 18 increase the number of A2B5 positive cells by 18.33, -10.34, 59 and 141.33 respectively. The increment realized in cell experiment example 18 (141.33) is greater than the sum of the former three (66.99).
In addition, in terms of the components used and the amount of components used, cell experiment example 21 is equivalent to the combination of cell experiment examples 6 and 13, or the combination of cell experiment examples 12 and 14, or the combination of cell experiment examples 4 and 15, or the combination of cell experiment examples 4, 6 and 12. Compared with blank control group (cell experiment example 1), - Cell experiment example 21 increased the number ofA2B5 positive cells by 146.47, - cell experiment examples 6 and 13 increased the number of A2B5 positive cells by 51.33 and 28.33 respectively, with a sum of 80.16, which is less than the increment realized in cell experiment example 21 (146.47), - cell experiment examples 12 and 14 increased the number of A2B5 positive cells by 59 and 24 respectively, with a sum of 83, which is less than the increment realized in cell experiment example 21 (146.47), - cell experiment examples 4 and 15 increased the number of A2B5 positive cells by 39.33 and 26.83 respectively, with a sum of 66.16, which is less than the increment realized in cell experiment example 21 (146.47), - cell experiment examples 4, 6 and 12 increased the number of A2B5 positive cells by 39.33, 51.33 and 59 respectively, with a sum of 149.66, which is slightly greater than the increment realized in cell experiment example 21 (146.47), with a difference of A4=3.19, which is far less than the difference A1=69.5, A2=66.66, and A3=83.5.
Date Regue/Date Received 2022-12-12 In addition, cell experiment example 22 is equivalent to the combination of cell experiment examples 9 and 14, or the combination of cell experiment examples 4, 6 and 9, in terms of the components used and the amount of the components used.
Relative to the blank control group (cell experiment example 1), cell experiment examples 4, 6, 9, 14 and 22 increase the number of A2B5 positive cells by 39.33, 51.33, 7.39, 24 and 129.54 respectively. The increment realized in cell experiment example 22 (129.54) is greater than the sum of the respective increments of cell experiment examples 9 and 14 (31.39), and is also greater than the sum of the respective increments of cell experiment examples 4, 6 and 9 (98.05).
In addition, cell experiment example 23 is equivalent to the combination of cell experiment examples 7 and 13, or the combination of cell experiment examples 4, 7 and 12, in terms of components used and the amount of the components used.
Relative to the blank control group (cell experiment example 1), cell experiment examples 4, 7, 12, 13 and 23 increase the number of A2B5 positive cells by 39.33, 14.66, 59, 28.83 and 138.55 respectively. The increment realized in cell experiment example 23 (138.55) is greater than the sum of the respective increments of cell experiment examples 7 and 13 (43.49), and greater than the sum of the respective increments of cell experiment examples 4, 7 and 12 (112.99).
Thus, it can be seen that when the three of 2'-FL, milk fat global membrane and taurine are used in combination, a significantly reduction in inter-component antagonism is enabled. There is a synergistic effect among the three components, which can synergistically increase the number of A2B5 positive cells and thus the proliferation of oligodendrocyte precursor cells.
2.2 The effect of various samples on OPC cell myelination In order to measure the effect of mixed nutrition or single nutrition treatment on OPC cell myelination, we evaluated the number of positive cells labelled MAG
after Date Regue/Date Received 2022-12-12 18 DIVs. The measured average number of MAG positive cells per well is shown in Table 4.
Table 4. Effect of different nutrient composition samples containing 2'-FL, milk fat global membrane and/or taurine on the number of MAG positive cells number of MAG
cell experiment positive cells dosage group example (mean standard deviation) 1 blank control group 40.67 4.04 2 positive control group Olesoxime 87.00 4.36**
3 2'-FL (low dosage) 54.00 6.08**
4 2'-FL (medium dosage) 76.33 4.51**
5 2'-FL (high dosage) 62.00 4.00**
6 milk fat globule membrane (low dosage) 70.33 4.04**
7 milk fat globule membrane (medium dosage) 58.67 3.51**
8 milk fat globule membrane (high dosage) 42.33 3.21 9 taurine (low dosage 1) 58.01 4.39**
taurine (low dosage 2) 44.00 3.61 11 taurine (medium dosage) 70.33 4.16**
12 taurine (high dosage) 85.33 4.73**
13 2 '-FL+taurine 70.50 7.196**
14 2'-FL+milk fat globule membrane 66.50 6.662**
milk fat globule membrane +taurine 66.33 7.957**
2'-FL (low dosage)+milk fat globule membrane 16 84.67 4.51**
(low dosage)+taurine (low dosage) 2'-FL (medium dosage)+milk fat globule 17 membrane (medium dosage)+taurine (medium 92.00 4.58**
dosage) 2'-FL (high dosage)+milk fat globule membrane 18 110.67 4.04**
(high dosage)+taurine (high dosage) 2'-FL (low to medium dosage)+milk fat globule 19 99.00 3.61**
membrane (low to medium dosage)+taurine (low Date Regue/Date Received 2022-12-12 to medium dosage) 2'-FL (medium to high dosage)+milk fat globule 20 membrane (medium to high dosage)+taurine 68.00 2.65**
(medium to high dosage) 21 2'-FL+milk fat globule membrane +taurine 128.54 7.38**
22 2'-FL+milk fat globule membrane +taurine 121.30 8.47**
23 2'-FL+milk fat globule membrane +taurine 124.36 8.08**
N.B.: * p < 0.05, in comparison with the blank control group, ** p < 0.01, in comparison with the blank control group The results of sample processing showed that all of 2'-FL, milk fat global membrane and taurine could increase the number of MAG positive cells when used alone, compared with blank control group (cell experiment example 1), which indicates that these three components, when used alone, help the myelination of oligodendrocyte precursor cell.
However, the inventors found that when any two of the three components were used in combination, there was a strong antagonism.
In particular, it can be seen from cell experiment examples 13-15 that:
- In terms of the components used and the amount of the components used, cell experiment example 13 is equivalent to the combination of cell experiment examples 4 and 12. Relative to the blank control group (cell experiment example 1), cell experiment examples 4 and 12 increase the number of MAG positive cells by 35.66 and 44.66 respectively, while cell experiment example 13 increases the number of MAG positive cells by 29.83, which is not only far less than the sum of the former two (80.32) (the difference from the sum of the former two A1=50.49), but also less than either of the former two.
- Cell experment example 14 is equivalent to the combination of cell experiment examples 4 and 6. However, relative to the blank control group (cell experiment Date Regue/Date Received 2022-12-12 example 1), cell experiment example 4 and 6 increase the number of MAG
positive cells by 35.66 and 29.66 respectively, while cell experiment example 14 increases the number of MAG positive cells by 25.83, which is not only far less than the sum of the former two (65.32) (the difference from the sum ofthe former two A2=39.49), but also less than either of the former two.
- Cell experiment example 15 is equivalent to the combination of cell experiment examples 6 and 12. However, relative to the blank control group (cell experiment example 1), cell experiment examples 6 and 12 increase the number of MAG
positive cells by 29.66 and 44.66 respectively, while cell experiment example
sphingophospholipid (SM) 15-36 %, phosphatidylcholine (PC) 20-40 %, phosphatidylethanolamine (PE) 20-38 %, phosphatidylserine (PS) 5-18 %, and phosphatidylinositol (PI) 3-11 %.
In one embodiment, the taurine may be provided in the form of, or originate from monomeric taurine. The monomeric taurine may commonly have a taurine amount of 98.9-100% by weight.
In one embodiment, the mass ratio of the human milk oligosaccharide (for example neurtral fucosylated human milk oligosaccharide (HMO) selected from the group consisting of 2'-fucosyl lactose (2'-FL), 3'-fucosyl lactose (3'-FL), lacto-N-fucopentaose I (LNFP I), lacto-N-difucohexaose I (LNDFH I), lacto-N-difucohexaose II (LNDFH II), for example 2'-fucosyl lactose (2'-FL)) to the milk fat globule membrane in said nutrient composition may be 1:0.01-500, preferably 1:0.02-100, preferably 1:0.05-50, preferably 1:0.1-10, preferably 1:0.15-6, for example may be 1:0.01, 1:0.015, 1:0.02, 1:0.025, 1:0.03, 1:0.04, 1:0.05, 1:0.06, 1:0.07, 1:0.08, 1:0.09, 1:0.1, 1:0.15, 1:0.2, 1:0.25, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1.0, 1:1.5, 1: 2.0, 1:2.5, 1:3.0, 1:3.5, 1:4.0, 1:4.5, 1:5.0, 1:5.5, 1:6.0, 1:7.0, 1:8.0, 1:9.0, 1:10.0, 1:11.0, 1:12.0, 1:13.0, 1:14.0, 1:15.0, 1:16.0, 1:17.0, 1:18.0, 1:19.0, 1:20.0, 1:21.0, 1:22.0, 1:23.0, 1:24.0, 1:25.0, 1:26.0, 1:27.0, 1:28.0, 1:29.0, 1:30.0, 1:31.0, 1:32.0, 1:33.0, 1:34.0, 1:35.0, 1:36.0, 1:37.0, 1:38.0, 1:39.0, 1:40.0, 1:41.0, 1:42.0, 1:43.0, 1:44.0, 1:45.0, 1:46.0, 1:47.0, 1:48.0, 1:49.0, 1:50.0, Date Recue/Date Received 2022-12-12 1:51.0, 1:52.0, 1:53.0, 1:54.0, 1:55.0, 1:56.0, 1:57.0, 1:58.0, 1:59.0, 1:60.0, 1:61.0, 1:62.0, 1:63.0, 1:64.0, 1:65.0, 1:66.0, 1:67.0, 1:68.0, 1:69.0, 1:70.0, 1:71.0, 1:72.0, 1:73.0, 1:74.0, 1:75.0, 1:76.0, 1:77.0, 1:78.0, 1:79.0, 1:80.0, 1:81.0, 1:82.0, 1:83.0, 1:84.0, 1:85.0, 1:86.0, 1:87.0, 1:88.0, 1:89.0, 1:90.0, 1:91.0, 1:92.0, 1:93.0, 1:94.0, 1:95.0,1:96.0, 1:97.0, 1:98.0, 1:99.0, 1:100,1:110, 1:120,1:130, 1:140, 1:150, 1:160, 1:170, 1:180, 1:190, 1:200, 1:210, 1:220, 1:230, 1:240, 1:250, 1:260, 1:270, 1:280, 1:290, 1:300, 1:310, 1:320, 1:330, 1:340, 1:350, 1:360, 1:370, 1:380, 1:390, 1:400, 1:410, 1:420, 1:430, 1:440, 1:450, 1:460, 1:470, 1:480, 1:490, 1:500, or a range defined by any two thereof and any value and subrange contained within the range.
In one embodiment, the mass ratio of the human milk oligosaccharide (for example neurtral fucosylated human milk oligosaccharide (HMO) selected from the group consisting of 2'-fucosyl lactose (2'-FL), 3'-fucosyl lactose (3'-FL), lacto-N-fucopentaose I (LNFP I), lacto-N-difucohexaose I (LNDFH I), lacto-N-difucohexaose II (LNDFH II), for example 2'-fucosyl lactose (2'-FL)) to the taurine in said nutrient composition may be 1:0.0005-10, preferably 1:0.001-5, preferably 1:0.005-1, preferably 1:0.01-0.5, for example may be 1:0.0005, 1:0.0006, 1:0.0007, 1:0.0008, 1:0.0009, 1:0.001, 1:0.0015, 1:0.002, 1:0.0025, 1:0.003, 1:0.0035, 1:0.004, 1:0.0045, 1:0.005, 1:0.0055, 1:0.006, 1:0.0065, 1:0.007, 1:0.0075, 1:0.008, 1:0.0085, 1:0.009, 1:0.0095, 1:0.01, 1:0.015, 1:0.02, 1:0.025, 1:0.03, 1:0.035, 1:0.04, 1:0.045, 1:0.05, 1:0.055, 1:0.06, 1:0.065, 1:0.07, 1:0.075, 1:0.08, 1:0.085, 1:0.09, 1:0.095, 1:0.1, 1:0.15, 1:0.2, 1:0.25, 1:0.3, 1:0.35, 1:0.4, 1:0.45, 1:0.5, 1:0.55, 1:0.6, 1:0.65, 1:0.7, 1:0.75, 1:0.8, 1:0.85, 1:0.9, 1:0.95, 1:1.0, 1:1.5, 1:2.0, 1:2.5, 1:3.0, 1:3.5, 1:4.0, 1:4.5, 1:5.0, 1:6.0, 1:7.0, 1:8.0, 1:9.0, 1:10.0, or a range defined by any two thereof and any value and subrange contained within the range.
In one embodiment, said nutrient composition may have a mass ratio of the human milk oligosaccharide (for example neurtral fucosylated human milk oligosaccharide (HMO) selected from the group consisting of 2'-fucosyl lactose (2'-FL), 3'-fucosyl lactose (3'-FL), lacto-N-fucopentaose I (LNFP I), lacto-N-difucohexaose I
(LNDFH
Date Recue/Date Received 2022-12-12 I), lacto-N-difucohexaose II (LNDFH II), for example 2'-fucosyl lactose (2'-FL)) to the milk fat globule membrane to the taurine of 1:0.01-500:0.0005-10, preferably 1:0.02-100:0.0005-10, preferably 1:0.05-50:0.001-5, preferably 1:0.1-10:0.005-1, preferably 1:0.15-6:0.01-0.5, or a mass ratio obtained by any combination of the .. ratios described for the mass ratio of the human milk oligosaccharide (for example neurtral fucosylated human milk oligosaccharide (HMO) selected from the group consisting of 2'-fucosyl lactose (2'-FL), 3'-fucosyl lactose (3'-FL), lacto-N-fucopentaose I (LNFP I), lacto-N-difucohexaose I (LNDFH I), lacto-N-difucohexaose II (LNDFH II), for example 2'-fucosyl lactose (2'-FL)) to the milk .. fat globule membrane with the ratios described for the mass ratio of the human milk oligosaccharide (for example neurtral fucosylated human milk oligosaccharide (HMO) selected from the group consisting of 2'-fucosyl lactose (2'-FL), 3'-fucosyl lactose (3'-FL), lacto-N-fucopentaose I (LNFP I), lacto-N-difucohexaose I
(LNDFH
I), lacto-N-difucohexaose II (LNDFH II), for example 2'-fucosyl lactose (2'-FL)) to the taurine.
When the mass ratio of the human milk oligosaccharide (for example neurtral fucosylated human milk oligosaccharide (HMO) selected from the group consisting of 2'-fucosyl lactose (2'-FL), 3'-fucosyl lactose (3'-FL), lacto-N-fucopentaose I
(LNFP I), lacto-N-difucohexaose I (LNDFH I), lacto-N-difucohexaose II (LNDFH
II), for example 2'-fucosyl lactose (2'-FL)) to the milk fat globule membraneto the taurine in the nutrient composition falls within the above-mentioned ranges, more significant promotion in terms of neurodevelopment such as neuron maturation, synaptogenesis and myelination, in particular promotion in terms of OPC
proliferation, maturation and differentiation into OL and/or of OL myelination characteristics, can be realized, and there is more significant synergistic action among various components in terms of these aspects.
Food In another aspect, the present invention also relates to a food containing said nutrient Date Regue/Date Received 2022-12-12 composition.
The food of the present invention may be in a form of powder, and it may also be in a form of liquid.
The food of the present invention may be a formula food for infants and young children (e.g. a formula food for infants, a formula food for more grown-up infants, and a formula food for young children), for example a formula milk powder for infants and young children (e.g. a formula milk powder for infants, and a formula milk powder for young children), a complementary food for infants, nutritional or dietary supplements, or a formulated milk powder for pregnant women.
In one embodiment, said nutrient composition is added in an amount such that the human milk oligosaccharide (e.g. neurtral fucosylated human milk oligosaccharide (HMO) selected from the group consisting of 2'-fucosyl lactose (2'-FL), 3'-fucosyl lactose (3'-FL), lacto-N-fucopentaose I (LNFP I), lacto-N-difucohexaose I
(LNDFH
I), lacto-N-difucohexaose II (LNDFH II), for example 2'-fucosyl lactose (2'-FL)) is at a content by weight of at least 0.01%, preferably at least 0.05%, preferably at least 0.1% and at most 10.0%, preferably at most 5.0%, preferably at most 1.0%, relative to the total weight of said food. For example, 2'-fucosyl lactose (2'-FL) may be at a content by weight, relative to the total weight of said food, of 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 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%, Date Recue/Date Received 2022-12-12 9.7%, 9.8%, 9.9%, 10.0%, or a range defined by any two thereof and any value and subrange contained within the range.
In one embodiment, said nutrient composition is added in an amount such that the milk fat globule membrane is at a content by weight, relative to the total weight of said food, of at least 0.01%, preferably at least 0.05%, preferably at least 0.1% and at most 5.0%, preferably at most 1.0%, preferably at most 0.6%. For example, the milk fat globule membrane may be at a content by weight, relative to the total weight of said food, of 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, .. 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%, or a range defined by any two thereof and any value and subrange contained within the range.
In one embodiment, said nutrient composition is added in an amount such that the taurine is at a content by weigh, relative to the total weight of said food, of at least 0.001%, preferably at least 0.005%, preferably at least 0.01% and at most 1.0%, preferably at most 0.5%, preferably at most 0.1%. For example, the taurine may be at a content by weight, relative to the total weight of said food, of 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%, 0.015%, 0.02%, 0.025%, 0.03%, 0.035%, 0.04%, 0.045%, 0.05%, 0.055%, 0.06%, 0.065%, 0.07%, 0.075%, 0.08%, 0.085%, 0.09%, 0.095%, 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%, Date Recue/Date Received 2022-12-12 0.91%, 0.92%, 0.93%, 0.94%, 0.95%, 0.96%, 0.97%, 0.98%, 0.99%, 1.0%, or a range defined by any two thereof and any value and subrange contained within the range.
In addition the constituents described above for said nutrient composition, said food may have other constituents, for example other proteins, carbohydrates, fat, vitamins, minerals and the like, which are commonly contained in formula food, for example formula food like milk powder for infants and young children.
Use In another aspect, the present invention relates to use of the nutrient composition or food described above for non-curing purposes (i.e., non-medical purpose) of improving the brain development and intelligence of infants and young children, especially promoting neurodevelopment (for example neuron maturation, synaptogenesis and myelination, for example promoting OPC proliferation, maturation, and differentiation into oligodendrocytes (OLs) and/or myelination of oligodendrocytes (OLs)).
Example The present invention will be described in greater detail hereinbelow in combination with the examples, such that the objects, technical solutions and advantages of the present invention will be more apparent. It should be understood that the specific examples described herein is only for explanation of the present invention rather than limination of the present invention. The reagents, methods and devices employed in the present invention are ordinary reagents, methods and devices in the art, unless specifically indicated.
Raw materials The following raw materials are used in the example section which follows, unless indicated otherwise.
Date Regue/Date Received 2022-12-12 2'-fucosyl lactose (2'-FL): GlyCareTM 2'-FL 9000, 2'-fucosyl lactose content 96.0 % by mass Milk fat globule membrane: Tatua of New Zealand PLC1, phospholipid content 12.3% by mass, protein 49.6% by mass;
Taurine: taurine form Beijing Jinkangpu Food Technology Co., Ltd, taurine content 99%.
In the following section, unless indicated otherwise, when a part by mass and ratio of the constituents in the nutrient composition are mentioned, the part by mass refers to the part by mass of 2'-fucosyl lactose (2'-FL), milk fat globule membrane, and taurine, which are active constituents, and the ratio refers to the mass ratio among 2'-fucosyl lactose (2'-FL), milk fat globule membrane, and taurine, which are active constituents.
Several nutrient compositions are formulated by mixing the raw materials 2'-fucosyl lactose (2'-FL), milk fat globule membrane, and taurine according to the ratios shown in the following examples, the composition of which are shown in table 1.
Table 1. Composition of the nutrient compositions No. Part by mass Part by mass of milk fat Part by mass of 2'-FL globule membrane of taurine Example 1 1 2.75 0.05 Example 2 1 0.275 0.5 Example 3 1 0.275 0.01 Example 4 1 2.75 0.5 Comparative 0 0 1 Example 1 Comparative 1 0 0 Example 2 Date Regue/Date Received 2022-12-12 Comparative 0 1 0 Example 3 Comparative 1 0 0.5 Example 4 Comparative 1 0.275 0 Example 5 Comparative 0 0.55 1 Example 6 Cell Experiment Example Current studies on brain development are limited to studies on passive memory using animal experiments. There is no discussion on the development of neuron cells, nor is there exploration on the effect of specific dosage of the composition on early brain development. The present invention uses an in vitro model of culture of primary cell containing neurons and OPC to evaluate the effect of a nutrient mixture on myelination and neurons. Through experimental research on the effects of components containing 2'-FL, milk fat globle membrane and taurine in varying proportions on the brain neurve cell development, this method systematically and intuitively evaluated the effects on early brain development, which is of profound significance in terms of guiding the application of the composition.
1. Materials and methods 1.1 Apparatus and reagent consumables Cell incubator; Laser confocal fluorescence microscope; Centrifuge; Electronic balance; Vortexer, water bath, tissue homogenizer.
Nerve cell culture medium; A2B5, MAG, MBP and other antibodies.
1.2 Experimental Method 1.2.1 Acquisition of nerve primary cells All experiments were approved by ethics, and the primary mixed culture of neurons Date Regue/Date Received 2022-12-12 and OL were carried out according to the following steps. Briefly, the forebrain of newborn rats and mice were dissociated with trypsin (Trypsin EDTA 1X, PAN
BIOTECH) at 37 C for 20 minutes. After addition of Dulbecco modified Eagle medium (DMEM, PAN BIOTECH) containing DNAase I Grade 11 (0.1 mg/ml, PAN
BIOTECH) and 10% fetal bovine serum (FCS, GIBCO), the reaction was stopped.
The cells were mechanically separated three times through a 10 ml pipette, and then centrifuged at 4 C under 515g for 10 minutes.
Living cells were inoculated in 96-well plates (20000/well), which were pre-coated with poly-L-lysine (BD Falcon) and laminin (Sigma). The culture medium consists of Neurobasal (GIBCO) added with 2% B27 (GIBCO), 2 mM L-glutamine (L Glu, PAN BIOTECH), 2% P/S solution (PAN BIOTECH), 1% FCS and 10 ng/ml platelet-derived growth factor (PDGF-AA, PAN BIOTECH). The 96-well plates are stored in a humidified incubator at a temperature of 37 C and with an environment of air (95%) - CO2 (5%).
1.2.2 Nerve cell culture A same number of cells were placed on 48-well plates, and then incubated for 12, 18 or 30 DIVs. Half of the medium were replaced every other day. A mixture or separate nutrition were added to the fresh medium (the nutrient composition prepared above, containing 2'-FL, taurine and/or milk fat global membrane).
1.2.3 Immunohistochemical experiment After 12, 18 and 30 DIVs, the cells were fixed with a cold mixture of 95%
ethanol and acetic acid (5%) for 5 minutes. The non-specific sites were then blocked for 15 minutes at room temperature with a phosphate buffered saline (PBS) solution containing 0.1% saponin (Sigma) and 1% FCS (GIBCO).
At 12 DIVs, nerve cells were co-incubated with mouse monoclonal antibody A2B5 (dilution: 1/200, Millipore, MAB312RX) at room temperature for 2h, and then co-Date Recue/Date Received 2022-12-12 incubated with neurofilament antibody (dilution: 1/500, Sigma, N4142) at room temperature for 2h. Finally, a secondary goat anti-rabbit antibody (diluted 1/400, SIGMA, 5AB460084) was used to co-incubate at room temperature for 1 h.
At 18 DIVs, nerve cells were co-incubated with mouse monoclonal antibody MAG
(dilution: 1/400, Millipore, MAB1567) and neurofilament protein antibody (dilution:
1/500, Sigma, N4142) for 2h. Then a secondary goat anti-rabbit antibody (dilution:
1/400, Sigma, 5AB4600042) and a secondary goat anti-rabbit antibody (dilution:
1/400, SIGMA, 5AB4600084) were used to co-incubate at room temperature for lh.
At 30 DIVs, nerve cells were co-incubated with mouse monoclonal antibody MBP
(dilution: 1/1000, Novus, NBP1-05204) and neurofilament protein antibody (dilution: 1/500, Sigma, N4142) for 2 hours. Then a secondary goat anti-mouse antibody (dilution: 1/800, Sigma, 5AB4600042) and a secondary goat anti-rabbit antibody (dilution: 1/400, SIGMA, 5AB4600084) were used to co-incubate at room temperature for lh.
1.2.4 Microscrope imaging ImageXpress equipped with LED lights (360/480/565 for excitation and 460/535/620 for emission) is used for 20x amplification. All images are acquired using the same settings.
Under the condition of 12 DIVs, the number of OPC was calculated by quantifying the number of A2B5 expressing cells, and the result was expressed as the average number of A2B5 expressing cells per image and per well.
The differentiation of OPC into OL was evaluated by counting the number of MAG
positive cells in cell culture. The results were expressed as the average number of cells per image and per well. The morphological maturity of MAG positive cells were assessed by measuring the average surface area of MAG positive cells in Date Recue/Date Received 2022-12-12 DIV wells ( M/image/well).
At 30 DIVs, the maturity of OL was estimated by calculating the number of MBP
positive cells (average number of cells per imge, per well) and the average surface area of MBP positive cells at 30 DIVs ( M, per image, per well).
1.3 cell experiment grouping Cells were inoculated on a 96-well plate and cultured for a certain period of time.
Half of the culture medium was replaced every other day. Varying concentrations of mixed or separate 2'-FL mixtures were added to the special culture medium for fresh primary cells (added on day 12, 18 and 30, respectively). 6 replicas for each sample.
Oleoxime (300 nM, proved to accelerate OL maturation and myelination in vitro and in vivo) was taken as the positive control. The blank control group, positive control group and sample intervention group were compared, respectively. The effects of milk fat global membrane, 2'-FL and taurine, alone or in mixture, on OPC
population, OL maturation and differentiation, myelin formation and neurite growth was determined by immunohistochemistry (MBP, NF, A2B5). See Table 2 below for specific experimental dosage.
Table 2. Dosage for Cell Experiments milk fat Cell Corresponding 2'-FL globule taurine Experiment Dosage group Example (mg/ml) membrane (mg/ml) Example (mg/ml) 1 Control blank control group positive control group 2 positive control Olesoxime Comparative 3 2'-FL (low dosage) 0.2 Example 2 Comparative 4 2'-FL (medium dosage) 2 Example 2 Date Regue/Date Received 2022-12-12 Comparative 2'-FL (high dosage) 20 Example 2 Comparative milk fat globule 6 0.55 Example 3 membrane (low dosage) milk fat globule Comparative 7 membrane (medium 5.5 Example 3 dosage) Comparative milk fat globule Example 3 membrane (high dosage) Comparative 9 taurine (low dosage 1) 0.02 Example 1 Comparative taurine (low dosage 2) 0.01 Example 1 Comparative 11 taurine (medium dosage) 0.1 Example 1 Comparative 12 taurine (high dosage) 1 Example 1 Comparative 13 2'-FL+taurine 2 1 Example 4 Comparative 2'-FL+milk fat globule 14 2 0.55 Example 5 membrane Comparative milk fat globule 0.55 1 Example 6 membrane +taurine 2'-FL (low dosage)+milk fat globule 16 Example 1 membrane (low 0.2 0.55 0.01 dosage)+taurine (low dosage) 2'-FL (medium dosage)+milk fat globule 17 Example 1 membrane (medium 2 5.5 0.1 dosage)+taurine (medium dosage) 18 Example 1 2'-FL (high 20 55 1 Date Regue/Date Received 2022-12-12 dosage)+milk fat globule membrane (high dosage)+taurine (high dosage) 2'-FL (low to medium dosage)+milk fat globule 19 Example 1 membrane (low to 1 2.75 0.05 medium dosage)+taurine (low to medium dosage) 2'-FL (medium to high dosage)+milk fat globule 20 Example 1 membrane (medium to 4 11 0.2 high dosage)+taurine (medium to high dosage) 2'-FL+milk fat globule 21 Example 2 2 0.55 1 membrane +taurine 2'-FL+milk fat globule 22 Example 3 2 0.55 0.02 membrane +taurine 2'-FL+milk fat globule 23 Example 4 2 5.5 1 membrane +taurine 1.4 Statistics analysis The results were expressed as mean standard error. SPSS software was used for T-test and one-way ANOVA test. When p<0.05, it was judged that there was a significant difference 2. Experimental Results 2.1 Effect of various samples on nerve cells In order to measure the effect of mixed nutrition or single nutrition treatment on OPC, we evaluated the number of positive cells labeled A2B5 after 12 DIVs to estimate the number of OPCs. The average number of A2B5 positive cells per well measured is shown in Table 3.
Date Regue/Date Received 2022-12-12 Table 3. Effect of different nutrient composition samples comprising 2'-FL, milk fat global membrane and/or taurine on the number ofA2B5 positive cells number of A2B5 Cell positive cells Experiment dosage group (mean standard Example deviation) 1 blank control group 116.67 3.79 2 positive control group Olesoxime 171.33 3.51**
3 2'-FL (low) 151.33 4.73**
4 2'-FL(medium) 156.00 5.57**
2'-FL (high) 135.00 6.08**
6 milk fat globule membrane (low) 168.00 5.29**
7 milk fat globule membrane (medium) 131.33 6.11**
8 milk fat globule membrane (high) 106.33 8.74*
9 taurine (low 1) 124.06 8.269**
taurine (low 2) 114.00 5.29 11 taurine (medium) 135.00 5.00**
12 taurine (high) 175.67 4.04 **
13 2'-FL+taurine 145.50 8.469**
14 2'-FL+milk fat globule membrane 140.67 11.354**
milk fat globule membrane +taurine 143.50 8.386**
2'-FL (low dosage)+milk fat globule 16 membrane (low dosage)+taurine (low 182.67 5.69 **
dosage) 2'-FL (medium dosage)+milk fat 17 globule membrane (medium 178.67 5.13 **
dosage)+taurine (medium dosage) 2'-FL (high dosage)+milk fat globule 18 258.00 7.00 **
membrane (high dosage)+taurine Date Regue/Date Received 2022-12-12 (high dosage) 2'-FL (low to medium dosage)+milk fat globule membrane (low to 19 214.67 5.51**
medium dosage)+taurine (low to medium dosage) 2'-FL (medium to high dosage)+milk fat globule membrane (medium to 20 137.00 3.61**
high dosage)+taurine (medium to high dosage) 2'-FL+milk fat globule membrane 263.14 12.71**
+taurine 2'-FL+milk fat globule membrane 246.21 10.79**
+taurine 2'-FL+milk fat globule membrane 255.22 9.03**
+taurine N.B.: * p < 0.05, in comparison with the blank control group, ** p < 0.01, in comparison with the blank control group The results of sample treatment showed that 2'- FL, milk fat global membrane and taurine could increase the number of A2B5 positive cells when used alone, relative to the blank control group (cell experiment example 1), which indicates that these three constituents help the proliferation of oligodendrocyte precursor cell when used alone.
However, the inventors discovered that when any two of the three components were used in combination, there was a strong antagonism.
In particular, it can be seen according to cell experiment examples 13-15 that:
- In terms of components used and the amount of the components used, cell Date Regue/Date Received 2022-12-12 experiment example 13 is equivalent to the combination of cell experiment examples 4 and 12. Relative to the blank control group (cell experiment example 1), cell experiment examples 4 and 12 increase the number of A2B5 positive cells by 39.33 and 59 respectively, while cell experiment example 13 increases the number of A2B5 positive cells by 28.83, which is not only far less than the sum of the former two (98.33) (the difference from the sum of the former two being A1=69.5), but also less than either one of the former two.
- Cell experiment example 14 is equivalent to the combination of cell experiment examples 4 and 6. However, relative to the blank control group (cell experiment example 1), cell experiment examples 4 and 6 increase the number of A2B5 positive cells by 39.33 and 51.33 respectively, while cell experiment example 14 increases the number of A2B5 positive cells by 24, which is not only far less than the sum of the former two (90.66) (the difference from the sum of the former two being A2=66.66), but also less than either one of the former two.
- Cell experiment example 15 is equivalent to the combination of cell experiment examples 6 and 12. However, relative to the blank control group (cell experiment example 1), cell experiment examples 6 and 12 increase the number of A2B5 positive cells by 51.33 and 59 respectively, while cell experiment example 15 increases the number of A2B5 positive cells by 26.83, which is not only far less than the sum of the former two (110.33) (the difference from the sum of the former two being A3=83.5), but also less than either one of the former two.
This indicates that when any two of 2'-FL, milk fat global membrane and taurine are used in combination, there is a strong antagonism in terms of the number of positive cells and thus the proliferation of oligodendrocyte precursor cells, and the effect of their use in combination is less than that of any one of the components when it is used alone.
Moreover, the inventors found that when the three of 2'-FL, milk fat global membrane and taurine are used in combination, a significant reduction in inter-Date Regue/Date Received 2022-12-12 component antagonism, and a synergistic increase in the number of A2B5 positive cells and thus the proliferation of oligodendrocyte precursor cells are enabled.
In particular, cell experiment example 18 is equivalent to the combination of cell experiment examples 5, 8 and 12 in terms of the components used and the amount of components used. With respect to cell experiment example 1, cell experiment examples 5, 8, 12 and 18 increase the number of A2B5 positive cells by 18.33, -10.34, 59 and 141.33 respectively. The increment realized in cell experiment example 18 (141.33) is greater than the sum of the former three (66.99).
In addition, in terms of the components used and the amount of components used, cell experiment example 21 is equivalent to the combination of cell experiment examples 6 and 13, or the combination of cell experiment examples 12 and 14, or the combination of cell experiment examples 4 and 15, or the combination of cell experiment examples 4, 6 and 12. Compared with blank control group (cell experiment example 1), - Cell experiment example 21 increased the number ofA2B5 positive cells by 146.47, - cell experiment examples 6 and 13 increased the number of A2B5 positive cells by 51.33 and 28.33 respectively, with a sum of 80.16, which is less than the increment realized in cell experiment example 21 (146.47), - cell experiment examples 12 and 14 increased the number of A2B5 positive cells by 59 and 24 respectively, with a sum of 83, which is less than the increment realized in cell experiment example 21 (146.47), - cell experiment examples 4 and 15 increased the number of A2B5 positive cells by 39.33 and 26.83 respectively, with a sum of 66.16, which is less than the increment realized in cell experiment example 21 (146.47), - cell experiment examples 4, 6 and 12 increased the number of A2B5 positive cells by 39.33, 51.33 and 59 respectively, with a sum of 149.66, which is slightly greater than the increment realized in cell experiment example 21 (146.47), with a difference of A4=3.19, which is far less than the difference A1=69.5, A2=66.66, and A3=83.5.
Date Regue/Date Received 2022-12-12 In addition, cell experiment example 22 is equivalent to the combination of cell experiment examples 9 and 14, or the combination of cell experiment examples 4, 6 and 9, in terms of the components used and the amount of the components used.
Relative to the blank control group (cell experiment example 1), cell experiment examples 4, 6, 9, 14 and 22 increase the number of A2B5 positive cells by 39.33, 51.33, 7.39, 24 and 129.54 respectively. The increment realized in cell experiment example 22 (129.54) is greater than the sum of the respective increments of cell experiment examples 9 and 14 (31.39), and is also greater than the sum of the respective increments of cell experiment examples 4, 6 and 9 (98.05).
In addition, cell experiment example 23 is equivalent to the combination of cell experiment examples 7 and 13, or the combination of cell experiment examples 4, 7 and 12, in terms of components used and the amount of the components used.
Relative to the blank control group (cell experiment example 1), cell experiment examples 4, 7, 12, 13 and 23 increase the number of A2B5 positive cells by 39.33, 14.66, 59, 28.83 and 138.55 respectively. The increment realized in cell experiment example 23 (138.55) is greater than the sum of the respective increments of cell experiment examples 7 and 13 (43.49), and greater than the sum of the respective increments of cell experiment examples 4, 7 and 12 (112.99).
Thus, it can be seen that when the three of 2'-FL, milk fat global membrane and taurine are used in combination, a significantly reduction in inter-component antagonism is enabled. There is a synergistic effect among the three components, which can synergistically increase the number of A2B5 positive cells and thus the proliferation of oligodendrocyte precursor cells.
2.2 The effect of various samples on OPC cell myelination In order to measure the effect of mixed nutrition or single nutrition treatment on OPC cell myelination, we evaluated the number of positive cells labelled MAG
after Date Regue/Date Received 2022-12-12 18 DIVs. The measured average number of MAG positive cells per well is shown in Table 4.
Table 4. Effect of different nutrient composition samples containing 2'-FL, milk fat global membrane and/or taurine on the number of MAG positive cells number of MAG
cell experiment positive cells dosage group example (mean standard deviation) 1 blank control group 40.67 4.04 2 positive control group Olesoxime 87.00 4.36**
3 2'-FL (low dosage) 54.00 6.08**
4 2'-FL (medium dosage) 76.33 4.51**
5 2'-FL (high dosage) 62.00 4.00**
6 milk fat globule membrane (low dosage) 70.33 4.04**
7 milk fat globule membrane (medium dosage) 58.67 3.51**
8 milk fat globule membrane (high dosage) 42.33 3.21 9 taurine (low dosage 1) 58.01 4.39**
taurine (low dosage 2) 44.00 3.61 11 taurine (medium dosage) 70.33 4.16**
12 taurine (high dosage) 85.33 4.73**
13 2 '-FL+taurine 70.50 7.196**
14 2'-FL+milk fat globule membrane 66.50 6.662**
milk fat globule membrane +taurine 66.33 7.957**
2'-FL (low dosage)+milk fat globule membrane 16 84.67 4.51**
(low dosage)+taurine (low dosage) 2'-FL (medium dosage)+milk fat globule 17 membrane (medium dosage)+taurine (medium 92.00 4.58**
dosage) 2'-FL (high dosage)+milk fat globule membrane 18 110.67 4.04**
(high dosage)+taurine (high dosage) 2'-FL (low to medium dosage)+milk fat globule 19 99.00 3.61**
membrane (low to medium dosage)+taurine (low Date Regue/Date Received 2022-12-12 to medium dosage) 2'-FL (medium to high dosage)+milk fat globule 20 membrane (medium to high dosage)+taurine 68.00 2.65**
(medium to high dosage) 21 2'-FL+milk fat globule membrane +taurine 128.54 7.38**
22 2'-FL+milk fat globule membrane +taurine 121.30 8.47**
23 2'-FL+milk fat globule membrane +taurine 124.36 8.08**
N.B.: * p < 0.05, in comparison with the blank control group, ** p < 0.01, in comparison with the blank control group The results of sample processing showed that all of 2'-FL, milk fat global membrane and taurine could increase the number of MAG positive cells when used alone, compared with blank control group (cell experiment example 1), which indicates that these three components, when used alone, help the myelination of oligodendrocyte precursor cell.
However, the inventors found that when any two of the three components were used in combination, there was a strong antagonism.
In particular, it can be seen from cell experiment examples 13-15 that:
- In terms of the components used and the amount of the components used, cell experiment example 13 is equivalent to the combination of cell experiment examples 4 and 12. Relative to the blank control group (cell experiment example 1), cell experiment examples 4 and 12 increase the number of MAG positive cells by 35.66 and 44.66 respectively, while cell experiment example 13 increases the number of MAG positive cells by 29.83, which is not only far less than the sum of the former two (80.32) (the difference from the sum of the former two A1=50.49), but also less than either of the former two.
- Cell experment example 14 is equivalent to the combination of cell experiment examples 4 and 6. However, relative to the blank control group (cell experiment Date Regue/Date Received 2022-12-12 example 1), cell experiment example 4 and 6 increase the number of MAG
positive cells by 35.66 and 29.66 respectively, while cell experiment example 14 increases the number of MAG positive cells by 25.83, which is not only far less than the sum of the former two (65.32) (the difference from the sum ofthe former two A2=39.49), but also less than either of the former two.
- Cell experiment example 15 is equivalent to the combination of cell experiment examples 6 and 12. However, relative to the blank control group (cell experiment example 1), cell experiment examples 6 and 12 increase the number of MAG
positive cells by 29.66 and 44.66 respectively, while cell experiment example
15 increases the number of MAG positive cells by 25.66, which is not only far less than the sum of the former two (74.32) (the difference from the sum of the former two A3=48.66), but also smaller than either of the former two.
This indicates that when any two of 2'-FL, milk fat global membrane and taurine are used in combination, there is a strong antagonistm in terms of the number of MAG
positive cells and thus the myelination (differentiation into oligodendrocyte OL) of oligodendrocyte precursor cells, and the effect of the use in combination is smaller than that of any one of the components when used alone.
Furthermore, the inventors found that when 2'- FL, milk fat global membrane and taurine are used in combination, a significant reduction in inter-component antagonism, and a synergistic increase in the number of MAG positive cells and thus oligodendrocyte precursor cell myelination are enabled.
In particular, cell experiment example 18 is equivalent to the combination of cell experiment examples 5, 8 and 12 in terms of the components used and the amount of the components used. Compared with cell experiment example 1, cell experiment examples 5,8, 12 and 18 increase the number of MAG positive cells by 21.33, 1.66, 44.66 and 70 respectively. The increment in the number of MAG positive cells in cell experiment example 18 (70) is greater than the sum of the former three (67.65).
Date Regue/Date Received 2022-12-12 In addition, in terms of the components used and the amount of the components used, cell experiment example 21 is equivalent to the combination of cell experiment examples 6 and 13, or the combination of cell experiment examples 12 and 14, or the combination of cell experiment examples 4 and 15, or the combination of cell experiment examples 4, 6 and 12. Compared with blank control group (cell experiment example 1):
- Cell experiment example 21 increased the number of MAG positive cells by 87.87, - Cell experiment examples 6 and 13 increased the number of MAG positive cells by 29.66 and 29.83 respectively, with a sum of 59.49, which is less than the increment realized in cell experiment example 21 (87.87), - Cell experiment examples 12 and 14 increased the number of MAG positive cells by 44.66 and 25.83 respectively, with a sum of 70.49, which is less than the increment realized in cell experiment example 21 (87.87), - Cell experiment examples 4 and 15 increased the number of MAG positive cells by 35.66 and 25.66 respectively, with a sum of 61.32, which is less than the increment realized in cell experiment example 21 (87.87), - Cell experiment examples 4, 6 and 12 increased the number of MAG positive cells by 35.66, 29.66 and 44.66 respectively, with a sum of 109.98, slightly greater than the increment of 87.87 realized in cell experiment example 21, with a difference therebetween A4=22.11, far less than the difference A1=50.49, A2=39.49, and A3=48.66.
In addition, cell experiment example 22 is equivalent to the combination of cell experiment examples 9 and 14, or the combination of cell experiment examples 4, 6 and 9, in terms of components used and the amount of the components used.
Relative to the blank control group (cell experiment example 1), cell experiment examples 4, 6, 9, 14 and 22 increase the number of MAG positive cells by 35.66, 29.66, 17.34, 25.83 and 80.63 respectively. The imcrement in the number of MAG positive cells .. in cell experiment example 22 (80.63) is greater than the sum of the respective Date Regue/Date Received 2022-12-12 increment in cell experiment examples 9 and 14 (43.17), which is slightly less than the sum of the respective increments of cell experiment examples 4, 6 and 9 (82.66) (a difference therebetween of A5=2.03, far less than the difference A2=39.49).
In addition, cell experiment example 23 is equivalent to the combination of cell experiment example 7 and 13, or the combination of cell experiment examples 4, and 12, in terms of components used and the amount of the components used.
Relative to the blank control group (cell experiment example 1), cell experiment examples 4, 7, 12, 13 and 23 increase the number of MAG positive cells by 35.66, 18, 44.66, 29.83 and 83.69 respectively. The increment in the number of MAG
positive cells in cell experiment example 23 (83.69) is greater than the sum of the respective increments in cell experiment examples 7 and 13 (47.83), which is slightly less than the sum of the respective increments of cell experiment examples 4, 7 and 12 (98.32) (a difference therebetween of A6=14.46, far less than the difference A1=50.49).
Thus, it can be seen that when 2'-FL, milk fat global membrane and taurine are used in combination, the inter-component antagonism is significantly reduced. There is a synergistic effect among the three components, which can synergistically increase the number of MAG positive cells and therefore myelination of oligodendrocyte precursor cells.
2.3 Effects of various samples on OPC cell maturation In order to measure the effect of mixed nutrition or single nutrition treatment on OPC cell maturation, we evaluated the number of MBP positive cells after 30DIVs.
The measured average number of MBP positive cells per well is shown in Table 5.
Table 5. Effect of different nutrient composition samples containing 2'-FL, milk fat global membrane and/or taurine on the number of MBP positive cells Date Regue/Date Received 2022-12-12 cell dosage group number of MBP positive experiment cells example (mean standard deviation) 1 blank control group 62.33 4.51 2 positive control groupOlesoxime 124.00 3.61**
3 2'-FL (low dosage) 104.00 4.58**
4 2'-FL (medium dosage) 104.67 5.03**
2'-FL (high dosage) 83.00 5.29**
6 milk fat globule membrane (low 106.67 5.51**
dosage) 7 milk fat globule membrane 92.00 6.24**
(medium dosage) 8 milk fat globule membrane (high 52.33 6.11 dosage) 9 taurine (low dosage 1) 69.67 5.91 taurine (low dosage 2) 59.67 4.51 11 taurine (medium dosage) 80.67 5.51**
12 taurine (high dosage) 109.33 4.51**
13 2'-FL+taurine 85.33 7.06**
14 2'-FL+milk fat globule membrane 82.50 6.74**
milk fat globule membrane 84.00 7.36**
+taurine
This indicates that when any two of 2'-FL, milk fat global membrane and taurine are used in combination, there is a strong antagonistm in terms of the number of MAG
positive cells and thus the myelination (differentiation into oligodendrocyte OL) of oligodendrocyte precursor cells, and the effect of the use in combination is smaller than that of any one of the components when used alone.
Furthermore, the inventors found that when 2'- FL, milk fat global membrane and taurine are used in combination, a significant reduction in inter-component antagonism, and a synergistic increase in the number of MAG positive cells and thus oligodendrocyte precursor cell myelination are enabled.
In particular, cell experiment example 18 is equivalent to the combination of cell experiment examples 5, 8 and 12 in terms of the components used and the amount of the components used. Compared with cell experiment example 1, cell experiment examples 5,8, 12 and 18 increase the number of MAG positive cells by 21.33, 1.66, 44.66 and 70 respectively. The increment in the number of MAG positive cells in cell experiment example 18 (70) is greater than the sum of the former three (67.65).
Date Regue/Date Received 2022-12-12 In addition, in terms of the components used and the amount of the components used, cell experiment example 21 is equivalent to the combination of cell experiment examples 6 and 13, or the combination of cell experiment examples 12 and 14, or the combination of cell experiment examples 4 and 15, or the combination of cell experiment examples 4, 6 and 12. Compared with blank control group (cell experiment example 1):
- Cell experiment example 21 increased the number of MAG positive cells by 87.87, - Cell experiment examples 6 and 13 increased the number of MAG positive cells by 29.66 and 29.83 respectively, with a sum of 59.49, which is less than the increment realized in cell experiment example 21 (87.87), - Cell experiment examples 12 and 14 increased the number of MAG positive cells by 44.66 and 25.83 respectively, with a sum of 70.49, which is less than the increment realized in cell experiment example 21 (87.87), - Cell experiment examples 4 and 15 increased the number of MAG positive cells by 35.66 and 25.66 respectively, with a sum of 61.32, which is less than the increment realized in cell experiment example 21 (87.87), - Cell experiment examples 4, 6 and 12 increased the number of MAG positive cells by 35.66, 29.66 and 44.66 respectively, with a sum of 109.98, slightly greater than the increment of 87.87 realized in cell experiment example 21, with a difference therebetween A4=22.11, far less than the difference A1=50.49, A2=39.49, and A3=48.66.
In addition, cell experiment example 22 is equivalent to the combination of cell experiment examples 9 and 14, or the combination of cell experiment examples 4, 6 and 9, in terms of components used and the amount of the components used.
Relative to the blank control group (cell experiment example 1), cell experiment examples 4, 6, 9, 14 and 22 increase the number of MAG positive cells by 35.66, 29.66, 17.34, 25.83 and 80.63 respectively. The imcrement in the number of MAG positive cells .. in cell experiment example 22 (80.63) is greater than the sum of the respective Date Regue/Date Received 2022-12-12 increment in cell experiment examples 9 and 14 (43.17), which is slightly less than the sum of the respective increments of cell experiment examples 4, 6 and 9 (82.66) (a difference therebetween of A5=2.03, far less than the difference A2=39.49).
In addition, cell experiment example 23 is equivalent to the combination of cell experiment example 7 and 13, or the combination of cell experiment examples 4, and 12, in terms of components used and the amount of the components used.
Relative to the blank control group (cell experiment example 1), cell experiment examples 4, 7, 12, 13 and 23 increase the number of MAG positive cells by 35.66, 18, 44.66, 29.83 and 83.69 respectively. The increment in the number of MAG
positive cells in cell experiment example 23 (83.69) is greater than the sum of the respective increments in cell experiment examples 7 and 13 (47.83), which is slightly less than the sum of the respective increments of cell experiment examples 4, 7 and 12 (98.32) (a difference therebetween of A6=14.46, far less than the difference A1=50.49).
Thus, it can be seen that when 2'-FL, milk fat global membrane and taurine are used in combination, the inter-component antagonism is significantly reduced. There is a synergistic effect among the three components, which can synergistically increase the number of MAG positive cells and therefore myelination of oligodendrocyte precursor cells.
2.3 Effects of various samples on OPC cell maturation In order to measure the effect of mixed nutrition or single nutrition treatment on OPC cell maturation, we evaluated the number of MBP positive cells after 30DIVs.
The measured average number of MBP positive cells per well is shown in Table 5.
Table 5. Effect of different nutrient composition samples containing 2'-FL, milk fat global membrane and/or taurine on the number of MBP positive cells Date Regue/Date Received 2022-12-12 cell dosage group number of MBP positive experiment cells example (mean standard deviation) 1 blank control group 62.33 4.51 2 positive control groupOlesoxime 124.00 3.61**
3 2'-FL (low dosage) 104.00 4.58**
4 2'-FL (medium dosage) 104.67 5.03**
2'-FL (high dosage) 83.00 5.29**
6 milk fat globule membrane (low 106.67 5.51**
dosage) 7 milk fat globule membrane 92.00 6.24**
(medium dosage) 8 milk fat globule membrane (high 52.33 6.11 dosage) 9 taurine (low dosage 1) 69.67 5.91 taurine (low dosage 2) 59.67 4.51 11 taurine (medium dosage) 80.67 5.51**
12 taurine (high dosage) 109.33 4.51**
13 2'-FL+taurine 85.33 7.06**
14 2'-FL+milk fat globule membrane 82.50 6.74**
milk fat globule membrane 84.00 7.36**
+taurine
16 2'-FL (low dosage)+milk fat 115.00 7.81**
globule membrane (low dosage)+taurine (low dosage)
globule membrane (low dosage)+taurine (low dosage)
17 2'-FL (medium dosage)+milk fat 121.33 3.51**
globule membrane (medium dosage)+taurine (medium dosage)
globule membrane (medium dosage)+taurine (medium dosage)
18 2'-FL (high dosage)+milk fat 142.00 4.58**
Date Regue/Date Received 2022-12-12 globule membrane (high dosage)+taurine (high dosage)
Date Regue/Date Received 2022-12-12 globule membrane (high dosage)+taurine (high dosage)
19 2'-FL (low to medium 108.33 6.43**
dosage)+milk fat globule membrane (low to medium dosage)+taurine (low to medium dosage)
dosage)+milk fat globule membrane (low to medium dosage)+taurine (low to medium dosage)
20 2'-FL (medium to high 73.67 4.16**
dosage)+milk fat globule membrane (medium to high dosage)+taurine (medium to high dosage)
dosage)+milk fat globule membrane (medium to high dosage)+taurine (medium to high dosage)
21 2'-FL+milk fat globule membrane +taurine 167.98 7.90**
22 2'-FL+milk fat globule membrane +taurine 154.70 8.32**
23 2'-FL+milk fat globule membrane +taurine 156.77 7.46**
N.B.: * p < 0.05, in comparison with the blank control group, ** p < 0.01, in comparison with the blank control group The sample treatment results showed that, relative to the blank control group (cell experiment example 1), each one of 2'-FL, milk fat global membrane, and taurine, when used alone, can increase the number of MBP positive cells, which indicates that these three ingredients, when used alone, can contribute to the maturation of the oligodendrocyte precursor cells.
However, the inventors found that when any two of the three components were used together, there was a strong antagonism.
Date Regue/Date Received 2022-12-12 In particular, according to cell experiment examples 13-15, it can be seen that:
- In terms of the components used and the amount of the components used, cell experiment example 13 is equivalent to the combination of cell experiment examples 4 and 12. Relative to the blank control group (cell experiment example 1), cell experiment examples 4 and 12 increase the number of MBP positive cells by 42.34 and 47 respectively, while cell experiment example 13 increases the number of MBP
positive cells by 23, which is not only far less than the sum of the former two (89.34) (the difference from the sum of the former two A1=66.34), but also less than either of the former two.
- Cell experiment example 14 is equivalent to the combination of cell experiment examples 4 and 6. However, compared with the blank control group (cell experiment example 1), cell experiment examples 4 and 6 increase the number of MBP
positive cells by 42.34 and 44.34 respectively, while cell experiment example 14 increases the number of MBP positive cells by 20.17, which is not only far less than the sum of the former two (86.68) (the difference from the sum of the former two A2=66.51), but also less than either of the former two.
- Cell experiment example 15 is equivalent to the combination of cell experiment examples 6 and 12. However, relative to the blank control group (cell experiment example 1), cell experiment examples 6 and 12 increase the number ofMBP
positive cells by 44.34 and 47 respectively, while cell experiment example 15 increases the number of MBP positive cells by 21.67, which is not only far less than the sum of the former two (91.34) (the difference from the sum of the former two A3=69.67), but also less than either of the former two.
This indicates that when any two of 2'-FL, milk fat global membrane and taurine are used in combination, there is a strong antagonism in terms of the number of MBP
positive cells and thus the maturation of oligodendrocyte precursor cells, and the effect of their use in combination is less than that when any one of the components is used alone.
Date Regue/Date Received 2022-12-12 The inventors further found that when 2'-FL, milk fat global membrane and taurine are used in combination, a significant reduction in inter-component antagonism, and a synergistic increase in the number of MBP positive cells and thus maturation of oligodendrocyte precursor cells.
In particular, cell experiment example 18 is equivalent to the combination of cell experiment examples 5, 8 and 12, in terms of the components used and the amount of the components used. Relative to cell experiment example 1, cell experiment examples 5, 8, 12 and 18 increased the number of MBP positive cells by 20.67, -10, 47 and 79.67 respectively. The increment in the number of MBP positive cells in case of cell experiment example 18 (79.67) is greater than the sum of the former three (57.67).
In addition, in terms of the components used and the amount of the components used, cell experiment example 21 is equivalent to the combination of cell experiment examples 6 and 13, or the combination of cell experiment examples 12 and 14, or the combination of cell experiment examples 4 and 15, or the combination of cell experiment examples 4, 6 and 12. Realtive to the blank control group (cell experiment example 1), - cell experiment example 21 increased the number of MBP positive cells by 105.65, - cell experiment examples 6 and 13 increase the number of MBP positive cells by 44.34 and 23 respectively, with a sum of 67.34, which is less than the increment realized in cell experiment example 21 (105.65), - cell experiment examples 12 and 14 increased the number of MBP positive cells by 47 and 20.17 respectively, with a sum of 67.17, which is less than the increment realized in cell experiment example 21 (105.65), - cell experiment examples 4 and 15 increase the number of MBP positive cells by 42.34 and 21.67 respectively, with a sum of 64.01, which is less than the increment realized in cell experiment example 21 (105.65), Date Regue/Date Received 2022-12-12 - cell experiment examples 4, 6 and 12 increased the number of MBP positive cells by 42.34, 44.34 and 47 respectively, with a sum of 133.68, which is slightly greater than the increment realized in cell experiment example 21 (105.65), with a difference therebetween A4=28.03, far less than the difference A 1=66.34, A2=66.51, and A3=69.67.
In addition, cell experiment example 22 is equivalent to the combination of cell experiment examples 9 and 14, or the combination of cell experiment examples 4, 6 and 9, in terms of the components used and the amount of the components used.
Relative to the blank control group (cell experiment example 1), cell experiment examples 4, 6, 9, 14 and 22 increase the number of MBP positive cells by 42.34, 44.34, 7.34, 20.17 and 92.37 respectively. The increment in the number of MBP
positive cells in cell experiment example 22 (92.37) is greater than the sum of the respective increments in cell experiment examples 9 and 14 (27.51), and slightly less than the sum of the respective increments in cell experiment examples 4, 6 and (94.02) (a difference therebetween of A5=1.65, far less than the difference A2=66.51).
In addition, cell experiment example 23 is equivalent to the combination of cell experiment examples 7 and 13, or the combination of cell experiment examples 4, 7 and 12, in terms of the components used and the amount of the components used.
Relative to the blank control group (cell experiment example 1), cell experiment examples 4, 7, 12, 13 and 23 increase the number of MBP positive cells by 42.34, 29.67, 47, 23 and 94.44 respectively. The incrment in the number of MBP
positive cells in cell experiment example 23 (94.44) is greater than the sum of the respective increments in cell experiment examples 7 and 13 (52.67), and slightly less than the sum of the respective increments in cell experiment examples 4, 7 and 12 (119.01) (a difference therebetween of A6=24.57, far less than the difference A1=66.34).
Thus, it can be seen that when the three of 2'-FL, milk fat global membrane and Date Regue/Date Received 2022-12-12 taurine are used in combination, a significant reduction in inter-component antagonism is enabled. There is a synergistic effect among the three components, which can synergistically increase the number of MBP positive cells and thus the maturation of oligodendrocyte precursor cells.
The present invention provides a research concerning a composition of a human milk oligosaccharide (preferably neural fucosylated human milk oligosaccharide (HMO), which is preferably one or more selected from the group consisting of 2'-fluorosyl lactose (2'-FL), 3'-fluorosyl lactose (3'-FL), lacto-N-fucopentaose I (LNFP
I), lacto-N-difucoexaose I (LNDFH I), lacto-N-difucoexaose II (LNDFH II), preferably 2'-fluorosyl lactose (2'-FL)), milk fat globule membrane, and taurine on brain development, especially on neurodevelopment, in particular on oligodendrocyte precursor cell (OPC) proliferation, differentiation or maturation into ligodendrocyte (OL) and the myelination characteristics of oligodendrocyte (OL). It provides a new idea for the development of functional food in the future. Human milk oligosaccharide (preferably neurtral fucosylated human milk oligosaccharide (HMO), which is preferably one or more selected from the group consisting of 2'-fucosyl lactose (2'-FL), 3'-fucosyl lactose (3'-FL), lacto-N-fucopentaose I
(LNFP
I), lacto-N-difucohexaose I (LNDFH I), lacto-N-difucohexaose II (LNDFH II), preferably 2'-fucosyl lactose (2'-FL)), milk fat globule membrane and taurine has a broad prospect in terms of improving memory and brain development. It is found that during the development of central nervous system, extracellular environment plays an important role in regulating brain homeostasis and controlling myelin formation and other cellular mechanisms. Deficiency of key nutrients will significantly affect brain development. Our research shows that in in vitro models, brain cell cultures treated with a combination of 2'-FL, milk fat globle membrane and taurine increase OPC numbers, differentiation or maturion into OL, and the myelination characteristics of OL. There is a good inter-component synergistic effect.
Date Regue/Date Received 2022-12-12 Application Example All "Part(s)" in the following application examples are parts by weight. A %
content of an ingredient is a % by weight content.
In addition, in each of the following application examples, the following raw material sources are used unless otherwise stated.
Raw milk: Heilongjiang Feihe Dairy Co., Ltd Whole milk powder: Heilongjiang Feihe Dairy Co., Ltd Skimmed milk powder: Kerry, Ireland 2'-fucosyl lactose (2'-fucosyl lactose 96.0%) : GlyCare TM 2'-FL 9000 Concentrated whey protein powder rich in milk fat globule membrane (milk fat globle membrane 7%): Lacprodane MFGM-10, Denmark Milk fat globle membrane powder (phospholipid 12.3%): Tatua of New Zealand Taurine (taurine 99%): Beijing Jinkangpu Food Technology Co., Ltd Desalinated whey powder: Euroserum (Red Bird), France Oligogalactose: Baolingbao Biology Co., Ltd Mixed vegetable oil: Cargill Cereals and Oils (Nantong) Co., Ltd Mixed vegetable oil (containing 1,3-dioleate-2-palmitate triglyceride): Bunge Loders Croklaan (Xiamen) Oil Technology Co., Ltd Formulated vitamin: DSM Vitamin (Shanghai) Co., Ltd Formulated minerals: DSM Vitamin (Shanghai) Co., Ltd Solid corn syrup: Baolingbao Biology Co., Ltd Oligofructose: Baolingbao Biology Co., Ltd Oligoisomaltose: Baolingbao Biology Co., Ltd Application Example 1 A formula milk powder for infants, containing 2'-fucosyl lactose, milk fat globule membrane and taurine, is prepared, per 1000 parts of the formula milk powder, by the following constituents in parts by weight:
Date Regue/Date Received 2022-12-12 the present milk powder uses the raw materials of: 195 parts of raw milk (on a dry basis) (each part contains 0.2% milk fat global membrane), 28.5 parts of concentrated whey protein powder rich in milk fat global membrane (each part contains 7% milk fat global membrane), 10.42 parts of 2'-fluorosyl lactose (96.0%
milk fat global membrane in each part), 0.38 parts of taurine (99% taurine in each part), 400 parts of desalinated whey powder, 83.7 parts of lactose, 37 parts of oligogalactose, 200 parts of mixed vegetable oil, 16 parts of arachidonic acid oil powder (10%), 14 parts of docosahexaenoic acid oil powder (7%), 2 parts of sodium citrate, 2 parts of potassium chloride, 6 parts of calcium citrate, 3 parts of formulated vitamin, and 2 parts of formulated minerals; after the above raw materials have been mixed evenly, they underwent pasteurization, homogenization, evaporation and concentration, and spray drying, forming powder-like semi-finished products.
The evenly mixed milk powder is packed with filled-in nitrogen to obtain the final product.
Application Example 2 A formula milk powder for infants, containing 2'-fucosyl lactose, milk fat globule membrane and taurine, is prepared, per 1000 parts of the formula milk powder, by the following constituents in parts by weight:
the present milk powder uses the raw materials of: 220 parts of raw milk (on a dry basis) (0.2% of milk fat global membrane in each part), 15 parts of concentrated whey protein powder rich in milk fat global membrane (7% milk fat global membrane in each part), 1.04 parts of 2'-fluorosyl lactose (96.0% of 2'-fluorosyl lactose in each part), 0.51 parts of taurine (99% of taurine in each part), 400 parts of desalinated whey powder, 86.45 parts of lactose, 37 parts of oligolactose, 195 parts of mixed vegetable oil, 16 parts of arachidonic acid oil powder (10%), 14 parts of docosahexaenoic acid oil powder (7%), 2 parts of sodium citrate, 2 parts of potassium chloride, 6 parts of calcium citrate, 3 parts of formulated vitamin, 2 parts of formulated minerals; after the above raw materials have been mixed evenly, they underwent pasteurization, homogenization, evaporation and concentration, and Date Regue/Date Received 2022-12-12 spray drying, forming powder-like semi-finished products. The evenly mixed milk powder is packed with filled-in nitrogen to obtain the final product.
Application Example 3 A formula milk powder for young children, containing 2'-fucosyl lactose, milk fat globule membrane and taurine, is prepared, per 1000 parts of the formula milk powder, by the following constituents in parts by weight:
the present milk powder uses the raw materials of: 220 parts of raw milk (on a dry basis) (0.2% of milk fat global membrane in each part), 15 parts of concentrated whey almubin powder rich in milk fat global membrane (7% milk fat global membrane in each part), 10.42 parts of 2'-fluorosyl lactose (96.0% of 2'-fluorosyl lactose in each part), 0.51 parts of taurine (99% of taurine in each portion), 350 parts of desalinated whey powder, 120 parts of skimmed milk powder, 92.42 parts of lactose, 40 parts of oligolactose, 130 parts of mixed vegetable oil (containing 1,3-dioleate 2-palmitate triglyceride), 5 parts of arachidonic acid oil powder (10%), 7 parts of docosahexaenoic acid oil powder (7%), 5 parts of calcium citrate, 3 parts of formulated vitamin, 1 part of formulated minerals, and 0.65 parts of formulated nucleotides; after the above raw materials have been mixed evenly, they underwent pasteurization, homogenization, evaporation and concentration, and spray drying, forming powder-like semi-finished products. The evenly mixed milk powder is packed with filled-in nitrogen to obtain the final product.
Application Example 4 A formulated milk powder, containing 2'-fucosyl lactose, milk fat globule membrane and taurine, suitable for pregnant women, is prepared, per 1000 parts of the formulated milk powder, by the following constituents in parts by weight:
the present milk powder uses the raw materials of: 436 parts of whole milk powder (0.2% milk fat globle membrane in each part), 40.65 parts of cow milk fat globle membrane powder (12.3% milk fat globle membrane in each part), 10.42 parts of 2'-fucosyl lactose (96.0% 2'-fucosyl lactose in each part), 0.3 parts of taurine (99%
Date Regue/Date Received 2022-12-12 taurine in each part), 200 parts of skimmed milk powder, 73.13 parts of lactose, 168 parts of maltodextrin, 60 parts of oligoisomaltose, 7 parts of DHA powder (7%), 3.5 parts of formulated vitamins, 1 part of formulated mineral; after the above raw materials have been mixed evenly, they underwent pasteurization, homogenization, evaporation and concentration, and spray drying, forming powder-like semi-finished products. The evenly mixed milk powder is packed with filled-in nitrogen to obtain the final product.
Application Example 5 A formulated milk powder, containing 2'-fucosyl lactose, milk fat globule membrane and taurine, suitable for pregnant women, is prepared, per 1000 parts of the formulated milk powder, by the following constituents in parts by weight:
the present milk powder uses the raw materials of: 436 parts of raw milk (on a dry basis) (0.2% milk fat global membrane in each part), 8.13 parts of cow milk fat global membrane powder (12.3% milk fat global membrane in each part), 10.42 parts of 2'-fluorosyl lactose (96.0% 2'-fluorosyl lactose in each portion), 0.51 parts of taurine (99% taurine in each part), 250 parts of skimmed milk powder, 76.44 parts of lactose, 137 parts of maltodextrin, 70 parts of oligoisomaltose, 7 parts of DHA
powder (7%), 3.5 parts of formulated vitamin, 1 part of formulated mineral;
after the above raw materials have been mixed evenly, they underwent pasteurization, homogenization, evaporation and concentration, and spray drying, forming powder-like semi-finished products. The evenly mixed milk powder is packed with filled-in nitrogen to obtain the final product.
Application Example 6 A formulated milk powder, containing 2'-fucosyl lactose, milk fat globule membrane and taurine, suitable for middle aged and older people, is prepared, per 1000 parts of the formulated milk powder, by the following constituents in parts by weight:
the present milk powder uses the raw materials of: 436 parts of whole milk powder (0.2% milk fat globle membrane in each part), 40.65 parts of cow milk fat globle Date Regue/Date Received 2022-12-12 membrane powder (12.3% milk fat globle membrane in each part), 1.04 parts of 2'-fucosyl lactose (96.0% 2'-fucosyl lactose in each part), 0.51 parts of taurine (99%
taurine in each part), 210 parts of skimmed milk powder, 72.3 parts of lactose, 168 parts of maltodextrin, 60 parts of oligoisomaltose, 7 parts of DHA powder (7%), 3.5 parts of formulated vitamin, 1 part of formulated mineral; after the above raw materials have been mixed evenly, they underwent pasteurization, homogenization, evaporation and concentration, and spray drying, forming powder-like semi-finished products. The evenly mixed milk powder is packed with filled-in nitrogen to obtain the final product.
What is described above is only an exemplary embodiment of the present invention.
It should be pointed out here that, for those of ordinary skills in the art, modifications can be made without departing from the scope of the present invention, yet all these belong to the scope of the present invention.
Date Recue/Date Received 2022-12-12
N.B.: * p < 0.05, in comparison with the blank control group, ** p < 0.01, in comparison with the blank control group The sample treatment results showed that, relative to the blank control group (cell experiment example 1), each one of 2'-FL, milk fat global membrane, and taurine, when used alone, can increase the number of MBP positive cells, which indicates that these three ingredients, when used alone, can contribute to the maturation of the oligodendrocyte precursor cells.
However, the inventors found that when any two of the three components were used together, there was a strong antagonism.
Date Regue/Date Received 2022-12-12 In particular, according to cell experiment examples 13-15, it can be seen that:
- In terms of the components used and the amount of the components used, cell experiment example 13 is equivalent to the combination of cell experiment examples 4 and 12. Relative to the blank control group (cell experiment example 1), cell experiment examples 4 and 12 increase the number of MBP positive cells by 42.34 and 47 respectively, while cell experiment example 13 increases the number of MBP
positive cells by 23, which is not only far less than the sum of the former two (89.34) (the difference from the sum of the former two A1=66.34), but also less than either of the former two.
- Cell experiment example 14 is equivalent to the combination of cell experiment examples 4 and 6. However, compared with the blank control group (cell experiment example 1), cell experiment examples 4 and 6 increase the number of MBP
positive cells by 42.34 and 44.34 respectively, while cell experiment example 14 increases the number of MBP positive cells by 20.17, which is not only far less than the sum of the former two (86.68) (the difference from the sum of the former two A2=66.51), but also less than either of the former two.
- Cell experiment example 15 is equivalent to the combination of cell experiment examples 6 and 12. However, relative to the blank control group (cell experiment example 1), cell experiment examples 6 and 12 increase the number ofMBP
positive cells by 44.34 and 47 respectively, while cell experiment example 15 increases the number of MBP positive cells by 21.67, which is not only far less than the sum of the former two (91.34) (the difference from the sum of the former two A3=69.67), but also less than either of the former two.
This indicates that when any two of 2'-FL, milk fat global membrane and taurine are used in combination, there is a strong antagonism in terms of the number of MBP
positive cells and thus the maturation of oligodendrocyte precursor cells, and the effect of their use in combination is less than that when any one of the components is used alone.
Date Regue/Date Received 2022-12-12 The inventors further found that when 2'-FL, milk fat global membrane and taurine are used in combination, a significant reduction in inter-component antagonism, and a synergistic increase in the number of MBP positive cells and thus maturation of oligodendrocyte precursor cells.
In particular, cell experiment example 18 is equivalent to the combination of cell experiment examples 5, 8 and 12, in terms of the components used and the amount of the components used. Relative to cell experiment example 1, cell experiment examples 5, 8, 12 and 18 increased the number of MBP positive cells by 20.67, -10, 47 and 79.67 respectively. The increment in the number of MBP positive cells in case of cell experiment example 18 (79.67) is greater than the sum of the former three (57.67).
In addition, in terms of the components used and the amount of the components used, cell experiment example 21 is equivalent to the combination of cell experiment examples 6 and 13, or the combination of cell experiment examples 12 and 14, or the combination of cell experiment examples 4 and 15, or the combination of cell experiment examples 4, 6 and 12. Realtive to the blank control group (cell experiment example 1), - cell experiment example 21 increased the number of MBP positive cells by 105.65, - cell experiment examples 6 and 13 increase the number of MBP positive cells by 44.34 and 23 respectively, with a sum of 67.34, which is less than the increment realized in cell experiment example 21 (105.65), - cell experiment examples 12 and 14 increased the number of MBP positive cells by 47 and 20.17 respectively, with a sum of 67.17, which is less than the increment realized in cell experiment example 21 (105.65), - cell experiment examples 4 and 15 increase the number of MBP positive cells by 42.34 and 21.67 respectively, with a sum of 64.01, which is less than the increment realized in cell experiment example 21 (105.65), Date Regue/Date Received 2022-12-12 - cell experiment examples 4, 6 and 12 increased the number of MBP positive cells by 42.34, 44.34 and 47 respectively, with a sum of 133.68, which is slightly greater than the increment realized in cell experiment example 21 (105.65), with a difference therebetween A4=28.03, far less than the difference A 1=66.34, A2=66.51, and A3=69.67.
In addition, cell experiment example 22 is equivalent to the combination of cell experiment examples 9 and 14, or the combination of cell experiment examples 4, 6 and 9, in terms of the components used and the amount of the components used.
Relative to the blank control group (cell experiment example 1), cell experiment examples 4, 6, 9, 14 and 22 increase the number of MBP positive cells by 42.34, 44.34, 7.34, 20.17 and 92.37 respectively. The increment in the number of MBP
positive cells in cell experiment example 22 (92.37) is greater than the sum of the respective increments in cell experiment examples 9 and 14 (27.51), and slightly less than the sum of the respective increments in cell experiment examples 4, 6 and (94.02) (a difference therebetween of A5=1.65, far less than the difference A2=66.51).
In addition, cell experiment example 23 is equivalent to the combination of cell experiment examples 7 and 13, or the combination of cell experiment examples 4, 7 and 12, in terms of the components used and the amount of the components used.
Relative to the blank control group (cell experiment example 1), cell experiment examples 4, 7, 12, 13 and 23 increase the number of MBP positive cells by 42.34, 29.67, 47, 23 and 94.44 respectively. The incrment in the number of MBP
positive cells in cell experiment example 23 (94.44) is greater than the sum of the respective increments in cell experiment examples 7 and 13 (52.67), and slightly less than the sum of the respective increments in cell experiment examples 4, 7 and 12 (119.01) (a difference therebetween of A6=24.57, far less than the difference A1=66.34).
Thus, it can be seen that when the three of 2'-FL, milk fat global membrane and Date Regue/Date Received 2022-12-12 taurine are used in combination, a significant reduction in inter-component antagonism is enabled. There is a synergistic effect among the three components, which can synergistically increase the number of MBP positive cells and thus the maturation of oligodendrocyte precursor cells.
The present invention provides a research concerning a composition of a human milk oligosaccharide (preferably neural fucosylated human milk oligosaccharide (HMO), which is preferably one or more selected from the group consisting of 2'-fluorosyl lactose (2'-FL), 3'-fluorosyl lactose (3'-FL), lacto-N-fucopentaose I (LNFP
I), lacto-N-difucoexaose I (LNDFH I), lacto-N-difucoexaose II (LNDFH II), preferably 2'-fluorosyl lactose (2'-FL)), milk fat globule membrane, and taurine on brain development, especially on neurodevelopment, in particular on oligodendrocyte precursor cell (OPC) proliferation, differentiation or maturation into ligodendrocyte (OL) and the myelination characteristics of oligodendrocyte (OL). It provides a new idea for the development of functional food in the future. Human milk oligosaccharide (preferably neurtral fucosylated human milk oligosaccharide (HMO), which is preferably one or more selected from the group consisting of 2'-fucosyl lactose (2'-FL), 3'-fucosyl lactose (3'-FL), lacto-N-fucopentaose I
(LNFP
I), lacto-N-difucohexaose I (LNDFH I), lacto-N-difucohexaose II (LNDFH II), preferably 2'-fucosyl lactose (2'-FL)), milk fat globule membrane and taurine has a broad prospect in terms of improving memory and brain development. It is found that during the development of central nervous system, extracellular environment plays an important role in regulating brain homeostasis and controlling myelin formation and other cellular mechanisms. Deficiency of key nutrients will significantly affect brain development. Our research shows that in in vitro models, brain cell cultures treated with a combination of 2'-FL, milk fat globle membrane and taurine increase OPC numbers, differentiation or maturion into OL, and the myelination characteristics of OL. There is a good inter-component synergistic effect.
Date Regue/Date Received 2022-12-12 Application Example All "Part(s)" in the following application examples are parts by weight. A %
content of an ingredient is a % by weight content.
In addition, in each of the following application examples, the following raw material sources are used unless otherwise stated.
Raw milk: Heilongjiang Feihe Dairy Co., Ltd Whole milk powder: Heilongjiang Feihe Dairy Co., Ltd Skimmed milk powder: Kerry, Ireland 2'-fucosyl lactose (2'-fucosyl lactose 96.0%) : GlyCare TM 2'-FL 9000 Concentrated whey protein powder rich in milk fat globule membrane (milk fat globle membrane 7%): Lacprodane MFGM-10, Denmark Milk fat globle membrane powder (phospholipid 12.3%): Tatua of New Zealand Taurine (taurine 99%): Beijing Jinkangpu Food Technology Co., Ltd Desalinated whey powder: Euroserum (Red Bird), France Oligogalactose: Baolingbao Biology Co., Ltd Mixed vegetable oil: Cargill Cereals and Oils (Nantong) Co., Ltd Mixed vegetable oil (containing 1,3-dioleate-2-palmitate triglyceride): Bunge Loders Croklaan (Xiamen) Oil Technology Co., Ltd Formulated vitamin: DSM Vitamin (Shanghai) Co., Ltd Formulated minerals: DSM Vitamin (Shanghai) Co., Ltd Solid corn syrup: Baolingbao Biology Co., Ltd Oligofructose: Baolingbao Biology Co., Ltd Oligoisomaltose: Baolingbao Biology Co., Ltd Application Example 1 A formula milk powder for infants, containing 2'-fucosyl lactose, milk fat globule membrane and taurine, is prepared, per 1000 parts of the formula milk powder, by the following constituents in parts by weight:
Date Regue/Date Received 2022-12-12 the present milk powder uses the raw materials of: 195 parts of raw milk (on a dry basis) (each part contains 0.2% milk fat global membrane), 28.5 parts of concentrated whey protein powder rich in milk fat global membrane (each part contains 7% milk fat global membrane), 10.42 parts of 2'-fluorosyl lactose (96.0%
milk fat global membrane in each part), 0.38 parts of taurine (99% taurine in each part), 400 parts of desalinated whey powder, 83.7 parts of lactose, 37 parts of oligogalactose, 200 parts of mixed vegetable oil, 16 parts of arachidonic acid oil powder (10%), 14 parts of docosahexaenoic acid oil powder (7%), 2 parts of sodium citrate, 2 parts of potassium chloride, 6 parts of calcium citrate, 3 parts of formulated vitamin, and 2 parts of formulated minerals; after the above raw materials have been mixed evenly, they underwent pasteurization, homogenization, evaporation and concentration, and spray drying, forming powder-like semi-finished products.
The evenly mixed milk powder is packed with filled-in nitrogen to obtain the final product.
Application Example 2 A formula milk powder for infants, containing 2'-fucosyl lactose, milk fat globule membrane and taurine, is prepared, per 1000 parts of the formula milk powder, by the following constituents in parts by weight:
the present milk powder uses the raw materials of: 220 parts of raw milk (on a dry basis) (0.2% of milk fat global membrane in each part), 15 parts of concentrated whey protein powder rich in milk fat global membrane (7% milk fat global membrane in each part), 1.04 parts of 2'-fluorosyl lactose (96.0% of 2'-fluorosyl lactose in each part), 0.51 parts of taurine (99% of taurine in each part), 400 parts of desalinated whey powder, 86.45 parts of lactose, 37 parts of oligolactose, 195 parts of mixed vegetable oil, 16 parts of arachidonic acid oil powder (10%), 14 parts of docosahexaenoic acid oil powder (7%), 2 parts of sodium citrate, 2 parts of potassium chloride, 6 parts of calcium citrate, 3 parts of formulated vitamin, 2 parts of formulated minerals; after the above raw materials have been mixed evenly, they underwent pasteurization, homogenization, evaporation and concentration, and Date Regue/Date Received 2022-12-12 spray drying, forming powder-like semi-finished products. The evenly mixed milk powder is packed with filled-in nitrogen to obtain the final product.
Application Example 3 A formula milk powder for young children, containing 2'-fucosyl lactose, milk fat globule membrane and taurine, is prepared, per 1000 parts of the formula milk powder, by the following constituents in parts by weight:
the present milk powder uses the raw materials of: 220 parts of raw milk (on a dry basis) (0.2% of milk fat global membrane in each part), 15 parts of concentrated whey almubin powder rich in milk fat global membrane (7% milk fat global membrane in each part), 10.42 parts of 2'-fluorosyl lactose (96.0% of 2'-fluorosyl lactose in each part), 0.51 parts of taurine (99% of taurine in each portion), 350 parts of desalinated whey powder, 120 parts of skimmed milk powder, 92.42 parts of lactose, 40 parts of oligolactose, 130 parts of mixed vegetable oil (containing 1,3-dioleate 2-palmitate triglyceride), 5 parts of arachidonic acid oil powder (10%), 7 parts of docosahexaenoic acid oil powder (7%), 5 parts of calcium citrate, 3 parts of formulated vitamin, 1 part of formulated minerals, and 0.65 parts of formulated nucleotides; after the above raw materials have been mixed evenly, they underwent pasteurization, homogenization, evaporation and concentration, and spray drying, forming powder-like semi-finished products. The evenly mixed milk powder is packed with filled-in nitrogen to obtain the final product.
Application Example 4 A formulated milk powder, containing 2'-fucosyl lactose, milk fat globule membrane and taurine, suitable for pregnant women, is prepared, per 1000 parts of the formulated milk powder, by the following constituents in parts by weight:
the present milk powder uses the raw materials of: 436 parts of whole milk powder (0.2% milk fat globle membrane in each part), 40.65 parts of cow milk fat globle membrane powder (12.3% milk fat globle membrane in each part), 10.42 parts of 2'-fucosyl lactose (96.0% 2'-fucosyl lactose in each part), 0.3 parts of taurine (99%
Date Regue/Date Received 2022-12-12 taurine in each part), 200 parts of skimmed milk powder, 73.13 parts of lactose, 168 parts of maltodextrin, 60 parts of oligoisomaltose, 7 parts of DHA powder (7%), 3.5 parts of formulated vitamins, 1 part of formulated mineral; after the above raw materials have been mixed evenly, they underwent pasteurization, homogenization, evaporation and concentration, and spray drying, forming powder-like semi-finished products. The evenly mixed milk powder is packed with filled-in nitrogen to obtain the final product.
Application Example 5 A formulated milk powder, containing 2'-fucosyl lactose, milk fat globule membrane and taurine, suitable for pregnant women, is prepared, per 1000 parts of the formulated milk powder, by the following constituents in parts by weight:
the present milk powder uses the raw materials of: 436 parts of raw milk (on a dry basis) (0.2% milk fat global membrane in each part), 8.13 parts of cow milk fat global membrane powder (12.3% milk fat global membrane in each part), 10.42 parts of 2'-fluorosyl lactose (96.0% 2'-fluorosyl lactose in each portion), 0.51 parts of taurine (99% taurine in each part), 250 parts of skimmed milk powder, 76.44 parts of lactose, 137 parts of maltodextrin, 70 parts of oligoisomaltose, 7 parts of DHA
powder (7%), 3.5 parts of formulated vitamin, 1 part of formulated mineral;
after the above raw materials have been mixed evenly, they underwent pasteurization, homogenization, evaporation and concentration, and spray drying, forming powder-like semi-finished products. The evenly mixed milk powder is packed with filled-in nitrogen to obtain the final product.
Application Example 6 A formulated milk powder, containing 2'-fucosyl lactose, milk fat globule membrane and taurine, suitable for middle aged and older people, is prepared, per 1000 parts of the formulated milk powder, by the following constituents in parts by weight:
the present milk powder uses the raw materials of: 436 parts of whole milk powder (0.2% milk fat globle membrane in each part), 40.65 parts of cow milk fat globle Date Regue/Date Received 2022-12-12 membrane powder (12.3% milk fat globle membrane in each part), 1.04 parts of 2'-fucosyl lactose (96.0% 2'-fucosyl lactose in each part), 0.51 parts of taurine (99%
taurine in each part), 210 parts of skimmed milk powder, 72.3 parts of lactose, 168 parts of maltodextrin, 60 parts of oligoisomaltose, 7 parts of DHA powder (7%), 3.5 parts of formulated vitamin, 1 part of formulated mineral; after the above raw materials have been mixed evenly, they underwent pasteurization, homogenization, evaporation and concentration, and spray drying, forming powder-like semi-finished products. The evenly mixed milk powder is packed with filled-in nitrogen to obtain the final product.
What is described above is only an exemplary embodiment of the present invention.
It should be pointed out here that, for those of ordinary skills in the art, modifications can be made without departing from the scope of the present invention, yet all these belong to the scope of the present invention.
Date Recue/Date Received 2022-12-12
Claims (10)
1. A nutrient composition comprising:
- human milk oligosaccharide (HMO), preferably neurtral fucosylated human milk oligosaccharide (HMO), which is preferably one or more selected from the group consisting of 2'-fucosyl lactose, 3'-fucosyl lactose, lacto-N-fucopentaose I, lacto-N-difucohexaose I, and lacto-N-difucohexaose II, preferably 2'-fucosyl lactose;
- milk fat globule membrane; and - taurine.
- human milk oligosaccharide (HMO), preferably neurtral fucosylated human milk oligosaccharide (HMO), which is preferably one or more selected from the group consisting of 2'-fucosyl lactose, 3'-fucosyl lactose, lacto-N-fucopentaose I, lacto-N-difucohexaose I, and lacto-N-difucohexaose II, preferably 2'-fucosyl lactose;
- milk fat globule membrane; and - taurine.
2. The nutrient composition of claim 1, consisting of the human milk oligosaccharide, the milk fat globule membrane, and the taurine.
3. The nutrient composition of either of claims 1 and 2, wherein the human milk oligosaccharide is provided in a form of natural origin, and/or synthetic origin, and/or bacterial fermentation origin.
4. The nutrient composition of any one of claims 1 to 3, wherein:
the milk fat globule membrane is cow and/or sheep milk-origin phospholipid ;
and/or the milk fat globule membrane is provided in the form of an protein powder containing milk fat globule membrane, said protein powder containing milk fat globule membrane preferably having a milk fat globule membrane content of 6-25%
by weight; and/or of a cow milk-origin phospholipid, said cow milk-origin .. phospholipid preferably having a milk fat globule membrane content of 9-60%
by weight; and/or the milk fat globule membrane at least contains sphingophospholipid and phosphatidylcholine, and optionally further contains phosphatidylserine and/or phosphatidylethanolamine, wherein the sphingophospholipid represents 10% by weight or more of the total milk fat globule membrane, and the phosphatidylcholine Date Regue/Date Received 2022-1 2-1 2 represents 15% by weight or more of the total milk fat globule membrane.
the milk fat globule membrane is cow and/or sheep milk-origin phospholipid ;
and/or the milk fat globule membrane is provided in the form of an protein powder containing milk fat globule membrane, said protein powder containing milk fat globule membrane preferably having a milk fat globule membrane content of 6-25%
by weight; and/or of a cow milk-origin phospholipid, said cow milk-origin .. phospholipid preferably having a milk fat globule membrane content of 9-60%
by weight; and/or the milk fat globule membrane at least contains sphingophospholipid and phosphatidylcholine, and optionally further contains phosphatidylserine and/or phosphatidylethanolamine, wherein the sphingophospholipid represents 10% by weight or more of the total milk fat globule membrane, and the phosphatidylcholine Date Regue/Date Received 2022-1 2-1 2 represents 15% by weight or more of the total milk fat globule membrane.
5. The nutrient composition of any one of claims 1 to 4, wherein the taurine is provided in the form of monomeric taurine.
6. The nutrient composition of any one of claims 1 to 5, wherein:
the weight ratio of the human milk oligosaccharide to the milk fat globule membrane is 1:0.01-500, preferably 1:0.02-100, preferably 1:0.05-50, preferably 1:0.1-10, preferably 1:0.15-6; and the weight ratio of the human milk oligosaccharide to the taurine is 1:0.0005-10, preferably 1:0.001-5, preferably 1: 0.005-1, preferably 1:0.01-0.5;
preferably, the weight ratio ofthe human milk oligosaccharide to the milk fat globule membrane to the taurine is 1:0.01-500:0.0005-10, preferably 1:0.02-100:0.0005-10, preferably 1:0.05-50:0.001-5, preferably 1:0.1-10:0.005-1, preferably 1:0.15-6:0.01-0.5.
the weight ratio of the human milk oligosaccharide to the milk fat globule membrane is 1:0.01-500, preferably 1:0.02-100, preferably 1:0.05-50, preferably 1:0.1-10, preferably 1:0.15-6; and the weight ratio of the human milk oligosaccharide to the taurine is 1:0.0005-10, preferably 1:0.001-5, preferably 1: 0.005-1, preferably 1:0.01-0.5;
preferably, the weight ratio ofthe human milk oligosaccharide to the milk fat globule membrane to the taurine is 1:0.01-500:0.0005-10, preferably 1:0.02-100:0.0005-10, preferably 1:0.05-50:0.001-5, preferably 1:0.1-10:0.005-1, preferably 1:0.15-6:0.01-0.5.
7. Food comprising the nutrient composition of any one of claims 1 to 6, the food is preferably in powder or liquid form.
8. The food of any one of claims 7 , which is a formula food for infants and young children, for example a formula food for infants, a formula food for more grown-up infants, a formula food for young children, for example a formula milk powder for infants and young children, for example a foimula milk powder for infants, and a formula milk powder for young children; a complementary food for infants;
nutritional or dietary supplements; or a formulated milk powder for pregnant women.
nutritional or dietary supplements; or a formulated milk powder for pregnant women.
9. The food of any one of claims 7 to 8, wherein the amount of said nutrient composition added, relative to the total weight of said food, is such that:
the human milk oligosaccharide is at a content by weight of at least 0.01%, preferably at least 0.05%, preferably at least 0.1% and at most 10.0%, preferably at Date Recue/Date Received 2022-1 2-1 2 most 5.0%, preferably at most 1.0%, the milk fat globule membrane is at a content by weight of at least 0.01%, preferably at least 0.05%, preferably at least 0.1% and at most 5.0%, preferably at most 1.0%, preferably at most 0.6%, and the taurine is at a content by weight of at least 0.001%, preferably at least 0.005%, preferably at least 0.01% and at most 1.0%, preferably at most 0.5%, preferably at most 0.1%.
the human milk oligosaccharide is at a content by weight of at least 0.01%, preferably at least 0.05%, preferably at least 0.1% and at most 10.0%, preferably at Date Recue/Date Received 2022-1 2-1 2 most 5.0%, preferably at most 1.0%, the milk fat globule membrane is at a content by weight of at least 0.01%, preferably at least 0.05%, preferably at least 0.1% and at most 5.0%, preferably at most 1.0%, preferably at most 0.6%, and the taurine is at a content by weight of at least 0.001%, preferably at least 0.005%, preferably at least 0.01% and at most 1.0%, preferably at most 0.5%, preferably at most 0.1%.
10. Use of the nutrient composition of any one of claims 1 to 6 or the food of any one of claims 7 to 9 for non-curing purposes of improving the brain development and intelligence of infants and young children, especially promoting neurodevelopment such as neuron maturation, synaptogenesis and myelination, in particular promoting the the oligodendrocyte precursor cell proliferation, maturation, and differentiation into oligodendrocytes and/or myelination of oligodendrocytes.
Date Recue/Date Received 2022-1 2-1 2
Date Recue/Date Received 2022-1 2-1 2
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