CN109276711A - Manganese type high stability superoxide dismutase is improving application and product in self-closing disease - Google Patents
Manganese type high stability superoxide dismutase is improving application and product in self-closing disease Download PDFInfo
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- CN109276711A CN109276711A CN201811216980.3A CN201811216980A CN109276711A CN 109276711 A CN109276711 A CN 109276711A CN 201811216980 A CN201811216980 A CN 201811216980A CN 109276711 A CN109276711 A CN 109276711A
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- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/44—Oxidoreductases (1)
- A61K38/446—Superoxide dismutase (1.15)
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y115/00—Oxidoreductases acting on superoxide as acceptor (1.15)
- C12Y115/01—Oxidoreductases acting on superoxide as acceptor (1.15) with NAD or NADP as acceptor (1.15.1)
- C12Y115/01001—Superoxide dismutase (1.15.1.1)
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
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- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
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- Epidemiology (AREA)
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- Organic Chemistry (AREA)
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- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Abstract
Application of the manganese type high stability superoxide dismutase as shown in SEQ ID NO:4 in treatment self-closing disease that the present invention provides sequences.The manganese type high stability superoxide dismutase that the present invention uses can improve the disruption of ecological balance of intestinal flora, adjust the expression of intestines shielding GAP-associated protein GAP, so as to improve the oxidative pressure of enteron aisle and brain, plays alleviation and improve the purpose of self-closing disease behavior, new approach is provided to the treatment of self-closing disease.
Description
Technical field
The invention belongs to medical fields, are related to the improvement and treatment of self-closing disease symptom.
Background technique
Autism spectrum disorder (autism spectrum disorders, ASD) is a kind of pervasive developmental disorders, with
Different degrees of social activity, communication disorders, repeat and mechanical sample behavior is main feature.The disease severity of Different Individual is not
One, often merge one or more of other diseases, including dysnoesia, anxiety and gastrointestinal symptom etc..The cause of disease of ASD is not
Clear, the pathogenic mechanism proposed at present includes[1-8]: 1) gene mutation causes the polymorphism of certain specific genes；2) gene expression
When epigenetic variation；3) environmental pollution；4) pathogenic infection during mother's pregnancy；5) gastrointestinal tract dysfunction；
6) immunoregulatory abnormality；7) connection of enteron aisle brain is unbalance；8) response to oxidative stress；9) mitochondria dysfunction；10) it developed
Neuroinflamation in journey.On the other hand, the disease incidence of ASD also persistently rises, and soars to 2010 from the 1:110 of report in 2006
1:68[9].Currently, so severe situation is one to family and society for ASD still without preferably therapeutic scheme
Great burden.ASD has had aroused widespread concern in all circles of society.
Summary of the invention
The present inventor has found by long-term research, and in self-closing disease morbid state, enteron aisle internal oxidition stress be lost
Weighing apparatus can cause gut barrier injury and intestinal flora disruption of ecological balance, and cause self-closing disease sample behavior.SOD is used as can be single-minded
Property remove superoxide anion antioxidase, from the pathogenesis angle of self-closing disease improve self-closing disease symptom.
Based on this, the present invention proposes the disease for improving self-closing disease using manganese type high stability superoxide dismutase (MS-SOD)
Shape.
First aspect, it is self-closing in preparation improvement that the present invention provides manganese type high stability superoxide dismutase (MS-SOD)
Application in the product of disease symptom, wherein the sequence of the manganese type high stability superoxide dismutase such as SEQ ID NO:4 institute
Show.
Preferably, the product is drug, food or health care product.
It is further preferred that the drug is oral, injection or the administration of stomach-filling approach when the product is drug；More
It is further preferred that the injection is intravenous injection or intraperitoneal injection.
Preferably, the dosage form of the drug is tablet, capsule, powder needle, injection or aerosol.
Preferably, the drug further includes acceptable auxiliary material in one or more pharmaceutics, as diluent, adhesive,
Wetting agent, disintegrating agent, solvent and/or buffer etc..These auxiliary materials in a manner known in the art with manganese type high stability super oxygen
Compound mutase prepares patent medicine, dosage be also skilled person will appreciate that.
It preferably, further include acceptable auxiliary on one or more galenic pharmacies when the product is food or health care product
Material, such as filler, taste improver, solvent and/or buffer.These auxiliary materials are high steady with manganese type in a manner known in the art
Qualitative superoxide dismutase is prepared into product, dosage be also skilled person will appreciate that.
Preferably, the improvement self-closing disease symptom is to alleviate or treat self-closing disease.
In the second aspect, the present invention provides a kind of product for improving self-closing disease symptom, and the product includes that manganese type is high steady
Qualitative superoxide dismutase (MS-SOD), sequence is as shown in SEQ ID NO:4.
Preferably, the product is drug, food or health care product.
According to experimental result it is found that the manganese type high stability superoxide dismutase that the present invention uses can improve enterobacteriaceae
The disruption of ecological balance of group adjusts the expression of intestines shielding GAP-associated protein GAP, so as to improve the oxidative pressure of enteron aisle and brain, play alleviation and
The purpose for improving self-closing disease behavior, provides new approach to the treatment of self-closing disease.
Detailed description of the invention
Figure 1A is that WST method detects mouse intestinal superoxide anion result；It is matched reagent in kit that NADH is indicated in figure；
Figure 1B is the photo that fluorescence probe dihydro second ingot method detects that mouse intestinal is sliced ROS level；
Fig. 2 is that Gut barrie r correlation is combined closely protein mRNA relative expression levels' measurement result；
Fig. 3 is that enteron aisle serotonin, interleukin-6 and endotoxin molecule enter blood situation testing result；
Fig. 4 is the result that fluorescence probe dihydro second ingot method detects that Mice brain tissues after MS-SOD intervenes are sliced ROS level；
Fig. 5 is the result of oxidative stress pathway associated protein expression；
Fig. 6 is stereotypic behavior (burying pearl and Li Mao) observed result；
Fig. 7 A is mouse Social behaviors observed result；
Fig. 7 B is the selection observation of mouse social activity preference；
Fig. 8 is mouse intestinal flora α-multifarious result；
Fig. 9 is mouse intestinal flora β-multifarious result.
Specific embodiment
It will illustrate the present invention by specific embodiment below, but the contents of the present invention are without being limited thereto.Following embodiment
To prove that manganese type high stability superoxide dismutase is improving the effect in self-closing disease symptom.Those skilled in the art should be bright
It is white, when the manganese type high stability superoxide dismutase has above-mentioned effect, product is prepared into as effective component
And related check etc. is carried out to product, it is the ordinary skill in the art.
Unless specific instructions, reagent used in the following embodiment, instrument are this field conventional reagent, instrument, can be with
It is obtained by commercial form；Experimental method used in the following embodiment is also conventional method in that art, those skilled in the art
The experiment can be unambiguously completed according to experiment purpose and obtains corresponding result.
Embodiment 1: the preparation of manganese type high stability superoxide dismutase (MS-SOD)
Genome with Thermophilic Bacteria HB27 (being purchased from U.S. ATCC cell bank, deposit number is ATCC BAA-163) is mould
Plate is expanded to obtain target gene with following primer sequence: forward primer: 5 '-
Agaattcatgccgtacccgttcaagct-3 ' (SEQ ID NO:1) reverse primer: 5 '-
ctgtcgactcaggccttcttgaagaac-3'(SEQ ID NO:2)；With QIAquick Gel Extraction Kit (purchased from raw work bioengineering Shanghai
(share) Co., Ltd) recycling amplified production, with enzyme EcoRI and Sal I double digestion, and it is connected to the matter with same enzyme double digestion
In grain carrier pET28a (+) (purchased from raw work bioengineering Shanghai (share) Co., Ltd), by recombinant plasmid transformed to competence
E. coli bl21 (DE3) (purchased from raw work bioengineering Shanghai (share) Co., Ltd), screens MS-SOD nucleosides by sequencing
The correct bacterial strain of acid sequence, cultivates the bacterial strain, obtains MS-SOD albumen.Wherein, the nucleotide sequence of MS-SOD encoding gene are as follows:
atgccgtacccgttcaagcttcctgacctaggctacccctacgaggccctcgagccccacattgacgc
caagaccatggagatccaccaccagaagcaccacggggcctacgtgacgaacctcaacgccgccctggagaagtac
ccctacctccacggggtggaggtggaggtcctcctgaggcacctcgccgcccttccccaggacatccagaccgccg
tgcgcaacaacgggggcgggcacctgaaccacagcctcttctggaggctcctcacccccgggggggccaaggagcc
cgtgggggagctgaagaaggccattgacgagcagttcgggggcttccaggccctcaaggagaagctcacccaggcg
gccatgggccggttcggctcgggctgggcctggctcgtgaaggaccccttcggcaagctccacgtcctctccaccc
ccaaccaagacaaccccgtgatggagggcttcacccccatcgtgggcattgacgtctgggagcacgcctactacct
caagtaccagaaccgccgggccgattacctccaggccatctggaacgtcctcaactgggacgtggccgaggagttc
ttcaagaaggcctga(SEQ ID NO:3)。
The amino acid sequence of MS-SOD are as follows:
MPYPFKLPDLGYPYEALEPHIDAKTMEIHHQKHHGAYVTNLNAALEKYPYLHGVEVEVLLRHLAALPQ
DIQTAVRNNGGGHLNHSLFWRLLTPGGAKEPVGELKKAIDEQFGGFQALKEKLTQAAMGRFGSGWAWLVKDPFGKL
HVLSTPNQDNPVMEGFTPIVGIDVWEHAYYLKYQNRRADYLQAIWNVLNWDVAEEFFKKA(SEQ ID NO:4)。
Embodiment 2: the building of self-closing disease mouse model
(1) mouse source: adult C57 female mice and male mouse are purchased from Guangdong Province's Experimental Animal Center.It raises to after 8 weeks, it will
30 mouse female mices (20-25g) and male mouse (25-30g) are in periodical illumination (7:00AM~7:00PM), 25 DEG C of constant temperature and constant humidity
The raising a few days is allowed to adapt to environment under the conditions of 55%.Then in female: hero is that 1:1 ratio mates overnight.Morning checks
The female mice of negative bolt is denoted as E1 (embryo first day, embryoic 1), then cage is divided individually to raise.The female rat that will become pregnant is grouped at random.
(2) self-closing disease mouse modeling:
VPA (sodium vedproate) modeling is generally acknowledged one of modeling mode, is usually used in epilepsy and other Neuropsychological disorders
Research and treatment.
VPA model (sodium vedproate model): pregnant mouse is pregnant the 12nd day, injects valproic acid.Valproic acid concentration: 150mg/ml；
Injection volume: 5mg/10g weight.
Control group: pregnant mouse is pregnant the 12nd day, and 0.9% normal saline solution, 50 μ l is injected intraperitoneally.
Embodiment 3: test experiments
1, MS-SOD intervention experiment is grouped:
It is (every to be randomly divided into following each group after wean in three weeks for mouse used in this experiment (newborn mouse that above-mentioned pregnant mouse produces)
Group 10), persistently intervene 4 weeks, collects excrement weekly.Start within 8th week to detect behaviouristics (SuperMaze animal behavior experiment point
Analyse software).After completing test, with being dissected after chloral hydrate anesthesia mouse, each section of intestinal segment tissue and brain tissue are acquired.
A group: normal mouse (NC group): free water；
B group: normal mouse+MS-SOD intervention group (NC+MS-SOD group): MS-SOD solution (30U/10g weight) is drunk；
C group: self-closing disease mouse (ASD group): free water；
D group: self-closing disease mouse+MS-SOD intervention group (ASD+MS-SOD group): MS-SOD solution (30U/10g body is drunk
Weight)；
E group: self-closing disease mouse+MS-SOD intervenes low dose group (AS_L group): drinking MS-SOD solution (20U/10g body
Weight)；
F group: self-closing disease mouse+MS-SOD intervenes high dose group (AS_H group): drinking MS-SOD solution (30U/10g body
Weight).
2, the active oxygen (ROS) of fluorescence probe method detection intestinal tissue and brain tissue
ROS fluorescence probe-dihydro second pyridine (Dihydroethidium, DHE), freely can enter cell through living cells film
It is interior, and aoxidized by intracellular ROS, oxidation second pyridine is formed, oxidation second pyridine can mix in chromosomal DNA, generate red fluorescence.Carefully
Karyon is blue (blue-fluorescence illustrates that dyestuff has entrance as substrate value), according to the generation of red fluorescence in cell, can be sentenced
Disconnected cell ROS content number and variation.
Probe label:
1) according to the difference of cell ROS content, dihydro second pyridine final concentration may be selected the range at 1 μM~100 μM, when incubation
Between may be selected 30min.It carries out being protected from light incubation at 37 DEG C.
2) after being incubated for, with fresh solution cleansing tissue.
Fluorescence micrograph operating method:
It 1), can be directly in fluorescence microscopy microscopic observation to adherent growth cell or living tissue；To suspension growth cell, take
25-50 μ l cell suspension drips on a microscope slides, then covers a coverslip.
2) it under fluorescence microscope, is excited with blue light or green light, observation and shooting cell red emission image, ROS is positive thin
Born of the same parents are dyed to red in entire core area；When with ultraviolet excitation, the unoxidized capable of emitting blue-fluorescence of dihydro second pyridine in endochylema.
3, enteron aisle produces the detection of superoxide anion situation
It is detected using the superoxides detection kit of the green skies Bioisystech Co., Ltd in Shanghai.Kit is former
Reason: using superoxides can restore water-soluble tetrazole -1 (WST-1) generate it is super to detect based on soluble coloring matter
Oxide.
(1) 200 microlitres of superoxides buffers of addition in ELISA Plate detection hole, 10 microlitres of WST-1 liquid, 2 microlitres
Catalase solution；
(2) sample to be tested (enteron stool) handled well is added in detection hole；
(3) 37 DEG C are incubated for 3 minutes；Absorbance is measured at 450nm.
4, intestinal flora bacterial 16 S rDNA sequencing analysis
The bacteria total DNA in fecal sample is extracted according to easily auspicious fecal bacteria total DNA paramagnetic particle method extracts kit specification.
The amplification of the variable region 16S rDNA V4 is carried out using the total DNA of extraction as template.Using general with barcode in this experiment
Primer, wherein V4 upstream primer F-5'-gtgtgccagcmgccgcggtaa-3'(SEQ ID NO:5) and V4 downstream primer R-
5'-ccggactachvgggtwtctaat-3'(SEQ ID NO:6).Using Illumina HiSeq2000 sequencing technologies to 16S
The area rDNA V4 PCR product is sequenced.
Obtained initial data obtains height by processing (removal joint sequence, Sequences of Low Complexity and low quality sequence)
Original base sequence under flux sequencing data after machine analyzes data using QIIME.Bioanalysis mainly includes activity classification list
The generation and principal component analysis (PCoA) of first (OTU) and the analysis of flora characteristic, the analysis of Pseudomonas richness, structure of community diversity
Comparison in difference analysis (LEfSe Online statistics analysis tool) etc. between analysis, flora.
5, the measurement of intestinal tissue and brain tissue GAP-associated protein GAP relative expression quantity
Including intestinal tissue TJP-1, TJP-2, Occludin, CLDN2, CLDN3, CLDN4, CLDN7, CLDN8,
The relative expression quantity of the albumen such as CLDN12, brain tissue Nrf-2, SOD measures.
(1) the TRIzol reagent (Invitrogen) of lml is added in 100mg intestinal tissue, and electronic homogenate lmin is stored at room temperature
5min。
(2) 4 DEG C, 12000g, it is centrifuged 5min.200 μ l chloroforms are pre-applied in 1.5ml EP pipe, it is spare.After centrifugation,
Supernatant is taken, is added in chloroform.After mixing 15s with forced oscillation, it is stored at room temperature 5min.4 DEG C, 12000g, it is centrifuged 15min.Prepare 500
μ l isopropanol is pre-applied in 1.5ml EP pipe, spare.
(3) upper layer colourless aqueous phase (middle white thin layer is albumen, and lower layer's red phenol-chloroform mutually contains DNA) is slowly extracted to add
Enter in isopropanol, turns upside down for several times, be stored at room temperature 10min.4 DEG C, 12000g, it is centrifuged 10min, abandons supernatant, sheet RNA precipitate
In tube bottom.
(4) the ethanol washing precipitating for taking lml 75% to be pre-chilled, 4 DEG C, 7500g, is centrifuged 5min, abandons supernatant, RNA is sunken to pipe
Bottom, drying at room temperature.
(5) RNA is dissolved with suitable pyrocarbonic acid diethyl ester (EDPC) treated water.
(6) spectrophotometer detectable concentration is used, it is quantitative to carry out RNA.
(7) RT-PCR (20 μ l system) is carried out with TaKaRa company kit, using β-actin as internal reference, calculates mRNA
Relative expression quantity, to detect the expression of Gut barrie r related gene.
6, Behaviors survey method
(1) pearl experiment is buried
Mouse 12, for burying pearl experiment (marble burying test).About 5cm thickness corncob padding is spread in mouse cage,
It paves padding surface and is equidistantly uniformly laid with 20 beades (every row 4, totally 5 row).When test, mouse is put into from one jiao, is allowed
It move freely 30min, and records mouse activity.Mouse will use four limbs or nose pushes padding to bury bead, survey
After the completion of examination, statistics mouse buries pearl number, and the anxiety level of mouse can be detected by burying bead number.Evaluation criterion is super
It crosses 1/2 and bead is buried by being denoted as padding covering.
(2) grooming is tested
Grooming is a kind of repetition stereotypic behavior performance that self-closing disease model mice is often shown.Mouse is placed in
Sound insulation is observed in case, prevents external interference, and mouse can move freely in the case.Mouse is first set to adapt to 10 minutes in the case, so
Grooming using camera record mouse in 10 minutes afterwards, it is continuous to record 5 days groomings of mouse.Hair is managed in this experiment
Judgment criteria be mouse arrange with any one hair time.
The experiment of (3) three chests
Three casees social activity test philosophies are that characteristic that is gregarious, having exploration tendency to new object is innately liked based on mouse.And society
Bank of Communications is that reduce be the common symptom of another self-closing disease, this experimental selection social row of three casees social activity testing inspection mouse
For.By the way that after mouse has been familiar with environment, detection mouse is close to the metal cage that the strange mouse of another is housed in experimental box
Time, reflect the sociability of mouse.Experimental box is that a length × width × height is 60cm × 45cm × 25cm chest, is used
Two pieces of blanks are classified as the cell of three same sizes.There is the wicket of 5cm in adjacent room, and mouse can be by wicket at three
Room travels freely.Mouse is shot and recorded in the residence time in each room using camera.Social mouse one day before testing
It is put into experimental box and adapts to 30min.
Social behaviors detection: two metal cages are individually positioned in two rooms in left and right, one of metal cage places one
Strange mouse (strange mouse 1), another metal cage are sky.The gender of strange mouse, age should be consistent with tested mouse, not with
Tested mouse is raised jointly and lived.Tested mouse is placed on intermediate room and start recording later, the record time is similarly
5min, after experiment, record left and right room institute to the time difference for tested mouse social time.
Social preference detection: the strange mouse of another (strange mouse 2) is put into empty metal cage, therefrom by tested mouse
Between room be put into, equally record tested mouse respectively with 2 room residence time of strange mouse 1 and strange mouse.
Experimental result
1, oral supplementation SOD can improve self-closing disease mouse intestinal oxidative pressure it is unbalance
Figure 1A is WST method detection mouse intestinal superoxide anion as a result, abscissa is the time, and ordinate is strong light
Degree, shows the concentration level of superoxide anion.Found by the testing result, with the variation of time, it is normal organize super oxygen yin from
Sub- horizontal stable, and the superoxide anion that self-closing disease group generates significantly increases.When normal group mouse and self-closing disease group mouse feeding
After MS-SOD, superoxide anion concentration is not increased, after illustrating feeding MS-SOD, can adjust the enteron aisle super oxygen of self-closing disease mouse
Anion is to normal level.
Using fluorescence probe-dihydro second pyridine method measurement processing intestinal tissue slice equally it can be found that (Figure 1B), self-closing disease is small
Mouse intestinal tissue red fluorescence intensity is higher than normal group mouse intestinal tissue, illustrates superoxide anion water in self-closing disease mouse intestinal tissue
It is flat to want high.Regardless of being self-closing disease mouse or normal mouse after feeding MS-SOD, intestinal tissue superoxide anion concentration does not all have
Have significant change.Self-closing disease mouse intestinal superoxide anion concentration can be reduced by illustrating feeding MS-SOD, and superoxide anion concentration
Raising play a role in self-closing disease generating process, thus illustrate that MS-SOD will have an effect in the treatment of self-closing disease.
2, oral supplementation SOD can significantly improve the gut barrier damage situations of self-closing disease mouse
Before studies have shown that self-closing disease patient generally entail enteron aisle exception, when inflammation occurs in enteron aisle, enteron aisle can be caused
Cellular swelling, space between cells become larger, and intestines is caused to leak, and cause macromolecular substances that can penetrate intestinal wall and enter in vivo.Serious enteron aisle
Problem may be easier to enter enteron aisle with the breakage and ulcer of enteron aisle, macromolecular substances.It is self-closing as shown in the result of Fig. 2
Disease mouse intestinal barrier correlation tight junction protein TJP-1, TJP-2, Occludin, CLDN2, CLDN3, CLDN4, CLDN7,
The gene expression of CLDN8, CLDN12 etc. are impaired, the expression of Gut barrie r gene can be significantly reversed after MS-SOD intervenes, to change
The symptom of kind self-closing disease mouse (see Fig. 2).
3, the molecules such as intestinal endotoxin, interleukin-6 and serotonin enter blood situation
Self-closing disease mouse is impaired due to Gut barrie r, and macromolecular can enter blood by impaired enteron aisle, can pass through inspection
After surveying the understanding self-closing disease generation of these molecules, the impaired situation of mouse intestinal barrier.The experimental results showed that five in self-closing disease mouse
Hydroxytryptamine (5-HT), interleukin-6 (IL-6) and endotoxin (LPS) equal size significantly increase, and after MS-SOD intervenes, this
A little indexs are remarkably decreased, and illustrate that Gut barrie r is repaired (see Fig. 3), so as to improve the self-closing disease behavior of mouse.
4, Mice brain tissues slice ROS is horizontal after MS-SOD intervenes
From fig. 4, it can be seen that after MS-SOD intervenes, self-closing disease mouse brain oxidative pressure, brain barrier and brain inflammation shape
State improves.
Using fluorescence probe-dihydro second pyridine method measurement processing brain tissue it can be found that self-closing disease mouse (ASD) brain tissue is red
Color fluorescence intensity ratio normally organizes Mice brain tissues height, illustrates that superoxide anion level wants high in self-closing disease Mice brain tissues.And
After feeding MS-SOD, brain tissue superoxide anion level is all remarkably decreased either self-closing disease mouse or normal mouse
(see Fig. 4).
Nrf-2 is the important albumen of oxidative stress access, and the activation of Nrf-2 can star a variety of protective genes in downstream
Expression, such as the expression of itself SOD antioxidase improve total antioxidant capacity (T-AOC), with protect brain tissue not by super oxygen from
It is damaged by base.By experimental result it is found that the expression apparent increase of Nrf-2 is (see figure in the self-closing disease mouse of MS-SOD feeding
5), illustrate that MS-SOD has therapeutic effect for self-closing disease.
5, stereotypic behavior experimental result
It buries pearl behavior and grooming is a kind of repetition stereotypic behavior performance that self-closing disease model mice is often shown.
Experiment shows that self-closing disease group mouse all has a significant growth compared with normal mouse burying pearl quantity and Li Mao time, and passes through feeding MS-
After SOD, both the self-closing disease sample behaviors of self-closing disease mouse decline 23% and 33% (Fig. 6) respectively.Illustrate that MS-SOD can be reduced
The anxiety symptom of self-closing disease mouse reduces the appearance of its self-closing disease behavior.
6, mouse Social behaviors observed result
Mouse is social animal, there is curious explore to be inclined to strange things.Fig. 7 A is indicated and familiar and strange mouse
Social time, Fig. 7 B indicate in Fig. 7 A the strange time for subtracting with the social time of strange mouse with being familiar with mouse, and negative value indicates
Experiment mice is shorter than with the social time of strange mouse with the social time for being familiar with mouse, this is different with normal mouse
's.It significantly reduces the experimental results showed that self-closing disease mouse Social behaviors more normally organize mouse, is also tended in social preference selection
Contacted with more familiar mouse, and after feeding SOD, Social behaviors are restored, and be relatively happy to it is strange small
Mouse carries out contact ac (see Fig. 7 A, 7B).
7, the intestinal flora experimental result of mouse
Macro gene order-checking is carried out to mouse intestinal flora, by the analysis to chao index, shannon index etc., certainly
It closes disease mouse and normal mouse is shown in Table and reveals significant difference, and various dose MS-SOD (low dosage, high dose, that is, E group and F group
Mouse) it can make flora α-diversity of self-closing disease mouse that the trend restored be presented (see Fig. 8).
Macro gene order-checking is carried out to mouse intestinal flora, three-dimensional PCoA figure is shown, self-closing disease mouse and normal mouse intestines
Road flora shows apparent differentiation trend, and the MS-SOD of various dose can be such that self-closing disease mouse intestinal flora is restored to just
Normal state (see Fig. 9).
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signaling:A mosaic of malformations.Seminars in Perinatology,2015.39(1):p.36-
43.
[2].Balan,S.,et al.,Exon resequencing of H3K9methyltransferase
complex genes,EHMT1,EHTM2and WIZ,in Japanese autism subjects.Mol Autism,
2014.5(1):p.49.
[3].Volk,H.E.,et al.,Autism Spectrum Disorder.Epidemiology,2014.25
(1):p.44-47.
[4].Maternal Infection during Pregnancy and Autism Spectrum
Disorders.
[5].Pediatric Neurology.
[6].Decreased Levels of EGF in Plasma of Children with Autism
Spectrum Disorder.
[7].Thioredoxin:A novel,independent diagnosis marker in children with
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[8].Dachtler,J.,et al.,Deletion ofα-neurexin II results in autism-
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Sequence table
<110>Hangzhou Rui Dao Pharmaceutical Technology Co., Ltd
<120>manganese type high stability superoxide dismutase is improving application and product in self-closing disease
<130> DP1F180596BY
<160> 6
<170> SIPOSequenceListing 1.0
<210> 1
<211> 27
<212> DNA
<213>artificial sequence (Artificial Sequence)
<400> 1
agaattcatg ccgtacccgt tcaagct 27
<210> 2
<211> 27
<212> DNA
<213>artificial sequence (Artificial Sequence)
<400> 2
ctgtcgactc aggccttctt gaagaac 27
<210> 3
<211> 615
<212> DNA
<213>Thermophilic Bacteria (Thermus thermophilus)
<400> 3
atgccgtacc cgttcaagct tcctgaccta ggctacccct acgaggccct cgagccccac 60
attgacgcca agaccatgga gatccaccac cagaagcacc acggggccta cgtgacgaac 120
ctcaacgccg ccctggagaa gtacccctac ctccacgggg tggaggtgga ggtcctcctg 180
aggcacctcg ccgcccttcc ccaggacatc cagaccgccg tgcgcaacaa cgggggcggg 240
cacctgaacc acagcctctt ctggaggctc ctcacccccg ggggggccaa ggagcccgtg 300
ggggagctga agaaggccat tgacgagcag ttcgggggct tccaggccct caaggagaag 360
ctcacccagg cggccatggg ccggttcggc tcgggctggg cctggctcgt gaaggacccc 420
ttcggcaagc tccacgtcct ctccaccccc aaccaagaca accccgtgat ggagggcttc 480
acccccatcg tgggcattga cgtctgggag cacgcctact acctcaagta ccagaaccgc 540
cgggccgatt acctccaggc catctggaac gtcctcaact gggacgtggc cgaggagttc 600
ttcaagaagg cctga 615
<210> 4
<211> 204
<212> PRT
<213>Thermophilic Bacteria (Thermus thermophilus)
<400> 4
Met Pro Tyr Pro Phe Lys Leu Pro Asp Leu Gly Tyr Pro Tyr Glu Ala
1 5 10 15
Leu Glu Pro His Ile Asp Ala Lys Thr Met Glu Ile His His Gln Lys
20 25 30
His His Gly Ala Tyr Val Thr Asn Leu Asn Ala Ala Leu Glu Lys Tyr
35 40 45
Pro Tyr Leu His Gly Val Glu Val Glu Val Leu Leu Arg His Leu Ala
50 55 60
Ala Leu Pro Gln Asp Ile Gln Thr Ala Val Arg Asn Asn Gly Gly Gly
65 70 75 80
His Leu Asn His Ser Leu Phe Trp Arg Leu Leu Thr Pro Gly Gly Ala
85 90 95
Lys Glu Pro Val Gly Glu Leu Lys Lys Ala Ile Asp Glu Gln Phe Gly
100 105 110
Gly Phe Gln Ala Leu Lys Glu Lys Leu Thr Gln Ala Ala Met Gly Arg
115 120 125
Phe Gly Ser Gly Trp Ala Trp Leu Val Lys Asp Pro Phe Gly Lys Leu
130 135 140
His Val Leu Ser Thr Pro Asn Gln Asp Asn Pro Val Met Glu Gly Phe
145 150 155 160
Thr Pro Ile Val Gly Ile Asp Val Trp Glu His Ala Tyr Tyr Leu Lys
165 170 175
Tyr Gln Asn Arg Arg Ala Asp Tyr Leu Gln Ala Ile Trp Asn Val Leu
180 185 190
Asn Trp Asp Val Ala Glu Glu Phe Phe Lys Lys Ala
195 200
<210> 5
<211> 21
<212> DNA
<213>artificial sequence (Artificial Sequence)
<400> 5
gtgtgccagc mgccgcggta a 21
<210> 6
<211> 22
<212> DNA
<213>artificial sequence (Artificial Sequence)
<400> 6
ccggactach vgggtwtcta at 22
Claims (10)
1. application of the manganese type high stability superoxide dismutase in the product that preparation improves self-closing disease symptom, wherein described
The sequence of manganese type high stability superoxide dismutase is as shown in SEQ ID NO:4.
2. application according to claim 1, wherein the product is drug, food or health care product.
3. application according to claim 2, wherein when the product is drug, the drug is oral, injection or fills
The administration of stomach approach.
4. application according to claim 3, wherein the injection is intravenous injection or intraperitoneal injection.
5. application according to claim 3, wherein the dosage form of the drug be tablet, capsule, powder needle, injection or
Aerosol.
6. application according to claim 5, wherein the drug further includes acceptable auxiliary in one or more pharmaceutics
Material；Preferably, the auxiliary material is diluent, adhesive, wetting agent, disintegrating agent, solvent and/or buffer.
7. application according to claim 2, wherein further include a kind of or more when the product is food or health care product
Acceptable auxiliary material on kind galenic pharmacy；Preferably, the auxiliary material is filler, taste improver, solvent and/or buffer.
8. described in any item applications according to claim 1~7, wherein the improvement self-closing disease symptom is to alleviate or treat certainly
Close disease.
It include manganese type high stability superoxide dismutase, sequence such as SEQ ID NO:4 9. improving the product of self-closing disease symptom
It is shown.
10. product according to claim 9, wherein the product is drug, food or health care product.
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| CN112891521A (en) * | 2019-12-04 | 2021-06-04 | 凯睿恒济生物医药(杭州)有限公司 | Application of manganese type high-stability superoxide dismutase in preventing or treating cerebral apoplexy |
| WO2021110049A1 (en) * | 2019-12-04 | 2021-06-10 | 凯睿恒济生物医药(杭州)有限公司 | Application of manganese-type high-stability superoxide dismutase in prevention or treatment of stroke |
| US20220168400A1 (en) * | 2019-12-04 | 2022-06-02 | Carry Health Biopharmaceuticals (Hangzhou) Co., Ltd. | Use of a manganese superoxide dismutase with high stability in the prevention or treatment of cerebral stroke |
| JP2022530600A (en) * | 2019-12-04 | 2022-06-30 | キャリー ヘルス バイオファーマスーティカルズ （ハンジョウ） カンパニー リミテッド | Use of highly stable manganese-type superoxide dismutase in the prevention or treatment of stroke |
| JP7255056B2 (en) | 2019-12-04 | 2023-04-11 | キャリー ヘルス バイオファーマスーティカルズ （ハンジョウ） カンパニー リミテッド | Use of a highly stable manganese-type superoxide dismutase in the prevention or treatment of stroke |
| CN112725295A (en) * | 2020-05-27 | 2021-04-30 | 浙江工业大学 | Recombinant superoxide dismutase and coding gene and preparation method thereof |
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