WO2024004931A1 - Composition pour immunomodulation - Google Patents

Composition pour immunomodulation Download PDF

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Publication number
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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Prior art keywords
cyclo
pro
val
composition
gly
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PCT/JP2023/023554
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English (en)
Japanese (ja)
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ダニエル チュンシン タン
シャンメイ ヨン
シャージャン リン
チンチン ヤオ
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サントリーホールディングス株式会社
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Publication of WO2024004931A1 publication Critical patent/WO2024004931A1/fr

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • 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
    • A23L33/18—Peptides; Protein hydrolysates
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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.

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Abstract

L'invention a pour objet de fournir une composition pour immunomodulation. Plus précisément, l'invention concerne une composition pour immunomodulation qui contient, en tant que principe actif au moins un élément choisi dans un groupe constitué d'un Ｃｙｃｌｏ（Ｖａｌ－Ｐｒｏ）, d'un Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ） et d'un sel de ceux-ci.
PCT/JP2023/023554 2022-06-30 2023-06-26 Composition pour immunomodulation WO2024004931A1 (fr)

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Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
GAO-XUE WANG; YONG WANG; ZONG-FAN WU; HAI-FENG JIANG; RUI-QIANG DONG; FU-YUAN LI; XIAO-LIN LIU;: "Immunomodulatory effects of secondary metabolites from thermophilicXA-1 on carp,", FISH & SHELLFISH IMMUNOLOGY, ACADEMIC PRESS, LONDON,, GB, vol. 30, no. 6, 12 March 2011 (2011-03-12), GB , pages 1331 - 1338, XP028212567, ISSN: 1050-4648, DOI: 10.1016/j.fsi.2011.03.011 *
KHAN RUKAIYYA, BASHA AMEER, GOVERDHANAM RAGAVENDRA, RAO POORNA CHANDRA, TANEMURA YUHEI, FUJIMOTO YOSHINORI, BEGUM AHIL SAJELI: "Attenuation of TNF-α secretion by l-proline-based cyclic dipeptides produced by culture broth of Pseudomonas aeruginosa", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, ELSEVIER, AMSTERDAM NL, vol. 25, no. 24, 1 December 2015 (2015-12-01), Amsterdam NL , pages 5756 - 5761, XP093123881, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2015.10.075 *
LEE DAHAE, LEE SEOUNG RAK, KANG KI SUNG, KIM KI HYUN: "Bioactive Phytochemicals from Mulberry: Potential Anti-Inflammatory Effects in Lipopolysaccharide-Stimulated RAW 264.7 Macrophages", INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, vol. 22, no. 15, pages 8120, XP055943651, DOI: 10.3390/ijms22158120 *
LIU J., LEI Y., WANG F., YI Y., LIU Y., WANG G.: "Immunostimulatory activities of specific bacterial secondary metabolite of Anoxybacillus flavithermus strain SX-4 on carp, Cyprinus carpio", JOURNAL OF APPLIED MICROBIOLOG, vol. 110, no. 4, 1 April 2011 (2011-04-01), pages 1056 - 1064, XP009552090, DOI: 10.1111/j.1365-2672.2011.04963.x *
NI YINHUA; ZHOU KEXIN; ZHANG LIQIAN; NAN SUJIE; FU ZHENGWEI: "Hydrolyzed chicken meat extract boosts the immunoregulatory effect by regulating M1/M2 Macrophage polarization", JOURNAL OF FUNCTIONAL FOODS, ELSEVIER BV, NL, vol. 95, 27 July 2022 (2022-07-27), NL , XP087135203, ISSN: 1756-4646, DOI: 10.1016/j.jff.2022.105194 *

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