Inhibitors of advanced glycosylation end product production

Abstract

This inhibitor for the production of advanced glycosylation end products contains a bacillus natto culture extract as an active ingredient. According to the present invention, a bacillus natto culture extract derived from a food material is contained as a main component, and can be safely ingested without concern of side effects. In addition, mass production can be realized, and market circulation is easy.

Description

Technical Field

[0001] The present invention relates to inhibitors of advanced glycation end products (AGEs) production. Background Art

[0002] In recent years, the incidence of type 2 diabetes has continued to rise, and its complications (such as nephropathy, retinopathy, and peripheral neuropathy, which can lead to vascular disorders) have become a major factor in seriously reducing healthy life expectancy. If left unchecked, these complications can become fatal, including hemodialysis due to nephropathy, blindness due to retinopathy, and painless myocardial infarction and gangrene due to vascular diseases such as neuropathy.

[0003] Furthermore, the involvement of "AGEs" (Advanced Glycation Endproducts) in type 2 diabetic nephropathy has been reported (e.g., Non-Patent Documents 1-5), and their relationship to the progression of the disease has been extensively studied. AGEs, also known as "advanced glycation endproducts" or "end-glycation products," are a general term for modified proteins formed by oxidation / non-oxidation reactions starting with non-enzymatic reactions (glycosylation reactions) between proteins and sugars. The series of reactions involved in the formation of AGEs is also known as the Maillard reaction.

[0004] The increase in AGEs in type 2 diabetes is believed to be related not only to hyperglycemia but also to the increased oxidative stress caused by metabolic abnormalities such as hypertension, hyperlipidemia, obesity, and hyperinsulinemia.

[0005] Therefore, there is a need to establish a technology for inhibiting the production of AGEs in vivo and suppressing the onset and progression of the above-mentioned type 2 diabetes and the like.

[0006] Prior art literature

[0007] Non-patent literature

[0008] Non-patent literature 1: Kang J et al., Acta Diabetol. 2005 Jun; 42(2): 110-6;

[0009] Non-patent document 2: Miyata T et al., Kidney Int. 1998 Feb; 53(2): 416-22;

[0010] Non-patent document 3: Friedman EA, Nephrol Dial Transplant. 1999; 14 Suppl 3: 1-9;

[0011] Non-patent document 4: Christensen EI et al., Nat Rev Mol Cell Biol. 2002, Apr; 3(4): 256-66;

[0012] Non-patent document 5: Gugliucci A et al., Diabetologia. 1996 Feb; 39(2): 149-60. Summary of the Invention

[0013] Technical problem to be solved by the invention

[0014] The present invention aims to solve the above-mentioned problems and aims to provide an advanced glycation end product production inhibitor that can effectively inhibit the production of AGEs in vivo and has excellent safety.

[0015] Technical solutions to technical problems

[0016] The present invention is an advanced glycation end product generation inhibitor containing a Bacillus natto culture extract as an effective ingredient.

[0017] In one embodiment, the Bacillus natto culture extract contains nattokinase.

[0018] In one embodiment, the Bacillus natto culture extract is in the form of dry powder.

[0019] In one embodiment, the content of vitamin K2 contained in the Bacillus natto culture extract is 1 μg or less per 1 g of the dry mass of the Bacillus natto culture extract.

[0020] In one embodiment, the Bacillus natto culture extract has a nattokinase activity of 100 FU / g to 80,000 FU / g.

[0021] In one embodiment, the inhibitor of advanced glycation end products formation of the present invention is an oral preparation.

[0022] The present invention is also a method for inhibiting the production of advanced glycation end products in an organism, comprising the step of administering a Bacillus natto culture extract as an active ingredient to the organism.

[0023] In one embodiment, the above-mentioned administration to an organism is performed orally.

[0024] The present invention also relates to the use of a composition containing a Bacillus natto culture extract as an effective ingredient for inhibiting the generation of advanced glycation end products.

[0025] Effects of the Invention

[0026] According to the present invention, since the Bacillus natto culture extract derived from food materials is contained as a main component, it can be safely ingested without worrying about side effects. In addition, it can be mass-produced and easily distributed in the market. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 This is a diagram showing the experimental plan performed in Example 3.

[0028] Figure 2 This is a photograph showing the surface of a thin section of a tissue specimen used in the pathological tissue evaluation of the nephron performed in Example 3.

[0029] Figure 3 This is a graph showing the glycosylation status of renal tubules in the pathological tissue evaluation of nephrons performed in Example 3, using vacuolation of epithelial cells and PAS staining positivity scores.

[0030] Figure 4 This is a graph showing the results of measuring the plasma advanced glycation end products (AGEs) concentration performed in Example 3. DETAILED DESCRIPTION

[0031] The advanced glycation end product production inhibitor of the present invention contains a Bacillus natto culture extract as an active ingredient.

[0032] The term "advanced glycation end products (hereinafter sometimes referred to as AGEs)" as used herein refers to a general term for modified proteins formed by oxidation / non-oxidation reactions starting with a non-enzymatic reaction (glycosylation reaction) between a protein and a sugar. Furthermore, the term "inhibition of advanced glycation end product production" as used herein also encompasses both suppressing the increase in the amount of AGEs produced in vivo or in vitro, such as by the Maillard reaction, to maintain a substantially constant level, and suppressing the production of AGEs themselves to reduce the amount of AGEs produced.

[0033] The Bacillus natto culture extract is an extract obtained from the culture broth of Bacillus natto, a type of Bacillus subtilis (representatively, Bacillus subtilis natto). The Bacillus natto can be any species as long as it is a microorganism capable of producing nattokinase, which will be described later. It can also be Bacillus natto isolated from commercially available natto.

[0034] The Bacillus natto culture extract may be in the form of a dry powder, a liquid, or a paste. For reasons of ease of handling and commercial availability, the Bacillus natto culture extract is preferably in the form of a dry powder.

[0035] Furthermore, to facilitate consumption by a wider audience, the Bacillus natto culture extract is preferably one that has reduced or eliminated the strong natto odor, a characteristic taste of natto. For example, to reduce or eliminate this natto odor, the Bacillus natto culture extract is preferably one that has previously been freed of prescribed impurities. Specifically, the Bacillus natto culture extract is preferably freed of impurities having a molecular weight of preferably 1,000 or less, and more preferably 20,000 or less.

[0036] Bacillus natto culture extract contains nattokinase as a main component.

[0037] Nattokinase (NK) is a substance in the viscous substance of natto that has fibrin-degrading activity. It is a serine protease of the subtilisin family composed of 275 amino acids. For example, in vivo experiments show a high thrombolytic effect in vivo. It is known to have effects such as improving blood flow in peripheral blood vessels, inhibiting platelet aggregation, lowering blood pressure in hypertension, and enhancing immunity. In addition, for example, in in vitro experiments, it is known to have higher fibrin-degrading activity than plasmin, and can decompose and inactivate PAI-1, thereby increasing tissue plasminogen activator (tPA).

[0038] Bacillus natto culture extract has the nattokinase activity of regulation.Nattokinase activity is used to represent the unit of FU (fibrin degradation unit) in every 1g, for example, according to the method etc. of Experientia43 volume, 1110 pages (1987) record, can detect whether to form lytic plaque on fibrin plate.

[0039] The Bacillus natto culture extract of the present invention preferably has a nattokinase activity of 100 FU / g to 80,000 FU / g, more preferably 4,000 FU / g to 80,000 FU / g. When the nattokinase activity of the Bacillus natto culture extract is lower than 100 FU / g, in order to obtain the desired effect of efficiently inhibiting the generation of advanced glycation end products, a contradiction may arise in that more Bacillus natto culture extract is required.

[0040] In addition, the nattokinase activity in commercially available natto is generally only 20FU / g to 40FU / g. In contrast, the nattokinase activity of each prescribed amount of the Bacillus natto culture extract is very high compared to such commercially available natto. Therefore, the advanced glycation end product generation inhibitor of the present invention containing this Bacillus natto culture extract can have a high nattokinase activity that is ultimately unavailable when utilizing commercially available natto.

[0041] Typically, when Bacillus natto is cultured, the culture medium contains both nattokinase, a factor in the thrombolytic system, and vitamin K, a factor in the thrombolytic system. This vitamin K is known to counteract the effects of nattokinase and is therefore a component that should be preferably removed in the present invention. Therefore, in the present invention, the vitamin K2 content in the Bacillus natto culture extract is preferably adjusted to 1 μg or less, more preferably 0.1 μg or less, per 1 g of the dry mass of the Bacillus natto culture extract.

[0042] Vitamin K2 contained in a Bacillus natto culture extract can be removed by mixing a Bacillus natto culture solution containing vitamin K2 with an aqueous chitosan solution, adsorbing the vitamin K2 onto the chitosan, and then filtering and removing the chitosan adsorbed with the vitamin K2, as described in, for example, Japanese Patent Application Laid-Open No. 2006-325597.

[0043] The inhibitor of advanced glycation end products production of the present invention may contain an oily substance to improve the dispersibility of the Bacillus natto culture extract. The oily substance is preferably one that does not solidify at temperatures below 50°C, preferably below 40°C. Examples of oily substances include soybean oil, glycerol fatty acid esters, beeswax, rapeseed oil, jojoba oil, palm oil, coconut oil, and combinations thereof.

[0044] The content of the oily substance in the AGE production inhibitor of the present invention is not particularly limited. For example, a person skilled in the art can select an appropriate amount based on the nattokinase activity of the Bacillus natto culture extract used in combination.

[0045] In addition, the advanced glycation end product production inhibitor of the present invention may contain other additives in addition to the Bacillus natto culture extract. Examples of such other additives include those commonly used in the food and / or pharmaceutical fields. Specific examples include excipients, stabilizers, lubricants, binders, flow agents, disintegrants, sweeteners, flavorings, colorants, and combinations thereof.

[0046] Examples of excipients include erythritol, sorbitol, xylitol, maltitol, lactose, sucrose, trehalose hydrate, reduced maltose syrup, crystalline cellulose, dextrin, corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, sodium bicarbonate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate hydrate, tricalcium phosphate, calcium carbonate, precipitated calcium carbonate, calcium silicate, calcium lactate, and combinations thereof.

[0047] Examples of the stabilizer include dextrin, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, sucrose fatty acid ester, hydroxypropyl-β-cyclodextrin, hydroxypropylcyclodextrin, mannitol, and combinations thereof.

[0048] Examples of the lubricant include stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, sucrose fatty acid esters, hydrogenated oil, glycerin, glycerin fatty acid esters, carnauba wax, talc, and combinations thereof.

[0049] As the binder, for example, pullulan, pectin, sodium alginate, gum arabic, guar gum, agar, starch syrup, hydroxypropyl cellulose, pregelatinized starch, polyvinyl pyrrolidone, carboxyvinyl polymer, polyvinyl alcohol, aminoalkyl methacrylate copolymer, ethyl cellulose, carboxyvinyl polymer, carboxymethyl ethyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, methyl cellulose, beeswax, polyethylene glycol, and methacrylic acid copolymer and combinations thereof can be cited.

[0050] Examples of the fluidizing agent include silicon dioxide, light anhydrous silicic acid, magnesium aluminum metasilicate, fumed silica, and combinations thereof.

[0051] Examples of the disintegrant include hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, corn starch, partially pregelatinized starch, sodium carboxymethyl starch, crospovidone, and combinations thereof.

[0052] Examples of the sweetener include aspartame, saccharin, stevia, sweet tea powder (sweet hydrangea leaf powder), sucralose, acesulfame potassium, sucrose, sorbitol, reduced maltose syrup, o-sulfonylbenzoylmide, licorice, thaumatin, and combinations thereof.

[0053] Examples of the flavor include orange, vanilla, strawberry, yogurt, menthol, anise oil, cinnamon oil, spruce oil, mint oil, green tea powder, and combinations thereof.

[0054] Examples of the colorant include red iron oxide, yellow iron oxide, black iron oxide, titanium dioxide, talc, Food Yellow No. 4, Food Yellow No. 4 aluminum lake, Food Yellow No. 5, Food Red No. 2, Food Red No. 3, Food Red No. 102, Food Blue No. 1, methylene blue, carmine, riboflavin, and combinations thereof.

[0055] The content of the above-mentioned additives in the advanced glycation end product production inhibitor of the present invention is not particularly limited. For example, those skilled in the art can select an appropriate amount based on the nattokinase activity of the Bacillus natto culture extract used in combination.

[0056] The dosage of the advanced glycation end product formation inhibitor for adults (weighing 60-65 kg) is preferably 1000-4000 FU (fibrin degrading units) per day, more preferably 2000-4000 FU, which can be administered in divided doses over the day.

[0057] The advanced glycation end product formation inhibitor of the present invention is an oral preparation that can be ingested by humans or animals such as pets, livestock, poultry, and farmed fish, and can be used as a food, beverage, feed (bait), or pharmaceutical itself or as a component of these.

[0058] Furthermore, the inhibitor of advanced glycation end products production of the present invention can have any dosage form, and examples thereof include powders, granules, pills, tablets, and liquid preparations. When such an inhibitor of advanced glycation end products production is used as a food or beverage, examples thereof include: ordinary foods; supplements; health functional foods such as foods for specific health uses, nutritional functional foods, and functionally labeled foods; soft drinks; tea drinks; coffee drinks; processed milk; dairy drinks; soy milk; and alcoholic beverages.

[0059] The advanced glycation endproducts production inhibitor of the present invention contains, as an active ingredient, a Bacillus natto culture extract obtained from natto, which is useful as a common food. Therefore, it is fully safe for ingestion by living organisms (e.g., humans). Furthermore, it can be safely ingested by a wide range of people, from young children to adults and the elderly.

[0060] The advanced glycation end product production inhibitors of the present invention can also inhibit the onset and progression of type 2 diabetes, etc., by, for example, inhibiting the production of AGEs in vivo. Alternatively, the advanced glycation end product production inhibitors of the present invention can also be used as blood AGE concentration-lowering agents for reducing the concentration of AGEs in the blood, when ingested by humans.

[0061] Example

[0062] Next, the present invention will be further described with reference to examples, but the present invention is not limited to these examples.

[0063] (Example 1: Preparation of feed containing low dosage of nattokinase (NK-L))

[0064] As a Bacillus natto culture extract containing nattokinase (NK), we accepted the supply of NSK-SD (manufactured by Japan Bioscience Research Institute Co., Ltd.). This product is a powder obtained by filtering the culture extract obtained from Bacillus natto fermentation to remove impurities with a molecular weight of 20,000 or less, and then drying it by spray drying (containing dextrin as a stabilizer). It contains 3.4% by mass of nattokinase and has a nattokinase activity of 20,000 FU / g.

[0065] Next, CLEA Co., Ltd. of Japan was commissioned to prepare a feed containing 0.6% of the above-mentioned Natto Bacillus culture extract (NSK-SD) in 1 g of ordinary solid feed (CE-2 manufactured by CLEA Co., Ltd. of Japan), thereby obtaining a low-dose nattokinase feed (NK-L) (an inhibitor of advanced glycation end products) containing 0.2 mg of nattokinase (NK) per 1 g of feed.

[0066] (Example 2: Preparation of feed containing high dosage of nattokinase (NK-H))

[0067] The same operation as in Example 1 was performed except that 1.8% of the above-mentioned natto culture extract (NSK-SD) was contained in 1 g of ordinary solid feed (CE-2 manufactured by CLEA Co., Ltd. of Japan) by entrusting CLEA Co., Ltd. of Japan to prepare a feed, thereby obtaining a high-dose nattokinase feed (NK-H) (an inhibitor of advanced glycation end products) containing 0.6 mg of nattokinase (NK) per 1 g of feed.

[0068] (Example 3: Construction of STZ-induced Type II Diabetes Model Animals and Administration of Nattokinase-Containing Feeds)

[0069] In order to evaluate the low-amount nattokinase-containing feed (NK-L) and the high-amount nattokinase-containing feed (NK-H) obtained in Examples 1 and 2, the following animals and reagents were used.

[0070] (1) Animals

[0071] All experimental procedures complied with the Animal Protection and Management Act and other experimental-related laws and regulations and the Hiroshima University Guidelines for Experimental Animals, and animal experiments were conducted in accordance with ethical considerations.

[0072] Six-week-old male Spragur-Dawly (SD) rats were purchased from SLC Co., Ltd., Japan. They were housed at a density of three rats per cage in a housing facility (Hiroshima University Kure Campus) under conditions of 23±1°C, 55±5% humidity, and a 12-hour light-dark cycle (light: 8:00–20:00, dark: 20:00–8:00) for 10 days of acclimation. Animals weighing 240–280 g were used in this experiment. During acclimation, animals were provided with a standard solid diet (CE-2, manufactured by Clea Co., Ltd., Japan) and free access to drinking water via an automatic drinking valve.

[0073] (2) Reagents

[0074] Streptozotocin (STZ), diethyl ether (special grade), pH 4.5 sodium citrate buffer, cholesterol E-test Wako, and LabAssay were purchased from Fujifilm Wako Pure Chemical Industries, Ltd. TM Triglycerides.

[0075] Novo-Heparin heparin injection 10,000 units / 10 mL was purchased from Mochida Pharmaceutical Co., Ltd. and used.

[0076] A self-diagnosis blood glucose meter, Diasensor, was purchased from Arkray Co., Ltd. and used.

[0077] The Oxi Select™ Advanced Glycation End Products (AGE) competitive ELISA kit was purchased from Cosmo Bio Co., Ltd. and used.

[0078] 1 mL of Sureads Protein G Magnetic Beads was purchased from Bio-Lad and used.

[0079] Glucose was purchased from Merck and used.

[0080] (3) Experimental methods

[0081] based on Figure 1 The experiment was carried out according to the plan shown. Specifically, it was carried out as follows.

[0082] Based on the fasting blood glucose and body weight of SD male rats (8 weeks old) after 10 days of acclimation and rearing, they were divided into three groups (n=6) by stratified random sampling to make the mean and variance of each parameter uniform. After a single intraperitoneal administration of streptozotocin (STZ) adjusted to pH 4.5 with sodium citrate at a dose of 55 mg / 3 mL / kg body weight, the rats were reared for 14 days.

[0083] Just after STZ administration, the control group was provided with a normal solid feed (CE-2 manufactured by CLEA Co., Ltd. of Japan), the NK low-dose feeding group was provided with a feed containing a low amount of nattokinase obtained in Example 1 (NK-L) (0.2 mg NK / g CE-2), and the NK high-dose feeding group was provided with a feed containing a high amount of nattokinase obtained in Example 2 (NK-H) (0.6 mg NK / g CE-2) for free intake for 14 days.

[0084] Only animals that exhibited fasting blood glucose levels of 200 mg / dL or higher, indicating diabetic status, on day 7 after STZ administration were allowed to continue the experiment. This was based on the empirical rule that in individuals whose blood glucose levels did not reach abnormal values ​​on day 7 after STZ administration, no increase in blood glucose levels was observed until the end of the experiment. Rabbits were housed in stainless steel cages at a density of 3 rabbits per cage. Food intake was measured three times per week for each cage during the experimental period.

[0085] Blood glucose levels were measured and blood was collected immediately before STZ administration, and on the 7th and 14th day after the start of test substance administration. Immediately before STZ administration, and 7 and 14 days after the start of test substance administration (the final day of the study), 500 μL of blood (heparinized) was collected from the tail vein of rats that had fasted for 15 hours (7:00 PM to 10:00 AM) the previous day. Blood (30 μL) that flowed out before hemostasis was used as a sample for measurement of blood glucose levels using a self-testing blood glucose meter (GT-1670, manufactured by Arkray Co., Ltd.). The heparinized blood was centrifuged (1500 × g, 10 minutes) using a micro high-speed refrigerated centrifuge (MX-100, manufactured by Tomy Seiko Co., Ltd.), and the resulting plasma was stored at -80°C until used as a sample for measurement of blood biochemical parameters.

[0086] Immediately after blood collection, the abdominal aorta was cut, and the rats were euthanized by exsanguination. The left kidney was then removed and fixed in 10% formalin buffer (pH 6.8). Separately, male SD rats (8 weeks old) were housed normally for 14 days and their left kidneys were removed in the same manner as above to serve as normal specimens.

[0087] (4) Determination of blood biochemical markers

[0088] The plasma obtained in the experiment (4) above was used as a sample to measure AGEs.

[0089] AGEs were determined using the Oxi Select™ Advanced Glycation End Products (AGE) competitive ELISA kit.

[0090] (5) Pathological evaluation of kidney

[0091] On day 14 after STZ administration, the left kidneys of individuals in each group were removed, dehydrated using an automatic processor, and embedded in paraffin. Tissue specimens (4 μm) were stained with hematoxylin-eosin (HE), periodic acid-silver hexaamine (PAM), and periodic acid-Schiff (PAS) to observe the renal corpuscles and tubules.

[0092] (6) Results

[0093] (body weight and food intake)

[0094] Table 1 shows the respective weight gain and food intake of the control group, the NK low-dose feeding group (hereinafter also referred to as "NK-L feeding group of Example 1") which was fed with the feed (NK-L) containing the low dose of nattokinase obtained in feeding Example 1, and the NK high-dose feeding group (hereinafter also referred to as "NK-H feeding group of Example 2") which was fed with the feed (NK-H) containing the high dose of nattokinase obtained in feeding Example 2.

[0095] [Table 1]

[0096]

[0097] As shown in Table 1, the average weight gain over the 14 days from the start of test substance administration was approximately 2 g / day in all groups, with no difference between the groups. No difference was observed in food intake either.

[0098] (Blood biochemistry data)

[0099] Table 2 shows the blood sugar levels of the normal value group, the control group, the NK-L feeding group of Example 1, and the NK-H feeding group of Example 2.

[0100] [Table 2]

[0101]

[0102] #:P<0.05

[0103] As shown in Table 2, blood glucose levels in all groups rose to 200 mg / dL or higher on day 7 after STZ administration (day 7 from the start of test substance administration). On day 14, blood glucose levels rose to 326.75 ± 17.0 mg / dL in the control group, 419.8 ± 23.3 mg / dL in the NK-L-fed group of Example 1, and 401 ± 31.0 mg / dL in the NK-H-fed group of Example 2. These values ​​were significantly different from the normal value (67.11 ± 1.3 mg / dL). However, no significant differences were found between the groups.

[0104] (Pathological evaluation of nephron)

[0105] The periphery of the left kidney nephron removed from the rats of each group was evaluated for pathological tissue.

[0106] Specifically, as described in the experimental method (4) above, the left kidney of each group of rats was removed, dehydrated with an automatic processor, and embedded in paraffin. For the normal group (N), SD male rats (8 weeks old) were fed with ordinary solid feed (CE-2 manufactured by CLEA Co., Ltd., Japan) for 14 days and treated in the same way as above. The tissue specimens were thinly sliced ​​(4 μm) and stained with hematoxylin-eosin (HE), periodic acid-hexaamine silver (PAM), and periodic acid-Schiff (PAS) to observe the renal corpuscles and renal tubules ( Figure 2 ).

[0107] Next, the glycosylation status of the renal tubules was scored based on the vacuolation of the epithelial cells and the positive PAS staining. The evaluation was performed by scoring on a 5-point scale (no change: -, slight change: +, moderate change: ++, severe change: +++, and significant change: ++++) according to the following criteria. The Mann-Whitney's U test was used to test the P value (*: P < 0.05). The results are shown in Figure 3 .

[0108] like Figure 2 As shown, regarding the renal corpuscles (HE staining; left column), in comparison with the normal group, no lesions were observed around the renal corpuscles in the control group, the NK-L feeding group of Example 1, and the NK-H feeding group of Example 2, and no abnormalities were found. Regarding the renal tubules (HE staining; central column), in comparison with the normal group, as shown by the arrows, vacuolation of epithelial cells was confirmed in all groups. Regarding the renal tubules (PAS staining; right column), in comparison with the normal group, as shown by the arrows, glycosylation of epithelial cells was confirmed in all groups (PAS staining positive: glycogen deposition). In addition, as shown Figure 3 As shown, glycation rated ++ was observed in all individuals in the control group and the NK-L-fed group of Example 1, but only mild cases rated + were observed in the NK-H-fed group of Example 2. Mild cases were observed in 3 of 6 individuals in the NK-H-fed group of Example 2, and the average score was significantly lower than that of the control group.

[0109] (Plasma advanced glycation end products (AGEs) concentration)

[0110] The plasma advanced glycation end products (AGEs) concentrations were measured for the normal value group, the control group, the NK-L feeding group of Example 1, and the NK-H feeding group of Example 2.

[0111] Specifically, as described in the experimental method (4) above, the plasma samples of the rats in each group were used for measurement, and the measured values ​​were expressed as mean ± standard error. The Dunnet method was used for statistical analysis, and the differences with the control group were compared (*: P < 0.05). The results are shown in Figure 4 .

[0112] The plasma AGEs concentration in the control group was 4.12±0.48 μg / dL, significantly higher than the normal value group (2.06±0.19 μg / dL). In contrast, the NK-L-fed group of Example 1 was 2.81±0.75 μg / dL, and the NK-H-fed group of Example 2 was 1.30±0.36 μg / dL. Compared to the control group, these values ​​decreased with the amount of NK used, and were significantly lower in the NK-H-fed group of Example 2.

[0113] Industrial applicability

[0114] The present invention is useful in technical fields such as the food field and the pharmaceutical field.

Claims

1. An inhibitor of advanced glycation end products formation, characterized in that: Contains Bacillus natto culture extract as an active ingredient.

2. The advanced glycation end product formation inhibitor according to claim 1, characterized in that: The Bacillus natto culture extract contains nattokinase.

3. The advanced glycation end product formation inhibitor according to claim 1, wherein: The Bacillus natto culture extract is in the form of dry powder.

4. The advanced glycation end product formation inhibitor according to claim 1, wherein: The content of vitamin K2 contained in the Bacillus natto culture extract is 1 μg or less per 1 g of the dry mass of the Bacillus natto culture extract.

5. The advanced glycation end product formation inhibitor according to claim 1, wherein: The Bacillus natto culture extract has a nattokinase activity of 100 FU / g to 80,000 FU / g.

6. The advanced glycation end product formation inhibitor according to claim 1, wherein: It is an oral preparation.

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