CN112679581B - Tilapia mossambica scale bone formation promoting peptide and application thereof - Google Patents
Tilapia mossambica scale bone formation promoting peptide and application thereof Download PDFInfo
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Abstract
The invention relates to tilapia mossambica scale bone formation promoting peptide and application thereof. The tilapia mossambica scale bone formation promoting peptide has an amino acid sequence as follows: TPERYY. The tilapia mossambica scale bone formation promoting peptide provided by the invention has good activity of promoting osteoblast proliferation, can promote the ALP expression of osteoblasts, is beneficial to differentiation and mineralization of osteoblasts, and is safe and nontoxic.
Description
Technical Field
The invention belongs to the technical field of biological materials, and particularly relates to tilapia mossambica scale bone formation promoting peptide and application thereof.
Background
Osteoporosis is a skeletal disease characterized mainly by a decrease in bone mass, destruction of bone microarchitecture, a decrease in bone strength, an increase in bone fragility, and susceptibility to fracture. As the world population ages, osteoporosis becomes one of the major public health problems facing china and even the world. Fracture caused by osteoporosis is one of the main causes of disability and death of old patients at present, so the diagnosis and treatment situation of osteoporosis is becoming serious. At present, the drugs for clinically treating osteoporosis comprise calcium salt, diphosphate, estrogen supplement, calcitonin and the like. However, long-term use of these drugs may cause serious side effects such as increased risk of breast cancer, weight loss, upper gastrointestinal pain and sciatica. Therefore, the search for effective functional foods having positive effects on bone health but not having such side effects on the human body has been the hot spot of the current research.
China is the biggest tilapia culture processing country in the world, the culture yield in 2016 is 158 million tons, which accounts for about 13% of the global total yield in the same year, and most tilapia in the country is used for fillet processing. According to statistics, the by-products generated in the tilapia processing process can account for 54 percent of the total mass of the used fish body, wherein the by-products comprise tilapia scales which are rich in collagen. However, the reasonable utilization rate of the processing by-products is low at present in China, so that not only is the waste of biological resources caused, but also the burden is increased for the environment. Therefore, the development and utilization of tilapia mossambica by-products have rich raw material bases and wide application prospects.
Bone is a dynamic living tissue, tightly regulated by osteoblasts and osteoclasts. During bone metabolism, osteoclasts form erosive cavities and bone matrix by removing bone mineral, while osteocytes fill the cavities and mineralize by making bone matrix. Thus, osteoblasts play an important role in bone formation, development and growth. Epidermal Growth Factor (EGF) induces receptor dimerization, activates the ERK pathway, and stimulates osteoblast proliferation and differentiation by binding to the extracellular region of Epidermal Growth Factor Receptor (EGFR). Thus, activation of EGFR has a significant impact on in vitro matrix regeneration. Bioactive peptides that induce activation of EGFR are considered as indicators that promote bone formation. Patent CN108586604A discloses bioactive peptides that induce EGFR activation and contribute to bone.
China is the biggest tilapia culture processing country in the world, the culture yield in 2016 is 158 million tons, which accounts for about 13% of the global total yield in the same year, and most tilapia in the country is used for fillet processing. According to statistics, the by-products generated in the tilapia processing process can account for 54% of the total mass of the used fish bodies, however, the reasonable utilization rate of the processing by-products in China is low at present, so that not only is the biological resource waste caused, but also the burden is increased for the environment. Therefore, the development and utilization of tilapia mossambica by-products have rich raw material bases and wide application prospects.
Disclosure of Invention
The invention aims to overcome the defect or deficiency of the lack of the existing research on the bioavailability of tilapia mossambica bone monomeric peptide, and provides a tilapia mossambica bone scale osteogenesis promoting peptide. The tilapia mossambica scale bone formation promoting peptide provided by the invention has good activity of promoting osteoblast proliferation, can promote the ALP expression of osteoblasts, is beneficial to differentiation and mineralization of osteoblasts, and is safe and nontoxic.
The invention also aims to provide application of the tilapia mossambica scale bone formation promoting peptide in preparation of medicines for promoting proliferation, differentiation or mineralization of osteoblasts.
The invention also aims to provide application of the tilapia mossambica scale bone formation promoting peptide in preparing functional food or health care product for promoting osteoblast proliferation, differentiation or mineralization
In order to achieve the purpose, the invention adopts the following technical scheme:
a tilapia fish scale bone formation promoting peptide has an amino acid sequence as follows: TPERYY (Thr-Pro-Glu-Arg-Tyr-Tyr).
The tilapia mossambica scale bone formation promoting peptide provided by the invention has good activity of promoting osteoblast proliferation, can promote the ALP expression of osteoblasts, is beneficial to differentiation and mineralization of osteoblasts, and is safe and nontoxic.
Preferably, the tilapia mossambica scale bone formation promoting peptide has a molecular weight of 827.3813 Da.
Preferably, the tilapia mossambica scale bone formation promoting peptide has a mass-to-charge ratio of 414.6975.
Preferably, the tilapia mossambica scale osteogenesis promoting peptide has hydrogen bonding effect with EGFR, and comprises one or more of ARG285, ASN12, GLN408, GLN8, GLY9, SER11 or THR 378.
Preferably, the hydrophobic interaction of tilapia mossambica scale osteogenesis promoting peptide and EGFR comprises one or more of ASP344, GLY317, GLY343, GLY39, HIS346, HIS409, ILE318, LEU17, LYS407, PHE380, SER342, THR10 or THR 406.
The tilapia mossambica scale bone formation promoting peptide can be prepared by the following steps:
s1, repeatedly washing the tilapia mossambica scales with distilled water for three times to remove impurities;
s2, alkaline washing and degreasing: putting tilapia scales into 0.1mol/L NaOH solution (w/v1:10), stirring for 24h, and washing to be neutral;
s3, decalcification treatment: putting tilapia scales into 10% EDTA-2Na (pH7.2, w/v1:10), placing in a refrigerator at 4 ℃, stirring for 5 days, and cleaning the fish scales to be neutral for later use;
s4, acid treatment: treating the decalcified tilapia scales with hydrochloric acid with the mass fraction of 4% for 18h, and washing the tilapia scales with water to be neutral to obtain tilapia scale collagen; draining water in the tilapia mossambica scale collagen washed to be neutral, then placing the tilapia mossambica scale collagen in an oven at 55 ℃ for drying, taking out and placing the tilapia mossambica scale collagen in a sealed bag for later use;
s5, enzymolysis: papain is selected for enzymolysis, the ratio of material to liquid is 8 percent, the enzymolysis time is 2 hours, the ratio of enzyme to substrate is 0.3 percent, the pH value is 7, and the temperature is 60 ℃.
The application of the tilapia mossambica scale bone formation promoting peptide in preparing the medicament for promoting the proliferation, differentiation or mineralization of osteoblasts is also within the protection scope of the invention.
Preferably, the tilapia mossambica scale bone formation promoting peptide is applied to preparation of a medicine for treating osteoporosis.
Preferably, the medicament comprises a pharmaceutically acceptable salt, carrier and/or excipient.
The application of the tilapia mossambica scale bone formation promoting peptide in preparing functional food or health care products for promoting osteoblast proliferation, differentiation or mineralization is also within the protection scope of the invention.
Preferably, the tilapia mossambica scale bone formation promoting peptide is applied to preparation of milk powder, liquid dairy products, calcium tablets, calcium supplement preparations or oral liquid.
Compared with the prior art, the invention has the following beneficial effects:
the tilapia mossambica scale bone formation promoting peptide provided by the invention has good activity of promoting osteoblast proliferation, can promote the ALP expression of osteoblasts, is beneficial to differentiation and mineralization of osteoblasts, and is safe and nontoxic.
Drawings
FIG. 1 is an EGFR geometry and docking box (PDB ID:1 IVO);
FIG. 2 is a three-dimensional graph of the interaction between TPERYY and EGFR;
FIG. 3 is a 2D plot of TPERYY and EGFR interaction; wherein, the green dotted line: hydrogen bonding interactions; counting: bond length; red fort: hydrophobic interactions;
FIG. 4 is a graph of the proliferative effect of TPERYY at various concentrations;
FIG. 5 is a graph showing the effect of the enzyme activity of ALP of TPERYY;
FIG. 6 is a graph of the mineralization effect of TPERYY;
FIG. 7 is a TPERYY peptide spectrum.
Detailed Description
The invention is further illustrated by the following examples. These examples are intended to illustrate the invention and are not intended to limit the scope of the invention. Experimental procedures without specific conditions noted in the examples below, generally according to conditions conventional in the art or as suggested by the manufacturer; the raw materials, reagents and the like used are, unless otherwise specified, those commercially available from the conventional markets and the like. Any insubstantial changes and substitutions made by those skilled in the art based on the present invention are intended to be covered by the claims.
Example 1 separation preparation of Tilapia mossambica scale osteogenesis promoting peptide
The embodiment provides a tilapia mossambica scale bone formation promoting peptide, the amino acid sequence of which is as follows: TPERYY
(Thr-Pro-Glu-Arg-Tyr-Tyr)。
The tilapia mossambica scale bone formation promoting peptide can be prepared by the following preparation method:
(I) pretreatment of tilapia scales
(1) And repeatedly washing the tilapia scales with distilled water for three times to remove impurities.
(2) Alkali washing and degreasing: the tilapia scales are put into 0.1mol/L NaOH solution (w/v1:10), stirred for 24 hours and washed to be neutral.
(3) Decalcification treatment: the tilapia scales are put into 10 percent EDTA-2Na (pH7.2, w/v1:10) and are placed in a refrigerator at 4 ℃ while stirring for 5 days, and then the tilapia scales are washed to be neutral for standby.
(4) Acid treatment: treating the decalcified tilapia scales with hydrochloric acid with the mass fraction of 4% for 18h, and washing the tilapia scales with water to be neutral to obtain tilapia scale collagen; and (3) dripping water in the tilapia mossambica scale collagen washed to be neutral, then placing the tilapia mossambica scale collagen in an oven at 55 ℃ for drying, taking out and placing the tilapia mossambica scale collagen in a sealed bag for later use.
Enzymolysis experiment of (II) tilapia scales calcium binding peptide
Performing enzymolysis in water bath at 60 deg.C under pH7 for 2 hr at a ratio of 8% and 0.3% at feed liquid ratio, inactivating enzyme at 100 deg.C for 10mm, centrifuging at 4000r/min for 20min, collecting supernatant, and freeze drying.
(III) enrichment of Tilapia mossambica scale calcium binding peptides
Adding the freeze-dried tilapia scales calcium binding peptide into distilled water to form a 5mg/mL system, adding anhydrous calcium chloride according to the peptide-calcium ratio of 1:1, adjusting the pH value to 8, chelating for 42min in water bath at 47 ℃, adding 5 times of volume of anhydrous ethanol into the reaction system after the chelation reaction is finished, centrifuging for 20min at 4000r/min, removing supernatant, taking precipitate, and freeze-drying.
(1) Mass spectrum sequence: analyzing the tilapia fish scale calcium binding peptide by using HPLC-MS/MS.
The HPLC-MS/MS method treatment process and conditions are as follows: the column containing C18 desalted column was flushed 5 times in the equilibrium solution (50% ACN), washed 5 times with Washing buffer (0.1% FA, 2% ACN), the sample was aspirated, flushed 10 times slowly, eluted with Elution buffer (0.1% FA, 60% ACN), the eluted solution was transferred to a new tube, concentrated by centrifugation and dried, ready for mass spectrometry. The desalted polypeptide sample was dried by centrifugation, re-dissolved in Nano-LC mobile phase A (0.1% formic acid/water) and bottled for on-line LCMS analysis. The solubilized sample was loaded onto a nanobipe C18 pre-column in a volume of 2 μ L (3 μm,
) Then desalted by 20ul volume flush. The liquid phase is Easy nLC 1200 nanoliter liquid phase system (ThermoFisher, USA), the sample is desalted and retained on the pre-column, and then separated by analytical column, the specification of the analytical column is C18 reversed phase chromatographic column (Acclaim PepMap RSLC,75 μm × 25cm C18-2 μm)
) The gradient used in the experiment was an increase of mobile phase B (80% acetonitrile, 0.1% formic acid) from 5% to 38% within 60 min. Mass Spectrometry A ThermoFisher Q active system (ThermoFisher, USA) was used in combination with a nanoliter nebulizing Nano Flex ion source (ThermoFisher, USA), the nebulizing voltage was 1.9kV, and the ion transfer tube heating temperature was 275 ℃. The mass spectrum scanning mode is in an information-Dependent acquisition working mode (DDA, Data Dependent Analysis), the primary mass spectrum scanning resolution is 70000, the scanning range is 350-. Maximum 20 acquisitions per DDA cycleThe secondary spectrum with the charge of 2+ to 5+ and the maximum ion injection time of the secondary mass spectrum of 50 ms. The collision cell energy (high energy collision induced dissociation, HCD) was set to 28eV for all precursor ions and the dynamic exclusion was set to 25 seconds. Raw profile files from mass spectrometry were processed and retrieved for analysis using PEAKS Studio 8.5(Bioinformatics Solutions inc.
The amino acid sequence of tilapia fish scale calcium binding peptide is measured by HPLC-MS/MS method to obtain 133 peptide sequences, the molecular mass range is 519-3736Da, the length of the peptide segment is 5-43, and the peptide segment comprises polypeptide with the sequence TPERYY (as shown in figure 7).
Example 2 molecular docking screening of Tilapia mossambica scale bone formation promoting peptide
(1) Molecular docking
EGFR geometry (see FIG. 1) was downloaded from the RCSB protein database, PDD ID:1 IVO. Water ions and other extraneous atoms are removed and ready for docking. Peptide TPERYY and other peptides were constructed using pymol1.7, followed by energy minimization using UFF (universal force field) molecular mechanics force field, using the avigadro software. Molecular docking was performed with AutoDock Vina 1.2, the docking pocket defined as a 50A by 50A cassette (fig. 1), including all active sites reported. All parameters not mentioned above are set to default values.
(2) Molecular docking screening of monomers
The energy of binding of peptide segment TPERYY and EGFR is shown in Table 1, and the binding of TPERYY and EGFR is very stable according to the binding energy.
TABLE 1 Tilapia scales calbindin AutoDock Vina molecular docking analysis identified by HPLC-MS/MS
(3) Molecular docking monomer analysis:
hydrogen bonding of TPERYY to EGFR (see fig. 2 and 3) includes ARG285, ASN12, GLN408, GLN8, GLY9, SER11 and THR 378. Hydrophobic interactions of TPERYY with EGFR include ASP344, GLY317, GLY343, GLY39, HIS346, HIS409, ILE318, LEU17, LYS407, PHE380, SER342, THR10 and THR 406.
(4) Monomer synthesis
Synthetic peptide TPERYY with a purity higher than 95% was obtained from Synpeptide co, Ltd (south kyo, china).
Example 3 Activity verification of Tilapia mossambica scale osteogenesis promoting peptide
(1) Osteoblast culture:
MC3T3-E1 subclone14 cells were purchased from the cell resource center of Shanghai Life sciences research institute of Chinese academy of sciences. Cells were cultured in complete medium (10% fetal bovine serum, 1% double antibody in α -MEM). When 80% -90% of the cells are confluent, passage is carried out by trypsin-EDTA.
(2) Cell proliferation rate:
varying concentrations of TPERYY were tested for toxicity to MC3T 3-E1. MC3T3-E1 cells at 5X 103Individual cells/well density were plated in 96-well plates (Costar, Corning, NY) and plated in 5% CO2Incubate in the incubator at 37 ℃ for 24 hours. Subsequently, cells were treated with 100 μ L of medium with different concentrations (0, 1, 10, 50, 100, 200 μ g/mL) of peptide (TPERYY) and incubated for 24 hours. After incubation, cells were treated with 100. mu.L of 0.5mg/mL MTT solution for 4 hours. Then, 150. mu.L of dimethyl sulfoxide was used in place of the MTT solution. The 96-well plate was placed on a shaker for 15 min. Finally, the light absorption was measured at a wavelength of 570nm using a microplate reader. Sample concentrations with absorbance decreases by more than 10% compared to the control group are considered cytotoxic.
FIG. 4 shows that TPERYY has no negative effect on cell viability in the concentration range of 1, 10, 50, 100, 200. mu.g/mL, and the cell viability reaches the highest value at 10. mu.g/mL, with the increase rate of 119.48%, and according to the MTT test result, 0, 1, 10, 50. mu.g/mL is selected for the differentiation and mineralization experiment.
(3) Alkaline phosphatase (ALP) activity:
MC3T3-E1 cells at 1X 106The density of each cell/well was plated in 6-well plates (Costar, Corning, NY), and after cell fusion, the differentiation completion medium (containing 50 μ g/mL VC and 10mmol/L β -glycerols) containing TPERYY at different concentrations (0, 1, 10, 50 μ g/mL) was replaced respectivelySodium oleyl phosphate) was cultured for 7 days. After the seventh day, ALP activity was detected according to ALP kit (Nanjing kit).
As shown in fig. 5, compared with the blank control, the alkaline phosphatase activity of the sample group containing tperys was significantly improved, indicating that tperys can promote the ALP expression of osteoblasts and is beneficial to the differentiation of osteoblasts.
(4) Alizarin red staining:
MC3T3-E1 cells at 1X 106The density of each cell/well was plated in 6-well plates (Costar, Corning, NY), after cell fusion, the differentiation complete medium (containing 50 μ g/mL VC and 10mmol/L β -sodium glycerophosphate) containing TPERYY at different concentrations (0, 1, 10, 50 μ g/mL) was replaced for 21 days, every other day for the first 14 days, and half a day for the next 7 days. After 21 days, the culture frame is discarded, cells are washed with PBS for 2 times, fixed with 4% paraformaldehyde for 30min, formaldehyde is discarded, distilled water is washed for 2 times, 1mL alizarin red staining solution is added for dyeing for 5min, the staining solution is discarded, distilled water is washed for 3 times, PBS is used for removing specific binding at 37 ℃ for 10min, and pictures are taken. Dissolving calcium nodules by using a 10% cetylpyridinium chloride solution, and performing calcium content determination at 562nm of an enzyme-labeling instrument.
FIG. 6 shows that TPERYY has a significant effect on MC3T3-E1 mineralization. The mineralized nodules in osteoblasts containing TPERYY were all increased to varying degrees relative to the blank group; in the quantitative analysis of calcium nodules, it can be seen visually that TPERYY sample group has good mineralization effect compared with blank control, and the result shows that TPERYY can promote osteoblast mineralization. Therefore, the tilapia mossambica scale bone formation promoting peptide provided by the invention has good activity of promoting osteoblast proliferation, can promote the expression of ALP of osteoblast, is beneficial to differentiation and mineralization of osteoblast, and is safe and nontoxic.
Finally, it should be noted that the above embodiments are only representative examples of the present invention. Obviously, the technical solution of the present invention is not limited to the above-described embodiments, and many variations are possible. All modifications which can be derived or suggested by a person skilled in the art from the present disclosure are to be considered within the scope of the claims of the present invention.
Sequence listing
<110> southern China university of agriculture
<120> novel tilapia mossambica scale bone formation promoting peptide and application thereof
<160> 1
<170> SIPOSequenceListing 1.0
<210> 1
<211> 6
<212> PRT
<213> peptide for promoting bone formation from scales of tilapia (1)
<400> 1
Thr Pro Glu Arg Tyr Tyr
1 5
Claims (4)
1. The tilapia mossambica scale bone formation promoting peptide is characterized in that the amino acid sequence of the tilapia mossambica scale bone formation promoting peptide is as follows: TPERYY.
2. The use of tilapia mossambica scale osteogenesis promoting peptide of claim 1 in the preparation of a medicament for promoting osteoblast proliferation, differentiation or mineralization.
3. The use of claim 2, wherein the tilapia mossambica scale osteogenesis promoting peptide is used for preparing a medicament for treating osteoporosis.
4. The use of claim 2, wherein the medicament comprises a pharmaceutically acceptable salt, carrier and/or excipient.
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| CN101709319A (en) * | 2009-11-20 | 2010-05-19 | 华南理工大学 | Method for preparing fish skin and scale collagen peptide |
| JP2013107850A (en) * | 2011-11-21 | 2013-06-06 | Meiji Co Ltd | Production method for collagen peptide |
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| KR101131223B1 (en) * | 2010-07-30 | 2012-03-28 | 부경대학교 산학협력단 | Antioxidant peptide isolated from Nile tilapia and antioxidant composition comprising of the same |
| CN102172393A (en) * | 2010-12-17 | 2011-09-07 | 中国海洋大学 | Calcium supplement of fish scale protein peptide calcium chelate and preparation method thereof |
| GB201308828D0 (en) * | 2013-03-12 | 2013-07-03 | Verenium Corp | Phytase |
| CN106755241B (en) * | 2016-12-28 | 2021-05-04 | 北京化工大学 | Tuna bone collagen polypeptide for promoting bone cell growth and preparation method thereof |
| CN107280015A (en) * | 2017-06-22 | 2017-10-24 | 新昌县南翔食品科技有限公司 | Compound based on large yellow croaker fish scale activity extract |
| CN109265536B (en) * | 2018-09-03 | 2021-06-15 | 华南农业大学 | Calcium chelating peptide and preparation method and application thereof |
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| CN101709319A (en) * | 2009-11-20 | 2010-05-19 | 华南理工大学 | Method for preparing fish skin and scale collagen peptide |
| JP2013107850A (en) * | 2011-11-21 | 2013-06-06 | Meiji Co Ltd | Production method for collagen peptide |
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