CN110960522A - Application of genipin in preparation of drugs for preventing and treating Tau protein abnormality - Google Patents
Application of genipin in preparation of drugs for preventing and treating Tau protein abnormality Download PDFInfo
- Publication number
- CN110960522A CN110960522A CN201911399552.3A CN201911399552A CN110960522A CN 110960522 A CN110960522 A CN 110960522A CN 201911399552 A CN201911399552 A CN 201911399552A CN 110960522 A CN110960522 A CN 110960522A
- Authority
- CN
- China
- Prior art keywords
- tau protein
- genipin
- application
- disease
- tau
- 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
- 108010026424 tau Proteins Proteins 0.000 title claims abstract description 106
- 102000013498 tau Proteins Human genes 0.000 title claims abstract description 106
- AZKVWQKMDGGDSV-BCMRRPTOSA-N Genipin Chemical compound COC(=O)C1=CO[C@@H](O)[C@@H]2C(CO)=CC[C@H]12 AZKVWQKMDGGDSV-BCMRRPTOSA-N 0.000 title claims abstract description 67
- AZKVWQKMDGGDSV-UHFFFAOYSA-N genipin Natural products COC(=O)C1=COC(O)C2C(CO)=CCC12 AZKVWQKMDGGDSV-UHFFFAOYSA-N 0.000 title claims abstract description 67
- 239000003814 drug Substances 0.000 title claims abstract description 15
- 229940079593 drug Drugs 0.000 title claims abstract description 9
- 238000002360 preparation method Methods 0.000 title claims description 6
- 230000005856 abnormality Effects 0.000 title abstract description 7
- 239000003112 inhibitor Substances 0.000 claims abstract description 12
- 206010016654 Fibrosis Diseases 0.000 claims abstract description 8
- 230000004761 fibrosis Effects 0.000 claims abstract description 8
- 230000006951 hyperphosphorylation Effects 0.000 claims abstract description 7
- 238000006384 oligomerization reaction Methods 0.000 claims abstract description 4
- 210000002682 neurofibrillary tangle Anatomy 0.000 claims description 14
- 206010012289 Dementia Diseases 0.000 claims description 13
- 201000010099 disease Diseases 0.000 claims description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 13
- 108090000623 proteins and genes Proteins 0.000 claims description 11
- 102000004169 proteins and genes Human genes 0.000 claims description 8
- 206010034010 Parkinsonism Diseases 0.000 claims description 7
- 208000034799 Tauopathies Diseases 0.000 claims description 7
- 230000002159 abnormal effect Effects 0.000 claims description 7
- 201000011240 Frontotemporal dementia Diseases 0.000 claims description 5
- 230000002776 aggregation Effects 0.000 claims description 5
- 238000004220 aggregation Methods 0.000 claims description 5
- 210000004556 brain Anatomy 0.000 claims description 5
- 208000005264 motor neuron disease Diseases 0.000 claims description 5
- 230000000750 progressive effect Effects 0.000 claims description 5
- 208000024827 Alzheimer disease Diseases 0.000 claims description 4
- 206010018341 Gliosis Diseases 0.000 claims description 4
- 208000026072 Motor neurone disease Diseases 0.000 claims description 4
- 208000036757 Postencephalitic parkinsonism Diseases 0.000 claims description 4
- 102000029797 Prion Human genes 0.000 claims description 4
- 108091000054 Prion Proteins 0.000 claims description 4
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 4
- 230000007387 gliosis Effects 0.000 claims description 4
- 208000000170 postencephalitic Parkinson disease Diseases 0.000 claims description 4
- 208000005145 Cerebral amyloid angiopathy Diseases 0.000 claims description 3
- 208000011990 Corticobasal Degeneration Diseases 0.000 claims description 3
- 208000020406 Creutzfeldt Jacob disease Diseases 0.000 claims description 3
- 208000003407 Creutzfeldt-Jakob Syndrome Diseases 0.000 claims description 3
- 208000010859 Creutzfeldt-Jakob disease Diseases 0.000 claims description 3
- 201000010374 Down Syndrome Diseases 0.000 claims description 3
- 206010061533 Myotonia Diseases 0.000 claims description 3
- 208000010577 Niemann-Pick disease type C Diseases 0.000 claims description 3
- 208000000609 Pick Disease of the Brain Diseases 0.000 claims description 3
- 208000037065 Subacute sclerosing leukoencephalitis Diseases 0.000 claims description 3
- 206010042297 Subacute sclerosing panencephalitis Diseases 0.000 claims description 3
- 206010044688 Trisomy 21 Diseases 0.000 claims description 3
- 208000007930 Type C Niemann-Pick Disease Diseases 0.000 claims description 3
- 208000017004 dementia pugilistica Diseases 0.000 claims description 3
- 230000002518 glial effect Effects 0.000 claims description 3
- 201000002212 progressive supranuclear palsy Diseases 0.000 claims description 3
- 230000002739 subcortical effect Effects 0.000 claims description 3
- 208000009093 Diffuse Neurofibrillary Tangles with Calcification Diseases 0.000 claims description 2
- 208000003736 Gerstmann-Straussler-Scheinker Disease Diseases 0.000 claims description 2
- 206010072075 Gerstmann-Straussler-Scheinker syndrome Diseases 0.000 claims description 2
- 208000002593 pantothenate kinase-associated neurodegeneration Diseases 0.000 claims description 2
- 239000002245 particle Substances 0.000 claims 1
- 238000003032 molecular docking Methods 0.000 abstract description 12
- 230000026731 phosphorylation Effects 0.000 abstract description 11
- 238000006366 phosphorylation reaction Methods 0.000 abstract description 11
- 239000000835 fiber Substances 0.000 abstract description 10
- 229920000669 heparin Polymers 0.000 abstract description 8
- 238000002474 experimental method Methods 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 abstract description 4
- 239000000178 monomer Substances 0.000 abstract description 4
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 abstract description 3
- 229960002897 heparin Drugs 0.000 abstract description 3
- 101100495314 Caenorhabditis elegans cdk-5 gene Proteins 0.000 abstract description 2
- 235000013376 functional food Nutrition 0.000 abstract description 2
- 230000002265 prevention Effects 0.000 abstract description 2
- 210000004027 cell Anatomy 0.000 description 21
- 230000004845 protein aggregation Effects 0.000 description 10
- JADVWWSKYZXRGX-UHFFFAOYSA-M thioflavine T Chemical compound [Cl-].C1=CC(N(C)C)=CC=C1C1=[N+](C)C2=CC=C(C)C=C2S1 JADVWWSKYZXRGX-UHFFFAOYSA-M 0.000 description 9
- 102000013717 Cyclin-Dependent Kinase 5 Human genes 0.000 description 7
- 108010025454 Cyclin-Dependent Kinase 5 Proteins 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 5
- 229960001008 heparin sodium Drugs 0.000 description 5
- 102000029749 Microtubule Human genes 0.000 description 4
- 108091022875 Microtubule Proteins 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 210000004688 microtubule Anatomy 0.000 description 4
- 208000011580 syndromic disease Diseases 0.000 description 4
- 238000001262 western blot Methods 0.000 description 4
- 230000005540 biological transmission Effects 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 230000004770 neurodegeneration Effects 0.000 description 3
- 208000015122 neurodegenerative disease Diseases 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 208000018737 Parkinson disease Diseases 0.000 description 2
- 238000005094 computer simulation Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000004017 serum-free culture medium Substances 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- 244000186140 Asperula odorata Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 235000008526 Galium odoratum Nutrition 0.000 description 1
- IBFYXTRXDNAPMM-BVTMAQQCSA-N Geniposide Chemical compound O([C@@H]1OC=C([C@@H]2[C@H]1C(=CC2)CO)C(=O)OC)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O IBFYXTRXDNAPMM-BVTMAQQCSA-N 0.000 description 1
- IBFYXTRXDNAPMM-FZEIBHLUSA-N Geniposide Natural products COC(=O)C1=CO[C@@H](O[C@H]2O[C@@H](CO)[C@H](O)[C@@H](O)[C@@H]2O)[C@H]2[C@@H]1CC=C2CO IBFYXTRXDNAPMM-FZEIBHLUSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 101150070547 MAPT gene Proteins 0.000 description 1
- 102000009664 Microtubule-Associated Proteins Human genes 0.000 description 1
- 108010020004 Microtubule-Associated Proteins Proteins 0.000 description 1
- 206010068871 Myotonic dystrophy Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- 239000012124 Opti-MEM Substances 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 201000009594 Systemic Scleroderma Diseases 0.000 description 1
- 206010042953 Systemic sclerosis Diseases 0.000 description 1
- 238000003917 TEM image Methods 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 102000004243 Tubulin Human genes 0.000 description 1
- 108090000704 Tubulin Proteins 0.000 description 1
- COQLPRJCUIATTQ-UHFFFAOYSA-N Uranyl acetate Chemical compound O.O.O=[U]=O.CC(O)=O.CC(O)=O COQLPRJCUIATTQ-UHFFFAOYSA-N 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- VGLLGNISLBPZNL-RBUKDIBWSA-N arborescoside Natural products O=C(OC)C=1[C@@H]2C([C@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O3)OC=1)=C(CO)CC2 VGLLGNISLBPZNL-RBUKDIBWSA-N 0.000 description 1
- 230000008335 axon cargo transport Effects 0.000 description 1
- 102000006995 beta-Glucosidase Human genes 0.000 description 1
- 108010047754 beta-Glucosidase Proteins 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 230000002308 calcification Effects 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- 239000003431 cross linking reagent Substances 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 238000001506 fluorescence spectroscopy Methods 0.000 description 1
- 210000000232 gallbladder Anatomy 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 201000010901 lateral sclerosis Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 238000002610 neuroimaging Methods 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- DKVBOUDTNWVDEP-NJCHZNEYSA-N teicoplanin aglycone Chemical compound N([C@H](C(N[C@@H](C1=CC(O)=CC(O)=C1C=1C(O)=CC=C2C=1)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)OC=1C=C3C=C(C=1O)OC1=CC=C(C=C1Cl)C[C@H](C(=O)N1)NC([C@H](N)C=4C=C(O5)C(O)=CC=4)=O)C(=O)[C@@H]2NC(=O)[C@@H]3NC(=O)[C@@H]1C1=CC5=CC(O)=C1 DKVBOUDTNWVDEP-NJCHZNEYSA-N 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
Images
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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Neurology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Neurosurgery (AREA)
- General Health & Medical Sciences (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Mycology (AREA)
- Nutrition Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the technical field of medicines, in particular to a new application of genipin, and an application of genipin in preparing medicines for preventing and treating Tau protein abnormality, including an application in preparing a Tau protein oligomerization inhibitor, an application in preparing a Tau protein fibrosis inhibitor, an application in preparing a Tau protein hyperphosphorylation inhibitor and an application in preparing a medicine for resisting Tau protein. Experiments prove that genipin can effectively inhibit the formation of Tau protein fibers induced by heparin, and the combination mode of genipin and Tau protein fiber monomers is confirmed by utilizing computer molecular docking; genipin can also reduce the phosphorylation level of Tau protein at serine 396 and 404 sites in SH-SY5Y/Tau cells; genipin inhibits phosphorylation of Tau protein by reducing the activity of CDK 5. In conclusion, genipin can be used for preparing medicaments, functional foods and health-care products related to prevention and/or treatment of Tau protein abnormality.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a new application of genipin, and an application of genipin in preparing medicines for preventing and treating Tau protein abnormality, including an application in preparing a Tau protein oligomerization inhibitor, an application in preparing a Tau protein fibrosis inhibitor, an application in preparing a Tau protein hyperphosphorylation inhibitor and an application in preparing a medicine for resisting Tau protein.
Background
Tau protein is a microtubule-associated protein encoded by the MAPT gene in chromosome17, maintains normal axonal transport and microtubule structural stability of nerves under physiological conditions, and has the basic function of promoting the assembly of tubulin into microtubules and further stabilizing the assembled microtubules. Normally, two to three amino acids of Tau protein are phosphorylated, and when Tau protein is abnormally over-phosphorylated, mutated or induced by other molecules, Tau protein will be depolymerized from microtubules and form neurofibrillary tangles (NFTs), which affect the basic form and function of neurons, thereby impairing the normal functional execution of nervous system.
Tauopathies (tauopathies) are a group of neurodegenerative diseases that have gained increasing attention in recent years that are closely related to cognitive dysfunction. These diseases accompanied by abnormal phosphorylation of Tau protein and defects in the gene encoding it are collectively referred to as tauopathies, including Alzheimer's disease, Amyotrophic lateral sclerosis/Parkinson syndrome-dementia complex (Amyotrophic lateral sclerosis/Parkinson's disease complex), dementia granulophilus (Argyrophilic dementia), corticobasal degeneration (Corticobanalegeneration), Creutzfeldt-Jakob disease, dementia pugilistica (Dementialillica), Diffuse neurofibrillary tangle (Difference neurofibrillary tangle with calcification), Down's syndrome, temporal dementia with Parkinson's syndrome linked to chromosome17 (Frontotor lateral sclerosis-Parkinson's disease), Watson-Schwann's syndrome (Woodwan's syndrome), and Watson-Schwann syndrome (Frontorelbilis-dementia with Parkinson's syndrome) linked to chromosome17 (Woodward syndrome), and Alzheimer's disease (Woodward-Schwann-25), and their gene defects in coding genes, Dystrophic myotonia (Myotonic dystrophy), Niemann-Pick type C (Niemann-Pick disease type C), Non-guarantal motor neuron disease with neurofibrillary tangles (Non-guarantal motor neuron disease with neurofibrillary tangles), Pick's disease, Postencephalitic parkinsonism (Postencephalitic parkinsonism), Prion protein cerebral amyloid angiopathy (Prion protein vascular disease), Progressive subcortical gliosis (Progressive cortical gliosis), Progressive supranuclear palsy (Progressive Subacute sclerosing encephalitis), Subacute sclerosing panencephalitis (systemic sclerosis), neurofibrillary dementia (cardiac dementia), and recent years's brain-derived protein ″), and other diseases. Although tauopathies have diverse phenotypic and clinical characteristics, they all share the presence of neurofibrillary tangles (NFTs) of insoluble, hyperphosphorylated Tau in fibrillar/fibril/fibrillar form (e.g., twisted, linear, or paired helices). Although the clinical symptoms, signs and neuroimaging changes of the above diseases are greatly different, the common characteristic of the diseases is that abnormal Tau protein is deposited in the brain, so the research level of protein is newly assigned, and a disease group which is gradually spotlighted as 'whole brain glial Tau protein disease' is formed. By inhibiting the aggregation of Tau protein and reducing the expression of Tau protein and multi-site phosphorylation Tau protein in cells, the Tau protein disease can be effectively treated.
Genipin (Genipin) mainly exists in plants such as fructus Gardeniae and Eucommiae cortex, is aglycon obtained by hydrolyzing geniposide with β -glucosidase, has iridoid structure and molecular formula C11H14O5Molecular weight 226.23, structure formula is shown in figure 1. Genipin is a natural cross-linking agent and has various good biological activities, and the productThe traditional Chinese medicine composition has the effects of protecting liver and benefiting gallbladder, resisting inflammation, tumors, thrombus and fibrosis, treating diabetes, part of neurodegenerative diseases and the like, especially obtains more and more attention from people in preventing and treating various experimental liver diseases, and has good clinical application prospect.
Disclosure of Invention
Aiming at the problem that genipin needs to be further developed and utilized in the prior art, the invention provides a new application of genipin.
In a first aspect of the invention, the application of genipin in preparing an oligomerization inhibitor of Tau protein is provided.
In another aspect of the invention, the application of genipin in preparing the Tau protein fibrosis inhibitor is provided.
In another aspect of the invention, the application of genipin in preparing Tau protein hyperphosphorylation inhibitors is provided.
In another aspect of the invention, an application of genipin in preparing a drug for resisting Tau protein is provided.
Further, the application of genipin in preparing the medicament for resisting the Tau protein disease is the disease caused by abnormal aggregation and/or hyperphosphorylation of the Tau protein.
Further, the tauopathies include Alzheimer's disease, amyotrophic lateral sclerosis/Parkinson's syndrome-dementia complex, silver-tropic dementia, corticobasal degeneration, Creutzfeldt-Jakob disease, dementia pugilistica, diffuse neurofibrillary tangles with calcification, Down's syndrome, frontotemporal dementia with Parkinson's syndrome linked to chromosome17, Gerstmann-Straussler-Scheinker disease, Hallervorden-Spatz disease, dystrophic myotonia, niemann-pick disease type C, non-guaranty's motor neuron disease accompanied by neurofibrillary tangles, pick's disease, postencephalitic parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, neurofibrillary tangle-only dementia, whole brain glial Tau proteinopathy, and the like.
The invention relates to a new application of a compound genipin, in particular to an application in preparing medicines for treating various diseases caused by Tau protein abnormality. The invention uses Tau protein as a target point for research, and establishes an experiment for detecting Tau protein aggregation by in vitro ThT fluorescence, and finds that genipin can obviously reduce ThT fluorescence value. Meanwhile, a core structure part of a genipin docking Tau protein monomer is obtained by simulating molecular docking through a computer, and the genipin and the Tau protein are assisted to prove that the genipin and the Tau protein have a binding effect and potential binding sites. In cells, genipin can remarkably reduce the phosphorylation levels of Tau protein of SH-SY5Y/Tau cells at Ser396 and Ser404 sites, has concentration dependence, and is further researched and found to inhibit the phosphorylation of the Tau protein by reducing the activity of CDK 5. These results indicate that genipin can inhibit Tau protein aggregation and reduce the expression of multi-site phosphorylated Tau protein, and can be used for preventing or treating diseases caused by abnormal Tau protein aggregation. In conclusion, genipin can be used for preparing medicaments, functional foods and health-care products related to prevention and/or treatment of Tau protein abnormality.
Drawings
FIG. 1 is a chemical structural formula of genipin;
FIG. 2 is a graph showing the relative fluorescence intensity of Tau protein added with thioflavin T, heparin sodium, and genipin, respectively, with time;
FIG. 3 is a transmission electron micrograph of genipin inhibiting Tau protein fibrosis;
FIG. 4 shows the docking results of genipin and Tau protein molecules;
FIG. 5 shows the results of the changes in the expression levels of Tau protein, pS396-Tau protein and pS404-Tau protein after genipin was allowed to act on SH-SY5Y/Tau cells;
FIG. 6 shows the change of CDK5 protein expression after genipin acts on SH-SY5Y/Tau cells.
Detailed Description
In order to more fully understand the technical contents of the present invention, the technical solutions of the present invention will be further described and illustrated with reference to the following specific embodiments. The experimental procedures not described in detail in the experiments are all routine experimental procedures well known to the person skilled in the art.
1. Experimental materials and reagents:
genipin (chemical structure formula shown in figure 1), heparin sodium, thioflavin t (tht) purchased from Sigma company; high-glucose DMEM medium, F12-DMEM medium, opti-MEM medium, penicillin, streptomycin, and fetal bovine serum were purchased from Gibco; tau, pS396-Tau, pS404-Tau, CDK5 antibodies were purchased from Abcam; ECL luminophores were purchased from Thermo Fisher scientific, Inc., and other conventional chemicals were purchased from Sigma, Inc.
2. Genipin inhibits heparin-induced Tau protein aggregation
The Tau protein can be induced by heparin sodium in vitro, self-aggregates to form fibers, so as to simulate the pathological process of abnormal Tau protein aggregation to generate neurofibrillary tangles in vivo, the thioflavin T (ThT) can be combined on β structures of the fibers to emit fluorescence, so the process of fibrosis of the Tau protein can be tracked through the fluorescence value of the ThT, the Tau protein is dissolved into 20 mu M by using Tris-HCl buffer solution and added into a black enzyme label plate, then the thioflavin T, the heparin sodium and the genipin (20 mu M) are respectively added, a full-wavelength fluorescence enzyme label instrument is used for continuously detecting for 25h under the conditions that the emitted light is 440nm and the excitation light is 485nm, a relative fluorescence value is used for drawing, a relative fluorescence intensity graph which changes along with time is shown in figure 2, in vitro, the Tau protein aggregates under the induction of the heparin sodium, and when the genipin is added into the system, the aggregation of the Tau protein is obviously inhibited.
The fibrosis condition of the Tau protein sample can be directly observed by using a Transmission Electron Microscope (TEM), and the result of the ThT fluorescence experiment can be further verified. Taking 5 mu L of samples in the Tau protein ThT experiment, dripping the samples on a 230-mesh copper net, then absorbing redundant samples by using filter paper, dripping 5 mu L of uranyl acetate after drying, absorbing redundant liquid after dyeing for 1min, drying, placing in a transmission electron microscope (NIPPON TEKNO, JEM-1230), observing and taking pictures. The result is shown in fig. 3, the dense Tau protein fibers can be observed under the transmission electron microscope of the control group, and the Tau protein fibers are sparse and are broken after the genipin is added, which indicates that the genipin can effectively block the formation of the Tau protein fibers.
3. Molecular docking of genipin with Tau protein
Molecular docking was performed using Sybyl-X2.0 software to study the binding pattern between genipin and Tau protein. The core structure of Tau protein fiber (PDB No. 5O3L) was downloaded from the RCSB protein database (http:// www.rcsb.org/PDB/home. do). The 2D results for genipin were plotted by ChemBioDraw Ultra 14.0 software and optimized by ChemBio3D Ultra 14.0 to yield the 3D structure of the molecule. Docking was performed using the Surflex-Dock program, the best docking mode was selected by docking scoring, and visual analysis was performed by Chimera and ligalot software.
As shown in figure 4, genipin molecule is combined with the hydrophobic pocket of Tau protein and is surrounded by His-362, Gly-367, Asn-368 and Lys-369, and more importantly, two hydrogen bonds are formed between genipin molecule and Lys-369, and the bond length is 2.72 and
all the interactions can help genipin to be anchored in an R3 structural domain of Tau protein, block the aggregation of Tau protein and further inhibit the formation of Tau protein fibers, so that the neurotoxicity can be effectively reduced, and the potential of preventing and treating neurodegenerative diseases caused by Tau protein aggregation is realized.
4. Genipin reduces phosphorylation level of Tau protein multi-site in SH-SY5Y/Tau cells
SH-SY5Y/Tau cells are inoculated in a culture plate, supernatant is discarded after the cells are attached to the wall, and serum-free culture medium containing genipin is added for treatment for 24 h. Extracting total cell protein by using cell lysate, and detecting the expression quantity of phosphorylated Tau protein in cells by using a Western Blot method.
As shown in FIG. 5, the Western Blot method detects that genipin can significantly reduce the phosphorylation levels of the Tau protein of SH-SY5Y/Tau cells at the sites of serine 396 and 404, and has concentration dependence.
5. Genipin reduces expression of CDK5 protein in SH-SY5Y/Tau cells
SH-SY5Y/Tau cells are inoculated in a culture plate, supernatant is discarded after the cells are attached to the wall, and serum-free culture medium containing genipin is added for treatment for 24 h. Total cell protein was extracted from the lysate, and the expression level of CDK5 protein in the cells was determined by Western Blot.
As shown in FIG. 6, the Western Blot method detects that genipin can significantly reduce the expression of SH-SY5Y/Tau cell CDK5 protein.
The experimental results show that genipin can effectively inhibit Tau protein aggregation induced by heparin and effectively inhibit the formation of Tau protein fibers. The computer simulation molecule docking is utilized to confirm that genipin can be combined with the core structure part of the Tau protein monomer, and the combination effect and potential combination sites between genipin and Tau protein are proved in an auxiliary way. In addition, genipin can inhibit the phosphorylation level of Tau protein at serine 396 and 404 sites by reducing the expression of CDK5 in SH-SY5Y/Tau cells. From the above experiment, the following conclusions can be drawn:
firstly, the method comprises the following steps: the genipin can effectively inhibit Tau protein aggregation in vitro, and further inhibit the formation of neurofibrillary tangles.
Secondly, the method comprises the following steps: the core structure part of the genipin docking Tau protein monomer is obtained through computer simulation molecular docking, and the genipin and Tau protein are assisted to prove that the genipin and the Tau protein have a binding effect and potential binding sites.
Thirdly, the method comprises the following steps: genipin can reduce the expression of CDK5 in SH-SY5Y/Tau cells, thereby reducing the phosphorylation level of Tau protein in the cells at serine 396 and 404 sites.
In conclusion, genipin can inhibit Tau protein aggregation and reduce phosphorylation levels of Tau protein at multiple sites in cells, and can be used for preventing or treating diseases caused by abnormal Tau protein aggregation and hyperphosphorylation.
The technical contents of the present invention are further illustrated by the examples, so as to facilitate the understanding of the reader, but the embodiments of the present invention are not limited thereto, and any technical extension or re-creation based on the present invention is protected by the present invention.
Claims (6)
1. Application of genipin in preparation of Tau protein oligomerization inhibitor.
2. Application of genipin in preparation of Tau protein fibrosis inhibitor.
3. Application of genipin in preparation of Tau protein hyperphosphorylation inhibitors.
4. Application of genipin in preparation of anti-Tau protein drugs.
5. The use of claim 4, wherein: the tauopathy is a disease caused by abnormal aggregation and/or hyperphosphorylation of Tau protein.
6. The use of claim 5, wherein: the tauopathies include Alzheimer's disease, amyotrophic lateral sclerosis/Parkinson's syndrome-dementia complex, silvery-particle dementia, corticobasal degeneration, Creutzfeldt-Jakob disease, dementia pugilistica, diffuse neurofibrillary tangles with calcification, Down's syndrome, frontotemporal dementia with Parkinson's syndrome linked to chromosome17, Gerstmann-Straussler-Scheinker disease, Hallervorden-Spatz disease, dystrophic myotonia, niemann-pick disease type C, non-guaranty's motor neuron disease with neurofibrillary tangles, pick's disease, postencephalitic parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, neurofibrillary tangle-only dementia, whole brain glial Tau proteinopathy.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911399552.3A CN110960522A (en) | 2019-12-30 | 2019-12-30 | Application of genipin in preparation of drugs for preventing and treating Tau protein abnormality |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911399552.3A CN110960522A (en) | 2019-12-30 | 2019-12-30 | Application of genipin in preparation of drugs for preventing and treating Tau protein abnormality |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN110960522A true CN110960522A (en) | 2020-04-07 |
Family
ID=70037430
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201911399552.3A Pending CN110960522A (en) | 2019-12-30 | 2019-12-30 | Application of genipin in preparation of drugs for preventing and treating Tau protein abnormality |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110960522A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103860575A (en) * | 2014-04-03 | 2014-06-18 | 重庆理工大学 | Application of geniposide used as acetylcholin esterase inhibitor |
| US20140370134A1 (en) * | 2013-06-13 | 2014-12-18 | Hong Kong Baptist University | Composition comprising Rhizoma Coptidis, Cortex Phellodendri and Fructus Gardeniae and For Treating Neurodegenerative Diseases |
| US20190282646A1 (en) * | 2018-03-16 | 2019-09-19 | Hong Kong Baptist University | Uses and Development of Neurodefend for Treating neurodegenerative Diseases |
-
2019
- 2019-12-30 CN CN201911399552.3A patent/CN110960522A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20140370134A1 (en) * | 2013-06-13 | 2014-12-18 | Hong Kong Baptist University | Composition comprising Rhizoma Coptidis, Cortex Phellodendri and Fructus Gardeniae and For Treating Neurodegenerative Diseases |
| CN103860575A (en) * | 2014-04-03 | 2014-06-18 | 重庆理工大学 | Application of geniposide used as acetylcholin esterase inhibitor |
| US20190282646A1 (en) * | 2018-03-16 | 2019-09-19 | Hong Kong Baptist University | Uses and Development of Neurodefend for Treating neurodegenerative Diseases |
| CN110269894A (en) * | 2018-03-16 | 2019-09-24 | 香港浸会大学 | Herbal-composition and its purposes for treating neurodegenerative disease |
Non-Patent Citations (6)
| Title |
|---|
| LI Y, LI L, HÖLSCHER C. 等: "Therapeutic potential of genipin in central neurodegenerative diseases", 《 CNS DRUGS 》 * |
| YAMAZAKI M, SAKURA N, CHIBA K: "Prevention of the neurotoxicity of the amyloid β protein by genipin", 《 BIOLOGICAL AND PHARMACEUTICAL BULLETIN 》 * |
| ZHANG Y , YIN F , LIU J 等: "Geniposide Attenuates the Phosphorylation of Tau Protein in Cellular and Insulin-deficient APP/PS1 Transgenic Mouse Model of Alzheimer"s Disease", 《 CHEMICAL BIOLOGY & DRUG DESIGN 》 * |
| 向绍通等: "栀子苷通过ERK1/2-Nrf2通路发挥对Aβ25-35诱导的阿尔兹海默病大鼠模型的神经保护作用", 《华中科技大学学报(医学版)》 * |
| 王玉骏等: "京尼平及其衍生物抗阿尔兹海默病作用的研究进展", 《化学试剂》 * |
| 陈金燕等: "复方通络救脑促进神经细胞突触可塑性", 《中国实验方剂学杂志》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Qiang et al. | Tau does not stabilize axonal microtubules but rather enables them to have long labile domains | |
| Verwilst et al. | Shedding light on tau protein aggregation: the progress in developing highly selective fluorophores | |
| Beck et al. | Human Pso4 is a metnase (SETMAR)-binding partner that regulates metnase function in DNA repair | |
| Kavli et al. | hUNG2 is the major repair enzyme for removal of uracil from U: A matches, U: G mismatches, and U in single-stranded DNA, with hSMUG1 as a broad specificity backup | |
| Wilden et al. | Light-dependent phosphorylation of rhodopsin: number of phosphorylation sites | |
| Beardsley et al. | Loss of caveolin-1 polarity impedes endothelial cell polarization and directional movement | |
| Yao et al. | Discovery of novel tacrine–pyrimidone hybrids as potent dual AChE/GSK-3 inhibitors for the treatment of Alzheimer’s disease | |
| Di Domizio et al. | Binding with nucleic acids or glycosaminoglycans converts soluble protein oligomers to amyloid | |
| Pillon et al. | Grc3 programs the essential endoribonuclease Las1 for specific RNA cleavage | |
| Cosconati et al. | Shooting for selective druglike G-quadruplex binders: evidence for telomeric DNA damage and tumor cell death | |
| Gonçalves et al. | Nesprin-2 recruitment of BicD2 to the nuclear envelope controls dynein/kinesin-mediated neuronal migration in vivo | |
| Li et al. | MicroRNA‐214‐3p modified tetrahedral framework nucleic acids target survivin to induce tumour cell apoptosis | |
| Meng et al. | Hyperphosphorylated tau self-assembles into amorphous aggregates eliciting TLR4-dependent responses | |
| Clark et al. | Circadian control of heparan sulfate levels times phagocytosis of amyloid beta aggregates | |
| Chen et al. | Contribution of telomere G-quadruplex stabilization to the inhibition of telomerase-mediated telomere extension by chemical ligands | |
| Tang et al. | 4β‐Hydroxywithanolide E selectively induces oxidative DNA damage for selective killing of oral cancer cells | |
| Du et al. | Rational design of a “sense and treat” system to target amyloid aggregates related to Alzheimer’s disease | |
| Zhang et al. | Glycogen synthase kinase-3β inhibitor SB216763 promotes DNA repair in ischemic retinal neurons | |
| Gila et al. | p53-associated 3′→ 5′ exonuclease activity in nuclear and cytoplasmic compartments of cells | |
| Serpionov et al. | A protein polymerization cascade mediates toxicity of non-pathological human huntingtin in yeast | |
| Jin et al. | Near-Infrared small molecule as a specific fluorescent probe for ultrasensitive recognition of antiparallel human telomere G-Quadruplexes | |
| Ayyubova | Dysfunctional microglia and tau pathology in Alzheimer’s disease | |
| Lozano-Torres et al. | β-Galactosidase-activatable nile blue-based nir senoprobe for the real-time detection of cellular senescence | |
| CN110960522A (en) | Application of genipin in preparation of drugs for preventing and treating Tau protein abnormality | |
| Gu et al. | Research Progress on G‐Quadruplexes in Human Telomeres and Human Telomerase Reverse Transcriptase (hTERT) Promoter |
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 |
Application publication date: 20200407 |
|
| RJ01 | Rejection of invention patent application after publication |