CN109265514A - A kind of improvement memory peptide and application thereof that anti-gastrointestinal tract digests - Google Patents
A kind of improvement memory peptide and application thereof that anti-gastrointestinal tract digests Download PDFInfo
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- CN109265514A CN109265514A CN201811136670.0A CN201811136670A CN109265514A CN 109265514 A CN109265514 A CN 109265514A CN 201811136670 A CN201811136670 A CN 201811136670A CN 109265514 A CN109265514 A CN 109265514A
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- 239000003814 drug Substances 0.000 claims abstract description 13
- 230000036541 health Effects 0.000 claims abstract description 9
- 238000002360 preparation method Methods 0.000 claims abstract description 4
- 125000003275 alpha amino acid group Chemical group 0.000 claims abstract 2
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
-
- 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
- A61P25/00—Drugs for disorders of the nervous system
-
- 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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- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Neurology (AREA)
- Biophysics (AREA)
- Polymers & Plastics (AREA)
- Genetics & Genomics (AREA)
- Food Science & Technology (AREA)
- Mycology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Nutrition Science (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention discloses improvement memory peptides of a kind of anti-gastrointestinal tract digestion and application thereof, and the amino acid sequence of the polypeptide is Pro-Ala-Try.Improvement memory peptide of the invention is obtained by solid-state chemical reaction method, pipe intestinal digesting can be resisted, and there is apparent memory improvement effect in dull-witted mouse model, can either be individually used for preparation improves memory drug or improves memory health care product, also related substances can be remembered with the improvement of the prior art to be used in compounding, improve the effect of memory to obtain preferably collaboration.
Description
Technical field
The invention belongs to field of health care products, in particular to it is a kind of can anti-gastrointestinal tract digestion, have and improve dull-witted mouse memory
The tripeptides of ability and its application.
Background technique
In current research, biologically active polypeptide needs that human body or mouse GI tract is undergone to digest, and inhales by small intestine
Target position is reached after receiving, and then plays its physiological action.Important barrier due to pipe intestinal digesting as human body and animal,
Influence whether the structure and activity of polypeptide, therefore, only some biologically active polypeptide test in vivo in have and in vitro
The same bioactivity.Especially long-chain polypeptide is easy the enzymatic hydrolysis by gastrointestinal tract enzyme system, is fractured into small peptide or amino acid.
And short chain polypeptides are influenced smaller by gastrointestinal tract enzyme system, are easy to be absorbed.
Studies have found that the active peptides of Man Chege cheese (Manchego cheese) are derived from, by simulated gastrointestinal tract
After digestion, Angiotensin-Converting (ACE) inhibitory activity of TQPKTNAIPY improves 6 times, and VRYL and KKYNVPQL two
But there is part and declines in the ACE inhibitory activity of polypeptide.
In addition the study found that oldwife Fish protein enzymolysis product (FPH) has in vitro presses down compared with strong anti-oxidation and ACE
System activity, the antioxygen of the FPH and FPH isolated polypeptide component after in-vitro simulated pipe intestinal digesting and intestinal epithelial cell absorb
Change activity to remain unchanged, but ACE inhibitory activity has different degrees of change.
It follows that polypeptide has a certain impact to its activity tool by intracorporal digest and assimilate.
As muscarinic receptor antagonist, the memory of journey in short-term and study that will affect human body and animal obtained hyoscine
Journey.Therefore, hyoscine is chiefly used in constructing senile dementia pathological model.Some researches show that treated is dull-witted for, hyoscine
Mouse intracerebral Antioxidant Enzymes change, and intracerebral glutathione peroxidase (GSH-px) and superoxidase (SOD) occur
Phenomena such as activity reduces, and MDA content rises.
In the drug now reported, in addition to Chinese herbal medicine extract and DHA, only Cerebrolysin is natural active matter.Cerebrolysin its
Simple with preparation process, the features such as having no toxic side effect, it is to hydrolyze the hydrolysate got by pig brain, is used as clinical application
In the drug of the nerve degenerations class diseases such as treatment cerebral injury, there is neurotrophic activity.However, people in Cerebrolysin for acting as
The research of specific polypeptide sequence is not goed deep into, and the drug is entered in vivo using injection system, daily can not be supplemented.
107226836 A of Chinese patent application CN 107325154 A and CN individually discloses a kind of with improvement memory
The polypeptide of effect, amino acid sequence are Tyr-Ser-Gly-Val-Cys and Tyr-Asn-Glu respectively.It is worth noting that, raw
Object active peptides need to be after pipe intestinal digesting, intestinal epithelial cell absorb, into vivo and reaching target position and play a role.
The process of the process of this series of complex, especially gastrointestinal proteases digestion influences whether the sequence of polypeptide, and then influences more
The bioactivity of peptide.But it is above-mentioned two parts application do not carry out in-vitro simulated pipe intestinal digesting verification experimental verification its whether have it is anti-
Pipe intestinal digesting characteristic, and carry out zoopery verify its can be played in dull-witted mouse model body improvement memory effect.
Summary of the invention
In order to overcome existing improvement memory peptide to influence to change by degradation or Partial digestion may occur when gastrointestinal tract
The defect of kind memory effect, the primary purpose of the present invention is that providing a kind of improvement memory peptide PAY of anti-gastrointestinal tract digestion.
Another object of the present invention is to provide the purposes of above-mentioned improvement memory peptide.
The purpose of the invention is achieved by the following technical solution:
A kind of tripeptides, amino acid sequence are Pro-Ala-Try, can be obtained by the solid-state chemical reaction method method of the prior art
?.
Tripeptides of the invention after gastrointestinal tract, still has effects that improve Model of Dementia mouse memory ability, have
The ability for resisting pipe intestinal digesting can be used for preparing the drug and health care product for improving memory；
The drug and health care product also has effects that improve the active constituent and/or acceptable auxiliary of memory containing other
Material；
The drug and health care product can be the various dosage forms of the prior art, such as oral solution, capsule, tablet, powder
Agent or granule.
The present invention has the following advantages and effects with respect to the prior art:
Improvement memory peptide of the invention is obtained by solid-state chemical reaction method, can resist pipe intestinal digesting, and silly
There is apparent memory improvement effect in slow-witted mouse model, can either be individually used for preparation improves memory drug or improve memory health care
Product also can remember related substances with the improvement of the prior art and be used in compounding, and improve the effect of memory to obtain preferably collaboration
Fruit.
Detailed description of the invention
Fig. 1 is the first mass spectrometric figure of Pep-PAYCS.
Fig. 2 is the first mass spectrometric figure of Pepsin-PAYCS.
Fig. 3 is the first mass spectrometric figure of Pancreatin-PAYCS.
Fig. 4 is the first mass spectrometric figure of Digestion-PAYCS.
Specific embodiment
Present invention will now be described in further detail with reference to the embodiments and the accompanying drawings, but embodiments of the present invention are unlimited
In this.
Embodiment 1: the anti-gastrointestinal tract digestion characteristics of polypeptide PAY
1, in vitro digestion
The operation of two step in vitro digestion methods.Synthesis polypeptide (PAYCS) is configured to 10mg/mL aqueous solution.Make first
With pepsin (sigma, EC 3.4.4.1；1:60,000,3,400U mg-1) (ratio of enzyme-to-substrate is hydrolyzed peptide solution
1:50, w/w), 120min, pH 2.0 are digested at 37 DEG C.After hydrolysis, pH to 7.5 is slowly adjusted, pancreatin is added
(sigma, enzyme-to-substrate ratio are 1:25, w/w), continues to digest 240min at 37 DEG C.Entire enzymolysis process is in constant temperature water bath
It is carried out in shaking table, after pancreatin digests, zymolyte is heated to 95 DEG C, maintain 10min enzyme deactivation, and by external digestion final product
And intermediate product is stored in -20 DEG C for subsequent index determining.
2, UPLC-MS/MS analyzes PAYCS digestion product
Using the system combined Acquity UPLC HSS T3 column of Acquity UPLC I-Class (2.1 × 100mm, 1.8 μ
M, Waters, Ireland) separation identification is carried out to PAYCS and its in vitro digestion product.Elution samples applied sample amount is 5 μ L,
Concentration is 1mg/mL.Flow rate set is 0.2mL/min.Mobile phase A is the ultrapure water containing 0.1% formic acid, and Mobile phase B is second
Nitrile.Elution program is set as 0-2min, 10%B；2-10min, 10-50%B；10-13min, 50-10%B；13-15min,
10%B；Column temperature is set as 25 DEG C.Elution fraction is detected at 220nm.
Wherein, the identification of (pure peptide and digestion product) polypeptide sequence and accurate molecular weight measurement are electric using electron spray in sample
Analysis is carried out from quadrupole rod time of-flight mass spectrometer (ESI-Q-TOF-MS/MS) and by Bruker maxis impact superelevation point
Resolution mass spectrograph acquires data.The setting of mass spectrum relevant parameter is as follows, and level four bars electron energy is 3.0eV；In collision cell, collision
Energy, transfer time and prepulsing storage are respectively 20eV, 50 μ s and 8 μ s.ESI relevant parameter are as follows: capillary voltage 3.5kV,
200 DEG C of dry gas temperature, 4.0L/min dry gas flow velocity and 0.5bar ESI nebulizer pressure.
This experiment carries out manual de novo sequencing analysis using 3.0 software of Data analysis, obtains subject polypeptide sequence.
The peptide molecule quality of measurement should match (error ± 0.002Da) with its theoretical value.This research has detected PAYCS, stomach respectively
Protease digestion PAYCS product, pancreatin digest the mass signal (figure of PAYCS product and complete pipe intestinal digesting PAYCS product
1 to Fig. 4).
After PAYCS and its peptic digest 2h, enteron aisle digestion 4h, digestion product mass spectrometry results are as shown in Figure 1.
Fig. 1 shows the pure peptide first mass spectrometric figure of PAYCS, accurate molecular weight is 540.1936Da (+H).
Fig. 2 indicates the first mass spectrometric figure by PAYCS digestion product (pepsin-PAYCS) after pepsin digestion, by figure
It is found that detecting the pure peptide 562.1915Da (+Na) signal of PAYCS, and detectable digestion produces after pepsin digestion
Object has the PA etc. that PAY accurate molecular weight is 350.1710Da (+H) and signal is weaker.
Fig. 3 is then indicated by the postdigestive PAYCS digestion product (tripsin-PAYCS) of pancreatin, wherein what is detected is more
Peptide has PAY and PA etc., and detects the first mass spectrometric signal of arginine (R).
Fig. 4 is then PAYCS digestion product (digestion-PAYCS) first mass spectrometric figure after pipe intestinal digesting, by
Figure is it is found that PAYCS obtains PAYCS, the first mass spectrometric signal of two polypeptides of PAY by Partial digestion.
From the above results, PAYCS cannot fully against pipe intestinal digesting, under the enzymolysis of pepsin,
Portion fractures are the sequences such as PAY to PAYCS.The sequences such as PAYCS and PAY all exist in next digestion process, therefore
PAY is the PAYCS digestion product that can resist pipe intestinal digesting.
Oral polypeptide is produced fracture by will receive the effect of pepsin and pancreatin when pipe intestinal digesting.In stomach
Digestion process in, pepsin is more likely to cutting hydrophobicity and aromatic amino acid (such as phenylalanine, tryptophan and junket
Propylhomoserin etc.) between peptide bond.Therefore, PAYCS can be broken under pepsin effect at tyrosine, PAY polypeptide occur
Sequence.PAY can keep complete during pipe intestinal digesting.Therefore, PAY, which is one, has anti-gastrointestinal tract digestive function
Polypeptide.
Influence of the embodiment 2:PAY to Model of Dementia mouse memory ability
Selection SPF grades kunming mice 48, half male and half female, weight 18-22g, by Traditional Chinese Medicine University Of Guangzhou experimental animal
Center provides.Test mice feeding environment is room temperature (21 ± 2) DEG C, and relative humidity control is handed in 50%-60%, 12/12h light and shade
It replaces, the free diet of mouse during test takes the photograph water.Mouse 7d before testing is placed in laboratory and adapts to environment.48 mouse are random
It is divided into 4 groups (every group 12, n=12), respectively blank control group, hyoscine group (model group), Piracetam group are (positive right
According to group), PAY (0.2mmol/kg).Blank group and model group gavage isometric distilled water, and positive controls gavage Piracetam
(400mg/kg), tested group gavages corresponding polypeptide sample by upper face dosage, daily stomach-filling 1 time, and continuous gavage 20 days.
PAY is evaluated by Morris water maze, and learning and acquisition disturbance model mice learning and memory is caused to hyoscine
The influence of ability.Morris water maze test includes orientation navigation test (place navigation) and space exploration test
Two parts (probe test).
Grouping advance action object screening, shaves the abnormal animal that is not able to swim or swims, self administration of medication starts the 14th day, carries out
Orientation navigation experiment.Animal is allowed to pass through spatial cues study to remember position of platform, experiment carries out 5 days, daily training 4 times.It is real
Testing the previous day, that mouse is placed in free swimming 2min in water maze is aqueous to be familiar with.Training when, pond be divided into 4 quadrants (the Ith,
II, III, IV quadrant).Training first day is visible mobile platform, and platform is higher than water surface 1-2cm at this time, and is inserted on platform red
The small flag of color is convenient for animal identification.Every training is primary, and platform sequence is mobile primary.The 2-5 days are fixed hiding plateau, low
In water surface 1-2cm.According to the I, the III, sequence of IV quadrant when experiment, into the water towards and close to pool wall by mouse, using view
Frequency tracking system records it and searches out platform and stop 3 seconds or more required time for the first time in 60s, is denoted as escape latency
(escape latency).During training, scopolamine hydrobromide injection is injected intraperitoneally in positive control and administration each group
1.0mg/kg, model and normal group give same amount of normal saline, enter water training after 30min, and continuous 5 days.
Space exploration experiment, for testing the ability of learning and memory of animal, terminates next day in orientation navigation experiment, this
Between need to remove security platform in pond.It is administered from the 15th day, mouse is put into pond from test point, measures in its 60s flat
The swimming time of platform quadrant.After last dose 1h, mouse is swum into the water, records mouse using computer locating and tracking system
Swimming track in 60s, and record its spanning platform number, activity distance around swimming time (s) and platform around platform
(mm)。
Measurement result is as shown in table 1 and table 2.
Influence of 1 PAY of table to memory disorders mouse Morris water maze orientation navigation boat is obtained
#It represents compared with Normal group, p < 0.05,##Represent p < 0.01 compared with Normal group.*Expression and model
Control group compares, p < 0.05,**Indicate p < 0.01 compared with model control group.
As can be seen from Table 1 after Memory acquisition training, the escape latency of model group mouse and total swimming road
Journey is significantly higher than blank control (p < 0.01), illustrates hyoscine induced mice dysmnesia model modeling success.It can by result
Know, compared with model group, the mouse escape latency and swimming total distance of Piracetam group (positive control) and PAY group significantly contract
Short (p < 0.05 or p < 0.01).Piracetam is a kind of clinical medicine, is mainly used for treating amnesia and different degrees of
Brain disorder.As can be seen from the results, after taking in PAY, mouse escape latency and swimming total distance shorten degree and are significantly higher than
Piracetam group (p < 0.05).
Influence of 2 PAY of table to memory disorders mouse Morris water maze space exploration is obtained
#Represent p < 0.05 compared with Normal group.*It indicates compared with model control group, p < 0.05,**Expression and model
Control group compares, p < 0.01.
As shown in Table 2, compared with control group mice, swimming time and swimming distance of the model group mouse around platform are aobvious
It writes and shortens (p < 0.05), which illustrates that model group mouse can not accurately remember position of platform.Generate Learning memory disorder.And
The intake of PAY significantly increases swimming time (p < 0.01,0.05) of the mouse around platform, can increase mouse around platform
Activity distance.
Influence of the embodiment 3:PAY to the anti-oxidant index of correlation of Mice brain tissues
Each group mouse is put to death after the water maze test of embodiment 2 and is breaked end, in separation brain on ice, uses ice-cold normal
Salt water cleans bloodstain, and physiological saline homogenate is added by 1:9 mass ratio.Homogenate is centrifuged 10min at 4 DEG C with 3500r/min, inhales
Take supernatant as sample to be tested, -20 DEG C save backup.SOD and GSH-Px activity is measured in strict accordance with kit specification, separately
The total protein concentration of external application BCA kit measurement sample to be tested.
The results are shown in Table 3.
Influence of 3 PAY of table to the anti-oxidant index of correlation of Mice brain tissues
##Represent p < 0.01 compared with Normal group.**Indicate p < 0.01 compared with model control group.
Compared with normal group, the SOD activity of dysmnesia model Mice brain tissues caused by hyoscine be remarkably decreased (p <
0.01), show response to oxidative stress occur in memory impaired Mice brain tissues.Compared with model group, piracetam group and PAY
It is active (p < 0.01) that processing group can increase the SOD in Mice brain tissues.
In conclusion tripeptides PAY of the invention can not only resist pipe intestinal digesting, and after by pipe intestinal digesting
Still there is good activity in vivo, improve memory effect and do not lose.Tripeptides PAY is obtained in the mouse that hyoscine induces
Obtaining has good memory improvement effect in dysmnesia model, and the improvement result may regulate and control in Antioxidant Enzymes with it
SOD activity is related, the antioxidation may in PAY tyrosine (as) there are related.Reactive phenolic in tyrosine
Sulfhydryl structure in structure and cysteine can be used as hydrogen donor, for the polypeptide containing these amino acid provide it is stronger from
By base Scavenging activity to improve dull-witted mouse intracerebral oxidation stress damage state.
Embodiment 4
A kind of tablet improving memory, the auxiliary material of PAY and 85wt% containing 15wt%, auxiliary material are starch, sucrose, malt
One or more of dextrin or magnesium stearate.
Embodiment 5
A kind of soft capsule improving memory, the auxiliary material of PAY and 90wt% containing 10wt%, auxiliary material are phosphatidyl silk ammonia
Acid, gelatin, glycerol, D-sorbitol solution, titanium dioxide, burnt sugar coloring and purified water etc..
The above embodiment is a preferred embodiment of the present invention, but embodiments of the present invention are not by above-described embodiment
Limitation, other any changes, modifications, substitutions, combinations, simplifications made without departing from the spirit and principles of the present invention,
It should be equivalent substitute mode, be included within the scope of the present invention.
Claims (4)
1. a kind of tripeptides, it is characterised in that amino acid sequence is Pro-Ala-Try.
2. application of the tripeptides described in claim 1 in the drug and health care product that preparation improves memory.
3. application according to claim 2, it is characterised in that: the drug and health care product, which contains other, has improvement note
Recall the active constituent and/or acceptable auxiliary material of effect.
4. application according to claim 2, it is characterised in that: the drug and health care product is oral solution, capsule, piece
Agent, pulvis or granule.
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