JP2013241380A - Sirtuin 1 (sirt 1) gene activator - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a sirtuin 1(SIRT 1) gene activator.SOLUTION: Provided is a sirtuin 1 (SIRT 1) gene activator containing proanthocyanidin as an active ingredient.

Description

  The present invention relates to a sirtuin 1 (SIRT1) gene activator.

Sirtuins are deacetylases consisting of SIRT1-7. In recent years, research on the function of sirtuins has become active. In particular, sirtuin 1 (SIRT1) has an anti-aging effect, diabetes improvement effect, cardiovascular protection effect, renal disease improvement effect, inflammatory cytokine production suppression effect, neuroprotective effect. It became clear that it has various functions.
Compounds such as resveratrol and quercetin have been developed as factors that enhance SIRT1 deacetylation activity, and anti-aging agents (anti-aging agents), diabetes treatment drugs, cardiovascular disease treatment drugs, neurological disease treatment drugs In order to use it as an anti-inflammatory agent, active research has been conducted (for example, see Non-Patent Document 1).

Experimental Medicine 2010, Vol. 28, No. 19, 3068-3076

  An object of the present invention is to provide a sirtuin 1 (SIRT1) gene activator.

One embodiment of the present invention is a sirtuin 1 (SIRT1) gene activator containing proanthocyanidins as an active ingredient. The proanthocyanidins have the following formula

(Wherein R ₁ is a hydrogen atom or a hydroxyl group, R ₂ is a hydrogen atom, a hydroxyl group, or an alkoxy group having 1 to 4 carbon atoms, R ₃ and R ₄ are each independently selected from a hydroxyl group or a carbon number of 1 to 4) 4 alkoxy group, R ₅ represents hydrogen or an organic group.)
2 or more and 11 or less, preferably 2 or more and 7 or less, and more preferably 2 in the following manner (I), (II), or (III) It may have a structure of 4 or less, most preferably 2 bonded to each other.
(I) Bond between the 4-position carbon and the 8-position carbon (II) Bond between the 4-position carbon and the 6-position carbon (III) Bond between the 4-position carbon and the 8-position carbon, and a bond between the 2-position carbon and the 7-position carbon

Proanthocyanidins may be represented by the following formula.

(Wherein R ₁ is a hydrogen atom or a hydroxyl group, R ₂ and R ₆ are independently selected hydrogen atoms, a hydroxyl group or an alkoxy group having 1 to 4 carbon atoms, R ₃ , R ₄ , R ₇ and R ₈ are Each independently selected hydroxyl group or alkoxy group having 1 to 4 carbon atoms, R ₅ and R ₉ represent hydrogen or an organic group, n is 1 to 10, preferably 1 to 6, more preferably 1 to 3. Is an integer.)

Proanthocyanidins may be represented by the following formula.

Examples of the monovalent organic group represented by R ₅ and R ₉ include a gallate group, an organic acid residue, and a sugar residue. Examples of organic acids that form organic acid residues include p-coumaric acid, caffeic acid, ferulic acid, sinapinic acid, p-hydroxybenzoic acid, acetic acid, oxalic acid, malonic acid, succinic acid, malic acid, and the like. It is done. R ₅ and R ₉ may be a glycoside in which a saccharide is bonded to a gallate group or an organic acid group. In this case, for example, the sugar is bonded to a phenolic hydroxyl group of a gallate group or an organic acid group at an arbitrary position via an ester bond. Examples of the sugar of the glycoside include pyranose type hexis, furanose type pentose and the like. Examples of sugar forms include disaccharides and trisaccharides in addition to monosaccharides such as glucose, galactose, rhamnose, xylose, and arabinose. In particular, R ₅ and R ₉ preferably represent a gallate group which may have a substituent. The “gallate group optionally having substituent (s)” includes “gallate group” and “gallate group having substituent (s)”, and “gallate group having substituent (s)” includes “gallate to which sugar is bound. Group "and the like.

  In addition, at least one of the hydroxyl groups at the 5th and 7th positions of each monomer may be a modifying group to which a gallate group, a sugar, an organic acid, or the like is bonded, and the gallate group or the organic acid group has a sugar. It may be bonded. Here, examples of the sugar include disaccharides and trisaccharides in addition to monosaccharides such as glucose, galactose, rhamnose, xylose, and arabinose. Examples of the organic acid include p-coumaric acid, caffeic acid, ferulic acid, sinapinic acid, p-hydroxybenzoic acid, acetic acid, oxalic acid, malonic acid, succinic acid, malic acid and the like.

  Other embodiments of the present invention include anti-aging agents, diabetes treatment agents and prevention agents, cardiovascular disease treatment agents and prevention agents, nervous system disease treatment agents and prevention agents, renal disease treatment agents and prevention agents, and anti-inflammatory agents. A pharmaceutical used as any one or more of the agents, containing the proanthocyanidins as an active ingredient. The diabetes may be type 2 diabetes, the cardiovascular disease may be myocardial infarction or arteriosclerosis, and the nervous system disease is amyotrophic lateral sclerosis, Alzheimer's disease, or dementia. The renal disease may be nephrosis or renal dysfunction, and the inflammation may be colitis such as pneumonia, hepatitis, pancreatitis, or ulcerative colitis.

  Another embodiment of the present invention is an NF-kappaB inhibitor containing the above proanthocyanidins as an active ingredient.

  Another embodiment of the present invention is an anti-aging cosmetic containing the proanthocyanidins as an active ingredient. This cosmetic may be an application agent.

  Another embodiment of the present invention is a sirtuin 1 (SIRT1) gene activator comprising the above-mentioned proanthocyanidins as an active ingredient and being used in combination with another sirtuin 1 (SIRT1) activator.

Another embodiment of the present invention is a method for examining sirtuin 1 (SIRT1) gene activation ability, comprising the step of examining whether a proanthocyanidin derivative has transcription activation ability of a sirtuin 1 (SIRT1) gene. . Another embodiment of the present invention is a method for screening an activator of a sirtuin 1 (SIRT1) gene, wherein one or more proanthocyanidin derivatives have the ability to activate transcription of the sirtuin 1 (SIRT1) gene. And a step of specifying a compound having transcription activation ability as the activator. In these methods, the proanthocyanidin derivative has the following formula:

(Wherein R ₁ is a hydrogen atom or a hydroxyl group, R ₂ is a hydrogen atom, a hydroxyl group, or an alkoxy group having 1 to 4 carbon atoms, R ₃ and R ₄ are each independently selected from a hydroxyl group or a carbon number of 1 to 4) 4 alkoxy group, R ₅ , R ₁₀ and R ₁₁ represent hydrogen or an organic group.)
2 or more and 11 or less, preferably 2 or more and 7 or less, and more preferably 2 in the following manner (I), (II), or (III) It may have a structure of 4 or less, most preferably 2 bonded to each other.
(I) Bond between the 4-position carbon and the 8-position carbon (II) Bond between the 4-position carbon and the 6-position carbon (III) Bond between the 4-position carbon and the 8-position carbon, and a bond between the 2-position carbon and the 7-position carbon

Examples of the monovalent organic group represented by R ₅ , R ₁₀ and R ₁₁ include a gallate group, an organic acid residue, and a sugar residue. Examples of organic acids that form organic acid residues include p-coumaric acid, caffeic acid, ferulic acid, sinapinic acid, p-hydroxybenzoic acid, acetic acid, oxalic acid, malonic acid, succinic acid, malic acid, and the like. It is done. R ₅ , R ₆ and R ₇ may be glycosides in which a saccharide is bonded to a gallate group or an organic acid group. In this case, for example, the sugar is bonded to a phenolic hydroxyl group of a gallate group or an organic acid group at an arbitrary position via an ester bond. Examples of the sugar of the glycoside include pyranose type hexis, furanose type pentose and the like. Examples of these sugar forms include disaccharides and trisaccharides in addition to monosaccharides such as glucose, galactose, rhamnose, xylose, and arabinose.

  In the present specification, the term “SIRT1 activity” means SIRT1 deacetylation activity.

  According to the present invention, a sirtuin 1 (SIRT1) gene activator can be provided.

In one Example of this invention, it is a graph which shows the result of having measured the SIRT1 gene promoter activation ability of proanthocyanidin.

  The objects, features, advantages, and ideas of the present invention will be apparent to those skilled in the art from the description of the present specification, and those skilled in the art can easily reproduce the present invention from the description of the present specification. The embodiments and specific examples of the invention described below show preferred embodiments of the present invention, and are shown for illustration or explanation. It is not limited. It will be apparent to those skilled in the art that various modifications and variations can be made based on the description of the present specification within the spirit and scope of the present invention disclosed herein.

(1) Proanthocyanidins The sirtuin 1 (SIRT1) gene activator of the present invention includes proanthocyanidins. Proanthocyanidins have the formula

(Wherein R ₁ is a hydrogen atom or a hydroxyl group, R ₂ is a hydrogen atom, a hydroxyl group, or an alkoxy group having 1 to 4 carbon atoms, R ₃ and R ₄ are each independently selected from a hydroxyl group or a carbon number of 1 to 4) 4 alkoxy group, R ₅ represents hydrogen or an organic group.)
2 or more and 11 or less, preferably 2 or more and 7 or less, and more preferably 2 in the following manner (I), (II), or (III) More than four, most preferably two, have a structure bonded to each other.
(I) 4-position and 8-position carbon bond (II) 4-position and 6-position carbon bond (III) 4-position and 8-position carbon, and 2-position and 7-position carbon Each bond may be an α bond or a β bond.

For example, proanthocyanidins may be represented by the following formula.

(Wherein R ₁ is a hydrogen atom or a hydroxyl group, R ₂ and R ₆ are independently selected hydrogen atoms, a hydroxyl group or an alkoxy group having 1 to 4 carbon atoms, R ₃ , R ₄ , R ₇ and R ₈ are Each independently selected hydroxyl group or alkoxy group having 1 to 4 carbon atoms, R ₅ and R ₉ represent hydrogen or an organic group, n is 1 to 10, preferably 1 to 6, more preferably 1 to 3. Is an integer.)

Examples of the monovalent organic group represented by R ₅ and R ₉ include a gallate group, an organic acid residue, and a sugar residue. Examples of organic acids that form organic acid residues include p-coumaric acid, caffeic acid, ferulic acid, sinapinic acid, p-hydroxybenzoic acid, acetic acid, oxalic acid, malonic acid, succinic acid, malic acid, and the like. It is done. R ₅ and R ₉ may be a glycoside in which a saccharide is bonded to a gallate group or an organic acid group. In this case, for example, the sugar is bonded to a phenolic hydroxyl group of a gallate group or an organic acid group at an arbitrary position via an ester bond. Examples of the sugar of the glycoside include pyranose type hexose residue, furanose type pentose residue and the like. Examples of sugar forms include disaccharides and trisaccharides in addition to monosaccharides such as glucose, galactose, rhamnose, xylose, and arabinose. In particular, R ₅ and R ₉ preferably represent a gallate group which may have a substituent. The “gallate group optionally having substituent (s)” includes “gallate group” and “gallate group having substituent (s)”, and “gallate group having substituent (s)” includes “gallate to which sugar is bound. Group "and the like.

  In addition, at least one of the hydroxyl groups at the 5th and 7th positions of each monomer may be a modifying group to which a gallate group, a sugar, an organic acid, or the like is bonded. It may be bonded. Here, examples of the sugar include disaccharides and trisaccharides in addition to monosaccharides such as glucose, galactose, rhamnose, xylose, and arabinose. Examples of the organic acid include p-coumaric acid, caffeic acid, ferulic acid, sinapinic acid, p-hydroxybenzoic acid, acetic acid, oxalic acid, malonic acid, succinic acid, malic acid and the like.

Particularly preferably, the proanthocyanidins are represented by any of the following formulae.

  Proanthocyanidins can be produced by known methods. For example, tea, cacao, grains such as soybeans and wheat, fruits such as grapes, berries and apples (especially seeds and skins), and purification from bark such as cedars. And preferably separated.

(2) SIRT1 gene activator Since proanthocyanidins can activate the expression of SIRT1 gene, it is used as a pharmaceutical composition (pharmaceutical composition and reagent product composition), food composition, or cosmetic composition. It is possible to use these compositions as SIRT1 gene activators by formulating them. In this specification, “gene activation” is synonymous with “enhancement of gene expression”. Here, the SIRT1 gene may be derived from humans or non-human mammals.

  SIRT1 has various functions such as aging prevention (anti-aging) action, diabetes improvement action, cardiovascular protection action, kidney disease improvement action, inflammatory cytokine production suppression action, neuroprotection action, etc. By activating the SIRT1 gene and increasing the concentration of SIRT1 in the body, it is possible to exert an anti-aging effect, diabetes-improving effect, cardiovascular protective effect, inflammatory cytokine suppressing effect, neuroprotective effect, and the like. Therefore, SIRT1 gene activator containing proanthocyanidins or derivatives thereof as an active ingredient is an anti-aging agent (anti-aging) agent, a diabetic agent and a prophylactic agent, a cardiovascular disease agent and a prophylactic agent, and a nervous system disease agent. And a preventive agent, a renal disease therapeutic agent and preventive agent, and an anti-inflammatory agent. Specific target diseases include, for example, diabetes such as type 2 diabetes, cardiovascular diseases such as arteriosclerosis and myocardial infarction, neurological diseases such as amyotrophic lateral sclerosis, Alzheimer's disease, or dementia, nephrosis or Various inflammatory diseases such as renal diseases such as renal dysfunction, colitis such as pneumonia, hepatitis, pancreatitis and ulcerative colitis can be mentioned. In particular, these target diseases are effective against the “senile disease”, which is a systemic disease caused by a decline in the function of multiple organs (heart, liver, pancreas, kidney, etc.) It is extremely effective in that the disease can be treated or prevented centrally. Thus, the SIRT1 gene activator containing proanthocyanidins or derivatives thereof as an active ingredient is expected to radically change the way of medical care for the elderly.

  Since SIRT1 has an NF-kappaB inhibitory action, proanthocyanidins can also be used as an NF-kappaB inhibitor. Proanthocyanidins can activate NO signaling through NF-kappaB suppression and suppress inflammatory cytokines such as TNF-alfa, ICAM-1, IL-6, and IL-1 and inducible NOS (i-NOS) Therefore, it is considered that at least a part of the cardiovascular protective action and the anti-inflammatory action is due to this NF-kappaB inhibitory action.

(3) Use of proanthocyanidins Proanthocyanidins can be used in pharmaceutical compositions (pharmaceutical compositions and reagent product compositions), food and beverage compositions, cosmetic compositions, etc., respectively, and methods well known to those skilled in the art are used. It can be used to produce foods and drinks, medicines (medicines and reagents), cosmetics. As a raw material of these compositions, purified proanthocyanidins may be used, but extracts such as fruits mixed with impurities may be used. Here, the fruit is not particularly limited as long as it contains proanthocyanidins, but berries such as blueberries, raspberries and black raspberries containing a large amount of proanthocyanidins are particularly preferable.

  Although there is no restriction | limiting in particular as food / beverage products containing a proanthocyanidin, From the simplicity, it is preferable to add to the existing food / beverage products as an additive, or to use the fruit extract as mentioned above. In addition, when manufacturing the food / beverage products containing proanthocyanidin, you may use the other additive etc. which are used normally.

  Proanthocyanidins as foods and drinks can be used as supplements, dietary supplements, health supplements, functional foods, health functional foods, foods for specified health use, foods with nutritive function, etc., having SIRT1 gene activation effect However, it is particularly preferable to use it as a supplement or supplement. Examples of the food and drink include confectionery such as chocolate, biscuits, gum, candy, cookies, gummi, and tableted confectionery, cereals, powdered drinks, soft drinks, milk drinks, nutrition drinks, carbonated drinks, jelly drinks, and the like, Ice cream, sherbet and other frozen desserts. Further, in the case of food for specified health use, dietary supplement, etc., any form such as powder, granule, capsule, syrup, tablet, sugar-coated tablet, etc. may be used.

  As a medicament containing proanthocyanidins, any of the diseases described in (2) can be targeted. The pharmaceutical preparation may be performed by a method well known to those skilled in the art, and the shape is not particularly limited, and may be a tablet, capsule, bagging, syrup, suppository, bottling, ointment, cream, spray, lotion, etc. Even if it is in shape, it is preferably a skin external medicine.

  Reagents containing proanthocyanidins can also be used as various research reagents in vitro or in vivo. The purpose is not limited, and may be, for example, drug development or basic research. Moreover, the object to be used is not limited, and for example, it may be extracted from a cell, a cell, or a living body.

  Further, a cosmetic containing proanthocyanidins and thereby having a SIRT1 gene activating effect can also be produced, but the shape is not particularly limited, and examples thereof include emulsifiers, gels, lotions, and powders. Even so, it is preferably a coating agent. In the cosmetic, various main ingredients and auxiliaries usually used in the production of cosmetics and other components can be used as long as the effects of the present invention are not impaired.

(4) Combination of SIRT1 activator and SIRT1 gene activator
In order to obtain a stronger activity of SIRT1, a SIRT1 activator and a SIRT1 gene activator may be used in combination. This is because the effect of SIRT1 is synergistically enhanced by combining drugs with different mechanisms. For example, concomitant use of SIRT1 gene activator, proanthocyanidins, and SIRT1 activator, resveratrol, quercetin, ptein, pyrroloquinosaline, oxazolopyridine, or SRT1720 is conceivable.

  Here, the SIRT1 activator and the SIRT1 gene activator may be used together as a single agent or in combination as a composite agent. When used in combination as a single agent, it is preferable to administer the SIRT1 activator and the SIRT1 gene activator simultaneously, but “simultaneous” may or may not be exactly the same in time. Means administration of the other while effective.

(5) How to use foods and drinks, medicines (medicines and reagents), and cosmetics Foods and drinks containing proanthocyanidins are diets for human diets or mammals other than humans, and are similar to normal diets and diets. In addition, you can drink and eat. As supplementary foods, in addition to a normal meal or diet, an appropriate amount may be taken regularly. In addition, human beings who eat and drink and mammals other than humans mean healthy individuals (in this specification, humans who do not suffer from any of the diseases described in (2). They may suffer from other diseases. Or a patient suffering from the disease described in (2).
The administration target of the pharmaceutical containing proanthocyanidins is a human or a non-human mammal suffering from the disease described in (2). The administration method is not limited, and it may be oral, parenteral, systemic administration or local administration, but transdermal administration is preferred from the viewpoint of absorbability.
The reagent product containing proanthocyanidins can be used in vivo such as in mammals other than humans and in vitro such as cultured cells and cultured tissues.
Cosmetics containing proanthocyanidins can be used in the same manner as ordinary cosmetics. The human to be used may be a healthy body or a patient suffering from any of the diseases described in (2), but the cosmetic is preferably used for anti-aging.

(6) Screening method of compound that activates SIRT1 gene As shown in the examples, proanthocyanidins can activate SIRT1 gene, and therefore, proanthocyanidin derivatives may activate SIRT1 gene. It is considered high. Therefore, when trying to obtain a compound that activates the SIRT1 gene, it is easier to examine the proanthocyanidin derivative if it has the ability to activate the transcription of the SIRT1 gene than to examine other compounds. Can be obtained.

  Therefore, in order to screen for a compound that activates the SIRT1 gene, it is preferable to first examine whether the derivative of proanthocyanidins has the ability to activate transcription of the SIRT1 gene. The assay system for this may be in vivo or in vitro, and is not particularly limited. From the viewpoint of simplicity, a reporter assay using a reporter plasmid into which a promoter of SIRT1 gene is introduced may be performed using cultured cells. preferable. And if the compound which has transcription activation ability is obtained, it will be specified as an activator and it can be used for the use described in this specification as a SIRT1 gene activator similarly to proanthocyanidins after that.

Here, the derivative of proanthocyanidins that can be used is not particularly limited, but the following formula

(Wherein R ₁ is a hydrogen atom or a hydroxyl group, R ₂ is a hydrogen atom, a hydroxyl group, or an alkoxy group having 1 to 4 carbon atoms, R ₃ and R ₄ are each independently selected from a hydroxyl group or a carbon number of 1 to 4) 4 alkoxy groups, R ₅ , R ₁₀ and R ₁₁ are hydrogen or an organic group.) Is a bond of the following (I), (II) or (III) 2 to 20 or less, preferably 2 or more and 11 or less, preferably 2 or more and 7 or less, more preferably 2 or more and 4 or less, and most preferably 2, having a structure bonded to each other The derivatives are preferred.
(I) Bond between the 4-position carbon and the 8-position carbon (II) Bond between the 4-position carbon and the 6-position carbon (III) Bond between the 4-position carbon and the 8-position carbon, and a bond between the 2-position carbon and the 7-position carbon

Examples of the monovalent organic group represented by R ₅ , R ₁₀ and R ₁₁ include a gallate group, an organic acid residue, and a sugar residue. Examples of organic acids that form organic acid residues include p-coumaric acid, caffeic acid, ferulic acid, sinapinic acid, p-hydroxybenzoic acid, acetic acid, oxalic acid, malonic acid, succinic acid, malic acid, and the like. It is done. R ₅ , R ₆ and R ₇ may be glycosides in which a saccharide is bonded to a gallate group or an organic acid group. In this case, for example, the sugar is bonded to a phenolic hydroxyl group of a gallate group or an organic acid group at an arbitrary position via an ester bond. Examples of the sugar of the glycoside include pyranose type hexis, furanose type pentose and the like. Examples of these sugar forms include disaccharides and trisaccharides in addition to monosaccharides such as glucose, galactose, rhamnose, xylose, and arabinose.

(1) Purification of proanthocyanidins In this example, the following compounds were used as proanthocyanidins.

  The purification method was in accordance with the method described in J. Agric. Food Chem. Vol. 59 p. 10594-10603 (2011). The method will be briefly described below.

  First, n-pentane was added to the juice obtained by press-compressing black raspberries and degreased to obtain an aqueous layer fraction. Proanthocyanidins were extracted from the aqueous layer fraction with acetone / water (70:30 v / v), and after removing the acetone, the aqueous layer was extracted three times with ethyl acetate to recover proanthocyanidins. The extract was dried with an evaporator to obtain a powder. This powder was dissolved in a small amount of ethanol, subjected to Sephadex LH20 column chromatography, and proanthocyanidins were fractionated by monitoring the ultraviolet absorbance of each fraction. Further, each fraction was subjected to MCICHP20P column chromatography, and eluted and eluted with linear gradients of water / methanol (80:20, v / v) and water / methanol (20:80, v / v). . Each structural analysis of proanthocyanidins was performed with a mass spectrometer, a magnetic resonance spectrometer, and a circular dichroism spectrometer.

(2) Luciferase Assay Using Sirtuin 1 (SIRT1) Gene Promoter First, firefly luciferase reporter plasmid pGL4.10 [Luc2] (Promega) was digested with restriction enzyme Kpn I and restriction enzyme Xho I. A reporter plasmid in which a luciferase gene was inserted downstream of the SIRT1 gene promoter was prepared by inserting nucleotide sequences corresponding to human SIRT1 gene promoters from 20448573 to 20448961 in NT_030059.13.

Next, 2 × 10 ⁶ HeLa S3 cells were seeded in a 10 cm dish using Dulbecco's modified Eagle medium (DMEM) (low glucose) containing 10% fetal bovine serum (FCS) in the culture medium, 5% CO ₂ , 37 ° C. The cells were cultured for 24 hours under the conditions described above. 4 μg of each reporter plasmid was introduced into the cells using “FuGENE HD Transfection Reagent” (Roche). Furthermore, after culturing for 24 hours, the cells were collected, suspended in the same culture solution so as to be 1 × 10 ⁴ cells / mL, and seeded in a 96-well dish at 100 μL / well. Thereafter, the cells were cultured for 24 hours, and then replaced with a culture solution containing proanthocyanidins at a final concentration of 30 μM or a culture solution containing no proanthocyanidins (control), and further cultured for 24 hours. Then, after removing the culture solution, 30 μL / well of a lysis reagent “Passive Lysis Buffer” (Promega) was added and repeated freeze-thawing three times. Then, the cell lysate was collected and the residue was removed by centrifugation. The supernatant was recovered. 100 μL of “luciferase assay reagent (II)” (Promega) was added to 20 μL of the obtained supernatant, and the luminescence intensity was measured. The result is shown in FIG.

(3) Results As shown in FIG. 1, proanthocyanidins enhanced the transcription activity of SIRT1 gene. Thus, proanthocyanidins are effective as transcription activators of the SIRT1 gene.

Claims (16)

  A sirtuin 1 (SIRT1) gene activator containing proanthocyanidins as an active ingredient. The proanthocyanidins have the following formula
(Wherein R ₁ is a hydrogen atom or a hydroxyl group, R ₂ is a hydrogen atom, a hydroxyl group, or an alkoxy group having 1 to 4 carbon atoms, R ₃ and R ₄ are each independently selected from a hydroxyl group or a carbon number of 1 to 4) 4 alkoxy group, R ₅ represents hydrogen or an organic group.)
The flavan-3-ol skeleton represented by the formula (1) has a structure in which 2 or more and 11 or less are bonded to each other in the bonding mode of (I), (II), or (III) below. Sirtuin 1 (SIRT1) gene activator.
(I) Bond between the 4-position carbon and the 8-position carbon (II) Bond between the 4-position carbon and the 6-position carbon (III) Bond between the 4-position carbon and the 8-position carbon, and a bond between the 2-position carbon and the 7-position carbon The sirtuin 1 (SIRT1) gene activator according to claim 1, wherein the proanthocyanidins are represented by the following formula.
(Wherein R ₁ is a hydrogen atom or a hydroxyl group, R ₂ and R ₆ are independently selected hydrogen atoms, a hydroxyl group or an alkoxy group having 1 to 4 carbon atoms, R ₃ , R ₄ , R ₇ and R ₈ are Each independently selected hydroxyl group or alkoxy group having 1 to 4 carbon atoms, R ₅ and R ₉ represent hydrogen or an organic group, and n is an integer of 1 to 10.) The sirtuin 1 (SIRT1) gene activator according to claim 1, wherein the proanthocyanidins are represented by the following formula.
  At least one of the hydroxyl groups at the 5th and 7th positions of each monomer is a modifying group to which a gallate group, a sugar, or an organic acid is bonded. The sirtuin 1 (SIRT1) gene activator described. Any one or more of an anti-aging agent, a therapeutic agent and a preventive agent for diabetes, a therapeutic agent and a preventive agent for cardiovascular diseases, a therapeutic agent and a preventive agent for nervous system diseases, a therapeutic agent and a preventive agent for renal diseases, and an anti-inflammatory agent A medicine used as
The pharmaceutical which contains the proanthocyanidins of any one of Claim 1 to 5 as an active ingredient.   The medicament according to claim 6, wherein the diabetes is type 2 diabetes.   The medicament according to claim 6, wherein the cardiovascular disease is myocardial infarction or arteriosclerosis.   The medicament according to claim 6, wherein the nervous system disease is amyotrophic lateral sclerosis, Alzheimer's disease, or dementia.   The medicine according to claim 6, wherein the renal disease is nephrosis or renal dysfunction.   The medicament according to claim 6, wherein the inflammation is pneumonia, hepatitis, pancreatitis, or ulcerative colitis.   An NF-kappaB inhibitor comprising the proanthocyanidins according to any one of claims 1 to 5 as an active ingredient.   A sirtuin 1 (SIRT1) gene activator comprising the proanthocyanidins according to any one of claims 1 to 5 as an active ingredient and used in combination with another sirtuin 1 (SIRT1) activator . A method for examining sirtuin 1 (SIRT1) gene activation ability,
A method comprising a step of examining whether a proanthocyanidin derivative has a transcriptional activation ability of a sirtuin 1 (SIRT1) gene. A method for screening an activator of a sirtuin 1 (SIRT1) gene,
Examining whether one or more proanthocyanidin derivatives have the ability to activate transcription of the sirtuin 1 (SIRT1) gene;
Identifying the compound having transcription activation ability as the activator;
Including methods. The proanthocyanidin derivative has the following formula:
(Wherein R ₁ is a hydrogen atom or a hydroxyl group, R ₂ is a hydrogen atom, a hydroxyl group, or an alkoxy group having 1 to 4 carbon atoms, R ₃ and R ₄ are each independently selected from a hydroxyl group or a carbon number of 1 to 4) 4 alkoxy group, R ₅ , R ₁₀ and R ₁₁ represent hydrogen or an organic group.)
The flavan-3-ol skeleton represented by the formula (I), (II), or (III) has a structure in which 2 or more and 11 or less are bonded to each other in the bonding mode of the following (I), (II), or (III): The method described in 1.
(I) Bond between the 4-position carbon and the 8-position carbon (II) Bond between the 4-position carbon and the 6-position carbon (III) Bond between the 4-position carbon and the 8-position carbon, and a bond between the 2-position carbon and the 7-position carbon