WO2010005012A1 - アポラクトフェリン含有組成物 - Google Patents
アポラクトフェリン含有組成物 Download PDFInfo
- Publication number
- WO2010005012A1 WO2010005012A1 PCT/JP2009/062411 JP2009062411W WO2010005012A1 WO 2010005012 A1 WO2010005012 A1 WO 2010005012A1 JP 2009062411 W JP2009062411 W JP 2009062411W WO 2010005012 A1 WO2010005012 A1 WO 2010005012A1
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- WIPO (PCT)
- Prior art keywords
- apolactoferrin
- solution
- derived
- age
- glyceraldehyde
- Prior art date
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Definitions
- the present invention relates to a composition containing apolactoferrin.
- Lactoferrin is a transferrin family iron-binding glycoprotein responsible for iron transport in the living body and was isolated in 1960. Regarding the function of lactoferrin, many studies have been conducted on bactericidal or bacteriostatic action, immune function regulating action, protection and growth of useful intestinal bacteria, suppression of free radicals (containing active oxygen), Research has progressed because bactericidal or bacteriostatic effects are clear. The mechanism of bactericidal or bacteriostatic is that lactoferrin attaches to bacterial and viral cell membranes and kills the bacteria directly by breaking the cell membrane, or lactoferrin takes away the iron necessary for the growth and maintenance of the bacteria, This is thought to be due to the effect of suppressing the survival of bacteria in a deficient state.
- Lactoferrin consists of about 690 chain amino acids, and its three-dimensional structure has two iron binding pockets, and iron binds to the pockets one by one.
- a material in which 100% of iron is bound to this pocket is called “hololactoferrin”, and a material in which iron is not bound is called “apolactoferrin”. Since normal bovine lactoferrin contains iron in 15 to 20% of the pockets, the powder and solution are pink, and the redness increases as the degree of binding of iron increases. On the other hand, apolactoferrin from which iron has been removed is white and can be easily distinguished by its appearance. Apolactoferrin has higher ironophilicity than normal lactoferrin and has a much higher antibacterial or bacteriostatic effect.
- Lactoferrin is also classified as an antioxidant because it binds and fixes free iron. This apolactoferrin having a large iron-fering action has a higher ability as an antioxidant than lactoferrin.
- apolactoferrin Since apolactoferrin has the useful properties as described above, it is used in various fields. For example, various compositions using apolactoferrin are known, such as ophthalmic compositions and cosmetics (Patent Documents 1 to 4).
- the Maillard reaction that occurs between various reducing sugars and proteins proceeds by the processing or storage of foods, imparts color or fragrance to processed foods, and further stabilizes food components, It is known to increase antioxidant activity or antimutagenicity.
- a terminal glycation product AGEs
- AGEs terminal glycation product
- Hemoglobin A 1C (HbA 1C ) is an Amadori transfer product in the early Maillard reaction and is not affected by diet, and thus is an important indicator for diagnosis of diabetes.
- the Amadori transition product reduces oxygen (O 2 ) by one electron to generate a superoxide anion which is active oxygen.
- the generated superoxide anion derives hydrogen peroxide (H 2 O 2 ) and a hydroxy radical (.OH).
- these active oxygens react with nitric oxide (NO) in the body to produce peroxynitrite (ONOO ⁇ ) having a high oxidizing power, and these free radicals are the organs of the delicate eye, kidney Injuries vascular endothelium.
- NO nitric oxide
- ONOO ⁇ peroxynitrite
- free radicals are the organs of the delicate eye, kidney Injuries vascular endothelium.
- generated (irreversible) AGEs are signaled into vascular endothelial cells, vascular smooth muscle cells, or macrophage cells via AGEs receptors (Receptor of AGEs; abbreviated as RAGE).
- RAGE AGEs receptors
- lactoferrin has high binding properties with AGEs, but the detailed research results have been announced since the 1990s. Lactoferrin has two domains that bind to AGEs, which have been found to be a loop of 17 to 18 amino acids. Since each end of this loop has a cysteine, it is sometimes called a cysteine loop. This loop has been shown to exhibit significant hydrophilicity, and binding sites such as lysozyme and defensin, which are peptides that are relatively easy to bind to other AGEs, also exhibit high hydrophilicity. It has been suggested that a hydrophilic environment is advantageous for binding to.
- the object of the present invention is to provide a useful composition containing apolactoferrin.
- the present invention provides a composition comprising apolactoferrin and at least one selected from the group consisting of a terminal glycation product binder, an antioxidant substance and an antibacterial substance.
- the glycation end product binder is a milk component hydrolyzate obtained by hydrolyzing whey with endoprotease, exoprotease, and endopeptidase.
- a composition exhibiting a useful effect is provided by combining apolactoferrin with a terminal glycation product binder, an antioxidant or an antibacterial substance.
- coli culture solution by apolactoferrin alone (no addition of glyceraldehyde-derived AGE), apolactoferrin when glyceraldehyde-derived AGE is added, and apolactoferrin and glycation end product binder when glyceraldehyde-derived AGE is added
- It is. 2 is a graph showing the antioxidant power of combinations of apolactoferrin and various concentrations of ⁇ -tocopherol. It is a graph which shows the antioxidant power of the combination of apolactoferrin and various concentrations of ascorbic acid.
- Apolactoferrin is a glycoprotein molecule from which iron bound in the lactoferrin molecule is released.
- the apolactoferrin used in the present invention is not particularly limited, but preferably has the following characteristics.
- Apolactoferrin preferably has an iron bond degree in the molecule of 5% or less, preferably 4% or less, more preferably 3% or less.
- the degree of iron binding refers to the ratio of the number of moles of iron to the number of moles of apolactoferrin.
- the degree of iron binding can be determined by measuring the absorbance of apolactoferrin by spectroscopic analysis, or by directly measuring the amount of iron in apolactoferrin by atomic absorption analysis or inductively coupled plasma (ICP) spectroscopy.
- the degree of iron binding refers to a value obtained by dissolving apolactoferrin powder in pure water to make a 1 w / v% solution, and measuring this at an absorbance of 470 nm.
- the total cation concentration in the aqueous solution is preferably 5 mmol / L or less.
- the total cation concentration is determined by dissolving apolactoferrin powder in 0.1N hydrochloric acid to prepare a 0.1 w / v% solution, and measuring the amount of each cation by atomic absorption photometry. And add them together.
- the total cation concentration may correspond to a salt (ion) contained as an impurity in the apolactoferrin powder.
- the total cation concentration is preferably 3 mmol / L or less, more preferably 1 mmol / L or less.
- Apolactoferrin can be usually produced by adjusting the pH of an aqueous solution containing lactoferrin to the acidic side to dissociate divalent iron ions of the lactoferrin molecule.
- Lactoferrin which is a raw material for apolactoferrin, is separated and purified from mammalian secretions such as milk (eg, milk) or processed milk products such as skim milk and whey (eg, whey) (eg, adsorbed on a cation exchange resin). Then, it may be obtained by utilizing a method of desorption with a high-concentration salt solution, a separation method by electrophoresis, a separation method by affinity chromatography, or the like. Further, it may be produced by various genetically modified cells (including microorganisms, plant cells, animal cells, insect cells, etc.), plants, animals and the like. Lactoferrin may be commercially available as pharmaceuticals, reagents, and the like.
- mammalian secretions such as milk (eg, milk) or processed milk products such as skim milk and whey (eg, whey) (eg, adsorbed on a cation exchange resin). Then, it may be obtained by
- Lactoferrin is preferably derived from natural products, more preferably from whey. Whey obtained as a by-product generated when producing a dairy product (for example, cheese, casein, etc.) from cow milk or skim milk can be suitably used as a source of lactoferrin.
- a dairy product for example, cheese, casein, etc.
- Apolactoferrin can be preferably produced, for example, by adding an acid to the solution when the lactoferrin-containing solution is ultrafiltered to dissociate iron ions bound to lactoferrin.
- the acid that can be used here include citric acid, hydrochloric acid, phosphoric acid, malic acid, and acetic acid (0.4 M or more), and citric acid is preferable.
- apolactoferrin is partitioned by these membranes in which bipolar membranes and cation exchange membranes, which are composite ion exchange membranes having a structure in which a cation exchange membrane and an anion exchange membrane are laminated, are alternately arranged. It can be suitably manufactured also by using an electrodialyzer having an acid chamber and a base chamber (for example, Patent Document 5). In this case, hydrochloric acid produced during the manufacturing process in the electrodialyzer is used as the acid.
- the pH on the acidic side to be adjusted is preferably 0.5 to 3, more preferably 1.5 to 2.5.
- the pH is close to neutral (for example, 5.5)
- the antibacterial properties of the obtained apolactoferrin may be weakened.
- a pH adjuster of an aqueous solution containing lactoferrin not only the acid but also phthalic acid, glycine and the like can be used. These pH adjusting agents are added to an aqueous solution containing lactoferrin in an amount suitable for adjusting the pH to the above value.
- the temperature at which the pH of the aqueous solution containing lactoferrin is adjusted to the acidic side is preferably not high considering protein denaturation. Usually, it is 5 ° C to 60 ° C, more preferably 15 ° C to 35 ° C, and even more preferably room temperature.
- apolactoferrin in the present invention will be described in detail in Preparation Example 1 below, but the production method of apolactoferrin is not limited to these. Moreover, you may modify
- apolactoferrin can usually be obtained in the form of an aqueous solution. You may use the form of aqueous solution, or you may use the form which removed the solvent and pulverized.
- a milk component hydrolyzate As the terminal glycation product binder, a milk component hydrolyzate can be suitably used. Milk component hydrolysates can be prepared by treating whey with endoproteases, exopeptidases, and endopeptidases. For this reason, it is also referred to as “whey hydrolyzate”. Whey is a milk-derived component in which casein, which is the main component of milk protein, is removed from raw milk (eg, milk). Whey obtained as a by-product generated when producing a dairy product (for example, cheese, casein, etc.) from cow's milk or skim milk can be suitably used for preparing a milk component hydrolyzate.
- casein which is the main component of milk protein
- the type of enzyme for treating whey and the mode of action are not limited.
- mammalian secretions such as milk (eg, milk) or skim milk can also be used, in which case the casein is removed prior to treatment with the enzyme. It is preferable to do.
- the processing conditions (including temperature and time) of the proteolytic enzyme for milk-derived protein in whey can be appropriately determined in consideration of protein denaturation and the enzyme's working temperature.
- the endoprotease is preferably bovine gastric mucosa-derived pepsin; EC3.4.23.1 is preferred, and the exopeptidase is preferably Aeromonas Proteolytica-derived aminopeptidase; EC3.4.11.10 is preferred, and the endopeptidase is bovine pancreas-derived chymotrypsin type II; EC3.4 .21.1 is preferred.
- the processing temperature of the endoprotease, exopeptidase, and endopeptidase enzyme is preferably 20-60 ° C, more preferably 40-60 ° C, and even more preferably about 50 ° C.
- the endoprotease, exopeptidase, and endopeptidase may act simultaneously or separately.
- the treatment time is preferably 0.5 to 5 hours, more preferably 1 to 3.5 hours.
- the ratio of the combination to act is Unit / 1 kg protein, preferably 1-1000: 1-10: 1-100, more preferably 100-1000: 1-2: 5-20 and even more Preferably, it is about 1000: 1: 10.
- a proteolytic enzyme In order to prepare a milk component hydrolyzate, it is preferable to cause a proteolytic enzyme to act on whey in substantially the same manner as in Preparation Example 2 below.
- the milk component hydrolyzate When the milk component hydrolyzate is contained in a product or composition, it may be in the form of an aqueous solution, or may be in the form of powder by removing the solvent (for example, by freeze drying).
- the milk component hydrolyzate has binding properties to AGEs, particularly glyceraldehyde-derived AGEs.
- AGEs particularly glyceraldehyde-derived AGEs.
- a milk component hydrolyzate when ingested as a food, a milk component hydrolyzate adsorbs food AGEs and inhibits absorption from the intestinal tract, thereby reducing the amount of AGE derived from glyceraldehyde that is converted from food AGEs in the body. .
- it when introduced into the body, it is useful as an anti-glyceraldehyde-derived AGE agent or as a preventive or therapeutic agent for diseases involving glyceraldehyde-derived AGE, for example, diabetes and its complications, or Alzheimer's disease.
- Monocytes which are known to increase blood AGEs concentration in patients suffering from diabetes or with aging, and increase blood AGEs (especially glucose-derived AGE), which is a marker of vascular disorders in blood Chemotactic activator (MCP-1) can also increase, but milk component hydrolysates can suppress the increase in MCP-1 that can be attributed to such increased levels of AGEs in the blood.
- MCP-1 Chemotactic activator
- the milk component hydrolyzate can preferably penetrate the skin.
- Such a milk component hydrolyzate can permeate a commercially available artificial skin membrane (for example, available from Toray Industries, Inc.).
- the artificial skin membrane may be a membrane capable of cutting off a molecular weight of about 2000.
- Such a milk component hydrolyzate can be used as a material for suppressing the accumulation of subcutaneous AGEs, and is used as a cosmetic.
- Antioxidant means any substance having free radical scavenging ability. Those having an excellent antioxidant effect or those having high safety to living bodies are preferable. Antioxidants that are suitable for the products in the fields detailed below or approved for application thereto are preferred. Examples of antioxidants include ascorbic acid, ⁇ -tocopherol, polyphenols (catechin, curcumin, anthocyanin, cacao mass polyphenol, isoflavone, rutin, etc.), carotenoids (lycopene, ⁇ -carotene, capsaicin, etc.), allyl sulfide, saponin, Examples include, but are not limited to sesamin. Antioxidants are readily available to those skilled in the art and can be obtained commercially or by means such as in-house preparation.
- the antibacterial substance refers to any substance having a bactericidal action, a sterilizing action, or a bacteriostatic action on bacterial cells. Those having excellent antibacterial action or those having high safety to living bodies are preferable. Antibacterial substances that are suitable for the products in the fields detailed below or approved for application thereto are preferred. As used herein, “antibacterial substance” excludes apolactoferrin.
- Antibacterial substances include, for example, citric acid, nisin, ascorbic acid, poly-L-lysine, glycine, methylparaben, cetylpyridinium chloride (CPC), benzoic acid, sorbic acid, silver, vitamin K2 (menaquinone), picolinic acid, imidazole 1,2-hexanediol, 1,2-pentanediol, 1,2-octanediol, 1,3-butylene glycol and the like, but are not limited thereto.
- the advanced glycation end product binders described above can also be used as antimicrobial substances.
- Antibacterial substances are readily available to those skilled in the art and can be obtained commercially or by means such as self-preparation.
- composition consisting of a combination can exert a useful action or effect in combination with at least one of a terminal glycation product binder, an antioxidant and an antibacterial substance.
- Apolactoferrin can enhance antibacterial properties in combination with a terminal glycation product binder, and can also exhibit antibacterial properties even in a state of excessive AGEs.
- Antioxidant power can be enhanced in combination with an antioxidant.
- Antibacterial properties can be enhanced in combination with antibacterial substances. Therefore, a composition comprising the combination shown above is provided.
- compositions comprising the combinations shown above can be used as a form of use by adding individual substances to the product separately (used as additives) so that the combination shown above is used, or from the combination shown above May be provided as a product comprising the composition.
- Such products may contain any other materials, additives, etc. as long as they do not interfere with the effect of the combination.
- Compositions comprising the combinations shown above include foods, cosmetics, mouth cleansing agents, topical skin preparations, ophthalmic products, surface coating agents (for example, food packaging containers or cans), polymer additives, deodorants (for example, , Deodorant mist), detergent, perfume and the like.
- an ophthalmic product can be prepared by combining apolactoferrin and an antimicrobial substance with ingredients that can be commonly used in ophthalmic products.
- the product may be in the form of a solution or may be in the form of powder by removing the solvent (for example, by lyophilization).
- the apolactoferrin is contained in the product in a concentration of, for example, 0.01 to 20, preferably 0.1 to 10, more preferably 0.5 to 5 (unit: w / v%).
- the terminal glycation product binder may be contained or added so as to have a concentration (unit: w / v%) of, for example, 0.05 to 20, preferably 0.1 to 10, more preferably 0.5 to 3.
- the antioxidant may be contained or added so as to have a concentration (unit: w / v%) of, for example, 0.01 to 10, preferably 0.05 to 5, more preferably 0.1 to 2.
- the antibacterial substance can be contained or added so as to have a concentration (unit: w / v%) of, for example, 0.01 to 10, preferably 0.05 to 5, more preferably 0.1 to 2.
- lactoferrin 10 kg of 50 mg / mL lactoferrin (manufactured by Fontera; iron binding degree is about 20%) was used.
- lactoferrin was treated with 0.1M citric acid.
- the lactoferrin solution was put into a supply tank of the apparatus, circulated for 10 minutes, and then circulated in the reverse direction for 5 seconds to concentrate the solution.
- the pressure and circulating fluid flow rate at the inlet and outlet of the UF membrane were set to 0.12 Mpa, 0.08 Mpa, and 15 L / min, respectively. This operation was repeated until the non-permeated concentrate was halved (this was defined as one round).
- the citric acid solution was put into the tank instead of the lactoferrin solution, and the same operation as above was performed for two rounds. Subsequently, 8 M ⁇ ⁇ cm or more of pure water was put into the tank, and the above operation was performed for 5 rounds to remove the acid remaining in the non-permeated concentrate.
- the temperature of the circulating liquid was in the range of 10 to 28 ° C. throughout the production process, and the pH was 2 to 3.
- the powder obtained by each acid treatment was apolactoferrin and the purity of apolactoferrin was measured using BIOXYTECH (registered trademark) Lacto f EIA TM (OXIS International Inc., Oregon, USA) after dissolving the powder in pure water. Determined by performing antibody quantification.
- the iron binding degree of the powder obtained by each acid treatment is dissolved in pure water so as to have a concentration of 1 w / v%, and then the amount of iron bound to apolactoferrin is measured at an absorbance of 470 nm. Determined by measuring.
- Table 1 shows the degree of iron binding of the obtained apolactoferrin.
- the iron bond degree was 2.95%.
- the total cation concentration of apolactoferrin having an iron binding degree of 2.95% was measured.
- 0.1N hydrochloric acid to the lyophilized powder of apolactoferrin, preparing a 0.1 w / v% apolactoferrin solution and measuring for Na, K, Ca, Mg, and Cu by atomic absorption spectrophotometry, these When the concentration of each cation was determined and the total was converted to the total cation concentration, the total cation concentration was 3.9 mmol / L.
- the lyophilized whey hydrolyzate was dissolved in pure water so as to be 10 mg / mL, and this was designated as A solution.
- a transverse membrane permeable cell having phases on both sides sandwiching an artificial skin membrane (Toray Industries, Inc.) was produced. Liquid A was put in one phase of the membrane permeation cell, and pure water was put in the other phase, and the whole cell was brought to a constant temperature by circulating water at 25 ° C. Both phases were stirred for 10 minutes at a speed of 120 rpm. After stirring for 10 minutes, the solution was taken out from the phase containing pure water, and this was designated as solution B.
- solution A solution before starting stirring
- solution B in which lyophilized whey hydrolyzate was dissolved in pure water were subjected to the conditions described below according to the method used in the transdermal absorption evaluation test.
- HPLC high performance liquid chromatography
- freeze-dried whey hydrolyzate (hereinafter simply referred to as “freeze-dried whey hydrolyzate”) that was freeze-dried after the enzyme treatment as described above was used.
- the obtained solution was made into a sterile solution by passing through a filter having a pore size of 0.22 ⁇ m in a clean bench.
- the lid of the 50 mL falcon tube was sealed with parafilm and incubated at 37 ° C. for 1 week to react DL-glucose and HSA.
- the solution was applied to a PD-10 column (GE Healthcare Bioscience) to remove unreacted DL-glucose, and the result was confirmed by HPLC to obtain a glucose-derived terminal glycation product (glucose-derived AGE) fraction. It was.
- DL-glyceraldehyde and 39 mg of diethylenetriamine-pentaacetic acid as a chelating agent were weighed and placed in a 50 mL falcon tube.
- 20 mL of 0.2 M phosphate buffer (pH 7.4) was added to the falcon tube, and DL-glyceraldehyde and diethylenetriamine-pentaacetic acid were dissolved with a vortex mixer.
- 500 mg of human serum albumin (HSA) (manufactured by Sigma) was added to the falcon tube and dissolved with a vortex mixer.
- the obtained solution was made into a sterile solution by passing through a filter having a pore size of 0.22 ⁇ m in a clean bench.
- the lid of the 50 mL falcon tube was sealed with parafilm and incubated at 37 ° C. for 1 week to react DL-glyceraldehyde with HSA.
- the solution was applied to a PD-10 column (manufactured by GE Healthcare Bioscience) to remove unreacted DL-glyceraldehyde, the result was confirmed by HPLC, and glyceraldehyde-derived glycation product (glyceraldehyde-derived AGE) ) A fraction was obtained.
- glucose-derived AGE or glyceraldehyde-derived AGE in the fraction obtained as described above was confirmed by an ELISA method using a monoclonal antibody.
- the anti-glucose-derived AGE monoclonal antibody or the anti-glyceraldehyde-derived AGE monoclonal antibody was consigned to Toyobo Co., Ltd. and produced from mice using glucose-derived AGE or glyceraldehyde-derived AGE as an antigen.
- anti-monoclonal antibodies are biotinylated with the biotinylation reagent EZ-Link (registered trademark) Sulfo-NHS-Biotinylation Kit (PIERCE, product code 21420), and the biotinylated anti-monoclonal antibody is labeled with streptavidin peroxidase (Nacalai Tesque, product). Code 02517-61) was coupled.
- any of the terminal glycation products prepared above and peroxidase-labeled streptavidin were bound to wells on which HSA antibodies (RayBiotech, Inc.) were immobilized. Biotinylated anti-monoclonal antibodies were added and chemiluminescence was detected to confirm the production of these terminal glycation products, glucose-derived AGE and glyceraldehyde-derived AGE.
- Example 1 Bacteria used for the antibacterial test were prepared as follows. Escherichia coli (NBRC 3972) purchased from the National Institute of Biotechnology, Biotechnology Headquarters (NBRC), was stored in a liquid by subculture in 5 mL of SCD bouillon (Nissui Pharmaceutical Co., Ltd.) . 50 ⁇ L of the stored E. coli solution was inoculated into 5 mL of SCD bouillon (Nissui Pharmaceutical Co., Ltd.) and cultured at 30 ° C. for 16 hours in a shaking water bath. The cultured bacterial solution was diluted with sterilized water to prepare 10-fold serial dilutions up to 10 7 -fold.
- a test series for examining antibacterial properties was prepared as follows. In a 96-well flat-bottom microplate (BDalFalcon), an 8 w / v% aqueous solution of apolactoferrin (prepared in Preparation Example 1) (sterilized with a filter having a pore size of 0.22 ⁇ m) was diluted several times with sterile water, and 50 ⁇ L each. A dilution series was prepared. The concentration of apolactoferrin in the wells was 0-2 w / v%.
- freeze-dried whey hydrolyzate (terminal glycation product binder) prepared in Preparation Example 2 is added to the addition series of glucose-derived AGE or glyceraldehyde-derived AGE so that the final concentration is 2.5 w / v%.
- a terminal glycation product binder addition series was also obtained.
- the microplate test system and the petri dish test system were cultured at 35 ° C. for 24 hours. After culturing, the test microplate was measured for turbidity (absorbance) at a wavelength of 630 nm with a microplate reader (Multiscan JX Thermo Labsystems), and the increase or decrease in the number of bacteria after the culture was examined.
- FIG. 2 shows the results of investigating the antibacterial properties of the combined use of apolactoferrin and a terminal glycation end product binder when a terminal glycation product is added (Figure 1: When glucose-derived AGE is added; Figure 2: Derived from glyceraldehyde) When AGE is added).
- FIG. 1 is a graph showing the absorbance in an E. coli culture solution by apolactoferrin alone (no addition of glucose-derived AGE), apolactoferrin when glucose-derived AGE is added, and apolactoferrin and a terminal glycation product binder when glucose-derived AGE is added.
- FIG. 2 shows an E.
- FIG. 1 is glucose-derived AGE
- FIG. 2 is glyceraldehyde-derived AGE
- the white squares represent the results when each AGE and the terminal glycation product binder were added to the apolactoferrin solution.
- Example 2 The bacterial cells were prepared in the same manner as in Example 1. Next, a 96-well flat-bottom microplate (BD Falcon) was diluted 8 times with an aqueous solution of 8 w / v% apolactoferrin (prepared in Preparation Example 1) using sterile water with a pore size of 0.22 ⁇ m. A 50 ⁇ L dilution series was prepared. The concentration of apolactoferrin in the wells was 0-2 w / v%.
- each apolactoferrin concentration system 50 ⁇ L each of various reagents (shown in Table 1 below) having been sterilized with a pore size of 0.22 ⁇ m and multiple dilutions of 8 w / v% with sterile water was added. was prepared.
- the combination reagents used are as follows: citric acid (Nacalai Tesque), lyophilized whey hydrolyzate (prepared in Preparation Example 2), nisin (SIGMA), ascorbic acid (Nacalai Tesque), poly -L-lysine (SERVA Electrophoresis GmbH), glycine (Wako Pure Chemical Industries, Ltd.), methylparaben (Wako Pure Chemical Industries, Ltd.), cetylpyridinium chloride (CPC) (Wako Pure Chemical Industries, Ltd.).
- Apolactoferrin and a combination reagent were combined at concentrations of 0, 0.03, 0.06, 0.13, 0.25, 0.5, 1 and 2 (unit: w / v%) to prepare a test system. Subsequently, these test systems were inoculated and cultured in the same manner as in Example 1, and the increase or decrease in the number of bacteria after the culture was examined.
- Antimicrobial properties were enhanced by combining any of the reagents used with apolactoferrin.
- Example 3 A dimethyl sulfoxide solution of 20 w / v% DL- ⁇ -tocopherol (CALBIOCHEM) was prepared. 5 ⁇ L of this was added to 500 ⁇ L of an aqueous solution of 2 w / v% apolactoferrin (prepared in Preparation Example 1), and then prepared with ultrapure water so that the ⁇ -tocopherol concentration was 0.1 w / v%. Similarly, ⁇ -tocopherol concentrations were adjusted to 0.05, 0.025, and 0.01 (unit: w / v%) to obtain test samples.
- test sample was subjected to FRAS4 (active oxygen / free radical automatic analyzer; Wismer Co., Ltd.) according to the manufacturer's protocol, and the antioxidant power was measured.
- FRAS4 active oxygen / free radical automatic analyzer
- FIG. 3 shows the antioxidant power of the combination of apolactoferrin and various concentrations of ⁇ -tocopherol.
- the horizontal axis represents the ⁇ -tocopherol concentration (%) (w / v) in the culture solution.
- the vertical axis shows the antioxidant power ( ⁇ mol / L).
- white circles show the results when ⁇ -tocopherol is used alone, and black circles show the results when ⁇ -tocopherol is added to the apolactoferrin solution. It became clear that it has an additive effect in the antioxidant effect.
- FIG. 4 shows the antioxidant power of combinations of apolactoferrin and various concentrations of ascorbic acid.
- the horizontal axis indicates the concentration (%) (w / v) of ascorbic acid in the culture solution.
- the vertical axis shows the antioxidant power ( ⁇ mol / L).
- the white circle represents the result when ascorbic acid alone, and the black circle represents the result when ascorbic acid was added to the apolactoferrin solution. It became clear that it has an additive effect in the antioxidant effect.
- foods, cosmetics, mouth cleansing agents, external preparations for skin, ophthalmic products, surface coating agents (for example, for food packaging containers or cans), polymer additives, deodorizing agents (for example, deodorizing mist) A composition that can be suitably used for detergents, perfumes and the like is obtained.
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Abstract
Description
アポラクトフェリンとは、ラクフェリン分子中に結合されている鉄が遊離した糖蛋白分子である。本発明で使用するアポラクトフェリンは特に限定されないが、以下の特性を有することが好ましい。
終末糖化産物結合剤としては、乳成分加水分解物が好適に用いられ得る。乳成分加水分解物は、ホエイをエンドプロテアーゼ、エキソペプチダーゼ、およびエンドペプチダーゼで処理することにより調製され得る。このため、「ホエイ加水分解物」ともいう。ホエイは、乳タンパク質の主成分であるカゼインが生乳(例えば牛乳)から取り除かれている乳由来成分である。牛乳または脱脂乳から乳製品(例えば、チーズ、カゼインなど)を製造する際に発生する副産物として得られるホエイは、乳成分加水分解物を調製するために好適に用いられ得る。
抗酸化物質とは、フリーラジカル捕捉能を有する任意の物質をいう。抗酸化作用が優れるもの、または生体への安全性の高いものが好ましい。以下に詳述する分野の製品に適した、あるいはそれらへの適用が認可されている抗酸化物質が好ましい。抗酸化物質としては、例えば、アスコルビン酸、α-トコフェロール、ポリフェノール類(カテキン、クルクミン、アントシアニン、カカオマスポリフェノール、イソフラボン、ルチンなど)、カロテノイド(リコピン、α-カロテン、カプサイシンなど)、硫化アリル、サポニン、セサミンなどが挙げられるが、これらに限定されない。また、抗酸化物質は当業者に容易に入手可能であり、市販または自家調製などの手段によって入手され得る。
抗菌物質とは、菌体への殺菌作用、滅菌作用、または静菌作用を有する任意の物質をいう。抗菌作用が優れるもの、または生体への安全性の高いものが好ましい。以下に詳述する分野の製品に適した、あるいはそれらへの適用が認可されている抗菌物質が好ましい。本明細書中でいう「抗菌物質」とは、アポラクトフェリンを除く。抗菌物質としては、例えば、クエン酸、ナイシン、アスコルビン酸、ポリ-L-リジン、グリシン、メチルパラベン、塩化セチルピリジニウム(CPC)、安息香酸、ソルビン酸、銀、ビタミンK2(メナキノン)、ピコリン酸、イミダゾール、1,2-ヘキサンジオール、1,2-ペンタンジオール、1,2-オクタンジオール、1,3-ブチレングリコールなどが挙げられるが、これらに限定されない。上で説明した終末糖化産物結合剤(特に、乳成分加水分解物)は、抗菌物質としても用いられ得る。また、抗菌物質は当業者に容易に入手可能であり、市販または自家調製などの手段によって入手され得る。
アポラクトフェリンは、終末糖化産物結合剤、抗酸化物質および抗菌物質のうちの少なくとも1種との組み合わせで有用な作用または効果を発揮し得る。アポラクトフェリンは、終末糖化産物結合剤との組み合わせで抗菌性を増強し得、またAGEs過多の状態であっても抗菌性を発揮し得る。抗酸化物質との組み合わせで抗酸化力を増強し得る。抗菌物質との組み合わせで抗菌性を増強し得る。したがって、上記に示した組み合わせからなる組成物が提供される。
マイクローザUFラボテスト機(LX-22001;旭化成ケミカルズ株式会社)に、同社製のUFモジュールであるLOV(中空糸モジュール:膜内径0.8mm、有効膜面積41m2、膜素材:ポリアクリロニトリル、公称分画分子量:50,000)を組み込んだ限外濾過装置を用いて、以下のようにアポラクトフェリンを製造した。
ウシの生乳からカゼインナトリウムを製造した後の残りのホエイをタツア・ジャパン株式会社から入手した。このホエイにエンドプロテアーゼ(ウシ胃粘膜由来ペプシン;E.C.3.4.23.1;シグマ社)1000Unit/1kgタンパク質、エキソペプチダーゼ(Aeromonas Proteolytica由来アミノペプチダーゼ;E.C.3.4.11.10;シグマ社)1Unit/1kgタンパク質、およびエンドペプチダーゼ(ウシ膵臓由来キモトリプシンII型;E.C.3.4.21.1;シグマ社)10Unit/1kgタンパク質を添加し、50℃にて3.5時間処理した。このような酵素処理により得られた加水分解物を凍結乾燥し、ホエイ加水分解物を得た。
カラム ODS(資生堂製) 4.6×150mm
溶離液 A:0.02%(v/v)TFA(溶媒H2O)
B:0.016%(v/v)TFA(溶媒ACN)
A:B=95:5(v/v)で使用
流速 0.75ml/分
温度 40℃
検出器UV 220nm。
まず、360mgのDL-グルコースおよびキレート剤として39mgのジエチレントリアミン-五酢酸をそれぞれ秤量し、50mLのファルコンチューブに入れた。次いでファルコンチューブに0.2Mリン酸緩衝液(pH7.4)を20mL添加して、ボルテックスミキサーにてDL-グルコースおよびジエチレントリアミン-五酢酸を溶解した。さらにファルコンチューブにヒト血清アルブミン(HSA)(Sigma社製)を500mg添加し、ボルテックスミキサーにて溶解した。次いで、得られた溶液をクリーンベンチ内でポアサイズ0.22μmのフィルターを通すことによって無菌溶液とした。パラフィルムにて50mLファルコンチューブの蓋を密封し、37℃で1週間インキュベートし、DL-グルコースとHSAとを反応させた。インキュベーション後、溶液をPD-10カラム(GEヘルスケアバイオサイエンス社製)にかけて未反応のDL-グルコースを除き、その結果をHPLCで確認し、グルコース由来終末糖化産物(グルコース由来AGE)画分を得た。
抗菌性試験に用いる菌体を以下のように調製した。独立行政法人 製品評価技術基盤機構 バイオテクノロジー本部 生物遺伝資源部門(NBRC)から購入した大腸菌(NBRC 3972)をSCDブイヨン(日水製薬株式会社)5mL中に継代培養法にて液体中に保存した。この保存していた大腸菌液50μLをSCDブイヨン(日水製薬株式会社)5mL中に接種し、振盪水浴中で30℃にて16時間培養した。培養後の菌液を滅菌水で希釈し、107倍までの10倍段階希釈液を調製した。
菌体の調製は、実施例1と同様に行った。次いで、96ウェル平底マイクロプレート(BD Falcon)に、8w/v%のアポラクトフェリン(調製例1にて調製)の水溶液(ポアサイズ0.22μmのフィルターで除菌)を滅菌水で倍数希釈し、各50μLの希釈系列を調製した。ウェル中のアポラクトフェリン濃度は、0~2w/v%であった。それぞれのアポラクトフェリン濃度の系に、ポアサイズ0.22μmのフィルターで除菌8w/v%の種々の試薬(以下の表1に示す)を滅菌水で倍数希釈したものを50μLずつ添加し、試験系を調製した。用いた組み合わせ試薬は以下の通りである:クエン酸(ナカライテスク株式会社)、凍結乾燥ホエイ加水分解物(調製例2にて調製)、ナイシン(SIGMA)、アスコルビン酸(ナカライテスク株式会社)、ポリ-L-リジン(SERVA Electrophoresis GmbH)、グリシン(和光純薬工業株式会社)、メチルパラベン(和光純薬工業株式会社)、塩化セチルピリジニウム(CPC)(和光純薬工業株式会社)。アポラクトフェリンおよび組み合わせ試薬をそれぞれ0、0.03、0.06、0.13、0.25、0.5、1、2(単位はw/v%)の濃度で組み合わせて試験系とした。次いで、これらの試験系に対して、実施例1と同様に菌体接種および培養し、培養後の菌の増減を調べた。最小発育阻止濃度(MIC)を決定し、fractional inhibitory concentration index (FIC index)を下記の計算式に従い算出した:
FIC index
=併用時のApo溶液MIC/単独時のApo溶液MIC+併用時の併用試薬MIC/単独時の併用試薬MIC
20w/v%のDL-α-トコフェロール(CALBIOCHEM)のジメチルスルホキシド溶液を調製した。この5μLを2w/v%のアポラクトフェリン(調製例1にて調製)の水溶液500μLに添加し、次いで超純水にてα-トコフェロール濃度が0.1w/v%となるよう調製した。同様にして、α-トコフェロール濃度が0.05、0.025、および0.01(単位はw/v%)となるよう調製し、試験試料を得た。
Claims (2)
- アポラクトフェリンと、終末糖化産物結合剤、抗酸化物質および抗菌物質からなる群から選択される少なくとも1種とからなる組成物。
- 前記終末糖化産物結合剤が、ホエイをエンドプロテアーゼ、エキソプロテアーゼ、およびエンドペプチダーゼで加水分解することにより得られる乳成分加水分解物である、請求項1に記載の組成物。
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EP2692355A1 (en) | 2012-08-01 | 2014-02-05 | Biagio Biancardi | Apolactoferrin for the treatment of iron accumulation diseases |
WO2015026747A1 (en) * | 2013-08-20 | 2015-02-26 | Trish Choudhary | Separating and demineralizing biomolecule solutions by electrodialysis |
IT202000009430A1 (it) | 2020-04-29 | 2021-10-29 | Tdc Tech Dedicated To Care Srl | Composizione per la prevenzione e/o il trattamento delle infezioni delle vie respiratorie |
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WO2015026747A1 (en) * | 2013-08-20 | 2015-02-26 | Trish Choudhary | Separating and demineralizing biomolecule solutions by electrodialysis |
IT202000009430A1 (it) | 2020-04-29 | 2021-10-29 | Tdc Tech Dedicated To Care Srl | Composizione per la prevenzione e/o il trattamento delle infezioni delle vie respiratorie |
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