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CN104043109A - Use of neuronal axon guidance factor Netrin 1 in preparation of cornea damage restoration-promoting product - Google Patents

Use of neuronal axon guidance factor Netrin 1 in preparation of cornea damage restoration-promoting product Download PDF

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CN104043109A
CN104043109A CN201410086629.2A CN201410086629A CN104043109A CN 104043109 A CN104043109 A CN 104043109A CN 201410086629 A CN201410086629 A CN 201410086629A CN 104043109 A CN104043109 A CN 104043109A
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netrin1
cell
corneal
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mice
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CN104043109B (en
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周庆军
张阳阳
谢立信
陈鹏
高华
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SPECIALTY OF OPHTHALMOLOGY RESEARCH INSTITUTE SHANDONG PROV
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SPECIALTY OF OPHTHALMOLOGY RESEARCH INSTITUTE SHANDONG PROV
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Abstract

The invention provides a use of a neuronal axon guidance factor Netrin 1 in preparation of a cornea damage restoration-promoting product. The use comprises that the neuronal axon guidance factor Netrin 1 is used for preparation of a drug and a preparation for inhibiting corneal epithelium damage-caused inflammatory response and promoting corneal epithelium restoration. The Netrin 1 can promote corneal limbal stem cell proliferation and migration capability, can inhibit inflammatory response caused by corneal epithelium damage of normal mice and diabetic mice, can promote corneal epithelium restoration of normal mice and diabetic mice, and can be used for ocular surface cornea and conjunctiva epithelial stem cell culture, diabetic keratopathy treatment and neuropathic keratitis treatment.

Description

The neural axon guiding factor promotes corneal injury to repair the application in goods in preparation
Technical field
The invention belongs to treatment of eye disorders medicine preparing technical field, be specifically related to a kind of neural axon guiding factor and preparing the application promoting in corneal injury reparation goods, the neural axon guiding factor affects the application in cornea reparation disease at treatment diabetes keratopathy, neurotrophic keratitis etc.
Background technology
Transparent and the function of cornea complete depends on the normal of the structure of each layer tissue of cornea and metabolism, and be positioned at outermost corneal epithelial tissue, undoubtedly this played considerable effect.Corneal epithelium is the physical barriers that the extraneous virulence factor of defence is invaded, and its integrity maintains and depends on epithelial iuntercellular, and cell was connected with grappling and epithelial continuous self renewal with tight connection the between basement membrane.
Corneal epithelium is impaired affects intercellular connection, causes that the permeability of cell membrane and selectivity change, thereby affects its barrier function, and the infringement that causes cornea to be subject to extraneous virulence factor causes inflammation and causes the corneal opacity, even causes blind.Re-epithelialization after corneal injury is a process the most basic of injury repairing, and epithelization can be rebuild rapidly epithelium barrier, and this is extremely important for keeping structural integrity and the normal function of cornea.Various physical damnifications, chemical damage, mechanical damage, pathogenic microorganism, endocrine and immunity factor all can cause corneal epithelial wound.As diabetic keratopathy, there are some researches show: constitutional keratopathy may appear in the diabetics of 47%-64%, its Clinical symptoms main manifestations is the symptoms such as corneal sensitivity decline, associated with epithelial healing delay, neurotrophic corneal ulcer.Diabetics may occur that after carrying out cataract or operation on retina regeneration of corneal epithelium postpones, and even occurs repeatedly stripping off phenomenon.
Agglutination after corneal epithelial wound is very complicated, there are many factors to participate in regulating: 1. to come from the continuous propagation of basal cell and limbal stem cell, rapid re-epithelialization, the reconstruction epithelium barrier of the epithelial self renewal of differentiation after to epithelial cell damage, thereby keep structural integrity and the normal function of cornea extremely important; 2. in corneal epithelium agglutination, by different extracellular matrix molecules and the cell surface receptor of cellular expression, the cell adhesion being mediated by cytoskeleton and motion aspect are played to key effect; 3. many somatomedin are as EGF, KGF, HGF, TGF, PDGF etc.) pass through autocrine or/and paracrine approach participates in regulating propagation and the migration of corneal epithelial cell, maintain the normal of cornea structure and function; 4. the cell adhesion molecule (as integrin) that is positioned at cell surface plays a role with the form of receptor-ligand, in corneal wound healing, plays an important role; 5. in addition, some other factor is as also barrier function and wound healing of participation adjusting corneal epithelial cell such as nerve factors.
No matter can the corneal epithelial defect which kind of reason causes, intactly repair rapidly, be the barrier function that recovers corneal epithelial cell, the key that promotes wound healing, maintenance good vision.Therefore fully understand the adjusting factor of corneal epithelial cell barrier function and wound healing, to treating clinically corneal epithelial cell barrier function obstacle and promoting that incompatible the saying of wound healing is very important.
Summary of the invention
The object of this invention is to provide a kind of neural axon guiding factor promotes corneal injury to repair the application in goods in preparation, utilize the neural axon guiding factor to prepare to suppress after corneal epithelial wound inflammatory reaction and promote medicine or the preparation that corneal epithelium is repaired, thereby making up the deficiencies in the prior art.
Inventor finds, the neural axon guiding factor Netrin1(that adds doses in the culture medium KSFM of mouse cornea epithelial cell line TKE2 is 10-20ng/ml for example) can effectively promote limbal stem cell propagation.In the high sugared guidance model of TKE2 cell, the Netrin1(that adds doses in culture medium is 10-100ng/ml for example) can effectively promote limbal stem cell migration.Meanwhile, in the diabetic mice of normal C57 mice and STZ induction, set up corneal epithelium and strike off after damage model, the Netrin1(of subconjunctival injection doses is 50ng for example), can effectively promote corneal epithelial wound reparation, inflammation-inhibiting reaction; Thereby facilitated the present invention.
First the present invention provides a kind of new purposes of Netrin1, in the application for the preparation of promoting in corneal epithelial wound reparation goods or inhibition Corneal inflammation reaction goods.
Described goods are eye drop, wherein include the neural axon guiding factor of pharmacology valid density;
Described goods can also be injection;
Wherein pharmacology valid density, is 10-100ng/ml, preferably 50ng/ml;
The described neural axon guiding factor, its aminoacid sequence is SEQ ID NO:1;
In order to improve the neural axon guiding factor inflammation and the effect promoting in corneal epithelial wound reparation after treatment corneal epithelial wound, inventor transforms the aminoacid sequence of the neural axon factor, and improved aminoacid sequence is SEQ ID NO:2;
The present invention finds that Netrin1 can not only promote limbal stem cell propagation and transfer ability, can also suppress the inflammatory reaction after normal mouse and diabetic mice corneal epithelial wound, promote the injury repairing of the corneal epithelium of normal mouse and diabetic mice, can be used for cultivation, the treatment of diabetes keratopathy, the treatment of nerve keratitis of eye table Cornea and conjunctiva epithelial stem cell.
Accompanying drawing explanation
Fig. 1: the impact of the Netrin1 that adds variable concentrations in the culture medium of TKE2 on cell clone multiplication capacity, the Netrin1 that adds 10ng/ml in culture fluid can effectively promote the propagation of TKE2 cell clone.
Fig. 2: add the impact of the Netrin1 on cell migration ability of variable concentrations under the high sugared environment of TKE2 in the culture medium of damage model, the Netrin1 that adds 50ng/ml or 100ng/ml in culture fluid can effectively promote the transfer ability of TKE2 cell.
The impact that Fig. 3: Netrin1 repairs normal mouse cornea epithelial damage, subconjunctival injection 50ngNetrin1 can effectively promote the injury repairing of corneal epithelium.
The impact that Fig. 4: Netrin1 repairs the diabetic mice corneal epithelial wound of STZ induction, subconjunctival injection 50ng Netrin1 can effectively promote the injury repairing of diabetic mice corneal epithelium.
The impact of Fig. 5: Netrin1 on normal mouse and STZ induction diabetic mice corneal injury inflammatory reaction, subconjunctival injection 50ng Netrin1 can effectively reduce the infiltration of inflammatory cell in the corneal epithelium of mice damage.
The specific embodiment
The neural axon guiding factor (Netrin1) belongs to Netrin family member, is the solubility nervous process guiding factor of finding the earliest.Netrin1 carries out gene analysis and is found sudden change nematicide defect UNC-6 gene, and the called after axon guidance factor, now claims the neural axon guiding factor.Netrin1 is a kind of emiocytosis type soluble protein of high conservative, and molecular weight is 70~80kD approximately, and its aminoacid sequence is SEQ ID NO:1.Netrin1 just can regulate and control renal tubular epithelial inflammation and apoptosis for acute injury of kidney model at present; In the growth of cell migration, tumor cell survival ability, embryonic cell, obtained application.
Below in conjunction with embodiment, the present invention is described in detail:
Embodiment 1: add the impact of variable concentrations Netrin1 on TKE2 cell proliferation and transfer ability
1. application KSFM(Keratinocyte-SFM adds BPE (50 μ g/mL) and rEGF (5ng/mL): GIBCO, 10724-011) culture fluid cellar culture TKE2 cell, by 4 * 10 4individual cell is seeded in 60mm culture dish, respectively to the Netrin1 (0,5,10 and 20ng/ml) that adds variable concentrations in each ware, then under the condition of 5%CO2 and 37 ℃, cultivate, within every 3 days, more renew culture medium, add the Netrin1 factor of above-mentioned concentration simultaneously, cultivate and utilize cell counter to carry out cell counting after 6 days, cell quantity statistics is shown in Fig. 1.As shown in Figure 1, not adding the TKE2 cell quantity that Netrin1 cultivates is 2.7 * 10 5, and the TKE2 cell number that interpolation 10 and 20ng/ml Netrin1 culture fluid are cultivated is respectively 4.4 * 10 5, 4.7 * 10 5, the TKE2 cell quantity of cultivating compared with blank has increased 1.5-2 doubly (* P<0.01).Thus, proved that the Netrin1 that adds 10-20ng/ml can effectively promote the propagation of TKE2 cell.
2. application KSFM(Keratinocyte-SFM adds BPE (50 μ g/mL) and rEGF (5ng/mL): GIBCO, 10724-011) culture fluid cellar culture TKE2 cell, by 1 * 10 5individual cell is seeded in six orifice plates, selects a hole in contrast, and a hole adds the mannitol 25 μ l/ml of 1mol/L, and all the other 4 holes add respectively the glucose 25 μ l/ml of 1mol/L, then in 5%CO 2with under the condition of 37 ℃, cultivate, after 2 days, in six orifice plate expert cell scratch tests, microscope 10x takes a picture in the hole of backward interpolation glucose and adds Netrin1(0,10,50,100ng/ml), microphotograph after 24h, observes cut position TKE2 cell and sees Fig. 2 to the situation of central authorities' migration.As shown in Figure 2, after matched group TKE2 cell cut 24h, cell migration area accounts for the damaged area 60% of cut, and the cell migration area of interpolation 1mol/L glucose group accounts for 20%, and visible high sugared environmental energy effectively suppresses the migration of TKE2 cell; And the TKE2 cell migration area that adds respectively 10ng/ml, 50ng/ml and 100ng/ml Netrin1 cultivation is about respectively 50%, 70% and 60%, Netrin1 can effectively reverse the inhibitory action of high concentration glucose on cell migration as can be seen here, promotes TKE2 cell migration.
Embodiment 2: the impact of exogenous interpolation Netrin1 corneal epithelial injury repairing
1.Netrin1 the impact that normal mouse cornea epithelial damage is repaired.
12 C57BL/6 mices (6-8 age in week) are divided into matched group and experimental group at random, use 3mm trepan and epithelium scraper to strike off the epithelium in the mice cornea of right eye 3mm of central authorities region, while control group mice conjunctiva of right eye hemostasis 7 μ l PBS, experimental mice conjunctiva of right eye hemostasis 50ng Netrin1 (being dissolved in 7 μ l PBS), after modeling 0,24,48 and 72h use respectively under fluorescein sodium dyeing and slit lamp and take a picture, the situation of observing the epithelial damage reparation of respectively organizing mice, Fig. 3 is shown in by representative slit lamp observation photo.As shown in Figure 3, normal mouse 24h, the 48h of subconjunctival injection PBS and the epithelial defect rate of 72h are respectively 0.83,0.65 and 0.32; Normal mouse 24h, the 48h of subconjunctival injection 50ng Netrin1 and the epithelial defect rate of 72h are respectively 0.83,0.54 and 0.16.As can be seen here, Netrin1 can effectively promote the injury repairing of mouse cornea epithelium.
The impact that 2.Netrin1 repairs the diabetic mice corneal epithelial wound of STZ induction
The C57BL/6 diabetic mice of 12 STZ inductions is divided into matched group and experimental group at random, use 3mm trepan and epithelium scraper to strike off the epithelium in the mice cornea of right eye 3mm of central authorities region, while control group mice conjunctiva of right eye hemostasis 7 μ l PBS, experimental mice conjunctiva of right eye hemostasis 50ngNetrin1 (being dissolved in 7 μ l PBS), after modeling 0,24,48 and 72h use respectively under fluorescein sodium dyeing and slit lamp and take a picture, the situation of observing the epithelial damage reparation of respectively organizing mice, Fig. 4 is shown in by representative slit lamp observation photo.As shown in Figure 4, diabetic mice 24h, the 48h of subconjunctival injection PBS and the epithelial defect rate of 72h are respectively 0.83,0.70 and 0.46; Diabetic mice 24h, the 48h of subconjunctival injection 50ng Netrin1 and the epithelial defect rate of 72h are respectively 0.74,0.33 and 0.07.As can be seen here, Netrin1 can effectively promote the injury repairing of diabetic mice corneal epithelium.
3.Netrin1 on the diabetic mice corneal epithelial wound of normal and STZ induction after the impact of inflammatory reaction
The eyeball of mouse of getting C57BL/6 diabetic mice that normal and STZ induce 48h and 72h after above-mentioned processing, is placed in OCT and makes freezing sample.With freezing microtome, make 8 μ m thickness frozen sections, by immunofluorescence method, detect the impact of Netrin1 centering granulocyte labelling (Ly6G).As shown in Figure 5, Netrin1 can obviously reduce the infiltration of the C57BL/6 diabetic mice corneal epithelial wound position neutrophilic granulocyte of normal and STZ induction, suppresses the inflammatory reaction after corneal epithelial wound.
The character transformation of embodiment 3:Netrin1
In order to improve the neural axon guiding factor inflammation and the effect promoting in corneal epithelial wound reparation after treatment corneal epithelial wound, aminoacid sequence to neural axon guiding factor Netrin1 is transformed, Netrin1 0th~21 amino acids are sheared, retained from 22~604 amino acids.The transformation body Human Netrin1 (Val22Ala604) that obtains Netrin1, its aminoacid sequence is SEQ IDNO:2.
Concrete adaptation step is as follows:
Take people Netrin1cDNA as template, by totally 583 the amino acid whose coded sequences of 22-604 position (Netrin1-truncate) in pcr amplification Netrin1 full-length proteins sequence, Netrin1-truncate primer sequence is AGACACGAATTCGTGCGCGGCGGGCCCGGGCTCA, AGACTCGAGGGCCTTCTTGCACTTGCC, is respectively manually-injected EcoR I and Xho I restriction enzyme site at the two ends of primer sequence.With EcoRI and XhoI difference double digestion empty carrier pGEX-4T-1 and pcr amplification product, Netrin1-truncate is connected with pGEX-4T-1 carrier with correct frame, obtain GST and Netrin1-truncate fusion protein expression plasmid pGEX-Netrin1-truncate.The recombinant expression carrier obtaining is applied respectively the method for enzyme action and order-checking and is identified; result shows that the size of endonuclease bamhi is correct; and sequencing result demonstration conforms to completely with reference sequences, and known according to sequencing result and reading frame position, the aminoacid sequence after translation is SEQ ID NO:2;
The gst fusion protein expression plasmid of structure is transformed in escherichia coli BL-21, picking monoclonal inoculation in 3ml LB culture fluid, 37 ℃, 250rpm shaken overnight; Again by 3 ‰ inoculum concentrations switchings, 37 ℃ be cultured to bacterium liquid A value and reach 0.6~0.8 after, adding IPTG is 500 mol/L to final concentration, continuation shaken cultivation 2h; Then 4 ℃, the centrifugal 30min collection of 3000rpm thalline, add the resuspended thalline of bacterial lysate in the ratios of 40: 1, ultrasonication antibacterial, centrifugal collection supernatant; Application Glutathione Sepharose4B purification column (purchased from Amersham Biosciences company) purification GST-Netrin1-truncate fusion rotein; After GST-Netrin1-truncate fusion rotein is cut away with Thrombin thrombin, after a purification column, collect and penetrated liquid, then by dialysis and lyophilizing, obtain Netrin1-truncated protein, then use PBS buffer to be again dissolved as the liquid storage of 100ng/ul, frozen standby in-80 ℃.And verify improved Netrin1(Netrin1-truncated protein) in treatment limbal stem cell propagation with promote the effect of corneal epithelial wound in repairing.
One, the impact of Netrin1-truncated protein on TKE2 cell
The culture fluid of application TKE2 cell (Keratinocyte-SFM adds BPE (50 μ g/mL) and rEGF (5ng/mL): GIBCO, 10724-011) cellar culture TKE2 cell, by 4 * 10 4individual cell is seeded in 60mm culture dish, adds Netrin1 (10ng/ml) and Netrin1-truncate (10ng/ml) respectively, then in 5%CO in two wares 2with under the condition of 37 ℃, cultivate, within every 3 days, more renew culture medium, add Netrin1 and the Netrin1-truncate factor of above-mentioned concentration simultaneously, cultivating utilized cell counter to carry out cell counting after 6 days, the demonstration of cell quantity statistics, the TKE2 cell number that interpolation 10 and 20ng/ml Netrin1 culture fluid are cultivated is respectively 4.5 * 10 5, 4.7 * 10 5, and the TKE2 cell number that interpolation 10 and 20ng/mlNetrin1-truncate culture fluid are cultivated is respectively 5.6 * 10 5, 6.8 * 10 5, the TKE2 cell quantity of cultivating compared with blank has increased 1-1.5 doubly (* P<0.05).As can be seen here, compare with adding the Netrin1 factor, add the propagation that the Netrin1-truncate factor can more effectively promote TKE2 cell.
2. application KSFM(Keratinocyte-SFM adds BPE (50 μ g/mL) and rEGF (5ng/mL): GIBCO, 10724-011) culture fluid cellar culture TKE2 cell, by 1 * 10 5individual cell is seeded in six orifice plates, and each hole adds the glucose 25 μ l/ml of 1mol/L, then in 5%CO 2with under the condition of 37 ℃, cultivate, row cell scratch test after 2 days, microscope 10x takes a picture in backward hole and adds respectively Netrin1(10,50,100ng/ml) and the Netrin1-truncate factor (10,50,100ng/ml), microphotograph after 24h, observes cut position TKE2 cell to the situation of central authorities' migration.After the TKE2 cell cut 24h of interpolation Netrin1, cell migration area accounts for respectively the damaged area 50%, 70% and 60% of cut, and after the TKE2 cell cut 24h of the interpolation Netrin1-truncate factor, cell migration area accounts for respectively the damaged area 60%, 85% and 60% of cut.The Netrin1-truncate factor promotes that the effect of TKE2 cell migration is more obvious as can be seen here.
Two: the impact of exogenous interpolation NETRIN1 corneal epithelial injury repairing
1.Netrin1 the impact that normal mouse cornea epithelial damage is repaired
12 C57BL/6 mices (6-8 age in week) are divided into matched group and experimental group at random, use 3mm trepan and epithelium scraper to strike off the epithelium in the mice cornea of right eye 3mm of central authorities region, while control group mice conjunctiva of right eye hemostasis 50ng Netrin1 (being dissolved in 7ul PBS), experimental mice conjunctiva of right eye hemostasis 50ng Netrin1-truncate (being dissolved in 7ul PBS), after modeling 0, 24, 48 and 72h use respectively under fluorescein sodium dyeing and slit lamp and take a picture, observe the situation of the epithelial damage reparation of respectively organizing mice, the normal mouse 24h of subconjunctival injection 50ng Netrin1, the epithelial defect rate of 48h and 72h is respectively 0.83, 0.53 and 0.17, normal mouse 24h, the 48h of the subconjunctival injection 50ng Netrin1-truncate factor and the epithelial defect rate of 72h are respectively 0.76,0.33 and 0.08.Result shows the injury repairing of the more effective promotion corneal epithelium of subconjunctival injection 50ngNetrin1-truncate factor energy.
The impact that 2.Netrin1 repairs the diabetic mice corneal epithelial wound of STZ induction
The C57BL/6 diabetic mice of 12 STZ inductions is divided into matched group and experimental group at random, use 3mm trepan and epithelium scraper to strike off the epithelium in the mice cornea of right eye 3mm of central authorities region, while control group mice conjunctiva of right eye hemostasis 50ng Netrin1 (being dissolved in 7ul PBS), experimental mice conjunctiva of right eye hemostasis 50ng Netrin1-truncate (being dissolved in 7ul PBS), after modeling 0, 24, 48 and 72h use respectively under fluorescein sodium dyeing and slit lamp and take a picture, observe the situation of the epithelial damage reparation of respectively organizing mice, the diabetic mice 24h of subconjunctival injection 50ng Netrin1, the epithelial defect rate of 48h and 72h is respectively 0.75, 0.32 and 0.07, diabetic mice 24h, the 48h of the subconjunctival injection 50ng Netrin1-truncate factor and the epithelial defect rate of 72h are respectively 0.68,0.26 and 0.04.Result shows the injury repairing of the more effective promotion diabetic mice corneal epithelium of subconjunctival injection 50ng Netrin1-truncate factor energy.

Claims (7)

1. a purposes for the neural axon guiding factor, is characterized in that, is in the application for the preparation of promoting in corneal epithelial wound reparation goods or inhibition Corneal inflammation reaction goods.
2. purposes as claimed in claim 1, is characterized in that the described neural axon guiding factor, and its aminoacid sequence is SEQ ID NO:1.
3. purposes as claimed in claim 1, is characterized in that the aminoacid sequence of the described neural axon guiding factor is SEQ ID NO:2.
4. purposes as claimed in claim 1, is characterized in that described goods are eye drop or the injection that includes the neural axon guiding factor of pharmacology valid density.
5. purposes as claimed in claim 4, is characterized in that described pharmacology valid density is 10-100ng/ml.
6. purposes as claimed in claim 4, is characterized in that described pharmacology valid density is 50ng/ml.
7. the goods for promoting that corneal epithelial wound is repaired, is characterized in that, described goods are the medicine that includes the neural axon guiding factor of pharmacology valid density.
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CN111544658A (en) * 2020-06-24 2020-08-18 中国人民解放军陆军军医大学 Cardiovascular implant for regulating immune response and promoting intimal regeneration and preparation method thereof
CN113827548A (en) * 2021-06-16 2021-12-24 温州医科大学 A kind of magnetic graphene nanocomposite gel for targeting and inhibiting corneal pathology and its preparation method, application and treatment method
CN115887614A (en) * 2022-10-21 2023-04-04 中国人民解放军海军军医大学第一附属医院 Application of Netrin-1 in promoting diabetic skin wound repair

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Publication number Priority date Publication date Assignee Title
CN111544658A (en) * 2020-06-24 2020-08-18 中国人民解放军陆军军医大学 Cardiovascular implant for regulating immune response and promoting intimal regeneration and preparation method thereof
CN111544658B (en) * 2020-06-24 2022-02-01 中国人民解放军陆军军医大学 Cardiovascular implant for regulating and controlling immune response and promoting intimal regeneration and preparation method thereof
CN113827548A (en) * 2021-06-16 2021-12-24 温州医科大学 A kind of magnetic graphene nanocomposite gel for targeting and inhibiting corneal pathology and its preparation method, application and treatment method
CN113827548B (en) * 2021-06-16 2023-08-22 温州医科大学 Magnetic graphene nanocomposite gel for targeted inhibition of keratopathy, preparation method and application thereof, and treatment method
CN115887614A (en) * 2022-10-21 2023-04-04 中国人民解放军海军军医大学第一附属医院 Application of Netrin-1 in promoting diabetic skin wound repair

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