CN109265514B - Memory improving peptide for resisting gastrointestinal tract digestion and application thereof - Google Patents

Memory improving peptide for resisting gastrointestinal tract digestion and application thereof Download PDF

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CN109265514B
CN109265514B CN201811136670.0A CN201811136670A CN109265514B CN 109265514 B CN109265514 B CN 109265514B CN 201811136670 A CN201811136670 A CN 201811136670A CN 109265514 B CN109265514 B CN 109265514B
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digestion
memory improving
memory
gastrointestinal tract
peptide
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CN109265514A (en
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赵谋明
赵甜甜
苏国万
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South China University of Technology SCUT
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    • 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

Abstract

The invention discloses a memory improving peptide for resisting gastrointestinal tract digestion and application thereof, wherein the amino acid sequence of the peptide is Pro-Ala-Try. The memory improving peptide is obtained by solid phase chemical synthesis, can resist gastrointestinal tract digestion, has obvious memory improving effect in a dementia mouse model, can be independently used for preparing a memory improving medicine or a memory improving health care product, and can also be compounded with memory improving related substances in the prior art for use, so that a better synergistic memory improving effect is obtained.

Description

Memory improving peptide for resisting gastrointestinal tract digestion and application thereof
Technical Field
The invention belongs to the field of health care products, and particularly relates to tripeptide capable of resisting gastrointestinal tract digestion and improving memory capacity of dementia mice and application thereof.
Background
In current research, bioactive polypeptides need to undergo gastrointestinal digestion in humans or mice, and reach a target site after being absorbed by the small intestine, thereby exerting their physiological effects. Since gastrointestinal digestion serves as an important barrier in humans and animals, affecting the structure and activity of the polypeptide, only a fraction of biologically active polypeptides have the same biological activity in vivo assays as in vitro. Especially long-chain polypeptides are easily subjected to enzymolysis of gastrointestinal enzyme systems and are broken into short peptides or amino acids. The short-chain polypeptide is less affected by gastrointestinal enzyme systems and is easy to absorb.
It has been found that TQPKTNAIPY shows 6 times higher Angiotensin Converting Enzyme (ACE) inhibitory activity of active polypeptide derived from Manchester cheese (Manchego cheese) after simulated gastrointestinal digestion, while VRYL and KKYNFVQL show partial decrease in ACE inhibitory activity.
In addition, the research finds that the proteolysis product (FPH) of the Pacific codfish has stronger antioxidant and ACE inhibitory activity in vitro, and the antioxidant activity of the FPH and FPH separated polypeptide components after in vitro simulation of gastrointestinal tract digestion and absorption of small intestine epithelial cells is maintained unchanged, but the ACE inhibitory activity is changed in different degrees.
It is known that the polypeptide has a certain influence on its activity by digestion and absorption in vivo.
Scopolamine, as a muscarinic receptor antagonist, affects the short-term memory and learning acquisition processes in humans and animals. Therefore, scopolamine is mostly used for constructing pathological models of senile dementia. Research shows that the antioxidant enzyme system in the brain of the dementia mouse treated by the scopolamine changes, and the phenomena of activity reduction of glutathione peroxidase (GSH-px) and superoxide dismutase (SOD) in the brain, MDA content increase and the like occur.
In the reported medicines, except for Chinese herbal medicine extract and DHA, only the cerebrolysin is a natural active substance. The brain activating agent is prepared with pig brain and through hydrolysis, and has nerve nourishing activity. However, the research on the specific polypeptide sequence playing a role in the brain activity is not deep, and the medicine enters the body by adopting an injection mode and cannot be supplemented daily.
Chinese patent applications CN 107325154A and CN 107226836A respectively disclose a polypeptide with memory improving effect, and the amino acid sequences are Tyr-Ser-Gly-Val-Cys and Tyr-Asn-Glu. It is noted that the bioactive polypeptide enters the body and reaches the target site to play a role after being digested by gastrointestinal tract and absorbed by epithelial cells of small intestine. This complex series of processes, particularly the digestion by proteases in the gastrointestinal tract, affects the sequence and thus the biological activity of the polypeptide. However, the above two applications do not perform in vitro simulated gastrointestinal digestion tests to verify whether they have gastrointestinal digestion resistance, and do not perform animal experiments to verify whether they can exert memory improving effects in vivo in mouse models with dementia.
Disclosure of Invention
In order to overcome the defect that the memory improving effect is influenced by the possibility of degradation or partial degradation of the existing memory improving peptide when the memory improving peptide passes through the gastrointestinal tract, the invention mainly aims to provide the memory improving peptide PAY for resisting gastrointestinal tract digestion.
Another object of the present invention is to provide the use of the above memory improving peptide.
The purpose of the invention is realized by the following technical scheme:
a tripeptide, the amino acid sequence of which is Pro-Ala-Try, obtainable by solid phase chemical synthesis methods of the prior art.
The tripeptide still has the effect of improving the memory capacity of a dementia model mouse after passing through the gastrointestinal tract, has the capacity of resisting gastrointestinal tract digestion, and can be used for preparing medicines and health-care products for improving memory;
the medicine and the health care product also contain other active ingredients with the effect of improving memory and/or acceptable auxiliary materials;
the medicine and health care product can be various dosage forms in the prior art, such as oral liquid, capsules, tablets, powder or granules.
Compared with the prior art, the invention has the following advantages and effects:
the memory improving peptide is obtained by solid phase chemical synthesis, can resist gastrointestinal tract digestion, has obvious memory improving effect in a dementia mouse model, can be independently used for preparing a memory improving medicine or a memory improving health care product, and can also be compounded with memory improving related substances in the prior art for use, so that a better synergistic memory improving effect is obtained.
Drawings
FIG. 1 is a primary mass spectrum of Pep-PAYCS.
FIG. 2 is a primary mass spectrum of Pepsin-PAYCS.
FIG. 3 is a primary mass spectrum of Pancatatin-PAYCS.
FIG. 4 is a primary mass spectrum of Digestinon-PAYCS.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but the present invention is not limited thereto.
Example 1: anti-gastrointestinal digestion Properties of polypeptide PAY
1. In vitro simulated digestion
Two-step in vitro simulated digestion procedure. Will synthesize a plurality ofThe Peptide (PAYCS) was formulated as a 10mg/mL aqueous solution. Pepsin (sigma, EC 3.4.4.1; 1:60,000,3,400U mg) was first used-1) Hydrolyzing the polypeptide solution (enzyme to substrate ratio of 1:50, w/w), and performing enzymolysis at 37 deg.C for 120min, wherein pH is 2.0. After hydrolysis, the pH was slowly adjusted to 7.5, pancreatin (sigma, enzyme to substrate ratio 1:25, w/w) was added and the hydrolysis continued at 37 ℃ for 240 min. The whole enzymolysis process is carried out in a water bath constant temperature shaking table, after the enzymolysis of the pancreatin is finished, the zymolyte is heated to 95 ℃, enzyme deactivation is maintained for 10min, and the in vitro digestion final product and the intermediate product are stored at the temperature of minus 20 ℃ for subsequent index determination.
2. UPLC-MS/MS analysis of PAYCS digestates
The identification of PAYCS and its in vitro simulated digestion products was carried out using the acquisition UPLC I-Class system in combination with the acquisition UPLC HSS T3 column (2.1X 100mm,1.8 μm, Waters, Ireland). The loading of the eluted sample was 5. mu.L at a concentration of 1 mg/mL. The flow rate was set to 0.2 mL/min. Mobile phase a was ultrapure water containing 0.1% formic acid and mobile phase B was acetonitrile. The elution program is set to 0-2min, 10% B; 2-10min, 10-50% B; 10-13min, 50-10% B; 13-15min, 10% B; the column temperature was set to 25 ℃. The eluted fractions were detected at 220 nm.
Wherein, the peptide sequence identification and accurate molecular weight determination in the sample (pure peptide and digestion product) are carried out by adopting an electrospray ionization quadrupole time-of-flight mass spectrometer (ESI-Q-TOF-MS/MS) and collecting data by a Bruker maxis impact ultra-high resolution mass spectrometer. The mass spectrum related parameters are set as follows, the quadrupole electron energy is 3.0 eV; in the collision cell, collision energy, transfer time and pre-pulse storage are 20eV, 50 μ s and 8 μ s, respectively. The ESI related parameters are: capillary voltage 3.5kV, drying gas temperature 200 deg.C, drying gas flow rate 4.0L/min, and ESI atomizer pressure 0.5 bar.
In the experiment, Data analysis 3.0 software is adopted to perform manual de novo sequencing analysis to obtain a target polypeptide sequence. The measured mass of the polypeptide molecule should match its theoretical value (error. + -. 0.002 Da). The present study examined mass spectra signals of PAYCS, pepsin digested PAYCS product, pancreatin digested PAYCS product and intact gastrointestinal digested PAYCS product, respectively (fig. 1 to fig. 4).
The results of mass spectrometry analysis of the products of PAYCS and its stomach digestion for 2h and intestinal digestion for 4h are shown in FIG. 1.
FIG. 1 shows a PAYCS pure peptide primary mass spectrum with an accurate molecular weight of 540.1936Da (+ H).
FIG. 2 shows a primary mass spectrum of a PAYCS digestion product (pepsin-PAYCS) after pepsin digestion, and it can be seen that after pepsin digestion, a PAYCS pure peptide 562.1915Da (+ Na) signal is detected, and the detectable digestion product comprises PA with a PAY precise molecular weight of 350.1710Da (+ H) and a weaker PA signal.
FIG. 3 shows a pancreatically digested PAYCS product (tripsin-PAYCS), in which PAY, PA, etc. are detected as polypeptides and a primary mass spectrum signal of arginine (R) is detected.
FIG. 4 is a primary mass spectrum of a PAYCS digestion product (digestion-PAYCS) after gastrointestinal digestion, and it can be seen that PAYCS is partially degraded to obtain a primary mass spectrum signal of two polypeptides of PAYCS and PAY.
From the above results, it is known that PAYCS is not completely resistant to gastrointestinal digestion, and that PAYCS has been partially cleaved into sequences such as PAY, etc., by the enzymatic action of pepsin. Sequences such as PAYCS and PAY are present in the subsequent digestion process, and thus PAY is a product of PAYCS digestion that is resistant to gastrointestinal digestion.
Oral polypeptides are subject to cleavage by pepsin and pancreatin when digested in the gastrointestinal tract. During digestion in the stomach, pepsin is more prone to cleave peptide bonds between hydrophobic and aromatic amino acids (e.g., phenylalanine, tryptophan, tyrosine, etc.). Thus, PAYCS is cleaved at tyrosine by pepsin, resulting in the presence of a PAY polypeptide sequence. The PAY remains intact during the gastrointestinal tract digestion. Thus, PAY is a polypeptide with the function of resisting gastrointestinal tract digestion.
Example 2: effect of PAY on memory Capacity in dementia model mice
Selecting 48 SPF-grade Kunming mice with half male and half female, the body weight of 18-22g, and provided by the Experimental animal center of Guangzhou university of traditional Chinese medicine. The experimental mouse breeding environment is room temperature (21 +/-2) DEG C, the relative humidity is controlled to be 50% -60%, the relative humidity is controlled to be in alternation of light and shade at 12/12h, and the mouse can eat and take water freely during the experimental period. Mice were placed in the laboratory acclimation 7d prior to the experiment. The 48 mice were randomly divided into 4 groups (12 per group, n-12) as a blank control group, a scopolamine group (model group), a piracetam group (positive control group), and a PAY (0.2 mmol/kg). The blank group and the model group are infused with distilled water with the same volume, the positive control group is infused with piracetam (400mg/kg), the tested group is infused with corresponding polypeptide samples according to the dosage, and the gavage is carried out for 1 time every day and for 20 days continuously.
The influence of PAY on learning and memory acquisition disorder caused by scopolamine model mice learning and memory capacity is evaluated by a Morris water maze method. The Morris water maze test comprises two parts, namely a positioning navigation test (place navigation) and a space exploration test (probe test).
The animals were screened by forward movement in groups, and animals that did not swim or swim abnormally were shaved off, and a pilot voyage experiment was performed on day 14 from the start of dosing. Animals were allowed to learn by spatial cues to remember the platform position, and the experiment was performed for 5 days with 4 trains per day. Mice were placed in a water maze for free swimming for 2min the day before the experiment to become familiar with the aqueous nature. During training, the pool is divided into 4 quadrants (quadrants I, II, III, and IV). The visible moving platform is trained in the first day, the platform is 1-2cm higher than the water surface, and a red small flag is inserted into the platform, so that the animal identification is facilitated. The platform moves sequentially once per training. The 2 nd to 5 th days are fixed hiding platform periods which are 1 cm to 2cm lower than the water surface. During the experiment, according to the sequence of quadrants I, III and IV, a mouse is placed in water facing and close to the wall of the pool, and a video tracking system is adopted to record the time required for the mouse to find the platform for the first time within 60s and stay for more than 3 seconds, and the time is recorded as an escape latency. In the training period, positive control and administration groups are injected with scopolamine hydrobromide 1.0mg/kg in abdominal cavity, and the model and normal groups are administered with normal saline with the same amount, and are trained in water after 30min for 5 days continuously.
And the space exploration experiment is used for testing the learning and memory ability of the animals, and the safety platform in the water tank needs to be removed in the next day after the positioning navigation experiment is finished. From day 15 of dosing, mice were placed in the pool from the test site and their 60s swimming time in the plateau quadrant was measured. After the last administration for 1h, the mice are put into water for swimming, a computer positioning and tracking system is adopted to record the swimming track of the mice within 60s, and the times of passing through the platform, the swimming time(s) around the platform and the moving distance (mm) around the platform are recorded.
The measurement results are shown in tables 1 and 2.
TABLE 1 influence of PAY on acquisition of dysmnesia mouse Morris water maze positioning navigation
Figure BDA0001814855290000061
#Representative vs. normal control, p<0.05，##Representative vs. normal control, p<0.01。*Representation in comparison with model control, p<0.05，**Representation in comparison with model control, p<0.01。
It can be seen from table 1 that after the memory acquisition training, the escape latency and the total swimming distance of the mice in the model group are significantly higher than those of the blank control (p <0.01), which indicates that the model modeling of the mouse dysmnesia caused by scopolamine is successful. From the results, it was found that mice in the piracetam group (positive control) and the PAY group had significantly reduced escape latency and total swimming distance (p <0.05 or p <0.01) compared to the model group. The piracetam tablet is a clinical medicine and is mainly used for treating hypomnesis and brain dysfunction in different degrees. The results show that after the intake of PAY, the mice escape from the incubation period and shorten the total swimming route to a significantly higher extent than the piracetam group (p < 0.05).
TABLE 2 Effect of PAY on acquisition of Morris Water maze spatial exploration in mice with memory impairment
Figure BDA0001814855290000062
#Representative vs. normal control, p<0.05。*Representation in comparison with model control, p<0.05，**The representation is compared to a model control group,p<0.01。
as can be seen from table 2, the swimming time and the swimming distance around the platform were significantly shortened (p <0.05) in the model group mice compared to the control group mice, which indicates that the model group mice could not accurately memorize the platform position. Resulting in spatial memory impairment. While the intake of the PAY significantly increased the swimming time of the mice around the platform (p <0.01, 0.05), which increased the distance of the mice's activity around the platform.
Example 3: effect of PAY on mouse brain tissue antioxidant related index
After completion of the water maze test of example 2, each group of mice was sacrificed and their heads were separated from the mice on ice, blood was washed with ice-cold physiological saline, and homogenized with physiological saline at a mass ratio of 1: 9. Centrifuging the homogenate at 3500r/min for 10min at 4 deg.C, sucking the supernatant as the sample to be tested, and storing at-20 deg.C for use. SOD and GSH-Px activities were determined strictly according to the kit instructions, and total protein concentration of the sample to be tested was additionally determined using the BCA kit.
The results are shown in Table 3.
TABLE 3 Effect of PAY on mouse brain tissue antioxidant related indices
Figure BDA0001814855290000071
##Representative vs. normal control, p<0.01。**Representation in comparison with model control, p<0.01。
Compared with the normal group, the SOD activity of the brain tissue of the mouse model with dysmnesia caused by scopolamine is obviously reduced (p is less than 0.01), which indicates that the brain tissue of the mouse with impaired memory has oxidative stress reaction. Compared with the model group, the piracetam group and the PAY treatment group can increase the SOD activity in the brain tissue of the mouse (p < 0.01).
In conclusion, the tripeptide PAY of the present invention can not only resist gastrointestinal digestion, but also has good in vivo activity after gastrointestinal digestion, and the memory improving effect is not lost. The tripeptide PAY has good memory improvement effect in a scopolamine induced mouse acquired dysmnesia model, and the improvement effect may be related to the regulation and control of SOD activity in an antioxidant enzyme system, and the antioxidant effect may be related to the existence of tyrosine (serving as) in the PAY. The active phenolic structure in tyrosine and the sulfhydryl structure in cysteine can be used as hydrogen donors, and provide stronger free radical scavenging capacity for the polypeptide containing the amino acids so as to improve the oxidative stress injury state in the brain of the dementia mouse.
Example 4
A tablet for improving memory contains 15 wt% of PAY and 85 wt% of adjuvants, wherein the adjuvants are more than one of starch, sucrose, maltodextrin or magnesium stearate.
Example 5
A soft capsule for improving memory comprises PAY 10 wt% and adjuvants 90 wt%, wherein the adjuvants include phosphatidyl serine, gelatin, glycerol, sorbitol solution, titanium dioxide, caramel color and purified water.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.

Claims (3)

1. The application of tripeptide in preparing a medicine and a health-care product for improving memory is characterized in that:
the amino acid sequence of the tripeptide is Pro-Ala-Tyr.
2. Use according to claim 1, characterized in that: the medicine and the health care product contain other active ingredients with the effect of improving memory and/or acceptable auxiliary materials.
3. Use according to claim 1, characterized in that: the medicine and the health care product are oral liquid, capsules, tablets, powder or granules.
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CN111153963B (en) * 2020-01-19 2021-08-10 华南理工大学 Anti-inflammatory pentapeptide, extraction and separation method thereof and application of anti-inflammatory pentapeptide in memory improvement
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CN113402587B (en) * 2021-07-08 2022-05-10 荣成泰祥食品股份有限公司 Octapeptide and application thereof in preparation of medicines for improving memory
CN114699505B (en) * 2022-02-17 2023-05-26 广东省农业科学院蚕业与农产品加工研究所 Application of PAYCS in regulation of intestinal flora, metabolites and brain neurotransmitters

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