JP2022084029A - Liver function improver - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new liver function improver having high efficacy.

SOLUTION: An oxidation stress reducer contains phenethyl amine or a salt thereof as an active ingredient.

SELECTED DRAWING: None

COPYRIGHT: (C)2022,JPO&INPIT

Description

The present invention relates to a liver function improving agent.

The liver is the largest organ in the body, responsible for many functions such as metabolism, excretion, detoxification, maintenance of body fluid homeostasis, and secretion of bile into the duodenum. Known liver diseases include fatty liver, hepatitis, liver cirrhosis, and liver cancer. In fatty liver and hepatitis, AST (aspartate aminotransferase) and ALT (alanine aminotransferase) levels in the blood are used. It is known that the representative liver function markers are elevated.
When liver function declines, it becomes impossible to synthesize substances necessary for the living body, decompose waste products produced in the living body, and cannot decompose harmful substances and drugs from outside the body, and the liver function further deteriorates.

Examples of the drug for improving these liver functions include ursodeoxycholic acid and glycyrrhizin. In addition, in order to improve liver function, it is recommended to limit alcohol intake, diet such as limiting carbohydrates and lipids, and exercise to prevent obesity.

Further, as a liver function improving agent, a combination of garlic, plum and oyster (Patent Document 1), maltitol (Patent Document 2), a combination of various plant extracts and amino acids (Patent Document 3) and the like have been reported. ..

Japanese Unexamined Patent Publication No. 2013-241340 Japanese Unexamined Patent Publication No. 2014-129324 Japanese Unexamined Patent Publication No. 2017-141199 U.S. Patent Application Publication No. 2006/2045999 U.S. Patent Application Publication No. 2008/0260881 US Pat. No. 9,526,793

Japan Fragrance Industry Association homepage Toxicol. Res. Vol. 30, No. 3, pp193-198 (2014) Can. J. Physiology. Pharmacol. 88; 273-284 (2010) Biochimica et Biophysica Acta 1637 (2003) 98-106 INTERRNATIONAL JOURNAL OF MOLECULAR MEDICINE 41; 3527-35536, 2018

However, the effectiveness of the liver function improving agents reported so far is not sufficient, and a new liver function improving agent has been sought.
Therefore, an object of the present invention is to provide a new liver function improving agent having high efficacy.

Therefore, the present inventor investigated not only the action on liver function markers but also the action on markers such as glycolytic enzymes and oxidative stress using various components, and surprisingly, phenylalkylamine or a salt thereof. However, with a small amount of oral administration, it lowers the liver function markers selected from AST and ALT in the blood, reduces oxidative stress, enhances GAPDH (glyceraldehyde-3-phosphate dehydrogenase), and has a short chain. The present invention has been completed by finding that it is useful as a liver function improving agent or a food composition for improving liver function by suppressing the production of aldehyde.

That is, the present invention provides the following inventions [1] to [13].
[1] A liver function improving agent containing phenylalkylamine or a salt thereof as an active ingredient.
[2] An agent for lowering a liver function marker selected from AST and ALT in blood, which comprises a phenylalkylamine or a salt thereof as an active ingredient.
[3] An oxidative stress reducing agent containing phenylalkylamine or a salt thereof as an active ingredient.
[4] A GAPDH enhancer containing phenylalkylamine or a salt thereof as an active ingredient.
[5] A short chain aldehyde production inhibitor containing phenylalkylamine or a salt thereof as an active ingredient.
[6] The agent according to any one of [1] to [5], wherein the active ingredient is an algae extract containing phenylalkylamine or a salt thereof.
[7] The agent according to any one of [1] to [6] for oral ingestion.
[8] A food composition for improving liver function containing phenylalkylamine or a salt thereof.
[9] A food composition for lowering liver function markers selected from AST and ALT in blood, which contains phenylalkylamine or a salt thereof.
[10] A food composition for reducing oxidative stress containing phenylalkylamine or a salt thereof.
[11] A food composition for enhancing GAPDH containing phenylalkylamine or a salt thereof.
[12] A food composition for suppressing the production of short chain aldehydes containing phenylalkylamine or a salt thereof.
[13] The composition according to any one of [8] to [12], which contains an algae extract containing phenylalkylamine or a salt thereof.

The liver function improving agent of the present invention not only lowers AST and ALT in blood by oral administration of a trace amount of phenylalkylamine or a salt thereof, but also suppresses the production of short-chain aldehyde by enhancing GAPDH. It reduces oxidative stress and enhances antioxidant enzyme activity, resulting in improved liver function.

It is a figure which shows the change of the body weight and the liver weight. ND: normal diet group, HFD: high-fat diet group, WEC: chlorella hot water extract intake group, PL: phenethylamine low-dose group, PH: phenethylamine high-dose group (same in the following figure). It is a figure which shows the change of the AST concentration and the ALT concentration in plasma. It is a figure which shows the change of TBARS, GSH / GSSG and SOD-like activity. It is a figure which shows the change of SOD-1. It is a figure which shows the change of GOX-1. It is a figure which shows the change of GAPDH. It is a figure which shows the change of β-actin. It is a figure which shows the change of methylglyoxal. It is a figure which shows the change of cysteine.

The active ingredient of the liver function improving agent of the present invention is phenylalkylamine or a salt thereof.
Examples of the phenylalkylamine include phenyl-C1-C6 alkylamine, and phenylC1-C4 alkylamine is more preferable. Specific examples thereof include benzylamine, phenethylamine, 3-phenylpropylamine, 2-phenylpropylamine, 4-phenylbutylamine and 5-phenylpentylamine. Of these, phenethylamine is more preferable.
Further, the phenyl group of the phenylalkylamine may be substituted with a halogen atom, a hydroxy group, a C1-C3 alkyl group, an alkoxy group or the like.

Phenethylamine is a compound found in cheese, processed fish products, wine, cabbage, cocoa, beer and the like. In Europe and the United States, it is used as a flavoring agent for various foods for the purpose of reproducing aroma and improving flavor. Also in Japan, its use as a food additive flavoring is approved (Non-Patent Document 1).

It is known that acacia exhibits a weight gain inhibitory effect and phenethylamine is a component contained in acacia (Patent Document 4). It has been reported that blue-green algae are useful as diet supplements, and that the blue-green algae contain phycocyanin and phenethylamine (Patent Document 5). It has also been reported that phenethylamine nitrate or nitrite can be used as a diet supplement (Patent Document 6).
However, the effects of phenylalkylamines such as phenethylamine on the liver are completely unknown.

Examples of the salt of phenylalkylamine include inorganic acid salts such as hydrochloride, sulfate, nitrate and phosphate, and organic acid salts such as acetate, tartrate and citrate.

Phenylalkylamines or salts thereof, as described in the Examples below, significantly reduce AST and ALT elevated in a high-fat diet by oral administration at a low dose of 10 μg / kg / day to mice.
In addition, phenylalkylamine or a salt thereof significantly reduces TBARS (2-thiobarbituric acid-reactive substance), which is a marker of oxidative stress (lipid peroxidation) increased by a high-fat diet, at the same low dose as described above. Let me. It also enhances SOD-like activity, which is an antioxidant enzyme.
In addition, phenylalkylamine or a salt thereof significantly enhances GAPDH, which is a glycolytic enzyme reduced in a high-fat diet, at the same low dose as described above. In addition, phenylalkylamines or salts thereof enhance glutathione and cysteine at similar low doses, while reducing short chain aldehydes (methylglyoxal).

Here, it is known that methylglyoxal, which is a short-chain aldehyde, exerts glycation stress and oxidative stress on a living body and affects the progression of liver disease (Non-Patent Documents 2 and 3). On the other hand, methylglyoxal is produced from glyceraldehyde 3-phosphate (GAP) or its isomer dihydroxyacetone phosphate (DHAP), and the enzyme that metabolizes both is GAPDH. Methylglyoxal is also known to react with cysteine. The amount of methylglyoxal is inversely proportional to the GAPDH activity of erythrocytes and proportional to DHAP. If GAPDH metabolizes GAP / DHAP, methylglyoxal decreases (Non-Patent Document 4). However, GAPDH is said to have little fluctuation and is considered as a so-called Housekeeping gene. Even if ethanol is administered to mice to induce acute hepatitis, it shows a decreasing tendency, but no significant difference is observed (Non-Patent Document 5).
This time, when a high-fat diet was administered to mice, fat was accumulated in the liver and free cysteine was drastically reduced. It is considered that this is because the aldehyde produced by the high-fat diet reacted with cysteine and depleted cysteine in the liver. In contrast, phenylalkylamines increase GAPDH by a little less than 2-fold, resulting in a decrease in the short-chain aldehyde methylglyoxal and a reduction in oxidative stress, resulting in the maintenance of cysteine, which is susceptible to reaction with short-chain aldehydes. This increases the activity of cysteine-containing antioxidant enzymes such as SOD and maintains the antioxidant system. As described above, phenylalkylamine is considered to improve liver function by reducing oxidative stress due to a high-fat diet and suppressing the production of short-chain aldehyde by increasing the expression of GAPDH.

The phenylalkylamine or a salt thereof is useful as a liver function improving agent and a food composition for improving liver function due to various physiological actions as described above. Therefore, the liver function improving agent and the food composition for improving liver function of the present invention may contain phenylalkylamine or a salt thereof, but may contain various plant extracts containing phenylalkylamine or a salt thereof. You may.
As the plant extract containing such a phenylalkylamine or a salt thereof, an algae extract containing phenethylamine or a salt thereof is preferable, and a chlorella extract containing phenethylamine or a salt thereof is more preferable. As the chlorella, Chlorella pyrenoidosa is preferable.
Examples of the plant extract include extracts made from water, alcohol, polyhydric alcohol and the like, but water extracts are preferable. Here, the water may be cold water or hot water. The extraction method may be a dipping method, a Soxhlet method or the like.

The liver function improving agent or the food composition for improving liver function of the present invention is preferably in the form for oral ingestion. Examples of forms for oral ingestion include tablets, capsules, granules, sugar-coated tablets, pills, fine granules, powders, powders, sustained-release preparations, suspensions, emulsions, syrups, emulsions, and freeze-drying. Examples thereof include agents, liquids, syrups, oral jellies, drinks, gums, confectionery and the like.

In addition, a form for oral ingestion of a liver function improving agent or a food composition for improving liver function can be produced by a conventional method, and a plant extract containing phenylalkylamine or a salt thereof or phenylalkylamine or a salt thereof can be used alone. It may be used or may be used in combination with a pharmaceutically or food-acceptable carrier. Examples of the pharmaceutical or food acceptable carrier include excipients, binders, disintegrants, surfactants, lubricants, fluidity promoters, syrups, colorants, fragrances, diluents and sterilizers. Agents, osmotic pressure regulators, pH regulators, emulsifiers, preservatives, stabilizers, absorption aids, antioxidants, UV absorbers, wetting agents, thickeners, brighteners, activity enhancers, anti-inflammatory agents, Examples thereof include isotonic agents, soothing agents, deodorants and the like.

Examples of the binder include starch, dextrin, gum arabic powder, gelatin, hydroxypropyl starch, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, ethyl cellulose, polyvinylpyrrolidone, macrogol and the like.

Examples of the disintegrant include starch, hydroxypropyl starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, low-substituted hydroxypropyl cellulose and the like.

Examples of the surfactant include sodium lauryl sulfate, soybean lecithin, sucrose fatty acid ester, polysorbate 80 and the like.
Examples of the lubricant include talc, waxes, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, polyethylene glycol and the like.
Examples of the fluidity accelerator include light anhydrous silicic acid, dry aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate and the like.

Examples of the diluent include distilled water for injection, physiological saline, aqueous glucose solution, olive oil, sesame oil, lacquer oil, soybean oil, corn oil, propylene glycol, polyethylene glycol and the like.

In addition, there are no strict restrictions on the dose of phenylalkylamine or a salt thereof, which is the active ingredient of the liver function improving agent or the food composition for improving liver function of the present invention. Since the effect obtained differs depending on the subject and various usage modes such as symptoms, it is desirable to set the dose appropriately. However, in terms of the effect of improving liver function, phenylalkylamine or a salt thereof is used as 0. It is preferably 1 mg to 200 mg, more preferably 0.5 mg to 150 mg, and even more preferably 1 mg to 100 mg.

Next, the present invention will be described in detail with reference to examples, but the present invention is not limited thereto.

Example 1

(1) Materials and methods a. Materials A hot water extract of Chlorella pyrenoidosa (WEC) was prepared and supplied by Sun Chlorella (Kyoto, Japan).
Phenethylamine, Proteinase Inhibitor Cocktail, Butylhydroxytoluene (BHA), Diethylenetriamine pentaacetic acid (DTPA), 1,1,3,3-tetraethoxypropane (TEP), Thiobarbituric acid (TBA), Glutathione (GSH), Glutathione Disulfide (GSSG), N-ethylmaleimide (NEM), and enhanced chemical fluorescence (ECL) reagents were obtained from Nakalai Tesque (Kyoto, Japan).
Heparin sodium was obtained from Nipro (Osaka, Japan).
The cytolytic reagent was obtained from Sigma-Aldrich (St. Louis, MO, USA). Rabbit immunoglobulin G (IgG) for mouse superoxide dismutase (SOD) -1 and mouse glutathione peroxidase (GPX) 1 was obtained from Abcam (Cambridge, UK).
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and β-actin, which are capable of reacting mouse monoclonal antibodies with GAPDH and β-actin, include Proteintech Group (Chicago, IL, USA) and Santa Cruz Biotechnology (Dallas, TX,). Obtained from USA).
Goat IgG-Horseradish peroxidase (HRP) conjugates for rabbit and mouse IgG were obtained from Cell Signaling Technology (Davers, MA, USA).

stomach. Animal experiments Male C57bl / 6J mice (7 weeks old, 21-23 g) were purchased from Japan SLC (Shizuoka, Japan). All mice were randomly divided into 6 groups as follows (n = 6).
For mice, normal diet and tap water (ND group), high-fat diet (60% on a calorie basis, CLEA Japan) and tap water (HFD group), high-fat diet and WEC (WEC group) in tap water with a body weight of 100 mg / kg ), And a high-fat diet and phenethylamine (PL and PH groups) in tap water weighing 10 and 100 μg / kg, respectively.
All mice were sacrificed after 12 weeks under isoflurane anesthesia without fasting.
Blood was collected from the inferior vena cava with a heparin sodium-treated syringe.
Plasma was prepared by centrifugation at 3500 rpm for 5 minutes.
Liver was harvested and blood in the liver was purged by injecting cold PBS into the portal vein. Plasma and liver were stored at -30 ° C.

Methylglyoxal was derivatized by 2,3-diaminonaphthalene (DAN) and then quantified by liquid chromatography tandem mass spectrometer (LC-MS / MS).
The liver was ground in the same amount of phosphate buffer, 6 times (v / w) ethanol per liver weight was added to the crushed material, and the mixture was stirred well. The suspension was centrifuged at 14200 g to obtain a supernatant. 50 μL of 0.1% DAN solution was added to 10 μL of the supernatant or a solution of the standard substance, and the mixture was reacted at 50 ° C. for 1 hour. After the reaction, 500 μL of ethyl acetate was added and the mixture was stirred well. 400 μL of the ethyl acetate layer was taken and dried. The residue was dissolved in a 30% aqueous acetonitrile solution, filtered, and analyzed by LC-MS / MS. 0.1% formic acid solution (solution A) and 0.1% formic acid at a flow rate of 0.2 mL / min using an Inertsil ODS-3 column (2.1 mm × 250 mm, GL Science) equilibrated with 0.1% formic acid. Separation was performed by gradient elution using 80% acetonitrile (solution B) containing. The gradient conditions are as follows; 0-15 minutes; 0-10% B solution, 15-18 minutes; 100% B solution, 18.1-25 minutes; 0% B. The column was kept at 40 ° C. The detection was performed in the multi-reaction monitoring mode.

Cysteine was labeled with a thiol group with 4-vinylpyridine (4-VP) and an amino group with a 6-aminoquioolyl-N-hydroxysuccinimidyl carbamate (AccQ) and quantified by LC-MS / MS. 22.5 μL of pure water was added to 75 μL of the above-mentioned mouse liver extract, and 2.5 μL of 4-VP was further added and reacted at 37 ° C. for 2 hours. 500 μL of ethyl acetate and 100 μL of pure water were added to the reaction mixture, and the mixture was stirred well. 50 μL of the aqueous phase was collected and dried. To this, 80 μL of 50 mM sodium borate buffer pH 8.8 was added, and further 20 μL of 0.3% AccQ acetonitrile solution was added, and the mixture was reacted at 50 ° C. for 10 minutes.
The reaction solution was quantified by the above-mentioned LC-MS / MS in MRM mode.

hare. Liver SOD-like active Liver tissue in 5 volume (w / v)% 10 mM Tris-HCl buffer containing 0.25 M sucrose and 1 mM EDTA by using BioMaster II (Nippi, 24 Tokyo, Japan). It was homogenized in pH 7.4).
The homogenate was centrifuged at 10000 g for 60 minutes and the supernatant was collected for the SOD-like activity assay of soluble compounds in the liver. In addition, liver tissue was homogenized in the same volume (w / v) of PBS and then 6 volumes (w / v)% of ethanol was added. The resulting solution was centrifuged at 10000 g for 10 minutes, the supernatant was collected and used as a low molecular weight compound fraction. The SOD-like activity in the supernatant was assayed using the WST-1 SOD assay kit (Dojin, Kumamoto, Japan).

workman. Plasma biochemical analysis Plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities were measured by consignment to Oriental yeast.
Thiobarbituric Acid Reactive Substance (TBARS) Assay DTPA was dissolved in 1M sodium acetate buffer (pH 3.5) to give a 2 mM solution. BHA was dissolved in methanol to give a 10% (w / v) solution. 5 ml of DTPA solution, 45 mL of hot water, and 100 μL of BHA solution were added to 0.1 grams of TBA to give a 0.2% TBA solution.
This solution was used as a TBA reagent.
10 ml of methanol was added to 4.8 μL of TEP, which is a malondialdehyde precursor, to give a 2 mM TEP solution. The TEP solution was diluted with methanol to 2-50 mM to make a standard solution. Liver tissue was homogenized in 9 volumes (w / v) of 1.15% KCl solution. The homogenate was centrifuged at 2000 g for 1 minute.
The supernatant or standard solution (25 μL) was mixed with TBA reagent (100 μL), vortexed and then heated at 95 ° C. for 60 minutes. The reaction was stopped by cooling on ice for 5 minutes. The reactants were centrifuged at 14200 g for 10 minutes. The absorbance of the supernatant at 515 nm was measured. The TBARS value was expressed as μM malondialdehyde.
Glutathione and Glutathione Disulfide Measurements of glutathione and its disulfides were determined by liquid chromatography tandem mass analysis (LC-MS / MS) following derivatization with NEM and AccQ by the method of Yamada et al.

E. Western blotting Liver aliquots (approximately 50 mg) were homogenized in 300 μL of cytolytic reagent containing 1% proteinase inhibitor in BioMaster II. After centrifugation at 12000 g for 15 minutes (4 ° C.), the protein concentration in the supernatant was measured by BCA Protein Assay Kit (Thermo Scientific, Rockford, IL, USA) and adjusted to 10 μg / 15 μL with the same buffer. Proteins are separated by SDS-PAGE using a 12.5% gel and then by using a semi-dry blotting device (WSE 4020, ATTO, Tokyo, Japan), a PVDF membrane (0.45 μm pores, GE healthcare). Moved to Life Sciences, Chicago, IL, USA).
The membrane was then blocked with 4% block ace (Megmilk Snow Brand, Sapporo, Japan) at room temperature for 30 minutes, followed by 2.68 mM KCl, 0.05% (v / v) Tween 20 (TBST). Washed with a pH 7.5 50 mM Tris-HCl buffer containing 137 mM NaCl for 5 minutes (5 times) at room temperature.
Primary antibodies against SOD-1, GPX-1, β-actin, and GAPDH in 0.4% Block Ace solution containing 0.05% (v / v) Tween 20 at 1: 5000, 1: 5000, respectively. It was diluted 1: 1000 and 1: 8000. After overnight incubation with the primary antibody, the membrane was washed with TBST for 5 minutes (5 times). The HRP-secondary antibody conjugate was diluted 1: 10000 with 0.4% block Ace containing 0.05% (v / v) Tween 20. Membranes were incubated with HRP-secondary antibody conjugates for 1 hour and then washed with TBST for 5 minutes (5 times) at room temperature. The membrane was immersed in ECL reagent for 1 minute and bands were detected by using Luminograph I (ATTO).

power. Statistical analysis The difference in band intensity of proteins detected by Western blotting in the same membrane between a group and the HFD group was analyzed by t-test.
Statistical differences in other parameters between the HFD group and the other groups were analyzed using one-way ANOVA, followed by Dunnett's test for multiple comparisons.
This difference was considered significant at p <0.05 and tended to be constant at 0.05 <p <0.1.
GraphPad Prism 7 software (GraphPad Software, CA, USA) was used for statistical analysis.

(2) Results a. Body Weight and Liver Weight As shown in FIG. 1, the body weight of the group fed a high-fat diet (HFD, WEC, PL, PH group) was significantly higher than that of the group fed a normal diet after 4 weeks (ND group). rice field. However, administration of WEC and phenethylamine had no significant effect on weight gain. The liver weight (FIG. 1C) of the HFD group was significantly higher than that of the ND group. The liver / body weight ratio (Fig. 1B) in the HFD group tended to be higher than that in the ND group, but there was no statistical difference. This ratio tended to decrease in mice treated with phenethylamine (PL and PH groups) compared to the HFD group (p <0.1).

stomach. Plasma biochemical parameters Plasma AST and ALT activity (FIGS. 2A and B) were significantly higher in the HFD group than in the ND group, indicating that high-fat dieting induced liver damage.
In contrast, low doses of phenethylamine (10 μg / kg / day, PL group) significantly reduced plasma AST and ALT activity compared to the HFD group, while high doses of phenethylamine (100 μg / kg / day). , PH group) showed only a decreasing tendency of ALT.

hare. Oxidative stress in the liver High-fat diet intake (HFD group) is an indicator of lipid peroxidation in liver extract compared to normal diet intake (ND group), a thiobarbituric acid-reactive substance (TBARS, FIG. 3A). ) Value was significantly increased and SOD-like activity was decreased (Fig. 3C).
Furthermore, the high-fat diet intake group tended to reduce the ratio of glutathione to glutathione disulfide, which is an oxidative stress marker (GSH / GSSG, FIG. 3B). These facts indicate that a high-fat diet increases oxidative stress in the liver and reduces the endogenous antioxidant system.
In contrast, administration of WEC, both low and high doses of phenethylamine significantly suppressed high fat diet-induced lipid oxidation.
Administration of WEC and low doses of phenethylamine significantly increased SOD-like activity in liver extracts compared to the HFD group.
Liver GSH / GSSG was also significantly increased in the PL group compared to the HFD group (Fig. 3B).

workman. Antioxidant enzyme levels of endogenous antioxidant enzymes, SOD-1 (FIG. 4) and GPX-1 (FIG. 5), in the liver were evaluated by Western blot analysis.
Surprisingly, high-fat diet intake and / or administration of WEC and phenethylamine significantly affected GAPDH and β-actin levels (Figs. 6 and 7).
In addition, the band intensity of α-tubulin was much lower than that of the target protein (data not shown).
The intensity of the protein band in each group was compared with that of the HFD group divided on the same membrane by t-test.
SOD-like activity was significantly increased by WEC and low doses of phenylethylamine (Fig. 4). High-fat diet intake significantly reduced GPX-1 and β-actin protein levels in the liver compared to the ND group (FIGS. 5 and 7).
Administration of low doses of phenethylamine tended to increase GPX-1 compared to HFD groups (p = 0.058, FIG. 5) and significantly increased β-actin levels (FIG. 7).
Although there was no significant difference in GAPDH levels between the HFD and ND groups, oral administration of phenethylamine and WEC significantly increased GAPDH levels compared to the HFD group (FIG. 6).

The levels of glyoxal and methylglyoxal, which are short chain aldehydes, in the liver were significantly reduced by oral administration of WEC and phenethylamine (Fig. 8).
In addition, free cysteine levels in the liver were significantly increased by oral administration of WEC and phenethylamine (Fig. 9).

Claims (7)

An oxidative stress reducing agent containing phenethylamine or a salt thereof as an active ingredient. A GAPDH enhancer containing phenethylamine or a salt thereof as an active ingredient. A short chain aldehyde production inhibitor containing phenethylamine or a salt thereof as an active ingredient. The agent according to any one of claims 1 to 3, which is for oral ingestion. A food composition for reducing oxidative stress containing phenethylamine or a salt thereof. A food composition for enhancing GAPDH containing phenethylamine or a salt thereof. A food composition for suppressing the production of short chain aldehydes containing phenethylamine or a salt thereof.

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