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CN106109491A - Alimentation composition and the application in preparation treatment aplastic anemia medicine - Google Patents

Alimentation composition and the application in preparation treatment aplastic anemia medicine Download PDF

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Publication number
CN106109491A
CN106109491A CN201610719521.1A CN201610719521A CN106109491A CN 106109491 A CN106109491 A CN 106109491A CN 201610719521 A CN201610719521 A CN 201610719521A CN 106109491 A CN106109491 A CN 106109491A
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China
Prior art keywords
aplastic anemia
group
vitamin
rat
alimentation composition
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CN201610719521.1A
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Chinese (zh)
Inventor
吴文国
贾莉
杨佩满
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Dalian Jinfu Biological Technology Development Co Ltd
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Dalian Jinfu Biological Technology Development Co Ltd
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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Abstract

The present invention discloses a kind of alimentation composition and the application in preparation treatment aplastic anemia medicine, is by lysine, methionine, phenylalanine, threonine, tryptophan, arginine, histidine, glycine, aspartic acid, leucine, isoleucine, valine, serine, glutamine, taurine, orotic acid, nucleotide, vitamin A, vitamin D, vitamin B2, vitamin B6, vitamin B12, nicotinic acid, folic acid, vitamin C, ferrum, zinc, manganese, copper, selenium, chromium, potassium, calcium, magnesium, inositol and soybean phospholipid the most formulated, can repair aplastic anemia body comprehensively, thus reach to treat the effect of aplastic anemia.

Description

Alimentation composition and the application in preparation treatment aplastic anemia medicine
Technical field
The present invention relates to life science preventive medicine and treatment medical science, especially a kind of alimentation composition and in preparation Application in treatment aplastic anemia medicine.
Background technology
Aplastic anemia (aplastic anemia) is one group and is caused by chemical substance, biological factor, lonizing radiation or unknown cause Marrow hematopoiesis function failure, the disease being characterized with hematopoietic stem cell injuries, bone marrow steatosis, peripheral blood pancytopenia. Aplastic anemia pathogenesis is extremely complex, it is now recognized that relevant with following several respects:
(1) at propagating defects in hematopoietic stem cell
1. in aplastic anemia bone marrow, hematopoietic stem cell significantly reduces, and hematopoietic stem cell Colony forming ability significantly reduces, and abnormal hematopoiesis is done Cell can suppress normal haematopoetic function；
2. SAA patient's (Severe aplastic anemia) DNA repair ability substantially reduces, after treating with antilymphocyte globulin (ALG) the most not Can correct；
3. part is through the effective case of immunosuppressant treatment, develops into Clonal disease during long term follow-up；
4. aplastic anemia the most all has a number of complement sensitive cells, and experiment in vitro also demonstrates that aplastic anemia hematopoietic stem/progenitor Complement sensitivity is strengthened.
(2) abnormal immune reaction damage hematopoietic stem cell
Aplastic anemia patient himself hemopoietic function after immunosuppressant therapy is likely to be obtained improvement, and this makes for abnormal immune reaction damage The most direct evidence of hemocytoblast.
(3) hematopoieticmicroenviron-ment supports functional defect
Hematopoieticmicroenviron-ment includes the cytokine of stromal cell and secretion thereof, plays hematopoiesis support cell proliferation and promotes various cell The effect of growth promoter.Although hematopoieticmicroenviron-ment be not the beginning causing AA because of, but the state of an illness can be increased the weight of.
(4) genetic predisposition
Aplastic anemia often has the HLA-DR2 chain tendency of type antigen, child's aplastic anemia HLA-DPW3 type antigen significantly to increase, in family numbers of patients often Proliferation of hematopoietic progenitors ability is had substantially to reduce, and visible familial aplastic anemia.
Aplastic anemia serious harm health, Inst. of Hematology, Chinese Academy of Medical Sciences (1985) analyzes the aplastic anemia patient that is in hospital 392 examples, follow up time 1～26 years, case fatality rate is 42.6%, and wherein acute aplastic anemia is 91.6%, and chronic aplastic anemia is 24.6%, aplastic anemia Prognosis closely related with Therapeutic Method.
The Chinese invention patent of China Patent No. Patent No. 200710012788.8 discloses one and " promotes that Hematopoietic Stem is thin The alimentation composition that born of the same parents' propagation synthesizes with hemoglobin ".Raw material and the weight ratio of this alimentation composition are as follows: nucleotide 90 ~ 110, arginase 12 0 ~ 30, lysine 20 ~ 30, cysteine 10 ~ 20, glycine 25 ~ 35, histidine 20 ~ 30, lecithin 110 ~ 130, cephalin 50 ~ 70, vitamin E 0.4 ~ 0.6, vitamin C 5 ~ 7, folic acid 0.02 ~ 0.04, vitamin B2 0.05~0.07、 Vitamin B6 0.07 ~ 0.08, vitamin B12 0.0001 ~ 0.0002, ferrum 0.5 ~ 1.5, zinc 0.5 ~ 0.7, manganese 0.4 ~ 0.6, Fructus Lycii are many Sugar 14 ~ 16, Semen Vitis viniferae extract 14 ~ 16.Blood hemoglobin (Hb), erythrocyte (RBC), leukocyte (WBC) can be significantly improved And platelet (Plt) quantity；The propagation of marrow hemopoietic stem cells can be stimulated, make hematopoietic stem cell showed increased；Significantly improve thin Intracellular mitochondria number；Damage to liver, spleen has obvious restitution.The middle promulgated by the State Council of Patent No. 201010129033.8 Bright patent discloses this alimentation composition and provides basic nutrition condition as the recovery that medicine can be mismatch repair gene damage, from And reach to recover the purpose of mismatch repair gene damage.The Chinese invention patent of Patent No. 201010129027.2 discloses State alimentation composition and can provide basic nutrition condition to the recovery of mitochondrial injury, and then give full play to body to mitochondrial injury Independently repair instinct, reach recover mitochondrial injury purpose, but be limited only to the mitochondrion to liver, spleen increment and Repair.The Chinese invention patent of Patent No. 201010129030.4 also discloses this alimentation composition can promote liver stem cells Propagation.Although above-mentioned alimentation composition has described function, but due to the limitation of effect, this alimentation composition is the most applicable In treatment malnutritional anemia (iron deficiency anemia and folic acid and vitamin B12Malnutritional anemia), erythropoiesis reduce Anemia and hematoclasis too much or lose Anemia, are unable to the medicine as treatment aplastic anemia Thing.
Summary of the invention
The present invention is to solve the above-mentioned technical problem existing for prior art, it is provided that a kind of alimentation composition and in system Application in standby treatment acquired aplastic anemia medicine,
The technical solution of the present invention is: a kind of alimentation composition, it is characterised in that each constituent mass ratio is as follows: lysine 200 ~ 1200, methionine 100 ~ 1600, phenylalanine 150 ~ 1400, threonine 50 ~ 600, tryptophan 50 ~ 400, arginine 200 ~ 1500, histidine 100 ~ 1000, glycine 100 ~ 600, aspartic acid 100 ~ 600, leucine 100 ~ 600, isoleucine 100 ~ 600, valine 100 ~ 800, serine 100 ~ 400, glutamine 200 ~ 600, taurine 100 ~ 500, orotic acid 100 ~ 300, nucleotide 200 ~ 1200, vitamin A 0.2 ~ 0.6, vitamin D 0.002 ~ 0.006, vitamin B2 1 ~ 4, vitamin B6 1 ~ 4, vitamin B120.001 ~ 0.006, nicotinic acid 5 ~ 20, folic acid 0.01 ~ 1.2, vitamin C 50 ~ 150, ferrum 2 ~ 10, zinc 2 ~ 10, Manganese 2 ~ 10, copper 0.5 ~ 2, selenium 0.01 ~ 0.1, chromium 0.01 ~ 0.02, potassium 10 ~ 300, calcium 100 ~ 300, magnesium 100 ~ 200, inositol 50 ~ 60, soybean phospholipid 100 ~ 2500.
Each component optimum quality ratio is as follows: lysine 600, methionine 800, phenylalanine 700, threonine 300, color ammonia Acid 200, arginine 760, histidine 500, glycine 300, aspartic acid 300, leucine 300, isoleucine 300, valine 400, serine 200, glutamine 300, taurine 500, orotic acid 300, nucleotide 400, vitamin A 0.6, vitamin D0.006, vitamin B22, vitamin B62, vitamin B12 0.004, nicotinic acid 12, folic acid 0.9, vitamin C 100, ferrum 10, zinc 10, Manganese 8, copper 2, selenium 0.1, chromium 0.02, potassium 300, calcium 300, magnesium 200, inositol 60, soybean phospholipid 1200.
The application in preparation treatment aplastic anemia medicine of the above-mentioned alimentation composition.
DNA Excision Repair Gene is damaged by the alimentation composition of the present invention, DNA mismatch revision points damages, DNA homology weight Group revision points damage and DNA erroneous tendancy revision points damage etc. all have restitution；Can make hepatocyte, splenic B cells, Renal cells and cerebral hippocampal portion neuronal cell mitochondrial proliferation, to hepatocyte, the damage of splenic B cells mitochondrial gene Repair；There is promotion hematopoietic stem cell, liver stem cells, mescenchymal stem cell, kidney stem cells hyperplasia and gastric mucosa do The effect of cell proliferation；Hepar damnification, splenic injury, kidney injury, cerebral lesion and skeletal injury etc. had repair； Multiple protein moleculars of aplastic anemia rat high expressed there is obvious inhibitory action.I.e. can repair aplastic anemia body comprehensively, thus reach Effect to treatment aplastic anemia.
Accompanying drawing explanation
Fig. 1 is that the embodiment of the present invention affects schematic diagram to aplastic anemia rat body weight.
Fig. 2 be the embodiment of the present invention on aplastic anemia rats'liver, bone marrow, brain nucleotide excision repair gene affect schematic diagram.
Fig. 3 be the embodiment of the present invention on aplastic anemia rats'liver, bone marrow, brain base excision repair gene affect schematic diagram.
Fig. 4 is that the impact of mismatch repair gene in aplastic anemia rat liver, bone marrow and cerebral tissue is shown by the embodiment of the present invention It is intended to.
Fig. 5 be the embodiment of the present invention on aplastic anemia rats'liver, bone marrow, brain homologous recombination repair gene affect schematic diagram.
Fig. 6 be the embodiment of the present invention on aplastic anemia rats'liver, bone marrow, brain SOS revision points affect schematic diagram.
Fig. 7 is that the embodiment of the present invention affects schematic diagram (Electronic Speculum) to aplastic anemia rat liver cells is mitochondrial.
Fig. 8 is that the embodiment of the present invention affects schematic diagram (Electronic Speculum) to aplastic anemia Rats Spleen cell mitochondrial.
Fig. 9 is that the embodiment of the present invention affects schematic diagram (Electronic Speculum) to aplastic anemia rat renal tubular epithelial cells is mitochondrial.
Figure 10 is that the embodiment of the present invention affects schematic diagram (Electronic Speculum) to aplastic anemia rat hippocampal portion.
Figure 11 is that the embodiment of the present invention affects schematic diagram to aplastic anemia rat mitochondrial membrane potential.
Figure 12 is the embodiment of the present invention impact on aplastic anemia rat mitochondrial DNA content.
Figure 13 is that the embodiment of the present invention affects schematic diagram to aplastic anemia rat marrow hematopoietic stem cell.
Figure 14 is that the embodiment of the present invention affects schematic diagram to aplastic anemia rat liver stem cell.
Figure 15 is that the embodiment of the present invention affects schematic diagram to aplastic anemia rat kidney stem cell.
Figure 16 is that the embodiment of the present invention affects schematic diagram to aplastic anemia rat stomach stem cell.
Figure 17 is that the embodiment of the present invention affects schematic diagram to aplastic anemia Intestinal Mucosa stem cell.
Figure 18 is that the embodiment of the present invention affects schematic diagram to aplastic anemia neural stem cells in rats.
Figure 19 is that the embodiment of the present invention affects schematic diagram to aplastic anemia pancreas in rat stem cell.
Figure 20 is that the embodiment of the present invention affects schematic diagram to aplastic anemia rat muscle stem cell.
Figure 21 is that the embodiment of the present invention affects schematic diagram to aplastic anemia rat bone marrow mesenchymal stem cells.
Figure 22 be the embodiment of the present invention on aplastic anemia rat liver,spleen,kidney, brain affect schematic diagram (HE dyeing).
Figure 23 be the embodiment of the present invention on aplastic anemia rat intestine, muscle affect schematic diagram (HE dyeing).
Figure 24 is the kidney segment transmission electron microscope picture of each experimental group of the present invention.
Figure 25 is that the embodiment of the present invention affects schematic diagram to what aplastic anemia rat bone marrow mesenchymal stem cells grew.
Figure 26 is induction and the expression schematic diagram of lipoblast related gene of the present invention each experimental group adipose cell.
Figure 27 is the present invention osteoblastic induction of each experimental group and the expression schematic diagram of osteoblast related gene.
Figure 28 is that the embodiment of the present invention affects schematic diagram to aplastic anemia rat marrow hematopoietic cell.
Figure 29-1, Figure 29-2, Figure 29-3 are the embodiment of the present invention shadows to aplastic anemia Rat Mesenchymal Stem Cells protein expression Ring schematic diagram (protein chip spectrogram).
Figure 30-1, Figure 30-2, Figure 30-3 are that the impact of aplastic anemia rat bone marrow cell protein expression is shown by the embodiment of the present invention It is intended to (protein chip spectrogram).
Figure 31-1, Figure 31-2, Figure 31-3 are that the impact of aplastic anemia rat liver cells protein expression is shown by the embodiment of the present invention It is intended to (protein chip spectrogram).
Detailed description of the invention
Embodiment 1: alimentation composition each constituent mass (mg) ratio of the present invention is as follows: lysine 200 ~ 1200, first sulfur ammonia Acid 100 ~ 1600, phenylalanine 150 ~ 1400, threonine 50 ~ 600, tryptophan 50 ~ 400, arginase 12 00 ~ 1500, histidine 100 ~ 1000, glycine 100 ~ 600, aspartic acid 100 ~ 600, leucine 100 ~ 600, isoleucine 100 ~ 600, valine 100 ~ 800, serine 100 ~ 400, glutamine 200 ~ 600, taurine 100 ~ 500, orotic acid 100 ~ 300, nucleotide 200 ~ 1200, vitamin A 0.2 ~ 0.6, vitamin D 0.002 ~ 0.006, vitamin B2 1 ~ 4, vitamin B6 1 ~ 4, vitamin B12 0.001 ~ 0.006, nicotinic acid 5 ~ 20, folic acid 0.01 ~ 1.2, vitamin C 50 ~ 150, ferrum 2 ~ 10, zinc 2 ~ 10, manganese 2 ~ 10, copper 0.5 ~ 2, selenium 0.01 ~ 0.1, chromium 0.01 ~ 0.02, potassium 10 ~ 300, calcium 100 ~ 300, magnesium 100 ~ 200, inositol 50 ~ 60, soybean phospholipid 100 ~ 2500。
Embodiment 2: each constituent mass (mg) ratio is as follows: lysine 600, methionine 800, phenylalanine 700, threonine 300, tryptophan 200, arginine 760, histidine 500, glycine 300, aspartic acid 300, leucine 300, isoleucine 300, valine 400, serine 200, glutamine 300, taurine 500, orotic acid 300, nucleotide 400, vitamin A 0.6, vitamin D 0.006, vitamin B22, vitamin B62, vitamin B12 0.004, nicotinic acid 12, folic acid 0.9, vitamin C 100, Ferrum 10, zinc 10, manganese 8, copper 2, selenium 0.1, chromium 0.02, potassium 300, calcium 300, magnesium 200, inositol 60, soybean phospholipid 1200.
Described alimentation composition can be applied in preparation treatment aplastic anemia medicine.
Raw material sources such as table 1:
Table 1
Experiment:
One. the foundation of aplastic anemia rat model
This experiment uses SD rat.Experimental procedure: after X-ray 2.5Gy was irradiated in first day, gave ring phosphorus respectively in the 4th, 6,8 days Amide 35mg/kg, chloromycetin 45 mg/kg lumbar injection.15th day repeats above step.Corresponding with simple normal saline Injection location is Normal group.
Experiment packet: according to drug dose and the design analysis of compbined test of animal pharmacology, be divided into: 1. normal control Group；2. model with aplastic anemia group；3. embodiment 2 alimentation composition high dose group, with 2266.95mg/kg.d to rat oral gavage；4. implement Dosage group in example 2 alimentation composition, with 1511.3mg/kg.d to rat oral gavage；5. embodiment 2 alimentation composition low dose group, With 1057.91mg/kg.d to rat oral gavage.
Experiment process: first, sets up model by the method for building up of aforementioned aplastic anemia rat model, from the beginning of the 5th day, and nutrition group The high, medium and low dosage component of compound does not carry out gavage with corresponding dosage to rat, once a day, until the 60th day, draw neck to put to death big Mus, sampling detects.Carry out whole observation simultaneously every day, measure body weight.
Two. experimental technique
1. peripheral blood detection
Each experimental group the 60th day, animal of weighing, take blood through eye socket, use Automatic Blood Cell Analyzer to measure peripheral blood blood red Protein content, erythrocyte, leukocyte and platelet count；Basis of microscopic observation peripheral blood film.
2. erythropoietin (Epo) detection
ELISA Plate every hole addition titer, comparison liquid and the testing sample 100ul diluted with sample diluting liquid in advance, shrouding, 37 ° C hatches 90 minutes.After reaction in drying hole after liquid, by ready biotin anti-mouse EPO antibody working solution by every hole 100ul is sequentially added into (except TMB blank colour developing hole), and after shrouding, 37 ° of C react 60 minutes, and 0.01M PBS washs 3 times, soaks every time Steep about 1 minute.Add ready Avidin-peroxydase complex working solution and be sequentially added into (TMB by every hole 100ul Except blank colour developing hole), 37 ° of C react 30 minutes.It is sequentially added into by every hole 90 l in 37 DEG C, balances TMB colour developing in 30 minutes Liquid, 37 ° of C lucifuge reactions, every hole 100 l is sequentially added into TMB stop buffer.At 450nm wavelength, absorbance (OD is read by microplate reader Value), record sample Epo concentration (pg/ml) according to standard curve.
3. bone marrow detection
Cervical dislocation put to death rat, separate bilateral femur open medullary cavity carry out bone marrow smear, BMNC counting, Marrow protection inspection, Proliferation of Bone Mesenchymal Stem Cells and the analysis of differentiation due.
4. the separation and Extraction of mesenchymal stem cells MSCs (BMSCs)
After SD rats by intraperitoneal injection anesthetics, de-neck is put to death, 75% soak with ethanol rat 20 min；Aseptic take double hind leg, put into The ethanol of 75% soaks 5 min；Remove lower limb muscles, from knee joint dialysis femur, cut off femur two ends；With 10 mL injections Device is drawn the F-12K culture fluid of 10% hyclone and is rinsed medullary cavity, collects bone marrow irrigation liquid, makes single cell suspension, 200 mesh With 1 × 10 after screen cloth filtration8It is inoculated in culture bottle.It is placed in 37 ° of C, 5% CO2 incubator cultivation.Within 72 hours, change first Culture fluid, removes non-attached cell, changed liquid 1 time every 2 days later.When cell is paved with the 80% ~ 90% of whole culture bottle floor space Time, Secondary Culture.
5. the adipogenic induction differentiation of mescenchymal stem cell (BMSCs)
Adipogenic induction method: by isolated and purified mesenchymal stem cells MSCs cellar culture, had digestive transfer culture, with 1 × 105/ hole close Degree, 400ul/ hole is inoculated in 6 well culture plates being pre-placed coverslip, prepares cell climbing sheet, when cell growth reaches 80% During fusion, the hyclone of addition 10%, 1 μm ol/L dexamethasone, 0.5 mmol/L IBMX, the H-of 10 mg/L bovine insulins DMEM induces 3 days, then processes 1 day with the hyclone of 10%, the H-DMEM of 10 mg/L bovine insulins, after so circulating 3 times, Hyclone, the H-DMEM of 10 mg/L bovine insulins with 10% process 7 days, change liquid 1 time every three or four days.Matched group adds all the time Enter containing the hyclone that volume fraction is 10%, the H-DMEM of 10 mg/L bovine insulins, changed liquid 1 time every three or four days.After induction Cells rinsed with PBS 2 ~ 3 times, 10% formaldehyde room temperature fixes 40min.PBS washes 2 ~ 3 times, and saturated oil red O dye liquor steams water with 3 with one: 2 dilutions, room temperature dyeing 30min, PBS wash for several times until nothing is observed visually sediment, om observation.
6. mescenchymal stem cell (BMSCs) osteoblasts cultivation and qualification
Take P2 for mesenchymal stem cells MSCs, by 2 × 105Individual/hole is inoculated in 12 orifice plates, when cell attachment growth reaches 80% fusion Time, absorb culture fluid in hole, be changed to osteoblast induction liquid (containing DMEM in high glucose, volume fraction be 10% hyclone, 10-8 Mol/L dexamethasone, 10-2 Mol/L sodium β-glycerophosphate, 50 mg/L ascorbic acid), within every 3 days, change induction liquid 1 time.Cultivate After 14 days, absorbing culture fluid, PBS washes 2 times, and 10% formaldehyde room temperature fixes 40 min, and PBS washes 3 times, adds 0.1% alizarin red agent (3:2 Dilution), room temperature dyeing 10min, removes dye liquor, after PBS washes 3 times, basis of microscopic observation.
7. RNA extracts and RT-PCR analyzes
Conventional application Trizol method extracts the total serum IgE of each specimen, and ultraviolet spectrophotometer measures A260And A280, contain detecting RNA Amount and purity, and it is placed in-70 ° of C preservations.
Reverse transcription system 20 μ l, comprises sample RNA 1 μ l, the description provided according to the Reverse Transcription box of TaKaRa Operate.Reverse transcription reaction condition is: 65 ° of C 1min, 30 ° of C 5min, 65 ° of C 15min, 98 ° of C 5min, 5 ° of C 5min.
PCR reaction system 50 μ l, comprises reverse transcription liquid 10 μ l.PCR reaction condition: 94 ° of C denaturations 1min；97°C Degeneration 20s, 64 ° of C annealing 20s, 72 ° of C 20s extend, and circulate 30 times；72 ° of C extend 5min, and 4 ° of C are constant.Take 5 μ l PCR to expand Volume increase thing through 1% agarose gel electrophoresis, gel imaging under uviol lamp.
8. transmission electron microscope observing
3 sections taking different parts in rat portions liver, spleen, brain, nephridial tissue specimen are carried out transmission electron microscope (JEM-100CXE Type) Ultrastructural observation, every section respectively random observation 5-6 position, and take the photograph sheet by identical amplification, often group with Machine extraction l0 opens photo, uses Epson microcomputer and Summa Sketch PIus digitizer, and uses Sigmascan software, The form that each group of photo is made sem image is analyzed, and counts mitochondrial average number simultaneously.
9. mitochondrial membrane potential measures
Cell (5 × 105Individual) it is inoculated in 25cm2In culture bottle, after 37 DEG C are cultivated 24 h, the curcumin adding variable concentrations divides After not acting on 1 h and 6 h, harvesting, PBS washes twice, is resuspended in the 2ml fresh cultured containing 1.0 M Rhodamine 123s In liquid, 10 min are hatched in 37 ° of C water-bath shakings, the centrifugal cell that removes, and in Fluorescence Colorimeter mensuration culture fluid, Rhodamine 123 is strong Degree, excitation wavelength 490 nm, launch wavelength 520 nm, result represents with the fluorescence intensity of the Rhodamine 123 that cell absorbs.
10. mitochondrial DNA content measures
By BMNC (5 × 107), flesh tissue liver, spleen, brain, kidney be homogenized, crack, centrifugal, obtain mitochondrion. Illustrate to extract the DNA in mitochondrion according to DNA extraction kit, use ultraviolet spectrophotometer to measure its content.Computing formula As follows:
DNA concentration (μ g/ μ l)=A260 × 50 μ g/ml × extension rate × 10-3
11. pathological observations
Rat portions liver, spleen, brain, kidney, intestinal, muscle are placed in 4 % paraformaldehydes fixing, sequentially pass through conventional dehydration, paraffin Soaking embedding, section, HE dyeing, microscope observes each histiocytic morphosis.
12. immunohistochemical stainings
Paraffin section de-waxing, aquation；PBS wash 2-3 time each 5 minutes；3% H2O2(80% methanol) drips on slide, and room temperature stands 10 minutes；PBS wash 2-3 time each 5 minutes；Antigen retrieval；PBS wash 2-3 time each 5 minutes；Dropping Normal Goat Serum confining liquid, room Temperature 20 minutes.Getting rid of surplus liquid, dropping one resists 50 μ l, and 4 ° of C are overnight.The most afterwards need to be 37 ° of C rewarmings 45 minutes.PBS washes 3 times Each 5 minutes；Dripping two anti-40-50 μ l, room temperature stands, or 37 ° of C 1 hour；PBS wash 3 times each 5 minutes；DAB colour developing 5-10 divides Clock, grasps dye levels under the microscope；PBS or tap water rinse 10 minutes；Haematoxylin redyeing 2 minutes, hydrochloride alcohol breaks up； Tap water rinses 10-15 minute；Dehydration, transparent, mounting, microscopy.
13. flow cytometry analysis
Take rat left tibia, remove superficial musculature, prune bone dirt, insert tibia ankle end with No. 18 pins, rush with PBS 5mL Wash in test tube, filter with 200 eye mesh screens.1000 r/min are centrifuged 5min, abandon supernatant.Cell is added 5mL Percoll separates liquid (relative proportion 1.073g/L), 2000r/min, centrifugal 25min, takes middle mononuclearcell layer.PBS washes Adjusting mononuclearcell number after washing is l × 106/ pipe, every sample 3 is managed, and measures pipe and adds CD34 or the CD45 antibody of FITC labelling, 37 ° of C hatch 2 hours.Then PBS washed once.The change of CD34/45 positive cell quantity is expressed with flow cytomery, with The cell percentage that traget antibody is positive is as the metering mark expressing CD34/45 albumen (marrow hemopoietic stem cells mark) Accurate.Goat anti-rabbit igg and the cell being not added with antibody with fluorescein of only labelling make negative control simultaneously.
14. protein chip analyses
Rat portions BMNC, mesenchymal stem cells MSCs, liver organization are carried out protein chip analysis, this part Work is completed by upper Cannes Garden company.
15. statistical analysis
All data all carry out statistical analysis with SPSS 17.0 software.Analyze at least three results for each.Numerical value mean ± SD represents, uses t inspection.P < 0.05 thinks there is significant difference, and the most meaningful.
Three, experimental result
(1) alimentation composition impact on aplastic anemia rat body situation
Compared with Normal group, it is fluffy and disorderly that model with aplastic anemia group rat occurs that from 6 days fur relaxes successively, and glossiness reduces, portion Rat is divided to have depilation and skin lesion.Rat becomes thin simultaneously, spirit is faded in the best, the minimizing pale, movable of color of the lip eyelid, few food, body weight Decline.Wherein model with aplastic anemia group rat body weight (218.23 ± 33.52 g) and Normal group (366.54 ± 49.68 g, *p < 0.05) decline is compared substantially.
The alimentation composition group of various dose compares with model with aplastic anemia group, and the rat mental status is the best, and food-intake increases, body Heavily increase (see figure 1).Show that alimentation composition has notable restitution to Induced Aplastic Anemia Mice whole body.
(2) alimentation composition impact on aplastic anemia rat peripheral blood
Compared with Normal group, erythrocyte (RBC), leukocyte (WBC), platelet (PLT) in model with aplastic anemia group peripheral blood And hemoglobin (Hb) is all remarkably decreased (table 1, #p < 0.05)；Various dose alimentation composition group and model with aplastic anemia group ratio Relatively, in its peripheral blood, indices significantly raises (table 2, * p < 0.05), and in dose-effect dependency.
Compared with Normal group, model with aplastic anemia group EPO of rats (EPO) content is significantly raised, and EPO Reduction with RBC, Hb is negative correlation, r=-0.91 and r=-0.93(*p< 0.05), show EPO level and the red system of aplastic anemia bone marrow Generative capacity reduces, EPO reactivity reduced capability, and EPO is that compensatory raises relevant.(table 1, *p<0.01).EPO is a kind of weight The hematopoietic regulation factor wanted, has promotion CFU-E propagation, differentiation and maturation, maintains erythrocyte in peripheral blood, blood red egg The effect of Bai Hengding, in blood, EPO level can reflect the erythropoiesis ability in body.And the alimentation composition of various dose Group compares with model with aplastic anemia group, and erythropoietin (Epo) reduces (* due to compensation contentp<0.01)；And in agent Amount-effect relation.
Result above is pointed out, and alimentation composition has promotion rising effect to the aplastic anemia various hemocyte of rat peripheral blood.
The impact on aplastic anemia rat peripheral blood of table 2 alimentation composition
#P < 0.05 aplastic anemia group and normal group；*P < 0.05 alimentation composition group and aplastic anemia group
(3) embodiment of the present invention alimentation composition impact on aplastic anemia rat gene injury recovery
1. Excision Repair Gene
1.1 nucleotide excision repair gene
Nucleotide Sequence Analysis (NER) path is considered as main in body and most important injury repairing path, mainly Repair the DNA damage that exogenous material causes, such as pyrimidine dimer, optical compounds and other big compound and crosslinking to be led The damage caused.This experiment have chosen 3 NER genes (Ercc1, Ercc2, Xpc), have detected it in battalion from transcriptional level The expression change (see figure 2) supported in compositions group in liver, bone marrow and brain.
In liver organization, compared with Normal group, the excision of model with aplastic anemia group rat liver tissue nucleotide is repaired Gene Xpc expression is lowered；After alimentation composition processes aplastic anemia rat, in rat liver tissue, the expression of Xpc is with nutrition Composition dosage increases and increases.Nucleotide excision repair gene Ercc1, Ercc2 are without significant change.
In bone marrow, compared with Normal group, model with aplastic anemia group rat marrow hematopoietic cell nucleotide excision repair group Because Ercc2 expression is lowered；Alimentation composition processes after aplastic anemia rat, the expression of rat marrow hematopoietic cell Ercc2 with Alimentation composition dosage increases and increases.Nucleotide excision repair gene Ercc1, Xpc are without significant change.
In cerebral tissue, compared with Normal group, model with aplastic anemia group rat cerebral tissue nucleotide Excision Repair Gene Ercc2 expression is lowered；After alimentation composition processes aplastic anemia rat, in rat cerebral tissue, the expression of Ercc1 is with nutrition group Compound dosage increases and increases.Nucleotide excision repair gene Ercc1, Xpc are without significant change.
Result shows that embodiment of the present invention alimentation composition has one to the damage of aplastic anemia rat nucleotide Excision Repair Gene Fixed restitution.
1.2 base excision repair genes
Base excision repair (base excision repair, BER) gene is primarily involved in repairing endogenous alkylating agent with outer The alkanisation of the source property carcinogen DNA base that such as nitrous ammonia causes and intracellular spontaneous and due to ionizing radiation and ultraviolet The oxidation of radiation-induced DNA base.This experiment have chosen 4 BER genes (Apex1, Ogg1, Polb, MTH1), have detected its expression alimentation composition group change (see figure 3) from transcriptional level.
In liver organization, each group base excision repair gene is without significant change.
In bone marrow, compared with Normal group, model with aplastic anemia group rat marrow hematopoietic cell base excision repair gene Ogg1, MTH1 expression is lowered；After alimentation composition processes aplastic anemia rat, rat marrow hematopoietic cell base excision repair gene The expression of Ogg1, MTH1 increases with alimentation composition dosage and increases.Base excision repair Gene A pex1, Polb are without substantially Change.
In cerebral tissue, compared with Normal group, model with aplastic anemia group rat marrow hematopoietic cell base excision repair base Because Ogg1, MTH1 expression is lowered；After alimentation composition processes aplastic anemia rat, base excision repair in rat marrow hematopoietic cell The expression of gene Ogg1, MTH1 increases with alimentation composition dosage and increases.Base excision repair Gene A pex1, Polb without Significant change.
Result shows that aplastic anemia rat base excision repair gene damage is had necessarily by embodiment of the present invention alimentation composition Restitution.
2. mismatch repair gene
DNA mismatch repair system (MMR) is the efficient public security system of a kind of energy DNA plerosis base mispairing of human body cell, by Enzyme molecule (mismatch repair gene product) composition of a series of specificity DNA plerosis base mispairings.This system can eliminate DNA and close Become mistake, keep integrity and the stability of hereditary material, it is to avoid hereditary material is undergone mutation, it is ensured that the fidelity of DNA replication dna. 4 the most frequently used mismatch repair genes MSH2, MSH3, MLH1, PMS2 are selected in this experiment.
In liver, bone marrow and cerebral tissue, compared with Normal group, 4 mispairing reparations in model with aplastic anemia group rat The expressing quantity of gene is all lowered；After alimentation composition processes aplastic anemia rat, rat liver, mispairing in bone marrow and cerebral tissue The expression of revision points increases with alimentation composition dosage and increases (see figure 4).
Result shows that alimentation composition of the present invention has restitution to the damage of aplastic anemia rat mismatch repair gene.
3. homologous recombination repair gene (double-strand break reparation)
When being exposed to when cell under conditions of the various cause DNA such as ionizing radiation, DNA cross-linking agent and anoxia damage, dye often occurs Colour solid DNA double chain interruption.In eukaryotic cells, it is known that there are two kinds of main ways repairing chromosomal DNA double-strand break Footpath, i.e. homologous recombination and non-homogeneous DNA end connect.DNA repairs the premise being to maintain chromosome integrity, homology accurately Restructuring then plays pivotal role in DNA repair process.4 the most frequently used homologous recombination repair genes are selected in this experiment Rad51、Rad52、Xrcc1、Xrcc2。
In liver, bone marrow and cerebral tissue, compared with Normal group, model with aplastic anemia group rat syngeneic recombination repair gene Rad51, Rad52, Xrcc1 expression is all lowered；After alimentation composition processes aplastic anemia rat, rat recombination repair gene Rad51, The expression of Rad52, Xrcc1 increases with alimentation composition dosage and increases, and Xrcc2 is without significant change (see figure 5).
Result shows that the damage of aplastic anemia rat syngeneic recombination repair gene is had extensive by embodiment of the present invention alimentation composition Multiple effect.
4. erroneous tendancy reparation (SOS reparation) gene
When two chains of DNA have damage and injury site adjacent to time, damage can not cut reparation or recombination repair, at this moment exist The DNA vacancy of injury region is caused under the effect of Restriction Endoneuclease and Exoneuclease, then by damaging A whole set of the special archaeal dna polymerase that induction produces-SOS repairs enzyme, the synthesis of catalysis vacancy position DNA, at this moment fills Nucleotide be almost random, the most finally maintain the integrity of DNA double chain, make cell existence.This experiment is selected Two the most frequently used SOS revision points RecA, LexA.
In liver, myeloid tissue, compared with Normal group, model with aplastic anemia group rat SOS revision points RecA expresses Amount is all lowered；After alimentation composition processes aplastic anemia rat, the expression of rat SOS revision points RecA is with alimentation composition dosage Increase and increase.SOS revision points LexA is without significant change (see figure 6).
In cerebral tissue, between each group, SOS revision points is without significant change.
Result shows that embodiment of the present invention alimentation composition has recovery and makees the damage of aplastic anemia rat SOS revision points With.
(4) alimentation composition impact mitochondrial on aplastic anemia rat
1. Mitochondrial Shape is observed
Hepatic tissue (portal area) transmission electron microscope shows (Fig. 7), compared with Normal group, and model with aplastic anemia group rat hepatocytes interior lines Plastochondria number significantly reduces, and ridge is unclear or disappears, and cytoplasm is loosened；The alimentation composition group of various dose and model with aplastic anemia group Relatively, rat hepatocytes mitochondrial number showed increased, endochylema gradually recovers normal.
Spleen transmission electron microscope shows (Fig. 8), compared with Normal group, and model with aplastic anemia group Rats Spleen B cell mitochondrial Number significantly reduces；The alimentation composition group of various dose compares with model with aplastic anemia group, intracellular mitochondrial number showed increased.
Renal cells transmission electron microscope shows (Fig. 9), compared with Normal group, and model with aplastic anemia group kidney of rats tubule Epithelial cell mitochondrial number significantly reduces, arrangement disorder；The alimentation composition group of various dose compares with model with aplastic anemia group, Renal tubules basilar part epithelial cell mitochondria number showed increased, marshalling.
Brain transmission electron microscope shows (Figure 10), and compared with Normal group, model with aplastic anemia group rat hippocampal portion neuron is thin Intracellular mitochondria number significantly reduces；The alimentation composition group of various dose compares with model with aplastic anemia group, rat cerebral cell interior lines Plastochondria number slightly increases.
Result shows that embodiment of the present invention alimentation composition can promote aplastic anemia rat hepatocytes mitochondrion, splenic B cells line Plastochondria, renal cells mitochondrion and the mitochondrial increase of neuronal cell of cerebral hippocampal portion.
2. mitochondrial membrane potential measures
Mitochondrial membrane potential is the important indicator of observation line mitochondria function, and the change of mitochondrial function shows as transmembrane potential more and reduces Instability with film.Fluorescent probe Rhodamine 123 (Rh123) is used to measure the alimentation composition impact on mitochondrial membrane potential. Rh123 is lipophilic cation fluorescein, can pass through cell membrane and the mitochondrial membrane of living cells, after entering mitochondrion, by In the nagative potential official post Rh123 selective enrichment of mitochondrial membrane on mitochondrion, combine in endochylema is considerably less.Mitochondrion pair The intake of Rh123 depends on that the height of its transmembrane potential, certain transmembrane potential form certain fluorescence intensity, be directly proportional, intensity Size reflection the mitochondrial membrane extent of damage.
Compared with Normal group, model with aplastic anemia group rat marrow hematopoietic cell, hepatocyte and splenocyte inner mitochondria film Current potential, in being decreased obviously trend, shows that mitochondrial function lacks (table 2)；The alimentation composition group of various dose and model with aplastic anemia group Relatively, rat marrow hematopoietic cell, hepatocyte and splenocyte mitochondrial transmembrane potential substantially increase, in dose-effect relationship (table 3).
Table 3
#P < 0.05 aplastic anemia group and normal group；*P < 0.05 alimentation composition group and aplastic anemia group
Compared with Normal group, model with aplastic anemia group rat brain, nephrocyte mitochondrial membrane potential reduce (Figure 11), but without significance difference Different；The alimentation composition group of various dose compares with model with aplastic anemia group, and rat brain, nephrocyte mitochondrial membrane potential are increased slightly, But without significant difference (Figure 11).
Result shows that alimentation composition can promote aplastic anemia rat marrow mononuclearcell, hepatocyte and splenocyte mitochondrial membrane Current potential raises；And brain, the nephrocyte mitochondrial membrane potential of aplastic anemia rat is not made significant difference.
3. UV spectrophotometer measuring mitochondrial DNA content
Compared with Normal group, the content of model with aplastic anemia group rat marrow hematopoietic cell, hepatocyte and splenocyte mtDNA is obvious Downward trend；The alimentation composition group of various dose compares with model with aplastic anemia group, and rat marrow hematopoietic cell, hepatocyte and spleen are thin The content of born of the same parents mtDNA substantially increases, in dose-effect relationship (table 4).
Table 4
#P < 0.05 aplastic anemia group and normal group；*P < 0.05 alimentation composition group and aplastic anemia group
Compared with Normal group, model with aplastic anemia group rat brain, the content of nephrocyte mitochondrion mtDNA reduce (Figure 12), but nothing Significant difference；The alimentation composition group of various dose compares with model with aplastic anemia group, rat brain, nephrocyte mtDNA content slightly Increase, but without significant difference (Figure 12).
Result above shows that alimentation composition is to aplastic anemia rat marrow mononuclearcell, hepatocyte and splenocyte mtDNA Damage has restitution；And brain, the nephrocyte mtDNA content of aplastic anemia rat is not made significant difference.
(5) embodiment of the present invention alimentation composition impact on aplastic anemia Murine Stem
1. marrow hemopoietic stem cells
It is expressed on hematopoietic stem cell film to CD34 selection of antigen, is the mark of hematopoietic stem cell.CD45 is single transmembrane sugar egg In vain, belong to protein tyrosine phosphatase family member, be widely present in hemopoietic stem cell surface.This experiment uses SABC inspection Survey the expression of aplastic anemia rat marrow hematopoietic stem cell mark CD34, CD45.Result as shown in figure 13, with Normal group Comparing, model with aplastic anemia group rat marrow hemopoietic stem cell CD 34, the expression of CD45 significantly reduce, and show that aplastic anemia rat marrow is made Hemocytoblast quantity reduces；After alimentation composition intervenes aplastic anemia rat, rat marrow hemopoietic stem cell CD 34, the expression of CD45 It is dose dependent with alimentation composition, shows that alimentation composition has the work promoting aplastic anemia rat marrow hemopoietic stem cell proliferation With.
2. liver stem cells
CD90 is a kind of cell surface glycoprotein, is the mark of liver stem cells, is also that the antigen of blood stem cell is determined simultaneously Fixed bunch.Hepatic oval cells is to study more a kind of liver stem cells at present, and its surface has specific marker cytokeratin 19(CK19) expression is higher.This experiment uses the expression of SABC detection aplastic anemia Rat Hepatic Stem Cells mark CD90, CK19 Situation.As shown in figure 14, compared with Normal group, model with aplastic anemia group rat liver stem cell population significantly reduces result, battalion After supporting compositions-treated aplastic anemia rat, the content of rat liver stem cell increases with alimentation composition dosage and increases, and shows battalion Foster compositions can promote the propagation of aplastic anemia rat liver stem cell.
3. kidney stem cell
In kidney, CD133 is distributed in renal medulla mamillary region, and ability of cell proliferation is strong, it is believed that this district is kidney stem cell settlement. OCT4 is to maintain stem cell versatility and the transcription factor of self renewal.This experiment uses SABC detection aplastic anemia rat kidney The expression of stem cell markers CD133, OCT4, as shown in figure 15, compared with Normal group, model with aplastic anemia group is big for result The expression of Mus CD133, OCT4 significantly reduces, and after alimentation composition processes aplastic anemia rat, its expression is with nutrient combination agent Amount increases and increases, and shows that alimentation composition promotes the propagation of aplastic anemia rat kidney stem cell.
4. stomach stem cell
Lgr5 has another name called GPR49, and Recent study shows, Lgr5 is the tumor stem cell labelling such as colorectal cancer, glue blastoma, all Label CD133, CD44 more specificity relatively previously.Musashi-1 mainly expresses at gastric epithelial isthmus, can be as people The label of class normal gastrointestinal tract epithelial stem cell.This experiment uses SABC detection aplastic anemia rat stomach stem cell markers The expression of Lgr5.As shown in figure 16, compared with Normal group, model with aplastic anemia group rat stomach stem cell population substantially subtracts result Few；After alimentation composition processes aplastic anemia rat, the expression of rat stomach stem cell Lgr5 increases with alimentation composition dosage and increases, Show that alimentation composition has the propagation promoting aplastic anemia rat stomach stem cell.But respectively organize the nothing of stomach stem cell Musashi-1 Significant change.
5. intestinal mucosa stem cell
Little intestinal stem cell is a kind of undifferentiated initial cell, is positioned at the nearly basilar part of crypts of small intestine.There is self renewal and propagation It is divided into the function of various ripe intestinal epithelial cell.Research shows, Musashi-1 is the selected marker of intestinal stem cell. Lgr5 limitation in the small intestinal and big intestinal crypt of muroid is expressed, and is one of the mark of intestinal stem cell.This experiment employing is exempted from The expression of epidemic disease groupization detection aplastic anemia intestine in rats stem cell markers Musashi-1, Lgr5.Result as shown in figure 17, each group Small intestinal stem cell population is without significant change.Show that the alimentation composition propagation to aplastic anemia rat small intestine stem cell is without remarkable effect.
6. neural stem cell
Nestin is one of mark of neural stem cell or neural precursor during development of central nervous system.CD133 is Hematopoietic stem cell, the mark of endothelial progenitor cells, later CD133 be proved its as a kind of stem cell labeling thing, be also current The brain Tumor Stem Cells relatively generally acknowledged and the surface marker of neural stem cell.This experiment uses SABC detection aplastic anemia rat The expression of neural stem cell mark Nestin, CD133, as shown in figure 18, alimentation composition processes aplastic anemia rat to result After, the expression of Nestin, CD133 is without notable change.Show the alimentation composition propagation nothing to aplastic anemia rat brain neural stem cell Appreciable impact.
7. pancreatic stem cells
Cyfra21-1 (CK19) is the distinctive mark of epithelial cell, has positive expression at pancreatic stem cells.
Nestin is in the specific expression of neuroepithelial stem cell, and studies display at present, and Nestin is at pancreatic stem cells In also in high expressed.This experiment uses the expression of SABC detection aplastic anemia pancreas in rat stem cell markers CK19, Nestin Situation, as shown in figure 19, each group pancreatic stem cells quantity is without significant change for result.Show that alimentation composition is to aplastic anemia pancreas in rat The propagation of stem cell is without remarkable effect.
8. muscle stem cell
At present, flesh stem cell still lacks Specific marker.Desmin is considered in close relations with the early differentiation of myocyte, In Muscle-derived Stem Cells, the positive rate of Desmin is up to 90%, frequently as the mark of flesh stem cell.CD34 is the saliva of cell surface Liquid mucin is it is considered to be the label of hematopoietic stem cell, but also has substantially expression in flesh stem cell.This experiment uses immunity The expression of groupization detection aplastic anemia rat muscle stem cell markers Desmin, CD34.As shown in figure 20, each group intestinal is dry thin for result Born of the same parents' quantity is without significant change.Show that the alimentation composition propagation to aplastic anemia intestine in rats stem cell is without obvious effect.
9. mesenchymal stem cells MSCs
Each group Proliferation of Bone Mesenchymal Stem Cells capability result is shown in that Figure 21, aplastic anemia group are substantially less than normal group, low dose group with again Barrier group zero difference, middle dosage group, high dose group and aplastic anemia group have notable difference.Between showing that alimentation composition is to aplastic anemia rat marrow The propagation of mesenchymal stem cells has obvious effect.
(6) embodiment of the present invention alimentation composition impact on aplastic anemia rat organ's injury repairing
1. the impact repaired for the organ injury such as liver,spleen,kidney, brain, intestinal and muscle is as can be seen from Figure 22:
The pathological section HE dyeing display of liver, compared with Normal group, model with aplastic anemia group rat liver tissue leaflet structure is owed Clearly, liver cell nuclear pyknosis, chromatin contaminates deeply, hepatic sinusoid and central vein expansion, congested.The alimentation composition group of various dose Comparing with model with aplastic anemia group, liver organization leaflet structure is substantially clear, and hepatocyte form is close to normal.
The pathological section HE dyeing display of spleen, compared with Normal group, model with aplastic anemia group Rats Spleen slightly enlargement, spleen Organizational structure is loosened, and acini lienalis number reduces, and germinal center is inconspicuous, and white pulp reduces, splenic sinusoid expansion, hyperemia, subregion Visible splenic arterioles wall thickening and vitreous degeneration.The alimentation composition group of various dose compares with model with aplastic anemia group, acini lienalis number Amount increases, and white pulp increases.
The pathological section HE dyeing display of kidney, compared with Normal group, model with aplastic anemia group Renal Glomeruli In Rats volume reduces, Part is not of uniform size, renal tubules edema.The alimentation composition group of various dose compares with model with aplastic anemia group, and glomerular volume tends to Normally, renal tubules edema alleviates.
The pathological section HE dyeing display of brain, compared with Normal group, model with aplastic anemia group rat brain hippocampus Neuronal cell arrangement disorder.The alimentation composition group of various dose compares with model with aplastic anemia group, and neuronal cell arrangement tends to Neatly.
As can be seen from Figure 23:
Intestinal, the tissue slice of muscle show and have no significant change.
Figure 24 is the kidney segment transmission electron microscope picture of each experimental group of the present invention.As can be seen from Figure 24: with Normal group phase Ratio, model with aplastic anemia group Renal Glomeruli In Rats basement membrane podocytic process large area merges；The alimentation composition group of various dose and model with aplastic anemia Group compares, and Renal Glomeruli In Rats basement membrane podocytic process fusion degree lowers, and arrangement tends to normal.
Result shows, aplastic anemia rat liver,spleen,kidney, brain injury are had and significantly recover to make by embodiment of the present invention alimentation composition With.
2. impact skeletal injury repaired
The impact that aplastic anemia rat bone marrow mesenchymal stem cells is grown by 2.1 embodiment of the present invention alimentation compositions
Each group Proliferation of Bone Mesenchymal Stem Cells capability result is shown in that Figure 25, aplastic anemia group are substantially less than normal group, low dose group with again Barrier group zero difference, middle dosage group, high dose group and aplastic anemia group have notable difference.
The impact on aplastic anemia rat bone marrow mesenchymal stem cells differentiation due of 2.2 embodiment of the present invention
2.2.1 the induction of adipose cell and the expression of lipoblast related gene
As shown in figure 26:
Normal group, aplastic anemia group, high dose group, middle dosage group and low dose group P2 for mesenchymal stem cells MSCs respectively with become fat Cell induction culture fluid carries out inducing culture, and the fat drop time of occurrence of aplastic anemia group induced synthesis the 7th day is early than normal group the 12nd About d.Continuing inducing culture, fat drop significantly increases and merges.After inducing 19 days, the fat drop of fusion is contaminated by oil red O Color is bright redness；Basis of microscopic observation, aplastic anemia group mesenchymal stem cells MSCs lipoblast induction ability is higher than Normal group, after alimentation composition processes aplastic anemia rat, mescenchymal stem cell lipoblast induction ability declines, and along with Alimentation composition dosage increases and declines, and shows that alimentation composition weakens the differentiation of aplastic anemia Rat Mesenchymal Stem Cells lipoblast Inducibility.
For the Comparative nutrition compositions impact on rat bone marrow mesenchymal stem cells lipoblast more objectively, further Have detected lipoblast related gene Pparr mRNA, the expression of Fabp4 mRNA.Result shows, Fabp4 and Pparr The metering intervened of expression and alimentation composition be negative correlation.
Result above show aplastic anemia group compared with Normal group, aplastic anemia Os Mus bone marrow-drived mesenchymal stem divides to adipose cell Change ability strengthens；And after alimentation composition is intervened, aplastic anemia Os Mus bone marrow-drived mesenchymal stem weakens to lipoblast differentiation capability.
The most osteoblastic induction and the expression of osteoblast related gene
As shown in figure 27:
Normal group, aplastic anemia group, high dose group, middle dosage group and low dose group P2 are thin with skeletonization respectively for mesenchymal stem cells MSCs Born of the same parents' induction broth inducing culture, cultivates 5 ~ 7 days continuously, it is seen that black deposit occurs in cell colony center, alizarin red after 14 days Uniformly dyeing color.Aplastic anemia group mesenchymal stem cells MSCs black deposit occurs later, and calcium tuberosity quantity is considerably less than normal group.Nutrition After compositions-treated aplastic anemia rat, mescenchymal stem cell osteoblast differentiation inducibility strengthens, and along with nutrient combination agent Amount increases and increases, and shows that alimentation composition can strengthen aplastic anemia Rat Mesenchymal Stem Cells osteoblast differentiation inducibility.
For the impact on aplastic anemia rat bone marrow mesenchymal stem cells osteoblast process of the Comparative nutrition compositions, examine further Osteoblast related gene mRNA and the expression of Bglap mRNA are surveyed.Result shows, the expression of Alp and Bglap Metering with alimentation composition intervention is proportionate.
Result show aplastic anemia group with normal according to compared with group, aplastic anemia Mus differentiation capability of bone mesenchymal stem cell to osteoblast Weaken；And after alimentation composition is intervened, aplastic anemia Mus differentiation capability of bone mesenchymal stem cell to osteoblast strengthens.
The impact on aplastic anemia rat marrow hematopoietic cell of 2.3 embodiment of the present invention
Bone marrow smear (Figure 28) shows, compared with Normal group, oil droplet, bone occurs in model with aplastic anemia group rat portions bone marrow smear The comprehensive exhaustion of marrow is hyperplasia disorder, and hematopoietic cell reduces, and non-hematopoietic cell increases；Mature erythrocyte is in the same size, without the lightest Dye district；Megalokaryocyte lacks such as, and thrombocytopenia is dispersed in distribution (Figure 28 A)；BMNC counting display, model with aplastic anemia Group is significantly lower than Normal group (Figure 28 B, table 5).Each alimentation composition group compares with model with aplastic anemia group, marrow protection change by Gradually improve, medullary cell showed increased (Figure 28 A)；Each alimentation composition group mononuclearcell number is apparently higher than model with aplastic anemia group (Figure 28 B, table 5).
Table 5
#P < 0.05 aplastic anemia group and normal group；*P < 0.05 alimentation composition group and aplastic anemia group
Result shows, alimentation composition can promote the propagation of aplastic anemia rat marrow hematopoietic cell, and aplastic anemia rat marrow is damaged shape State has notable repair.
In sum, embodiment of the present invention alimentation composition has notable repair to aplastic anemia Rat Skeletal faulted condition.
(7) impact (protein chip) that aplastic anemia rat protein is expressed by alimentation composition
1. the impact of aplastic anemia Rat Mesenchymal Stem Cells protein expression
Aplastic anemia group is (Figure 29-1) compared with normal group, and 17 protein molecular expressions raise, including: RELM beta (RELM-β), beta-Catenin (β-Catenin), MIP-2, CNTF, Growth Hormone R (GHR), beta-NGF (β-NGF), Neuropilin-2 (NRP-2), Leptin (OB), IL-2, IL-12/IL-23 p40, IP-10, Fas Ligand/TNFSF6 (CD178), GFR alpha-2, IFN-gamma, MIP-1 alpha (MIP-1 α), MIP-3 alpha (MIP-3 α), Growth Hormone (GH).
High dose group is (Figure 29-2) compared with normal group, and 2 protein molecular expressions reduce, including RALT/MIG-6 (SG-16), Follostatin-like-1 (FSL1).
High dose group is (Figure 29-3) compared with aplastic anemia group, and 11 protein molecular expressions reduce, including: RELM Beta, RALT/MIG-6, IL-2, TIMP-1, GFR alpha-2, Fractalkine, Follostatin-like-1 (FSL1), TGF-beta1, IFN-gamma, VEGF, beta-NGF.
Result above shows, the alimentation composition 5 protein moleculars to aplastic anemia Rat Mesenchymal Stem Cells high expressed The expression of (RELM-β, β-NGF, IL-2, GFR alpha-2, IFN-gamma) has obvious inhibitory action.Additionally, high dose Group is compared with normal group, and differential protein number significantly reduces, it was demonstrated that the alimentation composition egg to aplastic anemia rat interstital stem cell White expression has certain restitution.
2. the expression impact of aplastic anemia rat bone marrow cell albumen
Aplastic anemia group is (Figure 30-1) compared with normal group, and 12 protein molecular expressions raise, including: VEGF-C, TAL1A, MIP-2, MIF, Adiponectin/Acrp30, MuSK, NGFR, RALT/MIG-6, FGF-BP, TIMP-1, Fas/TNFRSF6, IL-4.8 protein molecular expressions reduce, Fas Ligand/TNFSF6, IL-3, CD106, TNF-alpha, Activin A, GM-CSF, IL-1 alpha, B7-1/CD80.
High dose group is (Figure 30-2) compared with normal group, and 7 protein molecular expressions raise, including Adiponectin/Acrp30, IL-12/IL-23 p40, TAL1A, ICAM-1/CD54, VEGF-C, VEGF, MDC.23 albumen Developed by molecule amount reduces: IL-1 R6/IL-1 R rp2, Follostatin-like-1 (FSL1), Fractalkine, RAGE, L-Selectin/CD62L, PDGF-AA, IL-2, IFN-gamma, GFR alpha-1, Fas Ligand/TNFSF6, Hepassocin, CD106, Leptin (OB), beta-Catenin, IL-3, CNTF, CNTF R alpha, IL-1 alpha, LIX, IL-13, CXCR4, MIP-1 alpha, B7-1/CD80.
High dose group is (Figure 30-3) compared with aplastic anemia group, and 3 protein molecular expressions raise, including: IL-12/IL-23 P40, VEGF, RELM beta.10 protein molecular expressions reduce: Hepassocin, beta-Catenin, MIP-1 Alpha, IFN-gamma, RAGE, NGFR, Follostatin-like-1 (FSL1), IL-2, MuSK, CNTF.
Result above shows, the MuSK protein molecular expression that aplastic anemia group raises has declined in high dose group, obtains Certain recovery, illustrates that alimentation composition has significantly suppression to the expression of the MuSK albumen of aplastic anemia rat bone marrow cell high expressed Effect.
3. the expression impact of aplastic anemia rat liver albumen
Aplastic anemia group is (Figure 31-1) compared with normal group, and IL-6 expression raises, and IL-1 R6/IL-1 R rp2 expression reduces.
High dose group is (Figure 31-2) compared with normal group, and MCP-1, IL-4 expression raises.ADFP, Prolactin R, BDNF expression reduces.
High dose group is (Figure 31-3) compared with aplastic anemia group, and IL-13, Neuropilin-2 expression reduces.

Claims (3)

1. an alimentation composition, it is characterised in that each constituent mass ratio is as follows: lysine 200 ~ 1200, methionine 100 ~ 1600, phenylalanine 150 ~ 1400, threonine 50 ~ 600, tryptophan 50 ~ 400, arginase 12 00 ~ 1500, histidine 100 ~ 1000, glycine 100 ~ 600, aspartic acid 100 ~ 600, leucine 100 ~ 600, isoleucine 100 ~ 600, valine 100 ~ 800, serine 100 ~ 400, glutamine 200 ~ 600, taurine 100 ~ 500, orotic acid 100 ~ 300, nucleotide 200 ~ 1200, Vitamin A 0.2 ~
0.6, vitamin D 0.002 ~ 0.006, vitamin B2 1 ~ 4, vitamin B6 1 ~ 4, vitamin B120.001 ~ 0.006, cigarette Acid 5 ~ 20, folic acid 0.01 ~ 1.2, vitamin C 50 ~ 150, ferrum 2 ~ 10, zinc 2 ~ 10, manganese 2 ~ 10, copper 0.5 ~ 2, selenium 0.01 ~ 0.1, Chromium 0.01 ~ 0.02, potassium 10 ~ 300, calcium 100 ~ 300, magnesium 100 ~ 200, inositol 50 ~ 60, soybean phospholipid 100 ~ 2500.
Alimentation composition the most according to claim 1, it is characterised in that each constituent mass ratio is as follows: lysine 600, first sulfur Propylhomoserin 800, phenylalanine 700, threonine 300, tryptophan 200, arginine 760, histidine 500, glycine 300, Radix Asparagi ammonia Acid 300, leucine 300, isoleucine 300, valine 400, serine 200, glutamine 300, taurine 500, orotic acid 300, nucleotide 400, vitamin A 0.6, vitamin D 0.006, vitamin B22, vitamin B62, vitamin B12 0.004, nicotinic acid 12, folic acid 0.9, vitamin C 100, ferrum 10, zinc 10, manganese 8, copper 2, selenium 0.1, chromium 0.02, potassium 300, calcium 300, magnesium 200, flesh Alcohol 60, soybean phospholipid 1200.
3. an alimentation composition as claimed in claim 1 or 2 is preparing the application treated in aplastic anemia medicine.
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