WO2008059870A1 - Inducteur de protéine de choc thermique, préparation de la peau pour un usage externe, aliment et médicament le contenant, et procédé de fabrication d'un inducteur de protéine de choc thermique - Google Patents

Inducteur de protéine de choc thermique, préparation de la peau pour un usage externe, aliment et médicament le contenant, et procédé de fabrication d'un inducteur de protéine de choc thermique Download PDF

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Publication number
WO2008059870A1
WO2008059870A1 PCT/JP2007/072086 JP2007072086W WO2008059870A1 WO 2008059870 A1 WO2008059870 A1 WO 2008059870A1 JP 2007072086 W JP2007072086 W JP 2007072086W WO 2008059870 A1 WO2008059870 A1 WO 2008059870A1
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Prior art keywords
heat shock
shock protein
protein inducer
inducer
plant extract
Prior art date
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PCT/JP2007/072086
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English (en)
Japanese (ja)
Inventor
Tohru Mizushima
Yutaka Mizushima
Yoshimi Niwano
Noriko Sugasawa
Hisashi Suzuki
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Ltt Bio-Pharma Co., Ltd.
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Application filed by Ltt Bio-Pharma Co., Ltd. filed Critical Ltt Bio-Pharma Co., Ltd.
Publication of WO2008059870A1 publication Critical patent/WO2008059870A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • 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
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/906—Zingiberaceae (Ginger family)
    • 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
    • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
    • A61K8/9783—Angiosperms [Magnoliophyta]
    • A61K8/9789—Magnoliopsida [dicotyledons]
    • 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
    • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
    • A61K8/9783—Angiosperms [Magnoliophyta]
    • A61K8/9794—Liliopsida [monocotyledons]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/70—Biological properties of the composition as a whole

Definitions

  • Heat shock protein inducer external preparation for skin containing the same, food, medicine and method for producing heat shock protein inducer
  • the present invention relates to a plant-derived heat shock protein inducer, which is the origin of a herbal medicine having a property corresponding to temperature or flatness among the four characteristics of herbal medicine, and an external preparation for skin and food containing the same And a method for producing a heat shock protein inducer.
  • HSP heat shock proteins
  • HSPs The family of HSPs is formed by their molecular weight.
  • HSP90 family molecular weight is 90 kDa or more and 1 lOkDa or less
  • HSP70 family molecular weight is 70 kDa or more and less than 80 kDa
  • HSP60 family molecular weight is 60 kDa or more and less than 70 kDa
  • It is classified as a small molecule HSP family (molecular weight less than 60 kDa).
  • HSP HSP70 family and the HSP60 family are capable of binding to denatured proteins and rewinding them to natural folding (higher-order structures / folded structures), third proteins and nucleic acids. It has been clarified that it has a function called a molecular chaperone, such as its association with DNA, localization in cells, and involvement in membrane permeation (Non-patent document 1, Non-patent document 2).
  • Abnormal protein folding in cells has become clear to cause various diseases and is called protein folding abnormal disease It ’s like that.
  • protein folding abnormal disease It aggregation occurs due to abnormal folding of the causative protein of / 3 amyloid, and it develops when neurons aggregate or die due to the aggregate.
  • geranylgeranylacetone is a non-toxic heat shock protein inducer, but its induction ability is weak.
  • Artemia extract has limitations such as the contraindication of combination with protein-degrading enzyme, which is desirable to be 40 ° C or less.
  • Non-Patent Document 2 Georgopoulos, C. and Welch. W. J. (1993) Ann. Rev. Cell Biol. 9, 601-634
  • Patent Document 1 International Publication WO2003 / 035052 Pamphlet
  • Patent Document 2 JP 2004-238297 Koyuki
  • the present invention has been made based on the problem, and an object thereof is to provide a novel HSP inducer having high HSP-inducing activity.
  • a heat shock protein inducer containing a plant extract selected from the family Ginger and / or Compositae selected from the family Ginger and / or Compositae.
  • a heat shock protein inducer comprising a plant extract selected from a plant belonging to the genus Amomum or Hanamijoga of the ginger family.
  • a heat shock protein inducer comprising a plant extract selected from the group consisting of Yoshiyunsha, Stasha and Nankiyosou.
  • a heat shock protein inducer comprising a plant extract selected from plants belonging to the genus Hydrobana or Odalma.
  • a heat shock protein inducer comprising a plant extract selected from the group consisting of sharks hollybirds, oguruma and hosobaodharma.
  • Heat shock protein inducer force The heat according to (1) to (6), which is a heat shock protein that induces a heat shock protein having a molecular weight of 7 OkDa or more and less than 80 kDa as measured by SDS-PAGE. Shock protein inducer.
  • Heat shock protein inducer force The heat shock protein according to (1) to (6), which induces a heat shock protein having a molecular weight of 72 kDa as measured by SDS-PAGE, and the heat shock protein according to 1. Quality inducer.
  • a whitening cosmetic composition, an anti-wrinkle cosmetic composition or an anti-smudge cosmetic composition comprising the heat shock protein inducer according to item 1, wherein any one of (1) to (8) is used.
  • a pharmaceutical product comprising the heat shock protein inducer according to any one of (1) to (8),
  • a therapeutic agent for peptic ulcer or a therapeutic agent for neurodegenerative disease comprising any one of the powers of (1) to (8), the heat shock protein inducer according to 1.
  • a method for producing a heat shock protein inducer comprising extracting a plant that is a source of a herbal medicine having a property corresponding to warm or normal out of the four characteristics of herbal medicine.
  • the heat shock in the present invention is preferably when the temperature is 3 ° C. or more higher than the physiological temperature. This means that the temperature is 6 ° C higher than the physiological temperature.
  • the HSP inducer in the present invention effectively induces HSP having a molecular weight of 70 kDa or more and less than 80 kDa (hereinafter sometimes referred to as “HSP70 family”), and induces HSP having a molecular weight of 72 kDa more effectively. To do. It also effectively induces 70 kDa HSP.
  • the molecular weight of HSP in the present invention refers to the molecular weight measured by SDS-PAGE. More specifically, the molecular weight is estimated by comparison with a standard protein band having a known molecular weight, and Western blotting using an antibody. The value determined by law.
  • HSP72 is synthesized in the cytoplasm, and can be detected in the cell nucleus immediately after synthesis, and thereafter in the nucleolus.
  • the rate of cell damage due to ischemia given thereafter significantly decreased depending on the concentration of HSP expression level! /, And! / Have been reported (Hutter, MM., Sievers, RE, Wolfe, C ⁇ . (1994) Circulation, 89, 355-360).
  • Hutter, MM., Sievers, RE, Wolfe, C ⁇ . (1994) Circulation, 89, 355-360 no naturally-occurring materials having HSP72-inducing activity and low toxicity without applying heat stress have been found so far. That is, a naturally-derived HSP inducer that induces HSP72 has been strongly demanded, but has not been obtained until the present invention.
  • the HSP inducer of the present invention can be further blended even at a temperature higher than 40 ° C, or can be blended with a protein-degrading enzyme, and has a wide range of applications.
  • the HSP inducer of the present invention refers to a plant that is a source of a herbal medicine having a property corresponding to warm or normal among the four characteristics of herbal medicine. Shiki means expressing the nature of herbal medicine The four basic properties are cold, heat, cool and warm. Cold and cool, heat and temperature are similar in nature, but cool is slightly cooler than cold and warm is slightly warmer than heat. In addition, herbal medicines that do not belong to either are expressed as flat, and because of their mild action, they are used for both cold and fever. In the invention of the present application, for example, plants can be classified according to the description in the Chugoku University Encyclopedia (Shogakukan).
  • a plant belonging to the family Ginger a plant belonging to the genus Hamomum or Hanamiyouga is preferred.
  • plants belonging to the genus Ammomum Yoshiyunsha (Amumum viilosum Lour.) And Stasha (Amumum xanthioides Wall.) are preferred.
  • Yoshiyunsha Amumum viilosum Lour.
  • Stasha Amumum xanthioides Wall.
  • Noyuna Miyoga Alpinia galanga (L.) Swartz is preferable.
  • plants belonging to the genus Hydrobana or Odalma are preferred.
  • a plant belonging to the genus Hydrobana Eupatorium lindleyanum DC. Is preferable.
  • plants belonging to the genus Odalma Oguruma (Inula japonica Thun b.) And Hosobao Guruma (Inula linariaefolia Turcz.) are preferable.
  • a plant extract is used.
  • the extraction method of the plant is not particularly defined as long as it has an extract fraction having HSP induction ability.
  • the plant is preferably pulverized to extract its strength.
  • an organic solvent for example, ethanol
  • the extraction may be performed by standing or may be performed by stirring.
  • the extracted liquid may be used as it is as an HSP inducer, but it is preferably concentrated before use to enhance the effect.
  • the degree of concentration is the usage environment It depends on. For example, it may be used as a solution at a concentration of about 10%, or the solvent may be removed until it becomes powdery.
  • the plant extract only one kind of the above may be adopted, or two or more kinds may be adopted. Furthermore, as another plant-derived material, a material having HSP induction ability It is a good idea to use both.
  • the HSP inducer of the present invention can be used in various modes depending on the purpose.
  • a pharmaceutical product such as an external preparation for skin such as whitening cosmetics, anti-wrinkle cosmetics and anti-smudge cosmetics, foods (including beverages), peptic ulcers and neurodegenerative diseases. It can be used effectively.
  • lotions, emulsions, gels, creams, ointments, powders, granules and the like When used as an external preparation for skin, it can be provided in various dosage forms such as lotions, emulsions, gels, creams, ointments, powders, granules and the like.
  • skin cosmetics such as lotions, emulsions, creams, cosmetics, packs, etc.
  • base cosmetics such as makeup base lotions and makeup base creams, emulsions, oils, solids, etc.
  • makeup cosmetics such as foundation, eye color, and cheek color
  • body cosmetics such as hand cream, leg cream, neck cream, and body lotion.
  • functional foods and functional beverages can be obtained by including in various foods (including beverages). For example, it can be added to black tea, soft drinks, juice, candy, starchy foods, various processed foods, and the like.
  • the amount of the HSP inducer of the present invention can be set within a range of about 0 .; Moreover, if necessary, the food texture may be improved by adding a gelling agent or the like.
  • HSP inducer of the present invention can be administered orally or parenterally.
  • rectal administration intranasal administration, vaginal administration, sublingual administration, intravaginal administration, intramuscular administration, subcutaneous administration, and intravenous administration can be performed.
  • preparations suitable for oral administration include tablets, capsules, powders, fine granules, granules, solutions, syrups, etc.
  • preparations suitable for parenteral administration include injections and infusions. Suppositories, suppositories, inhalants, transdermal absorbents, transmucosal absorbents, patches and the like. injection The agent may be used for intravenous injection, intramuscular injection, subcutaneous injection, infusion and the like.
  • a pharmacologically and pharmaceutically acceptable additive can be added to the HSP inducer of the present invention as needed.
  • a propellant, an adhesive, a wetting agent, and the like can be used.
  • the HSP inducer of the present invention can have various additional functions. For example, it can be designed to allow the active ingredient to be released slowly as needed. It can also be designed so that the active ingredient is released intensively at the required location in the body.
  • sustained-release preparations and drug delivery systems can be designed and manufactured according to methods well known in the pharmaceutical industry.
  • an organic or inorganic carrier can be used for the HSP inducer of the present invention.
  • examples of such carriers are lactose, starch, vegetable and animal fats and oils.
  • the HSP inducer of the present invention is used in the range of 0.01 to 100% by weight.
  • the dosage of the HSP inducer of the present invention depends on various conditions such as the purpose of treatment or prevention, the sex, weight, age, type and degree of disease, dosage form, administration route, number of administrations, etc. of the patient. Make an appropriate decision. For example, when administered orally, 0.1 11 g or more;! OOmg (dry weight of active ingredient) / kg body weight / day can be administered once to several times a day. The amount is not limited to this range.
  • Nankiyosou Korean (red bean?): (Manufacturer Eijin Shoji, product number C089)
  • the raw plant was pulverized as it was, freeze-dried, and pulverized again in a miller.
  • the dried product was returned to water, pulverized with a miller, freeze-dried, and pulverized again with a miller.
  • 10 to 100 ml of ethanol was added to the obtained dried pulverized product lg, stirred for 2 hours, filtered through a buchner, and the filtrate was recovered. This operation was repeated twice.
  • the obtained filtrate was concentrated under reduced pressure until it became paste-like or dry-solid to obtain a plant extract.
  • N1RGB Human fibroblast cell line (NB1RGB) (obtained from: RIKEN BioResource Center) was seeded in a 35mm culture dish so that the cell suspension would be 2.0 ⁇ 10 5 cells / 2mL. In a CO incubator, 37 The cells were cultured at ° C for 24 hours. To this, the plant extracts (A) to (D) were added so that the concentrations were as shown in Table 1, and further cultured at 37 ° C for 4 hours in a CO incubator. Next, the supernatant medium was removed, the cells were washed with the medium, and the cells were removed from the dish with trypsin, and the cells were collected.
  • N1RGB Human fibroblast cell line
  • lysis buffer for cultured cells (RIPA buffer, 50 mM Tris-HCl (pH 7.2), 150 mM NaCl, 1% nonidet P_40, 0.5% sodium deoxysholate, 0.1% SDS) and freeze and thaw.
  • the cells were lysed once and the supernatant was collected by centrifugation. The obtained elution fraction was subjected to protein quantification by the Bradford method.
  • the cell extract is subjected to polyacrylamide gel (SDS-PAGE) electrophoresis, followed by anti-HSP.
  • SDS-PAGE polyacrylamide gel
  • anti-HSP anti-HSP.
  • the expression level of HSP72 was examined by Western blotting using 72 antibody (Stressgen).
  • SDS-PAGE gel was transferred to and immobilized on a membrane to prepare a plot, and the blot was reacted with an antibody against HSP72 (primary antibody). Thereafter, the secondary body labeled with the HRP enzyme was reverted to the primary body, and the color developed with the Super Signal West Dura Extended Duration Substrate was quantified by the chemifluorescence method. The intensity of the obtained band was quantified by MH-Image 1.62 and digitized.
  • the measured band intensity was corrected by the band intensity of the actin that is constantly expressed in the cell, and was calculated as the relative hand intensity when the band intensity of the positive control was 1. The results are shown in Table 1.
  • the relative band intensity may be 1 or more by adjusting the additive concentration of the plant extract, and human fibroblasts subjected to heat shock were observed. It was shown that HSP72 expression by plant extracts was higher than cell lines.
  • Example 2 In Example 1, the human fibroblast cell line (NB1RGB) was replaced with a human epidermis cell line (HaCaT) (obtained from: Cell lines service), and others were performed in the same manner to measure HSP72-inducing activity.
  • HaCaT human epidermis cell line
  • the measured band intensity was corrected by the band intensity of the actin that is constantly expressed in the cell, and was calculated as the relative hand intensity when the band intensity of the positive control was 1. The results are shown in Table 2.
  • the relative band intensity may be 1 or more, and the plant extract is more than the human epidermal cell line subjected to heat shock. It was shown that the HSP72 expression by

Abstract

L'invention concerne un nouvel inducteur de protéine de choc thermique (HSP) pourvu d'une activité induisant HSP élevée qui comprend un extrait de plante servant d'origine pour un médicament brut pourvu de propriétés correspond à « chaud » ou à « tiède » parmi les quatre caractéristiques des médicaments chinois à base d'herbes.
PCT/JP2007/072086 2006-11-17 2007-11-14 Inducteur de protéine de choc thermique, préparation de la peau pour un usage externe, aliment et médicament le contenant, et procédé de fabrication d'un inducteur de protéine de choc thermique WO2008059870A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2006311353A JP5080065B2 (ja) 2006-11-17 2006-11-17 熱ショックタンパク質誘導剤、およびこれを含む皮膚用外用剤、食品、並びに、熱ショックタンパク質誘導剤の製造方法
JP2006-311353 2006-11-17

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WO2008059870A1 true WO2008059870A1 (fr) 2008-05-22

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JP2009091355A (ja) * 2007-09-19 2009-04-30 Noevir Co Ltd 保湿剤、抗老化剤、抗酸化剤、免疫賦活剤、美白剤、及び皮膚外用剤、機能性経口組成物
JP2010083804A (ja) * 2008-09-30 2010-04-15 Saishunkan Seiyakusho:Kk 美白化粧料
JP2013071901A (ja) * 2011-09-27 2013-04-22 Saishunkan Seiyakusho:Kk メラニン産生抑制化粧料
JP2015508748A (ja) * 2012-01-30 2015-03-23 ユリエヴィッチ レシコフ，セルゲイ ヒト及び動物細胞において熱ショックタンパク質の合成を誘導する剤；修復過程を促進するための化粧品；侵襲的美容処置の副作用を低減するための化粧品；栄養補助食品；食料品；侵襲的美容処置の副作用を低減する方法
CN113456683A (zh) * 2020-03-31 2021-10-01 北京大学 野马追的医药用途

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JP5697879B2 (ja) * 2010-03-12 2015-04-08 株式会社再春館製薬所 熱ショックタンパク質の発現誘導剤
JP2013071902A (ja) * 2011-09-27 2013-04-22 Ltt Bio-Pharma Co Ltd ヒートショックプロテイン発現誘導剤
US20150025077A1 (en) 2012-02-29 2015-01-22 Coyote Pharmaceuticals, Inc. Gga and gga derivatives compositions thereof and methods for treating neurodegenerative diseases including paralysis including them
US9119808B1 (en) 2012-10-08 2015-09-01 Coyote Pharmaceuticals, Inc. Treating neurodegenerative diseases with GGA or a derivative thereof
JP6025122B2 (ja) * 2013-04-18 2016-11-16 有限会社バイオシステムコンサルティング 抗熱ストレス用組成物

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