JP2005255574A - IgA-PRODUCTION-LEVELING AGENT AND STRESS DISEASE-PREVENTING AND/OR TREATING COMPOSITION CONTAINING THE SAME - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a material suppressing or recovering the reduction of production capacity of IgA governing intestinal tract immunocompetence caused by a stress, while having an IgA production-leveling activity which does not act in the case that the production capacity is in a normal level, also gentle to a human body and having less adverse effect. <P>SOLUTION: The IgA production-leveling agent consisting of a citrus fruit or its processed material, especially a compressed material or fruit rind of an Onsyu mandarin orange is used by blending in an external agent (preparations of ointment, lotion, patch, spray, oral cavity use, liniment, or the like), an internal medicine or feeds for animals/fishes and shell fishes, to level the IgA production capacity for effectively improving the reduction of the intestinal immunocompetence caused by the load of the stress to maintain a normal immune system. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to an IgA-producing homeostatic agent comprising citrus fruits such as Unshu mandarin or processed products thereof. Specifically, the present invention restores the ability to produce IgA that has been reduced by stress load, or suppresses the decrease in IgA production ability by stress load, and does not increase the IgA concentration more than necessary, so that the immune system is always normal. The present invention relates to an IgA producing and stabilizing agent having an effect of maintaining a level, and a composition for preventing and / or treating stress-related diseases such as livestock feed containing the same.

  Today is an era of stress overload, and more or less living in the present age lives under the influence of stress. The influence of such stress on the human body has recently been investigated in detail, and it is becoming clear that it has an unexpectedly large effect.

  A person always responds to a stimulus (stress) from the external environment through the nervous system-endocrine system-immune system and maintains homeostasis, but this homeostasis is disturbed by excessive stress, The immunity tends to be such that the immunity of the skin and mucous membranes is reduced or the circulatory function is increased, and as a result, it tends to be susceptible to infection. As an example, it is known that an animal that is raised in an overcrowded environment and always under stress has low infection resistance.

  Especially in poultry farms, pig farms, cattle barns, etc., in recent years, there has been no pursuit of their efficiency, and their livestock and poultry have been pushed into extremely limited living spaces and produced by breeding methods that only meet the purpose of production. ing. Therefore, these livestock and poultry are suffering from various stresses resulting from the living environment and breeding, leading to a decrease in health status and a decrease in infection resistance, and the frequency of outbreaks of infectious diseases is increasing. .

  Furthermore, compounded feeds given to livestock and poultry tend to be added with large amounts of chemicals and antibiotics for the purpose of preventing such harmful effects and morbidity. It causes problems such as occurrence of side effects, further reduction of drug effects due to the emergence of resistant bacteria, or various adverse effects caused by ingestion of these drugs into the human body.

  Therefore, preventing a decrease in infection resistance, which is one of the factors leading to various diseases related to stress, has become an important issue in modern society, also called a stress society. It also depends on drugs such as chemicals and antibiotics in order to increase the immunity and infection resistance of livestock and poultry, improve their productivity and quality, and prevent harmful effects on the human body that consumes them. Development of safe feed that does not occur is desired.

  Here, an infectious disease is a disease that manifests as various diseases and manifests as a disease because the pathogenicity on the bacteria side and the defense power on the host side are intricately intertwined. Since the defense against infection of animals including humans greatly depends on their immunity, various substances that activate the immunity have been proposed as means for solving the above problems.

  For example, an immunostimulant containing herbs containing essential oils, spices, saponins, and tannins, or herbs consisting of ingredients derived from citrus fruits, and animal or seafood feeds to which the same has been proposed ( Patent Document 1).

  In addition, fermented products obtained by treating soybean, wheat, citrus fruits, fruits or raw materials containing these processed products with filamentous fungi, natto bacteria, and / or filamentous gold, natto bacteria enzymes as substances having immunostimulatory activity are proposed. (See Patent Document 2).

  However, the higher the immunity, the better. If it is too high, it can cause an autoimmune disease that attacks itself. Therefore, in order to prevent such a phenomenon from occurring normally in the living body, immunity is systematized, various cells are responsible for various actions such as enhancement and suppression, antagonism, promotion, synchronization, etc. Has built a mechanism that prevents the system from moving significantly.

  Therefore, in order to maintain a normal immune system by overcoming the decline in immune capacity and resistance to infection caused by stress, and maintaining a healthy body in a modern stress society, immune capacity is not simply increased. However, when the immune system is at a normal level, there is no particular effect, but only when the immune system is reduced due to stress or other causes, the immune system activates or suppresses the decrease in immune system to return the immune system to the normal level. The development of a substance that exerts the function to make it, that is, the immunity homeostasis action is truly needed.

JP 2002-370993 A JP 2003-327540 A

  The present invention suppresses immunity reduction due to stress or restores the reduced immunity, but does not act in a normal state, thereby normalizing the immune system, that is, stabilizing the immunity. It is an object of the present invention to provide a material that is friendly to the human body and has few side effects, and a feed for animals or fish and shellfish containing the material.

  In light of the above-described problems, the present inventor has intensively studied the influence of stress on immune ability using an overcrowded stress model. As a result, IgA (which functions as intestinal immunity) is required by the living body in a normal state. It was found that the state of the intestine producing immunoglobulin A) is affected by stress, and the production of IgA is suppressed to become deficient, resulting in a decrease in immunity.

  And, as a result of further research by administering various food materials to the overstress stress model that caused the phenomenon of reduced IgA production ability, by taking orally citrus fruits or processed products thereof, normal stress It was found that the ability to produce IgA was restored to a state where it was not subjected to the treatment, and that the ability to produce IgA did not change even when further administration was performed in a normal state where such stress was not received, thereby completing the present invention.

That is, this invention relates to the IgA production | generation homeostasis and composition shown to the following (1)-(5).
(1) An IgA production constant agent comprising citrus fruits or processed products thereof.
(2) The IgA production constant agent according to (1), wherein the citrus fruit is Wenzhou mandarin.
(3) The IgA production constanting agent according to (1) or (2), wherein the citrus fruit or a processed product thereof is a citrus pressing product.
(4) The IgA production stabilizing agent according to (1) or (2), wherein the citrus fruit or processed product thereof is a citrus peel.
(5) A composition for preventing and / or treating stress-related diseases, comprising the IgA-producing homeostatic agent according to any one of (1) to (4).
(6) The composition for preventing and / or treating stress-related diseases according to (5), which is a feed for animals or fish and shellfish.

  Here, the immune system of humans and animals includes an innate immune system and an acquired immune system, and the well-known natural killer cell is one of cells that control the main immunity in the innate immune system. On the other hand, in the acquired immune system, mainly B cells and T lymphocytes control immunity.

  The immune system is roughly divided into a systemic immune system and a mucosal immune system. For example, when the systemic immune system works normally, canceration is suppressed, and when the balance is lost, cancer tends to develop. On the other hand, the mucosal immune system existing in the intestinal mucosa and the like works by a mechanism different from that of the systemic immune system, and its main role is to prevent foreign substances from entering.

  In other words, since the intestinal mucosa is a place where it comes into contact with many viruses, bacteria, parasites, pathogenic antigens and food antigens, there exists an intestinal immunity system to protect the body from these foreign antigens and functions as intestinal immunity It is IgA (immunoglobulin A). IgA is an antibody produced and secreted by B cells in the mucous membrane, and binds to pathogens and foreign substances such as bacteria and viruses and prevents them from entering the body.

  The present inventor has eagerly studied the response to the stress that a living body (human or animal) receives and its influence using an overcrowded stress model (mental stress) of the animal, and as a result, one of the characteristic changes of the living body due to the stress. As a result, it was found for the first time that the concentration of IgA in the feces decreases.

  IgA binds to pathogens and foreign substances in the mucous membrane to prevent invasion, and the rest is finally excreted in feces. Therefore, the concentration of IgA in feces can be used as an index representing the intestinal immunity of the living body, that is, the mucosal infection protection ability. The decrease in IgA concentration in the overcrowded stress model found this time indicates that the immune system of the intestinal mucosa is decreased by stress for the first time.

  That is, in the normal state where normal stress is not received, the state of the intestine producing the necessary amount of IgA is affected by the stress load, and the ability to produce IgA is reduced, resulting in an IgA deficient state, resulting in immune capacity. This is the first time that a decreasing phenomenon has been found, and the present invention has been made based on such new findings.

Therefore, it is considered that a substance having an action of enhancing IgA production ability is effective for reducing immune ability due to stress.
However, as described above, it is not necessary that the immunity is high. Therefore, it is not only necessary to have an effect of enhancing the IgA production ability. In order to maintain normal immunity and maintain a healthy body, it has the effect of suppressing the decrease in IgA production ability due to stress or recovering the reduced IgA production ability, but when the IgA production ability is at a normal level It is most desirable that it does not act, that is, has a function of normalizing the ability to produce IgA (in other words, a constant action of producing IgA).

  In this respect, the IgA production-stabilizing agent composed of citrus fruits or processed products found in the present invention has an IgA production-stabilizing effect of promoting production when IgA is insufficient, and ineffective if sufficient. It is a substance that can fully meet such demands.

  On the other hand, Patent Document 1 discloses that the immunostimulant has an effect of stimulating T cells to activate immune functions, but the ability to produce IgA produced and secreted by B cells. There is no suggestion of a substance having an action of activating.

  Moreover, although the said patent document 2 discloses that the said immunostimulatory active substance has an IgA production promotion effect | action, the effect | action which does not raise an IgA density | concentration more than necessary even if it administers to the place of a normal level IgA density | concentration That is, there is no suggestion of a substance having an IgA production homeostasis effect of promoting production when IgA is deficient, and ineffective if sufficient.

  The IgA-producing homeostatic agent of the present invention has the effect of suppressing or recovering the stress-induced decrease in IgA-producing ability that fulfills the immunity in the mucosal immune system of the intestinal mucosa of the living body and has a normal level of IgA-producing ability. Since it is sometimes ineffective, it is effective in maintaining a healthy body and maintaining a normal immune system in a modern stress society.

  Moreover, since the IgA production constanting agent of the present invention is a citrus pressed product such as Unshu mandarin or a processed product such as fruit skin, which is a familiar food material, there are few problems with regard to safety, and its action is also reduced and has side effects. There is an advantage that there are few. Therefore, it can be safely ingested by mixing with various foods or animal feeds.

Hereinafter, embodiments of the present invention will be described.
(1) IgA production constant agent The IgA production constant agent of this invention consists of citrus fruits or its processed material. Examples of citrus fruits include Wenzhou mandarin orange, Valencia orange, Navel orange, Kumquat, Ponkan, Summer mandarin orange, Sweet summer mandarin orange, Iyokan, Grapefruit, Lemon, Yuzu, Sudachi, Suruga orange, Dekopon, Zabon, Bunton and the like. Of these, particularly preferred is Satsuma mandarin.

  Citrus or processed product thereof is a citrus pressed product, that is, a juice (juice), a concentrated solution obtained by concentrating the juice, or a juice obtained by drying the juice or a concentrated solution thereof, if necessary. (Solid), pressing residue and the like. Moreover, the thing which dried the citrus peel as it is or dried, or those ground materials etc. are mentioned.

Citrus pressing residue remains after citrus juice is squeezed, and includes fiber, pectin and the like. As the pressing residue used in the present invention, the residue after squeezing may be used as it is, or a powdered product after drying may be used.
Of these, particularly preferred are citrus pressed products (juice) and fruit peels (raw products as they are, freeze-dried products, ventilation-dried products, sun-dried products, etc.).

(2) Composition for the prevention and / or treatment of stress-related diseases The composition for the prevention and / or treatment of stress-related diseases of the present invention comprises the above-mentioned IgA production constant agent comprising citrus fruits or processed products thereof as an active ingredient. Is included. As such a composition for preventing and / or treating a stress-related disease, the administration route and the dosage form are not particularly limited as long as the living body can reach a place affected by stress. Specifically, in the case of transdermal administration, skin external preparations such as cosmetics and skin external medicines may be mentioned, and in the case of oral administration, liquids or internal preparations such as foods or pharmaceuticals may be mentioned.
Examples of the composition for preventing and / or treating stress-related diseases according to the present invention include animal (livestock / poultry) or fish and shellfish feed.

  Examples of the external preparation include ointments, liquids, patches, sprays, oral preparations, liniments and the like, and the composition can be absorbed into the body by oral (transmucosal) administration or transdermal administration.

  In the case of an ointment, as an optional component other than citrus fruits or processed products thereof, those used in general ointments can be appropriately blended as necessary. For example, fat, fatty oil, lanolin, Vaseline, wax, resin, glycols, higher alcohol, glycerin, emulsifier, suspending agent and the like can be blended. Although the content rate of citrus or its processed material is not specifically limited, For example, about 0.5 to 5 weight% is good.

  In the case of a liquid preparation, as an optional component other than citrus fruits or processed products thereof, those used in general liquid preparations can be appropriately blended as necessary. For example, a preservative (methyl paraoxybenzoate, propyl paraoxybenzoate) ), Sugars, sweeteners, ethanol, fatty oils, soap, glycerin, emulsifiers, suspending agents and the like. Although the content rate of citrus or its processed material is not specifically limited, For example, about 1 to 10 weight% is good.

  In the case of a patch, as an optional ingredient other than citrus fruits or processed products thereof, those used in general patches can be appropriately blended as necessary. For example, kaolin, essential oil ingredients, l-menthol, mint Oil, eucalyptus oil, glycerin, propylene glycol, suspending agent, emulsifier, water and the like can be blended. Although the content rate of citrus or its processed material is not specifically limited, For example, about 0.5 to 5 weight% is good.

  When used as cosmetics, for example, hydrocarbons such as squalane, petrolatum, microcrystalline wax, esters such as jojoba oil, carnauba wax, octyldodecyl oleate, triglycerides such as olive oil, beef tallow, coconut oil, etc. , Fatty acids such as stearic acid, oleic acid, lithinolic acid, higher alcohols such as oleyl alcohol, stearyl alcohol, octyldodecanol, anionic surfactants such as sulfosuccinic acid ester and sodium polyoxyethylene alkyl sulfate, alkylbetaine salts, etc. Amphoteric surfactants, cationic surfactants such as dialkylammonium salts, sorbitan fatty acid esters, fatty acid monoglycerides, these polyoxyethylene adducts, polyoxyethylene alkyl ethers, poly Nonionic surfactants such as xylethylene fatty acid esters, polyhydric alcohols such as polyethylene glycol, glycerin and 1,3-butanediol, thickening / gelling agents, antioxidants, UV absorbers, colorants, preservatives , Powder and the like can be contained. Of these, polyhydric alcohols are particularly preferred. This is because, for example, when the external preparation for skin of the present invention is used during stress loading, the skin barrier function may have been lowered by stress that has already been applied. This is because the monohydric alcohol can enhance the water retention capacity of the skin and complement the skin barrier function.

  Examples of internal preparations such as foods and pharmaceuticals include solid preparations such as tablets, powders and granules, liquid preparations and semi-solid preparations, and the composition can be absorbed into the body by oral administration.

  As optional ingredients other than citrus fruits or processed products thereof, if the above-mentioned oral preparation is a food, for example, a seasoning such as a sweetening agent, salting agent, spice, acidulant, umami seasoning, emulsifying / dispersing agent, antioxidant, Preservatives, thickeners, binders, fragrances and the like can be exemplified. For pharmaceuticals, excipients, binders, disintegrants, coating agents, lubricants, extenders, diluents, pH adjusters, emulsifying / dispersing agents, stabilizers, miso odorants, coloring An agent etc. can be illustrated.

  In addition, when used as an external preparation for skin, it contains a component that suppresses inflammation, for example, non-steroidal anti-inflammatory agents such as indomethacin and bufexamac, anti-inflammatory herbal agents such as burdock root extract, birch extract and / or extracts thereof. However, it is preferable because an adverse effect of the already appearing stress can be suppressed and an additive or synergistic effect can be obtained.

  When the composition for preventing and / or treating a stress-related disease of the present invention is used as a feed, examples of the target animal or fish and shellfish include animals such as poultry and farmed fish and shellfish. More specifically, domestic animals such as pigs, cows, horses, goats, deer, rabbits, goats and sheep; chickens such as broilers and hens; poultry such as ducks, quails, ducks, turkeys, pheasants and geese; monkeys , Mice, rats, guinea pigs, etc .; yellowtail, red sea bream, puffer fish, tuna, flounder, striped mackerel, horse mackerel, salmon, coho salmon, carp, eel, rainbow trout, sweetfish, shrimp (carr shrimp, button shrimp, lobster, lobster, black Aquaculture animals such as tigers), crabs (crab crab, snow crab, blue crab, crab etc.), shellfish (abalone, turban shell etc.).

  The IgA producing and stabilizing agent of the present invention can be used in any feed as long as it is conventionally used for animals or fish and shellfish. Such feed is usually corn, bran, rice, wheat, cottonseed meal, milo, soybean meal, fish meal, defatted rice bran, fats and oils, alfalfa, calcium carbonate, calcium phosphate, sodium chloride, choline chloride, various vitamins (vitamins) A, vitamin D, vitamin E, vitamin B1, vitamin B2, vitamin B6, vitamin B12, calcium pantothenate, nicotinic acid amide, folic acid, inorganic salts (magnesium sulfate, iron sulfate, copper sulfate, zinc sulfate, potassium iodide, It is prepared by mixing a part or all of (such as cobalt sulfate).

  Major ingredients in the feed include corn, ground corn, corn flour, corn germ meal, milo, millet, oats, wheat, wheat flour, wheat germ flour, barley, rice, rye, buckwheat and other grains Cereal by-products; rice bran, bran, barley bran and other potatoes, pea seeds, peanut flour, soybeans and other legumes, potato flour and other potatoes; soybean meal, defatted soybeans, cottonseed meal, rapeseed meal , Vegetable oil meal such as sesame meal, sunflower meal, safflower meal, coco coarse powder, etc .; barley malt, beer meal, sake lees, glutamic acid fermentation meal, corn fermentation meal, corn gluten feed, corn germ meal, konjac meal Manufactured fish; fish meal, meat meal, meat and bone meal, meat meal, meat bone meal, blood meal, feather meal, skim milk powder, dried whey Animal materials such as heavy meal, krill meal, casein and gelatin; yeasts such as brewer's yeast; sugars such as corn starch and dextrin; alfalfa, dried alfalfa powder, grass powder, various leaf meals, soy protein, wheat gluten, Plant proteins such as corn zein; fine powders of inorganic substances such as crystalline cellulose, talc, silica, muscovite, zeolite; inorganic calcium compounds such as calcium carbonate; and inorganic phosphates such as calcium phosphate; Can do. If necessary, the feed may further contain other additives permitted in the livestock field (for example, other antibiotics, fungicides, anthelmintics, antioxidants, etc.).

The content of the IgA production homeostasis in the feed of the present invention is generally 0 . It is 0001 wt% to 1 wt%, preferably 0.001 wt% to 3.0 wt%. However, the content of herbs in the feed is not limited to the above amount, and depends on the type of target animal, growth stage, age, weight, environmental conditions, physical condition, type of feed material, feeding season, etc. Thus, the required amount can be appropriately selected and added and blended, and thereby the effect obtained can be adjusted.

  EXAMPLES Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited to these examples.

  In this experiment, animals that were stressed by environmental changes and overloading were used to verify the effect of stress loading on IgA production ability.

I. Experimental method <Animal used>
HOS: Hr-1 hairless mice (female, 12 weeks) were acclimated at a rate of 5 mice per cage and then used in the following 4 groups.
(1) Normal: 5 animals per cage, fed with a commercial feed and raised for 1 week.
(2) Stress: Three groups of 10 animals, 15 animals, and 20 animals per cage were given a commercial feed and raised for 1 week.

<Experimental procedure>
Commercial feed (manufacturer: Oriental Co., Ltd., trade name: normal feed “MF”) was fed to each of the four groups in the amount shown in Table 1 (Food Intake), and feces one week after the start of the experiment. The IgA concentration in the medium was measured. The IgA concentration was determined by an IgA measurement ELISA Kit.
Using.

II. Results of Experiment Table 1 shows the results of measuring the concentration of IgA in the feces of experimental animals.

  According to the result of Experiment 1, the concentration of IgA in feces is reduced by applying overstress stress (Stress). Therefore, it can be seen that the state of the intestine producing IgA is affected by the stress load, and the ability to produce IgA (intestinal immunity) is suppressed.

  In this experiment, a change in IgA production ability was examined when a test substance derived from citrus was administered to an animal that was stressed by an environmental change / overcrowding load.

I. Experimental method <test substance>
(1) Commercial feed (manufacturer: Oriental Co., Ltd., trade name: normal feed “MF”), (2) squeezed citrus juice (Juice), and (3) citrus peel (Peel) It was. The pericarp is obtained by freeze-drying and crushing (finely) the raw pericarp of Unshu mandarin.

<Animal used>
HOS: Hr-1 hairless mice (female, 12 weeks) were acclimated at a rate of 5 animals per cage and then used in the following 5 groups.
(1) Normal: 5 animals per cage, fed in the amount shown in Table 2 and bred for 1 week.
(2) Normal (Orange Juice); put 5 animals per cage, give 3% by weight of squeezed mandarin orange juice (juice) as a test substance to a commercial feed, and give it for 1 week. What you did.
(3) Control (stress): 15 animals per cage, fed commercially available feed in the amount shown in Table 2, and raised for 1 week.
(4) Orange Juice; 15 animals per cage, and 3% by weight of Satsuma mandarin pressed product (juice) added to the commercial feed as test substance, given in the amount shown in Table 2 and raised for 1 week.
(5) Orange Peel; 15 animals per cage, and 3% by weight of Satsuma mandarin peel added as a test substance to a commercial feed, fed in the amount shown in Table 2 and raised for 1 week.

<Experimental procedure>
For the five groups (1) to (5) described above, the IgA concentration in feces was measured one week after the start of the experiment (start of feeding of the test substance). The IgA concentration was determined by an IgA measurement ELISA Kit.

II. Results of Experiment Table 2 shows the results of measuring the IgA concentration in the feces of each group of animals used in the experiment and the food intake (Food Intake).

  From the above results, it can be seen that the concentration of IgA (intestinal immunity) in feces was decreased by applying overstress stress (Control (stress)). This decrease was clearly improved by ingesting peels and juices prepared from the test substance, Wenzhou mandarin (Stress (Orange Juice), Stress (Orange Peel)). On the other hand, in a state where normal stress is not applied, the IgA level does not change even when the test substance is administered (Control (Orange Juice)). That is, oral ingestion of Unshu mandarin peel or pressed product restores the IgA production ability reduced by stress to a normal state, but if the IgA production ability is at a normal level, the IgA production ability is increased more than necessary. Does not work. Therefore, the IgA production constitutive action of this test substance was recognized.

  The IgA production-stabilizing agent of the present invention has an effect of suppressing or recovering a decrease in IgA production ability, which is a cause of a decrease in intestinal immunity of a living body due to stress, and particularly when the IgA production ability is at a normal level. Does not exert the effect of. And this serves to normalize the immune system.

In addition, because it is made from familiar food materials, its action is mild, safe and has few side effects. Such an IgA-producing homeostatic agent of the present invention is expected to be very useful in the prevention and treatment of various diseases and infectious diseases associated with a decrease in intestinal immunity that is greatly affected by stress in a modern stress society. The In particular, it is expected to be useful for making livestock with high infection resistance by using it in a safe feed for animals and seafood.

Claims (6)

An IgA production constant agent comprising citrus fruits or processed products thereof. The IgA-producing constanting agent according to claim 1, wherein the citrus fruit is Satsuma mandarin. The IgA production constanting agent according to claim 1 or 2, wherein the citrus fruits or processed product thereof is a citrus pressing product. The IgA production constanting agent according to claim 1 or 2, wherein the citrus fruit or processed product thereof is a citrus peel. A composition for preventing and / or treating stress-related diseases, comprising the IgA-producing homeostatic agent according to any one of claims 1 to 4. The composition for preventing and / or treating stress-related diseases according to claim 5, wherein the composition is an animal or seafood feed.