Prophylactic or therapeutic agent for hepatocellular carcinoma derived from non-alcoholic steatohepatitis

Abstract

The purpose of the present invention is to provide a drug or food for preventing, treating or ameliorating hepatocellular carcinoma derived from non-alcoholic steatohepatitis. The present invention relates to a CD36 inhibitor comprising taxifolin or a salt thereof. In addition, the present invention also relates to a pharmaceutical or food composition for preventing, treating or ameliorating hepatocellular carcinoma derived from non-alcoholic steatohepatitis, said pharmaceutical or food composition containing the CD36 inhibitor.

Description

Technical Field

[0001] The present invention relates to a CD36 inhibitor comprising taxifolin or a pharmaceutically acceptable salt thereof, and pharmaceutical and food compositions comprising the same, wherein the pharmaceutical and food compositions are used for preventing, treating and / or ameliorating diseases associated with CD36 activation, in particular hepatocellular carcinoma derived from non-alcoholic steatohepatitis. Background Art

[0002] CD36, a scavenger receptor for fatty acid uptake, has been proposed as a prognostic marker for various cancers, primarily epithelial (breast, prostate, ovary, and colon), as well as hepatocellular carcinoma and glioma. CD36 is known to promote fatty acid intracellular uptake (as a translocase), thereby removing adhesion receptors (Non-Patent Document 1), activate the glycolytic system (Warburg effect) in cancer cells (Non-Patent Document 2), induce cancer cell migration and metastasis (Non-Patent Document 3), and promote scaffold-independent proliferation (Non-Patent Document 4), suggesting that inhibiting CD36 function is beneficial for suppressing cancer metastasis.

[0003] However, clinical trials using antibodies targeting CD36 have shown no effect on the treatment of cancer metastasis, demonstrating the difficulty of targeting CD36 (Non-Patent Document 5). Therefore, there is a desire to develop methods for inhibiting CD36 activity that are different from the use of anti-CD36 antibodies that directly act on CD36.

[0004] Taxifolin is the following formula (1):

[0005] [Chemistry 1]

[0006]

[0007] The compound shown is a plant extract from the xylem of Dahurian larch and Siberian larch. Recently, it has been confirmed that the safety of dithyroxine in ingestion has been confirmed (Non-Patent Document 6). It also has antioxidant effects in acute pancreatitis model mice (Non-Patent Document 7), blood sugar-improving effects in type 1 diabetes model rats (Non-Patent Document 8), and β-amyloid aggregation inhibitory effects, cerebral blood flow improvement effects, and dementia-improving effects in Alzheimer's disease model mice (Patent Document 1, Non-Patent Document 9). In addition, the present inventors have found that dithyroxine is useful for preventing nonalcoholic steatohepatitis (hereinafter referred to as "NASH") (Patent Document 2).

[0008] Due to Westernized diets and insufficient exercise, obesity is also increasing in Japan, with diabetes and metabolic syndrome exceeding 22 million and 20 million people, respectively, including those at risk. Furthermore, with the recent rise in obesity, the number of patients with nonalcoholic fatty liver disease (NAFLD), such as NASH, has increased dramatically, reaching approximately 30% of health checkups, estimated to be close to 15 to 23 million people. According to the latest data, approximately 25% of these individuals develop NASH, and approximately 1 in 16 NASH patients will develop hepatocellular carcinoma within 10 years. However, to date, there have been no reports on the inhibitory effects of taxifolin on CD36 and the development of hepatocellular carcinoma in subjects with NASH who are at risk of developing hepatocellular carcinoma.

[0009] Prior art literature

[0010] Patent Literature

[0011] Patent Document 1: International Publication No. 2017 / 199755

[0012] Patent Document 2: International Publication No. 2020 / 262703

[0013] Non-patent literature

[0014] Non-patent literature 1: J. Lipid Res. 2018; 59: 1084-1093

[0015] Non-patent literature 2: Cell Death and Disease, 2021; 12: 328-341

[0016] Non-patent literature 3: Frontiers in Genetics, 2019; 10: Article 680

[0017] Non-patent literature 4: Oncogene. 2018; 37(17): 2285-2301

[0018] Non-patent literature 5: BioMed Res Int. 2018; Article ID 7801202

[0019] Non-patent literature 6: Int. J. Toxicol. 2015; 34(2): 162-181

[0020] Non-patent literature 7: J. Ethnopharmacol. 2018; 224: 261-272

[0021] Non-patent literature 8: J. Cell. Biochem. 2019; 120(1): 425-438

[0022] Non-patent literature 9: Acta Neuropathol. Commun. 2017; 5(1): 26, doi: 10.1186 / s40478-017-0429-5 Summary of the Invention

[0023] Problems to be solved by the invention

[0024] The present invention aims to provide a CD36 inhibitor targeting subjects (e.g., mammals) with NASH at risk of developing hepatocellular carcinoma, and a drug for preventing or treating hepatocellular carcinoma derived from NASH. The present invention also aims to provide a drug or food composition for preventing, treating, and / or ameliorating diseases other than hepatocellular carcinoma derived from NASH that are associated with CD36 activation.

[0025] Means for solving problems

[0026] Under the above circumstances, the present inventors conducted intensive research and discovered that taxifolin or a pharmaceutically acceptable salt thereof exhibits excellent CD36 inhibitory activity. Furthermore, they discovered for the first time that it can be a useful and safe drug or food for preventing, treating, and / or ameliorating NASH-derived hepatocellular carcinoma, for which there has been no effective preventive, therapeutic, or ameliorating method to date. This led to the completion of the present invention. Specifically, the present invention is as follows.

[0027] [1] A CD36 inhibitor for use in mammals suffering from non-alcoholic steatohepatitis (hereinafter, sometimes also referred to as "the CD36 inhibitor of the present invention"), comprising taxifolin or a pharmaceutically acceptable salt thereof.

[0028] [2] A drug (hereinafter sometimes referred to as "the drug of the present invention") for preventing or treating a disease associated with CD36 activation by administering the drug to a mammal suffering from non-alcoholic steatohepatitis, the drug comprising a pharmaceutically effective amount of the agent described in [1] above.

[0029] [3] The drug according to [2] above, wherein the disease associated with CD36 activation is hepatocellular carcinoma derived from non-alcoholic steatohepatitis.

[0030] [4] The drug according to [2] or [3] above, characterized in that it is prepared in the form of tablets, pills, capsules, powders, granules, fine particles, lozenges, liquids, nasal drops or injections.

[0031] [5] The drug according to any one of [2] to [4] above, wherein the pharmaceutically effective amount is in the range of 0.2 to 200 mg / day / kg of mammal body weight as taxifolin.

[0032] [6] A food composition (hereinafter sometimes referred to as the "food composition of the present invention") for preventing or ameliorating a disease associated with CD36 activation by ingestion by a mammal suffering from non-alcoholic steatohepatitis, the food composition comprising an effective amount of the agent described in [1] above.

[0033] [7] The food composition according to [6] above, wherein the disease associated with CD36 activation is hepatocellular carcinoma derived from non-alcoholic steatohepatitis.

[0034] [8] A method for inhibiting CD36 in a mammal, comprising administering a pharmaceutically effective amount of the agent described in [1] above to the mammal.

[0035] [9] A method for treating or preventing hepatocellular carcinoma derived from nonalcoholic steatohepatitis, comprising administering a pharmaceutically effective amount of the agent described in [1] above to a mammal.

[0036]

[10] The method according to [8] or [9] above, wherein the pharmaceutically effective amount is in the range of 0.2 to 200 mg / day / kg of mammal body weight as taxifolin.

[0037]

[11] A food composition for preventing or improving hepatocellular carcinoma derived from nonalcoholic steatohepatitis, comprising an effective amount of taxifolin or a salt thereof.

[0038]

[12] The food composition according to

[11] above, which is labeled as “for reducing the risk of hepatocellular carcinoma” and / or “for creating a body that is less susceptible to hepatocellular carcinoma”.

[0039]

[13] The food composition according to

[11] or

[12] above, characterized in that it is prepared as a supplement, a functionally labeled food, a health food, a special purpose food, an insurance functional food, a specific health food or a nutritional functional food.

[0040]

[14] The food composition according to any one of

[11] to

[13] above, characterized in that it is prepared in the form of tablets, pills, capsules, powders, granules, fine particles, lozenges, liquids, nasal tube nutrition or enteral nutrition.

[0041]

[15] Taxifolin or a pharmaceutically acceptable salt thereof, for use in a subject suffering from non-alcoholic steatohepatitis, for preventing and / or treating hepatocellular carcinoma derived from non-alcoholic steatohepatitis.

[0042]

[16] Use of taxifolin or a pharmaceutically acceptable salt thereof for the preparation of a preventive and / or therapeutic agent for hepatocellular carcinoma derived from nonalcoholic steatohepatitis in a subject suffering from nonalcoholic steatohepatitis.

[0043] Effects of the Invention

[0044] According to the present invention, an excellent CD36 inhibitor comprising taxifolin or a pharmaceutically acceptable salt thereof as a safe plant-derived ingredient can be provided. The CD36 inhibitor of the present invention can inhibit the activity of CD36 at a low concentration, and is also effective for subjects (e.g., mammals) suffering from NASH at risk of developing hepatocellular carcinoma, and thus can effectively inhibit the onset and progression of hepatocellular carcinoma derived from NASH. That is, according to the present invention, a drug or food composition containing taxifolin or a pharmaceutically acceptable salt thereof as an active ingredient for preventing, treating and / or improving hepatocellular carcinoma derived from NASH can be provided. In addition, according to the present invention, a drug or food composition containing taxifolin or a pharmaceutically acceptable salt thereof as an active ingredient for preventing, treating and / or improving diseases related to the activation of CD36 other than hepatocellular carcinoma derived from NASH can also be provided. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 : Figure 1 The figure shows the effect of taxifolin on the expression of CD36 gene in liver tissue of high-fat diet-induced obesity model mice.

[0046] Figure 2 : Figure 2 The effect of taxifolin on fatty acid uptake in HepG2 cells is shown. (A) shows the effect of taxifolin under low glucose (0.1%) conditions, (B) shows the effect of taxifolin under high glucose (0.45%) conditions, and (C) shows the effect of taxifolin in the absence of glucose.

[0047] Figure 3 : Figure 3 Figures show the effect of taxifolin on the development of hepatocellular carcinoma in MC4R-deficient mice fed a high-fat diet. (A) shows the effect of taxifolin on the number of precancerous lesions, (B) shows the effect of taxifolin on the number of tumors clustered with precancerous lesions, and (C) shows the effect of taxifolin on tumor size. DETAILED DESCRIPTION

[0048] The terms used in this specification are defined as follows.

[0049] In this specification, "digestive acid alkaloid" refers to the compound represented by the aforementioned formula (1), which is a flavonoid that accounts for the majority (90% or more) of the active ingredients of zikbertin, a bioflavonoid complex isolated from the xylem of Larix gmelinii or Larix dasyphylla.

[0050] In this specification, the salt of taxifolin may be any salt known in the art as long as it is not excessively toxic. Specifically, pharmaceutically acceptable salts that can be easily formed by reacting with a pharmaceutically acceptable base are mentioned. Examples of such salts include alkali metal salts such as sodium salts and potassium salts.

[0051] Taxifolin from Siberian larch is an optically active substance ((+)-taxifolin). The taxifolin of the present invention includes not only (+)-taxifolin, but also (-)-taxifolin as its enantiomer, compounds with low optical purity (substances obtained by mixing two optically pure enantiomers in an appropriate ratio), and racemic forms. In addition, the taxifolin of the present invention also includes labeled substances, that is, one or more atoms constituting taxifolin are labeled with isotopes (for example, 2 H. 3 H. 11 C. 13 C. 14 C. 15 N. 18 O. 18 F. 35 S, etc.) labeled compounds.

[0052] The optically active form of the diacetyl or pharmaceutically acceptable salt thereof of the present invention can be produced by chemical synthesis by a method known per se, or by extraction and / or purification from the xylem of Dahurian larch or Siberian larch. Specifically, an optically active form can be obtained by using an optically active synthetic intermediate or by optically resolving the racemate of the final product according to a conventional method (see, for example, "Enantiomers, Racemates and Resolution" by J. Jacques et al., John Wiley And Sons, Inc.). In addition, (+)-diacetyl is commercially available, and a commercially available product can also be used directly.

[0053] The dithyrafenib or its pharmaceutically acceptable salt of the present invention may be a crystal, and both a single crystal form and a mixture of crystal forms are included in the dithyrafenib or its salt. The crystal can be produced by applying a known crystallization method.

[0054] The taxifolin or its pharmaceutically acceptable salt of the present invention may also include solvates thereof. These solvates are formed by the coordination of solvent molecules with taxifolin or its pharmaceutically acceptable salt, and also include hydrates. Examples include hydrates, ethanol solvates, and dimethyl sulfoxide solvates of taxifolin or its pharmaceutically acceptable salt.

[0055] In this specification, "inhibiting CD36" means eliminating or reducing the activity of CD36, for example, inhibiting the gene expression or function of CD36 under the conditions of Test Example 1 or 2 described below. Elimination or reduction of CD36 activity is preferably performed under clinical conditions suitable for humans.

[0056] "Inhibit CD36" is preferably "inhibit human CD36".

[0057] "CD36 inhibitor" means a substance that inhibits the gene expression of CD36. As the "CD36 inhibitor", a "human CD36 inhibitor" is preferred.

[0058] In this specification, "diseases associated with CD36 activation" means diseases that worsen the condition and / or symptoms due to enhanced expression of the CD36 gene. Examples of "diseases associated with CD36 activation" include, for example, hepatocellular carcinoma derived from NASH, breast cancer, prostate cancer, ovarian cancer, colon cancer, lung cancer, glioma, chronic myeloid leukemia and other malignant tumors, NASH, hepatitis C, heart disease, stroke, senile cardiomyopathy, kidney disease, diabetes, insulin resistance, arteriosclerotic disease, lipid metabolism disorders, metabolic syndrome, obesity, cerebral amyloid angiopathy, Alzheimer's disease, thrombin-dependent hypercoagulopathy, asthma, inflammatory bowel disease, epilepsy, Kawasaki disease, mycobacterial infection, etc. As "diseases associated with CD36 activation", hepatocellular carcinoma derived from NASH is preferred.

[0059] In this specification, "prevention" includes suppressing the onset of symptoms.

[0060] In this specification, "treatment" includes improving symptoms, preventing aggravation, maintaining remission, preventing relapse, secondary prevention and preventing recurrence.

[0061] In this specification, "preventive or therapeutic agent" also includes a drug for prevention and / or treatment, or a food composition for prevention and / or improvement.

[0062] In this specification, "pharmaceutically effective amount" means the amount of taxifolin or a pharmaceutically acceptable salt thereof administered to a subject orally or parenterally (topically, rectally, intravenously, intramuscularly, subcutaneously, nasally, etc.).

[0063] As used herein, "subject" refers to a subject to whom a drug or food containing an effective amount of an active ingredient required for the prevention and / or treatment (or amelioration) of a disease or disease condition is administered or ingested. Examples of such "subjects" include mammals such as humans, mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cattle, horses, sheep, and monkeys, preferably humans.

[0064] The drug of the present invention (or the pharmaceutical composition of the present invention)

[0065] As shown in the test examples described below, taxifolin can inhibit CD36 at low concentrations. Therefore, taxifolin or a pharmaceutically acceptable salt thereof, or a drug containing the same as an active ingredient can be suitably used as a drug for preventing and / or treating diseases associated with CD36 activation, particularly hepatocellular carcinoma derived from NASH.

[0066] The drug of the present invention may be any one of a drug containing only taxifolin or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising taxifolin or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier or the like. The drug or pharmaceutical composition of the present invention may be administered to a subject in a pharmaceutically effective amount. Examples of methods for administering the drug or pharmaceutical composition of the present invention include oral administration, intravenous administration, intraperitoneal administration, transdermal administration, intramuscular administration, intranasal administration, and mucosal administration, with oral administration being preferred.

[0067] Examples of pharmaceutically acceptable carriers include excipients (e.g., starch, corn starch, lactose, granulated sugar, calcium carbonate, calcium phosphate, etc.), binders (e.g., starch, gum arabic, carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, etc.), lubricants (e.g., magnesium stearate, talc, hydrogenated rapeseed oil, etc.), disintegrants (e.g., carboxymethyl cellulose, talc, etc.), solvents (e.g., water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil, etc.), Cosolvents (e.g., polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate, etc.), suspending agents (e.g., stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate and other surfactants; coatings such as polyvinyl alcohol, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, etc.) Base material; polysorbates, polyoxyethylene hydrogenated castor oil, etc.), isotonic agents (e.g., sodium chloride, glycerol, D-mannitol, D-sorbitol, glucose, etc.), buffers (e.g., phosphate, acetate, carbonate, citrate, etc.), thickeners (e.g., sodium alginate, xanthan gum, sodium chondroitin sulfate, polyvinyl alcohol, povidone, etc.), preservatives (e.g., parabens, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, sorbic acid, etc.), antioxidants (e.g., sulfites, ascorbate (vitamin Vitamin C), tocopherol (vitamin E), etc.), colorants (for example, water-soluble edible tar pigments (for example, edible red No. 2 and No. 3, edible yellow No. 4 and No. 5, edible blue No. 1 and No. 2, etc.), water-insoluble lake pigments (for example, aluminum salts of the aforementioned water-soluble edible tar pigments), natural pigments (for example, β-carotene, chlorophyll, red iron oxide), etc.), sweeteners (for example, sodium saccharin, dipotassium glycyrrhizate, aspartame, stevia, etc.), other ingredients (for example, larch cambium and wood extract, etc.), etc.

[0068] The pharmaceutical composition of the present invention can be prepared by mixing the above-mentioned ingredients and then preparing the mixture into, for example, tablets, pills, capsules (including hard capsules, soft capsules, and microcapsules), powders, granules, fine granules, lozenges, liquids (including syrups, emulsions, and suspensions), nasal drops, injections, and the like according to known methods.

[0069] Pharmaceutical compositions in the form of tablets, granules, or fine granules can be coated using the aforementioned coating base material by a known method for the purpose of taste masking, improving photostability, improving appearance, or improving enteric solubility.

[0070] The content of taxifolin or a pharmaceutically acceptable salt thereof in the medicament of the present invention is not particularly limited. For example, it varies depending on the form of the preparation and is 1% to 100% by weight of the total preparation. The lower limit is preferably 5% by weight or more, more preferably 30% by weight or more. The upper limit is preferably 100% by weight or less, more preferably 95% by weight or less.

[0071] The dosage of difolinic acid or its pharmaceutically acceptable salt (i.e., pharmaceutically effective amount) is not particularly limited. For example, it varies according to the subject of administration, disease, symptom, dosage form, route of administration, etc. When orally administered to human adult patients, the dosage per day, per kg of body weight, converted to difolinic acid as an active ingredient, is 0.001 mg / kg / day or more and 200 mg / kg / day or less. As the lower limit, it is preferably 0.01 mg / kg / day or more, more preferably 0.1 mg / kg / day or more, and further preferably 0.2 mg / kg / day or more. On the other hand, as the upper limit, it is preferably 50 mg / kg / day or less, more preferably 10 mg / kg / day or less.

[0072] There is no particular limitation on the frequency of administration of taxifolin or a pharmaceutically acceptable salt thereof, and for example, it can be administered three times a day, twice a day, once a day, every other day, every other day, or every other day. Furthermore, administration can be before, after, or between meals.

[0073] The administration period of taxifolin or a pharmaceutically acceptable salt thereof is not particularly limited.

[0074] Taxifolin or a pharmaceutically acceptable salt thereof can also be used in combination with other therapies (e.g., chemotherapy, surgery (e.g., surgical resection, radiofrequency ablation, hepatic artery embolization, etc.), radiotherapy (e.g., X-ray, particle beam therapy, etc.)). This can enhance the preventive and / or therapeutic effects of taxifolin or a pharmaceutically acceptable salt thereof. Among them, combination with chemotherapy is particularly preferred. Specific forms of combination with chemotherapy are shown below.

[0075] As long as the efficacy is not impaired, taxifolin or a pharmaceutically acceptable salt thereof can be used in combination with other pharmaceutical agents (concomitant medications). In this case, the administration period is not limited, and they can be administered to the subject simultaneously or at intervals. In addition, a single preparation containing taxifolin or a pharmaceutically acceptable salt thereof and a concomitant medication can also be prepared for administration.

[0076] The dosage of the concomitant drug can be appropriately selected based on the dosage used clinically. In addition, the mixing ratio of taxifolin or a pharmaceutically acceptable salt thereof to the concomitant drug can be appropriately selected according to the administration target, administration route, target disease, symptoms, type of concomitant drug, etc.

[0077] Examples of concomitant drugs when taxifolin or a pharmaceutically acceptable salt thereof is used for the prevention and / or treatment of hepatocellular carcinoma derived from NASH include molecular targeted drugs, immune checkpoint inhibitors, chemotherapeutic agents, and hepatoprotective drugs.

[0078] As "molecular targeted drugs", for example, EGFR inhibitors such as afatinib, erlotinib, gefitinib, cetuximab, and panitumumab; ALK inhibitors such as crizotinib; EGFR / HER2 inhibitors such as lapatinib; HER2 inhibitors such as trastuzumab, trastuzumab imatinib, and pertuzumab; bevacizumab, axitinib, sunitinib, sorafenib, Angiogenesis inhibitors such as pazopanib, regorafenib, lenvatinib, and ramucirumab; mTOR inhibitors such as irolimus and temsirolimus; BCR-ABL inhibitors such as imatinib, dasatinib, and nilotinib; membranous differentiation antigen-targeted drugs such as ibritumomab tiuxetan, ofatumumab, rituximab, vegetuzumab, ogamicin, and moglizumab; denosumab; bortezomib, etc.

[0079] Examples of the “immune checkpoint inhibitors” include anti-PD-1 antibodies such as nivolumab and pembrolizumab; anti-CTLA-4 antibodies such as ipilimumab; and anti-PD-L1 antibodies such as avelumab, atezolizumab, and durvalumab.

[0080] Examples of the “chemotherapeutic agent” include busulfan, cyclophosphamide, dacarbazine, ifosfamide, melphalan, nimustine hydrochloride, procarbazine hydrochloride, ranimustine, temozolomide, and thiotepa; fluorouracil, mercaptopurine hydrate, cladribine, carmofur, cytarabine octadecyl phosphate hydrate, cytarabine, doxifluridine, enocitabine, fludarabine phosphate, gemcitabine hydrochloride, hydroxyurea, and methotrexate. Metabolic antagonists such as quinolones, nelarabine, pemetrexed sodium hydrate, pentostatin, tegafur, tegafur / uracil combination, tegafur / gimeracil / oteracil combination; vinca alkaloids such as vinblastine hydrochloride, vincristine hydrochloride, vindesine hydrochloride, vinorelbine tartrate; taxanes such as docetaxel hydrate and paclitaxel; aclarubicin hydrochloride, actinomycin D, amrubicin hydrochloride, bleomycin hydrochloride, daunorubicin Antitumor antibiotics such as mycin hydrochloride, doxorubicin hydrochloride, epirubicin hydrochloride, idarubicin hydrochloride, mitomycin C, mitoxantrone hydrochloride, pelopycin sulfate, pirarubicin hydrochloride; topoisomerase inhibitors such as etoposide, irinotecan hydrochloride hydrate, nortecan hydrochloride, sobuzosine; platinum preparations such as carboplatin, cisplatin, nedaplatin, oxaliplatin; anastrozole, exemestane, letrozole, tamoxifen citrate, torelax Hormone preparations such as imiphene citrate, phadazole hydrochloride hydrate, estramustine sodium phosphate, flutamide, goserelin acetate, leuprorelin acetate, medroxyprogesterone acetate, and metistat; anti-tumor streptozotocin preparations such as bixibanib; acetoglucuronolide, arsenic trioxide, versicolor polysaccharide preparation powder, L-asparaginase, lentinan, levulinic acid, mitotane, porfimer sodium, cisoflavone, tamibarotene, tretinoin, and ubenimex, etc.

[0081] Examples of the “hepatoprotective drug” include ursodeoxycholic acid, glycyrrhizic acid preparations, Xiao Chaihu decoction, taurine, potent glycyrrhizin C, glutathione, and diisopropylamine dichloroacetate.

[0082] In certain embodiments, the CD36 inhibitor of the present invention or a drug (or pharmaceutical composition) containing the same may also be provided in the form of a kit (such as an administration, treatment, and / or prevention kit), packaging (such as packaging materials), and pharmaceutical kit (and / or container) that also includes a material indicating that the drug can be used or should be used for treatment and / or prevention. Such a kit, packaging, and pharmaceutical kit may also include one or more containers filled with a CD36 inhibitor and / or other drugs or drugs (or ingredients). Examples of such a kit, packaging, and pharmaceutical kit include commercial kits, commercial packaging, and commercial pharmaceutical kits suitable for the treatment and / or prevention of a target disease. Examples of materials included in such a kit, packaging, and pharmaceutical kit include a notice or accompanying document in a format prescribed by a government agency regulating the manufacture, use, or sale of drugs or biological products, and indicating the approval of the government agency for the manufacture, use, or sale of the product for human administration. The above-mentioned kits, packages and pharmaceutical kits also include packaged products, and may also include structures configured for appropriate administration procedures (steps), and may also include structures configured in a manner that can achieve more preferred medical treatment and / or prevention, including treatment and / or prevention of the target disease.

[0083] Food composition of the present invention

[0084] The food composition of the present invention may be any one of a food composition comprising only taxifolin or a salt thereof, or a food composition comprising taxifolin or a salt thereof in combination with a food additive or the like. As the food composition of the present invention, as long as it contains taxifolin or a salt thereof and can be orally ingested by a subject, the type and shape of the food composition are not particularly limited. In addition, as shown in the test examples described below, taxifolin exhibits an excellent CD36 inhibitory effect on subjects suffering from NASH. Therefore, the food composition of the present invention can be used for the prevention and / or improvement of hepatocellular carcinoma derived from NASH, etc.

[0085] Examples of the food composition of the present invention include confectionery such as lozenges, hard candies, candies, ramune, soft candies, and chewing gum; Western confectionery such as cookies, crackers, biscuits, potato chips, bread, cakes, chocolate, donuts, puddings, and jellies; Japanese confectionery such as rice crackers, yokan, daifuku, bean cakes, bean buns, and Nagasaki cakes; frozen desserts such as ice cream, popsicles, sorbet, and gelato; breads such as white bread, French bread, and croissants; noodles such as udon, soba, Chinese noodles, and wide noodles; fish paste products such as fish cakes, chikuwa rolls, and fish sausages; animal meat products such as ham, sausage, hamburger steak, and corned beef; salt, pepper, miso, soy sauce, seasoning, sauce, mayonnaise, ketchup, sweets, and sour cream. Seasonings such as flavoring agents (for example, sugar, honey, powdered sugar, starch syrup, jam, marmalade, etc.), spicy seasonings (for example, mustard, pepper, etc.); teppanyaki foods such as akashiyaki, takoyaki, monjayaki, miyaki, fried noodles, and grilled udon; dairy products such as cheese, butter, margarine, and yogurt; various side dishes such as natto, fried tofu, tofu, konjac, meatballs, pickles, tsukudani, dumplings, steamed buns, croquettes, sandwiches, pizza, hamburgers, and salads; livestock products such as beef, pork, and chicken; aquatic products such as shrimp, scallops, clams, and kelp; various powders obtained by powdering vegetables, fruits, plants, yeast, algae, etc.; substances obtained by solidifying powders of oils and spices (vanilla, citrus fruits, bonito, etc.); beverages, etc.

[0086] Examples of beverages include: drinks such as miso soup and miso soup; powdered drinks such as instant coffee, instant black tea, instant milk, instant miso soup and instant miso soup; alcoholic beverages such as whiskey, bourbon, distilled spirits, liqueurs, wine, fruit wine, Japanese sake, Chinese wine, shochu, beer, non-alcoholic beer with an alcohol content of 1% or less, sparkling wine, and carbonated wine; drinks with added fruit juices (e.g., juices of apple, orange, grape, banana, pear, and ume plums), drinks with added vegetable juices (e.g., For example, beverages containing vegetable juices such as tomato, carrot, celery, cucumber, and watermelon, beverages with added fruit juices and vegetables, soft drinks, milk, soy milk, milk drinks, drink-type yogurt, coffee, cocoa, tea drinks (black tea, green tea, barley tea, brown rice tea, sencha, gyokuro tea, hojicha, oolong tea, turmeric tea, Pu'er tea, cinnamon tea, rose tea, chrysanthemum tea, herbal tea (for example, mint tea, jasmine tea), etc.), nutritional drinks, sports drinks, mineral water and other non-alcoholic beverages, etc.

[0087] Preferable examples of the food composition include jelly, tea drinks, alcoholic beverages, hard candies, candies, soda candies, cookies, crackers, biscuits, chocolate, cheese, butter, margarine, and chewing gum.

[0088] In addition, the food composition of the present invention can be prepared as a functionally labeled food, a health food, a food for specific health care, a food for special use (for example, a food for patients such as hospital food, patient food, and nursing food), a supplement, etc., and is preferably prepared as a food for specific health care, a food for special use, or a supplement.

[0089] The shape of the food composition of the present invention may include, for example, tablets, pills, capsules (including hard capsules, soft capsules, microcapsules), powders, granules, fine granules, lozenges, liquids (including syrups, emulsions, suspensions), nasal tube nutrients, enteral nutrients, etc., preferably tablets or capsules.

[0090] As the food composition of the present invention, a food for specific health care, a food for special use, or a supplement in the form of a tablet or capsule is particularly preferred.

[0091] In this specification, supplements refer not only to nutritional supplements and nutritional functional foods used to supplement nutrients, but also to health supplements and health functional foods that have functions that contribute to the maintenance, restoration, and improvement of health (especially the prevention of hepatocellular carcinoma).

[0092] Food composition of the present invention can be manufactured by, for example, adding dithyramb or its salt in food by known method.Particularly, for example, the food composition of tablet can be manufactured by, for example, adding, mixing dithyramb or its salt and materials such as excipient (for example, lactose, white sugar, mannitol, corn starch etc.), sweetener, flavoring agent, and applying pressure by tablet press etc. and being shaped into the shape of tablet.As required, other materials (for example, minerals such as vitamins such as vitamin C, iron, dietary fiber, crystalline cellulose, rapeseed (hydrogenated rapeseed oil), larch cambium xylem extract etc.) can also be added. The food composition of capsule can be manufactured by, for example, being filled in capsule with the liquid, suspended, pasty, powdery or granular food composition containing dithyramb or its salt or being coated with capsule base.

[0093] In the food compositions of the present invention, as long as do not suppress effect of the present invention, then except normally used food raw materials, food additives, various nutrients, vitamins, local flavoring substances (for example, cheese, chocolate etc.) etc., can also cooperate physiologically acceptable carrier etc. As physiologically acceptable carrier etc., can use customary various organic or inorganic carrier materials, can enumerate excipient, adhesive, disintegrating agent, lubricant, coloring agent, sweetener, preservative, antioxidant, thickening agent, emulsifying agent etc. In addition, as food additives, can enumerate coloring agent, sweetener, preservative, antioxidant, flavoring agent etc. And then can also contain other materials, for example, dietary fibers such as minerals such as iron, calcium, pectin, carrageenan, mannan etc.

[0094] Examples of the excipient, binder, disintegrant, lubricant, solvent, solubilizer, suspending agent, buffer, thickener, colorant, sweetener, preservative, and antioxidant include the same ones as those used in the aforementioned medicament of the present invention.

[0095] Vitamins may be water-soluble or fat-soluble, and examples thereof include retinyl palmitate, tocopherol (vitamin E), bisbenzimidazole, riboflavin, pyridoxine hydrochloride, cyanocobalamin, sodium ascorbate (vitamin C), cholecalciferol, nicotinamide, calcium pantothenate, folic acid, biotin, choline bitartrate, niacin, and nicotinamide mononucleotide (NMN).

[0096] Regarding food compositions in the form of tablets, granules, or fine granules, they can be coated using a coating base material by a method known per se for the purpose of masking taste, improving photostability, improving appearance, or improving enteric solubility. Examples of such coating base materials include those similar to those used in the aforementioned medicaments of the present invention, and the same methods can be used.

[0097] The content of taxifolin or its salt in the food composition of the present invention is not particularly limited. For example, it is 0.1% by weight or more and 50% by weight or less relative to the entire food composition. As a lower limit, it is preferably 0.5% by weight or more, more preferably 1.0% by weight or more. On the other hand, as an upper limit, it is preferably 20% by weight or less, more preferably 10% by weight or less.

[0098] The food composition thus obtained is safe and can be continuously administered to a subject, particularly preferably to a human.

[0099] The intake amount of the food composition of the present invention is not particularly limited as long as it is within the effective amount of taxifolin or its salt to inhibit CD36, or within the effective amount for preventing and / or improving hepatocellular carcinoma from NASH. For example, when an adult ingests the food composition of the present invention for the purpose of preventing and / or improving hepatocellular carcinoma from NASH, the intake amount of taxifolin or its salt varies according to the object of ingestion, the form of ingestion, the amount of food intake, etc., and is different per day, per 1 kg of body weight, as the active ingredient, the taxifolin is converted to 0.001 mg / kg / day or more and 200 mg / kg / day or less. As a lower limit, it is preferably 0.01 mg / kg / day or more, more preferably 0.1 mg / kg / day or more, and further preferably 0.2 mg / kg / day or more. On the other hand, as an upper limit, it is preferably 50 mg / kg / day or less, more preferably 10 mg / kg / day or less. In addition, from the viewpoint of showing the effect without affecting the hobby or food intake, the above-mentioned intake amount is also preferred. The same amount can also be ingested when the subject is other mammals.

[0100] There is no particular limitation on the frequency of administration of taxifolin or a pharmaceutically acceptable salt thereof, and for example, it can be three times a day, twice a day, once a day, every other day, every other day, or every third day. Furthermore, administration can be before, after, or between meals.

[0101] Food composition of the present invention can be used alone, or in combination with other therapies (i.e., chemotherapy, surgery, radiotherapy). Specifically, for example, it can be used in combination with other pharmaceutical compositions, food compositions or feeds that have liver function improvement effects. By combining with other therapies, it is possible to further improve the prevention and / or improvement effects of hepatocellular carcinoma.

[0102] In addition, the food composition of the present invention also includes health food, functional label food, specific health food, health function food, food with disease risk reduction label, or special purpose food (for example, hospital food, patient food, nursing food and other patient food). As the disease risk reduction label, for example, the indication of the subject matter of "for reducing the risk of hepatocellular carcinoma" or "creating a body that is not prone to hepatocellular carcinoma" can be cited. Therefore, the food composition of the present invention is, for example, a food and beverage containing taxifolin or a salt thereof and with a label such as the subject matter of reducing the risk of hepatocellular carcinoma.

[0103] Here, the functional labels of these food compositions may be formed on any one of the product body, container, packaging, instructions, accompanying documents or promotional materials.

[0104] Example

[0105] The present invention is described in more detail below based on test examples and formulation examples. However, the present invention is not limited to these test examples and formulation examples and may be modified without departing from the scope of the present invention. Furthermore, reagents, devices, materials, etc. used in the present invention are commercially available unless otherwise specified. % represents weight % unless otherwise specified.

[0106] The taxifolin used in the following test examples was purchased from Ametis JSC (Russia) and used as it is.

[0107] [Test Example 1: Inhibitory Effect of Taxifolin on CD36 Gene Expression]

[0108] In Test Example 1, the effect of taxifolin on CD36 gene expression in liver tissue was investigated using high-fat diet-induced obesity model mice.

[0109] (Mouse feeding and feeding experiment)

[0110] Adult (7-week-old) C57BL / 6J male mice (CLEA Co., Ltd., Japan) were acclimated and raised for 1 week with free access to a normal solid feed (MF, Oriental Yeast Industry Co., Ltd.) and water.

[0111] The 8-week-old mice that had been acclimated and reared were divided into four groups of 5 mice each: a group in which the diet for 12 weeks until the age of 20 weeks was a normal solid diet (hereinafter referred to as the "ND group"), a group in which the diet was a high-fat diet (HFD-60 (506 kcal / 100 g, containing 60% fat in terms of energy ratio, Oriental Yeast Industry Co., Ltd.) (hereinafter referred to as the "HFD group"), a group in which the diet was a high-fat diet containing 1% by weight of taxifolin (hereinafter referred to as the "HFD + 1% TX administration group"), and a group in which the diet was a high-fat diet containing 3% by weight of taxifolin (hereinafter referred to as the "HFD + 3% TX administration group").

[0112] (Preparation of Measurement Samples)

[0113] Mice raised to 20 weeks of age were anesthetized with ether and euthanized by cervical dislocation, and the liver of each individual was removed.

[0114] The excised liver was cut into rectangular blocks of about 2 to 3 mm on a side, and total RNA was extracted using an RNA extraction kit (RNeasy Mini kit, Kiagen Co., Ltd.) The extracted total RNA was subjected to cDNA synthesis using a reverse transcription reaction to prepare a measurement sample.

[0115] (Determination of CD36 gene expression)

[0116] The measurement samples were subjected to real-time PCR using a real-time PCR apparatus (SYBR Green Realtime PCR Master Mix, ThermoFisher SCIENTIFIC).

[0117] The expression level of CD36 mRNA was corrected for the expression level of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and quantitatively compared using the ΔΔCt method. The primers used in PCR are shown in Table 1 below.

[0118] [Table 1]

[0119]

[0120] (Statistical Analysis)

[0121] Statistical analysis was performed using Student's t-test.

[0122] Figure 1The CD36 mRNA expression values are expressed as the mean ± standard error of each group. A P value of less than 0.05 was considered statistically significant and was indicated with an "*." A P value of less than 0.001 was indicated with a "**."

[0123] (Result 1)

[0124] Figure 1 The graph shows the CD36 mRNA levels in the liver tissues of mice in each group 12 weeks after the start of the feeding experiment.

[0125] like Figure 1 As shown, the HFD group, which was fed a high-fat diet, showed significantly increased CD36 mRNA expression in liver tissue compared to the ND group, which was fed a normal solid diet. Furthermore, CD36 mRNA expression, which had increased with the high-fat diet, was significantly reduced in the HFD + 1% TX and HFD + 3% TX groups, depending on the dose of taxifolin. In particular, CD36 mRNA expression in the HFD + 3% TX group was suppressed to the same level as in the ND group, which was fed a normal solid diet, maintaining normal values.

[0126] Therefore, it was found that taxifolin significantly inhibited CD36 gene expression that was hyperexpressed due to obesity.

[0127] [Test Example 2: Inhibitory Effect of Taxifolin on Fatty Acid Uptake]

[0128] In Test Example 2, the effect of taxifolin on fatty acid uptake was investigated using HepG2 cells, a cell line derived from human liver cancer.

[0129] (Cell culture fatty acid uptake experiment)

[0130] HepG2 cells were grown in 24-well plates at a density of 0.2 × 10 6 HepG2 cells were seeded at a density of 100 μg / well and cultured in DMEM medium supplemented with 10% FBS until 70-80% of the surface area of the culture vessel was covered. HepG2 cells cultured in this medium were washed with phosphate-buffered saline (PBS) and then cultured for 24 hours in serum-free medium containing 400 μM palmitic acid, various concentrations of taxifolin, and 1% BSA as shown in Table 2. The n = 6 cells for each of Groups A to E.

[0131] The glucose concentration in the culture medium and serum-free medium was set to 0%, 0.1% (low glucose), or 0.45% (high glucose).

[0132] [Table 2]

[0133]

[0134] (Fat droplet staining and determination)

[0135] HepG2 cells cultured in serum-free medium for 24 hours were washed with PBS and fixed with 4% paraformaldehyde. The fixed HepG2 cells were treated with 60% isopropanol, and the fat droplets in the cells were stained using Oil Red O (Wako Pure Chemical Industries, Ltd.). Then, the cells were washed with 60% isopropanol and PBS. The washed HepG2 cells were treated with 100% isopropanol to dissolve the Oil Red O. The dissolved Oil Red O was recovered in a 96-well plate, and the absorbance (550 nm) was measured using a microplate reader (Multiskan SkyHigh, Thermo Fisher Scientific).

[0136] (Statistical Analysis)

[0137] Statistical analysis was performed using Student's t-test.

[0138] Figure 2 The values of fatty acid intake in the test group were expressed as the mean ± standard error of each group. When the P value was less than 0.01, it was considered to be statistically significant and marked with "**".

[0139] (Result 2)

[0140] Figure 2 The fatty acid uptake amount in HepG2 cells of each group is shown. The fatty acid uptake amount in HepG2 cells of each group A to E is expressed as a percentage relative to that of group A.

[0141] like Figure 2 As shown in A, under low glucose conditions, in group B, where palmitic acid as a fatty acid was added to the culture medium, a significant increase in palmitic acid uptake by HepG2 cells was observed compared to group A, which served as the control group. In contrast, palmitic acid uptake by HepG2 cells was significantly reduced in the presence of 0.1 nM or more taxifolin. Figure 2 (B) The same tendency was observed in the effect of taxifolin on palmitic acid uptake in HepG2 cells under high glucose conditions.

[0142] Therefore, it was found that taxifolin inhibited fatty acid uptake in liver cells at a low concentration of 0.1 nM.

[0143] On the other hand, in the absence of glucose, no uptake of palmitic acid was observed in HepG2 cells ( Figure 2 C).

[0144] The fatty acid uptake capacity of HepG2 cells is dependent on extracellular glucose, thus suggesting the involvement of ATP.

[0145] The representative fatty acid uptake molecule CD36 is mobilized to the cell surface when extracellular fatty acid concentrations rise, thereby activating fatty acid uptake into the cell. The migration of CD36 to the cell membrane is facilitated by ATPases with ATP pockets.

[0146] Therefore, it is believed that the inhibitory effect of taxifolin on fatty acid uptake in hepatocytes is caused by the functional inhibition of CD36.

[0147] According to the above results 1 and 2, taxifolin not only inhibits CD36 gene expression but also inhibits the function of expressed CD36. Therefore, the CD36 inhibitor of the present invention can provide an excellent method for inhibiting CD36 activity.

[0148] [Test Example 3: Preventive Effect of Taxifolin on Hepatocellular Carcinoma in MC4R-Deficient Mice]

[0149] In Test Example 3, the effect of taxifolin on hepatocellular carcinoma was investigated using melanocortin type 4 receptor-deficient mice (hereinafter referred to as "MC4R-deficient mice") that were fed a high-fat diet.

[0150] (Preparation of MC4R-deficient mice)

[0151] MC4R-deficient mice were provided by Joel K. Elmquist of the University of Texas Medical Center based on the descriptions of Japanese Patent Application Laid-Open Nos. 2020-065454 and 2017-006022 (Cell, 2005; 123(3): 493-505). The genetic background of the MC4R-deficient mice was C57BL / 6J.

[0152] Unless otherwise specified, these mice were maintained in an environment with controlled temperature, humidity, and lighting (12-hour light-dark cycle). Furthermore, after weaning (4 weeks after birth), they were housed with free access to a high-fat diet (D12492 (524 kcal / 100 g, 60% fat by energy ratio), Research Diets, Inc.) and water.

[0153] (Hepatocellular carcinoma induction experiment)

[0154] It is known that MC4R-deficient mice fed a high-fat diet develop NASH-like liver lesions in all individuals before 20 weeks of age, followed by the development of hepatocellular carcinoma (Am. J. Pathol., 2011; 179(5): 2454-2463).

[0155] Twenty-week-old MC4R-deficient mice fed a high-fat diet were divided into two groups: a control group (n=13) in which the high-fat diet was continued until 50 weeks of age under the same housing conditions, and a taxifolin-administered group (n=12) in which the high-fat diet containing 3% taxifolin was maintained.

[0156] (Determination of Hepatocellular Carcinoma Lesions)

[0157] Mice raised to 50 weeks of age were euthanized by deep anesthesia using a three-drug mixed anesthetic, and their livers were removed.

[0158] The number of precancerous lesions (Foci) in the removed liver, the number of tumors clustered with precancerous lesions, and the size of the tumors were measured.

[0159] (Statistical Analysis)

[0160] Statistical analysis was performed using Student's t-test.

[0161] Figure 3 The values for the number of precancerous lesions, the number of tumors clustered with precancerous lesions, and tumor size are expressed as the mean ± standard error for each group. A P value of less than 0.05 was considered statistically significant and was indicated with an "*." A P value of less than 0.01 was indicated with a "**."

[0162] (Result 3)

[0163] Figure 3 The numbers of precancerous lesions, the numbers of tumors clustered with precancerous lesions, and the sizes of tumors are shown for the control group and the taxifolin-administered group.

[0164] like Figure 3 As shown in A, the number of precancerous lesions in the taxifolin-treated group was significantly reduced compared to the control group. Figure 3 As shown in B, the number of tumors with precancerous lesions clustered in the taxifolin-treated group was significantly reduced compared with the control group.

[0165] Further, if Figure 3 As shown in C, the number of tumors with a size of 1 to 5 mm was significantly reduced in the taxifolin-treated group compared with the control group.

[0166] Therefore, it was found that taxifolin inhibits the development of NASH-related hepatocellular carcinoma.

[0167] According to Result 3 above, it was confirmed that taxifolin inhibits the onset of NASH-related hepatocellular carcinoma. Therefore, the CD36 inhibitor of the present invention can provide a pharmaceutical or food composition for preventing, treating, or ameliorating NASH-related hepatocellular carcinoma.

[0168] Examples of the preparations of the present invention include the following preparations, but the present invention is not limited to these preparations.

[0169] Preparation Example 1 (Manufacture of Tablets)

[0170]

[0171] The total amount of 1), 2), and 3) and 12 g of 4) were kneaded with water, vacuum-dried, and then granulated. 5 g of 4) and 3 g of 5) were mixed with the granulated powder and compressed using a tablet press. This yielded 1,000 tablets, each containing 50 mg of taxifolin.

[0172] Preparation Example 2 (Manufacture of Tablets)

[0173]

[0174] The total amount of 1) and 2) and 40 g of 3) were kneaded with water, vacuum-dried, and then granulated. The granulated powder was mixed with the total amount of 4), 5), and 6) and 22 g of 3) and compressed using a tablet press. This yielded 1,000 tablets containing 18 mg of taxifolin per tablet.

[0175] Preparation Example 3 (Manufacture of Tablets)

[0176]

[0177] The total amount of 1) and 2) and 40 g of 3) were kneaded with water, vacuum-dried, and then granulated. The granulated powder was mixed with the total amount of 4), 5), and 6) and 22 g of 3) and compressed using a tablet press. This yielded 1,000 tablets containing 18 mg of taxifolin per tablet.

[0178] Preparation Example 4 (Manufacture of Capsules)

[0179]

[0180] 1), 2) and 3) are mixed and filled into gelatin capsules.

[0181] Preparation Example 5 (Manufacture of Capsules)

[0182]

[0183] 1), 2) and 3) are mixed and filled into gelatin capsules.

[0184] Industrial Applicability

[0185] According to the present invention, an excellent CD36 inhibitor comprising taxifolin or a pharmaceutically acceptable salt thereof as a safe plant-derived ingredient can be provided. The CD36 inhibitor of the present invention can inhibit the expression of CD36 at a low concentration, and is also effective for subjects (e.g., mammals) suffering from NASH at risk of developing hepatocellular carcinoma, and thus can effectively inhibit the onset and progression of hepatocellular carcinoma derived from NASH. That is, according to the present invention, a medicine or food composition containing taxifolin or a pharmaceutically acceptable salt thereof as an active ingredient for preventing, treating and / or improving hepatocellular carcinoma derived from NASH can be provided. In addition, according to the present invention, a medicine or food composition containing taxifolin or a pharmaceutically acceptable salt thereof as an active ingredient for preventing, treating and / or improving diseases related to the activation of CD36 other than hepatocellular carcinoma derived from NASH can also be provided.

[0186] This application is based on Japanese Patent Application No. 2022-100812 filed in Japan on June 23, 2022, the entire contents of which are incorporated herein by reference.

Claims

A CD36 inhibitor for use in a mammal suffering from non-alcoholic steatohepatitis, comprising taxifolin or a pharmaceutically acceptable salt thereof.

2. A medicament for preventing or treating a disease associated with CD36 activation by administering the medicament to a mammal suffering from non-alcoholic steatohepatitis, the medicament comprising a pharmaceutically effective amount of the agent according to claim 1.

3. The drug according to claim 2, wherein A disease associated with CD36 activation is hepatocellular carcinoma derived from nonalcoholic steatohepatitis.

4. A food composition for preventing or ameliorating a disease associated with CD36 activation by ingestion by a mammal suffering from non-alcoholic steatohepatitis, the food composition comprising an effective amount of the agent according to claim 1.

5. The food composition according to claim 4, wherein A disease associated with CD36 activation is hepatocellular carcinoma arising from nonalcoholic steatohepatitis.

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