WO2012050162A1 - Cellular life span extending agent, and telomerase activator - Google Patents

Cellular life span extending agent, and telomerase activator Download PDF

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Publication number
WO2012050162A1
WO2012050162A1 PCT/JP2011/073548 JP2011073548W WO2012050162A1 WO 2012050162 A1 WO2012050162 A1 WO 2012050162A1 JP 2011073548 W JP2011073548 W JP 2011073548W WO 2012050162 A1 WO2012050162 A1 WO 2012050162A1
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cell
extract
telomerase
cinnamon
derived
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PCT/JP2011/073548
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French (fr)
Japanese (ja)
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健太朗 加治屋
伸幸 高倉
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株式会社資生堂
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILET PREPARATIONS
    • A61Q19/00Preparations for care of the skin
    • A61Q19/08Anti-ageing preparations
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K36/00Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18Magnoliophyta (angiosperms)
    • A61K36/185Magnoliopsida (dicotyledons)
    • A61K36/54Lauraceae (Laurel family), e.g. cinnamon or sassafras
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K8/00Cosmetics or similar toilet preparations
    • A61K8/18Cosmetics or similar toilet preparations characterised by the composition
    • A61K8/96Cosmetics or similar toilet preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/97Cosmetics or similar toilet preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof

Abstract

The present invention provides: a novel cellular life span extending agent, particularly an agent for extending the life span of an endothelial cell, which comprises an extract derived from a plant belonging to the genus Cinnamomum; and a telomerase activator.

Description

Cell life extender and telomerase activator

The invention Nikkei (Cinnamomum) genus plants consisting in particular silicate (Cinnamomum cassia Blume) species plant-derived extracts, cell survival extender, provides in particular vascular endothelial cell survival extender, and telomerase activator.

Arterial blood was ejected from the left ventricle, through the aorta, through muscular arteries, arterioles, carried capillaries. Then, venous blood collected in the venules, through the vena cava, come back to the right atrium. Blood flows from the right atrium to the right ventricle is ejected into the lungs, oxygenated blood is returned to the left atrium and the left ventricle, the pulmonary. That the aorta and vena cava are exclusively the function as a blood conduit, for vena cava, thicker than the aorta, when the arterial bleeding occurs, provided the depletion blood by blood loss, pooled blood It has a function. The muscular arteries to control blood pressure by its contraction, arterioles can penetrate deep tissue, allowing the circulation of blood to the tissue detail by capillary branching therefrom. The capillaries, the supply of oxygen and nutrients organization running the permeability function, venules when such symptoms occur serves as an outlet port to the inflammatory cells of the tissue. Vascular function, such as above is well known, that the blood vessels in recent years also functions to tissue formation itself has been found. For example, self-renewing tissue-specific stem cells that comes with organ-organs, be Itonama in the vascular region has been reported (Non-Patent Documents 1 and 2), namely the maintenance of tissue is Itonama around the vessel indicating that.

Vessels lumen cover even more endothelial cells that, outside the vascular smooth muscle cells and pericytes, which are generically referred parietal cells recruited to (basal side) forms a stable structure lining. As described above, the blood vessel is adapted to carry oxygen and nutrients and inflammatory cells as basic functions for life support, also involved in tissue formation itself. Therefore, when the vascular endothelial cells greet life, blood vessels degenerate, oxygen and nutrients as well does not reach the local vascular structure becomes brittle so that raising the inflammatory response. This is the same also in the skin, the supply of oxygen and nutrients not only spread in every corner, it will induce skin inflammatory response. For example, if the vessel has insufficient oxygen and nutrients by reduced blood flow resulting from degeneration, aging, such as wrinkles due to a decrease in fibroblasts has been reported (Non-Patent Document 3), vasculature brittle the became mouse, inflammatory response and increased the knowledge that the formation of wrinkles is accelerated is obtained (non-Patent Document 4). Furthermore, skin site photoaged is known that the number of capillaries is reduced (Non-Patent Document 5), to extend the life span of endothelial cells is to normalize the condition of the skin, aging, thus would be able to prevent wrinkle formation.
Further vessels, in the context of tissue stem cells, because it has the function of tissue formation maintain its collapse, loss and excessive hyperplasia causes of various diseases. For example, cancer, myocardial infarction, the so-called three major disease of major causes of death, such as cerebral infarction, it is known to increase with occurrence of aging and lifestyle diseases, vascular abnormalities in any of these three major diseases There is observed. Changes in the blood vessels inside and outside environmental factors due to aging and lifestyle-related diseases, have a stress against the vessel, the vascular endothelial cells has been clarified to induce cellular senescence, and this is the medical condition of a variety of diseases it has been found to be involved deeply in progress. For example, breakdown of the blood vessel by vascular aging, renal failure, osteoporosis, Alzheimer's disease, retinopathy, erectile dysfunction is known to result in a reduced function of various organs such as the lungs dysfunction (Non-patent Document 6).

Normal cells are impossible to divide permanently, after division of a constant number, irreversibly arrest cell division. This phenomenon is cellular senescence, cellular senescence induced by this cell division, telomere shortening structure on the chromosome causes (non-patent document 7). The telomeres were present at the end of chromosomes carrying the center of the genetic information of cells, and DNA having a characteristic repeat sequence, constituted by structures made of various proteins. Cause with cells divide, the telomeres gradually shortened, the telomeres become shorter than a certain length, are recognized as DNA damage, that the DNA damage response pathway is activated, proliferating capacity loss in cell aging are (non-Patent Document 8). In vascular endothelial cells, by overexpressing telomerase with telomeric extension action (Non-Patent Document 9) Since it is possible to inhibit cell senescence, telomere seen to play an important role in cell aging.

As described above, the telomere length shortened to induce cell senescence, but it has been found that various stress induces senescence of vascular endothelial cells. Examples of such cellular senescence factors are known pathology and molecular as follows. 1) angiotensin II (Non-Patent Document 10 involved in hypertension), 2) diabetes mellitus hyperglycemia, which are a major condition (Non-Patent Document 11) and glycosylated proteins (Non-Patent Document 12), 3) the DNA damage of vascular endothelial cells induced, thought to promote cellular senescence, oxidized LDL that increases with hyperlipidemia and obesity (non-patent Document 13), 4) is believed to induce cell senescence through the formation and DNA damage oxidized LDL, smoking . Here, conditions and lifestyle according to the above 1) to 4) are all may be arteriosclerosis risk factors, such risk factors commonly, by enhancing oxidative stress, as well as DNA damage , to promote telomere shortening has also been reported (non-Patent Document 14). Furthermore, the inflammation caused by the collapse of the blood vessel, the enhanced inflammatory cytokines such as interferon-γ and TNF [alpha], has also been reported to accelerate the aging of endothelial cells (Non-Patent Document 15).
Cause induce senescence of vascular endothelial cells, but are not limited to the above, generally, the blood stream caused by aging or lifestyle / lifestyle diseases, and stress from the outside vessel, vascular endothelial cells to induce senescence and induces vascular underlying various diseases abnormalities.

In view of the above, in order to suppress vascular abnormalities due to aging of the vascular endothelial cells involved in fundamental, such as aging or lifestyle / lifestyle diseases, it may be necessary to maintain the telomeres activity in vascular endothelial cells . By prolonging the telomere activity in vascular endothelial cells, caused by aging or lifestyle / lifestyle diseases, and resistance to various stresses, vascular endothelial cell senescence is suppressed, transport of oxygen and nutrients to the various organs , anti-inflammatory action due to infiltration of inflammatory cells of ordered is promptly performed, also been made to maintain the tissue-specific stem cells underlying the tissue maintenance, the maintenance of the organ is made. Thus, substances capable of maintaining the telomere activity in vascular endothelial cells, oral or by injection, and if possible by coating can be an anti-aging agent suppresses the aging of individuals.

.. Takakura N, Huang XL, Naruse T, Hamaguchi I, Dumont DJ, Yancopoulos GD, Suda T .: Critical role of the TIE2 endothelial cell receptor in the development of definitive hematopoiesis Immunity 1998 Nov; 9 (5): 677-86 . Butler JM, Nolan DJ, Vertes EL, Varnum-Finney B, Kobayashi H, Hooper AT, Seandel M, shido K, White IA, Kobayashi M, Witte L, May C, Shawber C, Kimura Y, Kitajewski J, Rosenwaks Z , Bernstein ID, Rafii S.:. .. Endothelial cells are essential for the self-renewal and repopulation of Notch-dependent hematopoietic stem cells Cell Stem Cell 2010 Mar 5; 6 (3): 251-64 Chung JH, Eun HC. . Angiogenesis in skin aging and photoaging J Dermatol 2007; 34:..... 593-600 Chung JH, Yano K, Lee MK, et al Differential effects of photoaging vs intrinsic aging on the vascularization of human skin Arch Dermatol 2002; 138 : 1437-1442 Hirakawa S, Fujii S, Kajiya K, Yano K, Detmar M. Vascular endothelial growth factor promotes sensitivity to ultraviolet B-induced cutaneous photodamage Blood 2005; 105:... 2392-2399. Herrera MD, Mingorance C, Rodriguez -Rodriguez R, Alvarez de Sotomayor M.: Endothelial dysfunction and aging:.. An update Ageing Res Rev. 2010 Apr; 9 (2): 142-52 Collado M, Blasco MA, Serrano .. M .: Cellular senescence in cancer and aging Cell 2007 Jul 27; 130 (2): 223-33 d'Adda di Fagagna F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, Von Zglinicki T, Saretzki . G, Carter NP, Jackson SP .: A DNA damage checkpoint response in telomere-initiated senescence Nature 2003 Nov 13; 426 (6963):.. 194-8 Minamino T, Miyauchi H, Yoshida T, Ishida Y, Yoshida H, . Komuro I .: Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction Circulation 2002 Apr 2; 105 (13):.. 1541-4 Imanishi T, Moriwaki C, Hano T, Nishio I .: Endothelial progenitor cell senescence . is accelerated in both experimental hypertensive rats and patients with essential hypertension J Hypertens 2005 Oct; 23 (10):.. 1831-7 Yokoi T, Fukuo K, Yasuda O, Hotta M, Miyazaki J, Takemura Y, Kawamoto H, Ichijo H, Ogi . hara T .: Apoptosis signal-regulating kinase 1 mediates cellular senescence induced by high glucose in endothelial cells Diabetes 2006 Jun; 55 (6):.. 1660-5 Chen J, Brodsky SV, Goligorsky DM, Hampel DJ, Li H, . Gross SS, Goligorsky MS .: Glycated collagen I induces premature senescence-like phenotypic changes in endothelial cells Circ Res 2002 Jun 28; 90 (12):.. 1290-8 Breitschopf K, Zeiher AM, Dimmeler S .: Pro-atherogenic . factors induce telomerase inactivation in endothelial cells through an Akt-dependent mechanism FEBS Lett 2001 Mar 23; 493 (1):... 21-5 Ben-Porath I, Weinberg RA .: The signals and pathways activating cellular senescence Int J Biochem Cell Biol 2005 May; 37 (5 ):... 961-76 Kim KS, Kang KW, Seu YB, Baek SH, Kim JR .: Interferon-gamma induces cellular senescence through p53-dependent DNA damage signaling in human endothelial cells Mech . Ageing Dev 2009 Mar; 130 ( 3): 179-88.

An object of the present invention, a novel, cell life extender is especially vascular endothelial cells life extenders, and to provide a telomerase activator.

The present inventors, from the examined by the action of various herbal extract experiments, the Nikkei (Cinnamomum) genus plant-derived extracts found that an effect of activating telomerase, the present invention has been completed .

Accordingly, the present application encompasses the following inventions:
(1) consisting of Cinnamomum plant-derived extracts, cell survival extender.
(2) wherein the extract is derived from silicate species plant, cell life extender (1).
(3) wherein the extract is derived from cinnamon twig or cinnamon bark, cell survival extender (2).
(4) the extract is a water extract, (1) any cell life extender to (3).
(5) wherein the cell is a vascular endothelial cells, (1) to any cell life extender (4).
(6) progression of cellular senescence delay or stop, or to improve cell senescence state for prolonging the cell life, the use of either cell life extender of (1) to (5).
(7) Cinnamomum made from a plant-derived extracts, telomerase activator.
(8) wherein the extract is derived from silicate species plant, telomerase activator (7).
(9) wherein the extract is derived from cinnamon twig or cinnamon bark, telomerase activator (8).
(10) wherein the extract is a water extract, (7) any of telomerase activator to (9).

1, with and without cinnamic extract added, shows a comparison of telomerase activity in HUVEC.

Cinnamomum is a plant of laurales (Lauraceae), Lauraceae (Lauraceae), there are more than 300 species, for example silicic (Cinnamomum cassia Blume), camphor (C. camphora), Malva Nikkei (C. daphnoides) Shibanikkei (C. doederleinii), Cinnamomum Pedunculatum (C. japonicum), Ogasawara bush Nikkei (C. pseudo-pedunculatum), Nikkei (C. sieboldii), lawn bush Nikkei Ceylon cinnamon (C. verum), cinnamon (C. zeylanicum) is known. Cell life extender in the present invention, extraction, especially vascular endothelial cells life extenders, and as preferably telomerase activator silicate (Cinnamomum cassia Blume), derived from twig (Keishi) or cinnamon (cinnamon) in particular shoots Kay object is used. Extracts from a bark Kay cinnamon is useful as an active ingredient, for example, hair growth agents (JP-A-10-265350), Tie2 (tyrosine kinase with Ig and EGF homology domain-2) phosphorylation activity it (JP 2009-263358) is known to have, it is not known at all to have cell life extension properties, particularly vascular endothelial cells extended life characteristics, and the like telomerase activation properties.

The extract can be obtained by a conventional method, for example, by immersing or heated to reflux at room temperature or heated with plant an extraction solvent becomes its origin, filtered, can be concentrated. As the extraction solvent, if any solvent usually used for extraction can be optionally used, for example, aqueous solvents such as water, saline, phosphate buffer, borate buffer, or an organic solvent, such as ethanol, propylene glycol, 1,3-butylene glycol, alcohols such as glycerin, hydrous alcohols, chloroform, dichloroethane, carbon tetrachloride, acetone, ethyl acetate, hexane and the like, can be used alone or in combination. Preferably, water is used as solvent. As it extracts obtained by extraction with the solvent, or, for example can use the concentrated extract by freeze drying, also adsorption method, if necessary, for example, those obtained by removing impurities using ion exchange resins, porous after adsorption by column polymers (e.g. Amberlite XAD-2), eluting with a desired solvent can be used that further concentrated.
As the extract, for example, it may be used cinnamon extract (Nippon dry chemical, Ltd.) commercially available.

As used herein, "cell life extension" is not particularly limited, caused bloodstream caused by aging or lifestyle / lifestyle diseases, and the stress from extravascular the progress of cell senescence delay or stop, or cellular senescence state to improve, refers to prolonging cell life.
Cell is not particularly limited, but is preferably vascular endothelial cells.

As used herein, "telomerase activation" refers to improving or promoting the activity of telomerase, the activity can be examined by known methods (e.g., Quantitative Telomerase Detection Kit; Allied Biotech , use a Inc).

Cell life extender of the present invention, particularly vascular endothelial cells life extenders, and telomerase activator, prevention of various diseases and aging caused by cell senescence, can be utilized as an effective pharmaceutical or cosmetic improvement. The various diseases and aging caused by the cellular aging, various inflammatory diseases, immune diseases, such as adult diseases, such as various infectious diseases, rheumatoid arthritis, gout, hypertension, diabetes, arteriosclerosis, hyperlipidemia hyperlipidemia, obesity, such as organ dysfunction, and the like. Furthermore, cell survival extender of the present invention, particularly vascular endothelial cells life extenders, and telomerase activator, prevention of diseases and aging of the skin caused by cell senescence, can be utilized as an effective pharmaceutical or cosmetic improvement. Diseases and aging of the skin caused by the cell senescence, skin roughness, formation of wrinkles, colored plaques, sallow of the formation of slack, easily damaged, atrophy and the like.
Furthermore, the present invention is the prevention of the diseases and aging the cell lifespan extender, for improvement, the prevention also provides therapeutic or cosmetic method applied to a site containing cells that need improvement.

Cell life extender of the present invention, particularly vascular endothelial cells life extenders, and telomerase activator, can be appropriately determined dose, regimen, dosage form and in accordance with the intended use. For example, dosage forms of cell life extender, especially vascular endothelial cells life extenders, and telomerase activator of the present invention may be administered orally, parenterally, or a topical like. The dosage form, such as tablets, powders, capsules, granules, extracts, oral agents such as syrup or injections, parenteral administration ointment such as drops, or suppositories, creams, milks, lotions , mention may be made of the pack, the external agent such as a bath agent.

The amount of cell life extender, especially vascular endothelial cells life extenders, and Nikkei plant-derived extract activates telomerase in telomerase activator of the present invention can be suitably determined in accordance with the application, the inhibition is generally during agents total amount from 0.0001 to 20.0 mass% as dry matter, preferably 0.0001 to 10.0 mass%.

Furthermore, cell survival extender of the present invention, particularly vascular endothelial cells life extenders, and during telomerase activator, in addition to the Nikkei plant-derived extracts, for example, excipients that are commonly used in foods and medicines moisture-proof agents, preservatives, reinforcing agents, thickeners, emulsifiers, antioxidants, sweeteners, acidulants, seasonings, colorants, flavors and the like, usually used in cosmetics whitening agents, humectants, oil components, UV absorbers, surfactants, thickeners, alcohols, powder components, coloring material, an aqueous component, water, may be blended as needed a variety of skin nutrients and the like.

Furthermore, cell survival extender of the present invention, particularly vascular endothelial cells life extender, and when using a telomerase activator as a skin external preparation, customary auxiliaries skin external agents, such as sodium edetate, edetate trisodium sodium, sodium citrate, sodium polyphosphate, sodium metaphosphate, sequestering agents such as gluconic acid, caffeine, tannin, verapamil, tranexamic acid and its derivatives, licorice extract, glabridin, hot water extract of quince fruit, various crude drugs, tocopherol acetate, glycyrrhizic acid and its derivatives or salts or the like, vitamin C, magnesium ascorbyl phosphate, ascorbic acid glucoside, arbutin, whitening agents such as kojic acid, glucose, fructose, mannose, sucrose, trehalose sugars etc., retinoic acid Retinol, retinol acetate, can also be suitably incorporated, such as vitamin A such as retinol palmitate.

It will now be described in detail by way of examples the invention. The present invention is not limited thereto. The amount is percent by weight.

Example 1: Preparation cinnamon twig hot water extract dry residue Preparation twig (Cinnamomum cassia Blume) 400.7g of water 2L added for 3 hours heating extracted and filtered. The resulting residue, 2L of water was added, repeating the same operation was performed twice more heat extraction. The resulting filtrate was lyophilized to obtain a hot water extract dry residue of 39.7 g.

Keishiekisu HP-20 column processing diamonds hot water extract 10g obtained above ion HP-20 (Mitsubishi Chemical) and eluted with a charge and aqueous ethanol system in the column, for the purpose elution fraction of 50% ethanol eluted fraction Obtained.

Cinnamon bark hot water extract dry residue of preparing cinnamic (Cinnamomum cassia Blume) 20.12g water 200ml was added to perform heating for 3 hours extraction, water 200ml added to the residue obtained by filtration, repeating the same operation, the heating extraction was carried out two more times. The resulting filtrate was lyophilized to obtain a hot water extract dry residue of 1.35 g.

Example 2: telomerase activity Evaluation 1) in culture usual medium of vascular endothelial cells (HUVEC) were cultured HUVEC (Promocell), using cells of P10, EBM supplemented with 2% FBS (R) -2 (Lonza ) cinnamic extract V (lot number: 080919CE, Japan and medium added powdered chemicals Co.) at a final concentration of 0.01%, in two media of control of cinnamic not added, and cultured for 10 days in 6-well plates .

2) In the analysis test for the return and telomerase activity of the cells, was used Quantitative Telomerase Detection Kit (Allied Biotech, Inc).
The 6-well plates were washed twice with PBS, it was added 1 × Lysis Buffer of 200 [mu] l. After standing on ice for 30 min, cells were harvested with a cell scraper. 12,000g (MX-305, TOMY) for 5 minutes, and centrifuged at 4 ° C., to obtain a supernatant 160 [mu] l. And stored at -80 ° C., using these as a sample.

Upon quantifying telomerase activity, 0.1 Control Template TSR at 1 × Lysis Buffer amol / μl, 0.02 amol / μl, 0.004 amol / μl, it was used diluted to 0.0008 amol / μl.
After allowed to 20 minutes telomerase reaction in an incubator at 25 ° C., it was Real-time PCR to detect the telomerase activity in accordance with the protocol (Roche Applied Science LightCycler 480 Instrument, Roche).

The results are shown in Figure 1. HUVEC cultured with cinnamon extract-supplemented medium, as compared to controls incubated with cinnamon extract free medium, it was observed indicating a significant telomerase activity (P <0.05). Accordingly, cinnamon extract activates the telomerase, it can be extended resulting cell lifetime was suggested.

Claims (9)

  1. Consisting Nikkei (Cinnamomum) genus plant-derived extracts, cell survival extender.
  2. Wherein the extract is derived from silicon (Cinnamomum cassia Blume) species plants, cell life extension agent according to claim 1.
  3. Wherein the extract is derived from cinnamon twig (Keishi) or cinnamon (cinnamon), cell life extension agent according to claim 2.
  4. Wherein the extract is a water extract, cell life extension agent according to any one of claims 1-3.
  5. Wherein the cell is a vascular endothelial cell, cell life extender of any one of claims 1-4.
  6. Consisting extracts from Cinnamomum plant telomerase activator.
  7. Wherein the extract is derived from silicate species plant, telomerase activator of claim 6.
  8. Wherein the extract is derived from cinnamon twig or cinnamon bark, telomerase activator of claim 7.
  9. Wherein the extract is a water extract, telomerase activator of any one of claims 6-8.
PCT/JP2011/073548 2010-10-15 2011-10-13 Cellular life span extending agent, and telomerase activator WO2012050162A1 (en)

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
CN104758451A (en) * 2015-04-28 2015-07-08 童长虹 Traditional Chinese medicine composite for treating gout

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JP2005075812A (en) * 2003-09-03 2005-03-24 Shiseido Co Ltd Plasmin-specific activity inhibitor
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JP2007261996A (en) * 2006-03-28 2007-10-11 Naris Cosmetics Co Ltd Acrolein adduct-forming inhibitor, and skin external preparation and food and drink containing the same
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JP2009263358A (en) * 2008-03-31 2009-11-12 Shiseido Co Ltd Maturing, normalizing or stabilizing agent of blood vessel and wrinkle preventing/improving agent
JP2010083787A (en) * 2008-09-30 2010-04-15 Kirin Holdings Co Ltd Cinnamic aldehyde and cassia extract as cb1 receptor antagonist
JP2010518117A (en) * 2007-02-09 2010-05-27 エフエイチジー・コーポレイション・ディ・ビー・エイ・インテグリティ・ニュートラスーティカルズ Methods and materials to reduce or eliminate the risk factors associated syndromes x

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WO2002047699A1 (en) * 2000-12-12 2002-06-20 Kaneka Corporation Compositions for preventing or ameliorating multiple risk factor syndromes
JP2005075812A (en) * 2003-09-03 2005-03-24 Shiseido Co Ltd Plasmin-specific activity inhibitor
JP2006225297A (en) * 2005-02-16 2006-08-31 Fancl Corp Agent for treating/preventing obesity, hyperlipemia and arteriosclerotic disease
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CN104758451A (en) * 2015-04-28 2015-07-08 童长虹 Traditional Chinese medicine composite for treating gout

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