CN117883427A - 没食子酸在制备治疗或预防阿尔茨海默病药物中的应用 - Google Patents
没食子酸在制备治疗或预防阿尔茨海默病药物中的应用 Download PDFInfo
- Publication number
- CN117883427A CN117883427A CN202311833005.8A CN202311833005A CN117883427A CN 117883427 A CN117883427 A CN 117883427A CN 202311833005 A CN202311833005 A CN 202311833005A CN 117883427 A CN117883427 A CN 117883427A
- Authority
- CN
- China
- Prior art keywords
- gallic acid
- amyloid
- medicament
- beta
- aggregation
- 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
- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical compound OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 title claims abstract description 177
- 229940074391 gallic acid Drugs 0.000 title claims abstract description 87
- 235000004515 gallic acid Nutrition 0.000 title claims abstract description 87
- 239000003814 drug Substances 0.000 title claims abstract description 41
- 208000024827 Alzheimer disease Diseases 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 229940079593 drug Drugs 0.000 title description 15
- 108010090849 Amyloid beta-Peptides Proteins 0.000 claims abstract description 41
- 102000013455 Amyloid beta-Peptides Human genes 0.000 claims abstract description 41
- 230000002025 microglial effect Effects 0.000 claims abstract description 40
- 238000004220 aggregation Methods 0.000 claims abstract description 23
- 230000002776 aggregation Effects 0.000 claims abstract description 22
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 12
- 208000036110 Neuroinflammatory disease Diseases 0.000 claims abstract description 11
- 230000003959 neuroinflammation Effects 0.000 claims abstract description 11
- 210000004027 cell Anatomy 0.000 claims description 37
- 210000000274 microglia Anatomy 0.000 claims description 21
- 230000000770 proinflammatory effect Effects 0.000 claims description 10
- 230000004913 activation Effects 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 230000010287 polarization Effects 0.000 claims description 7
- 230000002438 mitochondrial effect Effects 0.000 claims description 5
- 230000007102 metabolic function Effects 0.000 claims description 3
- 230000001575 pathological effect Effects 0.000 claims description 3
- 206010061218 Inflammation Diseases 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 230000004054 inflammatory process Effects 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 238000002474 experimental method Methods 0.000 abstract description 23
- 230000006677 mitochondrial metabolism Effects 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 7
- 206010057249 Phagocytosis Diseases 0.000 abstract description 2
- 210000003710 cerebral cortex Anatomy 0.000 abstract description 2
- 230000003832 immune regulation Effects 0.000 abstract description 2
- 239000008267 milk Substances 0.000 abstract description 2
- 210000004080 milk Anatomy 0.000 abstract description 2
- 235000013336 milk Nutrition 0.000 abstract description 2
- 230000008782 phagocytosis Effects 0.000 abstract description 2
- 108010064539 amyloid beta-protein (1-42) Proteins 0.000 description 18
- DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 230000002757 inflammatory effect Effects 0.000 description 13
- 238000001514 detection method Methods 0.000 description 11
- 230000002829 reductive effect Effects 0.000 description 11
- 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 10
- 239000000835 fiber Substances 0.000 description 9
- 238000000684 flow cytometry Methods 0.000 description 7
- 239000000523 sample Substances 0.000 description 7
- 241001559542 Hippocampus hippocampus Species 0.000 description 6
- 230000029058 respiratory gaseous exchange Effects 0.000 description 6
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 6
- 238000002965 ELISA Methods 0.000 description 5
- 108090001005 Interleukin-6 Proteins 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 4
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 4
- 230000006933 amyloid-beta aggregation Effects 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 230000000638 stimulation Effects 0.000 description 4
- 231100000331 toxic Toxicity 0.000 description 4
- 230000002588 toxic effect Effects 0.000 description 4
- 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 description 3
- 230000002407 ATP formation Effects 0.000 description 3
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 3
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 3
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 3
- 230000005284 excitation Effects 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 230000028709 inflammatory response Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000036542 oxidative stress Effects 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 229910052710 silicon Inorganic materials 0.000 description 3
- 239000010703 silicon Substances 0.000 description 3
- 238000007619 statistical method Methods 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- PRDFBSVERLRRMY-UHFFFAOYSA-N 2'-(4-ethoxyphenyl)-5-(4-methylpiperazin-1-yl)-2,5'-bibenzimidazole Chemical compound C1=CC(OCC)=CC=C1C1=NC2=CC=C(C=3NC4=CC(=CC=C4N=3)N3CCN(C)CC3)C=C2N1 PRDFBSVERLRRMY-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- 208000037259 Amyloid Plaque Diseases 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 238000010609 cell counting kit-8 assay Methods 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000004140 cleaning Methods 0.000 description 2
- 230000003920 cognitive function Effects 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 230000006866 deterioration Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 231100000676 disease causative agent Toxicity 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 210000002865 immune cell Anatomy 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 230000006386 memory function Effects 0.000 description 2
- 230000006756 microglial proliferation Effects 0.000 description 2
- 230000004770 neurodegeneration Effects 0.000 description 2
- 208000015122 neurodegenerative disease Diseases 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 230000036284 oxygen consumption Effects 0.000 description 2
- 230000007505 plaque formation Effects 0.000 description 2
- 235000013824 polyphenols Nutrition 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
- 238000012360 testing method Methods 0.000 description 2
- MNULEGDCPYONBU-WMBHJXFZSA-N (1r,4s,5e,5'r,6'r,7e,10s,11r,12s,14r,15s,16s,18r,19s,20r,21e,25s,26r,27s,29s)-4-ethyl-11,12,15,19-tetrahydroxy-6'-[(2s)-2-hydroxypropyl]-5',10,12,14,16,18,20,26,29-nonamethylspiro[24,28-dioxabicyclo[23.3.1]nonacosa-5,7,21-triene-27,2'-oxane]-13,17,23-trio Polymers O([C@@H]1CC[C@@H](/C=C/C=C/C[C@H](C)[C@@H](O)[C@](C)(O)C(=O)[C@H](C)[C@@H](O)[C@H](C)C(=O)[C@H](C)[C@@H](O)[C@H](C)/C=C/C(=O)O[C@H]([C@H]2C)[C@H]1C)CC)[C@]12CC[C@@H](C)[C@@H](C[C@H](C)O)O1 MNULEGDCPYONBU-WMBHJXFZSA-N 0.000 description 1
- MNULEGDCPYONBU-DJRUDOHVSA-N (1s,4r,5z,5'r,6'r,7e,10s,11r,12s,14r,15s,18r,19r,20s,21e,26r,27s)-4-ethyl-11,12,15,19-tetrahydroxy-6'-(2-hydroxypropyl)-5',10,12,14,16,18,20,26,29-nonamethylspiro[24,28-dioxabicyclo[23.3.1]nonacosa-5,7,21-triene-27,2'-oxane]-13,17,23-trione Polymers O([C@H]1CC[C@H](\C=C/C=C/C[C@H](C)[C@@H](O)[C@](C)(O)C(=O)[C@H](C)[C@@H](O)C(C)C(=O)[C@H](C)[C@H](O)[C@@H](C)/C=C/C(=O)OC([C@H]2C)C1C)CC)[C@]12CC[C@@H](C)[C@@H](CC(C)O)O1 MNULEGDCPYONBU-DJRUDOHVSA-N 0.000 description 1
- MNULEGDCPYONBU-YNZHUHFTSA-N (4Z,18Z,20Z)-22-ethyl-7,11,14,15-tetrahydroxy-6'-(2-hydroxypropyl)-5',6,8,10,12,14,16,28,29-nonamethylspiro[2,26-dioxabicyclo[23.3.1]nonacosa-4,18,20-triene-27,2'-oxane]-3,9,13-trione Polymers CC1C(C2C)OC(=O)\C=C/C(C)C(O)C(C)C(=O)C(C)C(O)C(C)C(=O)C(C)(O)C(O)C(C)C\C=C/C=C\C(CC)CCC2OC21CCC(C)C(CC(C)O)O2 MNULEGDCPYONBU-YNZHUHFTSA-N 0.000 description 1
- MNULEGDCPYONBU-VVXVDZGXSA-N (5e,5'r,7e,10s,11r,12s,14s,15r,16r,18r,19s,20r,21e,26r,29s)-4-ethyl-11,12,15,19-tetrahydroxy-6'-[(2s)-2-hydroxypropyl]-5',10,12,14,16,18,20,26,29-nonamethylspiro[24,28-dioxabicyclo[23.3.1]nonacosa-5,7,21-triene-27,2'-oxane]-13,17,23-trione Polymers C([C@H](C)[C@@H](O)[C@](C)(O)C(=O)[C@@H](C)[C@H](O)[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@H](C)/C=C/C(=O)OC([C@H]1C)[C@H]2C)\C=C\C=C\C(CC)CCC2OC21CC[C@@H](C)C(C[C@H](C)O)O2 MNULEGDCPYONBU-VVXVDZGXSA-N 0.000 description 1
- MNULEGDCPYONBU-UHFFFAOYSA-N 4-ethyl-11,12,15,19-tetrahydroxy-6'-(2-hydroxypropyl)-5',10,12,14,16,18,20,26,29-nonamethylspiro[24,28-dioxabicyclo[23.3.1]nonacosa-5,7,21-triene-27,2'-oxane]-13,17,23-trione Polymers CC1C(C2C)OC(=O)C=CC(C)C(O)C(C)C(=O)C(C)C(O)C(C)C(=O)C(C)(O)C(O)C(C)CC=CC=CC(CC)CCC2OC21CCC(C)C(CC(C)O)O2 MNULEGDCPYONBU-UHFFFAOYSA-N 0.000 description 1
- 102000009091 Amyloidogenic Proteins Human genes 0.000 description 1
- 108010048112 Amyloidogenic Proteins Proteins 0.000 description 1
- 230000006974 Aβ toxicity Effects 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- BMZRVOVNUMQTIN-UHFFFAOYSA-N Carbonyl Cyanide para-Trifluoromethoxyphenylhydrazone Chemical compound FC(F)(F)OC1=CC=C(NN=C(C#N)C#N)C=C1 BMZRVOVNUMQTIN-UHFFFAOYSA-N 0.000 description 1
- 238000012286 ELISA Assay Methods 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 101001046686 Homo sapiens Integrin alpha-M Proteins 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 102100022338 Integrin alpha-M Human genes 0.000 description 1
- 102000016943 Muramidase Human genes 0.000 description 1
- 108010014251 Muramidase Proteins 0.000 description 1
- 108010062010 N-Acetylmuramoyl-L-alanine Amidase Proteins 0.000 description 1
- 208000028389 Nerve injury Diseases 0.000 description 1
- 208000018737 Parkinson disease 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
- 102000029797 Prion Human genes 0.000 description 1
- 108091000054 Prion Proteins 0.000 description 1
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 1
- 108010087230 Sincalide Proteins 0.000 description 1
- 241001122767 Theaceae Species 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 102000003802 alpha-Synuclein Human genes 0.000 description 1
- 108090000185 alpha-Synuclein Proteins 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000003942 amyloidogenic effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000020411 cell activation Effects 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000000326 densiometry Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 238000001917 fluorescence detection Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 239000003517 fume Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229960000274 lysozyme Drugs 0.000 description 1
- 235000010335 lysozyme Nutrition 0.000 description 1
- 239000004325 lysozyme Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 230000006724 microglial activation Effects 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000008764 nerve damage Effects 0.000 description 1
- 230000007658 neurological function Effects 0.000 description 1
- 229930191479 oligomycin Natural products 0.000 description 1
- MNULEGDCPYONBU-AWJDAWNUSA-N oligomycin A Polymers O([C@H]1CC[C@H](/C=C/C=C/C[C@@H](C)[C@H](O)[C@@](C)(O)C(=O)[C@@H](C)[C@H](O)[C@@H](C)C(=O)[C@@H](C)[C@H](O)[C@@H](C)/C=C/C(=O)O[C@@H]([C@@H]2C)[C@@H]1C)CC)[C@@]12CC[C@H](C)[C@H](C[C@@H](C)O)O1 MNULEGDCPYONBU-AWJDAWNUSA-N 0.000 description 1
- 238000012261 overproduction Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 150000008442 polyphenolic compounds Chemical class 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 239000003642 reactive oxygen metabolite Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- -1 salt ions Chemical class 0.000 description 1
- 230000002000 scavenging effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000012192 staining solution Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 235000018553 tannin Nutrition 0.000 description 1
- 229920001864 tannin Polymers 0.000 description 1
- 239000001648 tannin Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000009210 therapy by ultrasound Methods 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Epidemiology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明公开了一种没食子酸在制备治疗或预防阿尔茨海默病药物中的应用,涉及药物应用技术领域。本发明采用没食子酸具有抑制β淀粉样蛋白聚集的能力外,通过联合生物实验应用C57BL‑6乳鼠大脑皮层中培养的原代小胶质细胞,验证没食子酸通过抑制β淀粉样蛋白聚集,调节小胶质细胞线粒体代谢功能,促进小胶质细胞对β淀粉样蛋白吞噬清除等免疫调控等作用,可有效抑制β淀粉样蛋白所引起的神经炎症,拓展了没食子酸在阿尔茨海默病中的应用。
Description
技术领域
本发明涉及药物应用技术领域,具体涉及一种没食子酸在制备治疗或预防阿尔茨海默病药物中的应用。
背景技术
阿尔茨海默病(Aizheimer's disease,AD)是最常见的一种神经退行性疾病,预计2050年AD患者将增加到1.35亿人。神经退行性疾病多数与蛋白质错误折叠高度结构化相关,如阿尔茨海默病相关的β淀粉样蛋白,帕金森病相关的α-突触核蛋白,非系统性淀粉样变的溶菌酶以及朊病毒等。大量研究表明淀粉样斑块形成之前的可溶性Aβ1-42寡聚体对神经元的毒性最大,这可能是AD的主要发病原因。小胶质细胞是中枢神经系统中的免疫细胞,β淀粉样蛋白在大脑中错误折叠聚集会刺激小胶质细胞增生激活、炎症因子生成、氧化应激等而引发神经炎症,最终导致记忆和认知功能逐渐退化。目前没有治疗AD的特效药,因此迫切需要寻找治疗性的化合物或重新定位天然的化合物来治疗或缓解AD。
发明内容
为了解决上述背景技术中存在的不足,本发明提供一种没食子酸在制备治疗或预防阿尔茨海默病药物中的应用。没食子酸能够抑制Aβ淀粉样纤维的聚集,调节线粒体代谢控制小胶质细胞极化方向,对β淀粉样蛋白过度聚集造成的神经炎症具有很好的保护和抑制作用。因此,其可用于制备预防或治疗阿尔茨海默病的药物。
为了实现上述目的,本发明第一个目的是提供一种没食子酸在制备治疗或预防阿尔茨海默病药物中的应用。
优选的,所述没食子酸在制备抑制β淀粉样蛋白过度聚集的药物中的应用。
优选的,所述没食子酸在制备治疗或预防病理性β淀粉样蛋白过度聚集引发的神经炎症的药物中的应用。
优选的,所述没食子酸在制备抑制β淀粉样蛋白激活小胶质细胞促炎表型极化的药物中的应用。
优选的,所述没食子酸在制备改善β淀粉样蛋白过度聚集引起小胶质细胞活化所产生的炎症反应的药物中的应用。
优选的,所述没食子酸在制备调控小胶质细胞线粒体代谢功能的药物中的应用。
本发明第二个目的是提供一种药物制剂,所述药物制剂包括上述的药物和药学上接受的载体或辅料组成。
与现有技术相比,本发明的有益效果是:
本发明提供的一种没食子酸在制备治疗或预防阿尔茨海默病药物中的应用,没食子酸能够与Aβ1-42的Lys28和Ala42残基之间的氢键相互作用可能会打破Lys28和Ala42之间的盐桥,破坏Aβ纤维的稳定性,最终导致Aβ1-42解聚使毒性降低并抑制β淀粉样蛋白的聚集。
尽管有多组数据间接表明多酚类化合物可能在减少阿尔茨海默病发病中的有益作用,但其分子机制仍然无法确定。本发明提供的数据表明没食子酸处理过的小胶质细胞M1表型减少,以及炎症因子和ROS的表达量降低。这种炎症反应的减少我们推测没食子酸在其中起到了三点作用,第一,抑制Aβ1-42在细胞培养中聚集程度,减轻了Aβ1-42的毒性。第二,通过抑制小胶质细胞M1表型的转化抑制小胶质细胞分泌炎症因子。第三,没食子酸调控小胶质细胞线粒体代谢,抑制ROS的过度生成。这些数据为没食子酸保护和治疗神经功能的潜在作用提供了新的线索,并支持没食子酸有潜力成为延缓和治疗人类阿尔茨海默病的酚类化合药物。
附图说明
图1为ThT荧光追踪实验结果图;
图2为原子力显微镜实验结果图;
图3为CCK8实验结果图;
图4为ELISA实验结果图;
图5流式细胞术实验结果图;
图6为ROS激光共聚焦实验结果图;
图7为Seahorse线粒体代谢OCR图;
图8为Seahorse线粒体代谢分析图。
具体实施方式
为了使本领域技术人员更好地理解本发明的技术方案能予以实施,下面结合具体实施例和附图对本发明作进一步说明,但所举实施例不作为对本发明的限定。
3,4,5三羟基苯甲酸又称没食子酸(GA),既能够游离存在也是单宁分子的一部分广泛存在于多种水果和茶叶中。具有清除自由基、抗氧化抗炎的作用,英文名为Gallicacid,CAS号为149-91-7;结构式为:
本发明除了能在分子层面上证明没食子酸具有抑制β淀粉样蛋白聚集的能力外,通过联合生物实验应用C57BL-6乳鼠大脑皮层中培养的原代小胶质细胞,验证没食子酸通过抑制β淀粉样蛋白聚集,调节小胶质细胞线粒体代谢功能,促进小胶质细胞对β淀粉样蛋白吞噬清除等免疫调控等作用,可有效抑制β淀粉样蛋白所引起的神经炎症,拓展了没食子酸在阿尔茨海默病中的应用。
本发提供一种没食子酸在制备治疗或预防阿尔茨海默病的药物中的应用。
需要说明的是,大量研究表明淀粉样斑块形成之前的可溶性Aβ1-42寡聚体对神经元的毒性最大,这可能是AD的主要发病原因。小胶质细胞是中枢神经系统中的免疫细胞,β淀粉样蛋白在大脑中错误折叠聚集会刺激小胶质细胞增生激活、炎症因子生成、氧化应激等而引发神经炎症,最终导致记忆和认知功能逐渐退化。没食子酸能够抑制β淀粉样蛋白的聚集,抑制小胶质细胞极化,降低小胶质细胞炎症因子以及活性氧的产生,调控小胶质细胞线粒体代谢,具有很好的保护和治疗神经炎症的作用,这些特征使没食子酸适用于阿尔茨海默病的治疗。
进一步,所述没食子酸在制备抑制β淀粉样蛋白过度聚集的药物中的应用。
所述没食子酸在制备治疗或预防病理性β淀粉样蛋白过度聚集引发的神经炎症的药物中的应用。
所述没食子酸在制备抑制β淀粉样蛋白激活小胶质细胞促炎表型极化的药物中的应用。
所述没食子酸在制备改善β淀粉样蛋白过度聚集引起小胶质细胞活化所产生的炎症反应的药物中的应用。
所述没食子酸在制备调控小胶质细胞线粒体代谢功能的药物中的应用。
没食子酸在治疗或预防阿尔茨海默病时,其实验的使用方法如下:
没食子酸给药剂量分别为10μM、50μM、100μM。
Aβ1-42体外实验浓度为20μM、细胞实验给药浓度为1μM。
本发明将没食子酸应用于治疗阿尔茨海默病等神经炎症,并通过体外抑制Aβ1-42聚集实验,体外原代培养小胶质细胞建立模型进行效果评价:(1)硫磺素T(ThT)荧光追踪实验(2)CCK8实验;(2)ELISA实验;(3)流式细胞术实验;(4)Seahorse等生化实验。
本发明通过体外实验证明:没食子酸在100μM时抑制Aβ1-42聚集效果最佳。
本发明通过生物学实验证明:没食子酸在浓度超过100μM时对小胶质细胞才具有明显的毒性。
本发明通过生物学实验证明:没食子酸可以抑制β淀粉样蛋白所引起的小胶质细胞促炎表型的极化。
本发明通过生物学实验证明:没食子酸可以减少β淀粉样蛋白引起的小胶质细胞炎症因子的表达,清除多余活性氧。
本发明通过生物学实验证明:没食子酸能够调控β淀粉样蛋白引起的小胶质细胞线粒体代谢功能。
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。具体为没食子酸在制备治疗或预防阿尔茨海默病药理实验资料。
需要说明的是,下述实施例结合附图对本发明进行说明时,附图中涉及的Aβ指的是Aβ1-42体外聚集药物;GA10表示剂量为10μM的没食子酸,GA50表示剂量为50μM的没食子酸,GA100表示剂量为100μM的没食子酸。
实施例1
用ThT荧光追踪中检测没食子酸抑制β淀粉样蛋白的聚集。
没食子酸抑制Aβ1-42体外聚集药物浓度范围评估实验材料:Aβ1-42产品购置于rPeptide公司,将Aβ1-42梯度降温至4℃,水浴超声5min后用PBS配置成浓度100μM,涡旋仪上涡旋5min,在4℃冰箱孵育72h后Aβ1-42寡聚体制备完成。
实验方法:
(1-1)用ThT荧光追踪中检测没食子酸抑制β淀粉样蛋白聚集的最适浓度。
用浓度为20μM的ThT溶液将Aβ1-42配置成浓度20μM,分别给予不同剂量梯度的没食子酸(0、10、50、100μM)。用多功能细胞成像仪检测系统,温度设置为37℃,开启温育器,荧光参数设置激发波长:440nm,发射波长:485nm,持续线性振板,动力学检测运行48h,时间间隔5min,检测ThT与β折叠区域结合时的荧光强度。
参见图1所示,为ThT荧光追踪实验结果图,没食子酸在浓度10μM-100μM范围内对β淀粉样蛋白聚集影响随着药物剂量的增加而增强,当药物浓度达到100μM时ThT荧光值最低β淀粉样蛋白聚集程度减少。
从图1可知,通过ThT荧光检测我们得出GA能够抑制Aβ的聚集,硫磺素T荧光密度测定法用于检测没食子酸干预后Aβ纤维减少其荧光值降低。当药物浓度高达100μM时,随着时间的延长没食子酸显著降低了溶液中ThT荧光,减缓Aβ1-42单体转化为β折叠结构。
(1-2)原子力显微镜材料准备:将孵育48h的Aβ1-42纤维溶液或者加入不同浓度的没食子酸的Aβ1-42纤维溶液,取30μL滴入新鲜切割的AFM专用硅片表面上。样品在硅片上静置孵育10min,用去离子水冲洗三次去除盐离子和未结合的多肽。硅片表面在通风橱中吹干。在室温下,在MFP-3DInfinity AFM(牛津仪器公司)上进行了空气中轻敲模式的AFM实验。
参见图2a所示,为原子力显微镜实验结果图;
图2b、c为NanoScope软件进行分析和测量原子力显微镜图片中β淀粉样蛋白纤维的长度与高度,Aβ在加入不同浓度的没食子酸共同孵育后其纤维的长度和高度都随着药物剂量的增高而减小(****P<0.0001VS Aβgroup),当没食子酸剂量达到100μM时已经没有明显的纤维。
实施例2
使用CCK8试剂检测没食子酸对小胶质细胞的最适浓度。
实验方法:通过24h内新生的C57BL/6乳鼠原代培养小胶质细胞,使用DMEM加入10%的胎牛血清与1%青霉素链霉素的培养基培养12天。购置MEC公司的Cell CountingKit-8试剂盒,用于检测没食子酸对原代皮层小胶质细胞的安全使用范围。将100μL细胞悬液接种于96孔板中,每孔20000个细胞。小胶质细胞贴壁后加入不同浓度的没食子酸37℃的CO2培养箱孵育培养24h后每孔加入10μL的CCK-8溶液,孵育4h后用酶标仪测450nm处的吸光度值。
参见图3所示,为CCK8实验结果图,检测没食子酸安全用药范围。通过CCK8实验,没食子酸药物浓度在1-100μM范围内不会对小胶质细胞产生毒性作用并影响其生物活性。
实施例3
没食子酸能够减少β淀粉样蛋白引起的小胶质细胞激活,抑制促炎表型小胶质细胞的表达,减少炎症因子的产生。
实验方法:
(1-1)酶联免疫吸附实验(ELISA)
购置Biolegend公司的ELISA试剂盒进行检测TNF-α、IL-6炎症因子的表达水平。原代小胶质细胞在24孔板中培养分别给予不同浓度的没食子酸(10、50、100μM)干预12h加入β淀粉样蛋白刺激12h,培养基收集以3000rmp离心20min后取上清液。培养基按照特定的比例稀释,用细胞多功能成像仪(Cytation 5)检测450nm处的吸光度值,制定标准曲线计算炎症因子的表达量,结果以pg/ml表示。
图4为ELISA实验结果图,检测原代小胶质细胞激活后产生的炎症因子TNF-α、IL-6的表达量。图4(a)和图4(b)分别为TNF-α和IL-6的表达量(****p<0.0001VS controlgroup,#P<0.05,##<0.01,####P<0.001VS Aβ42group)。参见图4所示,小胶质细胞经过没食子酸不同浓度10、50、100μM干预12h后与Aβ42组相比,小胶质细胞分泌炎症因子的表达情况,药物干预组中β淀粉样蛋白刺激小胶质细胞后炎症因子TNF-α、IL-6的释放量显著下降,强烈提示没食子酸改善β淀粉样蛋白对神经损伤的机制之一是通过减轻神经炎症。
图4可知,通过ELISA检测促炎因子IL-6、TNF-α的表水平。β淀粉样蛋白感染后原代小胶质细胞中IL-6、TNF-α炎症因子水平显著增加,而没食子酸处理的小胶质细胞的炎症因子显著降低了。
(1-2)流式细胞术
将原代小胶质细胞接种于24孔板中培养至贴壁。用不同浓度的没食子酸处理细胞12h后加入Aβ42蛋白处理12h。收集细胞加入FITC-CD11b单克隆抗体和PE-CD86单克隆抗体(Biolegend)避光孵育30min,再用PBS清洗两次后加入500μl的细胞重悬液,立即用贝克曼流式细胞仪进行检测,采用Kaluza 2.1软件对样品进行采集和分析。
图5(a)为流式细胞术实验结果图,图5(b)是经过三次独立流式细胞术实验将数值进行统计分析。参见图5(a)和图5(b)所示,没食子酸降低β淀粉样蛋白毒性的作用下还能够抑制小胶质细胞促炎表型的极化。表现为没食子酸药物干预组促炎表型的小胶质细胞特异性标志物(CD11b+、CD86+)表达量减少(*P<005****P<0.0001VS control,###P<0.001VS Aβ42group)。
图5(a)和图5(b)可知,通过流式细胞术,小胶质细胞经没食子酸不同浓度10、50、100μM干预12h后与对照组相比,小胶质细胞内CD11b、CD86的表达情况,药物干预组中β淀粉样蛋白激活促炎表型的小胶质细胞程度明显下降,表现为促炎表型小胶质细胞特异性标志物CD11b+、CD86+表达量下降。
实施例4
没食子酸能够调控小胶质细胞吞噬β淀粉样蛋白后的线粒体代谢功能,抑制ROS的生成减少氧化应激。
实验方法:
(1-1)将原代小胶质细胞培养至贴壁后加入不同浓度组的没食子酸干预12h后加入Aβ刺激12h。用激光共聚焦检测ROS荧光值,购置碧云天公司的活性氧检测试剂盒,用PBS将DCFH-DA荧光探针稀释成浓度为10μM,弃去原有培养基加入400μL的DCFH-DA溶液在CO2培养箱中孵育20min。PBS清洗两次加入碧云天的Hoechst 33342活细胞染色液500μL于CO2培养箱中孵育10min,PBS清洗两次后用激光共聚焦显微镜检测。DCFH-DA选用488nm激发波长,525nm发射波长,Hoechst 33342选用346nm激发波长,460发射波长。
参见图6(a)所示,为激光共聚焦实验结果图,结果显示没食子酸能够抑制β淀粉样蛋白刺激小胶质细胞产生过量的ROS。图6(a)可知,β淀粉样蛋白刺激小胶质细胞后DCF探针荧光值增强,ROS生成增多,没食子酸干预后DCF探针荧光值变弱ROS的生成减少。图6(b)为ImageJ软件定量分析DC F探针的荧光值并进行统计分析。其中Aβ42组的DCF探针荧光值最高,当加入不同浓度的没食子酸后其荧光值下降即ROS生成减少。(*P<0.05,***P<0.001,****P<0.0001VS control group,####P<0.0001VS Aβgroup)。
(1-2)Seahorse线粒体压力试验,购置安捷伦公司Seahorse XF细胞线粒体压力测定试剂盒,将培养好的小胶细胞收集,接种于XF24细胞培养板中原代小胶质细胞最佳密度为1×105个,于超净工作台中静置1h使细胞自然沉降后置于CO2培养箱中使细胞贴壁。配置检测液:97mL的Seahorse XF DMEM Medium中加入1mL glucose、1mL pyruvate、1mLglutamine混匀。将检测液置于37℃水浴锅中进行温浴后清洗细胞,用1mL的检测液清洗细胞两次后加入500μL的检测液放入37℃无CO2的培养箱中40min等待上机检测。准备好提前水化的探针板,A孔加入Oligomycin 56μL,B孔加入FCCP 62μL,C孔加入Rot/AA 69μL进行上机检测。
图7通过Seahorse线粒体压力检测试剂盒检测原代小胶质细胞的氧气消耗速率OCR值,通过氧气消耗速率反映线粒体的代谢功能。
图8(a)、(b)、(c)是通过没食子酸干预后小胶质细胞的OCR值分析计算出ATP生成值、基础呼吸以及最大呼吸速率。根据图7OCR值结果进行统计分析发现当加入Aβ42刺激原代小胶质细胞后ATP的生成、基础呼吸以及最大呼吸速率上升,意味着小胶质细胞受到毒性蛋白刺激后对能量需求增多,当加入没食子酸提前干预12h后,ATP生成、基础呼吸以及最大呼吸速率有所下降,没食子酸能够降低小胶质细胞经β淀粉样蛋白刺激后生理上的能量需求。(*P<0.05,**P<0.01VS Aβ42group)。
尽管已经示出和描述了本发明的实施例,对于本领域的普通技术人员而言,可以理解在不脱离本发明的原理和精神的情况下可以对这些实施例进行多种变化、修改、替换和变型,本发明的范围由所附权利要求及其等同物限定。
Claims (7)
1.一种没食子酸在制备治疗或预防阿尔茨海默病的药物中的应用。
2.根据权利要求1所述的应用,其特征在于,所述没食子酸在制备抑制β淀粉样蛋白过度聚集的药物中的应用。
3.根据权利要求1所述的应用,其特征在于,所述没食子酸在制备治疗或预防病理性β淀粉样蛋白过度聚集引发的神经炎症的药物中的应用。
4.根据权利要求1所述的应用,其特征在于,所述没食子酸在制备抑制β淀粉样蛋白激活小胶质细胞促炎表型极化的药物中的应用。
5.根据权利要求1所述的应用,其特征在于,所述没食子酸在制备改善β淀粉样蛋白过度聚集引起小胶质细胞活化所产生的炎症反应的药物中的应用。
6.根据权利要求1所述的应用,其特征在于,所述没食子酸在制备调控小胶质细胞线粒体代谢功能的药物中的应用。
7.一种药物制剂,其特征在于,所述药物制剂包括权利要求1~6任一项所述的药物和药学上接受的载体或辅料组成。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202311833005.8A CN117883427A (zh) | 2023-12-27 | 2023-12-27 | 没食子酸在制备治疗或预防阿尔茨海默病药物中的应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202311833005.8A CN117883427A (zh) | 2023-12-27 | 2023-12-27 | 没食子酸在制备治疗或预防阿尔茨海默病药物中的应用 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN117883427A true CN117883427A (zh) | 2024-04-16 |
Family
ID=90638767
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202311833005.8A Pending CN117883427A (zh) | 2023-12-27 | 2023-12-27 | 没食子酸在制备治疗或预防阿尔茨海默病药物中的应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN117883427A (zh) |
-
2023
- 2023-12-27 CN CN202311833005.8A patent/CN117883427A/zh active Pending
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Yang et al. | Influenza vaccination in early Alzheimer’s disease rescues amyloidosis and ameliorates cognitive deficits in APP/PS1 mice by inhibiting regulatory T cells | |
KR101723265B1 (ko) | mTOR/STAT3 신호억제제 처리된 면역조절능을 갖는 간엽줄기세포 및 이를 포함하는 면역질환의 예방 또는 치료용 세포치료제 조성물 | |
Li et al. | Urolithin B suppressed osteoclast activation and reduced bone loss of osteoporosis via inhibiting ERK/NF‐κB pathway | |
Liu et al. | Hyperglycemia induces endoplasmic reticulum stress‑dependent CHOP expression in osteoblasts | |
Hai-Na et al. | Atorvastatin ameliorates depressive behaviors and neuroinflammatory in streptozotocin-induced diabetic mice | |
CA2986431C (en) | Galantamine clearance of amyloid.beta. | |
Kim et al. | Inhibitory effect of Asparagus cochinchinensis on tumor necrosis factor-alpha secretion from astrocytes | |
US11000587B2 (en) | Use as immune enhancer or pharmaceutical composition for treatment of dementia, comprising phytosphingosine-1-phosphate or derivative thereof | |
Li et al. | Coeloglossum viride var. bracteatum extract attenuates Aβ-induced toxicity by inhibiting RIP1–driven inflammation and necroptosis | |
Zeng et al. | Alpinetin alleviates osteoporosis by promoting osteogenic differentiation in BMSCs by triggering autophagy via PKA/mTOR/ULK1 signaling | |
Shi et al. | Role of Adaptive Immune and Impacts of Risk Factors on Adaptive Immune in Alzheimer’s Disease: Are Immunotherapies Effective or Off-Target? | |
Li et al. | Anfibatide alleviates inflammation and apoptosis via inhibiting NF-kappaB/NLRP3 axis in ischemic stroke | |
Lee et al. | Tellurium compound AS101 ameliorates experimental autoimmune encephalomyelitis by VLA-4 inhibition and suppression of monocyte and T cell infiltration into the CNS | |
Wan et al. | Icariin improves learning and memory function in Aβ1-42-induced AD mice through regulation of the BDNF-TrκB signaling pathway | |
WO2008047880A1 (fr) | Agent thérapeutique pour la polyarthrite rhumatoïde | |
KR20180032540A (ko) | 피토스핑고신-1-포스페이트 또는 그 유도체의 면역증강제 용도 | |
CN117883427A (zh) | 没食子酸在制备治疗或预防阿尔茨海默病药物中的应用 | |
US8536178B2 (en) | Pharmaceutical composition for preventing or treating diseases associated with beta-amyloid accumulation containing morpholin or piperazine based compounds having SO3H or COOH as active ingredient | |
WO2023078325A1 (zh) | 一种含有依达拉奉右莰醇组合物在治疗认知障碍中的应用 | |
WO2012144501A1 (ja) | 抗アレルギー物質、抗アレルギー剤及び食品 | |
TWI706780B (zh) | 粒線體用於製備治療阿茲海默症之醫藥組合物的用途 | |
He et al. | Amygdalin ameliorates alopecia areata on C3H/HeJ mice by inhibiting inflammation through JAK2/STAT3 pathway | |
EP4353234A1 (en) | Use of pyrrolopyrimidine compound | |
Shen et al. | Carnosine ameliorates postoperative cognitive dysfunction of aged rats by limiting astrocytes pyroptosis | |
KR101581508B1 (ko) | 코엔자임 q10을 유효성분으로 포함하는 염증성 질환 또는 면역거부질환의 예방 또는 치료용 조성물 |
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 |