CN113577288A - Mst4相关物质在制备治疗脑出血后神经炎症反应的药物中的应用 - Google Patents
Mst4相关物质在制备治疗脑出血后神经炎症反应的药物中的应用 Download PDFInfo
- Publication number
- CN113577288A CN113577288A CN202111080992.XA CN202111080992A CN113577288A CN 113577288 A CN113577288 A CN 113577288A CN 202111080992 A CN202111080992 A CN 202111080992A CN 113577288 A CN113577288 A CN 113577288A
- Authority
- CN
- China
- Prior art keywords
- mst4
- expression
- nlrp3
- preparing
- nlrp
- 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
- 101000701393 Homo sapiens Serine/threonine-protein kinase 26 Proteins 0.000 title claims abstract description 115
- 102100030617 Serine/threonine-protein kinase 26 Human genes 0.000 title claims abstract description 115
- 206010008111 Cerebral haemorrhage Diseases 0.000 title claims abstract description 34
- 239000000126 substance Substances 0.000 title claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 title claims abstract description 11
- 208000036110 Neuroinflammatory disease Diseases 0.000 title claims abstract description 8
- 230000003959 neuroinflammation Effects 0.000 title claims abstract description 8
- 239000003814 drug Substances 0.000 title description 8
- 102000000874 Pyrin Domain-Containing 3 Protein NLR Family Human genes 0.000 claims abstract description 58
- 108010001946 Pyrin Domain-Containing 3 Protein NLR Family Proteins 0.000 claims abstract description 58
- HUUSXLKCTQDPGL-UHFFFAOYSA-N 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonylurea Chemical compound CC(C)(O)C1=COC(S(=O)(=O)NC(=O)NC=2C=3CCCC=3C=C3CCCC3=2)=C1 HUUSXLKCTQDPGL-UHFFFAOYSA-N 0.000 claims abstract description 26
- 102000003777 Interleukin-1 beta Human genes 0.000 claims abstract description 22
- 108090000193 Interleukin-1 beta Proteins 0.000 claims abstract description 22
- 230000003993 interaction Effects 0.000 claims abstract description 15
- 102100038243 Mitogen-activated protein kinase kinase kinase 10 Human genes 0.000 claims abstract description 13
- GOZMBJCYMQQACI-UHFFFAOYSA-N 6,7-dimethyl-3-[[methyl-[2-[methyl-[[1-[3-(trifluoromethyl)phenyl]indol-3-yl]methyl]amino]ethyl]amino]methyl]chromen-4-one;dihydrochloride Chemical compound Cl.Cl.C=1OC2=CC(C)=C(C)C=C2C(=O)C=1CN(C)CCN(C)CC(C1=CC=CC=C11)=CN1C1=CC=CC(C(F)(F)F)=C1 GOZMBJCYMQQACI-UHFFFAOYSA-N 0.000 claims abstract description 12
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 12
- 230000007971 neurological deficit Effects 0.000 claims abstract description 12
- 206010048962 Brain oedema Diseases 0.000 claims abstract description 11
- 208000006752 brain edema Diseases 0.000 claims abstract description 11
- 230000001737 promoting effect Effects 0.000 claims abstract description 5
- 239000003112 inhibitor Substances 0.000 claims description 14
- GLDSKRNGVVYJAB-DQSJHHFOSA-N hesperadin Chemical compound C12=CC(NS(=O)(=O)CC)=CC=C2NC(=O)\C1=C(C=1C=CC=CC=1)/NC(C=C1)=CC=C1CN1CCCCC1 GLDSKRNGVVYJAB-DQSJHHFOSA-N 0.000 claims description 11
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 claims description 7
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 7
- 230000002314 neuroinflammatory effect Effects 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 2
- LFQQNXFKPNZRFT-UHFFFAOYSA-M sodium 1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl-[4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonylazanide Chemical compound [Na+].CC(C)(O)c1coc(c1)S(=O)(=O)[N-]C(=O)Nc1c2CCCc2cc2CCCc12 LFQQNXFKPNZRFT-UHFFFAOYSA-M 0.000 claims description 2
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 claims 1
- 238000012360 testing method Methods 0.000 abstract description 13
- 230000002829 reductive effect Effects 0.000 abstract description 10
- 210000000274 microglia Anatomy 0.000 abstract description 5
- 230000003962 neuroinflammatory response Effects 0.000 abstract description 2
- 102000007469 Actins Human genes 0.000 description 18
- 108010085238 Actins Proteins 0.000 description 18
- 241000699670 Mus sp. Species 0.000 description 14
- 206010061218 Inflammation Diseases 0.000 description 13
- 102100035904 Caspase-1 Human genes 0.000 description 12
- 108090000426 Caspase-1 Proteins 0.000 description 12
- 230000004054 inflammatory process Effects 0.000 description 12
- 108091008099 NLRP3 inflammasome Proteins 0.000 description 9
- 238000002474 experimental method Methods 0.000 description 8
- 238000010166 immunofluorescence Methods 0.000 description 8
- 210000004556 brain Anatomy 0.000 description 7
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- 102100040247 Tumor necrosis factor Human genes 0.000 description 6
- 230000003542 behavioural effect Effects 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000001262 western blot Methods 0.000 description 6
- 241000283973 Oryctolagus cuniculus Species 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 208000029028 brain injury Diseases 0.000 description 5
- 238000009825 accumulation Methods 0.000 description 4
- 210000005013 brain tissue Anatomy 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- QUQPHWDTPGMPEX-QJBIFVCTSA-N hesperidin Chemical compound C1=C(O)C(OC)=CC=C1[C@H]1OC2=CC(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO[C@H]4[C@@H]([C@H](O)[C@@H](O)[C@H](C)O4)O)O3)O)=CC(O)=C2C(=O)C1 QUQPHWDTPGMPEX-QJBIFVCTSA-N 0.000 description 4
- 230000002757 inflammatory effect Effects 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 230000003827 upregulation Effects 0.000 description 4
- 239000001100 (2S)-5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)chroman-4-one Substances 0.000 description 3
- 102000029816 Collagenase Human genes 0.000 description 3
- 108060005980 Collagenase Proteins 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 206010018852 Haematoma Diseases 0.000 description 3
- QUQPHWDTPGMPEX-UHFFFAOYSA-N Hesperidine Natural products C1=C(O)C(OC)=CC=C1C1OC2=CC(OC3C(C(O)C(O)C(COC4C(C(O)C(O)C(C)O4)O)O3)O)=CC(O)=C2C(=O)C1 QUQPHWDTPGMPEX-UHFFFAOYSA-N 0.000 description 3
- QUQPHWDTPGMPEX-UTWYECKDSA-N aurantiamarin Natural products COc1ccc(cc1O)[C@H]1CC(=O)c2c(O)cc(O[C@@H]3O[C@H](CO[C@@H]4O[C@@H](C)[C@H](O)[C@@H](O)[C@H]4O)[C@@H](O)[C@H](O)[C@H]3O)cc2O1 QUQPHWDTPGMPEX-UTWYECKDSA-N 0.000 description 3
- 210000004227 basal ganglia Anatomy 0.000 description 3
- APSNPMVGBGZYAJ-GLOOOPAXSA-N clematine Natural products COc1cc(ccc1O)[C@@H]2CC(=O)c3c(O)cc(O[C@@H]4O[C@H](CO[C@H]5O[C@@H](C)[C@H](O)[C@@H](O)[C@H]5O)[C@@H](O)[C@H](O)[C@H]4O)cc3O2 APSNPMVGBGZYAJ-GLOOOPAXSA-N 0.000 description 3
- 229960002424 collagenase Drugs 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- VUYDGVRIQRPHFX-UHFFFAOYSA-N hesperidin Natural products COc1cc(ccc1O)C2CC(=O)c3c(O)cc(OC4OC(COC5OC(O)C(O)C(O)C5O)C(O)C(O)C4O)cc3O2 VUYDGVRIQRPHFX-UHFFFAOYSA-N 0.000 description 3
- 229940025878 hesperidin Drugs 0.000 description 3
- 238000003119 immunoblot Methods 0.000 description 3
- 230000006759 inflammatory activation Effects 0.000 description 3
- 238000002372 labelling Methods 0.000 description 3
- 210000003140 lateral ventricle Anatomy 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- ARGKVCXINMKCAZ-UHFFFAOYSA-N neohesperidine Natural products C1=C(O)C(OC)=CC=C1C1OC2=CC(OC3C(C(O)C(O)C(CO)O3)OC3C(C(O)C(O)C(C)O3)O)=CC(O)=C2C(=O)C1 ARGKVCXINMKCAZ-UHFFFAOYSA-N 0.000 description 3
- 230000007658 neurological function Effects 0.000 description 3
- 239000002953 phosphate buffered saline Substances 0.000 description 3
- 238000011002 quantification Methods 0.000 description 3
- 241000283707 Capra Species 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 229940127107 NLRP3 inflammasome inhibitor Drugs 0.000 description 2
- 102000003714 TNF receptor-associated factor 6 Human genes 0.000 description 2
- 108090000009 TNF receptor-associated factor 6 Proteins 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 230000002238 attenuated effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000006931 brain damage Effects 0.000 description 2
- 231100000874 brain damage Toxicity 0.000 description 2
- 230000030570 cellular localization Effects 0.000 description 2
- 230000008045 co-localization Effects 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000003090 exacerbative effect Effects 0.000 description 2
- 238000013401 experimental design Methods 0.000 description 2
- 238000003125 immunofluorescent labeling Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 230000003447 ipsilateral effect Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 238000010984 neurological examination Methods 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- LOGFVTREOLYCPF-KXNHARMFSA-N (2s,3r)-2-[[(2r)-1-[(2s)-2,6-diaminohexanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxybutanoic acid Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H]1CCCN1C(=O)[C@@H](N)CCCCN LOGFVTREOLYCPF-KXNHARMFSA-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
- 101150053137 AIF1 gene Proteins 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 108010034143 Inflammasomes Proteins 0.000 description 1
- 101150023049 MST4 gene Proteins 0.000 description 1
- HYHIYZMIFPJROG-UHFFFAOYSA-N N-[2-hydroxy-3-[C-phenyl-N-[4-(piperidin-1-ylmethyl)phenyl]carbonimidoyl]-1H-indol-5-yl]ethanesulfonamide Chemical compound CCS(=O)(=O)NC1=CC=C2NC(O)=C(C(=NC3=CC=C(CN4CCCCC4)C=C3)C3=CC=CC=C3)C2=C1 HYHIYZMIFPJROG-UHFFFAOYSA-N 0.000 description 1
- 208000028389 Nerve injury Diseases 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- 102100037629 Serine/threonine-protein kinase 4 Human genes 0.000 description 1
- 101710202845 Serine/threonine-protein kinase 4 Proteins 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000003110 anti-inflammatory 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
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000002886 autophagic effect Effects 0.000 description 1
- 230000004642 autophagic pathway Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 238000009227 behaviour therapy Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 210000001638 cerebellum Anatomy 0.000 description 1
- 239000005482 chemotactic factor Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000009194 climbing Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 210000003414 extremity Anatomy 0.000 description 1
- 210000003194 forelimb Anatomy 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000006303 immediate early viral mRNA transcription Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000003960 inflammatory cascade Effects 0.000 description 1
- 230000006749 inflammatory damage Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 102000014909 interleukin-1 receptor activity proteins Human genes 0.000 description 1
- 108040006732 interleukin-1 receptor activity proteins Proteins 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 210000001577 neostriatum Anatomy 0.000 description 1
- 230000008764 nerve damage Effects 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 230000009251 neurologic dysfunction Effects 0.000 description 1
- 208000015015 neurological dysfunction Diseases 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 230000009023 proprioceptive sensation Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000002747 voluntary effect Effects 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Images
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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- 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
- A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了MST4相关物质作为如下(a)和/或(b)和/或(c)和/或(d)和/或(e)和/或(f)和/或(g)的应用,(a)制备促进MST4和NLRP3的表达的物质;(b)制备抑制MST4表达的物质;(c)制备抑制NLRP3的表达的物质;(d)制备抑制MST4表达,而促进NLRP3表达的物质;(e)制备抑制IL‑1β和TNF‑α的释放的物质;(f)制备预防和/或治疗神经功能缺损、脑水肿的物质;(g)制备预防和/或治疗脑出血后神经炎症反应的物质。本发明的试验证明:MCC950抑制MST4与NLRP3相互作用抑制脑出血后神经炎症反应;与sham组相比,ICH后内源性MST4和NLRP3的表达增加,MST4和NLRP3分别共定位于小胶质细胞中;MCC950显着减轻神经功能缺损、脑水肿,而对MST4蛋白的表达没有影响。
Description
技术领域
本发明涉及MST4相关物质在制备治疗脑出血后神经炎症反应的药物中的应用。
背景技术
脑出血(ICH)是一种严重的中风,占10%-15%,伴有严重的神经功能障碍。原发性脑损伤是由ICH后的血肿引起的。炎症级联加速血肿并导致细胞死亡。ICH后小胶质细胞被迅速激活,然后释放促炎因子和趋化因子引起继发性脑损伤。越来越多的证据表明,神经炎症在ICH后继发性脑损伤的病理机制中起着至关重要的作用。
哺乳动物丝氨酸/苏氨酸蛋白激酶4(mammalian Ste20-like kinase 4)MST4是炎症的负调节因子,MST4被归类为GCK亚科成员,属于MST激酶,在胸腺和大脑中大量表达。除了影响细胞迁移、分化和细胞增殖外,MST4还介导细胞生长和凋亡。MST4敲低小鼠在感染性休克后会增加炎症并降低存活率,这与MST4对TRAF6磷酸化的限制有关。hesperadin是一种选择性有效的MST4激酶抑制剂。目前尚无关于MST4是否参与ICH后免疫炎症的报道。
NLRP3炎症小体是炎症小体的典型代表,已被广泛研究。NLRP3炎症小体调节caspase-1的裂解并参与白细胞介素1β(IL-1β)的加工。研究证实ICH诱导的NLRP3炎症小体激活导致IL-1β的释放并促进中性粒细胞浸润,加重炎症,加重脑水肿。作为一种有效的NLRP3炎症小体抑制剂,MCC950可减轻ICH后的炎症和脑损伤。TRAF6对于通过TLR/IL-1R途径介导NLRP3是必不可少的。
综上所述,如何研发一种MST4相关物质在制备治疗脑出血后神经炎症反应的药物中应用,是亟待解决的技术问题。
发明内容
为此,本发明提供一种MST4相关物质在制备治疗脑出血后神经炎症反应的药物中的应用。
为了实现上述目的,本发明提供如下技术方案:
本发明提供MST4相关物质作为如下(a)和/或(b)和/或(c)和/或(d)和/或(e)和/或(f)和/或(g)的应用,
(a)制备促进MST4和NLRP3的表达的产品;
(b)制备抑制MST4表达的产品;
(c)制备抑制NLRP3的表达的产品;
(d)制备抑制MST4表达,而促进NLRP3表达的产品;
(e)制备抑制IL-1β和TNF-α的释放的产品;
(f)制备预防和/或治疗神经功能缺损、脑水肿的产品;
(g)制备预防和/或治疗脑出血后神经炎症反应的产品。
本发明的一个实施例中,所述MST4相关物质包括MST4的表达促进物,MST4的表达抑制物,MST4和NLRP3相互作用的促进物,MST4和NLRP3相互作用的抑制物。
本发明的一个实施例中,所述MST4的表达促进物为MST4 AAV。
本发明的一个实施例中,所述MST4的表达抑制物为Hesperadin。
本发明的一个实施例中,所述MST4和NLRP3相互作用的抑制物为Hesperadin或/和MCC950。
本发明的一个实施例中,所述Hesperadin的化学式如式(I)所示:
所述MCC950的化学式如式(II)所示:
本发明的一个实施例中,所述MST4和NLRP3相互作用的促进物为MST4AAV。
本发明还提供一种产品,其活性成分为MST4相关物质,所述产品的用途为如下(a)和/或(b)和/或(c)和/或(d)和/或(e)和/或(f)和/或(g):
(a)促进MST4和NLRP3的表达;
(b)抑制MST4表达;
(c)抑制NLRP3的表达;
(d)抑制MST4表达,而促进NLRP3表达;
(e)抑制IL-1β和TNF-α的释放;
(f)预防和/或治疗神经功能缺损、脑水肿;
(g)预防和/或治疗脑出血后神经炎症反应。
本发明的一个实施例中,所述MST4相关物质包括MST4的表达促进物,MST4的表达抑制物,MST4和NLRP3相互作用的促进物,MST4和NLRP3相互作用的抑制物。
本发明具有如下优点:
本发明的试验证明:MCC950抑制MST4与NLRP3相互作用抑制脑出血后神经炎症反应;与sham组相比,ICH后内源性MST4和NLRP3的表达增加,MST4和NLRP3分别共定位于小胶质细胞中;MCC950显着减轻神经功能缺损、脑水肿,而对MST4蛋白的表达没有影响。
Hesperadin预处理抑制MST4的表达并增加NLRP3炎性体药物蛋白的表达,从而加重神经功能缺损和脑水肿。
本发明的结果表明,MST4基因的上调抑制了NLRP3炎症小体的激活、IL-1β和TNF-α的释放,显着改善了脑水肿和神经功能缺损。MST4通过NLRP3炎症小体激活减轻ICH小鼠的炎症进展和脑损伤。MST4可以减轻ICH小鼠的神经炎症,改善神经功能,这与抑制nlrp3介导的炎症有关。
附图说明
为了更清楚地说明本发明的实施方式或现有技术中的技术方案,下面将对实施方式或现有技术描述中所需要使用的附图作简单地介绍。显而易见地,下面描述中的附图仅仅是示例性的,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据提供的附图引伸获得其它的实施附图。
本说明书所绘示的结构、比例、大小等,均仅用以配合说明书所揭示的内容,以供熟悉此技术的人士了解与阅读,并非用以限定本发明可实施的限定条件,故不具技术上的实质意义,任何结构的修饰、比例关系的改变或大小的调整,在不影响本发明所能产生的功效及所能达成的目的下,均应仍落在本发明所揭示的技术内容得能涵盖的范围内。
图1为本发明实施例提供的MST4相关物质在制备治疗脑出血后神经炎症反应的药物中的应用试验设计流程图;
图2为本发明实施例提供的ICH后MST4、NLRP3的表达及其细胞定位的结果示意图,其中,(A)假手术组和小鼠脑出血后6、12、24、72h各时间点MST4和NLRP3表达的代表性条带;(B C)MST4/actin、NLRP3/actin灰度值定量,每组n=6只;(D)脑出血后24h用Iba1-MST4及Ibal1-NLRP3免疫荧光双标检测,每组n=3只,*p<0.05vs.假手术组;
图3为本发明实施例提供的MST4 AAV抑制NLRP3炎性体激活结果的示意图,其中,(A)MST4、NLRP3、IL-1β、caspase-1,TNF-α代表性免疫印迹条带;(B C D E F)MST4/actin、NLRP3/actin、IL-1β/actin、caspase-1/actin、TNF-α/actin灰度值定量,每组n=6只;(G)Garcia Test行为学检测,n=15只/组;(H)Corner Test行为学检测,n=15只/组;(I)BWC水含量评估,n=6只/组;*p<0.05vs.sham,#p<0.05vs.脑出血组;
图4为本发明实施例提供的Hesperadin增加NLRP3炎性体激活结果的示意图,其中,(A)MST4、NLRP3、IL-1β、caspase-1,TNF-α代表性免疫印迹条带;(B C D E F)MST4/actin、NLRP3/actin、IL-1β/actin、caspase-1/actin、TNF-α/actin灰度值定量,每组n=6只;(G)脑出血组与Hesperidin给药组Garcia Test行为学检测,n=15只/组;(H)脑出血组与Hesperidin给药组Corner Test行为学检测,n=15只/组;(I)脑出血组与Hesperidin给药组BWC水含量评估,n=6只/组;*p<0.05vs.sham,#p<0.05vs.脑出血组;
图5为本发明实施例提供的MCC950减弱炎症对MST4/NLRP3信号的影响结果的示意图;其中,(A)MST4、NLRP3、IL-1β、caspase-1,TNF-α代表性免疫印迹条带;(B C D E F)MST4/actin、NLRP3/actin、IL-1β/actin、caspase-1/actin、TNF-α/actin灰度值定量,每组n=6只;(G)脑出血组与MCC950给药组Garcia Test行为学检测,n=15只/组;(H)脑出血组与MCC950给药组Corner Test行为学检测,n=15只/组;(I)脑出血组与MCC950给药组BWC水含量评估,n=6只/组;*p<0.05vs.sham,#p<0.05vs.脑出血;
图6为本发明实施例提供的Hesperadin和MCC950均可抑制MST4与NLRP3的结合与共定位的结果示意图,其中,实验2、3、4中各组MST4和NLRP3的免疫荧光染色,MST4(红色)与NLRP3(绿色)共标记,比例尺:20μm,每组n=3只。
具体实施方式
以下由特定的具体实施例说明本发明的实施方式,熟悉此技术的人士可由本说明书所揭露的内容轻易地了解本发明的其他优点及功效,显然,所描述的实施例是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
本发明的材料,MST4 AAV购买自美国Vigenebio Biosciences公司;MCC950和Hesperidin均购买自美国MedChemExpress公司。
本发明的材料,实验对象为C57BL/6雄性小鼠。7-8周龄,体重24-28克,购自南京青龙山繁殖场。
实施例1、试验设计
1、试验设计:如图1所示,小鼠被分配到四个独立的实验,并列出了所有的设计细节。
实验1:30只小鼠分为假手术组和脑出血后6h、12h、24h和72h组。western blot检测MST4和NLRP3水平。取脑组织进行免疫荧光(IF)检测。
实验2:随机分为假手术组、ICH组、ICH+对照AAV组、ICH+MST4 AAV组各60只。western blot检测MST4、NLRP3、IL-1β、caspase-1和TNF-α蛋白水平(n=6),收集脑组织IF(n=3),在脑出血后24h进行神经功能测试(n=15)和脑含水量(n=6)。
实验3:ICH组和ICH+Hesperidin组各30只。所有小鼠于脑出血后24h处死,进行western blot(n=6)、BWC(n=6)、神经学检测(n=15),IF(n=3)。
实验4:ICH组和ICH+MCC950组各30只。所有小鼠于脑出血后24h处死,进行westernblot(n=6)、BWC(n=6)、神经学检测(n=15),IF(n=3)。
2、脑出血建模
通过注射胶原酶IV建立小鼠ICH模型。用保温垫将小鼠的体温保持在37.5℃,在bregma右侧钻孔2mm,在bregma正面钻孔0.8mm。入针深度3.5mm。接下来,向纹状体注射细菌胶原酶IV 10分钟(500nl PBS中0.07单位)。注射后静置15分钟,防止胶原酶泄漏。最后缝合切口并消毒。
3、侧脑室注射给药
侧脑室(ICV)注射位置在嵴后0.3mm,嵴侧1.0mm。插入深度2.3mm。MST4 AAV(Vigenebio Biosciences,Maryland,USA,4.95 1013vg/ml)于脑出血前4周注入侧脑室,总体积为10μl。Hesperadin(MCE,HY-12054,0.4μg/μl)溶于1%DMSO溶剂中,于ICH前1小时通过ICV给药,给药剂量为2ul。将mc950溶于磷酸盐缓冲生理盐水中,每只小鼠10mg/kg剂量,连续3天。MCC950的剂量是根据以往的报道选择的,表明它能有效预防损伤(Ren et al.,2018)。对照组只给予磷酸盐缓冲盐水。
4、行为学评估
Garcia测试总分为21分,包括攀爬、侧翻、触感本体感觉、自发活动、抓握、前肢行走、肢体运动对称性和轴向感觉。让老鼠前进到一个30度角的角落,然后转身离开这个角落。离开拐角时,记录鼠标转弯的方向。向右转的老鼠越多,说明神经损伤越严重。
5、脑水含量评估
脑出血后24小时处死小鼠取脑。无灌注时,将组织分为五个部分:小脑、同侧皮质(ipsi-cx)、基底神经节(ipsi-bg)、基底神经节(contc-bg)、对侧皮质(contc)。湿重(WW)和干重(DW)在100℃下蒸发,持续24小时。生物用水量计算公式:[(WW DW)/WW]100%。
6、蛋白免疫印迹Western Blot
Western blot如前所述。所有一抗均显示:兔多克隆抗mst4(1:1500,10847-1-AP,Proteintech),兔多克隆抗nlrp3抗体(1:1500,19771-1-AP,Proteintech),兔多克隆抗il-1β抗体(1:1000,ab9722,Abcam),兔多克隆抗caspase-1抗体(1:1500,22915-1-AP,Proteintech),兔多克隆抗tnf-α抗体(1:1500,346654,ZEN-BIOSCIENCE),β-actin(1:1000,GB1101,Servicebio Technology,China)。
7、免疫荧光Immunofluorescence
脑标本按脱水、石蜡包埋、切片的顺序进行处理。切片用二甲苯和不同梯度乙醇(100%、85%、75%)脱蜡,置于EDTA抗原回收缓冲液中,微波炉加热孵育。用3%牛血清白蛋白封闭切片30分钟。脑切片用一抗、二抗和DAPI孵育。一抗:MST4(1:50,10847-1-AP,Proteintech),Iba1(1:50,GB11105,Servicebio Technology),NLRP3(1:50,19771-1-AP,Proteintech)。二抗:cy3偶联山羊抗兔(1:50 0,GB21303,Servicebio Technology)、fitc偶联山羊抗兔(1:500,GB22303,Servicebio Technology)。
实施例2、ICH后MST4、NLRP3的表达及其细胞定位
MST4蛋白水平在ICH后12小时、24小时显着升高,在12小时达到峰值(*p<0.05与假手术;图2A、B)。在ICH后12和24小时观察到NLRP3蛋白水平升高,在24小时达到峰值(*p<0.05与假手术,图2A、C)。MST4和NLRP3水平均随峰值下降。ICH后24小时是选择作为实验2、3和4的观察时间点。进行MST4或NLRP3与Iba1的免疫荧光。MST4和NLRP3均在小胶质细胞中表达,并在ICH后增加(图2D)。
实施例3、MST4 AAV抑制NLRP3炎性体激活
ICH后MST4、NLRP3炎性体成分、IL-1β、TNF-α的表达增加(*p<0.05与假手术;图3A-F)。MST4 AAV减弱caspase-1激活、IL-1β和TNF-α分泌(#p<0.05vs.ICH;图3A-F)。MST4 AAV给药显着改善神经功能缺损(*p<0.05,*p与假手术,#p<0.05与ICH,图3G-H)。与神经学评估一致,BWC在ICH后同侧半球升高,而MST4 AAV死亡BWC(*p<0.05,*与假手术,#p<0.05与ICH,图3I)。
实施例4、Hesperadin增加NLRP3炎性体激活
Hesperadin预处理抑制MST4蛋白表达,同时增加NLRP3、IL-1β、caspase-1和TNF-α的表达(#p<0.05vs.ICH,图4A-F)。hesperadin在ICH小鼠中加重神经功能缺损(#p<0.05vs.ICH,图4G-H)并增加BWC(#p<0.05vs.ICH,图4I)。
实施例5、MCC950减弱炎症对MST4/NLRP3信号的影响
ICH+MCC950组的ICH NLRP3蛋白含量降低(#p<0.05vs.ICH,图5A、C)。同时,IL-1β、caspase-1和TNF-α的表达相应降低(#p<0.05vs.ICH,图5A,DF),而MCC950处理显示MST4表达没有差异(#p<0.05与ICH,图5B)。MCC950改善NLRP3介导的ICH后神经功能损伤(#p<0.05vs.ICH,图5G,H)。MCC950干扰降低了ICH后受影响基底神经节的BWC(#p<0.05与ICH,图5I)。
实施例6、Hesperadin和MCC950均可抑制MST4与NLRP3的结合与共定位
在ICH后24小时在血肿周围的脑组织中进行MST和NLRP3的双重免疫荧光染色。观察到MST4、NLRP3的免疫荧光共标记,并且MST4 AAV减少了ICH后MST4-NLRP3荧光积累(图6)。MST4 AAV减少了ICH后MST4-NLRP3荧光积累。在ICH+Hesperadin组中,MST4的荧光强度较弱,而NLRP3的荧光强度增加。MCC950的给药显着降低了NLRP3的荧光强度。
本实施例通过免疫荧光双标技术对脑出血后24小时血肿周围的脑组织中MST4和NLRP3荧光染色。在脑出血组中观察到较强MST4和NLRP3荧光强度,并且MST4 AAV减少了ICH后MST4-NLRP3荧光积累,MST4AAV减弱了MST4-NLRP3之间相互作用。同时在MCC950给药组,MST4-NLRP3荧光积累也减少,MCC950也减弱了MST4-NLRP3之间结合。相反的在Hesperadin组中,MST4的荧光强度较弱,而NLRP3的荧光强度增加。
本发明实施例检测到ICH增加了小鼠大脑中MST4蛋白的表达。MST4在小胶质细胞中表达并参与ICH的炎症病理过程。MST4通过调节NLRP3药物信号通路影响ICH的行为结果。在ICH条件下,MST4的上调显示出有益的结果并降低了BWC,而MST4抑制剂hesperadin的给药显示出相反的效果。此外,NLRP3炎症小体抑制剂MCC950降低了ICH小鼠的BWC并改善了神经功能。此外,MST4蛋白含量的增加表明ICH后抗炎作用得到加强。
本发明的实施例报告了MST4在ICH动物模型中对免疫反应的作用。MST4蛋白的上调可能与抑制炎症反应避免过度炎症加重损伤有关。本发明的研究表明MST4和NLRP3蛋白水平在ICH后增加。MST4的峰值在ICH后12小时,而NLRP3的峰值在ICH后24小时。选择ICH后24小时作为机制研究的时间点,因为本发明的研究侧重于下游炎症,而不是MST4相关的自噬途径。
本发明实施例进行了MST4 AAV的给药,结果表明,MST4的上调负调节NLRP3炎症小体并降低IL-1β和TNF-α的表达,这表明MST4可能是ICH引起的炎症的潜在治疗靶点。
本发明使用了MST4抑制剂hesperadin并抑制了MST4的表达,同时激活了NLRP3炎症小体并增加了炎症因子。它加重了神经功能缺损并减少了脑水肿。在一定程度上,不同时间点增大的MST4可能介导自噬损伤。此外,MCC950抑制了NLRP3炎症小体对NLRP3、IL-1β、caspase-1和TNF-α表达的影响,而MST4蛋白水平没有差异。NLRP3抑制ICH诱导的MST4增加可能通过抑制NLRP3介导的炎症在改善神经功能方面发挥重要作用。
虽然,上文中已经用一般性说明及具体实施例对本发明作了详尽的描述,但在本发明基础上,可以对之作一些修改或改进,这对本领域技术人员而言是显而易见的。因此,在不偏离本发明精神的基础上所做的这些修改或改进,均属于本发明要求保护的范围。
参考文献:
1.Espada,C.E.,St Gelais,C.,Bonifati,S.,Maksimova,V.V.,Cahill,M.P.,Kim,S.H.,Wu,L.,2021.TRAF6 and TAK1 Contribute to SAMHD1-Mediated NegativeRegulation of NF-κB Signaling.J Virol.95.
2.Feng,L.,Chen,Y.,Ding,R.,Fu,Z.,Yang,S.,Deng,X.,Zeng,J.,2015.P2X7Rblockade prevents NLRP3 inflammasome activation and brain injury in a ratmodel of intracerebral hemorrhage:involvement of peroxynitrite.JNeuroinflammation.12,190.
3.Gao,Y.,Ma,L.,Luo,C.L.,Wang,T.,Zhang,M.Y.,Shen,X.,Meng,H.H.,Ji,M.M.,Wang,Z.F.,Chen,X.P.,Tao,L.Y.,2017.IL-33Exerts Neuroprotective Effect in MiceIntracerebral Hemorrhage Model Through Suppressing Inflammation/Apoptotic/Autophagic Pathway.Mol Neurobiol.54,3879-3892.
4.Hamarsheh,S.,Zeiser,R.,2020.NLRP3 Inflammasome Activation inCancer:A Double-Edged Sword.Front Immunol.11,1444.
5.Han,X.M.,Tian,P.Y.,Zhang,J.L.,2019.MicroRNA-486-5p inhibits ovariangranulosa cell proliferation and participates in the development of PCOS viatargeting MST4.Eur Rev Med Pharmacol Sci.23,7217-7223.
6.Jiao,S.,Zhang,Z.,Li,C.,Huang,M.,Shi,Z.,Wang,Y.,Song,X.,Liu,H.,Li,C.,Chen,M.,Wang,W.,Zhao,Y.,Jiang,Z.,Wang,H.,Wong,C.C.,Wang,C.,Zhou,Z.,2015.The kinase MST4 limits inflammatory responses through directphosphorylation of the adaptor TRAF6.Nat Immunol.16,246-57.
7.Keep,R.F.,Hua,Y.,Xi,G.,2012.Intracerebral haemorrhage:mechanisms ofinjury and therapeutic targets.Lancet Neurol.11,720-31.
8.Kelley,N.,Jeltema,D.,Duan,Y.,He,Y.,2019.The NLRP3 Inflammasome:AnOverview of Mechanisms of Activation and Regulation.Int J Mol Sci.20.
9.Kim,C.K.,Ryu,W.S.,Choi,I.Y.,Kim,Y.J.,Rim,D.,Kim,B.J.,Jang,H.,Yoon,B.W.,Lee,S.H.,2013.Detrimental effects of leptin on intracerebral hemorrhagevia the STAT3 signal pathway.J Cereb Blood Flow Metab.33,944-53.
10.Krafft,P.R.,McBride,D.W.,Lekic,T.,Rolland,W.B.,Mansell,C.E.,Ma,Q.,Tang,J.,Zhang,J.H.,2014.Correlation between subacute sensorimotor deficitsand brain edema in two mouse models of intracerebral hemorrhage.Behav BrainRes.264,151-60.
11.Krafft,P.R.,McBride,D.,Rolland,W.B.,Lekic,T.,Flores,J.J.,Zhang,J.H.,2017.α7 Nicotinic Acetylcholine Receptor Stimulation AttenuatesNeuroinflammation through JAK2-STAT3 Activation in Murine Models ofIntracerebral Hemorrhage.Biomed Res Int.2017,8134653.
12.Kuramatsu,J.B.,Huttner,H.B.,Schwab,S.,2013.Advances in themanagement of intracerebral hemorrhage.J Neural Transm(Vienna).120 Suppl 1,S35-41.13.Lin,J.L.,Chen,H.C.,Fang,H.I.,Robinson,D.,Kung,H.J.,Shih,H.M.,2001.MST4,a new Ste20-related kinase that mediates cell growth andtransformation via modulating ERK pathway.Oncogene.20,6559-69.
14.Ling,P.,Lu,T.J.,Yuan,C.J.,Lai,M.D.,2008.Biosignaling of mammalianSte20-related kinases.Cell Signal.20,1237-47.
15.Liu,X.,You,J.,Peng,X.,Wang,Q.,Li,C.,Jiang,N.,Che,C.,Zhou,Y.,Zheng,H.,Zhang,Z.,Zhao,G.,Lin,J.,2020.Mammalian Ste20-like kinase 4 inhibits theinflammatory response in Aspergillus fumigatus keratitis.IntImmunopharmacol.88,107021.
16.Lu,Q.,Liu,R.,Sherchan,P.,Ren,R.,He,W.,Fang,Y.,Huang,Y.,Shi,H.,Tang,L.,Yang,S.,Zhang,J.H.,Tang,J.,2021.TREM(Triggering Receptor Expressed onMyeloid Cells)-1 Inhibition Attenuates Neuroinflammation via PKC(ProteinKinase C)δ/CARD9(Caspase Recruitment Domain Family Member 9)Signaling PathwayAfter Intracerebral Hemorrhage in Mice.Stroke.Strokeaha120032736.
17.Lu,T.,Wang,Z.,Prativa,S.,Xu,Y.,Wang,T.,Zhang,Y.,Yu,L.,Xu,N.,Tang,J.,You,W.,Chen,G.,Zhang,J.H.,2019.Macrophage stimulating protein preservesblood brain barrier integrity after intracerebral hemorrhage throughrecepteur d'origine nantais dependent GAB1/Src/β-catenin pathway activationin a mouse model.J Neurochem.148,114-126.
18.Ma,Q.,Chen,S.,Hu,Q.,Feng,H.,Zhang,J.H.,Tang,J.,2014.NLRP3inflammasome contributes to inflammation after intracerebral hemorrhage.AnnNeurol.75,209-19.
19.Qian,Z.,Lin,C.,Espinosa,R.,LeBeau,M.,Rosner,M.R.,2001.Cloning andcharacterization of MST4,a novel Ste20-like kinase.J Biol Chem.276,22439-45.
20.Ren,H.,Kong,Y.,Liu,Z.,Zang,D.,Yang,X.,Wood,K.,Li,M.,Liu,Q.,2018.Selective NLRP3(Pyrin Domain-Containing Protein 3)Inflammasome InhibitorReduces Brain Injury After Intracerebral Hemorrhage.Stroke.49,184-192.
21.Roh,K.H.,Lee,Y.,Yoon,J.H.,Lee,D.,Kim,E.,Park,E.,Lee,I.Y.,Kim,T.S.,Song,H.K.,Shin,J.,Lim,D.S.,Choi,E.J.,2021.TRAF6-mediated ubiquitination ofMST1/STK4 attenuates the TLR4-NF-κB signaling pathway in macrophages.Cell MolLife Sci.78,2315-2328.
22.Sheth,K.N.,Rosand,J.,2014.Targeting the immune system inintracerebral hemorrhage.JAMA Neurol.71,1083-4.
23.Shi,S.X.,Li,Y.J.,Shi,K.,Wood,K.,Ducruet,A.F.,Liu,Q.,2020.IL(Interleukin)-15 Bridges Astrocyte-Microglia Crosstalk and Exacerbates BrainInjury Following Intracerebral Hemorrhage.Stroke.51,967-974.
24.Speir,M.,Lawlor,K.E.,2021.RIP-roaring inflammation:RIPK1 and RIPK3driven NLRP3 inflammasome activation and autoinflammatory disease.Semin CellDev Biol.109,114-124.
25.Unamuno,X.,Gómez-Ambrosi,J.,Ramírez,B.,Rodríguez,A.,Becerril,S.,Valentí,V.,Moncada,R.,Silva,C.,Salvador,J.,Frühbeck,G.,Catalán,V.,2021.NLRP3inflammasome blockade reduces adipose tissue inflammation and extracellularmatrix remodeling.Cell Mol Immunol.18,1045-1057.
26.Wan,S.Y.,Li,G.S.,Tu,C.,Chen,W.L.,Wang,X.W.,Wang,Y.N.,Peng,L.B.,Tan,F.,2021.MicroNAR-194-5p hinders the activation of NLRP3 inflammasomes andalleviates neuroinflammation during intracerebral hemorrhage by blocking theinteraction between TRAF6 and NLRP3.Brain Res.1752,147228.
27.Wu,H.,Arron,J.R.,2003.TRAF6,a molecular bridge spanning adaptiveimmunity,innate immunity and osteoimmunology.Bioessays.25,1096-105.
28.Wu,X.,Wu,J.,Hu,W.,Wang,Q.,Liu,H.,Chu,Z.,Lv,K.,Xu,Y.,2020.MST4Kinase Inhibitor Hesperadin Attenuates Autophagy and Behavioral Disorder viathe MST4/AKT Pathway in Intracerebral Hemorrhage Mice.Behav Neurol.2020,2476861.
29.Xing,Y.,Yao,X.,Li,H.,Xue,G.,Guo,Q.,Yang,G.,An,L.,Zhang,Y.,Meng,G.,2017.Cutting Edge:TRAF6 Mediates TLR/IL-1R Signaling-InducedNontranscriptional Priming of the NLRP3 Inflammasome.J Immunol.199,1561-1566.
30.Xiong,W.,Matheson,C.J.,Xu,M.,Backos,D.S.,Mills,T.S.,Salian-Mehta,S.,Kiseljak-Vassiliades,K.,Reigan,P.,Wierman,M.E.,2016.Structure-Based ScreenIdentification of a Mammalian Ste20-like Kinase 4(MST4)Inhibitor withTherapeutic Potential for Pituitary Tumors.Mol Cancer Ther.15,412-20.
31.Xu,Y.,Nowrangi,D.,Liang,H.,Wang,T.,Yu,L.,Lu,T.,Lu,Z.,Zhang,J.H.,Luo,B.,Tang,J.,2020.DKK3 attenuates JNK and AP-1 induced inflammation viaKremen-1 and DVL-1 in mice following intracerebral hemorrhage.JNeuroinflammation.17,130.
32.Xu,Y.,Wu,X.,Hu,W.,Yu,D.,Shao,Z.,Li,W.,Huang,T.,Zhang,J.,Zhu,X.,Li,X.,Yang,H.,Chu,Z.,Lv,K.,2021.RIP3 facilitates necroptosis through CaMKII andAIF after intracerebral hemorrhage in mice.Neurosci Lett.749,135699.
33.Yang,Z.,Zhong,L.,Xian,R.,Yuan,B.,2015.MicroRNA-223 regulatesinflammation and brain injury via feedback to NLRP3 inflammasome afterintracerebral hemorrhage.Mol Immunol.65,267-76.
34.Yao,S.T.,Cao,F.,Chen,J.L.,Chen,W.,Fan,R.M.,Li,G.,Zeng,Y.C.,Jiao,S.,Xia,X.P.,Han,C.,Ran,Q.S.,2017.NLRP3 is Required for Complement-MediatedCaspase-1 and IL-1beta Activation in ICH.J Mol Neurosci.61,385-395.
35.Yuan,B.,Shen,H.,Lin,L.,Su,T.,Zhong,S.,Yang,Z.,2015.Recombinantadenovirus encoding NLRP3 RNAi attenuate inflammation and brain injury afterintracerebral hemorrhage.J Neuroimmunol.287,71-5.
Claims (9)
1.MST4相关物质作为如下(a)和/或(b)和/或(c)和/或(d)和/或(e)和/或(f)和/或(g)的应用,
(a)制备促进MST4和NLRP3的表达的产品;
(b)制备抑制MST4表达的产品;
(c)制备抑制NLRP3的表达的产品;
(d)制备抑制MST4表达,而促进NLRP3表达的产品;
(e)制备抑制IL-1β和TNF-α的释放的产品;
(f)制备预防和/或治疗神经功能缺损、脑水肿的产品;
(g)制备预防和/或治疗脑出血后神经炎症反应的产品。
2.如权利要求1所述的应用,其特征在于,
所述MST4相关物质包括MST4的表达促进物,MST4的表达抑制物,MST4和NLRP3相互作用的促进物,MST4和NLRP3相互作用的抑制物。
3.如权利要求2所述的应用,其特征在于,
所述MST4的表达促进物为MST4 AAV。
4.如权利要求2所述的应用,其特征在于,
所述MST4的表达抑制物为Hesperadin。
5.如权利要求2所述的应用,其特征在于,
所述MST4和NLRP3相互作用的抑制物为Hesperadin或/和MCC950。
7.如权利要求2所述的应用,其特征在于,
所述MST4和NLRP3相互作用的促进物为MST4 AAV。
8.一种产品,其活性成分为MST4相关物质,所述产品的用途为如下(a)和/或(b)和/或(c)和/或(d)和/或(e)和/或(f)和/或(g):
(a)促进MST4和NLRP3的表达;
(b)抑制MST4表达;
(c)抑制NLRP3的表达;
(d)抑制MST4表达,而促进NLRP3表达;
(e)抑制IL-1β和TNF-α的释放;
(f)预防和/或治疗神经功能缺损、脑水肿;
(g)预防和/或治疗脑出血后神经炎症反应。
9.如权利要求9所述的产品,其特征在于,
所述MST4相关物质包括MST4的表达促进物,MST4的表达抑制物,MST4和NLRP3相互作用的促进物,MST4和NLRP3相互作用的抑制物。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111080992.XA CN113577288A (zh) | 2021-09-15 | 2021-09-15 | Mst4相关物质在制备治疗脑出血后神经炎症反应的药物中的应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111080992.XA CN113577288A (zh) | 2021-09-15 | 2021-09-15 | Mst4相关物质在制备治疗脑出血后神经炎症反应的药物中的应用 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN113577288A true CN113577288A (zh) | 2021-11-02 |
Family
ID=78242052
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202111080992.XA Pending CN113577288A (zh) | 2021-09-15 | 2021-09-15 | Mst4相关物质在制备治疗脑出血后神经炎症反应的药物中的应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN113577288A (zh) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101050473A (zh) * | 2007-02-09 | 2007-10-10 | 北京大学 | 抗细胞增殖或抗肿瘤药物的筛选试剂盒、筛选方法及用途 |
US20170268001A1 (en) * | 2016-03-16 | 2017-09-21 | The University Of Chicago | Rnas with tumor radio/chemo-sensitizing and immunomodulatory properties and methods of their preparation and application |
CN110151749A (zh) * | 2018-02-13 | 2019-08-23 | 中国科学技术大学 | 冬凌草甲素在制备预防或治疗nlrp3炎症小体相关疾病的药物中的应用 |
US20210267996A1 (en) * | 2018-06-27 | 2021-09-02 | Children`S Medical Center Corporation | Compounds for inhibition of inflammation |
-
2021
- 2021-09-15 CN CN202111080992.XA patent/CN113577288A/zh active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101050473A (zh) * | 2007-02-09 | 2007-10-10 | 北京大学 | 抗细胞增殖或抗肿瘤药物的筛选试剂盒、筛选方法及用途 |
US20170268001A1 (en) * | 2016-03-16 | 2017-09-21 | The University Of Chicago | Rnas with tumor radio/chemo-sensitizing and immunomodulatory properties and methods of their preparation and application |
CN110151749A (zh) * | 2018-02-13 | 2019-08-23 | 中国科学技术大学 | 冬凌草甲素在制备预防或治疗nlrp3炎症小体相关疾病的药物中的应用 |
US20210267996A1 (en) * | 2018-06-27 | 2021-09-02 | Children`S Medical Center Corporation | Compounds for inhibition of inflammation |
Non-Patent Citations (1)
Title |
---|
XIAODONG WU 等: "MST4 attenuates NLRP3 inflammasome-mediated neuroinflammation and affects the prognosis after intracerebral hemorrhage in mice", 《BRAIN RESEARCH BULLETIN》 * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Li et al. | Senolytic therapy ameliorates renal fibrosis postacute kidney injury by alleviating renal senescence | |
Liu et al. | Mesenchymal stem cells alleviate the early brain injury of subarachnoid hemorrhage partly by suppression of Notch1-dependent neuroinflammation: involvement of Botch | |
Su et al. | Necrostatin-1 ameliorates intracerebral hemorrhage-induced brain injury in mice through inhibiting RIP1/RIP3 pathway | |
Rubio et al. | Mesenchymal stromal cells prevent bleomycin‐induced lung and skin fibrosis in aged mice and restore wound healing | |
Liang et al. | Lymphatic endothelial cells efferent to inflamed joints produce iNOS and inhibit lymphatic vessel contraction and drainage in TNF-induced arthritis in mice | |
Halwani et al. | CC and CXC chemokines induce airway smooth muscle proliferation and survival | |
Xiong et al. | Glycyrrhizin protects against focal cerebral ischemia via inhibition of T cell activity and HMGB1-mediated mechanisms | |
Bridle et al. | Rapamycin inhibits hepatic fibrosis in rats by attenuating multiple profibrogenic pathways | |
Freitas et al. | Blockade of Janus kinase‐2 signaling ameliorates mouse liver damage due to ischemia and reperfusion | |
Wang et al. | The regulatory peptide apelin: a novel inhibitor of renal interstitial fibrosis | |
Wang et al. | Tongxinluo ameliorates renal structure and function by regulating miR-21-induced epithelial-to-mesenchymal transition in diabetic nephropathy | |
Morrison et al. | The contribution of mannose binding lectin to reperfusion injury after ischemic stroke | |
Yang et al. | Beneficial effects of ginsenoside-Rg1 on ischemia-induced angiogenesis in diabetic mice | |
Yang et al. | The role of STAT3/mTOR-regulated autophagy in angiotensin II-induced senescence of human glomerular mesangial cells | |
Tabony et al. | Protein phosphatase 2C-alpha knockdown reduces angiotensin II-mediated skeletal muscle wasting via restoration of mitochondrial recycling and function | |
Wu et al. | Dissection of the mechanism of traditional Chinese medical prescription-Yiqihuoxue formula as an effective anti-fibrotic treatment for systemic sclerosis | |
Wu et al. | MST4 attenuates NLRP3 inflammasome-mediated neuroinflammation and affects the prognosis after intracerebral hemorrhage in mice | |
Mathew | Pulmonary hypertension and metabolic syndrome: Possible connection, PPARγ and Caveolin-1 | |
Cao et al. | Rhynchophylline prevents cardiac dysfunction and improves survival in lipopolysaccharide-challenged mice via suppressing macrophage I-κBα phosphorylation | |
Chen et al. | 2, 3, 5, 4′-Tetrahydroxystilbene-2-O-β-d-glucoside exerted protective effects on diabetic nephropathy in mice with hyperglycemia induced by streptozotocin | |
Liu et al. | Schisantherin A improves learning and memory of mice with D-galactose-induced learning and memory impairment through its antioxidation and regulation of p19/p53/p21/Cyclin D1/CDK4/RB gene expressions | |
Lu et al. | Short time tripterine treatment enhances endothelial progenitor cell function via heat shock protein 32 | |
Xu et al. | Angiotensin-(1-7) protects against sepsis-associated left ventricular dysfunction induced by lipopolysaccharide | |
Lan et al. | Polydatin attenuates hepatic stellate cell proliferation and liver fibrosis by suppressing sphingosine kinase 1 | |
Zhao et al. | Oleoylethanolamide alleviates macrophage formation via AMPK/PPARα/STAT3 pathway |
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: 20211102 |