JP2010116371A - Composition for prevention or amelioration of metabolic syndrome - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide drugs, drinks and foods highly useful for prevention and amelioration of metabolic syndrome. <P>SOLUTION: There are provided a plant of family Acanthaceae containing a compound of general formula (I) (in the formula; X is H; and R1 and R2 are each H or together form O), and a treated material of the plant. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a composition for preventing or ameliorating metabolic syndrome. More specifically, the present invention relates to a composition for preventing or ameliorating metabolic syndrome containing a foxtail plant or a processed product thereof, and pharmaceuticals containing the composition and It relates to food and drink.

Metabolic syndrome is a complex lifestyle-related disease also called metabolic syndrome, syndrome X, death quartet, insulin resistance syndrome, visceral fat syndrome, and in addition to visceral fat obesity, one of hyperglycemia, hypertension, dyslipidemia This refers to the state of two or more. When it comes to metabolic syndrome, at least one step before diabetes, hypertension, and hyperlipidemia, these multiple layers based on visceral fat obesity promote arteriosclerosis and cause arteriosclerotic diseases such as heart disease and stroke Domestic and international epidemiological studies have shown that the relative risk of onset increases.
In Japan, specific health checkups have been started in April 2008 for citizens over the age of 40 with the aim of preventing the development of metabolic syndrome, and the public's interest in metabolic syndrome has increased greatly. Currently, therapeutic agents for diabetes, hyperlipidemia or hypertension are applied for prevention and treatment of metabolic syndrome, and depending on the disease state, a plurality of drugs are taken.

  The Foxtail (Justicia procumbens L. var. Leucantha Honda) may be abbreviated as “FX” below. It is an annual plant of Acanthaceae and is a wild grass distributed in temperate areas from Japan to Taiwan. Especially in Japan, it is widely distributed from Honshu to Okinawa and grows naturally in fields, wastelands and roadsides. The height is 10 to 40 centimeters, the leaves are facing each other, and light red flowers bloom at the end of the branch from July to September. In traditional Chinese medicine, the foliage is described in the Chinese classic drug book “Shinnohonkaku” as “Shakujou” and has been used for blood purification, antipyretic, coughing, etc. In the private sector, methods of use such as decoction of dried products on the ground part during neuralgia, rheumatism, muscular pain, or fever, or application of squeezed juice from raw stems and leaves to the affected part are known.

As FX components, several types of lignans such as Justicedin A, Justicedin B, Neo Justine A (Justice Dine D), Neo Justine B (Justice Zine C), Diffyrin, Taiwanin E and Taiwanin E methyl ether are identified. Has been. These components are reported to have actions such as anticancer, antiviral, anti-inflammatory and platelet aggregation suppression in an in vitro system, and regarding the anticancer action of Justicidin A in vivo, immunodeficiency model NOD -It is recognized by continuous oral administration to SCID mice (see Non-Patent Documents 1 and 2). In addition, the fact that justicedin A, justicedin B, and diphylline have a bone resorption suppressing action has been clarified (see, for example, Patent Document 1).
However, the effects of FX or its processed product components on metabolic syndrome, that is, the effects on body weight, body fat, sugar metabolism, lipid metabolism, etc. have not been reported yet.
Japanese Patent No. 3099243 Lee, J.-C., Lee, C.-H., Su, C.-L., Huang, C.-W., Liu, H.-S., Lin, C.-N. and Won, S.-J. Justicidin A decreases the level of cytosolic Ku70 leading to apoptosis in human colorectal cancer cells. Carcinogenesis 26: 1716-1730 (2005) Su, C.-L., Huang, LLH, Huang, L.-M., Lee, J.-C., Lin, C.-N. and Won, S.-J. Caspase-8 acts as a key upstream executor of mitochondria during justicidin A-induced apoptosis in human hepatoma cells.FEBS Lett 580: 3185-3191 (2006)

As described above, currently, treatments for diabetes, hyperlipidemia or hypertension are indicated for the prevention and treatment of metabolic syndrome, and depending on the disease state, it is necessary to take multiple drugs. It is. On the other hand, the development of foods and drinks that can be easily used is becoming active, and the development of foods and drinks that can be expected to have higher effects is desired.
Then, an object of this invention is to discover the substance or component which has utility in prevention or improvement of a metabolic syndrome, and it aims at providing the pharmaceutical and food-drinks containing this.

The present inventor has found that FX or a component thereof is useful for preventing or improving metabolic syndrome, and has completed the present invention. That is, this invention includes the following invention useful for prevention or improvement of metabolic syndrome.
[1] A composition for preventing or improving metabolic syndrome, comprising a foxtail plant or a processed product thereof.
[2] The composition for preventing or improving metabolic syndrome according to [1], wherein the treated product is an extract.
[3] The extract has the following general formula (I)

(In the formula, A ring and B ring may be substituted, X represents a hydrogen atom, a hydroxyl group or an optionally substituted alkoxy group, and R ¹ and R ² are both hydrogen atoms and R ³ and R ⁴ together represents an oxygen atom, or R ³ and R ⁴ are both hydrogen atoms and R ¹ and R ² together represent an oxygen atom)
The composition for preventing or improving metabolic syndrome according to the above [2] to [5], comprising a compound represented by the formula:
[4] The following general formula (I)

(In the formula, A ring and B ring may be substituted, X represents a hydrogen atom, a hydroxyl group or an optionally substituted alkoxy group, and R ¹ and R ² are both hydrogen atoms and R ³ and R ⁴ together represents an oxygen atom, or R ³ and R ⁴ are both hydrogen atoms and R ¹ and R ² together represent an oxygen atom)
A composition for preventing or improving metabolic syndrome, comprising a compound represented by:
[5] The composition for preventing or improving metabolic syndrome according to any one of [1] to [4], which is a composition for improving leptin resistance.
[6] The following general formula (I)

(In the formula, A ring and B ring may be substituted, X represents a hydrogen atom, a hydroxyl group or an optionally substituted alkoxy group, and R ¹ and R ² are both hydrogen atoms and R ³ and R ⁴ together represents an oxygen atom, or R ³ and R ⁴ are both hydrogen atoms and R ¹ and R ² together represent an oxygen atom)
A food or drink for preventing or improving metabolic syndrome, comprising a compound represented by:
[7] A pharmaceutical comprising the composition for preventing or improving metabolic syndrome according to any one of [1] to [5].
[8] A food or drink comprising the composition for preventing or improving metabolic syndrome according to any one of [1] to [5].

  According to the present invention, a composition for preventing or improving metabolic syndrome, which can reduce the level of blood leptin, decrease the amount of hepatic triglyceride, improve lipid metabolism, and suppress weight gain, and Can be provided.

  The composition for preventing or improving metabolic syndrome of the present invention comprises a foxtail family or a processed product thereof.

The foxtail family used in the present invention is not particularly limited, a plant belonging to the genus Acanthus, a plant belonging to the genus Aphelandra, a plant belonging to the genus Beloperone, a plant belonging to the genus Codonacanthus, Plants belonging to the genus Crossandra, plants belonging to the genus Dicliptera, plants belonging to the genus Eranthemum, plants belonging to the genus Fittonia, plants belonging to the genus Hemigraphis, Hygrophila Plants belonging to the genus Hypoestes, plants belonging to the genus Jacobinia, plants belonging to the genus Justicia, plants belonging to the genus Lepidagathis, plants belonging to the genus Pachystachys , A plant belonging to the genus Peristrophe, Louis May be mentioned plants belonging to Saw genus (Ruellia), plants belonging to Isehanabi genus (Strobilanthes), and plants belonging to Thunbergia (Thunbergia). Among these, a plant belonging to the genus Foxticia is more preferable, and particularly preferable is a foxtail (Justicia procumbens L. var. Leucantha Honda, hereinafter referred to as “FX”).
As mentioned above, FX is a wild grass distributed in temperate regions from Japan to Taiwan. In Japan, it is widely distributed from Honshu to Okinawa, and is a plant that grows naturally in fields, wastelands, roadsides, etc., so it is easily acquired. be able to. It is also possible to grow and use in large quantities.

  Examples of the treated product include a part of a plant body (leaves, stems, roots, flowers, etc.) or a cut product of whole plant, pulverized product, crushed product, dried product, juice, extract and the like. Especially, it is preferable that it is an extract containing the compound represented by general formula (I).

(In the formula, A ring and B ring may be substituted, X represents a hydrogen atom, a hydroxyl group or an optionally substituted alkoxy group, and R ¹ and R ² are both hydrogen atoms and R ³ and R ⁴ or represents an oxygen atom together represent an oxygen atom R ¹ and R ² R ³ and R ⁴ in each is hydrogen atom together)
In the general formula (I), examples of the substituent in the case where the A ring or the B ring is substituted include a halogen atom, an alkyl group, an aryl group, an alkenyl group, and a hydroxyl group, which may be substituted, respectively. . The number of substitutions is 1 to 4, respectively.
Examples of the halogen atom include fluorine, chlorine, bromine and iodine, and fluorine or chlorine is preferable.

  The alkyl group in the optionally substituted alkyl group may be linear, branched or cyclic having 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. Those are preferred. Examples of the substituent that the alkyl group may have include, for example, halogen, nitro, amino (acyl, alkyl, iminomethyl, imino (aryl-substituted) methyl, amidino, amino may be used as a substituent), Sulfo, cyano, hydroxy, carboxy, hydrazino, imino, amidino, carbamoyl, aryl (halogen, alkyl, alkoxy, alkylamino, amino, carbamoyl, sulfo, alkylsulfonyl, cyano, hydroxy, carboxy, nitro, acyloxy, aralkyloxy, sulfonyl Oxy may be substituted), heterocyclic ring (nitro, oxo, aryl, alkenylene, halogenoalkyl, alkylsulfonyl, alkyl, alkoxy, alkylamino, amino, halogen, carbamoyl, hydride Alkoxy, cyano, carboxy, sulfo which may have a substituent group).

  Examples of the aryl group in the optionally substituted aryl group include phenyl, naphthyl, biphenyl, anthryl, indenyl and the like. Examples of the substituent that the aryl group may have include halogen, nitro, cyano, amino (which may have an alkyl, alkenyl, cycloalkyl, aryl as a substituent), sulfonyl, hydroxy, sulfooxy, Examples include sulfamoyl, alkyl (which may have amino, halogen, hydroxy, cyano as a substituent), alkoxy, aralkyloxy, alkylsulfonamide, methylenedioxy, alkylsulfonyl, alkylsulfonylamino and the like. Further, it may form a condensed ring (for example, tetrahydronaphthyl, indanyl, acenaphthyl, etc.) with cycloalkyl.

  The alkenyl group in the optionally substituted alkenyl group may be linear, branched or cyclic having 2 to 10 carbon atoms, such as allyl, vinyl, crotyl, 2-penten-1-yl. , 3-penten-1-yl, 2-hexen-1-yl, 3-hexen-1-yl, 2-cyclohexenyl, 2-cyclopentenyl, 2-methyl-2-propen-1-yl, 3-methyl -2-buten-1-yl and the like, and those having 2 to 6 carbon atoms are preferred. Examples of the substituent that the alkenyl may have include, for example, alkyl having 1 to 6 carbon atoms (may have the same group as the substituent that the alkyl group may have), halogen , Nitro, amino (may have acyl, iminomethylene, amidino, alkyl, aryl as substituents), sulfo, cyano, hydroxy, carboxyalkyloxycarbonyl, carbamoyl, alkylthio, allylthio, alkylsulfinyl, arylsulfinyl, Examples include alkylsulfonyl, arylsulfonyl, sulfamoyl, aryl, and acyl groups. The alkenyl or alkenylene includes isomers (E-form, Z-form) relating to double bonds.

  Examples of the halogen in the description of the substituent include chlorine, bromine, fluorine, and iodine. The alkyl in the description of the substituent is preferably an alkyl having 1 to 10 carbon atoms, more preferably 1 to 6, particularly 1 to 4, and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl. Tert-butyl, sec-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, heptyl, octyl, nonyl, decyl and the like. The cycloalkyl as the substituent is preferably one having 3 to 6 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The alkoxy as the substituent is preferably one having 1 to 4 carbon atoms, and examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy and the like. Examples of the aryl as the substituent include phenyl and naphthyl. Examples of the heterocyclic ring as the substituent include 2-pyridyl, 3-pyridyl, imidazolyl, thiazolyl, pyrrolidinyl, pyrido [2,3-d] pyrimidyl and the like. The acyl as the substituent is preferably one having 1 to 6 carbon atoms, and examples include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl and the like. Examples of the aralkyl as the substituent include benzyl, phenethyl, phenylpropyl and the like. Examples of the alkenyl or alkenylene as the substituent include the same as the above-mentioned alkenyl or methylene.

  Specific examples of the substituted alkyl include, for example, trifluoromethyl, trifluoroethyl, difluoromethyl, trichloromethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyethyl, ethoxyethyl, 1-methoxyethyl, 2 -Methoxyethyl, 2,2-dimethoxyethyl, 2,2-diethoxyethyl and the like can be mentioned. Specific examples of the substituted aryl group include 4-chlorophenyl, 4-fluorophenyl, 2,4-dichlorophenyl, p-tolyl, 4-methoxyphenyl, 4- (N, N-dimethylamino) phenyl and the like. It is done. Specific examples of the substituted alkenyl include 2,2-dichlorovinyl, 3-hydroxy-2-propen-1-yl, 2-methoxyvinyl and the like.

Examples of the optionally substituted hydroxyl group include a hydroxyl group and an appropriate substituent for the hydroxyl group, particularly those used as a protecting group for the hydroxyl group, for example, aryloxy in addition to alkoxy, alkenyloxy, aralkyloxy, acyloxy and the like. Can be mentioned. Examples of the alkoxy include alkoxy having 1 to 10 carbon atoms (for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, hexyloxy, Heptyloxy, nonyloxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy and the like are preferred. Examples of the alkenyloxy include those having 2 to 10 carbon atoms such as allyloxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy, 2-cyclopentenylmethoxy, 2-cyclohexenylmethoxy and the like. For example, phenyl-C _1-4 alkyloxy (for example, benzyloxy, phenethyloxy, etc.). The acyloxy is preferably an alkanoyloxy having 2 to 4 carbon atoms (for example, acetyloxy, propionyloxy, n-butyryloxy, isobutyryloxy, etc.). Examples of the aryloxy include phenoxy and 4-chlorophenoxy.

  In the above alkoxy, alkenyloxy, aralkyloxy, acyloxy, and aryloxy, each group of alkyl, alkenyl, acyl, and aryl may have a substituent, and examples of the substituent include halogen (for example, fluorine , Chlorine, bromine, iodine, etc.), hydroxyl group, alkoxy having 1 to 6 carbon atoms (for example, methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, etc.) and the like. 1-3 are preferable. Specific examples thereof include trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, 2-methoxyethoxy, 4-chlorobenzyloxy, 2- (3,4-dimethoxyphenyl) ethoxy and the like. .

The substituent in the case where the A ring or the B ring is substituted is preferably a hydroxyl group which may be substituted among the substituents exemplified above. Further, in any of the above cases, when there are two or more substituents, they may form a ring with a divalent hydrocarbon residue. As a specific example in such a case, two substituents are connected to form — (CH ₂ ) _P —, — (CH═CH) _m — or —O (CH ₂ ) _n O— (P, m and n Each of which represents an integer), and such a ring may form a 5-, 6-, or 7-membered ring with two adjacent carbon atoms of the benzene ring.

  Examples of the alkoxy group in the optionally substituted alkoxy group represented by X include alkoxy having 1 to 10 carbon atoms (for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert -Butoxy, n-pentoxy, isopentoxy, neopentoxy, hexyloxy, heptyloxy, nonyloxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, etc.), and alkoxy having 1 to 6 carbon atoms is preferable. Examples of the substituent that the alkoxy may have include, for example, a halogen (for example, fluorine, chlorine, bromine, iodine, etc.), a hydroxyl group, and an alkoxy having 1 to 6 carbon atoms (for example, methoxy, ethoxy, n-propoxy, isopropoxy, Butoxy, pentyloxy, hexyloxy and the like, and the number of substituents is preferably 1 to 3. Specific examples of the substituted alkoxy include trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, 2-methoxyethoxy and the like.

A compound in which R ¹ and R ² are both hydrogen atoms and R ³ and R ⁴ together represent an oxygen atom is represented by the following general formula (II).

(In the formula, A ring and B ring may be substituted, and X represents a hydrogen atom, a hydroxyl group or an optionally substituted alkoxy group)
A compound in which R ³ and R ⁴ are both hydrogen atoms and R ¹ and R ² together represent an oxygen atom is represented by the following general formula (III).

(In the formula, A ring and B ring may be substituted, and X represents a hydrogen atom, a hydroxyl group or an optionally substituted alkoxy group)
Known lignan components (for example, Justicidin A, Justicidin B, etc.) of the foxgill represented by the above general formula (I) can be obtained by known methods (for example, Planta Medica, 36, 200 (1979), Tetrahedron Letters, No. 36). , 3517 (1967), Tetrahedron Letters, 47 4167 (1965), Pharmaceutical Journal, 81, 1596 (1961), etc.) or a method analogous thereto, can be produced using FX or other foxtail family as raw materials it can.

  The compound described in the above general formula (I) can be extracted from a foxtail plant by the following method, for example. That is, the dried powder of the foxtail plant is extracted with alcohols such as ethanol and methanol, esters such as ethyl acetate, ketones such as acetone, ethers such as diethyl ether and dioxane, or alkyl halides such as dichloromethane and chloroform. The amount of the extraction solvent is usually 3 to 20 times (w / w) with respect to the dry powder of the raw material. The extraction temperature may be any range from room temperature to the boiling point of the solvent used. In the case of a solvent miscible with water, the efficiency of extraction work can be improved by using a mixed solvent as appropriate. The extract is filtered to separate from the residue, and then concentrated to produce an extract. The obtained extract is subjected to column chromatography using usually 100 to 300 times (w / w) of silica gel as a stationary phase, and is eluted with dichloromethane or chloroform and then with acetone. The lignan component in the eluent can be detected by TLC described later. After collecting and concentrating the eluent containing the main components, justicedins A and B, the concentrated residue is subjected to column chromatography using a reversed-phase silica gel usually in an amount of 100 to 300 times (w / w) as a stationary phase. Elution with 40-60% aqueous methanol to obtain a fraction containing Justicidin B and then Justicidin A, followed by TLC and HPLC, and concentrated to obtain a powdery residue. When both are recrystallized from dichloromethane-diethyl ether, most of justicedins A and B are obtained as colorless plate crystals. By repeating the above column chromatography for all fractions and recrystallized mother liquor obtained in the above operation process while being followed by TLC and HPLC, other justicidin components can be obtained.

Thin layer chromatography (TLC) or high performance liquid chromatography (HPLC) is appropriately used as a means for tracking the lignan component in the process of extraction and production.
TLC condition- (1) plate; silica gel 60F254 (manufactured by Merck & Co., Inc.), developing solvent; diethyl ether, detection method; ultraviolet lamp (254 nm)
(2) Plate: TLC plate RP-8F254s (Merck), developing solvent: acetonitrile-water (7: 3), detection method: UV lamp (254 nm)
HPLC conditions-column; ERC-ODS-1161 (6 × 100 mm), moving bed; acetonitrile-water (35:65), column temperature; 40 degrees, flow rate; 1 ml / min, detection wavelength: 254 nm

  The compound represented by the above general formula (I) is, for example, Patent Document 1, J. Org. Chem., 36, 3450 (1971), Chem. Pharm. Bull., 25, 1803 (1977), Chem. Pharm. Bull., 37, 68 (1989), Chem. Commun., 653, (1968), Chem. Commun., 354, (1980), J. Chem. Soc. (C), 2091, (1971), J. It can be synthesized according to the method described in Chem. Soc. (C), 1755, (1966), etc. and a method analogous thereto.

  As mentioned above, metabolic syndrome is a complex lifestyle-related disease also called metabolic syndrome, syndrome X, death quartet, insulin resistance syndrome, visceral fat syndrome, and in addition to visceral fat type obesity, hyperglycemia, hypertension, lipid This refers to a condition that includes any two or more abnormalities. When it comes to metabolic syndrome, at least one step before diabetes, hypertension, and hyperlipidemia, these multiple layers based on visceral fat obesity promote arteriosclerosis and cause arteriosclerotic diseases such as heart disease and stroke Domestic and international epidemiological studies have shown that the relative risk of onset increases.

In Japan, metabolic syndrome is diagnosed when two or more of (2) to (4) are applied in addition to the following (1).
(1) Waist circumference (around navel) is 85 cm or more for men, 90 cm or more for women (2) Neutral fat is 150 mg / dL or more, HDL cholesterol is less than 40 mg / dL, or both ( 3) Either the highest (systolic) blood pressure is 130 mmHg or higher, the lowest (diastolic) blood pressure is 85 mmHg or higher, or both (4) Fasting blood glucose level is 110 mg / dL or higher

As shown in detail in the examples, when ethanol extract of foxtail (FX) or justicedin A, which is one of the components of the foxtail family, is fed to hereditary obese diabetic mouse KKA ^y for 4 weeks, the plasma leptin level becomes FX. It was observed that the ethanol extract decreased depending on the dose. Leptin is a hormone that is secreted from adipocytes and acts on the central system to not only suppress feeding but also increase energy consumption, and is involved in the control of obesity and weight gain. In addition, the fact of regulating sugar / lipid metabolism in peripheral tissues is also known. However, in obese individuals, the amount of leptin production increases with the enlargement of fat cells, and the body fat mass and plasma leptin level are positively correlated. That is, it is considered that obesity despite high blood leptin concentration is in a leptin-resistant state and there is a leptin action disorder. Therefore, improvement of leptin resistance is expected as a means of anti-obesity by inducing increased energy consumption and reducing body weight. It is known that KKA ^y mice develop hyperleptinemia with the development of obesity and exhibit leptin resistance commonly seen in obese states without inducing a decrease in food intake. The present inventors have found that an ethanol extract of FX and Justicidin A can reduce blood leptin level and improve leptin resistance in KKA ^y mice, and are useful for prevention or improvement of metabolic syndrome. It was found to have sex.

Specifically, both the ethanol extract of FX and Justicidin A both reduce blood leptin levels in KKA ^y mice, and Justicedin A suppresses weight gain without a decrease in food intake, Suppresses blood glucose levels, suppresses plasma triglyceride levels, suppresses plasma free fatty acid levels, suppresses plasma HDL cholesterol and LDL / VLDL cholesterol levels, significantly increases liver triglyceride levels ALT (alanine aminotransferase) was significantly reduced (see Examples). In addition, FX suppressed the increase of plasma HDL cholesterol and LDL / VLDL cholesterol levels, significantly decreased the amount of liver triglycerides, and significantly decreased ALT (see Examples).

Although the mechanism by which FX ethanol extract and Justicidin A reduced the leptin level in blood is not clear, administration of FX ethanol extract decreases the amount of hepatic triglyceride that increases with the development of obesity, and plasma The fact that HDL cholesterol and LDL / VLDL cholesterol levels showed a tendency to decrease is considered to be due to the leptin resistance improving action of the ethanol extract of FX. Furthermore, the administration of FX ethanol extract or Justicidin A significantly reduced the blood ALT level, which is a marker of liver function, so that FX and Justicidin A directly or indirectly affect the liver. The possibility of effect is suggested.
As with leptin, the adiponectin level secreted from adipocytes was not changed by the administration of FX ethanol extract or Justicidin A, so that FX ethanol extract and Justicidin A act on adipocytes. Thus, the function of the whole adipose tissue is not considered to be affected. In contrast to leptin, adiponectin generally decreases its expression / secretion due to obesity and is thought to be the cause of the development of insulin resistance. In addition, adiponectin expression / secretion increases during weight reduction, improving insulin resistance. It is known to contribute. In addition, in KKA ^y mice, it has been reported that blood adiponectin decreases due to the development of obesity and insulin resistance is improved by administration of adiponectin (Nat Med 7: 941-946 (2001)).

  FX's ethanol extract contains about 2% Justicedin A, and changes in the FX's ethanol extract were also observed during the administration of Justicedin A, which may reflect the effects of Justicedin A Sex is conceivable. However, the tendency to suppress the increase in body weight or the decrease in blood glucose, triglycerides and free fatty acids observed by administration of Justicidin A was not observed when the ethanol extract of FX was administered. It is presumed that the component ratio required for expression is related. Moreover, it is imagined that the ethanol extract of FX contains various components, and there are components that antagonize the action of Justicidin A, which may be the result of their interaction.

Regarding the safety of FX ethanol extract, abnormalities caused by FX ethanol extract in both single-dose toxicity test (0.5, 1, 2 g / kg) and genotoxicity test (reversion mutation test) Sex was not observed (unpublished data). The high dose (0.5%) of the FX ethanol extract used in this report was equivalent to about 0.76 g / kg / day when converted to the food intake of KKA ^y mice, but administered for 4 weeks. Under these conditions, no autopsy, organ weight and blood parameters were considered to be toxic. Therefore, it can be said that FX has utility as a composition for preventing or improving metabolic syndrome.

The pharmaceutical of this invention should just contain the composition for prevention or improvement of the metabolic syndrome of the said invention, and has the prevention or treatment effect of metabolic syndrome. Specifically, it may be effective for at least one of prevention or improvement of obesity, prevention or treatment of diabetes, prevention or treatment of hypertension, prevention or treatment of dyslipidemia (hyperlipidemia).
The pharmaceutical agent of the present invention can be administered to a mammal by any of oral, parenteral or topical routes. The dosage form is not particularly limited, and may be combined with various pharmaceutically acceptable inert carriers to form tablets, capsules, lozenges, troches, hard candy, powders, sprays, creams, and coatings. , Suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injection solutions, elixirs, syrups and the like can be employed.

  The food / beverage products of this invention should just contain the composition for prevention or improvement of the said metabolic syndrome of this invention. The food or drink suitable for the present invention is not particularly limited. Specific examples include tablets, granules, powders, and drinks as so-called dietary supplements (supplements). Other than this, for example, beverages such as tea drinks, soft drinks, carbonated drinks, nutrition drinks, fruit drinks, lactic acid drinks, noodles such as buckwheat, udon, Chinese noodles, instant noodles, strawberries, candy, gum, chocolate, snacks, Biscuits, jelly, jam, cream, baked confectionery, confectionery such as bread, bakery products, fishery products such as kamaboko, ham, sausage, dairy products such as processed milk, fermented milk, salad oil, tempura oil, margarine, mayonnaise , Shortening, whipped cream, dressing and other fats and oils and processed foods, sauces, sauces and other seasonings, curry, stew, rice cakes, rice cakes, and other retort pouch foods, ice cream, sorbets, shaved ice and other frozen desserts Can be mentioned.

The pharmaceuticals and foods and drinks of the present invention are suitably applied to humans, but can also be applied to animals other than humans as long as the effect of preventing or improving metabolic syndrome can be expected.
The pharmaceuticals and foods and drinks of the present invention can be used for pharmaceuticals and foods and drinks as long as they do not impair the effects of the present invention, if necessary, in addition to the foxtail family or processed products thereof, or the compounds represented by the general formula (I). It can mix | blend combining the well-known additive etc. which are used.

EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to these Examples at all.
[Influence on hereditary obese diabetic mouse KKA ^y ]
1. Materials and Methods (1) Animals Seven-week-old female KKA ^y / Ta mice were purchased from Nippon Claire Co., Ltd. and used for experiments after acclimatization for 1 week. Each mouse is housed in an individual plastic cage, and CE-2 powder feed (manufactured by CLEA Japan, Inc.), which is a normal diet, and water are freely ingested. Room temperature: 23 ± 2 ° C., humidity: 50 ± 15% and 12 hours Raised in an environment with lighting (7: 00-19: 00).

(2) Test substance The test substance, FX ethanol extract, was reported by Okigawa et al. Using whole FX collected in the Kansai area, mainly in Hyogo Prefecture (Tetrahedron 26: 4301-4305 (1970) ) For reference. Next, the extract was prepared 10 times using dextran and mixed with CE-2 powder feed. Moreover, justicedin A was separated and purified and crystallized from the collected FX whole plant with reference to the method of Munakata et al. (Tetrahedron Lett 47: 4167-4170 (1965)) and mixed with feed. The doses administered to mice were set to FX ethanol extract: 0.1%, 0.5% and Justicidin A: 0.065%, and the administration period was 4 weeks. The dose of Justicidin A is about 0.065 with the amount of Justicidin A contained in 0.5% of the FX ethanol extract (contained 2% in the extract) in consideration of the absorbability. %.

(3) Grouping of animals The mice acclimated and bred were divided into 4 groups (8 patients / blood glucose) so that the average body weight and blood glucose value of each administration group were equal using the body weight and blood glucose value on the administration start day as indices. Group).
(4) Body weight and food consumption The body weight was measured once a week, and the food consumption was measured twice a week.

(5) Blood biochemical parameters On the day before and after the administration of the test substance, blood from the incision portion of the mouse tail vein with a razor was drawn into a blood glucose meter sensor portion (Nipro Freestyle Meter) to measure the blood glucose level. . Further, partial blood collection was performed from the tail vein with a heparinized capillary. The blood is centrifuged (5,000 rpm, 10 min, 0-4 ° C), and then the supernatant (plasma) is collected, and free fatty acid (NEFA) is measured for free fatty acid measurement kit (NEFA C Test Wako: Wako Pure Chemical) It measured using. On the day when the test substance was administered, whole blood was collected from the abdominal aorta using a heparin-treated syringe under ether anesthesia. From the collected blood, plasma is prepared by centrifugation, and triglyceride (Drychem System: Fuji Film Medical), leptin (Morinaga Mouse Leptin Measurement Kit: Morinaga Bioscience Institute), insulin (Levis Insulin-Mouse U-type: Shibayagi) ), LDL / VLDL cholesterol, HDL cholesterol (HDL and LDL / VLDL Cholesterol Quantification Kit, BioVision), adiponectin (mouse / rat adiponectin ELISA kit: Otsuka Pharmaceutical), AST (aspartate aminotransferase) (Drychem system: Fuji Film Medical) And ALT (Alanine Aminotransferase) (Dry Chem System: Fuji Film Medical) were measured using measurement kits in parentheses.

(6) Organectomy After whole blood collection on the test substance administration end date, peritoneal adipose tissue, perirenal adipose tissue, subcutaneous adipose tissue near femur, interscapular brown adipose tissue, liver, kidney, heart, spleen, thymus, lung The uterus was removed and the weight of each organ was measured.
(7) Liver triglyceride The amount of triglyceride was measured according to the method of Folch et al. (J Biol Chem 226: 479-509 (1957)) using a part of the liver cryopreserved after extraction from mice.
(8) Grade display and statistical processing The grades were expressed as mean ± standard error (SE). The dose display in the table was 0.1% (low dose) and 0.5% (high dose) as the amount of FX ethanol extract.
The significant difference test between the FX ethanol extract extract administration group and the control group was performed by Dunnett's test. In addition, the significant difference test between the Justicidin A administration group and the control group followed the Student test. In any test, a risk rate of 5% or less was determined to be significant.

2. Results (1) Body weight The 8-week-old KKA ^y mice (control group) used in this experiment showed an increase in body weight of 11.3 ± 0.6 g (mean ± SE) during the experimental period (4 weeks) ( Table 1). The FX ethanol extract was administered to KKA ^y mice for 4 weeks at a dose of 0.1% or 0.5%, but the weight gain was similar to that of the control group. However, administration of Justicidin A (0.065%) showed a significant suppression of body weight gain. That is, the weight gain for 4 weeks was 11.3 ± 0.6 g (mean value ± SE) in the control group, and 8.8 ± 0.9 g (Table 1) in the justicidin A administration group, The increase was suppressed by 22.1%.

(2) Food intake Table 2 shows the food intake for each week during the experimental period. Compared to the control group, there was no change in food consumption over 4 weeks in the FX ethanol extract (0.1%, 0.5%) or justicedin A (0.065%) administration groups.

(3) Blood parameters All blood parameter values measured are shown in Table 3.

In (i) KKA ^y mice used in the glucose present experiment (control group), at the beginning the blood glucose value is experimentally mild high (242 ± 33 mg / dl, mean ± SE), further 315 ± 29 mg than after 4 weeks / Dl. In the FX ethanol extract (0.1%, 0.5%) administration group, the same changes as in the control group were observed. However, in the justicedin A (0.065%) administration group, the blood glucose average value is maintained at a value of 300 mg / dl or less (271 ± 35 mg / dl), and the increase in blood glucose level tends to be suppressed ( 14% lower than the control group).
(ii) Insulin No change was observed in plasma insulin level compared to the control group even when either the ethanol extract of FX or Justicidin A was administered.

(iii) Lipid The KKA ^y mice (control group) in this experiment exhibited plasma triglyceride values of 400 mg / dl or more and were hypertriglyceridemia. Administration of FX with ethanol extract did not affect plasma triglyceride levels. However, when Justicidin A was administered, it showed a downward trend (28.8% reduction) compared to the control group.
The plasma free fatty acid level did not change with the administration of the ethanol extract of FX, but it showed a 20.8% decreasing tendency with the administration of Justicidin A compared with the control group.
Plasma HDL cholesterol and LDL / VLDL cholesterol levels did not change at low doses (0.1%) of FX ethanol extract, but not significant at high doses (0.5%) It showed a downward trend. There was a tendency to decrease (24.6% decrease) by administration of Justicidin A.

(iv) Adipocyte secretion factor Plasma leptin levels tended to decrease at low doses (0.1%) of FX ethanol extract and decreased significantly at high doses (0.5%) . In addition, significant decrease was also observed by administration of Justicidin A.
On the other hand, the adiponectin level was not changed by administration of the ethanol extract of FX or Justicidin A.
(v) Liver function No change was observed in AST (aspartate aminotransferase) due to the administration of FX ethanol extract or Justicidin A. On the other hand, ALT (alanine aminotransferase) was significantly decreased by administration of a high dose (0.5%) of FX ethanol extract or justicedin A administration.

(4) Amount of liver triglyceride Table 4 shows the results of measuring the amount of triglyceride in the liver extracted on the last day of administration of the test substance. As is clear from Table 4, the amount of hepatic triglyceride decreased by administration of the ethanol extract of FX, and significantly decreased in the high dose (0.5%) administration group. In the Justicidin A administration group, the amount of hepatic triglyceride was significantly reduced.

(5) Necropsy and organ weight No abnormalities were observed in the appearance and behavior of the mice during the period of administration of FX ethanol extract or justicedin A. Also, no abnormality was observed in the mice at the time of necropsy. The weight of all organs removed by dissection, that is, periuterine, perirenal, subcutaneous white adipose tissue, interscapular brown adipose tissue, liver, kidney, heart, spleen, thymus and lungs is low in ethanol extract of FX There was no change in the dose (0.1%) administration group, the FX ethanol extract high dose (0.5%) administration group, or the justicidin A administration group compared to the control group (Table). 1). The weight of the uterus was significantly high in the group administered with a high dose (0.5%) of an ethanol extract of FX, but the effect was mild.
As described above, the ethanol extract of FX reduces the blood leptin level of KKA ^y mice, suppresses the increase of plasma HDL cholesterol and LDL / VLDL cholesterol levels, significantly decreases the amount of liver triglycerides, and reduces ALT. It became clear that it decreased significantly. Justicidin A also decreases blood leptin levels in KKA ^y mice, significantly suppresses body weight gain without decreasing food intake, suppresses blood glucose levels, and increases plasma triglyceride levels. It was revealed that the increase in plasma free fatty acid levels was suppressed, the increase in plasma HDL cholesterol and LDL / VLDL cholesterol levels were suppressed, the amount of hepatic triglycerides was significantly decreased, and ALT was significantly decreased. It was. Therefore, FX and Justicidin A are useful as a composition for preventing or improving metabolic syndrome.

  The present invention is not limited to the above-described embodiments and examples, and various modifications are possible within the scope shown in the claims, and technical means disclosed in different embodiments are appropriately combined. The obtained embodiment is also included in the technical scope of the present invention. Moreover, all the academic literatures and patent literatures described in this specification are incorporated herein by reference.

Claims (8)

  A composition for preventing or improving metabolic syndrome, comprising a foxtail family or a processed product thereof.   The composition for preventing or improving metabolic syndrome according to claim 1, wherein the treated product is an extract. The extract has the following general formula (I)

(In the formula, A ring and B ring may be substituted, X represents a hydrogen atom, a hydroxyl group or an optionally substituted alkoxy group, and R ¹ and R ² are both hydrogen atoms and R ³ and R ⁴ together represents an oxygen atom, or R ³ and R ⁴ are both hydrogen atoms and R ¹ and R ² together represent an oxygen atom)
The composition for preventing or improving metabolic syndrome according to claim 2, comprising a compound represented by the formula: The following general formula (I)

(In the formula, A ring and B ring may be substituted, X represents a hydrogen atom, a hydroxyl group or an optionally substituted alkoxy group, and R ¹ and R ² are both hydrogen atoms and R ³ and R ⁴ together represents an oxygen atom, or R ³ and R ⁴ are both hydrogen atoms and R ¹ and R ² together represent an oxygen atom)
A composition for preventing or improving metabolic syndrome, comprising a compound represented by:   The composition for preventing or improving metabolic syndrome according to any one of claims 1 to 4, which is a composition for improving leptin resistance. The following general formula (I)

(In the formula, A ring and B ring may be substituted, X represents a hydrogen atom, a hydroxyl group or an optionally substituted alkoxy group, both R ¹ and R ² is a hydrogen atom R ³ and R ⁴ together represents an oxygen atom, or R ³ and R ⁴ are both hydrogen atoms and R ¹ and R ² together represent an oxygen atom)
A food or drink for preventing or improving metabolic syndrome, comprising a compound represented by:   A pharmaceutical comprising the composition for preventing or improving metabolic syndrome according to any one of claims 1 to 5.   A food or drink comprising the composition for preventing or improving metabolic syndrome according to any one of claims 1 to 5.