CN109528738A - Glycyrrhizic acid promotes the application of Remyelination inhibition neuroinflamation drug in preparation - Google Patents
Glycyrrhizic acid promotes the application of Remyelination inhibition neuroinflamation drug in preparation Download PDFInfo
- Publication number
- CN109528738A CN109528738A CN201811580991.XA CN201811580991A CN109528738A CN 109528738 A CN109528738 A CN 109528738A CN 201811580991 A CN201811580991 A CN 201811580991A CN 109528738 A CN109528738 A CN 109528738A
- Authority
- CN
- China
- Prior art keywords
- glycyrrhizic acid
- remyelination
- drug
- application
- differentiation
- 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
- 235000019410 glycyrrhizin Nutrition 0.000 title claims abstract description 97
- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 title claims abstract description 95
- 229960004949 glycyrrhizic acid Drugs 0.000 title claims abstract description 95
- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 title claims abstract description 95
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 title claims abstract description 94
- VTAJIXDZFCRWBR-UHFFFAOYSA-N Licoricesaponin B2 Natural products C1C(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2)C(O)=O)C)(C)CC2)(C)C2C(C)(C)CC1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O VTAJIXDZFCRWBR-UHFFFAOYSA-N 0.000 title claims abstract description 92
- 239000001685 glycyrrhizic acid Substances 0.000 title claims abstract description 92
- 239000003814 drug Substances 0.000 title claims abstract description 15
- 229940079593 drug Drugs 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title claims description 8
- 230000005764 inhibitory process Effects 0.000 title claims description 4
- 102000006386 Myelin Proteins Human genes 0.000 claims abstract description 16
- 108010083674 Myelin Proteins Proteins 0.000 claims abstract description 16
- 210000003169 central nervous system Anatomy 0.000 claims abstract description 14
- 208000016192 Demyelinating disease Diseases 0.000 claims abstract description 12
- 201000006417 multiple sclerosis Diseases 0.000 claims abstract description 8
- 230000001737 promoting effect Effects 0.000 claims abstract description 6
- 206010012305 Demyelination Diseases 0.000 claims abstract description 4
- 210000005012 myelin Anatomy 0.000 claims description 13
- 230000006378 damage Effects 0.000 claims description 5
- 210000004885 white matter Anatomy 0.000 claims description 2
- 208000037976 chronic inflammation Diseases 0.000 claims 1
- 230000006020 chronic inflammation Effects 0.000 claims 1
- 210000004248 oligodendroglia Anatomy 0.000 abstract description 21
- -1 copper hydrazone Chemical class 0.000 abstract description 15
- 229910052802 copper Inorganic materials 0.000 abstract description 14
- 239000010949 copper Substances 0.000 abstract description 14
- 230000001684 chronic effect Effects 0.000 abstract description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 11
- 201000010099 disease Diseases 0.000 abstract description 9
- 238000002474 experimental method Methods 0.000 abstract description 9
- 230000004069 differentiation Effects 0.000 abstract description 8
- 230000001154 acute effect Effects 0.000 abstract description 7
- 230000004054 inflammatory process Effects 0.000 abstract description 7
- 206010061218 Inflammation Diseases 0.000 abstract description 6
- 230000003902 lesion Effects 0.000 abstract description 4
- 210000000535 oligodendrocyte precursor cell Anatomy 0.000 abstract description 4
- 208000032116 Autoimmune Experimental Encephalomyelitis Diseases 0.000 abstract description 3
- 208000012997 experimental autoimmune encephalomyelitis Diseases 0.000 abstract description 3
- 238000000338 in vitro Methods 0.000 abstract description 3
- 230000007246 mechanism Effects 0.000 abstract description 3
- 230000000638 stimulation Effects 0.000 abstract description 3
- 230000002401 inhibitory effect Effects 0.000 abstract description 2
- 102000019058 Glycogen Synthase Kinase 3 beta Human genes 0.000 abstract 1
- 108010051975 Glycogen Synthase Kinase 3 beta Proteins 0.000 abstract 1
- 208000036110 Neuroinflammatory disease Diseases 0.000 abstract 1
- 230000024245 cell differentiation Effects 0.000 abstract 1
- 230000011748 cell maturation Effects 0.000 abstract 1
- 230000003210 demyelinating effect Effects 0.000 abstract 1
- 230000003959 neuroinflammation Effects 0.000 abstract 1
- 238000001243 protein synthesis Methods 0.000 abstract 1
- 230000001105 regulatory effect Effects 0.000 abstract 1
- 230000019491 signal transduction Effects 0.000 abstract 1
- 230000014616 translation Effects 0.000 abstract 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 26
- 201000002491 encephalomyelitis Diseases 0.000 description 24
- 238000012545 processing Methods 0.000 description 19
- 210000004556 brain Anatomy 0.000 description 9
- 238000012744 immunostaining Methods 0.000 description 8
- 238000004043 dyeing Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 230000014509 gene expression Effects 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 230000001575 pathological effect Effects 0.000 description 5
- 210000000278 spinal cord Anatomy 0.000 description 5
- 238000011740 C57BL/6 mouse Methods 0.000 description 4
- 239000006160 differential media Substances 0.000 description 4
- 238000010166 immunofluorescence Methods 0.000 description 4
- 230000006698 induction Effects 0.000 description 4
- 102000012438 2',3'-Cyclic-Nucleotide Phosphodiesterases Human genes 0.000 description 3
- 108010022794 2',3'-Cyclic-Nucleotide Phosphodiesterases Proteins 0.000 description 3
- 239000004378 Glycyrrhizin Substances 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 210000000877 corpus callosum Anatomy 0.000 description 3
- 238000002651 drug therapy Methods 0.000 description 3
- 238000011532 immunohistochemical staining Methods 0.000 description 3
- 230000008595 infiltration Effects 0.000 description 3
- 238000001764 infiltration Methods 0.000 description 3
- 239000007928 intraperitoneal injection Substances 0.000 description 3
- 238000012805 post-processing Methods 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- DSRJIHMZAQEUJV-UHFFFAOYSA-N Cuprizon Chemical compound C1CCCCC1=NNC(=O)C(=O)NN=C1CCCCC1 DSRJIHMZAQEUJV-UHFFFAOYSA-N 0.000 description 2
- 206010033799 Paralysis Diseases 0.000 description 2
- 206010037714 Quadriplegia Diseases 0.000 description 2
- REFJWTPEDVJJIY-UHFFFAOYSA-N Quercetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC=C(O)C(O)=C1 REFJWTPEDVJJIY-UHFFFAOYSA-N 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 230000000767 anti-ulcer Effects 0.000 description 2
- 230000001363 autoimmune Effects 0.000 description 2
- 230000008499 blood brain barrier function Effects 0.000 description 2
- 210000001218 blood-brain barrier Anatomy 0.000 description 2
- 210000005013 brain tissue Anatomy 0.000 description 2
- 210000001638 cerebellum Anatomy 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000009089 cytolysis Effects 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 210000003414 extremity Anatomy 0.000 description 2
- 238000002991 immunohistochemical analysis Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 210000004969 inflammatory cell Anatomy 0.000 description 2
- 230000009545 invasion Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000035800 maturation Effects 0.000 description 2
- 230000009456 molecular mechanism Effects 0.000 description 2
- 230000010412 perfusion Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 238000011069 regeneration method Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- MPDGHEJMBKOTSU-YKLVYJNSSA-N 18beta-glycyrrhetic acid Chemical compound C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C(O)=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-YKLVYJNSSA-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
- KSDSYIXRWHRPMN-UHFFFAOYSA-N 4'-O-beta-D-Galactopyranoside-6''-p-Coumaroylprunin-4',5,7-Trihydroxyflavanone Natural products OC1C(O)C(O)C(CO)OC1OC1=CC=C(C2OC3=CC(O)=CC(O)=C3C(=O)C2)C=C1 KSDSYIXRWHRPMN-UHFFFAOYSA-N 0.000 description 1
- QCVGEOXPDFCNHA-UHFFFAOYSA-N 5,5-dimethyl-2,4-dioxo-1,3-oxazolidine-3-carboxamide Chemical compound CC1(C)OC(=O)N(C(N)=O)C1=O QCVGEOXPDFCNHA-UHFFFAOYSA-N 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 208000003643 Callosities Diseases 0.000 description 1
- 108010005939 Ciliary Neurotrophic Factor Proteins 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- 241001492222 Epicoccum Species 0.000 description 1
- 102000002254 Glycogen Synthase Kinase 3 Human genes 0.000 description 1
- 108010014905 Glycogen Synthase Kinase 3 Proteins 0.000 description 1
- MPDGHEJMBKOTSU-UHFFFAOYSA-N Glycyrrhetinsaeure Natural products C12C(=O)C=C3C4CC(C)(C(O)=O)CCC4(C)CCC3(C)C1(C)CCC1C2(C)CCC(O)C1(C)C MPDGHEJMBKOTSU-UHFFFAOYSA-N 0.000 description 1
- 241000202807 Glycyrrhiza Species 0.000 description 1
- 244000303040 Glycyrrhiza glabra Species 0.000 description 1
- 235000006200 Glycyrrhiza glabra Nutrition 0.000 description 1
- 241000725303 Human immunodeficiency virus Species 0.000 description 1
- 206010020649 Hyperkeratosis Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 229930194248 Licoflavone Natural products 0.000 description 1
- MEHHCBRCXIDGKZ-UHFFFAOYSA-N Licoflavone C Natural products CC(C)=CCC1=C(O)C=C(O)C(C(C=2)=O)=C1OC=2C1=CC=C(O)C=C1 MEHHCBRCXIDGKZ-UHFFFAOYSA-N 0.000 description 1
- DEMKZLAVQYISIA-ONJCETCRSA-N Liquiritin Natural products O([C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1)c1ccc([C@@H]2Oc3c(C(=O)C2)ccc(O)c3)cc1 DEMKZLAVQYISIA-ONJCETCRSA-N 0.000 description 1
- DEMKZLAVQYISIA-UHFFFAOYSA-N Liquirtin Natural products OC1C(O)C(O)C(CO)OC1OC1=CC=C(C2OC3=CC(O)=CC=C3C(=O)C2)C=C1 DEMKZLAVQYISIA-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 101100310648 Mus musculus Sox17 gene Proteins 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 1
- 208000003926 Myelitis Diseases 0.000 description 1
- 201000005702 Pertussis Diseases 0.000 description 1
- 108010081690 Pertussis Toxin Proteins 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- ZVOLCUVKHLEPEV-UHFFFAOYSA-N Quercetagetin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=C(O)C(O)=C(O)C=C2O1 ZVOLCUVKHLEPEV-UHFFFAOYSA-N 0.000 description 1
- HWTZYBCRDDUBJY-UHFFFAOYSA-N Rhynchosin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=CC(O)=C(O)C=C2O1 HWTZYBCRDDUBJY-UHFFFAOYSA-N 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 201000009961 allergic asthma Diseases 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000002686 anti-diuretic effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 206010003549 asthenia Diseases 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000003376 axonal effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 229940126678 chinese medicines Drugs 0.000 description 1
- 230000002380 cytological effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 235000014103 egg white Nutrition 0.000 description 1
- 210000000969 egg white Anatomy 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229960003720 enoxolone Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 229930003935 flavonoid Natural products 0.000 description 1
- 235000017173 flavonoids Nutrition 0.000 description 1
- HKQYGTCOTHHOMP-UHFFFAOYSA-N formononetin Chemical compound C1=CC(OC)=CC=C1C1=COC2=CC(O)=CC=C2C1=O HKQYGTCOTHHOMP-UHFFFAOYSA-N 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 238000003364 immunohistochemistry Methods 0.000 description 1
- 238000013388 immunohistochemistry analysis Methods 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- LTINPJMVDKPJJI-UHFFFAOYSA-N iodinated glycerol Chemical compound CC(I)C1OCC(CO)O1 LTINPJMVDKPJJI-UHFFFAOYSA-N 0.000 description 1
- 235000008718 isoliquiritigenin Nutrition 0.000 description 1
- JBQATDIMBVLPRB-UHFFFAOYSA-N isoliquiritigenin Natural products OC1=CC(O)=CC=C1C1OC2=CC(O)=CC=C2C(=O)C1 JBQATDIMBVLPRB-UHFFFAOYSA-N 0.000 description 1
- DXDRHHKMWQZJHT-FPYGCLRLSA-N isoliquiritigenin Chemical compound C1=CC(O)=CC=C1\C=C\C(=O)C1=CC=C(O)C=C1O DXDRHHKMWQZJHT-FPYGCLRLSA-N 0.000 description 1
- MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 description 1
- DEMKZLAVQYISIA-ZRWXNEIDSA-N liquiritin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC=C([C@H]2OC3=CC(O)=CC=C3C(=O)C2)C=C1 DEMKZLAVQYISIA-ZRWXNEIDSA-N 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- 230000004898 mitochondrial function Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 210000000272 myelencephalon Anatomy 0.000 description 1
- 210000003007 myelin sheath Anatomy 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 235000021096 natural sweeteners Nutrition 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 210000002706 plastid Anatomy 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 229960001285 quercetin Drugs 0.000 description 1
- 235000005875 quercetin Nutrition 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- GSZUGBAEBARHAW-UHFFFAOYSA-N sophoraflavone B Natural products OC1C(O)C(O)C(CO)OC1OC1=CC=C(C=2OC3=CC(O)=CC=C3C(=O)C=2)C=C1 GSZUGBAEBARHAW-UHFFFAOYSA-N 0.000 description 1
- 101150077014 sox10 gene Proteins 0.000 description 1
- 208000020431 spinal cord injury Diseases 0.000 description 1
- WNIFXKPDILJURQ-UHFFFAOYSA-N stearyl glycyrrhizinate Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C)CCC(C(=O)OCCCCCCCCCCCCCCCCCC)(C)CC5C4=CC(=O)C3C21C WNIFXKPDILJURQ-UHFFFAOYSA-N 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 150000008130 triterpenoid saponins Chemical class 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了甘草酸在制备促进髓鞘再生抑制神经炎症药物的应用，经实验表明，甘草酸能有效地缓解炎症反应和抑制脱髓鞘病变，缓解急性和慢性实验性自身免疫性脑脊髓炎病程发展，在铜腙诱导的脱髓鞘模型中促进髓鞘再生，体外机制研究发现甘草酸能直接通过调节GSK‑3β信号通路诱导少突胶质前体细胞的分化，显著促进少突胶质细胞的成熟分化和刺激髓鞘蛋白的合成。甘草酸促进髓鞘再生机制的阐明为治疗脱髓鞘疾病和多发性硬化症提供了新的依据，为中枢神经系统脱髓鞘疾病等提供了临床可用的新药物。The invention discloses the application of glycyrrhizic acid in preparing a drug for promoting remyelination and inhibiting neuroinflammation. Experiments show that glycyrrhizic acid can effectively relieve inflammation, inhibit demyelinating lesions, and relieve acute and chronic experimental autoimmune encephalomyelitis. The course of the disease promotes remyelination in a copper hydrazone-induced demyelination model. In vitro mechanism studies have found that glycyrrhizic acid can directly induce the differentiation of oligodendrocyte precursor cells by regulating the GSK-3β signaling pathway, and significantly promote oligodendrocyte differentiation. Cell maturation and differentiation and stimulation of myelin protein synthesis. The elucidation of the mechanism of glycyrrhizic acid promoting remyelination provides a new basis for the treatment of demyelinating diseases and multiple sclerosis, and provides new clinically available drugs for central nervous system demyelinating diseases.
Description
Technical field
The invention belongs to the pharmaceutical product technical fields of the effective component containing natural drug, and in particular to glycyrrhizic acid
The new application of (Glycyrrhizic Acid) in terms of pharmacy.
Background technique
Multiple sclerosis (Multiple Sclerosis, MS) and its animal model experimental autoimmune myelencephalon
Scorching (Experimental Autoimmune Encephalomyelitis, EAE), is central nervous system (Central
Nervous System, CNS) chronic autoimmune disease, with significant spinal cord injury and inflammation, Quantifying axonal loss and de- marrow
Sheath.Lysis can be broadly defined as acute neurological inflammatory reaction and chronic demyelinating disease.China disease incidence by
Year improves, and is mainly in 20-40 years old women, and 80% or so is in recurrence-alleviation course of disease.In MS initial phase, myelin reactivity CD4+T
Cell is activated in periphery and is largely proliferated, and crosses blood-brain barrier (Blood-Brain Barrier, BBB) into CNS, and swash
A series of CNS immune responses characterized by attacking myelin living.In the chronic phase of MS/EAE, progression of disease and demyelinate, axis
Prominent damage is related with neuron loss.The common methods of clinical treatment are the progress for reducing inflammatory reaction to delay disease at present,
But effective immunotherapy targeted autoantibody measure there is no to the myelin damaged, be the bottleneck of demyelinate class disease treatment.
Mature oligodendroglia (Oligodendrocyte, OLG) is the cell that myelin is formed in central nervous system
(myelin-forming cell), by oligodendrocyte precursor cells (Oligodendrocyte precursor cells, OPC)
It is differentiated to form.After myelin sheath damage, OPC activation is raised to damaged part by being proliferated, migrating and is broken up as new oligodendroglia
Cell realizes Remyelination.Although in Multiple Sclerosis lesions region, there are a large amount of oligodendroglia precursor, differentiation
It is then very limited for mature oligodendrocyte numbers.Existing research the result shows that, in Multiple Sclerosis lesions region, have big
The inhibition molecule of amount hinders differentiation of the oligodendroglia precursor to mature oligodendroglia.However, these inhibit to divide
The molecular mechanism how son inhibits oligodendroglia precursor to break up is still not clear, this is also to lack effective Remyelination at present
The reason of drug.
Many Chinese medicines and herb ingredients show remarkable result in terms for the treatment of EAE in recent years.Wherein glycyrrhizic acid (GA) is
A kind of triterpenoid saponin is the natural component obtained from the root and rhizome of Radix Glycyrrhizae (Glycyrrhiza glabra).Radix Glycyrrhizae by
It is widely used as herbal medicine and natural sweetener, it is such as anti-inflammatory with extensive pharmacological activity, it is antiviral and antitumor etc..
Radix Glycyrrhizae has been accepted and has used as a kind of conventional Chinese medicine, main component be glycyrrhizin, liquiritin,
Glycyrrhizic acid flavonoids of Glycyrrhiza, rear curtain are than wingceltis element, formoononetin, Quercetin etc..
The effects of glycyrrhizic acid (GA) has removing toxic substances, and anti-inflammatory, antibechic is antitumor, antiulcer, antibacterial.Meanwhile glycyrrhizin pair
AIDS virus has Inhibit proliferaton effect；Enoxolone has inhibiting effect to myeloma and Example Ascites hepatoma.Glycyrrhizic acid has
Apparent antidiuretic activity；Glycyrrhizin, isoliquiritigenin have antiulcer and spasmolysis；Licoflavone class still has antioxygen and suppression
Bacterium effect.
According to relevant report, GA is effective in several diseases associated with inflammation or related experiment model, including allergic reaction and asthma.
Although these discoveries show that GA may also be beneficial to autoimmune diseases such as MS, about its pharmacological activity, Cytological Basis
It still requires study with the major issue of the molecular mechanism of GA effect.
Summary of the invention
The object of the present invention is to provide glycyrrhizic acids to be used to prepare the new use for promoting Remyelination to inhibit neuroinflamation drug
On the way, to provide a kind of new drug candidate for multiple sclerosis and central nervous system demyelinating disease etc..
Applicant is tested by vitro and in vivo, is carried out to function and effect of the glycyrrhizic acid to neuroinflamation and Remyelination
It investigates.Result of study discovery, GA effectively improve the serious journey of clinical disease of experimental autoimmune encephalomyelitis (EAE)
Degree.Histological evaluation shows that GA significantly inhibits infiltration of the inflammatory cell to CNS white matter demyelinate focal zone.In chronic phase, GA is lured
It leads oligodendrocyte progenitor cells (OPC) and is divided into mature oligodendroglia in vivo, to effectively accelerate myelin again
It is raw.Myelinoclasis-regeneration mouse model of copper hydrazone induction and the result table of in vitro brain section culture and external OPC test of maturity
Bright, the effect of glycyrrhizic acid is to directly facilitate Remyelination rather than immunosupress.
Present invention discloses glycyrrhizic acids to promote Remyelination to inhibit neuroinflamation new medicine use in preparation, not only widens
The application range of glycyrrhizic acid, and useful clinically novel drugs are provided for central nervous system demyelinating disease etc..
Detailed description of the invention
Fig. 1 is in EAE acute stage, PBS control group and glycyrrhizic acid GA (50mg/kg/d) treatment group mouse invasion situation pair
Than.
Fig. 2 is immune 30th day PBS control group and glycyrrhizic acid (GA) treatment group mouse spinal cord lumbosacral enlargement pathological section
H&E and LFB immunostaining figure.
Fig. 3 is immune 30th day PBS control group and glycyrrhizic acid (GA) treatment group mouse spinal cord lumbosacral enlargement pathological section
MBP immunostaining figure.
Fig. 4 is in EAE chronic phase, PBS control group and glycyrrhizic acid GA (50mg/kg/d) treatment group mouse invasion situation pair
Than.
Fig. 5 is the LFB of immune 60 days PBS control groups and glycyrrhizic acid (GA) treatment group mouse spinal cord lumbosacral enlargement pathological section
Immunostaining figure.
Fig. 6 is immune 60th day PBS control group and glycyrrhizic acid (GA) treatment group mouse spinal cord lumbosacral enlargement pathological section
MBP immunostaining figure.
Fig. 7 is immune 60th day PBS control group and glycyrrhizic acid (GA) treatment group mouse spinal cord lumbosacral enlargement pathological section
APC immunostaining figure.
Fig. 8 is copper hydrazone feeding 6 weeks, PBS control group and glycyrrhizic acid (GA) treatment group's weight figure and brain corpus callosum immunohistochemistry
Colored graph.
Fig. 9 be 4 weeks demyelinates of copper hydrazone feeding after, PBS control group and glycyrrhizic acid (GA) treatment group processing 2 weeks weight figure and
Brain corpus callosum immunohistochemical staining figure.
Figure 10 is the APC immunostaining figure of PBS (LPS+PBS) control group, UA treatment group (LPC+GA) mouse cerebellum slice.
Figure 11 is the MBP immunostaining figure of PBS (LPS+PBS) control group, UA treatment group (LPC+GA) mouse cerebellum slice.
Figure 12 is that primary OPC cultivates CNPase immunofluorescence after 7d in the differential medium with or without GA (10 μM)
Analysis chart.
Figure 13 is that primary OPC cultivates Ki67 immunofluorescence point after 7d in the differential medium with or without GA (10 μM)
Analysis figure.
Figure 14 is that primary OPC cultivates 7d in or without GA (10 μM) differential medium, and use is customized
RT2Profiler PCR array measures OPC/ oligodendroglia related gene expression.
Below in conjunction with drawings and examples, the present invention is described in further detail.
Specific embodiment
Material therefor, reagent, instrument and method in following embodiment are the routine in this field without specified otherwise
Material, reagent, instrument and method can be obtained by commercial channel.
Preventive effect of the embodiment 1:GA to the MOG acute EAE model induced
1, the preparation of EAE model and drug therapy
Female C57BL/6 mouse (8 weeks) is purchased from Xi'an Jiao great medical college animal center.Myelin oligodendroglia sugar egg
White MOG35-55 polypeptide, is purchased from Genescript company, and pertussis toxin is purchased from Sigma-Aldrich company, containing tuberculosis point
The complete Freund's complete adjuvant of branch bacillus, is purchased from BD Difco company, glycyrrhizic acid (GA) is purchased from Sigma-Aldrich company.
With PBS dissolve MOG35-55 polypeptide, then with isometric complete Freund's adjuvant (mycobacterium tuberculosis containing 5mg/ml)
Mixing pushes away the white antigen emulsion beaten to Water-In-Oil shape with glass syringe.
Mouse is immunized in two sites at back, respectively in intraperitoneal injection pertussis dilution on the day of being immunized and after 2 days
(200ng/ is only).
EAE mouse is randomly divided into following processing group:
1) control group of PBS processing: EAE mouse is injected intraperitoneally with PBS.
2) glycyrrhizic acid (GA) processing group: GA (50mg/kg/d) intraperitoneal injection daily since 0th day immune.According to optimization
Research selection dosage.
2, experiment post-processing
(1) EAE model score standard
After mouse immune, observes its limbs strength situation and carry out clinical score, EAE standards of grading are as follows: 0: without clinic
Symptom；0.5: stiff tail；1: tail portion paralysis；1.5: paralysing and lurch in tail portion；2: side quadriplegia；2.5: side
Quadriplegia, side limb adynamia；3: hind leg is paralysed completely；4: dying；5: dead.
(2) histopathology
30th day after immune, put to death mouse and carry out heart perfusion PBS, win control group and GA administration group mouse respectively
Spinal column marrow carry out immunohistochemical analysis.
3, experimental result
(1) in the acute phase of EAE, GA (50mg/kg/d) treatment significantly reduces the serious journey of disease compared to PBS group
It spends (Fig. 1).
(2) HE and LFB dyeing display, compared with the control group, GA administration group inflammatory cell infiltration substantially reduces, demyelinate journey
Degree significantly reduces (Fig. 2).
(3) MBP immunostaining shows that GA treatment group obviously increases (Fig. 3) compared with control group MBP expression.
In short, GA treatment reduces CNS inflammation and myelin damage in acute EAE.
Lysis is effectively relieved when EAE chronic phase starts treatment in embodiment 2:GA
1, the preparation of EAE model and drug therapy
EAE model preparation such as embodiment 1, is randomly divided into following processing group for EAE mouse:
1) control group of PBS processing: EAE mouse is injected intraperitoneally with PBS.
2) glycyrrhizic acid (GA) processing group: GA (50mg/kg/d) intraperitoneal injection daily since 30th day immune.
2. experiment post-processing
60th day after immune, put to death mouse and carry out heart perfusion PBS, win control group and GA administration group mouse respectively
Spinal column marrow carry out immunohistochemical analysis.
3, experimental result
(1) in the chronic phase of EAE, GA (50mg/kg/d) treats the morbidity journey for reducing EAE significant compared to PBS group
It spends (Fig. 4).
(2) LFB dyeing display, compared with PBS group, the significant reduction (Fig. 5) in demyelination after GA processing.
(3) MBP dyeing display, compared with PBS group, GA administration group is expressed with higher MBP, shows that GA treatment not only may be used
To be further reduced myelin damage, myelin can also be promoted to restore (Fig. 6).
(4) APC dyeing display, detects significant increased APC+ oligodendroglia number, table in the mouse of GA processing
Bright GA induces OPC mature (Fig. 7) in CNS lesion.
In short, GA treatment improves the clinical symptoms of chronic EAE, and promote the regeneration of EAE chronic phase myelin.
Embodiment 3:GA promotes the Remyelination in the demyelinated model of copper hydrazone induction
1, copper hydrazone model preparation and drug therapy to 8 week old male C57BL/6 mouse feeding standard rodent mouse grains with
The mixed cuprizone mouse grain of 0.2% copper chelator cuprizone inhibits mitochondrial function and causes CNS demyelinate.
Demyelinate experiment is divided into two groups:
1) PBS control group: feeding copper hydrazone mouse grain 6 weeks, and PBS is injected intraperitoneally daily.
2) GA processing group: feeding copper hydrazone mouse grain 6 weeks, and GA (50mg/kg/d) is injected intraperitoneally daily.
Remyelination experiment is divided into two groups:
1) PBS control group: PBS is injected intraperitoneally in feeding copper hydrazone mouse grain 4 weeks daily in 4-6 weeks.
2) GA processing group: GA (50mg/kg/d) is injected intraperitoneally in feeding copper hydrazone mouse grain 4 weeks daily in 4-6 weeks.
2, experiment post-processing
Mice brain tissues are fixed to all euthanizing animals, and with the PFA that concentration is 4%.In order to whether study GA
Remyelination is removed in influence, and brain is further embedded in paraffin, is sliced and dyes for histopathology and immunohistochemistry
Analysis.
3, experimental result
(1) weight figure and brain corpus callosum immunohistochemical staining are shown, continued weight mitigation and callosity between 6 period of copper hydrazone feeding
Zhi body has apparent demyelinate.However, weight loss and demyelinate are not handled by GA and change (Fig. 8) in the demyelinate stage.
(2) Remyelination is tested, at the 6th week, weight did not had significant variation, but observed gently in PBS processing group
Micro- Remyelination.It is assessed by histochemistry (LFB) and immunohistochemical staining (myelin), GA treatment increases weight simultaneously
Promote Remyelination (Fig. 9).
In short, GA administration directly stimulation oligodendroglia is mature and promotes Remyelination after copper hydrazone induces demyelinate.
Embodiment 4:GA promotes the Remyelination in organotypic slice culture
1, experiment process
After birth the 3rd day (P3) execution C57BL/6 mouse and cerebella slice is prepared with brain.Every newborn rat cuts 350 μm
Brain piece 4-5 piece is placed on the filter membrane of Gey ' s buffer infiltration of preheating.After random grouping, brain piece is transferred to culture solution
In, 37 DEG C, the CO2 of concentration 5% LPC (0.5mg/ml) culture 18h is added after cultivating 2 days to induce demyelinate, then PBS is cleaned
It is handled 14 days with PBS or GA afterwards.Pass through immunofluorescence dyeing assessment Remyelination (MBP+NFH+) and maturation OLG (APC after 14d
+) quantity.
2, experimental result
(1) compared with PBS processing group, the APC+ maturation oligodendroglia significantly increased is observed in the slice handled with GA
Cell (Figure 10).
(2) LPC induces brain tissue MBP expression to be remarkably decreased, and compared with PBS processing, MBP expression is dramatically increased after GA processing
(Figure 11).
In short, GA effectively increases mature oligodendrocyte numbers in organotypic slice culture, promote the de- of LPC induction
The generation of myelin protein in myelin.
Embodiment 5:GA promotes OPC mature in vitro
1, experiment process
(1) primary OPC is prepared from newborn C57BL/6 mouse brain, in the differentiation culture with or without GA (10 μM)
Immunofluorescence dyeing is carried out with CNPase and Ki67 after culture 7d in base, nucleus is dyed with DAPI (blue).Mature is few prominent
Spongiocyte is dyed with CNPase, and the OPCs being proliferated is marked with Ki67.
(2) primary OPC cultivates 7d in or without GA (10 μM) differential medium, with customized RT2Profiler
PCR array measures OPC/ oligodendroglia related gene expression.
2, experimental result
(1) the complicated branching pattern more extended, and and PBS are shown after culture 2 weeks by the OPCs of GA processing
Control group is compared, and total branch length of oligodendroglia increases 4 times or more (Figure 12) in GA processing group.
(2) in the OPCs of GA processing, percentage of the Ki67+ proliferative OPCs under differentiation condition significantly reduces (figure
13)。
(3) GA processing up-regulation oligodendroglia idiosyncratic transcription factor (such as Olig2, Sox10, Sox17) and glue of dashing forward less
The expression (Figure 14) of the transcriptional level and neurotrophic factor CNTF of cell plastid Specific marker MBP.
Above-described embodiment explore glycyrrhizic acid can effectively alleviate inflammatory reaction and inhibit Demyelination, alleviate it is acute and
Chronic experi Autoimmune Encephalomyelitis disease promotes Remyelination, body in the demyelinated model of copper hydrazone induction
Outer Mechanism Study discovery glycyrrhizic acid can directly induce the differentiation of oligodendrocyte precursor cells by adjusting GSK-3 signal beta access, show
The synthesis of the mature differentiation and stimulation myelin protein that promote oligodendroglia is write, for treatment demyelinating disease and multiple sclerosis
Disease provides new foundation, provides useful clinically novel drugs for the treatment of central nervous system demyelinating disease.
Claims (4)
1. the application that glycyrrhizic acid promotes Remyelination inhibition neuroinflamation drug in preparation.
2. application as described in claim 1, which is characterized in that the drug for promoting Remyelination to inhibit neuroinflamation is used
In treatment multiple sclerosis.
3. application as described in claim 1, which is characterized in that the drug for promoting Remyelination to inhibit neuroinflamation is used
In treating myelin damage caused by central nervous system white matter chronic inflammation Demyelination.
4. application as described in claim 1, which is characterized in that the drug for promoting Remyelination to inhibit neuroinflamation is used
In treatment central nervous system demyelinating disease.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811580991.XA CN109528738A (en) | 2018-12-24 | 2018-12-24 | Glycyrrhizic acid promotes the application of Remyelination inhibition neuroinflamation drug in preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811580991.XA CN109528738A (en) | 2018-12-24 | 2018-12-24 | Glycyrrhizic acid promotes the application of Remyelination inhibition neuroinflamation drug in preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109528738A true CN109528738A (en) | 2019-03-29 |
Family
ID=65856791
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811580991.XA Pending CN109528738A (en) | 2018-12-24 | 2018-12-24 | Glycyrrhizic acid promotes the application of Remyelination inhibition neuroinflamation drug in preparation |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109528738A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110327332A (en) * | 2019-07-06 | 2019-10-15 | 河北医科大学第二医院 | Amlexanox is alleviating application and its experimental method in EAE morbidity |
| CN113975256A (en) * | 2021-12-15 | 2022-01-28 | 山东省妇幼保健院 | Application of isoliquiritigenin in the preparation of medicaments for the treatment of premature infants with cerebral white matter injury |
| CN117442618A (en) * | 2023-10-23 | 2024-01-26 | 国科大杭州高等研究院 | Application of compound LY2940094 in the preparation of drugs for the treatment of demyelinating diseases of the central nervous system |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060127512A1 (en) * | 2001-06-20 | 2006-06-15 | Tripp Matthew L | Modulation of inflammation by hops fractions and derivatives |
| CN101115758A (en) * | 2005-02-04 | 2008-01-30 | 韩美药品株式会社 | Amorphous tacrolimus solid dispersion with enhanced solubility and pharmaceutical composition comprising the same |
| CN101610673A (en) * | 2006-11-20 | 2009-12-23 | 萨托里医药公司 | Can be used for treating the compound of neurodegenerative disorders |
-
2018
- 2018-12-24 CN CN201811580991.XA patent/CN109528738A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060127512A1 (en) * | 2001-06-20 | 2006-06-15 | Tripp Matthew L | Modulation of inflammation by hops fractions and derivatives |
| CN101115758A (en) * | 2005-02-04 | 2008-01-30 | 韩美药品株式会社 | Amorphous tacrolimus solid dispersion with enhanced solubility and pharmaceutical composition comprising the same |
| CN101610673A (en) * | 2006-11-20 | 2009-12-23 | 萨托里医药公司 | Can be used for treating the compound of neurodegenerative disorders |
Non-Patent Citations (3)
| Title |
|---|
| JING TIAN ET AL: "Glycyrrhizic acid promotes neural repair by directly driving functional remyelination", 《FOOD & FUNCTION》 * |
| JI-SUN KIM ET AL: "Glycyrrhizic acid prevents astrocyte death by neuromyelitis optica-specific IgG via inhibition of C1q binding", 《BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS》 * |
| SUAT KAMISLI ET AL.: "The beneficial effects of 18β-glycyrrhetinic acid on the experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mouse model", 《IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110327332A (en) * | 2019-07-06 | 2019-10-15 | 河北医科大学第二医院 | Amlexanox is alleviating application and its experimental method in EAE morbidity |
| CN113975256A (en) * | 2021-12-15 | 2022-01-28 | 山东省妇幼保健院 | Application of isoliquiritigenin in the preparation of medicaments for the treatment of premature infants with cerebral white matter injury |
| CN117442618A (en) * | 2023-10-23 | 2024-01-26 | 国科大杭州高等研究院 | Application of compound LY2940094 in the preparation of drugs for the treatment of demyelinating diseases of the central nervous system |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Cai et al. | Kaemperfol alleviates pyroptosis and microglia-mediated neuroinflammation in Parkinson's disease via inhibiting p38MAPK/NF-κB signaling pathway | |
| Emili et al. | Treatment with the flavonoid 7, 8-Dihydroxyflavone: a promising strategy for a constellation of body and brain disorders | |
| Wu et al. | Hippocampal overexpression of TREM2 ameliorates high fat diet induced cognitive impairment and modulates phenotypic polarization of the microglia | |
| Jiang et al. | Phillyrin protects mice from traumatic brain injury by inhibiting the inflammation of microglia via PPARγ signaling pathway | |
| Liu et al. | Lyophilized powder of catalpol and puerarin protected cerebral vessels from ischemia by its anti-apoptosis on endothelial cells | |
| Yang et al. | Esculin ameliorates obesity-induced insulin resistance by improving adipose tissue remodeling and activating the IRS1/PI3K/AKT/GLUT4 pathway | |
| He et al. | Chinese medicine Bu-Fei decoction attenuates epithelial-mesenchymal transition of non-small cell lung cancer via inhibition of transforming growth factor β1 signaling pathway in vitro and in vivo | |
| Catalin et al. | Cerebrolysin and aquaporin 4 inhibition improve pathological and motor recovery after ischemic stroke | |
| Cheng et al. | The Achyranthes bidentata polypeptide k fraction enhances neuronal growth in vitro and promotes peripheral nerve regeneration after crush injury in vivo | |
| Li et al. | HDAC3 inhibitor (BRD3308) modulates microglial pyroptosis and neuroinflammation through PPARγ/NLRP3/GSDMD to improve neurological function after intraventricular hemorrhage in mice | |
| CN109528738A (en) | Glycyrrhizic acid promotes the application of Remyelination inhibition neuroinflamation drug in preparation | |
| Huang et al. | Melatonin reduces neuropathic pain behavior and glial activation through MT2 melatonin receptor modulation in a rat model of lysophosphatidylcholine-induced demyelination neuropathy | |
| Dhillon et al. | Adverse neural effects of delayed, intermittent treatment with rEPO after asphyxia in preterm fetal sheep | |
| Essam et al. | P-CREB and p-DARPP-32 orchestrating the modulatory role of cAMP/PKA signaling pathway enhanced by Roflumilast in rotenone-induced Parkinson's disease in rats | |
| Zhou et al. | CircDYM attenuates microglial apoptosis via CEBPB/ZC3H4 axis in LPS-induced mouse model of depression | |
| Li et al. | Osthole ameliorates early diabetic kidney damage by suppressing oxidative stress, inflammation and inhibiting TGF-β1/Smads signaling pathway | |
| Liu et al. | Protective effects and mechanisms of Momordica charantia polysaccharide on early-stage diabetic retinopathy in type 1 diabetes | |
| Luo et al. | Intestinal metabolite UroB alleviates cerebral ischemia/reperfusion injury by promoting competition between TRIM65 and TXNIP for binding to NLRP3 inflammasome in response to neuroinflammation | |
| Tao et al. | Inhibition of P2X7R alleviates neuroinflammation and brain edema after traumatic brain injury by suppressing the NF-κB/NLRP3 inflammasome pathway | |
| Song et al. | Ginsenoside Rb1 alleviates blood-brain barrier damage and demyelination in experimental autoimmune encephalomyelitis mice by regulating JNK/ERK/NF-κB signaling pathway | |
| Zhang et al. | Study on anti-inflammatory effect of Shangkehuangshui in vitro and in vivo based on TLR4/TLR2-NF-κB signaling pathway | |
| Chen et al. | The role of the GRP78/PERK/ATF4 pathway in the ability of Gua Lou Gui Zhi decoction to attenuate apoptosis by inhibiting endoplasmic reticulum stress after ischemia-reperfusion injury | |
| Tao et al. | Integrated network pharmacology, molecular docking and pharmacodynamic study reveals protective effects and mechanisms of corilagin against cerebral ischemia-induced injury | |
| Tao et al. | 20 (R)-ginsenoside Rg3 protects against focal cerebral ischemia‒reperfusion injury by suppressing autophagy via PI3K/Akt/mTOR signaling pathway | |
| JP6626094B2 (en) | Use of ginsenoside M1 for inhibiting renal fibrosis |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20190329 |