CN117838833A - Hydrolyzed casein oligopeptide with auxiliary blood pressure reducing function, and preparation method and application thereof - Google Patents
Hydrolyzed casein oligopeptide with auxiliary blood pressure reducing function, and preparation method and application thereof Download PDFInfo
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- CN117838833A CN117838833A CN202311593366.XA CN202311593366A CN117838833A CN 117838833 A CN117838833 A CN 117838833A CN 202311593366 A CN202311593366 A CN 202311593366A CN 117838833 A CN117838833 A CN 117838833A
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- oligopeptide
- blood pressure
- hydrolyzed casein
- casein
- pressure reducing
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- 239000005018 casein Substances 0.000 title claims abstract description 36
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 title claims abstract description 36
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- ILZZTQYNTRWQSJ-UHFFFAOYSA-N Phe-Phe-Val-Ala-Pro-Phe-Pro-Glu-Val-Phe-Gly-Lys Natural products CC(C)C(NC(=O)C(Cc1ccccc1)NC(=O)C(N)Cc2ccccc2)C(=O)NC(C)C(=O)N3CCCC3C(=O)NC(Cc4ccccc4)C(=O)N5CCCC5C(=O)NC(CCC(=O)O)C(=O)NC(C(C)C)C(=O)NC(Cc6ccccc6)C(=O)NCC(=O)NC(CCCCN)C(=O)O ILZZTQYNTRWQSJ-UHFFFAOYSA-N 0.000 abstract description 2
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- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 9
- 230000035487 diastolic blood pressure Effects 0.000 description 9
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- 206010048554 Endothelial dysfunction Diseases 0.000 description 2
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 2
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
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- ORWYRWWVDCYOMK-HBZPZAIKSA-N angiotensin I Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 ORWYRWWVDCYOMK-HBZPZAIKSA-N 0.000 description 2
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- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
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- 102000035195 Peptidases Human genes 0.000 description 1
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- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
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- ZUBDGKVDJUIMQQ-UBFCDGJISA-N endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 description 1
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/17—Amino acids, peptides or proteins
- A23L33/18—Peptides; Protein hydrolysates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4732—Casein
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P21/00—Preparation of peptides or proteins
- C12P21/06—Preparation of peptides or proteins produced by the hydrolysis of a peptide bond, e.g. hydrolysate products
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Zoology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Heart & Thoracic Surgery (AREA)
- Biochemistry (AREA)
- Wood Science & Technology (AREA)
- Gastroenterology & Hepatology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Genetics & Genomics (AREA)
- Cardiology (AREA)
- Microbiology (AREA)
- Polymers & Plastics (AREA)
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Abstract
The invention belongs to the technical field of functional oligopeptides, and discloses a hydrolyzed casein oligopeptide with an auxiliary blood pressure reducing function, and a preparation method and application thereof. Simultaneously has the effects of reducing blood fat and improving endothelial function and vascular elasticity. In the invention, the hydrolyzed casein oligopeptide with the blood pressure reducing function contains VNEISK, LQSW, VLPVPQK, MIMKEP, GPFPIIV, FFVAPFPEVFGK as a main sequence of the blood pressure reducing function, wherein VNEISK is the hydrolyzed casein oligopeptide with the greatest activity and higher content and auxiliary blood pressure reducing function, and has the effects of auxiliary blood pressure reduction, blood vessel softening, blood vessel elasticity improvement, and various effects of improving headache, dizziness, palpitation, tinnitus, insomnia and the like caused by hypertension. The antihypertensive peptide prepared by the invention can be used in various products such as milk powder, beverage, pressed candy and the like.
Description
Technical Field
The invention belongs to the technical field of functional oligopeptides, and in particular relates to a hydrolyzed casein oligopeptide with an auxiliary blood pressure reducing function, and a preparation method and application thereof.
Background
Antihypertensive peptides derived from food are a general term for small molecule polypeptides capable of reducing blood pressure of a human body. The molecular weight of the antihypertensive peptides, which are generally active, is below 1000Da, and is generally obtained by hydrolyzing proteins with proteases under relatively mild conditions. The traditional Chinese medicine composition has obvious blood pressure reducing effect, has no influence on normal blood pressure, has no side effect and the like, and becomes a research hot spot.
The mechanism of action of antihypertensive peptides is to achieve the function of lowering blood pressure by inhibiting the activity of Angiotensin Converting Enzyme (ACE). ACE has important physiological functions in the renal-angiotensin system to regulate blood pressure. Renin acts on angiotensinogen to release inactive angiotensin i, and angiotensin ii with vascular smooth muscle activity is produced by the action of ACE, thereby causing an increase in blood pressure. Antihypertensive peptides inhibit peripheral vasoconstriction and prevent elevation of blood pressure by inhibiting the activity of angiotensin converting enzyme, so that angiotensin I (inactive) cannot be converted into angiotensin II (active).
The existing antihypertensive peptides have the efficacy of reducing blood pressure, but the variation of blood fat, endothelial function and vascular elasticity is uncertain, and meanwhile, the number of the milk-source antihypertensive peptides is small.
Disclosure of Invention
The technical problem to be solved by the invention is to overcome the problems in the prior art, and firstly, a milk-derived antihypertensive peptide is provided.
A second object of the present invention is to provide a method for producing the above antihypertensive peptide.
It is a third object of the present invention to provide a functional product comprising the above antihypertensive peptide.
The aim of the invention is achieved by the following technical scheme:
a hydrolyzed casein oligopeptide with auxiliary blood pressure lowering function has an amino acid sequence of VNEISK.
The invention takes casein as raw material, collects casein hydrolysate containing active peptide through directional controllable enzymolysis, and obtains the hydrolyzed casein oligopeptide which has remarkable blood pressure reducing function.
The invention provides application of the hydrolyzed casein oligopeptide in preparing a product with an auxiliary blood pressure reducing function.
Preferably, the amount of the hydrolyzed casein oligopeptide is 600-1000 mg/day.
Preferably, the product is a health product, a medicine or a functional food.
Preferably, the hydrolyzed casein oligopeptide has at least one of the following functions:
(1) Lowering blood pressure;
(2) Decreasing the activity of lipoprotein phospholipase a 2;
(3) Enhancing vasodilation function.
The invention also provides a preparation method of the hydrolyzed casein oligopeptide, which comprises the following steps:
(1) Adding water 3-4 times of casein, stirring and dissolving at 40-50deg.C;
(2) Adding trypsin for enzymolysis, wherein the enzyme amount is 0.1-0.2% of the mass of casein, the reaction temperature is 40-50 ℃, the reaction time is 1-2 h, and the pH is 7.0-9.0;
after the enzymolysis of trypsin is completed, pepsin accounting for 0.05 to 0.1 percent of the mass of casein is added for enzymolysis for 1 to 2 hours;
(3) Adjusting the temperature to 80-90deg.C, maintaining the temperature for 20-30 min, and sterilizing;
(4) Regulating pH value to 4.0-5.0, filtering to remove non-enzymatic macromolecular protein precipitate;
(5) Purifying: regulating pH to 3.0-5.0, keeping at-20deg.C to 4deg.C and ethanol concentration of 40-60%, standing for 4-6 hr, centrifuging, and removing precipitate;
(6) Anion exchange resin purification: adjusting pH of the supernatant to 7.0, purifying with 717 anion exchange resin for 2 hr, washing with water, discarding the water washing solution, and eluting with 0.5% hydrochloric acid;
(7) Purifying reverse phase silica gel: the eluent is purified by reverse phase silica gel,
HPLC system: preparing a high performance liquid chromatograph by using LC-8A Shimadzu; chromatographic column: HW-0121; chromatographic conditions: flow rate: 8mL/min; detection wavelength: 214nm; sample injection amount: 2mL; mobile phase: ultrapure water (containing 0.1% (v/v) TFA) was pumped A, acetonitrile was pumped B, and the initial concentration of B was 25%; elution mode: binary gradient elution; elution gradient: 0.01 to 60min,25 to 36 percent; 60.01 to 80min,36 percent; 80.01 min-90 min,90% -90%; 90.01 to 100min,90 to 25 percent; repeating sample injection, and collecting T16 elution peak;
(8) And (3) drying: through any one of freeze drying, spray drying and vacuum drying, the obtained product is dried into powder, and the hydrolyzed casein oligopeptide is obtained.
Compared with the prior art, the invention has the following beneficial effects:
the invention takes casein as raw material, collects casein hydrolysate containing active peptide through directional controllable enzymolysis, and obtains the hydrolyzed casein oligopeptide which has remarkable blood pressure reducing function. Simultaneously has the effects of reducing blood fat and improving endothelial function and vascular elasticity. The invention can fully utilize milk product resources, provides a new way for the high-value utilization of milk peptide, and simultaneously, the hydrolyzed casein oligopeptide prepared by the invention is safe and nontoxic and has wide application value. Researches prove that the hydrolyzed casein oligopeptide has the effects of assisting in reducing blood pressure, softening blood vessels, improving blood vessel elasticity, and improving various diseases such as headache, dizziness, palpitation, tinnitus, insomnia and the like caused by hypertension. The antihypertensive peptide prepared by the invention can be used in various products such as milk powder, solid beverage, pressed candy and the like.
Drawings
FIG. 1 shows the change in blood pressure before and after application of antihypertensive peptides;
FIG. 2 shows the change of lipoprotein phospholipase a2 before and after application of antihypertensive peptide;
FIG. 3 shows the change of FMD of vasodilation function before and after application of antihypertensive peptide;
FIG. 4 shows the integral change of symptoms before and after application of antihypertensive peptides;
fig. 5 is a summary of symptom score improvement rates before and after application of antihypertensive peptides.
Detailed Description
The following describes the invention in more detail. The description of these embodiments is provided to assist understanding of the present invention, but is not intended to limit the present invention. In addition, the technical features of the embodiments of the present invention described below may be combined with each other as long as they do not collide with each other.
EXAMPLE 1 preparation of antihypertensive peptides
Casein is taken as a raw material, and casein hydrolysate containing active peptide is obtained through directional controllable enzymolysis.
A method for preparing a high purity antihypertensive peptide, comprising the steps of:
(1) To the beaker, 400mL of pure water was added, and 200rpm of stirring was started, 100g of casein was slowly poured into the beaker, and the mixture was dissolved by stirring at 40 ℃.
(2) Adding trypsin for enzymolysis, wherein the enzymolysis conditions are as follows: the enzyme addition amount is 0.1% of the mass of casein, the reaction temperature is 40 ℃, the reaction time is 1h, and the pH is 7.0. After trypsin enzymolysis, the pH value is adjusted to 4.0, pepsin with the mass of 0.05% of casein is added, and enzymolysis is carried out for 1 hour.
(3) Adjusting the temperature to 80 ℃, preserving the heat for 30min, and sterilizing.
(4) Regulating pH value to 4.0, centrifuging at 3000r/min for 30min, and removing non-enzymatic macromolecular protein precipitate.
(5) Regulating pH value of supernatant to 2.0, regulating temperature to-20deg.C, regulating ethanol concentration to 60%, standing for 4 hr, centrifuging, discarding precipitate, and collecting supernatant;
(6) And (5) purifying the anion exchange resin. The supernatant was adjusted to pH 7.0, and purified with 717 anion exchange resin for 2 hours, washed with water, and then eluted with 0.5% hydrochloric acid.
(7) And (5) purifying reverse phase silica gel. The eluate was further purified on reverse phase silica gel, HPLC system: preparing a high performance liquid chromatograph by using LC-8A Shimadzu; chromatographic column: HW-0121; chromatographic conditions: flow rate: 8mL/min; detection wavelength: 214nm; sample injection amount: 2mL; mobile phase: ultrapure water (containing 0.1% (v/v) TFA) was pumped A, acetonitrile was pumped B, and the initial concentration of B was 25%; elution mode: binary gradient elution; elution gradient: 0.01 to 60min,25 to 36 percent; 60.01 to 80min,36 percent; 80.01 min-90 min,90% -90%; 90.01 min-100 min,90% -25%. The sample injection was repeated and the T16 elution peak was collected.
(8) Concentrating and drying. Collecting eluting peak, vacuum concentrating, and freeze drying to obtain the peptide for lowering T16 blood pressure.
(9) ACE (angiotensin converting enzyme) inhibition activity assay: the hippuric acid method.
Under the above conditions, 2.55g of T16 antihypertensive peptide with a molecular weight of 971.2Da is obtained, the inhibition rate of ACE enzyme is 51.8% at a concentration of 1mg/mL, the solubility is good, and an ethanol solution of 20% antihypertensive peptide is clear and transparent.
The amino acid sequence of the T16 antihypertensive peptide is determined as follows: VNEISK.
EXAMPLE 2ACE inhibitory Activity
The T16 antihypertensive peptide prepared in example 1 and CEI12 peptide isolated in the previous study were used to study the ACE inhibitory activity of both and the combined peptide, and the detection method was a maleic acid method.
Experimental grouping
Group 1:500 μg/mLT16 antihypertensive peptide; group 2:500 μg/mL CEI12 peptide; group 3: the T6 antihypertensive peptide and the CEI12 peptide are mixed so that the final concentration of both the T6 antihypertensive peptide and the CEI12 peptide in the mixed solution is 500. Mu.g/mL.
Results: ACE inhibition rates of group 1, group 2 and group 3 were 91.34%, 86.67% and 68.19%, respectively.
CEI12 peptide N-terminal sequence FFVAPFPEVFGK
EXAMPLE 3 use of antihypertensive peptides
Sample: green extract hydrolyzed casein oligopeptide powder (T16 antihypertensive peptide), light yellow to white appearance, adding adjuvants, and making into tablet. Specification of: 250 mg/tablet, the effective amount of hydrolyzed casein oligopeptide is 200 mg/tablet, 60 tablet/bottle. Lot number: 20210908. placebo is identical to sample in dosage form, mouthfeel, appearance and packaging, lot number: 20210908.
experimental design and grouping requirements: by adopting two control designs between the test subjects and the control subjects, 70 test subjects are randomly divided into a test feeding group and a control group according to the requirement of a random blind method, and main factors affecting the result, such as disease course and the like, are considered as far as possible to carry out equilibrium test so as to ensure comparability between the groups. 35 subjects per group. The test group took the test sample, the control group took the placebo, and the test period was 120 days.
A subject: all subjects were adults 18 years-65 years old, who signed informed consent; the systolic pressure is 120-159 mmHg and the diastolic pressure is 80-99 mmHg, and any one of the systolic pressure and the diastolic pressure can be taken in (wherein the systolic pressure of a hypertension subject is more than or equal to 140mmHg and/or the diastolic pressure is more than or equal to 90mmHg, and the medicine is taken stably in the first 3 months).
Dose and time of consumption: the test food group takes the tested products according to the recommended taking method and the taking amount, and takes 4 tablets daily for 120 days continuously; the control group was orally administered placebo, 4 tablets per day, for 120 days. Each index was tested once at the beginning and end of the test, and blood pressure and heart rate were measured every 15 days.
Efficacy index criterion: according to the health food function evaluation method (2020 edition) (solicited opinion manuscript), the test food group before and after test food itself is compared, the measurement value of diastolic pressure or systolic pressure is obviously reduced, the difference is obvious, and the diastolic pressure is more than or equal to 10mmHg or reduced to normal, or the systolic pressure is more than or equal to 20mmHg or reduced to normal, the difference of the measurement value of diastolic pressure or systolic pressure or the reduction percentage thereof is obvious, and the tested sample has the function of maintaining the blood pressure health level.
And (3) observing the indexes: safety, blood pressure and heart rate, symptom score, blood lipid (total cholesterol TC, total triglycerides TG, low density cholesterol LDL-C), blood rheology (whole blood viscosity, plasma viscosity, fibrin concentration, hematocrit, erythrocyte aggregation index, erythrocyte deformation index, erythrocyte rigidity index, erythrocyte electrophoresis time), endothelial function (endothelin ET-1, cell adhesion molecule ICAM-1, lipoprotein phospholipase a 2), vascular elasticity (vascular thickness, vascular dilation function FMD).
1. Equalization comparison
89 subjects were included, 44 subjects were tested, 45 subjects were controlled, 9 subjects were removed from the test, 5 subjects were removed from the control, 75 subjects were actual, 35 subjects were tested, and 40 subjects were controlled. Both groups had equilibrium comparability (table 1).
TABLE 1
| Project | Test food group (n=44) | Control group (n=45) |
| Age (age) | 59.45±6.91 | 61.04±4.27 |
| Sex (Male/female) | 11/33 | 10/35 |
| Systolic blood pressure (mmHg) | 144.66±15.11 | 142.49±15.92 |
| Diastolic blood pressure (mmHg) | 80.14±11.04 | 78.98±7.62 |
2. Security index analysis 1
The test person is subjected to inquiry investigation on the mental, sleeping, eating and urination conditions, and statistics are carried out according to good, general and differential levels. Most subjects were generally good, and the subjects were not adversely affected by the test diet (Table 2).
TABLE 2
3. Security index analysis 2
The results of the test on white blood cells, red blood cells, hemoglobin, platelets, and liver and kidney functions were all substantially within the normal range after the test on the subjects (Table 3).
TABLE 3 Table 3
4. Blood pressure and heart rate
TABLE 4 Table 4
Note that: the difference value is the difference value between the end of the test food and the before the test food; self-comparison ** P<0.01; group-to-group comparison # P<0.05； ## P<0.01。
The blood pressure changes are shown in FIG. 1, and the systolic pressure and the diastolic pressure are reduced by comparison before the test food group tests, the difference is remarkable, and the systolic pressure of the test food group is reduced by 14.54mmHg on average and the diastolic pressure of the test food group is reduced by 10.17mmHg on average.
5. Hemorheology
The four blood lipid items were not significantly changed (P > 0.05) by comparison of the test groups before and after test (table 5).
TABLE 5
6. Endothelial function
As shown in Table 6, endothelin decreased and the difference was not significant (P > 0.05) in the test groups compared with each other before and after the test.
TABLE 6
7. Lipoprotein phospholipase a2
Lipoprotein phospholipase a2 is a human vascular specific inflammatory marker, which is also an independent risk factor for coronary heart disease and ischemic stroke. The reference range for adult serum is 131-376 (male), if the result is high, considering the possibility of cardiovascular diseases. It is recommended to check the index at regular intervals to the hospital, pay attention to the diet with low salt and low fat at ordinary times, ensure balanced nutrition, normal life and rest and sufficient sleep.
The lipoprotein phospholipase a2 has a descending trend compared with the test food before and after test food; the comparison of the control group before and after trial feeding shows that the lipoprotein phospholipase a2 is increased, and the difference is significant (P is less than 0.01).
As shown in fig. 2 and table 7, the difference was significant (P < 0.01) in the test group after the test, with lipoprotein phospholipase a2 being lower than the control group.
TABLE 7
Note that: self-comparison ** P<0.01; group-to-group comparison ## P<0.01。
8. Vascular elasticity
The results are shown in table 8, aided by non-invasive brachial artery ultrasound, a method of assessing vascular endothelial function by measuring brachial artery blood flow mediated vasodilation Function (FMD).
TABLE 8
Note that: self comparison P < 0.05P <0.01 inter-group comparison #p <0.05.
FMD (%) =expanded inner diameter (inner diameter after decompression release-base inner diameter)/base inner diameter×100.
FMD decrease suggests peripheral vascular endothelial dysfunction, meta analysis shows that every 1% decrease in brachial artery FMD, the risk of developing cardiovascular disease increases 8% in the future; can be used for evaluating coronary endothelial dysfunction, and has accuracy comparable to angiography.
9. Symptom score
Such as tables 9 and 10.
TABLE 9
| Grouping | Number of examples | Before taking the test food | Test food for 45d | After taking the food |
| Test food group | 35 | 2.51±0.89 | 1.94±1.06 ** | 1.26±0.95** ## |
| Control group | 40 | 2.17±0.71 | 2.25±0.87 | 2.28±0.91 |
Note that: self-comparison of P<0.01, group comparisons ## P<0.01。
Table 10
() The data of the control group are shown in the inner part. The symptom score change is shown in fig. 4, and the symptom score improvement rate is shown in fig. 5.
10. Failure rate and adverse reaction observation
89 subjects were enrolled, 14 were not reviewed on time at the prescribed time, and met the subject exclusion criteria, 75 subjects were effective, and the subject loss rate was 15.7%.
During the experiment, no allergic or other adverse reactions were seen (Table 11). The experiment summary is shown in table 12, and according to the judgment standard of the scheme, the tested sample can be shown to be positive in the human test feeding test for maintaining the healthy level of blood pressure.
TABLE 11
Table 12
The embodiments of the present invention have been described in detail above, but the present invention is not limited to the described embodiments. It will be apparent to those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, and yet fall within the scope of the invention.
Claims (5)
1. The application of the hydrolyzed casein oligopeptide in preparing a product with an auxiliary blood pressure reducing function is characterized in that the amino acid sequence of the hydrolyzed casein oligopeptide is VNEISK.
2. The use according to claim 1, wherein the amount of hydrolyzed casein oligopeptide is 600-1000 mg/day.
3. The use according to claim 1, wherein the method for preparing the hydrolyzed casein oligopeptide comprises the steps of:
(1) Adding water 3-4 times of casein, stirring and dissolving at 40-50deg.C;
(2) Adding trypsin for enzymolysis, wherein the enzyme amount is 0.1-0.2% of the mass of casein, the reaction temperature is 40-50 ℃, the reaction time is 1-2 h, and the pH is 7.0-9.0;
after the enzymolysis of trypsin is completed, pepsin accounting for 0.05 to 0.1 percent of the mass of casein is added for enzymolysis for 1 to 2 hours;
(3) Adjusting the temperature to 80-90deg.C, maintaining the temperature for 20-30 min, and sterilizing;
(4) Regulating pH value to 4.0-5.0, filtering to remove non-enzymatic macromolecular protein precipitate;
(5) Purifying: regulating pH to 3.0-5.0, keeping at-20deg.C to 4deg.C and ethanol concentration of 40-60%, standing for 4-6 hr, centrifuging, and removing precipitate;
(6) Anion exchange resin purification: adjusting pH of the supernatant to 7.0, purifying with 717 anion exchange resin for 2 hr, washing with water, discarding the water washing solution, and eluting with 0.5% hydrochloric acid;
(7) Purifying reverse phase silica gel: the eluent is purified by reverse phase silica gel,
HPLC system: preparing a high performance liquid chromatograph by using LC-8A Shimadzu; chromatographic column: HW-0121; chromatographic conditions: flow rate: 8mL/min; detection wavelength: 214nm; sample injection amount: 2mL; mobile phase: ultrapure water containing 0.1% (v/v) TFA was pumped by A, acetonitrile was pumped by B, and the initial concentration of B was 25%; elution mode: binary gradient elution; elution gradient: 0.01 to 60min,25 to 36 percent; 60.01 to 80min,36 percent; 80.01 min-90 min,90% -90%; 90.01 to 100min,90 to 25 percent; repeating sample injection, and collecting T16 elution peak;
(8) And (3) drying: through any one of freeze drying, spray drying and vacuum drying, the obtained product is dried into powder, and the hydrolyzed casein oligopeptide is obtained.
4. The use according to claim 1, wherein the product is a health product, a pharmaceutical product, a functional food.
5. The use according to claim 4, wherein the hydrolyzed casein oligopeptide has at least one of the following functions:
(1) Lowering blood pressure;
(2) Decreasing the activity of lipoprotein phospholipase a 2;
(3) Enhancing vasodilation function.
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| CN101326953A (en) * | 2007-06-19 | 2008-12-24 | 光明乳业股份有限公司 | Anti-hypertensive casein active peptide and method for producing the same as well as use thereof |
| CN102296100A (en) * | 2011-09-09 | 2011-12-28 | 江南大学 | Preparation method of casein antihypertensive peptides |
| CN108796018A (en) * | 2018-06-27 | 2018-11-13 | 马学 | A method of extracting active antihypertensive peptide from casein |
| WO2022242339A1 (en) * | 2021-05-20 | 2022-11-24 | 澳优乳业（中国）有限公司 | Oligopeptide, preparation method therefor, and application thereof |
| US20230097644A1 (en) * | 2017-11-13 | 2023-03-30 | Jiangsu University | Ultrasound-assisted simulated digestion method of casein active peptide and application there of in health foods |
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| CN101326953A (en) * | 2007-06-19 | 2008-12-24 | 光明乳业股份有限公司 | Anti-hypertensive casein active peptide and method for producing the same as well as use thereof |
| CN102296100A (en) * | 2011-09-09 | 2011-12-28 | 江南大学 | Preparation method of casein antihypertensive peptides |
| US20230097644A1 (en) * | 2017-11-13 | 2023-03-30 | Jiangsu University | Ultrasound-assisted simulated digestion method of casein active peptide and application there of in health foods |
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