JP4472282B2 - Nephritis or neuropathy inhibitor caused by hyperglycemia - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to an inhibitor that suppresses nephritis or neuropathy caused by hyperglycemia, and a food or pharmaceutical product containing the inhibitor.
[0002]
[Prior art]
In recent years, Japanese dietary habits have shifted to high-fat, high-energy Western styles, and so-called lifestyle-related diseases such as obesity, hyperglycemia, and hyperlipidemia are increasing. These diseases now extend to not only middle-aged and older people but also to younger people, and are a major social problem. In particular, it is estimated that there are 15 million patients annually called diabetes mellitus and diabetic reserve army, and an increase in patients with various diseases caused by hyperglycemia is expected in the future.
[0003]
If hyperglycemia persists, blood sugar binds to plasma proteins in the body to produce Amadori metastases, and cells and tissues are damaged by active oxygen and radicals generated from these Amadori products, nephritis and neuropathy, Causes complications such as retinopathy.
[0004]
All of these symptoms are major obstacles to daily life. If the symptoms progress further, there is a risk of renal failure, blindness, etc. Prevention and treatment of these diseases is an important issue. Although the control of blood glucose and the control of blood pressure are effective for the prevention and treatment of these symptoms, it is difficult to prevent or improve them sufficiently with modern therapies.
[0005]
Conventionally, dietary therapy, exercise therapy, and the like have been generally employed as treatments that reduce the risk of these diseases. However, it cannot be denied that such treatments cause great mental and physical stress on the patient.
[0006]
For the purpose of disease prevention, conventionally, for example, cacao bean extract (Japanese Patent Laid-Open No. 9-234018), arginine composition (Japanese Patent Laid-Open No. 2000-83623), catechins (Japanese Patent Laid-Open No. 11-302168, Japanese Patent Laid-Open No. 6-122626). Although materials such as polyphenols (Japanese Patent Laid-Open No. 2003-211) have been developed, considering the use as food and consumer preference, development of new materials is desired. Yes.
[0007]
[Problems to be Solved by the Invention]
In order to develop the above-mentioned new material, the present inventors have found that there is a material that suppresses nephritis and neuropathy caused by hyperglycemia in Brassicaceae plants as a result of intensive studies, and to complete the present invention. It came.
[0008]
The object of the present invention is to prevent hyperglycemia disorder, which is a lifestyle-related disease, to prevent diabetic complications in advance, find a material useful for maintaining health from cruciferous plants, and improve the above-mentioned drawbacks in the known art An object of the present invention is to provide a disorder inhibitor and a food or drug containing the inhibitor.
[0009]
[Means for Solving the Problems]
In order to achieve the above object, according to the present invention, 6-methylsulfinyl isothiocyanate contained in a cruciferous plant is contained as an active ingredient, and it suppresses nephritis and neuropathy caused by hyperglycemia in vivo. Features.
[0010]
BEST MODE FOR CARRYING OUT THE INVENTION
Hereinafter, the present invention will be described in detail.
[0011]
The above-mentioned 6-methylsulfinyl isothiocyanate can be obtained by physical means such as grinding, grated, or frozen grated cruciferous plants, or by water, methanol, ethanol, acetone, ethyl acetate, diethyl ether, dichloromethane, dichloroethane, etc. It can be obtained by solvent extraction means, further by drying means such as hot air drying, vacuum drying, freeze vacuum drying or the like, or further by combining these physical means, solvent extraction means, and drying means.
[0012]
Examples of the cruciferous plants used here include Japanese horseradish and horseradish . In the present invention, these cruciferous plants are used singly or in combination.
[0013]
Furthermore, the above-mentioned 6-methylsulfinyl isothiocyanate is synthesized by various chemical synthesis methods. Here, a chemical synthesis method of 6-methylsulfinyl isothiocyanate will be described, for example, as follows.
[0014]
In principle, follow the method of Chière. (See Kiaer et al. Acta chem. Scand, 11, 1298, 1957). 6-Chlorohexenol is used as a starting material and refluxed with CH ₃ -SNa to give 6-methylthiohexenol , which is allowed to react with SOCl ₂ to give 6-chlorohexenol methyl sulfide .
[0015]
Next, an amino group is introduced using the Gabriel method to produce N- (6-methylthiohexyl ) -phthalimide , and hydrazine hydrate is added to the resultant to reflux to obtain 6-methylthiohexylamine . Further, according to the method of Li et al. (See Li et al. J. Org. Chem., 62, 4539, 1997), 6-methylthiohexyl isothiocyanate obtained via laurim disulfide was converted into m-chloroperbenzoic acid. The methylthio group is oxidized with acid to give 6-methylsulfinylhexyl isothiocyanate .
[0016]
The 6-methylsulfinyl isothiocyanate according to the present invention thus obtained suppresses various disorders caused by hyperglycemia such as diabetes, such as neurosis and nephropathy, and is added as a pharmaceutical or to foods. Used. Here, the drug includes quasi-drugs in addition to normal drugs. Specific examples of this quasi-drug include, for example, drinks that have a pharmacological effect on the human body stipulated by the Pharmaceutical Affairs Law. Here, food is not only normal food, but also health food, beverage Including health functional foods.
[0017]
The above-mentioned health functional food is institutionalized as a food between quasi-drugs and health food, and is treated separately from general health food. For example, it is handled in the form of yogurt, tea, tablets and the like. Furthermore, as the above-mentioned food or health food, for example, tablets tableted with the addition of the hyperglycemia disorder inhibitor according to the present invention processed into powder into fructose, or arabe, dried vegetables, paste, salt, Ochazuke element obtained by mixing the powdered hyperglycemic disorder inhibitor according to the present invention with a powder seasoning or the like, and further, the hyperglycemic disorder inhibitor according to the present invention processed into a concentrated solution is desired for commercially available vegetable drinks For example, beverages obtained by mixing at a concentration of 0.5%. In addition, the extracted oil can be processed into a capsule shape, mixed with dressing, fried oil, cooking oil, or the like.
[0018]
Hereinafter, the present invention will be described in more detail with reference to examples.
[0019]
Example 1
1.0 kg of this wasabi was grated, an enzyme reaction was allowed to occur at a temperature of 37 ° C. for 3 hours, and reduced in pressure to remove the pungent taste. Next, 4 times the amount of 50% ethanol was added thereto, and the mixture was extracted by stirring at room temperature for 3 hours. The extract was filtered and then concentrated under reduced pressure.
[0020]
The obtained concentrated liquid was freeze-dried to obtain 25.2 g of wasabi powder (WP) having a content of 0.7% of 6-methylsulfinylhexyl isothiocyanate (6-MSITC).
[0021]
Example 2
Synthesis of 6-methylsulfinylhexyl isothiocyanate 26 g of 15% methyl mercaptan sodium solution was added to 80 ml of methanol, and 10 g of 6-bromohexanenitrile was slowly added dropwise thereto under ice cooling. After the dropwise addition, the mixture was stirred for 2 minutes under ice cooling, and further stirred at room temperature for 3 hours. Next, methanol was completely distilled off with an evaporator, 40 ml of water was added to the obtained residue, and the mixture was extracted three times with 40 ml of diethyl ether to obtain an ether layer. This was washed sequentially with 5% hydrochloric acid, water, and saturated brine to obtain 7.5 g of 6-methylthiohexanenitrile.
[0022]
Next, 4 g of lithium aluminum hydride was added to 160 ml of diethyl ether while stirring, and after substitution with argon, a diethyl ether solution of 6-methylthiohexanenitrile was added and stirred at room temperature for 2 hours. Next, 4 ml of water, 4 ml of 15% sodium hydroxide aqueous solution, and 10 ml of water were sequentially added under ice cooling, followed by filtration, and the filtrate was extracted with 50 ml of diethyl ether. The obtained ether layer was washed with water and saturated brine in this order, dehydrated with sodium sulfate, and then concentrated under reduced pressure with an evaporator to obtain 6.9 g of 6-methylthiohexylamine.
[0023]
Next, 1.8 g / 4 ml of an aqueous sodium hydroxide solution was added to 3.4 g of carbon disulfide, and further 6.4 g of 6-methylthiohexanenitrile was slowly added at 10 ° C., and the reaction temperature was gradually raised, followed by 2 hours at 80 ° C. Stir. Thereafter, the mixture was cooled to 40 ° C., 4.8 g of ethyl chloroformate was slowly added, and the mixture was stirred for 1 hour. This was extracted with dichloromethane, and the extract was dehydrated with sodium sulfate and evaporated under reduced pressure using an evaporator. The residue was stirred at 100 ° C. for 2 hours and then cooled. This was subjected to silica gel column chromatography to obtain 6.4 g of 6-methylthiohexyl isothiocyanate.
[0024]
Furthermore, 2.0 g of 6-methylthiohexyl isothiocyanate was dissolved in 400 ml of ethyl acetate, 2.5 g of m-chloroperbenzoic acid was slowly added under ice cooling, and the mixture was stirred for 1 hour. This was washed successively with 5% sodium hydrogen carbonate solution, water, and saturated brine, dehydrated with sodium sulfate, and then concentrated to dryness with an evaporator. The obtained dried product was subjected to silica gel column chromatography to obtain 1.5 g of 6-methylsulfinylhexyl isothiocyanate (6-MSITC).
[0025]
Example 3
Type 2 diabetes model mouse KK-A ^Y 6 weeks old, 37 males (Japan Claire Co., Ltd.) in an experimental laboratory animal room, temperature 20-26 ° C., humidity 50-60%, ventilation rate 10-15 times / The animals were reared under conditions of time, wind speed of 15 to 20 cm / sec, lighting time of 12 hours, and extinguishing 12 hours. Table 1 shows the feed fed to the mice. In Table 1, the solid feed is CRF-1 manufactured by Oriental Yeast Co., Ltd.
[0026]
The high fat diet of Table 1 was ingested for 4 weeks from 6 weeks to 9 weeks of age. Thereafter, 7 animals whose body weight and blood glucose level were significantly different from the average values were excluded, and 10 animals were divided into 3 groups so that the blood glucose level of each group was equal, and the weight (g) after grouping and after grouping The blood glucose levels (mg / dL) were measured and are shown in Table 2. The numerical values in Table 2 show the average value ± standard deviation.
[0027]
[Table 1]
[0028]
[Table 2]
[0029]
The experiment was performed at 13 weeks of age in a metabolic chamber (manufactured by Claire Japan), collecting urine for 24 hours, measuring the amount of drinking water and urine volume, and further measuring the amount of urinary albumin and urinary creatinine as indicators of nephritis The amount and creatinine clearance (urine volume × urine creatinine amount / blood creatinine amount) were measured. Levis albumin ELISA kit (Shibayagi Co., Ltd.) was used to measure the amount of urinary albumin, and a creatinine test kit (Wako Pure Chemical Industries, Ltd.) was used to measure the amount of urinary creatinine. The results are shown in Table 3.
[0030]
[Table 3]
[0031]
In Table 3, it shows that diabetes related symptom is so severe that a numerical value is large. Furthermore, in Table 3, all numerical values show mean values ± standard deviation, and different alphabets show significant differences. (P <0.05)
[0032]
As is apparent from Table 3, the amount of urine was significantly decreased in the wasabi powder administration group (WP group), a decrease tendency was observed in the 6-MSITC group, and the albumin amount was also decreasing in the WP administration group. , 6-MSITC administration group significantly decreased. A decrease in creatinine content and creatinine clearance is also confirmed, confirming that nephritis is suppressed, and is expected to be used as a pharmaceutical product.
[0033]
Example 4
A tail flick test was performed in which the tail of the 13-week-old mouse of Example 3 was irradiated with light and the time until thermal reaction was measured, and the degree of neuropathy was observed. The test was conducted using MK-330B (tail flick analgesia meter (Muromachi Co., Ltd.)), and the results are shown in FIG.
[0034]
FIG. 1 is a graph showing reaction times of a control group, a WP group, and a 6-MSITC group. From FIG. 1, it was confirmed that the reaction time was shortened in the WP group and the 6-MSITC group as compared with the control group, and that neuropathy was suppressed by this, and this is expected to be used as a medicine. The
[0035]
Example 5
Formulation examples as quasi-drugs using the hyperglycemia disorder inhibitor according to the present invention, as well as formulation examples as health functional foods, various foods, and health foods are shown below.
[0036]
Using the wasabi powder (WP) obtained in Example 1, tablet confectionery was produced by the following formulation.
Wasabi powder (WP) 50 parts by weight
Indigestible dextrin 23 parts by weight
Concentrated fruit juice 7 parts by weight
5 parts by weight of citric acid
Sucrose fatty acid ester 2 parts by weight
2 parts by weight of silicon dioxide
Fragrance 1 part by weight [0037]
Using the wasabi powder (WP) obtained in Example 1, an alcoholic beverage was produced by the following formulation.
Commercial shochu 90 parts by weight This wasabi stem (cut into 5 mm width) 7 parts by weight Wasabi powder (WP) 2 parts by weight Fragrance 1 part by weight [0038]
Using wasabi powder (WP) obtained in Example 1, a wasabi processed product was produced by the following composition.
Wasabi Rhizome (freeze crushed) 80 parts by weight Wasabi Stem (freeze crushed) 10 parts by weight Edible oil 4 parts by weight Wasabi powder (WP) 3 parts by weight Dietary fiber 2.9 parts by weight Colorant 0.1 weight Department [0039]
Using the wasabi powder (WP) obtained in Example 1, a beverage as a quasi-drug of the following composition was produced.
Sucrose 12g
Vitamin B1 10mg
Vitamin B2 5mg
Vitamin B6 10mg
Nicotinamide 30mg
Taurine 1000mg
Anhydrous caffeine 50mg
Wasabi powder (WP) (as wasabi extract) 1000mg
[0040]
By ingesting various foods, health foods, health functional foods, and quasi drugs containing the hyperglycemia disorder inhibitor (WP) according to the present invention described above, hyperglycemia as described above shown in mouse experiments can be obtained. It is expected to prevent nephritis and neuropathy .
[0041]
【The invention's effect】
As described above, according to the present invention, 6- methylsulfinylhexyl isothiocyanate contained in Brassicaceae plants suppresses hyperglycemia disorder, which is a lifestyle-related disease. For example, by ingesting this as a pharmaceutical, and further ingesting it in foods, health foods, health functional foods, or quasi drugs, nephritis, neuropathy, etc. caused by hyperglycemia can occur in advance. Is prevented.
[Brief description of the drawings]
[0042]
FIG. 1 is a graph showing thermal reaction time (seconds) due to light irradiation corresponding to each of a control group, a WP group, and a 6-MSITC group.

Claims (6)

A nephritis inhibitor caused by hyperglycemia, comprising 6-methylsulfinylhexyl isothiocyanate as an active ingredient. The nephritis inhibitor according to claim 1, wherein 6-methylsulfinylhexyl isothiocyanate is contained in the present wasabi which is a cruciferous plant. The nephritis inhibitor according to claim 1, wherein 6-methylsulfinylhexyl isothiocyanate is contained in horseradish which is a cruciferous plant . An inhibitor of neuropathy caused by hyperglycemia, comprising 6-methylsulfinylhexyl isothiocyanate as an active ingredient. 5. The neuropathy inhibitor according to claim 4, wherein 6-methylsulfinylhexyl isothiocyanate is contained in this wasabi which is a cruciferous plant. The neuropathy inhibitor according to claim 4, wherein 6-methylsulfinylhexyl isothiocyanate is contained in horseradish which is a cruciferous plant.