JP2020070257A - Peptide, composition for suppressing or recovering atrophy or functional decline of salivary glands, and composition for suppressing or recovering lung atrophy or functional decline - Google Patents

Abstract

To provide novel peptides having a suppressive or recovering effect on atrophy or functional decline of organs such as salivary glands, to provide compositions for suppressing or recovering atrophy or functional decline of salivary glands, and to provide compositions for suppressing or recovering lung atrophy or functional decline.SOLUTION: Provided is a peptide consisting of an amino acid sequence of Leu-His-Lys or Leu-Leu-His-Lys or a salt thereof. Provided is a composition for suppressing or recovering atrophy or functional decline of salivary glands which contains a peptide containing a His-Lys amino acid sequence, or a salt thereof as an active ingredient.SELECTED DRAWING: None

Description

The present invention relates to a peptide or a salt thereof having an action of suppressing or recovering atrophy or functional decline of salivary glands. The present invention also relates to a composition for suppressing or recovering atrophy or functional deterioration of salivary glands and a composition for suppressing or recovering atrophy or functional deterioration of the lung.

It is known that with aging (aging, aging), the individual volume of parenchymal cells decreases or the number of parenchymal cells decreases, and tissues and organs (organs) gradually atrophy. This is called physiologic atrophy or senile atrophy. Due to such physiological atrophy of the tissue, the function of the tissue also deteriorates, which causes various symptoms and pathological conditions in the body.

For example, when the lungs atrophy, the ability to take up oxygen into the blood decreases, resulting in disorders such as shortness of breath, hypoxemia, and respiratory failure. In addition, when gland cells such as salivary glands and lacrimal glands involved in exocrine atrophy, the functions of organs composed of these cells deteriorate, and "dry mouth" (dry mouth), "dry eye" (dry eye), " Dry symptoms such as "dry nose" (nasal dryness), "dry skin" (dry skin) and "driver jain" (vaginal dryness) occur. Moreover, disorders such as chronic pancreatitis, chronic gastritis, and chronic bronchitis occur due to reduced exocrine secretion. Not only aging, but also disease may cause atrophy and functional deterioration of organs such as salivary glands and lungs.

In particular, the salivary secretion disorder caused by atrophy of the salivary glands causes the above-mentioned “dry mouth” (xerostomia). Dry mouth directly causes dry mouth and dry mouth due to decreased saliva secretion, which causes disorders such as dry mouth, dry mouth mucosa and burning sensation, but also other taste disorders and periodontal disease. It also causes caries, masticatory disorders, dysphagia, aspiration pneumonia, atrophy of digestive tract mucosa, and reflux esophagitis. It has also been pointed out that the lack of saliva increases the incidence of adult diseases (arteriosclerosis, myocardial infarction, stroke, cerebral infarction, diabetes). Therefore, salivary dysfunction is a pathological condition that is closely related not only to elderly people who are prone to aspiration pneumonia due to dysphagia, but also to maintaining good health in middle-aged and older people. As a treatment method for salivation disorders, especially dry mouth, medicines are prescribed for severe patients, but for those with relatively mild symptoms, a method using commercially available mouthwash or artificial saliva, chewing gum is used. Only symptomatic treatments such as a chewing method and a method of gradually drinking a liquid all day are performed (Non-Patent Document 1), and a drastic improvement method is desired.

Lancet 366, 321-331, 2005

Non-Patent Document 1 does not describe a peptide having an action of suppressing or restoring atrophy or functional decline of organs such as salivary glands.

An object of the present invention is to provide a novel peptide having an action of suppressing or recovering atrophy or functional decline of organs such as salivary glands. Another object of the present invention is to provide a composition for suppressing or recovering atrophy or functional deterioration of salivary glands and a composition for suppressing or recovering atrophy or functional deterioration of lungs.

The present inventors have conducted extensive studies to solve the above-mentioned problems, and as a result, a peptide containing a His-Lys (histidine-leucine) amino acid sequence or a salt thereof suppresses or restores atrophy or functional decline of salivary glands and lungs. It has been found to have an action. It has not been reported until now that a peptide containing a His-Lys amino acid sequence has an action of suppressing or restoring atrophy or functional decline of organs such as salivary glands. The present inventors have conducted further research based on such findings to complete the present invention.

That is, the present invention provides the following peptides or salts thereof, a composition for suppressing or recovering atrophy or functional decline of salivary glands, a composition for suppressing or recovering lung atrophy or functional deterioration, and the like.
[1] A peptide comprising the amino acid sequence of Leu-His-Lys or Leu-Leu-His-Lys (SEQ ID NO: 1) or a salt thereof.
[2] A composition containing the peptide according to [1] or a salt thereof.
[3] A composition for suppressing or recovering atrophy or functional decline of salivary glands, which comprises a peptide containing a His-Lys amino acid sequence or a salt thereof as an active ingredient.
[4] The composition according to the above [3], which is used for the prevention or amelioration of dry mouth or aspiration pneumonia.
[5] A composition for suppressing or recovering lung atrophy or functional decline, which comprises a peptide containing a His-Lys amino acid sequence or a salt thereof as an active ingredient.
[6] The composition according to the above [5], which is used for reduction of vital capacity, prevention or amelioration of emphysema or obstructive pulmonary disease.
[7] The composition according to any one of [3] to [6] above, wherein the peptide containing the His-Lys amino acid sequence is any of the following peptides (a) to (c).
(A) X ¹ -His-Lys-Z ¹ (X ¹ is absent, or is the n1-58th position of the amino acid sequence shown in SEQ ID NO: 2 (n1 represents any integer of 1-58) ) Is absent, or Z ¹ represents the 61st to m1st amino acid sequence (m1 represents any integer of 61 to 162) of the amino acid sequence shown in SEQ ID NO: 2. (B) an amino acid sequence represented by SEQ ID NO: 2 in which a 1-9 amino acid is deleted, substituted and / or added in a region other than the 59-60th region (C) A peptide comprising a partial sequence of the peptide of (b) above, comprising a His-Lys amino acid sequence [8] a peptide containing the His-Lys amino acid sequence De, the compositions according to any of the above comprising the amino acid sequence of His-Lys at the C-terminus [3] to [7].
[9] The peptide containing the His-Lys amino acid sequence is X ¹ -His-Lys (X ¹ is absent, or n1-58th position (n1 is 1 in the amino acid sequence shown in SEQ ID NO: 2. The composition according to any one of the above [3] to [8], which is a peptide consisting of the amino acid sequence represented by the above), which represents the amino acid sequence of any of the above).
[10] The peptide containing the His-Lys amino acid sequence is X ² -His-Lys (X ² does not exist, or the n2 to the 18th amino acids in the amino acid sequence shown in SEQ ID NO: 3 (n2 is 1 The composition according to any one of [3] to [9] above, which is a peptide consisting of the amino acid sequence represented by 1) representing the amino acid sequence of 1) to 18).
[11] The peptide containing the His-Lys amino acid sequence is a peptide consisting of the amino acid sequence of His-Lys, Leu-His-Lys or Leu-Leu-His-Lys (SEQ ID NO: 1) [3] to The composition according to any one of [10].
[12] The composition according to any one of [2] to [11] above, which is an oral composition.

According to the present invention, a novel peptide or salt thereof having an action of suppressing or recovering atrophy or functional decline of salivary glands is provided. According to the present invention, a novel peptide or a salt thereof having an action of suppressing or recovering lung atrophy or functional decline is provided. Further, according to the present invention, there is provided a composition containing a peptide or a salt thereof as an active ingredient for suppressing or recovering atrophy or functional deterioration of salivary glands, and a composition for suppressing or recovering lung atrophy or functional deterioration. To be done. The peptide or its salt used as an active ingredient in the present invention is highly safe and applicable to foods and drinks, pharmaceuticals and the like. Therefore, according to the present invention, it is possible to safely suppress or restore atrophy or functional decline of salivary glands and lungs due to aging and the like.

According to the present invention, by suppressing or recovering the atrophy of the salivary glands, the functional deterioration of the salivary glands caused by the atrophy is suppressed or recovered, and conditions or diseases caused by the functional deterioration, such as dry mouth (dry mouth), etc. It becomes possible to prevent or improve. Further, by suppressing or recovering lung atrophy, it is possible to suppress or recover the functional decline of the lungs due to the atrophy, for example, it is possible to prevent or improve conditions or diseases such as emphysema and obstructive ventilation disorders. Become. Therefore, the present invention can provide a new means that contributes to maintaining the health of the elderly and the like.

FIG. 1 is a photograph showing the results of analysis of the amount of amylase contained in the rat sublingual gland by Western blotting. FIG. 2 is a photograph showing the results of analysis of the amount of proline-rich protein contained in the rat sublingual gland by Western blotting. 3 (a) to 3 (e) are micrographs showing the results of HE staining of the rat sublingual gland (scale bar: 50 μm). 4 (a) to 4 (e) are micrographs showing the results of HE staining of the right middle lobe of the lung of a rat (scale bar: 50 μm).

The peptide of the present invention or a salt thereof is a peptide having an amino acid sequence of Leu-His-Lys or Leu-Leu-His-Lys (SEQ ID NO: 1) or a salt thereof.
The peptide salt is not particularly limited as long as it is a pharmacologically acceptable salt, and may be either an acidic salt or a basic salt. As the acid salt, for example, inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate; acetate, citrate, maleate, malate, oxalate, lactate, succinate, fumarate. Examples thereof include organic acid salts such as acid salts and propionates. Examples of the basic salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt.

The method for producing the peptide of the present invention or a salt thereof is not particularly limited. The peptide of the present invention can be produced, for example, by a known peptide synthesis method. When the peptide of the present invention is obtained by chemical synthesis, it can be synthesized by either solid phase method or liquid phase method. The peptide obtained by the synthesis can be purified by a usual purification method using reverse phase high performance liquid chromatography, ion exchange resin, chromatography using a high porous polymer resin, affinity chromatography and the like. In addition, Leu-His-Lys and the amino acid sequence shown in SEQ ID NO: 1 (Leu-Leu-His-Lys) are sequences contained in β-lactoglobulin C contained in milk of cows of Jersey, and β- It can also be produced by decomposing lactoglobulin C with an enzyme or the like. The amino acid sequence of Jersey bovine β-lactoglobulin C is shown in SEQ ID NO: 2. Salts of peptides can be readily prepared by those of skill in the art by any method known in the art. A peptide containing a His-Lys amino acid sequence other than the peptide of the present invention described below or a salt thereof can also be produced by a known peptide synthesis method or the like.

The peptide of the present invention or a salt thereof is highly safe and applicable to foods and drinks. The peptide of the present invention or a salt thereof can be used alone or in the form of a composition by blending components other than the peptide or a salt thereof, for example, as a food or drink, a pharmaceutical product, a feed or the like. Components other than the peptide of the present invention or a salt thereof can be appropriately selected depending on the form of the composition and the like. For example, components that can be used in the composition for suppressing or recovering atrophy or functional decline of salivary glands described below can be appropriately mixed. The content of the peptide of the present invention or the salt thereof in the composition is not particularly limited and may be, for example, 0.001 to 99.9% by weight. The peptide of the present invention or a salt thereof can be used, for example, for suppressing or recovering atrophy or functional decline of the salivary glands, for suppressing or recovering atrophy or functional deterioration of the lung.

It is known that the salivary glands and lung gradually atrophy with age. Atrophy of salivary glands may also occur due to salivary gland diseases and the like. Lung atrophy can also occur in lung diseases such as obstructive lung disease. When these organs are atrophied due to factors such as aging and diseases, their functions also deteriorate. In one embodiment of the present invention, the hypofunction of the salivary glands is a hypofunction resulting from atrophy of the salivary glands (accompanied by atrophy). In one aspect, the reduced lung function is a reduced function due to lung atrophy.

As shown in Examples described later, the weight of the salivary gland was higher in rats fed the peptide containing the His-Lys amino acid sequence or a salt thereof, and the amino acid of His-Lys was higher than that in the control rats. Rats fed with the peptide containing the sequence or its salt have more salivary amount, amylase and cystatin in saliva than controls, and proteins that play an important role in the function of salivary glands (for example, proline-rich protein). And cystatin) were also frequently expressed. In rats fed the peptide containing the His-Lys amino acid sequence or a salt thereof, the acinar cells of the sublingual gland were larger than those in the control. From this, the peptide containing the His-Lys amino acid sequence or a salt thereof suppressed or restored atrophy or functional decline of the salivary glands. When rats were ingested with a peptide containing a His-Lys amino acid sequence or a salt thereof, lung atrophy was suppressed or recovered, and lung functional decline was suppressed or recovered. Therefore, a peptide containing a His-Lys amino acid sequence or a salt thereof suppresses salivary gland atrophy or functional decline, and thus restores salivary atrophy or functional decline (restored salivary gland restored, reduced salivary gland function restored). Therefore, it can be used for suppression of lung atrophy or functional decline, or for recovery of lung atrophy or functional decline (recovery of atrophied lung, recovery of reduced lung function). The use of such peptides or salts thereof may be therapeutic or non-therapeutic. “Non-therapeutic” is a concept that does not include medical practice, ie, surgery, treatment or diagnosis.

As used herein, the salivary glands include the sublingual, submandibular, parotid and small salivary glands. The suppression or recovery of atrophy or hypofunction of the salivary glands may be the suppression or recovery of one or more atrophy or hypofunction of the sublingual glands, submandibular glands, parotid glands and small salivary glands, preferably sublingual glands, jaws. Suppression or recovery of atrophy or hypofunction of the parotid and parotid glands.

In the present specification, a peptide containing a His-Lys amino acid sequence is also referred to as an HK-containing peptide. The HK-containing peptide or a salt thereof can be used as an active ingredient for suppressing or restoring atrophy or functional decline of salivary glands. In addition, the HK-containing peptide or a salt thereof can be used as an active ingredient for suppressing or recovering lung atrophy or functional decline. Atrophy or functional decline of the salivary gland includes atrophy or functional decline of the salivary gland due to aging, and atrophy or functional decline of the salivary gland due to disease. Atrophy or functional decline of the lung includes atrophy or functional decline of the lung due to aging, and atrophy or functional decline of the lung due to disease. Atrophy of organs such as salivary glands due to aging (atrophy of organs caused by aging) can also be referred to as senescent atrophy. In one embodiment of the present invention, a peptide containing a His-Lys amino acid sequence or a salt thereof is for suppressing or recovering atrophy or functional decline of salivary glands due to aging, for suppressing or recovering lung atrophy or functional decline due to aging. It is preferably used for.

The composition for suppressing or recovering atrophy or functional decline of salivary glands of the present invention contains a peptide containing a His-Lys amino acid sequence (HK-containing peptide) or a salt thereof as an active ingredient. The composition for suppressing or recovering lung atrophy or functional decline of the present invention contains a peptide containing a His-Lys amino acid sequence (HK-containing peptide) or a salt thereof as an active ingredient. Hereinafter, the composition for suppressing or recovering atrophy or functional decline of the salivary glands and the composition for suppressing or recovering atrophy or functional deterioration of the lung are also collectively referred to as a composition for suppressing or recovering atrophy or functional decline. The HK-containing peptide or its salt may be used alone or in combination of two or more kinds. As the salt of the peptide, the same salts as those mentioned above can be mentioned.

The HK-containing peptide may be any peptide containing a His-Lys amino acid sequence and exerting an action of suppressing or recovering atrophy or functional decline of the salivary glands and an effect of suppressing or restoring lung atrophy or functional decline. The peptides (a) to (c) below are preferable as the HK-containing peptide from the viewpoint of obtaining the effect of suppressing or recovering the atrophy or functional decline of the salivary glands and the effect of suppressing or recovering the atrophy or functional decline of the lung when orally ingested. ..
(A) X ¹ -His-Lys-Z ¹ (X ¹ is absent, or is the n1-58th position of the amino acid sequence shown in SEQ ID NO: 2 (n1 represents any integer of 1-58) ) Is absent, or Z ¹ represents the 61st to m1st amino acid sequence (m1 represents any integer of 61 to 162) of the amino acid sequence shown in SEQ ID NO: 2. (B) an amino acid sequence represented by SEQ ID NO: 2 in which a 1-9 amino acid is deleted, substituted and / or added in a region other than the 59-60th region (C) A peptide consisting of a partial sequence of the peptide of (b) above, which is a peptide containing the His-Lys amino acid sequence, or a salt thereof, which is a peptide of (a) above. Plastid or a salt are more preferable.

In the present specification, in the amino acid sequence, 1 to 9 amino acids are deleted, substituted and / or added to mean that 1 to 9 amino acids are present in any position in the same sequence and in the amino acid sequence of 1 to 9 It means that there are amino acid deletions, substitutions and / or additions, and two or more of the deletions, substitutions and additions may occur simultaneously.
The peptide of (b) above is preferably 1-8 (more preferably 1-7, 1-6, 1-5 in the region other than the 59-60th region in the amino acid sequence shown in SEQ ID NO: 2). One or one to four, more preferably one to three, one to two or one amino acid) deleted, substituted and / or added sequences.
The peptide of (c) above is a peptide consisting of the partial sequence of (b) above and containing the His-Lys amino acid sequence.

From the viewpoint of suppressing or recovering the atrophy or functional decline of the salivary glands and suppressing or recovering the atrophy or functional deterioration of the lung, the HK-containing peptide preferably contains the His-Lys amino acid sequence at the C-terminal. For example, as a preferred embodiment of the peptide of (a), X ¹ -His-Lys (X ¹ is absent, or the n1-58th position (n1 is 1-58 of the amino acid sequence shown in SEQ ID NO: 2). A peptide consisting of the amino acid sequence represented by (representing any integer) is represented. n1 preferably represents any integer of 41 to 58. In one aspect, as the peptide of (a), X ² -His-Lys (X ² is absent, or n2 to the 18th position (n2 is 1 to 18 of the amino acid sequence shown in SEQ ID NO: 3). The peptide consisting of the amino acid sequence represented by 1) is more preferable. The amino acid sequence shown in SEQ ID NO: 3 is the 41-60th amino acid sequence of the amino acid sequence shown in SEQ ID NO: 2. Among them, the HK-containing peptide is more preferably a peptide having an amino acid sequence of His-Lys, Leu-His-Lys or Leu-Leu-His-Lys (SEQ ID NO: 1). The dipeptide having the amino acid sequence of His-Lys, the tripeptide having the amino acid sequence of Leu-His-Lys, and the tetrapeptide having the amino acid sequence of Leu-Leu-His-Lys are preferable as the HK-containing peptide. That is, as the HK-containing peptide or salt thereof, a peptide having an amino acid sequence of His-Lys, Leu-His-Lys, or Leu-Leu-His-Lys (SEQ ID NO: 1) or a salt thereof is particularly preferable.

The composition for suppressing or recovering atrophy or functional decline of the present invention can be provided in the form of, for example, food and drink (food and drink composition), pharmaceutical (pharmaceutical composition), feed (feed composition) and the like. However, the present invention is not limited to these. The composition for suppressing or recovering atrophy or functional decline of the present invention may itself be a food or drink, a pharmaceutical product, a feed or the like, or may be a preparation or a material such as an additive used therein. In one aspect, from the viewpoint that the effects of the present invention can be more sufficiently exhibited, the composition for suppressing or recovering atrophy or functional decline is preferably an oral composition, and is a food or drink or an oral drug. More preferably, it is more preferable that it is a food or drink.

The composition for suppressing or recovering atrophy or functional decline of the present invention contains, in addition to the HK-containing peptide or its salt used as an active ingredient, any additive and any ingredient as long as the effect of the present invention is not impaired. Can be included. As these additives and components, those generally usable in foods and drinks, pharmaceuticals, feeds and the like can be used.
The composition for suppressing or recovering atrophy or functional decline of the present invention can be provided in the form of an agent, for example, but is not limited to this form. The agent can be provided as a composition as it is or as a composition containing the agent.

When the composition for suppressing or recovering atrophy or functional decline of the present invention is used as a food or drink, the HK-containing peptide or a salt thereof is used as a component that can be used in the food or drink (for example, a food or drink material, if necessary, used Various foods and drinks can be prepared by blending food additives and the like). The food and drink is not particularly limited, and examples thereof include general food and drink, health foods, and raw materials thereof. The form of the food or drink is not particularly limited, and examples thereof include solid form, semi-liquid form, and liquid form. Beverages and foods include oral solid preparations such as tablets, coated tablets, fine granules, granules, powders, pills, capsules, dry syrups and chewable preparations; oral liquid preparations such as oral liquid preparations and syrups. It can also be

When the composition for suppressing or recovering atrophy or functional decline of the present invention is used as a drug, a HK-containing peptide or a salt thereof is mixed with a pharmacologically acceptable excipient or the like to obtain a drug of various dosage forms. can do. The dosage form of the drug is not particularly limited, and may be oral administration or parenteral administration. From the viewpoint of more sufficiently obtaining the effects of the present invention, the pharmaceutical dosage form is preferably oral administration. The dosage form of the drug may be a dosage form suitable for the dosage form. As a dosage form of an oral drug, for example, oral solid preparations such as tablets, coated tablets, fine granules, granules, powders, pills, capsules, dry syrups, chewables; oral liquids, syrups, etc. Liquid formulations are included. Examples of the dosage form of the drug for parenteral administration include injections, drops, ointments, lotions, patches, suppositories, nasal agents, transpulmonary agents (inhalants) and the like. The drug may be a non-human animal drug.

When the composition for suppressing or recovering atrophy or functional decline of the present invention is used as a feed, the HK-containing peptide or a salt thereof can be mixed with a component that can be used in a feed to form a feed. Examples of the feed include feed for livestock used for cattle, pigs, chickens, sheep, horses, etc .; feed for small animals used for rabbits, guinea pigs, rats, mice, etc .; pet food used for dogs, cats, birds, etc. ..
When the composition for suppressing or recovering atrophy or functional decline of the present invention is used as a food or drink, a drug, a feed, etc., its production method is not particularly limited. For example, it can be produced by a general method using the HK-containing peptide or its salt used as an active ingredient.

The content of the HK-containing peptide or its salt in the composition for suppressing or recovering atrophy or functional decline of the present invention is not particularly limited, and can be appropriately set according to its form and the like. For example, when the composition for suppressing or recovering atrophy or functional decline is used as a food or drink, a pharmaceutical product, a feed, etc., the total content of the HK-containing peptide or its salt (of the HK-containing peptide and its salt The total content) may be, for example, 0.001% by weight or more in the composition, preferably 0.01% by weight or more, and 90% by weight or less, preferably 80% by weight or less. In one aspect, the total content of HK-containing peptides or salts thereof may be, for example, 0.001 to 90% by weight, preferably 0.01 to 90% by weight in the composition for suppressing or restoring atrophy or functional decline. It can be 80% by weight.

The composition for suppressing or recovering atrophy or functional decline of the present invention can be administered or ingested by an appropriate method depending on its form, and is preferably orally administered or ingested.
The intake amount (also referred to as a dose) of the composition for suppressing or recovering atrophy or functional decline of the present invention is not particularly limited, and the effect of suppressing or recovering the atrophy or functional deterioration of the salivary glands, of the atrophy or the functional deterioration of lungs. The amount (effective amount) may be such that a suppressing or restoring effect is obtained, and may be appropriately set depending on the administration form, administration method, and the like. In one aspect, when a human (adult) is orally administered or ingested to a subject, the intake amount of the HK-containing peptide or a salt thereof is, for example, 0.1 mg to 2. 5g is preferable and 2.5mg-250mg is more preferable. It is preferable that the above amount is orally administered or ingested once a day or divided into a plurality of times (for example, 2 to 3 times). It is preferable to ingest or administer the composition for suppressing or recovering atrophy or functional decline of the present invention to a subject so that the intake amount of the HK-containing peptide or its salt falls within the above range.

The composition for suppressing or recovering atrophy or functional decline of the present invention is preferably one that is continuously ingested (administered). By continuously ingesting the HK-containing peptide or its salt, the effect of suppressing or recovering the atrophy or functional decline of the salivary glands and the effect of suppressing or recovering the atrophy or functional decline of the lungs are enhanced. In one embodiment of the present invention, the composition for suppressing or recovering atrophy or functional decline is preferably continuously ingested for 2 weeks or more, more preferably 4 weeks or more.

By administering or ingesting the HK-containing peptide or its salt, it is possible to suppress or restore the atrophy of the salivary glands. As a result, it is possible to suppress or restore the functional deterioration of the salivary glands caused by atrophy, and it is possible to prevent or improve the condition or disease caused by the functional deterioration. Examples of the functional deterioration of the salivary glands include impaired salivation and decreased stimulation response of the salivary glands. Examples of the condition or disease caused by the functional deterioration of the salivary glands include dry symptoms such as dry mouth (periodic mouth), periodontal disease, dental caries, aspiration, aspiration pneumonia and the like. In one aspect, the composition for suppressing or recovering atrophy or hypofunction of the salivary glands of the present invention, by suppressing or recovering atrophy or hypofunction of the salivary glands, to prevent or improve dry mouth or aspiration pneumonia. It is preferably used for. The composition for suppressing or recovering the atrophy or functional decline of the salivary glands of the present invention is a composition for suppressing or recovering the atrophy or functional deterioration of the salivary glands as described above, which is effective for its prevention or improvement. It is preferably used for. Prevention includes prevention of onset, delay, reduction of incidence. Improvement includes alleviation of symptoms, inhibition of progression of symptoms, and cure of symptoms.

Further, by administering or ingesting the HK-containing peptide or its salt, it is possible to suppress or restore lung atrophy. As a result, it is possible to suppress or recover the functional decline of the lung due to atrophy, and it is possible to prevent or improve the condition or disease caused by the functional decline. Examples of lung function deterioration include a decrease in the ability of the lungs to take up oxygen into the blood. The composition for suppressing or recovering lung atrophy or functional decline of the present invention is suitable for preventing or improving a condition or disease in which suppressing or recovering lung atrophy or functional deterioration is effective in its prevention or improvement. Used for. Such conditions or diseases include, for example, obstructive pulmonary disease, decreased vital capacity, emphysema, decreased ability to take oxygen into the blood due to decreased lung function, resulting in shortness of breath, hypoxemia, respiratory failure, etc. Be done. In one aspect, the composition for suppressing or recovering lung atrophy of the present invention is suitable for preventing or ameliorating a decrease in vital capacity, emphysema or obstructive pulmonary disease by suppressing or recovering lung atrophy or functional decline. Used for.

The subject to be administered or ingested the composition for suppressing or recovering atrophy or functional decline of the present invention (hereinafter, also simply referred to as an administration subject) is preferably a human or non-human animal, and a mammal (human or non-human mammal) Is more preferred, and human is even more preferred. Examples of non-human mammals include cows, pigs, sheep, horses, rabbits, dogs, cats, guinea pigs, rats, mice, monkeys, and the like. In addition, the subject of administration of the composition for suppressing or recovering atrophy or functional decline is a subject who requires or desires suppression or recovery of atrophy or functional deterioration of salivary glands, and suppression or recovery of lung atrophy or functional deterioration. Target is preferred. Since salivary glands and lungs atrophy due to aging, as an example of a preferred administration subject in the present invention, a subject requiring or wishing to suppress or recover atrophy or functional decline of salivary glands due to aging, lung atrophy or function due to aging. Examples include subjects who need or desire to suppress or recover a decrease. In one aspect, the subject is preferably an elderly person. The above-mentioned HK-containing peptide or a salt thereof is effective in suppressing or recovering atrophy or functional deterioration of the salivary glands due to aging, and in suppressing or recovering atrophy or functional deterioration of the lung due to aging. In one embodiment of the present invention, as an administration subject, an elderly person who needs or desires suppression or recovery of atrophy or functional decline of salivary glands due to aging; prevention or amelioration of xerostomia due to aging; An elderly person who needs or desires to suppress lung atrophy or functional decline due to aging; an elderly person who needs or desires to use artificial saliva is preferable.

The composition for suppressing or recovering atrophy or functional decline of the present invention has one or more of uses in packaging, containers or instructions, types of active ingredients, the above-mentioned effects, methods of use (eg, ingestion method, administration method), or the like. Two or more may be displayed. The composition for suppressing or recovering the atrophy or functional decline of the salivary glands of the present invention has an action of suppressing or recovering the atrophy or the functional decline of the salivary glands, or even with a display indicating that it has an action based on this action. Good. As such a display, for example, a display indicating that it has an action of preventing or ameliorating dry mouth (dry mouth), or that it is used to obtain the action may be attached. Further, the composition for suppressing or recovering lung atrophy or functional decline of the present invention has an action of suppressing or recovering lung atrophy or functional decline, or a display indicating that it has an action based on this action. May be. As such a display, for example, a display indicating that it has an action of preventing or ameliorating emphysema or obstructive pulmonary disease, and a display that it is used to obtain the action may be attached.

In one aspect, the composition for suppressing or recovering atrophy or hypofunction of the salivary glands of the present invention includes "prevention or improvement of dry mouth", "increasing saliva amount", "making saliva amount appropriate", etc. It may be marked. The composition for suppressing or recovering lung atrophy or functional decline of the present invention has a label such as "increase vital capacity", "for those who feel dyspnea", "for those who are concerned about lung function", etc. It may have been done. In one embodiment of the present invention, the composition for suppressing or recovering atrophy or functional decline of the present invention is preferably a food or drink with the above-mentioned function indication. Further, the display may be a display indicating that the display is used to obtain the above function.

The present invention also includes the following methods.
A method for suppressing or recovering salivary gland atrophy or functional decline, which comprises administering a peptide containing a His-Lys amino acid sequence (HK-containing peptide) or a salt thereof to a subject. A method for suppressing or recovering lung atrophy or functional decline, which comprises administering a peptide containing a His-Lys amino acid sequence or a salt thereof to a subject. A method for preventing or ameliorating xerostomia or aspiration pneumonia, which comprises administering a peptide containing a His-Lys amino acid sequence or a salt thereof to a subject. A method for preventing or ameliorating a reduction in vital capacity, emphysema or obstructive pulmonary disease, which comprises administering a peptide containing a His-Lys amino acid sequence or a salt thereof to a subject.
The HK-containing peptide or its salt, the administration subject, the administration method, the dose, and the preferred embodiments thereof are the same as those in the composition for suppressing or restoring atrophy or functional decline described above. The dose of the HK-containing peptide or a salt thereof may be an amount capable of suppressing or recovering atrophy or functional decline of salivary glands, or suppressing or recovering lung atrophy or functional decline, that is, an effective amount, in particular, Not limited. For example, it is preferable to administer the above intake. The HK-containing peptide or its salt may be administered as it is, or may be administered as a composition containing the HK-containing peptide or its salt. For example, the composition for suppressing or recovering atrophy or functional decline of the present invention described above can be administered. ADVANTAGE OF THE INVENTION According to this invention, the atrophy or functional decline of a salivary gland or a lung can be suppressed or recovered safely, and the functional decline of the salivary gland or a lung resulting from this atrophy can be suppressed or recovered. In addition, by suppressing or recovering the functional deterioration of the salivary glands or lungs, it becomes possible to prevent or improve the condition or disease caused by the functional deterioration. The above method may be a therapeutic method or a non-therapeutic method. In one aspect, salivary gland atrophy or dysfunction may be age-related salivary gland atrophy or dysfunction. The lung atrophy or dysfunction may be aging lung atrophy or dysfunction. By suppressing or recovering atrophy or functional decline of the salivary glands due to aging and the like, it becomes possible to prevent or ameliorate conditions or diseases such as dry mouth, aspiration pneumonia and the like. By suppressing or recovering lung atrophy or functional decline due to aging or the like, it becomes possible to prevent or ameliorate conditions or diseases such as a decrease in vital capacity, emphysema, and obstructive pulmonary disease.

The present invention also includes the following uses.
Use of a peptide containing a His-Lys amino acid sequence (HK-containing peptide) or a salt thereof to suppress or restore atrophy or functional decline of salivary glands. Use of a peptide containing a His-Lys amino acid sequence (HK-containing peptide) or a salt thereof to suppress or restore lung atrophy or functional decline. Use of a peptide containing a His-Lys amino acid sequence or a salt thereof for the prevention or amelioration of dry mouth or aspiration pneumonia. Use of a peptide containing a His-Lys amino acid sequence or a salt thereof for the reduction of vital capacity, the prevention or amelioration of emphysema or obstructive pulmonary disease.
The above uses are in humans or non-human animals. The use may be therapeutic or non-therapeutic. The HK-containing peptide or its salt, the subject, the method of administration, the dose, and preferred embodiments thereof are the same as those in the composition for suppressing or restoring atrophy or functional decline described above. The present invention further relates to the use of a peptide containing a His-Lys amino acid sequence or a salt thereof for producing a composition for suppressing or recovering atrophy or functional decline of salivary glands; for suppressing or recovering lung atrophy or functional deterioration. It also includes the use of a peptide containing the His-Lys amino acid sequence or a salt thereof for producing a composition. The composition for suppressing or recovering atrophy or deterioration of function and its preferred embodiments are the same as described above.

Hereinafter, examples will be described which more specifically describe the present invention. The present invention is not limited to these examples.

Animal experiments were conducted in accordance with the plan approved by the director of the institution, in compliance with the Animal Welfare Management Act and other related laws and regulations, after undergoing internal and internal animal experiment committee reviews.

<Example 1>
(1) Preparation of test sample As a test sample, the following dipeptide, tripeptide and tetrapeptide acetates were synthesized.
Acetate of dipeptide consisting of His-Lys amino acid sequence (hereinafter referred to as HK)
Acetate of tripeptide consisting of Leu-His-Lys amino acid sequence (hereinafter referred to as LHK)
Acetate of a tetrapeptide consisting of the amino acid sequence of Leu-Leu-His-Lys (SEQ ID NO: 1) (hereinafter referred to as LLHK)

(2) Experimental method LLHK prepared above is 30 mg / 30 mL, LHK is 23 mg / 30 mL, HK is dissolved in tap water to be 16 mg / 30 mL, and each test sample aqueous solution of LLHK aqueous solution, LHK aqueous solution, and HK aqueous solution is dissolved. Prepared. A 17-month-old Wistar male rat (aged rat) was added to an LLHK aqueous solution (LLHK drinking group), an LHK aqueous solution (LHK drinking group), an HK aqueous solution (HK drinking group) or tap water (water drinking group: control (aged control)). ) Was allowed to drink freely and was bred for 1 month (n = 2 for each group). During this period, both the test sample (LLHK, LHK or HK) drinking group and the water drinking group were allowed to freely ingest the same solid feed (trade name MF, manufactured by Oriental Yeast Co., Ltd.).

(2-1) Body Weight Measurement The body weight of the rat was measured before drinking the test sample (before the start of the experiment) and after drinking the test sample for 1 month. The body weight of the drinking water group was also measured before and after the start of the experiment.

(2-2) Evaluation of amount and quality of saliva (2-2-1) Measurement of amount of saliva 10 mg / day of cevimeline (manufactured by Daiichi Sankyo Co., Ltd.) was added to a rat in which a test sample or water was drunk for 1 month. After intraperitoneal administration of kg, saliva for 5 to 15 minutes after administration was sampled from the cavity with a dropper, and the total amount was measured.

(2-2-2) Measurement of amylase activity and cystatin amount in saliva Amylase activity and cystatin amount in saliva were measured according to the following methods (a) and (b).
It is known that cystatin in saliva inhibits cysteine protease, exerts an antiviral action and an antibacterial action, and suppresses the growth of periodontal disease bacteria. In addition, amylase in saliva has a digestive action in the oral cavity and a self-cleaning action of decomposing components in the food residue. Usually, these components contained in saliva are combined to maintain the original oral food intake functions (digestion function, taste) and maintenance of the oral environment (self-cleaning action, antibacterial action, anti-inflammatory action, remineralization action, Immunity, etc.) is performed in a balanced manner. Therefore, the high activity of amylase in saliva and the large amount of cystatin mean that the salivary function of salivary glands is high.
(A) Measurement of amylase activity Using the saliva collected above as a sample, the amount of amylase in the saliva was measured according to the method of Bernfeld (Methods Enzymol, 1, 149-154, 1955).
(B) Measurement of Cystatin Amount Using the saliva collected above as a sample, the amount of cystatin in saliva was measured according to the method of Abrahamson (Methods Enzymol, 244, 685-700, 1994).

(2-3) Evaluation of organ weight and quality (2-3-1) Measurement of organ weight After ingesting a test sample or water for 1 month, various organs were extracted from the rats of each group and the weight was measured. (N = 4 for each group, but n = 2 for sublingual gland and lung).

(2-3-2) Measurement of parotid gland amylase activity The amylase activity in the parotid gland homogenate extracted above was measured according to the method of Bernfeld (Methods Enzymol, 1, 149-154, 1955), and the amylase activity was measured. And

(2-3-3) Measurement of amount of cystatin in parotid gland The amount of cystatin in the extracted parotid gland homogenate was measured according to the method of Abrahamson (Methods Enzymol, 244, 685-700, 1994).

(2-3-4) Measurement of salivary gland proline-rich protein amount and amylase amount To the sublingual gland homogenate extracted above, SDS was added to a concentration of 5%, and the mixture was placed on a polyacrylamide gel, and SDS- It was subjected to PAGE. The proteins separated by this polyacrylamide gel were transferred to a nitrocellulose membrane, the nitrocellulose membrane was reacted with an anti-proline rich protein antibody and an anti-amylase antibody, and each protein was detected as a band by Western blotting.

(2-4) Measurement of gene expression The sublingual gland or lung extracted above was immediately put into RNA later (Ambion, Austin, TX, USA), and total RNA was purified by RNeasy Mini Kit (Qiagen GmbH, Hilton, Germany). ) And QIAcube (Qiagen GmbH). As for the purity of RNA, NanoDrop ND-1000 spectro (ABPbeta) photometer (NanoDrop Technologies, Inc., Wilmington, DE, USA) and Agilent 2100 Bioanalyzer (Agilent), and Agilent 2100 Bioanalyzer (Agilent), Agilent, A. It was synthesized using a Whole Transcript (WT) Expression Kit (Ambion) (Thermo Fisher Scientific). The cDNA was fragmented and labeled using the GeneChip® WT Terminal Labeling Kit (Affymetrix, Santa Clara, Calif., USA). The labeled cDNA fragments were hybridized for 17 hours at 45 ° C. using Affymetrix GeneChip® Rat Gene 2.0 ST Array (Affymetrix) and GeneChip® Hybridization Oven 640 (Affymetrix). This Array can analyze about 27,000 genes. GeneSpring GX version 12 (Agilent, Santa Clara, CA, USA) was used for the analysis.

(2-5) Hematoxylin and eosin (HE) staining of organs (2-5-1) HE staining of salivary glands After fixing the sublingual glands extracted above with formalin, paraffin-embedded sections were prepared and stained with HE, The cells were observed with a biological microscope (BX53, manufactured by Olympus Corporation) at a magnification of 10 × 20.

(2-5-2) HE Staining of Lung After fixing the right middle lobe of the lung extracted above with formalin, a paraffin-embedded section was prepared, HE-stained, and 10 × with a biological microscope (BX53, manufactured by Olympus Corporation). It was observed at a magnification of 4 times.
For comparison, sublingual glands and lungs were extracted from 20-week-old male Wistar rats (young control), and HE staining was performed by the same method as above, and observation was performed. It should be noted that 16-week-old Wistar male rats were allowed to freely ingest tap water and solid feed (trade name MF, manufactured by Oriental Yeast Co., Ltd.) and bred for 1 month, and then the young control (20-week-old). And

(3) Experimental results The experimental results are shown below. The obtained value was shown by the average value +/- standard error. The significant difference test is a test result for a water-drinking group (control), which was carried out by t-test (test with two samples assuming equal variance, p-value, one-sided test) using Excel's analysis tool (*: p <0.05, **: p <0.01).

(3-1) Body weight (effects of LLHK, LHK and HK on body weight)
Table 1 shows the body weights of the rats before the start of the experiment and after drinking the test sample (LLHK, LHK or HK) or water for 1 month (after the end of the experiment). There was no significant difference in the effect on body weight between the test sample drinking group and the water drinking group.

(3-2) Saliva Amount and Quality (3-2-1) Saliva Amount Table 2 shows the results of measuring the saliva amount of the test sample or the rat after 1 month of drinking water by the above method. Saliva volume was significantly higher in the test sample drinking group. This indicates that LLHK, LHK, and HK suppressed or restored the hypofunction of the salivary glands.

(3-2-2) Amylase activity in saliva Table 3 shows the activity of amylase contained in rat saliva one month after the test sample or drinking water. A significant increase in amylase activity was observed in the test sample drinking group compared to the water drinking group. For example, in the LLHK drinking group, about 1.8 times higher amylase activity was observed than in the water drinking group. From this, it is understood that LLHK, LHK, and HK have an action of improving saliva quality.

(3-2-3) Amount of Cystatin in Saliva Table 4 shows the amount of cystatin contained in the saliva of the rat one month after the test sample or drinking water. In the test sample group, a 3-fold or more increase in the amount of cystatin was observed as compared with the water-drinking group. From this, it is understood that LLHK, LHK, and HK have an action of improving saliva quality.

(3-3) Organ weight and quality (3-3-1) Organ weight (effects of LLHK, LHK and HK on organ weight)
Table 5 shows the weight of the rat parotid gland, submandibular gland, sublingual gland, left upper lobe and right lower lobe of the lung of the test sample or one month after drinking water. As shown in Table 5, the weights of the parotid gland, the submandibular gland, the sublingual gland, the left upper lobe of the lung, and the lower right lobe of the lung were significantly increased in the test sample drinking group as compared with the water drinking group.

The organs shown in Table 5 were heavier in the test sample drinking group than in the water drinking group. Regarding the Wistar male rats used in Example 1, it was reported that the weight of the parotid gland was 196 mg and that of the sublingual gland was 48 mg in 16-week-old young rats (Journal of Functional Foods 21, 349). -358, 2016 Table 1 Water group).
In Example 1, the weight of the parotid gland in the water-drinking rats (18 months old) was 178 ± 11 mg, which was decreased as compared with the young rats. On the other hand, in the rat (18 months old) in the LLHK drinking group, for example, the weight of the parotid gland was 244 ± 23 mg. From this, it can be said that drinking LLHK suppressed or restored atrophy of the parotid gland due to aging. In Example 1, the rat (18 months old) who drew water had a sublingual gland weight of 46 mg, which was smaller than that of the young rat. On the other hand, in a rat (18 months old) that drew the LLHK aqueous solution, the weight of the sublingual gland was 66 mg. From this, LLHK drinking suppressed or restored the atrophy of the sublingual gland due to aging. As for the submandibular gland and lung (upper left lobe and lower right lobe), drinking LLHK suppressed or restored atrophy of these organs due to aging. Drinking LHK or HK also suppressed or restored atrophy of the above organs. Therefore, it was shown that LLHK, LHK, and HK suppress or restore atrophy with age in the organs shown in Table 5.

(3-3-2) Amylase activity of parotid gland The amylase amount contained in the rat parotid gland after 1 month of test sample or water drinking is shown in Table 6 as amylase activity. The amylase activity of the test sample drinking group was higher than that of the water drinking group. For example, in the LLHK drinking group, an approximately 2-fold increase in amylase activity was observed as compared with the water drinking group. From these, it can be seen that LLHK, LHK and HK have an action of suppressing or restoring the functional decline of salivary glands.

(3-3-3) Amount of cystatin in parotid gland Table 7 shows the amount of cystatin contained in the parotid gland of rats one month after the test sample or water drinking. An increase in the amount of cystatin was observed in the test sample drinking group compared to the water drinking group. For example, in the LLHK drinking group and the LHK drinking group, the amount of cystatin was about twice as high as that in the water drinking group. From this, it is understood that LLHK, LHK, and HK have an action of suppressing or recovering the functional decline of the salivary glands.

(3-3-4) Amylase amount in salivary gland and proline-rich protein amount The result of analysis of the amount of amylase and proline-rich protein contained in the sublingual gland after one month of LLHK or water drinking by Western blotting method is shown. The photographs are shown in FIGS. 1 and 2 (FIG. 1: amylase, FIG. 2: proline-rich protein). The arrow in FIG. 1 indicates the amylase band, and the arrow in FIG. 2 indicates the proline-rich protein band. Amylase and proline-rich protein contained in the sublingual gland were increased by drinking LLHK as compared with the control (drinking by water). From this, it can be seen that LLHK has an action of suppressing or recovering the functional decline of the salivary glands.

(3-4) Gene expression level Tables 8 to 9 show the results of examining the gene expression level in the sublingual gland or lung of a rat after 1 month of drinking water or LLHK. The expression levels (relative values) shown in Tables 8 to 9 are the expression levels of each gene in the LLHK drinking group, where the expression level (average value of n = 2) of each gene in the control (water drinking group) is 1. It is a relative value of (average value of n = 2).
As a gene of a main protein specifically expressed in salivary glands (a protein that is specifically expressed in salivary glands and plays an important role in the function of salivary glands), salivary protein 1 (Spt1) (NM — 019171), proline-rich protein lacrimal gland type ( Table 8 shows the gene expression levels of Prol1) (NM — 133513), mucin-like1 (Mucl1) (XM — 006242469), cystatinS (Cyss) (NM — 198685), and lysozyme2 (Lyz2). As genes of minor proteins specifically expressed in salivary glands (proteins that are specifically expressed in salivary glands but are not important for salivary gland functions), secretoglobulin, family 1B (Scgb1b30) (NM_001100859) and immunoglobulin kappaconstan ( Table 8 shows the results of examining the gene expression level of Igkc).

Androgen-related genes in the sublingual gland (ABP beta (LOC494538) (XM_002725567), serine endopeptidase (Prostatic glandular kallikrein-6-like (LOC103690048) (XM_0087751044), kallikreinplecelaterelate)). The results of examining the amounts are shown in Table 9.
Table 9 shows the results of examining the gene expression level of serine protease (granzyme C (Gzmc) (NM — 134332)) in the lung.

Each gene shown in Table 8 is specific to salivary glands and encodes an important protein involved in its function. For example, salivary protein 1 and proline-rich protein have a protective effect on mucous membranes and teeth. Mucin-like1 has a mucosal protective action, food bolus formation, and a lubricating action. Lysozyme2 contributes to the defense of infection in the oral cavity. Therefore, an increase in the expression of these genes indicates that the hypofunction of the salivary glands was suppressed or recovered. The androgen-related gene, serine endopeptidase, and serine protease gene shown in Table 9 are genes for maintaining homeostasis. The increase in the expression levels of these genes in the sublingual gland and the lung by the ingestion of LLHK indicates that LLHK suppressed or restored the hypofunction of the salivary gland and the hypofunction of the lung.

(3-5) HE Staining of Organs (3-5-1) HE Staining of Salivary Glands FIGS. 3 (a) to 3 (e) are micrographs showing the results of HE staining the rat sublingual glands (scale bar). : 50 μm). 3 (a) to 3 (e), (a) is a young control (20-week-old rat), (b) is an old control (rat of water drinking group), (c) is a rat of LLHK drinking group, (D) is a rat in the LHK drinking group, and (e) is a rat in the HK drinking group.
In the LLHK, LHK, and HK drinking groups, the size of acinar cells increased and the connective tissue decreased compared to the control group. This means that drinking LLHK, LHK, and HK facilitates the storage of digestive enzymes and antibacterial substances by the acinar cells of the salivary glands.

(3-5-2) Hematoxylin and Eosin (HE) Staining of Lungs FIGS. 4 (a) to 4 (e) are micrographs showing the results of HE staining of the right middle lobe of the rat lung (scale bar: 50 μm). 4 (a) to (e), (a) is a young control (20-week-old rat), (b) is an old control (rat in water drinking group), (c) is a rat in LLHK drinking group, (D) is a rat in the LHK drinking group, and (e) is a rat in the HK drinking group. The white parts in FIGS. 4A to 4E are air spaces of the lungs.
With aging, the air spaces of the lungs expand and the lung surface area decreases. In the LLHK, LHK, or HK drinking group, the size of the air space was smaller and the number of tissue cells and blood vessels was larger than in the control group (aged control). This means that drinking LLHK, LHK, and HK facilitates the uptake of oxygen into the blood.

Claims (12)

A peptide comprising an amino acid sequence of Leu-His-Lys or Leu-Leu-His-Lys (SEQ ID NO: 1) or a salt thereof. A composition comprising the peptide according to claim 1 or a salt thereof. A composition for suppressing or recovering atrophy or functional decline of a salivary gland, which comprises a peptide containing a His-Lys amino acid sequence or a salt thereof as an active ingredient. The composition according to claim 3, which is used for the prevention or amelioration of dry mouth or aspiration pneumonia. A composition for suppressing or recovering lung atrophy or functional decline, which comprises a peptide containing a His-Lys amino acid sequence or a salt thereof as an active ingredient. The composition according to claim 5, which is used for reduction of vital capacity, prevention or amelioration of emphysema or obstructive pulmonary disease. The composition according to any one of claims 3 to 6, wherein the peptide containing the His-Lys amino acid sequence is any of the peptides (a) to (c) below.
(A) X ¹ -His-Lys-Z ¹ (X ¹ is absent, or is the n1-58th position of the amino acid sequence shown in SEQ ID NO: 2 (n1 represents any integer of 1-58) ) Is absent, or Z ¹ represents the 61st to m1st amino acid sequence (m1 represents any integer of 61 to 162) of the amino acid sequence shown in SEQ ID NO: 2. (B) an amino acid sequence represented by SEQ ID NO: 2 in which a 1-9 amino acid is deleted, substituted and / or added in a region other than the 59-60th region (C) A peptide comprising a partial sequence of the peptide of (b) above, comprising a His-Lys amino acid sequence The composition according to any one of claims 3 to 7, wherein the peptide containing the His-Lys amino acid sequence contains a His-Lys amino acid sequence at the C-terminus. The peptide containing the amino acid sequence of His-Lys is X ¹ -His-Lys (X ¹ is absent, or n1-58th position (n1 is 1-58 of the amino acid sequence shown in SEQ ID NO: 2). The composition according to any one of claims 3 to 8, which is a peptide consisting of an amino acid sequence represented by (representing any integer). Peptide comprising the amino acid sequence of the His-Lys ^{is, X 2 -His-Lys (X} 2 is absent, or, n2~18 th (n2 of the amino acid sequence shown in SEQ ID NO: 3, 1-18 The composition according to any one of claims 3 to 9, which is a peptide consisting of the amino acid sequence represented by (representing any integer)). The peptide containing the His-Lys amino acid sequence is a peptide having the amino acid sequence of His-Lys, Leu-His-Lys or Leu-Leu-His-Lys (SEQ ID NO: 1). The composition according to one paragraph. The composition according to any one of claims 2 to 11, which is an oral composition.

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