WO2024004931A1 - Immunomodulation composition - Google Patents
Immunomodulation composition Download PDFInfo
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- WO2024004931A1 WO2024004931A1 PCT/JP2023/023554 JP2023023554W WO2024004931A1 WO 2024004931 A1 WO2024004931 A1 WO 2024004931A1 JP 2023023554 W JP2023023554 W JP 2023023554W WO 2024004931 A1 WO2024004931 A1 WO 2024004931A1
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Classifications
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- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/17—Amino acids, peptides or proteins
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
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- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
Definitions
- the present invention relates to immunomodulatory compositions and the like.
- Macrophages are one of the important factors in the immune system. Macrophages become polarized in response to signals from the environment, such as cytokines and bacterial stimulatory components. Polarized macrophages are broadly classified into pro-inflammatory M1 type and anti-inflammatory M2 type.
- M1 type macrophages are induced by interferon- ⁇ (IFN- ⁇ ), cytokines (eg, TNF- ⁇ , GM-CSF), bacterial components (eg, lipopolysaccharide (LPS)), and the like.
- IFN- ⁇ interferon- ⁇
- cytokines eg, TNF- ⁇ , GM-CSF
- bacterial components eg, lipopolysaccharide (LPS)
- M2 type macrophages are induced by cytokines such as interleukin 4 (IL-4) and IL-13.
- M1 macrophages produce inflammatory cytokines such as TNF- ⁇ , reactive oxygen species (ROS), and the like, and play a role in biological defense against diseases such as infectious diseases as part of the immune system.
- ROS reactive oxygen species
- M1 macrophages play a negative role in chronic inflammation, autoimmune diseases, and the like.
- M2 macrophages function in anti-inflammatory responses, immune regulation, wound healing, pathogen clearance, tissue remodeling, etc.
- M1 macrophages and M2 macrophages maintain a constant balance with each other, but disruption of this balance causes various diseases. For example, excessive polarization into M1 macrophages that persists for long periods of time causes inflammatory diseases.
- Patent Document 1 describes cyclic dipeptides such as Cyclo (Gln-Lys) as immunomodulatory diketopiperazines.
- M1 macrophages When M1 macrophages are excessively activated, they excessively produce inflammatory cytokines, reactive oxygen species, etc., causing inflammatory diseases and tissue damage. Substances that have an immune (immune system) modulating effect are useful, for example, to suppress excessive activity of the immune system and return the immune system to its basal level.
- the present invention aims to provide immunomodulatory compositions.
- the present invention relates to the following immunomodulatory compositions, etc., although not limited thereto.
- An immunomodulating composition containing as an active ingredient at least one member selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro), and salts thereof.
- the immunomodulating agent according to [1] above which contains the Cyclo (Val-Pro) or a salt thereof as an active ingredient and is used to regulate immunity by regulating M1/M2 macrophage polarization. Composition.
- the immunomodulatory composition according to [1] or [2] above which is used for regulating immunity by promoting defense against reactive oxygen species in macrophages.
- an immunomodulatory composition can be provided.
- FIG. 1A, FIG. 1B, and FIG. 1C are diagrams showing the results of examining mRNA expression of M1 macrophage marker in RAW264.7 cells treated with Cyclo (Val-Pro) under lipopolysaccharide (LPS) stimulation.
- FIG. 1A shows the relative mRNA expression level of TNF- ⁇
- FIG. 1B shows the relative mRNA expression level of IL-6
- FIG. 1C shows the relative mRNA expression level of IL-1 ⁇ .
- C indicates the control group
- LPS indicates the LPS-treated group
- CVP indicates the LPS and Cyclo (Val-Pro) treated group.
- FIGS. 2A, 2B, and 2C are diagrams showing the results of examining the mRNA expression of M2 macrophage markers in RAW264.7 cells treated with Cyclo (Val-Pro) under interleukin-4 (IL-4) stimulation.
- FIG. 2A shows the relative mRNA expression level of CD206
- FIG. 2B shows the relative mRNA expression level of Arg1
- FIG. 2C shows the relative mRNA expression level of Mgl2.
- C represents the control group
- IL-4 represents the IL-4 treated group
- CVP represents the IL-4 and Cyclo (Val-Pro) treated group.
- FIGS. 3A, 3B, and 3C are diagrams showing the results of examining mRNA expression of antioxidant enzymes in RAW264.7 cells treated with Cyclo (Val-Pro) or Cyclo (Gly-Pro) under LPS stimulation.
- FIG. 3A shows the relative mRNA expression level of SOD1
- FIG. 3B shows the relative mRNA expression level of CAT
- FIG. 3C shows the relative mRNA expression level of Gpx.
- C represents the control group
- LPS represents the LPS treatment group
- CGP represents the LPS and Cyclo (Gly-Pro) treatment group
- CVP represents the LPS and Cyclo (Val-Pro) treatment group. .
- the immunomodulating composition of the present invention contains as an active ingredient at least one member selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro), and salts thereof.
- the immunoregulatory composition of the present invention may also be referred to as the composition of the present invention.
- the composition of the present invention is used for regulating immunity (immune system).
- the composition of the present invention may contain one kind of the above-mentioned compounds as an active ingredient, or may contain two or more kinds as an active ingredient.
- Cyclo(Val-Pro) (cyclovalylproline) is a cyclic dipeptide having a structure in which the amino acids valine and proline are fused together.
- Cyclo(Gly-Pro) (cycloglycylproline) is a cyclic dipeptide having a structure in which the amino acids glycine and proline are fused together.
- cyclic dipeptide is characterized by having an amino acid as a constituent unit, and has a diketopiperazine structure formed by dehydration condensation of the amino group of the N-terminal amino acid and the carboxyl group of the C-terminal amino acid. Refers to a compound that has the following.
- Cyclo(Val-Pro) and Cyclo(Pro-Val) represent the same cyclic dipeptide.
- Cyclo(Gly-Pro) and Cyclo(Pro-Gly) (cycloglycylproline) represent the same cyclic dipeptide.
- the salt of Cyclo (Val-Pro) or Cyclo (Gly-Pro) is not particularly limited as long as it is a pharmacologically acceptable salt or a salt that is acceptable for foods and drinks, and any acid salt or basic salt may be used. It may be.
- Acid salts include, for example, inorganic acid salts such as hydrochlorides, sulfates, nitrates, phosphates; acetates, citrates, maleates, malates, oxalates, lactates, succinates, fumarates; Examples include organic acid salts such as acid salts and propionate salts.
- Examples of basic salts include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts. Salts of cyclic dipeptides can be readily prepared by those skilled in the art by any method known in the art.
- Cyclo(Val-Pro), Cyclo(Gly-Pro) and their salts are not particularly limited. Cyclo (Val-Pro), Cyclo (Gly-Pro) and their salts can be produced according to known methods. Cyclo (Val-Pro), Cyclo (Gly-Pro) and their salts may be derived from natural products or may be artificially synthesized, and may be produced by an enzymatic method or a microbial fermentation method. It may be synthesized by dehydrating and cyclizing a linear dipeptide.
- a heat-treated peptide product rich in cyclic dipeptides such as Cyclo (Val-Pro) and Cyclo (Gly-Pro) can be obtained.
- Cyclo (Val-Pro), Cyclo (Gly-Pro) and their salts may be blended into a composition using a protein hydrolyzate containing them or a heat-treated product thereof, or a protein hydrolyzate or a heat-treated product thereof. Concentrates, dry powders, or highly refined heat-treated products may be used in the composition.
- composition of the present invention contains, for example, a protein hydrolyzate or a heat-treated product thereof, and at least one selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro), and salts thereof, It may be a part of a protein hydrolyzate or a heat-treated product thereof.
- Commercially available products can also be used as Cyclo (Val-Pro), Cyclo (Gly-Pro) and salts thereof.
- immunomodulation refers to adjusting the immune response from an abnormal state to a normal state, and suppressing the immune response from changing from a normal state to an abnormal state.
- Abnormal states of immune response include states of excessive immune response.
- Immunomodulation includes suppressing excessive immune responses.
- the composition of the present invention is preferably used to adjust an excessive state of immune reaction to a normal state or to suppress the state of immune reaction from a normal state to an excessive state.
- the composition of the present invention is preferably used to suppress excessive immune reactions. For example, by modulating M1/M2 macrophage polarization, immunity can be modulated. Furthermore, promoting defense against active oxygen in macrophages is also effective for immune regulation.
- the compositions of the invention can be preferably used to modulate immunity by modulating M1/M2 macrophage polarization and/or by promoting protection against reactive oxygen species in macrophages. can.
- Macrophages can be polarized (differentiated) into either M1 macrophages or M2 macrophages.
- M1 macrophages are characterized by high production of proinflammatory cytokines such as interleukin-1 (IL-1), IL-6, tumor necrosis factor- ⁇ (TNF- ⁇ ), and reactive oxygen species (ROS).
- IL-1 interleukin-1
- IL-6 tumor necrosis factor- ⁇
- ROS reactive oxygen species
- M2 macrophages can be characterized by the expression of macrophage mannose receptor type C type 1 (CD206), arginase-1 (Arg1), macrophage galactose type C lectin 2 (Mgl2), and the like.
- CD206 macrophage mannose receptor type C type 1
- Arg1 arginase-1
- Mgl2 macrophage galactose type C lectin 2
- regulation of M1/M2 macrophage polarization is promoting polarization to M2 macrophages (increase in M2 macrophages) and suppressing polarization to M1 macrophages (increase in M1 macrophages).
- effects such as maintenance of normal immune function (immune system) and wound healing can be obtained.
- Cyclo (Val-Pro) and its salts have the effect of promoting polarization into M2 macrophages (increase in M2 macrophages) and suppressing polarization into M1 macrophages (increase in M1 macrophages).
- the composition of the present invention preferably contains Cyclo (Val-Pro) or a salt thereof as an active ingredient.
- the composition of the present invention contains Cyclo (Val-Pro) or a salt thereof as an active ingredient, and is preferably used to regulate immunity by regulating M1/M2 macrophage polarization.
- the composition of the invention can be preferably used to modulate M1/M2 macrophage polarization. M2 macrophages have anti-inflammatory effects and the like.
- Cyclo (Val-Pro), Cyclo (Gly-Pro) and their salts promote the expression of antioxidant enzymes (e.g. superoxide dismutase 1 (SOD1), catalase (CAT), glutathione peroxidase (Gpx)) in macrophages. It has the effect of Cyclo (Val-Pro), Cyclo (Gly-Pro) and their salts can be used to promote the expression of antioxidant enzymes in macrophages.
- Antioxidant enzymes have the role of removing reactive oxygen species. By promoting the expression of antioxidant enzymes, it can be expected that the effect of promoting the removal of reactive oxygen species can be obtained.
- compositions of the invention are preferably used to modulate immunity by promoting protection against reactive oxygen species in macrophages.
- the composition of the present invention can be used, for example, to treat immunomodulatory disorders, conditions or diseases associated with immunoregulated disorders (e.g., conditions or diseases caused by immunoregulated disorders), or those caused by excessive immune reactions. It is useful for the prevention or amelioration of conditions or diseases. Such conditions or diseases include inflammatory diseases.
- the composition of the present invention can be used, for example, to prevent or improve inflammatory diseases such as asthma, irritable bowel syndrome, arthritis, rheumatoid arthritis, eczema, and allergies. In one embodiment, the composition of the present invention can be used to prevent or ameliorate an excessive immune response.
- prevention of a condition or disease includes preventing onset, delaying onset, reducing incidence, reducing risk of onset, and the like.
- Ameliorating a condition or disease includes recovering a subject from the condition or disease, alleviating the symptoms of the condition or disease, improving the symptoms of the condition or disease, delaying the progression of the condition or disease, or preventing the progression of the condition or disease. etc.
- compositions of the invention can be applied for either therapeutic (medical) or non-therapeutic (non-medical) uses.
- Non-therapeutic is a concept that does not include medical procedures, ie, surgery, treatment, or diagnosis of humans.
- the immunomodulatory composition of the present invention can be provided in the form of a drug, 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.
- the immunomodulatory composition of the present invention can also be referred to as an immunomodulatory agent.
- the composition of the present invention may be for oral or parenteral use.
- the composition of the invention is preferably an oral composition.
- the composition of the present invention can be in the form of, for example, a food or drink, a drug, a quasi-drug, a feed, etc., and food or drink or a drug is preferred.
- the composition of the present invention can also be used by being added to foods and drinks, pharmaceuticals, quasi-drugs, feeds, and the like.
- the form of the composition of the present invention is not particularly limited, and may be solid (for example, powder, granules, tablets, etc.), liquid, paste, or the like.
- composition of the present invention contains at least one member selected from the group consisting of Cyclo(Val-Pro), Cyclo(Gly-Pro), and salts thereof, and is further acceptable as an additive to foods, drinks, medicines, etc.
- Various diluents, acidulants, antioxidants, stabilizers, preservatives, fragrances, emulsifiers, pigments, seasonings, pH adjusters, nutritional fortifiers, etc. may be added.
- composition of the present invention when used as a food or drink, at least one selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro), and salts thereof is added as an ingredient that can be used in the food or drink.
- food materials, food additives used as needed, etc. can be blended into various foods and drinks.
- Foods and drinks are not particularly limited, and include, for example, general foods and drinks, health foods, foods with functional claims, foods for specified health uses, health supplements, foods for patients, and the like.
- the above health foods, foods with functional claims, foods for specified health uses, health supplements, etc. include various preparations such as liquids, fine granules, tablets, granules, powders, capsules, chewables, dry syrups, and liquid foods. It can be used as a form.
- composition of the present invention When the composition of the present invention is used as a drug or a quasi-drug, at least one member selected from the group consisting of Cyclo(Val-Pro), Cyclo(Gly-Pro), and salts thereof may be pharmacologically acceptable. It is possible to form various dosage forms of pharmaceuticals or quasi-drugs by blending carriers to be used, additives to be added as necessary, and the like. Such carriers, additives, etc. may be pharmacologically acceptable ones that can be used in pharmaceuticals or quasi-drugs, such as excipients, binders, disintegrants, lubricants, One or more of antioxidants, colorants, etc. may be used.
- Examples of the administration (ingestion) form of pharmaceuticals or quasi-drugs include oral or parenteral (transdermal, transmucosal, rectal, injection, etc.) administration forms.
- oral or parenteral (transdermal, transmucosal, rectal, injection, etc.) administration forms When the composition of the present invention is used as a drug or quasi-drug, it is preferably an oral drug or an oral quasi-drug.
- Dosage forms for oral administration include, for example, liquids, tablets, powders, fine granules, granules, sugar-coated tablets, capsules, suspensions, emulsions, chewables, and the like.
- dosage forms for parenteral administration include injections, drops, ointments, lotions, patches, suppositories, nasal preparations, and pulmonary preparations (inhalants).
- the drug may be a non-human veterinary drug.
- composition of the present invention When the composition of the present invention is used as feed, at least one selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro) and salts thereof may be added to the feed.
- Feed also includes feed additives. Examples of the feed include livestock feed for cows, pigs, chickens, sheep, horses, etc.; small animal feed for rabbits, rats, mice, etc.; pet foods for dogs, cats, small birds, etc.
- the manufacturing method is not particularly limited, and Cyclo (Val-Pro), Cyclo (Gly-Pro) and It can be produced by a general method using at least one selected from the group consisting of salts.
- the composition of the present invention is preferably a liquid composition, more preferably a beverage.
- the beverage may be, for example, a functional beverage.
- the form of the beverage is not particularly limited, and may be a packaged beverage.
- Containers for packaged beverages are not particularly limited, and containers of any form and material may be used; for example, metal containers such as aluminum cans and steel cans; resin containers such as plastic bottles; paper such as paper packs.
- Containers Any commonly used containers such as glass containers such as glass bottles; wooden containers such as barrels can be used.
- a packaged beverage can be obtained by filling such a container with a beverage and sealing the container.
- the content of at least one selected from the group consisting of Cyclo(Val-Pro), Cyclo(Gly-Pro) and their salts contained in the composition of the present invention is not particularly limited, and may vary depending on the form etc. Can be set.
- the total content of Cyclo(Val-Pro), Cyclo(Gly-Pro) and their salts in the composition of the present invention is preferably 0.0000001% by weight or more, and 0.000001% by weight or more, for example. is more preferable, and also preferably 99% by weight or less, and more preferably 90% by weight or less.
- the total content of Cyclo(Val-Pro), Cyclo(Gly-Pro) and their salts is preferably 0.0000001 to 99% by weight, and 0.000001 to 99% by weight, for example, in the composition of the present invention. 90% by weight is more preferred.
- Cyclo(Val-Pro), Cyclo(Gly-Pro) and their salts can be quantified by a known method, for example, by liquid chromatography mass spectrometry (LC/MS).
- the composition of the present invention is preferably taken orally (orally administered).
- the dosage (also referred to as the intake amount) of the composition of the present invention is not particularly limited.
- the dosage of the composition of the present invention may be an amount that provides an immunomodulatory effect, and may be appropriately determined depending on the dosage form, administration method, body weight of the subject, and the like.
- the dose is the sum of Cyclo(Val-Pro), Cyclo(Gly-Pro), and their salts (cyclic (dipeptide equivalent) per day, preferably 0.001 mg or more, more preferably 0.01 mg or more, even more preferably 0.1 mg or more, and preferably 50,000 mg or less, more preferably 10,000 mg or less, even more preferably is 1000 mg or less.
- the total dose (in terms of cyclic dipeptide) of Cyclo (Val-Pro), Cyclo (Gly-Pro) and their salts is , preferably 0.001 to 50,000 mg, more preferably 0.01 to 10,000 mg, and even more preferably 0.1 to 1,000 mg per day.
- the above amount is preferably taken or administered at least once a day, for example, once a day or divided into several times (for example, 2 to 3 times).
- the above amount of at least one selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro) and their salts can be ingested or administered per 60 kg of body weight per day.
- the composition of the present invention provides a human with the above amount of at least one selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro) and salts thereof per 60 kg of body weight per day. It may be an oral composition for ingesting or administering the seeds.
- cyclic dipeptide Cyclo (Val-Pro) or Cyclo (Gly-Pro)
- the expression equivalent to a cyclic dipeptide amount refers to the amount of the cyclic dipeptide.
- the cyclic dipeptide is in the form of a salt, it means the value obtained by multiplying the number of moles of the salt by the molecular weight of the corresponding cyclic dipeptide.
- the composition of the present invention be taken or administered continuously. It is expected that higher effects will be obtained by continuously ingesting or administering at least one selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro), and their salts. .
- the composition of the present invention is preferably taken or administered continuously for one week or more, more preferably for four weeks or more, even more preferably for eight weeks or more. Cyclo (Val-Pro), Cyclo (Gly-Pro) and their salts can be ingested as foods and drinks, and from the viewpoint of safety, it is thought that there are few problems with long-term ingestion, for example.
- the subject to whom the composition of the present invention is ingested or administered is not particularly limited. Preferably it is a human or non-human mammal, more preferably a human.
- the subject to whom the composition of the present invention is administered is a subject who requires or desires immunomodulation (regulation of the immune system), a subject who requires or desires prevention or amelioration of an immunoregulatory disorder, an immunoregulatory disorder.
- the subject requires or desires prevention or amelioration of a condition or disease related to.
- patients with inflammatory diseases such as asthma, irritable bowel syndrome, arthritis, rheumatoid arthritis, eczema, and allergies are preferred as subjects for administration in the present invention.
- subjects for administration in the present invention also include subjects who require or desire prevention or amelioration of excessive immune responses.
- subjects for administration in the present invention include middle-aged and elderly people.
- Middle-aged and elderly people include the elderly.
- a middle-aged person may be, for example, a person over 40 years old.
- elderly people are preferred as subjects.
- An elderly person may be, for example, a person over 60 years old or over 65 years old.
- the subject to whom the composition of the present invention is administered may be a healthy person.
- it can also be used in healthy individuals for the purpose of preventing immune dysregulation, preventing conditions or diseases associated with immunomodulatory disorders, preventing excessive immune reactions, and the like.
- the composition of the present invention may be labeled with a function exerted by regulating the immune system.
- a display is also called a functional display.
- the above display is not particularly limited.
- Such claims include, for example, "improving immunity,””strengthening immune function,””preventing inflammatory diseases,””preventingallergies,””promoting wound healing,””promoting tissue repair or regeneration,” and “clearing pathogens.””improvement” and indications or functionality indications that can be regarded as the same as these.
- the composition of the present invention is preferably a food or drink labeled with one or more of the above labels.
- the above-mentioned indication may be an indication that the above-mentioned composition is used to obtain the above-mentioned function.
- the label may be attached to the composition itself or to the container or packaging of the composition.
- the invention also encompasses the following methods and uses.
- An immunomodulation method comprising administering at least one member selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro), and salts thereof.
- the above methods may be therapeutic or non-therapeutic.
- the above uses may be therapeutic or non-therapeutic.
- At least one selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro) and salts thereof can be used to promote defense against reactive oxygen species in macrophages. At least one selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro) and salts thereof is used to regulate immunity by promoting defense against reactive oxygen species in macrophages. be able to.
- Cyclo (Val-Pro) or a salt thereof is preferably administered. In the above use, it is preferable to use Cyclo (Val-Pro) or a salt thereof. In one embodiment, Cyclo (Val-Pro) or a salt thereof can be used to modulate M1/M2 macrophage polarization. Cyclo (Val-Pro) or its salts can be preferably used to modulate immunity by modulating M1/M2 macrophage polarization. Cyclo (Val-Pro) or a salt thereof can be preferably used to promote polarization into M2 macrophages and suppress polarization into M1 macrophages.
- Cyclo (Val-Pro), Cyclo (Gly-Pro) and salts thereof are used at least once a day, for example, once to several times a day (for example, 2 to 3 times). It is preferable that at least one selected from the group is ingested or administered to a subject.
- the above uses are preferably in humans or non-human mammals, more preferably in humans.
- at least one selected from the group consisting of Cyclo(Val-Pro), Cyclo(Gly-Pro), and salts thereof is for preventing or ameliorating immune dysregulation by regulating the immune system. , can be preferably used to prevent or ameliorate conditions or diseases associated with immune dysregulation.
- a method for preventing or ameliorating an immune regulation disorder or a condition or disease associated with an immune regulation disorder comprising administering at least one member selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro), and salts thereof. Included in the present invention. In one aspect, at least one selected from the group consisting of Cyclo(Val-Pro), Cyclo(Gly-Pro), and salts thereof is preferably used to prevent or improve an excessive state of immune response. Can be done. In one embodiment, at least one selected from the group consisting of Cyclo(Val-Pro), Cyclo(Gly-Pro), and salts thereof is used to treat inflammatory diseases (e.g., asthma, irritable bowel syndrome, arthritis, rheumatoid arthritis). , eczema, allergies, etc.).
- inflammatory diseases e.g., asthma, irritable bowel syndrome, arthritis, rheumatoid arthritis.
- eczema eczema, allergies, etc.
- an effective amount of Cyclo (Val-Pro) or a salt thereof is used.
- Cyclo (Val-Pro) or a salt thereof is preferably used in an amount that promotes polarization into M2 macrophages and suppresses polarization into M1 macrophages.
- Preferred dosages, administration methods, subjects for administration, etc. of Cyclo (Val-Pro), Cyclo (Gly-Pro) and their salts are the same as those for the composition of the present invention described above.
- At least one selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro), and salts thereof may be taken or administered as is, or may be taken or administered as a composition containing it. good.
- compositions of the invention may be ingested or administered.
- At least one selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro) and their salts can be used in foods and drinks used for immunomodulation, pharmaceuticals, quasi-drugs, feeds, etc. Can be used for manufacturing.
- the present invention also encompasses the use of at least one selected from the group consisting of Cyclo(Val-Pro), Cyclo(Gly-Pro), and salts thereof in the manufacture of an immunomodulatory composition.
- At least one selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro) and salts thereof is used for the prevention or amelioration of immune regulation disorders or for the prevention or prevention of conditions or diseases associated with immune regulation disorders. It can be preferably used for the production of improving compositions.
- the numerical range expressed by a lower limit value and an upper limit value includes the lower limit value and upper limit value.
- the range represented by "1 to 2" means 1 or more and 2 or less, and includes 1 and 2.
- the upper limit and the lower limit may be any combination of ranges.
- Example 1 In the examples, the following cyclic dipeptides were used. Cyclo (Val-Pro) (Bachem, USA) Cyclo (Gly-Pro) (Bachem, USA)
- Macrophages were stimulated with lipopolysaccharide (LPS) or interleukin 4 (IL-4) (both Sigma-Aldrich, USA) to examine the effect of Cyclo (Val-Pro) on macrophage polarization. Furthermore, macrophages were stimulated with LPS, and the effects of Cyclo (Val-Pro) and Cyclo (Gly-Pro) on the expression of antioxidant enzymes in macrophages were investigated.
- LPS lipopolysaccharide
- IL-4 interleukin 4
- RAW264.7 cells were cultured for 16 hours in a medium supplemented with a cyclic dipeptide (Cyclo (Val-Pro) or Cyclo (Gly-Pro)) and LPS (LPS final concentration in medium: 1 ⁇ g/mL). After culturing, the amount of mRNA was measured by the method described below. Cells cultured in a medium to which cyclic dipeptide and LPS were not added served as a control group. In addition, cells cultured in a medium to which LPS (final concentration in medium: 1 ⁇ g/mL) was added without addition of a cyclic dipeptide were defined as an LPS treatment group.
- a cyclic dipeptide Cyclo (Val-Pro) or Cyclo (Gly-Pro)
- LPS LPS final concentration in medium: 1 ⁇ g/mL
- RAW264.7 cells were cultured for 16 hours in a medium supplemented with Cyclo (Val-Pro) and IL-4 (IL-4 final concentration in medium: 10 ng/mL). After culturing, the amount of mRNA was measured by the method described below. Cells cultured in a medium to which Cyclo (Val-Pro) and IL-4 were not added served as a control group. In addition, cells cultured in a medium to which IL-4 (final concentration in medium: 10 ng/mL) was added without Cyclo (Val-Pro) were defined as an IL-4 treated group.
- RNA concentration was assessed using a Biotek ND5000 instrument (BioTeke, Beijing, China) and cDNA was isolated using a high-capacity cDNA reverse transcriptase kit (Tsingke Co., Ltd., Beijing, China). A was synthesized. Quantitative real-time was performed on a CFX Connect Real-Time PCR System (Bio-rad, USA) using SYBR Green Real-time PCR Master Mix (Tsingke Co., Ltd., Beijing, China) as previously described. PCR was performed (Ma et al., “Bifidobacterium animalis subsp.
- the mRNA expression levels of antioxidant enzymes superoxide dismutase 1 (SOD1), catalase (CAT), and glutathione peroxidase (Gpx) were investigated.
- the sequences of the primers are shown in Table 1.
- FIG. 1 shows the results of investigating the effect of Cyclo (Val-Pro) on macrophage polarization in vitro.
- FIG. 3 shows the results of investigating the effects of Cyclo (Val-Pro) and Cyclo (Gly-Pro) on the expression of antioxidant enzymes in macrophages.
- the mRNA expression level of the marker gene was expressed as a relative amount (relative mRNA expression level) with respect to the ⁇ -actin mRNA expression level.
- FIG. 1A, FIG. 1B, and FIG. 1C are diagrams showing the results of examining the mRNA expression of M1 macrophage marker in RAW264.7 cells treated with Cyclo (Val-Pro) under LPS stimulation for 16 hours.
- FIG. 1A shows the relative mRNA expression level of TNF- ⁇
- FIG. 1B shows the relative mRNA expression level of IL-6
- FIG. 1C shows the relative mRNA expression level of IL-1 ⁇ .
- C is the control group
- LPS is the LPS treatment group
- CVP is the LPS and Cyclo (Val-Pro) treatment group.
- FIG. 2A, FIG. 2B, and FIG. 2C are diagrams showing the results of examining mRNA expression of M2 macrophage markers in RAW264.7 cells treated with Cyclo (Val-Pro) under IL-4 stimulation for 16 hours.
- FIG. 2A shows the relative mRNA expression level of CD206
- FIG. 2B shows the relative mRNA expression level of Arg1
- FIG. 2C shows the relative mRNA expression level of Mgl2.
- C is the control group
- IL-4 is the IL-4 treated group
- CVP is the IL-4 and Cyclo (Val-Pro) treated group.
- FIGS. 3A, 3B, and 3C show the results of examining mRNA expression of antioxidant enzymes in RAW264.7 cells treated with Cyclo (Val-Pro) or Cyclo (Gly-Pro) under LPS stimulation for 16 hours.
- FIG. 3A shows the relative mRNA expression level of SOD1
- FIG. 3B shows the relative mRNA expression level of CAT
- FIG. 3C shows the relative mRNA expression level of Gpx.
- C is the control group
- LPS is the LPS treatment group
- CGP is the LPS and Cyclo (Gly-Pro) treatment group
- CVP is the LPS and Cyclo (Val-Pro) treatment group. .
- FIGS. 1A, 1B and 1C, 2A, 2B and 2C, 3A, 3B and 3C data are expressed as mean ⁇ SEM. * and ** indicate significant differences with respect to the control group (*: P ⁇ 0.05, **: P ⁇ 0.01, vs control group).
- FIGS. 1A, 1B, and 1C and 3A, 3B, and 3C # and ## indicate significant differences (#: P ⁇ 0.05, ##: P ⁇ 0.01, vs. LPS treatment group).
- Figures 2A, 2B, and 2C, # and ## indicate significant differences (#: P ⁇ 0.05, ##: P ⁇ 0.01, vs IL-4 treated group). show.
- Cyclo (Val-Pro) promoted polarization into M2 macrophages (increase in the number of M2 macrophages) and exerted the effect of suppressing polarization into M1 macrophages (increase in the number of M1 macrophages).
- Cyclo(Val-Pro) and Cyclo-(Gly-Pro) increased the expression of antioxidant enzymes (SOD1, CAT, Gpx) in M1 macrophages. Increased expression of antioxidant enzymes in M1 macrophages promotes protection against reactive oxygen species in macrophages. This makes it possible to suppress excessive immune reactions. Cyclo(Val-Pro) and Cyclo-(Gly-Pro) treatments alleviated the inflammation of RAW264.7 cells induced by LPS.
- Cyclo (Val-Pro) and Cyclo (Gly-Pro) exerted strong anti-inflammatory and antioxidant effects on macrophages during immune responses. These cyclic dipeptides and their salts were found to have immunomodulatory effects.
Abstract
The purpose of the present invention is to provide an immunomodulation composition. The present invention relates to an immunomodulation composition that includes, as an active ingredient, at least one compound selected from the group that consists of Cyclo(Val-Pro), Cyclo(Gly-Pro), and salts of Cyclo(Val-Pro) and Cyclo(Gly-Pro).
Description
本発明は、免疫調節用組成物等に関する。
TECHNICAL FIELD The present invention relates to immunomodulatory compositions and the like.
マクロファージは、免疫系において重要な因子の一つである。マクロファージは、サイトカイン、細菌性の刺激成分等の環境からのシグナルに応じて分極化する。分極化したマクロファージは、大別して、炎症促進性のＭ１型と、抗炎症性のＭ２型の表現型に分類される。
Macrophages are one of the important factors in the immune system. Macrophages become polarized in response to signals from the environment, such as cytokines and bacterial stimulatory components. Polarized macrophages are broadly classified into pro-inflammatory M1 type and anti-inflammatory M2 type.
Ｍ１型のマクロファージ（Ｍ１マクロファージ）は、インターフェロンγ（ＩＦＮ－γ）、サイトカイン（例えば、ＴＮＦ－α、ＧＭ－ＣＳＦ）、細菌成分（例えば、リポ多糖（ＬＰＳ））等によって誘導される。一方、Ｍ２型のマクロファージ（Ｍ２マクロファージ）は、インターロイキン４（ＩＬ－４）、ＩＬ－１３等のサイトカインに誘導される。Ｍ１マクロファージは、ＴＮＦ－αなどの炎症性サイトカイン、活性酸素種（ＲＯＳ）等を産生し、免疫系の一部として感染症等の疾患に対する生体防御の役割を有する。一方で、Ｍ１マクロファージは、慢性炎症、自己免疫疾患等においては負の役割を果たす。Ｍ２マクロファージは、抗炎症反応、免疫調節、創傷治癒、病原体のクリアランス、組織再構成等において機能する。Ｍ１マクロファージとＭ２マクロファージは、互いに恒常的にバランスを取り合っているが、このバランスが崩れると、様々な疾患の原因となる。例えば、Ｍ１マクロファージへの分極化が過剰な形で長期間持続すると、炎症性疾患が引き起こされる。
M1 type macrophages (M1 macrophages) are induced by interferon-γ (IFN-γ), cytokines (eg, TNF-α, GM-CSF), bacterial components (eg, lipopolysaccharide (LPS)), and the like. On the other hand, M2 type macrophages (M2 macrophages) are induced by cytokines such as interleukin 4 (IL-4) and IL-13. M1 macrophages produce inflammatory cytokines such as TNF-α, reactive oxygen species (ROS), and the like, and play a role in biological defense against diseases such as infectious diseases as part of the immune system. On the other hand, M1 macrophages play a negative role in chronic inflammation, autoimmune diseases, and the like. M2 macrophages function in anti-inflammatory responses, immune regulation, wound healing, pathogen clearance, tissue remodeling, etc. M1 macrophages and M2 macrophages maintain a constant balance with each other, but disruption of this balance causes various diseases. For example, excessive polarization into M1 macrophages that persists for long periods of time causes inflammatory diseases.
ところで、環状ジペプチドは、様々な生理活性を有することが報告されている。特許文献１には、免疫調整ジケトピペラジンとして、Ｃｙｃｌｏ（Ｇｌｎ－Ｌｙｓ）等の環状ジペプチドが記載されている。
By the way, cyclic dipeptides have been reported to have various physiological activities. Patent Document 1 describes cyclic dipeptides such as Cyclo (Gln-Lys) as immunomodulatory diketopiperazines.
Ｍ１マクロファージは、過剰に活性化されると、炎症性サイトカイン、活性酸素種等を過剰に産生し、炎症性疾患及び組織の損傷を引き起こす。免疫（免疫系）調節作用を有する物質は、例えば、免疫系の過剰な活動を抑制して、免疫系を基礎レベルに戻すために有用である。
When M1 macrophages are excessively activated, they excessively produce inflammatory cytokines, reactive oxygen species, etc., causing inflammatory diseases and tissue damage. Substances that have an immune (immune system) modulating effect are useful, for example, to suppress excessive activity of the immune system and return the immune system to its basal level.
本発明は、免疫調節用組成物を提供することを目的とする。
The present invention aims to provide immunomodulatory compositions.
本発明者らは、上記課題に鑑み鋭意研究した結果、環状ジペプチドであるＣｙｃｌｏ（Ｖａｌ－Ｐｒｏ）（シクロバリルプロリン）及びＣｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）（シクログリシルプロリン）が、免疫調節作用を有することを見出した。
As a result of intensive research in view of the above problems, the present inventors found that the cyclic dipeptides Cyclo(Val-Pro) (cyclovalylproline) and Cyclo(Gly-Pro) (cycloglycylproline) have immunomodulatory effects. I discovered that.
すなわち、本発明は、これに限定されるものではないが、以下の免疫調節用組成物等に関する。
〔１〕Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩からなる群より選択される少なくとも１種を有効成分として含む、免疫調節用組成物。
〔２〕上記Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）又はその塩を有効成分として含み、Ｍ１／Ｍ２マクロファージ分極化を調節することによって免疫を調節するために使用される、上記〔１〕に記載の免疫調節用組成物。
〔３〕マクロファージにおける活性酸素種に対する防御を促進することによって、免疫を調節するために使用される、上記〔１〕又は〔２〕に記載の免疫調節用組成物。
〔４〕上記組成物が、経口組成物である、上記〔１〕～〔３〕のいずれかに記載の免疫調節用組成物。
〔５〕上記組成物が、飲食品又は医薬品である、上記〔１〕～〔４〕のいずれかに記載の免疫調節用組成物。
〔６〕免疫調節用組成物の製造における、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩からなる群より選択される少なくとも１種の使用。 That is, the present invention relates to the following immunomodulatory compositions, etc., although not limited thereto.
[1] An immunomodulating composition containing as an active ingredient at least one member selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro), and salts thereof.
[2] The immunomodulating agent according to [1] above, which contains the Cyclo (Val-Pro) or a salt thereof as an active ingredient and is used to regulate immunity by regulating M1/M2 macrophage polarization. Composition.
[3] The immunomodulatory composition according to [1] or [2] above, which is used for regulating immunity by promoting defense against reactive oxygen species in macrophages.
[4] The immunomodulating composition according to any one of [1] to [3] above, wherein the composition is an oral composition.
[5] The immunomodulating composition according to any one of [1] to [4] above, wherein the composition is a food or drink or a pharmaceutical.
[6] Use of at least one member selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro), and salts thereof in the production of an immunomodulatory composition.
〔１〕Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩からなる群より選択される少なくとも１種を有効成分として含む、免疫調節用組成物。
〔２〕上記Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）又はその塩を有効成分として含み、Ｍ１／Ｍ２マクロファージ分極化を調節することによって免疫を調節するために使用される、上記〔１〕に記載の免疫調節用組成物。
〔３〕マクロファージにおける活性酸素種に対する防御を促進することによって、免疫を調節するために使用される、上記〔１〕又は〔２〕に記載の免疫調節用組成物。
〔４〕上記組成物が、経口組成物である、上記〔１〕～〔３〕のいずれかに記載の免疫調節用組成物。
〔５〕上記組成物が、飲食品又は医薬品である、上記〔１〕～〔４〕のいずれかに記載の免疫調節用組成物。
〔６〕免疫調節用組成物の製造における、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩からなる群より選択される少なくとも１種の使用。 That is, the present invention relates to the following immunomodulatory compositions, etc., although not limited thereto.
[1] An immunomodulating composition containing as an active ingredient at least one member selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro), and salts thereof.
[2] The immunomodulating agent according to [1] above, which contains the Cyclo (Val-Pro) or a salt thereof as an active ingredient and is used to regulate immunity by regulating M1/M2 macrophage polarization. Composition.
[3] The immunomodulatory composition according to [1] or [2] above, which is used for regulating immunity by promoting defense against reactive oxygen species in macrophages.
[4] The immunomodulating composition according to any one of [1] to [3] above, wherein the composition is an oral composition.
[5] The immunomodulating composition according to any one of [1] to [4] above, wherein the composition is a food or drink or a pharmaceutical.
[6] Use of at least one member selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro), and salts thereof in the production of an immunomodulatory composition.
本発明によれば、免疫調節用組成物を提供することができる。
According to the present invention, an immunomodulatory composition can be provided.
本発明の免疫調節用組成物は、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩からなる群より選択される少なくとも１種を有効成分として含む。本明細書中、本発明の免疫調節用組成物を、本発明の組成物ということもある。本発明の組成物は、免疫（免疫系）を調節するために使用されるものである。本発明の組成物は、上記の化合物の１種を有効成分として含んでいてもよく、２種以上を有効成分として含んでいてもよい。
The immunomodulating composition of the present invention contains as an active ingredient at least one member selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro), and salts thereof. In this specification, the immunoregulatory composition of the present invention may also be referred to as the composition of the present invention. The composition of the present invention is used for regulating immunity (immune system). The composition of the present invention may contain one kind of the above-mentioned compounds as an active ingredient, or may contain two or more kinds as an active ingredient.
Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）（シクロバリルプロリン）は、アミノ酸のバリン及びプロリンが縮合結合した構造を有する環状ジペプチドである。Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）（シクログリシルプロリン）は、アミノ酸のグリシン及びプロリンが縮合結合した構造を有する環状ジペプチドである。
本明細書において「環状ジペプチド」とは、アミノ酸を構成単位とすることを特徴とし、Ｎ末端側アミノ酸のアミノ基とＣ末端側アミノ酸のカルボキシル基とが脱水縮合することにより生成したジケトピペラジン構造を有する化合物をいう。なお、本明細書において、環状ジペプチドのアミノ酸構成が同じであれば、それらの記載順序はいずれが先でも構わなく、例えば、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）とＣｙｃｌｏ（Ｐｒｏ－Ｖａｌ）（シクロプロリルバリン）とは同じ環状ジペプチドを表す。Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）とＣｙｃｌｏ（Ｐｒｏ－Ｇｌｙ）（シクログリシルプロリン）とは同じ環状ジペプチドを表す。 Cyclo(Val-Pro) (cyclovalylproline) is a cyclic dipeptide having a structure in which the amino acids valine and proline are fused together. Cyclo(Gly-Pro) (cycloglycylproline) is a cyclic dipeptide having a structure in which the amino acids glycine and proline are fused together.
As used herein, "cyclic dipeptide" is characterized by having an amino acid as a constituent unit, and has a diketopiperazine structure formed by dehydration condensation of the amino group of the N-terminal amino acid and the carboxyl group of the C-terminal amino acid. Refers to a compound that has the following. In this specification, as long as the cyclic dipeptides have the same amino acid composition, it does not matter which order they are listed first. For example, Cyclo(Val-Pro) and Cyclo(Pro-Val) (cycloprolylvaline) ) represents the same cyclic dipeptide. Cyclo(Gly-Pro) and Cyclo(Pro-Gly) (cycloglycylproline) represent the same cyclic dipeptide.
本明細書において「環状ジペプチド」とは、アミノ酸を構成単位とすることを特徴とし、Ｎ末端側アミノ酸のアミノ基とＣ末端側アミノ酸のカルボキシル基とが脱水縮合することにより生成したジケトピペラジン構造を有する化合物をいう。なお、本明細書において、環状ジペプチドのアミノ酸構成が同じであれば、それらの記載順序はいずれが先でも構わなく、例えば、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）とＣｙｃｌｏ（Ｐｒｏ－Ｖａｌ）（シクロプロリルバリン）とは同じ環状ジペプチドを表す。Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）とＣｙｃｌｏ（Ｐｒｏ－Ｇｌｙ）（シクログリシルプロリン）とは同じ環状ジペプチドを表す。 Cyclo(Val-Pro) (cyclovalylproline) is a cyclic dipeptide having a structure in which the amino acids valine and proline are fused together. Cyclo(Gly-Pro) (cycloglycylproline) is a cyclic dipeptide having a structure in which the amino acids glycine and proline are fused together.
As used herein, "cyclic dipeptide" is characterized by having an amino acid as a constituent unit, and has a diketopiperazine structure formed by dehydration condensation of the amino group of the N-terminal amino acid and the carboxyl group of the C-terminal amino acid. Refers to a compound that has the following. In this specification, as long as the cyclic dipeptides have the same amino acid composition, it does not matter which order they are listed first. For example, Cyclo(Val-Pro) and Cyclo(Pro-Val) (cycloprolylvaline) ) represents the same cyclic dipeptide. Cyclo(Gly-Pro) and Cyclo(Pro-Gly) (cycloglycylproline) represent the same cyclic dipeptide.
Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）又はＣｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）の塩としては、薬理学的に許容される塩又は飲食品に許容される塩であれば特に限定されず、酸性塩及び塩基性塩のいずれであってもよい。酸性塩として、例えば、塩酸塩、硫酸塩、硝酸塩、リン酸塩等の無機酸塩；酢酸塩、クエン酸塩、マレイン酸塩、リンゴ酸塩、シュウ酸塩、乳酸塩、コハク酸塩、フマル酸塩、プロピオン酸塩等の有機酸塩等が挙げられる。塩基性塩として、例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩；カルシウム塩、マグネシウム塩等のアルカリ土類金属塩等が挙げられる。環状ジペプチドの塩は、当該分野で公知の任意の方法により、当業者によって容易に調製され得る。
The salt of Cyclo (Val-Pro) or Cyclo (Gly-Pro) is not particularly limited as long as it is a pharmacologically acceptable salt or a salt that is acceptable for foods and drinks, and any acid salt or basic salt may be used. It may be. Acid salts include, for example, inorganic acid salts such as hydrochlorides, sulfates, nitrates, phosphates; acetates, citrates, maleates, malates, oxalates, lactates, succinates, fumarates; Examples include organic acid salts such as acid salts and propionate salts. Examples of basic salts include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts. Salts of cyclic dipeptides can be readily prepared by those skilled in the art by any method known in the art.
Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩の由来及び製造方法は特に制限されない。Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩は、公知の方法に従って製造することができる。Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩は、天然物由来のものであってもよく、人工的に合成したものであってもよく、酵素法又は微生物発酵法により製造されてもよく、直鎖状ジペプチドを脱水及び環化させることによって合成されてもよい。例えば、コラーゲン加水分解物などのタンパク質加水分解物を加熱して、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）等の環状ジペプチドを豊富に含むペプチド熱処理物を得ることができる。
Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩は、これを含むタンパク質加水分解物又はその熱処理物を使用して組成物に配合してもよいし、タンパク質加水分解物若しくはその熱処理物の濃縮物、乾燥粉末又は精製度を高めたものを使用して組成物に配合してもよい。本発明の組成物は、例えば、タンパク質加水分解物又はその熱処理物を含有し、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩からなる群より選択される少なくとも１種は、タンパク質加水分解物又はその熱処理物の一部であってもよい。Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩は、市販品を使用することもできる。 The origins and production methods of Cyclo(Val-Pro), Cyclo(Gly-Pro) and their salts are not particularly limited. Cyclo (Val-Pro), Cyclo (Gly-Pro) and their salts can be produced according to known methods. Cyclo (Val-Pro), Cyclo (Gly-Pro) and their salts may be derived from natural products or may be artificially synthesized, and may be produced by an enzymatic method or a microbial fermentation method. It may be synthesized by dehydrating and cyclizing a linear dipeptide. For example, by heating a protein hydrolyzate such as collagen hydrolyzate, a heat-treated peptide product rich in cyclic dipeptides such as Cyclo (Val-Pro) and Cyclo (Gly-Pro) can be obtained.
Cyclo (Val-Pro), Cyclo (Gly-Pro) and their salts may be blended into a composition using a protein hydrolyzate containing them or a heat-treated product thereof, or a protein hydrolyzate or a heat-treated product thereof. Concentrates, dry powders, or highly refined heat-treated products may be used in the composition. The composition of the present invention contains, for example, a protein hydrolyzate or a heat-treated product thereof, and at least one selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro), and salts thereof, It may be a part of a protein hydrolyzate or a heat-treated product thereof. Commercially available products can also be used as Cyclo (Val-Pro), Cyclo (Gly-Pro) and salts thereof.
Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩は、これを含むタンパク質加水分解物又はその熱処理物を使用して組成物に配合してもよいし、タンパク質加水分解物若しくはその熱処理物の濃縮物、乾燥粉末又は精製度を高めたものを使用して組成物に配合してもよい。本発明の組成物は、例えば、タンパク質加水分解物又はその熱処理物を含有し、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩からなる群より選択される少なくとも１種は、タンパク質加水分解物又はその熱処理物の一部であってもよい。Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩は、市販品を使用することもできる。 The origins and production methods of Cyclo(Val-Pro), Cyclo(Gly-Pro) and their salts are not particularly limited. Cyclo (Val-Pro), Cyclo (Gly-Pro) and their salts can be produced according to known methods. Cyclo (Val-Pro), Cyclo (Gly-Pro) and their salts may be derived from natural products or may be artificially synthesized, and may be produced by an enzymatic method or a microbial fermentation method. It may be synthesized by dehydrating and cyclizing a linear dipeptide. For example, by heating a protein hydrolyzate such as collagen hydrolyzate, a heat-treated peptide product rich in cyclic dipeptides such as Cyclo (Val-Pro) and Cyclo (Gly-Pro) can be obtained.
Cyclo (Val-Pro), Cyclo (Gly-Pro) and their salts may be blended into a composition using a protein hydrolyzate containing them or a heat-treated product thereof, or a protein hydrolyzate or a heat-treated product thereof. Concentrates, dry powders, or highly refined heat-treated products may be used in the composition. The composition of the present invention contains, for example, a protein hydrolyzate or a heat-treated product thereof, and at least one selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro), and salts thereof, It may be a part of a protein hydrolyzate or a heat-treated product thereof. Commercially available products can also be used as Cyclo (Val-Pro), Cyclo (Gly-Pro) and salts thereof.
本発明において、免疫調節とは、免疫反応を異常な状態から正常な状態へと調整すること、免疫反応が正常な状態から異常な状態になることを抑制することをいう。免疫反応の異常な状態には、免疫反応が過剰な状態が含まれる。免疫調節には、過剰な免疫反応を抑制することが含まれる。本発明の組成物は、免疫反応の過剰な状態を正常な状態へ調整するため、又は、免疫反応が正常な状態から過剰な状態になることを抑制するために好ましく使用される。本発明の組成物は、過剰な免疫反応を抑制するために好ましく使用される。例えば、Ｍ１／Ｍ２マクロファージ分極化を調節することによって、免疫を調節することができる。また、マクロファージにおける活性酸素に対する防御を促進することも、免疫調節に有効である。一態様において、本発明の組成物は、Ｍ１／Ｍ２マクロファージ分極化を調節することによって、及び／又は、マクロファージにおける活性酸素に対する防御を促進することによって、免疫を調節するために好ましく使用することができる。
In the present invention, immunomodulation refers to adjusting the immune response from an abnormal state to a normal state, and suppressing the immune response from changing from a normal state to an abnormal state. Abnormal states of immune response include states of excessive immune response. Immunomodulation includes suppressing excessive immune responses. The composition of the present invention is preferably used to adjust an excessive state of immune reaction to a normal state or to suppress the state of immune reaction from a normal state to an excessive state. The composition of the present invention is preferably used to suppress excessive immune reactions. For example, by modulating M1/M2 macrophage polarization, immunity can be modulated. Furthermore, promoting defense against active oxygen in macrophages is also effective for immune regulation. In one aspect, the compositions of the invention can be preferably used to modulate immunity by modulating M1/M2 macrophage polarization and/or by promoting protection against reactive oxygen species in macrophages. can.
マクロファージは、Ｍ１マクロファージ、Ｍ２マクロファージのいずれにも分極化（分化）することができる。Ｍ１マクロファージは、インターロイキン１（ＩＬ－１）、ＩＬ－６、腫瘍壊死因子－α（ＴＮＦ－α）等の炎症誘発性サイトカイン、活性酸素種（ＲＯＳ）等を高産生することによって特徴づけられる。Ｍ２マクロファージは、マクロファージマンノース受容体Ｃ型１（ＣＤ２０６）、アルギナーゼ－１（Ａｒｇ１）、マクロファージガラクトース型Ｃ型レクチン２（Ｍｇｌ２）等の発現によって特徴づけることができる。
本発明において、Ｍ１／Ｍ２マクロファージ分極化の調節は、Ｍ２マクロファージへの分極化（Ｍ２マクロファージの増加）の促進、及び、Ｍ１マクロファージへの分極化（Ｍ１マクロファージの増加）の抑制である。Ｍ１／Ｍ２マクロファージ分極化を調節することで、正常な免疫機能（免疫系）の維持、創傷治癒等の効果が得られる。 Macrophages can be polarized (differentiated) into either M1 macrophages or M2 macrophages. M1 macrophages are characterized by high production of proinflammatory cytokines such as interleukin-1 (IL-1), IL-6, tumor necrosis factor-α (TNF-α), and reactive oxygen species (ROS). . M2 macrophages can be characterized by the expression of macrophage mannose receptor type C type 1 (CD206), arginase-1 (Arg1), macrophage galactose type C lectin 2 (Mgl2), and the like.
In the present invention, regulation of M1/M2 macrophage polarization is promoting polarization to M2 macrophages (increase in M2 macrophages) and suppressing polarization to M1 macrophages (increase in M1 macrophages). By regulating M1/M2 macrophage polarization, effects such as maintenance of normal immune function (immune system) and wound healing can be obtained.
本発明において、Ｍ１／Ｍ２マクロファージ分極化の調節は、Ｍ２マクロファージへの分極化（Ｍ２マクロファージの増加）の促進、及び、Ｍ１マクロファージへの分極化（Ｍ１マクロファージの増加）の抑制である。Ｍ１／Ｍ２マクロファージ分極化を調節することで、正常な免疫機能（免疫系）の維持、創傷治癒等の効果が得られる。 Macrophages can be polarized (differentiated) into either M1 macrophages or M2 macrophages. M1 macrophages are characterized by high production of proinflammatory cytokines such as interleukin-1 (IL-1), IL-6, tumor necrosis factor-α (TNF-α), and reactive oxygen species (ROS). . M2 macrophages can be characterized by the expression of macrophage mannose receptor type C type 1 (CD206), arginase-1 (Arg1), macrophage galactose type C lectin 2 (Mgl2), and the like.
In the present invention, regulation of M1/M2 macrophage polarization is promoting polarization to M2 macrophages (increase in M2 macrophages) and suppressing polarization to M1 macrophages (increase in M1 macrophages). By regulating M1/M2 macrophage polarization, effects such as maintenance of normal immune function (immune system) and wound healing can be obtained.
Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）及びその塩は、Ｍ２マクロファージへの分極化（Ｍ２マクロファージの増加）を促進し、Ｍ１マクロファージへの分極化（Ｍ１マクロファージの増加）を抑制する作用を有する。一態様において、本発明の組成物は、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）又はその塩を有効成分として含むことが好ましい。一態様において、本発明の組成物は、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）又はその塩を有効成分として含み、Ｍ１／Ｍ２マクロファージ分極化を調節することによって免疫を調節するために使用されることが好ましい。一態様において、本発明の組成物は、Ｍ１／Ｍ２マクロファージ分極化を調節するために好ましく使用することができる。
Ｍ２マクロファージは、抗炎症作用等を有する。このため、Ｍ２マクロファージへの分極化を促進し、Ｍ１マクロファージへの分極化を抑制することによって、過剰な免疫反応を調節することができる。Ｍ２マクロファージへの分極化を促進し、Ｍ１マクロファージへの分極化を抑制することは、例えば、過剰な免疫反応を抑制し、過剰な炎症及び酸化ストレスを抑制することによって、正常な免疫機能（免疫系）を維持するために有用である。 Cyclo (Val-Pro) and its salts have the effect of promoting polarization into M2 macrophages (increase in M2 macrophages) and suppressing polarization into M1 macrophages (increase in M1 macrophages). In one embodiment, the composition of the present invention preferably contains Cyclo (Val-Pro) or a salt thereof as an active ingredient. In one embodiment, the composition of the present invention contains Cyclo (Val-Pro) or a salt thereof as an active ingredient, and is preferably used to regulate immunity by regulating M1/M2 macrophage polarization. In one aspect, the composition of the invention can be preferably used to modulate M1/M2 macrophage polarization.
M2 macrophages have anti-inflammatory effects and the like. Therefore, by promoting polarization into M2 macrophages and suppressing polarization into M1 macrophages, excessive immune reactions can be regulated. Promoting polarization into M2 macrophages and suppressing polarization into M1 macrophages can promote normal immune function (immune system).
Ｍ２マクロファージは、抗炎症作用等を有する。このため、Ｍ２マクロファージへの分極化を促進し、Ｍ１マクロファージへの分極化を抑制することによって、過剰な免疫反応を調節することができる。Ｍ２マクロファージへの分極化を促進し、Ｍ１マクロファージへの分極化を抑制することは、例えば、過剰な免疫反応を抑制し、過剰な炎症及び酸化ストレスを抑制することによって、正常な免疫機能（免疫系）を維持するために有用である。 Cyclo (Val-Pro) and its salts have the effect of promoting polarization into M2 macrophages (increase in M2 macrophages) and suppressing polarization into M1 macrophages (increase in M1 macrophages). In one embodiment, the composition of the present invention preferably contains Cyclo (Val-Pro) or a salt thereof as an active ingredient. In one embodiment, the composition of the present invention contains Cyclo (Val-Pro) or a salt thereof as an active ingredient, and is preferably used to regulate immunity by regulating M1/M2 macrophage polarization. In one aspect, the composition of the invention can be preferably used to modulate M1/M2 macrophage polarization.
M2 macrophages have anti-inflammatory effects and the like. Therefore, by promoting polarization into M2 macrophages and suppressing polarization into M1 macrophages, excessive immune reactions can be regulated. Promoting polarization into M2 macrophages and suppressing polarization into M1 macrophages can promote normal immune function (immune system).
Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩は、マクロファージにおける抗酸化酵素（例えば、スーパーオキシドジスムターゼ１（ＳＯＤ１）、カタラーゼ（ＣＡＴ）、グルタチオンペルオキシダーゼ（Ｇｐｘ））の発現を促進する作用を有する。Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩は、マクロファージにおける抗酸化酵素の発現を促進するために使用することができる。抗酸化酵素は、活性酸素種を除去する役割を有する。抗酸化酵素の発現促進によって、活性酸素種の除去を促進する効果が得られることが期待できる。
Cyclo (Val-Pro), Cyclo (Gly-Pro) and their salts promote the expression of antioxidant enzymes (e.g. superoxide dismutase 1 (SOD1), catalase (CAT), glutathione peroxidase (Gpx)) in macrophages. It has the effect of Cyclo (Val-Pro), Cyclo (Gly-Pro) and their salts can be used to promote the expression of antioxidant enzymes in macrophages. Antioxidant enzymes have the role of removing reactive oxygen species. By promoting the expression of antioxidant enzymes, it can be expected that the effect of promoting the removal of reactive oxygen species can be obtained.
抗酸化酵素の発現を促進することで、マクロファージにおける活性酸素種に対する防御を促進することができる。マクロファージにおける活性酸素種に対する防御を促進することによって、例えば、過剰な炎症又は過剰な免疫反応を抑制することができる。一態様において、本発明の組成物は、マクロファージにおける活性酸素種に対する防御を促進することによって、免疫を調節するために好ましく使用される。
Promoting the expression of antioxidant enzymes can promote defense against reactive oxygen species in macrophages. By promoting defense against reactive oxygen species in macrophages, for example, excessive inflammation or excessive immune responses can be suppressed. In one aspect, the compositions of the invention are preferably used to modulate immunity by promoting protection against reactive oxygen species in macrophages.
本発明の組成物は、免疫調節作用を有することから、例えば、免疫調節障害、免疫調節障害に関連する状態又は疾患（例えば、免疫調節障害に起因する状態又は疾患）、過剰な免疫反応に起因する状態又は疾患の予防又は改善のために有用である。このような状態又は疾患として、炎症性疾患が挙げられる。本発明の組成物は、例えば、喘息、過敏性腸症候群、関節炎、関節リウマチ、湿疹、アレルギーなどの炎症性疾患の予防又は改善のために使用することができる。一態様において、本発明の組成物は、免疫反応の過剰な状態を予防又は改善するために使用することができる。
本明細書において、状態又は疾患の予防は、発症を防止すること、発症を遅延させること、発症率を低下させること、発症のリスクを軽減すること等を包含する。状態又は疾患の改善は、対象を状態又は疾患から回復させること、状態又は疾患の症状を軽減すること、状態又は疾患の症状を好転させること、状態又は疾患の進行を遅延させること、防止すること等を包含する。 Since the composition of the present invention has an immunomodulatory effect, it can be used, for example, to treat immunomodulatory disorders, conditions or diseases associated with immunoregulated disorders (e.g., conditions or diseases caused by immunoregulated disorders), or those caused by excessive immune reactions. It is useful for the prevention or amelioration of conditions or diseases. Such conditions or diseases include inflammatory diseases. The composition of the present invention can be used, for example, to prevent or improve inflammatory diseases such as asthma, irritable bowel syndrome, arthritis, rheumatoid arthritis, eczema, and allergies. In one embodiment, the composition of the present invention can be used to prevent or ameliorate an excessive immune response.
As used herein, prevention of a condition or disease includes preventing onset, delaying onset, reducing incidence, reducing risk of onset, and the like. Ameliorating a condition or disease includes recovering a subject from the condition or disease, alleviating the symptoms of the condition or disease, improving the symptoms of the condition or disease, delaying the progression of the condition or disease, or preventing the progression of the condition or disease. etc.
本明細書において、状態又は疾患の予防は、発症を防止すること、発症を遅延させること、発症率を低下させること、発症のリスクを軽減すること等を包含する。状態又は疾患の改善は、対象を状態又は疾患から回復させること、状態又は疾患の症状を軽減すること、状態又は疾患の症状を好転させること、状態又は疾患の進行を遅延させること、防止すること等を包含する。 Since the composition of the present invention has an immunomodulatory effect, it can be used, for example, to treat immunomodulatory disorders, conditions or diseases associated with immunoregulated disorders (e.g., conditions or diseases caused by immunoregulated disorders), or those caused by excessive immune reactions. It is useful for the prevention or amelioration of conditions or diseases. Such conditions or diseases include inflammatory diseases. The composition of the present invention can be used, for example, to prevent or improve inflammatory diseases such as asthma, irritable bowel syndrome, arthritis, rheumatoid arthritis, eczema, and allergies. In one embodiment, the composition of the present invention can be used to prevent or ameliorate an excessive immune response.
As used herein, prevention of a condition or disease includes preventing onset, delaying onset, reducing incidence, reducing risk of onset, and the like. Ameliorating a condition or disease includes recovering a subject from the condition or disease, alleviating the symptoms of the condition or disease, improving the symptoms of the condition or disease, delaying the progression of the condition or disease, or preventing the progression of the condition or disease. etc.
本発明の組成物は、治療的用途（医療用途）又は非治療的用途（非医療用途）のいずれにも適用することができる。非治療的とは、医療行為、すなわち人間の手術、治療又は診断を含まない概念である。
本発明の免疫調節用組成物は、一例として、剤の形態で提供することができるが、本形態に限定されるものではない。当該剤をそのまま組成物として、又は、当該剤を含む組成物として提供することもできる。一態様において、本発明の免疫調節用組成物は、免疫調節剤ということもできる。 The compositions of the invention can be applied for either therapeutic (medical) or non-therapeutic (non-medical) uses. Non-therapeutic is a concept that does not include medical procedures, ie, surgery, treatment, or diagnosis of humans.
The immunomodulatory composition of the present invention can be provided in the form of a drug, 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. In one embodiment, the immunomodulatory composition of the present invention can also be referred to as an immunomodulatory agent.
本発明の免疫調節用組成物は、一例として、剤の形態で提供することができるが、本形態に限定されるものではない。当該剤をそのまま組成物として、又は、当該剤を含む組成物として提供することもできる。一態様において、本発明の免疫調節用組成物は、免疫調節剤ということもできる。 The compositions of the invention can be applied for either therapeutic (medical) or non-therapeutic (non-medical) uses. Non-therapeutic is a concept that does not include medical procedures, ie, surgery, treatment, or diagnosis of humans.
The immunomodulatory composition of the present invention can be provided in the form of a drug, 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. In one embodiment, the immunomodulatory composition of the present invention can also be referred to as an immunomodulatory agent.
本発明の組成物は、経口用又は非経口用のいずれであってもよい。本発明の組成物は、好ましくは経口用組成物である。本発明の組成物は、例えば、飲食品、医薬品、医薬部外品、飼料等の形態とすることができ、飲食品又は医薬品が好ましい。本発明の組成物は、飲食品、医薬品、医薬部外品、飼料等に添加して使用することもできる。本発明の組成物の形態は特に限定されず、固体状（例えば、粉末状、顆粒状、タブレット状等）、液状、ペースト状等のいずれであってもよい。
The composition of the present invention may be for oral or parenteral use. The composition of the invention is preferably an oral composition. The composition of the present invention can be in the form of, for example, a food or drink, a drug, a quasi-drug, a feed, etc., and food or drink or a drug is preferred. The composition of the present invention can also be used by being added to foods and drinks, pharmaceuticals, quasi-drugs, feeds, and the like. The form of the composition of the present invention is not particularly limited, and may be solid (for example, powder, granules, tablets, etc.), liquid, paste, or the like.
本発明の組成物は、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩からなる群より選択される少なくとも１種を含み、更に飲食品又は医薬品等への添加物として許容されている各種の希釈剤、酸味料、抗酸化剤、安定剤、保存料、香料、乳化剤、色素類、調味料、ｐＨ調整剤、栄養強化剤等が添加されていてもよい。
The composition of the present invention contains at least one member selected from the group consisting of Cyclo(Val-Pro), Cyclo(Gly-Pro), and salts thereof, and is further acceptable as an additive to foods, drinks, medicines, etc. Various diluents, acidulants, antioxidants, stabilizers, preservatives, fragrances, emulsifiers, pigments, seasonings, pH adjusters, nutritional fortifiers, etc. may be added.
例えば、本発明の組成物を飲食品とする場合、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩からなる群より選択される少なくとも１種に、飲食品に使用可能な成分（例えば、食品素材、必要に応じて使用される食品添加物等）を配合して、種々の飲食品とすることができる。飲食品は特に限定されず、例えば、一般的な飲食品、健康食品、機能性表示食品、特定保健用食品、健康補助食品、病者用食品等が挙げられる。上記健康食品、機能性表示食品、特定保健用食品、健康補助食品等は、例えば、液剤、細粒剤、錠剤、顆粒剤、散剤、カプセル剤、チュアブル剤、ドライシロップ剤、流動食等の各種製剤形態として使用することができる。
For example, when the composition of the present invention is used as a food or drink, at least one selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro), and salts thereof is added as an ingredient that can be used in the food or drink. (For example, food materials, food additives used as needed, etc.) can be blended into various foods and drinks. Foods and drinks are not particularly limited, and include, for example, general foods and drinks, health foods, foods with functional claims, foods for specified health uses, health supplements, foods for patients, and the like. The above health foods, foods with functional claims, foods for specified health uses, health supplements, etc. include various preparations such as liquids, fine granules, tablets, granules, powders, capsules, chewables, dry syrups, and liquid foods. It can be used as a form.
本発明の組成物を医薬品又は医薬部外品とする場合、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩からなる群より選択される少なくとも１種に、薬理学的に許容される担体、必要に応じて添加される添加剤等を配合して、各種剤形の医薬品又は医薬部外品とすることができる。そのような担体、添加剤等は、医薬品又は医薬部外品に使用可能な、薬理学的に許容されるものであればよく、例えば、賦形剤、結合剤、崩壊剤、滑沢剤、抗酸化剤、着色剤等の１又は２以上が挙げられる。医薬品又は医薬部外品の投与（摂取）形態としては、経口又は非経口（経皮、経粘膜、経腸、注射等）投与の形態が挙げられる。本発明の組成物を医薬品又は医薬部外品とする場合、経口用医薬品又は経口用医薬部外品とすることが好ましい。経口投与のための剤形としては、例えば、液剤、錠剤、散剤、細粒剤、顆粒剤、糖衣錠、カプセル剤、懸濁液、乳剤、チュアブル剤等が挙げられる。非経口投与のための剤形としては、例えば、注射剤、点滴剤、軟膏剤、ローション剤、貼付剤、坐剤、経鼻剤、経肺剤（吸入剤）等が挙げられる。医薬品は、非ヒト動物用医薬であってもよい。
When the composition of the present invention is used as a drug or a quasi-drug, at least one member selected from the group consisting of Cyclo(Val-Pro), Cyclo(Gly-Pro), and salts thereof may be pharmacologically acceptable. It is possible to form various dosage forms of pharmaceuticals or quasi-drugs by blending carriers to be used, additives to be added as necessary, and the like. Such carriers, additives, etc. may be pharmacologically acceptable ones that can be used in pharmaceuticals or quasi-drugs, such as excipients, binders, disintegrants, lubricants, One or more of antioxidants, colorants, etc. may be used. Examples of the administration (ingestion) form of pharmaceuticals or quasi-drugs include oral or parenteral (transdermal, transmucosal, rectal, injection, etc.) administration forms. When the composition of the present invention is used as a drug or quasi-drug, it is preferably an oral drug or an oral quasi-drug. Dosage forms for oral administration include, for example, liquids, tablets, powders, fine granules, granules, sugar-coated tablets, capsules, suspensions, emulsions, chewables, and the like. Examples of dosage forms for parenteral administration include injections, drops, ointments, lotions, patches, suppositories, nasal preparations, and pulmonary preparations (inhalants). The drug may be a non-human veterinary drug.
本発明の組成物を飼料とする場合には、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩からなる群より選択される少なくとも１種を飼料に配合すればよい。飼料には飼料添加剤も含まれる。飼料としては、例えば、牛、豚、鶏、羊、馬等に用いる家畜用飼料；ウサギ、ラット、マウス等に用いる小動物用飼料；犬、猫、小鳥等に用いるペットフードなどが挙げられる。
When the composition of the present invention is used as feed, at least one selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro) and salts thereof may be added to the feed. Feed also includes feed additives. Examples of the feed include livestock feed for cows, pigs, chickens, sheep, horses, etc.; small animal feed for rabbits, rats, mice, etc.; pet foods for dogs, cats, small birds, etc.
本発明の組成物を、例えば、飲食品、医薬品、医薬部外品、飼料等とする場合、その製造方法は特に限定されず、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩からなる群より選択される少なくとも１種を用いて、一般的な方法により製造することができる。
When the composition of the present invention is used, for example, as a food or drink, a drug, a quasi-drug, a feed, etc., the manufacturing method is not particularly limited, and Cyclo (Val-Pro), Cyclo (Gly-Pro) and It can be produced by a general method using at least one selected from the group consisting of salts.
一態様において、本発明の組成物は、液状組成物であることが好ましく、飲料であることがより好ましい。飲料は、例えば、機能性飲料であってよい。飲料の形態は特に限定されず、容器詰飲料であってよい。容器詰飲料の容器は特に限定されず、いずれの形態及び材質の容器を用いてもよく、例えば、アルミ缶、スチール缶等の金属製容器；ペットボトル等の樹脂製容器；紙パック等の紙容器；ガラス瓶等のガラス製容器；樽等の木製容器等の通常用いられる容器のいずれも用いることができる。このような容器に飲料を充填及び密閉することにより、容器詰飲料が得られる。
In one embodiment, the composition of the present invention is preferably a liquid composition, more preferably a beverage. The beverage may be, for example, a functional beverage. The form of the beverage is not particularly limited, and may be a packaged beverage. Containers for packaged beverages are not particularly limited, and containers of any form and material may be used; for example, metal containers such as aluminum cans and steel cans; resin containers such as plastic bottles; paper such as paper packs. Containers: Any commonly used containers such as glass containers such as glass bottles; wooden containers such as barrels can be used. A packaged beverage can be obtained by filling such a container with a beverage and sealing the container.
本発明の組成物に含まれるＣｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩からなる群より選択される少なくとも１種の含有量は特に限定されず、その形態等に応じて設定することができる。
一態様において、本発明の組成物におけるＣｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩の合計含有量は、例えば、０．００００００１重量％以上が好ましく、０．０００００１重量％以上がより好ましく、また、９９重量％以下が好ましく、９０重量％以下がより好ましい。一態様において、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩の合計含有量は、例えば、本発明の組成物中に０．００００００１～９９重量％が好ましく、０．０００００１～９０重量％がより好ましい。
Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩は、例えば、液体クロマトグラフィー質量分析法（ＬＣ／ＭＳ）により公知の方法で定量することが可能である。 The content of at least one selected from the group consisting of Cyclo(Val-Pro), Cyclo(Gly-Pro) and their salts contained in the composition of the present invention is not particularly limited, and may vary depending on the form etc. Can be set.
In one aspect, the total content of Cyclo(Val-Pro), Cyclo(Gly-Pro) and their salts in the composition of the present invention is preferably 0.0000001% by weight or more, and 0.000001% by weight or more, for example. is more preferable, and also preferably 99% by weight or less, and more preferably 90% by weight or less. In one embodiment, the total content of Cyclo(Val-Pro), Cyclo(Gly-Pro) and their salts is preferably 0.0000001 to 99% by weight, and 0.000001 to 99% by weight, for example, in the composition of the present invention. 90% by weight is more preferred.
Cyclo(Val-Pro), Cyclo(Gly-Pro) and their salts can be quantified by a known method, for example, by liquid chromatography mass spectrometry (LC/MS).
一態様において、本発明の組成物におけるＣｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩の合計含有量は、例えば、０．００００００１重量％以上が好ましく、０．０００００１重量％以上がより好ましく、また、９９重量％以下が好ましく、９０重量％以下がより好ましい。一態様において、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩の合計含有量は、例えば、本発明の組成物中に０．００００００１～９９重量％が好ましく、０．０００００１～９０重量％がより好ましい。
Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩は、例えば、液体クロマトグラフィー質量分析法（ＬＣ／ＭＳ）により公知の方法で定量することが可能である。 The content of at least one selected from the group consisting of Cyclo(Val-Pro), Cyclo(Gly-Pro) and their salts contained in the composition of the present invention is not particularly limited, and may vary depending on the form etc. Can be set.
In one aspect, the total content of Cyclo(Val-Pro), Cyclo(Gly-Pro) and their salts in the composition of the present invention is preferably 0.0000001% by weight or more, and 0.000001% by weight or more, for example. is more preferable, and also preferably 99% by weight or less, and more preferably 90% by weight or less. In one embodiment, the total content of Cyclo(Val-Pro), Cyclo(Gly-Pro) and their salts is preferably 0.0000001 to 99% by weight, and 0.000001 to 99% by weight, for example, in the composition of the present invention. 90% by weight is more preferred.
Cyclo(Val-Pro), Cyclo(Gly-Pro) and their salts can be quantified by a known method, for example, by liquid chromatography mass spectrometry (LC/MS).
本発明の組成物は、経口で摂取（経口投与）されることが好ましい。本発明の組成物の投与量（摂取量ということもできる）は特に限定されない。本発明の組成物の投与量は、免疫調節効果が得られるような量であればよく、投与形態、投与方法、対象の体重等に応じて適宜設定すればよい。
The composition of the present invention is preferably taken orally (orally administered). The dosage (also referred to as the intake amount) of the composition of the present invention is not particularly limited. The dosage of the composition of the present invention may be an amount that provides an immunomodulatory effect, and may be appropriately determined depending on the dosage form, administration method, body weight of the subject, and the like.
一態様において、本発明の組成物をヒト（成人）を対象に摂取させる又は投与する場合、その投与量は、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩の合計（環状ジペプチド換算）の投与量として、１日あたり、好ましくは０．００１ｍｇ以上、より好ましくは０．０１ｍｇ以上、さらに好ましくは０．１ｍｇ以上、また、好ましくは５００００ｍｇ以下、より好ましくは１００００ｍｇ以下、さらに好ましくは１０００ｍｇ以下である。一態様において、本発明の組成物をヒト（成人）に摂取させる又は投与する場合、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩の合計（環状ジペプチド換算）の投与量として、１日あたり、好ましくは０．００１～５００００ｍｇ、より好ましくは０．０１～１００００ｍｇ、さらに好ましくは０．１～１０００ｍｇである。
上記量を、１日１回以上、例えば、１日１回で又は数回（例えば２～３回）に分けて、摂取又は投与することが好ましい。一態様においては、上記量のＣｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩からなる群より選択される少なくとも１種を、経口で摂取させる又は投与することが好ましい。ヒト（成人）の場合、１日当たり体重６０ｋｇ当たり上記量のＣｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩からなる群より選択される少なくとも１種を摂取させる又は投与することが好ましい。一態様において、本発明の組成物は、ヒトに、体重６０ｋｇあたり、１日あたり上記量のＣｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩からなる群より選択される少なくとも１種を摂取させる又は投与するための経口用組成物であってよい。
本明細書中、環状ジペプチド換算の量、又はこれに類する表現は、環状ジペプチド（Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）又はＣｙｃｌｏ（Ｇｌｙ－Ｐｒｏ））の場合は、当該環状ジペプチドの量を指す。環状ジペプチドが塩の形態である場合は、当該塩のモル数に、対応する環状ジペプチドの分子量を乗じて得られる値を意味する。 In one aspect, when the composition of the present invention is ingested or administered to a human (adult) subject, the dose is the sum of Cyclo(Val-Pro), Cyclo(Gly-Pro), and their salts (cyclic (dipeptide equivalent) per day, preferably 0.001 mg or more, more preferably 0.01 mg or more, even more preferably 0.1 mg or more, and preferably 50,000 mg or less, more preferably 10,000 mg or less, even more preferably is 1000 mg or less. In one aspect, when the composition of the present invention is ingested or administered to humans (adults), the total dose (in terms of cyclic dipeptide) of Cyclo (Val-Pro), Cyclo (Gly-Pro) and their salts is , preferably 0.001 to 50,000 mg, more preferably 0.01 to 10,000 mg, and even more preferably 0.1 to 1,000 mg per day.
The above amount is preferably taken or administered at least once a day, for example, once a day or divided into several times (for example, 2 to 3 times). In one embodiment, it is preferable to orally ingest or administer at least one selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro), and salts thereof in the above amount. In the case of humans (adults), the above amount of at least one selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro) and their salts can be ingested or administered per 60 kg of body weight per day. preferable. In one embodiment, the composition of the present invention provides a human with the above amount of at least one selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro) and salts thereof per 60 kg of body weight per day. It may be an oral composition for ingesting or administering the seeds.
In the present specification, in the case of a cyclic dipeptide (Cyclo (Val-Pro) or Cyclo (Gly-Pro)), the expression equivalent to a cyclic dipeptide amount refers to the amount of the cyclic dipeptide. When the cyclic dipeptide is in the form of a salt, it means the value obtained by multiplying the number of moles of the salt by the molecular weight of the corresponding cyclic dipeptide.
上記量を、１日１回以上、例えば、１日１回で又は数回（例えば２～３回）に分けて、摂取又は投与することが好ましい。一態様においては、上記量のＣｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩からなる群より選択される少なくとも１種を、経口で摂取させる又は投与することが好ましい。ヒト（成人）の場合、１日当たり体重６０ｋｇ当たり上記量のＣｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩からなる群より選択される少なくとも１種を摂取させる又は投与することが好ましい。一態様において、本発明の組成物は、ヒトに、体重６０ｋｇあたり、１日あたり上記量のＣｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩からなる群より選択される少なくとも１種を摂取させる又は投与するための経口用組成物であってよい。
本明細書中、環状ジペプチド換算の量、又はこれに類する表現は、環状ジペプチド（Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）又はＣｙｃｌｏ（Ｇｌｙ－Ｐｒｏ））の場合は、当該環状ジペプチドの量を指す。環状ジペプチドが塩の形態である場合は、当該塩のモル数に、対応する環状ジペプチドの分子量を乗じて得られる値を意味する。 In one aspect, when the composition of the present invention is ingested or administered to a human (adult) subject, the dose is the sum of Cyclo(Val-Pro), Cyclo(Gly-Pro), and their salts (cyclic (dipeptide equivalent) per day, preferably 0.001 mg or more, more preferably 0.01 mg or more, even more preferably 0.1 mg or more, and preferably 50,000 mg or less, more preferably 10,000 mg or less, even more preferably is 1000 mg or less. In one aspect, when the composition of the present invention is ingested or administered to humans (adults), the total dose (in terms of cyclic dipeptide) of Cyclo (Val-Pro), Cyclo (Gly-Pro) and their salts is , preferably 0.001 to 50,000 mg, more preferably 0.01 to 10,000 mg, and even more preferably 0.1 to 1,000 mg per day.
The above amount is preferably taken or administered at least once a day, for example, once a day or divided into several times (for example, 2 to 3 times). In one embodiment, it is preferable to orally ingest or administer at least one selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro), and salts thereof in the above amount. In the case of humans (adults), the above amount of at least one selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro) and their salts can be ingested or administered per 60 kg of body weight per day. preferable. In one embodiment, the composition of the present invention provides a human with the above amount of at least one selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro) and salts thereof per 60 kg of body weight per day. It may be an oral composition for ingesting or administering the seeds.
In the present specification, in the case of a cyclic dipeptide (Cyclo (Val-Pro) or Cyclo (Gly-Pro)), the expression equivalent to a cyclic dipeptide amount refers to the amount of the cyclic dipeptide. When the cyclic dipeptide is in the form of a salt, it means the value obtained by multiplying the number of moles of the salt by the molecular weight of the corresponding cyclic dipeptide.
本発明の組成物は、継続して摂取又は投与されるものであることが好ましい。Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩からなる群より選択される少なくとも１種を継続的に摂取させる又は投与することによって、より高い効果が得られることが期待される。一態様において、本発明の組成物は、好ましくは１週間以上、より好ましくは４週間以上、さらに好ましくは８週間以上継続して摂取又は投与されることが好ましい。Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩は、飲食品などとして摂取可能であり、安全性の観点から、例えば長期摂取することにも問題が少ないと考えられる。
It is preferable that the composition of the present invention be taken or administered continuously. It is expected that higher effects will be obtained by continuously ingesting or administering at least one selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro), and their salts. . In one embodiment, the composition of the present invention is preferably taken or administered continuously for one week or more, more preferably for four weeks or more, even more preferably for eight weeks or more. Cyclo (Val-Pro), Cyclo (Gly-Pro) and their salts can be ingested as foods and drinks, and from the viewpoint of safety, it is thought that there are few problems with long-term ingestion, for example.
本発明の組成物を摂取させる又は投与する対象（投与対象ということもできる）は、特に限定されない。好ましくはヒト又は非ヒト哺乳動物であり、より好ましくはヒトである。
一態様において、本発明の組成物の投与対象として、免疫調節（免疫系の調節）を必要とする又は希望する対象、免疫調節障害の予防又は改善を必要とする又は希望する対象、免疫調節障害に関連する状態又は疾患の予防又は改善を必要とする又は希望する対象等が好ましい。一態様において、本発明における投与対象として、喘息、過敏性腸症候群、関節炎、関節リウマチ、湿疹、アレルギーなどの炎症性疾患の患者が好ましい。本発明における好ましい投与対象として、過剰な免疫反応の予防又は改善を必要とする又は希望する対象も挙げられる。一態様において、本発明における投与対象として、中高年者が挙げられる。中高年者は、高齢者を含む。中高年者は、例えば、４０歳以上のヒトであってよい。一態様において中高年者の中でも、対象として高齢者が好ましい。高齢者は、例えば、６０歳以上又は６５歳以上のヒトであってよい。一態様において、本発明の組成物の投与対象は、健常者であってよい。例えば、免疫調節障害の予防、免疫調節障害に関連する状態又は疾患の予防、過剰な免疫反応の予防等を目的として、健常者に対して使用することもできる。 The subject to whom the composition of the present invention is ingested or administered (also referred to as the subject of administration) is not particularly limited. Preferably it is a human or non-human mammal, more preferably a human.
In one embodiment, the subject to whom the composition of the present invention is administered is a subject who requires or desires immunomodulation (regulation of the immune system), a subject who requires or desires prevention or amelioration of an immunoregulatory disorder, an immunoregulatory disorder. Preferably, the subject requires or desires prevention or amelioration of a condition or disease related to. In one embodiment, patients with inflammatory diseases such as asthma, irritable bowel syndrome, arthritis, rheumatoid arthritis, eczema, and allergies are preferred as subjects for administration in the present invention. Preferred subjects for administration in the present invention also include subjects who require or desire prevention or amelioration of excessive immune responses. In one embodiment, subjects for administration in the present invention include middle-aged and elderly people. Middle-aged and elderly people include the elderly. A middle-aged person may be, for example, a person over 40 years old. In one embodiment, among middle-aged and elderly people, elderly people are preferred as subjects. An elderly person may be, for example, a person over 60 years old or over 65 years old. In one embodiment, the subject to whom the composition of the present invention is administered may be a healthy person. For example, it can also be used in healthy individuals for the purpose of preventing immune dysregulation, preventing conditions or diseases associated with immunomodulatory disorders, preventing excessive immune reactions, and the like.
一態様において、本発明の組成物の投与対象として、免疫調節（免疫系の調節）を必要とする又は希望する対象、免疫調節障害の予防又は改善を必要とする又は希望する対象、免疫調節障害に関連する状態又は疾患の予防又は改善を必要とする又は希望する対象等が好ましい。一態様において、本発明における投与対象として、喘息、過敏性腸症候群、関節炎、関節リウマチ、湿疹、アレルギーなどの炎症性疾患の患者が好ましい。本発明における好ましい投与対象として、過剰な免疫反応の予防又は改善を必要とする又は希望する対象も挙げられる。一態様において、本発明における投与対象として、中高年者が挙げられる。中高年者は、高齢者を含む。中高年者は、例えば、４０歳以上のヒトであってよい。一態様において中高年者の中でも、対象として高齢者が好ましい。高齢者は、例えば、６０歳以上又は６５歳以上のヒトであってよい。一態様において、本発明の組成物の投与対象は、健常者であってよい。例えば、免疫調節障害の予防、免疫調節障害に関連する状態又は疾患の予防、過剰な免疫反応の予防等を目的として、健常者に対して使用することもできる。 The subject to whom the composition of the present invention is ingested or administered (also referred to as the subject of administration) is not particularly limited. Preferably it is a human or non-human mammal, more preferably a human.
In one embodiment, the subject to whom the composition of the present invention is administered is a subject who requires or desires immunomodulation (regulation of the immune system), a subject who requires or desires prevention or amelioration of an immunoregulatory disorder, an immunoregulatory disorder. Preferably, the subject requires or desires prevention or amelioration of a condition or disease related to. In one embodiment, patients with inflammatory diseases such as asthma, irritable bowel syndrome, arthritis, rheumatoid arthritis, eczema, and allergies are preferred as subjects for administration in the present invention. Preferred subjects for administration in the present invention also include subjects who require or desire prevention or amelioration of excessive immune responses. In one embodiment, subjects for administration in the present invention include middle-aged and elderly people. Middle-aged and elderly people include the elderly. A middle-aged person may be, for example, a person over 40 years old. In one embodiment, among middle-aged and elderly people, elderly people are preferred as subjects. An elderly person may be, for example, a person over 60 years old or over 65 years old. In one embodiment, the subject to whom the composition of the present invention is administered may be a healthy person. For example, it can also be used in healthy individuals for the purpose of preventing immune dysregulation, preventing conditions or diseases associated with immunomodulatory disorders, preventing excessive immune reactions, and the like.
本発明の組成物には、免疫系の調節により発揮される機能の表示が付されていてもよい。このような表示は機能性表示ともいう。上記表示は、特に限定されない。このような表示として、例えば、「免疫力向上」、「免疫機能強化」、「炎症性疾患予防」、「アレルギー予防」、「創傷治癒促進」、「組織修復又は再生促進」、「病原体のクリアランス向上」、及び、これらと同視できる表示又は機能性表示が挙げられる。
本発明の一態様において、本発明の組成物は、上記の表示が１又は２以上付された飲食品であることが好ましい。また上記の表示は、上記の機能を得るために上記組成物を用いる旨の表示であってもよい。当該表示は、組成物自体に付されてもよいし、組成物の容器又は包装に付されていてもよい。 The composition of the present invention may be labeled with a function exerted by regulating the immune system. Such a display is also called a functional display. The above display is not particularly limited. Such claims include, for example, "improving immunity,""strengthening immune function,""preventing inflammatory diseases,""preventingallergies,""promoting wound healing,""promoting tissue repair or regeneration," and "clearing pathogens.""improvement" and indications or functionality indications that can be regarded as the same as these.
In one aspect of the present invention, the composition of the present invention is preferably a food or drink labeled with one or more of the above labels. Moreover, the above-mentioned indication may be an indication that the above-mentioned composition is used to obtain the above-mentioned function. The label may be attached to the composition itself or to the container or packaging of the composition.
本発明の一態様において、本発明の組成物は、上記の表示が１又は２以上付された飲食品であることが好ましい。また上記の表示は、上記の機能を得るために上記組成物を用いる旨の表示であってもよい。当該表示は、組成物自体に付されてもよいし、組成物の容器又は包装に付されていてもよい。 The composition of the present invention may be labeled with a function exerted by regulating the immune system. Such a display is also called a functional display. The above display is not particularly limited. Such claims include, for example, "improving immunity,""strengthening immune function,""preventing inflammatory diseases,""preventingallergies,""promoting wound healing,""promoting tissue repair or regeneration," and "clearing pathogens.""improvement" and indications or functionality indications that can be regarded as the same as these.
In one aspect of the present invention, the composition of the present invention is preferably a food or drink labeled with one or more of the above labels. Moreover, the above-mentioned indication may be an indication that the above-mentioned composition is used to obtain the above-mentioned function. The label may be attached to the composition itself or to the container or packaging of the composition.
本発明は、以下の方法及び使用も包含する。
Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩からなる群より選択される少なくとも１種を投与する、免疫調節方法。
免疫調節のための、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩からなる群より選択される少なくとも１種の使用。
上記方法は、治療的な方法であってもよく、非治療的な方法であってもよい。上記使用は、治療的な使用であってもよく、非治療的な使用であってもよい。 The invention also encompasses the following methods and uses.
An immunomodulation method comprising administering at least one member selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro), and salts thereof.
Use of at least one selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro) and salts thereof for immunomodulation.
The above methods may be therapeutic or non-therapeutic. The above uses may be therapeutic or non-therapeutic.
Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩からなる群より選択される少なくとも１種を投与する、免疫調節方法。
免疫調節のための、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩からなる群より選択される少なくとも１種の使用。
上記方法は、治療的な方法であってもよく、非治療的な方法であってもよい。上記使用は、治療的な使用であってもよく、非治療的な使用であってもよい。 The invention also encompasses the following methods and uses.
An immunomodulation method comprising administering at least one member selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro), and salts thereof.
Use of at least one selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro) and salts thereof for immunomodulation.
The above methods may be therapeutic or non-therapeutic. The above uses may be therapeutic or non-therapeutic.
Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩からなる群より選択される少なくとも１種は、マクロファージにおける活性酸素種に対する防御を促進するために使用することができる。Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩からなる群より選択される少なくとも１種は、マクロファージにおける活性酸素種に対する防御を促進することによって、免疫を調節するために使用することができる。
At least one selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro) and salts thereof can be used to promote defense against reactive oxygen species in macrophages. At least one selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro) and salts thereof is used to regulate immunity by promoting defense against reactive oxygen species in macrophages. be able to.
一態様において、上記方法においては、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）又はその塩を投与することが好ましい。上記使用においては、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）又はその塩を使用することが好ましい。
一態様において、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）又はその塩は、Ｍ１／Ｍ２マクロファージ分極化を調節するために使用することができる。Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）又はその塩は、Ｍ１／Ｍ２マクロファージ分極化を調節することによって、免疫を調節するために好ましく使用することができる。Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）又はその塩は、Ｍ２マクロファージへの分極化を促進し、Ｍ１マクロファージへの分極化を抑制するために好ましく使用することができる。 In one embodiment, in the above method, Cyclo (Val-Pro) or a salt thereof is preferably administered. In the above use, it is preferable to use Cyclo (Val-Pro) or a salt thereof.
In one embodiment, Cyclo (Val-Pro) or a salt thereof can be used to modulate M1/M2 macrophage polarization. Cyclo (Val-Pro) or its salts can be preferably used to modulate immunity by modulating M1/M2 macrophage polarization. Cyclo (Val-Pro) or a salt thereof can be preferably used to promote polarization into M2 macrophages and suppress polarization into M1 macrophages.
一態様において、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）又はその塩は、Ｍ１／Ｍ２マクロファージ分極化を調節するために使用することができる。Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）又はその塩は、Ｍ１／Ｍ２マクロファージ分極化を調節することによって、免疫を調節するために好ましく使用することができる。Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）又はその塩は、Ｍ２マクロファージへの分極化を促進し、Ｍ１マクロファージへの分極化を抑制するために好ましく使用することができる。 In one embodiment, in the above method, Cyclo (Val-Pro) or a salt thereof is preferably administered. In the above use, it is preferable to use Cyclo (Val-Pro) or a salt thereof.
In one embodiment, Cyclo (Val-Pro) or a salt thereof can be used to modulate M1/M2 macrophage polarization. Cyclo (Val-Pro) or its salts can be preferably used to modulate immunity by modulating M1/M2 macrophage polarization. Cyclo (Val-Pro) or a salt thereof can be preferably used to promote polarization into M2 macrophages and suppress polarization into M1 macrophages.
上記方法及び使用においては、１日に１回以上、例えば、１日１回～数回（例えば２～３回）、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩からなる群より選択される少なくとも１種を対象に摂取させる又は投与することが好ましい。上記の使用は、好ましくはヒト又は非ヒト哺乳動物、より好ましくはヒトにおける使用である。一態様において、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩からなる群より選択される少なくとも１種は、免疫系を調節することによって、免疫調節障害を予防又は改善するため、免疫調節障害に関連する状態又は疾患を予防又は改善するために好ましく使用することができる。Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩からなる群より選択される少なくとも１種を投与する、免疫調節障害又は免疫調節障害に関連する状態又は疾患の予防又は改善方法も本発明に包含される。一態様において、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩からなる群より選択される少なくとも１種は、免疫反応の過剰な状態を予防又は改善するために好ましく使用することができる。一態様において、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩からなる群より選択される少なくとも１種は、炎症性疾患（例えば、喘息、過敏性腸症候群、関節炎、関節リウマチ、湿疹、アレルギーなど）を予防又は改善するために好ましく使用することができる。
In the above method and use, Cyclo (Val-Pro), Cyclo (Gly-Pro) and salts thereof are used at least once a day, for example, once to several times a day (for example, 2 to 3 times). It is preferable that at least one selected from the group is ingested or administered to a subject. The above uses are preferably in humans or non-human mammals, more preferably in humans. In one aspect, at least one selected from the group consisting of Cyclo(Val-Pro), Cyclo(Gly-Pro), and salts thereof is for preventing or ameliorating immune dysregulation by regulating the immune system. , can be preferably used to prevent or ameliorate conditions or diseases associated with immune dysregulation. A method for preventing or ameliorating an immune regulation disorder or a condition or disease associated with an immune regulation disorder, comprising administering at least one member selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro), and salts thereof. Included in the present invention. In one aspect, at least one selected from the group consisting of Cyclo(Val-Pro), Cyclo(Gly-Pro), and salts thereof is preferably used to prevent or improve an excessive state of immune response. Can be done. In one embodiment, at least one selected from the group consisting of Cyclo(Val-Pro), Cyclo(Gly-Pro), and salts thereof is used to treat inflammatory diseases (e.g., asthma, irritable bowel syndrome, arthritis, rheumatoid arthritis). , eczema, allergies, etc.).
上記方法及び使用においては、免疫調節効果が得られる量（有効量ということもできる）のＣｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩からなる群より選択される少なくとも１種を使用すればよい。一態様において、好ましくは、有効量のＣｙｃｌｏ（Ｖａｌ－Ｐｒｏ）又はその塩を使用する。一態様において、好ましくは、Ｍ２マクロファージへの分極化を促進し、Ｍ１マクロファージへの分極化を抑制する効果が得られる量のＣｙｃｌｏ（Ｖａｌ－Ｐｒｏ）又はその塩を使用する。Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩の好ましい投与量、投与方法、投与対象等は上述した本発明の組成物と同じである。Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩からなる群より選択される少なくとも１種は、そのまま摂取又は投与してもよく、これを含む組成物として摂取又は投与してもよい。例えば、本発明の組成物を摂取又は投与してもよい。
In the above methods and uses, at least one member selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro), and salts thereof, in an amount (also referred to as an effective amount) that provides an immunomodulatory effect. You can use . In one embodiment, preferably an effective amount of Cyclo (Val-Pro) or a salt thereof is used. In one embodiment, Cyclo (Val-Pro) or a salt thereof is preferably used in an amount that promotes polarization into M2 macrophages and suppresses polarization into M1 macrophages. Preferred dosages, administration methods, subjects for administration, etc. of Cyclo (Val-Pro), Cyclo (Gly-Pro) and their salts are the same as those for the composition of the present invention described above. At least one selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro), and salts thereof may be taken or administered as is, or may be taken or administered as a composition containing it. good. For example, compositions of the invention may be ingested or administered.
Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩からなる群より選択される少なくとも１種は、免疫調節のために使用される飲食品、医薬品、医薬部外品、飼料等の製造のために使用することができる。一態様において、本発明は、免疫調節用組成物の製造における、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩からなる群より選択される少なくとも１種の使用、も包含する。Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩からなる群より選択される少なくとも１種は、免疫調節障害の予防又は改善用又は免疫調節障害に関連する状態又は疾患の予防又は改善用組成物の製造のために好ましく使用することができる。
At least one selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro) and their salts can be used in foods and drinks used for immunomodulation, pharmaceuticals, quasi-drugs, feeds, etc. Can be used for manufacturing. In one aspect, the present invention also encompasses the use of at least one selected from the group consisting of Cyclo(Val-Pro), Cyclo(Gly-Pro), and salts thereof in the manufacture of an immunomodulatory composition. . At least one selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro) and salts thereof is used for the prevention or amelioration of immune regulation disorders or for the prevention or prevention of conditions or diseases associated with immune regulation disorders. It can be preferably used for the production of improving compositions.
本明細書において下限値と上限値によって表されている数値範囲、即ち「下限値～上限値」は、それら下限値及び上限値を含む。例えば、「１～２」により表される範囲は、１以上２以下を意味し、１及び２を含む。本明細書において、上限及び下限は、いずれの組み合わせによる範囲としてもよい。
In this specification, the numerical range expressed by a lower limit value and an upper limit value, ie, "lower limit value to upper limit value" includes the lower limit value and upper limit value. For example, the range represented by "1 to 2" means 1 or more and 2 or less, and includes 1 and 2. In this specification, the upper limit and the lower limit may be any combination of ranges.
以下、本発明を実施例によりさらに詳しく説明するが、これにより本発明の範囲を限定するものではない。
EXAMPLES Hereinafter, the present invention will be explained in more detail with reference to Examples, but the scope of the present invention is not limited thereby.
＜実施例１＞
実施例においては、下記の環状ジペプチドを使用した。
Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）（Ｂａｃｈｅｍ社、ＵＳＡ）
Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）（Ｂａｃｈｅｍ社、ＵＳＡ） <Example 1>
In the examples, the following cyclic dipeptides were used.
Cyclo (Val-Pro) (Bachem, USA)
Cyclo (Gly-Pro) (Bachem, USA)
実施例においては、下記の環状ジペプチドを使用した。
Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）（Ｂａｃｈｅｍ社、ＵＳＡ）
Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）（Ｂａｃｈｅｍ社、ＵＳＡ） <Example 1>
In the examples, the following cyclic dipeptides were used.
Cyclo (Val-Pro) (Bachem, USA)
Cyclo (Gly-Pro) (Bachem, USA)
マクロファージをリポ多糖（ＬＰＳ）又はインターロイキン４（ＩＬ－４）（いずれもＳｉｇｍａ－Ａｌｄｒｉｃｈ社、ＵＳＡ）で刺激して、マクロファージの分極化に対するＣｙｃｌｏ（Ｖａｌ－Ｐｒｏ）の効果を調べた。また、マクロファージをＬＰＳで刺激して、マクロファージにおける抗酸化酵素の発現に対するＣｙｃｌｏ（Ｖａｌ－Ｐｒｏ）及びＣｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）の効果を調べた。
Macrophages were stimulated with lipopolysaccharide (LPS) or interleukin 4 (IL-4) (both Sigma-Aldrich, USA) to examine the effect of Cyclo (Val-Pro) on macrophage polarization. Furthermore, macrophages were stimulated with LPS, and the effects of Cyclo (Val-Pro) and Cyclo (Gly-Pro) on the expression of antioxidant enzymes in macrophages were investigated.
（細胞培養と処理）
マウスマクロファージＲａｗ２６４．７細胞（ＣｈｕａｎＱｉｕ Ｂｉｏｔｅｃｈｎｏｌｏｇｙ Ｃｏ．， Ｌｔｄ．、上海、中国）を、ウシ胎児血清（ＨＡＫＡＴＡ、 ＣｈｕａｎＱｉｕ Ｂｉｏｔｅｃｈｎｏｌｏｇｙ Ｃｏ．， Ｌｔｄ．、上海、中国）を１０％（ｖｏｌ／ｖｏｌ）含み、１％ ペニシリン－ストレプトマイシン溶液（Ｇｉｂｃｏ、ＵＳＡ）を補充したＤＭＥＭ中で、加湿雰囲気下（５％ ＣＯ２、９５％ ａｉｒ、３７℃）で培養した。次いで、下記の方法でＬＰＳ又はＩＬ－４刺激下で培養を行った。 (Cell culture and processing)
Mouse macrophage Raw264.7 cells (ChuanQiu Biotechnology Co., Ltd., Shanghai, China) containing 10% (vol/vol) fetal bovine serum (HAKATA, ChuanQiu Biotechnology Co., Ltd., Shanghai, China), 1 % penicillin-streptomycin solution (Gibco, USA) under a humidified atmosphere (5% CO 2 , 95% air, 37° C.). Next, culture was performed under LPS or IL-4 stimulation using the method described below.
マウスマクロファージＲａｗ２６４．７細胞（ＣｈｕａｎＱｉｕ Ｂｉｏｔｅｃｈｎｏｌｏｇｙ Ｃｏ．， Ｌｔｄ．、上海、中国）を、ウシ胎児血清（ＨＡＫＡＴＡ、 ＣｈｕａｎＱｉｕ Ｂｉｏｔｅｃｈｎｏｌｏｇｙ Ｃｏ．， Ｌｔｄ．、上海、中国）を１０％（ｖｏｌ／ｖｏｌ）含み、１％ ペニシリン－ストレプトマイシン溶液（Ｇｉｂｃｏ、ＵＳＡ）を補充したＤＭＥＭ中で、加湿雰囲気下（５％ ＣＯ２、９５％ ａｉｒ、３７℃）で培養した。次いで、下記の方法でＬＰＳ又はＩＬ－４刺激下で培養を行った。 (Cell culture and processing)
Mouse macrophage Raw264.7 cells (ChuanQiu Biotechnology Co., Ltd., Shanghai, China) containing 10% (vol/vol) fetal bovine serum (HAKATA, ChuanQiu Biotechnology Co., Ltd., Shanghai, China), 1 % penicillin-streptomycin solution (Gibco, USA) under a humidified atmosphere (5% CO 2 , 95% air, 37° C.). Next, culture was performed under LPS or IL-4 stimulation using the method described below.
（ＬＰＳ刺激下での培養）
ＲＡＷ２６４．７細胞を、環状ジペプチド（Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）又はＣｙｃｌｏ（Ｇｌｙ－Ｐｒｏ））及びＬＰＳ（培地中のＬＰＳ終濃度：１μｇ／ｍＬ）を添加した培地で、１６時間培養した。培養後、後記の方法でｍＲＮＡ量を測定した。環状ジペプチド及びＬＰＳを添加しない培地で培養した細胞を、対照群とした。また、環状ジペプチドを添加せず、ＬＰＳ（培地中の終濃度：１μｇ／ｍＬ）を添加した培地で培養した細胞を、ＬＰＳ処理群とした。 (Culture under LPS stimulation)
RAW264.7 cells were cultured for 16 hours in a medium supplemented with a cyclic dipeptide (Cyclo (Val-Pro) or Cyclo (Gly-Pro)) and LPS (LPS final concentration in medium: 1 μg/mL). After culturing, the amount of mRNA was measured by the method described below. Cells cultured in a medium to which cyclic dipeptide and LPS were not added served as a control group. In addition, cells cultured in a medium to which LPS (final concentration in medium: 1 μg/mL) was added without addition of a cyclic dipeptide were defined as an LPS treatment group.
ＲＡＷ２６４．７細胞を、環状ジペプチド（Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）又はＣｙｃｌｏ（Ｇｌｙ－Ｐｒｏ））及びＬＰＳ（培地中のＬＰＳ終濃度：１μｇ／ｍＬ）を添加した培地で、１６時間培養した。培養後、後記の方法でｍＲＮＡ量を測定した。環状ジペプチド及びＬＰＳを添加しない培地で培養した細胞を、対照群とした。また、環状ジペプチドを添加せず、ＬＰＳ（培地中の終濃度：１μｇ／ｍＬ）を添加した培地で培養した細胞を、ＬＰＳ処理群とした。 (Culture under LPS stimulation)
RAW264.7 cells were cultured for 16 hours in a medium supplemented with a cyclic dipeptide (Cyclo (Val-Pro) or Cyclo (Gly-Pro)) and LPS (LPS final concentration in medium: 1 μg/mL). After culturing, the amount of mRNA was measured by the method described below. Cells cultured in a medium to which cyclic dipeptide and LPS were not added served as a control group. In addition, cells cultured in a medium to which LPS (final concentration in medium: 1 μg/mL) was added without addition of a cyclic dipeptide were defined as an LPS treatment group.
（ＩＬ－４刺激下での培養）
ＲＡＷ２６４．７細胞を、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）及びＩＬ－４（培地中のＩＬ－４終濃度：１０ｎｇ／ｍＬ）を添加した培地で、１６時間培養した。培養後、後記の方法でｍＲＮＡ量を測定した。Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）及びＩＬ－４を添加しない培地で培養した細胞を、対照群とした。また、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）を添加せず、ＩＬ－４（培地中の終濃度：１０ｎｇ／ｍＬ）を添加した培地で培養した細胞を、ＩＬ－４処理群とした。 (Culture under IL-4 stimulation)
RAW264.7 cells were cultured for 16 hours in a medium supplemented with Cyclo (Val-Pro) and IL-4 (IL-4 final concentration in medium: 10 ng/mL). After culturing, the amount of mRNA was measured by the method described below. Cells cultured in a medium to which Cyclo (Val-Pro) and IL-4 were not added served as a control group. In addition, cells cultured in a medium to which IL-4 (final concentration in medium: 10 ng/mL) was added without Cyclo (Val-Pro) were defined as an IL-4 treated group.
ＲＡＷ２６４．７細胞を、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）及びＩＬ－４（培地中のＩＬ－４終濃度：１０ｎｇ／ｍＬ）を添加した培地で、１６時間培養した。培養後、後記の方法でｍＲＮＡ量を測定した。Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）及びＩＬ－４を添加しない培地で培養した細胞を、対照群とした。また、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）を添加せず、ＩＬ－４（培地中の終濃度：１０ｎｇ／ｍＬ）を添加した培地で培養した細胞を、ＩＬ－４処理群とした。 (Culture under IL-4 stimulation)
RAW264.7 cells were cultured for 16 hours in a medium supplemented with Cyclo (Val-Pro) and IL-4 (IL-4 final concentration in medium: 10 ng/mL). After culturing, the amount of mRNA was measured by the method described below. Cells cultured in a medium to which Cyclo (Val-Pro) and IL-4 were not added served as a control group. In addition, cells cultured in a medium to which IL-4 (final concentration in medium: 10 ng/mL) was added without Cyclo (Val-Pro) were defined as an IL-4 treated group.
上記の培養において、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）は、終濃度が１．６８μｇ／ｍＬとなるように培地に添加した。Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）は、終濃度が３．５２５μｇ／ｍＬとなるように培地に添加した。
すべての実験を６回繰り返して行った。 In the above culture, Cyclo (Val-Pro) was added to the medium at a final concentration of 1.68 μg/mL. Cyclo (Gly-Pro) was added to the medium at a final concentration of 3.525 μg/mL.
All experiments were performed in six replicates.
すべての実験を６回繰り返して行った。 In the above culture, Cyclo (Val-Pro) was added to the medium at a final concentration of 1.68 μg/mL. Cyclo (Gly-Pro) was added to the medium at a final concentration of 3.525 μg/mL.
All experiments were performed in six replicates.
（定量リアルタイムポリメラーゼ連鎖反応）
細胞のトータルＲＮＡを、Ｂｉｏｚｏｌ ｒｅａｇｅｎｔ（Ｂｉｏｍｉｇａ Ｂｉｏｃｈｅｍｉｃａｌｓ、ＵＳＡ）を使用して抽出した。ＲＮＡ濃度を、Ｂｉｏｔｅｋ ＮＤ５０００ ｉｎｓｔｒｕｍｅｎｔ（ＢｉｏＴｅｋｅ社、北京、中国）を使用して評価し、ｈｉｇｈ－ｃａｐａｃｉｔｙ ｃＤＮＡ ｒｅｖｅｒｓｅ ｔｒａｎｓｃｒｉｐｔａｓｅ ｋｉｔ（Ｔｓｉｎｇｋｅ Ｃｏ．， Ｌｔｄ．、北京、中国）を使用してｃＤＮＡを合成した。以前記載されたように、ＳＹＢＲ Ｇｒｅｅｎ Ｒｅａｌ－ｔｉｍｅ ＰＣＲ Ｍａｓｔｅｒ Ｍｉｘ（Ｔｓｉｎｇｋｅ Ｃｏ．， Ｌｔｄ．、北京、中国）を使用して、ＣＦＸ Ｃｏｎｎｅｃｔ Ｒｅａｌ－Ｔｉｍｅ ＰＣＲ Ｓｙｓｔｅｍ（Ｂｉｏ－ｒａｄ社、ＵＳＡ）で定量リアルタイムＰＣＲを行った（Ｍａ ｅｔ ａｌ．， “Ｂｉｆｉｄｏｂａｃｔｅｒｉｕｍ ａｎｉｍａｌｉｓ ｓｕｂｓｐ． ｌａｃｔｉｓ ｌｋｍ５１２ Ａｔｔｅｎｕａｔｅｓ Ｏｂｅｓｉｔｙ－Ａｓｓｏｃｉａｔｅｄ Ｉｎｆｌａｍｍａｔｉｏｎ ａｎｄ Ｉｎｓｕｌｉｎ Ｒｅｓｉｓｔａｎｃｅ Ｔｈｒｏｕｇｈ ｔｈｅ Ｍｏｄｉｆｉｃａｔｉｏｎ ｏｆ Ｇｕｔ Ｍｉｃｒｏｂｉｏｔａ ｉｎ Ｈｉｇｈ－Ｆａｔ Ｄｉｅｔ－Ｉｎｄｕｃｅｄ Ｏｂｅｓｅ Ｍｉｃｅ．”， Ｍｏｌ Ｎｕｔｒ Ｆｏｏｄ Ｒｅｓ， ２０２２， ６６（３）， ｅ２１００６３９． ｄｏｉ：１０．１００２／ｍｎｆｒ．２０２１００６３９）。β－アクチンの転写を、ハウスキーピング遺伝子としてデータの標準化に使用した。 (Quantitative real-time polymerase chain reaction)
Cellular total RNA was extracted using Biozol reagent (Biomiga Biochemicals, USA). RNA concentration was assessed using a Biotek ND5000 instrument (BioTeke, Beijing, China) and cDNA was isolated using a high-capacity cDNA reverse transcriptase kit (Tsingke Co., Ltd., Beijing, China). A was synthesized. Quantitative real-time was performed on a CFX Connect Real-Time PCR System (Bio-rad, USA) using SYBR Green Real-time PCR Master Mix (Tsingke Co., Ltd., Beijing, China) as previously described. PCR was performed (Ma et al., “Bifidobacterium animalis subsp. "stance Through the Modification of Gut Microbiota in High-Fat Diet-Induced Obese Mice.", Mol Nutr Food Res, 2022, 66(3), e2100639. doi:10.1002/mnfr.202100639). β-actin transcription was used as a housekeeping gene for data normalization.
細胞のトータルＲＮＡを、Ｂｉｏｚｏｌ ｒｅａｇｅｎｔ（Ｂｉｏｍｉｇａ Ｂｉｏｃｈｅｍｉｃａｌｓ、ＵＳＡ）を使用して抽出した。ＲＮＡ濃度を、Ｂｉｏｔｅｋ ＮＤ５０００ ｉｎｓｔｒｕｍｅｎｔ（ＢｉｏＴｅｋｅ社、北京、中国）を使用して評価し、ｈｉｇｈ－ｃａｐａｃｉｔｙ ｃＤＮＡ ｒｅｖｅｒｓｅ ｔｒａｎｓｃｒｉｐｔａｓｅ ｋｉｔ（Ｔｓｉｎｇｋｅ Ｃｏ．， Ｌｔｄ．、北京、中国）を使用してｃＤＮＡを合成した。以前記載されたように、ＳＹＢＲ Ｇｒｅｅｎ Ｒｅａｌ－ｔｉｍｅ ＰＣＲ Ｍａｓｔｅｒ Ｍｉｘ（Ｔｓｉｎｇｋｅ Ｃｏ．， Ｌｔｄ．、北京、中国）を使用して、ＣＦＸ Ｃｏｎｎｅｃｔ Ｒｅａｌ－Ｔｉｍｅ ＰＣＲ Ｓｙｓｔｅｍ（Ｂｉｏ－ｒａｄ社、ＵＳＡ）で定量リアルタイムＰＣＲを行った（Ｍａ ｅｔ ａｌ．， “Ｂｉｆｉｄｏｂａｃｔｅｒｉｕｍ ａｎｉｍａｌｉｓ ｓｕｂｓｐ． ｌａｃｔｉｓ ｌｋｍ５１２ Ａｔｔｅｎｕａｔｅｓ Ｏｂｅｓｉｔｙ－Ａｓｓｏｃｉａｔｅｄ Ｉｎｆｌａｍｍａｔｉｏｎ ａｎｄ Ｉｎｓｕｌｉｎ Ｒｅｓｉｓｔａｎｃｅ Ｔｈｒｏｕｇｈ ｔｈｅ Ｍｏｄｉｆｉｃａｔｉｏｎ ｏｆ Ｇｕｔ Ｍｉｃｒｏｂｉｏｔａ ｉｎ Ｈｉｇｈ－Ｆａｔ Ｄｉｅｔ－Ｉｎｄｕｃｅｄ Ｏｂｅｓｅ Ｍｉｃｅ．”， Ｍｏｌ Ｎｕｔｒ Ｆｏｏｄ Ｒｅｓ， ２０２２， ６６（３）， ｅ２１００６３９． ｄｏｉ：１０．１００２／ｍｎｆｒ．２０２１００６３９）。β－アクチンの転写を、ハウスキーピング遺伝子としてデータの標準化に使用した。 (Quantitative real-time polymerase chain reaction)
Cellular total RNA was extracted using Biozol reagent (Biomiga Biochemicals, USA). RNA concentration was assessed using a Biotek ND5000 instrument (BioTeke, Beijing, China) and cDNA was isolated using a high-capacity cDNA reverse transcriptase kit (Tsingke Co., Ltd., Beijing, China). A was synthesized. Quantitative real-time was performed on a CFX Connect Real-Time PCR System (Bio-rad, USA) using SYBR Green Real-time PCR Master Mix (Tsingke Co., Ltd., Beijing, China) as previously described. PCR was performed (Ma et al., “Bifidobacterium animalis subsp. "stance Through the Modification of Gut Microbiota in High-Fat Diet-Induced Obese Mice.", Mol Nutr Food Res, 2022, 66(3), e2100639. doi:10.1002/mnfr.202100639). β-actin transcription was used as a housekeeping gene for data normalization.
Ｍ１マクロファージマーカーである、腫瘍壊死因子－α（ＴＮＦ－α）、インターロイキン－６（ＩＬ－６）及びインターロイキン－１β（ＩＬ－１β）のｍＲＮＡ発現量を調べた。Ｍ２マクロファージマーカーである、マクロファージマンノース受容体Ｃ型１（ＣＤ２０６）、アルギナーゼ－１（Ａｒｇ１）、マクロファージガラクトース型Ｃ型レクチン２（Ｍｇｌ２）のｍＲＮＡ発現量を調べた。抗酸化酵素である、スーパーオキシドジスムターゼ１（ＳＯＤ１）、カタラーゼ（ＣＡＴ）、グルタチオンペルオキシダーゼ（Ｇｐｘ）のｍＲＮＡ発現量を調べた。
プライマーの配列を表１に示した。 The mRNA expression levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β), which are M1 macrophage markers, were examined. The mRNA expression levels of M2 macrophage markers, macrophage mannose receptor type C 1 (CD206), arginase-1 (Arg1), and macrophage galactose type C lectin 2 (Mgl2) were investigated. The mRNA expression levels of antioxidant enzymes superoxide dismutase 1 (SOD1), catalase (CAT), and glutathione peroxidase (Gpx) were investigated.
The sequences of the primers are shown in Table 1.
プライマーの配列を表１に示した。 The mRNA expression levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β), which are M1 macrophage markers, were examined. The mRNA expression levels of M2 macrophage markers, macrophage mannose receptor type C 1 (CD206), arginase-1 (Arg1), and macrophage galactose type C lectin 2 (Mgl2) were investigated. The mRNA expression levels of antioxidant enzymes superoxide dismutase 1 (SOD1), catalase (CAT), and glutathione peroxidase (Gpx) were investigated.
The sequences of the primers are shown in Table 1.
（統計分析）
すべてのデータは、平均±ＳＥＭとして示した。異なるグループ間の比較は、一元配置分散分析（ＡＮＯＶＡ）とそれに続くＳｔｕｄｅｎｔ－Ｎｅｗｍａｎ－Ｋｅｕｌｓ検定によって分析した。Ｐ値が＜０．０５又は０．０１を、統計的に有意であると見なした。 (statistical analysis)
All data are presented as mean ± SEM. Comparisons between different groups were analyzed by one-way analysis of variance (ANOVA) followed by the Student-Newman-Keuls test. P values <0.05 or 0.01 were considered statistically significant.
すべてのデータは、平均±ＳＥＭとして示した。異なるグループ間の比較は、一元配置分散分析（ＡＮＯＶＡ）とそれに続くＳｔｕｄｅｎｔ－Ｎｅｗｍａｎ－Ｋｅｕｌｓ検定によって分析した。Ｐ値が＜０．０５又は０．０１を、統計的に有意であると見なした。 (statistical analysis)
All data are presented as mean ± SEM. Comparisons between different groups were analyzed by one-way analysis of variance (ANOVA) followed by the Student-Newman-Keuls test. P values <0.05 or 0.01 were considered statistically significant.
（結果）
マクロファージをＬＰＳで刺激することによって、Ｍ１マクロファージへの分極が誘導される。マクロファージをＩＬ－４で刺激することによって、Ｍ２マクロファージへの分極が誘導される。
図１及び図２に、インビトロでのマクロファージの分極化に対するＣｙｃｌｏ（Ｖａｌ－Ｐｒｏ）の効果を調べた結果を示す。図３に、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）及びＣｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）のマクロ―ファージにおける抗酸化酵素の発現への影響を調べた結果を示す。マーカー遺伝子のｍＲＮＡ発現量は、β－アクチンのｍＲＮＡ発現量に対する相対量（相対ｍＲＮＡ発現量）として示した。 (result)
Stimulating macrophages with LPS induces polarization into M1 macrophages. Stimulating macrophages with IL-4 induces polarization into M2 macrophages.
Figures 1 and 2 show the results of investigating the effect of Cyclo (Val-Pro) on macrophage polarization in vitro. FIG. 3 shows the results of investigating the effects of Cyclo (Val-Pro) and Cyclo (Gly-Pro) on the expression of antioxidant enzymes in macrophages. The mRNA expression level of the marker gene was expressed as a relative amount (relative mRNA expression level) with respect to the β-actin mRNA expression level.
マクロファージをＬＰＳで刺激することによって、Ｍ１マクロファージへの分極が誘導される。マクロファージをＩＬ－４で刺激することによって、Ｍ２マクロファージへの分極が誘導される。
図１及び図２に、インビトロでのマクロファージの分極化に対するＣｙｃｌｏ（Ｖａｌ－Ｐｒｏ）の効果を調べた結果を示す。図３に、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）及びＣｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）のマクロ―ファージにおける抗酸化酵素の発現への影響を調べた結果を示す。マーカー遺伝子のｍＲＮＡ発現量は、β－アクチンのｍＲＮＡ発現量に対する相対量（相対ｍＲＮＡ発現量）として示した。 (result)
Stimulating macrophages with LPS induces polarization into M1 macrophages. Stimulating macrophages with IL-4 induces polarization into M2 macrophages.
Figures 1 and 2 show the results of investigating the effect of Cyclo (Val-Pro) on macrophage polarization in vitro. FIG. 3 shows the results of investigating the effects of Cyclo (Val-Pro) and Cyclo (Gly-Pro) on the expression of antioxidant enzymes in macrophages. The mRNA expression level of the marker gene was expressed as a relative amount (relative mRNA expression level) with respect to the β-actin mRNA expression level.
図１Ａ、図１Ｂ及び図１Ｃは、１６時間、ＬＰＳ刺激下で、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）で処理したＲＡＷ２６４．７細胞におけるＭ１マクロファージマーカーのｍＲＮＡ発現を調べた結果を示す図である。図１Ａは、ＴＮＦ－αの相対ｍＲＮＡ発現量、図１Ｂは、ＩＬ－６の相対ｍＲＮＡ発現量、図１Ｃは、ＩＬ－１βの相対ｍＲＮＡ発現量を示す。図１Ａ、図１Ｂ及び図１Ｃ中、Ｃは対照群、ＬＰＳはＬＰＳ処理群、ＣＶＰは、ＬＰＳ及びＣｙｃｌｏ（Ｖａｌ－Ｐｒｏ）処理群である。
FIG. 1A, FIG. 1B, and FIG. 1C are diagrams showing the results of examining the mRNA expression of M1 macrophage marker in RAW264.7 cells treated with Cyclo (Val-Pro) under LPS stimulation for 16 hours. FIG. 1A shows the relative mRNA expression level of TNF-α, FIG. 1B shows the relative mRNA expression level of IL-6, and FIG. 1C shows the relative mRNA expression level of IL-1β. In FIGS. 1A, 1B, and 1C, C is the control group, LPS is the LPS treatment group, and CVP is the LPS and Cyclo (Val-Pro) treatment group.
図２Ａ、図２Ｂ及び図２Ｃは、１６時間、ＩＬ－４刺激下で、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）で処理したＲＡＷ２６４．７細胞におけるＭ２マクロファージマーカーのｍＲＮＡ発現を調べた結果を示す図である。図２Ａは、ＣＤ２０６の相対ｍＲＮＡ発現量、図２Ｂは、Ａｒｇ１の相対ｍＲＮＡ発現量、図２Ｃは、Ｍｇｌ２の相対ｍＲＮＡ発現量である。図２Ａ、図２Ｂ及び図２Ｃ中、Ｃは対照群、ＩＬ－４はＩＬ－４処理群、ＣＶＰは、ＩＬ－４及びＣｙｃｌｏ（Ｖａｌ－Ｐｒｏ）処理群である。
FIG. 2A, FIG. 2B, and FIG. 2C are diagrams showing the results of examining mRNA expression of M2 macrophage markers in RAW264.7 cells treated with Cyclo (Val-Pro) under IL-4 stimulation for 16 hours. FIG. 2A shows the relative mRNA expression level of CD206, FIG. 2B shows the relative mRNA expression level of Arg1, and FIG. 2C shows the relative mRNA expression level of Mgl2. In FIGS. 2A, 2B, and 2C, C is the control group, IL-4 is the IL-4 treated group, and CVP is the IL-4 and Cyclo (Val-Pro) treated group.
図３Ａ、図３Ｂ及び図３Ｃは、１６時間、ＬＰＳ刺激下で、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）又はＣｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）で処理したＲＡＷ２６４．７細胞における抗酸化酵素のｍＲＮＡ発現を調べた結果を示す図である。図３Ａは、ＳＯＤ１の相対ｍＲＮＡ発現量、図３Ｂは、ＣＡＴの相対ｍＲＮＡ発現量、図３Ｃは、Ｇｐｘの相対ｍＲＮＡ発現量を示す。図３Ａ、図３Ｂ及び図３Ｃ中、Ｃは対照群、ＬＰＳはＬＰＳ処理群、ＣＧＰは、ＬＰＳ及びＣｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）処理群、ＣＶＰは、ＬＰＳ及びＣｙｃｌｏ（Ｖａｌ－Ｐｒｏ）処理群である。
Figures 3A, 3B, and 3C show the results of examining mRNA expression of antioxidant enzymes in RAW264.7 cells treated with Cyclo (Val-Pro) or Cyclo (Gly-Pro) under LPS stimulation for 16 hours. FIG. FIG. 3A shows the relative mRNA expression level of SOD1, FIG. 3B shows the relative mRNA expression level of CAT, and FIG. 3C shows the relative mRNA expression level of Gpx. In FIGS. 3A, 3B, and 3C, C is the control group, LPS is the LPS treatment group, CGP is the LPS and Cyclo (Gly-Pro) treatment group, and CVP is the LPS and Cyclo (Val-Pro) treatment group. .
図１Ａ、図１Ｂ及び図１Ｃ、図２Ａ、図２Ｂ及び図２Ｃ、図３Ａ、図３Ｂ及び図３Ｃにおいては、データは平均±ＳＥＭで示した。＊及び＊＊は、対照群に対する有意差（＊：Ｐ＜０．０５、＊＊：Ｐ＜０．０１、ｖｓ対照群）を示す。図１Ａ、図１Ｂ及び図１Ｃ並びに図３Ａ、図３Ｂ及び図３Ｃ中、＃及び＃＃は、ＬＰＳ処理群に対する有意差（＃：Ｐ＜０．０５、＃＃：Ｐ＜０．０１、ｖｓ ＬＰＳ処理群）を示す。
図２Ａ、図２Ｂ及び図２Ｃ中、＃及び＃＃は、ＩＬ－４処理群に対する有意差（＃：Ｐ＜０．０５、＃＃：Ｐ＜０．０１、ｖｓ ＩＬ－４処理群）を示す。 In FIGS. 1A, 1B and 1C, 2A, 2B and 2C, 3A, 3B and 3C, data are expressed as mean ± SEM. * and ** indicate significant differences with respect to the control group (*: P<0.05, **: P<0.01, vs control group). In FIGS. 1A, 1B, and 1C and 3A, 3B, and 3C, # and ## indicate significant differences (#: P<0.05, ##: P<0.01, vs. LPS treatment group).
In Figures 2A, 2B, and 2C, # and ## indicate significant differences (#: P<0.05, ##: P<0.01, vs IL-4 treated group). show.
図２Ａ、図２Ｂ及び図２Ｃ中、＃及び＃＃は、ＩＬ－４処理群に対する有意差（＃：Ｐ＜０．０５、＃＃：Ｐ＜０．０１、ｖｓ ＩＬ－４処理群）を示す。 In FIGS. 1A, 1B and 1C, 2A, 2B and 2C, 3A, 3B and 3C, data are expressed as mean ± SEM. * and ** indicate significant differences with respect to the control group (*: P<0.05, **: P<0.01, vs control group). In FIGS. 1A, 1B, and 1C and 3A, 3B, and 3C, # and ## indicate significant differences (#: P<0.05, ##: P<0.01, vs. LPS treatment group).
In Figures 2A, 2B, and 2C, # and ## indicate significant differences (#: P<0.05, ##: P<0.01, vs IL-4 treated group). show.
マクロファージ分極化に対する環状ジペプチドの関与を評価するために、細胞をＬＰＳ及びＣｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、又は、ＩＬ－４及びＣｙｃｌｏ（Ｖａｌ－Ｐｒｏ）で共処理した。ＬＰＳ処理細胞において、Ｍ１炎症性マクロファージマーカー（ＴＮＦ－α、ＩＬ－６、ＩＬ－１β）のｍＲＮＡ発現は、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）によって有意に減少した（図１Ａ、図１Ｂ及び図１Ｃ）。一方、ＩＬ－４処理細胞において、Ｍ２抗炎症マクロファージマーカー（Ａｒｇ１、ＣＤ２０６及びＭｇｌ２）のｍＲＮＡ発現は、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）によって有意に増加した（図２Ａ、図２Ｂ及び図２Ｃ）。Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）はＭ２マクロファージへの分極化（Ｍ２マクロファージの増加）を促進し、Ｍ１マクロファージへの分極化（Ｍ１マクロファージの増加）を抑制する効果を発揮した。
To assess the involvement of cyclic dipeptides in macrophage polarization, cells were co-treated with LPS and Cyclo (Val-Pro) or IL-4 and Cyclo (Val-Pro). In LPS-treated cells, the mRNA expression of M1 inflammatory macrophage markers (TNF-α, IL-6, IL-1β) was significantly reduced by Cyclo (Val-Pro) (FIG. 1A, FIG. 1B, and FIG. 1C). On the other hand, in IL-4-treated cells, the mRNA expression of M2 anti-inflammatory macrophage markers (Arg1, CD206, and Mgl2) was significantly increased by Cyclo (Val-Pro) (FIG. 2A, FIG. 2B, and FIG. 2C). Cyclo (Val-Pro) promoted polarization into M2 macrophages (increase in the number of M2 macrophages) and exerted the effect of suppressing polarization into M1 macrophages (increase in the number of M1 macrophages).
図３Ａ、図３Ｂ及び図３Ｃから、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）及びＣｙｃｌｏ－（Ｇｌｙ－Ｐｒｏ）は、Ｍ１マクロファージにおける、抗酸化酵素（ＳＯＤ１、ＣＡＴ、Ｇｐｘ）の発現を増加させた。Ｍ１マクロファージにおいて抗酸化酵素の発現が増加すると、マクロファージにおける活性酸素種に対する防御が促進される。これによって、過剰な免疫反応を抑制することができる。Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）処理及びＣｙｃｌｏ－（Ｇｌｙ－Ｐｒｏ）処理は、ＬＰＳによって誘発されたＲＡＷ２６４．７細胞の炎症を緩和した。
From FIG. 3A, FIG. 3B, and FIG. 3C, Cyclo(Val-Pro) and Cyclo-(Gly-Pro) increased the expression of antioxidant enzymes (SOD1, CAT, Gpx) in M1 macrophages. Increased expression of antioxidant enzymes in M1 macrophages promotes protection against reactive oxygen species in macrophages. This makes it possible to suppress excessive immune reactions. Cyclo(Val-Pro) and Cyclo-(Gly-Pro) treatments alleviated the inflammation of RAW264.7 cells induced by LPS.
以上の結果から、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）及びＣｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）は、免疫反応の間、マクロファージにおける強力な抗炎症及び抗酸化効果を発揮した。これらの環状ジペプチド及びそれらの塩は、免疫調節効果を有することが分かった。
From the above results, Cyclo (Val-Pro) and Cyclo (Gly-Pro) exerted strong anti-inflammatory and antioxidant effects on macrophages during immune responses. These cyclic dipeptides and their salts were found to have immunomodulatory effects.
Claims (6)
- Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩からなる群より選択される少なくとも１種を有効成分として含む、免疫調節用組成物。 An immunomodulatory composition containing as an active ingredient at least one member selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro), and salts thereof.
- 前記Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）又はその塩を有効成分として含み、Ｍ１／Ｍ２マクロファージ分極化を調節することによって免疫を調節するために使用される、請求項１に記載の免疫調節用組成物。 The immunomodulatory composition according to claim 1, which contains the Cyclo (Val-Pro) or a salt thereof as an active ingredient and is used for regulating immunity by regulating M1/M2 macrophage polarization.
- マクロファージにおける活性酸素種に対する防御を促進することによって、免疫を調節するために使用される、請求項１又は２に記載の免疫調節用組成物。 The immunomodulatory composition according to claim 1 or 2, which is used for regulating immunity by promoting defense against reactive oxygen species in macrophages.
- 前記組成物が、経口組成物である、請求項１又は２に記載の免疫調節用組成物。 The immunomodulatory composition according to claim 1 or 2, wherein the composition is an oral composition.
- 前記組成物が、飲食品又は医薬品である、請求項１又は２に記載の免疫調節用組成物。 The immunomodulating composition according to claim 1 or 2, wherein the composition is a food or drink or a pharmaceutical.
- 免疫調節用組成物の製造における、Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）及びそれらの塩からなる群より選択される少なくとも１種の使用。
Use of at least one member selected from the group consisting of Cyclo (Val-Pro), Cyclo (Gly-Pro) and salts thereof in the manufacture of an immunomodulatory composition.
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