JP2016027015A - Smad3 inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide pharmaceuticals, quasi drugs, and cosmetics that inhibit Smad3 and exert fibrillization inhibitory effect, and materials that exert the effect when blended with pharmaceuticals, quasi drugs, cosmetics, foods, feed and others.SOLUTION: The Smad3 inhibitor comprises a plant selected from rosemary, white tea, milk thistle, oolong tea, and peanut and extract thereof, and at least one selected from the group consisting of logwood dyes, litchi polyphenols, and apple polyphenols, as active ingredients.SELECTED DRAWING: None

Description

  The present invention relates to an Smad3 inhibitor that inhibits Smad3 and suppresses tissue fibrosis.

  Tissue fibrosis is caused by excessive production and accumulation of an extracellular matrix centering on collagen in the tissue. When tissues are damaged by stimuli such as oxidative stress, hypoxia, inflammation, or apoptosis, the damaged tissues are replaced with extracellular matrix for repair, but if the damage is severe or such stimuli become chronic In such cases, the extracellular matrix accumulates excessively and the tissue cannot perform its function sufficiently. Fibrosis is observed in various organs such as liver, pancreas, lung, kidney, bone marrow and heart, and collagen-producing cells such as fibroblasts are considered to be involved in the pathological condition. Such fibrosis of tissues / organs is observed in the onset or progression of the disease, and it is important in preventing or treating the disease not to cause it.

  Many studies have shown that TGF-β promotes fibrosis of tissues and organs through its activation, and excessive TGF-β signal is caused by fibrosis in the liver, kidney, and lung (non-patented). It is thought that it is a cause of literature 1-3) and renal tubulointerstitial fibrosis (nonpatent literature 4). In fact, drugs and methods for preventing or treating tissue fibrosis by inhibiting TGF-β have been reported, and by adding a TGF-β action inhibitor, etc., the production of α-actin and collagen is reduced, and serum It is described that IFN-β is improved and that fibrosis is suppressed by suppressing Smad3 expression (Patent Documents 1 to 3).

TGF-β / Activin is recognized by the type II receptor, which is a specific normally active serine / threonine kinase present on the cell membrane, and binds to the type I receptor (ALK4, ALK5, ALK7) in a ligand-dependent manner. To do. The type I receptor that has been activated by phosphorylation thereby phosphorylates the Smad2 / 3 complex, which is a kind of R-Smad (receptor-regulated Smad), which is an intracellular signal transduction molecule. The phosphorylated Smad2 / 3 complex forms a heterocomplex with Smad4, which is a Co-Smad (common partner Smad), and translocates into the nucleus to directly bind to DNA, bind to other transcription factors, or By binding to other transcription coupling factors, the expression of the target gene is controlled.
Inhibition of Smad3, an R-Smad, suppresses TGF-β signaling pathway and prevents fibrosis of various organs and tissues such as liver fibrosis, kidney fibrosis, lung fibrosis and renal tubulointerstitial fibrosis It is estimated that it is useful for improvement.

  Rosemary, on the other hand, is an evergreen small shrub belonging to the genus Lamiaceae, native to the Mediterranean region, and its leaves and flowers are widely used mainly for cooking, medicinal purposes, and fragrances. Rosemary contains many polyphenol components such as carnosic acid, carnosol, and rosmarinic acid, and is known to have an excellent antioxidant effect.

  White tea is obtained by finely fermenting the leaves of the camellia tea genus, and has a refreshing feeling and a subtle sweetness.

  Maria thistle is a plant belonging to the genus Maria thistle, also called the milk thistle, and has been used as a folk medicine for a long time in Europe. The seeds are widely used for diseases of the liver, gallbladder, spleen, digestive organs and lack of breast milk.

  Oolong tea is obtained by semi-fermenting the leaves of the camellia tea genus, mainly produced in China and widely used for drinking. Numerous reports have been made on oolong tea such as blood cholesterol elevation suppression, arteriosclerosis suppression, antioxidant, anti-inflammatory, anti-stress, anti-allergic, and anti-cariogenic effects.

  Peanut is a plant belonging to the genus Peanut, which contains proanthocyanidins, a type of polyphenol, and is known to have an antioxidant effect and a hematopoietic function recovery effect.

  Logwood pigment is obtained by extracting with heat water from the heart material of leguminous logwood, and is used for the purpose of coloring in blackish brown, and contains hematoxylin as a main pigment.

  The lychee polyphenol is a polyphenol extracted from the fruit of the genus Lepidoptera, including leucocyanidine, and is known to have an antioxidant action.

  Apple polyphenol is a polyphenol extracted from the fruit of the genus Rosaceae, which eliminates the sweetness left in the mouth while maintaining the unique sweetness, sourness and fruit flavor of low alcoholic beverages containing fruit wine. It is known that it has a good bacteriostatic action, has a bacteriostatic action, and can suppress unpleasant rust derived from iron ions.

  However, the effects of rosemary, white tea, Maria thistle, oolong tea, peanut, logwood pigment, lychee polyphenol, apple polyphenol on Smad3 are not known at all.

JP 2004-35475 A JP 2009-226069 A Special table 2010-529049 gazette

Schnabl B, et al. (2001) Hepatology. 34: 89-100 Inazaki K, et al. (2004) Kidney Int. 66: 597-604 Zhao Y, Geverd DA. (2002) Biochem Biophys Res Commun. 294: 319-323 Lee JM, et al. (2006) J Cell Biol. 172: 973-981

  The present invention exhibits Smad3 inhibitory action, and when blended with pharmaceuticals, quasi-drugs or cosmetics, and pharmaceuticals, quasi-drugs, cosmetics or foods, etc., that exhibit fibrosis-suppressing effects Related to providing materials to be used.

  As a result of searching for effective components for suppressing fibrosis, the present inventors have found that rosemary extract, white tea extract, maria thistle extract, oolong tea extract, peanut extract, logwood pigment, lychee polyphenol, It was found that apple polyphenol has a Smad3 inhibitory action and can suppress the TGF-β signal pathway.

That is, the present invention relates to the following.
(1) Smad3 inhibition containing as an active ingredient at least one selected from the group consisting of rosemary, white tea, maria thistle, oolong tea, peanuts and their extracts, and logwood pigment, lychee polyphenol, apple polyphenol Agent.
(2) Plants selected from rosemary, white tea, Maria thistle, oolong tea and peanuts and their extracts, and fibrosis containing one or more selected from the group consisting of logwood pigment, lychee polyphenol and apple polyphenol as active ingredients Inhibitor.

  According to the present invention, it has an excellent Smad3 inhibitory effect and is useful for suppressing fibrosis, etc., used for pharmaceuticals, quasi drugs, cosmetics, or pharmaceuticals, quasi drugs, cosmetics or foods Materials and methods can be provided. Therefore, according to the present invention, it is possible to inhibit Smad3 and prevent or improve the suppression of fibrosis.

It is a figure which shows the Smad3 phosphorylation promotion inhibitory effect (lane left; low concentration sample, lane right; high concentration sample).

  In the present invention, “Smad3 inhibition” refers to inhibiting the intracellular signal transduction system carried by Smad3. Specifically, Smad3 expression is reduced at the gene and / or protein level, or phosphorylation of Smad3 is suppressed. By doing this, it is suppressing the intracellular signal pathway which Smad3 bears, and as a result, suppressing the effect | action of TGF- (beta).

“Inhibition of fibrosis” in the present invention means suppression of fibroblast proliferation, suppression of fibrosis by activation of fibroblasts, and promotion of apoptosis of fibroblasts. Suppression of fibroblast proliferation or suppression of fibrosis by activation of fibroblasts is confirmed by measuring the expression level of mRNA and protein expression of fibrosis markers and observing the formation of stress fibers in fibroblasts can do.
Such fibrosis inhibition can prevent or improve fibrosis of various organs / tissues such as liver fibrosis, renal fibrosis, lung fibrosis, and renal tubulointerstitial fibrosis.

  Rosemary used in the present invention is Rosmarinus officinalis belonging to the family Lamiaceae Mannenrou, white tea is Camellia sinensis L., Camellia sinensis L. Camellia sinensis, and peanut means Arachis hypogaea L., which belongs to the legume peanut genus.

  The plant may be any part, for example, whole plant, leaf (leaf blade, petiole, etc.), bark, woody part, branch, fruit, seed, flower (petal, ovary, etc.), root, rhizome, etc., or a combination thereof. It is preferable to use leaves or flowers for rosemary, leaves for white tea, seeds for maria thistle, leaves for oolong tea, and seed coats for peanuts.

Such plants can be used by crushing, pulverizing or exploiting them as they are, or they can be used after drying or pulverizing those treated from these, or they can be used by extracting from them. Is preferred.
The said extract can be acquired by attaching | subjecting the said plant to an extraction process as it is, or attaching | subjecting an extraction process after grind | pulverizing, cutting | disconnecting or drying.

  As the above extract, commercially available ones may be used, or various solvent extracts obtained by a conventional method, or diluted solutions thereof, concentrated solutions thereof, dried powders thereof, pastes or activated carbon treatments thereof. There may be. As an example, an extract can be obtained by extraction means, such as extracting the said plant under fixed temperature (low temperature, normal temperature, or warming), or extracting using extraction tools, such as a Soxhlet extractor.

Known extraction methods include, for example, solid-liquid extraction, squeeze extraction, liquid-liquid extraction, immersion, decoction, leaching, reflux extraction, ultrasonic extraction, microwave extraction, stirring, and the like. In order to shorten the extraction time, solid-liquid extraction with stirring is desirable. Examples of suitable conditions for this solid-liquid extraction include stirring at 10 to 100 ° C. and 100 to 400 rpm / min for 1 to 30 minutes. As a suitable example of immersion, the immersion for 1 hour-14 days is mentioned at 10-50 degreeC. Moreover, when shortening extraction time, solid-liquid extraction with stirring is desirable.
In order to prevent oxidation of the extract, a means for extraction under a so-called non-oxidizing atmosphere while removing dissolved oxygen by bubbling degassing or inert gas such as nitrogen gas may be used in combination.

  As the solvent for extraction, either a polar solvent or a nonpolar solvent can be used. Examples of the extraction solvent include water; alcohols such as methanol, ethanol, propanol and butanol; polyhydric alcohols such as propylene glycol and butylene glycol; ketones such as acetone and methyl ethyl ketone; esters such as methyl acetate and ethyl acetate. Linear or cyclic ethers such as tetrahydrofuran and diethyl ether; polyethers such as polyethylene glycol; hydrocarbons such as squalene, hexane, cyclohexane and petroleum ether; aromatic hydrocarbons such as benzene and toluene; dichloromethane And halogenated hydrocarbons such as chloroform, dichloroethane and carbon tetrachloride; pyridines; carbon dioxide, supercritical carbon dioxide; organic solvents such as fats, waxes and other oils; and mixtures thereof. These solvents can be used alone or in combination as a mixture.

  Among these solvents, one or more selected from water, alcohols (more preferably having 1 to 5 carbon atoms), ketones, and hydrocarbons are preferable. Among these, water, ethanol, a water-ethanol mixed solution, acetone, and hexane are more preferable. When a water-ethanol mixed solution is used, the ethanol concentration (V / V) in the mixed solution is preferably 0.01% by volume or more, more preferably 20% by volume or more, still more preferably 40% by volume or more, Preferably it is less than 100 volume%, More preferably, it is 99.5 volume% or less. Moreover, 0.01 volume% or more and less than 100 volume% are preferable, 20 volume% or more and less than 100 volume% are more preferable, and 40-99.5 volume% is still more preferable.

  As a usage-amount of a solvent, 1-50 mass parts is preferable with respect to 1 mass part of the said plants (dry mass conversion), and 2-30 mass parts is more preferable. As extraction temperature, 0-100 degreeC is preferable, 4-85 degreeC is more preferable, and 4-60 degreeC is still more preferable. The extraction time is preferably 1 minute to 150 days, more preferably 5 minutes to 50 days, and even more preferably 10 minutes to 30 days.

  The extract thus obtained may be used as it is, alone or mixed with the extract or fraction, and may be used as a diluted solution diluted with an appropriate solvent, or may be a concentrated extract or a dry powder. A paste prepared may be used. In addition, when lyophilized and used, a solvent usually used for extraction, such as water, ethanol, propylene glycol, butylene glycol, water-ethanol mixed solution, water-propylene glycol mixed solution, water-butylene glycol mixed solution, etc. It can also be used after diluting. It can also be used by encapsulating in vesicles such as liposomes or microcapsules.

  The extract may be a crude product as long as it conforms to food and pharmaceutical acceptable standards and exhibits the effects of the present invention, and the obtained crude product is further purified by a known separation and purification method. These purities may be combined appropriately to remove inactive impurities and increase their purity. Examples of the purification means include organic solvent precipitation, centrifugation, ultrafiltration membrane, high performance liquid chromatograph and column chromatograph, liquid-liquid distribution, gel filtration separation, activated carbon treatment and the like.

  As a specific extract, for example, rosemary extract is extracted with warm or hot water-containing ethanol or ethanol in an environment in which leaves or flowers are replaced with carbon dioxide, or warm to hot hexane, methanol. Alternatively, a product obtained by extracting with water-containing methanol and removing the solvent, or a commercially available “RM-21B base” (Mitsubishi Chemical Foods) can be used. As the oolong tea extract, for example, a semi-fermented tea made from leaves and extracted with water when heated, or a commercially available “oolong tea extract” (San-Eigen FFI) can be used. As the white tea extract, the Maria thistle extract, and the peanut extract, various commercially available products shown in Examples below can be used.

  The logwood pigment used in the present invention means a pigment component obtained by extracting a heartwood of Haematoxylon campechiumum belonging to the leguminous logwood genus. Specifically, log wood heartwood obtained by extraction with hot water or a commercially available “Hematein” (Ichimaru Falcos) can be used.

  The lychee polyphenol used in the present invention means a polyphenol obtained by extracting the fruit of Litchi chinensis belonging to the genus Lepidoptera. Specifically, lychee fruits extracted with water-containing ethanol, then mixed with green tea extract and heated to lower molecular weight, or commercially available "Oligonol" (Amino Up Chemical) are used. be able to.

  The apple polyphenol used by this invention means the polyphenol obtained by extracting the immature fruit of Malus pumila of the Rosaceae apple genus. Specifically, it is possible to use a product obtained by compressing and extracting an immature fruit of an apple and then producing it by resin purification, or a commercially available product “Applephenon C-100” (Asahi Food and Healthcare).

  As shown in Examples below, rosemary extract, white tea extract, maria thistle extract, oolong tea extract, peanut extract, logwood pigment, lychee polyphenol, and apple polyphenol have an action of inhibiting Smad3. Therefore, the above rosemary, white tea, Maria thistle, oolong tea, peanut, logwood pigment, lychee polyphenol, and apple polyphenol suppress TGF-β stimulation-responsive Smad3 phosphorylation and are useful for Smad3 inhibition. is there. In addition, by suppressing the Smad3 signal, the TGF-β signal can be suppressed and a fibrosis suppressing effect can be expected.

  Therefore, the plant selected from the above rosemary, white tea, Maria thistle, oolong tea, peanut used in the present invention and their extracts, logwood pigment, lychee polyphenol, apple polyphenol are Smad3 inhibitors or fibrosis inhibitors (hereinafter, As "Smad3 inhibitors") and can be used to produce these agents.

The use can be in humans or non-human animals, or specimens derived therefrom, and can be either therapeutic or non-therapeutic.
Here, “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 for performing surgery, treatment, or diagnosis on the subject.

  Therefore, the composition containing the Smad3 inhibitor or the like of the present invention becomes a pharmaceutical, quasi-drug, cosmetic or food that exhibits the effects of inhibiting Smad3 and suppressing fibrosis, and the Smad3 inhibitor is a pharmaceutical, pharmaceutical or pharmaceutical. It is useful as a raw material or preparation for blending into quasi-drugs, cosmetics or foods.

  The dosage form of the above-mentioned pharmaceutical (including quasi-drugs) may be any of injections, suppositories, inhalants, transdermal absorption agents, various external preparations, tablets, capsules, granules, powders, syrups, etc. The dosage form may be any of oral administration (internal use) and parenteral administration (external use, injection). In order to prepare pharmaceutical preparations of such various dosage forms, for example, the active ingredient of the present invention, or other pharmaceutically acceptable excipients, binders, extenders, disintegrants, surfactants, Lubricants, dispersants, buffers, preservatives, flavoring agents, fragrances, coating agents, carriers, diluents, other medicinal ingredients, and the like can be used in appropriate combinations.

  The cosmetics (including quasi-drugs) can be in the form of external preparations for skin, cleaning agents, makeup cosmetics, etc., depending on the method of use, lotions, emulsions, gels, creams, ointments, It can be provided in various dosage forms such as powder and granules. Such cosmetics in various dosage forms include, for example, the active ingredient of the present invention and oily ingredients, moisturizers, powders, pigments, emulsifiers, solubilizers, detergents, UV absorbers that can be blended in skin cosmetics. It can be prepared by appropriately combining agents, thickeners, medicinal ingredients, fragrances, resins, antibacterial and antifungal agents, plant extracts, alcohols, vitamins and the like.

  The content of the active ingredient of the present invention (in terms of dry matter) in the above pharmaceuticals and cosmetics (including quasi drugs) is not particularly limited, but is 0.01% by mass or more, preferably 0.1% of the total formulation mass. % By mass or more, more preferably 1.0% by mass or more, and 95% by mass or less, preferably 80% by mass or less, more preferably 60% by mass or less. Moreover, 0.01-95 mass%, Preferably it is 0.1-80 mass%, More preferably, 1.0 mass%-60 mass% is mentioned.

  The food includes functional foods such as foods for sick persons, nutritional functional foods, and foods for specified health, which are based on the concept of fibrosis suppression and the like, as necessary.

The form of the food product can be solid, semi-solid or liquid. Examples of food include confectionery such as breads, noodles, cookies, jelly, dairy products, frozen foods, frozen foods, instant foods, processed starch products, processed meat products, other processed foods, tea and coffee drinks, fruit drinks, carbonic acid Examples include beverages such as beverages and jelly-like beverages, soups, seasonings, nutritional supplements, and the like, and raw materials thereof.
In addition, like a supplement, the food may be in tablet form, pill form, capsule form, liquid form, syrup form, powder form, granule form, etc. as in the above-mentioned oral administration preparation.

  Such foods include any food and drink materials, solvents, softeners, oils, emulsifiers, preservatives, fragrances, stabilizers, colorants, ultraviolet absorbers, antioxidants, moisturizers, thickeners, sticking agents. , A dispersant, a wetting agent, and the like can be mixed and prepared as appropriate.

  The content of the active ingredient of the present invention (in terms of dry matter) in the food is not particularly limited, but is 0.0001% by mass or more, preferably 0.001% by mass or more, more preferably 0.001% by mass or more of the total mass of the preparation. It is 01 mass% or more, and 50 mass% or less, Preferably it is 20 mass% or less, More preferably, it is 10 mass% or less. For example, 0.0001% to 50% by mass, preferably 0.001 to 20% by mass, and more preferably 0.01 to 10% by mass.

  The dosage when the active ingredient of the present invention is used in combination with pharmaceuticals or supplements may vary according to the subject's condition, body weight, sex, age or other factors, but per adult per oral administration The daily dose is not particularly limited, but is usually 1 mg or more, preferably 5 mg or more, more preferably 15 mg or more, and 10 g or less, preferably 5 g or less, more preferably as the active ingredient (in terms of dry matter). Is 1 g or less.

Moreover, although the said formulation can be administered according to arbitrary administration schedules, it is preferable to divide once to several times a day, and to administer continuously for several weeks to several months.
In addition, the administration or ingestion target is not particularly limited as long as it is an animal that needs or desires it, but includes a human who needs or desires Smad3 inhibition or fibrosis suppression.

With respect to the above-described embodiment, the following aspects are further disclosed in the present invention.
<1> Smad3 inhibition containing at least one plant selected from the group consisting of rosemary, white tea, Maria thistle, oolong tea, peanuts and their extracts, and logwood pigment, lychee polyphenol, apple polyphenol as an active ingredient Agent.
<2> Fibrosis containing as an active ingredient at least one selected from the group consisting of a plant selected from rosemary, white tea, Maria thistle, oolong tea, peanuts and their extracts, and logwood pigment, lychee polyphenol, apple polyphenol Inhibitor.
<3> A plant selected from rosemary, white tea, maria thistle, oolong tea, and peanut, and an extract thereof, and logwood pigment, lychee polyphenol, and apple polyphenol for producing a Smad3 inhibitor or a fibrosis inhibitor Use of one or more selected from the group.
<4> A plant selected from rosemary, white tea, maria thistle, oolong tea, and peanut, and an extract thereof, and logwood pigment, lychee polyphenol, and apple polyphenol for use in Smad3 inhibitor or fibrosis inhibitor One or more selected from the group.
<5> Plants selected from rosemary, white tea, Maria thistle, oolong tea, peanuts and their extracts, and one or more effective amounts selected from the group consisting of logwood pigment, lychee polyphenol, apple polyphenol, or A method for inhibiting Smad3 or a method for suppressing fibrosis, which is characterized by being ingested.
<6> In the above item <3>, the use is a non-therapeutic use.
<7> In the above item <5>, the method is a non-therapeutic method.
<8> In the above item <5>, the subject of administration or ingestion is a human who needs or desires fibrosis suppression.

(1) Analysis of influence on phosphorylation of Smad3 HEK293 cells were seeded in 6-well dish to 3 × 10 ⁵ cells / well, and cultured overnight in High glucose DMEM (Invitrogen) containing 5% charcoal-treated FBS. did. On the next day, the following materials were replaced with serum-free DMEM added at a final concentration of 0.002% by mass (low concentration sample) or a final concentration of 0.01% by mass (high concentration sample), respectively. Two hours later, 0.03 μg / mL TGF-β1 (Wako Pure Chemical Industries, Ltd.) was added, and the cells incubated for 20 minutes were removed of the medium and washed with PBS.

  As materials, rosemary extract is the product name “RM-21B Base” (Mitsubishi Chemical Foods), white tea extract is White tea extract (Organic Herb Inc.), and Maria Thistle extract is Maria Thistle Extract (Kenko Kosho). ), Logwood pigment is the product name “Hematein” (Ichimaru Falcos), peanut extract is the peanut seed coat extract powder (Tokiban Phytochemistry), lychee polyphenol is the product name “Oligonol” (Amino Up Chemical), apple polyphenol Used the product name “Applephenon C-100” (Asahi Food and Healthcare), and Oolong tea used the product name “Oolong tea extract” (San-Eigen FFI).

(2) Western blotting The following Lysis buffer was added to the cells washed with PBS and well homogenized. After standing on ice for 15 minutes, the mixture was sonicated and centrifuged at 12000 rpm, 4 ° C. for 10 minutes to obtain a protein solution. For SDS-PAGE, a sample prepared by heat denaturation at 95 ° C. for 5 minutes was used for a prepared sample containing 25 μg of protein per lane and ¼ volume of 4 × SDS Sample buffer (Novagen). It was transferred to Immuno-Blot ^™ PVDF Membrane (BioRad), blocked and antibody-reacted by the following procedures, and Smad3 and phosphorylated Smad3 were detected using ECL prime Western detection system (Amersham). This evaluated whether each material inhibits Smad3 phosphorylation enhancement responsive to TGF-β stimulation. As an internal standard, α-Tubulin and Smad3 were detected together. In FIG. 1, (−) indicates that the TGF-β1 is not added, and (+) indicates that the TGF-β1 is added.

5% skim milk / TBS-T, 1 hour (room temperature)
↓ Wash with TBS-T Primary antibody / Can Get Signal ™ solution 1 (TOYOBO), O / N (4 ° C)
↓ Wash with TBS-T Secondary antibody / Can Get Signal ™ solution 2 (TOYOBO), 1 hour (room temperature)
↓ Washed with TBS-T Detection * TBS-T; 0.1% Tween20 / Tris Buffered Saline (TBS)

Lysis buffer: RIPA buffer (SIGMA)
Protease inhibitor cocktail (1/1000 quantity, SIGMA)
Phosphatase Inhibitor Cocktail 1 (1/100 quantity, SIGMA)
Phosphatase Inhibitor Cocktail 2 (1/100 quantity, SIGMA)
Primary antibody: anti-Smad3 (Cell signaling # 9513), diluted 1000 times
anti-phospho Smad3 (Cell signaling # 9520), diluted 1000 times
anti-α-tubulin (Cell signaling # 2144), diluted 1000 times Secondary antibody: anti-rabbit IgG, HRP linked (GE Healthcare), diluted 1000 times

  As shown in FIG. 1, rosemary extract, white tea extract, maria thistle extract, oolong tea extract, peanut extract, logwood pigment, lychee polyphenol, and apple polyphenol have enhanced Smad3 phosphorylation in response to TGF-β stimulation. In the high-concentration treatment group (lane right side), a more remarkable inhibitory effect was observed.

Claims (2)

  A Smad3 inhibitor comprising as an active ingredient at least one selected from the group consisting of a plant selected from rosemary, white tea, Maria thistle, oolong tea, and peanuts, and an extract thereof, and logwood pigment, lychee polyphenol, and apple polyphenol.   A fibrosis inhibitor comprising as an active ingredient at least one selected from the group consisting of a plant selected from rosemary, white tea, Maria thistle, oolong tea, and peanuts and their extracts, and logwood pigment, lychee polyphenol, and apple polyphenol.