US20130196937A1 - Age production inhibitor - Google Patents

Age production inhibitor Download PDF

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US20130196937A1
US20130196937A1 US13/576,433 US201113576433A US2013196937A1 US 20130196937 A1 US20130196937 A1 US 20130196937A1 US 201113576433 A US201113576433 A US 201113576433A US 2013196937 A1 US2013196937 A1 US 2013196937A1
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extract
glucopyranoside
cherry
age
collagen
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Hiroshi Shimoda
Takashi Watanabe
Hiromichi Murai
Masayuki Yoshikawa
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Oryza Oil and Fat Chemical Co Ltd
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Oryza Oil and Fat Chemical Co Ltd
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Assigned to ORYZA OIL & FAT CHEMICAL CO., LTD. reassignment ORYZA OIL & FAT CHEMICAL CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: YOSHIKAWA, MASAYUKI, WATANABE, TAKASHI, MURAI, HIROMICHI, SHIMODA, HIROSHI
Publication of US20130196937A1 publication Critical patent/US20130196937A1/en
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    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/73—Rosaceae (Rose family), e.g. strawberry, chokeberry, blackberry, pear or firethorn
    • A61K36/736—Prunus, e.g. plum, cherry, peach, apricot or almond
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    • A23C9/13—Fermented milk preparations; Treatment using microorganisms or enzymes using additives
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    • A23G3/00—Sweetmeats; Confectionery; Marzipan; Coated or filled products
    • A23G3/34—Sweetmeats, confectionery or marzipan; Processes for the preparation thereof
    • A23G3/36—Sweetmeats, confectionery or marzipan; Processes for the preparation thereof characterised by the composition containing organic or inorganic compounds
    • A—HUMAN NECESSITIES
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    • A23G—COCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
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    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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    • 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
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    • 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
    • A61Q19/08—Anti-ageing preparations
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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    • A61K2236/30—Extraction of the material

Definitions

  • the AGE production inhibitor has an inhibitory effect on fibroblast apoptosis which is induced by CML-collagen (carboxymethyl lysine-collagen), an AGE, and is widely used as a material for foods, medicines, cosmetics or the like.
  • CML-collagen carboxymethyl lysine-collagen
  • AGE Advanced Glycation End-products
  • the key factor of AGE is a non-enzymatic glycation.
  • an amino group that exists in protein and an aldehyde group which is a reducing sugar such as glucose or the like non-enzymatically react to each other (i.e. glycation), which produces Amadori-rearrangement products through Schiff's base.
  • glycation non-enzymatically react to each other
  • AGE is produced after a long period of complex cleavages and condensations.
  • Diabetes complication includes retinopathy, nephropathia, neuropathy, ischemic cardiac disease, cerebrovascular disease and others. It is known that one of the factors for the cause of these diseases relates to AGE produced in a hyperglycemic biological body. (For instance, refer to non-patent reference 1)
  • Diabetic nephropathy is renal microvascular damage caused by diabetes. Its basic pathological change includes the thickening of the glomerular basement membrane and the expansion of the mesangial area. Recently a number of diabetic patients stricken with the end-stage renal disease, caused by diabetic nephropathy increases and so were treated with dialysis. It is thought that AGE which is produced by a continuous state of hyperglycemia is involved in the development of nephropathy which is developed by 1. enhanced vascular permeability, 2. enhanced deposition of protein and lipoprotein, 3. inactivation of nitric oxide (NO), and 4. accelerated production of extracellular matrix. (See Non-patent Reference 2.)
  • Patent References 3 to 5 show compositions of extracts of plants used for food, which inhibit AGE production.
  • AGE relates closely not only to diabetes but also to the aging of the skin.
  • AGE increases with aging, and when Maillard reaction occurs in the collagen part [of the skin] which is the skin protein, the carbonyl group of glucide, non-enzymatically reacts with either the amino group of lysine residue or with the guanidyl group or arginine group in the protein to produce AGE, thus resulting in collagen cross-linking.
  • the link structure is formed, the molecule is hardened, and inherent elasticity of the skin is lost.
  • crosslink substances are treated as foreign substances, and the volume of secretion of degrading enzyme (collagenase, elastase) increases, which decreases skin tone and firmness and weakens the skin, thus resulting in wrinkles, slackness and dullness of the skin.
  • degrading enzyme collagenase, elastase
  • the inventors conducted research on the components and amount of the components contained in the extract and of the various plant origins. They focused on “cherry tree” which contains plenty of polyphenol. After conducting various experiments, they realized that the extract of cherry blossoms and cherry leaves, especially, contain phenylpropanoid glycoside (caffeoyl glucose, coumaroyl glucose, cinnamoyl glucose) and flavonoid glycoside (kaempferol glucoside, quercetin glucoside, kaempferol malonyl glucose, quercetin malonyl glucose), which effectively inhibits AGE production and promotes the formation of fibroblast-collagen grating.
  • phenylpropanoid glycoside caffeoyl glucose, coumaroyl glucose, cinnamoyl glucose
  • flavonoid glycoside kaempferol glucoside, quercetin glucoside, kaempferol malonyl glucose, quercetin malonyl glucose
  • the inventors learned of a new physiological activity of cherry tree extract, which effectively inhibits fibroblast apoptosis caused by an AGE, CML-collagen (i.e. Carboxymethyl Lysine-collagen), thus providing this invention.
  • CML-collagen i.e. Carboxymethyl Lysine-collagen
  • This invention is to solve the problems, above, and its purpose is effectively to inhibit AGE production and to provide a biologically safe AGE production inhibitor for the human body.
  • Another purpose of the invention is to provide an apoptosis inhibitor to inhibit the formation of human fibroblast apoptosis caused by AGE, such as CML-collagen (Carboxymethyl lysine-collagen).
  • CML-collagen Carboxymethyl lysine-collagen
  • Another purpose of the invention is to provide a fibroblast collagen grating formation promoter.
  • Still another purpose of the invention is to provide an AGE production inhibitor effectively to inhibit AGE production within the fibroblast.
  • the AGE production inhibitor of this invention contains cherry extract and/or its processed substance as an active substance.
  • the AGE production inhibitor of this invention contains cherry blossom extract and/or its processed substance as an active substance.
  • the AGE production inhibitor of this invention contains cherry leaf extract and/or its processed substance as an active substance.
  • the AGE production inhibitor of this invention contains at least one compound as an active substance selected from among 1-O-(E)-Caffeoyl- ⁇ -D-glucopyranoside, 1-O-(E)-Coumaroyl- ⁇ -D-glucopyranoside, 1-O-(E)-Cinnamoyl- ⁇ -D-glucopyranoside, Kaempferol 3- ⁇ -D-glucopyranoside, Quercetin 3-O- ⁇ -D-glucopyranoside, Kaempferol 3-O-(6′′-malony)- ⁇ -D-glucopyranoside, and (Quercetin 3-O-(6′′-malony)- ⁇ -D-glucopyranoside.
  • the AGE production inhibitor of this invention contains 1-O-(E)-Caffeoyl- ⁇ -D-glucopyranoside, as an active substance.
  • the AGE production inhibitor of this invention contains Quercetin 3-O- ⁇ -D-glucopyranoside as an active substance.
  • the AGE production inhibitor of this invention allows the edible and safe cherry-derived extract to inhibit effectively AGE production and to avoid side effects, thus providing an ingredient for foods, medicines, cosmetics and other products which are helpful in effectively preventing or treating diabetic complications.
  • the apoptosis inhibitor of this invention contains cherry extract and/or its processed substance as an active substance, which inhibits fibroblast apoptosis caused by CML-collagen (i.e. Carboxymethyl lysine-collagen) which is an AGE.
  • CML-collagen i.e. Carboxymethyl lysine-collagen
  • the apoptosis inhibitor of this invention contains cherry blossom extract and/or its processed substance as an active substance, which inhibits fibroblast apoptosis caused by CML-collagen (i.e. Carboxymethyl lysine-collagen) which is an AGE.
  • CML-collagen i.e. Carboxymethyl lysine-collagen
  • the apoptosis inhibitor of this invention contains cherry leaf extract and/or its processed substance as an active substance, which inhibits fibroblast apoptosis caused by CML-collagen (i.e. Carboxymethyl lysine-collagen) which is an AGE.
  • CML-collagen i.e. Carboxymethyl lysine-collagen
  • the apoptosis inhibitor of this invention contains at least one active substance selected from among 1-O-(E)-Caffeoyl- ⁇ -D-glucopyranoside, 1-O-(E)-Coumaroyl- ⁇ -D-glucopyranoside, 1-O-(E)-Cinnamoyl- ⁇ -D-glucopyranoside, Kaempferol 3-O- ⁇ -D-glucopyranoside, Quercetin 3-O- ⁇ -D-glucopyranoside, Kaempferol 3-O-(6′′-malony)- ⁇ -D-glucopyranoside and Quercetin 3-O-(6′′-malony)- ⁇ -D-glucopyranoside, which inhibits the fibroblast apoptosis caused by the CML-collagen (i.e. Carboxymethyl lysine-collagen) which is an AGE.
  • CML-collagen i.e. Carboxymethyl lysine-collagen
  • the apoptosis inhibitor of this invention contains 1-O-(E)-Caffeoyl- ⁇ -D-glucopyranoside as an active substance, which inhibits fibroblast apoptosis caused by CML-collagen (i.e. Carboxymethyl lysine-collagen) which is an AGE.
  • CML-collagen i.e. Carboxymethyl lysine-collagen
  • the apoptosis inhibitor of this invention contains Quercetin 3-O- ⁇ -D-glucopyranoside and/or Quercetin 3-O-(6′′-malony)- ⁇ -D-glucopyranoside as an active substance, which inhibits fibroblast apoptosis caused by CML-collagen (i.e. Carboxymethyl lysine-collagen) which is an AGE.
  • CML-collagen i.e. Carboxymethyl lysine-collagen
  • the AGE production inhibitor of this invention allows cherry-derived extract, which is safe for food, to inhibit effectively the fibroblast apoptosis caused by CML-collagen (Carboxymethyl lysine-collagen), thus providing a material for foods, medicines, cosmetics and other products, which is helpful in effectively preventing or inhibiting the skin from aging.
  • CML-collagen Carboxymethyl lysine-collagen
  • the human fibroblast-collagen grating-formation promoter of this invention contains cherry-tree extract and/or its processed substance as an active substance.
  • the human fibroblast-collagen grating-formation promoter of this invention contains cherry-blossom extract and/or its processed substance as an active substance.
  • the human fibroblast-collagen grating-formation promoter of this invention contains cherry-leaf extract and/or its processed substance as an active substance.
  • the human fibroblast-collagen grating-formation promoter of this invention contains at least one active substance selected from among this group of compounds: 1-O-(E)-Caffeoyl- ⁇ -D-glucopyranoside, 1-O-(E)-Coumaroyl- ⁇ -D-glucopyranoside, 1-O-(E)-Cinnamoyl- ⁇ -D-glucopyranoside, Kaempferol 3-O- ⁇ -D-glucopyranoside, Quercetin 3-O- ⁇ -D-glucopyranoside, Kaempferol 3-O-(6′′-malony)- ⁇ -D-glucopyranoside and Quercetin 3-O-(6′′-malony)- ⁇ -D-glucopyranoside.
  • the human fibroblast-collagen grating-formation promoter of this invention contains 1-O-(E)-Caffeoyl- ⁇ -D-glucopyranoside as an active substance.
  • the human fibroblast-collagen grating-formulation promoter of this invention contains Quercetin 3-O- ⁇ -D-glucopyranoside as an active substance.
  • the human fibroblast-collagen grating-formulation promoter of this invention allows cherry-derived extract, which is safe for food, to promote effectively human fibroblast collagen grating formulation, thus providing a material for foods, medicines, cosmetics and other products which are helpful in effectively preventing or inhibiting the skin from aging.
  • the AGE production inhibitor within the fibroblast of this invention contains cherry-tree extract and/or its processed substances as active substances.
  • the AGE production inhibitor within the fibroblast of this invention contains cherry-blossom extract and/or its processed substance as an active substance.
  • the AGE production inhibitor within the fibroblast of this invention contains cherry-leaf extract and/or its processed substance as an active substance.
  • the AGE production inhibitor within the fibroblast of this invention contains at least one active substance selected from among this group of compounds, i.e. 1-O-(E)-Caffeoyl- ⁇ -D-glucopyranoside, 1-O-(E)-Coumaroyl- ⁇ -D-glucopyranoside, 1-O-(E)-Cinnamoyl- ⁇ -D-glucopyranoside, Kaempferol 3-O- ⁇ -D-glucopyranoside, Quercetin 3-O- ⁇ -D-glucopyranoside, Kaempferol 3-O-(6′′-malony)- ⁇ -D-glucopyranoside and Quercetin 3-O-(6′′-malony)- ⁇ -D-glucopyranoside.
  • the AGE production inhibitor within the fibroblast of this invention contains 1-O-(E)-Caffeoyl- ⁇ -D-glucopyranoside as an active substance.
  • the AGE production inhibitor within the fibroblast of this invention contains Quercetin 3-O- ⁇ -D-glucopyranoside as an active substance.
  • the AGE production inhibitor within the fibroblast of this invention allows cherry-derived extract, which is safe for food, to effectively inhibit AGE production within the fibroblast, thus providing a material for foods, medicines, cosmetics and other products which are helpful in effectively preventing or inhibiting the skin from aging.
  • the cherry-tree extract of this invention holds at least one active substance selected from among this group of compounds, i.e. 1-O-(E)-Caffeoyl- ⁇ -D-glucopyranoside, 1-O-(E)-Coumaroyl- ⁇ -D-glucopyranoside, 1-O-(E)-Cinnamoyl-6-D-glucopyranoside, Kaempferol 3-O- ⁇ -D-glucopyranoside, Quercetin 3-O- ⁇ -D-glucopyranoside, Kaempferol 3-O-(6′′-malony)- ⁇ -D-glucopyranoside, and Quercetin 3-O-(6′′-malony)- ⁇ -D-glucopyranoside.
  • the cherry-tree extract of this invention holds all of the substances of this group of compounds, i.e. 1-O-(E)-Caffeoyl- ⁇ -D-glucopyranoside, 1-O-(E)-Coumaroyl- ⁇ -D-glucopyranoside, 1-O-(E)-Cinnamoyl- ⁇ -D-glucopyranoside, Kaempferol 3-O- ⁇ -D-glucopyranoside, Quercetin 3-O- ⁇ -D-glucopyranoside, Kaempferol 3-O-(6′′-malony)- ⁇ -D-glucopyranoside, and Quercetin 3-O-(6′′-malony)- ⁇ -D-glucopyranoside.
  • the cherry-tree extract of this invention holds all compounds, 1-O-(E)-Caffeoyl- ⁇ -D-glucopyranoside, 1-O-(E)-Coumaroyl- ⁇ -D-glucopyranoside, 1-O-(E)-Cinnamoyl- ⁇ -D-glucopyranoside, Kaempferol 3-O- ⁇ -D-glucopyranoside, Quercetin 3-O- ⁇ -D-glucopyranoside, Kaempferol 3-O-(6′′-malony)- ⁇ -D-glucopyranoside, Quercetin 3-O-(6′′-malony)- ⁇ -D-glucopyranoside and said cherry-tree extract is obtained by a manufacturing method having the following three steps:
  • step (a) extracting one or both cherry blossom extract and the cherry leaf extract with 20 to 50 wt % hydrous ethanol, (b) absorbing the extract obtained in step (a) by an absorbent comprising porous synthetic resin, elute the extract in water and remove the eluted extract, and (c) after step (b) further eluting the eluted extract with a lower alcohol content (carbon numbers 1 to 5), and then concentrate the further eluted extract.
  • the AGE production inhibitor of this invention holds cherry-tree extract and/or its processed active substance according to the above feature 27.
  • the apoptosis inhibitor of this invention holds cherry-tree extract and its processed substance as an active substance, according to the above feature 27, and inhibits fibroblast apoptosis caused by the CML-collagen (i.e. Carboxymethyl lysine-collagen) which is an AGE.
  • CML-collagen i.e. Carboxymethyl lysine-collagen
  • the human fibroblast-collagen grating-formulation promoter of this invention holds cherry-tree extract and/or its processed substance as an active substance according to the above feature 27.
  • the AGE production inhibitor within the fibroblast of this invention holds cherry-tree extract and/or its processed substance as an active substance according to the above feature 27.
  • the agent, to prevent and cure the diabetic complications, of this invention holds cherry-tree extract and/or its processed substance as an active substance according to the above feature 27.
  • the agent, to prevent the skin from aging and to improve it, of this invention holds cherry-tree extract and/or its processed substance as an active substance according to the above feature 27.
  • the invention allows the cherry-derived extract, which is safe for food, to inhibit AGE production effectively without side effects, thus providing a material for foods, medicines, cosmetics and other products which are helpful in effectively preventing or treating diabetic complications.
  • the invention also effectively inhibits fibroblast apoptosis caused by CML-collagen (Carboxymethyl lysine-collagen), thus effectively promoting the human fibroblast-collagen grating-formulation, thus effectively inhibiting AGE production within the fibroblast, thus providing a material for foods, medicines, cosmetics and other products which are helpful in effectively preventing the aging of the skin and for improving it.
  • CML-collagen Carboxymethyl lysine-collagen
  • FIG. 1 is a chart explaining the search for the substances contained in the cherry-blossom extract.
  • FIG. 2 is a microscopic image of fibroblast caused by CML-collagen (Carboxymethyl lysine-collagen) regarding the cherry blossom extract of the example of this invention.
  • CML-collagen Carboxymethyl lysine-collagen
  • FIG. 3 is a megascopic image of 24 and 48 hours of a culture of collagen-grating formulations of fibroblasts glycosylated by glyoxal.
  • FIG. 4 shows microscopic images ( ⁇ 100) in 24 hours of culture according to FIG. 3 .
  • FIG. 5 shows microscopic images ( ⁇ 200) in 48 hours of culture according to FIG. 3 .
  • FIG. 6 shows the effect on AGE production (carboxy methyllsin protein), using Western blotting, within the fibroblast (human diploid fibroblast) caused by glyoxal.
  • FIG. 7 shows the effect on AGE production within the glyoxal-induced skin, using Western blotting, regarding the cherry blossom extract as an example of this invention.
  • FIG. 8 shows microscopic images ( ⁇ 400) of TUNEL positive cells which identify the effect on dermal cell apoptosis induced by CML-collagen (Carboxymethyl lysine-collagen), regarding the cherry blossom extract as an example of this invention.
  • CML-collagen Carboxymethyl lysine-collagen
  • the AGE production inhibitor and fibroblast apoptosis inhibitor and human fibroblast-collagen grating-formulation promoter and AGE production inhibitor within the fibroblast and cherry extract contain, as a bioactive substance, at least one substance selected from among 1-O-(E)-Caffeoyl- ⁇ -D-glucopyranoside, 1-O-(E)-Coumaroyl- ⁇ -D-glucopyranoside, 1-O-(E)-Cinnamoyl- ⁇ -D-glucopyranoside, Kaempferol 3-O- ⁇ -D-glucopyranoside, Quercetin 3-O- ⁇ -D-glucopyranoside, Kaempferol 3-O-(6′′-malony)- ⁇ -D-glucopyranoside and Quercetin 3-O-(6′′-malony)- ⁇ -D-glucopyranoside.
  • 1-O-(E)-Caffeoyl- ⁇ -D-glucopyranoside is a compound as described in Formula 1, below.
  • 1-O-(E)-Coumaroyl-3-D-glucopyranoside is a compound as described in Formula 2, below.
  • 1-O-(E)-Cinnamoyl- ⁇ -D-glucopyranoside is a compound as described in Formula 3, below.
  • Kaempferol 3-O- ⁇ -D-glucopyranoside is a compound as described in Formula 4, below.
  • Quercetin 3-O- ⁇ -D-glucopyranoside is a compound as described in Formula 5, below.
  • Kaempferol 3-O-(6′′-malony)- ⁇ -D-glucopyranoside is a compound as described in Formula 6, below.
  • Quercetin 3-O-(6′′-malony)- ⁇ -D-glucopyranoside is a compound as described in Formula 7, below.
  • AGE production inhibitor of this invention contain at least the compound 1-O-(E)-Caffeoyl- ⁇ -D-glucopyranoside (Formula 1) or Quercetin 3-O- ⁇ -D-glucopyranoside (Formula 5), which are selected from among the compounds, as described in Formulae 1 to 7, or especially the compound, 1-O-(E)-Caffeoyl- ⁇ -D-glucopyranoside (Formula 1).
  • Any method used in obtaining the compound as described in Formulae 1 to 7, above, is not specifically limited. Such a compound is, however, preferably to be extracted from plants, which makes it simple to obtain. Also, when extracting the compound from plants, it is preferable to extract it from the cherry tree.
  • Cherry blossom (referred to as Sakura in Japanese) is the generic name of the Genus Cerasus of Rosaceae, excluding apricots and peaches, and refers to plants belonging to Subgenus Cerasus.
  • Cherry blossoms of this invention include, for example, prunus yamazakukra ( Cerasus jamasakura ), edohigan ( Cerasus spachiana Lavalee ex H. Otto var. spachiana forma ascendens (Makino) H. Ohba), mamezakura ( Prunus incisa Thunb. ex Murray) choujizakura ( Prunus apetara Fr. et Sav.), miyamazakura ( Prunus maximowiczii Rupr.), shinamizakura ( Prunus pseudo - cerasus Lindl.) and others, but not limited to these.
  • the part of the cherry which is used for the material of this invention, is not specifically limited but includes its leaf, stem, trunk, blossom, fruit and other parts. However, it is preferable to use the cherry leaf or blossom.
  • a polar solvent is not limited but includes water, methanol, ethanol, isopropanol, acetone, 1,3-butylene glycol, ethylene glycol, propylene glycol, glycerin, acetic acid, ethyl acetate, ether, hexane and others.
  • water, methanol, and ethanol are especially preferable, which efficiently extracts the active substance.
  • only one or more solvents from among the polar solvents, above, can be used.
  • the extraction temperature is to be set between 20 and 100 degrees centigrade, preferably between 40 and 70 degrees centigrade. If the temperature is too low, the active substance will not efficiently be extracted. On the other hand, if the temperature is too high, cyanogen compounds contained in the cherry-tree (sakura) will be eluted and remain in the water, and the active substance will be degraded in such a high temperature, which is not preferable, either.
  • the types of water used for the extraction are not specifically limited but include tap water, distilled water, mineral water, ionized alkaline water and others.
  • the concentration of alcohol is preferably to be set at 25 to 50 wt % (percent by weight), preferably at 25 to 30 wt %. If the level of alcohol concentration is below 20 wt %, it will be hard to get a high level of active substance. Contrarily, if the concentration of alcohol is over 50 wt %, the yield will be low, due to impurities or the like.
  • the extraction temperature is preferably to be set at 0 to 95 degrees centigrade, more preferably at 0 to 60 degrees centigrade.
  • the extraction of aqueous ethanol it is preferable to repeat the extractions in various concentrations so as to improve the content rate of the active substance.
  • the method of extraction is not specifically limited.
  • the method of the extraction includes a continuous extraction, a soaking extraction, a countercurrent extraction or any other extraction which can be used with any optional equipment at room temperature or by heating under reflux. Also, any one, or any combination of the above methods can be used for the extraction. Furthermore, the extraction can be conducted once or more than once.
  • the extraction is conducted with the extracting solvent approximately 3 to 100 times as much weight as the extraction ingredient, from one to 150 minutes. After the active substance seeps into the solvent, filter it and remove the residue to obtain the extracted liquid. After that, according to the ordinary method, apply the dilution, concentration, drying, refining method or the like to the extracted liquid, so as to obtain the extract containing polyphenol, as described in the above Formulae 1 to 7 or the like.
  • the refining method includes, for example, an activated carbon treatment, a resin absorption treatment, a silica gel treatment as well as another method using ion-exchange resin, and liquid-liquid countercurrent distribution, and membrane separation, or the like.
  • the supercritical fluid is not specifically limited but includes, for instance, carbon dioxide, nitrogen or the like, of which one or more fluids can be used at the same time.
  • carbon dioxide is preferable, since it can easily elute the active substance.
  • the known conventional method of extraction can also be used. After the extraction, according to the ordinary method, apply the dilution, concentration, drying, refining method or the like to the extracted liquid, so as to obtain the extract containing polyphenol, as described in the above Formulae 1 to 7, or the like.
  • one or more absorbents can be selected and used from among the known conventional absorbent such as an ion-exchange resin, a synthetic absorbent resin, an activated carbon, a chelating resin, silica gel, an alumina gel series absorbent, a porous glass or the like. It is preferable to use a column chromatography with porous synthetic absorbent resin such as DIAION®HP-20 (Mitsubishi Chemical Corporation), SEPABEADS®SP-207 (Mitsubishi Chemical Corporation) or the like.
  • DIAION®HP-20 Mitsubishi Chemical Corporation
  • SEPABEADS®SP-207 Mitsubishi Chemical Corporation
  • aqueous solvent used in the above referenced process (c) a lower alcohol content (carbon numbers 1 to 5) can be used. Methanol and/or ethanol is especially preferable.
  • the AGE production inhibitor or the like of this invention effectively inhibits AGE production and prevents diabetic complications such as nephropathy, retinopathy or the like. Also, it especially inhibits AGE production within the fibroblast to improve the crosslink of the collagen part of the skin, thus preventing the skin from hardening. Moreover, it inhibits fibroblast apoptosis occurring after the production of AGE, thus retaining the elasticity of the skin, thus preventing flecks and dullness of the skin. Furthermore, it improves collagen cross-linking after AGE production, thus preventing the skin from hardening.
  • the AGE production inhibitor or the like of this invention can be used as an ingredient for any food and drink such as, edible oils (salad oils), confectionary (chewing gums, candies, caramels, chocolates, cookies, jellies, gummies, tablet shaped sweets or the like), noodles (Japanese buckwheat noodles called Soba, Japanese wheat noodles called Udon, Chinese noodles called Ramen or the like), dairy food (milk, ice cream, yogurt, or the like), seasoning (fermented bean paste called Miso, Soy sauce called Shoyu, or the like), soups, drinks (juice, coffee, black tea, green tea, carbonated drink, sports supplement drinks or the like) including general foods and healthy food (tablet type, capsule type or the like), nutritional supplements (nutritious supplement drink or the like).
  • the AGE production inhibitor or the like of this invention can be used for the above foods and drinks.
  • the following ingredients can be added: Glucose, fructose, sucrose, maltose, sorbitol, stevioside, corn syrup, lactose, citric acid, tartaric acid, malic acid, saccinic acid, lactic acid, L-ascorbic acid, dl- ⁇ -tocopherol, sodium erythorbate, glycerin, propylene glycol, glycerin fatty acid ester, polyglycerol fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, propylene glycol fatty acid ester, Arabian gum, carrageenan, casein, gelatin, pectine, agar-agar (gelatin made from seaweed), vitamin B family, nicotinic-acid amide, pantothenate acid calcium, amino acids, calcium salts, pigment, aroma chemicals, preservatives, or the like.
  • antioxidants or compounding ingredients of healthy food include the antioxidant “reduced ascorbic acid” or vitamin C and also the antioxidants, vitamin E, reduced glutacin, tocotrienol, vitamin A derivative, lycopene, rutin, ⁇ -cryptoxanthin, astaxanthin, zeaxanthin, fucoxanthin, uric acid, ubiquinone, coenzyme Q-10, folic acid, garlic extract, allicin, sesamin, lignans, catechin, isoflavone, chalcone, tannins, flavonoids, coumarin, isocoumarines, blueberry extract, ingredients for healthy food (V.
  • vitamin A V.B1, V.B2, V.B6, V.B12, V.C, V.D, V.E, V.P, choline, niacin, pantothenic acid, calcium folic acid, EPA, oligosaccharide, dietary fiber, squalene, soybean lecithin, taurine, dunalliela, protein, octacosanol, DHA, egg-yolk lecithin, linoleic acid, lactoferrin, magnesium, zinc, chrome, selenium, kalium, hem iron, oyster extract, chitosan, chitin oligosaccharides, collagen, chondroitin, elastin, turmeric, sweetroot, extract of Chinese wolfberry fruit called kukoshi, cinnamon, may, ginger, bracket fungus, shijimi clam ( corbicula japonica ) extract, snapping turtle, sweetroot, lycii fructus, cin
  • a more specific use of the extracting method is herein described. Firstly, spray-dry or freeze-dry the cherry-tree extract with powdered cellulose, then make it a powder, a granule, a tablet, or liquid to easily use with different kinds of food and drinks (ready-to eat meals or the like). Also, it is possible to dissolve the cherry-tree extract, for instance, oil and fat, ethanol, glycerin, or a mixture of these substances, and to use such a liquid for dry food or drinks. Also it is possible to make it into a powder or granule by mixing it with a binder such as Arabian gum, dextrin, or the like to add to dry food or drinks.
  • a binder such as Arabian gum, dextrin, or the like to add to dry food or drinks.
  • the total amount of the active substance of the AGE production inhibitor or the like of this invention, which is added to the food and drinks, is preferably 1 to 20 wt % or less, since the major objective of this invention is health maintenance.
  • the AGE production inhibitor or the like of this invention can be used as the raw material of medicines (including drugs and quasi-drugs).
  • the AGE production inhibitor or the like of this invention can be appropriately mixed with raw materials for drug formulations, for instance, vehicles (glucose, sucrose, white soft sugar, sodium chloride, starch, calcium carbonate, kaolin, crystalline cellulose, cacao oil, hydrogenated vegetable oil, talc, or the like), binders (distilled water, normal saline solution, ethanol in water, ethanolic solution, simple syrup, dextrose in water, starch solution, gelatin solution, carboxymethyl cellulose, potassium phosphate, polyvinyl pyrrolidone, or the like), disintegrating agents (alginate sodium, agar-agar, sodium hydrogen carbonate, sodium lauryl sulphate, stearic acid monoglyceride, starch, lactose, powdered aracia, gelatin, ethanol, or the like), suppressive agents for disintegration (white soft sugar,
  • the AGE production inhibitor or the like of this invention can be orally administered in the form of tablets, pills, soft or hard capsules, subtle granules, powders, granules, liquids, or the like. However, it can also be parenterally administered in the different forms of solution or together with a dispersant, a suspending agent, a stabilizer, or the like such as a medical skin patch, a lotion, an ointment, a cream or the like.
  • the applied dose can be adjusted according to the method of administration, the condition of the disease, the age of the patient, or the like. However, adults can normally take approx. 1 to 1,000 mg of an active substance per day, while children can take 0.5 to 500 mg per day.
  • the compounding ratio of the AGE production inhibitor or the like of this invention can be adjusted according to the mode of administration.
  • the applied dose is preferably 0.3 to 15.0 wt %.
  • the dose is preferably 0.01 to 10 wt %.
  • the dose varies depending on the conditions. Therefore, a dose which is less than the above-stated amount may be sufficient, or a greater amount may sometimes be needed.
  • the AGE production inhibitor or the like of this invention can be mixed with cosmetics such as emulsions, soaps, facial cleansers, bath agents, creams, skin lotions, colognes, shaving creams, shaving lotion, beauty oils, tanning lotions, sunscreen lotions, face powders, foundations, perfumes, facial masks, nail creams, nail enamels, nail-polish removers, eyebrow pencils, blushers, eye creams, eye shadows, mascaras, eye liners, sticks, lip creams, shampoos, hair conditioners, hairdyes, dispersion liquids, cleansing preparations, or the like.
  • the AGE production inhibitor or the like of this invention can be mixed with drugs and quasi-drugs such as ointments, cream pharmaceuticals, liquids for external use or the like.
  • the above items for external skin use can be also mixed with the ingredients of cosmetics, quasi-drugs, or the like.
  • Those ingredients include, for example, oil, higher alcohol, fatty acids, ultraviolet absorbers, powders, pigments, surface active agents, polyhydric alcohol and sugar, polymers, biologically active ingredients, solvents, antioxidants, aroma chemicals (perfume material), antiseptics.
  • those ingredients usable in the present invention are not limited to these examples.
  • Animal oils and hardened oils thereof such as beef tallow, hardened beef tallow, lard, hardened lard, horse oil, hardened horse oil, mink oil, orange roughy oil, fish oil, hardened fish oil and egg yolk oil; plant oils and hardened oils thereof such as avocado oil, almond oil, olive oil, cacao oil, apricot kernel oil, kukui nut oil, sesame oil, wheat germ oil, rice germ oil, rice bran oil, safflower oil, shea butter, soybean oil, evening primrose oil, perilla oil, tea seed oil, tsubaki oil ( camellia japonica oil), corn oil, rapeseed oil, hardened rapeseed oil, palm kernel oil, hardened palm kernel oil, palm oil, hardened palm oil, peanut oil, hardened peanut oil, castor oil, hydrogenated castor oil, sunflower oil, grape seed oil, jojoba oil, hardened jojoba oil, macadamia nut oil, meadowfoam seed oil, cottonseed oil,
  • Dimethylpolysiloxane Dimethylpolysiloxane, methylphenylpolysiloxane, methylcyclopolysiloxane, octamethylpolysiloxane, decamethylpolysiloxane, dodecamethylcyclosiloxane, methylhydrogenpolysiloxane, polyether-modified organopolysiloxane, dimethylsiloxanemethylcetyloxysiloxane copolymer, dimethylsiloxane-methylstearoxysiloxane copolymer, alkyl-modified organopolysiloxane, terminal-modified organopolysiloxane, amino-modified silicone oil, amino-modified organopolysiloxane, dimethiconol, silicone gel, acryl silicone, trimethylsiloxysilicic acid and silicone RTV rubber. From among the above ingredients, one only can be used, or two or more can be used together.
  • Perfluoropolyether fluorine-modified organopolysiloxane, fluorinated pitch, fluorocarbon, fluoroalcohol and fluoroalkyl-polyoxyalkylene-comodified organopolysiloxane. From among the above ingredients, one only can be used, or two or more can be used together.
  • Lauryl alcohol myristyl alcohol, cetyl alcohol, stearyl alcohol, isostearyl alcohol, oleyl alcohol, behenyl alcohol, 2-ethylhexanol, hexadecyl alcohol and octyl dodecanol. From among the above ingredients, one only can be used, or two or more can be used together.
  • Caprylic acid capric acid, undecylenic acid, lauric acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, isostearic acid, oleic acid, linoleic acid, linolenic acid, arachic acid, arachidonic acid, behenic acid, erucic acid and 2-ethylhexanoic acid. From among the above ingredients, one only can be used, or two or more can be used together.
  • Para-aminobenzoic acid amyl para-aminobenzoate, ethyldihydroxypropyl para-aminobenzoate, glyceryl para-aminobenzoate, ethyl para-aminobenzoate, octyl para-aminobenzoate, octyldimethyl para-aminobenzoate, ethylene glycol salicylate, octyl salicylate, triethanolamine salicylate, phenyl salicylate, butylphenyl salicylate, benzyl salicylate, homomethyl salicylate, benzyl cinnamate, octyl para-methoxycinnamate, 2-ethylhexyl para-methoxycinnamate, glyceryl mono-2-ethyl hexanoate di-para-methoxycinnamate, isopropyl para-methoxycinnamate, diethanolamine para-
  • Pigments such as Food Red 104, Food Red 201, Food Yellow 4, Food Blue 1 and Food Black 401; lake pigments such as Food Yellow 4 AL lake and Food Yellow 203 BA lake; polymers such as nylon powder, silk powder, urethane powder, Teflon® powder, silicone powder, polymethyl methacrylate powder, cellulose powder, starch, silicone elastomer spherical powder and polyethylene powder; color pigments such as yellow iron oxide, red iron oxide, black iron oxide, chromium oxide, carbon black, ultramarine and iron blue; white pigments such as zinc oxide, titanium oxide and cerium oxide; extender pigments such as talc, mica, sericite, kaolin and plate barium sulfate; pearl pigments such as mica titanium; metal salts such as barium sulfate, calcium carbonate, magnesium carbonate, aluminum silicate and magnesium silicate; inorganic powders such as silica and alumina; metal soaps such as aluminum stearate, magnesium stearate, zinc palmitate, zinc my
  • the shape (e.g., sphere, bar, needle, plate, amorphous, scale, spindle) and the particle size of these powders are not particularly limited. These powders may or may not be previously surface-treated by a conventionally known surface treatment such as fluorine compound treatment, silicone treatment, silicone resin treatment, pendant treatment, saline coupling agent treatment, titanium coupling agent treatment, lubricant treatment, N-acylated lysine treatment, polyacrylic acid treatment, metal soap treatment, amino acid treatment, lecithin treatment, inorganic compound treatment, plasma treatment and mechanochemical treatment. From among the above ingredients, one only can be used, or two or more can be used together.
  • a conventionally known surface treatment such as fluorine compound treatment, silicone treatment, silicone resin treatment, pendant treatment, saline coupling agent treatment, titanium coupling agent treatment, lubricant treatment, N-acylated lysine treatment, polyacrylic acid treatment, metal soap treatment, amino acid treatment, lecithin treatment, inorganic compound treatment, plasma treatment
  • Fatty acid soap a-acyl sulfonate, alkyl sulfonate, alkylallyl sulfonate, alkylnaphthalene sulfonate, alkyl sulfate, POE alkyl ether sulfate, alkylamide sulfate, alkyl phosphate, POE alkyl phosphate, alkylamide phosphate, alkyloylalkyl taurine salt, N-acylamino acid salt, POE alkyl ether carbonate, alkyl sulfosuccinate, sodium alkylsulfoacetate, acylated hydrolyzed collagen peptide salt and perfluoroalkylphosphoric acid ester. From among the above ingredients, one only can be used, or two or more can be used together.
  • Carboxybetaine type amidobetaine type, sulfobetaine type, hydroxysulfobetaine type, amidosulfobetaine type, phosphobetaine type, aminocarboxylate type, imidazoline derivative type and amidoamine type. From among the above ingredients, one only can be used, or two or more can be used together.
  • Propylene glycol fatty acid ester Propylene glycol fatty acid ester, glycerin fatty acid ester, polyglycerin fatty acid ester, sorbitan fatty acid ester, POE sorbitan fatty acid ester, POE sorbitol fatty acid ester, POE glycerin fatty acid ester, POE alkyl ether, POE fatty acid ester, POE hydrogenated castor oil, POE castor oil, POE-POP copolymer, POE-POP alkyl ether, polyether-modified silicone lauric acid alkanolamide, alkylamine oxide and hydrogenated soybean phospholipid. From among the above ingredients, one only can be used, or two or more can be used together.
  • Lecithin, saponin and sugar-type surfactant One ingredient only can be used, or two or more can be used together.
  • Ethylene glycol diethylene glycol, polyethylene glycol, propylene glycol, dipropylene glycol, polypropylene glycol, glycerin, diglycerin, polyglycerin, 3-methyl-1,3-butanediol, 1,3-butylene glycol, sorbitol, mannitol, raffinose, erythritol, glucose, sucrose, fruit sugar, xylitol, lactose, maltose, maltitol, trehalose, alkylated trehalose, mixed isomerized sugar, sulfated trehalose and pullulan. Chemically modified products thereof can also be used. From among the above ingredients, one only can be used, or two or more can be used together.
  • Anionic polymer compounds such as acrylic acid ester/methacrylic acid ester copolymer (PLUS-SIZE, produced by Sogokagaku K. K.), vinyl acetate/crotonic acid copolymer (Resin 28-1310, produced by NSC), vinyl acetate/crotonic acid/vinyl neodecanate copolymer (28-2930, produced by NSC), methyl vinyl ether maleic acid half ester (GANTREZ ES, produced by ISP), T-butyl acrylate/ethyl acrylate/methacrylic acid copolymer (RUBIMER, produced by BASF), vinylpyrrolidone/vinyl acetate/vinyl propionate copolymer (RUBISCOL VAP, produced by BASF), vinyl acetate/crotonic acid copolymer (RUBISET CA, produced by BASF), vinyl acetate/crotonic acid copolymer (RUBISET CAP,
  • polymer compounds of natural origin such as cellulose and derivatives thereof, calcium alginate, pullulan, agar, gelatin, tamarind seed polysaccharides, xanthane gum, carrageenan, high-methoxyl pectin, low-methoxyl pectin, guar gum, gum arabi, crystal cellulose, arabino galactan, karaya gum, tragacanth gum, alginic acid, albumin, casein, cardrun, gellan gum and dextran, can also be suitably used. From among the above ingredients, one only can be used, or two or more can be used together.
  • the biologically active ingredient may include substances which are capable of imparting some biological activity to skin, when such a substance is applied to the skin. Specific examples thereof may include: whitening ingredient, age resistor, ultraviolet protection, slimming agent, skin tightening agent, antioxidant, hair restorer, hair growing agent, moisturizer, blood circulation accelerator, antibacterial agent, bactericide, desiccant, cooling agent, warming agent, vitamin compound, amino acid, wound healing accelerator, torpent, analgetic, cell activator and enzyme ingredient.
  • Suitable examples of the ingredient to be blended therefor may include: angelica extract, avocado extract, hydrangea extract, althea extract, arnica extract, aloe extract, apricot extract, apricot core extract, ginkgo extract, fennel extract, turmeric extract, oolong tea extract, rose fruit extract, echinacea leaf extract, scutellaria root extract, phellodendron bark extract, goldthread extract, barley extract, hypericum extract, white nettle extract, watercress extract, orange extract, sea salt, seaweed extract, hydrolyzed elastin, hydrolyzed wheat powder, hydrolyzed silk, chamomile extract, carrot extract, artemisia capillaris extract, glycyrrhiza extract, sabdariffa extract, pyracantha fortuneana fruit extract, cinchona extract, cucumber extract, guanosine, gardenia extract, sasa albo - marginata extract, sophora root extract, walnut
  • biopolymers such as deoxyribonucleic acid, mucopolysaccharide, sodium hyaluronate, sodium, elastin, chitin, chitosan and hydrolyzed eggshell membrane; moisture retentive ingredients such as amino acid, hydrolyzed peptide, sodium lactate, urea, sodium pyrrolidonecarboxylate, betaine, whey and trimethylglycine; oily ingredients such as sphingolipid, ceramide, phytosphingosine, cholesterol, cholesterol derivatives and phospholipid; anti-inflammatory such as E-aminocaproic acid, glycyrrhizic acid, -glycyrrhetic acid, lysozyme chloride, guaiazlene and hydrocortisone; vitamins such as vitamin A, vitamin B2, vitamin B6, vitamin D, vitamin E, calcium pantothenate, biotin and nicotinic acid amide; active ingredients such as allantoin
  • Example 1 The search for substances held in the cherry-blossom extract is shown in FIG. 1 .
  • Example 1 the cherry-blossom extract (90.10 grams) is suspended within the chromatography column (HP-20, Mitsubishi Chemical Corporation) to obtain eluted water (H2O) [of] (62.16 g, 68.88%), eluted methanol (MeOH) [of] (28.21 g, 31.31%) and eluted acetone (Acetone) [of] (0.60 g, 0.67%).
  • each yield (w/w) of the isolated substances as shown in FIG. 1 , means an isolated yield of the cherry-blossom extract, Example 1.
  • Example 2 Put the sample solution (100 mL) of the concentration of cherry-blossom extract (Example 1) and cherry-leaf extract (Example 2), as shown in the chart, below, into a phosphate buffer solution (pH: 7.4, 900 mL) containing D-glucose (10%) and into bovine serum albumin (fraction 5.1%) and leave it out at a temperature of 60 degrees centigrade for two days. Dilute the reaction solution with distilled water until the intensity of fluorescent light reaches about 500, thus determining its intensity (measurement wavelength: 370 nm, excitation wavelength: 440 nm).
  • the extract is to be diluted with distilled water, and the substance, after being dissolved in DMSO (dimethyl sulphoxide), is to be diluted with a phosphate buffer solution until DMSO concentration is of 1%.
  • DMSO dimethyl sulphoxide
  • Chart 1 Each value in Chart 1 indicates an average value with standard error of the three examples.
  • Asterisks (*, **) mean a significant difference (i.e. *: p ⁇ 0.05; **: p ⁇ 0.01) between the processed samples and the unprocessed samples as determined by Dunnett's Multiple Comparison Test.
  • the main polyphenol of cherry blossom i.e. 1-O-(E)-Caffeoyl-3-D-glucopyranoside (Example 3) in high concentration of 300 ⁇ g/mL, shows a 30% inhibitory activity.
  • the inhibitory activity of a related compound with less hydroxyl i.e. 1-O-(E)-Coumaroyl- ⁇ -D-Glucopyranoside (Example 4), and 1-O-(E)-Cinnamoyl- ⁇ -D-glucopyranoside (Example 5) is reduced.
  • the inhibitory activity of flavonoid glycoside is generally much, and the inhibitory activity of Quercetin 3-O- ⁇ -D-glucopyranoside (Example 7) and Quercetin 3-O-(6′′-malony)- ⁇ -D-glucopyranoside (Example 9) is much (IC50), more than twice as much as the inhibitory activity of other compounds with Kaempferol as an aglycon. (IC50: half-maximal (50%) inhibitory concentration)
  • Test 2-1 verifies the beneficial activity of cherry-blossom extract (Example 1) upon human fibroblast apoptosis caused by CML-collagen.
  • a human diploid fibroblast (female/age 40/normal skin-derived/PDL20) was cultured in the medium of fetal calf serum (FCS) with penicillin (100 units/mL) and streptomycin (100 mg/mL).
  • FCS fetal calf serum
  • penicillin 100 units/mL
  • streptomycin 100 mg/mL
  • the fibroblast (7 ⁇ 104 cells) was suspended in the D-MEM medium containing FCS (0.5%), penicillin (100 units/mL) and streptomycin (100 mg/mL) to be seeded within 96-well plates (100 mL/well). After 24 hours of culture, the dissolved CML-collagen solution (2 mg ⁇ mL) and the sample solution (13 mL) were added to the medium and cultured for 24 hours. Collagen, instead of CML-collagen, was added to Normal group.
  • the absorbent rate of the Control group is higher than that of the Normal group, and the cell survival rate was lowered due to CML-collagen.
  • the microscopic images identify the inhibition of formazan accumulation within the cell. By this situation, it is anticipated that fibroblast apoptosis is induced by CML-collagen. Contrarily, in the group of which 1000 mg/mL of the cherry-blossom extract (Example 1) is added, the formazan formation significantly increased.
  • caspase-3/7 activity of the Control group increases compared to that of the Normal group, and it is identified that apoptosis is induced by the CML-collagen. Contrarily, in the Normal group of which the cherry-blossom extract (more than 100 mL) was added, caspase-3/7 activity decreased. When the volume of cherry-blossom extract was more than 300 mg/mL, caspase-3/7 activity was lower in the Control group than that in the Normal group, which suggests that the cherry-blossom extract possibly inhibits enzyme activity and enzyme expression of caspase-3/7.
  • Example 2 respecting the cherry-blossom extract (Example 1), and the cherry-leaf extract (Example 2) and the seven substances contained in the cherry-blossom extract (Example 1): 1-O-(E)-Caffeoyl- ⁇ -D-glucopyranoside, 1-O-(E)-Coumaroyl- ⁇ -D-Glucopyranosideand, 1-O-(E)-Cinnamoyl- ⁇ -D-glucopyranoside, Kaempferol 3-O-3-D-glucopyranoside, Quercetin 3-O- ⁇ -D-glucopyranoside, Kaempferol 3-O-(6′′-malony)- ⁇ -D-glucopyranoside and Quercetin 3-O-(6′′-malony)- ⁇ -D-glucopyranoside (Examples 3 to 9), the activity against fibroblast apoptosis, caused by CML-collagen, was identified in the same way as in Test 2-1.
  • the cherry-blossom extract (Example 1, 10 to 100 mg/mL) lowered caspase-3/7 activity. From this result, it is suggested that the cherry-blossom extract (Example 1) inhibits apoptosis caused by CML-collagen.
  • Quercetin 3-O- ⁇ -D-glucopyranoside (Example 7), shown to be the strongest substance in the AGE production inhibitory Test 1, had the strongest inhibitory activity.
  • Similar compounds like Kaempferol 3-O- ⁇ -D-glucopyranoside (Example 6) and Quercetin 3-O-(6′′-malony)- ⁇ -D-Glucopyranoside (Example 9) showed strong inhibitory activity.
  • Kaempferol 3-O-(6′′-malony)- ⁇ -D-glucopyranoside (Example 8) showed relatively weak activity.
  • Kaempferol 3-O- ⁇ -D-glucopyranoside which contains the highest level of cinnamic acid, showed especially strong inhibitory activity.
  • the cherry blossom extract (Example 1), and the cherry leaf extract (Example 2) and their active substances have AGE production inhibitory activity which inhibits fibroblast apoptosis caused by CML-collagen.
  • these active substances function as a breaker that degrades CML-collagen, which is an AGE.
  • the AGE production inhibitor of this invention can be used to as an AGE decomposition agent or as an AGE remover.
  • the infant-derived NB1 RGB (passage number 22) was suspended in the D-MEM complete media (1.86 ⁇ 104 cells/mL). 15 mL each of it was seeded within each cell-culture dish of 14 cm in diameter. After 24 hours, each sample and glyoxal were added until the molecular mass of each dish became 200 mM and incubate the dishes for five days.
  • Bovine skin-derived collagen 25 mg was dissolved in 0.1% acetic acid (8.3 mL). Then, a 10-times concentration of Hanks solution (1.66 L) was added. Then, 0.1% acetic acid (3.5 mL) was added. 1M NaOH was added to neutralize the solution, which was sterilized by filteration to obtain the collagen solution.
  • the mixed solution of collected fibroblast (5.4 ⁇ 104 cell) was suspended in FCS (50 ⁇ m), and collagen (450 mL) was seeded within a 24-well cell-culture plate and allowed to culture for 24 hours and 48 hours. Each culture was observed through a microscope and by the naked eye. An image observed by the naked eye is shown in FIG. 3 . A microscopic image ( ⁇ 100), [taken] after the 24-hour culture, is shown in FIG. 4 . A microscopic image ( ⁇ 200) [taken] after the 48-hour culture, is shown in FIG. 5 . For the purpose of comparison, aminoguanidin hydrochloride which is an anti-glycation agent was also examined in the same way.
  • the result of the fibroblast and collagen solution culture, as shown in FIG. 3 is that collagen-grating formation was identified.
  • the white hazy part shows the extension and projection of the fibroblast and collagen grating.
  • the amount of collagen-grating formation of the Control group which was processed with glyoxal significantly decreased compared to that of Normal group.
  • the well of fibroblast, processed with 100 and 1000 mg/mL of cherry blossom-extract (Example 1) and glyoxal showed an increase in the amount of grating formation.
  • the well of fibroblast processed with 100 mg/mL of guanidine hydrochloride, compared to the control group showed no increase in the amount of grating formation.
  • FIG. 1 The result of the fibroblast and collagen solution culture, as shown in FIG. 3 , is that collagen-grating formation was identified.
  • the white hazy part shows the extension and projection of the fibroblast and collagen grating.
  • FIG. 4 showing the microscopic image after 24 hours of culture, it was identified that the fibroblast of the Normal group and of the Control group and of guanidine hydrochloride were spherically shaped.
  • the well of 100 and 1000 mg/mL of the cherry blossom-extract (Example 1) identified the extension and projection of the fibroblast.
  • FIG. 5 the 200-times enlarged microscopic image, after eight hours of culture, showed a few extensions of the fibroblast of the Control group. However, it was still weak compared to that of the well of 100 and 1000 mg/mL of the cherry blossom-extract (Example 1).
  • Test 4 examined the activity of the cherry blossom-extract (Example 1) and of the 1-O-(E)-Caffeoyl- ⁇ -D-glucopyranoside (Example 3) against the production of AGE (carbon methyl lysine protein) within the fibroblast (human diploid fibroblast) which was processed with glyoxal.
  • AGE carbon methyl lysine protein
  • Human diploid fibroblast (passage number 30) was suspended in a D-MEM complete culture media, and 20 mL each was seeded within a cell culture dish of 14 cm in diameter. After 48 hours of culture, samples of various concentrations and of 401M of glyoxal were added to 80%-confluent cells and cultured for 5 days. After that, each sample was collected and crushed. Then, protein 10 mg was examined by the Western Blotting method using an anti-AGE antibody to detect AGE. The result as shown in FIG. 6 shows a detection of AGE by the anti-AGE antibody (HRP staining system).
  • CaGlu means 1-O-(E)-Caffeoyl- ⁇ -D-glucopyranoside (Example 3).
  • Example 1 After continuously administrating the cherry-blossom extract (Example 1) in various concentrations, the AGE precursor, glyoxal, was intradermally administrated to observe its activity in the production of AGE. Based on this observation, a recommended dose of the cherry-blossom extract (Example 1) was determined.
  • the solution (10, 50 and 100 mg/kg) of the cherry-blossom extract (Example 1) was administered to a mouse (ICR, male, 5-week-old) once a day for 10 days. After completing the administration, glyoxal (800 mM 100 mL) was intradermally administered into the shaved back of the mouse. After 21 hours, the last administration of cherry-blossom extract (Example 1) was done to the mouse. Then, after another three hours, the mouse was immolated with an ether anesthesia, and the glyoxal-administered part was removed.
  • the removed skin of the mouse was then crushed in 2 mL of lysis buffer (50 mM tris, 150 mM NaCl, 1% Triton X100, pH: 7.2) using Polytron Homogenizer, and the crushed material was centrifugally separated (1000 ⁇ g, 7 min). Then, the supernatant was collected and refrigerated at the temperature of 20 degrees Centigrade below zero.
  • lysis buffer 50 mM tris, 150 mM NaCl, 1% Triton X100, pH: 7.2
  • the AGE content was measured using an ELISA kit (Trans Genic. Inc.) for measuring glucose-derived AGEs.
  • the AGE was detected by the Western Blotting method. The result is shown in Chart 5, as well as in FIG. 7 .
  • the cherry-blossom extract (Example 1) indicated no dosage dependency. It was identified that 10 to 100 mg/kg of the cherry-blossom extract, orally administration, inhibited the production of AGE. From this result, the recommended dosage of the cherry blossom-extract (Example 1) is to be set between 10 and 100 mg/day.
  • the CML-collagen was intradermally administrated to observe the activity against the apoptosis of dermal cells as well as the fibroblast.
  • the test was conducted in the following method.
  • the solution (10, 50 and 100 mg/kg) of cherry-blossom extract (Example 1) was administered to a mouse (ICR, male, 5-week-old) once a day for 10 days. After completing the administration, CML-collagen (100 mg/100 mL) was intradermally administered into the shaved skin area of the mouse where the biauricular line of the occipital region of the mouse crosses a midline. Collagen was administered to the Normal group. After 21 hours, the last administration of the cherry-blossom extract (Example 1) was done to the mouse. Then, after another three hours, the mouse was immolated after being administrated an ether anesthesia. The collagen-administered part of the mouse was removed.
  • the part removed from the mouse was immersed and fixed in a solution of 4% paraformadehyde, and the cut section was stained by TUNEL staining.
  • TUNEL staining To count the number of dermal cells, which were confirmed as being positive by the TUNEL staining, the image of the cross section of the skin was taken by a microscope ( ⁇ 400) and processed with color gradations from purple to orange to identify the number of cells.
  • a printed image of the cross section of the inner skin was measured by a digital planimeter, and the scale was multiplied. The result is shown in Chart 6, as well as in FIG. 8 .
  • the part marked with a ⁇ means TUNEL-positive cells.
  • Blending example 8 Tablets Lactose 54.0 wt % Crystaline Cellulose 30.0 Starch splitting product 10.0 Glycerin fatty acid ester 5.0 AGE production inhibitor, etc 1.0 100.0 wt %
  • CHART 18 Blending example 12 Cosmetic emulsion Squalene 4.0 wt % Vaseline 2.5 Cetanol 2.0 Glycerin 2.0 Oleophilic glycerine monostearate 1.0 Stearic acid 1.0 L-arginine 1.0 AGE production inhibitor 0.5 Potassium hydroxide 0.1 Aroma chemical Minute amount Distilled water Rest 100.0 wt %
  • this invention makes it possible to inhibit the production of AGE and to prevent cells and intercellular matrix from suffering damage induced by AGE. From this result, this invention also makes it possible to effectively prevent and cure diabetes and diabetic complications, thus effectively preventing the skin from aging.

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