JP4783576B2 - Antihypertensive - Google Patents

Description

The present invention relates to an antihypertension used for the prevention and improvement of hypertension, comprising as an active ingredient an ingredient extracted from a culture obtained by culturing mycelium of basidiomycetes in a medium containing plant fiber raw materials. about the agent.

  In general, blood pressure rises with age, and it is said that 1 of 2 people with hypertension, including mild cases, is a typical lifestyle-related disease that progresses slowly over 10 to 15 years.

  According to the standards of the World Health Organization (WHO) technical committee, hypertension is defined as a maximum blood pressure (systolic blood pressure) of 160 mmHg or higher and / or a minimum blood pressure (diastolic blood pressure) of 95 mmHg or higher.

  Damage caused by high blood pressure causes arteriosclerosis in the blood vessels throughout the body, including brain damage (cerebral hemorrhage, cerebral infarction), heart damage (cardiac hypertrophy, heart failure, angina pectoris, myocardial infarction), kidney damage (nephrosclerosis, renal failure), It induces various disorders throughout the body, such as eye disorders, and becomes life threatening. According to the overview of 2003 vital statistics (confirmed number), approximately 30% of deaths are caused by heart disease and cerebrovascular disease. Hypertension is also afraid of being called a silent killer because it has almost no subjective symptoms.

  It is said that 90 to 95% of hypertension is essential hypertension whose cause cannot be specified. Essential hypertension is thought to develop by intricately intertwining genetic factors and lifestyle habits (overdose of salt, obesity, lack of exercise, excessive drinking, smoking, stress, etc.).

  In order to improve hypertension, it is important to improve lifestyle and eliminate the cause, but it is not easy to continue daily intake such as salt reduction, diet, exercise, smoking cessation, optimization of alcohol consumption, etc. Absent. Furthermore, it is actually difficult to reduce stress.

  Moreover, drug treatment is required if blood pressure does not improve even with such lifestyle improvements. As drugs for hypertension, for example, diuretics, sympathetic nerve inhibitors (β-blockers, α-blockers, etc.), calcium antagonists, angiotensin (ACE) converting enzyme inhibitors, angiotensin receptor antagonists, etc. are used. . These drugs need to be combined if blood pressure reduction cannot be achieved.

  However, drugs are not only a burden on the body, but often have side effects, which may cause a decrease in QOL.

  Some foods have a blood pressure lowering effect, and it is considered to be an effective method to take a food having a blood pressure lowering effect together with lifestyle improvement in order to compensate for the drawbacks of drug treatment.

  As an example, a food for specified health use that improves hypertension has been developed from a hot water extract of bonito (see Non-Patent Document 1).

In addition, among edible mushrooms, maitake (see Non-Patent Document 2), beech haritake (see Non-Patent Documents 3 and 4), enokitake (see Patent Document 1), Hanabiratake (see Patent Document 2), eringi (Patent Document 3) As described above, those that lower blood pressure have been reported, and from the above-mentioned Bunaharitake, food for specified health use for people with high blood pressure has been developed.
Hiroyuki Fujita, Ryoichi Yasumoto, Akiyasu Hasegawa, Kazunori Oshima, Antihypertensive effect on human volunteers with bonito oligopeptide (II), Pharmacology and treatment, 25 2161-2165 (1997) Y. Kabir and S. Kimura, Dietary Mushrooms Reduce Blood Pressure in Spontaneously Hypertensive Rats (SHR), J. Nutr. Sci. Vitaminol, 35 91-94 (1989) Taku Sato, 2002 Mushroom Yearbook 259-265 (2002) Takashi Tsuchida, Kenshi Masuko, Hideyuki Nagata, Taku Sato, Pharmacology and Treatment 29 899-906 (2001) JP 2004-89128 A JP 2004-292414 A JP 2002-176975 A

  Hypertension progresses slowly over 10 to 15 years, triggers generalized arteriosclerosis, and is a risk factor for various diseases such as cerebrovascular disorder, ischemic heart disease, dissecting aortic aneurysm, kidney disease, retinopathy, etc. is there.

  Desirable lifestyle habits from a young age are important in order to prevent essential hypertension with unspecified causes. However, it is not easy to continue daily intake such as salt reduction, smoking cessation, exercise, optimization of meals and alcohol consumption, and it is stressful in a complicated social situation that requires time and efficiency. It is also difficult to reduce.

Accordingly, an object of the present invention is to provide an antihypertensive agent that has high side effects of preventing and improving hypertension that can be easily taken on a daily basis without side effects.

In order to achieve the above object, the present invention is a component extracted from a culture obtained by culturing mycelia of mannen mushrooms or shiitake mushrooms, which are basidiomycetes , in a medium containing plant fiber raw materials. The present invention provides an antihypertensive agent comprising, as an active ingredient, a component containing 30 to 50%, 8 to 15% protein, and 20 to 40% water-soluble lignin.

Oite The antihypertensive agent of the present invention, said culture after completion of the culture of the mycelium, it is preferable to use an enzyme inherent in mycelium is obtained by the mycelium was autolysed .

In the present invention, it is preferable that the plant fiber raw material is prepared from a plant of this family, and is selected from bagasse, corn stover, wheat bran, rice bran, rice bran, straw, bear cocoon, and bamboo. 1 type or 2 types or more are more preferable.

Ingredients extracted from the culture obtained by culturing mycelium of mannen mushrooms or shiitake mushrooms as basidiomycetes in a medium containing plant fiber raw materials, which are active ingredients of the present invention, are contained in the plant fiber raw materials Cellulose, hemicellulose, lignin, etc. produced by digestion, decomposition, and condensation by enzymes such as cellulase, phenol oxidase, laccase, peroxidase, protease, etc. produced by mycelium of basidiomycetes during the culture period The proteoglycan is composed of a substance in which a modified water-soluble lignin modified with an enzyme and rendered water-soluble is bound in a complex manner. This extract component significantly suppresses an increase in blood pressure when orally administered to spontaneously hypertensive rats, as shown in Examples described later.

Therefore, by taking the antihypertensive agent of the present invention, essential hypertension is prevented, and risk reduction of heart disease, cerebrovascular disorder, renal disease, eye disease and the like is expected.

  Even when hypertension has already occurred, taking the antihypertensive agent of the present invention is expected to lower blood pressure, facilitate blood pressure control, and prevent QOL reduction in hypertension treatment.

  The extract component, which is an active ingredient of the present invention, is a product obtained from a natural product, and can be easily ingested in daily life without worrying about side effects seen in chemicals and the like.

  Moreover, in addition to improving lifestyle habits even when hypertension has already occurred, further antihypertensive effects can be expected and blood pressure control is facilitated.

Furthermore, if it is not possible to lower the target blood pressure simply by improving life, it is necessary to take the drug. However, the antihypertensive agent of the present invention can be safely and easily inoculated, so the dose can be reduced by using it together with the drug. To improve patient QOL.

The basidiomycete are use in the present invention, Ru with Ma N'nen mushrooms or shiitake.

  In the present invention, mycelia of these basidiomycetes are cultured using a medium containing plant fiber raw material, and active ingredients are extracted from the culture. In this case, either a solid medium or a liquid medium can be used as the medium. As the plant fiber raw material used for the medium, those prepared from plants containing lignin are preferably used. As the lignin-containing plant, a plant family such as bagasse (squeezed sugar cane), corn stover, wheat bran, rice bran, rice straw, and straw are preferably used. In addition, bears, bamboo, etc. can be used. Particularly preferably, a culture medium containing at least one selected from bagasse, bear stems and corn stalks and rice bran is used. In addition, yeast extract, dry yeast, chlorella, spirulina, corn meal, okara, and the like may be added and mixed with the medium as other nutritional components as necessary.

  The mycelium of basidiomycetes is cultured by inoculating the mycelium of basidiomycetes in a medium containing the above-mentioned plant fiber raw material. In the case of a solid medium, the water content is adjusted to 60 to 80%, sterilized by autoclaving according to a conventional method, inoculated with mycelia, and, for example, 3 to 6 in a culture room conditioned at a temperature of 18 to 25 ° C. Incubate for months. The medium in which the mycelium has spread is preferably transferred to a temperature treatment chamber and subjected to a temperature change treatment. In the temperature change treatment, for example, the mixture is first heated at 30 to 34 ° C. for 24 to 48 hours, and then transferred to a low temperature chamber and treated for 3 to 5 days. After that, when it is moved to a culture room, the generation of fruiting bodies starts. At this point, the culture is terminated and the culture is crushed with a crusher.

  On the other hand, in the case of a liquid medium, the plant raw material is finely crushed, and if necessary, other nutrient components such as rice bran are added, and the medium is prepared so that the raw material becomes 5 to 20% by mass, and then aeration stirring culture or By shaking culture, culture is preferably performed at a temperature of 20 to 28 ° C. for about 1 week to 2 months. The culture is terminated when the pH of the medium is lowered to 3.5 to 5 and the mycelium is prevalent in the medium.

After completion of the culture, the mycelium is self-digested using an enzyme present in the mycelium and the culture is extracted. As a preferred method, in the case of a solid medium, the culture after culturing is crushed, a small amount of water is added as necessary, and the mixture is treated at 30 to 60 ° C. for 3 to 6 hours to advance the mycelial enzyme reaction, Let yourself digest. Subsequently, this crushed material is infiltrated with warm water or hot water of 50 ° C. or higher, and an active ingredient is extracted. The extraction can also be carried out under a high pressure such as 120 ° C. under a vapor pressure of 1.2 kg / cm ² , for example. The extract suspension thus obtained is preferably filtered or centrifuged to collect a filtrate or a supernatant, whereby an extract containing a medium degradation product, a mycelium metabolite, a mycelium cell degradation product, or the like is obtained. Can be obtained.

On the other hand, in the case of liquid culture, the whole culture is treated at 30 to 60 ° C. for 3 to 6 hours to self-digest the mycelium to obtain a liquid suspension culture. Then, if necessary, a small amount of water is added, and the mixture is heated to 50 ° C. or higher, sometimes under high pressure (for example, under a vapor pressure of 1.2 kg / cm ² ), and the extract is collected. The extract is filtered or centrifuged as necessary to obtain a filtrate or supernatant, thereby obtaining an extract containing a degradation product of the medium, a mycelium metabolite, a mycelium cell degradation product, or the like. Can do.

The extract thus obtained can be used as it is or after being concentrated, but can also be used after being pulverized by means such as freeze drying or spray drying. When using extract as such or concentrated to the Ru can also be a liquid or jelly drink type products. When the extract was powdered in a conventional manner by, powders, granules, tablets, Ru can be commercialized as a capsule.

Antihypertensive agent of the present invention, wear powder prepared as described above, granules, tablets, capsules, or as a drink in the market.

  The extract as an active ingredient of the present invention (a component extracted from a culture obtained by culturing mycelium of basidiomycetes in a medium containing plant fiber raw material) is a substance mainly composed of carbohydrates. However, it was confirmed that it has the following physicochemical properties.

(1) Molecular weight: 1 million or less
(2) Chemical composition Carbohydrate: 30-50%
Protein: 8-15%
Water-soluble lignin: 20-40%

In addition, the result of having tested safety | security about the said culture extract (powder) obtained using the mannen koji is as follows.
(A) Acute toxicity test (minimum lethal dose; LDL ₀ )
Rat single oral administration Male: 22500mg / Kg or more
Female: 22500mg / Kg or more Single oral administration of mouse Male: 2000mg / Kg or more
Female: 2000mg / Kg or more
(B) Rat 3-month repeated oral administration test (maximum no-effect level)
Male: 3610mg / Kg
Female: 4190mg / Kg

In addition, the effective dose of the antihypertensive agent of the present invention is 1 to 10 g per day for an adult in oral intake in terms of the extract. If the dose is smaller than this, the effect of suppressing blood pressure elevation cannot be sufficiently obtained in vivo, and if the dose is larger than this, loose stool or abdominal bloating may occur. However, there is no problem in safety even if the dose is larger than the above.

Example 1
(1) Solid culture of Mannentake fungus 90% bagasse and 10% defatted rice bran were mixed, and a solid medium was prepared by adjusting the water content to 70%. This was inoculated with mycelia mushrooms and cultured for 3 months in a culture chamber adjusted to 25 ° C. After the mycelium had spread in the medium, it was transferred to a temperature treatment chamber and heated at 35 ° C for 24 hours, and then 10 ° C. Treated in a cold room at 3 ° C for 3 days. Thereafter, the cells were cultured in a culture room for 3 days, and the medium was crushed to the size of a thumb with a crusher. The crushed medium was treated at 40 ° C. for 6 hours to promote autolysis, then packed in an extraction tank, and extracted for 16 hours while circulating hot water at 60 ° C. The obtained extract was filtered through a cartridge filter, further sterilized by filtration through a membrane filter, concentrated, and freeze-dried to obtain a brown powder. Hereinafter, this powder is referred to as “present powder”.

  As a result of analyzing the components of this powder, it was as follows.

Carbohydrate: 40% (phenol sulfate method)
Protein: 12% (semi-micro Kjeldahl method)
Water-soluble lignin: 30% (acetyl bromide method)
Inorganic: 13% (direct ashing method)

(2) Blood pressure increase inhibitory effect The blood pressure increase inhibitory effect of the spontaneously hypertensive rat (SHR) was measured about this powder. The development of hypertension in SHR is considered to be a pathological model of the development of essential hypertension in humans.

(i) Experimental animals After purchase, 4 weeks old SHR (manufactured by Saitama Experimental Animal Supply Co., Ltd.) was acclimated in an animal room in which temperature, humidity, and light irradiation time were controlled. Animals were randomly selected into a control group and this powder group. The food was powder CE-2 (trade name, manufactured by Saitama Experimental Animal Supply Co., Ltd.).

(ii) Administration method After fasting for one day, the control group was fed with powder CE-2, and the main powder group was fed with a powder CE-2 mixed with 0.5% main powder for 10 weeks.

(iii) Measurement of blood pressure, food intake and body weight As for blood pressure, systolic blood pressure was measured using a non-invasive blood pressure measuring device (trade name: MK2000: manufactured by Muromachi Kikai). Each rat was measured 5 times and the average value was recorded.

  Food intake and body weight were measured daily.

(iv) Measurement of mRNA level
After measuring blood pressure for 10 weeks, real-time RT-PCR was performed using total RNA extracted from the renal cortex, renal medulla, left ventricle and abdominal aorta, and the amount of fibronectin (fibronectin) mRNA was measured.

(v) Blood pressure measurement results FIG. 1 shows the results of measuring changes in blood pressure with age in SHR. In FIG. 1, the vertical axis represents blood pressure, the horizontal axis represents age, ○ represents a group administered with CE-2 only feed (hereinafter referred to as “CE-2 group”), and ● represents this powder on CE-2. A group to which a feed supplemented with 0.5% was administered (hereinafter referred to as “MAK group”). In the CE-2 group as a control, blood pressure increased with age. As shown in the figure, in the MAK group containing this powder, a sustained increase in blood pressure (about -20 mmHg) was observed from the 2nd week of feeding, and this difference was assumed to have an equal variance between the two groups. Significant by test.

(vi) Food intake and body weight FIG. 2 shows changes in food intake and FIG. 3 shows changes in body weight. In FIG. 2, the vertical axis represents food intake, the horizontal axis represents age, and in FIG. 3, the vertical axis represents body weight, and the horizontal axis represents age. ○ and ● have the same meaning as described above.

  From the results of FIGS. 2 and 3, there was no difference in food intake and body weight change between the control CE-2 group and the MAK group containing the present powder.

(vii) Measurement result of mRNA amount FIG. 4 shows the measurement result of the amount of mRNA of fibronectin (fibronectin). In FIG. 4, the vertical axis represents the amount of mRNA with the CE-2 group as 1, and the MAK group as a relative value, and the horizontal axis represents the measured tissue. The white bar graph represents the CE-2 group, and the black bar graph represents the MAK group.

  As shown in FIG. 4, the renal cortex, renal medulla, left ventricle (heart) and ventral arota were measured. In the MAK group administered with this powder, the amount of fibronectin mRNA was increased. In the MAK group to which this powder was administered, the heart (left ventricle) was reduced by about 50%.

Example 2
The mycelium of shiitake mushrooms were inoculated into the same medium as in Example 1 to perform solid culture, and the same treatment as in Example 1 was performed to obtain an extract. The components of the freeze-dried product of this extract were as follows.

Carbohydrate: 35%
Protein: 11%
Water-soluble lignin: 35%
Inorganic: 12%
This extract suppressed the increase in blood pressure of SHR as in Example 1.

Example 3
The leaves and stems of kumamushi are washed well, dried and crushed, and then mixed with rice bran so that the mass ratio is 20%, a solid medium is prepared, and the mycelium of shiitake mushroom is cultured on this, and the same as in Example 1 The extract was obtained by the method. This extract suppressed the increase in blood pressure of SHR as in Example 1.

Example 4
A liquid medium was prepared by adding 100 g of bagasse finely crushed with a mixer at a ratio of 20 g of rice bran and 5 g of yeast extract, followed by autoclaving as usual, and inoculating shiitake mycelium. After aeration (aeration rate: 5 liters / min) and stirring (50 rpm) for 2 weeks at 23 ° C., the culture was heated at 40 ° C. for 3 hours to allow the mycelial enzyme to self-digest. Thereafter, the mixture was sterilized by heating at 80 ° C. for 1 hour to extract metabolites. The extract was centrifuged at 3000 rpm for 30 minutes to remove the precipitate, and further centrifuged at 10,000 rpm to obtain a brown liquid. This extract was freeze-dried and had the following composition.

Carbohydrate: 35%
Water-soluble lignin: 40%
Protein: 12%
Other: 13%
This product suppressed the increase in blood pressure of SHR as in Example 1.

Example 5
Example of a 51 year old man:
Since his father had essential hypertension and he regularly used antihypertensive drugs from a young age, he himself was concerned about blood pressure rise and he was aware of lifestyle habits, but blood pressure has been on the rise for several years, and systolic blood pressure has 130-140 mmHg, diastolic blood pressure was 96 mmHg. When the dried extract obtained in Example 1 was drunk at 2 g / day for 2 weeks, the systolic blood pressure was 120 mmHg and the diastolic blood pressure was around 85 mmHg.

Example 6
Example of a 63 year old man:
The patient went to the hospital for essential hypertension and increased palpitations, and the maximum blood pressure was 200 mmHg. When the powder obtained in Example 2 was ingested 1 g / day for 3 months together with the palliative sedative, the maximum blood pressure decreased to 120 mmHg and the minimum blood pressure to 60 mmHg.

  The present invention relates to a pharmaceutical product and a health food for preventing hypertension prevention and treatment by suppressing a rise in blood pressure by daily intake for hypertension patients and persons with a possibility of hypertension Etc. can be used.

It is a graph which shows the result of having measured the time-dependent change of the blood pressure when the food containing 0.5% of the powder obtained in Example 1 is orally ingested by the spontaneously hypertensive rat (SHR). It is a graph which shows the result of having measured the time-dependent change of the amount of food intake when the food containing 0.5% of the powder obtained in Example 1 was orally ingested by spontaneously hypertensive rats (SHR). It is a graph which shows the result of having measured the time-dependent change of the body weight when the food containing 0.5% of the powder obtained in Example 1 was orally ingested by spontaneously hypertensive rats (SHR). The results of measuring the amount of mRNA for fibronectin in the renal cortex, renal medulla, left ventricle and abdominal aorta after 10 weeks of oral administration of a diet containing 0.5% of the powder obtained in Example 1 to spontaneously hypertensive rats (SHR) It is a chart shown.

Claims (4)

A component extracted from a culture obtained by culturing mycelium of basidiomycete mannen or shiitake mushroom in a medium containing plant fiber raw material, 30 to 50% of saccharide and 8 to 15 of protein %, And a component containing 20 to 40% of water-soluble lignin as an active ingredient.   The antihypertensive agent according to claim 1, wherein the culture is obtained by self-digesting the mycelium using an enzyme present in the mycelium after the cultivation of the mycelium.   3. The antihypertensive agent according to claim 1 or 2, wherein the plant fiber raw material is prepared from a plant of the family genus.   The antihypertensive agent according to claim 1 or 2, wherein the plant fiber raw material is one or more selected from bagasse, corn stover, wheat bran, rice bran, rice bran, straw, kumabana, and bamboo.

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