CN115066273A - Composition comprising cyclic dipeptide, purine nucleoside and/or amino acid and chicken extract, method for producing same and use of cyclic dipeptide, purine nucleoside and/or amino acid and chicken extract - Google Patents
Composition comprising cyclic dipeptide, purine nucleoside and/or amino acid and chicken extract, method for producing same and use of cyclic dipeptide, purine nucleoside and/or amino acid and chicken extract Download PDFInfo
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- CN115066273A CN115066273A CN202080090134.0A CN202080090134A CN115066273A CN 115066273 A CN115066273 A CN 115066273A CN 202080090134 A CN202080090134 A CN 202080090134A CN 115066273 A CN115066273 A CN 115066273A
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Abstract
The present invention aims to provide a novel composition comprising a cyclic dipeptide, a purine nucleoside, an amino acid and/or one or more salts thereof and a chicken extract, which has an anti-inflammatory effect. The present invention relates to a composition comprising at least one selected from the group consisting of cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and salts thereof, and a chicken extract.
Description
Technical Field
The present invention relates to a composition comprising a cyclic dipeptide, a purine nucleoside and/or an amino acid and a chicken extract and a method for producing the same. The invention also relates to the use of cyclic dipeptides, purine nucleosides and/or amino acids and chicken extracts for the production of an anti-inflammatory composition.
Background
Inflammation is a phenomenon in which histamine, kinins, etc. are released by damaged cells, causing vasodilation, increase in capillary permeability, and accumulation of macrophages at an inflammation site, which results in increased blood flow at an infection site, edema, immune cell and antibody transfer, pain, fever, etc.
Recently, ingredients capable of inhibiting the expression of proteins associated with inflammation have been studied to provide effective relief of inflammation. Although anti-inflammatory agents having various mechanisms, such as non-steroidal anti-inflammatory drugs (NSAIDs) and steroidal anti-inflammatory drugs (SAIDs), have been developed, these agents may have side effects. Thus, there is still a need for ingredients that are safer and have anti-inflammatory effects.
For example, patent document 1 discloses an anti-inflammatory composition containing, as an active ingredient, a peptide derived from telomerase having an anti-inflammatory activity.
CITATION LIST
Patent document
PTL 1:JP 2015-525768T
Disclosure of Invention
Technical problem
The present invention aims to provide a novel composition comprising: cyclic dipeptides, purine nucleosides, amino acids and/or one or more salts thereof, and chicken extracts.
The present invention also aims to provide compositions having an anti-inflammatory effect.
Technical scheme
The present inventors found that the anti-inflammatory activity is improved using a combination of at least one selected from the group consisting of cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and salts thereof with a chicken extract, and completed the present invention.
Specifically, the present invention is defined as follows.
(1) A composition, comprising: at least one selected from the group consisting of cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and salts thereof; and chicken extract.
(2) The composition according to the item (1), wherein the total amount of at least one member selected from the group consisting of cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and salts thereof is 0.01 to 99 wt%.
(3) The composition as described in the above (1) or (2), wherein the composition comprises a component of hydrolyzed type II collagen derived from chicken cartilage, and the component has a molecular weight of less than 1100 and a weight average molecular weight of 150-250 as determined by HPLC gel filtration.
(4) The composition according to any one of the above (1) to (3), wherein the composition comprises hydrolyzed type II collagen of chicken cartilage.
(5) The composition according to any one of the above (1) to (4), wherein the chicken extract comprises carnosine and/or anserine and/or one or more salts thereof.
(6) The composition according to any one of the above (1) to (5), wherein the composition is a food, a drink or a pharmaceutical.
(7) The composition according to any one of the above (1) to (6), wherein the composition is used for reducing inflammation.
(8) The composition according to any one of the above (1) to (7), wherein the composition inhibits production of at least one cytokine selected from the group consisting of: stimulated regulation of normal T cell expression and secretion factors (RANTES), monocyte chemotactic protein-1 (MCP-1), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-9 (IL-9), and macrophage inflammatory protein-1 (MIP-1).
(9) The composition according to any one of the above (1) to (8), wherein the composition is used for preventing or alleviating an inflammatory disorder or disease.
(10) A method of producing a composition, the method comprising: mixing at least one selected from the group consisting of cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and their combinations with the chicken extract.
(11) The production method according to the above (10), wherein the mixing comprises mixing hydrolyzed type II collagen of chicken cartilage, which contains at least one selected from the group consisting of: cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and salts thereof.
(12) The production process according to (10) or (11) above, wherein the chicken extract comprises carnosine and/or anserine and/or one or more salts thereof.
(13) Use of at least one selected from the group consisting of cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and salts thereof and a chicken extract for the production of an anti-inflammatory composition.
Advantageous effects
The present invention can provide a novel composition comprising at least one selected from the group consisting of cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and salts thereof, and a chicken extract. The composition of the present invention can be used as a food or drink composition or a pharmaceutical composition for reducing inflammation and joint pain. Cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and salts thereof and chicken extract can be consumed as food, drink and the like, and are also advantageous in terms of high safety.
Drawings
FIG. 1 is a flow chart summarizing the process for preparing hydrolyzed type II collagen from chicken cartilage.
Fig. 2 is a set of graphs showing the effect of fraction P6 on the inhibition of the production of inflammatory markers, wherein fraction P6 is one of seven fractions obtained in the examples by fractionation of hydrolyzed type II collagen (HCII) of chicken cartilage.
FIG. 3 is a graph showing the effect of HCII, fraction P6 and P6 mixture (combination of cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine and tryptophan) on the inhibition of IL-6 production.
FIG. 4 is a graph showing the effect of HCII, fraction P6, P6 mixture (combination of cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, and tryptophan) and cyclo (Pro-Gly) (cPG) on the inhibition of MCP-1 production.
Fig. 5 is a graph showing the synergistic effect of the combination of hydrolyzed type II collagen (HCII) of chicken cartilage and Chicken Extract (CE) on the inhibition of the production of the inflammatory marker MIP-1 β.
FIG. 6(a) and FIG. 6(b) are graphs showing the effect of HCII, CE, fraction P6, the synergistic effect of the combination of HCII and CE, and the synergistic effect of the combination of fraction P6 and CE in inhibiting the production of the inflammation markers MCP-1 and MIP-1 β.
FIG. 7-1 FIGS. 7-1(a) and 7-1(b) are graphs showing the following synergistic effect on the inhibition of the production of the inflammation markers IL-6 and IL-8: a combination of HCII and CE, a combination of P6 mixture and CE, a combination of cPG and CE, a combination of cyclo (Ala-Hyp) (cAH) and CE, a combination of guanosine and CE, or a combination of tryptophan and CE.
FIG. 7-2 FIGS. 7-2(c) and 7-2(d) are graphs showing the synergistic effect of inhibiting the production of IL-9 and MCP-1, which are inflammatory markers, as follows: a combination of HCII and CE, a combination of P6 mixture and CE, a combination of cPG and CE, a combination of cAH and CE, a combination of guanosine and CE, or a combination of tryptophan and CE.
FIGS. 7-3(e) and 7-3(f) are graphs showing the synergistic effect of inhibiting the production of the inflammation markers MIP-1 β and RANTES as follows: a combination of HCII and CE, a combination of P6 mixture and CE, a combination of cPG and CE, a combination of cAH and CE, a combination of guanosine and CE, or a combination of tryptophan and CE.
Fig. 8 is a graph showing the effect of hydrolyzed type II collagen (HCII) of chicken cartilage and the combination of HCII and Chicken Extract (CE) on VAS pain scores at day 7 and day 14 intake for 14 days in each treatment group of subjects who underwent less than the tenth percentile of the total resistance training period (n ═ 8).
Detailed Description
In an embodiment of the invention, the composition of the invention comprises: at least one selected from the group consisting of cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and salts thereof; and chicken extract.
Loop (Ala-Hyp) and loop (Pro-Gly) are cyclodipeptides. Herein, the term "cyclic dipeptide" refers to a compound containing an amino acid as a structural unit and having a diketopiperazine structure generated by dehydration condensation of the amino group of an N-terminal amino acid and the carboxyl group of a C-terminal. Herein, the order of description of the amino acids in the cyclic dipeptide is not limited as long as the amino acid composition is the same. For example, cyclo (Ala-Hyp) and cyclo (Hyp-Ala) represent the same cyclic dipeptide.
Guanosine is a purine nucleoside and tryptophan is an amino acid.
The cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine and tryptophan can be obtained by hydrolysis of animal/plant protein, etc., or can be synthesized artificially. The cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine and tryptophan are preferably derived from hydrolyzed type II collagen; more preferably hydrolyzed type II collagen derived from chicken cartilage; and even more preferably in a fraction of hydrolyzed type II collagen derived from chicken cartilage and having a molecular weight of less than 1100 and a weight average molecular weight of 150-250 as determined by HPLC gel filtration. Herein, the "fraction of hydrolyzed type II collagen derived from chicken cartilage and having a molecular weight of less than 1100 and a weight average molecular weight of 150-250 as determined by HPLC gel filtration" is also referred to as "fraction 6".
Cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine and tryptophan may be purified prior to use, may be included in the composition in the form of fraction 6 containing these components, or may be included in the composition in the form of hydrolyzed type II collagen comprising fraction 6 of chicken cartilage. In a preferred embodiment, the composition of the invention comprises hydrolyzed type II collagen or fraction 6 of chicken cartilage. The composition of the invention comprising hydrolyzed type II collagen of chicken cartilage or fraction 6 showed higher anti-inflammatory effect.
The ring (Ala-Hyp), ring (Pro-Gly) and tryptophan may be included in the composition of the present invention in the form of a salt with an inorganic or organic acid or a salt with an inorganic or organic base. Such acids or bases may be selected based on the application of the salt. The following dietary or pharmaceutically acceptable salts are preferable in view of application to foods, beverages, and medicines. Examples of the inorganic acid salt include hydrochloride, nitrate, sulfate, methanesulfonate and p-toluenesulfonate. Examples of the organic acid salts include salts with dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, maleic acid, and fumaric acid, and salts with monocarboxylic acids such as acetic acid, propionic acid, and butyric acid. Examples of inorganic bases include hydroxides, carbonates and bicarbonates of sodium, lithium, calcium, magnesium and aluminium and of ammonia. Examples of the salt with an organic base include mono-alkylamine salts, di-alkylamine salts or tri-alkylamine salts (for example, salts of methylamine, dimethylamine and triethylamine), mono-hydroxyalkylamine salts, di-hydroxyalkylamine salts or tri-hydroxyalkylamine salts, guanidine salts and N-methylglucamine salts.
The guanosine in the composition of the invention may be phosphorylated guanosine.
Hydrolyzed type II collagen of chicken cartilage
The composition of the invention preferably comprises hydrolyzed type II collagen of chicken cartilage.
Hydrolyzed type II collagen of chicken cartilage (hereinafter, "hydrolyzed type II collagen of chicken cartilage" is sometimes referred to as "HCII") can be obtained by hydrolyzing the type II collagen with an enzyme or the like. Type II collagen can be extracted from chicken cartilage by known methods. The hydrolyzed type II collagen used in the chicken cartilage of the present invention can be prepared from cartilage by a method commonly used in the art.
For example, hydrolyzed type II collagen can be obtained by treating chicken cartilage with enzymes. In particular, hydrolyzed type II collagen can be prepared by: a pretreatment step (1) in which chicken cartilage is heated in a liquid, and a step (2) in which the chicken cartilage after the pretreatment step is treated with an enzyme. The enzyme used in step (2) is not limited as long as it is an enzyme commonly used in the art. Examples include collagenase, papain, bromelain, actinidin, ficin, cathepsin, pepsin, chymosin, trypsin, protease, subtilisin, aminopeptidase, endopeptidase and exopeptidase and enzyme preparations obtained by mixing these enzymes. The method of preparing the hydrolyzed type II collagen is not limited to the enzymatic treatment method.
The hydrolyzed type II collagen of chicken cartilage may be a solution obtained by hydrolyzing chicken cartilage, a concentrate of the solution, or a dry powder, or may be a purified product of the concentrate or the dry powder. The purified product of hydrolyzed type II collagen of chicken cartilage can be obtained by increasing the purity by, for example, subjecting a solution obtained by hydrolyzing chicken cartilage to ultrafiltration, membrane treatment, liquid separation operation, resin fractionation treatment, or the like. After increasing the purity of hydrolyzed type II collagen containing at least one selected from the group consisting of cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and salts thereof, the purified product may be powdered by, for example, freeze-drying or spray-drying.
Hydrolyzed type II collagen of chicken cartilage is a peptide mixture that typically contains a loop (Ala-Hyp), a loop (Pro-Gly), and/or one or more salts thereof, and may be considered collagen peptides derived from type II collagen.
The hydrolyzed type II collagen of chicken cartilage has a weight average molecular weight of preferably 100-. The molecular weight and weight average molecular weight can be measured by the Eurofins HPAEC-PAD method.
In embodiments, one fraction or a combination of two or more fractions obtained by fractionation by molecular weight of hydrolyzed type II collagen of chicken cartilage by a method such as gel filtration may be used in the composition of the present invention.
The fraction obtained by fractionation of the hydrolyzed type II collagen of chicken cartilage used in the composition of the present invention is preferably the above-mentioned fraction 6. In this embodiment, fraction 6 and fractions other than fraction 6 can be used in combination of the composition.
Chicken extract
The chicken extract (hereinafter sometimes referred to as "CE") used in the present invention may be an extract obtained by heating chicken used as a raw material in a liquid, or may be a commercially available product. The material may include bone, cartilage, legs, etc., but preferably the material does not contain head or internal organs.
Examples of commercially available products of Chicken Extract (CE) include "Brand's Essence of Chicken (BEC) (by Sun juice)&Produced by Food Asia Pte Ltd) "," Scotch TM Expression of Chicken (manufactured by Scotch Industrial Co., Ltd., Ltd.), "Quaker expression of Chicken (manufactured by Standard Foods Corporation Co., Ltd.)," "Chiken stock and cloth of SWANSON manufactured by Campbell Sound Company (NYSE: CPB)") TM "," Drip Chicken Essence manufactured by Eu Yan san International Ltd. (Singapore), "Boned Chicken Tonic manufactured by Eu Yan san International Ltd. (Singapore)," and "Boiled Essence of Chicken manufactured by Lao Xie Zhen Co. Ltd. (Taiwan province). Any such commercially available product may be used, but preferably Brand's Essence of Chicken (BEC) is used.
When the chicken extract used in the present invention is produced by hot water extraction, the chicken extract can be produced by a method commonly used in the art. For example, the chicken extract can be produced by performing normal pressure extraction and/or pressure extraction using a liquid having a temperature of 100 ℃ or higher, preferably 125 ℃ or higher, and treating the resulting extract with a membrane or filtering. Specifically, the extract was obtained by: a pre-treatment step (3) in which the chicken is heated in a liquid; and (4) replacing the liquid with fresh liquid after the pretreatment, and heating the chicken again. The heat treatment in each of step (3) and step (4) is preferably carried out in a solvent. For example, the solvent is preferably water, ethanol or a mixture thereof.
The chicken extract comprises liquid extract obtained by the above method; a dilute solution, concentrate or dry powder of the liquid extract; and purified products of these. The purified product can be obtained by, for example, subjecting the chicken extract to ultrafiltration, membrane treatment, liquid separation operation, or resin fractionation treatment to improve the purity. After increasing the purity of the chicken extract, the purified product can be powdered, for example, by freeze drying or spray drying.
The chicken extract used in the present invention preferably contains carnosine and/or anserine and/or one or more salts thereof. Carnosine is β -alanyl histidine, which is a dipeptide of β -alanine and histidine. Anserine is β -alanyl 1-methylhistidine in which the histidine is methylated.
Examples of the carnosine salt and the anserine salt include the same salts as the above-mentioned salts of the ring (Ala-Hyp), ring (Pro-Gly), and tryptophan.
When the composition of the present invention contains carnosine and/or a salt thereof, for example, the amount of carnosine and/or a salt thereof in the composition is preferably 0.00001 wt% or more, more preferably 0.0001 wt% or more, and preferably 10 wt% or less, more preferably 1 wt% or less, based on the carnosine. In an embodiment, for example, the amount of carnosine and/or a salt thereof in the composition is preferably from 0.00001 wt% to 10 wt%, more preferably from 0.0001 wt% to 1 wt%, based on carnosine.
When the composition of the present invention contains anserine and/or a salt thereof, for example, the amount of anserine and/or a salt thereof in the composition is preferably 0.00001 wt% or more, more preferably 0.0001 wt% or more, and preferably 10 wt% or less, more preferably 1 wt% or less, based on the anserine. In an embodiment, for example, the amount of anserine and/or its salts in the composition is from 0.00001 wt% to 10 wt%, more preferably from 0.0001 wt% to 1 wt%, based on anserine.
For example, carnosine, anserine and salts thereof can be quantified by HPLC. The food or drink composition of the present invention more preferably contains carnosine and/or a salt thereof and anserine and/or a salt thereof.
The weight ratio of the total weight of carnosine, anserine and salts thereof in terms of carnosine and anserine to the total weight of the ring (Ala-Hyp), ring (Pro-Gly), guanosine, tryptophan and salts thereof in free form (sum of carnosine and anserine/sum in free form) is preferably 1/15000-200/1. The weight ratio is more preferably 1/200 to 200/1, and still more preferably 1/50 to 50/1.
In the expression "cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and salts thereof in free form", the free form from the cyclo (Ala-Hyp) salt is cyclo (Ala-Hyp), the free form from the cyclo (Pro-Gly) salt is cyclo (Pro-Gly), the free form from the guanosine salt is guanosine, and the free form from the tryptophan salt is tryptophan.
The weight ratio of fraction 6 to the total of carnosine, anserine and salts thereof (fraction 6/total of carnosine and anserine) in terms of carnosine and anserine is preferably 1/100-10/1. The weight ratio is more preferably 1/100-5/1.
The weight ratio of hydrolyzed type II collagen (on a solid basis) of chicken cartilage to the sum of carnosine, anserine and salts thereof (HCII/sum of carnosine and anserine) is preferably 10000/1-10/1. The weight ratio is more preferably 1000/1-100/1.
The amount of each component of the composition of the present invention is not limited and may be set according to the form of the composition, etc.
For example, in an embodiment, the total amount of cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and salts thereof in the composition of the present invention is preferably 0.01 wt% or more, more preferably 0.1 wt% or more, and preferably 99 wt% or less, more preferably 90 wt% or less. For example, in embodiments, the total amount of cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and salts thereof in the composition is preferably from 0.01% to 99% by weight, more preferably from 0.1% to 90% by weight.
For example, in an embodiment, the amount of fraction 6 in the composition of the present invention is preferably 0.01 wt% or more, more preferably 0.1 wt% or more, and is preferably 99 wt% or less, more preferably 90 wt% or less. For example, in embodiments, the amount of fraction 6 in the composition is preferably 0.01 wt% to 99 wt%, more preferably 0.1 wt% to 90 wt%. Herein, the amount of fraction 6 comprises the amount of cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and salts thereof.
For example, in an embodiment, the amount of hydrolyzed type II collagen (on a solid basis) of chicken cartilage in the composition of the present invention is preferably 0.1 wt% or more, more preferably 0.5 wt% or more, and preferably 99 wt% or less, more preferably 90 wt% or less. For example, in an embodiment, the amount of hydrolyzed type II collagen (on a solids basis) of chicken cartilage in the composition is preferably 0.1 wt% to 99 wt%, more preferably 0.5 wt% to 90 wt%.
Herein, the amount of hydrolyzed type II collagen of chicken cartilage comprises the amount of cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and fraction 6.
For example, in an embodiment, the amount of chicken extract (on a solids basis) in the composition of the invention is preferably 0.1 wt% or more, more preferably 0.5 wt% or more, and preferably 99 wt% or less, more preferably 90 wt% or less. For example, in embodiments, the amount of chicken extract (on a solids basis) in the composition is preferably 0.1 wt% to 99 wt%, more preferably 0.5 wt% to 90 wt%. Herein, the amount of chicken extract (on a solids basis) comprises the amount of carnosine and anserine.
The composition of the present invention is preferably used as food, drink or medicine. Examples of the food or drink include general foods or drinks, functional purported foods (foods with functions), health promoting foods, foods for special diets, dietary supplements, health supplements, and general supplements. The form of the food or beverage is not limited. For example, it may be a solid food or a liquid food. Preferably a beverage.
The form of the drug is not limited. Non-limiting examples include oral preparations such as capsules, tablets, powders, granules and dry syrups; external preparations such as ointments, adhesive skin patches, eye drops, suppositories; and an injection. The medicament is preferably an oral preparation (oral medicine).
The compositions of the present invention may contain pharmaceutically or dietetically acceptable additives such as various carriers, excipients, diluents, acidulants, antioxidants, stabilizers, preservatives, flavoring or masking agents, emulsifiers, colors, seasonings, pH adjusting agents and nutritional enhancers.
The compositions of the invention are suitable for therapeutic use (medical use) and non-therapeutic use (non-medical use). "non-treatment" is a concept that does not include medical activities, i.e., a concept that does not include a method of surgery, treatment, or diagnosis in a human.
Anti-inflammatory composition
In embodiments, the compositions of the present invention may be used to reduce inflammation. The compositions of the present invention may be anti-inflammatory compositions. The composition can be an anti-inflammatory composition containing at least one selected from the group consisting of cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and salts thereof, and a chicken extract as active ingredients.
In order to achieve the anti-inflammatory effect contemplated by the present invention, at least one selected from the group consisting of cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and salts thereof, and chicken extract were added to the composition in the same manner as described above for the above composition. Hydrolyzed type II collagen containing chicken cartilage selected from at least one of the group consisting of cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and salts thereof, and chicken extracts may be used as they are, or a concentrate, dried powder or purified product thereof may be added as described above, as long as the effect of the present invention is not impaired. The same additives as described above may be used. The same additives as described above may be used.
The composition of the invention is preferably fed orally (oral administration). The dosage (also referred to as "intake") of the composition of the present invention is not limited. The dose of the composition of the present invention may be appropriately determined depending on the body weight of the subject or the like, as long as the effect of reducing inflammation is achieved.
In an embodiment, when the composition of the present invention is orally fed or administered to a human (adult), the total dose of cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and salts thereof in free form per 60kg body weight per day is preferably 0.01mg or more, more preferably 0.1mg or more, and preferably 2000mg or less, more preferably 1000mg or less. In embodiments, the total dose of cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and salts thereof in free form per day per 60kg body weight in humans (adults) is preferably 0.01mg to 2000mg, more preferably 0.1mg to 1000 mg.
In an embodiment, when the composition of the invention is fed or administered orally to a human (adult), the dose of fraction 6 per 60kg body weight per day is preferably 0.01mg or more, more preferably 0.1mg or more, and preferably 2000mg or less, more preferably 1000mg or less. In embodiments, for humans (adults), the dose of fraction 6 per day per 60kg body weight is preferably 0.01mg-2000mg, more preferably 0.1mg-1000 mg.
Herein, the dose of fraction 6 contained the amount of cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and their salts.
In an embodiment, the dose (in solids) of hydrolyzed type II collagen per 60kg body weight per day of chicken cartilage is preferably 0.01mg or more, more preferably 0.1mg or more, and also preferably 4000mg or less, more preferably 3000mg or less, when the composition of the invention is orally fed or administered to a human (adult). In an embodiment, the dose of hydrolysed type II collagen (as solids) per 60kg body weight per day of chicken cartilage in humans (adults) is preferably 0.01mg to 4000mg, more preferably 0.1mg to 3000 mg.
Herein, the dose of hydrolyzed type II collagen of chicken cartilage contains the amount of cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and their salts or the amount of fraction 6.
In an embodiment, when the composition of the present invention is orally fed or administered to a human (adult), the dose (in terms of solids) of the chicken extract per day per 60kg body weight is preferably 0.1mg or more, more preferably 1mg or more, and is also preferably 15000mg or less, more preferably 13000mg or less. In an embodiment, the dose of chicken extract (on a solid basis) per 60kg body weight per day for humans (adults) is preferably 0.1mg-15000mg, more preferably 1mg-13000 mg. The dosage of chicken extract comprises the amount of carnosine, anserine and salts thereof.
In an embodiment, when the composition of the present invention is orally fed or administered to a human (adult), the total dose of carnosine, anserine, and salts thereof per day per 60kg body weight in terms of carnosine and anserine is preferably 0.001mg or more, more preferably 0.01mg or more, and further preferably 500mg or less, more preferably 400mg or less. In an embodiment, the total dose of carnosine, anserine and salts thereof fed to a human (adult) per 60kg of body weight per day, in terms of carnosine and anserine, is preferably 0.001mg to 500mg, more preferably 0.01mg to 400 mg.
In embodiments, the above amount of hydrolyzed type II collagen of chicken cartilage comprising cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and/or one or more salts thereof and the above amount of chicken extract are preferably fed or administered at least once daily, such as once or several times daily (e.g., 2 or 3 times). In an embodiment, the above amount of hydrolyzed type II collagen of chicken cartilage comprising cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and/or one or more salts thereof and the above amount of chicken extract are preferably fed or administered orally to a human. In an embodiment, the composition of the invention may be used for feeding or administering the above amount of hydrolyzed type II collagen of chicken cartilage comprising cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and/or one or more salts thereof as well as the above amount of chicken extract to a human (per 60kg body weight per day).
In embodiments, when feeding the composition of the invention to achieve an anti-inflammatory effect, it is preferred to feed the above amount of hydrolyzed type II collagen of chicken cartilage comprising cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and/or one or more salts thereof, and the above amount of chicken extract.
The compositions of the present invention inhibit the production of cytokines such as activation regulated normal T cell expressed and secreted factor (RANTES), monocyte chemoattractant protein-1 (MCP-1), interleukin 6(IL-6), interleukin 8(IL-8), interleukin 9(IL-9), and macrophage inflammatory protein-1 (MIP-1). The compositions of the invention are particularly effective in inhibiting the production of RANTES, MCP-1, IL-6, IL-8, IL-9 and MIP-1 β.
By inhibiting cytokine production, inflammation in vivo can be reduced.
The compositions of the present invention are useful for preventing or alleviating an inflammatory condition or disease. An inflammatory disorder or disease is, for example, a disorder or disease caused by inflammation or a disorder or disease accompanied by inflammation. Examples of such conditions or diseases include collagen diseases such as arthritis and rheumatoid arthritis, inflammatory bowel disease, osteoarthritis, tendonitis, sciatica, herniated intervertebral disc, stenosis, myelopathy, back pain, facet joint pain, carpal tunnel syndrome, tarsal tunnel syndrome, post-lumbar surgery pain syndrome, AIDS, arteriosclerosis, asthma, arthritis, diabetes, hepatitis, stroke, dementia, muscular dystrophy, viral infections, skin aging including photoaging, cancer, aging, allergic diseases, Parkinson's disease, cerebral infarction, cataracts, epilepsy, spinal cord injury, retinopathy of prematurity, nephropathy, peptic ulcer, pancreatitis, ulcerative colitis, myocardial infarction, adult respiratory distress syndrome, emphysema, vasculitis, edema, diabetic complications, UV injury, altitude sickness, porphyria, burns, frostbite, cold injury, pancreatitis, ulcerative colitis, myocardial infarction, inflammatory bowel disease, spinal cord disease, arthritis, muscle atrophy, viral infection, skin aging, allergic diseases, Parkinson's disease, cataract, epilepsy, and other diseases, Contact dermatitis, shock, multiple organ failure, DIC, fatigue, sarcopenia (muscle weakness), mitochondrial dysfunction, Alzheimer's disease, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, and systemic lupus erythematosus (lupus). The composition of the present invention is preferably used for preventing or alleviating these diseases. In particular, the food or drink composition is preferably used for preventing or alleviating diseases such as osteoarthritis, rheumatoid arthritis, and psoriatic arthritis.
As used herein, prevention of a condition or disease includes prevention of onset of disease, delay of onset of disease, reduction in incidence of disease, reduction in risk of onset of disease, and the like. Alleviation of a disorder or disease includes recovery of the subject from the disorder or disease, alleviation of symptoms of the disorder or disease, amelioration of symptoms of the disorder or disease, delay or prevention of progression of the disorder or disease, and the like.
The subject to which the composition of the present invention is fed or administered (which may also be referred to as "subject") is not limited. The subject is preferably a human or non-human mammal, more preferably a human.
In embodiments, the subject may be one who needs or wants to inhibit inflammation. Such a subject may be, for example, one in need or desire to prevent or reduce inflammation, or one in need or desire to prevent or reduce an inflammatory disorder or disease. In embodiments, the subject of the invention may be a middle aged or elderly human. The compositions of the present invention may also be used by healthy people, for example, for the purpose of preventing a condition that can be prevented or alleviated by attenuating inflammation.
The compositions of the present invention may be labeled with functional claims that demonstrate effects through attenuation of inflammation. Such tags are also referred to as tags with functional claims, and the content of the tags is not limited. Examples of such functional claims on the label include "alleviating joint pain", "attenuating joint pain", "managing knee condition", "maintaining knee health", "improving joint mobility", and other functional claims equivalent to the above.
In an embodiment of the present invention, the composition of the present invention is preferably a food or beverage, and more preferably a beverage, which is marked with the above-mentioned functional claims. The label may describe the use of the composition of the invention to achieve the above-described functionality. The label may be added to the composition itself or to a container or package for the composition.
Production method
The present invention also relates to a method for producing a composition comprising mixing at least one selected from the group consisting of cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and salts thereof with a chicken extract.
In this mixture, cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and/or one or more salts thereof may be directly mixed with the chicken extract. However, it is preferable to mix hydrolyzed type II collagen of chicken cartilage containing cyclo (Ala-Hyp) or the like with a chicken extract to produce a composition. In this case, for example, a hydrolysate obtained by hydrolyzing type II collagen of chicken cartilage with an enzyme or the like can be directly used for mixing with a chicken extract. As described above, fraction 6 containing a ring (Ala-Hyp) or the like of the hydrolyzed type II collagen derived from chicken cartilage, or a concentrate, dry powder or purified product of the hydrolyzed type II collagen of chicken cartilage may be added as long as the effect of the present invention is not impaired.
In the production method of the present invention, the order of adding the raw materials is not limited. For example, the following may be placed in a container first, and then the chicken extract added: cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and/or one or more salts thereof, or fraction 6, or hydrolyzed type II collagen of chicken cartilage comprising these components. Alternatively, the chicken extract may be placed in a container first, followed by addition of cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and/or one or more salts thereof, or fraction 6 or hydrolyzed type II collagen of chicken cartilage containing these components.
In the production method of the present invention, preferred embodiments of the hydrolyzed type II collagen of chicken cartilage are as described above. Preferred embodiments of the chicken extract are described above.
In the production method of the present invention, the chicken extract preferably contains carnosine and/or anserine and/or one or more salts thereof.
In the production method of the present invention, a commercially available chicken extract or a chicken extract produced by hot water extraction may be directly mixed with: cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and/or one or more salts thereof, or fraction 6 or hydrolyzed type II collagen of chicken cartilage containing these components. However, for example, when the chicken extract is in the form of a concentrate, a dry powder, or a purified product of a concentrate or a dry powder, the chicken extract may be diluted, dissolved, or the like in a liquid (e.g., water, ethanol, or a mixture of water and ethanol), and then mixed with: cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and/or one or more salts thereof, or fraction 6 or hydrolyzed type II collagen of chicken cartilage containing these components. When fraction 6 of hydrolyzed type II collagen of chicken cartilage containing cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and/or one or more salts thereof is in the form of a concentrate, a dry powder, or a purified product thereof, such product may be similarly diluted, dissolved, etc. in a liquid or the like prior to addition. Alternatively, such a product may be added without prior dilution, dissolution, or the like, and then mixed with a liquid to be diluted, dissolved, or the like in the liquid.
The composition produced in the production method of the present invention may contain the above-mentioned additives in addition to cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and/or one or more salts thereof and hydrolyzed type II collagen of chicken cartilage and chicken extract.
The invention also relates to the use of at least one selected from the group consisting of cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and their salts and of chicken extracts for producing an anti-inflammatory composition.
Examples of anti-inflammatory compositions include compositions similar to the compositions described above, comprising: cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and/or one or more salts thereof, and chicken extract. Cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and/or one or more salts thereof may be used in fraction 6 or in the form of hydrolyzed type II collagen of chicken cartilage containing these components. The same chicken extract and the same additives as described above can be used.
Examples
The present invention is described more specifically below with reference to examples. The invention is not limited to the embodiments described.
The raw materials, reagents and the like used in the following examples and comparative examples are as follows.
Preparation of hydrolyzed type II collagen from chicken cartilage
FIG. 1 shows a flow chart schematically describing the process for the preparation of HCII. First, frozen chicken cartilage was thawed in water at 40 ℃ and washed in water at 40 ℃ (1 hour). Next, the washing water was poured off, and the clear water was poured into a 1200L pot to make it 3 times as much as the chicken cartilage. The water was heated to the optimum working temperature for the enzyme treatment and the washed chicken cartilage was immersed therein for the enzyme treatment for several hours. After the enzyme treatment, the pot containing the chicken cartilage was heated to 90 ℃ or higher and incubated at 90 ℃ or higher for 30 minutes, thereby inactivating the enzyme used in the previous enzyme treatment. The resulting mixture (liquid and enzyme treated chicken cartilage) was filtered. The resulting liquid was concentrated. Finally, the resulting concentrate was spray-dried at 200 ℃, thereby preparing HCII powder.
Determination of the molecular weight of HCII powder
The molecular weight distribution of the resulting HCII was determined by the Eurofins HPAEC-PAD method. Table 1 below shows the molecular weight distribution of the resulting HCII. The resulting HCII had a weight average molecular weight of 4582, calculated using methods common in the art.
TABLE 1
Fractionation of HCII fractions
(materials and methods for HCII fractionation and biological Activity identification)
(Material)
Formic acid was purchased from Tokyo Chemical Industry co. Ultrapure water was obtained from Merck Milli-Q water purification system.
(preparative Gel Permeation Chromatography (GPC))
Fractionation of HCII was performed using a preparative VERITY 271HPLC system (Gilson). HCII was dissolved in ultrapure water to prepare a solution of 10mg/mL (w/v). After centrifugation at 14000rpm for 5 minutes, a 1000. mu.L aliquot was injected onto a preparative GPC column (BioSep 5. mu.m SEC-s 2000) attached to a guard column (SecurityGuard PREP card C1215X 21.2mm ID (Phenomenex))LC column 300 × 21.2mm (phenomenex)), and eluting with eluent a (ultrapure water: formic acid 100:0.1(v/v)) was eluted at a rate of 5mL/min for 30 minutes in an isocratic manner. Chromatograms were observed at 214 nm.
Fractions were collected every 0.5 min between 8 min to 28 min using a GX series fraction collector (Gilson), and the 40 individual fractions obtained were subsequently combined into 7 fractions, P1-P7 (P1: 8.5-12.0 min, P2: 12.0-13.5 min, P3: 13.5-14.5 min, P4: 14.5-16.0 min, P5: 16.0-17.5 min, P6: 17.5-19.0 min, P7: 19.0-27.5 min). The combined fractions were evaporated to dryness in a lyophilizer (ScanVac) and the dried samples were stored at-20 ℃ until further use.
In addition, table 2 shows the molecular weights of the fractions obtained above. In table 2, "Mw" and "Mp" represent the weight average molecular weight and the peak molecular weight, respectively. As shown in table 2, fraction 6(P6) consisted of typical small molecules with a molecular weight of less than 300.
The molecular weights of the fractions of HCII were measured by HPLC gel filtration under the following conditions.
The instrument comprises the following steps: agilent 1100 series
And (3) detection: UV 214nm
Flow rate: 1mL/min
Mobile phase: isocratic 0.1mM sodium phosphate buffer pH 6.8
Operating time: 20 minutes
TABLE 2
Fraction(s) of | Mw | Mp |
P1 | 1359 | 1626 |
P2 | 1092 | 1494 |
P3 | 1035 | 956 |
P4 | 784 | 783 |
P5 | 422 | 213 |
P6 | 211 | 225 |
Identification of the major component of fraction P6
By Phenomenex, Luna on an Agilent HPLC 1100 line TM The main component of Omega 5 μm PS C18100A 250 × 4.6mm fraction P6 was separated and eluted with eluent a (ultrapure water: formic acid: 100:0.1(v/v)) and eluent B (acetonitrile: formic acid: 100:0.1(v/v)) using the following linear gradient: 0-4.0 min: 100% eluent A; 4.0-12.0 min: 0-90% of eluent A; 12.0-15.5 minutes: 90-80% of eluent A; 15.5-17.0 min: 80% -15% of eluent A; 17.0-18.0 min: linear 15% eluent a; 18.0-19.0 min: 15% -100% of eluent A; and 19.0-21.0 minutes: 100% eluent A. The sample volume was 10 μ L, the flow rate was 1mL/min, and the UV absorbance of the eluate was monitored at 214 nm. The eluate was collected with a fraction collector equipped. Then mixing fourFractions were freeze dried and subsequently reconstituted in purified water for LC-MS analysis on an Agilent HPLC 1290 series coupled triple TOF 5600(AB Sciex) with a Duo Spray Turbo V ion source and gas generator (Peak Scientific). Some fractions were also subjected to proton-NMR experiments and characterized on Bruker ECA 400. The identity of the major component in the P6 fraction has been confirmed by commercially available chemicals.
Free amino acids in the HCII fraction were detected and quantified according to the AOAC 999.13 method.
According to the analysis results, the main components in fraction P6 were cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine and tryptophan.
Quantification of Loop (Ala-Hyp) and Loop (Pro-Gly)
The ring (Ala-Hyp) was reconstituted in ultra pure water and injected into a Zorbax Eclipse Plus C18 RRHD 1.8 μm 2.1 x 50mm column (Agilent) with UHPLC Guard Zorbax Eclipse Plus C182.1 x 5mm 1.8 μm (Agilent) and eluted with eluent a (ultra pure water: formic acid 100:0.1(v/v)) and eluent B (acetonitrile: formic acid 100:0.1(v/v)) using the following linear gradient: 0-0.5 min: 100% eluent A; 0.5-7.5 minutes: 100% -65% of eluent A; 7.5-10.0 min: 65% -0% of eluent A; 11.0-13.0 min: 0% eluent A; 13.0-13.1 min: 0-100% of eluent A; and 13.1-15.0 minutes: 100% eluent A.
The sample volume was 10. mu.L, the flow rate was 300. mu.L/min, and the UV absorbance of the eluate was monitored at 214 nm. The Collision Energy (CE) and Declustering Potential (DP) of the MS were optimized to 27.0V and 100V, respectively. The loop (Ala-Hyp) was detected at m/z 185.1/86.1 using Q1/Q3 ion transition, using a retention time of 2.45 min as quantitative and qualitative. Calibration curves were constructed by injecting standard loops (Ala-Hyp) of 31.25ng/mL, 62.5ng/mL, 125ng/mL or 250ng/mL into the mass spectrometer. Fraction P6 was redissolved to a solution of 100. mu.g/mL as the working solution. Quantification of the loop (Ala-Hyp) in fraction P6 was done by Sciex OS (AB Sciex).
The ring (Pro-Gly) was redissolved in ultrapure water and injected into a Zorbax Eclipse Plus C18 RRHD 1.8 μm 2.1 × 50mm chromatography column (Agilent) with UHPLC Guard Zorbax Eclipse Plus C182.1 × 5mm 1.8 μm (Agilent) and eluted with eluent a (ultrapure water: formic acid 100:0.1(v/v)) and eluent B (acetonitrile: formic acid 100:0.1(v/v)) using the following linear gradient: 0-0.5 min: 100% eluent A; 0.5-7.5 minutes: 100% -65% of eluent A; 7.5-10.0 min: 65% -0% of eluent A; 11.0-13.0 min: 0% eluent A; 13.0-13.1 min: 0-100% eluent A; and 13.1-15.0 minutes: 100% eluent A.
The sample volume was 10. mu.L, the flow rate was 300. mu.L/min, and the UV absorbance of the eluate was monitored at 214 nm. The Collision Energy (CE) and Declustering Potential (DP) of the MS were optimized to 30.0V and 100V, respectively. The loop (Pro-Gly) was detected at m/z 70.1/127.1Th using Q1/Q3 ion transition, using a retention time of 2.6 minutes as quantitative and qualitative. Calibration curves were constructed by injecting standard loops (Pro-Gly) of 70ng/mL, 140ng/mL, 280ng/mL or 560ng/mL into the mass spectrometer. Fraction P6 was reconstituted to a 100. mu.g/mL solution as the working solution. The quantification of the loop (Pro-Gly) in fraction P6 was done by Sciex OS (AB Sciex).
Quantitation of guanosine
Guanosine was reconstituted in ultrapure water and injected into a Zorbax Eclipse Plus C18 RRHD 1.8 μm 2.1 × 50mm column (Agilent) with UHPLC Guard Zorbax Eclipse Plus C182.1 × 5mm 1.8 μm (Agilent) and eluted with eluent a (ultrapure water: formic acid 100:0.1(v/v)) and eluent B (acetonitrile: formic acid 100:0.1(v/v)) using the following linear gradient: 0-0.5 min: 100% eluent A; 0.5-10.5 minutes: 100% -0% of eluent A; 10.5-14.0 min: 0% eluent A; 14.0-16.1 min: 0-100% eluent A; and 16.1-18.0 minutes: 100% eluent A. The sample volume was 10. mu.L, the flow rate was 300. mu.L/min, and the ultraviolet absorbance of the eluate was monitored at 214 nm. The Collision Energy (CE) and Declustering Potential (DP) of the MS were optimized to 10.0V and 80V, respectively. Guanosine was detected at m/z 152.1/284.1Th using Q1/Q3 ion transitions, using a retention time of 2.17 minutes as a quantitative and qualitative measure. Calibration curves were constructed by injecting standard guanosine at 31.25ng/mL, 62.5ng/mL, 125ng/mL, or 250ng/mL into the mass spectrometer. P6 was redissolved as a 100. mu.g/mL solution as the working solution. The quantification of guanosine in P6 was done by Sciex OS (AB Sciex).
Assuming that the total weight of HCII is 100 wt%, HCII contains 0.23 wt% of cyclo (Ala-Hyp), 0.30 wt% of cyclo (Pro-Gly), 0.10 wt% of guanosine and 0.132 wt% of tryptophan.
Quantification of carnosine and anserine
Quantitation of carnosine and anserine in chicken extracts was performed by HPLC under the following conditions.
A standard stock solution of carnosine was prepared by adding and dissolving carnosine powder in deionized water to a carnosine concentration of 2.50 mg/ml. The anserine standard stock solution was prepared by adding and dissolving L-anserine nitrate powder in deionized water to a L-anserine concentration of 3.96 mg/ml.
The weight of L-anserine was calculated by the following formula.
L-anserine (g) ═ 0.792 XL-anserine nitrate (g)
Analytical conditions of HPLC
The device comprises the following steps: high performance liquid chromatography system with UV detector (Agilent 1100 from Agilent Corp.)
Column: zorbax 300-SCX 4.6mm ID X250 mm (Agilent)
Mobile phase: 50mM potassium dihydrogen phosphate
Flow rate: 1.0mL/min
A flow channel: channel A (50mM potassium dihydrogen phosphate), channel B (acetonitrile), channel D (deionized water)
Wavelength of ultraviolet detector: 210nm
Sample injection volume: 10 μ L
Method for evaluating anti-inflammatory activity
In examples and comparative examples, the effect of inhibiting the production of inflammatory markers was evaluated by the following method.
(raw materials and reagents)
Chicken Extract (CE): brand's Essence of Chicken (Sun fashion Beverage & Food Asia Pte Ltd, carnosine content in 1 ml: 0.94mg/ml, anserine content in 1 ml: 1.9mg/ml)
Chondrocyte Culture Medium (CM), Fetal Bovine Serum (FBS), Chondrocyte Growth Supplement (CGS), and penicillin/streptomycin (P/S): ScienCell Research Laboratories
IL-1β:R&D Systems
Poly-L-lysine (PLL) -coated 96-well plates (Corning)
Cell culture and pretreatment
Human chondrocytes were isolated from human articular cartilage (HC-a, science cell Research Laboratories) and maintained in CM supplemented with 5% FBS, 1% CGS and 1% P/S. Cells were seeded at a cell density of 4000 cells/well in PLL-coated 96-well plates and at 37 ℃ in the presence of 5% CO 2 Incubated overnight in the humidified chamber of (1). Chondrocytes were washed once with PBS and treated as follows: chicken Extract (CE), HCII, fraction P6 fractionated from HCII, a combination of fraction P6 and CE, a P6 mixture containing cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine and tryptophan, a combination of P6 mixture and CE, cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan, or a combination of CE and any of cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine or tryptophan. After 24 hours of treatment, chondrocytes were further treated for 24 hours by adding 25ng/mL of IL-1 β. Cells were centrifuged at 1100g for 5 minutes and the supernatant was used for cytokine analysis. For comparison, cells treated with IL-1 β (IL-1 β -treated cells) without pretreatment with CE, HCII, fractions P6, P6 mixture, cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan were prepared.
Multiplex cytokine assay
Pro-Human Cytokine Multiplex Assays (Bio-Rad) were used to analyze cytokines in the media. The following 27 re-analyses were performed: IL-1 beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8(CXCL8), IL-9, IL-10, IL-12, IL-13, IL-15, IL-17, eotaxin (CCL11), macrophage colony stimulating factor (M-CSF), Interferon (IFN) -gamma, monocyte chemotactic protein 1 (MCP-1; CCL2), macrophage inflammatory protein-1 alpha (MIP-1 alpha; CCL3), MIP-1 beta (CCL4), stimulated regulation of normal T cell expression and secretion factor (TES RANs) (CCL5), TNF-alpha and Vascular Endothelial Growth Factor (VEGF). Multiplex assays were performed according to the manufacturer's instructions and run on the Luminex xPONENT for madix platform. Bio-Plex Manager version 6.0 was used for data processing. Cytokine and chemokine concentrations were calculated by reference to standard curves. The sensitivity of the multiplex kit was <5 pg/mL.
Statistical analysis
Statistical analysis was performed using GraphPad Prism version 5.0 (GraphPad). All results are expressed as mean ± standard deviation. Statistical analysis was performed by analysis of variance (ANOVA), followed by a post hoc Tukey multiple comparison test. Data were considered significant when p < 0.05.
Comparative example 1 Effect of fraction P6 on suppressing production of inflammatory marker
To evaluate the effect of HCII and fraction P6 fractionated from HCII on inflammatory markers (RANTES, MCP-1, IL-6, IL-8, IL-9 and MIP-1. beta.) produced by human chondrocytes, the following four different conditions were compared: cells before treatment (untreated control), cells treated with IL-1. beta. + HCII (comparative example 1), and cells treated with IL-1. beta. + fraction P6 (comparative example 1). HCII treated cells and fraction P6 treated cells were pretreated with HCII or fraction P6. In the pretreatment, the concentration of HCII was 5mg/ml and the concentration of fraction P6 was 5 mg/ml.
As shown in figure 2, 25ng/mL of IL-1 β induced inflammation in human chondrocytes, resulting in a significant increase in the levels of all inflammatory markers compared to untreated cells (control). Pretreatment of cells with HCII or fraction P6 reduced the levels of all inflammatory markers induced by IL-1 β. Data are presented as mean ± SD (n ═ 3). Unless otherwise stated, a significant difference of p <0.05, indicates p <0.01, and indicates p <0.001, compared to IL-1 β (IL-1 β treated cells).
Comparative example 2 Effect of combination of Cyclo (Ala-Hyp), Cyclo (Pro-Gly), guanosine and Tryptophan (P6 mixture) on inhibition of IL-6 production as an inflammation marker
To evaluate the effect of P6 mixture containing cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine and tryptophan (the proportions of these components are the same as in HCII) on the inflammatory marker IL-6 produced by human chondrocytes, the following five different conditions were compared: cells before treatment (untreated control), cells treated with IL-1 β + HCII (comparative example 2), cells treated with IL-1 β + fraction P6 (comparative example 2), and cells treated with IL-1 β + P6 mixture (comparative example 2). HCII treated cells, fraction P6 treated cells, and P6 mixture treated cells were pretreated with HCII, fraction P6, or P6 mixture. In the pretreatment, the concentration of HCII was 5mg/ml, the concentration of fraction P6 was 5mg/ml, and the concentration of the P6 mixture was 100 mg/ml.
As shown in fig. 3, 25ng/mL of IL-1 β induced inflammation in human chondrocytes, resulting in a significant increase in IL-6 levels, compared to untreated cells (control). Pretreatment of cells with HCII, P6 or P6 cocktail reduced the level of the inflammatory marker IL-6 induced by IL-1 β. Data are presented as mean ± SD (n ═ 3). Indicates a significant difference of p <0.05, indicates p <0.01, and indicates p <0.001, compared to IL-1 β.
Comparative example 3 Effect of the combination of Loop (Pro-Gly) and Loop (Ala-Hyp), Loop (Pro-Gly), guanosine and Tryptophan (P6 mixture) on the inhibition of the production of inflammation marker MCP-1(MCAF)
To evaluate the effect of a mixture of P6 comprising cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine and tryptophan in the same proportions as in HCII, and cyclo (Pro-Gly) (cPG) on MCP-1(MCAF), an inflammatory marker produced by human chondrocytes, six different conditions were compared: cells before treatment (untreated control), cells treated with IL-1 β + HCII (comparative example 3), cells treated with IL-1 β + fraction P6 (comparative example 3), cells treated with IL-1 β + P6 mixture (comparative example 3), and cells treated with IL-1 β + cPG mixture (comparative example 3). HCII treated cells, fraction P6 treated cells, P6 mixture treated cells, and cPG treated cells were pretreated with HCII, fraction P6, P6 mixture, or cPG. In the pretreatment, HCII was at a concentration of 5mg/ml, fraction P6 was at a concentration of 5mg/ml, the P6 mixture was at a concentration of 100mg/ml, and cPG was at a concentration of 50mg/ml, 100mg/ml, or 250 mg/ml.
As shown in fig. 4, IL-1 β at 25ng/mL induced inflammation in human chondrocytes, resulting in a significant increase in MCP-1(MCAF) levels compared to untreated cells (control). Pre-treatment of cells with HCII, P6, loop (Pro-Gly) or P6 cocktail reduced the level of MCP-1(MCAF), an inflammatory marker induced by IL-1 β. Data are presented as mean ± SD (n ═ 3). Indicates a significant difference of p <0.05, p <0.01, and p <0.001, compared to IL-1 β.
Example 1 synergistic Effect of HCII in combination with CE
To evaluate the synergistic effect of the combination of HCII and CE on the inhibition of the production of the inflammatory marker MIP-1 β, pre-treatment was performed with HCII alone, CE alone or a combination of HCII and CE. In the pretreatment, the concentration of HCII was 0.5mg/ml, and the concentration of CE was 1.25 mg/ml.
As shown in FIG. 5, the combination of 0.5mg/mL HCII and 1.25mg/mL CE provided a synergistic effect in reducing inflammation compared to treatment with HCII or CE alone. Data are presented as mean ± SD (n ═ 3). Unless otherwise stated, indicates a significant difference of p <0.05, p <0.01, and p <0.001, compared to IL-1 β (IL-1 β treated cells).
Example 2 synergistic Effect of the combination of HCII with CE and the combination of fraction P6 with CE on inhibiting the production of the inflammation markers MCP-1 and MIP-1 β
To evaluate the synergistic effect of the combination of HCII and CE and the synergistic effect of the combination of fraction P6 and CE in inhibiting the production of the inflammatory markers MCP-1 and MIP-1 β, pre-treatment with IL-1 β and either HCII alone, CE alone, P6 alone, HCII in combination with CE, or P6 in combination with CE was performed as described in example 1. In the pretreatment, the concentration of HCII was 2.5mg/mL or 5mg/mL, the concentration of P6 was 2.5mg/mL or 5mg/mL, and the concentration of CE was 6.25 mg/mL.
Fig. 6(a) and 6(b) show the results. Data are presented as mean ± SD (n ═ 3). Unless otherwise stated, a significant difference of p <0.05, indicates p <0.01, and indicates p <0.001, compared to IL-1 β (IL-1 β treated cells).
Example 3 synergistic effects of combination of HCII with CE, combination of P6 mixture with CE, combination of cyclo (Pro-Gly) and CE, combination of cyclo (Ala-Hyp) with CE, combination of guanosine with CE, and combination of tryptophan with CE to inhibit production of inflammatory markers
To evaluate the synergistic effect of HCII in combination with CE, P6 cocktail in combination with CE, cyclo (Pro-Gly) (cPG) in combination with CE, cyclo (Ala-Hyp) (cAH) in combination with CE, guanosine in combination with CE, and tryptophan in combination with CE in inhibiting the production of the inflammatory markers IL-6, IL-8, IL-9, MCP-1, MIP-1 β and RANTES, a pretreatment as described in example 1 was performed. In the pretreatment, HCII was at a concentration of 2.5mg/mL, P6 mixture was at a concentration of 25mg/mL, 125mg/mL, or 250mg/mL, cPG was at a concentration of 25mg/mL, 125mg/mL, or 250mg/mL, cAH was at a concentration of 25mg/mL, 125mg/mL, or 250mg/mL, guanosine was at a concentration of 25mg/mL, 125mg/mL, or 250mg/mL, tryptophan was at a concentration of 25mg/mL, 125mg/mL, or 250mg/mL, and CE was at a concentration of 6.25 mg/mL.
The results are shown in FIG. 7-1(a), FIG. 7-1(b), FIG. 7-2(c), FIG. 7-2(d), FIG. 7-3(e) and FIG. 7-3 (f). Data are presented as mean ± SD (n-3). Unless otherwise stated, indicates a significant difference of p <0.05, p <0.01, and p <0.001, compared to IL-1 β (IL-1 β treated cells).
Example 4 randomized, double-blind, four-arm trial study to evaluate the effects of HCII and CE on knee pain
This experimental study was conducted as a double-blind, randomized, placebo-controlled study in a single center.
(Subjects are grouped and randomized)
A total of 160 subjects 45-75 years of age were selected using inclusion and exclusion criteria summarized in table 3. Subjects were randomly assigned to four groups, namely "placebo", "glucosamine", "HCII" and "HCII and CE". Each group included 40 subjects.
TABLE 3
(products of investigation)
The "placebo" group took a mixture of 6.8g maltodextrin and 7mg xanthan gum.
Glucosamine the group was given 1.5g glucosamine hydrochloride. Glucosamine hydrochloride served as the activity comparator.
The "HCII" group was administered BRAND' S Collagen Hydrolysate (Sun liver juice & Food Asia Pte Ltd), which is a hydrolyzed chicken sternal cartilage extract consisting of hydrolyzed type II Collagen (HCII) and a naturally occurring matrix of low molecular weight chondroitin sulfate and Hyaluronic Acid (HA). The product comprises HCII containing cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine and tryptophan. Each bottle with a capacity of 68mL contained 2g of HCII, providing a naturally occurring composition of HCII (66.5%), depolymerized chondroitin sulfate (18%) and HA (11%). The uncharacterized thoracic cartilage component accounted for the remaining 4.5%.
The "HCII and CE" group took 68mL of the following mixture: 70g (5-6 g dry weight) of BRAND' S Essence of chicken (BEC) and 2g of HCII. All test products were made as liquid products in glass bottles, which were isocaloric, identical in appearance, and identical in flavor and texture. Participants had to take the study product once a day in the morning after meals.
Subjects were allowed to continue to take concomitant medications or supplements that were not believed to affect the results of the study. Analgesics or painkillers are allowed as prescribed rescue medication. The proportion of days of analgesic coverage (PDC) was calculated based on the record of the fraction of concomitant medication of the analgesic and was defined as the percentage of days of analgesic coverage to the total days of the interval between visits. Any treatment or dietary supplement that could support joint, bone and muscle health was banned throughout the study including: hormone therapy (growth hormone, progesterone, estrogen or testosterone), calcium and vitamin D, supplements rich in amino acids, peptides, proteins, omega-3, omega-6, glucosamine or chondroitin.
(procedure)
The study included a screening visit (28 days prior to baseline visit), a subsequent baseline visit (baseline visit considered day 0. screening and baseline visits may be on the same day), and 3 follow-up visits (weeks 8, 16, and 24). Subjects were screened from day-28 to day 0 to determine the eligibility of the study. Test product intake started the day after baseline visit for 168 consecutive days (24 weeks). For 168 consecutive days (24 weeks), subjects took one bottle of test product each morning (after meals). Intake compliance was recorded on a diary card.
Visual Analog Scale (VAS) of knee pain was scored at day 0, day 7 and day 14 post-ingestion.
During the study, subjects were advised to perform resistance training (optionally) twice a week at home, 30 minutes each, following the training program. The training is recorded on a diary card. The diet of the previous week of the visit was recorded using a food questionnaire.
(treatment compliance)
Compliance with study product intake was checked by collecting unused product and daily food records kept by subjects. Compliance was defined as the percentage of the indicated dose actually consumed in the days between visits. Consumption of 70% is considered compliant.
(exercise program)
All subjects were encouraged to perform 30 minutes of resistance training at home twice weekly according to the training manual provided at baseline visit. Compliance with the training program was recorded on a log card and calculated using the following formula:
mathematical formula 1
Compliance rates of > 50% are considered compliant.
(visual analog Scale for Knee pain (VAS))
The Visual Analog Scale (VAS) is rated from 0 to 100mm, where 0 means no pain and 100 means the most severe pain. On days 0, 7 and 14 after ingestion, the interviewee was asked to indicate the level of pain felt by drawing a straight line on the scale indicating the position along the solid line.
(tolerance and safety)
Spontaneously reported adverse events were recorded throughout the study. Vital signs were monitored at each visit. To assess the safety of the study products, all participants were assessed for serum and urine at each visit during the study.
(statistical analysis)
Statistical analysis of the compliance program was performed according to a prior statistical analysis plan. Randomized subjects with intake compliance ≧ 70% were included in the protocol-compliant analysis. Safety parameter analysis was performed based on subjects who had taken at least 28 bottles of study product. The dichotomous variables are reported using percentages, while the continuous variables are reported as mean and SD. The chi-square test was used for comparison of categorical variables, while the kruskal-wallis test was used to compare the differences between groups of continuous variables.
Repeated measures analysis of variance (ANOVA) was performed using a mixed effects model for testing the mean difference in variation between study groups, with the interaction of the interview intake as a fixed effector for consecutive primary and secondary endpoints. All results were considered statistically significant if the corresponding p-value was below 0.05. If the visit intake interaction term is significant, a post-hoc pairwise comparison between treatment groups is performed and an adjusted p-value is reported. Variables expected to affect the endpoint were included as factors in the model. Gender and gender interview interaction terms were included as factors in the joint health analysis.
In addition, a subgroup analysis was performed on subjects who underwent resistance training for less than the tenth percentile of the total training sessions. Independent statisticians performed the analysis using version 9.4 of SAS (Cary, USA).
Results
(Baseline characteristics and treatment compliance)
A total of 160 subjects were enrolled, and 151 subjects completed the study and were included in the statistical analysis (PP). Nine subjects were withdrawn during the study; there was no significant difference in the number of withdrawals between groups. None of the withdrawers were associated with any side effects caused by the intake of study product or placebo. No adverse events were noted. No clinically significant changes were observed for serum biochemical markers and urinalysis.
Overall, there were no statistical differences in compliance rates between all four groups (table 4). To assess the homogeneity of the data, all parameters between the four arms were compared. There were no statistically significant differences between the study groups at baseline (table 4).
TABLE 4
(Change in VAS of Knee pain)
A subgroup analysis of subjects who underwent a tenth percentile less than the total resistance training period after 14 days of intake showed that the pain score of the placebo group experienced a significant increase of 200% from baseline (p 0.047) compared to the increase of 42.9% from day 0 in the HCII + CE group (fig. 8, table 5).
In Table 5, "P value ($)" means the P value between groups; "(a)" indicates a method for determining a p value ((a) ═ one-factor analysis of variance); "95% c.i." means 95% confidence interval.
In fig. 8, two values in parentheses of each data are "mean-standard deviation" and "mean + standard deviation".
TABLE 5
(conclusion)
Overall, HCII and CE are well tolerated and provide rapid and significant symptomatic relief for patients with osteoarthritic pain. The combination of HCII and CE significantly reduced knee pain in subjects with low resistance training for only 14 days compared to placebo.
In vitro studies have shown that the mechanism of action may be through modification of the underlying disease process, in particular inhibition of inflammation leading to local pain sensation. In summary, the combination of HCII and CE can be considered a safe and effective supplement to current medical and dietary options for treating OA symptoms.
INDUSTRIAL APPLICABILITY
The present invention can provide a novel composition comprising at least one selected from the group consisting of cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and salts thereof, and a chicken extract. The composition of the present invention can be used as a food or drink composition or a pharmaceutical composition for reducing inflammation and joint pain. Cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and salts thereof, and chicken extract can be consumed as food, drink, etc., and are also advantageous in terms of safety.
Claims (13)
1. A composition, comprising:
at least one selected from the group consisting of cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and salts thereof; and
chicken extract.
2. The composition of claim 1, wherein the total amount of at least one selected from the group consisting of cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and salts thereof is 0.01 to 99 wt%.
3. The composition according to claim 1 or 2, wherein the composition comprises a fraction of hydrolyzed type II collagen derived from chicken cartilage and having a molecular weight of less than 1100 and a weight average molecular weight of 150-250 as determined by HPLC gel filtration.
4. The composition of any one of claims 1-3, wherein the composition comprises hydrolyzed type II collagen of chicken cartilage.
5. The composition of any one of claims 1-4, wherein the chicken extract comprises carnosine and/or anserine and/or one or more salts thereof.
6. The composition of any one of claims 1-5, wherein the composition is a food, beverage, or pharmaceutical.
7. The composition of any one of claims 1-6, wherein the composition is for reducing inflammation.
8. The composition of any one of claims 1-7, wherein the composition inhibits production of at least one cytokine selected from the group consisting of: activation regulates normal T cell expression and secretion factors (RANTES), monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-9 (IL-9), and macrophage inflammatory protein-1 (MIP-1).
9. The composition of any one of claims 1-8, wherein the composition is for preventing or alleviating an inflammatory condition or disease.
10. A method of producing a composition, the method comprising: mixing at least one selected from the group consisting of cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and salts thereof with the chicken extract.
11. The method of claim 10, wherein the mixing comprises mixing hydrolyzed type II collagen of chicken cartilage with a chicken extract, the hydrolyzed type II collagen comprising at least one selected from the group consisting of: cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and salts thereof.
12. The method of claim 10 or 11, wherein the chicken extract comprises carnosine and/or anserine and/or one or more salts thereof.
13. Use of at least one selected from the group consisting of cyclo (Ala-Hyp), cyclo (Pro-Gly), guanosine, tryptophan and salts thereof and a chicken extract for producing an anti-inflammatory composition.
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PCT/JP2020/025296 WO2021131106A1 (en) | 2019-12-27 | 2020-06-26 | Composition containing cyclic dipeptide, purine nucleoside and/or amino acid, and chicken extract, production method thereof, and use of cyclic dipeptide, purine nucleoside and/or amino acid, and chicken extract |
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US20070293427A1 (en) * | 2006-04-21 | 2007-12-20 | Eric Vouland | Hydrolysate of avian cartilage, process of preparation and uses thereof |
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JP2003048850A (en) * | 2001-06-01 | 2003-02-21 | Nippon Meat Packers Inc | Therapeutic agent of arthropathy, and functional food |
RU2255758C2 (en) * | 2003-09-18 | 2005-07-10 | Закрытое акционерное общество "Научно-производственное объединение "ТЕХКОН" | Biologically active carnosine-anserine-containing complex and method for its preparing |
JP2015193582A (en) * | 2014-03-28 | 2015-11-05 | 国立大学法人 東京大学 | Agent containing imidazoledipeptide |
CN111093770A (en) * | 2017-08-31 | 2020-05-01 | 伦萨有限责任公司 | Health promoting composition and related application of method using supplement |
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2020
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