CN116983408A - Glp-1受体激动剂在治疗下肢动脉闭塞中的应用 - Google Patents
Glp-1受体激动剂在治疗下肢动脉闭塞中的应用 Download PDFInfo
- Publication number
- CN116983408A CN116983408A CN202210444070.0A CN202210444070A CN116983408A CN 116983408 A CN116983408 A CN 116983408A CN 202210444070 A CN202210444070 A CN 202210444070A CN 116983408 A CN116983408 A CN 116983408A
- Authority
- CN
- China
- Prior art keywords
- glp
- epcs
- receptor agonist
- group
- high sugar
- 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.)
- Pending
Links
- 229940089838 Glucagon-like peptide 1 receptor agonist Drugs 0.000 title claims abstract description 68
- 239000003877 glucagon like peptide 1 receptor agonist Substances 0.000 title claims abstract description 52
- 210000003141 lower extremity Anatomy 0.000 title claims abstract description 46
- 208000031104 Arterial Occlusive disease Diseases 0.000 title claims abstract description 16
- 208000021328 arterial occlusion Diseases 0.000 title claims abstract description 16
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 24
- 230000006378 damage Effects 0.000 claims abstract description 17
- 239000003814 drug Substances 0.000 claims abstract description 13
- 210000001956 EPC Anatomy 0.000 claims abstract 4
- 108090000623 proteins and genes Proteins 0.000 claims description 18
- NGJOFQZEYQGZMB-KTKZVXAJSA-N (4S)-5-[[2-[[(2S,3R)-1-[[(2S)-1-[[(2S,3R)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S,3S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[2-[[(1S)-4-carbamimidamido-1-carboxybutyl]amino]-2-oxoethyl]amino]-1-oxohexan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-2-oxoethyl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-2-oxoethyl]amino]-4-[[(2S)-2-[[(2S)-2-amino-3-(1H-imidazol-4-yl)propanoyl]amino]propanoyl]amino]-5-oxopentanoic acid Chemical group C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 NGJOFQZEYQGZMB-KTKZVXAJSA-N 0.000 claims description 13
- 102000004169 proteins and genes Human genes 0.000 claims description 13
- 101800004295 Glucagon-like peptide 1(7-36) Proteins 0.000 claims description 10
- 108010019598 Liraglutide Proteins 0.000 claims description 9
- YSDQQAXHVYUZIW-QCIJIYAXSA-N Liraglutide Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)CC[C@H](NC(=O)CCCCCCCCCCCCCCC)C(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 YSDQQAXHVYUZIW-QCIJIYAXSA-N 0.000 claims description 9
- 229960002701 liraglutide Drugs 0.000 claims description 9
- 230000003902 lesion Effects 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 230000002093 peripheral effect Effects 0.000 claims description 3
- 230000033115 angiogenesis Effects 0.000 abstract description 19
- 230000017531 blood circulation Effects 0.000 abstract description 15
- 230000010412 perfusion Effects 0.000 abstract description 14
- 208000027418 Wounds and injury Diseases 0.000 abstract description 8
- 208000014674 injury Diseases 0.000 abstract description 8
- 230000001737 promoting effect Effects 0.000 abstract description 7
- 230000003064 anti-oxidating effect Effects 0.000 abstract description 6
- 230000005012 migration Effects 0.000 description 32
- 238000013508 migration Methods 0.000 description 32
- 230000006870 function Effects 0.000 description 26
- 230000000694 effects Effects 0.000 description 22
- 241000699670 Mus sp. Species 0.000 description 20
- 230000015572 biosynthetic process Effects 0.000 description 18
- 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 15
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 14
- 238000007619 statistical method Methods 0.000 description 14
- 230000002829 reductive effect Effects 0.000 description 13
- 108010018924 Heme Oxygenase-1 Proteins 0.000 description 12
- 230000001771 impaired effect Effects 0.000 description 12
- 108010086246 Glucagon-Like Peptide-1 Receptor Proteins 0.000 description 11
- 102100028006 Heme oxygenase 1 Human genes 0.000 description 11
- 230000000302 ischemic effect Effects 0.000 description 11
- 102100024616 Platelet endothelial cell adhesion molecule Human genes 0.000 description 10
- 102000010400 1-phosphatidylinositol-3-kinase activity proteins Human genes 0.000 description 9
- 101000588302 Homo sapiens Nuclear factor erythroid 2-related factor 2 Proteins 0.000 description 9
- 102100031701 Nuclear factor erythroid 2-related factor 2 Human genes 0.000 description 9
- 108091007960 PI3Ks Proteins 0.000 description 9
- 101001109714 Rhizobium meliloti (strain 1021) NAD(P)H dehydrogenase (quinone) 1 Proteins 0.000 description 9
- 210000004369 blood Anatomy 0.000 description 9
- 239000008280 blood Substances 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 9
- 238000010166 immunofluorescence Methods 0.000 description 9
- 102000007446 Glucagon-Like Peptide-1 Receptor Human genes 0.000 description 8
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 8
- 102100028452 Nitric oxide synthase, endothelial Human genes 0.000 description 8
- 101710090055 Nitric oxide synthase, endothelial Proteins 0.000 description 8
- 210000004204 blood vessel Anatomy 0.000 description 8
- 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 8
- 229930195725 Mannitol Natural products 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 7
- 235000021314 Palmitic acid Nutrition 0.000 description 7
- 210000003414 extremity Anatomy 0.000 description 7
- 230000006872 improvement Effects 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 208000028867 ischemia Diseases 0.000 description 7
- 239000000594 mannitol Substances 0.000 description 7
- 235000010355 mannitol Nutrition 0.000 description 7
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 7
- 108010051975 Glycogen Synthase Kinase 3 beta Proteins 0.000 description 6
- 102100038104 Glycogen synthase kinase-3 beta Human genes 0.000 description 6
- 102100033810 RAC-alpha serine/threonine-protein kinase Human genes 0.000 description 6
- 230000008081 blood perfusion Effects 0.000 description 6
- UQLDLKMNUJERMK-UHFFFAOYSA-L di(octadecanoyloxy)lead Chemical compound [Pb+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O UQLDLKMNUJERMK-UHFFFAOYSA-L 0.000 description 6
- 230000036542 oxidative stress Effects 0.000 description 6
- 230000037361 pathway Effects 0.000 description 6
- 238000001356 surgical procedure Methods 0.000 description 6
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 6
- 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 5
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 description 5
- 102100023347 Proto-oncogene tyrosine-protein kinase ROS Human genes 0.000 description 5
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 5
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 5
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 5
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 230000003247 decreasing effect Effects 0.000 description 5
- 230000003511 endothelial effect Effects 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000008103 glucose Substances 0.000 description 5
- 210000002027 skeletal muscle Anatomy 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 4
- 101000851018 Homo sapiens Vascular endothelial growth factor receptor 1 Proteins 0.000 description 4
- 102000004877 Insulin Human genes 0.000 description 4
- 108090001061 Insulin Proteins 0.000 description 4
- 108010045717 Proto-Oncogene Proteins c-akt Proteins 0.000 description 4
- 102000005765 Proto-Oncogene Proteins c-akt Human genes 0.000 description 4
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 description 4
- 210000002889 endothelial cell Anatomy 0.000 description 4
- 229940125396 insulin Drugs 0.000 description 4
- 108010082117 matrigel Proteins 0.000 description 4
- 108020004999 messenger RNA Proteins 0.000 description 4
- 230000026731 phosphorylation Effects 0.000 description 4
- 238000006366 phosphorylation reaction Methods 0.000 description 4
- 230000002980 postoperative effect Effects 0.000 description 4
- 230000001681 protective effect Effects 0.000 description 4
- 210000000130 stem cell Anatomy 0.000 description 4
- 230000002792 vascular Effects 0.000 description 4
- 208000021331 vascular occlusion disease Diseases 0.000 description 4
- 102100032882 Glucagon-like peptide 1 receptor Human genes 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 102100040918 Pro-glucagon Human genes 0.000 description 3
- 206010053648 Vascular occlusion Diseases 0.000 description 3
- 230000003078 antioxidant effect Effects 0.000 description 3
- -1 blood pressure Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003925 fat Substances 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 210000005259 peripheral blood Anatomy 0.000 description 3
- 239000011886 peripheral blood Substances 0.000 description 3
- 229920001184 polypeptide Polymers 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 3
- 229960001052 streptozocin Drugs 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- WSEVKKHALHSUMB-RYVRVIGHSA-N (4S)-4-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2R)-5-amino-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-3-carboxypropanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxypropanoyl]amino]hexanoyl]amino]-5-oxopentanoyl]amino]-4-methylsulfanylbutanoyl]amino]-4-carboxybutanoyl]amino]-4-carboxybutanoyl]amino]-5-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S,3S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-4-amino-1-[[2-[[2-[(2S)-2-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-1-[(2S)-2-[(2S)-2-[(2S)-2-[[(2S)-1-amino-3-hydroxy-1-oxopropan-2-yl]carbamoyl]pyrrolidine-1-carbonyl]pyrrolidine-1-carbonyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]carbamoyl]pyrrolidin-1-yl]-2-oxoethyl]amino]-2-oxoethyl]amino]-1,4-dioxobutan-2-yl]amino]-1-oxohexan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-1-oxopropan-2-yl]amino]-5-oxopentanoic acid Chemical compound CC[C@H](C)[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(N)=O WSEVKKHALHSUMB-RYVRVIGHSA-N 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- BPYKTIZUTYGOLE-IFADSCNNSA-N Bilirubin Chemical compound N1C(=O)C(C)=C(C=C)\C1=C\C1=C(C)C(CCC(O)=O)=C(CC2=C(C(C)=C(\C=C/3C(=C(C=C)C(=O)N\3)C)N2)CCC(O)=O)N1 BPYKTIZUTYGOLE-IFADSCNNSA-N 0.000 description 2
- 241000283707 Capra Species 0.000 description 2
- 206010048554 Endothelial dysfunction Diseases 0.000 description 2
- 101800000224 Glucagon-like peptide 1 Proteins 0.000 description 2
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 2
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 2
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 2
- 101150031207 NOS3 gene Proteins 0.000 description 2
- 238000011529 RT qPCR Methods 0.000 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- 208000025865 Ulcer Diseases 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000002491 angiogenic effect Effects 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 210000001185 bone marrow Anatomy 0.000 description 2
- 230000000254 damaging effect Effects 0.000 description 2
- 230000006735 deficit Effects 0.000 description 2
- 230000003828 downregulation Effects 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 230000008694 endothelial dysfunction Effects 0.000 description 2
- 108010024703 exendin (9-39) Proteins 0.000 description 2
- 210000001105 femoral artery Anatomy 0.000 description 2
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 229960002725 isoflurane Drugs 0.000 description 2
- 201000002818 limb ischemia Diseases 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 239000003642 reactive oxygen metabolite Substances 0.000 description 2
- 229940044601 receptor agonist Drugs 0.000 description 2
- 239000000018 receptor agonist Substances 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 230000008929 regeneration Effects 0.000 description 2
- 238000011069 regeneration method Methods 0.000 description 2
- 230000008439 repair process Effects 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 238000002604 ultrasonography Methods 0.000 description 2
- 238000001262 western blot Methods 0.000 description 2
- 230000006269 (delayed) early viral mRNA transcription Effects 0.000 description 1
- ZAUYNCUCMJDAHW-UHFFFAOYSA-N 1-ethenylpyrrolidin-2-one;hydrogen peroxide;molecular iodine Chemical compound OO.II.C=CN1CCCC1=O ZAUYNCUCMJDAHW-UHFFFAOYSA-N 0.000 description 1
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 1
- 108010005094 Advanced Glycation End Products Proteins 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010060965 Arterial stenosis Diseases 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 1
- 238000009010 Bradford assay Methods 0.000 description 1
- 101100337060 Caenorhabditis elegans glp-1 gene Proteins 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 102000001039 Dystrophin Human genes 0.000 description 1
- 108010069091 Dystrophin Proteins 0.000 description 1
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 description 1
- 206010017711 Gangrene Diseases 0.000 description 1
- 101800001586 Ghrelin Proteins 0.000 description 1
- 102400000442 Ghrelin-28 Human genes 0.000 description 1
- 101710088172 HTH-type transcriptional regulator RipA Proteins 0.000 description 1
- 101500028772 Homo sapiens Glucagon-like peptide 1(7-36) Proteins 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010029113 Neovascularisation Diseases 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- 239000012828 PI3K inhibitor Substances 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 208000032023 Signs and Symptoms Diseases 0.000 description 1
- 241000532784 Thelia <leafhopper> Species 0.000 description 1
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 208000024248 Vascular System injury Diseases 0.000 description 1
- 208000012339 Vascular injury Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 230000035508 accumulation Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000013228 adult male C57BL/6J mice Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000002266 amputation Methods 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 239000002870 angiogenesis inducing agent Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000000702 anti-platelet effect Effects 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 230000004900 autophagic degradation Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000006059 cover glass Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000000042 effect on ischemia Effects 0.000 description 1
- 210000003989 endothelium vascular Anatomy 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 210000003158 enteroendocrine cell Anatomy 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 210000004700 fetal blood Anatomy 0.000 description 1
- 238000007667 floating Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 230000005176 gastrointestinal motility Effects 0.000 description 1
- 238000012252 genetic analysis Methods 0.000 description 1
- GNKDKYIHGQKHHM-RJKLHVOGSA-N ghrelin Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)CN)COC(=O)CCCCCCC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C1=CC=CC=C1 GNKDKYIHGQKHHM-RJKLHVOGSA-N 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 150000003278 haem Chemical class 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- 238000012165 high-throughput sequencing Methods 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 238000003125 immunofluorescent labeling Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 210000004153 islets of langerhan Anatomy 0.000 description 1
- 210000003127 knee Anatomy 0.000 description 1
- 210000002414 leg Anatomy 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000010060 microvascular dysfunction Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 235000021590 normal diet Nutrition 0.000 description 1
- 230000004942 nuclear accumulation Effects 0.000 description 1
- 238000012261 overproduction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 230000003076 paracrine Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 229940043441 phosphoinositide 3-kinase inhibitor Drugs 0.000 description 1
- 230000000865 phosphorylative effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 230000001023 pro-angiogenic effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000009822 protein phosphorylation Effects 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 150000004053 quinones Chemical class 0.000 description 1
- 238000010814 radioimmunoprecipitation assay Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 230000005586 smoking cessation Effects 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 238000011476 stem cell transplantation Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000011285 therapeutic regimen Methods 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 230000006496 vascular abnormality Effects 0.000 description 1
- 230000004218 vascular function Effects 0.000 description 1
- 231100000216 vascular lesion Toxicity 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000003313 weakening effect Effects 0.000 description 1
- 238000004260 weight control Methods 0.000 description 1
- 239000013585 weight reducing agent Substances 0.000 description 1
- QDLHCMPXEPAAMD-QAIWCSMKSA-N wortmannin Chemical compound C1([C@]2(C)C3=C(C4=O)OC=C3C(=O)O[C@@H]2COC)=C4[C@@H]2CCC(=O)[C@@]2(C)C[C@H]1OC(C)=O QDLHCMPXEPAAMD-QAIWCSMKSA-N 0.000 description 1
- QDLHCMPXEPAAMD-UHFFFAOYSA-N wortmannin Natural products COCC1OC(=O)C2=COC(C3=O)=C2C1(C)C1=C3C2CCC(=O)C2(C)CC1OC(C)=O QDLHCMPXEPAAMD-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/26—Glucagons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Diabetes (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Vascular Medicine (AREA)
- Epidemiology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Endocrinology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Emergency Medicine (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Urology & Nephrology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
一种GLP‑1受体激动剂在制备治疗下肢动脉闭塞药物中的应用，增强EPCs抗氧化损伤，尤其是对EPCs的高糖损伤起到保护作用，改善其促血管生成功能，尤其是改善糖尿病下肢动脉闭塞后组织血流灌注，为DPAD的治疗提供新方案。
Description
技术领域
本发明涉及一种多肽的医药第二用途，尤其涉及一种GLP-1受体激动剂作为药物而促进缺血下肢新生血管形成的应用。
背景技术
糖尿病外周动脉病变(Diabetic PeripherialArterial Disease，DPAD)，是长期高糖诱发血管内皮受损，继而引起动脉粥样硬化病变或血栓形成而导致下肢动脉狭窄或闭塞，组织缺血缺氧，继发下肢损伤、溃疡、感染、坏疽、甚至截肢的一种外周血管病变。
DPAD的病变范围主要集中于膝以下末端小血管，究其原因可能与晚期糖基化终产物、氧化应激动脉硬化、血栓形成异常、低度感染、内皮功能障碍及微血管功能障碍相关。其中内皮细胞功能受损是其启动和关键的因素。内皮细胞在血管壁和管腔中分泌多种旁分泌因子。在病理情况下，内皮功能障碍引起结构性、血液动力学和功能性血管异常，改变血管反应性和舒张性，并形成动脉粥样硬化。
DPAD的治疗包括纠正不良生活方式，如戒烟、控制体重，严格控制血糖、血压、血脂，抗血小板及抗凝治疗，扩血管药物治疗，综合干预后仍不能改善症状和溃疡愈合时再考虑给予血管重建,但总体来说，治疗效果远不及预期。有部分研究也报道了干细胞移植有可能改善糖尿病下肢缺血的症状和体征，但是由于干细胞获取和使用涉及到的伦理问题及外周血动员后可能造成的凝血功能障碍，并未在临床广泛使用。DPAD当前的治疗方案主要为调脂、抗血小板聚集、扩血管等支持治疗，尚无特效药，亟需研发能改善糖尿病下肢缺血后促进血管新生的药物。
内皮祖细胞(Endothelial progenitor cells，EPCs)在触发血管生成以及维持内皮稳态方面起着关键作用。EPCs通过直接整合到缺血部位形成新血管(Autophagy,2018,14(10):1677-1692；Biol Rev Camb Philos Soc,2015,90(3):927-963)或分泌促血管生成因子(Diabetes,1993,42(6):801-813)来促进血管生成。局部或全身施用来自骨髓(FEBSLett,2003,546(1):154-158)、脐带血(Proc Natl Acad Sci U S A,2001,98(12):6611-6616)或外周血(Int J Cardiol,2014,174(2):230-242)的EPCs可以增强缺血部位新血管形成，改善患有后肢或心肌缺血动物缺血组织功能。然而，在1型(Cardiovasc Diabetol,2005,4:9)和2型(Curr Pharm Biotechnol,2011,12(3):386-391)糖尿病中，循环EPCs的数量均减少且功能受损，导致血管生成和修复能力减弱。研究表明，活性氧(Reactive OxygenSpecies,ROS)过量生成和炎症加剧导致EPCs功能障碍的重要因素(Pharmacol Res,2007,55(6):498-510；N Engl J Med,1988,318(20):1315-1321；Arterioscler Thromb VascBiol,2004,24(8):1342-1349)。因此，增强EPCs抗氧化损伤，改善EPCs促血管生成功能，是DPAD药物开发的策略之一。
发明内容
本发明的一个目的在于提供一种GLP-1受体激动剂在制备对EPC的高糖损伤起到保护作用的药物中的应用，增强EPCs抗氧化损伤，改善EPCs促血管生成功能。
本发明的另一个目的在于提供一种GLP-1受体激动剂在制备治疗血管闭塞疾病的药物中的应用，为血管闭塞提供治疗新方案。
本发明的再一个目的在于提供一种GLP-1受体激动剂在制备治疗下肢动脉闭塞的药物中的应用，改善糖尿病下肢动脉闭塞，为DPAD的治疗提供新方案。
胰高血糖素样肽-1(Glucagon like peptide-1，GLP-1)是一种主要由肠内分泌细胞产生的脑肠肽，通过调节胰岛素的分泌，胃肠道蠕动和食物摄入来控制葡萄糖代谢。GLP-1(7-36)系与beta胰岛细胞上的受体结合，并促进胰岛素的分泌的天然多肽。在此等发现的基础上，为了提高GLP-1的体内半衰期，延长给药周期，提高患者的给药顺应性等而应用生物手段，通过替换部分氨基酸提高酶切稳定性，和/或通过化学手段对人源性GLP-1(7-36)的多肽进行修饰(如：酰基化、聚乙二醇化或蛋白偶联)得到，如：利拉鲁肽和索马鲁肽。由此产生了各类GLP-1衍生物，均能在生物体内与GLP-1受体结合，在此统称为GLP-1受体激动剂。
经验证，激光多普勒超声检测1型糖尿病和db/db2型糖尿病小鼠各组下肢血流灌注量，与下肢股动脉结扎术前一天相比，各组小鼠术后当天后肢血流灌注量急剧减少(p<0.001)。与术后28天相比，各组小鼠后肢血流灌注量缓慢改善。与对照组相比，GLP-1受体激动剂给药组的动物体内CD31(主要在血管内皮表达)表达显著增加(p<0.001)。
内皮祖细胞(EPCs)是出生后促进血管新生的最关键细胞，验证了EPC上有GLP-1受体的表达。WB检测EPC上GLP-1受体蛋白表达，结果显示：糖浓度为5.5、15、25mM时，GLP1R蛋白表达量无明显改变。糖浓度为33mM时，GLP1R蛋白表达显著下降。选择糖浓度25mM于划痕实验及Matrigel管形成测定法检测EPC迁移、成管能力，结果显示：与对照组相比，高糖组EPC迁移、成管能力下降(p<0.01)。不同浓度(3μg/ml、6μg/ml和12μg/ml)GLP-1受体激动剂进行干预，与高糖组相比，浓度为6μg/ml时，EPC迁移能力改善(p<0.01)。浓度为12μg/ml时，迁移能力改善显著(p<0.01)，且成管能力改善(p<0.01)，
与对照组相比，高糖组一氧化氮(NO)表达量下降。与高糖组相比，GLP-1受体激动剂损伤干预组NO表达量改善。蛋白印迹WB检测各组动物的Akt、p-Akt、eNOS和p-eNOS蛋白表达变化显示：与对照组相比，高糖组Akt及eNOS磷酸化下降。与高糖组相比，GLP-1受体激动剂干预损伤组p-Akt、p-eNOS显著上升，且单独予以GLP-1受体激动剂处理，也具有提升效果。
由此，GLP-1受体激动剂可改善糖尿病后肢缺血小鼠下肢血流灌注量，其作用独立于降低血糖，而通过PI3k/Akt/eNOS/NO通路改善EPC成管迁移功能，促进缺血部位血管新生。对GLP-1受体激动剂的现有认知限于作为调节代谢，如：血糖和血脂等方面，本申请发现了GLP-1受体激动剂在受高糖损伤的EPCs具有保护作用，能增强EPCs抗氧化损伤，改善EPCs促血管生成功能，促进血管修复。
因此，将GLP-1受体激动剂作为活性成分制成药物，以改善受高糖损伤的动脉血管功能，改善患者的下肢血管闭塞临床症状，尤其是改善糖尿病下肢动脉闭塞，为DPAD的治疗提供新方案。
附图说明
图1为对2型糖尿病下肢动脉闭塞的下肢血流灌注的统计分析图，**P<0.01；
图2为对1型糖尿病下肢动脉闭塞的下肢血流灌注的统计分析图，**P<0.05；
图3为免疫荧光检测2型糖尿病组腓肠肌CD31表达统计分析图，**P<0.05；
图4为免疫荧光检测1型糖尿病组腓肠肌CD31表达统计分析图，**P<0.05；
图5为VEGF、VEGFR1和VEGFR2各自的相对mRNA表达量，*P＜0.05,**P＜0.01，***P＜0.001；
图6为EPCs管样结构形成功能分析统计图，*P<0.05相比于Mannitol，#P<0.05相比于高糖；
图7为EPCs迁移能力统计分析统计图，*P<0.05相比于Mannitol，#P<0.05相比于高糖；
图8为加入GLP-1受体拮抗剂后EPCs管样结构形成功能分析统计图，*P<0.05相比于Mannitol，**P<0.01相比于Mannitol，##P<0.01相比于高糖，&P<0.05相比于高糖和GLP-1激动剂给药组；
图9为加入GLP-1受体拮抗剂后EPCs迁移能力统计分析统计图，*P<0.05相比于Mannitol，**P<0.01相比于Mannitol，##P<0.01相比于高糖，&P<0.05相比于高糖和GLP-1激动剂给药组；
图10为P-AKT/AKT蛋白表达统计图，*P＜0.05，**P＜0.01，***P＜0.001；
图11为P-ENOS/ENOS蛋白表达统计图，*P＜0.05，**P＜0.01，***P＜0.001；
图12为各组EPCs成管统计图，**P<0.01为Ctrl-siRNA组或Nrf2-siRNA组相比于甘露醇组(Man)，#P<0.05为相比于Ctrl-siRNA高糖(HG)组或Nrf2-siRNA高糖(HG)组，&&P<0.01相比于Ctrl-siRNA-HG+Lira组；
图13为各组EPCs迁移统计图，**P<0.01为Ctrl-siRNA组或Nrf2-siRNA组相比于甘露醇组(Man)，#P<0.05为相比于Ctrl-siRNA高糖(HG)组或Nrf2-siRNA高糖(HG)组，&&P<0.01相比于Ctrl-siRNA-HG+Lira组；
图14为抑制PI3K后，WB检测GLP-1受体激动剂对高糖损伤的EPCs Akt/GSK-3β/Fyn统计图；其中，图A为p-Akt/Akt统计分析图，图B为p-GSK-3β/GSK-3β统计分析图，图C为核内Fyn蛋白量统计分析图，图D为核内Nrf2蛋白量统计分析图，*P<0.05相比于甘露醇组(Man)，**P<0.01相比于甘露醇组(Man)，#P<0.05相比于高糖组(HG)，##P<0.01相比于高糖组(HG)，&P<0.05相比于Lira给药高糖组(Lira+HG)，&&P<0.01相比于Lira给药高糖组(Lira+HG)；
图15位抑制PI3K后，WB检测GLP-1受体激动剂对高糖损伤的EPCs氧化应激影响的统计分析图；其中，图A为HO-1蛋白含量统计分析图，图B为ROS表达统计分析图，**P<0.01相比于甘露醇组(Man)，##P<0.01相比于高糖组(HG)，&&P<0.01相比于Lira给药高糖组(Lira+HG)；
图16位抑制PI3K后，GLP-1受体激动剂对高糖损伤的EPCs成管、迁移功能影响统计分析图，其中，图A为EPCs成管统计分析图，图B为EPCs迁移统计分析图，*P<0.05相比于甘露醇组(Man)，#P<0.05相比于高糖组(HG)，&P<0.05相比于Lira给药高糖组(Lira+HG)。
具体实施方式
以下结合附图详细描述本发明的技术方案。本发明实施例仅用以说明本发明的技术方案而非限制，尽管参照较佳实施例对本发明进行了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的精神和范围，其均应涵盖在本发明的权利要求范围中。
本发明以下实施例所用的各项试验方法具体说明如下：
1)动物和实验方案
购自江苏集萃药康生物科技有限公司(南京大学模式动物)的成年雄性C57BL/6J鼠(2-3月)和北京维通利华实验动物技术有限公司的成年雄性db/db鼠(2-3月)，在恒定的室温下以12:12小时的光-暗循环圈养。小鼠喂食正常饮食(ND，温州医科大学实验动物中心)，将雄性db/db小鼠和通过腹腔注射链脲佐菌素(Streptozocin，STZ)诱导的小鼠1型糖尿病模型，分别平均分为两组(n＝10/组)，建立HLI模型。一组在手术后每日皮下注射GLP-1受体激动剂(200μg/kg，一次)28天。另一组用生理盐水作为载体对照。手术后28天，小鼠被安乐死收集血液和腓肠肌和内收肌样本。HLI程序简述如下：在使用异氟烷(1-3％异氟烷，100％氧气，流速为1升/分钟)的情况下进行充分麻醉，后肢剃毛，然后用6-0线结扎整个右股动脉及其远端分支，剪刀剪断。用4-0线缝合皮肤。
2)血流灌注的测量
为了评估肢体灌注率[缺血性肢体(右)/正常肢体(左)]，使用激光多普勒血流灌注成像(Laser Doppler Perfusion Image，LDPI)(美国纽约州金斯公园的Perimed Inc.)在手术前以及手术后第0、3、7、14、21、28和35天进行了实时微循环成像分析。
3)免疫荧光染色
下肢缺血的模型建立后，28天处死小鼠，取右侧手术腿腓肠肌做冰冻切片，甲醇固定5分钟，PBST缓冲液浸泡3次，每次5分钟。5％的山羊血清封闭切片10分钟。PBST缓冲液浸泡3次，每次5分钟。加入入5％的山羊血清封闭液Dystrophin一抗稀释液(1:100)，4°孵育过夜。取出玻片，PBST缓冲液浸泡3次，每次5分钟。滴加一滴一定稀释度(1:100)的荧光二抗(594红，1:1000，溶液PBST),室温，30min，取出玻片，PBST缓冲液浸泡3次，每次5分钟。孵育CD31(绿色，1:250)，室温，1h。PBST缓冲液浸泡3次，每次5分钟。滴加一滴含DAPI的抗荧光淬灭剂封片，再覆以盖玻片封片。
4)成管试验
EPC的体外血管生成能力通过Matrigel管形成测定法确定。将血管生成载玻片涂上基质凝胶(10μl/孔，Corning 354230)。待30min后基质胶凝固，将EPC(1.75×105个细胞/孔)在37℃和5％CO2培养箱中孵育8小时形成管样结构。然后在存在或不存在GLP-1受体激动剂的情况下，在指定的时间内持续暴露于HG。使用倒置显微镜(Nikon Eclipse E600，Nikon，Kanagawa，Japan)获取每个孔中试管的图像。通过ImageJ软件计算成管长度。
5)迁移实验
胰酶消化细胞，并将细胞均匀接种至6孔板。待细胞生长至90％融合度时，将培养液换成无FBS培养液，放入培养箱中培养1h。每孔用200μL枪头比着直尺画一“十”字形划痕，尽量保证划痕宽度一致。PBS漂洗3次，去除漂浮的细胞，并加入无FBS培养液。培养48h后在显微镜下于固定位置取样并拍照。使用ImageJ软件测量细胞迁移距离。
6)蛋白质印迹分析(WB检测)
将腓肠肌组织和不同处理的细胞在冰冷的RIPA裂解缓冲液(Cell LysisBuffer(10×)CST,9803)中匀浆或裂解。使用Bradford蛋白测定试剂(Bio-Rad，Hercules，CA，美国)测定蛋白浓度。通过10％十二烷基硫酸钠聚丙烯酰胺凝胶电泳(SDS-PAGE)分离总蛋白质，并转移至硝酸纤维素膜(Bio-Rad)。将膜在含5％脱脂牛奶封闭1小时，然后与一抗在4℃下孵育过夜，然后与二抗在室温下孵育1小时经过标准的洗涤程序。3-磷酸甘油醛脱氢酶(GAPDH，1：5000)和b-肌动蛋白(1：3000)的一抗购自Santa Cruz Biotechnology；p-AKT(1：1000)、AKT(1:1000)购自Bioworld；CD31(1:1000)、p-eNOS(1:1000)、GLP-1R(1:1000)购自abcam；eNOS购自Affinity。所有辣根过氧化物酶(HRP)偶联的二抗均购自Santa CruzBiotechnology。使用SuperSignal West Femto最大灵敏度底物(Thermo Scientic)可视化印迹，并使用Quantity 5.2软件(Bio-Rad)定量。
实施例1GLP-1受体激动剂对糖尿病下肢动脉闭塞的下肢血流灌注影响
db/db小鼠为经典2型糖尿病自发模型，经HLI术处理后，用GLP-1受体激动剂(利拉鲁肽，GLP1RA)Lira干预，通过激光多普勒超声检测小鼠后肢血流灌注量，评估Lira对小鼠缺血后肢血流灌注影响。应用激光多普勒超声检测小鼠后肢的血流灌注，结果显示：与术前相比，各组小鼠术后当天后肢血流灌注量急剧减少，提示HLI造模成功。与术后当天相比，NS组与Lira组小鼠术后恢复期缺血后肢血流灌注量均有改善，且Lira组血流恢复较NS组好，在术后第14天出现显著性差异(P<0.01)，效果持续至实验结束(参见图1)。表明GLP-1受体激动剂对2型糖尿病T2DM HLI小鼠缺血后肢血流灌注有改善作用。
因为GLP-1RA对2型糖尿病同时具有降低血糖和减轻体重的作用，其血管新生功能可能是因为机体代谢改善后的结果，为进一步明确GLP-1RA独立于降糖以外的促进动脉闭塞后缺血部位的血管新生能力，本实施例又选用了第二种动物模型---1型糖尿病下肢动脉闭塞模型，通过注射STZ特异性破坏了小鼠胰腺β细胞造模，该模型可明确该药的血管新生作用不依赖于胰岛素的作用，与降糖减重的作用无关。同样观察到GLP1RA对1型糖尿病下肢动脉闭塞模型的下肢血管新生作用，结果显示，Lira组缺血后肢血流灌注改善优于NS组，在第21天出现显著性差异(P<0.05)，至第28天效果仍然持续，参见图2。表明GLP-1受体激动剂对1型糖尿病T1DM HLI小鼠缺血后肢血流灌注同样具有改善作用。
由此可见，GLP-1受体激动剂可促进糖尿病小鼠下肢血流恢复，且此作用独立于降糖作用。
实施例2GLP-1受体激动剂促进糖尿病下肢血管闭塞后的血管新生
血小板内皮细胞粘附分子CD31通常表达于内皮细胞，被用来评估血管数量。应用免疫荧光与WB检测NS组与GLP-1RA组缺血后肢腓肠肌CD31表达。免疫荧光结果显示(参见图3)，GLP-1RA组CD31表达较NS组明显增高(P<0.01)，WB结果与免疫荧光结果一致(P<0.01)。这表明GLP-1受体激动剂可促进Ⅱ型糖尿病T2DM-HLI小鼠缺血后血管生成。
应用免疫荧光与WB检测1型糖尿病T1DM HLI小鼠NS组与GLP-1RA组缺血后肢腓肠肌CD31表达。免疫荧光结果显示(参见图4)，GLP-1RA组CD31表达较NS组明显增高(P<0.01)。WB结果与免疫荧光结果一致(P<0.01)。这表明GLP-1受体激动剂同样可促进T1DM-HLI小鼠缺血后肢血管生成。
VEGF与VEGFR2的结合，是促进血管新生重要的因素。如图5所示：与正常对照组相比，高脂喂养(HFD)糖尿病组下肢骨骼肌VEGF、VEGFR1、VEGFR2的mRNA表达显著下降；GLP-1受体激动剂(lira)给药组的大鼠VEGF、VEGFR1、VEGFR2的mRNA表达显著增加(P<0.05)。GLP-1受体激动剂保留糖尿病组下肢骨骼肌毛细血管密度，又增加骨骼肌VEGF、VEGFR1、VEGFR2的mRNA表达，表明血管新生。
实施例3GLP-1受体激动剂对EPC迁移、成管功能的作用
当机体内因血管损伤发生缺血时，可诱导骨髓、外周血处的EPCs迁移至缺血处，形成新生血管，修复受损血管。而在糖尿病条件下，EPCs血管生成功能障碍。本实验通过体外基质胶成管实验、细胞划痕检测EPCs管样结构形成、迁移能力。如图6和图7所示：与甘露醇组相比(*)，高糖组(葡萄糖)EPCs成管(P<0.05)、迁移(P<0.05)功能降低，高糖损伤成管。与高糖组相比(#)，GLP-1受体激动剂(Lira)以剂量依赖性方式恢复了EPCs成管、迁移功能，减轻高糖对成管能力的损伤，且浓度为12μg/ml时，EPCs管样结构形成(P<0.05)、迁移(P<0.05)改善最显著。因此，选择Lira浓度12μg/ml用于后续实验。
Exendin(9-39)是公认的GLP-1R拮抗剂，应用Exendin(9-39)阻断GLP-1R后，观察Lira对高糖损伤的EPCs的成管、迁移功能影响。如图8和图9所示：与甘露醇相比(**)，高糖损伤成管。与高糖组相比(##)，GLP-1受体激动剂减轻高糖对成管能力的损伤，与GLP-1受体激动剂干预的高糖组相比(&&)，减少高糖对成管能力的损伤作用被抑制。高糖导致EPCs成管(P<0.01)、迁移(P<0.05)功能降低。GLP-1受体激动剂干预改善高糖对EPCs成管(P<0.01)、迁移(P<0.01)的损伤作用。而GLP-1受体被阻断后，GLP-1受体激动剂对EPCs成管(P<0.05)、迁移(P<0.05)的促进作用被抑制。
由此证实EPC上存在GLP-1受体激动剂受体表达。与对照组相比，高糖处理可损伤EPC迁移与成管能力，而GLP-1受体激动剂干预可改善其功能，且其作用存在量效关系。GLP-1受体激动剂改善糖尿病小鼠下肢血流灌注量与增强EPC迁移与成管功能相关。
实施例4GLP-1受体激动剂对高糖损伤的EPCs氧化应激基因NQO-1、HO-1表达影响
血管在高糖环境下处于氧化应激状态。大量活性氧的堆积损伤DNA、蛋白质、脂类的同时，也影响EPCs的成管与迁移功能。为探究Lira对EPCs成管、迁移的改善作用是否与减弱EPCs氧化应激相关，应用高通量测序对各组细胞进行基因分析。结果显示，GLP-1受体激动剂(Lira)使631个基因上调，509个基因下调，其中NQO-1、HO-1基因的表达被高葡萄糖抑制并在Lira处理后升高。NQO-1是一种还原辅因子，可将各种醌类化合物还原，从而阻断其通过代谢生成ROS。而HO-1可将机体内的血红素降解，并生成具有抗氧化作用的胆红素。应用qPCR与WB检测各组抗氧化基因NQO-1、HO-1mRNA含量及其蛋白的表达，对测序结果进行印证。qPCR结果显示，抗氧化基因NQO-1(P<0.05)和HO-1(P<0.05)在高糖作用下含量降低，而Lira可减轻高糖对NQO-1(P<0.05)和HO-1(P<0.05)基因的降低作用。WB结果显示，高糖组NQO-1(P<0.05)与HO-1(P<0.05)蛋白表达降低，而在Lira干预后，NQO-1(P<0.05)、HO-1(P<0.05)蛋白下降作用缓解。
实施例5GLP-1受体激动剂对高糖损伤的EPCs成管、迁移功能影响
Nrf2是一种关键的抗氧化转录因子，通过与抗氧化反应原件ARE结合，激活下游NQO-1、CAT、HO-1等抗氧化基因转录，发挥抗氧化作用。
通过siRNA-811敲低EPCs Nrf2后，通过成管、迁移实验测定各组EPCs功能。结果显示，高糖引起EPCs成管(P<0.01)、迁移(P<0.01)功能受损。GLP-1受体激动剂(Lira)干预后，可缓和高糖对EPCs成管(P<0.05)、迁移(P<0.05)的损伤作用。但敲低Nrf2后，Lira对高糖损伤的EPCs成管(P<0.01)、迁移(P<0.01)的保护作用被抑制，参见图12和图13。
因此，GLP-1受体激动剂对高糖损伤的EPCs保护作用与Nrf2相关。
实施例6受体激动剂通过PI3K/AKT/ENOS通路增加PA诱导HUVECs的eNOS活性
参见图10和图11，0.6nM软脂酸(PA)干预HUVECs18小时，导致内皮细胞胰岛素AKT/eNOS通路功能受损，通路蛋白磷酸化水平显著降低(P＜0.05)。PA干预18小时后，继续用100nM利拉鲁肽孵育30min，显著恢复由PA诱导降低的P-AKT、P-eNOS的水平(P＜0.05)。以胰岛素作为阳性对照，Wormannin是PI3K抑制剂，在GLP-1受体激动剂(Lira)作用前预先用100nM的Wormannin的浓度干预30min，之后Lira孵育30min，则Lira恢复P-AKT、P-eNOS的功能显著下降(P＜0.05)。表明GLP-1受体激动剂是通过PI3K/AKT/eNOS通路增加PA诱导HUVECs的eNOS活性。P-eNOS特异性抗体的细胞免疫荧光，也可以看出PA干预后P-eNOS蛋白表达减少，
实施例7对PI3K抑制后，考察给予GLP-1受体激动剂对EPCs产生的影响
应用Wortmannin抑制PI3K后，通过WB检测各组EPCs Akt/GSK-3β/Fyn通路相关蛋白表达。结果显示，Lira可缓和高糖对Akt/GSK-3β/Fyn的下调。但抑制PI3K后，Lira对高糖损伤的EPCs Akt磷酸化增加(P<0.05)，GSK-3β磷酸化增加(P<0.05)，核内Fyn(P<0.01)、Nrf2(P<0.01)水平降低的作用被抑制，参见图14。
通过WB与荧光染色检测各组EPCs HO-1蛋白及ROS水平。结果显示，Lira可缓解EPCs在高糖环境下的氧化应激水平。而抑制PI3K后，Lira对高糖损伤的EPCs HO-1(P<0.01)蛋白含量的上调作用及对ROS(P<0.01)的下调作用被抑制，参见图15。
通过成管、迁移实验评估各组EPCs功能。结果显示，与甘露醇组比，高糖引起EPCs成管(P<0.05)、迁移(P<0.05)功能下降。Lira干预可缓解高糖对EPCs成管(P<0.05)、迁移(P<0.05)功能的损伤作用。但抑制PI3K后，Lira对高糖损伤的EPCs成管(P<0.05)、迁移(P<0.05)的改善作用被抑制，参见图16。
由此可见，GLP-1受体激动剂可磷酸化Akt与GSK-3β蛋白，减少Fyn核积聚，提高核Nrf2的含量。当抑制剂抑制AKT的磷酸化后，GLP-1受体激动剂对Nrf2的激活，对EPCS的抗氧化损伤以及促进EPCs的成管、迁移作用都被抑制。这些结果证明了Lira是通磷酸化Akt促进Nrf2对抗氧化基因的转录作用，从而发挥对EPCs的保护作用。
Claims (10)
1.一种GLP-1受体激动剂在制备对EPCs的高糖损伤起到保护作用的药物中的应用。
2.根据权利要求1所述的用途，其特征在于所称的GLP-1受体激动剂为GLP-1(7-36)、酰基化的GLP-1(7-36)、聚乙二醇化的GLP-1(7-36)、蛋白偶联的GLP-1(7-36)、索马鲁肽或利拉鲁肽。
3.根据权利要求1所述的用途，其特征在于所称的GLP-1受体激动剂为利拉鲁肽。
4.一种GLP-1受体激动剂在制备治疗糖尿病外周动脉病变的药物中的应用。
5.根据权利要求4所述的用途，其特征在于所称的GLP-1受体激动剂为GLP-1(7-36)、酰基化的GLP-1(7-36)、聚乙二醇化的GLP-1(7-36)、蛋白偶联的GLP-1(7-36)、索马鲁肽或利拉鲁肽。
6.根据权利要求4所述的用途，其特征在于所称的GLP-1受体激动剂为利拉鲁肽。
7.一种GLP-1受体激动剂在制备治疗下肢动脉闭塞药物中的应用。
8.根据权利要求7所述的用途，其特征在于所称的GLP-1受体激动剂为GLP-1(7-36)、酰基化的GLP-1(7-36)、聚乙二醇化的GLP-1(7-36)、蛋白偶联的GLP-1(7-36)、索马鲁肽或利拉鲁肽。
9.根据权利要求7所述的用途，其特征在于所称的GLP-1受体激动剂为利拉鲁肽。
10.根据权利要求7所述的用途，其特征在于用于制备治疗糖尿病下肢动脉闭塞的药物中的应用。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210444070.0A CN116983408A (zh) | 2022-04-25 | 2022-04-25 | Glp-1受体激动剂在治疗下肢动脉闭塞中的应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210444070.0A CN116983408A (zh) | 2022-04-25 | 2022-04-25 | Glp-1受体激动剂在治疗下肢动脉闭塞中的应用 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116983408A true CN116983408A (zh) | 2023-11-03 |
Family
ID=88521952
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210444070.0A Pending CN116983408A (zh) | 2022-04-25 | 2022-04-25 | Glp-1受体激动剂在治疗下肢动脉闭塞中的应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116983408A (zh) |
-
2022
- 2022-04-25 CN CN202210444070.0A patent/CN116983408A/zh active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Guo et al. | Klotho protects the heart from hyperglycemia-induced injury by inactivating ROS and NF-κB-mediated inflammation both in vitro and in vivo | |
| Nystrom et al. | Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease | |
| Falcao-Pires et al. | Physiological, pathological and potential therapeutic roles of adipokines | |
| Almutairi et al. | Glucagon-like peptide-1 receptor action in the vasculature | |
| Hsieh et al. | Controlled delivery of PDGF-BB for myocardial protection using injectable self-assembling peptide nanofibers | |
| Talukdar et al. | FGF19 and FGF21: In NASH we trust | |
| Wu et al. | Ghrelin attenuates sepsis-induced acute lung injury and mortality in rats | |
| Alessi et al. | Production of plasminogen activator inhibitor 1 by human adipose tissue: possible link between visceral fat accumulation and vascular disease | |
| JP5197012B2 (ja) | 大腸連続性を伴う短腸症候群患者の治療 | |
| Wang et al. | BRD7 mediates hyperglycaemia‐induced myocardial apoptosis via endoplasmic reticulum stress signalling pathway | |
| KR20210024583A (ko) | 요법을 위한 gip/glp1 공효능제 사용 방법 | |
| JP2002512259A (ja) | 組換えヘパリン結合性上皮成長因子様成長因子（ｈｂ−ｅｇｆ）による間質性膀胱炎の治療方法 | |
| JP2010053145A (ja) | 血管形成的に有効なｆｇｆ−２の単位用量および使用方法 | |
| Villanueva et al. | Basic fibroblast growth factor reduces functional and structural damage in chronic kidney disease | |
| Kinsella et al. | Removal of heparan sulfate by heparinase treatment inhibits FGF-2-dependent smooth muscle cell proliferation in injured rat carotid arteries | |
| Wang et al. | Follistatin Attenuates Myocardial Fibrosis in Diabetic Cardiomyopathy via the TGF-β–Smad3 Pathway | |
| Li et al. | Soluble Klotho‐integrin β1/ERK1/2 pathway ameliorates myocardial fibrosis in diabetic cardiomyopathy | |
| WO2014025146A1 (ko) | Ｃ-펩타이드를 포함하는 당뇨성 혈관신생 장애의 예방 또는 치료용 조성물 | |
| US7423019B2 (en) | Agent for inducing conversion of intestinal cells into insulin-producing cells and antidiabetic drug | |
| Kumar et al. | Intravenous sildenafil citrate and post-cardiac surgery acute kidney injury: a double-blind, randomised, placebo-controlled trial | |
| CN116983408A (zh) | Glp-1受体激动剂在治疗下肢动脉闭塞中的应用 | |
| KR20240027053A (ko) | 마즈두타이드의 용도 | |
| CN111944035B (zh) | Fgf4及其应用 | |
| US10617736B2 (en) | Method for modulating insulin-independent glucose transport using teneurin C-terminal associated peptide (TCAP) | |
| WO2020173973A1 (en) | Glp-1 and glucagon receptor co-agonists for use for treating nash |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication |