WO2018181071A1 - Composition de dégradation de glycoprotéine non-collagène - Google Patents

Composition de dégradation de glycoprotéine non-collagène Download PDF

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WO2018181071A1
WO2018181071A1 PCT/JP2018/011923 JP2018011923W WO2018181071A1 WO 2018181071 A1 WO2018181071 A1 WO 2018181071A1 JP 2018011923 W JP2018011923 W JP 2018011923W WO 2018181071 A1 WO2018181071 A1 WO 2018181071A1
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bifidobacterium
bacterium
culture
composition
atcc
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Japanese (ja)
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琢磨 桜井
那波 橋倉
金忠 清水
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森永乳業株式会社
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Priority to JP2019509744A priority Critical patent/JP6954995B2/ja
Publication of WO2018181071A1 publication Critical patent/WO2018181071A1/fr

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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
    • 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
    • A23L33/195—Proteins from microorganisms
    • 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
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/745—Bifidobacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/745—Blood coagulation or fibrinolysis factors
    • 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
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20—Bacteria; Culture media therefor
    • 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
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/52—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from bacteria or Archaea
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/49—Urokinase; Tissue plasminogen activator

Definitions

  • the present invention relates to a non-collagenous glycoprotein degrading agent or a non-collagenous glycoprotein degrading composition, a non-collagenous glycoprotein degrading pharmaceutical composition and a non-collagenous glycoprotein degrading food / beverage composition.
  • Non-collagenous glycoprotein is a kind of cell adhesion molecule that forms a network structure of extracellular matrix surrounding cells and tissues.
  • Fibrinogen one of non-collagenous glycoproteins, is known to be involved in thrombus formation.
  • the blood coagulation system is activated along with the vasoconstriction, and fibrin is generated from fibrinogen, forming a fibrin clot and forming a thrombus.
  • Fibronectin and laminin are also known as non-collagenous glycoproteins that are components of the interface between the vitreous body of the eye and the retina.
  • the vitreous body of the eye is originally in close contact with the retina, but it is known that the vitreous body is denatured from a gel state to a liquid state with aging and peels from the retina (rear vitreous body peeling).
  • the posterior vitreous detachment itself is not a pathological change, but if the vitreous and the retina are firmly bonded, a retinal tear may be caused at the time of vitreal detachment and serious visual impairment may be caused.
  • Plasmin is classified as an endoprotease and exists in vivo as plasminogen, which is usually an inactive precursor.
  • a specific peptide bond of plasminogen is decomposed and activated by plasminogen activator (PA) to exert enzyme activity as plasmin.
  • PA plasminogen activator
  • Examples of plasminogen activators include tissue plasminogen activator (tPA) secreted from vascular endothelial cells and urokinase-type plasminogen activator (uPA) present in urine.
  • Plasmin is known to have an activity of degrading non-collagenous glycoproteins such as fibrinogen, fibronectin and laminin (Non-patent Document 1).
  • plasmin is an enzyme involved in a reaction that causes fibrinogenolysis and dissolves a fibrin clot, and has an action of dissolving a thrombus formed in the blood coagulation system. Therefore, plasmin is used in a conservative treatment method (fibrinolytic therapy) that prevents or reduces symptoms of ischemic injury caused by a thrombus formed by a fibrin clot (Non-patent Document 2).
  • Plasmin also has a degrading activity for fibronectin, which is a constituent component of the vitreous retinal interface, and is therefore used as an auxiliary substance when excising the vitreous from the retina (Patent Document 1).
  • the plasmin-containing fraction contains omega-amino acids.
  • Non-patent Document 3 an enzyme having plasmin activity derived from bacteria (natto) such as nattokinase enhances fibrinolytic activity in plasma.
  • natto contains abundant vitamin K produced by Bacillus natto, and by ingesting natto, vitamin K moves into the blood and reduces the efficacy of some antithrombotic drugs.
  • Non-Patent Document 4 and Non-Patent Document 5.
  • some Bifidobacterium bacteria that exist in the body bind to plasminogen on the cell surface and use the host plasminogen activator to bind to the cell surface. It has been reported that there is one having an activity of activating a gene and converting it into plasmin (Non-patent Document 6).
  • the Bifidobacterium genus, the culture of the bacterium, and / or the treated product of the bacterium have plasminogen activator activity and plasmin activity, thereby non-collagenous glycoprotein degradation effect It is not known to play.
  • the method for producing plasmin needs to undergo complicated steps so as not to impair plasmin activity. Moreover, when using natto kinase derived from natto, there is a concern about the side effect that vitamin K in natto promotes blood coagulation.
  • the present invention is a non-collagenous glycoprotein degrading agent or a non-collagenous glycoprotein degrading composition, a non-collagenous glycoprotein degrading pharmaceutical composition, and a non-collagenous glycoprotein degrading food and beverage that can be produced simply and without side effects.
  • An object is to provide a product composition.
  • the Bifidobacterium genus bacteria, the culture of the bacteria, and / or the treated product of the bacteria have plasminogen activator activity and plasmin activity. Based on this, it was found that a non-collagenous glycoprotein degradation effect was achieved, and the present invention was completed.
  • the present invention relates to a non-collagenous glycoprotein degrading agent or a composition for degrading non-collagenous glycoprotein, comprising as an active ingredient a Bifidobacterium bacterium, a culture of the bacterium, and / or a treated product of the bacterium. Offer things.
  • the degradation agent or the composition for degradation is preferably a mode in which the non-collagenous glycoprotein is fibrin, fibrinogen, fibronectin, laminin or plasminogen.
  • the decomposing agent or the decomposing composition is such that the Bifidobacterium genus bacterium is Bifidobacterium longum subspecies longum ATCC 15707 (Bifidobacterium longum subsp. Longum ATCC15707), Bifidobacterium longum subs. Spices Longum ATCC BAA-999 (Bifidobacterium longum subsp. Longum ATCC BAA-999) (or Bifidobacterium longum Subspecies longum BB536 (NITE BP-02621) (Bifidobacterium longum subsp. ))), Bifidobacterium longum subsp.
  • Infatis ATCC 15697 (Bifidobacterium longum subsp. Infantis tATCC15697), Bifidobacterium longum subsp. Infantis BCCM MG23728 (Bifidobacterium longum subsp. Infantis BCCM LMG23728) (or Bifidobacterium longum subspecies Infantis M-63 (NITE BP-02623) (Bifidobacterium longum subsp.
  • Bifidobacterium breve ATCC15700 Bifidobacterium breve ATCC15700
  • Bifidobacterium breve FERM BP-11175 Bifidobacterium breve BFERM BP-11175
  • Bifidobacterium breve BCCM LMG23729 Bifidobacterium breve GGCM Bifidobacterium breve M-16V (NITE BP-02622) (Bifidobacterium breve M-16V (NITE BP-02622))
  • Bifidobacterium bifidum ATCC29521 Bifidobacterium bifidum ATCC29521
  • Bi Fidobacterium adrecentis ATCC15703 Bifidobacterium adolescentis ATCC15703
  • Bifidobacterium angulatum ATCC 27535 Bifidobacterium breve ATCC15700
  • a preferred embodiment is one or more selected from the group consisting of:
  • the present invention provides a pharmaceutical composition for degrading non-collagenous glycoproteins comprising as an active ingredient a Bifidobacterium bacterium, a culture of the bacterium, and / or a treated product of the bacterium.
  • the pharmaceutical composition is cerebral infarction, limb arteriovenous thrombosis, pulmonary infarction, cerebral venous sinus thrombus, retinal detachment, retinal tear, vitreous hemorrhage, diabetic vitreous hemorrhage, proliferative diabetes, age-related macular degeneration, macular circle It is preferably used for prevention and / or treatment of pores, vitreous macular traction, fibrin deposition, retinal vein occlusion, retinal artery occlusion, glaucoma or retinitis pigmentosa.
  • the present invention also provides a non-collagenized glycoprotein degrading food / beverage composition
  • a non-collagenized glycoprotein degrading food / beverage composition comprising as an active ingredient a Bifidobacterium genus bacterium, a culture of the bacterium, and / or a treated product of the bacterium.
  • the food / beverage product composition preferably contains plasminogen.
  • the present invention includes a step of culturing Bifidobacterium, and a step of recovering a protein having plasminogen activator activity and / or plasmin activity produced in the culture after the culture.
  • a method for producing a protein having plasminogen activator activity and / or plasmin activity is provided.
  • the present invention provides a method for producing plasmin, comprising a step of culturing Bifidobacterium in a medium containing plasminogen, and a step of recovering plasmin produced in the culture after the culture. provide.
  • the present invention provides use of a Bifidobacterium bacterium, a culture of the bacterium, and / or a treated product of the bacterium in the manufacture of a composition for degrading non-collagenous glycoprotein.
  • the present invention also provides a Bifidobacterium genus used for non-collagenous glycoprotein degradation, a culture of the bacterium, and / or a treated product of the bacterium.
  • the present invention also provides use of a Bifidobacterium bacterium, a culture of the bacterium, and / or a treated product of the bacterium for non-collagenous glycoprotein degradation.
  • the present invention also provides a method for degrading non-collagenous glycoprotein, comprising the step of administering a Bifidobacterium bacterium, a culture of the bacterium, and / or a treated product of the bacterium to a mammal. To do.
  • a non-collagenous glycoprotein degrading agent or a non-collagenous glycoprotein degrading composition, a non-collagenous glycoprotein degrading pharmaceutical composition, and a non-collagenous glycoprotein degrading agent that can be easily produced and have no side effects.
  • the food-drinks composition can be provided.
  • the non-collagenous glycoprotein degrading agent according to the present invention contains a Bifidobacterium bacterium, a culture of the bacterium, and / or a treated product of the bacterium as an active ingredient.
  • the non-collagenous glycoprotein degrading agent according to the present invention contains a Bifidobacterium bacterium, a culture of the bacterium, and / or a treated product of the bacterium as an active ingredient. It does not prevent the inclusion of ingredients. That is, the non-collagenous glycoprotein degrading agent according to the present invention is equivalent to the non-collagenous glycoprotein degrading composition.
  • another aspect of the present invention is a composition for degrading non-collagenous glycoproteins comprising a Bifidobacterium bacterium, a culture of the bacterium, and / or a treated product of the bacterium as an active ingredient.
  • the content of Bifidobacterium in the composition is preferably 1 ⁇ 10 6 to 1 ⁇ 10 12 CFU / g or 1 ⁇ 10 6 to 1 ⁇ 10 12 CFU / mL, more preferably Is 1 ⁇ 10 7 to 1 ⁇ 10 11 CFU / g or 1 ⁇ 10 7 to 1 ⁇ 10 11 CFU / mL, more preferably 1 ⁇ 10 8 to 1 ⁇ 10 10 CFU / g or 1 ⁇ 10 8 1 ⁇ 10 10 CFU / mL. If the bacterium is dead, the CFU can be replaced with cells.
  • the Bifidobacterium bacterium, the culture of the bacterium, and / or the treated product of the bacterium have plasminogen activator activity and plasmin activity, and based on these, non-collagenous glycoprotein This shows the decomposition effect. Therefore, in the present invention, plasminogen can be converted to plasmin even if plasminogen is not bound to the cell surface as in Non-Patent Document 6. That is, the present invention does not require a step of binding plasminogen to the cell surface of Bifidobacterium.
  • Another aspect of the present invention is a method for producing a composition for degrading non-collagenous glycoprotein, comprising a step of adding the Bifidobacterium of the present invention to a composition raw material.
  • the said manufacturing method contains the manufacturing method of the food-drinks composition including the process of adding the Bifidobacterium genus bacteria of this invention to the food-drinks composition raw material.
  • the said manufacturing method contains the manufacturing method of pharmaceutical composition including the process of adding Bifidobacterium genus bacteria to pharmaceutical composition raw materials (for example, base etc.).
  • the Bifidobacterium genus bacterium used in the method for producing the composition for degrading non-collagenous glycoprotein may be live or dead, and includes both live and dead But you can.
  • the Bifidobacterium bacterium may be added to the composition raw material after culturing, concentrating or freeze-drying, and the Bifidobacterium bacterium The Bifidobacterium may be cultured after adding to the composition raw material.
  • Bifidobacterium genus Bacteria belonging to the genus Bifidobacterium can be used in the genus Bifidobacterium, as long as the effects of the present invention are not impaired.
  • Infantis Bifidobacterium breve (Bifidobacterium breve), Bifidobacterium bifidum, Bifidobacterium adolescentis, Bifidobacterium angulatum, Bifidobacterium dentium, Bifidobacterium adolescentis, Bifidobacterium angulatum Bifidobacterium psudocatenulatum, Bifidobacterium animalis subsp. Lactis, Bifidobacterium anima Bifidobacterium animalis subsp. Animalis, Bifidobacterium pseudolongum subsp.
  • Bifidobacterium pseudolongum subsp. Globosum Bifidobacterium pseudolongum subsp. Pseudolongm
  • Bifidobacterium thermophilum etc.
  • the Bifidobacterium longum subspecies longum may be simply referred to as Bifidobacterium longum.
  • Bifidobacterium longum sub-species Infantis is sometimes simply referred to as Bifidobacterium Infantis.
  • Bifidobacterium longum subsp. Longum ATCC 15707 Bifidobacterium longum subsp. Longum ATCC15707
  • Bifidobacterium longum subspice longum ATCC BAA-999 Bifidobacterium longum subsp. Longlong ATCC BABA- 999
  • Bifidobacterium longum subspecies longis BB536 NITE BP-02621
  • Bifidobacterium longum subsp. Longum BB536 NITE BP-02621
  • Bifidobacterium longum subspecies Infatis ATCC 15697 Bifidobacterium longum subsp.
  • Bifidobacterium breve ATCC15700 Bifidobacterium breve ATCC15700
  • Bifidobacterium breve FERM BP-11175 Bifidobacterium breve FERM BP-11175
  • Bifidobacterium breve BCCM LMG23729 Bifidobacterium breve bc BCCM LMG23729
  • Bifidobacterium breve M-16V NITE BP-0222
  • Bifidobacterium breve M-16V Bifidobacterium breve M-16V (NITE BP-02622)
  • Bifidobacterium bifidum ATCC29521 Bifidobacteriumifbifidum ATCC29521
  • Bifidobacterium adrecentis ATCC15703 Bifidobacterium adol escentis ATCC15703
  • Bifidobacterium angulatum B
  • Bifidobacterium Pseudolongum subspecies pseudolongum ATCC25526 Bifidobacterium pseudolongum subsp. Pseudolongm ATCC25526
  • Bifidobacterium thermofilm ATCC25525 Bifidobacterium thermophilum ATCC25525
  • the Bifidobacterium only one kind may be used, or any two or more kinds may be used.
  • Bacteria with ATCC numbers can be obtained from the American Type Culture Collection (address: 12301 Parklawn Drive, Rockville, Maryland 20852, United States of America). Bacteria to which a BCCM number is assigned can be obtained from Belgian Coordinated Collections of Microorganisms (Address: B-1000 Brussels, Ciens Street (Wetens Cup Street) 8), Belgium.
  • Bacteria to which the FERM BP-11175 accession number has been assigned were issued on August 25, 2009 at the National Institute of Advanced Industrial Science and Technology, Patent Biological Deposit Center (currently the National Institute for Product Evaluation Technology Patent Biological Deposit Center, 292-0818 2-5-8 Kazusa-Kamashita, Kisarazu City, Chiba Prefecture Room 120) has been deposited internationally based on the Budapest Treaty. Bacteria with DSM numbers can be obtained from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (address: Inhoffenstra ⁇ e 7B, 38124 Braunschweig, Germany).
  • Bifidobacterium longum sub-species longum ATCC BAA-999 is the same bacterium as Bifidobacterium longum sub-species longum BB536 (NITE BP-02621). Bacteria may be used. Bifidobacterium longum subspecies longum BB536 (NITE BP-02621) was established on January 26, 2018, by the National Institute for Product Evaluation Technology Patent Microorganism Depositary Center (Kazusa, Kisarazu City, Chiba Prefecture 292-0818). International deposit based on the Budapest Treaty was made in Nama BP-02621 under No. 122 (Kamaashi 2-5-8 122).
  • Bifidobacterium longum subspecies Infatis BCCM LMG23728 is the same bacterium as Bifidobacterium longum subspecies Infantis M-63 (NITE BP-02623), which is a preferred embodiment. In, any bacteria may be used. Bifidobacterium longum subspecies Infantis M-63 (NITE BP-02623) was established on January 26, 2018, by the National Institute of Technology and Evaluation of the National Institute of Technology and Evaluation (JAPAN) In the prefecture, Kisarazu City, Kazusa Kamashi, 2-5-8 122), the deposit number of NITE BP-02623 was made based on the Budapest Treaty.
  • Bifidobacterium breve BCCM LMG23729 is the same bacterium as Bifidobacterium breve M-16V (NITE BP-02622), and any bacterium may be used in a preferred embodiment.
  • Bifidobacterium breve M-16V (NITE BP-02622) was issued on January 26, 2018, by the National Institute for Product Evaluation Technology Patent Microorganisms Depositary Center (Kazusa Kamashi 2, Kisarazu City, Chiba Prefecture 292-0818) -5-8 Room 122), the deposit number of NITE BP-02622, which was internationally deposited under the Budapest Treaty.
  • the Bifidobacterium genus bacterium of the present invention is not limited to the deposited bacterium, and may be a bacterium substantially equivalent to the deposited bacterium.
  • the bacterium substantially equivalent to the deposited bacterium is a bacterium belonging to the same genus or the same species as the deposited bacterium, and allows the subject to ingest the bacterium, a culture of the bacterium, and / or a treated product of the bacterium.
  • non-collagenous glycoprotein can be degraded in the subject, and the base sequence of the 16S rRNA gene is 98% or more, preferably 99% or more of the base sequence of the 16S rRNA gene of the deposited bacterium.
  • the bacterium has a homology of 100%, and preferably a bacterium having the same mycological properties as the deposited bacterium in addition to the homology.
  • the Bifidobacterium genus bacterium of the present invention is selected from the deposited bacterium or a bacterium substantially equivalent thereto, mutation treatment, genetic recombination, selection of a natural mutant, etc. Bacteria bred by may be used.
  • Bifidobacterium spp. Live in insects and small animals in addition to humans, but the habitat (host) is limited by the species, and Bifidobacterium spp.
  • the bacterium is called a human resident Bifidobacterium (HRB), otherwise it is called non-HRB.
  • HRB includes Bifidobacterium longum, Bifidobacterium longum subsp.
  • Bifidobacterium bacteria derived from infants are more preferable among HRBs. Examples of HRB derived from infants include Bifidobacterium longum, Bifidobacterium longum subsp. Infantis, Bifidobacterium breve, Examples thereof include Bifidobacterium bifidum.
  • the Bifidobacterium bacterium used in the present invention may be a mutant strain of the Bifidobacterium bacterium as long as it has a non-collagenous glycoprotein degrading effect equivalent to or better than the Bifidobacterium bacterium. . Whether or not a mutant strain has a “non-collagenous glycoprotein degradation effect equal to or higher than that of the above-mentioned Bifidobacterium genus” can be determined, for example, by measuring the plasmin activity of Bifidobacterium genus described later, It can be confirmed by measuring gen activator activity.
  • Such a mutant strain may be constructed by introducing a mutation artificially into the Bifidobacterium. In addition, it may be constructed by introducing mutation into the bacterium by treatment with a mutagen such as UV, or may be constructed by introducing mutation into the bacterium by various gene manipulation methods.
  • the plasmin activity is the fluorescence of a culture obtained by mixing a Bifidobacterium bacterium, a culture of the bacterium, and / or a treated product of the bacterium with a fluorescent substrate specific to plasmin, and culturing the mixture. This can be confirmed by measuring the strength. That is, the fluorescent substance concentration in the culture is calculated from the fluorescent intensity of the culture using a calibration curve indicating the relationship between the fluorescent substance concentration and the fluorescent intensity derived from the fluorescent substrate, and further, in one minute.
  • cells are separated from a culture of Bifidobacterium and suspended in a PBS solution to prepare a suspension, and the suspension is diluted to a turbidity (OD600) of 0.1.
  • Boc-Val-Leu-Lys-AMC manufactured by BACHEM
  • BACHEM Boc-Val-Leu-Lys-AMC
  • the enzyme activity (plasmin activity) of Bifidobacterium is determined from the fluorescence intensity of the culture measured at an excitation wavelength of 380 nm and a measurement wavelength of 460 nm with a fluorescence measuring device such as reader SH-9000 (Corona Electric). be able to.
  • a fluorescence measuring device such as reader SH-9000 (Corona Electric).
  • the plasmin activity is preferably 40 ⁇ U or more, more preferably 80 ⁇ U or more, and even more preferably 100 ⁇ U or more, the non-collagenous glycoprotein degradation effect of the present invention can be suitably exhibited.
  • plasminogen activator activity is not a plasmin-specific fluorescent substrate, but a plasminogen activator-specific fluorescent substrate as Z-Gly-Gly-Arg-AMC.HCl (BACHEM). It can be determined in the same manner as in the case of the plasmin activity except that the product is used. In the present invention, if the plasminogen activator activity is preferably 10 ⁇ U or more, more preferably 20 ⁇ U or more, and even more preferably 50 ⁇ U or more, the non-collagenous glycoprotein degradation effect of the present invention can be suitably exhibited. it can.
  • the Bifidobacterium bacterium used in the present invention and the culture of the bacterium can be easily obtained by culturing the Bifidobacterium bacterium by a conventional method.
  • the culture method is not particularly limited as long as Bifidobacterium can grow, and culture can be performed under appropriate conditions according to the nature of the bacteria.
  • the culture temperature may be 25 to 50 ° C., preferably 35 to 42 ° C.
  • cultivation on anaerobic conditions for example, it can culture
  • the medium for culturing Bifidobacterium used in the present invention is not particularly limited, and a medium usually used for culturing Bifidobacterium can be used. That is, as the carbon source, for example, saccharides such as glucose, galactose, lactose, arabinose, mannose, sucrose, starch, starch hydrolyzate, and molasses can be used depending on utilization. As the nitrogen source, for example, ammonium salts such as ammonia, ammonium sulfate, ammonium chloride, and ammonium nitrate, and nitrates can be used.
  • the carbon source for example, saccharides such as glucose, galactose, lactose, arabinose, mannose, sucrose, starch, starch hydrolyzate, and molasses can be used depending on utilization.
  • the nitrogen source for example, ammonium salts such as ammonia, ammonium sulfate, ammonium chloride, and am
  • inorganic salts examples include sodium chloride, potassium chloride, potassium phosphate, magnesium sulfate, calcium chloride, calcium nitrate, manganese chloride, and ferrous sulfate.
  • Organic components such as peptone, soybean powder, defatted soybean meal, meat extract, yeast extract and the like may also be used.
  • the Bifidobacterium genus bacterium used in the present invention can be used in the form of a bacterium itself, a culture of the bacterium, or a treated product of the bacterium as described above. That is, the bacterium belonging to the genus Bifidobacterium itself may be used, and after culturing the bacterium belonging to the genus Bifidobacterium, the obtained culture may be used as it is, or may be used after being diluted or concentrated. Moreover, the Bifidobacterium genus bacteria used for this invention may be live or dead, and may contain both live and dead.
  • the bacterial cell processed product examples include, for example, an immobilized bacterial cell in which the bacterial cell is fixed with acrylamide, carrageenan, or the like, and the cell wall and cell membrane of the bacterial cell are partially processed by an ordinary method such as ultrasonic treatment or homogenizer treatment. Or the completely crushed cell crushed material etc. are mentioned.
  • the cell disrupted product may be the whole fraction after the disruption or a part of the fraction, the centrifuged supernatant after the disruption, the fraction obtained by partially purifying the supernatant by ammonium sulfate treatment, or the above
  • the concentrate may be concentrated.
  • Bifidobacterium genus bacteria used in the present invention include, for example, a cell suspension thereof, a water-soluble fraction of the cell disruption product of the cells (bacteria), and a resuspension suspension.
  • the water-soluble fraction of the cell disruption product of the cells (bacteria) is preferable because of its high non-collagenous glycoprotein degradation activity.
  • the “bacterial cell suspension” in the present specification is a solution obtained by suspending a cell obtained by centrifuging a culture solution of the genus Bifidobacterium used in the present invention, preferably This is a solution obtained by the treatment described in (2) of Test Example 3 in Examples described later.
  • the “water-soluble fraction” in the present specification is a supernatant obtained by centrifuging the cell disrupted product, and is preferably described in (2) of Test Example 3 in Examples described later. It is a supernatant finally obtained by the process.
  • the water-soluble fraction is more preferably a water-soluble fraction appropriately purified or concentrated by a conventional method.
  • the “precipitation resuspension” in the present specification is a solution in which a precipitate obtained by centrifuging the above-mentioned cell disruption is suspended, and preferably in Test Example 3 of Examples described later. It is a solution in which a precipitate finally obtained by the treatment described in (2) is suspended.
  • Non-collagenous glycoprotein of the present invention includes cell adhesion molecules that form a network structure of an extracellular matrix surrounding cells and tissues, and may be in a monomer state or a polymer state.
  • fibrin also referred to as “stabilized fibrin”
  • fibrin polymer also referred to as “stabilized fibrin”
  • fibrinogen also referred to as “stabilized fibrin”
  • fibrin polymer fibrin monomer
  • fibrinogen also referred to as “stabilized fibrin”
  • fibrinogen also referred to as “stabilized fibrin”
  • fibrinogen also referred to as “stabilized fibrin”
  • fibrin polymer fibrin monomer
  • fibrinogen also referred to as “stabilized fibrin”
  • fibrinogen also referred to as “stabilized fibrin”
  • fibrinogen also referred to as “stabilized fibrin”
  • fibrinogen fibrinogen
  • fibronectin laminin
  • plasminogen vitronectin
  • nidogen tenascin
  • the non-collagenous glycoprotein degradation agent or non-collagenous glycoprotein degradation composition of the present invention can be used as a pharmaceutical composition.
  • Plasmin is a retinal detachment, retinal tear, vitreous hemorrhage, diabetic vitreous hemorrhage, proliferative diabetes, age-related macular degeneration, macular hole, vitreous macular traction, fibrin deposition, retinal vein occlusion, retinal artery occlusion, Chemical vitrectomy that requires vitreal detachment for glaucoma and retinitis pigmentosa; fibrinolysis for ischemic disorders such as cerebral infarction, limb arteriovenous thrombosis, pulmonary infarction and cerebral venous sinus thrombus It is used for therapy (Patent Document 2, Non-Patent Document 1).
  • plasmin has a fibrinogen decomposing effect because it is effective for fibrinolytic therapy for ischemic disorders such as cerebral infarction, limb arteriovenous thrombosis, pulmonary infarction and cerebral venous sinus thrombus (non- Patent Document 1).
  • the pharmaceutical composition of the present invention comprises retinal detachment, retinal laceration, vitreous hemorrhage, diabetic vitreous hemorrhage, proliferative diabetes, age-related macular degeneration, macular hole, vitreous macular traction, fibrin deposition, retinal vein occlusion Prevention and / or treatment of ischemic disorders such as cerebral infarction, limb arteriovenous thrombosis, pulmonary infarction and cerebral venous sinus thrombosis Can be used for Moreover, since the pharmaceutical composition of the present invention contains a Bifidobacterium genus bacterium, a culture of the bacterium, and / or a treated product of the bacterium that have been used for many years as an oral composition component, It can be administered with peace of mind to patients suffering from various diseases.
  • the non-collagenous glycoprotein degrading agent or the non-collagenous glycoprotein degrading composition of the present invention comprises a Bifidobacterium bacterium, a culture of the bacterium, and / or a treated product of the bacterium as an active ingredient. Therefore, it can be safely administered to infants and children. Therefore, the non-collagenous glycoprotein degrading agent or the non-collagenous glycoprotein degrading composition of the present invention is suitable for the prevention and / or treatment of diseases of infants and children.
  • the pharmaceutical composition may be administered either orally or parenterally. Accordingly, it can be appropriately formulated into a desired dosage form.
  • a desired dosage form for example, in the case of oral administration, it can be formulated into solid preparations such as powders, granules, tablets and capsules; liquid preparations such as solutions, syrups, suspensions and emulsions.
  • parenteral administration it can be formulated into a suppository, an ointment, an eye drop or the like.
  • non-collagenous glycoprotein degrading agent or non-collagenous glycoprotein degrading composition according to the present invention excipients, pH adjusters, and colorants that are usually used for formulation. Ingredients such as flavoring agents can be used.
  • the non-collagenous glycoprotein degrading agent or the non-collagenous glycoprotein degrading composition according to the present invention and known or future non-collagenous glycoproteins are involved.
  • a component having an effect of preventing and / or treating a disease can be used in combination.
  • formulation can be performed by a known method as appropriate according to the dosage form.
  • a formulation carrier may be appropriately blended to formulate.
  • the intake or dose of the pharmaceutical composition of the present invention can be appropriately selected according to the dosage form.
  • the daily intake or dosage of Bifidobacterium per kg body weight is preferably 1 ⁇ 10 6 to 1 ⁇ 10 12 CFU / kg / day, and 1 ⁇ 10 7 to 1 ⁇ 10 11 CFU. / Kg / day is more preferable, and 1 ⁇ 10 8 to 1 ⁇ 10 10 CFU / kg / day is more preferable.
  • CFU is an abbreviation of colony forming units and is a colony forming unit. If the bacterium is dead, the CFU can be replaced with cells.
  • the intake or dose is the above when converted to the intake or dose of Bifidobacterium. It is preferable to be an intake or a dose.
  • the content of Bifidobacterium in the pharmaceutical composition of the present invention can be appropriately selected based on the intake or dose.
  • 1 ⁇ 10 6 to 1 ⁇ 10 12 CFU / g or 1 ⁇ 10 6 to 1 ⁇ 10 12 CFU / mL preferably 1 ⁇ 10 7 to 1 ⁇ 10 11 CFU / g or 1 ⁇ 10 7 to 1 ⁇
  • It can be 10 11 CFU / mL, more preferably 1 ⁇ 10 8 to 1 ⁇ 10 10 CFU / g or 1 ⁇ 10 8 to 1 ⁇ 10 10 CFU / mL.
  • the CFU can be replaced with cells.
  • the content may be the above content when converted to the content of Bifidobacterium bacteria. preferable.
  • preparation carrier various organic or inorganic carriers can be used depending on the dosage form.
  • examples of the carrier in the case of a solid preparation include excipients, binders, disintegrants, lubricants, stabilizers, and flavoring agents.
  • excipient examples include sugar derivatives such as lactose, sucrose, glucose, mannitol and sorbit; starch derivatives such as corn starch, potato starch, ⁇ -starch, dextrin and carboxymethyl starch; crystalline cellulose, hydroxypropyl cellulose, Cellulose derivatives such as hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium; gum arabic; dextran; pullulan; silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, magnesium magnesium magnesium silicate; phosphate derivatives such as calcium phosphate; And carbonate derivatives such as calcium; sulfate derivatives such as calcium sulfate and the like.
  • sugar derivatives such as lactose, sucrose, glucose, mannitol and sorbit
  • starch derivatives such as corn starch, potato starch, ⁇ -starch, dextrin and carboxymethyl starch
  • crystalline cellulose hydroxypropyl cellulose
  • binder examples include gelatin, polyvinyl pyrrolidone, macrogol and the like in addition to the above excipients.
  • disintegrant examples include, in addition to the above excipients, chemically modified starch or cellulose derivatives such as croscarmellose sodium, sodium carboxymethyl starch, and crosslinked polyvinylpyrrolidone.
  • talc stearic acid
  • stearic acid metal salts such as calcium stearate and magnesium stearate
  • colloidal silica waxes such as pea gum and geirow
  • boric acid glycol
  • carboxylic acids such as fumaric acid and adipic acid
  • Carboxylic acid sodium salts such as sodium benzoate
  • sulfates such as sodium sulfate; leucine
  • lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate
  • silicic acids such as anhydrous silicic acid and silicic acid hydrate; starch derivatives and the like It is done.
  • the stabilizer examples include paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; acetic anhydride; sorbic acid and the like.
  • flavoring agent examples include sweeteners, acidulants, and fragrances.
  • a carrier used in the case of a liquid for oral administration a solvent such as water, a flavoring agent and the like can be mentioned.
  • the non-collagenous glycoprotein degrading agent or the non-collagenous glycoprotein degrading composition of the present invention can be used as a food or drink composition.
  • the food / beverage composition of the present invention may be produced by adding a Bifidobacterium bacterium, a culture of the bacterium, and / or a treated product of the bacterium to a known food / beverage product. It is also possible to produce a new food / beverage product composition by mixing the bacteria belonging to the genus Fidobacterium, the culture of the bacteria, and / or the processed product of the bacteria into the raw material of the food / beverage product.
  • the food-drinks composition of this invention can also be manufactured by the manufacturing method including the process of culture
  • plasmin is also used for ripening dairy products and producing cheese (X. G. Song et al., Journal of the Japan Food Industry Association, Vol. 40, No. 4, April 1993).
  • plasmin exists as plasminogen in mammalian milk, and it is known that the mother's milk of a premature mother has a higher plasmin concentration than usual.
  • the non-collagenous glycoprotein degradation food / beverage composition of the present invention preferably contains plasminogen, an additive food material for promoting ripening of dairy products and cheese, and a preparation for childcare for premature infants. It can be suitably used as a food material for addition to powdered milk, breast milk or food.
  • the food / beverage composition in the present invention may be in the form of liquid, paste, solid, powder, etc.
  • liquid food, feed including for pets
  • the food / beverage composition of the present invention may use a component having a probiotic effect known in the future or a component assisting the probiotic effect. it can.
  • the food / beverage composition of the present invention comprises various proteins such as whey protein, casein protein, soy protein, pea protein (pea protein) or mixtures thereof, and degradation products thereof; amino acids such as leucine, valine, isoleucine or glutamine; Vitamins such as vitamin B6 or vitamin C; creatine; citric acid; fish oil; or components such as isomalt-oligosaccharide, galactooligosaccharide, xylo-oligosaccharide, soybean oligosaccharide, fructooligosaccharide, lactulose .
  • proteins such as whey protein, casein protein, soy protein, pea protein (pea protein) or mixtures thereof, and degradation products thereof; amino acids such as leucine, valine, isoleucine or glutamine; Vitamins such as vitamin B6 or vitamin C; creatine; citric acid; fish oil; or components such as isomalt-oligosaccharide, galactooligosaccharide,
  • the food / beverage product composition defined in the present invention is used for prevention of diseases in which non-collagenous glycoproteins effectively act, risk reduction of diseases, symptom alleviation of diseases, and / or treatment (including health uses).
  • the “display” act includes all acts for informing the consumer of the use, and if the expression can remind the user of the use, the purpose of the display, the content of the display, the display Regardless of the target object / medium, etc., all fall under the “display” act of the present invention.
  • the “display” is performed by an expression that allows the consumer to directly recognize the use. Specifically, it is the act of transferring, displaying, importing, displaying, or importing products that are related to food or drinks or products that describe the use, on advertisements, price lists, or transaction documents. For example, an act of describing and displaying the above uses or distributing them, or describing the above uses in information including the contents and providing them by an electromagnetic (Internet or the like) method can be given.
  • the display content is preferably a display approved by the government or the like (for example, a display that is approved based on various systems determined by the government and is performed in a mode based on such approval).
  • labeling includes health food, functional food, enteral nutrition food, special purpose food, health functional food, food for specified health use, nutrition functional food, functional label food, quasi-drug, etc.
  • a display is also included.
  • indications approved by the Consumer Affairs Agency for example, indications approved in systems related to foods for specified health use, functional nutritional foods, functional indication foods, or similar systems, etc. can be mentioned.
  • labeling as a food for specified health use labeling as a conditionally specified food for specified health use, labeling that affects the structure and function of the body, labeling for reducing the risk of disease, and functionality based on scientific evidence Labeling, etc., and more specifically, Cabinet Office Ordinance concerning permission for special purpose labeling provided for in the Health Promotion Act (Cabinet Office Ordinance No. 57, August 31, 2000)
  • the labeling as food for specified health (particularly the labeling of health use) and the like are the typical examples.
  • the intake of the food / beverage product composition of the present invention can be appropriately selected.
  • the daily intake of Bifidobacterium per kg of body weight is preferably 1 ⁇ 10 6 to 1 ⁇ 10 12 CFU / kg / day, and 1 ⁇ 10 7 to 1 ⁇ 10 11 CFU / kg / day. Day is more preferable, and 1 ⁇ 10 8 to 1 ⁇ 10 10 CFU / kg / day is more preferable. If the bacterium is dead, the CFU can be replaced with cells.
  • the intake may be the above intake when converted to the intake of Bifidobacterium. preferable.
  • the content of Bifidobacterium in the food and beverage composition of the present invention can be appropriately selected based on the intake.
  • 1 ⁇ 10 6 to 1 ⁇ 10 12 CFU / g or 1 ⁇ 10 6 to 1 ⁇ 10 12 CFU / mL preferably 1 ⁇ 10 7 to 1 ⁇ 10 11 CFU / g or 1 ⁇ 10 7 to 1 ⁇
  • It can be 10 11 CFU / mL, more preferably 1 ⁇ 10 8 to 1 ⁇ 10 10 CFU / g or 1 ⁇ 10 8 to 1 ⁇ 10 10 CFU / mL.
  • the CFU can be replaced with cells.
  • the content may be the above content when converted to the content of Bifidobacterium bacteria. preferable.
  • the non-collagenous glycoprotein degrading food / beverage composition according to the present invention can be used as a human or animal food / beverage composition.
  • the non-collagenous glycoprotein degradation food / beverage composition according to the present invention includes cerebral infarction, limb arteriovenous thrombosis, pulmonary infarction, cerebral venous sinus thrombus, retinal detachment, retinal tear, vitreous hemorrhage, diabetic vitreous Non-collagenous glycoprotein-related diseases such as bleeding, proliferative diabetes, age-related macular degeneration, macular hole, vitreous macular traction, fibrin deposition, retinal vein occlusion, retinal artery occlusion, glaucoma or retinitis pigmentosa It is effective for prevention and / or treatment.
  • the food and drink composition for degrading non-collagenous glycoprotein of the present invention contains Bifidobacterium, culture of the bacterium, and / or treated product of the bacterium as an active ingredient. Can also be safely administered. Therefore, the non-collagenous glycoprotein degradation food / beverage composition of the present invention is also suitable for the prevention and / or treatment of diseases in infants and children.
  • Another embodiment of the present invention is a method for producing a protein having plasminogen activator activity and / or plasmin activity.
  • a step of culturing Bifidobacterium (culture step), and a step of recovering a protein having plasminogen activator activity and / or plasmin activity produced in the culture after the culture (Recovery step) is included, but other steps may be included.
  • the protein having plasminogen activator activity and the protein having plasmin activity may be one protein or different proteins. That is, one protein may have both plasminogen activator activity and plasmin activity, or a protein having plasminogen activator activity and a protein having plasmin activity may be separate proteins. .
  • This step is a step of culturing Bifidobacterium bacteria, and known culture conditions that can culture Bifidobacterium bacteria can be employed. For example, it can be cultured at 25 to 45 ° C., but it is preferably cultured at 30 to 42 ° C., more preferably 37 to 42 ° C. Moreover, it is preferable to perform culture
  • This step is a step of recovering a protein having plasminogen activator activity and / or plasmin activity produced in the culture after the culture.
  • This step includes (a) separating the culture after the culture into a Bifidobacterium genus and a fraction containing a protein having plasminogen activator activity and / or plasmin activity, and (b)
  • the method includes a step of recovering a protein having plasminogen activator activity and / or plasmin activity from the fraction, but may include other steps. Steps (a) and (b) may be performed simultaneously, and step (b) may be performed after step (a).
  • a known method can be employed, and for example, a method such as filtration with a membrane or centrifugation can be employed.
  • the membrane may be either a flat membrane or a hollow fiber membrane (hollow fiber).
  • the step (a) may include a step of treating cells of the genus Bifidobacterium. That is, the step (a) is separated into a step of treating cells of the genus Bifidobacterium and a fraction containing the treated product and a protein having plasminogen activator activity and / or plasmin activity. And a step of performing. About the process of processing the microbial cell of Bifidobacterium genus, the description regarding the microbial cell processed material already demonstrated is used.
  • step (b) a known method can be employed, and examples thereof include various chromatography methods such as gel filtration chromatography and reverse phase HPLC. Chromatography may be low or high pressure. When filtration is performed using a hollow fiber membrane (hollow fiber), the steps (a) and (b) can be performed simultaneously.
  • the fraction containing a protein having plasminogen activator activity and / or plasmin activity contains other components such as medium components as long as the effect of the protein having plasminogen activator activity and / or plasmin activity is exhibited.
  • the component or the like may be completely or partially purified, and the mode is not particularly limited.
  • purification can be performed by combining suitably the method in the said process (a) and / or (b).
  • the properties of the fraction containing a protein having plasminogen activator activity and / or plasmin activity may be liquid or powder obtained by lyophilization or the like, and the mode is not particularly limited.
  • the protein having plasminogen activator activity and / or plasmin activity produced according to the present embodiment is based on the physiological action of the protein, quasi-drug, external preparation for skin, cosmetics, food and drink, food. It can mix
  • Another embodiment of the present invention is a method for producing plasmin.
  • This embodiment includes a step of culturing Bifidobacterium in a medium containing plasminogen (culturing step), and a step of recovering plasmin produced in the culture after the culturing (recovering step).
  • culturing step a step of culturing Bifidobacterium in a medium containing plasminogen
  • recovering step recovering plasmin produced in the culture after the culturing
  • This step is a step of culturing Bifidobacterium in a medium containing plasminogen.
  • plasminogen When plasminogen is added to the medium, it may be added before culturing or during culturing. Moreover, any of collective addition, sequential addition, and continuous addition may be sufficient.
  • the content of plasminogen in the medium is not particularly limited.
  • the description of the “culturing step” in ⁇ Method for producing protein having plasminogen activator activity and / or plasmin activity> is incorporated in the culture conditions of Bifidobacterium.
  • This step is a step of recovering plasmin produced in the culture after the culture.
  • This step includes (c) a step of separating the culture after the culture into a fraction containing Bifidobacterium and plasmin, and (d) a step of recovering plasmin from the fraction. These steps may be included. Steps (c) and (d) may be performed simultaneously, and step (d) may be performed after step (c). Further, the step (c) may include a step of treating cells of the genus Bifidobacterium. That is, the step (c) may include a step of treating the cells of the genus Bifidobacterium, and a step of separating the treated cells and a fraction containing plasmin.
  • the plasmin produced according to this embodiment can be blended in compositions such as pharmaceuticals, quasi drugs, external preparations for skin, cosmetics, foods and drinks, food additives, and feeds based on the physiological functions of the plasmin. Moreover, the plasmin produced by this embodiment can be suitably used as a food material for addition to dairy products and cheese, a formula powder for childcare for premature infants, breast milk or a food material for addition to food.
  • the present invention can employ the following configurations.
  • the following mammals include humans, cows, sheep, goats, pigs, dogs, cats, horses and the like.
  • Bifidobacterium genus bacteria used for the alleviation, prevention or treatment of diseases that can be alleviated, prevented or treated by degradation of non-collagenous glycoprotein, culture of the bacteria, and / or cell treatment of the bacteria object.
  • a method for degrading non-collagenous glycoprotein comprising administering a Bifidobacterium genus bacterium, a culture of the bacterium, and / or a treated product of the bacterium to a mammal.
  • a non-collagenous glycoprotein degrading agent or a composition for degrading non-collagenous glycoprotein comprising a Bifidobacterium bacterium, a culture of the bacterium, and / or a treated product of the bacterium as an active ingredient
  • a method for degrading non-collagenous glycoproteins comprising the step of administering to an animal.
  • It is alleviated, prevented or treated by degradation of non-collagenous glycoprotein, comprising administering a Bifidobacterium bacterium, a culture of the bacterium, and / or a treated product of the bacterium to a mammal.
  • a method for alleviating, preventing or treating a disease obtained.
  • a non-collagenous glycoprotein degrading agent or a composition for degrading non-collagenous glycoprotein comprising a Bifidobacterium bacterium, a culture of the bacterium, and / or a treated product of the bacterium as an active ingredient
  • a method for alleviating, preventing or treating a disease that can be alleviated, prevented or treated by degradation of non-collagenous glycoprotein, comprising a step of administering to an animal.
  • Test Example 1 A test was conducted to confirm that Bifidobacterium has plasminogen activator activity.
  • the MRS liquid medium is prepared by dissolving 5.5 g of Difco Lactobacilli MRS Broth (BD) and 50 mg of L-Cysteine Monohydrochloride, Monohydrate (Wako Pure Chemical Industries) in pure water so as to be 100 mL, and using an aqueous HCl solution. It was prepared by adjusting to pH 6.5 and sterilizing at 121 ° C. for 15 minutes.
  • HRB Human resident Bifidobacterium
  • the fluorescence intensity of the culture was measured using a microplate reader SH-9000 (manufactured by Corona Electric) at an excitation wavelength of 360 nm and a measurement wavelength of 460 nm.
  • the unit of fluorescence intensity was an arbitrary unit (au).
  • the AMC concentration in the culture is calculated using a calibration curve showing the relationship between the fluorescent substance-derived fluorescent substance (AMC: aminomethylcoumarin) concentration prepared in advance and the fluorescence intensity at a measurement wavelength of 460 nm. From this concentration, the enzyme activity (plasminogen activator activity) of each Bifidobacterium was calculated using 1 nmol of AMC produced per minute as 1 unit of enzyme (U).
  • Bifidobacterium bacterium and / or the Bifidobacterium culture according to the present invention exhibited plasminogen activator activity and / or plasmin activity. It was suggested to have a glycoprotein degradation effect.
  • Test Example 1 One or more selected from 17 kinds of Bifidobacterium used in Test Example 1 was added to 3 mL of each or the same MRS liquid medium, anaerobically cultured at 37 ° C. for 16 hours, and the culture solution was concentrated. Freeze-drying is performed to obtain bacterial powder of the one or more bacteria. The one or more bacterial powders and excipients are mixed as appropriate to form tablets. The tablets are taken daily for 3 months so that the total amount of bacteria taken is 1 ⁇ 10 6 to 1 ⁇ 10 12 cfu / kg body weight / day. By taking the tablet, a non-collagenous glycoprotein degradation effect can be expected.
  • bifidobacteria / oligosaccharide blended milk powder is prepared by adding 100 g of bacterial powder (1.8 ⁇ 10 11 cfu / g) obtained by concentrating and freeze-drying and then triturating with starch.
  • the prepared powdered milk was dissolved in water to prepare a formula having a total solid content of 14% (w / V) as a standard formula, the number of bifidobacteria in the formula was 2.7 ⁇ 10 9. cfu / 100 ml.

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Abstract

Le problème abordé par la présente invention est de pourvoir à un agent de dégradation de glycoprotéine non-collagène, une composition de dégradation de glycoprotéine non-collagène, une composition médicinale de dégradation de glycoprotéine non-collagène et une composition alimentaire ou de type boisson de dégradation de glycoprotéine non-collagène, chacun pouvant être facilement produit et ne générant aucun effet secondaire. La solution selon l'invention porte sur un agent de dégradation de glycoprotéine non-collagène, une composition de dégradation de glycoprotéine non-collagène, une composition médicinale de dégradation de glycoprotéine non-collagène et une composition alimentaire ou de type boisson de dégradation de glycoprotéine non-collagène, comprenant chacun, à titre de principe actif, une bactérie appartenant au genre Bifidobacterium, une culture de la bactérie et/ou des cellules traitées de la bactérie.
PCT/JP2018/011923 2017-03-28 2018-03-23 Composition de dégradation de glycoprotéine non-collagène WO2018181071A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
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WO2020116511A1 (fr) * 2018-12-07 2020-06-11 森永乳業株式会社 Composition servant à la suppression d'une infection au norovirus
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JP6978621B1 (ja) * 2021-03-12 2021-12-08 森永乳業株式会社 組成物
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WO2020116511A1 (fr) * 2018-12-07 2020-06-11 森永乳業株式会社 Composition servant à la suppression d'une infection au norovirus
EP3892331A4 (fr) * 2018-12-07 2022-09-07 Morinaga Milk Industry Co., Ltd. Composition servant à la suppression d'une infection au norovirus
JP2020162479A (ja) * 2019-03-29 2020-10-08 株式会社キティー 目の不調を改善する組成物及びその利用
JP2020164492A (ja) * 2019-03-29 2020-10-08 森永乳業株式会社 インドール乳酸化合物の製造方法
EP4176889A4 (fr) * 2020-05-22 2024-05-29 Morinaga Milk Industry Co Ltd Composition pour favoriser le développement du tractus intestinal, composition pour améliorer la fonction pulmonaire et composition pour augmenter la fonction immunitaire
JP6978621B1 (ja) * 2021-03-12 2021-12-08 森永乳業株式会社 組成物
WO2022191320A1 (fr) * 2021-03-12 2022-09-15 森永乳業株式会社 Composition
JP2022139601A (ja) * 2021-03-12 2022-09-26 森永乳業株式会社 組成物

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