JP2010106001A - Ppar activator - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To find a substance having agonistic activity against a peroxysome proliferator-activated receptor (PPAR) and having excellent safety, to provide a PPAR activator having the substance as an active ingredient, to provide a composition for preventing or ameliorating insulin-resistance syndromes, inflammatory diseases, nerve diseases, biorhythm disorders and to provide a composition effective for skin care. <P>SOLUTION: There is provided the peroxysome proliferator-activated receptor (PPAR) containing as an active ingredient at least one member selected from the group consisting of an extract of sugar beet, an extract of Sasa veitchii, a powder of ginger or an extract thereof, an extract of Allium victorialis subsp. platyphyllum, an extract of peppermint, an extract of jujube (Ziziphus jujuba), an extract of Red currant, an extract of honeyberry (Lonicera caerulea var. emphyllocalyx), an extract of Saffron crocus, an extract of sea buckthorn (Hippophae rhamnoides), an extract of olive, honey, cinnamic acid, a derivative thereof, or a pharmaceutically acceptable salt thereof, and tanshinone, a derivative thereof, or a pharmaceutically acceptable salt thereof. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to an activator for a peroxisome proliferator-activated receptor (PPAR: Peroxisome Proliferator Activated Receptor).

  PPAR is a transcription factor belonging to the nuclear receptor superfamily, and three subtypes of α, β / δ, and γ are known in mammals. PPARγ has two types of isoforms, γ1 and γ2, due to differences in splicing. Each subtype of PPAR forms a heterodimer with a retinoid X receptor (RXR) and induces expression of a target gene having a PPAR response element (PPRE) in the promoter region in a ligand-dependent manner (Non-patent Document 1, 2).

  There is tissue specificity in the expression between PPAR subtypes. PPARα is expressed in the liver, kidney, heart, skeletal muscle and the like, which have a high degree of fatty acid catabolism, and PPARβ / δ is universally expressed in each tissue including skeletal muscle. In addition to adipose tissue, PPARγ1 is expressed in immune system organs, kidneys, pancreas, colon, and the like, and PPARγ2 is strongly expressed in adipose tissue.

  PPARα agonists include fatty acids such as palmitic acid, oleic acid, linoleic acid, and arachidonic acid, and arachidonic acid metabolites such as leukotriene B4. As synthetic compounds, fibrate drugs (bezafibrate, fenofibrate, etc.) and WY14643, which are clinically applied as antihyperlipidemic agents, are known.

  PPARδ agonists include unsaturated fatty acids such as arachidonic acid and eicosapentaenoic acid, and prostacyclin. As synthetic compounds, carbaprostacyclin and GW501516 are known.

  PPARγ agonists include unsaturated fatty acids such as α-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid, and arachidonic acid, and prostaglandin metabolites. As synthetic compounds, thiazolidine derivatives (such as pioglitazone, troglitazone, and rosiglitazone) that are clinically applied as antidiabetic drugs are known.

  Although the functions of the PPARα, δ, and γ subtypes overlap, it has been found that each has a unique function.

  PPARα agonists improve insulin resistance by activating triglyceride breakdown and fatty acid metabolism, reducing blood triglyceride levels and organ triglyceride content. Furthermore, the PPARα agonist suppresses the expression of a constituent protein of low density lipoprotein (LDL) cholesterol and enhances the expression of a constituent protein of HDL (high density lipoprotein), thereby lowering the lipid concentration in blood and increasing high fat. Demonstrate the prevention and treatment of blood pressure.

  PPARα agonists directly interact with NF-kB (nuclear factor-kappa B) and AP-1 (activator protein 1), which are master regulators of inflammation, to suppress transcription of their target genes, or to express IkBα gene Is induced to exert an anti-inflammatory effect by suppressing NF-kB translocation into the nucleus (Non-patent Documents 3 and 4).

  A PPARα agonist has an action of inducing differentiation of epidermal cells and an action of suppressing differentiation of melanocytes, and exerts an effect of giving a transparent feeling to the skin or a whitening effect (Non-patent Documents 5 and 6).

  PPARα promotes the expression of the biological rhythm control gene Bmal1, while the PPARα gene is also a transcriptional target gene by Bmal1 (Non-patent Document 7). Recently, it has been reported that the activity time zone is normalized by feeding a model mouse with sleep phase regression syndrome (DSPS) with an activity of PPARα agonist together with food. Therefore, it has been suggested that PPARα agonists may have preventive and therapeutic effects on biological rhythm disorders such as sleep disorders (Non-patent Document 8).

  A PPARδ agonist has an effect of enhancing the expression of a target gene such as a heat production-related protein (UCP2) in muscle tissue, and also exhibits an anti-obesity effect when a PPARδ agonist is simultaneously fed to a high-fat diet-fed mouse. Therefore, PPARδ agonists are expected to have an improving effect on obesity. In addition, since PPARδ agonists exhibit glucose tolerance and insulin sensitivity in type 2 diabetes model mice, their potential as therapeutic agents for diabetes have been shown (Non-Patent Documents 9 and 10).

  PPARδ suppresses the expression of inflammatory proteins such as human monocyte chemotactic factor (MCP-1), interleukin (IL) -1β, matrix metalloproteinase 9 (MMP-9) at the transcription level in an agonist-dependent manner, It exhibits an anti-inflammatory effect (Non-patent Document 11). In addition, it is estimated that PPARδ agonists have the ability to improve diseases such as atherosclerosis and inflammatory bowel disease (Non-patent Document 12).

  It has been reported that PPARδ agonists have epidermal cell differentiation ability (Non-Patent Document 13), and that PPAR-δ is also involved in wound healing from analysis of PPARδ knockout cells (Non-Patent Document 14). Therefore, the PPARδ agonist may have a whitening effect and a useful effect on rough skin, dermatitis, and wound healing.

  PPARγ agonists promote adipocyte differentiation, thereby inducing apoptosis in large adipocytes that produce factors that induce insulin resistance (such as TNFα) and reducing the number of cells. To compensate for this, differentiation from preadipocytes to small adipocytes is promoted, and production of factors that improve insulin resistance such as adiponectin is increased. PPARγ agonists promote glucose uptake, fat synthesis and accumulation in adipocytes as well as peripheral tissues such as skeletal muscle and liver. Therefore, PPARγ agonists have the effect of preventing and treating insulin resistance diseases such as diabetes and obesity by improving insulin resistance.

  PPARγ agonists have the effect of preventing and treating hyperlipidemia by expressing the effect of reducing blood neutral fat and free fatty acids. Furthermore, PPARγ agonists have preventive and therapeutic effects on hypertension through the production of factors such as endothelin and plasminogen activator inhibitor 1 (PAI-1) involved in maintaining blood pressure.

  PPARγ acts antagonistically with transcription factors NF-kB and AP-1 (Non-patent Document 15), and PPARγ agonists have been shown to be effective in the treatment of allergic inflammation and inflammatory colitis. (Non-Patent Documents 16 and 17). Therefore, PPARγ agonists are expected to have preventive and therapeutic effects on inflammatory diseases.

  PPARγ agonists have been reported to suppress the accumulation of amyloid β, which is a major cause of Alzheimer's disease, in the brain (Non-patent Document 18). In addition, reduction of the infarct site has been confirmed by administering a PPARγ agonist to a cerebral infarction model mouse (Non-patent Document 19). Therefore, PPARγ agonists may have preventive and therapeutic effects on neurological diseases such as Alzheimer's disease and cerebral infarction.

  PPARγ agonists have been reported to have an action of promoting differentiation of epidermal cells and suppressing proliferation (Non-patent Documents 20 and 21). Furthermore, an effect of improving psoriasis, which is a skin disease accompanied by inflammation and immune reaction, has been reported (Non-patent Document 22). Therefore, PPARγ agonists are expected to have preventive and therapeutic effects on skin diseases including psoriasis.

  From the above, PPAR agonists are insulin resistance syndromes such as diabetes, hyperlipidemia and obesity, inflammatory diseases such as inflammatory bowel disease, neurological diseases such as Alzheimer's disease and cerebral infarction, biological rhythm disorder diseases such as sleep disorders Skin care effects such as prevention and improvement action against skin, and prevention and improvement of skin disorders are expected. However, fibrate drugs and thiazolidine drugs that have been confirmed to be effective so far have side effects such as serious liver damage due to long-term ingestion, and they must be used carefully. Moreover, unsaturated fatty acids and polyphenols are known as natural products derived from foods having PPAR agonist activity, but none of them have sufficient activity.

  Accordingly, an object of the present invention is to provide a food-derived natural material that has no problem of side effects even when taken daily and is excellent in safety and has a sufficiently high PPAR agonist activity.

  Sugar beet (scientific name: Beta vulgaris) is a biennial plant belonging to the genus Rhododendron. Also known as sugar beet or sugar radish, the root part becomes the raw material of sugar, and sugar is taken when the root is squeezed and the juice is boiled. The pomace (beet pulp) is also used as livestock feed. On the other hand, the leaves that are not used as a raw material for sugar are squeezed into the field and reused as green manure. The effectiveness of beet saponin contained in sugar beet for the prevention and improvement of hyperlipidemia and ulcer has been disclosed (Patent Document 1). It is also disclosed that beet saponin of sugar beet has a sugar absorption inhibitory effect and is effective in preventing obesity and suppressing hyperglycemia (Patent Document 2). In addition, sugar beet extract or sugar beet-containing pigment components betanin, betanidin, isobetanin and isobetanidin are also disclosed to have an effect of preventing and improving diabetes (Patent Document 2). Further, beet saponin derived from sugar beet has been reported to lower serum and liver cholesterol and triglycerides and to have a hyperlipidemia-improving action (Non-patent Document 23). However, sugar beet leaf extract has PPARα, δ, and γ agonistic effects, and the action of preventing and improving insulin resistance syndrome, inflammatory diseases, neurological diseases, biological rhythm disorders through the activation of PPAR As well as skin care effects are not known.

  Red currant (scientific name: Ribes rubrum) is a plant belonging to the family of currants (Yukinosita), and is also called red currant (red tufted acid mass) and redcurrant (red acid chunk). It has been reported that red currant extract has analgesic action, anti-inflammatory action and hypoglycemic action (Non-patent Document 24). However, it is known that red currant fruit extract has PPARα agonistic action, and prevention, amelioration action and skin care effect of insulin resistance syndrome, inflammatory disease, biological rhythm disorder disease through activation of PPARα. It is not done.

  Hasukap (scientific name: Lonicera caerulea var. Empylocalyx) is a deciduous shrub belonging to the genus Honeysuckle family, and is also referred to as Black-winged Kagura. In fact, it is edible and is rich in vitamin C, anthocyanins, calcium and the like. Hascup (ethanol extract) increases glutathione concentration, an antioxidant in the body, and prevents and treats various organ functions caused by deficiency of glutathione and various diseases (including arteriosclerotic diseases). It is disclosed that it is effective (Patent Document 4). Moreover, it has been disclosed that the Hascup extract has an inhibitory action on cyclooxygenase and inducible nitric oxide synthase, and is effective for prevention, treatment and alleviation of inflammatory diseases (Patent Document 5). Furthermore, it has been disclosed that lotus juice juice has a skin fibroblast activation effect and a whitening effect (Patent Document 6). In addition, it has been disclosed that a lotus fruit extract has an effect of suppressing or improving skin damage caused by UV exposure and can be a skin external preparation useful as a cosmetic or a pharmaceutical (Patent Document 7). However, the ethanol extract of Haskup fruit has PPARα agonistic activity, and the prevention, amelioration action and skin care effect of insulin resistance syndrome, inflammatory disease, biological rhythm disorder disease through activation of PPARα are known. It is not done.

  Kumazasa (scientific name: Sasa veitchii) is a monocotyledonous plant belonging to the genus Sasa genus and is sometimes referred to as cocoon. Kumazasa leaves contain triterpenoids, minerals, vitamins, etc., and are sometimes referred to as herbal medicines called tanchikuyo. Kumazasa (ethanol extract) suppresses the differentiation of preadipocytes, so it can contribute to the suppression and improvement of fat accumulation and obesity, and is effective in the prevention and treatment of cellulitis caused by fat cell hypertrophy. It is disclosed that there is (Patent Document 8). Further, it has been disclosed that Kumazasa extract has a lipolysis promoting action, promotes the degradation of fat accumulated in fat cells, and can contribute to the prevention and suppression of obesity (Patent Document 9). On the other hand, it has been reported that Kumazasa extract has anti-inflammatory action, blood pressure lowering action, diuretic action, antitumor action and the like (Non-patent Document 25). Furthermore, Kumazasa extract has an effect of promoting ceramide synthesis, has an excellent moisturizing effect on the skin, and has an effect of preventing and improving skin diseases such as dryness, dryness, itching, cracks, and redheads of skin. (Patent Document 10). Kumazasa contains a relatively large amount of choline, which is a component of acetylcholine, a neurotransmitter in the brain, and it has been disclosed that Kumazasa extract can be a therapeutic agent for senile dementia and Alzheimer's disease. (Patent Document 11). However, it is not known that Kumazasa leaf extract has a PPARγ agonistic action, and its insulin resistance syndrome, inflammatory disease, neurological disease prevention, ameliorating action, and skin care effect through activation of PPARγ.

  Peppermint (scientific name: Mentha x piperita L.) is a perennial plant belonging to the genus Menta, and is also called Western mint. Menthol is the main component of the refreshing taste and coolness of peppermint. Peppermint extract reduces blood cholesterol and triglycerides and raises HDL, and suppresses LDL oxidation by the antioxidant component, thereby causing hyperlipidemia and arteriosclerosis induced by hyperlipidemia It is disclosed that it is effective in the treatment of (patent document 12). Peppermint extract also activates lipid metabolism in the liver and reduces fat accumulated in the viscera and fat in the liver, thereby reducing various lifestyle-related diseases (diabetes, It has been disclosed that the onset, progression, and exacerbation of lipemia, arteriosclerosis, etc. can be prevented (Patent Document 13). Furthermore, menthol contained in peppermint induces adipocyte differentiation as an adipocyte TRP calcium channel agonist, and diseases caused by abnormal adipocyte differentiation (insulin resistance syndrome, obesity, hyperlipidemia, hypertension) (Patent Document 14). However, it is not known that peppermint leaf extract has a PPARγ agonistic action, and the prevention, ameliorating action, and skin care effect of insulin resistance syndrome, inflammatory disease, neurological disease through activation of PPARγ.

Spearmint (scientific name: Mentha spicata) is a perennial plant belonging to the family Labiatae genus and is also called Dutch mint, green mint (green light load), and green mint. The main scent of spearmint has a refreshing sensation. It is disclosed that the ethanol extract of spearmint has high PPARα ligand activity and is effective in preventing or improving metabolic syndrome related to obesity, insulin resistance, hyperlipidemia, diabetes and the like (Patent Document 15). Further, it is disclosed that the spearmint extract has a PPARβ / δ activity, and that the composition for external use containing this as an active ingredient is effective in preventing and improving rough skin, skin inflammation, and skin barrier function deterioration. (Patent Document 16). However, it is not known that spearmint leaf extract has a PPARγ agonistic action, and prevention, ameliorating action, and skin care effect of insulin resistance syndrome, inflammatory disease, neurological disease through activation of PPARγ .

  Ginger (ginger, ginger, scientific name: Zingiber officinale) is a perennial of the ginger family. Rhizome (enlarged rhizome) is used as a spice and herbal medicine. The stimulant (pungent) component of ginger is mainly gingerol, dehydrogingerone, and the like. Shogaol and gingerone are secondary products generated by heating and alkali treatment. It has been disclosed that ginger extract has an effect of inhibiting pancreatic lipase and is effective in suppressing and preventing obesity (Patent Document 17). Further, it has been disclosed that ginger extract has a glutamate decarboxylase (GAD) activating action, and an anti-obesity and arteriosclerosis preventing action is expected by enhancing production of γ-aminobutyric acid (GABA) by GAD activation ( Patent Document 18). Furthermore, it has been disclosed that gingerol, which is a component of ginger, has the effect of reducing blood glucose and blood lipid levels in type 2 diabetes through enhancement and promotion of adiponectin production by adipocytes (Patent Document 19). On the other hand, gingerol extracted from ginger has an anti-inflammatory action, and it is also disclosed that it has an effect on prevention and treatment of arthritis (Patent Document 20). Further, it is disclosed that gingerol and gingerol contained in the ginger extract have an action of repairing the stratum corneum of the skin and are effective for maintaining healthy skin (Patent Document 21). However, it is not known that ginger extract has a PPARγ agonistic action, and its insulin resistance syndrome, inflammatory disease, neurological disease prevention, ameliorating action, and skin care effect through activation of PPARγ.

  Olive (scientific name: Olea europaea L.) is a plant belonging to the genus Olive family. It is mainly used as olive oil. Olive oil is extracted from fruits and contains more oleic acid than other vegetable oils. Others are rich in linoleic acid, glycerides of palmitic acid, fat-soluble vitamins, including potassium, phosphorus and magnesium. It has been disclosed that vegetable oils such as olive oil and oleic acid and linoleic acid are applied for the treatment and prevention of inflammatory diseases and diabetes (Patent Document 22). On the other hand, the extract of olive leaf is combined with the extract of persimmon leaf and has an inhibitory effect on the increase in blood glucose level and exhibits an inhibitory effect on the onset of diabetes (Patent Document 23). It is also disclosed that it has an action and is effective in the prevention and treatment of arteriosclerosis (Patent Document 24). It has been reported that olive oil acts on monocytes and macrophages to suppress the activity of NF-kB and bring about an anti-inflammatory effect (Non-patent Document 26). However, it is not known that olive oil has a PPARδ agonistic action, and its insulin resistance syndrome, inflammatory disease prevention, ameliorating action, and skin care effect through activation of PPARδ.

  Saji (Sasa thorn, scientific name: Hippophae rhhamnoides L.) is a gummy family plant distributed mainly in the Yellow River basin of China and dry areas of Russia and the Middle East. There are many subspecies, and in addition to saji, there are known sea buckhorn, seabiktha, sandorn, and the like. Sagi fruit is rich in fatty acids such as linoleic acid, linolenic acid and palmitooleic acid, vitamins C, E, A, β-carotene, plant sterols and flavonoids. It has been disclosed that a sagi leaf extract contains a component exhibiting non-enzymatic glycation-inhibiting activity and is effective for the prevention and treatment of diabetes and diabetic complications (Patent Document 25). It has been reported to have an effect of promoting fatty acid β-oxidation and an effect of suppressing pancreatic lipase activity and to suppress body fat accumulation (Non-patent Document 27). In addition, savory flavonoids have an antioxidant action and are effective in the prevention of cardiovascular diseases (Non-patent Document 28), and sagi seed oil reduces serum cholesterol and is effective in preventing arteriosclerosis. (Non-patent Document 29). On the other hand, it has been disclosed that Sagise seed extract has an activity to induce apoptosis of eosinophils and is effective in the prevention and treatment of inflammatory diseases such as allergic rhinitis or atopic bronchial asthma (Patent Document) 26). In addition, a triterpene derivative has been disclosed as a compound having an anti-inflammatory effect derived from Sagi (Patent Document 27). Saji juice oil and seed oil have an effect of preventing skin aging and are disclosed for cosmetics containing the same (Patent Document 28). Moreover, it is disclosed that the polar solvent extract of a sagi fruit has the effect of suppressing or improving the skin disorder resulting from ultraviolet exposure (patent document 29). However, Sagi pulp oil and seed oil have PPARα, δ and γ agonistic effects, and preventive and ameliorating effects of insulin resistance syndrome, inflammatory diseases, neurological diseases, biological rhythm disorders through the activation of PPAR As well as skin care effects are not known.

  Honey (honey) is a natural sweetener that produces honey collected from flowers by bees as a main ingredient and stores it in the nest. In addition to glucose and fructose, it contains various vitamins, minerals, and amino acids (isomaltooligosaccharides). It is disclosed that honey suppresses the production of TNF-α and promotes the prevention and treatment of hypertension and obesity by promoting the production and release of calcitonin gene-related peptide in combination with isoflavone (patent) Reference 30). In addition, it has been reported that honey has the effect of reducing blood sugar levels, blood lipid levels, and C-reactive protein in healthy individuals, obese and hyperlipidemic patients (Non-patent Document 30). Furthermore, honey has an antibacterial action and an antioxidant action, and it has been reported that it is effective for wound healing and anti-inflammatory (Non-patent Documents 31 and 32). However, honey has a PPARα and δ agonistic action. In addition, insulin resistance syndrome, inflammatory disease, biological rhythm disorder disease prevention, ameliorating action and skin care effect through activation of PPAR are not known.

  Saffron (scientific name Crocus sativus L.) is a perennial plant of Iridaceae native to the Mediterranean coast, and is also known as a spice that dries the pistil. In Chinese herbal medicine, it is used as a medicinal herb. The main components include α, β, γ-carotene, pigment glycoside crocin, colorless bitter glycoside picrocrocin, and the like. It is disclosed that saffron has an effect of improving peripheral blood flow and is effective in preventing and treating diabetes related to peripheral circulatory failure (Patent Document 31). In addition, saffron extract has glutamate decarboxylase (GAD) activation action, and the possibility of obesity and arteriosclerosis prevention effect is disclosed by enhancing production of γ-aminobutyric acid (GABA) by GAD activation (patent) Reference 18). Furthermore, it has been reported that the saffron extract has an analgesic action and an anti-inflammatory action (Non-patent Document 33). On the other hand, the saffron pigment crocin has been reported to promote the synthesis of glutathione in neurons and suppress apoptosis by suppressing sphingomyelinase activity (Non-patent Document 34). Has the effect of suppressing the aggregation and accumulation of β-amyloid, and its potential as a preventive and therapeutic agent for neurological diseases such as Alzheimer's disease has been estimated (Non-patent Document 35). However, the saffron extract has PPARδ, γ agonistic action, and the prevention, improvement action and skin care effect of insulin resistance syndrome, inflammatory disease, neurological disease, biological rhythm disorder disease through activation of PPAR are unknown.

  A jujube (salmon, scientific name: Zizihus jujuba) is a deciduous tree in the family of Chrysanthemum. The fruit is dried (dried nails), edible as a confectionery material, and also used as a herbal medicine. A dried herb of the sunflower jujube or its related plants is a herbal medicine called Taiho, and the seed is a soy sauce. It has been disclosed that soy sauce is a combination of an edible pearl layer powder (substantially pure calcium) and an essential amino acid and has an effect of improving insomnia (Patent Document 32). In addition, it has been reported that an extract derived from acid nin acts on the expression of the receptor subunit of γ-aminobutyric acid (GABA) in the central nerve and promotes sleep induction by the anesthetic agent pentobarbital (non-patented). Reference 36). Furthermore, jujube-derived saponin has been reported to suppress glutamate nerve activity in the hippocampus of the brain and to have sedative and hypnotic effects in experiments using mice (Non-patent Documents 37 and 38). On the other hand, experiments using mice showed that oleic acid amide contained in jujube has an action of activating choline acetyltransferase and is effective in preventing amnesia induced by administration of the drug scopolamine. (Non-Patent Document 39). However, the extract of jujube seed has PPARα, δ and γ agonistic effects, and the prevention and improvement of insulin resistance syndrome, inflammatory disease, neurological disease, biological rhythm disorder disease through activation of PPAR, In addition, the skin care effect is not known.

  A garlic garlic (scientific name: Allium victoriais) is a perennial plant belonging to the genus Allium. There are other names such as human viro, chitopiro, humanville, yamavir, garlic or ainu. Like garlic, it is rich in allicin. Allicin has various biological activities, and antibacterial action and antifungal action are known (Non-patent Document 40). In addition, allicin has been reported to decrease serum cholesterol and triglyceride levels, and to reduce atherosclerotic plaque formation and platelet aggregation (Non-patent Documents 41 and 42). Garlic extract containing garlic-derived alliin and one kind of saponin, spirostanol, has been disclosed to have an effect of suppressing an increase in blood glucose level and an effect of improving glucose tolerance, and is expected to be effective in preventing and treating diabetes (patent) Reference 33). Furthermore, S-allylmercaptoglutathione, produced by the reaction of allicin with intracellular glutathione, is found in atherosclerosis, coronary artery disease, thrombosis, high levels of cholesterol and blood lipids, hypertension, weight control, Alzheimer's disease It is disclosed that it is useful for the treatment of glaucoma, cancer and inflammatory diseases (Patent Document 34). However, the extract of garlic garlic has PPARα, δ, and γ agonistic action, and the prevention and improvement of insulin resistance syndrome, inflammatory disease, neurological disease, biological rhythm disorder disease through activation of PPAR, In addition, the skin care effect is not known.

  Cinnamic acid is a compound having a fragrance separated from cinnamon or balsam bark. As its pharmacological action, antioxidant, antitumor, antibacterial action and the like have been reported (Non-patent Document 43, etc.), but no PPAR activation action has been reported.

  Tanshinones are compounds that are included as the main component of herbal danshen. As its pharmacological action, vasodilation, hypotension, sedation, analgesia, antibacterial action and the like have been reported (Non-Patent Document 44, etc.), but no PPAR activation action has been reported.

Japanese Patent Publication No. 5-7399 JP-A-8-40912 JP 2005-336069 A JP 2006-348053 A JP 2006-83149 A Japanese Patent Laid-Open No. 2002-20258 JP 2005-306850 A JP 2004-75640 A JP 2006-45120 A JP-A-11-199501 JP-A-10-276719 JP 11-246426 A JP 2006-36788 A JP 2006-199647 A JP 2007-22917 A JP 2007-119432 A JP 2002-275007 A JP 2003-206225 A JP 2006-45210 A JP 2007-210993A Japanese Patent Laid-Open No. 6-239736 Japanese National Patent Publication No. 9-502196 JP 2003-128571 A JP 2004-352626 A JP 2004-217544 A Special table 2007-526260 JP 2007-51101 A JP 63-145210 A JP 2006-188488 A JP 2007-291014 A Japanese Patent Laid-Open No. 10-287576 JP 2000-354470 A JP 2005-89419 A Special table 2003-514830 gazette Willson-TM. et al. , J .; Med. Chem. 43, p. 527-550, 2000 Lehrke-M. & Lazar-MA, Cell, Vol. 123, p. 993-999, 2005 Steels B.M. et al. , Nature, 399, p. 790-793, 1998 Deliverive P.M. et al. , J .; Biol. Chem. 275, p. 36703-36707, 2000 Hanley K. et al. , J .; Invest Dermatol. 110, p. 368-375, 1998 Di-Poi N. et al. Lipids, Vol. 39, p. 1093-1099, 2004 Canale L. et al. Mol. Endocrinol. , Volume 20, p. 1715-1727, 2006 Shirai H. et al. , Biochem Biophys Res Commun. 357, p. 679-82, 2007 Steels B.M. et al. Diabetes. 54, p. 2460-2470, 2005 Tanaka T. et al. , Proc. Natl. Acad. USA. 100, p. 15924-15929, 2003 Lee CH. et al. Science, 302, p. 453-457, 2003 Graham TL. et al. , Atherosclerosis. 181, p. 29-37, 2005 Schmuth M.M. et al. , J .; Invest Dermatol. 122, p. 971-983, 2004 Tan NS. et al. Mol. Cell. Biol. 27, p. 7161-7175, 2007 Ricote M.M. et al. , Nature, Vol. 391, p. 79-82, 1998 Woerly G. et al. , J .; Exp. Med. 198, p. 411-421, 2003 Su CG. et al. , J .; Clin Invest. 104, p. 383-389, 1999 Camacho IE. et al. , J .; Neurosci. 24, p. 10908-10917, 2004 Zhao Y. et al. , FASEB J. et al. , Volume 20, p. 1162-1175, 2006 Mao-Qiang M.M. et al. , J .; Invest. Dermatol. 123, p. 305-312, 2004 Bhagavathula N, J. et al. Invest. Dermatol. 122, p. 130-139, 2004 Elis CN. et al. , Arch. Dermatol. 136, p. 609-616, 2000 Yumiko Tani Bulletin of Nagoya Women's University, Volume 53, p. 59-66, 2007 Ojewole JAO, J.A. Ethnopharmacol. 113, p. 338-345, 2007 Showa Medical Society Journal, Volume 48 (No. 5), p. 596-600, 1998 Brunelleschi S. et al. et al. , Pharmacol Res. 56, p. 542-549, 2007 Nishi Shigenori, Journal of Japan Society for Food Science and Technology, Volume 54 (No. 11), p. 477-481, 2007 Suumela JP. et al. , J .; Agric. Food Chem, Vol. 54, p. 7364-7369, 2006 Basu M. et al. et al. , Pytomedicine, Vol. 14, p. 770-777, 2007 AI-Waile N.I. , J .; Med. Food, Volume 7, p. 100-107, 2004 Lusby PE. et al. , Archives of Medical Research, Vol. 36, p. 464-467, 2005 Henrikes A. et al. , J .; Antimicrob. Chemother. 58, p. 773-777, 2006 Hosseinadeh H.M. & Younesi HM, BMC Pharmacology, Volume 2, p. 1-8, 2002 Ochiai T. et al. Biochimica et Biophysica Acta, 1770, p. 578-584, 2007 Papadreou MA. et al. J Agric Food Chem. 54, p. 8762-8768, 2006 Yuan MA. et al. Biol. Pharm. Bull. 30, p. 1748-1753, 2007 Zhang M.M. et al. , Planta Med. 69, p. 692-695, 2003 Jiang JG. et al. Nat Prod Res. 21, p. 310-320, 2007 Heo HJ. et al. Biosci. Biotechnol. Biochem. 67, p. 1284-1291, Ankri S. et al. , Antimicrob. Agents Chemother. 41, p. 2286-2288, 1997 Kannar D. et al. , J .; Am. Coll. Nutr. , Volume 20, p. 225-231, 2001 Kojuri J. et al. et al. Lipids in Health and Disease, Vol. 6, p. 1-5, 2007 Cos P.M. et al. , J .; Pharm. Pharmacol. 55, p. 1291-1297, 2003 Ji X. et al. , Life Sci. 73, p. 1413-1426, 2003

  An object of the present invention is to provide a PPAR activator containing the substance as an active ingredient for the purpose of finding a substance having agonist activity against PPAR and having excellent safety. Furthermore, an object of the present invention is to provide a composition effective for the prevention, improvement, or skin care of insulin resistance syndrome and inflammatory diseases, neurological diseases, biological rhythm disorder diseases containing the substance.

  As a result of earnest search for PPAR agonists from natural materials derived from various foods, the present inventors have made various extractions from sugar beet, kumazasa, ginger, garlic garlic, peppermint, spearmint, jujube, red currant, lotus cup, saffron, sagi and olive. , Dried ginger powder, honey, cinnamic acid and tanshinone showed PPAR activating action, and based on these findings, further research was conducted and this research was completed.

That is, the present invention relates to the following inventions.
[1] Sugar beet extract, kumazasa extract, ginger powder and its extract, garlic garlic extract, peppermint extract, jujube extract, red currant extract, lotus cup extract, saffron extract From the group consisting of an extract, an extract of sazy, an extract of olive, honey, cinnamic acid and its derivatives and their pharmaceutically acceptable salts, and tanshinone and its derivatives and their pharmaceutically acceptable salts A PPAR activator comprising at least one selected as an active ingredient.
[2] The activator according to [1], which is used for prevention or amelioration of insulin resistance syndrome and / or inflammatory disease.
[3] The activity according to [2], wherein the insulin resistance syndrome has at least one symptom selected from diabetes, hyperinsulinemia, dyslipidemia, hypertension, obesity, and arteriosclerosis. Agent.
[4] The activator according to [2], wherein the inflammatory disease is at least one disease selected from colitis, pancreatitis, allergic bronchial asthma and dermatitis.
[5] The activator according to the above [1] or [2], which is for rough skin or whitening skin care.
[6] The activator according to any one of [1] to [5], wherein the PPAR is at least one of PPARα, δ, and γ.
[7] At least one selected from the group consisting of sugar beet extract, garlic garlic extract, jujube extract, red currant extract, lotus cup extract, sassy extract, and honey as an active ingredient A PPARα activator comprising:
[8] At least one selected from the group consisting of sugar beet extract, garlic garlic extract, jujube extract, saffron extract, sagi extract, olive extract, and honey as an active ingredient A PPARδ activator characterized by containing.
[9] Sugar beet extract, kumazasa extract, ginger powder and extract, garlic extract, peppermint extract, spearmint extract, jujube extract, saffron extract and sassy extract Cinnamic acid and its derivatives and pharmaceutically acceptable salts thereof, and at least one selected from the group consisting of tanshinone and its derivatives and pharmaceutically acceptable salts as an active ingredient PPARγ activator characterized.
[10] The activator according to [9] above, which is used for prevention or improvement of at least one disease selected from cerebral infarction, Alzheimer's disease and neurological disease.
[11] The activator according to [7], which is used for prevention or improvement of a biological rhythm disorder disease.
[12] The activator according to any one of [1] to [11], wherein the extract is obtained by squeezing or solvent extraction.
[13] The activator according to [12], wherein the solvent is water and / or ethyl alcohol.
[14] A composition for preventing or improving insulin resistance syndrome, comprising the activator according to any one of [1] to [13].
[15] A composition for preventing or ameliorating an inflammatory disease, comprising the activator according to any one of [1] to [13].
[16] A skin care composition containing the activator according to any one of [1] to [13].
[17] A composition for preventing or ameliorating a neurological disease comprising the activator according to [9] or [10].
[18] A composition for preventing or ameliorating a biological rhythm disorder disease comprising the activator according to [7] or [11].
[19] The composition according to any one of [14] to [18], which is for food and drink.
[20] The composition according to any one of [14] to [18], wherein the composition is for pharmaceutical use.
[21] The composition according to any one of [14] to [18], which is for non-human animals.

The present invention further relates to the following.
[22] sugar beet extract, kumazasa extract, ginger powder and extract, garlic extract, peppermint extract, spearmint extract, jujube extract to produce PPAR activator, At least one selected from the group consisting of saffron and saffron extracts, cinnamic acid and its derivatives and pharmaceutically acceptable salts thereof, and tanshinone and its derivatives and pharmaceutically acceptable salts thereof Use of seeds,
[23] Sugar beet extract, kumazasa extract, ginger powder and extract, garlic garlic extract, peppermint extract, spearmint extract, jujube extract, saffron extract and sassy extract Cinnamic acid and derivatives thereof and pharmaceutically acceptable salts thereof, and at least one selected from the group consisting of tanshinone and derivatives thereof and pharmaceutically acceptable salts thereof to an individual (such as a patient) A method for preventing or ameliorating at least one symptom or disease selected from insulin resistance syndrome, inflammatory disease, cerebral infarction, Alzheimer's disease, neurological disease and biological rhythm disorder disease, comprising a step of administering.

  According to the present invention, a food-derived PPAR activator and a composition containing it as an active ingredient are provided. The activator or composition of the present invention is useful in the prevention and amelioration of insulin resistance syndrome, inflammatory diseases, neurological diseases, biological rhythm disorder diseases, or skin care. Furthermore, since the composition of the present invention is a food-derived natural material, it is expected to have high safety, avoid serious side effects seen in synthetic pharmaceuticals, and allow long-term ingestion.

Since the activator or composition of the present invention can prevent or ameliorate insulin resistance syndrome, for example, diabetes (particularly non-insulin dependent diabetes or type II diabetes), hyperinsulinemia, dyslipidemia disease In addition, symptoms such as obesity (particularly visceral fat obesity), hypertension, arteriosclerosis, pathological conditions or diseases can be prevented or ameliorated.
Furthermore, since the activator or composition of the present invention can prevent or ameliorate insulin resistance syndrome, for example, visceral fat obesity can be treated with two or more of hyperglycemia (diabetes), hypertension and hyperlipidemia. Lifestyle-related diseases such as metabolic syndrome can also be prevented or ameliorated.

  Embodiments of the present invention will be described in detail below.

  In the PPAR activation in the present invention, PPAR transcriptional activity is activated by binding of a ligand (agonist) to the PPAR ligand binding region linked to the Gal4 DNA binding region, and the target reporter gene is activated via the DNA binding region. Including enhanced expression. PPAR activation can be assessed as the ratio of agonist strength to control PPAR activation strength.

  The PPAR activator according to the present invention has the ability to bind to the PPAR ligand binding region and exert the PPAR transcription ability, that is, the PPAR activation ability.

  The PPAR activator according to the present invention only needs to have an activation ability for at least one PPAR subtype of PPARα, δ, and γ.

Sugar beet extract, Kumazasa extract, dried ginger powder or extract thereof, garlic extract, peppermint extract, spearmint extract, jujube extract used in the PPAR activator of the present invention , Red currant extract, lotus cup extract, saffron extract, sagi extract or olive extract plant can be a whole or part of a plant (eg whole grass, leaves, roots, rhizomes, Stems, root barks, fruits, seeds or flowers) can be used as is or dried, depending on the plant, sugar beet leaves or roots, kumazasa leaves, ginger rhizomes, garlic garlic whole plants, Peppermint leaves, spearmint leaves, jujube seeds, red currant fruit, lotus cup fruit, saffron pistil, saji fruit or seed Bed It is preferable to use fruits. The powder can be produced using a known method such as a pulverizer.

  A plant extract can be obtained by squeezing a plant or extracting it with a solvent. Extraction conditions are not particularly limited, and can be carried out under conditions generally used for plant extraction.

  As a method of squeezing, for example, a screw type, gear type, cutter type or other squeezing machine or juicer, or a method of solid-liquid separation by stirring squeezing or centrifuging is used in combination of one or more. A method is mentioned. The juice can be subjected to operations such as deodorization and purification within a range not losing the PPAR activation effect. The squeezed liquid can be used as it is or after being concentrated, dried, or diluted with an appropriate solvent or carrier.

  Examples of the solvent used for the solvent extraction include water (for example, tap water, distilled water, purified water, cold water, hot water, hot water, etc., preferably hot water), or an organic solvent. Examples of the organic solvent include alcohol (eg, methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, butyl alcohol), methyl acetate, ethyl acetate, propyl acetate, butyl acetate, acetone, methyl isobutyl ketone, petroleum ether. , Cyclohexane, carbon tetrachloride, toluene, benzene, dichloromethane, chloroform, ether, pyridine, polyethylene glycol, propylene glycol, butylene glycol, or acetonitrile. These organic solvents can be used alone or in appropriate combination, mixed at a fixed ratio, and further used in an anhydrous or hydrous state. Preferably, ethyl alcohol-water mixed solvent, ethyl alcohol, ether, chloroform, benzene, acetone, hot petroleum ether or the like is desirable. Extraction may be performed under heating. Prior to solvent extraction, the ground plant may be dissolved or suspended in water, and then water-eluted fractions such as sugar may be removed by elution. Alternatively, after solvent extraction, the solvent extract may be concentrated and dissolved or suspended in water, and then the water-eluted fraction may be removed. The extract after solvent extraction can be used as it is, but may be used after removing the solvent. The removal of the solvent can be carried out by a known method such as concentration by heating, concentration under reduced pressure, lyophilization and the like. Further, these extracts can be subjected to operations such as deodorization and purification within a range not losing the PPAR activation effect. The extract from which the solvent has been removed can be used as it is or after being diluted with an appropriate solvent or carrier.

  Plant extracts include olive oil, surge pulp oil and surge seed oil.

  The honey used in the present invention is a natural sweet substance produced by, for example, a bee, from a plant nectar, a secretion from a plant living tissue, or a substance discharged by an insect sucking a plant juice on the plant living tissue. If it is, it will not be specifically limited but can be used. Honey includes flower honey (Blossom Honey) or nectar honey (Nectal Honey) derived from plant nectar, or dew honey (Honeydew Honey) derived from secretions from plant tissue.

Cinnamic acid has the following formula:
(C ₉ H ₈ O ₂ = 148.16). Cinnamic acid derivatives include cinnamic acid esters or ethers, and specific examples include methoxycinnamic acid, trans-cinnamic acid, methyl cinnamic acid, and ethyl cinnamic acid.

Tanshinone is a phenanthraquinone compound, and typical compounds include the following formula:
Tanshinone IIA (C ₁₉ H ₁₈ O ₃ = 294.3) represented by the following formula:

And cryptotanshinone represented by (C ₁₉ H ₂₀ O ₃ = 296.36).

  These pharmaceutically acceptable salts include inorganic acid addition salts (for example, hydrochloride, hydrobromide, sulfate, phosphate, etc.), organic carboxylic acid / sulfonic acid addition salts (for example, formate, Acetate, trifluoroacetate, maleate, tartrate, fumarate, citrate, lactate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.) or sodium, potassium, magnesium And metal salts such as calcium.

  Examples of the insulin resistance syndrome include symptoms, diseases or pathologies caused by a decrease in the function of insulin in tissues and cells. Insulin resistance syndrome includes, for example, diabetes, obesity, hyperinsulinemia, dyslipidemia, hypertension, arteriosclerosis and the like. Preferred examples of diabetes include insulin resistant diabetes and type II diabetes. Diabetes also includes impaired glucose tolerance. Examples of obesity include visceral fat type obesity and subcutaneous fat type obesity, and visceral fat type obesity is preferable. Examples of dyslipidemia diseases include hyperlipidemia, hypercholesterolemia, high LDL cholesterolemia, low LDL cholesterolemia, and high triglycerideemia. Examples of insulin resistance syndrome include lifestyle-related diseases such as metabolic syndrome in which visceral fat obesity is combined with two or more of hyperglycemia (diabetes), hypertension, and hyperlipidemia (dyslipidemia). Is also included.

Inflammatory diseases include inflammatory diseases caused by PPAR activity being suppressed or reduced. Specific examples of the inflammatory disease include colitis, pancreatitis, allergic bronchial asthma and dermatitis.
In the present invention, “disease” includes symptoms or pathological conditions.
Examples of neurological diseases include cerebrovascular disorder diseases such as cerebral infarction, which can be prevented or improved by PPARγ agonists, and neurodegenerative diseases such as Alzheimer's disease.

  An “agonist” is an agonist that generally acts on a receptor molecule in a living body and exhibits a function similar to that of a neurotransmitter, a hormone, etc., but binds to the receptor and has the same intracellular information transmission system as that of a substance in the living body. Including substances that actuate

  PPARγ agonists include sugar beet extract, kumazasa extract, ginger powder or extract thereof, garlic extract, peppermint extract, spearmint extract, jujube extract, saffron extract, saji Extract, cinnamic acid or tanshinone. Preferably, sugar beet leaf or root extract, Kumazasa leaf extract, ginger rhizome extract, garlic whole plant extract, peppermint leaf extract, spearmint leaf extract, jujube Seed extract, saffron pistil extract, sagi fruit or seed powder or extract.

  Examples of biological rhythm disorders include symptoms caused by circadian rhythm disturbances that can be prevented and improved by PPARα agonists. Examples of such symptoms include sleep disorder, jet lag, headache and judgment, and reduced concentration. Specific examples of biological rhythm disorders include insomnia.

  PPARα agonists include, for example, sugar beet extract, gourd garlic extract, jujube extract, red currant extract, lotus cup extract, sassy extract, honey, cinnamic acid or tanshinone. Preferably, sugar beet leaf or root extract, garlic whole plant extract, jujube seed extract, red currant fruit extract, lotus cup fruit extract, sassy fruit or seed extract Thing or honey.

  Examples of PPARδ agonists include sugar beet extract, garlic extract, jujube extract, saffron extract, sagi extract, olive extract or honey. Preferred are beet leaf or root extract, whole garlic extract, jujube seed extract, saffron pistil extract, sassy fruit or seed extract or honey.

  Examples of skin care include a whitening effect whose effectiveness is recognized by a PPAR agonist, and prevention and improvement effects of rough skin and dermatitis.

  The present invention includes sugar beet extract, kumazasa extract, ginger powder or extract thereof, garlic extract, peppermint extract, spearmint extract, jujube extract, red currant extract, lotus cup Extract, saffron extract, saffron extract, olive extract, honey, cinnamic acid or tanshinone as an active ingredient, insulin resistance syndrome, inflammatory Provided is a composition for preventing or improving diseases, neurological diseases, biological rhythm disorder diseases, or a composition effective for skin care. The composition of the present invention includes, for example, food and drink, medicine or animal. The composition is a “therapeutic agent”, “prophylactic agent”, “therapeutic agent”, “prophylactic agent”, “medicine”, “pharmaceutical composition”, “edible composition”, “beverage”, “food” or It can also be written as “feed”.

  The composition effective for the prevention or amelioration of insulin resistance syndrome, inflammatory disease, neurological disease, biological rhythm disorder disease or skin care of the present invention is a composition containing a PPAR agonist, and is an extract of sugar beet. , Kumazasa extract, ginger powder or extract thereof, garlic garlic extract, peppermint extract, spearmint extract, jujube extract, red currant extract, lotus cup extract, saffron extract Product, sassy extract, olive extract, honey, cinnamic acid or tanshinone as an active ingredient, and its form is not limited. Foods, nutritional functional foods) and health foods, etc., pharmaceuticals, quasi drugs and the like.

  One embodiment of the activator or composition of the present invention is for non-human animals, for example, for domestic animals or pets such as pets. It can also be used as feed and pet food for livestock and pets.

The necessary amount (effective amount) of the activator or composition of the present invention is administered to animals including humans within the safe dosage range. The dosage of the drug of the present invention can be determined as appropriate based on the judgment of a doctor or veterinarian in consideration of the type of dosage form, administration method, patient age and weight, patient symptoms, etc. .
Note that “prevention” or “improvement” in the present invention is not limited to the case of having a complete prevention effect or improvement effect, and may be a case of having a partial effect.

  The activator or composition of the present invention may be mixed with physiologically acceptable carriers, excipients, diluents and the like and administered orally or parenterally as a pharmaceutical or food-drinking composition. it can. As oral preparations, dosage forms such as granules, powders, tablets, capsules, solvents, emulsions or suspensions can be used. As the parenteral agent, a dosage form such as an injection, an infusion, an external medicine, or a suppository can be selected. Examples of the injection include subcutaneous injection, intramuscular injection, intravenous injection, arterial injection, intraperitoneal injection and the like. Examples of the medicine for external use include a nasal administration agent and an ointment. A known formulation technique can be used for the above dosage form.

  For example, a tablet for oral administration can be produced by adding an excipient, a disintegrant, a binder, a lubricant, and the like, and mixing and compression-molding. Examples of the excipient include lactose, starch, and mannitol. Examples of the disintegrant include calcium carbonate and carboxymethyl cellulose calcium. Examples of the binder include gum arabic, carboxymethyl cellulose, and polyvinyl pyrrolidone. Examples of the lubricant include talc and magnesium stearate.

  The activator or composition of the present invention can be appropriately blended in various foods and beverages such as beverages, snacks, dairy products, seasonings, processed starch products, processed meat products, Beverages are preferred.

  Examples of the beverage include tea-based beverages, soft drinks, fruit beverages, vegetable beverages, sparkling beverages, milk beverages, lactic acid bacteria beverages, and alcoholic beverages.

  Examples of the food and drink of the present invention include liquid, solid, and powdered beverages, seasonings and spices, and cooked processed foods. Health foods, functional foods, foods for specified health use Including nutritional supplements. The food and drink of the present invention preferably has an effect of preventing or improving the above-mentioned various diseases, symptoms or pathological conditions.

  The present invention also provides a method for preventing or ameliorating the various diseases described above, comprising the step of administering the activator or composition of the present invention to an individual (for example, a patient).

  The individual that is the target of the prevention or amelioration method of the present invention is not particularly limited as long as it is an organism that can develop the above-mentioned various diseases, but is preferably a human.

  Administration to an individual can be generally performed by methods known to those skilled in the art, such as oral administration, intraarterial injection, intravenous injection, and subcutaneous injection. The dose varies depending on the weight and age of the patient, the administration method, etc. For example, from the range of about 0.1 to 2000 mg / kg body weight per day for an adult, if it is a person skilled in the art (doctor, veterinarian, pharmacist, etc.) An appropriate dose can be selected as appropriate.

EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated further more concretely, this invention is not limited to these Examples. In the examples, the abbreviations mean:
PPAR: peroxisome proliferator-activated receptor
DMEM: Dulbecco's modified Eagle's Medium
FBS: Fetal Bovine Serum
CMV: cytomegalovirus
DMSO: dimethyl sulfoxide DNA: deoxyribonucleic acid
% Indicates mass% unless otherwise specified.

  A water-soluble extract of sugar beet leaves was prepared as follows. 10 g (10 g) of water was added to 2 g of dried sugar beet leaf pulverized and boiled, and this was solid-liquid separated by centrifugation to remove fine particles, and the filtrate was filtered with a membrane filter (Millipore, 0 .22 μm). The solution thus obtained was 1.5 mL (1.5 g), and the yield by water extraction was calculated as 12.5% according to the following formula 1.

Formula 1

  Yield of extract (%) = 100 × mass of extract of the present invention (g) ÷ mass of raw material before extraction (g)

  The beet leaf ethanol extract was prepared as follows. 5 g of ethanol was added to 2 g of dried beet leaf pulverized product, shaken at room temperature for 3 hours, solid-liquid separated by centrifugation, and the filtrate was filtered with a membrane filter (manufactured by Millipore, Inc. 22 μm). Of the resulting solution, 1 mL corresponding to 0.4 g of the mass of the raw material before extraction was dried under reduced pressure. The dried product was 40 mg, and the yield by ethanol extraction was calculated to be 10% according to Formula 1.

  The chopped sugar beet roots were allowed to stand in 70 ° C. water for 6 hours to extract sugar, and then the solid was dried into powder. To 2 g of powder, 5 mL of ethanol was added and shaken at room temperature for 3 hours. This was subjected to solid-liquid separation by centrifugation, and the filtrate was passed through a membrane filter (Millipore, 0.22 μm) to remove fine particles. Of the resulting solution, 1 mL corresponding to 0.4 g of the mass of the raw material before extraction was dried under reduced pressure. The dried product was 24 mg, and the yield by ethanol extraction was calculated to be 6% according to Formula 1.

  Red currant juice squeezed 0.7 g of fruit to obtain 0.3 mL of liquid. The yield was calculated as 43% according to Equation 1.

  After squeezing and stirring 67 g of fruit, the lotus juice was solid-liquid separated by centrifugation to obtain 40 mL of liquid. The yield was calculated as 60% according to Equation 1.

  The water-soluble extract of Kumazasa leaves was prepared as follows. After adding 12 mL (12 g) of water to 2 g of pulverized leaves and boiling, this was solid-liquid separated by centrifugation to remove fine particles, and the filtrate was applied to a membrane filter (Millipore, 0.22 μm). I passed. The solution thus obtained was 3 mL, and the yield by water extraction was calculated as 21% according to Equation 1.

  An ethanol extract of Kumazasa leaves was prepared as follows. 5 g of ethanol was added to 1 g of crushed dried Kumazasa leaves, shaken at room temperature for 3 hours, and then solid-liquid separated by centrifugation to remove fine particles. The filtrate was membrane filter (Millipore, 0.22 μm) Passed through. Of the resulting solution, 1 mL corresponding to 0.2 g of the raw material before extraction was dried under reduced pressure. The dried product was 7.5 mg, and the yield by ethanol extraction was calculated to be 3.8% according to the formula 1.

  Saffron used the dried powder of the saffron pistil marketed as a spice (made by S & B). A water-soluble extract of saffron was prepared as follows. 3 mL (3 g) of boiling water was added to 150 mg of saffron and allowed to stand for 30 minutes. This was subjected to solid-liquid separation by centrifugation, and the filtrate was passed through a membrane filter (Millipore, 0.22 μm) in order to remove fine particles. The solution thus obtained was 2.2 mL, and the yield by water extraction was calculated as 70% according to Equation 1.

  An ethanol extract of saffron was prepared as follows. To 150 mg of saffron, 2 mL of ethanol was added and shaken at room temperature for 3 hours. This was subjected to solid-liquid separation by centrifugation, and the filtrate was passed through a membrane filter (Millipore, 0.22 μm) to remove fine particles. Of the solution thus obtained, 0.3 mL corresponding to 22.5 mg of the raw material before extraction was dried under reduced pressure. The dried product was 5.0 mg, and the yield by ethanol extraction was calculated to be 22% according to Formula 1.

  A water-soluble extract of jujube seeds was prepared as follows. 10 mL (10 g) of water was added to 1 g of dried jujube seed pulverized product and boiled. This was solid-liquid separated by centrifugation (15,000 rpm) to remove fine particles. The product was passed through Milipore (0.22 μm). The solution thus obtained was 5 mL (5 g), and the yield by water extraction was calculated to be 45.5% according to Formula 1.

  An ethanol extract of jujube seeds was prepared as follows. To 1 g of dried jujube seed pulverized product, 4 mL of ethanol was added, shaken at room temperature for 3 hours, solid-liquid separated by centrifugation (15,000 rpm), and the filtrate was removed with a membrane filter (Milipore). And 0.22 μm). Of the resulting solution, 1 mL corresponding to 0.25 g of the raw material before extraction was dried under reduced pressure. The dried product was 29 mg, and the yield by ethanol extraction was calculated to be 11.6% according to Formula 1.

  A water-soluble extract of garlic garlic was prepared as follows. 10 mL (10 g) of water was added to 0.5 g of dried garlic pulverized product, boiled, and then solid-liquid separated by centrifugation (15,000 rpm) to remove fine particles. (Milipore, 0.22 μm). The solution thus obtained was 2.5 mL (2.5 g), and the yield by water extraction was calculated as 28.8% according to Formula 1.

  An ethanol extract of garlic garlic was prepared as follows. To 0.5 g of dried garlic pulverized product, 3 mL of ethanol was added, shaken at room temperature for 3 hours, solid-liquid separated by centrifugation (15,000 rpm), and the filtrate was removed with a membrane filter (to remove fine particles). The product was passed through Milipore (0.22 μm). Of the resulting solution, 1.5 mL corresponding to 0.25 g of the raw material before extraction was dried under reduced pressure. The dried product was 27 mg, and the yield by ethanol extraction was calculated to be 10.8% according to Formula 1.

  Spearmint leaf ethanol extract was prepared as follows. To 2.5 g of dried spearmint leaf crushed material, add 10 mL of ethanol, shake at room temperature for 3 hours, and then perform solid-liquid separation by centrifugation (15,000 rpm) to remove fine particles. (Milipore, 0.22 μm). Of the resulting solution, 5 mL corresponding to 1.25 g of the raw material before extraction was dried under reduced pressure. The dried product was 60 mg, and the yield by ethanol extraction was calculated to be 4.8% according to Formula 1.

  An ethanol extract of peppermint leaves was prepared as follows. To 2.5 g of dried peppermint leaf pulverized product, add 10 mL of ethanol, shake at room temperature for 3 hours, and then perform solid-liquid separation by centrifugation (15,000 rpm) to remove fine particles. (Milipore, 0.22 μm). Of the resulting solution, 5 mL corresponding to 1.25 g of the raw material before extraction was dried under reduced pressure. The dried product was 45 mg, and the yield by ethanol extraction was calculated to be 3.6% according to Formula 1.

PPARα activation test:
PPARα activity was examined using as an index PPARα-dependent gene transcription activity (luciferase activity). That is, the monkey-derived CV-1 cell line was seeded in a 6-well plate so as to be 2 × 10 ⁵ cells / well and cultured in DMEM (including 10% FBS) for 1 day. A reporter plasmid containing a Gal4 DNA binding domain (Gal4-DBD) and a PPARα ligand binding domain (PPARα-LBD) chimeric protein expression plasmid (pGal4DBD / PPARαLBD), a Gal4 response element (SEQ ID NO: 1 CGGAGGACAGTACTCCCG) and a firefly luciferase gene (PG5-Luc) and a control plasmid (pGL4.75hRluc-CMV; manufactured by Promega) linked with a CMV promoter upstream of the Renilla luciferase gene were simultaneously transferred to 1 μg, 0.9 μg, and 0.1 μg / well, respectively. A plasmid was introduced into the cultured cells by addition with a reaction reagent (FuGENE HD; manufactured by Roche). Thereafter, the transformed cells were peeled off with trypsin, the cells were washed with PBS, and seeded again in a 96-well plate to 1.6 × 10 ⁴ cells / well. At this time, the culture solution was replaced with a DMEM medium containing a test substance, and further cultured for 48 hours. After washing the cells with PBS, firefly luciferase and Renilla luciferase activities were measured using a dual luciferase assay system (Promega). That is, cells were lysed with a cell lysate, a substrate solution containing luciferin was added, and the amounts of firefly and Renilla luciferase luminescence were measured with a luminometer. In addition, the transcriptional activity (luciferase activity) of a PPARα-dependent gene was defined as follows.

  PPARα-dependent gene transcriptional activity (luciferase activity) = (firefly luciferase activity by pG5-Luc) / (renilla luciferase activity by hRluc-CMV)

Using the PPARα activation test described above, the luciferase activity of the test substance was measured.
The following [1] to [23] were used as test substances.

[1] Sugar beet leaf water extract: The water-soluble extract (solution) of sugar beet leaves obtained in Example 1 was used.
[2] Sugar beet leaf ethanol extract: The beet leaf ethanol extract (dried product) obtained in Example 2 was prepared in DMSO to a concentration of 500 mg / mL and used.
[3] Sugar beet root ethanol extract: The sugar beet root ethanol extract obtained in Example 3 was prepared and used at a concentration of 100 mg / mL in DMSO.
[4] Red currant pulp: The red currant juice prepared in Example 4 was used.
[5] Hascup pulp: The Hascup fruit juice prepared in Example 4 was used.
[6] Kumazasa leaf water extract: The water-soluble extract (solution) of Kumazasa obtained in Example 6 was used.
[7] Kumazasa leaf ethanol extract: The Kumazasa ethanol extract (dried product) obtained in Example 7 was prepared in DMSO to a concentration of 50 mg / mL and used.
[8] Saffron water extract: The water-soluble extract (solution) of saffron obtained in Example 8 was used.
[9] Saffron ethanol extract: The saffron ethanol extract (dried product) obtained in Example 9 was prepared in DMSO to a concentration of 100 mg / mL and used.
[10] Jujube seed water extract: The water-soluble extract (solution) of jujube seed obtained in Example 10 was used.
[11] Jujube seed ethanol extract: The jujube seed ethanol extract (dried product) obtained in Example 11 was prepared in DMSO to a concentration of 150 mg / mL and used.
[12] Carrot garlic water extract: The water-soluble extract (solution) of carrot garlic obtained in Example 12 was used.
[13] Carrot garlic ethanol extract: The ethanol extract (dry solid) of the carrot garlic obtained in Example 13 was prepared and used at a concentration of 100 mg / mL in DMSO.
[14] Spearmint leaf ethanol extract: The spearmint leaf ethanol extract (dried product) obtained in Example 14 was prepared in DMSO to a concentration of 200 mg / mL and used.
[15] Olive oil: A commercially available olive oil (manufactured by Nisshin Oillio Group Co., Ltd.) was diluted with DMSO to 1: 1 (V / V) and used.
[16] Honey: Commercially available honey (manufactured by Shijishi Japan Co., Ltd.) was diluted 1: 1 (V / V) with sterilized water.
[17] Ginger powder: Ginger dry powder commercially available as a spice (manufactured by Gaban Co., Ltd.) was dissolved in DMSO to give a concentration of 100 mg / mL.
[18] Sagi pulp oil (1): Obtained from China. Sagi pulp oil made from Mongolian Sagi was used as a 1: 1 (V / V) dilution with DMSO.
[19] Sagi pulp oil (2): Sagi pulp oil made from Chinese sagi obtained from China was diluted 1: 1 (V / V) with DMSO and used.
[20] Sagi seed oil (1): Sagi seed oil obtained from China was diluted 1: 1 (V / V) with DMSO.
[21] Sagi seed oil (2) :: Sagi seed oil obtained from China was diluted 1: 1 (V / V) with DMSO and used.
[22] Sagi pulp (1): Sagi juice obtained from China was used as a stock solution.
[23] Saji pulp (2): Saji juice obtained from China

  0.33% DMSO was added as a control (negative control), and WY14643 (manufactured by Tocris Bioscience) was added as 100 μM as a positive control (positive control).

  The results are shown in Table 1. PPARα agonistic activity was confirmed in sugar beet, garlic, jujube, red currant, lotus cup, various extracts of sassy, and honey.

PPARδ activation test:
The PPARδ activity was examined using the PPARδ-dependent gene transcription activity (luciferase activity) as an index. That is, in the method described in Example 1, the same procedure as in Example 1 was performed except that pGal4DBD / PPARδLBD was used instead of pGal4DBD / PPARαLBD. PGal4DBD / PPARδLBD is a chimeric protein expression plasmid of Gal4 DNA binding domain (Gal4-DBD) and PPARδ ligand binding domain (PPARδ-LBD).

  The luciferase activity of the test substance was measured using the PPARδ activation test described above. The test substance prepared in Example 16 was used as the test substance. A group to which 0.33% DMSO was added as a control (negative control) and a group to which GW501516 (manufactured by ALEXIS Biochemicals) was added to 1 μM were prepared as a positive control (positive control).

  As a result of the search, as shown in Table 2, agonistic activities of PPARδ were confirmed in sugar beet, garlic garlic, spearmint, jujube, saffron, and sagi extracts, and olive oil and honey.

PPARγ activation test:
The PPARγ activity was examined using the PPARγ-dependent gene transcription activity (luciferase activity) as an index. That is, in the method described in Example 1, the same procedure as in Example 1 was performed except that pGal4DBD / PPARγLBD was used instead of pGal4DBD / PPARαLBD. PGal4DBD / PPARγLBD is a chimeric protein expression plasmid of Gal4 DNA binding domain (Gal4-DBD) and PPARγ ligand binding domain (PPARγ-LBD).

  Using the PPARγ activation test described above, the luciferase activity of the test substance was measured. The test substance was prepared by dissolving the test substance, peppermint, cinnamic acid (manufactured by Wako Pure Chemical Industries, Ltd.), Tanshinone IIA (manufactured by Funakoshi Co., Ltd.) and cryptotanshinone (manufactured by Funakoshi Co., Ltd.) in DMSO. Used. A group to which 0.33% DMSO was added as a control (negative control) and a group to which pioglitazone (Pioglitazone; manufactured by Alexis Biochemical) was added to 10 μM were prepared as a positive control (positive control).

  As a result of the search, as shown in Table 3, the agonist activity of PPARγ was confirmed in various extracts of sugar beet, kumazasa, ginger, garlic garlic, peppermint, spearmint, jujube, saffron, sagi, cinnamic acid, tanshinone IIA and cryptotanshinone It was done.

  Since the activator or composition according to the present invention has PPAR agonist activity, it is effective in the prevention and improvement of insulin resistance syndrome, inflammatory diseases, neurological diseases, biological rhythm disorder diseases, or skin care. Furthermore, since the composition of the present invention is a food-derived natural material, it is expected to have high safety, avoid serious side effects seen in synthetic pharmaceuticals, and allow long-term ingestion.

Since the activator or composition of the present invention can prevent or ameliorate insulin resistance syndrome, for example, diabetes (particularly non-insulin dependent diabetes or type II diabetes), hyperinsulinemia, dyslipidemia disease In addition, symptoms such as obesity (particularly visceral fat obesity), hypertension, arteriosclerosis, pathological conditions or diseases can be prevented or ameliorated.
Furthermore, since the activator or composition of the present invention can prevent or ameliorate insulin resistance syndrome, for example, visceral fat obesity can be treated with two or more of hyperglycemia (diabetes), hypertension and hyperlipidemia. Lifestyle-related diseases such as metabolic syndrome can also be prevented or ameliorated.

Claims (21)

  Sugar beet extract, Kumazasa extract, ginger powder and its extract, garlic garlic extract, peppermint extract, jujube extract, red currant extract, lotus cup extract, saffron extract, Sagi extract, olive extract, honey, cinnamic acid and derivatives thereof and pharmaceutically acceptable salts thereof, and tanshinone and derivatives thereof and pharmaceutically acceptable salts thereof A peroxisome proliferator-activated receptor (PPAR) activator comprising at least one active ingredient.   The activator according to claim 1, which is used for prevention or amelioration of insulin resistance syndrome and / or inflammatory disease.   The activator according to claim 2, wherein the insulin resistance syndrome has at least one symptom selected from diabetes, hyperinsulinemia, dyslipidemia, hypertension, obesity and arteriosclerosis.   The activator according to claim 2, wherein the inflammatory disease is at least one disease selected from colitis, pancreatitis, allergic bronchial asthma and dermatitis.   The activator according to claim 1 or 2, which is used for rough skin or whitening skin care.   The activator according to any one of claims 1 to 5, wherein PPAR is at least one of PPARα, δ, and γ.   Contains at least one selected from the group consisting of sugar beet extract, garlic extract, jujube extract, red currant extract, lotus cup extract, sassy extract, and honey as an active ingredient A PPARα activator characterized by the above.   Contains at least one selected from the group consisting of sugar beet extract, garlic extract, jujube extract, saffron extract, sagi extract, olive extract, and honey as an active ingredient A PPARδ activator characterized by that.   Sugar beet extract, Kumazasa extract, ginger powder and extract, garlic garlic extract, peppermint extract, spearmint extract, jujube extract, saffron extract and sagi extract, cinnamic acid And a derivative thereof and a pharmaceutically acceptable salt thereof, and at least one selected from the group consisting of tanshinone and a derivative thereof and a pharmaceutically acceptable salt thereof as an active ingredient PPARγ activator.   The activator according to claim 9, which is used for prevention or amelioration of at least one disease selected from cerebral infarction, Alzheimer's disease and neurological disease.   The activator according to claim 7, which is used for prevention or improvement of a biological rhythm disorder disease.   The activator according to any one of claims 1 to 11, wherein the extract is obtained by squeezing or solvent extraction.   The activator according to claim 12, wherein the solvent is water and / or ethyl alcohol.   A composition for preventing or ameliorating insulin resistance syndrome, comprising the activator according to any one of claims 1 to 13.   The composition for prevention or improvement of the inflammatory disease containing the activator of any one of Claims 1-13.   The composition for skin care containing the activator of any one of Claims 1-13.   A composition for preventing or ameliorating a neurological disease, comprising the activator according to claim 9 or 10.   A composition for preventing or ameliorating a biological rhythm disorder disease comprising the activator according to claim 7 or 11.   The composition according to claim 14, wherein the composition is for eating and drinking.   The composition according to any one of claims 14 to 18, which is used for medicine.   The composition according to any one of claims 14 to 18, which is used for non-human animals.