Agent for inhibiting an increase in oxidized LDL and food composition for inhibiting an increase in oxidized LDL

Abstract

To provide a novel drug capable of suppressing an increment of an oxidative LDL that is known to promote an onset and development of arterial sclerosis and to suppress an increment of oxidative LDL is effective in treatment or prevention of the arterial sclerosis.SOLUTION: The present invention provides an oxidative LDL increment inhibitor and a food composition for suppressing an oxidative LDL increment, containing arctigenin and / or arctiin as active ingredients. The present invention also provides an FIB-4 index increment inhibitors and FIB-4 index increment-suppressing food compositions containing arctigenin and / or arctiin as active ingredients.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to an agent for suppressing an increase in oxidized LDL and a food composition for suppressing an increase in oxidized LDL. [Background technology]

[0002] Oxidized LDL is known to play an important role in the development and progression of arteriosclerosis. Oxidized LDL is taken up by macrophages in the vascular wall, forming foam cells and promoting the progression of plaque. Oxidized LDL also promotes vascular endothelial dysfunction, migration of vascular smooth muscle cells and macrophages, and production of inflammatory cytokines, exacerbating vascular disorders. In addition, oxidized LDL itself enhances oxidative stress in cells that compose the vascular wall, forming a vicious cycle that leads to further production of oxidized LDL.

[0003] In recent years, advances in measurement methods have made it possible to measure oxidized LDL in the blood, and many findings have been revealed about its use as a biomarker for arteriosclerosis. Many studies have been conducted on the relationship between oxidized LDL in the blood and obesity, and it has been suggested that oxidative stress accompanying obesity and an increase in adipose tissue affects the production of oxidized LDL in the blood (Non-Patent Document 1). It has also been shown that insulin resistance correlates with the level of oxidized LDL in the blood, independent of the degree of obesity (Non-Patent Document 2). It has also been reported that the level of oxidized LDL in the blood is a predictor of the future onset of metabolic syndrome (Non-Patent Document 3).

[0004] As an oxidized LDL inhibitor, Patent Document 1 discloses an oxidized LDL inhibitor containing Del-1 (Developmental endothelial locus-1) protein as an active ingredient.

[0005] In addition, the FIB-4 index is known as an index of liver fibrosis. The FIB-4 index is an index calculated from age, AST, ALT, and platelet count. The specific calculation formula is as follows: FIB-4 index = (age (years) × AST (IU / L)) / (platelet count (10 9 / L)×√ALT(IU / L)) In general, if the FIB-4 index is 1.3 or less, the risk of progression of fibrosis due to liver disease is diagnosed as low. If the FIB-4 index is an intermediate value between 1.3 and 2.67, the possibility of progression of fibrosis is suggested, and if it is a high value of 2.67 or more, the possibility of progression of fibrosis to a state close to cirrhosis is suggested.

[0006] It has been known that platelets decrease due to liver dysfunction and liver fibrosis. This is known to be caused by a decrease in the production of thrombopoietin, a protein essential for platelet production, and increased destruction of red blood cells and platelets in the spleen due to increased splenic function associated with decreased blood flow to the liver (Non-Patent Documents 4 and 5). In recent years, it has been revealed that platelets have a variety of functions, including not only physiological coagulation and hemostatic functions, but also tissue repair and angiogenesis (Non-Patent Documents 6 and 7). [Prior art documents] [Patent documents]

[0007] [Patent Document 1] International Publication No. 2013 / 118839 [Non-patent literature]

[0008] [Non-Patent Document 1] Yasushi Ishigaki, “Special feature: Elucidation of the molecular mechanism of diabetic vascular disease onset and the possibility of its treatment, 4. The importance of oxidized LDL in the blood in the onset and progression of arteriosclerosis”, Diabetes, Vol. 53(4), 2010, p.231-233 [Non-Patent Document 2] Park K, Gross M, Lee DH, Holvoet P, Himes JH, Shikany JM, Jacobs DR Jr, “Oxidative stress and insulin resistance: the coronary artery risk development in young adults study.”, 2009, Diabetes Care, Vol. 32, p.1302-1307 [Non-Patent Document 3] Holvoet P, Lee DH, Steffes M, Gross M, Jacobs DR Jr., “Association between circulating oxidized low density lipoprotein and incidence of the metabolic syndrome.”, 2008, JAMA, Vol. 299, p.2287-2293 [Non-Patent Document 4] Afdhal N, McHutchison J, Brown R, et al, “Thrombocytopenia associated with chronic liver disease.”, 2008, J Hepatol 48, p.1000-1007 [Non-Patent Document 5] Aster RH, “Pooling of platelets in the spleen:role in the pathogenesis of "hypersplenic" thrombocytopenia.", 1966, J Clin Invest 45, p. 645-657 [Non-Patent Document 6] Iannacone M, Sitia G, Isogawa M, et al, “Platelets mediate cytotoxic T lymphocyte-induced liver damage.”, 2005, Nat Med, Vol. 11, p.1167-1169 [Non-Patent Document 7] Lesurtel M, Graf R, Aleil B, et al, “Platelet-derived serotonin mediates liver regeneration.”, 2006, Science, Vol. 312, p.104-107 [Non-Patent Document 8] Furukawa S, Fujita T, Shimabukuro M, et al. “Increased oxidative stress in obesity and its impact on metabolic syndrome.” 2004, J Clin Invest, Vol. 114, p.1752-1761 [Non-Patent Document 9] Takayoshi Suganami, Yoshihiro Ogawa, "Special Feature: Obesity: Advances in Diagnosis and Treatment 2. Obesity and Inflammation", Journal of the Japanese Society of Internal Medicine, Vol. 100, No. 4, 2011 [Non-Patent Document 10] Takayoshi Suganami, Kanami Tanimoto-Koyama, Junko Nishida, Michiko Itoh, Xunmei Yuan, Shinji Mizuarai, Hidehito Kotani, Shoji Yamaoka, Kensuke Miyake, Seiichiro Aoe, Yasutomi Kamei, and Yoshihiro Ogawa, “Role of the Toll-like Receptor 4 / NF-κB Pathway in Saturated Fatty Acid-Induced Inflammatory Changes in the Interaction Between Adipocytes and Macrophages”, 2007, Arterioscler Thromb Vasc Biol, Vol.27, p.84-91 [Non-Patent Document 11] Shah AG, Lydecker A, Murray K, Tetri BN, Contos MJ, Sanyal AJ, “Nash Clinical Research Network. Comparison of noninvasive markers of fibrosis in patients with nonalcoholic fatty liver disease.”, 2009, Clin Gastroenterol Hepatol, Vol.7, p.1104-1112 Summary of the Invention [Problem to be solved by the invention]

[0009] As described above, it is known that oxidized LDL promotes the onset and progression of arteriosclerosis, and inhibiting an increase in oxidized LDL is effective in treating, ameliorating, or preventing arteriosclerosis.

[0010] Therefore, an object of the present invention is to provide a novel drug capable of suppressing an increase in oxidized LDL. [Means for solving the problem]

[0011] The present inventors conducted extensive research to solve the above problems and found that administration of burdock sprout extract to subjects (healthy individuals) for 12 weeks significantly suppressed the increase in oxidized LDL. Furthermore, the present inventors found that administration of burdock sprout extract reduced the FIB-4 index, which is an index of liver fibrosis. In addition, a decrease in platelet count was confirmed in the high oxidized LDL group, and it was found that burdock sprout extract suppresses the decrease in platelet count. The present inventors confirmed that arctigenin and / or arctiin are the active ingredients of burdock sprout extract through component analysis.

[0012] The present invention provides a food composition for suppressing an increase in oxidized LDL, which contains arctigenin and / or arctiin as active ingredients.

[0013] The present invention also provides a food composition for suppressing an increase in oxidized LDL, which contains arctigenin and / or arctiin as burdock, burdock fruit, burdock sprouts, or forsythia, or extracts thereof.

[0014] The present invention also relates to a BMI of 25 kg / m 2 The present invention provides a food composition for suppressing an increase in oxidized LDL for the above subjects.

[0015] The present invention also provides a food composition for suppressing an increase in the FIB-4 index, which contains arctigenin and / or arctiin as active ingredients.

[0016] The present invention also provides a food composition for suppressing an increase in the FIB-4 index, which contains arctigenin and / or arctiin as burdock, burdock fruit, burdock sprouts, or forsythia, or extracts thereof.

[0017] The present invention also provides an agent for suppressing an increase in oxidized LDL, comprising arctigenin and / or arctiin as active ingredients.

[0018] The present invention also provides an agent for suppressing an increase in oxidized LDL, comprising arctigenin and / or arctiin from burdock, burdock fruit, burdock sprout, or forsythia, or an extract thereof.

[0019] The present invention also relates to a BMI of 25 kg / m 2 The present invention provides an agent for suppressing an increase in oxidized LDL for the above subjects.

[0020] The present invention also provides an agent for suppressing an increase in FIB-4 index, comprising arctigenin and / or arctiin as active ingredients.

[0021] The present invention also provides an FIB-4 index increase inhibitor, which contains arctigenin and / or arctiin in the form of burdock, burdock fruit, burdock sprout, or forsythia, or an extract thereof.

[0022] The present invention also provides an agent for suppressing a decrease in platelet count, comprising arctigenin and / or arctiin as active ingredients.

[0023] The present invention also provides the above-mentioned agent for suppressing a decrease in platelet count, which contains arctigenin and / or arctiin in the form of burdock, burdock fruit, burdock sprout, or forsythia, or an extract thereof. Effect of the Invention

[0024] According to the present invention, an increase in oxidized LDL can be suppressed. Furthermore, according to the present invention, an increase in FIB-4 index can be suppressed. Furthermore, according to the present invention, a decrease in platelet count can be suppressed. Therefore, according to the present invention, it is expected that the onset and progression of arteriosclerosis caused by oxidized LDL and liver fibrosis can be suppressed. [Brief description of the drawings]

[0025] [Figure 1] Graph showing change in oxidized LDL in those with BMI of 25 kg / m2 or higher. [Diagram 2] Graph showing the change in FIB-4 index. [Diagram 3] Graph showing the change in platelet count (PLT). [Figure 4] Graph showing the correlation between the change in FIB-4 index (Δ12w) and oxidized LDL (initial value). [Diagram 5] Graph showing the correlation between the change in FIB-4 index (Δ12w) and visceral fat area (initial value). [Figure 6] Graph showing the correlation between the change in platelet count (PLT) (Δ8w) and oxidized LDL (initial value). [Figure 7] Graph showing the correlation between the change in platelet count (PLT) (Δ12w) and oxidized LDL (initial value). [Figure 8] FIG. 1 shows the correlation between the change in platelet count (PLT) (Δ8w) and the platelet count (initial value). [Figure 9] FIG. 1 shows the correlation between the change in platelet count (PLT) (Δ12w) and the platelet count (initial value). [Figure 10] FIG. 1 shows the correlation between RBC change (Δ12w) and RBC. [Figure 11] A graph showing the correlation between RBC change (Δ12w) and platelet count (PLT) change (Δ12w). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] The present invention provides an agent for suppressing an increase in oxidized LDL, which contains arctigenin and / or arctiin as active ingredients.

[0027] Oxidized LDL is low-density lipoprotein (LDL) that has been oxidized. The amount of oxidized LDL in the blood increases due to the accumulation of visceral fat, high blood pressure, increased oxidative stress, smoking, and dietary intake. Oxidized LDL is taken up by macrophages in the blood vessel walls and becomes a substance called plaque, which accumulates in the blood vessel walls and causes arteriosclerosis.

[0028] In this specification, "suppressing the increase of oxidized LDL" means to significantly suppress the increase of oxidized LDL in blood compared to the group that does not take arctigenin and / or arctiin.For example, "suppressing the increase of oxidized LDL" means that the change in oxidized LDL between before and after a certain period of administration is significantly smaller compared to the group that does not take it.In addition, in this specification, "suppressing the increase of oxidized LDL" includes reducing oxidized LDL and suppressing the production of oxidized LDL.

[0029] The oxidized LDL increase inhibitor of the present invention has a BMI of 25 kg / m 2The above subjects may be included in the study. BMI (Body Mass Index) is calculated by dividing [body weight (kg)] by [height (m)]. 2 The oxidized LDL increase inhibitor of the present invention is also, but is not particularly limited to, an index of obesity calculated from the BMI of 25 kg / m 2 More than 30 kg / m 2 The target audience may be persons under 18 years of age.

[0030] The present invention also provides an agent for suppressing an increase in FIB-4 index, comprising arctigenin and / or arctiin as active ingredients.

[0031] The FIB-4 index is an index of liver fibrosis and is calculated using the following formula: FIB-4 index = (age (years) × AST (IU / L)) / (platelet count (10 9 / L)×√ALT(IU / L)) In this specification, "suppressing the increase in FIB-4 index" means significantly suppressing the increase in FIB-4 index compared to a group that does not take arctigenin and / or arctiin. For example, "suppressing the increase in FIB-4 index" means that the change in FIB-4 index between before the start of administration and after a certain period of administration is significantly smaller compared to a group that does not take the administration. In addition, in this specification, "suppressing the increase in FIB-4 index" includes decreasing the FIB-4 index.

[0032] The present invention also provides an agent for suppressing a decrease in platelet count, comprising arctigenin and / or arctiin as active ingredients.

[0033] In this specification, "suppressing the decrease in platelet count" means significantly suppressing the decrease in platelet count compared to a group that does not take arctigenin and / or arctiin. For example, "suppressing the decrease in platelet count" means that the change in platelet count before the start of administration and after a certain period of administration is significantly greater than that of a group that does not take the drug. In addition, in this specification, "suppressing the decrease in platelet count" includes increasing the platelet count. The platelet count decrease inhibitor of the present invention can regulate hematopoietic function by suppressing the decrease in platelet count, and can also be called a hematopoietic function regulator.

[0034] Arctigenin and arctiin are one of the diphenylpropanoids (lignans) contained in plants such as burdock. Arctiin is a precursor of arctigenin, and is known to be metabolized in vivo to become arctigenin. Arctigenin and / or arctiin may be chemically synthesized arctigenin and / or arctiin, or may be isolated from a plant. In addition, arctigenin and / or arctiin may be a plant itself containing arctigenin and / or arctiin, or an extract of this plant. Plants containing arctigenin and / or arctiin include, for example, burdock (sprouts, leaves, rhizomes, burdock fruit), forsythia japonica (flowers, leaves, fruits, rhizomes), forsythia suavea (flowers, leaves, fruits, rhizomes), forsythia suavea (flowers, leaves, fruits, rhizomes), forsythia chinensis (flowers, leaves, fruits, rhizomes), safflower, cornflower, thistle, santoriso (syringa thistle), and cal These include Don, Gorotsuki thistle, Anisuru koyana, Sesame, Maple bindweed, Polygala gracilis, Korean vine, Trachelospermum gracilis, Munin vine, Scutellaria baicalensis, Tokyo oleander, Ketia japonica, Polygonum umbellata, Polygonum serrata, Japanese knotweed, Yamazakura, Arabidopsis thaliana, Amaranth, Walnut, Oat, Spelta, Soft wheat, Mexican cypress, and Japanese nut. Among them, Burdock (especially Burdock and Burdock sprouts) and Forsythia suspensa (especially leaves) are preferred because of their high content of arctigenin and / or arctiin. When using the plant itself, it can be used raw or dried and chopped, or dried and powdered.

[0035] For example, the inhibitor of an increase in oxidized LDL, an inhibitor of an increase in FIB-4 index, and an inhibitor of a decrease in platelet count of the present invention may contain arctigenin and / or arctiin in the form of burdock, burdock fruit, burdock sprout, or forsythia, or an extract thereof.

[0036] The plant extract used in the present invention may be extracted, for example, from a plant in two steps: an enzymatic conversion step and an organic solvent extraction step.

[0037] The enzymatic conversion process is a process of enzymatically converting arctiin contained in the plant to arctigenin by β-glucosidase, an enzyme endogenous to the plant. Specifically, the plant is dried, cut, and kept at an appropriate temperature to allow the endogenous β-glucosidase to act, and the reaction from arctiin to arctigenin proceeds. For example, the plant can be kept at an arbitrary temperature by adding any solution such as water to the cut plant and stirring at a temperature of around 30°C (20 to 50°C).

[0038] The organic solvent extraction process is a process of extracting an extract containing arctigenin and arctiin from a plant using any suitable organic solvent. That is, it is a process of extracting an extract from a plant by adding a suitable solvent in a state where arctigenin is highly contained by the above-mentioned enzymatic conversion process. For example, a suitable solvent is added to a plant, and the extract is extracted by heating and stirring for a suitable time. In addition to heating and stirring, the extract can be extracted by any extraction method known to those skilled in the art, such as heating and stirring under reflux, drip extraction, immersion extraction or pressure extraction.

[0039] Arctigenin is poorly soluble in water, so the yield of arctigenin can be improved by adding an organic solvent. Any organic solvent can be used. For example, alcohols such as methanol, ethanol, and propanol, as well as acetone can be used. Considering safety, it is preferable to use 30% ethanol as the organic solvent. By distilling off the solvent from the extract, a paste-like concentrate can be obtained, and by further drying this concentrate, a dry product can be obtained.

[0040] The oxidized LDL increase inhibitor, FIB-4 index increase inhibitor and platelet count decrease inhibitor of the present invention can be in any form of preparation. The oxidized LDL increase inhibitor, FIB-4 index increase inhibitor and platelet count decrease inhibitor can be in the form of tablets such as sugar-coated tablets, buccal tablets, coated tablets and chewable tablets, lozenges, pills, powders, capsules including hard capsules and soft capsules, granules, and liquids such as suspensions, emulsions, syrups and elixirs, as oral preparations.

[0041] In addition, the oxidized LDL increase inhibitor, FIB-4 index increase inhibitor, and platelet count decrease inhibitor of the present invention can be parenteral administration preparations such as intravenous injection, subcutaneous injection, intraperitoneal injection, intramuscular injection, transdermal administration, nasal administration, pulmonary administration, enteral administration, oral administration, and transmucosal administration. The oxidized LDL increase inhibitor, FIB-4 index increase inhibitor, and platelet count decrease inhibitor of the present invention can be, for example, an injection, a transdermal absorption tape, an aerosol, and a suppository.

[0042] In addition, the oxidized LDL increase inhibitor, FIB-4 index increase inhibitor, and platelet count decrease inhibitor of the present invention can be provided as an external preparation. The external preparation of the present invention can be a medicine, a cosmetic, etc. The external preparation of the present invention can be an external preparation for application to the skin, scalp, hair, mucous membrane, nails, etc. The external preparation includes, for example, a cream, an ointment, a liquid, a gel, a lotion, an emulsion, an aerosol, a stick, a sheet mask, a solid, a foam, an oil, and a tick; a patch such as a cataplasm, a plaster, a tape, and a patch; and a spray.

[0043] Furthermore, the oxidized LDL increase inhibitor, FIB-4 index increase inhibitor, and platelet count decrease inhibitor of the present invention may be in a form suitable for consumption, for example, a solid, liquid, granular, particulate, powder, capsule, cream, paste, etc.

[0044] The present invention also provides a composition for suppressing an increase in oxidized LDL, which contains arctigenin and / or arctiin as active ingredients.

[0045] The composition for suppressing an increase in oxidized LDL of the present invention can be a composition for use in medicines, cosmetics, foods, etc. The composition for suppressing an increase in oxidized LDL of the present invention can be a composition for use in medicines, cosmetics, foods, etc. 2 The composition for suppressing an increase in oxidized LDL of the present invention may further include any ingredient that is generally used in medicines, cosmetics, and foods. For example, the composition for suppressing an increase in oxidized LDL of the present invention may further include a pharma- ceutically acceptable base, carrier, excipient, binder, disintegrant, lubricant, colorant, etc.

[0046] The present invention also provides a composition for suppressing an increase in FIB-4 index, which contains arctigenin and / or arctiin as an active ingredient. The present invention also provides a composition for suppressing a decrease in platelet count, which contains arctigenin and / or arctiin as an active ingredient. The composition for suppressing an increase in FIB-4 index and the composition for suppressing a decrease in platelet count of the present invention can be a composition for use in medicines, cosmetics, foods, etc. The composition for suppressing an increase in FIB-4 index and the composition for suppressing a decrease in platelet count of the present invention can further contain any ingredient that is commonly used in medicines, cosmetics, and foods. For example, the composition for suppressing an increase in FIB-4 index and the composition for suppressing a decrease in platelet count of the present invention may further contain a pharma- ceutically acceptable base, carrier, excipient, binder, disintegrant, lubricant, colorant, etc.

[0047] Examples of carriers and excipients used in the compositions of the present invention include lactose, glucose, sucrose, mannitol, dextrin, gum arabic, potato starch, corn starch, calcium carbonate, calcium phosphate, calcium sulfate, and crystalline cellulose.

[0048] Examples of binders include starch, gelatin, syrup, tragacanth, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, carboxymethyl cellulose, and the like.

[0049] Examples of disintegrants include starch, agar, powdered gelatin, crystalline cellulose, calcium carbonate, sodium bicarbonate, sodium alginate, sodium carboxymethylcellulose, and calcium carboxymethylcellulose.

[0050] Examples of the lubricant include magnesium stearate, hydrogenated vegetable oil, talc, macrogol, etc. As the colorant, any colorant permitted to be added to pharmaceuticals, cosmetics, and foods can be used.

[0051] The compositions of the present invention may also be coated, if desired, with one or more layers of sucrose, gelatin, purified shellac, gelatin, glycerin, sorbitol, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, methyl methacrylate, methacrylic acid polymers, and the like.

[0052] Furthermore, the composition of the present invention may contain, as necessary, pH adjusting agents, buffering agents, stabilizers, preservatives, antiseptics, diluents, coating agents, sweeteners, flavorings, solubilizing agents, and the like.

[0053] In the present specification, the term "food composition" includes not only general foods and beverages, but also foods for the sick, health foods, functional foods, foods for specified health uses, nutritional supplements, and supplements. General foods and beverages include, for example, various beverages, various foods, processed foods, liquid foods (such as soups), seasonings, nutritional drinks, and confectioneries. In the present specification, the term "processed food" refers to natural foodstuffs (such as animals and plants) that have been processed and / or cooked, and includes, for example, processed meat products, processed vegetable products, processed fruit products, frozen foods, retort foods, canned foods, bottled foods, and instant foods. The food composition of the present invention may be a food labeled to suppress an increase in oxidized LDL, to suppress an increase in FIB-4 index, or to suppress a decrease in platelet count. The food composition of the present invention may also be provided in a form sealed in a bag, container, or the like. The bag and container used in the present invention may be any bag and container that is usually used for food.

[0054] The food compositions of the present invention may contain, in combination with active ingredients, carotenoids such as beta-carotene and astaxanthin, vitamin E, resveratrol, luteolin, apigenin, acteoside and anthocyanins.

[0055] The present invention also provides a medicine for suppressing an increase in oxidized LDL, comprising the above-mentioned agent for suppressing an increase in oxidized LDL.

[0056] The present invention also provides a pharmaceutical agent for suppressing an increase in an FIB-4 index, comprising the above-mentioned agent for suppressing an increase in an FIB-4 index.

[0057] The present invention also provides a pharmaceutical agent for suppressing a decrease in platelet count, comprising the above-mentioned agent for suppressing a decrease in platelet count.

[0058] The present invention can be a pharmaceutical or food composition for treating, improving and / or preventing coronary artery disease (ischemic heart disease, angina pectoris, myocardial infarction, etc.), cerebrovascular disease (cerebral hemorrhage and cerebral infarction), venous disease (thrombophlebitis, varicose veins of the lower extremities, superior vena cava syndrome, etc.), endothelial dysfunction, vasodilation disorder, arteriosclerosis, aortic aneurysm, Takayasu's arteritis, Raynaud's disease, and poor circulation, etc., through the inhibition of an increase in oxidized LDL.

[0059] The present invention can be a pharmaceutical or food composition for treating, improving and / or preventing diseases that affect hepatic blood flow (Budd-Chiari syndrome, heart failure, portal vein thrombosis and hepatic veno-occlusive disease), iron overload syndrome, hepatitis B, hepatitis C, hepatic fibrosis, non-alcoholic steatohepatitis, liver cirrhosis, liver cancer, portal hypertension, alcoholic hepatitis, and autoimmune diseases (autoimmune hepatitis, primary biliary cholangitis and primary sclerosing cholangitis), etc., through suppression of an increase in the FIB-4 index.

[0060] The present invention can be a pharmaceutical or food composition for treating, ameliorating and / or preventing thrombocytopenia, purpura, essential thrombocythemia, idiopathic thrombocytopenic purpura, autoimmune thrombocytopenic, thrombotic thrombocytopenic purpura, viral infection, liver cirrhosis, myelofibrosis, hemolytic uremic syndrome, Gaucher disease, heparin-dependent thrombocytopenia, systemic lupus erythematosus, drug-induced bone marrow suppression and post-transfusion purpura through suppression of a decrease in platelet count.

[0061] The content of arctigenin and / or arctiin in the oxidized LDL increase inhibitor and composition for inhibiting oxidized LDL increase of the present invention may be an amount that can inhibit the increase of oxidized LDL in blood in a subject, and can be appropriately set according to the subject, purpose, and administration method (ingestion method).For example, when orally ingested by a human, it is preferable to contain arctigenin so that the daily intake is 10 to 2000 mg.In addition, for example, when orally ingested by a human, it is preferable to contain arctiin so that the daily intake is 10 to 2000 mg.

[0062] The content of arctigenin and / or arctiin in the FIB-4 index increase inhibitor and composition for suppressing FIB-4 index increase of the present invention may be an amount capable of suppressing the increase of FIB-4 index, and may be appropriately set according to the subject, purpose, and administration method (ingestion method) to be applied. For example, when orally ingested by humans, it is preferable to contain arctigenin so that the daily intake is 10 to 2000 mg.

[0063] The content of arctigenin and / or arctiin in the platelet count decrease inhibitor and composition for suppressing platelet count decrease of the present invention may be an amount that can suppress the decrease in platelet count in a subject, and can be appropriately set according to the subject, purpose, and administration method (ingestion method) to be applied. For example, when orally ingested by humans, it is preferable to contain arctigenin so that the daily intake is 10 to 2000 mg.

[0064] The present invention also provides a method for suppressing the increase of oxidized LDL in a subject, comprising administering arctigenin and / or arctiin to the subject.In the method of the present invention, arctigenin and / or arctiin can be administered in the form of the above-mentioned agent or composition.

[0065] The present invention also provides a method for suppressing the increase of FIB-4 index, comprising administering arctigenin and / or arctiin to a subject.In the method of the present invention, arctigenin and / or arctiin can be administered in the form of the above-mentioned agent or composition.

[0066] The present invention also provides a method for suppressing the decrease in platelet count, comprising administering arctigenin and / or arctiin to a subject.In the method of the present invention, arctigenin and / or arctiin can be administered in the form of the above-mentioned agent or composition.

[0067] In the method of the present invention, the dosage of arctigenin and / or arctiin may be any amount that can exert its effect, and can be appropriately set according to the subject, purpose and administration method (ingestion method).For example, when orally ingested by humans, it is preferable to administer arctigenin so that the daily intake is 10-2000mg.

[0068] Subjects to which the method of the present invention can be applied include mammals such as humans, mice, rats, rabbits, cats, dogs, cows, horses and monkeys.

[0069] In the method of the present invention for suppressing an increase in oxidized LDL, the subject to be administered the drug is preferably, but not limited to, a subject having a BMI of 25 kg / m 2 The subjects to which the composition is administered may be, for example, subjects who need to suppress an increase in oxidized LDL, such as subjects with various diseases and / or symptoms, such as lipid metabolism disorders, diabetes, coronary artery disease (ischemic heart disease, angina pectoris, myocardial infarction, etc.), cerebrovascular disorders (cerebral hemorrhage and cerebral infarction), venous diseases (thrombophlebitis, varicose veins of the lower extremities, superior vena cava syndrome, etc.), endothelial dysfunction, vasodilation disorders, arteriosclerosis, aortic aneurysm, Takayasu's arteritis, Raynaud's disease, and / or poor circulation.

[0070] In the method of the present invention for suppressing an increase in FIB-4 index, the subject to which the drug is administered is not particularly limited, and may be, for example, a subject in which an increase in FIB-4 index needs to be suppressed, such as a subject with various diseases and / or symptoms, such as fatty liver, chronic liver disease, diseases affecting hepatic blood flow (Budd-Chiari syndrome, heart failure, portal vein thrombosis, and hepatic veno-occlusive disease), iron overload syndrome, hepatitis B, hepatitis C, hepatic fibrosis, non-alcoholic steatohepatitis, liver cirrhosis, liver cancer, portal hypertension, alcoholic hepatitis, and / or autoimmune diseases (autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis).

[0071] In the method of the present invention for suppressing a decrease in platelet count, the subject to which the agent is administered is not particularly limited, and may be, for example, a subject in which a decrease in platelet count needs to be suppressed, such as a subject having various diseases and / or symptoms, such as thrombocytopenia, purpura, essential thrombocythemia, idiopathic thrombocytopenic purpura, autoimmune thrombocytopenia, thrombotic thrombocytopenic purpura, viral infection, liver cirrhosis, myelofibrosis, hemolytic uremic syndrome, Gaucher disease, heparin-dependent thrombocytopenia, systemic lupus erythematosus, drug-induced bone marrow suppression, and post-transfusion purpura.

[0072] The present invention also provides arctigenin and / or arctiin for use in suppressing an increase in oxidized LDL.The present invention also provides arctigenin and / or arctiin for use in suppressing an increase in FIB-4 index.The present invention also provides arctigenin and / or arctiin for use in suppressing a decrease in platelet count.

[0073] The present invention also provides the use of arctigenin and / or arctiin to suppress the increase of oxidized LDL.The present invention also provides the use of arctigenin and / or arctiin to suppress the increase of FIB-4 index.The present invention also provides the use of arctigenin and / or arctiin to suppress the decrease of platelet.

[0074] The present invention also provides use of arctigenin and / or arctiin for producing an agent for suppressing an increase in oxidized LDL, a composition for suppressing an increase in oxidized LDL, or a food composition for suppressing an increase in oxidized LDL.

[0075] The present invention also provides use of arctigenin and / or arctiin for producing an FIB-4 index increase suppressor, a composition for suppressing an FIB-4 index increase, or a food composition for suppressing an FIB-4 index increase.

[0076] The present invention also provides use of arctigenin and / or arctiin for producing an agent for inhibiting platelet decline, a composition for inhibiting platelet decline, or a food composition for inhibiting platelet decline. EXAMPLES

[0077] Example 1: Burdock sprout extract (Preparation of Burdock Sprout Extract) An example of the preparation method of the agent and composition of the present invention is shown below. As an example of the present invention, an extract was extracted from burdock sprouts. 125 kg of dried burdock sprouts was added with 1680 kg of water, heated to 35±5°C, and stirred for 60 minutes. Then, 720 kg of ethanol was added, heated, stirred for another 2 hours, and filtered through an 80 mesh filter to obtain a burdock sprout extract. This was sterilized at 70°C for 1 hour, and about 30% of dextrin was added to the solid content of the extract, concentrated under reduced pressure, and spray-dried. The arctigenin and arctiin contents were 13.7% and 0.4%, respectively, and a burdock sprout extract powder with an arctigenin equivalent of 13.9% was obtained.

[0078] (Component analysis of burdock sprout extract) [Test example] The burdock sprout extract prepared in Example 1 was analyzed for nutritional components according to the method listed in the third column of Appendix 9 of the Food Labeling Standards (Cabinet Office Ordinance No. 10 of 2015), and found to contain normal nutritional components (lipids, proteins, carbohydrates, and minerals). In addition, the components were analyzed using liquid chromatography mass spectrometry (LS / MS) as follows, and chlorogenic acid was detected as a component other than arctigenin and arctiin. Other components confirmed were cynarin, matairesinol, and rapaol A, but only in trace amounts. Quantitative analysis was performed using high performance liquid chromatography (HPLC), and the arctigenin and arctiin contents were 13.9% (arctigenin equivalent), and the chlorogenic acid content was about 1.3%. These results showed that the main components of the burdock sprout extract were arctigenin and arctiin. [Sample pretreatment] 10 mg of the sample was dissolved in 1 mL of 50% methanol to prepare a measurement sample.

[0079] [Measurement conditions] <lc> Equipment: Acquity UPLC (Waters) Column: Acquity UPLC HSS T3 (2.1 x 100 mm 1.8 μm) Column temperature: 40℃ Mobile phase A: 0.1% formic acid in water Mobile phase B: Acetonitrile A:B = 99.5:0.5(0 min)→A:B = 99.5:0.5(1 min) →A:B = 40:60(21 min)→A:B = 0:100(23 min) Flow rate: 0.4 mL / min Injection volume: 5 μL Equipment: Xevo QTof MS (Waters) Ionization method: ESI Capillary voltage: 3.0 kV, Cone voltage: 15 V Mass range: m / z 50-1000

[0080] "Quantitative method for arctigenin and arctiin" 50 mg of the sample was dissolved in 100% methanol solution, subjected to ultrasonic treatment for 15 minutes, adjusted to 50 ml, and then filtered through a membrane filter to prepare a measurement sample. <hplc> Equipment: LC-10ADvp series CLASS-VP system (Shimadzu Corporation) Detection: UV spectrophotometer (measurement wavelength: 220 nm) Column: ODS-3 150mm x 4.6mm 5μm (GL Science) Mobile phase: 0.05 mol / L sodium dihydrogen phosphate:acetonitrile (72:28) Column temperature: 35℃ Flow rate: 1.0 ml / min

[0081] "Chlorogenic acid quantitative method" The sample was adjusted to 1 mg / mL with 50% ethanol, and the insoluble matter was filtered through a membrane filter. The resulting mixture was used as a measurement sample. <lc> Equipment: Prominence UFLC (Shimadzu Corporation) Column: Cadenza CD-C18 (2.0 mm x 150 mm, 3.0 μm) Column temperature: 40℃ Mobile phase A: 0.1% formic acid in water Mobile phase B: Acetonitrile A:B = 99.5:0.5(0 min)→A:B = 39.5:60.5(15 min) Flow rate: 0.4 mL / min Injection volume: 5 μL Equipment: Triple TOF 5600+ (AB SCIEX) Ionization method: ESI IonSpray Voltage Floating: 4.5 kV (Negative mode) Mass range: m / z 100-1000

[0082] (Method of preparing capsules containing burdock sprout extract) The capsule containing burdock sprout extract was obtained by filling burdock sprout extract powder, potato starch, calcium stearate and fine silicon dioxide into HPMC No. 2 capsule.

[0083] Example 2: Inhibitory effect of burdock sprout extract on the increase of oxidized LDL The burdock sprout extract was tested for its inhibitory effect on the increase of oxidized LDL. The study was a placebo-controlled, randomized, double-blind, parallel-group comparative study.

[0084] (subject) LDL-C < 140 mg / dl and BMI 23 kg / m 2 More than 30kg / m 2 The study participants were healthy Japanese men and women aged 30 to 65 years old who were under the age of 65. Subjects were excluded from the study if they were at risk of developing allergic symptoms to drugs or foods, if they regularly took medicines, health foods, or supplements that affected serum lipids or blood sugar, if they were pregnant or possibly pregnant, or if they were breastfeeding, or if the principal investigator deemed them ineligible.

[0085] (Test Food) The test foods were the capsules containing the burdock sprout extract of Example 1 (hereinafter referred to as the "test food" or "test meal") and the capsules not containing the burdock sprout extract (hereinafter referred to as the "placebo food"). The test food contained about 40 mg of arctigenin per day, and the placebo food did not contain arctigenin.

[0086] (allocation) The subjects were randomized using a stratified permuted block method with stratification factors of gender, age, LDL-C, and BMI, and assigned to two groups: the test food group and the placebo food group.

[0087] (Test Method) The subjects were instructed to continuously take two capsules of either the test food or the placebo food once a day. The following examinations were performed on the day that the test food intake started, and four, eight, and 12 weeks after intake. Abdominal CT scans were performed only before intake and after 12 weeks of intake.

[0088] (Test items) Evaluation items included LDL-C, TC, TG, HDL-C, oxidized LDL, body weight, and BMI. Abdominal CT scans were used to measure L / S ratio, visceral fat area, total abdominal fat area, and abdominal subcutaneous fat area. Safety evaluation items included vital signs (blood pressure, pulse rate at time of admission), general blood (WBC, RBC, Hb, Ht, Plt, MCH, MCHC, MCV), liver function (AST, ALT, γ-GTP, ALP, LDH, T-Bil, Alb), renal function (BUN, CRE, UA), blood glucose (fasting blood glucose, HbA1c), and urine test (pH, glucose qualitative, protein qualitative, occult blood, urobilinogen, ketone bodies, bilirubin).

[0089] (Analysis method) Between-group comparisons were performed using independent two-sample t-tests for actual measurements and changes. For changes, the effects of intake period, test food, and the interaction between intake period and test food were tested using repeated measures two-way analysis of variance. For within-group comparisons, paired t-tests were used to compare the results before intake began with each evaluation point for each intake group. In addition, significant differences in correlation between two variables were tested using Pearson's correlation coefficient.

[0090] (Efficacy analysis set) The efficacy analysis population for this study consisted of 92 subjects, including 48 subjects in the placebo group (18 men, 30 women; mean age 50.0 ± 7.7 years) and 44 subjects in the test food group (16 men, 28 women; mean age 50.7 ± 8.1 years). 2 and BMI 25 kg / m 2 The above groups were used as stratified analysis populations. Regarding background factors for each stratum, no significant differences were observed between the placebo group and the test food group in terms of gender, age, BMI, LDL-C, or intake rate.

[0091] <Oxidized LDL-C (U / L) results> The results for 43 subjects with a BMI of 25 kg / m2 or more are shown in Table 1 and Figure 1. As shown in Table 1 and Figure 1, the change in oxidized LDL at 12 weeks was significantly suppressed compared to the placebo group (p=0.009). The results at 12 weeks showed a unique trend, but considering the behavior of blood test values, this is thought to be due to seasonal fluctuations that caused the subjects to have a stronger appetite overall.

[0092] [Table 1]

[0093] <FIB-4 index> The FIB-4 index is an index calculated from age, AST, ALT, and platelet count. The FIB-4 index calculated from the data of this study is shown in Table 2 and Figure 2. The change in FIB-4 index was lower in the test food group compared to the placebo group from week 8 onwards (p=0.01, P-0.057). The change in FIB-4 index showed a similar tendency in all subjects, regardless of BMI value.

[0094] <Platelet count> In addition, the change in platelet count (PLT), which is a factor of the FIB-4 index, is shown in Table 2 and Figure 3. Regarding platelet count, the decrease in platelet count was significantly suppressed in the test diet group after 8 and 12 weeks compared to the placebo group, and this was linked to the increase or decrease in the FIB-4 index.

[0095] [Table 2]

[0096] (Correlation between changes in FIB-4 index and each item) The correlation between the change in FIB-4 index after 12 weeks (Δ12w) and each item is shown in Table 3. As shown in Table 3, a positive correlation was confirmed with oxidized LDL and visceral fat, and the correlation with oxidized LDL was significant.

[0097] In addition, the correlation between the change in FIB-4 index (Δ12w) and oxidized LDL (initial value) is shown in Figure 4, and the correlation between the change in FIB-4 index (Δ12w) and visceral fat area (initial value) is shown in Figure 5. When the subjects were divided into the test food group and the placebo group and analyzed, differences in reactivity were observed between the groups.

[0098] These results suggest that oxidized LDL is involved in the increase of the FIB-4 index, and that the test diet may suppress the increase of the FIB-4 index by controlling oxidized LDL. In addition, while it was confirmed that the increase in visceral fat area and FIB-4 index showed a positive correlation in the placebo group, this correlation disappeared in the test diet group, suggesting that the diet may control oxidized LDL through visceral fat and contribute to the suppression of the progression of liver fibrosis.

[0099] [Table 3]

[0100] (Correlation between changes in platelet count and oxidized LDL) In the test diet group, the decrease in platelet count was significantly suppressed after 8 and 12 weeks compared to the placebo group, and since this showed a negative correlation with the increase or decrease in the FIB-4 index, the correlation between the change in platelet count (Δ8w and Δ12w) and oxidized LDL was examined. The correlation between the change in platelet count (Δ8w) and oxidized LDL (initial value) is shown in Figure 6, and the correlation between the change in platelet count (Δ12w) and oxidized LDL (initial value) is shown in Figure 7. In addition, the correlation between the change in platelet count (Δ8w) and platelet count (initial value) is shown in Figure 8, and the correlation between the change in platelet count (Δ12w) and platelet count (initial value) is shown in Figure 9.

[0101] As shown in Figures 6 to 7, the higher the oxidized LDL level, the lower the platelet count, and it was confirmed that the decrease in platelet count was suppressed in the test diet group (the increase difference was large). In addition, as shown in Figures 8 to 9, it was confirmed that the platelet count increased when the initial platelet count was in the low range, and that this tendency was intensified by the intake of the test diet.

[0102] (RBC) The correlation between the amount of change in red blood cell (RBC) count (Δ12w) and RBC is shown in Figure 10, and the correlation between the amount of change in RBC count (Δ12w) and the amount of change in platelet count (Δ12w) is shown in Figure 11. A tendency was confirmed for the amount of change in RBC count (Δ12w) to increase with the ingestion of the test food when the initial RBC value was in the low range. Furthermore, in the test food group, a positive correlation was observed between the amount of change in platelet count (Δ12w) and the amount of change in RBC count (Δ12w), but no such tendency was observed in the placebo group. As described above, the test food group increased the platelet count and RBC in the low range, suggesting that the test food may act on hematopoietic cells and help maintain blood homeostasis.

[0103] (Consideration) From the above results, the test food was 2 In these subjects, the increase in oxidized LDL after 12 weeks of intake was significantly suppressed. There is a correlation between BMI and visceral fat area, and it is possible that the test food's effect of suppressing the increase in oxidized LDL is more likely to appear in subjects with a large amount of visceral fat. Table 4 below shows the correlation between oxidized LDL and each item. As shown in Table 4, there is a significant positive correlation between oxidized LDL and visceral fat area, suggesting that visceral fat accumulation affects the increase in oxidized LDL.

[0104] [Table 4]

[0105] In obese adipocytes, the expression of NADPH oxidase, an enzyme that produces reactive oxygen species (ROS), increases, while the expression of antioxidant enzymes such as superoxide dismutase (SOD) decreases, promoting ROS production and enhancing oxidative stress (Non-Patent Document 8). In addition, in enlarged adipocytes, the production of inflammatory cytokines such as TNF-α and IL-6 and chemokines such as MCP-1 is enhanced, and infiltration of immune cells, mainly macrophages, into adipocytes is observed (Non-Patent Document 9). Since phagocytes such as macrophages and neutrophils generate superoxide by NADPH oxidase in their cell membranes, inflammatory degeneration of adipocytes is also thought to contribute to increased oxidative stress.

[0106] It has also been reported that in obese adipose tissue, fatty acids function as endogenous inflammation-inducing substances, inducing the production of inflammatory cytokines from macrophages, and that Toll-like receptor 4 (TLR4), a pattern recognition receptor of the innate immune system, is involved in this (Non-Patent Document 10). It is known that stimulation of TLR4 damages mitochondria and generates reactive oxygen species, and it is speculated that TLR4 activation in adipose tissue is involved in the oxidation of LDL.

[0107] Thus, the mechanism by which oxidized LDL is produced remains unclear, and therefore antioxidant components cannot necessarily suppress the oxidation of LDL or reduce the amount of oxidized LDL that has already been produced.

[0108] In addition, the FIB-4 index is an index of liver fibrosis. In a previous study comparing the histopathological findings of liver biopsy, a negative predictive value of 90% was observed for a value of 1.30 or less (Non-Patent Document 11), so 1.30 is often used as the cutoff value. In this study, healthy subjects were the subjects, so there were not many subjects with an FIB-4 index of more than 1.30. However, it was confirmed that the test food significantly suppressed the decrease in platelets regardless of BMI and suppressed the increase in the FIB-4 index. Therefore, it was suggested that the test food may control oxidized LDL, maintain blood homeostasis such as platelets, which are important for liver function and tissue repair, and suppress the progression of liver fibrosis.

[0109] It has not been known that the FIB-4 index increases with an increase in oxidized LDL. Therefore, as shown in Example 2, it is a new finding that the FIB-4 index increases with an increase in oxidized LDL and that the increase in the FIB-4 index is suppressed by ingestion of the test diet.

[0110] In addition, the active ingredients of the burdock sprout extract in this embodiment, which suppress the increase of oxidized LDL, the increase of FIB-4 index, and the decrease of platelet count, are considered to be arctigenin and / or arctiin, for the reasons described below. According to the component analysis results of the burdock sprout extract in Example 1, in addition to the usual nutritional components (lipids, proteins, carbohydrates, and minerals), the burdock sprout extract contains arctigenin and arctiin (13% as arctigenin). In addition, chlorogenic acid was detected as a component that may be active, but its content is only 1.3%. The 308 mg extract dose shown in Example 2 contains 40 mg of arctigenin, but only 4 mg of chlorogenic acid. Considering that the chlorogenic acid content in one cup of coffee (140 mL) is about 10-100 mg, and that the standard for FOSHU (foods for specified health uses) is 270 mg, it is safe to assume that the chlorogenic acid in burdock sprout extract is not involved in the action. Furthermore, the other substances confirmed to be cynarin, matairesinol, and rappaol A were only trace amounts. Therefore, it can be said that the main components of burdock sprout extract are arctigenin and / or arctiin. [Industrial Applicability]

[0111] The present invention can be suitably used for pharmaceutical and food compositions capable of suppressing an increase in oxidized LDL in a subject. < / lc> < / hplc> < / lc>

Claims

1. A food composition for suppressing an increase in oxidized LDL in subjects with a BMI of 25 kg / m2 or higher, comprising arctigenin and / or arctiin as active ingredients.

2. 2. The food composition for suppressing an increase in oxidized LDL as described in claim 1, wherein the arctigenin and / or arctiin is contained in the form of burdock, burdock fruit, burdock sprouts, or forsythia, or an extract thereof.

3. A food composition for suppressing an increase in FIB-4 index, comprising arctigenin and / or arctiin as active ingredients.

4. The food composition for suppressing an increase in FIB-4 index according to claim 3, wherein the arctigenin and / or arctiin is contained in the form of burdock, burdock fruit, burdock sprouts, or forsythia, or an extract thereof.

5. An agent for suppressing the increase in oxidized LDL for subjects with a BMI of 25 kg / m2 or more, which contains arctigenin and / or arctiin as active ingredients.

6. The oxidized LDL increase inhibitor according to claim 5, wherein the arctigenin and / or arctiin is contained in the form of burdock, burdock fruit, burdock sprout, or forsythia, or an extract thereof.

7. An FIB-4 index increase inhibitor containing arctigenin and / or arctiin as active ingredients.

8. The FIB-4 index increase inhibitor according to claim 7, wherein the arctigenin and / or arctiin is contained in the form of burdock, burdock fruit, burdock sprout, or forsythia, or an extract thereof.

9. An agent for suppressing a decrease in platelet count associated with an increase in oxidized LDL, comprising arctigenin and / or arctiin as active ingredients.

10. The inhibitor according to claim 9, wherein the arctigenin and / or arctiin is contained in the form of burdock, burdock fruit, burdock sprout, or forsythia, or an extract thereof.

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