CN1290576C - Thymic hormone beta 15 to promote wound healing and generation of blood - Google Patents
Thymic hormone beta 15 to promote wound healing and generation of blood Download PDFInfo
- Publication number
- CN1290576C CN1290576C CN 03146158 CN03146158A CN1290576C CN 1290576 C CN1290576 C CN 1290576C CN 03146158 CN03146158 CN 03146158 CN 03146158 A CN03146158 A CN 03146158A CN 1290576 C CN1290576 C CN 1290576C
- Authority
- CN
- China
- Prior art keywords
- wound
- tissue
- extrasin beta
- ulcer
- cell
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 230000029663 wound healing Effects 0.000 title claims abstract description 31
- 210000004369 blood Anatomy 0.000 title description 14
- 239000008280 blood Substances 0.000 title description 14
- 239000000724 thymus hormone Substances 0.000 title 1
- 208000027418 Wounds and injury Diseases 0.000 claims abstract description 64
- 206010052428 Wound Diseases 0.000 claims abstract description 60
- 239000000203 mixture Substances 0.000 claims abstract description 21
- 230000000694 effects Effects 0.000 claims abstract description 19
- 230000017423 tissue regeneration Effects 0.000 claims abstract description 17
- 230000036770 blood supply Effects 0.000 claims abstract description 11
- 230000001737 promoting effect Effects 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 4
- 230000006378 damage Effects 0.000 claims description 16
- 208000025865 Ulcer Diseases 0.000 claims description 15
- 231100000397 ulcer Toxicity 0.000 claims description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 8
- 210000004087 cornea Anatomy 0.000 claims description 7
- 206010012601 diabetes mellitus Diseases 0.000 claims description 6
- 206010040943 Skin Ulcer Diseases 0.000 claims description 5
- 239000000463 material Substances 0.000 claims description 4
- 208000009084 Cold Injury Diseases 0.000 claims description 3
- 208000002720 Malnutrition Diseases 0.000 claims description 3
- 206010053615 Thermal burn Diseases 0.000 claims description 3
- 230000002595 cold damage Effects 0.000 claims description 3
- 230000000302 ischemic effect Effects 0.000 claims description 3
- 230000001071 malnutrition Effects 0.000 claims description 3
- 235000000824 malnutrition Nutrition 0.000 claims description 3
- 208000015380 nutritional deficiency disease Diseases 0.000 claims description 3
- 231100000019 skin ulcer Toxicity 0.000 claims description 3
- 102000057297 Pepsin A Human genes 0.000 claims description 2
- 108090000284 Pepsin A Proteins 0.000 claims description 2
- 230000002183 duodenal effect Effects 0.000 claims description 2
- 210000004211 gastric acid Anatomy 0.000 claims description 2
- 230000001524 infective effect Effects 0.000 claims description 2
- 229940111202 pepsin Drugs 0.000 claims description 2
- 210000002784 stomach Anatomy 0.000 claims description 2
- 206010020880 Hypertrophy Diseases 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 23
- 210000004204 blood vessel Anatomy 0.000 abstract description 16
- 230000008929 regeneration Effects 0.000 abstract description 6
- 238000011069 regeneration method Methods 0.000 abstract description 6
- 102000007501 Thymosin Human genes 0.000 abstract description 5
- 108010046075 Thymosin Proteins 0.000 abstract description 5
- LCJVIYPJPCBWKS-NXPQJCNCSA-N thymosin Chemical compound SC[C@@H](N)C(=O)N[C@H](CO)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CO)C(=O)N[C@H](CO)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@H]([C@H](C)O)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](C(C)C)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@H](CCC(O)=O)C(O)=O LCJVIYPJPCBWKS-NXPQJCNCSA-N 0.000 abstract description 5
- 208000024172 Cardiovascular disease Diseases 0.000 abstract description 4
- 230000000975 bioactive effect Effects 0.000 abstract description 4
- 230000007812 deficiency Effects 0.000 abstract 1
- 208000023589 ischemic disease Diseases 0.000 abstract 1
- 230000035755 proliferation Effects 0.000 abstract 1
- 210000001519 tissue Anatomy 0.000 description 38
- 210000004027 cell Anatomy 0.000 description 26
- 210000003491 skin Anatomy 0.000 description 15
- 230000008569 process Effects 0.000 description 14
- 238000002474 experimental method Methods 0.000 description 12
- 241001465754 Metazoa Species 0.000 description 11
- 230000012010 growth Effects 0.000 description 11
- 230000035876 healing Effects 0.000 description 11
- 206010020718 hyperplasia Diseases 0.000 description 11
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 10
- 102000013275 Somatomedins Human genes 0.000 description 10
- 230000005012 migration Effects 0.000 description 10
- 238000013508 migration Methods 0.000 description 10
- 206010063560 Excessive granulation tissue Diseases 0.000 description 9
- 210000001126 granulation tissue Anatomy 0.000 description 9
- 206010028980 Neoplasm Diseases 0.000 description 8
- 230000033115 angiogenesis Effects 0.000 description 8
- 230000010261 cell growth Effects 0.000 description 8
- 210000002889 endothelial cell Anatomy 0.000 description 8
- 210000002919 epithelial cell Anatomy 0.000 description 8
- 210000003606 umbilical vein Anatomy 0.000 description 8
- 230000017531 blood circulation Effects 0.000 description 7
- 230000012292 cell migration Effects 0.000 description 7
- 210000003780 hair follicle Anatomy 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 210000003556 vascular endothelial cell Anatomy 0.000 description 7
- 102000008186 Collagen Human genes 0.000 description 6
- 108010035532 Collagen Proteins 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 229920001436 collagen Polymers 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 230000003780 keratinization Effects 0.000 description 6
- 235000016709 nutrition Nutrition 0.000 description 6
- 108090000765 processed proteins & peptides Proteins 0.000 description 6
- 230000008439 repair process Effects 0.000 description 6
- 231100000241 scar Toxicity 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- 206010029113 Neovascularisation Diseases 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 210000003725 endotheliocyte Anatomy 0.000 description 5
- 210000002615 epidermis Anatomy 0.000 description 5
- 210000000981 epithelium Anatomy 0.000 description 5
- 239000003102 growth factor Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 229920001184 polypeptide Polymers 0.000 description 5
- 102000004196 processed proteins & peptides Human genes 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 230000004936 stimulating effect Effects 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 102000007469 Actins Human genes 0.000 description 4
- 108010085238 Actins Proteins 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- 239000002671 adjuvant Substances 0.000 description 4
- 230000002491 angiogenic effect Effects 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 210000003711 chorioallantoic membrane Anatomy 0.000 description 4
- 210000002950 fibroblast Anatomy 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 208000014674 injury Diseases 0.000 description 4
- 210000003141 lower extremity Anatomy 0.000 description 4
- 230000035764 nutrition Effects 0.000 description 4
- 239000002674 ointment Substances 0.000 description 4
- 239000013641 positive control Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 206010006187 Breast cancer Diseases 0.000 description 3
- 208000026310 Breast neoplasm Diseases 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 3
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 206010072170 Skin wound Diseases 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 150000001413 amino acids Chemical group 0.000 description 3
- 230000002924 anti-infective effect Effects 0.000 description 3
- 230000004069 differentiation Effects 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- 229940126864 fibroblast growth factor Drugs 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 210000004877 mucosa Anatomy 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- PHEDXBVPIONUQT-RGYGYFBISA-N phorbol 13-acetate 12-myristate Chemical compound C([C@]1(O)C(=O)C(C)=C[C@H]1[C@@]1(O)[C@H](C)[C@H]2OC(=O)CCCCCCCCCCCCC)C(CO)=C[C@H]1[C@H]1[C@]2(OC(C)=O)C1(C)C PHEDXBVPIONUQT-RGYGYFBISA-N 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 208000037816 tissue injury Diseases 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 108090000386 Fibroblast Growth Factor 1 Proteins 0.000 description 2
- 102100031706 Fibroblast growth factor 1 Human genes 0.000 description 2
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 2
- 102000003974 Fibroblast growth factor 2 Human genes 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 206010062575 Muscle contracture Diseases 0.000 description 2
- 206010028851 Necrosis Diseases 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 244000309466 calf Species 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 230000032823 cell division Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 208000006111 contracture Diseases 0.000 description 2
- 239000002537 cosmetic Substances 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 239000010408 film Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 210000003714 granulocyte Anatomy 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 210000003701 histiocyte Anatomy 0.000 description 2
- 230000001771 impaired effect Effects 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- 210000001161 mammalian embryo Anatomy 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 230000003387 muscular Effects 0.000 description 2
- 230000017074 necrotic cell death Effects 0.000 description 2
- GVUGOAYIVIDWIO-UFWWTJHBSA-N nepidermin Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CS)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CS)NC(=O)[C@H](C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C(C)C)C(C)C)C1=CC=C(O)C=C1 GVUGOAYIVIDWIO-UFWWTJHBSA-N 0.000 description 2
- 230000003448 neutrophilic effect Effects 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 238000006116 polymerization reaction Methods 0.000 description 2
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 2
- 210000004872 soft tissue Anatomy 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 201000004384 Alopecia Diseases 0.000 description 1
- 102000040717 Alpha family Human genes 0.000 description 1
- 108091071248 Alpha family Proteins 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010059245 Angiopathy Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 101001051969 Bos taurus Fibroblast growth factor 2 Proteins 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 208000018380 Chemical injury Diseases 0.000 description 1
- 206010069729 Collateral circulation Diseases 0.000 description 1
- 102000003712 Complement factor B Human genes 0.000 description 1
- 108090000056 Complement factor B Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 206010011953 Decreased activity Diseases 0.000 description 1
- 206010056340 Diabetic ulcer Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 101500025419 Homo sapiens Epidermal growth factor Proteins 0.000 description 1
- 101000851176 Homo sapiens Pro-epidermal growth factor Proteins 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241000192710 Microcystis aeruginosa Species 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 208000031481 Pathologic Constriction Diseases 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 101710172711 Structural protein Proteins 0.000 description 1
- 208000001435 Thromboembolism Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 1
- 102000009618 Transforming Growth Factors Human genes 0.000 description 1
- 108010009583 Transforming Growth Factors Proteins 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 206010048038 Wound infection Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 230000004520 agglutination Effects 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- 238000002266 amputation Methods 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 210000002469 basement membrane Anatomy 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000007541 cellular toxicity Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 231100000481 chemical toxicant Toxicity 0.000 description 1
- 210000000589 cicatrix Anatomy 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 210000004292 cytoskeleton Anatomy 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 230000007646 directional migration Effects 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 210000003278 egg shell Anatomy 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000010595 endothelial cell migration Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000004720 fertilization Effects 0.000 description 1
- 230000008175 fetal development Effects 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 230000003328 fibroblastic effect Effects 0.000 description 1
- 210000001061 forehead Anatomy 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 230000003660 hair regeneration Effects 0.000 description 1
- 230000012447 hatching Effects 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 201000011066 hemangioma Diseases 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940116978 human epidermal growth factor Drugs 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 239000008311 hydrophilic ointment Substances 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 230000007124 immune defense Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 208000006443 lactic acidosis Diseases 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 229940040145 liniment Drugs 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000004089 microcirculation Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 210000004493 neutrocyte Anatomy 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- 229940100691 oral capsule Drugs 0.000 description 1
- 210000003681 parotid gland Anatomy 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 210000003668 pericyte Anatomy 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 210000002826 placenta Anatomy 0.000 description 1
- 239000011505 plaster Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 239000002453 shampoo Substances 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 206010040882 skin lesion Diseases 0.000 description 1
- 231100000444 skin lesion Toxicity 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000000344 soap Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000007447 staining method Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 230000036262 stenosis Effects 0.000 description 1
- 208000037804 stenosis Diseases 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000012976 tarts Nutrition 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 210000000264 venule Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention relates to a method for using bioactive thymosin beta15 in tissue repair and wound healing. Thymosin beta15 has the effect of promoting the proliferation of the blood vessels and the regeneration and the restoration of the tissue. Thus, a medical composition containing an effective dose of thymosin beta15, bioactive variant thereof or salt thereof can be used for treating various wounds caused by various reasons and promoting wound healing and can be used for treating cardiovascular diseases and other ischemic diseases caused by the deficiency of blood supply.
Description
Technical field
The present invention relates to a kind of active small molecular polypeptide that promotes tissue repair and angiogenic growth effect that has: extrasin beta 15, its pharmaceutical composition can be used for promoting the tissue repair and the healing of wound, improve the blood supply of ischemic tissue.
Background technology
Skin is the exposed portions of health, be subjected to various damages especially easily, common reason has mechanical injuries (to break, cutting, friction), the chronic skin ulcer that causes of physics and chemical injury (the strong alkali damage of burn and scald, cold injury and strong acid), scalpel edge, decubital ulcer and some disease.Because important barrier and the physiological action of skin, the integrity of skin is most important to everyone normal existence, and any breach all needs body to make protective response with tearing.Except the damage of skin, various soft tissues and mucosa also are vulnerable to damage, as gastrointestinal mucosa, and cornea etc.
The patient of hormone or cell toxicity medicament treatment is damaged and accepted to serious symptom, immune defense function often occurs and repair underactivity, its wound infection rate increase and the state of an illness are increased the weight of, but also cause the delay of tissue repair even be difficult to healing, repairing quality is also relatively poor, and relapse rate is higher, bring great inconvenience and misery to the patient, serious also can cause other complication, as septic shock, digestive tract perforation, canceration etc., but threat to life.In addition, the depletion of histoorgan or dysbolismus also are to cause the major reason of some histopathology damages, as digestive tract ulcer, diabetic ulcer, disturbance of blood circulation ulcer etc., the key of treatment is to strengthen to repair function, improve the metabolism of these tissues, microcirculation improvement promotes the tissue regeneration healing.
Under the normal condition, wound can be repaired and heal naturally.The process of wound normal healing comprises: wound closure runs off with limit blood and prevents infections; Remove impaired tissue and blood clot; Various types of cells are invaded wound location and are formed granulation and cicatrix in the surrounding tissue that continues; Rebuild scar tissue at last and change cell colony, to cause the healing fully of wound.Generally speaking, as the wound scope less or the damage lighter, the normal healing process is effective.But wound is often because of being subjected to patient body quality, wound size and the order of severity and having or not the influence of factors such as accompanying infection, and wound healing in most cases needs medical intervention.And the chronic skin ulcer that some diseases caused be difficult to be cured, as the intractable cutaneous ulcer due to the diabetes.Diabetes are a kind of common diseases, mainly are because insulin definitely or relatively lacks caused metabolism obstacles of blood glucose, occur that blood glucose increases and glucose in urine.The present sickness rate of diabetes, in China up to 2%.After suffering from diabetes, have the patient of 30%-50% that skin lesion is arranged, happening part is many at the relatively poor lower limb of blood supply.Many diabeticss cause amputation at last because slight wound can not heal, even because of infection death.
The healing of wound is mainly finished by granulation tissue and skin tissue regeneration.Approximately since the 3rd day, the wound bottom grew granulation tissue, and gos deep in wound.Granulation tissue has following important function in wound healing: (1) infection and protection wound surface; (2) fast, the slough of machine blood clotting and other foreign bodies; (3) fill up wound or other are damaged.Therefore, granulation tissue is significant in tissue injury repairs.The main component of granulation tissue is vigorous outgrowth new capillary vessel and outgrowth fibroblast, wherein inflammatory cells such as the neutrophilic leukocyte that more or less in addition, macrophage.Secrete many somatomedin and cytokine by platelet generation aggreation at first, then by macrophage to the reaction of hypoxia and lactic acidosis and secrete, these factors can stimulate angiogenesis.As far back as hindering the back 2 or 3 days, new blood capillary promptly begins to obtain employment, and already present venule sprouts and to the injury growth, became high-visible in the microscope level in about the 4th day, and newborn blood capillary connects into netted.Angiogenesis is the key character that tissue injury repairs.
The Regeneration and Repair of epidermis and tissue thereof is finished by migration of epithelial cells, cell division and three processes of epithelium differentiation.After epithelium was impaired, the damaged basal layer cell of the epithelium broken ends of fractured bone on every side moved to wound surface, and the epithelial cell division is active, covers wound surface gradually, and epithelium further breaks up, and rebuilds the organizational structure and the function that lose, the keratinization of epithelium etc. can occur as skin.
The new drug that is used at present wound healing clinically mainly is the somatomedin albuminoid, as epithelical cell growth factor, and other albumen of regulating cell proliferation and differentiation, for example albumen transforming factor-B family (TGF-B).Gene recombinaton cattle alkali fibroblast growth factor (Recombinant bovine bFGF) and gene recombinaton human epidermal growth factor (Recombinant human EGF) have got the Green Light and have been used for the clinical treatment wound healing.Carry out at present the four kinds of gene recombinant proteins that also have of clinical three phases experiment, comprising human fibroblastic growth factor etc.This class treatment albumen costliness of using in the wound healing therapy stores unstable and the use trouble, and proteic unstability (protein,split) may cause unexpectedly to the deleterious inflammatory reaction of host.
Thymosin is to be present in human body and the intravital one group of micromolecule polypeptide of animal under the normal condition, can be divided into α type and β type protein family.The main representative of α family is a thymosin, has the raise immunity effect, has been used for clinical treatment hepatitis.β type family is one group and is the micromolecule polypeptide that tart aminoacid sequence has high homology, form by 43 to 45 aminoacid, 15 members have been found up till now, what wherein content and tissue distribution were maximum is extrasin beta 4, next is an extrasin beta-10, they can combine with the actin monomer, thereby suppress the polymerization of actin.Extrasin beta 15 finds from prostate gland cancer cell that at first it also is present in normal nervous tissue, parotid gland tissues, testis tissue and the superficial cell.Extrasin beta 15 can be incorporated on the actin monomer, thereby suppresses the polymerization of actin.
We find that through series of studies extrasin beta 15 has the function of tangible promotion epithelial cell keratinization, promotion neovascularization.Animal experiment study shows that this polypeptide small molecule can make the skin migration of epithelial cells to wound, stimulate wound to form newborn blood capillary, stimulate fibroblast and hypodermal cell in wound healing process, to produce structural protein and other conjunctive tissue composition, strengthen the formation of granulation tissue, thereby promotion tissue regeneration, promote wound healing, and shorten healing time.Has important clinical application value.
Extrasin beta 15 is different from the medicine of treatment wound healing that use on the market or just under development.Extrasin beta 15 is not a somatomedin, and comparing with various somatomedin on the treatment wound healing has following several respects advantage: 1) stimulate epithelial cell to move specifically, promote the epithelial cell keratinization; 2) stimulating endothelial cell moves specifically, promotes vascularization; 3) molecular weight is very little, has only 45 aminoacid (somatomedin belongs to high molecular weight protein), is easily organizing internal diffusion; 4) have no side effect, can use repeatedly the part; 5) be difficult for being degraded by proteolytic enzyme, acting duration is long, can reduce the medication number of times; 6) extrasin beta 15 can directly act on cytoskeleton system, has the effect of sustenticular cell structural stability.Therefore, extrasin beta 15 has very special important function in the cell regeneration reparation in the wound healing.
Summary of the invention
The present invention originates in the influence of 15 pair cells differentiation of research extrasin beta and on cell migration.Isolated test proof extrasin beta 15 promotes the factor can stimulate the directional migration of human umbilical vein's endotheliocyte as a cell migration.Tested the cell of number of different types with Boyden Chomber method, proved that extrasin beta 15 can stimulate the migration of human umbilical vein's endotheliocyte and epidermis cell specifically.In vivo, extrasin beta 15 can promote cell migration, and when extrasin beta 15 parts are used for mice and are subjected to the wound of wound model, observes complete promoting epidermization, and wound healing quickens.
The present invention has determined that further extrasin beta 15 can promote moving of vascular endothelial cell in vivo effectively, promotes vascularization, and the healing that promotes wound.Mice cornea vascularization result of the test shows, extrasin beta 15 promote angiopoietic effects with as the effect of the epithelical cell growth factor of positive control quite or better, and the test of animal wound shows that extrasin beta 15 has the effect of accelerating wound healing.Wound is local with after extrasin beta 15 processing, observes the formation and the tangible tissue regeneration of more neovascularity widely.Behind extrasin beta 15, wound collagen is synthetic also to be increased, and illustrates that extrasin beta 15 also can the accelerated in wounds contracture.
Promote tissue regeneration, wound healing
The pharmaceutical composition that the invention provides a kind of extrasin beta 15 polypeptide by will containing effective dosage is used for the method that local wound is come accelerating wound healing.The wound healing that the speed of 15 pairs of quickenings of extrasin beta wound normal healing and promotion are difficult to cure provides a kind of Therapeutic Method that special value is arranged.
But the zoopery result proves extrasin beta 15 accelerating wound healings of independent use biologically active.In addition, the form administration that extrasin beta 15 can also pharmaceutical compositions comprises that extrasin beta 15 and derivant thereof or its salt and one or more pharmaceutically suitable carrier and other therapeutic component of choosing wantonly be in the same place.Carrier refers to pharmaceutically useful delivery system, and it can be compatible with ingredient and the curee do not had detrimental effect.
Therefore, the present invention further provides and contain extrasin beta 15 or its officinal salt or its physiological function derivative and pharmaceutically useful carrier pharmaceutical composition together.
Extrasin beta 15 is inherent peptide species compositions in the normal body.Therefore, use highly purified extrasin beta 15, it is safe and reliable perhaps using extrasin beta 15 synthetic or that express, any have can bring out or stimulate the bioactive substance of body generation extrasin beta 15 also can add in the compositions.
The present invention can local be used for scratch, wound, burn, scald, the cold injury of top layer wound tissue treatment skin, the cornea damage, infective ulcer, the malnutrition ulcer, stop up ulcer, cornea ulcer, and the surface damage of other form, also can be used for the mucosa injury that some disease causes, as the stomach that causes by gastric acid and pepsin or duodenal mucosal ulcer etc.In addition, extrasin beta 15 can be directly used in the wound that surgical operation causes, and perhaps selects for use compositions-treated of the present invention to accelerate healing, for example is coated with active agents on the operation skin wound.
The present invention can be used for the regeneration and the reparation of stimulatory organs tissue.For example behind excision part colon or other tissue, coat pharmaceutical composition of the present invention at the organ-tissue position of operation and form and tissue regeneration, accelerate the agglutination of organ with the new vessels that promotes organ-tissue.
On the other hand, the present invention can reduce the formation of scar tissue and the reconstruction and the absorption of the scar tissue that promotes to be caused by a variety of causes.Cause the various factors of scar tissue to comprise operation process, radiation, broken wound, chemical toxicant, virus and bacterial infection or wound." scar tissue " used herein is meant that the recovery process neutralizes and forms fiber and collagen tissue in other pathological process.For example, extrasin beta 15 is made intermixture also throw near damaged tissue, and then promote tissue regeneration, blood vessel hyperplasia and microcirculqtory system form, and the reconstruction that acceleration is organized reduces the formation of scar tissue.
The present invention also can be used as effective ingredient and is used for cosmetic composition, can strengthen the metabolism and the protection function of skin, makes that skin is tender, plentiful, gloss and fitness, has healthcare applications and is worth.
In pharmaceutical composition of the present invention, can add other and have the active component that promotes wound healing, these compositions comprise various somatomedin, as insulin like growth factor (IGF-1), PDGF (PDGF), epidermal growth factor (EGF), transforming growth factor (TGF-Beta) and basic fibroblast growth factor (bFGF) or the like.
Can also go into into to have the various antibiotics of anti-infectious function in the pharmaceutical composition of the present invention, have the Chinese medicine preparation of anti-infectious function, and other natural materials with anti-infectious function.
In this article, " effective dose " is meant the requirement that contains extrasin beta 15 compositions.Will promote the tissue regeneration effect when this composition uses therapeutic dose in process of tissue reparation.Extrasin beta 15 can promote and nurse one's health process of tissue reparation.Process of tissue reparation usually occurs in after the injury disease.Process of tissue reparation obstacle occurs often owing to causing the reflection of growth is not enough at the various cells of wound such as fibroblast, stem cell, vascular endothelial cell, histiocyte.Therefore, the reparation that adding can be induced or the activating agent of stimulating cellular growth can help organizing." promotion " used herein speech is meant that cell growth mechanism or process have activation, stimulation, potentiation, initiation and keep effect.These cell growth mechanisms or generating process are that tissue forms, and repair or grow necessary.
The substrate or the adjuvant that contain active extrasin beta 15 can serve as delivery system.In the present invention, " delivery system " refers to active extrasin beta 15 to be the body of passing the human or animal when pharmaceutical composition (medicament preparation or dosage form) when being used.Therefore term " delivery system " comprises the substrate or the adjuvant of the form of ownership that common pharmaceutical composition can use, as solid, semisolid and fluid composition.Special relevant compositions is, for example, ointment, hydrophilic ointment, emulsifiable paste, paste, frost, gel, hydrogel, solution, emulsion, suspension, washing liquid, liniment, shampoo, soap agent, paste, spray, powder, thin film, bedding and padding, application, binder, plaster etc.
Wound topical application pharmaceutical composition of the present invention preferably contains the ointment or the frost of active component.When making ointment, active component can use paraffinic base or water miscibility ointment base, perhaps, makes the cream that active component contains water bloom base.The example of external type compositionss such as preparation masking liquid, ointment comprises mixing with additive aequum effective dose.These additives are selected from the substrate commonly used or the adjuvant of external used medicine or cosmetics usually, for example vaseline, liquid paraffin, lanoline, stearic acid list glyceride, Polyethylene Glycol, hexadecanol, glycerol, second alcohol and water etc.
If desired, the water of frost can comprise, for example, the polyhydric alcohol of 30%W/W at least promptly contains the alcohol of two or more bases, as propylene glycol, fourth-1, and 3-glycol, mannitol, sorbitol, glycerol and Polyethylene Glycol and their mixture.Topical preparation can increase or reduce contained active component as required.
Pharmaceutical composition of the present invention can also be the oral liquid compositions.The example of preparation oral liquid compositions comprises extrasin beta 15 or derivatives thereofs of effective dose and the fluid matrix mixing manufacture of aequum is formed that the example of this substrate comprises water or normal saline, wherein also can add other beneficiating ingredient or adjuvant.
Pharmaceutical composition of the present invention can also be the example of solid dosage forms compositionss such as oral capsule, tablet, powder, comprises the extrasin beta 15 or derivatives thereof dry powder of effective dose and the pharmaceutic adjuvant mixing manufacture of aequum are formed.
The present invention can also use with the mode that may command discharges intermixture.Herein " may command release intermixture " is meant any complex.This complex can be used for slowly discharging effective extrasin beta 15 compositions that comprise wherein.This complex contains biological effective components can be solid shape, infiltrative, and half shape admittedly is colloidality or aqueous.
Regulate the blood vessel hyperplasia process
The blood vessel hyperplasia process is the especially bioprocess of blood capillary growth of a kind of neovascularity, comprises endotheli ocytosis, shifts and migration, and endotheliocyte is deeply organized and the maturation of endotheliocyte.Described process can form in any development from three approach: 1) new vessels occurs with the form of germinateing from former already present vascular; 2) by precursor neovascularity takes place, breaks up, develops into; 3) existing little blood vessel diameter increases.The blood vessel hyperplasia process plays a crucial role in a series of biological phenomenons.These biological phenomenons comprise physiological and pathologic, as fetal development, and women's physiology breeding cycle, wound healing, retinopathy, rheumatoid arthritis, hemangioma and entity tumor etc.
In wound location, collagen, substrate are arranged and contain the granulation tissue deposition of enriching blood vessel, wound intensity is provided during tissue repair.The formation of known various cell growth factor regulations neovascularity, comprise vascular endothelial cell propagation, move and invade profit.Having identified to have promotes the active several somatomedin of endothelial cell growth to comprise acid and alkali fibroblast growth factor (FGF), vascular endothelial cell growth factor (VEGF) and Placenta Hominis derivative growth factor (PDGF) etc.
The present invention has determined that extrasin beta 15 can promote moving of vascular endothelial cell effectively external, in vivo can the vascularization of inducing mouse cornea.Extrasin beta 15 promote angiopoietic effects with as the effect of the epidermal growth stimulating factor of positive control quite or better.And the test of animal wound shows that extrasin beta 15 has the function of accelerating wound healing.Compares with matched group after using extrasin beta 15 to handle in animal wound part, more neovascularization are widely arranged, and wound collagen is synthetic also to be increased, and illustrates that extrasin beta 15 can accelerated in wounds contracture and promotion wound healing.
The present invention can be used for treating the skin ulcer that is caused by diabetes.The circulatory disturbance of blood vessel is to suffer from common pathological variation in the diabetics for a long time.Diabetics raises owing to blood glucose continues the higher blood fat that causes, and atherosclerosis and angiemphraxis appear in small artery, make the blood flow volume that flow to lower limb reduce.The function of blood is each tissue that nutrient substance is transported to health, the refuse that produces in also each being organized simultaneously transports out external, and after the blood circulation function reduced, at first affected was foot, because foot apart from heart farthest, blood arrives least easily.Therefore, the easy ischemic necrosis of the skin of lower limb and soft tissue forms the skin ulcer that is difficult to heal.Extrasin beta 15 can be used for skin of lower extremity ulcer place, promotes the damage local vascular to form, and improves blood supply, promotes wound healing.
The present invention can stimulating endothelial cell migration and growth, vasostimulant propagation increases the blood flow of tissue, thus the treatment cardiovascular disease.The feature of cardiovascular disease is that the blood supply of heart or other target organ suffers damage." cardiovascular disease " used herein is meant the disease that heart and blood vessel cause owing to blood supply insufficiency, including, but not limited to, coronary artery disease, congestive heart failure and periphery angiopathy.Heart disease is meant the heart change that causes owing to stenosis or occlusion coronarius, and characteristics are the required nutritional labeling of heart and hypoxgia and cause myocardial infarction.The extrasin beta 15 of effective dose can be by promoting blood vessel hyperplasia, induce extra blood capillary, set up collateral circulation, thereby increase the blood flow of cardiac muscular tissue, provide heart required nutritional labeling, improve hypoxgia, the oxygen of cardiac muscular tissue and effect are increased, play the tissue injury that myocardial ischemia that prevention and treatment cause owing to partially or completely thromboembolism coronarius causes.
The present invention provides a kind of promotion neovascularity outgrowth method for insufficient some tissue of blood supply.For example, the alopecia that the hair follicle blood supply minimizing that causes because of a variety of causes, hair follicle malnutrition (not destroying but there is hair follicle structure) cause.The extrasin beta 15 of effective dose can be by promoting the blood vessel hyperplasia of hair follicle tissue, induce extra blood capillary, thereby increase the blood flow of hair follicle tissue, improve blood supply, for the hair follicle tissue of ischemia provides nutrition, the nutrition improvement of hair follicle tissue can promote hair regeneration.
In addition, the method for the present invention's elaboration also can be applied to inductivity tissue regeneration engineering.At present, the medical skill personnel adopt inductivity tissue regeneration engineering to promote and accelerating wound when carrying out invasive surgery.Method is to promote the bioactive substance of histiocyte migration, differentiation to grow into the wound with having, and the cell of formative tissue structure is assembled in a large number in the wound.The present invention can be used to help the regeneration of human or animal's granulation tissue.Method is to contain the polymer of Bioabsorbable, and the complex of the solvent of solubility and extrasin beta 15 is positioned over regeneration place of human or animal's meat dental tissue.This complex promotes people or other mammiferous granulation tissue regeneration by the extrasin beta 15 that discharges effective dose.
The growth of solid tumor and transfer rely on angiogenesis.New vessels provides sufficient oxygen and nutrition for tumor cell, and the endotheliocyte of new vessels is expressed multiple somatomedin, stimulates tumor cell proliferation.Tumor vessel lacks pericyte, and basement membrane is imperfect, and therefore, tumor cell is easy to enter blood circulation.Because neovascularization plays an important role in tumor growth, be one of preferred oncotherapy embodiment so suppress the angiogenesis of tumor tissues.If there is not neovascularization in the tumor tissues, tumor tissues just can not obtain required nutrition, and tumor growth is slow or stop growing the also final necrosis of degenerating.Extrasin beta 15 has the promotion angiogenesis function among the present invention.Therefore, the inhibitor of extrasin beta 15 can be used for suppressing the angiogenesis of tumor tissues, thereby reaches the purpose of treatment tumor.
Description of drawings
The experiment of Fig. 1 mouse skin wound healing.The wound area of extrasin beta 15 processed group dwindles than matched group is obvious.Extrasin beta 15 tools significantly promote migration of epithelial cells, accelerated in wounds more and effect.
The experiment of Fig. 2 mouse skin wound healing.Mice is divided into extrasin beta 15 treatment groups and normal saline matched group, every group of each 8 mice.Measured wound area on the 7th day.The area of extrasin beta 15 treatment groups is significantly less than matched group, and statistics has extremely significant difference (P＜0.001).
The specific embodiment
Embodiment 1
Cell culture
Human umbilical vein endothelial cells (HUVECS) is used the RPMI1640 culture medium culturing.Culture medium contains: 5% Ox blood serum, and 100 units per ml green grass or young crops/chain enzymes, 50 mcg/ml are celebrated big enzyme element, the plain B of 2-7 mcg/ml both sexes enzyme, supplement such as 5 units per ml heparin and 200 units per ml vascular endothelial cell growth factor.People's keratinization of epidermis cell and forehead fibroblast are cultivated with DMEM and 10% calf serum, and human breast cancer cell's strain MDA-MB435 cell is cultivated with RPMI 1640 and 10% calf serum.Neutrophilic granulocyte separates from fresh human peripheral.Human vas smooth muscle cell smooth muscle cell culture medium culturing.
Embodiment 2
The cell migration experiment
Whether can cause specific cell migration in order to test after extrasin beta 15 stimulates, we use Boyden Chomber method to various kinds of cell strain test.Nitre film (aperture 0.8mm) both sides with Boyden Chamber two interventricular septum all cover Fibronection earlier, and concentration is 15 mcg/ml, place 60 minutes down for 37 ℃.Last chamber adds cell suspension, and following chamber is a complete culture solution, 5%CO
2Left standstill in the incubator 4 hours, and took out filter membrane, will go up chamber face cell and strike off, after fixing dyeing, at the microscopically cell counting.Every group of 3 films.Statistical variable is represented with mean standard deviation.The result shows the specific migration that causes Human umbilical vein endothelial cells and people's keratinization of epidermis cell of extrasin beta 15 energy, the quantity showed increased of wandering cell (the results are shown in Table 1).Experimental results show that extrasin beta 15 all obviously quickens the migration of Human umbilical vein endothelial cells in the concentration range of 10 to 1000 millimicro grams per milliliters, and be amount-result relation.On the contrary, extrasin beta 15 does not cause neutrophilic granulocyte, the isocellular obvious migration of MDA-MB435 human breast cancer cell strain and human vas smooth muscle cell,
Embodiment 3
" galling " wound is closed experiment
With one milliliter of suction pipe tip the monolayer Human umbilical vein endothelial cells of adherent growth is scratched scratch one, clean the cell that comes off with the PBS buffer.Extrasin beta 15 backs that add variable concentrations continue to cultivate, and observe broken trace and close situation.The extrasin beta 15 of 1000 millimicro grams per milliliters was handled after 4 hours, and Human umbilical vein endothelial cells is obviously supported the matched group of base more than only adding embryo to the quantity that the scratch place moves, and the time that scratch is closed also obviously accelerates.
Embodiment 4
Promote the blood vessel hyperplasia experiment
The facilitation of 15 pairs of angiogenesis of extrasin beta adopts chick chorioallantoic membrane (CAM) experiment to detect, and opens a 1cm hatching on 7 days the fertilization Embryo Gallus domesticus eggshell
2Left and right sides window on the sterilization filter paper, and is positioned over CAM with the chemosynthesis extrasin beta 15 albumen application of samples of variable concentrations, continues down for 37 ℃ to cultivate 48 hours at the constant temperature and humidity incubator then, observes the angiogenic growth situation.This experiment is the test contrast with the normal saline, phorbol myristate acetate (PMA) 0.5 microgram/positive contrast of 10 microlitres.The measuring result shows that extrasin beta 15 albumen application of sample group chick chorioallantoic membrane angiogenic growths are obviously vigorous, and caliber is thick and branch is many, is lobate distribution.With normal saline group angiogenic growth degree in contrast, the blood vessel hyperplasia degree of extrasin beta 15 5 micrograms/10 microlitres significantly increases than normal saline group, and the blood vessel hyperplasia degree of 10 micrograms/10 microlitres and PMA positive controls blood vessel hyperplasia degree are quite or slightly many.This experimental result shows that extrasin beta 15 has the effect of obvious promotion blood vessel hyperplasia.
Embodiment 5
The wound healing experiment
Behind the mouse anesthesia, remove the skin of mouse back, cause diameter to be about the wound of 4 millimeters sizes, at random animal is divided into extrasin beta 15 treatment groups and matched group (every group of 8 animals) subsequently with 4 millimeters sample of tissue device.The medicine liquid droplet of 50 microlitres (containing 5 microgram extrasin betas 15) is on wound, and matched group uses normal saline.Animal every other day receives seance, observes continuously after 7 days and puts to death mice.Wound area is used to assess the curative effect of extrasin beta 15.Wound skin is fixed in 10% formalin solution.H ﹠amp; E and collagen staining method are used to observe the pathology variation of skin.Repeated experiments comes to the same thing.The result shows that the wound area of extrasin beta 15 processed group dwindles one times than matched group, and there is complete promoting epidermization the wound part, neovascularization widely, and collagen is synthetic also obviously to be increased.Wound healing time is than the obvious shortening of matched group, and statistics has extremely significant difference (P＜0.001).These results show that extrasin beta 15 has tangible promotion wound healing effect (seeing accompanying drawing 1 and Fig. 2).
In sum, extrasin beta 15 tools significantly promote epithelial cell and migration of vascular endothelial cells, promote new vessels to form, stimulate granulation to form growth and accelerated in wounds heals and effect.
Table 1: the influence of extrasin beta 15 pair cell migration
| Cell category | Extrasin beta 15 concentration (millimicro grams per milliliter) | Positive control | ||||
| 1000 | 100 | 10 | 1 | 0 | ||
| People's keratinization of epidermis cell Human umbilical vein endothelial cells human neutrophil vascular smooth muscle cell human breast cancer cell | 77±2.1 71±2.4 5.2±0.5 1.0±0.4 0.9±0.4 | 63±1.2 58±1.4 4.8±0.7 0.5±0.5 1.3±0.7 | 52±1.4 46±1.5 5.0±0.4 1.0±0.4 1.8±0.4 | 18±1.0 14±1.3 5.0±0.4 1.0±0.3 2.4±0.8 | 8±0.3 11±0.6 5.0±0.3 0.9±0.3 2.0±0.5 | 51±1.3 54±1.6 32.3±0.9 36±3.5 66±3.7 |
Annotate: the data that example goes out in the table are meansigma methodss of cell migration number in three experiments
Claims (6)
1, a kind of compositions is made up of extrasin beta 15 or its salt and one or more pharmaceutically suitable carrier, and wherein carrier and pharmaceutical compositions are compatible and to by the harmless effect of therapist.
2, the described compositions of claim 1 is used for improving the purposes of material of blood supply of the ischemic tissue of local wound in preparation.
3, the described compositions of claim 1 is used for impelling and quickens the local wound healing, promotes the effect of material of the tissue repair of wound in preparation.
4, the described compositions of claim 1 preparation be used for top layer wound tissue treatment skin scratch, wound, burn, scald, cold injury, cornea damage, infective ulcer, malnutrition ulcer, stop up the purposes of the medicine of the surface damage of ulcer, cornea ulcer and other form and stomach that causes by gastric acid and pepsin or duodenal mucosal ulcer.
5, the described compositions of claim 1 is used for improving the purposes of the goods of the skin ulcer degree that is caused by diabetes in preparation.
6, the described compositions of claim 1 is used for promoting that in preparation the usefulness of neovascularity hypertrophy, the insufficient goods of treatment blood supply is coated with.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03146158 CN1290576C (en) | 2003-07-25 | 2003-07-25 | Thymic hormone beta 15 to promote wound healing and generation of blood |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03146158 CN1290576C (en) | 2003-07-25 | 2003-07-25 | Thymic hormone beta 15 to promote wound healing and generation of blood |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1579539A CN1579539A (en) | 2005-02-16 |
| CN1290576C true CN1290576C (en) | 2006-12-20 |
Family
ID=34579589
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 03146158 Expired - Lifetime CN1290576C (en) | 2003-07-25 | 2003-07-25 | Thymic hormone beta 15 to promote wound healing and generation of blood |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1290576C (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1948210A4 (en) * | 2005-11-08 | 2010-07-14 | Found Biomedical Res & Innov | Method of treatment for ischemic heart disease |
| ES2288118B1 (en) | 2006-05-10 | 2008-11-01 | Bcn Peptides, S.A. | PROCEDURE FOR SYNTHESIZING LYMPHOSINS. |
-
2003
- 2003-07-25 CN CN 03146158 patent/CN1290576C/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| CN1579539A (en) | 2005-02-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Rose et al. | Advances in the treatment of burn patients | |
| Knottenbelt | Equine wound management: are there significant differences in healing at different sites on the body? | |
| CN103083226B (en) | The preparation of fibroblast growth factor-1 modifier gel and the application in diabetic foot | |
| CN101143212B (en) | Recombination human acidic mechanocyte growth factor temperature sensitive type gel preparation and preparation method thereof | |
| CN108586575B (en) | Polypeptide and application of polypeptide in skin repair function | |
| JPH07505378A (en) | Wound treatment treatment for fibrotic disorders | |
| CN101152568A (en) | Polypeptide combination preparations having functions of accelerating angiogenesis, organ reactivation and wound healing | |
| CN108721320A (en) | The application of micromolecule hyaluronic acid segment | |
| CN111359010A (en) | Stem cell gel precursor composition for repairing skin injury, tissue engineering composition using box and application thereof | |
| CN104056258A (en) | Composition for promoting physiologically regulative regeneration of damaged tissue as well as preparation method and use thereof | |
| CN1649619A (en) | Method and composition for treating skin wounds with epidermal growth factor | |
| CN110903348A (en) | Small peptide for promoting wound healing and application thereof | |
| CN103405751B (en) | Composition with cell repairing function and preparation method and application thereof | |
| CN111759896A (en) | Pharmaceutical application of total triterpene of pawpaw | |
| CN117582545A (en) | Uterine cavity repairing material and preparation method and application thereof | |
| CN1290576C (en) | Thymic hormone beta 15 to promote wound healing and generation of blood | |
| CN103751768A (en) | Preparation helping to heal wound | |
| CN107722114A (en) | A kind of polypeptide and its application | |
| CN110638999A (en) | Application of Sipunculus nudus collagen peptide in wound repair | |
| CN1810842A (en) | Longleaf Grateloupia acuminata polysaccharide extract and its prepn and use | |
| CN1788790A (en) | Extrasin beta-16 for promoting vascularization, tissue regeneration and wound healing | |
| RU2527701C1 (en) | Method for preparing agent possessing property of cartilaginous, osseous, muscular tissue regeneration stimulation, and method for cartilaginous, osseous, muscular tissue regeneration stimulation with using prepared agent | |
| RU2481115C1 (en) | Cellgel wound healing product, method for preparing it and method for healing of wounds of various aethiologies by prepared product | |
| CN113143970A (en) | Methods and compositions for promoting tissue repair in diabetic subjects | |
| CN115721638B (en) | Application of lauroyl arginine ethyl ester hydrochloride in preparation of wound healing promoting medicine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20081212 Address after: A2 building, building 2, 4, University Science Park, Kunming hi tech Zone, Yunnan Patentee after: Yunnan Watson Biotechnology Co.,Ltd. Address before: A-337, Hua Ting, No. 6, Hui Hui Road, Beijing, Haidian District, May Patentee before: Gan Chunyu |
|
| ASS | Succession or assignment of patent right |
Owner name: YUNNAN WOSEN BIOLOGICAL TECHNOLOGY CO., LTD. Free format text: FORMER OWNER: JADE IN DRY SPRING Effective date: 20081212 |
|
| C56 | Change in the name or address of the patentee |
Owner name: YUNNAN WALVAX BIOTECHNOLOGY CO., LTD. Free format text: FORMER NAME: YUNNAN WOSEN BIOLOGICAL TECHNOLOGY CO., LTD. |
|
| CP03 | Change of name, title or address |
Address after: 650033, Kunming high tech Development Zone North Zone, Yunnan University science and Technology Park, 2, A3 building, 4 floor Patentee after: WALVAX BIOTECHNOLOGY CO.,LTD. Address before: 650106, Yunnan Kunming hi tech Zone University Science Park 2, A2 building, 4 floor Patentee before: Yunnan Watson Biotechnology Co.,Ltd. |
|
| CX01 | Expiry of patent term | ||
| CX01 | Expiry of patent term |
Granted publication date: 20061220 |
|
| DD01 | Delivery of document by public notice | ||
| DD01 | Delivery of document by public notice |
Addressee: Tang Yefeng Document name: Notice of Termination of Patent Rights |