Oxidative protein repair agent, and oxidative stress inhibitor via oxidative protein repair.

Abstract

In addition to oxidative protein repair agents and methods for repairing oxidative proteins, the present invention provides oxidative stress inhibitors and methods for suppressing oxidative stress through oxidative protein repair. [Solution] A water-soluble nucleoprotein, particularly a water-soluble nucleoprotein with a molecular weight of about 250 to 15,000 obtained by enzymatic treatment of fish milt, is contained in an oxidized protein repair agent and an oxidative stress inhibitor that acts through the repair of oxidized proteins, a health food containing the repair agent or oxidative stress inhibitor, and a method for repairing oxidized proteins damaged by oxidative stress or a method for suppressing oxidative stress through such repair by orally ingesting the repair agent or oxidative stress inhibitor.

Description

Technical Field

[0001] The present invention relates to a repair agent for oxidized proteins and a method for repairing oxidized proteins by oral ingestion thereof, and particularly to an antioxidant stress inhibitor through repair of oxidized proteins and a method for inhibiting antioxidant stress through repair of oxidized proteins by oral ingestion thereof. The present invention also relates to an agent for increasing the response of oxidized methionine repair enzyme gene and a method for increasing the response of oxidized methionine repair enzyme gene by oral ingestion thereof.

Background Art

[0002] In recent years, reflecting the increasing interest of the general public in health, health foods have been provided using deoxyribonucleic acid (DNA), ribonucleic acid (RNA), or a complex of these nucleic acids and proteins, salmon milt extract (also referred to as water-soluble nuclear protein), as a raw material or an active ingredient. For example, water-soluble nuclear protein is known to have an immunomodulatory effect, an antioxidant effect, a vasodilatory effect, and the like. There has also been a proposal of a cancer cell growth inhibitor containing a low-molecular-weight water-soluble nucleic acid or the water-soluble nucleic acid and an amino acid (Patent Document 1).

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0004] Heretofore, it has been reported that various actions and effects, including an antioxidant effect, are exhibited by ingestion of nucleic acids (DNA, RNA) or water-soluble nuclear proteins. However, no report has been made so far that these ingestions affect the repair of oxidized proteins.

[0005] The present invention aims to provide not only an agent for repairing oxidized proteins and a method for repairing oxidized proteins, but also an agent for suppressing oxidative stress and a method for suppressing oxidative stress through the repair of oxidized proteins. [Means for solving the problem]

[0006] The present invention relates to an oxidized protein repair agent, and more specifically to an oxidized protein repair agent containing a water-soluble nucleoprotein, and more particularly to an oxidized protein repair agent containing a water-soluble nucleoprotein with a molecular weight of 250 to 15,000 obtained by enzymatic treatment of fish milt. The present invention also relates to a health food for oxidative protein repair containing the aforementioned oxidative protein repair agent, and more particularly to a health food having the form of, for example, tablets, drinks, capsules, granules, pills, or jellies. Furthermore, the present invention also covers a method for repairing oxidized proteins damaged by oxidative stress, using the aforementioned oxidized protein repair agent.

[0007] In particular, the present invention relates to an oxidative stress inhibitor that acts through the repair of oxidized proteins, and more specifically to an oxidative stress inhibitor containing a water-soluble nucleoprotein, and more particularly to an oxidative stress inhibitor that contains a water-soluble nucleoprotein with a molecular weight of 250 to 15,000 obtained by enzymatic treatment of fish milt. The present invention also relates to a health food for suppressing oxidative stress through the repair of oxidized proteins, which includes the oxidative stress inhibitor, and more particularly to a health food in the form of tablets, drinks, capsules, granules, pills, or jellies. Furthermore, the present invention also covers a method for suppressing oxidative stress, which involves using the aforementioned oxidative stress inhibitor to repair oxidized proteins damaged by oxidative stress.

[0008] The present invention also relates to an oxidative methionine repair enzyme gene response enhancer containing a water-soluble nucleoprotein, and more particularly to an oxidative methionine repair enzyme gene response enhancer containing a water-soluble nucleoprotein with a molecular weight of 250 to 15,000 obtained by enzymatic treatment of fish milt. The present invention also relates to a health food for increasing the response of oxidized methionine repair enzyme genes, which includes the aforementioned oxidized methionine repair enzyme gene response increasing agent, and more particularly to a health food having the form of, for example, tablets, drinks, capsules, granules, pills, or jellies. Furthermore, the present invention also covers a method for increasing the response of oxidized methionine repair enzyme genes using the oxidized methionine repair enzyme gene response increasing agent. Effects of the present invention

[0009] According to the present invention, by using a water-soluble nucleoprotein containing low-molecular-weight DNA, for example by oral ingestion, the amount of methionine sulfoxide reductase (oxidized methionine repair enzyme; MSR), which is an enzyme that reduces oxidized methionine, increases, thereby providing the effect of repairing oxidized proteins, and also having the effect of suppressing oxidative stress. [Brief explanation of the drawing]

[0010] [Figure 1] Figure 1 shows the relative ratio of gene expression analysis results (by Thermo Fisher Scientific microarray) for methionine sulfohydrate reductase A (MSRA), thioredoxin (TXN), and methionine sulfohydrate reductase B2 (MSRB2) obtained from total RNA in the blood of subjects before and after administration (weeks 0 and 8) in a test tablet group in which subjects ingested a test tablet containing a water-soluble nucleoprotein for 8 weeks, and a placebo group in which subjects ingested a placebo tablet without a water-soluble nucleoprotein for 8 weeks ((A) MSRA, (B) TXN, (C) MSRB2 gene expression levels (percentage change from week 0 to week 8 (placebo group set to 1))). [Figure 2]Figure 2 shows the relative ratio of methionine sulfoxide reductase A (MSRA) results obtained from gene expression analysis of subjects' blood before and after administration (weeks 0 and 8) using digital PCR, between the test tablet group, in which subjects ingested a test tablet containing water-soluble nucleoprotein for 8 weeks, and the placebo group, in which subjects ingested a placebo tablet without water-soluble nucleoprotein for 8 weeks (percentage change in MSRA gene expression from week 0 to week 8 (placebo group set to 1)). [Figure 3] Figure 3 shows the results of the oxidative stress d-ROMs test and the oxidative stress index (OSI) measured in the blood of subjects before and after administration, in a test tablet group in which subjects ingested a test tablet containing water-soluble nucleoprotein for 8 weeks, and a placebo group in which subjects ingested a placebo tablet without water-soluble nucleoprotein for 8 weeks ((A) Oxidative stress level (d-ROMs), (B) Oxidative stress index (OSI)). [Figure 4] Figure 4 shows the survival rate of yeast after adding water-soluble nucleoprotein (and control) and then applying oxidative stress (hydrogen peroxide) (A), and the results of microarray and Realtime PCR methionine sulfoxide reductase 2 (MXR2) gene expression analysis obtained from the analysis of yeast treated with water-soluble nucleoprotein (B). [Modes for carrying out the invention]

[0011] The oxidative protein repair agent and oxidative stress inhibitor of the present invention contain a water-soluble nucleoprotein. The inventors have newly confirmed that this water-soluble nucleoprotein has the function of increasing oxidative methionine repair enzyme (methionine sulfoxide reductase; MSR), which is an enzyme that reduces and repairs methionine, which is particularly susceptible to oxidation among the amino acid residues that make up proteins. The inventors have found that oral intake of the above water-soluble nucleoprotein brings about the repair of oxidized proteins and leads to the suppression of oxidative stress through the repair of oxidized proteins. Conventional antioxidant mechanisms involve the decomposition and elimination of reactive oxygen species by antioxidant enzymes and antioxidants. However, the present invention aims to achieve antioxidant protection by repairing proteins damaged by oxidative stress, and is characterized by its completely different mechanism from the conventional mechanisms described above. In relation to the methionine sulfoxide reductase (Msr) mentioned above, cosmetic compositions containing oxidized peptides [oxidized methionine enkephalin (SEQ ID NO: 1: YGGFMO)] have been proposed, and there are reports that Msr gene expression was increased using these oxidized peptides (Japanese Patent Publication No. 2012-523436). In this report, skin damage caused by oxidative stress such as UV is prevented by applying the synthesized oxidized peptide. On the other hand, the water-soluble nucleoprotein related to the oxidative protein repair agent and oxidative stress inhibitor of the present invention reduces oxidative stress in the blood by promoting the expression of gene groups related to methionine sulfoxide reductase in the body when the naturally derived component is ingested as food. Therefore, it is thought that the oxidized peptide in the above report and the water-soluble nucleoprotein according to the present invention exert their effects through different mechanisms of action. The oxidized peptide in the above report aims for effects through skin application (transdermal absorption) such as cosmetics, while the present invention aims for effects by oral ingestion of water-soluble nucleoprotein, as will be described later.

[0012] Furthermore, the water-soluble nucleoprotein according to the present invention functions as a repair agent for oxidized proteins (oxidized proteins) and also as an inhibitor of oxidative stress through the repair of oxidized proteins. This specification discloses a method for repairing oxidized proteins using the water-soluble nucleoprotein (repair agent), and a method for suppressing oxidative stress by repairing oxidized proteins damaged by oxidative stress using the water-soluble nucleoprotein (inhibitor). Furthermore, the present invention also covers agents that increase the gene response of oxidized methionine repair enzymes. The present invention will be described in detail below.

[0013] The water-soluble nuclear protein used in the oxidated protein repair agent and the oxidative stress inhibitor of the present invention can be exemplified by a water-soluble nuclear protein obtained by extracting nucleic acid from biological cells and reducing its molecular weight by enzymatic treatment. That is, in this specification, the water-soluble nuclear protein can be rephrased as an extract of low-molecular-weight fish spermary. As an example of the above water-soluble nuclear protein, there is a water-soluble nuclear protein obtained by reducing the molecular weight of fish spermary by enzymatic treatment or the like to make it water-soluble. In this specification, "water-soluble" means the property of being able to dissolve in water at a concentration of 0.1% by mass or more.

[0014] Examples of the above fish include salmon, trout, herring, etc. Among these, the spermary of salmon, which contains a large amount of nucleic acid but has not been effectively utilized as a resource and has been mostly discarded, can be preferably used.

[0015] Examples of the enzymatic treatment of fish spermary include a method of treating a suspension obtained by pulverizing fish spermary with protease and then treating it with nuclease. Usually, when DNA or the like is extracted from spermary, the molecular weight becomes 1,000,000 or more, so it is reduced in molecular weight by enzymatic treatment. Preferred water-soluble nuclear proteins include those containing 20% by mass or more, more preferably 30% by mass or more, of nucleosides / nucleotides / oligonucleotides / polynucleotides (hereinafter also referred to as low molecular weight compounds) having a molecular weight of 250 to 100,000, such as 250 to 20,000, 250 to 15,000, 500 to 13,200, or 250 to 10,000, 250 to 6,600. More preferably, the water-soluble nuclear protein according to the present invention can contain 2% by mass or more of low molecular weight compounds having a molecular weight of 500 to 15,000 and 18% by mass or more of low molecular weight compounds having a molecular weight of 250 to 6,600.

[0016] The protease includes not only serine protease but also cysteine protease, metalloprotease, aspartic protease, etc. Since the fish sperm contains proteins other than protamine, those with relatively low substrate specificity are particularly preferred. Examples of good proteases include proteases manufactured by Novozymes Japan Co., Ltd. The hydrolysis treatment using the protease can be carried out at a temperature in the range of 30 to 60°C, for example, in the range of 40 to 50°C, and at a pH in the range of 6 to 7, taking into account the activation and deactivation of the protease. The nuclease hydrolyzes the 3,5'-phosphodiester bond of deoxyribonucleic acid (DNA) to generate 5'-nucleotides of oligomer polymerization. There are no particular restrictions on the properties of the nuclease, but it is preferably provided with a certain degree of thermal stability. Such nucleases are commercially available, for example, from Amano Enzyme Inc., Sigma, etc. The hydrolysis treatment using the nuclease can be carried out, for example, at a temperature in the range of 60 to 75°C and at a pH in the range of 5 to 6, considering the activation and deactivation of the nuclease. The specific procedure for the enzymatic treatment is as follows: First, protease treatment is performed on the salmon sperm to hydrolyze proteins and the like contained in the salmon sperm. After the hydrolysis is completed, nuclease treatment can be performed to reduce the molecular weight of the nucleic acid.

[0017] The present invention also targets a health food for repairing oxidized proteins containing the repair agent for oxidized proteins, and a health food for suppressing oxidative stress through the repair of oxidized proteins containing an oxidative stress inhibitor. The health food of the present invention contains, as an active ingredient, the repair agent for oxidized proteins or the oxidative stress inhibitor, that is, a water-soluble nuclear protein which is a low molecular weight product having a molecular weight of 250 to 15,000 obtained by subjecting, for example, the sperm of fish to enzymatic treatment, or having a molecular weight of about 250 to 10,000, and contains other formulation components according to various product forms described below. The content of the repair agent for oxidized proteins or the oxidative stress inhibitor in the health food can be appropriately adjusted referring to the clinical dosage described below.

[0018] The health food of the present invention can be mixed with various known ingredients such as sweeteners, acidulants, and vitamins to create a product that suits the user's preferences. Furthermore, it can be provided in various forms, such as tablets, capsules, granules, pills, syrups, liquids, emulsions, and suspensions, as well as in the form of drinks, jellies, dairy products such as yogurt, seasonings, processed foods, desserts, and confectionery.

[0019] For example, the aforementioned oral tablets, capsules, granules, pills, etc., can be formulated by conventional means, and these are prepared using excipients such as sucrose, lactose, glucose, starch, and mannitol; binders such as hydroxypropylcellulose, syrup, gum arabic, gelatin, sorbitol, tragacanth, methylcellulose, and polyvinylpyrrolidone; disintegrants such as starch, carboxymethylcellulose or its calcium salt, microcrystalline cellulose, and polyethylene glycol; lubricants such as talc, magnesium stearate, or calcium, and silica; and lubricants such as sodium lauryl sulfate and glycerol. Furthermore, the syrup, liquid, emulsion, suspension, etc., can also be formulated by conventional means, and are prepared using solvents for the active ingredient, which is the oxidized protein repair agent or oxidative stress inhibitor (water-soluble nucleoprotein), such as water, ethyl alcohol, isopropyl alcohol, propylene glycol, 1,3-butylene glycol, polyethylene glycol; surfactants, such as sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, polyoxyethylene ether of hydrogenated castor oil, lecithin; suspending agents, such as carboxymethyl sodium salt, cellulose derivatives such as methylcellulose, natural rubbers such as tragacanth and gum arabic; and preservatives, such as parahydroxybenzoic acid esters, benzalkonium chloride, sorbate, etc. Furthermore, the aforementioned beverages and jellies, as well as dairy products, seasonings, processed foods, desserts, confectionery, etc., may contain, in addition to their constituent ingredients, oligoRNA, zinc, collagen, chondroitin, hyaluronic acid, vitamins (vitamin B1, vitamin B2, vitamin B6, vitamin B12 and other B vitamins, vitamin C, etc.), and glutathione (glutathione-containing yeast extract, reduced glutathione, oxidized glutathione, etc.). More specifically, for example in beverage applications, although not limited to these applications, ingredients such as porcine collagen peptide, rare sugar-containing syrup, RNA-containing edible yeast extract, zinc-containing edible yeast, chondroitin-containing shark cartilage extract, hyaluronic acid-containing chicken comb extract / acidulant, vitamin C, arginine, magnesium carbonate, niacin, vitamin B6, vitamin B2, vitamin B1, folic acid, vitamin B12, anserine-containing fish extract, citrulline, salmon ovary membrane extract, and porcine placenta extract can also be included. Furthermore, for example in tablet applications, although not limited to these applications, ingredients such as brewer's yeast, ginkgo biloba extract, and S-allyl cysteine-containing garlic extract can also be included. In addition, for example in jelly applications, although not limited to these applications, ingredients such as fish collagen peptide can also be included.

[0020] Furthermore, in addition to the active ingredients, which are oxidized protein repair agents and oxidative stress inhibitors, the health food of the present invention may also contain other pharmaceutically or veterinarily active compounds.

[0021] The present invention also relates to a method for repairing oxidized proteins using the aforementioned oxidized protein repair agent, and further relates to a method for suppressing oxidative stress by repairing oxidized proteins damaged by oxidative stress using the aforementioned oxidative stress inhibitor. The present invention provides a method for repairing proteins or suppressing oxidative stress, which involves using a water-soluble nucleoprotein, specifically a low molecular weight product obtained by enzymatically treating fish milt, for example, with a molecular weight of 250 to 15,000 or 250 to 10,000. This repairs oxidized proteins and suppresses oxidative stress through the repair of oxidized proteins.

[0022] The clinical dosage of the oxidized protein repair agent or oxidative stress inhibitor of the present invention varies depending on age, weight, patient sensitivity, and severity of symptoms, but the usual effective dosage of water-soluble nucleoprotein can be approximately 100 mg to 950 mg per day for adults. However, amounts outside this range may be used if necessary. The above guidelines for effective dosage also apply to the oxidized protein repair agent and oxidative stress inhibitor of the present invention, as well as to health foods containing these. In the case of health foods, for example, the amount of the oxidized protein repair agent or oxidative stress inhibitor in the health food can be appropriately adjusted based on the above-mentioned daily dosage guidelines and the daily intake of the health food itself.

[0023] As mentioned above, the present invention focuses on an agent that increases the response of oxidized methionine repair enzyme genes, and further, on a health food for increasing the response of oxidized methionine repair enzyme genes containing the agent, and a method for increasing the response of oxidized methionine repair enzyme genes using the agent. The oxidized methionine repair gene (methionine sulfoxide lectase: MSR) has two forms, called MSRA and MSRB (MSRB2), related to the stereoisomerism of methionine sulfoxide. The above-mentioned oxidized methionine repair enzyme gene increasing agent contains a water-soluble nucleoprotein, and water-soluble nucleoproteins used in the aforementioned oxidized protein repair agents and oxidative stress inhibitors can be suitably used. The health food containing the above-mentioned oxidized methionine repair enzyme gene increasing agent can preferably utilize the embodiments, components, etc., listed for the health food containing the aforementioned oxidized protein repair agent and oxidative stress inhibitor. Furthermore, the method for increasing the oxidative methionine repair enzyme gene response described above can preferably be applied using the same methods, clinical dosages (guidelines), etc., as the methods for repairing oxidative proteins damaged by oxidative stress and the methods for suppressing oxidative stress through such repair. [Examples]

[0024] <Water-soluble nucleoprotein> Water-soluble nucleoproteins obtained from salmon milt using hydrolytic enzymes such as proteases and nucleases contained 20-30% by mass of nucleic acids (water-soluble nucleic acids with a molecular weight range of 250 to 15,000) and 50% by mass of amino acids (including 15% by mass of arginine).

[0025] <Manufacturing of test tablets> According to Table 1, a test tablet containing the water-soluble nucleoprotein obtained in the above manufacturing example (tablet A) and a placebo tablet without the water-soluble nucleoprotein (tablet B) were manufactured.

[0026] [Table 1]

[0027] <Example Test 1: Human Subject Test> A double-blind, randomized, placebo-controlled trial was conducted on 41 healthy male individuals aged 40 to under 60 who experienced daily fatigue (no medication, no underlying medical conditions, etc.). The subjects were divided into two groups: a test tablet group (tablet A, 20 subjects) and a placebo tablet group (tablet B, 21 subjects). Each test group was given either tablet A or tablet B for 8 weeks. The test tablet group was administered tablet A in quantities adjusted so that the daily intake of water-soluble nucleoprotein was 360 mg (6 tablets per day), while the placebo tablet group was administered the same quantity of tablet B as tablet A (6 tablets per day). Blood samples were collected from subjects before and after ingestion (weeks 0 and 8). Total RNA was extracted from the collected blood, and the gene expression levels of methionine sulfohydrate reductase A (MSRA), thioredoxin (TXN), and methionine sulfohydrate reductase B2 (MSRB2) were measured using a Thermo Fisher Scientific Clariom S Assay, Human microarray. Similarly, total RNA was extracted from the collected blood and the gene expression level of methionine sulfoxide reductase A (MSRA) was measured using the digital PCR method: QIAcuity One, 2plex (digital PCR instrument) (kit used: QIAcuity EG PCR KIT / Qiagen, plate used: QIAcuity Nanoplate 8.5K, 96-well) (Qiagen Corporation). The results obtained are shown in Figure 1 [Thermo Fisher Scientific microarray: (A) MSRA, (B) TXN, (C) MSRB2 gene expression level measurement results (percentage change from week 0 to week 8 (placebo group set to 1))] and Figure 2 [Digital PCR: MSRA measurement results (percentage change from week 0 to week 8 (placebo group set to 1))].

[0028] Furthermore, the d-ROMs (Reactive Oxygen Metabolites-derived compounds) test (Wismer test kit) was performed on the collected blood samples to comprehensively evaluate the state of oxidative stress in the body by measuring hydroperoxides, which are metabolites of free radicals in the blood. In addition, the BAP (Biologica Antioxidant Potential) test (Wismer test kit) was performed on the same blood samples to measure antioxidant capacity, and the Oxidative Stress Index (OSI) was calculated from the BAP (antioxidant capacity) results and the d-ROM (oxidative stress level) results. The results obtained are shown in Figure 3 [(A) Oxidative stress level (d-ROMs), (B) Oxidative stress index (OSI)]. Oxidative stress levels are evaluated by the balance between oxidation and antioxidant capacity, and the ratio of oxidation to antioxidant capacity is often used as an indicator. The oxidative stress index (OSI) adopted in this example is a method reported by Fukuda et al. in 2016 (Biological Psychology 118(2016)88-93), and is an indicator of oxidative balance calculated by multiplying the ratio of oxidative stress level (d-ROMs) and antioxidant capacity (BAP) by a correction factor (8.85) calculated based on data obtained from healthy Japanese individuals (see formula below). Oxidative stress index (OSI) = (d - ROMs / BAP) × correction factor (8.85) Note that an OSI value of 1 represents the average value for Japanese people, and an OSI value higher than 1 indicates a higher degree of oxidation than the average for Japanese people. Also, the OSI value generally increases with age.

[0029] As shown in Figure 1, microarray analysis revealed an increased trend in the gene expression levels of methionine sulfoxide reductase A (MSRA), thioredoxin (TXN), and methionine sulfoxide reductase B2 (MSRB2) compared to the placebo group. Thioredoxin is a type of oxidoreductase, and the cooperation of thioredoxin, MSRA, and MSRB2 repairs oxidized methionine (an amino acid residue that is particularly susceptible to oxidation among the amino acid residues that make up proteins). Furthermore, to verify the results in Figure 1, digital PCR analysis was performed, and as shown in Figure 2, the group that ingested tablet A containing water-soluble nucleoprotein for 8 weeks showed a significant increase in methionine sulfoxide reductase A (MSRA) gene expression compared to the placebo group. These results demonstrate that in humans, the intake of water-soluble nucleoproteins can lead to an increase in enzymes that reduce and repair oxidized methionine (an amino acid residue that is particularly susceptible to oxidation among the amino acid residues that make up proteins): oxidized methionine repair enzymes (MSRA, MSRB2) and thioredoxin (TXN), which works in cooperation with them, in short, it can lead to the repair of oxidized proteins. Furthermore, as shown in Figure 3, the group that took tablet A containing water-soluble nucleoprotein for 8 weeks showed a significant decrease in d-ROMs (reduction of oxidative stress markers) compared to the placebo group (Figure 3(A)), and also showed a significant decrease in the oxidative stress index (OSI) (Figure 3(B)). Thus, it was confirmed that the intake of water-soluble nucleoproteins promotes both the repair of oxidized proteins and the reduction of oxidative stress markers, and that there is a positive correlation between these oxidative protein repairs and the reduction of oxidative stress. While the relationship between protein repair and the reduction of oxidative stress markers was within the realm of previously expected findings, it is the first time that the intake of the water-soluble nucleoprotein targeted by this invention promotes the gene expression of enzymes involved in protein repair, and actually reduces oxidative stress markers and the oxidative stress index.

[0030] <Example Test 2: Yeast-Based Test> To allow budding yeast in liquid culture medium to absorb water-soluble nucleoprotein, the water-soluble nucleoprotein prepared in the above manufacturing example was added, and after 24 hours, the water-soluble nucleoprotein was removed to obtain the test sample. As a control, budding yeast without the addition of the above water-soluble nucleoprotein was prepared. This test sample or the control sample (without water-soluble nucleoprotein) was added to culture medium containing hydrogen peroxide as an oxidative stressor and to culture medium without hydrogen peroxide, respectively, and yeast culture was performed for 72 hours. For each sample, the ratio of yeast colonies in the hydrogen peroxide-free medium to the number of yeast colonies in the hydrogen peroxide-free medium was measured as the yeast viability (%). The results obtained are shown in Figure 4(A). Furthermore, total RNA was extracted from yeast supplemented with water-soluble nucleoprotein, and the expression level of the methionine sulfoxide reductase 2 (MXR2) gene was measured using the QuantStudio 7 Flex Realtime PCR system. The results are shown in Figure 4(B) (relative gene expression level with the control group set to 1). As shown in Figure 4(A), the group to which water-soluble nucleoprotein was added to the yeast showed a higher yeast survival rate compared to the control group. Furthermore, as shown in Figure 4(B), MXR2 levels were significantly increased (>1.5) in the group to which water-soluble nucleoprotein was added to the yeast, while MXR2 levels in the control group remained unchanged. The test results using yeast shown in Figures 4(A) and (B) also confirm that the ingestion of the water-soluble nucleoprotein according to the present invention promotes both the reduction of oxidative stress (improvement of yeast viability) and the increase of oxidative methionine repair enzyme (MXR2), and consequently the repair of oxidized proteins. A positive correlation was found between this oxidative protein repair and the reduction of oxidative stress.

[0031] In summary, these results suggest that ingesting water-soluble nucleoproteins can repair proteins damaged by oxidation, thereby suppressing (reducing) oxidative stress through the repair of oxidized proteins.

Claims

1. A biological oxidative protein repair agent containing water-soluble nucleoproteins, The aforementioned water-soluble nucleoprotein is a water-soluble nucleoprotein with a molecular weight of 250 to 15,000 obtained by enzymatic treatment of fish milt, and contains 20 to 30% by mass of nucleic acids (water-soluble nucleic acids with a molecular weight range of 250 to 15,000) and 50% by mass of amino acids (including 15% by mass of arginine). The aforementioned fish is salmon, The enzymes used in the aforementioned enzymatic treatment are proteases and nucleases. Oxidized protein repair agent.

2. A health food for oxidized protein repair, comprising the oxidized protein repair agent described in claim 1.

3. The health food according to claim 2, wherein the health food is in the form of a tablet, a drink, a capsule, a granule, a pill, or a jelly.

4. The oxidative protein repair agent according to Claim 1, for repairing oxidative proteins in a living organism that have been damaged by oxidative stress.

5. An oxidative stress inhibitor containing a water-soluble nucleoprotein, which acts by repairing oxidized proteins in the body, The aforementioned water-soluble nucleoprotein is a water-soluble nucleoprotein with a molecular weight of 250 to 15,000 obtained by enzymatic treatment of fish milt, and contains 20 to 30% by mass of nucleic acids (water-soluble nucleic acids with a molecular weight range of 250 to 15,000) and 50% by mass of amino acids (including 15% by mass of arginine). The aforementioned fish is salmon, The enzymes used in the aforementioned enzymatic treatment are proteases and nucleases. Oxidative stress inhibitor.

6. A health food for suppressing oxidative stress by repairing oxidized proteins, comprising the oxidative stress inhibitor described in claim 5.

7. The health food according to claim 6, wherein the health food is in the form of a tablet, a drink, a capsule, a granule, a pill, or a jelly.

8. The oxidative stress inhibitor according to claim 5, for suppressing oxidative stress by repairing oxidized proteins in the body that have been damaged by oxidative stress.

9. A gene response enhancer for oxidative methionine repair enzymes containing a water-soluble nucleoprotein, The aforementioned water-soluble nucleoprotein is a water-soluble nucleoprotein with a molecular weight of 250 to 15,000 obtained by enzymatic treatment of fish milt, and contains 20 to 30% by mass of nucleic acids (water-soluble nucleic acids with a molecular weight range of 250 to 15,000) and 50% by mass of amino acids (including 15% by mass of arginine). The aforementioned fish is salmon, The enzymes used in the aforementioned enzymatic treatment are proteases and nucleases. The aforementioned increase in the oxidative methionine repair enzyme gene response is due to an increase in the expression level of a gene selected from the group consisting of methionine sulfoxide reductase A (MSRA), thioredoxin (TXN), and methionine sulfoxide reductase B2 (MSRB2). An agent that increases the gene response of oxidized methionine repair enzymes.

10. A health food for increasing the gene response of oxidized methionine repair enzyme, comprising the oxidized methionine repair enzyme gene response increasing agent described in claim 9.

11. The health food according to claim 10, wherein the health food is in the form of a tablet, a drink, a capsule, a granule, a pill, or a jelly.

12. The oxidized methionine repair enzyme gene response increasing agent according to claim 9, for increasing the oxidized methionine repair enzyme gene response.