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WO2018199231A1 - Extrait de placenta - Google Patents

Extrait de placenta Download PDF

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Publication number
WO2018199231A1
WO2018199231A1 PCT/JP2018/016990 JP2018016990W WO2018199231A1 WO 2018199231 A1 WO2018199231 A1 WO 2018199231A1 JP 2018016990 W JP2018016990 W JP 2018016990W WO 2018199231 A1 WO2018199231 A1 WO 2018199231A1
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WO
WIPO (PCT)
Prior art keywords
extract
mir
placenta
base sequence
exosome
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.)
Ceased
Application number
PCT/JP2018/016990
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English (en)
Japanese (ja)
Inventor
和江 高山
栄俊 田原
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hiroshima University NUC
Ichimaru Pharcos Co Ltd
Original Assignee
Hiroshima University NUC
Ichimaru Pharcos Co Ltd
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Filing date
Publication date
Application filed by Hiroshima University NUC, Ichimaru Pharcos Co Ltd filed Critical Hiroshima University NUC
Priority to JP2019514618A priority Critical patent/JP7083818B2/ja
Publication of WO2018199231A1 publication Critical patent/WO2018199231A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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 OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/48—Reproductive organs
    • A61K35/50—Placenta; Placental stem cells; Amniotic fluid; Amnion; Amniotic stem cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/98—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution of animal origin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing

Definitions

  • the present invention relates to the provision of various compositions containing exosomes derived from placenta (oral compositions, cosmetic compositions, fibroblast proliferation promoters), placenta extracts containing exosomes, and methods for producing exosomes.
  • placenta oral compositions, cosmetic compositions, fibroblast proliferation promoters
  • placenta extracts containing exosomes and methods for producing exosomes.
  • Placenta (placenta) extract is formulated in cosmetics and supplements for the purpose of beauty and health benefits (Patent Document 1). Placenta extracts contain amino acids, peptides, nucleic acids, etc., which have been thought to synergistically contribute to physiological functions, but elucidate the identification of functionally involved components and their absorption into the body. There are many things that are not done. Against this background, the identification of functional components in placenta extracts has been desired in the food and pharmaceutical markets.
  • exosomes extracellular endoplasmic reticulum
  • exosomes are secreted from cells derived from various organs. These exosomes contain physiologically active substances such as miRNA (microRNA), amino acids and peptides, and are known to function as transporters and to help crosstalk between organs like hormones (Non-patent Document 1). ). It has also been reported that exosomes are released from the placenta at the time of pregnancy and work on the crosstalk between the fetus and the mother (Non-patent Document 2).
  • miRNA miRNA
  • amino acids amino acids
  • peptides amino acids and peptides
  • exosomes may be absorbed from the gastrointestinal tract because miRNA derived from food exosomes is detected in human serum (Non-patent Document 3). These food-derived exosomes have been reported to be absorbed and play a useful role in biological functions such as immune regulation, but there are many unclear points about the mechanism, and in particular, elucidation at the cellular level is not sufficient. There was not (nonpatent literature 4).
  • MiRNA is a small RNA consisting of 20 to 25 bases. It is known that thousands of miRNAs exist in living bodies such as humans. Although miRNA is RNA that is not translated into protein, expression of other genes can be directly regulated by binding partially complementary to messenger RNA (mRNA) sequences.
  • miRNA messenger RNA
  • One type of miRNA may be involved in the expression control of a plurality of genes, or the function may be exhibited by a combination of a plurality of miRNAs. That is, although miRNA may be able to function even if it is single, it cooperates with other kinds of miRNA to suppress gene expression of multiple mRNAs.
  • placenta extract has also been desired to be elucidated at the cellular level.
  • fibroblasts present in animal support tissues have a proliferating ability that decreases with an increase in the number of culture passages as in the case of aging of living bodies.
  • the number of passages in which the growth ability is reduced differs depending on the animal species, human fibroblasts do not grow in about 80 passages (Non-patent Document 5).
  • the cell size increases simultaneously with the decrease in proliferation ability. This phenomenon is due to changes in the molecular structure of proteins in the cells accompanying aging and a decrease in the metabolic capacity of the cells. (Non-patent paper 6)
  • Living body aging is also considered to reflect cellular aging, and even in rapidly growing organs such as skin, liver, and bone, growth capacity and metabolic speed may decrease with aging. It was known.
  • An object of the present invention is to find an active ingredient in a placenta extract whose active ingredient is unknown and a method for producing a placenta extract containing this active ingredient, and to provide a more active fractional ingredient.
  • the present inventors have extracted a exosome from a placenta extract and established a method for producing a porcine placenta extract having a high exosome and exosome content. Furthermore, 162 types of miRNAs described in Tables 1 to 3 are contained in the exosome, and these are identical to the base sequences of miRNAs contained in human-derived exosomes, of which 27 types (SEQ ID NO: 3, 8, 10, 18, 22, 29, 33, 34, 37, 39, 41, 51, 60, 61, 66, 71, 72, 75, 76, 77, 105, 108, 109, 138, 148, 157 and 159) were confirmed to decrease in senescent cells. In addition, when placenta-derived exosomes and synthetic miRNAs having the same base sequence as miRNAs contained in the exosomes were added to human fibroblasts, cell proliferation was promoted and the cell area decreased. confirmed.
  • the exosome according to one embodiment of the present invention has (i) a nucleic acid molecule having the base sequence represented by any one of SEQ ID NOs: 1 to 162, (ii) 90% or more identity with the base sequence of (i). Or (iii) at least one selected from the group consisting of nucleic acid molecules having a base sequence having a deletion, addition and / or substitution of one or two bases in the base sequence of (i)
  • T shown in each base sequence is U.
  • At least one nucleic acid molecule is SEQ ID NO: 3, 8, 10, 18, 22, 29, 33, 34, 37, 39, 41, 51, 60, 61, 66, 71, 72. 75, 76, 77, 105, 108, 109, 138, 148, 157 and 159.
  • the base sequence of each nucleic acid molecule has 90% or more identity with the base sequence, or has a deletion, addition and / or substitution of one or two bases in the base sequence. Also good.
  • At least one nucleic acid molecule contains a nucleic acid molecule having a base sequence represented by SEQ ID NOs: 16, 74 and 87.
  • the base sequence of each nucleic acid molecule has 90% or more identity with the base sequence, or has a deletion, addition and / or substitution of one or two bases in the base sequence. Also good.
  • an oral composition containing the exosome or mir-125a, mir-26a and / or mir-30c miRNA as an active ingredient is provided.
  • a cosmetic composition containing the exosome or mir-125a, mir-26a and / or mir-30c miRNA as an active ingredient is provided.
  • Yet another embodiment is a fibroblast proliferation promoter containing the exosome or mir-125a, mir-26a and / or mir-30c miRNA as an active ingredient.
  • a method for producing a placenta extract comprising extracting a placenta of a mammal with hot water, performing enzymatic degradation with a protease, and recovering a placenta extract containing a exosome having a spherical structure.
  • the present invention provides a method for suppressing cellular senescence, comprising administering the exosome, or mir-125a, mir-26a and / or mir-30c miRNA to mammalian cells.
  • the present invention it is possible to provide placenta-derived exosomes and miRNAs contained in exosomes. It was also confirmed that fibroblasts proliferated after adding exosomes to human fibroblasts. Based on the above, by providing a composition containing exosomes derived from placenta orally or transdermally, the structure of the dermis is strengthened, and it is provided as a beauty and anti-aging application that improves skin tension, wrinkles, sagging, etc. Became possible. Further, when a synthetic miRNA having the same base sequence as the miRNA contained in the exosome is added, the same effect is seen and the same effect can be expected.
  • the exosome in the present invention is a spherical composition comprising a lipid, encapsulating peptides, proteins, nucleic acids and the like.
  • Examples of the extraction solvent for the porcine placenta extract used in the present invention include water, lower alcohols such as methanol, ethanol, propyl alcohol, isopropyl alcohol, butanol, and isobutanol or hydrous lower alcohols, propylene glycol, 1,3-butylene glycol, 1,2-butylene glycol, 1,4-butylene glycol, 1,5-pentanediol, 1,2-pentanediol, 1,3-pentanediol, 1,4-pentanediol, 1,3,5-pentanetriol 1 selected from glycerin, acids (hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, etc.) and alkalis (sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonia, etc.) that have been appropriately adjusted.
  • lower alcohols such as methanol, ethanol, propyl alcohol, isopropy
  • the weight ratio of the solvent to the raw material or the extraction time can be arbitrarily set.
  • the weight ratio of the solvent to the raw material can be arbitrarily set within the range of, for example, raw material: solvent 4: 1 to 1: 100, and a weight ratio of 1: 1 to 1:20 is particularly preferable.
  • the porcine placenta extract used in the present invention can be further subjected to a purification operation after solvent extraction.
  • the purification operation include fractionation using chromatography, filter paper, membrane filter, ultrafiltration membrane, etc. Filtration, drying, pH adjustment, deodorization, decolorization, and long-term storage and storage can be exemplified, and these can be arbitrarily selected and combined treatments can be performed.
  • the exosome used in the present invention can be obtained at a high concentration by centrifuging the porcine placenta extract powder with water or from the porcine placenta extract by ultracentrifugation. Purification operations such as filtration can be performed before and after centrifugation.
  • Nucleic acid molecules are extracted from the exosomes obtained in this way, analyzed for nucleotide sequences using a next-generation sequencer, and searched for a database of human microRNAs. As a result, the nucleotide sequences shown in Tables 1 to 3 are found. I understood. That is, at least in pig placenta, there are nucleic acid molecules having the same sequence as these human microRNAs.
  • a preferred nucleic acid molecule is microRNA, in which case T (thymine) in the sequence is U (uracil).
  • the placenta refers to placental tissue that can be obtained from a mother after childbirth, and is an organ that is formed in the uterus of a pregnant animal and connects the mother and the fetus. Since the placenta of mammals is structurally and functionally similar, placenta other than pigs, such as sheep placenta, horse placenta, bovine placenta and human placenta, can also be used. Among these, pig placenta is preferable from the viewpoint of availability and safety.
  • microRNA typically means what is called mature miRNA.
  • a mature miRNA is an endogenous non-coding RNA of about 20 to 25 bases encoded on the genome. miRNA is first transcribed from a miRNA gene on genomic DNA as a primary transcript having a length of about several hundred to several thousand bases, and then processed to be a precursor miRNA having a hairpin structure of about 60 to 70 bases. It becomes. Thereafter, it moves from the nucleus into the cytoplasm and further undergoes processing to become a double-stranded mature miRNA of about 20-25 bases.
  • miRNA includes not only endogenous single-stranded and double-stranded miRNAs but also synthetic nucleic acids having the same base sequence as these miRNAs. MiRNA also encompasses its precursors.
  • miR-125a includes both the precursor and mature form of the microRNA, but is preferably a mature form, and examples of the mature form include miR-125a-5p (SEQ ID NO: 163) and miR-125a. -3p (SEQ ID NO: 166) is exemplified. “MiR-30c” includes miR-30c-5p (SEQ ID NO: 164) and miR-30c-3p (SEQ ID NO: 167) as mature forms. Similarly, “miR-26a” includes miR-26a-5p (SEQ ID NO: 165) and miR-26a-3p (SEQ ID NO: 168) as mature forms. The base sequences of these miRNAs are disclosed in, for example, the miRBase database created by Sanger Laboratories: http://microrna.sanger.ac.uk/.
  • RNA having a base sequence represented by any of SEQ ID NOs: 1 to 162 (Ii) RNA having 90% or more, preferably 95% or more identity with the base sequence represented by any of SEQ ID NOs: 1 to 162, or (iii) base sequence represented by any of SEQ ID NOs: 1 to 162 RNA having a nucleotide sequence having a deletion, addition and / or substitution of one or two bases.
  • T thymine
  • U uracil
  • seed sequences 7 bases starting from the 2nd to 7th bases from the 5 ′ end of the mature miRNA are called seed sequences. It is known that this sequence must be completely complementary to the sequence of the target mRNA, but the other bases do not necessarily have to be completely identical. Therefore, in the miRNA of the present invention, it is sufficient that the core sequences of the sequences shown in SEQ ID NOs: 1 to 162 are completely matched, and the 5 ′ side or 3 ′ side sequence thereof is a deletion of one or several bases. May have additions and / or substitutions.
  • the term “several” includes 1 to 10, preferably 5 or less, and more preferably 1 to 3.
  • the core sequence (seed sequence) can be identified by analyzing the target mRNA.
  • NCBI National Center for Biotechnology Information
  • the miRNA used in the present invention can be obtained by synthesizing as in the test conducted in the present invention, or by extracting and purifying miRNA having a similar base sequence.
  • it may be a chimeric nucleic acid in which a part of the bases in the miRNA base sequences shown in (i) to (iii) above are replaced with deoxyribonucleotides.
  • exosome, miRNA, porcine placenta extract, and oral composition containing them used in practicing the present invention may be in any form such as liquid, solid, powder, paste, etc. You can choose.
  • the contents of the extract, exosome, and miRNA are not particularly limited as long as the effects of the present invention can be confirmed, but generally 0.0001 mg / g to 10 mg / g (the denominator is denominator) (Indicating the weight of the preparation).
  • the range is preferably 0.001 mg / g to 10 mg / g, and most preferably 0.001 mg / g to 1 mg / g.
  • the exosome, miRNA, and fibroblast growth promoter in the present invention are preferably used in pharmaceutical preparations.
  • the pharmaceutical either oral administration or parenteral administration can be employed.
  • the active ingredient can be mixed with a solid or liquid nontoxic pharmaceutical carrier suitable for administration methods such as oral administration, rectal administration and injection, and administered in the form of a conventional pharmaceutical preparation.
  • a solid or liquid nontoxic pharmaceutical carrier suitable for administration methods such as oral administration, rectal administration and injection, and administered in the form of a conventional pharmaceutical preparation.
  • Such preparations include solid preparations such as tablets, granules, powders and capsules, liquid preparations such as solutions, suspensions and emulsions, freeze-dried preparations, and the like. It can be prepared by conventional means.
  • non-toxic pharmaceutical carrier examples include glucose, lactose, sucrose, starch, mannitol, dextrin, fatty acid glyceride, polyethylene glycol, hydroxyethyl starch, ethylene glycol, polyoxyethylene sorbitan fatty acid ester, amino acid, gelatin, Examples include albumin, water, and physiological saline. If necessary, conventional additives such as a stabilizer, a wetting agent, an emulsifier, a binder, and a tonicity agent can be appropriately added and used.
  • exosomes and miRNA are blended in oral compositions, cosmetics, and fibroblast proliferation promoters
  • the components and additives exemplified below are arbitrarily selected and used as long as the effects of the present invention are not impaired.
  • Various preparations can be produced, and the content in the preparation is not particularly limited, but a concentration range of 0.0001 to 50% is usually preferred.
  • an oral composition containing exosomes and miRNA as it is or after adding various nutritional supplements, nourishing tonics, fatigue recovery, constitution improvement, etc., it is contained in foods and drinks, nutritional supplements, health supplements, It is eaten as a nutritionally-adjusted food, functional health food, food for specified health use, functional nutrition food, functional indication food, supplement, and food material.
  • nutritional supplements for example, a nutritionally-adjusted food, functional health food, food for specified health use, functional nutrition food, functional indication food, supplement, and food material.
  • it may be used for edible by using conventional means, and forming into an edible form, for example, granular, granular, tablet, capsule, paste, etc.
  • various foods such as processed marine products such as kamaboko and chikuwa, livestock products such as sausage and ham, Western confectionery, Japanese confectionery, raw noodles, Chinese noodles, boiled noodles, buckwheat noodles, sauce, soy sauce, sauce, Seasonings such as sugar, honey, powdered candy, syrup, etc., spices such as curry powder, mustard powder, pepper powder, jam, marmalade, chocolate spread, pickles, red vegetables, sprinkles, canned and bottled vegetables and fruits Dairy products such as processed vegetables and fruits, cheese, butter, yogurt, miso soup, soup, fruit juice, vegetable juice, whey beverage, soft drink, alcoholic beverages, liquid food, etc.
  • cosmetics containing exosomes and miRNA can be used in various skin external preparations (including preparations used for animals) in general, specifically, ampoules, capsules, pills, tablets, powders, Granules, solids, liquids, gels, bubbles, emulsions, sheets, mists, sprays, etc. in suitable forms for use 1) Pharmaceuticals, 2) Quasi-drugs, 3) Topical or systemic skin cosmetics (For example, lotion, milky lotion, cream, cosmetic liquid, ointment, lotion, oil, pack, etc., cosmetics for eyelashes, cosmetics for eyelashes, eyelash treatments, permanents for eyelashes, hair restorers for eyelashes, etc.
  • Makeup cosmetics such as wave cream, foundation, lipstick
  • exosome, miRNA, and oral composition, cosmetic, and fibroblast growth promoter containing the exosome or miRNA of the present invention are within the range that does not impair the effects of the present invention, if necessary, in addition to the above essential components.
  • various preparations can be produced by arbitrarily selecting and using the components and additives exemplified below, and the content in the preparation is not particularly limited, but the concentration range is usually 0.0001 to 50%. preferable.
  • polymers, thickeners and gelling agents examples include guar gum, locust bean gum, queens seed, carrageenan, galactan, arabic gum, tara gum, tamarind, fur celeran, karaya gum, troarooi, cara gum, tragacanth gum, alginic acid and sodium salt Salt, mannan; starch such as rice, corn, potato, wheat; xanthan gum, dextran, succinoglucan, curdlan, hyaluronic acid and its salt, xanthan gum, pullulan, gellan gum, chitin, chitosan, agar, gypsophila extract, chondroitin sulfate, Casein, collagen, gelatin, albumin; methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose and Salts such as sodium, methyl hydroxypropyl cellulose, cellulose sodium sulfate, cellulose dialkyldimethyl
  • Antioxidants include ⁇ -lipoic acid, salts of ⁇ -lipoic acid, and derivatives of ⁇ -lipoic acid; tocopherol derivatives such as tocopherol (vitamin E), tocotrienol, tocopherol acetate; BHT, BHA; propyl gallate, etc.
  • Gallic acid derivatives include vitamin C (ascorbic acid) and / or derivatives thereof; erythorbic acid and derivatives thereof; sulfites such as sodium sulfite; bisulfites such as sodium bisulfite; thiosulfates such as sodium thiosulfate; metabisulfite Salts: thiotaurine, hypotaurine; thioglycerol, thiourea, thioglycolic acid, cysteine hydrochloride are preferred.
  • Preferred examples of the reducing agent include thioglycolic acid, cysteine, cysteamine and the like.
  • Preferred examples of the oxidizing agent include aqueous hydrogen peroxide, ammonium persulfate, sodium bromate, and percarbonate.
  • Antiseptic and antibacterial agents include hydroxybenzoic acid and its salts or esters such as methylparaben, ethylparaben, propylparaben, butylparaben; salicylic acid; sodium benzoate; phenoxyethanol; 1,2-pentanediol, 1,2-hexane 1,2-diols such as diols; isothiazolinone derivatives such as methylchloroisothiazolinone and methylisothiazolinone; imidazolinium urea; dehydroacetic acid and its salts; phenols; halogenated bisphenols such as triclosan, acid amides , Quaternary ammonium salts; trichlorocarbanide, zinc pyrithione, benzalkonium chloride, benzethonium chloride, sorbic acid, chlorhexidine, chlorhexidine gluconate, halocarban, hexachlorophene, No
  • chelating agents include edetate (ethylenediaminetetraacetate) such as EDTA, EDTA2Na, EDTA3Na, and EDTA4Na; hydroxyethylethylenediaminetriacetate such as HEDTA3Na; pentetate (diethylenetriaminepentaacetate); phytic acid; Phosphonic acid and its sodium salt; sodium oxalate; polyamino acids such as polyaspartic acid and polyglutamic acid; sodium polyphosphate, sodium metaphosphate, phosphoric acid; sodium citrate, citric acid, alanine, dihydroxyethylglycine Gluconic acid, ascorbic acid, succinic acid, and tartaric acid are preferable.
  • edetate ethylenediaminetetraacetate
  • HEDTA3Na EDTA3Na
  • EDTA4Na hydroxyethylethylenediaminetriacetate
  • pentetate diethylenetriaminepentaa
  • pH adjusters / acids / alkalis include citric acid, sodium citrate, lactic acid, sodium lactate, glycolic acid, succinic acid, acetic acid, sodium acetate, malic acid, tartaric acid, fumaric acid, phosphoric acid, hydrochloric acid, sulfuric acid, monoethanol Amine, diethanolamine, triethanolamine, isopropanolamine, triisopropanolamine, 2-amino-2-methyl-1,3-propanediol, 2-amino-2-hydroxymethyl-1,3-propanediol, arginine, hydroxylated Sodium, potassium hydroxide, aqueous ammonia, guanidine carbonate, and ammonium carbonate are preferable.
  • powders include mica, talc, kaolin, sericite, montmorillonite, kaolinite, mica, muscovite, phlogopite, synthetic mica, red mica, biotite, permiculite, magnesium carbonate, calcium carbonate, aluminum silicate, silica Barium acid, calcium silicate, magnesium silicate, strontium silicate, metal tungstate, magnesium, zeolite, barium sulfate, calcined calcium sulfate, calcium phosphate, fluorine apatite, hydroxyapatite, ceramic powder, bentonite, smectite, clay, mud, Metal soap (for example, zinc myristate, calcium palmitate, aluminum stearate), calcium carbonate, bengara, yellow iron oxide, black iron oxide, ultramarine, bitumen, carbon black, titanium oxide, fine particles and super Titanium oxide, zinc oxide, fine and ultrafine zinc oxide, alumina, silica, fumed silica (ultraf
  • Inorganic salts include sodium chloride-containing salts such as salt, common salt, rock salt, sea salt, natural salt; potassium chloride, aluminum chloride, calcium chloride, magnesium chloride, bittern, zinc chloride, ammonium chloride; sodium sulfate, aluminum sulfate, Aluminum sulfate / potassium sulfate (alum), aluminum sulfate / ammonium sulfate, barium sulfate, calcium sulfate, potassium sulfate, magnesium sulfate, zinc sulfate, iron sulfate, copper sulfate; sodium phosphates such as 1Na, 2Na and 3Na phosphates, phosphoric acid Potassium, calcium phosphates and magnesium phosphates are preferred.
  • sodium chloride-containing salts such as salt, common salt, rock salt, sea salt, natural salt
  • potassium chloride aluminum chloride, calcium chloride, magnesium chloride, bittern, zinc chloride, ammonium chlor
  • Vitamins and their derivatives include vitamin A such as retinol, retinol acetate, retinol palmitate; thiamine hydrochloride, thiamine sulfate, riboflavin, riboflavin acetate, pyridoxine hydrochloride, pyridoxine dioctanoate, pyridoxine dipalmitate, Flavin adenine dinucleotide, cyanocobalamin, folic acid, nicotinic acid such as nicotinic acid amide / benzyl nicotinate, vitamin B group such as choline; vitamin C such as ascorbic acid and its sodium salt; vitamin D; ⁇ , Vitamin E such as ⁇ , ⁇ , and ⁇ -tocopherol; other vitamins such as pantothenic acid and biotin; ascorbic acid phosphates such as ascorbic acid phosphate sodium salt and ascorbic acid phosphate magnesium salt, Ascorbic acid fatty acid esters
  • Anti-inflammatory and anti-inflammatory agents include glycyrrhizic acid and its derivatives, glycyrrhetinic acid derivatives, salicylic acid derivatives, hinokitiol, guaiazulene, allantoin, indomethacin, zinc oxide, hydrocortisone acetate, prednisone, diphedramine hydrochloride, chlorpheniramine maleate; peach leaf extract A plant extract such as a koji leaf extract is preferable.
  • hormones include estradiol, estrone, ethinyl estradiol, cortisone, hydrocortisone, prednisone and the like.
  • Pearl pigments such as aluminum powder, copper powder, gold; surface-treated inorganic and metal powder pigments; red 201, red 202, red 204, red 205, red 220, red 226, red 228, Red 405, Orange 203, Orange 204, Yellow 205, Yellow 401, Blue 404, Red 3, Red 104, Red 106, Red 227, Red 230, Red 401 , Red 505, Orange 205, Yellow 4, Yellow 5, Yellow 202, Yellow 203, Green 3 Organic pigments such as zirconium, barium or aluminum lakes such as Blue No.
  • anthraquinones such as astaxanthin and alizarin, anthocyanidins, ⁇ -carotene, catenal, capsanthin, chalcone, calsamine, quercetin, crocin, chlorophyll
  • Natural pigments and dyes such as naphthoquinones such as curcumin, cochineal, shikonin, bixin, flavones, betacyanidine, henna, hemoglobin, lycopene, riboflavin, rutin; p-phenylenediamine, toluene-2,5-diamine, o-, Oxidative dye intermediates and couplers such as m-, or p-aminophenol, m-phenylenediamine, 5-amino-2-methylphenol, resorcin, 1-naphthol, 2,6-diaminopyridine and their salts
  • An auto-oxidizing dye such as indo
  • ingredients described in the Japanese Pharmacopoeia, Pharmaceutical Additive Standards, Food Additives Official Standards, etc., and Japanese and foreign patent publications and patent publications whose international patent classification IPC belongs to the classification of A61K7 and A61K8 It is possible to contain known pharmaceutical ingredients, food ingredients, etc., such as ingredients described in the official gazette (including published and republished publications) in known combinations, blending ratios and blending amounts.
  • administering means administration of the above-mentioned composition at a dose effective for treatment.
  • amount effective for treatment means a dose that produces an effect of suppressing the aging of cells, and is preferably an amount that increases the vitality of mammalian cells and provides a cosmetic or health improvement effect. .
  • the exact dosage will vary depending on the purpose of the treatment and can be ascertained by one skilled in the art using known techniques. Those skilled in the art need to make adjustments for systemic versus local delivery, age, weight, general health, sex, diet, time of administration, drug interaction, and severity of symptoms. This can be confirmed by routine experimentation.
  • exosomes, miRNA, and pig placenta extract used in the present invention are described in detail below, but the exosomes and pig placenta extract of the present invention are not limited to the following production examples.
  • Test 1 Confirmation of exosome 1 g of placenta extract was dissolved in 1 mL of water and then filtered through a 0.22 ⁇ m filter to obtain a test sample.
  • a 10-fold diluted sample sample was dropped onto a copper grid mesh with a carbon indicator film, and the sample was dispersed by allowing to stand for 10 seconds.
  • a copper grid mesh with a carbon indicator film was moved onto the distilled water droplets, and was further allowed to stand at room temperature for 30 seconds for washing treatment.
  • Negative staining was performed by moving a copper grid mesh with a carbon indicator film onto a 2% uranyl acetate aqueous solution droplet and allowing it to stand at room temperature for 10 seconds.
  • the grid was dried and then photographed with a transmission electron microscope HITACHI H-7600 at an acceleration voltage of 100 kV.
  • Test 2 Confirmation of particle size of exosome 10 mg of placenta extract was dissolved in 1 mL of water and then filtered through a 0.22 ⁇ m filter to obtain a test sample. The test sample was further diluted 100 times, and the particle size was measured with a dynamic light scattering photometer (ZETASIZER NANO-ZS, manufactured by Malvern).
  • the cells used were TIG-3 (human fibroblasts) (purchased from Geriatric Research Bank).
  • MiRNA was extracted from TIG-3 at the 39th passage (hereinafter described as 39PDL) as young cells and TIG-3 at the 80th passage (hereinafter described as 80PDL) as senescent cells, using miRNeasy (manufactured by Qiagen).
  • Each miRNA was subjected to comparative analysis using 3D-Gene (manufactured by TORAY) DNA microarray (human miRNA ver12.1).
  • TIG-3 of passage 74 Evaluation when miRNA was added to fibroblasts TIG-3 of passage 74 was used as the cells.
  • the following synthetic miRNAs (both manufactured by QIAGEN) corresponding to three miRNAs containing the amounts shown in Table 4 among the miRNAs derived from the placenta extract were each diluted to 10 nM, and transferred to cells using lipofectamine RNAmax. Erected.
  • hsa-miR-125a-5p 5′-UCCCUGAGACCCUUUAACCUGUGA-3 ′
  • hsa-miR-30c-5p 5'-UGUAAACAUCCUACACUCUCAGC-3 '
  • hsa-miR-26a-5p 5′-UUCAAGUAAUCCAGGAUAGGCU-3 ′ (SEQ ID NO: 165)
  • Transfection is performed twice every 24 hours, and after 48 hours after addition, the cells are fixed, and actin and cell nuclei are fluorescently stained using Alexa Fluor 488 Phalloidin (manufactured by Thermo Fisher). The size was analyzed. Both the number of nuclei and the cell size are shown by comparison values with cells transfected with a control synthetic Hsa-miRNA (QIAGEN).
  • TIG3 human-derived fibroblasts
  • 66PDL passaged 66
  • 83PDL passage 83
  • 66PDL and 83PDL passage 83
  • the exosome solution diluted to 5.15 ⁇ 10 3 particles / mL with PBS was added to 66PDL fibroblasts, and the exosome solution diluted to 5.15 ⁇ 10 4 particles / mL was added to 83PDL fibroblasts.
  • Addition is performed twice every 24 hours, cells are fixed 48 hours after addition, and actin / nuclear cells are fluorescently stained using Alexa Fluor488 Phalloidin (Thermo Fisher), and the number and size of the stained cells are determined. Analyzed.
  • Fig. 3 shows a photograph after fluorescent staining of 66PDL
  • Fig. 4 shows the number of cells
  • Fig. 5 shows the cell size
  • Fig. 6 shows a photo after fluorescent staining of 83PDL
  • Fig. 7 shows the number of cells
  • Fig. 8 shows the cell size. . From FIG. 3 to FIG. 8, it was confirmed that both 66PDL and 83PDL increased the number of cells and decreased the cell size by adding exosomes. It is known that when cells age, cell growth stops and the shape of the cells becomes flattened, so exosomes are considered to have anti-aging activity.
  • Test 7 Evaluation of Macrophage Migration Ability by Transwell Migration Assay
  • the action of the exosome prepared in Production Example 2 was examined by a transwell migration assay using RAW264.7 mouse macrophage-like cells. 750 ⁇ L of serum-containing medium was added to each well of the 24-well plate, and the insert was placed. RAW264.7 cells were suspended in a serum-free medium at 2 ⁇ 10 6 cells / ml, and 100 ⁇ L each was seeded on the insert of each well. Each sample was added to the cells and cultured at 37 ° C. in the presence of 5% CO 2 . After 24 hours, each sample was added again and further cultured at 37 ° C. in the presence of 5% CO 2 .
  • the vertical axis in FIG. 9 indicates the number of migrated cells, and the horizontal axis indicates each sample used.
  • Untreated means a sample using a phosphate buffer (PBS).
  • Reagent only means a reagent of Total exosome isolation kit manufactured by Invitrogen Corporation used for purification of exosomes.
  • No treatment indicates that the exosome solution obtained in Production Example 2 was used as it was.
  • the “filter treatment” is obtained by treating the exosome solution obtained in Production Example 2 with a 0.22 ⁇ m filter.
  • Exosome removal means the supernatant during purification of the kit, and is a fraction that does not contain exosomes.
  • exosome means a precipitate fraction during purification of a kit containing exosomes.
  • exosome of the present invention has an activating effect on immune cells such as macrophages.
  • Repair rate (%) 100 ⁇ [(scratch width after 24 hours; ⁇ m) / (0 hour wound width; ⁇ m) ⁇ 100]
  • the repair rate was significantly higher when the purified fraction containing exosome was used, and the exosome of the present invention activated macrophage migration to recover the wound site. It was suggested to promote. From the above results, the exosome according to the present invention is also expected to be used as a macrophage migration promoter, immune cell activator or wound healing promoter.

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Abstract

Dans la présente invention, des exosomes sont extraits à partir d'extraits de placenta et un procédé est établi pour produire des extraits de placenta de porc, qui contiennent un taux élevé d'exosomes. Dans les exosomes, de multiples miARN présentant des effets anti-âge ont été découverts. Les exosomes contenant ces miARN peuvent être utilisés pour : des compositions orales telles que des comprimés, des suppléments et des boissons présentant un effet anti-âge ; des produits cosmétiques tels que des lotions, des huiles cosmétiques et des crèmes de nettoyage du visage ; et un promoteur de croissance de cellules fibroblastiques.
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WO2020214868A1 (fr) * 2019-04-16 2020-10-22 Lifenet Health Produits dérivés de tissus génitaux et préparation et utilisations associées
JP2021029154A (ja) * 2019-08-21 2021-03-01 アサヒグループ食品株式会社 栄養補助組成物及びその製造方法、動物抽出物又は栄養補助組成物の不快臭の抑制方法、並びに動物抽出物又は栄養補助組成物の不快臭抑制用組成物
TWI778915B (zh) * 2021-03-30 2022-09-21 日商新日本製藥股份有限公司 化妝料組成物之製造方法
CN115537374A (zh) * 2022-09-23 2022-12-30 杭州昱鼎生物科技有限公司 一种体液中提取外泌体的钠基蒙脱石（Na-MMT）吸附柱法
JP2023503973A (ja) * 2019-11-27 2023-02-01 プラコウス セラピューティクス，インコーポレイテッド 壊死性腸炎に対する無細胞胎盤療法
JP2025016223A (ja) * 2023-07-21 2025-01-31 株式会社東洋発酵 エクソソーム産生促進剤およびエクソソーム産生促進剤含有組成物

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WO2020214868A1 (fr) * 2019-04-16 2020-10-22 Lifenet Health Produits dérivés de tissus génitaux et préparation et utilisations associées
JP2021029154A (ja) * 2019-08-21 2021-03-01 アサヒグループ食品株式会社 栄養補助組成物及びその製造方法、動物抽出物又は栄養補助組成物の不快臭の抑制方法、並びに動物抽出物又は栄養補助組成物の不快臭抑制用組成物
JP7353101B2 (ja) 2019-08-21 2023-09-29 アサヒグループ食品株式会社 栄養補助組成物及びその製造方法、動物抽出物又は栄養補助組成物の不快臭の抑制方法、並びに動物抽出物又は栄養補助組成物の不快臭抑制用組成物
JP2023503973A (ja) * 2019-11-27 2023-02-01 プラコウス セラピューティクス，インコーポレイテッド 壊死性腸炎に対する無細胞胎盤療法
TWI778915B (zh) * 2021-03-30 2022-09-21 日商新日本製藥股份有限公司 化妝料組成物之製造方法
JP2022153936A (ja) * 2021-03-30 2022-10-13 新日本製薬株式会社 化粧料組成物の製造方法
CN115537374A (zh) * 2022-09-23 2022-12-30 杭州昱鼎生物科技有限公司 一种体液中提取外泌体的钠基蒙脱石（Na-MMT）吸附柱法
CN115537374B (zh) * 2022-09-23 2024-08-20 杭州昱鼎生物科技有限公司 一种体液中提取外泌体的钠基蒙脱石（Na-MMT）吸附柱法
JP2025016223A (ja) * 2023-07-21 2025-01-31 株式会社東洋発酵 エクソソーム産生促進剤およびエクソソーム産生促進剤含有組成物
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