JP2018039752A - Nrf2 activator - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pharmaceutical product, a food, a cosmetic product, etc., which has an Nrf2 expression promoting effect and exerts an effect of enhancing the antioxidant protection and detoxification ability of a living body, or a material blended therein. An Nrf2 activator containing avocado or an extract thereof as an active ingredient. A prophylactic, ameliorating or therapeutic agent for retinal degeneration, cataract and keratoconjunctivitis selected from retinal degeneration, cataract and keratoconjunctivitis, or renal disease selected from acute kidney injury and chronic kidney disease containing avocado or its extract as an active ingredient. An Nrf2 activator containing at least one selected from persenone A, persenone B and persin as an active ingredient. [Selection diagram] None

Description

  The present invention relates to an Nrf2 activator.

  Oxidative stress is defined as a state in which the balance between reactive oxygen species (ROS) and the antioxidant that removes them is broken (Non-Patent Document 1). ROS is generated by aging, tobacco, and UV, and oxidizes biomolecules such as lipids, proteins, and DNA, and damages cells and tissues. Since skin is a boundary with the outside world, it is exposed to a chronic oxidative stress environment caused by internal and external factors, and an antioxidant system is important for maintaining homeostasis of cells and tissues (Non-patent Document 2). .

  Biological antioxidant systems include antioxidant enzymes such as glutathione peroxidase (GPX) and glutathione reductase (GSR), and antioxidants such as α-tocopherol, ascorbic acid and glutathione (GSH) (non-enzymatic antioxidant). There are two systems. A key transcription factor that controls the expression of genes involved in these antioxidant systems is NF-E2-related factor2 (Nrf2).

  Nrf2 is a transcription factor that controls biological defense system genes such as antioxidant enzymes and detoxification enzymes (Non-patent Document 3). In steady state, Kelch-like ECH-associated protein 1 (Keap1) binds to Nrf2 and undergoes ubiquitin-proteasome degradation, but Keap1 dissociates in the presence of ROS and electrophilic substances, and ubiquitination of Nrf2 occurs. Stop. As a result, Nrf2 stabilizes and translocates to the nucleus, binds to an antioxidant response element (ARE), and a host defense system gene group such as heme oxygenase-1 (HO-1), NAD (P) H: It induces gene expression of quinone oxidoreductase-1 (NQO1), GPX, glutamate cysteine ligase regulatory subunit (GCLM), glutamylcysteine ligase (GCLC), thioredoxin (TXN) and the like.

  From this, activation of the Nrf2-ARE pathway is thought to lead to improvement of the antioxidant system and further activation of the biological defense mechanism. Actually, it is suggested that Nrf2 is important in protecting cells and tissues from a wide range of injuries (carcinogenic substances, electrophilic substances, reactive oxygen species, ultraviolet rays, cigarette smoke, etc.) (Non-Patent Document 4). Is considered to be effective in preventing or ameliorating various diseases involving oxidative stress. For example, sulforaphane, which is an Nrf2 activator, has been reported to suppress cell damage in retinal degeneration and cataract (Patent Document 1). Nrf2 contributes to the corneal epithelial wound healing process (Non-patent Document 5), and Nrf2 activator is effective against keratoconjunctival disorders such as dry eye, punctate superficial keratopathy, corneal epithelial defect, corneal erosion, and corneal ulcer. It is reported that it is effective (Patent Document 2).

  Moreover, it is thought that the renal function fall in kidney disease is caused by renal tissue damage due to increased oxidative stress (Non-patent Document 6). Bardoxolone methyl, an activator of Nrf2, is affected by renal failure. It is reported to be useful for diabetic nephropathy (Non-patent Document 7). It has also been reported that cremedin that suppresses the progression of renal dysfunction by lowering the serum level of indoxyl sulfate, which is a uremic toxin, can function as an Nrf2 activator (Patent Document 3).

On the other hand, avocado (Persea americana, also known as: crocodile pear) is eaten raw or baked, but it is rich in unsaturated fatty acids such as oleic acid and linoleic acid, vitamins and minerals. Are known.
For example, Patent Document 4 discloses that an avocado extract has a lipid degradation promoting action and can be used as a skin external preparation for slimming, and Patent Document 5 has an IgE production inhibitory action on an alligator extract. Is disclosed.

  However, it has not been known so far that avocado or components contained therein have an Nrf2 activating effect.

JP 2005-536449 A JP 2008-110762 A JP 2013-231013 A JP 11-246425 A JP 2010-180141 A

Durackova Z (2010) Some current insights into oxidative stress.Physiol Res 59 459-469 Briganti S, Picardo M (2003) Antioxidant activity, lipid peroxidation and skin diseases.What's new.J Eur Acad Dermatol Venereol 17 663-669 Taguchi K, Motohashi H, Yamamoto M (2011) Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution.Genes Cells 16 123-140 Lee JM, Li J, Johnson DA, Stein TD, Kraft AD, Calkins MJ, Jakel RJ, Johnson JA (2005) Nrf2, a multi-organ protector? FASEB 19 1061-1066 Ryuhei Hayashi et al (2013) The role of the Nrf2-mediated defense system in corneal epithelial wound healing.Free Radical Biology and Medicine 61, 333-342 Yoh K, Itoh K, Enomoto A, Hirayama A, Yamaguchi N, Kobayashi M, Morito N, Koyama A, Yamamoto M, Takahashi S (2001) Nrf2-deficient female mice develop lupus-like autoimmune nephritis.Kidney Int 60, 1343- 1353. Pergola P E, Raskin P, Toto R D, Meyer C J, Huff W, Grossman E B, Krauth M, Ruiz S, Audhya P, Christ-Schmidt H, Wittes J, Warnock D G (2011) N Engl J Med 365, 327-336.

  The present invention relates to providing pharmaceuticals, foods, cosmetics, or the like having an Nrf2 activating action and exhibiting the effect of enhancing the antioxidant defense and detoxifying ability of a living body, or materials to be blended with these.

  When the present inventors examined in view of said subject, there exists an Nrf2 activation effect | action excellent in the extract of avocado and the specific component contained in it, and these improve the antioxidant defense of a living body, and detoxification capability. Found useful.

That is, the present invention relates to the following 1) to 8).
1) An Nrf2 activator comprising avocado or an extract thereof as an active ingredient.
2) A preventive, ameliorating or therapeutic agent for an eye disease selected from retinal degeneration, cataract and keratoconjunctival disorder or a kidney disease selected from acute kidney injury and chronic kidney disease, comprising avocado or an extract thereof as an active ingredient.
3) An Nrf2 activator comprising one or more selected from persenone A, persenone B and persine as an active ingredient.
4) Prevention or improvement of eye diseases selected from retinal degeneration, cataracts and keratoconjunctival disorders, or acute kidney disorders, and kidney diseases selected from chronic kidney disease, comprising at least one selected from persenone A, persenone B and persine as an active ingredient. Or a therapeutic agent.
5) A food for Nrf2 activation comprising an avocado extract as an active ingredient.
6) A food for the prevention or amelioration of an eye disease selected from retinal degeneration, cataract and keratoconjunctival disorder, or kidney disease selected from acute kidney injury and chronic kidney disease, comprising an avocado extract as an active ingredient.
7) A food for activating Nrf2 comprising one or more selected from persenone A, persenone B and persine as an active ingredient.
8) Prevention or improvement of an eye disease selected from retinal degeneration, cataract and keratoconjunctival disorder or an renal disease selected from acute kidney injury and chronic kidney disease, comprising one or more selected from persenone A, persenone B and persine as an active ingredient For food.

  According to the Nrf2 activator of the present invention, through the activation of Nrf2, it becomes possible to protect the living body by improving the antioxidant defense, detoxification / metabolism, foreign body excretion, and stress response ability of the living body. Diseases and symptoms caused by invasion, such as retinal degeneration, cataract, keratoconjunctivopathy (dry eye, punctate superficial keratopathy, corneal epithelial defect, corneal erosion, corneal ulcer, conjunctival epithelial defect, dry keratoconjunctivitis, upper ring Ocular diseases, such as keratoconjunctivitis, filiform keratoconjunctivitis, infectious keratitis, non-infectious keratitis, infectious conjunctivitis, non-infectious conjunctivitis), kidney diseases (acute kidney injury, chronic kidney disease) In addition, it is possible to prevent, treat or improve diabetes associated with kidney disease, cardiovascular disease associated with kidney disease and the like.

Persenone A, persenone B and persine isolation process. HPLC chromatograph of persenone A, persenone B and persine. Compound 1: Persenone A, Compound 2: Persine, Compound 3: Persenone B. Expression induction activity of ARE downstream gene. A: avocado extract, baked avocado extract, B: persenone A, persenone B and persine. Nrf2 promotes nuclear translocation. The graph which shows the expression induction effect | action of an antioxidant gene. A: Gene expression level (baked avocado extract, B: Gene expression level (Persenon A, Persenone B and Persine), C: Protein expression level (Persenon A, Persenone B and Persine). Antioxidant gene expression inducing action via Nrf2. Increases the amount of glutathione. Reducing intracellular active oxygen.

In the present invention, “avocado” refers to Persea americana (scientific name) belonging to the genus Allenaceae, and is also referred to as “crocodile”. In the present invention, avocado can be used as its seeds, fruits, etc., but is preferably a fruit, more preferably a fruit pulp part of the fruit.
Avocado is extracted from the juice obtained by squeezing it as it is, the dried product obtained by drying the plant itself, the heat-treated product obtained by heat-treating the plant itself, or the crushed product, the pulverized product thereof, or the like. Although it can be used as an extract, it is preferably used as an extract, and more preferably an extract of a heat-treated product (baked avocado).
Here, as the heat treatment, for example, a plant body divided into 5 to 10 cm may be treated for a certain period of time using a heating device such as a microwave oven. The heating temperature is preferably 100 ° C. or higher, more preferably 150 ° C. or higher, more preferably 200 ° C. or higher, and preferably 300 ° C. or lower, more preferably 250 ° C. or lower, more preferably 230 ° C. or lower. Moreover, Preferably it is 100-300 degreeC, More preferably, it is 150-250 degreeC, More preferably, it is 200-230 degreeC. The heating time may be appropriately changed according to the heating temperature, but is generally 5 to 10 minutes, and preferably 6 to 8 minutes.
More preferable heat treatment includes treatment at 200 to 250 ° C. for 5 to 8 minutes, and treatment at 200 to 230 ° C. for 5 to 6 minutes.

  Avocado contains persenone A, persenone B, and persenone. As avocado used in the present invention, the content of persenone A, persenone B, or persenone is preferably 0.001 mass in terms of avocado dry weight. % Or more, more preferably 0.01% by mass or more, and preferably 10% by mass or less, more preferably 1% by mass or less, and preferably 0.001 to 10% by mass, more preferably 0.01 to 10% by mass. What is 1 mass% is mentioned.

  As the solvent for extraction, either a polar solvent or a nonpolar solvent can be used. Specific examples of the solvent include, for example, monovalent, divalent or polyhydric alcohols; ketones such as acetone and methyl ethyl ketone; esters such as methyl acetate and ethyl acetate; linear or cyclic such as diethyl ether and tetrahydrofuran Ethers; Polyethers such as polyethylene glycol; Saturated or unsaturated hydrocarbons such as hexane; Aromatic hydrocarbons such as benzene and toluene; Halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane, and carbon tetrachloride Pyridines; dimethyl sulfoxide; acetonitrile; carbon dioxide, supercritical carbon dioxide; fats and oils, waxes, other oils; and mixtures thereof. Preferable examples include alcohols and aqueous alcohol solutions in terms of pharmacological activity and versatility.

  Although it does not specifically limit as said alcohol, For example, monohydric alcohols, such as methanol, ethanol, propanol, butanol, amyl alcohol, hexanol, heptanol, octanol; 1, 3- butylene glycol, ethylene glycol, propylene glycol, 1 , 4-butanediol, 1,5-pentanediol, 1,6-hexanediol and other dihydric alcohols; trivalent or higher alcohols such as glycerin, and the like. Among these, monohydric alcohols and dihydric alcohols are preferable in terms of pharmacological activity and operability. Preferably, the alcohol may be an alcohol having 1 to 10 carbon atoms, more preferably an alcohol having 1 to 4 carbon atoms.

  Preferable examples of the alcohols include methanol, ethanol, 1,3-butylene glycol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, t-butanol and the like.

  The concentration of the alcohol in the aqueous alcohol solution is preferably 20% by mass or more, more preferably 30% by mass or more, and preferably 95% by mass or less, more preferably 90% by mass or less, and still more preferably 85% by mass. It is as follows. Moreover, the concentration of the alcohol in the aqueous solution of the alcohol is preferably 20 to 95% by mass, more preferably 20 to 90% by mass, and still more preferably 30 to 85% by mass.

Of the alcohols, ethanol is more preferable from the viewpoint of versatility. Therefore, more suitable solvents for preparing an avocado extract include ethanol and aqueous ethanol.
When using ethanol, the ethanol concentration is preferably 30% by mass or more, more preferably 40% by mass or more, more preferably 45% by mass or more, and 95% by mass or less, more preferably 90% by mass or less. More preferably, it is 85 mass% or less. Moreover, Preferably it is 30-95 mass%, More preferably, it is 40-90 mass%, More preferably, it is 45-95 mass%, More preferably, it is 45-85 mass%.

As a usage-amount of the solvent in extraction, 5-100 mL is preferable with respect to 1 g of avocado (dry mass conversion).
The extraction conditions are not particularly limited as long as sufficient extraction can be performed. For example, the extraction time is preferably 1 hour or longer, more preferably 3 hours or longer, while preferably 2 months or shorter, more preferably 5 weeks or shorter, more preferably 2 weeks or shorter. The extraction temperature is preferably 0 ° C. or higher, more preferably 5 ° C. or higher, on the other hand, the solvent boiling point or lower is preferable, and 90 ° C. or lower is more preferable. Usually, extraction is performed for a long time at a low temperature and for a short time at a high temperature. Examples of extraction conditions include 15 to 40 ° C. for 1 day to 5 weeks, preferably 1 to 2 weeks, 60 to 90 ° C. for 1 to 5 hours, and the like. Can be selected.

  Extraction means is not particularly limited, and for example, usual means such as solid-liquid extraction, liquid-liquid extraction, immersion, decoction, leaching, reflux extraction, Soxhlet extraction, ultrasonic extraction, microwave extraction, stirring, etc. may be used. it can. These extraction means may be combined. For example, dipping or solid-liquid extraction may be combined with liquid-liquid extraction, or when the extraction time is shortened, solid-liquid extraction with stirring may be performed. Furthermore, in order to prevent the extract from being oxidized, a means for extracting under a non-oxidizing atmosphere while removing dissolved oxygen by bubbling degassing or inert gas such as nitrogen gas may be used in combination. Moreover, extraction operation can be performed repeatedly, such as extracting the extracted filtration residue again, in order to aim at the improvement of a yield.

The avocado extract of the present invention may be a crude product as long as it conforms to, for example, food and pharmaceutical acceptable standards and exhibits the effects of the present invention. In addition, if necessary, treatment such as removal of inert impurities, deodorization, decolorization, etc. by known techniques such as liquid-liquid distribution, solid-liquid distribution, filtration membrane, activated carbon, adsorption resin, ion exchange resin, and starch. Can be applied.
Furthermore, these purities may be increased by appropriately combining known separation and purification methods. Examples of the purification means include organic solvent precipitation, centrifugation, ultrafiltration membrane, high performance liquid chromatograph, column chromatograph and the like.

  In the present invention, persenone A is acetic acid (5E, 12Z, 15Z) -2-hydroxy-4-oxagenicosa-5,12,15-trienyl, and persenone B is acetic acid (5E) -2-hydroxy-4-oxononadece-5. Enyl and persine are acetic acid (12Z, 15Z) -2-hydroxy-4-oxohenicosa-12,15-dienyl, and are represented by the following formula.

  In the present invention, such Persenone A, Persenone B, and Persin (also referred to as “the compound of the present invention”) may be used alone or in combination of two or more. May be used.

  Persenone A, persenone B, and persine can be obtained by extraction and purification from avocado. Specifically, it can be obtained by separating and purifying an extract obtained by solvent extraction from avocado fruit using an appropriate separation and purification means such as column chromatography, ion exchange chromatography, high performance liquid chromatography and the like. it can. The isolation example (refer FIG. 1) is shown below.

1) Add 50% by mass of ethanol to the dried avocado fruit, extract with stirring, and obtain an avocado extract.
2) After the solvent is distilled off from the avocado extract obtained in 1), the obtained solid is subjected to liquid-liquid partition with hexane-water, and the hexane layer is concentrated to obtain a concentrate.
3) The concentrate obtained in 2) is dissolved in hexane, applied to a silica gel column, and eluted with a mixed solvent of hexane-ethyl acetate to obtain 8 fractions.
4) One fraction (fraction 2) obtained in 3) is dissolved in hexane, subjected to preparative TLC, and developed with a chloroform-acetone mixed solvent to obtain six fractions.
5) One fraction (fraction 2 ') obtained in 4) is further fractionated by ODS-HPLC (mixed solvent of acetonitrile-formic acid aqueous solution) to isolate persenone A, persenone B and persine.

  The obtained persenone A, persenone B and persine may be used as they are, may be used as a diluted solution diluted with an appropriate solvent, or may be a concentrated extract, a dry powder, or a paste. Further, it can be freeze-dried and diluted with a solvent usually used for extraction at the time of use, for example, water, ethanol, water / ethanol mixed solution or the like. It can also be used by encapsulating in vesicles such as liposomes or microcapsules.

  As shown in Examples below, avocado extract, persenone A, persenone B, and persyn (hereinafter referred to as “avocado extract etc.”) promote Nrf2 gene expression and are further located downstream of ARE to which Nrf2 binds. Promotes the expression of HMOX1 (heme oxygenase 1) and GCLC (glutamylcysteine ligase). That is, the avocado extract and the like of the present invention can induce the expression of second-phase enzymes related to antioxidant defense, detoxification / metabolism, foreign body excretion, and stress response mechanism controlled by Nrf2. Protection (in vivo antioxidant action) and xenobiotic detoxification can be enhanced. This has been confirmed by promoting the production of glutathione in the avocado extract and the like and reducing the amount of intracellular active oxygen (see Examples 5 and 6). If the oxidative stress defense system and the foreign body metabolism system are enhanced, it becomes possible to prevent, ameliorate, or treat diseases and symptoms caused by oxidative stress and invasion of xenobiotics. Such diseases or symptoms include, for example, retinal degeneration, cataract, keratoconjunctive disorder (dry eye, punctate superficial keratopathy, corneal epithelial defect, corneal erosion, corneal ulcer, conjunctival epithelial defect, dry keratoconjunctivitis, upper limbal horn Eye diseases such as conjunctivitis, filiform keratoconjunctivitis, infectious keratitis, non-infectious keratitis, infectious conjunctivitis, non-infectious conjunctivitis, etc., kidney diseases (acute glomerulonephritis, chronic glomerulonephritis, rapidly progressive glomeruli) Nephritis, diabetic nephropathy, nephrosclerosis, polycystic kidney disease), diabetes associated with kidney disease, cardiovascular disease associated with kidney disease, etc. (see Patent Documents 1 and 2 and Non-patent Document 5) .

Therefore, the avocado extract and the like of the present invention is a preventive, ameliorating or treating agent for renal diseases selected from Nrf2 activators, eye diseases selected from retinal degeneration, cataracts and keratoconjunctival disorders or acute kidney disorders and chronic kidney diseases ( Hereinafter, it may be referred to as “a prophylactic, ameliorating or therapeutic agent for eye diseases or kidney diseases”) and can be used to produce them.
Moreover, the avocado extract etc. of this invention can be used in order to prevent, improve, or treat an eye disease or a kidney disease for activation of Nrf2. Here, the use can be in humans or non-human animals, or specimens derived therefrom, and can be either therapeutic or non-therapeutic. Note that “non-therapeutic” means a concept that does not include medical practice, that is, a concept that does not include a method for operating, treating, or diagnosing a person, more specifically, a doctor or a person who has received instructions from a doctor It is a concept that does not include a method of performing surgery, treatment or diagnosis.

  The Nrf2 activator of the present invention, an agent for preventing, improving or treating an eye disease or kidney disease is a pharmaceutical, quasi-drug, supplement for Nrf2 activation, prevention, improvement or treatment of an eye disease or kidney disease, It may be an embodiment as a food or feed, or an embodiment as a material or preparation for blending them.

In the present invention, “Nrf2 activation” means that Nrf2 transcription is promoted, Nrf2 expression is promoted, Nrf2 translation is promoted, Nrf2 mRNA and protein degradation is inhibited, and Keap1 is bound. Means to promote the expression of a gene whose expression is controlled by Nrf2, such as inhibiting or promoting dissociation, promoting Nrf2 nuclear translocation, promoting binding of Nrf2 to a target DNA sequence, etc. To do.
In addition, protection from oxidative stress (in vivo antioxidant) means reducing reactive oxygen species such as free radicals and active oxygen generated in the body, and reducing the amount of peroxides such as proteins, lipids, and DNA. means.

  The dosage forms of the above-mentioned pharmaceuticals (including quasi drugs or supplements) containing the avocado extract of the present invention are tablets, capsules, granules, powders, syrups, intravenous injections, intramuscular injections, sittings. Preparations, inhalants, transdermal agents, eye drops, nasal drops, poultices, poultices, ointments, lotions, creams, tinctures, liniments, suspensions, lotions, baps, pastes, gels, sprays, aerosols Or any of oil agents, oral preparations (dentifrice, liquid dentifrice, mouthwash, gingival massage cream, oral ointment, gargle tablet, troche, throat lozenge, etc.) may be used. As an administration form when used as a pharmaceutical, quasi-drug, or supplement, it can be used by any route such as oral administration, parenteral administration, or topical administration.

  Such pharmaceutical preparations of various dosage forms include the avocado extract of the present invention alone or other pharmaceutically acceptable excipients, binders, extenders, disintegrants, surfactants, lubricants. Swelling agent, dispersing agent, buffering agent, preservative, flavoring agent, flavoring agent, coating agent, carrier, diluent, osmotic pressure adjusting agent, fluidity promoter, absorption aid, pH adjusting agent, emulsifier, preservative, stable Agent, antioxidant, colorant, UV absorber, wetting agent, thickener, brightener, activity enhancer, anti-inflammatory agent, bactericidal agent, flavoring agent, flavoring agent, extender, surfactant, dispersant , Buffering agents, preservatives, fixing agents, fragrances, coating agents and the like can be prepared in appropriate combinations.

  Examples of the food containing the avocado extract of the present invention include, for example, the concept of Nrf2 activation, prevention or improvement of eye diseases and kidney diseases, and the like. Food, functional nutrition food, food for specified health use, functional indication food, and the like are included.

  The form of the food may be solid, semi-solid or liquid. Foods include confectionery such as breads, noodles, cookies, jelly, dairy products, frozen foods, instant foods, processed starch products, processed meat products, other processed foods, beverages such as coffee drinks, soups, seasonings , Various food compositions such as nutritional supplements, and raw materials thereof. In addition, the food composition may be in tablet form, pill form, capsule form, liquid form, syrup form, powder form, granule form and the like, similar to the above-mentioned preparation for oral administration.

  Such foods include, in addition to the active ingredient of the present invention, other food and drink materials, solvents, softeners, oils, emulsifiers, preservatives, fragrances, stabilizers, colorants, ultraviolet absorbers, antioxidants, moisturizing agents. An agent, a thickener, a sticking agent, a dispersant, a wetting agent, and the like can be blended and prepared as appropriate.

  Examples of the feed containing the avocado extract of the present invention include small animal feeds used for rabbits, rats, mice, etc., and feeds such as pet foods used for dogs, cats, etc. Can be prepared.

The content of the active ingredient of the present invention in the above-mentioned various preparations is preferably 0.01% by mass or more, more preferably 0.1% by mass or more in terms of the dry weight of the extract as an avocado extract. And, Preferably it is 50 mass% or less, More preferably, it is 10 mass% or less, Preferably it is 0.01-50 mass%, More preferably, it is 0.1-10 mass%.
Further, as persenone A, persenone B or persine, the total mass of the preparation is preferably 0.00001% by mass or more, more preferably 0.001% by mass or more, preferably 80% by mass or less, more preferably 20% by mass. % Or less. Moreover, Preferably it is 0.00001-80 mass%, More preferably, it is 0.001-20 mass%.

The Nrf2 activator of the present invention, an agent for preventing, improving or treating eye diseases or kidney diseases is used as a pharmaceutical or various functional foods (for example, foods for specific health use, functional indication foods, etc.) or used in combination with them. Dosage may vary according to subject's condition, weight, sex, age or other factors, but preferably as an avocado extract (dry matter equivalent) per adult per day for oral administration Is 0.01 g or more, more preferably 0.1 g or more, and preferably 10 g or less, more preferably 1.5 g or less.
Moreover, as persenone A, persenone B, or persine, Preferably it is 0.001 mg or more, More preferably, it is 0.1 mg or more, Preferably it is 10 g or less, More preferably, it is 1.5 g or less. Moreover, Preferably it is 0.01-10g, More preferably, it is 0.1-1.5g.
The above-mentioned preparation can be administered according to an arbitrary administration schedule, but is preferably divided into once to several times a day and continuously administered for several weeks to several months. Examples of the administration or ingestion target include humans who need or desire the enhancement of antioxidant defense and detoxification ability of the living body, for example, eye diseases such as retinal degeneration, cataract, keratoconjunctive disorder, kidney diseases (acute kidney injury, chronic Patients with kidney disease) and their reserves.

Regarding the above-described embodiment, the following aspects are further disclosed in the present invention.
<1> An Nrf2 activator comprising avocado or an extract thereof as an active ingredient.
<2> A preventive, ameliorating, or therapeutic agent for an eye disease selected from retinal degeneration, cataract and keratoconjunctival disorder, or kidney disease selected from acute kidney injury and chronic kidney disease, comprising avocado or an extract thereof as an active ingredient.
<3> An Nrf2 activator comprising one or more selected from persenone A, persenone B and persine as an active ingredient.
<4> Prevention of kidney disease selected from retinal degeneration, cataract and keratoconjunctival disorder selected from persenone A, persenone B and persine as an active ingredient, or from acute kidney injury and chronic kidney disease, Improvement or treatment agent.
<5> A food for Nrf2 activation comprising an avocado extract as an active ingredient.
<6> A food for preventing or ameliorating a kidney disease selected from an eye disease or acute kidney injury and chronic kidney disease selected from retinal degeneration, cataract and keratoconjunctival disorder, comprising an avocado extract as an active ingredient.
<7> A food for activating Nrf2, comprising one or more selected from persenone A, persenone B and persine as an active ingredient.
<8> Prevention of kidney disease selected from retinal degeneration, cataract and keratoconjunctival disorder or eye disease or acute kidney injury and chronic kidney disease comprising one or more selected from persenone A, persenone B and persine as active ingredients Food for improvement.

<9> Use of avocado or an extract thereof for producing an Nrf2 activator.
<10> Use of avocado or an extract thereof for producing an agent for the prevention, amelioration, or treatment of an eye disease selected from retinal degeneration, cataract and keratoconjunctival disorder, or kidney disease selected from acute kidney injury and chronic kidney disease.
<11> One or more types selected from persenone A, persenone B, and persyn for producing an Nrf2 activator.
<12> From persenone A, persenone B and persin for producing an agent for the prevention, amelioration, or treatment of an eye disease selected from retinal degeneration, cataract and keratoconjunctivopathy or kidney disease selected from acute kidney injury and chronic kidney disease Use of one or more selected.
<13> Use of an avocado extract to produce a food for Nrf2 activation.
<14> Use of an avocado extract for producing a food for the prevention or amelioration of an eye disease selected from retinal degeneration, cataract and keratoconjunctive disorder or kidney disease selected from acute kidney injury and chronic kidney disease.
<15> Use of one or more selected from persenone A, persenone B and persine for producing a food for Nrf2 activation.
<16> Selected from Persenone A, Persenone B, and Persin for producing a food for prevention or amelioration of eye diseases selected from retinal degeneration, cataracts and keratoconjunctival disorders or kidney diseases selected from acute kidney disorders and chronic kidney diseases One or more uses.

<17> Avocado or an extract thereof for use in Nrf2 activation.
<18> Avocado or an extract thereof for use in the prevention, amelioration, or treatment of an eye disease selected from cataract and keratoconjunctival disorder, or a kidney disease selected from acute kidney injury and chronic kidney disease.
<19> One or more selected from persenone A, persenone B, and persine for use in Nrf2 activation.
<20> Selected from persenone A, persenone B, and persine for use in the prevention, amelioration, or treatment of ocular diseases selected from retinal degeneration, cataracts and keratoconjunctival disorders or kidney diseases selected from acute kidney injury and chronic kidney disease One or more types.

<21> A method for activating Nrf2, wherein avocado or an extract thereof is administered to humans or animals.
<22> A method for the prevention, amelioration, or treatment of an eye disease selected from retinal degeneration, cataract and keratoconjunctival disorder or kidney disease selected from acute kidney injury and chronic kidney disease, wherein avocado or an extract thereof is administered to humans or animals.
<23> A method for activating Nrf2, wherein one or more selected from persenone A, persenone B, and persine are administered to humans or animals.
<24> An ophthalmic disease selected from retinal degeneration, cataract and keratoconjunctivopathy, or a renal disease selected from acute kidney injury and chronic kidney disease, wherein one or more selected from persenone A, persenone B and persine are administered to humans or animals. How to prevent, improve or treat.
<25> In <17> to <20>, the use is a non-therapeutic use.
<26> In <21> to <24>, the method is a non-therapeutic method.
<27> In <1>, <2>, <5>, <6>, the avocado is preferably an avocado heat-treated product.
<28><1>,<2>,<5>,<6>,<9>,<10>,<13>,<14>,<17>,<18>, the avocado extract is preferably Is an ethanol extract of avocado.
<29><1>,<2>,<5>,<6>,<9>,<10>,<13>,<14>,<17>,<18> and persenone in the avocado extract The content of A, persenone B or persine is preferably 0.01% by mass or more, more preferably 0.1% by mass or more, and preferably 50% by mass or less, more preferably 10% by mass or less, and preferably It is 0.01-50 mass%, More preferably, it is 0.1-10 mass%.

  EXAMPLES Hereinafter, although this invention is demonstrated further in detail based on an Example, this invention is not limited to this.

Production Example 1 Preparation of Avocado Extract 0.5 L of 50% by mass ethanol was added to 50.0 g of dried fruits obtained by freeze-drying the avocado pulp, and the mixture was allowed to stand at room temperature for 7 days. The extract was separated, and 0.5 L of 50% by mass ethanol was added to the residue again, followed by standing extraction at room temperature for 7 days. Each extract was concentrated by an evaporator to obtain 4.9 g of an oily concentrate.

Production Example 2 Preparation of Baked Avocado Extract 150-200 g of avocado fruit sliced to a thickness of about 5 mm was lyophilized. The dried fruit was heat-treated for 5 minutes in an oven set at 200 ° C. 0.5 L of 50% by mass ethanol was added to 50.0 g of avocado fruit that had been heat-treated, and the mixture was extracted by standing at room temperature for 7 days. The extract was separated, and 0.5 L of 50% by mass ethanol was added to the residue again, followed by standing extraction at room temperature for 7 days. Each extract was concentrated by an evaporator to obtain 5.8 g of an oily concentrate.

Production Example 3 Isolation of Persenone A, Persenone B and Persine (1) Separation funnel containing avocado ethanol extract obtained in Production Example 1 containing a two-phase immiscible solvent system consisting of 200 mL of hexane and 200 mL of water In addition, polar and nonpolar compounds in the extract were separated. Liquid-liquid partitioning with hexane and water was performed three times. The hexane layers were combined and evaporated to dryness with an evaporator to give 0.66 g of oily concentrate.

(2) 0.6 g of the oily concentrate of the hexane fraction obtained in (1) above was redissolved in 3 mL of hexane and applied to a silica gel column (HI-FLASH COLUMN 3L, manufactured by Yamazen Co., Ltd.) to change the composition. Elution with a solvent. The elution solvents used here were hexane / ethyl acetate (99/1 v / v%, 600 mL), hexane / ethyl acetate (95/5 v / v%, 600 mL), hexane / ethyl acetate (75/25 v / v). %, 900 mL), hexane / ethyl acetate (50/50 v / v%, 600 mL), ethyl acetate (900 mL), methanol (900 mL), and fractionated by collecting the eluate over time . These fractions of the eluate were subjected to thin layer chromatography (silica gel 60, Merck & Co., eluent: chloroform / methanol = 20/1), and the Rf value was measured using a UV lamp (wavelength 254 nm) as an index. The results were used as an index and finally divided into 8 fractions. The yield of each fraction was 33.5 mg for fraction [1], 140.3 mg for fraction [2], 14.5 mg for fraction [3], 50.5 mg for fraction [4] [5] was 33.7 mg, fraction [6] was 71.4 mg, fraction [7] was 15.6 mg, and fraction [8] was 195.7 mg. Table 1 shows the Rf value, the distribution ratio, and the composition of the elution solvent in the thin layer chromatography of each fraction.

Next, redissolved fraction [2] in hexane 1.5 mL, subjected to preparative TLC (Merck PLC silica gel _{60F 254),} were fractionated. The developing solvent was developed twice with chloroform / acetone (95/5). Separately, it was divided into 6 fractions using the Rf value with a UV lamp (wavelength 254 nm) having the same length developed as an index. The yield of each fraction was 8.2 mg for fraction [1 ′], 81.1 mg for fraction [2 ′], 28.4 mg for fraction [3], 10.8 mg for fraction [4], Fraction [5] was 6.0 mg and fraction [6] was 6.4 mg. Table 2 shows the Rf value and the distribution ratio in the thin layer chromatography of each fraction.

(3) Fraction [2 ′] was further fractionated by high performance liquid chromatography to identify the compound in the fraction. Adjust to 10 mg / mL with HPLC grade methanol and inject 100 μL each. The column used is L column 2 (ODS, 10 × 250 mm, 5.0 μm, Chemical Substances Evaluation and Research Organization), and the mobile phase is A phase (0.1% formic acid aqueous solution) 25% and B phase (acetonitrile). ) 75% was used. The column temperature was 40 ° C. and was supplied at a flow rate of 4.7 mL / min. The detector was set at a wavelength of 225 nm. The yield of each fraction was 18.8 mg for Compound 1, 27.1 mg for Compound 2, and 12.1 mg for Compound 3.
A typical chromatograph of fraction [2 ′] is shown in FIG. The range which was fractionated in the chromatogram is shown by 1-3.
The molecular weight of the fractions (equipment: TripleTOF ^™ 4600+ System, column manufactured by SCIEX, column: Capcell Core C18 (2.1 × 7.5 mm, 2.7 μm, Shiseido)) and NMR (Bruker, 600 MHz) were analyzed by persenone A ( Compound 1), persine (compound 2), and persenone B (compound 3) were identified. Each analysis value is as follows.

Compound 1 (Persenone A)
¹ H-NMR (600 MHz, CDCl ₃ ); 0.87 (t, 7.0, 3H), 1.27 (m, 2H), 1.27 (m, 2H), 1.33 (m, 2H), 1.33 (m, 2H), 1.33 (m, 2H), 1.46 (m, 2H), 2.03 (m, 2H), 2.04 (m, 2H), 2.11 (s, 3H), 2.23 (dt, 7.0, 6.4, 2H), 2.75 (m, 2H ), 2.76 (m, 2H), 4.09 (dd, 11.4, 6.3, 1H), 4.14 (dd, 11.4, 4.1, 1H), 4.32 (m, 1H), 5.32 (m, 1H), 5.32 (m, 1H ), 5.35 (m, 1H), 5.35 (m, 1H), 6.10 (d, 16.0, 1H), 6.87 (dt, 16.0, 7.0, 1H)
¹³ C-NMR (150 MHz, CDCl ₃ ); 14.1, 20.9, 22.6, 25.6, 27.0, 27.2, 27.9, 28.8, 29.3, 29.3, 31.5, 32.5, 42.3, 66.2, 67.3, 127.8, 128.3, 129.7, 130.3, 149.4, 171.0, 199.7
HRESIMS m / z 379.2843 (M + H ⁺ ), cald for C ₂₃ H ₃₉ O ₄ 379.2848

Compound 2 (Persine)
¹ H-NMR (600 MHz, CDCl ₃ ); 0.88 (t, 7.0, 3H), 1.27 (m, 2H), 1.27 (m, 2H), 1.27 (m, 2H), 1.27 (m, 2H), 1.27 (m, 2H), 1.32 (m, 2H), 1.32 (m, 2H), 1.56 (m, 2H), 2.03 (m, 2H), 2.04 (m, 2H), 2.10 (s, 3H), 2.44 ( t, 7.5, 2H), 2.61 (m, 2H), 2.76 (m, 2H), 4.04 (dd, 11.4, 6.3, 1H), 4.09 (dd, 11.4, 4.1, 1H), 4.29 (m, 1H), 5.32 (m, 1H), 5.32 (m, 1H), 5.35 (m, 1H), 5.35 (m, 1H)
¹³ C-NMR (150 MHz, CDCl ₃ ); 14.1, 20.8, 21.9, 22.5, 23.5, 25.6, 27.2, 27.2, 29.1, 29.1, 29.2, 29.3, 29.6, 31.5, 43.6, 45.1, 66.0, 67.2, 127.9, 127.9, 130.0, 130.2, 171.0
HRESIMS m / z 381.2999 (M + H ⁺ ), cald for C ₂₃ H ₄₁ O ₄ 381.3005

Compound 3 (Persenon B)
¹ H-NMR (600 MHz, CDCl ₃ ); 0.88 (t, 7.0, 3H), 1.27-1.28 (m, 2H), 1.27-1.28 (m, 2H), 1.27-1.28 (m, 2H), 1.27- 1.28 (m, 2H), 1.27-1.28 (m, 2H), 1.27-1.28 (m, 2H), 1.27-1.28 (m, 2H), 1.27-1.28 (m, 2H), 1.27-1.28 (m, 2H ), 1.27-1.28 (m, 2H), 1.47 (m, 2H), 2.11 (s, 3H), 2.23 (dt, 7.0, 6.4, 2H), 2.76 (m, 2H), 4.09 (dd, 11.4, 6.3 , 1H), 4.14 (dd, 11.4, 4.1, 1H), 4.34 (m, 1H), 6.10 (d, 16.0, 1H), 6.89 (dt, 16.0, 7.0, 1H)
¹³ C-NMR (150 MHz, CDCl ₃ ); 14.1, 20.8, 22.6, 28.8, 29.2-29.7, 29.2-29.7, 29.2-29.7, 29.2-29.7, 29.2-29.7, 29.2-29.7, 29.2-29.7, 29.2- 29.7, 31.9, 32.5, 42.2, 66.2, 67.3, 130.3, 149.6, 171.0, 199.7
HRESIMS m / z 355.2843 (M + H ⁺ ), cald for C ₂₁ H ₃₉ O ₄ 355.2848

Example 1 ARE-Luc Activity (1) Method 1) Plasmid Preparation A plasmid in which a sequence verified as a ARE sequence (GCLC: TCCCCGTGACTCAGCGCTTTG (SEQ ID NO: 1)) in humans is incorporated into pGL3-promoter vector (Promega) It produced as follows.
A 3x ARE tandem repeat sequence oligo DNA with NheI and XhoI recognition sites added to the ends and linkers was designed and synthesized (Gleiner). After 3 × ARE_F and 3xARE_R were added with a phosphate group (T4 Polynucleotide Kinase: Takara Bio), annealing was performed at 95 ° C. for 5 min and 37 ° C. for 30 min. The annealed DNA was ligated with pGL3-promoter vector previously treated with NheI and XhoI (Takara Bio), and transformed into E. coli (ECOS ^™ Competent E. coli DH5α: Wako Pure Chemical Industries). A plasmid was extracted from a colony of ampicillin selective medium, and the sequence was confirmed.

GCLC 3xARE F
CTAGCTCCCCGTGACTCAGCGCTTTGCCCTCCCCGTGACTCAGCGCTTTGCCCTCCCCGTGACTCAGCGCTTTGC (SEQ ID NO: 2)
GCLC 3xARE R
TCGAGCAAAGCGCTGAGTCACGGGGAGGGCAAAGCGCTGAGTCACGGGGAGGGCAAAGCGCTGAGTCACGGGGAG (SEQ ID NO: 3)

2) Luciferase assay HEK293 was inoculated on a 24 well plate and cultured in chalcol treated 5% FBS-containing DMEM medium (GIBCO). When subconfluent, ARE-Luc plasmid and phRL-TK (Promega) as an internal standard were transfected with SuperFect Transfection Reagent (QIAGEN). Thereafter, the evaluation material (avocado extract solvent: 50% EtOH, isolated product solvent: 99.5% EtOH) or the same volume of 50% EtOH or 99.5% EtOH as a control was added, and Dual-Luciferase after 16 hours. Luciferase activity was measured using Reporter Assay System (Promega). ARE-Luc activity (firefly luciferase activity) was corrected by phRL-TK activity (Renilla luciferase activity). FIG. 3 shows a relative value (average value of n = 2) with respect to Ctrl.

(2) Results An increase in ARE-Luc activity was observed in avocado and baked avocado extract (FIG. 3A). Similarly, a concentration-dependent increase in ARE-Luc activity was also observed in persenone A, persenone B, and persine (FIG. 3B).

Example 2 Nrf2 Nuclear Translocation Promoting Action (1) Method Normal human neonatal foreskin keratinocytes (NHEK) (Cascade Biologicals) were seeded in 10 cm dishes and cultured in growth life-containing EpiLife medium (Cascade. Biologics). When subconfluent, persenone A, B or persine (1000 × concentration, solvent: 99.5% EtOH) was added to a final concentration of 50 μM, and the same volume of 99.5% EtOH was added as a control. Time processed. The cells were divided into a cytoplasmic fraction and a nuclear fraction using a Nuclear Extract Kit (Active Motif) after PBS washes, and the protein extracted from the nuclear fraction was subjected to Western blotting. The primary antibody is anti-Nrf2 (Santa Cruz Biotechnology, sc-722), anti-Lamin A / C (Santa Cruz Biotechnology, sc-20681), and the secondary antibody is Anti Rabbit IgG, HRP Linked (GRP). It was. Lamin A / C was used as an internal standard.
(2) Results An increase in the amount of Nrf2 in the nucleus was observed by treatment with persenone A, persenone B, or persine (FIG. 4). From this, it was clarified that persenone A, persenone B, and persine promote Nrf2 nuclear translocation and activate the Nrf2 pathway.

Example 3 Antioxidant Gene Expression (1)
(1) Method 1) Normal human neonatal foreskin fibroblasts (NHDF) (Cascade Biology) were seeded in 12-well plates and cultured in DMEM medium (GIBCO) containing 10% FBS. When it became subconfluent, avocado or baked avocado extract (0.0025, 0.005, 0.01, 0.02%, solvent: 50% EtOH) was treated for 16 hours. Ctrl treated DMSO. RNA was extracted from the cells, and the gene expression level was analyzed by quantitative RT-PCR (n = 3, mean ± SE, * P <0.05 ** P <0.01 (vs Ctrl)). GCLC (Hs00155249_m1) and HO-1 (HMOX1, Hs01110250_m1) were used as TaqMan Gene Expression Assay (Applied Biosystems) probes that specifically detect the target gene. The target gene expression level was corrected by the expression level of the internal standard gene RPLP0 (Hs99999999_m1). For analysis, 7500 Fast Real-Time PCR System (Applied Biosystems) was used.

  2) Normal human neonatal foreskin keratinocytes (NHEK) (Cascade Biology) were seeded on a 12-well plate and cultured in EpiLife medium containing growth additives (Cascade. Biologics). When subconfluent, persenone A, persenone B, or persine (1000 × concentration, solvent: 99.5% EtOH) was added to a final concentration of 10, 25, 50 μM and treated for 24 hours. Ctrl was 99.5% EtOH. RNA was extracted from the cells, and the gene expression level was analyzed by quantitative RT-PCR (n = 3, mean ± SE, * P <0.05 ** P <0.01 (vs Ctrl)). GCLC (Hs00155249_m1) and HO-1 (HMOX1, Hs01110250_m1) were used as TaqMan Gene Expression Assay (Applied Biosystems) probes that specifically detect the target gene. The target gene expression level was corrected by the expression level of the internal standard gene RPLP0 (Hs99999992_m1). For analysis, 7500 Fast Real-Time PCR System (Applied Biosystems) was used.

  Similarly, after recovering the cells, the protein was extracted and subjected to Western blotting. The primary antibodies are anti-Heme Oxygenase 1 (Santa Cruz Biotechnology, sc-10789), anti-GCLC (Abcam, ab53179), anti-β-actin (Cell Signaling Technology, # 4970); HRP Linked secondary antibody (GE Healthcare) was used. β-actin was used as an internal standard.

(2) Results The HO-1 and GCLC gene expression inducing actions were observed in the grilled avocado (FIG. 5A). Furthermore, concentration-dependent HO-1, GCLC gene expression and protein expression-inducing actions were observed for persenone A, persenone B, and persine (FIGS. 5B and 5C).

Example 4 Antioxidant Gene Expression (2)
(1) Method Normal human neonatal foreskin epidermal keratinocytes (NHEK) (Cascade Biology) were seeded on a 12-well plate and cultured in a growth additive-containing EpiLife medium (Cascade. Biologics). When the cells became subconfluent, Nrf2 siRNA (Santa Cruz: sc-37030) or Control siRNA (Santa Cruz: sc-37007) was transfected with HiPerFect Transfection Reagent (QIAGEN). The next day, Persenone A, Persenone B, or Persine (1000 × concentration, solvent: 99.5% EtOH) was added to a final concentration of 50 μM and treated for 8 hours. Ctrl was 99.5% EtOH. RNA was extracted from the cells, and the gene expression level was analyzed by quantitative RT-PCR (n = 3, mean ± SE, ** P <0.01 (vs Ctrl), ^† P <0.05, ^†† P <0.01 (vs Control siRNA)). GCLC (Hs00155249_m1) and HO-1 (HMOX1, Hs01110250_m1) were used as the TaqMan Gene Expression Assay (Applied Biosystems) probe for specifically detecting the target gene. The target gene expression level was corrected by the expression level of the internal standard gene RPLP0 (Hs99999992_m1). For analysis, 7500 Fast Real-Time PCR System (Applied Biosystems) was used.

(2) Results HO-1, GCLC expression inducing action by persenone A, persenone B, and persyn was not observed by Nrf2 knockdown (FIG. 6). From this, it became clear that persenone A, persenone B, and persine enhance the antioxidant gene expression via Nrf2.

Example 5 Glutathione production promoting action (1) Method Normal human neonatal foreskin keratinocytes (NHEK) (Cascade Biologicals) were seeded on 12-well plates and cultured in EpiLife medium containing growth additives (Cascade. Biologics). When subconfluent, persenone A, persenone B, or persine (1000 × concentration, solvent: 99.5% EtOH) was added to a final concentration of 10, 25, 50 μM and treated for 24 hours. Ctrl was 99.5% EtOH. The cells were washed with PBS, suspended in 5% Metaphosphoric acid, and frozen at -80 ° C. After two freeze-thaw operations, the supernatant was collected by centrifugation at 1000 × g for 5 minutes. The total amount of glutathione in the supernatant (Total GSH = GSH + GSSG) was quantified using a glutathione measurement kit (Northwest Life Science Specialties) according to the protocol. Cells were collected from wells treated with the same material, and the protein concentration was measured using BCA protein assay kit (Pierce). The value was used to correct the GSH amount (n = 3, mean ± SE, * P <0.05, ** P <0.01 (vs Ctrl)).

(2) Results The amount of glutathione increased by 2.0, 1.5, and 1.7 times, respectively, compared to Ctrl by treatment with persenone A, persenone B, and persine (50 μM) (FIG. 7). That is, it was revealed that persenones induce the expression of GCLC, which is a glutathione synthase, and ultimately increase the amount of glutathione.

Example 6 Intracellular Reactive Oxygen Reduction Action (1) Method When normal human neonatal foreskin keratinocytes (NHEK) (Cascade Biologics) were seeded in a Biocoat Poly-D-Lycine 96well Black / Clear plate and became subconfluent. The experiment was conducted. Avocado, baked avocado extract, persenone A, persenone B, or persine was treated for 16 hours. Intracellular ROS levels were detected using 2 ′, 7′-dichlorohydrofluorescein diacetate (H ₂ DCFDA) (Invitrogen). The medium after the evaluation material treatment was replaced with Hank's Balanced salt solution (HBSS) (Invitrogen) prepared with H ₂ DCFDA to a final concentration of 10 μM, and treated at 37 ° C. in the dark for 20 minutes. _Then, the H 2 DCFDA solution was subjected to _H 2 _{O 2} treated by replacing the _H 2 _O 2 _(100μM) solution combined concentration HBSS. Excitation 485 nm and emission 535 nm were measured with a fluorescent microplate reader (EnVision 2104 Multilabel Reader, PerkinElmer) 30 minutes after H ₂ O ₂ treatment.

(2) Results When 50 μM pretreatment with persenone A, persenone B, or persine was performed, the increase in intracellular ROS amount by H ₂ O ₂ was reduced by 41, 38, and 32%, respectively (FIG. 8). Similarly, avocado and baked avocado (0.005% treatment) suppressed the increase in the amount of ROS by H ₂ O ₂ by 45 and 58%, respectively (FIG. 8). From the above, it was revealed that avocado, baked avocado extract, persenone A, persenone B, and persine activate Nrf2 and have an oxidative stress reducing action.

Claims (8)

  A Nrf2 activator comprising avocado or an extract thereof as an active ingredient.   An agent for the prevention, amelioration, or treatment of an eye disease selected from retinal degeneration, cataract and keratoconjunctival disorder, or kidney disease selected from acute kidney injury and chronic kidney disease, comprising avocado or an extract thereof as an active ingredient.   A Nrf2 activator comprising one or more selected from persenone A, persenone B and persine as an active ingredient.   Prevention, improvement or treatment of eye diseases selected from retinal degeneration, cataracts and keratoconjunctival disorders, or kidney diseases selected from acute kidney disorders and chronic kidney diseases, comprising at least one selected from persenone A, persenone B and persine as an active ingredient Agent.   A food for Nrf2 activation comprising an avocado extract as an active ingredient.   A food for the prevention or amelioration of an eye disease selected from retinal degeneration, cataract and keratoconjunctival disorder or kidney disease selected from acute kidney injury and chronic kidney disease, comprising an avocado extract as an active ingredient.   A food for activating Nrf2, comprising at least one selected from persenone A, persenone B and persine as an active ingredient.   Food for prevention or amelioration of eye diseases selected from retinal degeneration, cataract and keratoconjunctive disorder or acute kidney injury and chronic kidney disease comprising one or more selected from persenone A, persenone B and persine as an active ingredient .