CN113754737B - Medicament for treating lead poisoning, glycopeptides used by medicament and preparation method of glycopeptides - Google Patents
Medicament for treating lead poisoning, glycopeptides used by medicament and preparation method of glycopeptides Download PDFInfo
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- CN113754737B CN113754737B CN202111090573.4A CN202111090573A CN113754737B CN 113754737 B CN113754737 B CN 113754737B CN 202111090573 A CN202111090573 A CN 202111090573A CN 113754737 B CN113754737 B CN 113754737B
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- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
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- 229910017604 nitric acid Inorganic materials 0.000 description 1
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- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
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- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- DAJSVUQLFFJUSX-UHFFFAOYSA-M sodium;dodecane-1-sulfonate Chemical compound [Na+].CCCCCCCCCCCCS([O-])(=O)=O DAJSVUQLFFJUSX-UHFFFAOYSA-M 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
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- 235000013619 trace mineral Nutrition 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K9/00—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof
- C07K9/001—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence having less than 12 amino acids and not being part of a ring structure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Toxicology (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention discloses a medicament for treating lead poisoning, glycopeptides used by the medicament and a preparation method of the glycopeptides. The medicine for treating lead poisoning provided by the invention contains glycopeptides named APL and is derived from auricularia polytricha; the N-terminal sequence of the APL is shown as a sequence 1 in a sequence table. The APL contains mannose, rhamnose, glucose, galactose, xylose, glucuronic acid and galacturonic acid. Experiments prove that each dosage group containing the glycopeptide APL extracted by the invention can effectively remove lead in liver compared with a model group, especially the APL high dosage group has the liver lead removal rate of 17.96 percent and the effect is better than the positive medicine liver lead removal rate of 16.01 percent. The glycopeptide APL of the present invention is useful for treating lead poisoning.
Description
The application is a divisional application with the application number of 202011154452.7, the application date of 2020, 10 months and 26 days, and the invention and creation name of 'Auricularia auricula-judae glycopeptide with lead removing function, and a preparation method and application thereof'.
Technical Field
The invention relates to the technical field of biology, in particular to a medicament for treating lead poisoning, glycopeptides used by the medicament and a preparation method of the glycopeptides.
Background
Lead is a toxic heavy metal, has the characteristics of high utilization rate, low recovery rate and difficult degradation, and has great harm to human bodies. Besides the lead released in the natural environment, a great amount of pollution is generated in human activities such as mining, smelting and producing lead-containing products, and the lead pollution is very serious due to the weak environmental awareness, imperfect environmental protection mechanism and the like of people. Lead pollution mainly exists in the atmosphere, soil and food, and lead in the environment can finally enter the human body through biological enrichment or direct contact.
Lead metabolism in human body is very slow, half-life period is longer than one month in blood and soft tissue, lead is mostly combined with red blood cells or distributed in each tissue, the content in liver and kidney is highest, and lead has toxic effect on each system and organ, and mainly affects nervous system, reproductive system, cardiovascular system, urinary system, blood and the like. Lead has direct toxic effects on the central and peripheral nervous systems, and can cause depression or hyperactivity, etc., changes in personality, mental deterioration, sensory functions such as vision, hearing, dysolfaction, and muscle damage. At present, the medicines for treating lead poisoning mainly comprise chelating agents, metallothionein, antioxidants and traditional Chinese medicines, other problems can be caused when different treatment methods discharge lead, trace elements necessary for human bodies can be discharged when the chelating agents discharge lead toxin, some medicines can cause nausea, dizziness and hypodynamia, even kidney injury, the natural extract has definite lead discharge curative effect and small toxic and side effects, and the natural extract has great potential in research and development.
Disclosure of Invention
The invention aims to solve the technical problems of reducing the content of heavy metal lead in a human or animal body or effectively eliminating lead toxicity in the human or animal body or reducing the damage of the heavy metal lead to the human or animal body.
In order to solve the technical problems, the invention provides application of glycopeptides in preparing medicaments for treating lead poisoning.
The glycopeptide is named APL and is derived from auricularia polytricha in the application of the glycopeptide in preparing medicaments for treating lead poisoning; the N-terminal sequence of the APL is shown as a sequence 1 in a sequence table.
In the above application, the glycopeptide may be derived from Auricularia polytricha fruiting body.
In the above application, the APL contains mannose, rhamnose, glucose, galactose, xylose, glucuronic acid and galacturonic acid.
In the above application, the molar ratio of mannose, rhamnose, glucose, galactose, xylose, glucuronic acid and galacturonic acid was 27.8:8:19.3:22.7:8.7:30:9.
in the above application, the APL has a molecular weight of 34000 daltons.
In the application, the glycopeptide is extracted from the auricularia polytricha fruiting body water extract, and the auricularia polytricha fruiting body water extract is a water-soluble substance extracted from auricularia polytricha fruiting body by water.
In the above application, the glycopeptide may be prepared according to the following method:
a method of making a glycopeptide comprising:
b-1) preparing protein-removed auricularia auricula-judae crude glycopeptide, wherein the preparation method of the protein-removed auricularia auricula-judae crude glycopeptide comprises the steps of precipitating auricularia auricula-judae fruiting body water extract with ethanol, collecting precipitate, and removing protein in the precipitate to obtain the protein-removed auricularia auricula-judae crude glycopeptide; the auricularia polytricha fruiting body water extract is a water-soluble substance extracted from auricularia polytricha fruiting bodies by water;
b-2) separating and purifying the glycopeptide from the protein-removed auricularia polytricha crude glycopeptide to obtain the glycopeptide named APL.
In the step B-2) of the preparation method, the separation and purification of the glycopeptide from the protein-removed auricularia polytricha crude glycopeptide comprises the following steps:
b-2-1) carrying out anion exchange column chromatography on the protein-removed auricularia polytricha crude glycopeptide, wherein an anion exchange group adopted in the anion exchange column chromatography is DEAE, and an adopted elution procedure is two-step elution, wherein the first-step elution is carried out by water, and the second-step elution is carried out by the following solution with pH of 7.0: the solute is 0.8M NaCl, the solvent is water (namely 0.8M NaCl aqueous solution), the elution peak obtained in the second step is collected, and the elution peak is named as an elution peak D2;
b-2-2) subjecting the elution peak D2 to gel filtration chromatography to obtain the glycopeptide with molecular weight of 34000 daltons, namely APL glycopeptide.
In the above method for preparing glycopeptides, the water may be deionized water.
In the above glycopeptide preparation method, the chromatography medium of gel filtration chromatography may be Superdex 200, and the eluting buffer may be 0.2M NH with pH of 8.5 4 HCO 3 An aqueous solution. 0.2M NH at pH 8.5 4 HCO 3 The aqueous solution is 0.2M NH 4 HCO 3 The solvent is a solution of water. The water may be ultrapure water.
The glycopeptides described above are also within the scope of the present invention.
In order to solve the technical problems, the invention also provides a medicine for treating lead poisoning.
The medicine for treating lead poisoning provided by the invention contains the glycopeptides.
The active ingredient of the medicament for treating lead poisoning may be the glycopeptide, and the active ingredient of the medicament for treating lead poisoning may further contain other biological or non-biological components, and the other active ingredients of the medicament for treating lead poisoning may be determined by one skilled in the art according to the effect of removing lead.
The medicament for treating lead poisoning can contain a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers can be diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, aluminum silicate, and the like; pharmaceutically acceptable carriers can be humectants and binders such as water, glycerol, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, syrup, honey, dextrose solution, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, and the like; the pharmaceutically acceptable carrier may be a disintegrant such as dry starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene, sorbitol fatty acid ester, sodium dodecyl sulfonate, methylcellulose, ethylcellulose, etc.
Herein, treating lead poisoning may be embodied as at least one of:
a1 Inhibiting lead elevation in animal blood in a lead exposure environment;
a2 Reducing lead deposition in animals;
a3 Reducing blood lead content of animals with lead poisoning;
a4 Promoting lead excretion in animals;
a5 Improving lead clearance from animal livers;
a6 Reducing lead damage to various systems and/or organs of the animal body.
The animal described herein may be a mammal.
Experimental results show that each dosage group containing the glycopeptide APL extracted by the invention can effectively remove lead in liver compared with a model group, especially the APL high dosage group has a liver lead removal rate of 17.96%, and the effect is superior to the positive drug liver lead removal rate of 16.01% (Table 4). The glycopeptide APL of the present invention is useful for treating lead poisoning.
Drawings
FIG. 1 shows the DEAE-Cellulose elution profile.
FIG. 2 is a FPLC-Superdex 200 elution profile.
FIG. 3 is an APL IR spectrum analysis chart of glycopeptides. The absorbance is on the ordinate and the wave number (cm) -1 )。
FIG. 4 is an HPLC plot of monosaccharide and uronic acid analysis of glycopeptide APL. The ordinate is abundance (mAU) and the abscissa is time (min).
Detailed Description
The glycopeptide APPI in the examples below was prepared according to the method in example 1 of chinese patent application publication No. CN108727474a published 11/02 in 2018.
The following detailed description of the invention is provided in connection with the accompanying drawings that are presented to illustrate the invention and not to limit the scope thereof. The examples provided below are intended as guidelines for further modifications by one of ordinary skill in the art and are not to be construed as limiting the invention in any way.
The experimental methods in the following examples, unless otherwise specified, are conventional methods, and are carried out according to techniques or conditions described in the literature in the field or according to the product specifications. Materials, reagents and the like used in the examples described below are commercially available unless otherwise specified.
Example 1 preparation of Auricularia polytricha glycopeptide and its use in lead removal
1. Preparation of auricularia polytricha glycopeptide
1 test material
Auricularia polytricha (Auricularia polytricha (Mont.) Sacc.) No. 3 (Zhao Shuang et al. Optimization of polysaccharide-producing fermentation conditions of Auricularia polytricha mycelium. Food science and technology. 37 volume 4), hereinafter abbreviated as Auricularia polytricha.
Separation and purification of auricularia polytricha glycopeptide
2.1 extraction of crude glycopeptides by aqueous extraction and alcohol precipitation
And (5) putting the freeze-dried auricularia polytricha fruiting body into a high-speed universal crusher, repeatedly crushing for 4 times, and 20 seconds each time to prepare dry powder with uniform texture. Crushing the processed dry powder, weighing and quantifying, adding deionized water according to the proportion of 1:25, and standing overnight in a refrigerator at 4 ℃ to obtain the auricularia polytricha mixed solution. Shaking the auricularia polytricha mixed solution before water bath, sealing, controlling the temperature and the rotating speed by using a water bath shaking table, carrying out high-temperature water bath at the temperature of 4h and 90 ℃, centrifuging the mixture at 6000r/min for 30min after water bath, collecting supernatant (water-soluble substances), measuring the volume of the supernatant, adding absolute ethyl alcohol according to the proportion of 1:4 to separate out polysaccharide, uniformly stirring, covering tinfoil paper, standing for 12 h, carrying out solid-liquid separation, centrifuging for 6000g for 20min, collecting precipitate, drying the precipitate in an oven at the temperature of 60 ℃ until the quality is constant, and grinding the precipitate into powder, thus obtaining the auricularia polytricha crude glycopeptide.
2.2 isolation and purification of Auricularia polytricha crude glycopeptides
The protein in the auricularia polytricha crude glycopeptide in the step 1.2.1 is removed by using a Seveage method to obtain the protein-removed auricularia polytricha crude glycopeptide, and the specific method is as follows: and (2) dissolving the auricularia polytricha crude glycopeptide in the step (1.2.1) in deionized water to obtain auricularia polytricha crude glycopeptide solution. Adding Sevag reagent (prepared by mixing chloroform and n-butanol according to a volume ratio of 4:1) which is 1/3 of Auricularia auricula (L.) Underw crude glycopeptide solution into Auricularia auricula (L.) Underw crude glycopeptide solution, vortex oscillating for 5min, centrifuging for 15min at 4500g, collecting supernatant, and removing gelatinous precipitate generated by free protein. Sevag reagent 1/3 of the supernatant volume was added to the supernatant and vortexed for 5min, centrifuged at 4500g for 15min, and the supernatant was aspirated, and this was repeated a number of times until a supernatant was obtained without the presence of a protein layer. And reserving supernatant fluid after protein removal, mixing the supernatant fluid, adding absolute ethyl alcohol to obtain glycopeptide precipitate, drying at 60 ℃ and dissolving with deionized water to obtain Auricularia auricula-judae crude glycopeptide solution with protein removed.
2.3 separation and purification of the protein-removed Auricularia auricula-judae crude glycopeptide solution by anion exchange column chromatography
Purification was performed using anion exchange column chromatography DEAE-Cellulose, the anion exchange groups used were DEAE, and the DEAE-Cellulose elution conditions were as follows: deionized water was equilibrated with a DEAE-Cellulose column (column size: 1cm (inner diameter). Times.30 cm (column length)), and the sample was a crude glycopeptide solution of Auricularia polytricha from which proteins were removed, and two-step elution was carried out at a flow rate of 1.5mL/min, and the eluted liquid was collected continuously from the elution procedure, 6mL per tube, and the polysaccharide concentration of the eluate collected per tube was measured by sulfuric acid-phenol method. Eluting with deionized water in the first step, collecting the eluting peak obtained in the first step, and defining the eluting peak as eluting peak D1 (i.e. eluting solution with eluting volume of 7-18 mL); the second elution was performed with the following solution at pH 7.0: the solute was 0.8M NaCl and the solvent was deionized water, and the elution peak from the second elution step was collected and defined as elution peak D2 (i.e., the eluent having an elution volume of 37mL-48 mL) (FIG. 1).
Eluting peak D1 and eluting peak D2 were dialyzed in distilled water for 10-12 hours, respectively, and then 4 times of absolute ethanol was added to the mixture and allowed to stand for 12 hours, and the precipitate was collected by centrifugation, dried at 60℃and ground into powder to obtain a D1 component (from eluting peak D1) and a D2 component (from eluting peak D2), respectively.
And through in-vitro lead adsorption detection, the D2 component is determined to have a lead discharging function.
150 μl of 10ppm lead single unit element standard solution is added into 150 μl of sample, after mixing at room temperature, the mixture is placed in an oscillator at 160rpm/min for full shaking for 3 hours, four times of volume of absolute ethanol is rapidly added after the reaction is finished and mixed uniformly, the mixture is kept stand at room temperature for 1 hour, centrifuged at 9000rpm/min for 10 minutes, the supernatant is sucked, and the obtained supernatant is fixed to 5ml with 5% dilute nitric acid and mixed uniformly. The sample is sent to a feed titer and safety supervision testing center of the department of agriculture, the lead content is detected by using a Z-2000 atomic absorption spectrophotometer-graphite furnace method, and deionized water is used for replacing the sample as a control.
Adsorption rate of glycopeptides to lead:
2.4 purification of D2 Components by molecular sieve chromatography
Subjecting the D2 component to FPLC-Superdex 200 gel filtration chromatography (FPLC is rapid protein liquid chromatograph of GE company, model ATKAExplorer; superdex 200 is chromatography medium of GE company), eluting with buffer solution of 0.2M NH with pH of 8.5 4 HCO 3 Solution (solute 0.2M NH) 4 HCO 3 The solvent was a solution of ultrapure water), the column size was 30cm (column length). Times.1 cm (inner diameter), and the flow rate was 0.4mL/min. The eluate was collected in a fraction collector, the eluted liquid was collected continuously from the beginning of the elution procedure, 3mL was collected per tube, and the polysaccharide concentration of the eluate collected per tube was measured by the sulfuric acid-phenol method. The elution peak in the polysaccharide pool (elution volume 13mL-18mL of eluent) was collected and defined as APL elution peak (FIG. 2).
2.5 concentrating by ultrafiltration to obtain glycopeptide APL
Dialyzing APL eluting peak in distilled water for 10-12 hr, ultrafiltering and concentrating at 4deg.C to molecular weight cut-off of 5000 dalton, freezing at-80deg.C, and lyophilizing the frozen sample to obtain powder, which is called APL glycopeptide (glycopeptide APL for short).
Molecular characterization of 3 glycopeptides APL
3.1 Infrared Spectroscopy (IR) analysis of glycopeptides APL
And respectively taking 1-2mg of glycopeptide APL, tabletting by using a KBr tabletting method, and detecting and analyzing by using a Fourier transform infrared spectrometer Nicolet iS 5.
The infrared analysis results show that the glycopeptide APL has a structure of obvious sugar characteristic groups such as-OH, a telescopic vibration absorption peak of hydroxyl, c=o, a C-H absorption peak and the like, which indicates that the glycopeptide APL has a polysaccharide structure (fig. 3).
3.2 monosaccharide and uronic acid analysis of glycopeptide APL
3.2.1 reagents
Trifluoroacetic acid, acetonitrile (chromatographic purity), phosphate buffer (ph=6.8), standard of monosaccharides and uronic acids (mannose, rhamnose, glucose, xylose and galactose, galacturonic acid, glucuronic acid).
3.2.2 sample analysis methods
3.2.2.1, complete acid hydrolysis:
weighing a proper amount of lyophilized glycopeptide APL, adding 0.5mL of 2mol/L trifluoroacetic acid solution, and hydrolyzing at 120 ℃ for 120min. And (5) drying by a nitrogen blowing instrument.
Standard substance treatment: first, a 10mg/ml standard solution was prepared and placed at-20 ℃. When in use, the glass tube is taken out and melted, 5 mu L of each standard substance is added into the glass tube which can be sealed, and the mixture is uniformly mixed. Then 0.5mL of a 2mol/L TFA solution was added and the sample was hydrolyzed at 120℃for 120min. Drying by an air pump.
3.2.2.2, PMP derivatization:
to the sample obtained after the hydrolysis and drying, 0.5ml of each of 0.5mol/L of 1-phenyl-3-methyl-5-pyrazolone (PMP) reagent and 0.3mol/L of NaOH solution dissolved in anhydrous methanol was added, and after thoroughly mixing, the mixture was reacted in a water bath at 70℃for 30 minutes. Cooled to room temperature, added with 0.3mol/L HCl 0.5ml and thoroughly mixed. 0.5ml of chloroform was added, the extraction was performed with shaking, the chloroform layer was removed by centrifugation (5000 rpm,5 min), and the total extraction was performed three times. The aqueous layer (not less than 0.4 ml) was filtered through a 0.22 μm filter and then put on a machine.
3.2.2.3, instrument conditions:
chromatographic column: SHISEIDO C18 column (4.6X105 mm,5 μm),
the mobile phase is 0.1mol/L Phosphate Buffer (PB) with pH of 6.8, and acetonitrile is 82:18 (v/v);
the flow rate is 1.0mL/min per minute;
the column temperature is 25 ℃;
sample injection amount 10. Mu.L
The wavelength was 245nm.
Instrument: agilent 1200 high performance liquid chromatograph
The results of the assay are shown below (FIG. 4), which demonstrate that glycopeptide APL contains monosaccharides and uronic acid, wherein the monosaccharides include mannose, rhamnose, glucose, galactose and xylose; uronic acid was glucuronic acid and galacturonic acid (table 1). The molar ratio of mannose, rhamnose, glucose, galactose, xylose, glucuronic acid and galacturonic acid was 27.8:8:19.3:22.7:8.7:30:9.
TABLE 1 monosaccharide and uronic acid content of glycopeptide APL
1.3.3N-terminal amino acid sequence determination of glycopeptide APL
The N-terminal part amino acid sequence of glycopeptides APL was determined by an automated EDMAN degradation method using a protein sequencer equipped with an HPLC system in Hewlett Packard 1000A. The result shows that the APL N-terminal amino acid sequence is HDDMGMSAMM (sequence 1 in the sequence table), which indicates that the glycopeptide APL has a polypeptide structure.
1.3.4 molecular weight of glycopeptides APL
The molecular weight of glycopeptide APL was determined by gel filtration chromatography, and the result showed that the molecular weight of glycopeptide APL was 34000 daltons.
2. Application of auricularia polytricha glycopeptide in lead removal
Dissolving the glycopeptide APL prepared in the step 2.5 in normal saline to obtain a glycopeptide APL solution. The glycopeptide APPI prepared in step 6 of example 1 of chinese patent application publication No. CN108727474a was dissolved in physiological saline to obtain a glycopeptide APPI solution. The glycopeptide APPI is characterized in the paragraph 0081-0093 of Chinese patent application with the publication number CN 108727474A. Disodium edetate calcium salt (EDTA-2 NaCa) is dissolved in physiological saline to obtain EDTA-2NaCa solution.
The experiment was repeated three times, 40 male SD rats (8 weeks old, weight 150-180 g) were given a large dose of Pb-toxin daily for 7 days, specifically, once daily intraperitoneal injection of Pb (Ac) 2 Solution (solute is Pb (Ac) 2 The solvent is physiological saline solution) 0.5mL, pb (Ac) 2 The administration dose of (C) is 20mg/kg body weight. Stopping Pb (Ac) injection 2 Solution recovery was 3d and randomly divided into 8 groups of 5 animals each, which were model group (negative control group), positive control group (positive drug EDTA-2NaCa injection), APL treatment group (APL low dose group, APL medium dose group, APL high dose group), APPI treatment group (APPI low dose group, APPI medium dose group, and APPI high dose group), respectively. The administration was as follows:
APL low dose group: pb (Ac) was intraperitoneally injected 1 time per day for 30 consecutive days in each mouse 2 Solution 0.5mL and administration of glycopeptide APL solution by gavage 1.0mL, pb (Ac) each time 2 The dose of (a) was 5mg/kg body weight (a small dose of lead toxin was administered), and the dose of glycopeptide APL per administration was 40mg/kg body weight/d.
Dosage group in APL: pb (Ac) was intraperitoneally injected 1 time per day for 30 consecutive days in each mouse 2 Solution 0.5mL and administration of glycopeptide APL solution by gavage 1.0mL, pb (Ac) each time 2 The dose of (a) was 5mg/kg body weight (a small dose of lead toxin was administered), and the dose of glycopeptide APL per administration was 80mg/kg body weight/d.
APL high dose group: pb (Ac) was intraperitoneally injected 1 time per day for 30 consecutive days in each mouse 2 Solution 0.5mL and administration of glycopeptide APL solution by gavage 1.0mL, pb (Ac) each time 2 The dose of (a) was 5mg/kg body weight (a small dose of lead toxin was administered), and the dose of glycopeptide APL per administration was 160mg/kg body weight/d.
APPI low dose group: pb (Ac) was intraperitoneally injected 1 time per day for 30 consecutive days in each mouse 2 Solution 0.5mL and administration by gastric lavageGlycopeptide APPI solution 1.0mL, pb (Ac) at a time 2 The dose of glycopeptide APPI administered was 5mg/kg body weight (small doses of lead toxin were administered) and each dose of glycopeptide APPI administered was 40mg/kg body weight/d.
Dose group in APPI: pb (Ac) was intraperitoneally injected 1 time per day for 30 consecutive days in each mouse 2 Solution 0.5mL and intragastric administration glycopeptide APPI solution 1.0mL, pb (Ac) at a time 2 The dose of (a) was 5mg/kg body weight (a small dose of lead toxin was administered), and the dose of glycopeptide APPI per administration was 80mg/kg body weight/d.
APPI high dose group: pb (Ac) was intraperitoneally injected 1 time per day for 30 consecutive days in each mouse 2 Solution 0.5mL and intragastric administration glycopeptide APPI solution 1.0mL, pb (Ac) at a time 2 Is 5mg/kg body weight (administration of small doses of lead toxin), and each glycopeptide APPI is administered at a dose of 160mg/kg body weight/d.
Positive control group: pb (Ac) was intraperitoneally injected 1 time per day for 30 consecutive days in each mouse 2 0.5mL of solution and administration of EDTA-2NaCa solution 1.0mL, pb (Ac) each time by gavage 2 The dose of EDTA-2NaCa per administration was 5mg/kg body weight (administration of a small dose of lead) and 300mg/kg body weight/d.
Model group: pb (Ac) was intraperitoneally injected 1 time per day for 30 consecutive days in each mouse 2 0.5mL of the solution was administered by gavage with 1.0mL of physiological saline, each Pb (Ac) 2 The dose of (a) was 5mg/kg body weight (small dose of lead toxicity was administered) (Table 2).
From the beginning of administration, blood is taken from the eye socket every 6 days, a blood sample is preserved in a refrigerator at the temperature of minus 20 ℃, rats are anesthetized at the end of experiments, livers of the rats are taken, the rats are ground to powder after vacuum freeze drying, the blood sample and the livers are acidolyzed and digested in the refrigerator at the temperature of minus 20 ℃ at the end of the experiments, the blood sample and the livers are sent to an agricultural feed titer and safety supervision test center to detect the lead content by using a Z-2000 atomic absorption spectrophotometer-graphite furnace method, and a lead standard solution (Beijing North Innova biological technology research institute) is used as a standard sample, and the lead content is quantitatively analyzed by using a standard curve method (external standard method).
The hepatic lead removal rate formula is:
lead removal (%) = (model group mean-experimental group mean)/model group mean x 100%.
All data were tested using independent sample t-test treatment statistics of SPSS12.0 (SPSS inc., USA) statistics software.
TABLE 2 rat group and corresponding treatment with drug
TABLE 3 in vivo experiments on lead content in blood of rats of each group (μg/L)
Note that: "#" shows significant differences from model group (P < 0.05), and "#" shows extremely significant differences from model group (P < 0.01) n=5.
TABLE 4 in vivo experiments on the removal of liver lead from rats of each group
| Liver lead removal rate (%) | |
| Model group | 0 |
| Positive control group | 16.01 |
| APL low dose group | 9.92 |
| Dosage group in APL | 14.95 |
| APL high dose group | 17.96 |
| APPI low dose group | 3.09 |
| APPI Medium dose group | 2.56 |
| APPI high dose group | 2.33 |
After lead enters a human body, the lead enters a blood circulation system in an ionic form, and the study discovers that each dosage group containing the glycopeptide APL extracted by the invention can effectively inhibit the rise of blood lead of rats under the condition of lead exposure after 12 days of administration treatment compared with a model group, the difference is extremely remarkable (table 3), and the lead discharging effect is more obvious along with the rise of the dosage, but the APPI group does not show obvious trend of blood lead reduction even under the condition of high-dosage administration compared with the model group. After lead enters the human body, the lead enters organs along with blood circulation and is accumulated in organism tissues, thereby damaging the immune system, the urinary system and the like of the organism. The liver is the most important toxin expelling metabolism gland organ in the body, the detection of liver lead can reflect the deposition condition of the lead in the body, and experimental results show that each dosage group containing the glycopeptide APL extracted by the invention can effectively remove the lead in the liver compared with a model group, especially the APL high dosage group, the liver lead removal rate reaches 17.96 percent, and the effect is better than the positive medicament liver lead removal rate by 16.01 percent (Table 4). In conclusion, according to experimental results, the glycopeptide APL extracted by the invention can effectively remove lead in rat liver after lead enters the rat body. The glycopeptide APL of the present invention may be used for the treatment of lead poisoning.
Sequence listing
<110> academy of agriculture and forestry science in Beijing city
<120> medicament for treating lead poisoning, glycopeptides used therefor and process for producing the glycopeptides
<160> 1
<170> PatentIn version 3.5
<210> 1
<211> 10
<212> PRT
<213> Auricularia polytricha (Auricularia polytricha)
<400> 1
His Asp Asp Met Gly Met Ser Ala Met Met
1 5 10
Claims (5)
1. The preparation method of the glycopeptide is characterized by comprising the following steps: the glycopeptide is named APL and is derived from Auricularia polytricha; the N-terminal sequence of the glycopeptide is shown as a sequence 1 in a sequence table, and the preparation method of the glycopeptide comprises the following steps:
b-1) preparing protein-removed auricularia auricula-judae crude glycopeptide, wherein the preparation method of the protein-removed auricularia auricula-judae crude glycopeptide comprises the steps of precipitating auricularia auricula-judae fruiting body water extract with ethanol, collecting precipitate, and removing protein in the precipitate to obtain the protein-removed auricularia auricula-judae crude glycopeptide; the auricularia polytricha fruiting body water extract is a water-soluble substance extracted from auricularia polytricha fruiting bodies by water;
b-2) separating and purifying glycopeptides from the protein-removed auricularia polytricha crude glycopeptides to obtain glycopeptides named APL; in the B-2), the separation and purification of the glycopeptides from the protein-removed auricularia polytricha crude glycopeptides comprises the following steps:
b-2-1) carrying out anion exchange column chromatography on the protein-removed auricularia polytricha crude glycopeptide, wherein an anion exchange group adopted in the anion exchange column chromatography is DEAE, and an adopted elution procedure is two-step elution, wherein the first-step elution is carried out by water, and the second-step elution is carried out by the following solution with pH of 7.0: the solute is 0.8M NaCl, the solvent is water, the elution peak obtained in the second step is collected, and the elution peak is named as an elution peak D2;
b-2-2) subjecting the elution peak D2 to gel filtration chromatography to obtain the glycopeptide with molecular weight of 34000 daltons, namely APL glycopeptide.
2. The method of manufacturing according to claim 1, characterized in that: the glycopeptide contains mannose, rhamnose, glucose, galactose, xylose, glucuronic acid and galacturonic acid; in the glycopeptide, the molar ratio of mannose, rhamnose, glucose, galactose, xylose, glucuronic acid and galacturonic acid is 27.8:8:19.3:22.7:8.7:30:9.
3. a glycopeptide prepared by the process of claim 1 or 2.
4. A medicament for treating lead poisoning is characterized in that: the medicament contains the glycopeptide of claim 3.
5. A medicament according to claim 4, characterized in that: the treatment of lead poisoning is embodied as at least one of:
a1 Inhibiting lead elevation in animal blood in a lead exposure environment;
a2 Reducing lead deposition in animals;
a3 Reducing blood lead content of animals with lead poisoning;
a4 Promoting lead excretion in animals;
a5 Improving lead clearance from animal livers;
a6 Reducing lead damage to various systems and/or organs of the animal body.
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| JPH01228917A (en) * | 1988-03-09 | 1989-09-12 | Nippon Hai Potsukusu:Kk | Auricularia polytricha (mont.) sacc extract |
| JPH0253459A (en) * | 1988-08-19 | 1990-02-22 | Maruzen Kasei Co Ltd | Water-soluble dietary fiber |
| CN101486755A (en) * | 2009-02-20 | 2009-07-22 | 吴雄志 | House lizard, preparation and medical use |
| CN103110930B (en) * | 2013-02-20 | 2015-03-25 | 中山市神泉方特生物科技有限公司 | Lead-removing composition and preparation method thereof |
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