JP6082402B2 - 加齢に伴う機能障害の処置に使用するための薬学的組成物 - Google Patents
加齢に伴う機能障害の処置に使用するための薬学的組成物 Download PDFInfo
- Publication number
- JP6082402B2 JP6082402B2 JP2014542884A JP2014542884A JP6082402B2 JP 6082402 B2 JP6082402 B2 JP 6082402B2 JP 2014542884 A JP2014542884 A JP 2014542884A JP 2014542884 A JP2014542884 A JP 2014542884A JP 6082402 B2 JP6082402 B2 JP 6082402B2
- Authority
- JP
- Japan
- Prior art keywords
- apelin
- mice
- treated
- muscle
- antibody
- 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.)
- Active
Links
- 238000011282 treatment Methods 0.000 title claims description 66
- 230000004064 dysfunction Effects 0.000 title description 33
- 230000032683 aging Effects 0.000 title description 28
- 239000008194 pharmaceutical composition Substances 0.000 title description 4
- 102000018746 Apelin Human genes 0.000 claims description 257
- 108010052412 Apelin Proteins 0.000 claims description 257
- BWVPHIKGXQBZPV-QKFDDRBGSA-N apelin Chemical group NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N1[C@H](C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=2NC=NC=2)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=2NC=NC=2)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CCSC)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(O)=O)CCC1 BWVPHIKGXQBZPV-QKFDDRBGSA-N 0.000 claims description 241
- 238000000034 method Methods 0.000 claims description 77
- 230000014509 gene expression Effects 0.000 claims description 64
- 229940124752 APJ receptor agonist Drugs 0.000 claims description 25
- 239000000203 mixture Substances 0.000 claims description 19
- 208000001076 sarcopenia Diseases 0.000 claims description 16
- 230000002265 prevention Effects 0.000 claims description 12
- 239000000556 agonist Substances 0.000 claims description 8
- 241000699670 Mus sp. Species 0.000 description 129
- 210000003205 muscle Anatomy 0.000 description 73
- 108090000623 proteins and genes Proteins 0.000 description 65
- 210000002027 skeletal muscle Anatomy 0.000 description 57
- 102000004169 proteins and genes Human genes 0.000 description 51
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 50
- 235000018102 proteins Nutrition 0.000 description 41
- 230000002438 mitochondrial effect Effects 0.000 description 36
- 210000004027 cell Anatomy 0.000 description 35
- 108091008803 APLNR Proteins 0.000 description 33
- 230000000694 effects Effects 0.000 description 30
- 230000001965 increasing effect Effects 0.000 description 28
- 102000004877 Insulin Human genes 0.000 description 25
- 108090001061 Insulin Proteins 0.000 description 25
- 229940125396 insulin Drugs 0.000 description 25
- 108020004414 DNA Proteins 0.000 description 24
- 108090000765 processed proteins & peptides Proteins 0.000 description 24
- 230000001684 chronic effect Effects 0.000 description 23
- 229940024606 amino acid Drugs 0.000 description 19
- 150000001413 amino acids Chemical class 0.000 description 19
- 150000001875 compounds Chemical class 0.000 description 19
- 235000001014 amino acid Nutrition 0.000 description 17
- 239000000427 antigen Substances 0.000 description 16
- 230000015572 biosynthetic process Effects 0.000 description 16
- 230000006870 function Effects 0.000 description 16
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 16
- 235000009200 high fat diet Nutrition 0.000 description 16
- 108091007433 antigens Proteins 0.000 description 15
- 102000036639 antigens Human genes 0.000 description 15
- 229920001223 polyethylene glycol Polymers 0.000 description 15
- 102000004196 processed proteins & peptides Human genes 0.000 description 15
- 239000002202 Polyethylene glycol Substances 0.000 description 14
- MEFKEPWMEQBLKI-AIRLBKTGSA-O S-adenosyl-L-methionine Chemical compound O[C@@H]1[C@H](O)[C@@H](C[S+](CC[C@H]([NH3+])C([O-])=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 MEFKEPWMEQBLKI-AIRLBKTGSA-O 0.000 description 14
- 238000013461 design Methods 0.000 description 14
- 239000003814 drug Substances 0.000 description 14
- 210000003470 mitochondria Anatomy 0.000 description 14
- 238000003753 real-time PCR Methods 0.000 description 14
- 238000012360 testing method Methods 0.000 description 14
- 108020005196 Mitochondrial DNA Proteins 0.000 description 13
- 241000699666 Mus <mouse, genus> Species 0.000 description 13
- 239000013612 plasmid Substances 0.000 description 13
- 229920001184 polypeptide Polymers 0.000 description 13
- 210000001519 tissue Anatomy 0.000 description 13
- 102100036009 5'-AMP-activated protein kinase catalytic subunit alpha-2 Human genes 0.000 description 12
- 101000783681 Homo sapiens 5'-AMP-activated protein kinase catalytic subunit alpha-2 Proteins 0.000 description 12
- 108060003951 Immunoglobulin Proteins 0.000 description 12
- 241001465754 Metazoa Species 0.000 description 12
- 239000013604 expression vector Substances 0.000 description 12
- 239000012634 fragment Substances 0.000 description 12
- 102000018358 immunoglobulin Human genes 0.000 description 12
- 239000000523 sample Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 108010072220 Cyclophilin A Proteins 0.000 description 11
- 101000919849 Homo sapiens Cytochrome c oxidase subunit 1 Proteins 0.000 description 11
- 101000605122 Homo sapiens Prostaglandin G/H synthase 1 Proteins 0.000 description 11
- 102100034539 Peptidyl-prolyl cis-trans isomerase A Human genes 0.000 description 11
- 102100038277 Prostaglandin G/H synthase 1 Human genes 0.000 description 11
- 229940079593 drug Drugs 0.000 description 11
- 230000008437 mitochondrial biogenesis Effects 0.000 description 11
- 150000007523 nucleic acids Chemical class 0.000 description 11
- 210000002381 plasma Anatomy 0.000 description 11
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 10
- 230000003278 mimic effect Effects 0.000 description 10
- 230000003647 oxidation Effects 0.000 description 10
- 238000007254 oxidation reaction Methods 0.000 description 10
- 238000011002 quantification Methods 0.000 description 10
- 238000013218 HFD mouse model Methods 0.000 description 9
- 239000002552 dosage form Substances 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 9
- 230000004048 modification Effects 0.000 description 9
- 238000012986 modification Methods 0.000 description 9
- 229920000642 polymer Polymers 0.000 description 9
- 235000002639 sodium chloride Nutrition 0.000 description 9
- 239000013598 vector Substances 0.000 description 9
- 230000003612 virological effect Effects 0.000 description 9
- 238000001262 western blot Methods 0.000 description 9
- 101000793362 Homo sapiens Apelin receptor Proteins 0.000 description 8
- LTYOQGRJFJAKNA-KKIMTKSISA-N Malonyl CoA Natural products S(C(=O)CC(=O)O)CCNC(=O)CCNC(=O)[C@@H](O)C(CO[P@](=O)(O[P@](=O)(OC[C@H]1[C@@H](OP(=O)(O)O)[C@@H](O)[C@@H](n2c3ncnc(N)c3nc2)O1)O)O)(C)C LTYOQGRJFJAKNA-KKIMTKSISA-N 0.000 description 8
- 235000021314 Palmitic acid Nutrition 0.000 description 8
- 230000004913 activation Effects 0.000 description 8
- 239000000835 fiber Substances 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- LTYOQGRJFJAKNA-DVVLENMVSA-N malonyl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)CC(O)=O)O[C@H]1N1C2=NC=NC(N)=C2N=C1 LTYOQGRJFJAKNA-DVVLENMVSA-N 0.000 description 8
- 239000012528 membrane Substances 0.000 description 8
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 8
- 102000039446 nucleic acids Human genes 0.000 description 8
- 108020004707 nucleic acids Proteins 0.000 description 8
- 238000012216 screening Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 102100030949 Apelin receptor Human genes 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 7
- 108090000790 Enzymes Proteins 0.000 description 7
- 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 7
- 241000700605 Viruses Species 0.000 description 7
- 239000002671 adjuvant Substances 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
- 230000005540 biological transmission Effects 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 238000001514 detection method Methods 0.000 description 7
- 235000014113 dietary fatty acids Nutrition 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 239000000194 fatty acid Substances 0.000 description 7
- 229930195729 fatty acid Natural products 0.000 description 7
- 150000004665 fatty acids Chemical class 0.000 description 7
- 239000008103 glucose Substances 0.000 description 7
- 150000002632 lipids Chemical class 0.000 description 7
- 230000029058 respiratory gaseous exchange Effects 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 241001430294 unidentified retrovirus Species 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 241000702421 Dependoparvovirus Species 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 206010022489 Insulin Resistance Diseases 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 102000004472 Myostatin Human genes 0.000 description 6
- 108010056852 Myostatin Proteins 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000009471 action Effects 0.000 description 6
- 238000007792 addition Methods 0.000 description 6
- 230000002950 deficient Effects 0.000 description 6
- 230000001419 dependent effect Effects 0.000 description 6
- 238000005516 engineering process Methods 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 230000004190 glucose uptake Effects 0.000 description 6
- IPCSVZSSVZVIGE-VPMSBSONSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCC[14C](O)=O IPCSVZSSVZVIGE-VPMSBSONSA-N 0.000 description 6
- 239000003550 marker Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- 230000001590 oxidative effect Effects 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 230000001105 regulatory effect Effects 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 6
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 5
- 108091023037 Aptamer Proteins 0.000 description 5
- 102100029057 Coagulation factor XIII A chain Human genes 0.000 description 5
- 101000918352 Homo sapiens Coagulation factor XIII A chain Proteins 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000006185 dispersion Substances 0.000 description 5
- 230000003053 immunization Effects 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 238000007918 intramuscular administration Methods 0.000 description 5
- 239000003446 ligand Substances 0.000 description 5
- 108020004999 messenger RNA Proteins 0.000 description 5
- 238000001000 micrograph Methods 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- 238000006366 phosphorylation reaction Methods 0.000 description 5
- 238000007920 subcutaneous administration Methods 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 238000013518 transcription Methods 0.000 description 5
- 230000035897 transcription Effects 0.000 description 5
- VRYALKFFQXWPIH-PBXRRBTRSA-N (3r,4s,5r)-3,4,5,6-tetrahydroxyhexanal Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)CC=O VRYALKFFQXWPIH-PBXRRBTRSA-N 0.000 description 4
- 102400000252 Apelin-13 Human genes 0.000 description 4
- 108091026890 Coding region Proteins 0.000 description 4
- 238000002965 ELISA Methods 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 4
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 4
- 102100032970 Myogenin Human genes 0.000 description 4
- 108010056785 Myogenin Proteins 0.000 description 4
- XXCCRHIAIBQDPX-PEWBXTNBSA-N apelin-13 Chemical compound C([C@@H](C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCSC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](N)CCC(N)=O)C1=CN=CN1 XXCCRHIAIBQDPX-PEWBXTNBSA-N 0.000 description 4
- 108010040480 apelin-13 peptide Proteins 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 230000036772 blood pressure Effects 0.000 description 4
- 230000003247 decreasing effect Effects 0.000 description 4
- 210000004408 hybridoma Anatomy 0.000 description 4
- 238000002649 immunization Methods 0.000 description 4
- 238000007912 intraperitoneal administration Methods 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- 244000005700 microbiome Species 0.000 description 4
- 230000005996 muscular dysfunction Effects 0.000 description 4
- 230000002107 myocardial effect Effects 0.000 description 4
- 239000002773 nucleotide Substances 0.000 description 4
- 125000003729 nucleotide group Chemical group 0.000 description 4
- 230000026731 phosphorylation Effects 0.000 description 4
- 230000008488 polyadenylation Effects 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 230000010076 replication Effects 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- 108010008177 Fd immunoglobulins Proteins 0.000 description 3
- 208000025500 Hutchinson-Gilford progeria syndrome Diseases 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 3
- 239000004472 Lysine Substances 0.000 description 3
- 102100038380 Myogenic factor 5 Human genes 0.000 description 3
- 101710099061 Myogenic factor 5 Proteins 0.000 description 3
- 102000000524 Nuclear Respiratory Factor 1 Human genes 0.000 description 3
- 108010016592 Nuclear Respiratory Factor 1 Proteins 0.000 description 3
- 108091028043 Nucleic acid sequence Proteins 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 208000007932 Progeria Diseases 0.000 description 3
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 230000000890 antigenic effect Effects 0.000 description 3
- SVWSKJCJNAIKNH-MJZUAXFLSA-N apelin-17 Chemical compound C([C@@H](C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCSC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](N)CCCCN)C1=CN=CN1 SVWSKJCJNAIKNH-MJZUAXFLSA-N 0.000 description 3
- BVTLGARMSLXAHI-VDEROMQGSA-N apelin-36 Chemical compound C([C@@H](C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCSC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)CNC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)CNC(=O)[C@H]1N(CCC1)C(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H]1N(CCC1)C(=O)CNC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)C(C)C)C1=CN=CN1 BVTLGARMSLXAHI-VDEROMQGSA-N 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 239000011324 bead Substances 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 239000012472 biological sample Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- 238000012217 deletion Methods 0.000 description 3
- 230000037430 deletion Effects 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 238000012377 drug delivery Methods 0.000 description 3
- 239000003623 enhancer Substances 0.000 description 3
- 230000002255 enzymatic effect Effects 0.000 description 3
- 230000009760 functional impairment Effects 0.000 description 3
- 230000004927 fusion Effects 0.000 description 3
- 229960002989 glutamic acid Drugs 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 238000003364 immunohistochemistry Methods 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000003780 insertion Methods 0.000 description 3
- 230000037431 insertion Effects 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
- 239000002502 liposome Substances 0.000 description 3
- 230000006540 mitochondrial respiration Effects 0.000 description 3
- 230000001114 myogenic effect Effects 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000010647 peptide synthesis reaction Methods 0.000 description 3
- 239000013600 plasmid vector Substances 0.000 description 3
- 230000001323 posttranslational effect Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 238000010188 recombinant method Methods 0.000 description 3
- 230000007017 scission Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000000638 solvent extraction Methods 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 238000007447 staining method Methods 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 239000001384 succinic acid Substances 0.000 description 3
- 238000013268 sustained release Methods 0.000 description 3
- 239000012730 sustained-release form Substances 0.000 description 3
- 208000011580 syndromic disease Diseases 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 238000010361 transduction Methods 0.000 description 3
- 230000026683 transduction Effects 0.000 description 3
- 239000013603 viral vector Substances 0.000 description 3
- 239000003643 water by type Substances 0.000 description 3
- 229920003169 water-soluble polymer Polymers 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- 101710117290 Aldo-keto reductase family 1 member C4 Proteins 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- 108010032595 Antibody Binding Sites Proteins 0.000 description 2
- 102000016555 Apelin receptors Human genes 0.000 description 2
- 102400000251 Apelin-36 Human genes 0.000 description 2
- 101800001808 Apelin-36 Proteins 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 241000701022 Cytomegalovirus Species 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- 101000835023 Homo sapiens Transcription factor A, mitochondrial Proteins 0.000 description 2
- 102100034343 Integrase Human genes 0.000 description 2
- 239000012839 Krebs-Henseleit buffer Substances 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 108091034117 Oligonucleotide Proteins 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 241000233805 Phoenix Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 108010076504 Protein Sorting Signals Proteins 0.000 description 2
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 2
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 2
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 2
- 241000714474 Rous sarcoma virus Species 0.000 description 2
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 2
- 241000723873 Tobacco mosaic virus Species 0.000 description 2
- 101001023030 Toxoplasma gondii Myosin-D Proteins 0.000 description 2
- 102100026155 Transcription factor A, mitochondrial Human genes 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- ZSLZBFCDCINBPY-ZSJPKINUSA-N acetyl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 ZSLZBFCDCINBPY-ZSJPKINUSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- PMMURAAUARKVCB-UHFFFAOYSA-N alpha-D-ara-dHexp Natural products OCC1OC(O)CC(O)C1O PMMURAAUARKVCB-UHFFFAOYSA-N 0.000 description 2
- 125000000539 amino acid group Chemical group 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000000090 biomarker Substances 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 230000005978 brain dysfunction Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 210000004900 c-terminal fragment Anatomy 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 230000021615 conjugation Effects 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 150000001982 diacylglycerols Chemical class 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000002612 dispersion medium Substances 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 235000019197 fats Nutrition 0.000 description 2
- 238000000684 flow cytometry Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 238000001415 gene therapy Methods 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 230000006377 glucose transport Effects 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 2
- 102000047215 human APLNR Human genes 0.000 description 2
- 210000005260 human cell Anatomy 0.000 description 2
- 230000001077 hypotensive effect Effects 0.000 description 2
- 238000003018 immunoassay Methods 0.000 description 2
- 238000001114 immunoprecipitation Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- 239000007972 injectable composition Substances 0.000 description 2
- 230000010354 integration Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 230000037356 lipid metabolism Effects 0.000 description 2
- 229940049920 malate Drugs 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 235000021590 normal diet Nutrition 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 102000040430 polynucleotide Human genes 0.000 description 2
- 108091033319 polynucleotide Proteins 0.000 description 2
- 239000002157 polynucleotide Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 238000002731 protein assay Methods 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 238000003259 recombinant expression Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 230000022379 skeletal muscle tissue development Effects 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 239000001488 sodium phosphate Substances 0.000 description 2
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 238000007619 statistical method Methods 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 230000009261 transgenic effect Effects 0.000 description 2
- 230000014616 translation Effects 0.000 description 2
- 230000004102 tricarboxylic acid cycle Effects 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- 241000701161 unidentified adenovirus Species 0.000 description 2
- 241001515965 unidentified phage Species 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- DRCWOKJLSQUJPZ-DZGCQCFKSA-N (4ar,9as)-n-ethyl-1,4,9,9a-tetrahydrofluoren-4a-amine Chemical compound C1C2=CC=CC=C2[C@]2(NCC)[C@H]1CC=CC2 DRCWOKJLSQUJPZ-DZGCQCFKSA-N 0.000 description 1
- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical compound C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- 108020004463 18S ribosomal RNA Proteins 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 108010030844 2-methylcitrate synthase Proteins 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
- SEZVZMIKECAWEG-JXWNBHMPSA-N 5-[12-[[(5s)-6-[[(2s)-3-(1-benzyl-3-methylimidazol-1-ium-4-yl)-1-[(1-methylpiperidin-1-ium-4-yl)amino]-1-oxopropan-2-yl]amino]-5-[[2-(2-imino-3-methyl-3h-1,3-thiazol-3-ium-4-yl)acetyl]amino]-6-oxohexyl]carbamoylamino]dodecylsulfamoyl]-2-[3-(diethylamino)- Chemical compound [O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F.N([C@@H](CCCCNC(=O)NCCCCCCCCCCCCNS(=O)(=O)C1=CC=C(C(=C1)S([O-])(=O)=O)C=1C2=CC=C(C=C2OC2=CC(C=CC2=1)=[N+](CC)CC)N(CC)CC)C(=O)N[C@@H](CC=1[N+](=CN(CC=2C=CC=CC=2)C=1)C)C(=O)NC1CC[NH+](C)CC1)C(=O)CC1=CSC(=N)[NH+]1C SEZVZMIKECAWEG-JXWNBHMPSA-N 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 241000702423 Adeno-associated virus - 2 Species 0.000 description 1
- 102000011690 Adiponectin Human genes 0.000 description 1
- 108010076365 Adiponectin Proteins 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 239000012099 Alexa Fluor family Substances 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 244000303258 Annona diversifolia Species 0.000 description 1
- 235000002198 Annona diversifolia Nutrition 0.000 description 1
- 108020000948 Antisense Oligonucleotides Proteins 0.000 description 1
- 108010053026 Apelin receptors Proteins 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 108090001008 Avidin Proteins 0.000 description 1
- RTMBGDBBDQKNNZ-UHFFFAOYSA-L C.I. Acid Blue 3 Chemical compound [Ca+2].C1=CC(N(CC)CC)=CC=C1C(C=1C(=CC(=C(O)C=1)S([O-])(=O)=O)S([O-])(=O)=O)=C1C=CC(=[N+](CC)CC)C=C1.C1=CC(N(CC)CC)=CC=C1C(C=1C(=CC(=C(O)C=1)S([O-])(=O)=O)S([O-])(=O)=O)=C1C=CC(=[N+](CC)CC)C=C1 RTMBGDBBDQKNNZ-UHFFFAOYSA-L 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 241000282836 Camelus dromedarius Species 0.000 description 1
- 206010007556 Cardiac failure acute Diseases 0.000 description 1
- 206010007558 Cardiac failure chronic Diseases 0.000 description 1
- 102000053642 Catalytic RNA Human genes 0.000 description 1
- 108090000994 Catalytic RNA Proteins 0.000 description 1
- 241000701489 Cauliflower mosaic virus Species 0.000 description 1
- 108010071536 Citrate (Si)-synthase Proteins 0.000 description 1
- 102000006732 Citrate synthase Human genes 0.000 description 1
- UDMBCSSLTHHNCD-UHFFFAOYSA-N Coenzym Q(11) Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(O)=O)C(O)C1O UDMBCSSLTHHNCD-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 108010041986 DNA Vaccines Proteins 0.000 description 1
- 229940021995 DNA vaccine Drugs 0.000 description 1
- 241000450599 DNA viruses Species 0.000 description 1
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 1
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 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
- 238000008157 ELISA kit Methods 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000991587 Enterovirus C Species 0.000 description 1
- 108700039887 Essential Genes Proteins 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 208000036119 Frailty Diseases 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 241000713858 Harvey murine sarcoma virus Species 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 101000690301 Homo sapiens Aldo-keto reductase family 1 member C4 Proteins 0.000 description 1
- 101000771523 Homo sapiens Apelin Proteins 0.000 description 1
- 101000935587 Homo sapiens Flavin reductase (NADPH) Proteins 0.000 description 1
- 101001008429 Homo sapiens Nucleobindin-2 Proteins 0.000 description 1
- 101001116548 Homo sapiens Protein CBFA2T1 Proteins 0.000 description 1
- 238000012450 HuMAb Mouse Methods 0.000 description 1
- 108010000521 Human Growth Hormone Proteins 0.000 description 1
- 238000009015 Human TaqMan MicroRNA Assay kit Methods 0.000 description 1
- 241000701024 Human betaherpesvirus 5 Species 0.000 description 1
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 1
- 108700001097 Insect Genes Proteins 0.000 description 1
- VHJLVAABSRFDPM-IMJSIDKUSA-N L-1,4-dithiothreitol Chemical compound SC[C@H](O)[C@@H](O)CS VHJLVAABSRFDPM-IMJSIDKUSA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- 241000713666 Lentivirus Species 0.000 description 1
- 102000016267 Leptin Human genes 0.000 description 1
- 108010092277 Leptin Proteins 0.000 description 1
- 108700005443 Microbial Genes Proteins 0.000 description 1
- 241000713869 Moloney murine leukemia virus Species 0.000 description 1
- 241000713333 Mouse mammary tumor virus Species 0.000 description 1
- 208000029578 Muscle disease Diseases 0.000 description 1
- 208000021642 Muscular disease Diseases 0.000 description 1
- 201000009623 Myopathy Diseases 0.000 description 1
- 241001644525 Nastus productus Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- 108091093105 Nuclear DNA Proteins 0.000 description 1
- 102100027441 Nucleobindin-2 Human genes 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 239000002033 PVDF binder Substances 0.000 description 1
- 241001631646 Papillomaviridae Species 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 108010079855 Peptide Aptamers Proteins 0.000 description 1
- 102000003921 Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Human genes 0.000 description 1
- 108090000310 Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Proteins 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 241000276498 Pollachius virens Species 0.000 description 1
- 241001505332 Polyomavirus sp. Species 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102000007568 Proto-Oncogene Proteins c-fos Human genes 0.000 description 1
- 108010071563 Proto-Oncogene Proteins c-fos Proteins 0.000 description 1
- 241000125945 Protoparvovirus Species 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 238000011529 RT qPCR Methods 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 206010038997 Retroviral infections Diseases 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 108010073443 Ribi adjuvant Proteins 0.000 description 1
- 108091027967 Small hairpin RNA Proteins 0.000 description 1
- 108020004459 Small interfering RNA Proteins 0.000 description 1
- 206010042566 Superinfection Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 102000002933 Thioredoxin Human genes 0.000 description 1
- 241000700618 Vaccinia virus Species 0.000 description 1
- 108700005077 Viral Genes Proteins 0.000 description 1
- 108020000999 Viral RNA Proteins 0.000 description 1
- 238000012452 Xenomouse strains Methods 0.000 description 1
- INAPMGSXUVUWAF-GCVPSNMTSA-N [(2r,3s,5r,6r)-2,3,4,5,6-pentahydroxycyclohexyl] dihydrogen phosphate Chemical compound OC1[C@H](O)[C@@H](O)C(OP(O)(O)=O)[C@H](O)[C@@H]1O INAPMGSXUVUWAF-GCVPSNMTSA-N 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- UDMBCSSLTHHNCD-KQYNXXCUSA-N adenosine 5'-monophosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O UDMBCSSLTHHNCD-KQYNXXCUSA-N 0.000 description 1
- 229950006790 adenosine phosphate Drugs 0.000 description 1
- 210000001789 adipocyte Anatomy 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000004520 agglutination Effects 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 125000005213 alkyl heteroaryl group Chemical group 0.000 description 1
- 229940037003 alum Drugs 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- WLDHEUZGFKACJH-UHFFFAOYSA-K amaranth Chemical compound [Na+].[Na+].[Na+].C12=CC=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(O)=C1N=NC1=CC=C(S([O-])(=O)=O)C2=CC=CC=C12 WLDHEUZGFKACJH-UHFFFAOYSA-K 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- -1 antibodies Proteins 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000000074 antisense oligonucleotide Substances 0.000 description 1
- 238000012230 antisense oligonucleotides Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 239000012131 assay buffer Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 108010006025 bovine growth hormone Proteins 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000003491 cAMP production Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000021523 carboxylation Effects 0.000 description 1
- 238000006473 carboxylation reaction Methods 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000009084 cardiovascular function Effects 0.000 description 1
- 229960004203 carnitine Drugs 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 108091092356 cellular DNA Proteins 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 230000004700 cellular uptake Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 230000024203 complement activation Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 230000000120 cytopathologic effect Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 239000000412 dendrimer Substances 0.000 description 1
- 229920000736 dendritic polymer Polymers 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- SIYLLGKDQZGJHK-UHFFFAOYSA-N dimethyl-(phenylmethyl)-[2-[2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]ethoxy]ethyl]ammonium Chemical compound C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 SIYLLGKDQZGJHK-UHFFFAOYSA-N 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 238000001493 electron microscopy Methods 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 230000013020 embryo development Effects 0.000 description 1
- 239000008393 encapsulating agent Substances 0.000 description 1
- 239000006274 endogenous ligand Substances 0.000 description 1
- 230000037149 energy metabolism Effects 0.000 description 1
- 230000007515 enzymatic degradation Effects 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000000446 fuel Substances 0.000 description 1
- 230000007661 gastrointestinal function Effects 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 210000004602 germ cell Anatomy 0.000 description 1
- 230000024924 glomerular filtration Effects 0.000 description 1
- 230000010030 glucose lowering effect Effects 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 229940049906 glutamate Drugs 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 description 1
- 102000006602 glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 1
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 102000048606 human APLN Human genes 0.000 description 1
- 102000054751 human RUNX1T1 Human genes 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 229940127121 immunoconjugate Drugs 0.000 description 1
- 238000000760 immunoelectrophoresis Methods 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 238000012151 immunohistochemical method Methods 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000004941 influx Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 235000014413 iron hydroxide Nutrition 0.000 description 1
- NCNCGGDMXMBVIA-UHFFFAOYSA-L iron(ii) hydroxide Chemical compound [OH-].[OH-].[Fe+2] NCNCGGDMXMBVIA-UHFFFAOYSA-L 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000004816 latex Substances 0.000 description 1
- 229920000126 latex Polymers 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- NRYBAZVQPHGZNS-ZSOCWYAHSA-N leptin Chemical compound O=C([C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(C)C)CCSC)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CS)C(O)=O NRYBAZVQPHGZNS-ZSOCWYAHSA-N 0.000 description 1
- 229940039781 leptin Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000029226 lipidation Effects 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 235000011147 magnesium chloride Nutrition 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000003818 metabolic dysfunction Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004898 mitochondrial function Effects 0.000 description 1
- 230000006705 mitochondrial oxidative phosphorylation Effects 0.000 description 1
- 108010045576 mitochondrial transcription factor A Proteins 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 210000003365 myofibril Anatomy 0.000 description 1
- 210000001087 myotubule Anatomy 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 125000000449 nitro group Chemical class [O-][N+](*)=O 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 230000010627 oxidative phosphorylation Effects 0.000 description 1
- GGMAXEWLXWJGSF-PEWBXTNBSA-N p-Glu-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Phe Chemical compound C([C@@H](C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCSC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H]1NC(=O)CC1)C1=CN=CN1 GGMAXEWLXWJGSF-PEWBXTNBSA-N 0.000 description 1
- 238000007427 paired t-test Methods 0.000 description 1
- 235000012736 patent blue V Nutrition 0.000 description 1
- 239000004177 patent blue V Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 230000006320 pegylation Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 102000013415 peroxidase activity proteins Human genes 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 238000002823 phage display Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 108010079892 phosphoglycerol kinase Proteins 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- 229920000915 polyvinyl chloride Polymers 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000001566 pro-viral effect Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000004952 protein activity Effects 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 230000006337 proteolytic cleavage Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000004451 qualitative analysis Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 239000001397 quillaja saponaria molina bark Substances 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000003127 radioimmunoassay Methods 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 229940100618 rectal suppository Drugs 0.000 description 1
- 239000006215 rectal suppository Substances 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 230000001177 retroviral effect Effects 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 238000003757 reverse transcription PCR Methods 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- MUSLHCJRTRQOSP-UHFFFAOYSA-N rhodamine 101 Chemical compound [O-]C(=O)C1=CC=CC=C1C(C1=CC=2CCCN3CCCC(C=23)=C1O1)=C2C1=C(CCC1)C3=[N+]1CCCC3=C2 MUSLHCJRTRQOSP-UHFFFAOYSA-N 0.000 description 1
- 108020004418 ribosomal RNA Proteins 0.000 description 1
- 108091092562 ribozyme Proteins 0.000 description 1
- JUVIOZPCNVVQFO-UHFFFAOYSA-N rotenone Natural products O1C2=C3CC(C(C)=C)OC3=CC=C2C(=O)C2C1COC1=C2C=C(OC)C(OC)=C1 JUVIOZPCNVVQFO-UHFFFAOYSA-N 0.000 description 1
- 229940080817 rotenone Drugs 0.000 description 1
- 229930182490 saponin Natural products 0.000 description 1
- 150000007949 saponins Chemical class 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000002924 silencing RNA Substances 0.000 description 1
- 239000004055 small Interfering RNA Substances 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000007863 steatosis Effects 0.000 description 1
- 231100000240 steatosis hepatitis Toxicity 0.000 description 1
- 238000011146 sterile filtration Methods 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- MPLHNVLQVRSVEE-UHFFFAOYSA-N texas red Chemical compound [O-]S(=O)(=O)C1=CC(S(Cl)(=O)=O)=CC=C1C(C1=CC=2CCCN3CCCC(C=23)=C1O1)=C2C1=C(CCC1)C3=[N+]1CCCC3=C2 MPLHNVLQVRSVEE-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 108060008226 thioredoxin Proteins 0.000 description 1
- 229940094937 thioredoxin Drugs 0.000 description 1
- 239000003104 tissue culture media Substances 0.000 description 1
- 108091006108 transcriptional coactivators Proteins 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 238000010396 two-hybrid screening Methods 0.000 description 1
- 238000007492 two-way ANOVA Methods 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 238000012762 unpaired Student’s t-test Methods 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 210000003501 vero cell Anatomy 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 230000003313 weakening effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B60—VEHICLES IN GENERAL
- B60G—VEHICLE SUSPENSION ARRANGEMENTS
- B60G21/00—Interconnection systems for two or more resiliently-suspended wheels, e.g. for stabilising a vehicle body with respect to acceleration, deceleration or centrifugal forces
- B60G21/02—Interconnection systems for two or more resiliently-suspended wheels, e.g. for stabilising a vehicle body with respect to acceleration, deceleration or centrifugal forces permanently interconnected
- B60G21/04—Interconnection systems for two or more resiliently-suspended wheels, e.g. for stabilising a vehicle body with respect to acceleration, deceleration or centrifugal forces permanently interconnected mechanically
- B60G21/05—Interconnection systems for two or more resiliently-suspended wheels, e.g. for stabilising a vehicle body with respect to acceleration, deceleration or centrifugal forces permanently interconnected mechanically between wheels on the same axle but on different sides of the vehicle, i.e. the left and right wheel suspensions being interconnected
- B60G21/055—Stabiliser bars
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B60—VEHICLES IN GENERAL
- B60G—VEHICLE SUSPENSION ARRANGEMENTS
- B60G21/00—Interconnection systems for two or more resiliently-suspended wheels, e.g. for stabilising a vehicle body with respect to acceleration, deceleration or centrifugal forces
- B60G21/02—Interconnection systems for two or more resiliently-suspended wheels, e.g. for stabilising a vehicle body with respect to acceleration, deceleration or centrifugal forces permanently interconnected
- B60G21/04—Interconnection systems for two or more resiliently-suspended wheels, e.g. for stabilising a vehicle body with respect to acceleration, deceleration or centrifugal forces permanently interconnected mechanically
- B60G21/05—Interconnection systems for two or more resiliently-suspended wheels, e.g. for stabilising a vehicle body with respect to acceleration, deceleration or centrifugal forces permanently interconnected mechanically between wheels on the same axle but on different sides of the vehicle, i.e. the left and right wheel suspensions being interconnected
- B60G21/055—Stabiliser bars
- B60G21/0551—Mounting means therefor
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B60—VEHICLES IN GENERAL
- B60G—VEHICLE SUSPENSION ARRANGEMENTS
- B60G2202/00—Indexing codes relating to the type of spring, damper or actuator
- B60G2202/10—Type of spring
- B60G2202/13—Torsion spring
- B60G2202/135—Stabiliser bar and/or tube
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B60—VEHICLES IN GENERAL
- B60G—VEHICLE SUSPENSION ARRANGEMENTS
- B60G2204/00—Indexing codes related to suspensions per se or to auxiliary parts
- B60G2204/10—Mounting of suspension elements
- B60G2204/12—Mounting of springs or dampers
- B60G2204/122—Mounting of torsion springs
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B60—VEHICLES IN GENERAL
- B60G—VEHICLE SUSPENSION ARRANGEMENTS
- B60G2204/00—Indexing codes related to suspensions per se or to auxiliary parts
- B60G2204/10—Mounting of suspension elements
- B60G2204/12—Mounting of springs or dampers
- B60G2204/122—Mounting of torsion springs
- B60G2204/1224—End mounts of stabiliser on wheel suspension
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B60—VEHICLES IN GENERAL
- B60G—VEHICLE SUSPENSION ARRANGEMENTS
- B60G2204/00—Indexing codes related to suspensions per se or to auxiliary parts
- B60G2204/10—Mounting of suspension elements
- B60G2204/14—Mounting of suspension arms
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B60—VEHICLES IN GENERAL
- B60G—VEHICLE SUSPENSION ARRANGEMENTS
- B60G2206/00—Indexing codes related to the manufacturing of suspensions: constructional features, the materials used, procedures or tools
- B60G2206/01—Constructional features of suspension elements, e.g. arms, dampers, springs
- B60G2206/10—Constructional features of arms
- B60G2206/11—Constructional features of arms the arm being a radius or track or torque or steering rod or stabiliser end link
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B60—VEHICLES IN GENERAL
- B60G—VEHICLE SUSPENSION ARRANGEMENTS
- B60G2206/00—Indexing codes related to the manufacturing of suspensions: constructional features, the materials used, procedures or tools
- B60G2206/01—Constructional features of suspension elements, e.g. arms, dampers, springs
- B60G2206/40—Constructional features of dampers and/or springs
- B60G2206/42—Springs
- B60G2206/427—Stabiliser bars or tubes
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/118—Prognosis of disease development
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/158—Expression markers
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
- G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/50—Determining the risk of developing a disease
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/70—Mechanisms involved in disease identification
- G01N2800/7042—Aging, e.g. cellular aging
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Hematology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Analytical Chemistry (AREA)
- Zoology (AREA)
- Biomedical Technology (AREA)
- Urology & Nephrology (AREA)
- Microbiology (AREA)
- Biotechnology (AREA)
- Pathology (AREA)
- Biochemistry (AREA)
- Physics & Mathematics (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Genetics & Genomics (AREA)
- Wood Science & Technology (AREA)
- General Physics & Mathematics (AREA)
- Mechanical Engineering (AREA)
- Epidemiology (AREA)
- Food Science & Technology (AREA)
- Gastroenterology & Hepatology (AREA)
- Marine Sciences & Fisheries (AREA)
- Cell Biology (AREA)
- Biophysics (AREA)
- General Engineering & Computer Science (AREA)
- Orthopedic Medicine & Surgery (AREA)
Description
本発明は、加齢に伴う機能障害の処置又は予防に使用するためのAPJレセプターアゴニスト又はアペリン模倣体に関する。
加齢に関連した機能障害は、加齢に関連したヒト臓器の機能低下として定義することができる。多くの機能障害が脳に出現し得、そして一部の変性疾患の原因となり得るが、また筋肉にも出現し得る。この場合、その筋肉の機能障害を有する人々は筋肉減少症に苦しむ。
本発明者らは、アペリンが、エネルギー代謝、特にミトコンドリアにおけるエネルギー機序において役割を果たすことを示す。本発明者らは、アペリンによる処置が、インシュリン耐性マウスの筋肉において、完全な脂肪酸酸化(FAO)、グルコース輸送、ミトコンドリア酸化能及びミトコンドリア生合成を増加させることを示す。さらに、本発明者らは、骨格筋がアペリン作用にとっての主要な組織標的のように見えることを示し、その場所で増加した燃料の消費を媒介する。従って、アペリンは、ミトコンドリアにおけるエネルギー機序の問題に関連した疾病に使用することができる。
APJレセプターアゴニスト又はアペリン模倣体及びその使用
本発明の第1の目的は、加齢に伴う機能障害の処置又は予防に使用するためのAPJレセプターアゴニスト又はアペリン模倣体に関する。
(式中、
R1は、アリール基、アルキルアリール基、ヘテロアリール基又はアルキルヘテロアリール基であり、
R2は、水素原子又はアリール基であり、
R3及びR4は、水素原子又はヘテロシクロアルキル基を示し、ただし、R3及びR4は同時に水素原子を示すことはできず、そしてR3及びR4は両方共に、ヘテロシクロアルキル基の一部であることができ、
R5は、boc、fmoc、テキサスレッド、パテントブルーV、リサミン、及びローダミン101からなる群より選択された基を示し、
nは0〜1の整数であり、
Yは、−CO−(NH)n’−A−NH−基を示し、ここで
n’は、0〜1の整数であり、
Aは、−(CH2)n''−、
−[(CH2)2−O]n'''−(CH2)2−、
−(CH2)m−NH−CO−(CH2)m’−、
−(CH2)m−NH−CO−(CH2)m’−NH−CO−(CH2)m''−、
−(CH2)m−CO−NH−(CH2)m’−、
−(CH2)m−CO−NH−(CH2)m’−CO−NH−(CH2)m''−、
からなる群より選択された基であり、
n''は、1〜20の整数を示し、
n'''は、1〜10の整数を示し、
m、m’及びm''は、互いに独立して、1〜15の整数を示し、
Xは、以下のリスト
から選択された基を示す)
を有する。
第2の局面において、本発明は、患者から得られたサンプル中でアペリンの発現を検出することからなる工程を含む、加齢に伴う機能障害に患者が罹患する能力をex vivoにおいて予測するための方法に関する。
1)抗原賦活化(例えば圧力鍋にかける、プロテアーゼによる処理、電子レンジにかける、適切な緩衝液中での加熱などによって);
2)一次抗体(すなわち抗アペリンタンパク質抗体)の適用及び洗浄;
3)一次抗体に結合する標識された二次抗体(しばしば、工程5での検出を可能とする二次抗体コンジュゲート)の適用及び洗浄;
4)増幅工程が含まれ得る;
5)検出試薬の適用(例えば、色原体、蛍光でタグ化された分子、又はアッセイに必要とされるレベル又は感度を達成するために適切なダイナミックレンジを有する任意の分子);
6)対比染色を使用し得る、そして
7)定性的又は定量的分析のための、タンパク質の存在を可視化(肉眼又は自動分析システムのいずれかに対して)する検出システムを使用した検出。
a)前記被験者の生物学的サンプル中のアペリン発現レベルを決定する工程;
b)健康個体、好ましくは100人の健康個体の集団の生物学的サンプル中のアペリンの平均発現レベルを決定する工程;及び
c)a)で得られた比を、b)で得られた比と比較する工程。
実施例1:
材料及び方法
動物
マウスを、国立衛生医学研究所(INSERM)によって確立された原則及びガイドラインに従って取り扱った。C57Bl6/J野生型マウスは、Harlan (Gannat, France)から入手した。CMV−KOアペリンマウスは、Genoway (Lyon, France)から入手した。マウスを、12時間/12時間の明暗サイクル(午前8時に点灯)の一定温度(20〜22℃)の加湿した(50〜60%)動物部屋で、食物及び水に自由に近付けるようにして慣用的に飼育した。マウスに、離乳から10週令まで固形飼料を与え、その後、固形飼料で維持した(Research Diet, NJ)。
アペリンによる処置を、31週令から35週令のマウスに行なった。マウスに1日1回、28日間、以前に記載されているように(Higuchi et al 2005; Yue et al 2010)アペリンの腹腔内注射液(0.1μmol/kg/日)を注射した。年齢の一致した対照マウスに、同じ期間中、PBSを注射した。全マウスを、摂食状態で最後のアペリンの腹腔内注射から24時間後に屠殺した。腹腔内アペリン(0.1μmol/kg/日)のボーラス後に測定した血漿中アペリン濃度は、注射から10分後に丁度2.5倍を超えて増加した。
全RNA(1mg)を、GeneJET RNA精製キット(Fermentas, USA)を使用して筋肉から単離した。全RNAを、ランダムヘキサマー及びSuperscriptII逆転写酵素(Invitrogen, UK)を使用して逆転写した。リアルタイムPCRを、以前に記載されているように(Boucher et al. 2005)実施した。
I.アペリンによる処置
1)ミオスタチン
図1A及びBは、アペリンによる処置が、中年の年齢のマウスの大腿四頭筋におけるミオゲニン、MyoD及びMyf5などの筋原性マーカー発現を増加させたことを明瞭に実証する。平行して、この28日間の処置は、これらの筋肉におけるミオスタチンの発現を減少させることができ、これは、筋形成におけるアペリンの有益な役割を確認する。
材料及び方法
ニューマン指数に従って筋肉減少症と診断された高齢の個体(n=30)又は健康な高齢の個体(n=30)の血漿中のアペリンを、市販のELISAキット(Pheonix Pharmaceutical Inc., USA)によって単純盲検法で測定した。この指数は、付属器官の筋肉量及び脂肪量を考慮する。個体の四分位は、そのニューマン指数に従って実施し、そして極端な4分位数を選択して、筋肉減少症状態又は筋肉減少症ではない状態を決定した。
図3は、血漿中アペリンレベルは、筋肉減少症個体(ヒト)において有意に減少していることを示す。この減少は、肥満度指数又はインシュリンに相関しておらず、このことは、血漿中アペリンレベルは、加齢に伴う筋疾病の強力なバイオマーカーと考えることができることを示唆する。
材料及び方法
マウスを、INSERMによって確立された原則及びガイドラインに従って取り扱った。C57Bl6/J野生型(WT)マウスはHarlan (Gannat, France)から入手した。筋肉特異的な不活性AMPKを有するマウス(AMPK−DNマウス)は、Moris J. Birnbaum博士(Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, PA)によって提供された。アペリン欠損(アペリン−/−)マウスは以前に記載されているように(10)作成され、そしてC57Bl6/Jマウスに10回超で戻し交配された。マウスを12時間/12時間の明暗サイクル(午前7時に点灯)の一定温度(20〜22℃)の加湿した(50〜60%)動物部屋で、食物及び水に自由に近付けるようにして慣用的に飼育した。C57Bl6/J及びAMPK−DNマウスに、離乳から10週令まで正常食を与え、その後、正常食(対照群)で維持するか、又は20%のタンパク質、35%の炭水化物及び45%の脂肪を含む高脂肪食を与えた(Research Diets, New Brunswick, NJ)。アペリン処置は、23週令の雄におけるインシュリン耐性の発症後に開始した。マウスに、28日間、以前に記載されているように(7)、0.1μmol/kg/日のアペリン−13(Phoenix Biotech)を腹腔内に1日1回注射した。年齢の一致した対照マウスに、同じ期間中、PBSを注射した。標準的なマウスもまた、28日間の間、0.2μmol/kg/日の特異的APJレセプターアンタゴニスト(F13A)(Phoenix Biotech)(11)で、又はアペリンとF13Aとの組合せで処置した。全マウスを、摂食状態で最後のアペリン注射から24時間後に殺滅した。高脂肪食マウスへのアペリン(0.1μmol/kgを腹腔内に)のボーラス後に測定された血漿中アペリン濃度は、注射から10分後に2.4倍超で増加したが(注射前には4.12±0.96vs1.73±0.24ng/mL、n=5)、血漿中アペリン濃度は、処置終了時にPBS処置マウスとアペリン処置マウスとの間で差異はなかった。
和光NEFAキット(和光ケミカル)及びPAP150キット(bioMerieux)をそれぞれ用いて比色定量技術によって測定された血漿中脂肪酸(FA)及びTG、並びに、血漿中レプチン、アディポネクチン(Quantikine; R&D Systems)及びアペリン(Phoenix Pharmaceuticals, Inc.)が、処置終了時に摂食状態で測定された。血糖値計(Accu-check; Roche Diagnostics)を用いて測定されたインシュリン血症(Mercodia, Uppsala, Sweden)及び糖血症が、断食状態で尾静脈からの血液で測定された。
全ヒラメ筋又は脂肪組織におけるパルミチン酸の酸化が、以前に記載されているように決定された(12)。前記組織を、1.5%FA非含有BSA、5mmol/Lのグルコース、1mmol/Lのパルミチン酸、及び0.5μCi/mLの[14C]パルミチン酸(PerkinElmer)を含む改変クレブス・ヘンセレイト緩衝液中で60分間かけてインキュベーションした。インキュベーション終了時に、組織を取り出し、そして800μLの溶解緩衝液中でホモジナイズした。完全酸化は、インキュベーション緩衝液を1mLの1mol/LのH2SO4を用いて酸性化することによって決定され、そして14CO2を、封をしたガラスバイアル中の0.5mLのマイクロチューブ中に入れた水酸化ベンゼトニウム(Sigma-Aldrich)によって補足した。120分後、マイクロチューブを取り出し、そしてシンチレーションバイアル中に入れ、そして放射能を計測した(Cytoscint; MP Biomedicals)。合計で500μLのホモジネートをガラスチューブに入れて、クロロホルム−メタノール(2:1)及び2mol/LのKCl−HClで脂質を抽出した。遠心分離後、水相(500μL)を液体シンチレーションによって定量して、酸に可溶性の代謝物の産生(不完全酸化)を決定し、そして有機相(200μL)を使用して、以前に記載されているように(12)パルミチン酸のエステル化を測定した。
O2の消費を、以前に記載されているように(13、14)、呼吸計(Oxygraph-2k; OROBOROS INSTRUMENTS, Innsbruck, Austria)を使用してヒラメ筋から調製された新鮮な透過処理された線維上で測定した。最初に、4mmol/Lのリンゴ酸塩混合物あたり20mmol/Lのグルタミン酸を注入して、複合体Iの活性(gmState2)を評価した。その後、複合体Iを、5μmol/Lのロテノンの添加によって遮断した。その後、10mmol/Lのコハク酸を加えて、複合体IIの活性(sState2)を評価した。State3の呼吸が、10mmol/LのADPのさらなる添加によって得られた。各状態についてのO2消費を、DataGraphソフトウェアを使用して計算した。
ヒラメ筋を切断して小さな破片とし、そして以前に報告されているように(15)固定した。その後、組織を切断し、そして銅グリッド上に載せ、そして高分解能カメラを備えた日立HU12A透過型電子顕微鏡を用いて観察した。得られた写真をLuciaGソフトウェアを用いて分析した。
全DNAを、市販のキット(DNeasy; QIAGEN)を使用してヒラメ筋から抽出した。ミトコンドリア(mt)DNAの含量を、以前に記載されているように(15)、ミトコンドリアにコードされる遺伝子(COX1)と核にコードされている遺伝子(シクロフィリンA)の閾値サイクル比を測定することによって、リアルタイム定量PCRを使用して計算した。
筋ホモジネートの一部(20μL)を、フィルター膜(Protein Saver 903 cards; Whatman)上にスポットした。その後、乾燥したスポットを、報告されているように(17)処理した。簡潔に言えば、アシルカルニチンを、ブタノールHClの添加によって誘導体化し、そしてNeoGramMSMS−AAACキット(PerkinElmer)の試薬を用いて処理した。遊離カルニチン及びアシルカルニチンを、液体クロマトグラフィー−タンデム質量分析計によって定量した。データを、2795高速液体クロマトグラフィーモジュール及びMassLynx4.1オペレーティングシステムによって制御されたデータシステムの備えられた、Micromass Quattro Micro API分光計(Waters, Milford, MA)を使用して得た。
筋肉(5〜10mg)を、5mmol/LのEGTAあたり2mLのメタノール(2:1v/v)中でFAST−PREP(MP Biomedicals)を用いてホモジナイズした。全100μLを蒸発させ、乾燥ペレットを0.1mLのNaOH(0.1mol/L)中に一晩かけて溶解し、そしてタンパク質をBio−Radアッセイを用いて測定した。0.9mLのホモジネートに対応する中性脂質を、Bligh and Dyer (18)に従って、クロロホルム/メタノール/水(2.5:2.5:2.1、v/v/v)中で内部標準の存在下で抽出し、そして以前に記載されているように(19)測定した。
マロニル−CoAレベルを、以前に記載されているように(20)凍結したヒラメ筋上で測定した。簡潔に言えば、筋肉をポッターを用いて氷上でホモジナイズし(1mol/LのKPO4及び10mmol/LのEDTAを含む250μLのリン酸緩衝液(pH7.0)中10mgの組織)、そしてその後、遠心分離にかけた。その後、上清(100μL)を1時間かけて37℃でアッセイ緩衝液(2.5mmol/Lのジチオトレイトール、0.2mmol/LのNADPH、0.01%の遊離FA BSA、13μmol/Lのアセチル−CoA、及び0.63μCiの3H−アセチル−CoAを含むリン酸緩衝液)(PerkinElmer)、及び25mUのFAシンターゼ(Marc Prentki博士, Centre Hospitalier de l'Universite de Montreal Research Centre, Montreal, Ontario, Canadaによって提供された)と共にインキュベーションした。反応を25μLの過塩素酸を用いて停止させ、その後、エタノール及び石油酸を加えた。全4mLの上層を、2mLの水を含む新しいチューブに移し、そして遠心分離後、3mLの上層を乾燥させ、そして10mLのシンチレーション液を添加した後に放射能を測定した。
ウェスタンブロット分析を、4〜12%のCriterion/XTゲル(Bio-Rad)上にサンプル(溶解した筋肉)をローディングし、そして1/1,000の希釈率で使用される抗リン酸化−AMPK−α抗体(Thr172)、抗リン酸化−アセチルCoAカルボキシラーゼ抗体(ACC)(Ser79)(Cell Signaling Technology, Beverly, MA)又は抗OxPhos抗体(MitoSciences, Mundolsheim, France)でプローブしておいたニトロセルロース膜(Schleicher & Schuell Bioscience)に転写することによって以前に記載されているように(4)実施した。膜を、全タンパク質についてβ−アクチン抗体又はAMPK抗体又はACC抗体を用いてプローブした。
サンプルの濃度を、製造業者の指示に従ってDCタンパク質アッセイキット(Bio-Rad)を使用して決定した。
全RNA(1μg)を、RNA STAT(AMS Technology, Lutterworth, U.K.)を使用して筋肉から単離し、そしてランダムヘキサマー及びSuperscript II逆転写酵素(Invitrogen, Paisley, U.K.)を使用して逆転写した。リアルタイムPCRを、以前に記載されているように(1)実施した。18SリボソームRNAの分析を、リボソームRNA対照TaqManアッセイキット(Applied Biosystems)を使用して実施して、遺伝子発現を規準化した。
筋肉を単離し、そして2mg/mLのBSA、2mmol/Lのピルビン酸ナトリウム、及び20mmol/LのHEPESを含むクレブス−ヘンセレイト緩衝液(pH7.4)中で10分間プレインキュベーションした。その後、筋肉を45分間、100nmol/Lのインシュリンの非存在下又は存在下で以前に報告されているように(4)インキュベーションした。
データは平均±SEMとして提示する。群間の比較は、Prism5.0ソフトウェア(GraphPad Software)を使用して種々のパラメーターに関して行なった。二元配置分散分析を適用して、処置と時間との間の相互作用を検出した。適切である場合には、対応のある又は対応のないスチューデントt検定を適用した。P<0.05の差異を統計学的に有意と判断した。
HFD(高脂肪食)マウスの骨格筋脂質代謝に対するex vivoにおけるアペリンによる慢性的な処置の効果
HFDマウスにおけるアペリン処置は、PBS処置と比較した場合、IMTG及びDAGの量を減少させない(図4A)。アペリンによる処置はまた、TGへのパルミチン酸の取り込みの速度に対して全く影響を及ぼさない(図4B)。脂質の運命をさらに調査するために、完全及び不完全な[14C]パルミチン酸の酸化の両方を評価した。アペリンによる慢性的な処置は、PBS処置と比較した場合、ヒラメ筋において、[14C]パルミテートからCO2への完全な酸化を有意に増加させた(図4C)。興味深いことに、不完全な酸化は、アペリンによる慢性的な処置によって有意に増加しなかった(図4C)。さらに、HFDアペリン−/−マウスのヒラメ筋において、完全な酸化は増加しなかった(アペリン−/−マウスにおいてタンパク質1gあたり243.5±9.6vs198.4±59.9nmolのCO2が放出される、n=3〜4)。総合すると、これらの結果は、アペリンによる処置が、肥満及びインシュリン耐性マウスの骨格筋における完全なFAO(脂肪酸の酸化)を促進することを示す。
アペリンの効果に対するさらなる洞察を得るために、ミトコンドリア呼吸をまず、新鮮な透過処理された筋肉線維で評価した。グルタミン酸/リンゴ酸により駆動されるミトコンドリア呼吸における差異は、PBS処置マウスとアペリン処置マウスの間には全く見られず、このことは、複合体I活性は、アペリンによる処置によって影響を受けなかったことを示唆する(データは示していない)。しかしながら、コハク酸により駆動されるミトコンドリア呼吸は、対照と比較してアペリン処置マウスの線維においては有意により高く、このことは、FAOに由来する補酵素を使用する複合体IIの酸化能の増加を示唆する(図5A)。コハク酸及びアデニル酸により駆動される呼吸もまた、アペリン処置マウスにおいて有意により高く、このことは、酸化的リン酸化能は、アペリンによる処置後にヒラメ筋において増加したことを示す。複合体II、III及びVのタンパク質発現もまた、アペリン処置マウスにおいて有意に増加した(図5B)。さらに、ミトコンドリア含量の定量マーカーである増加したクエン酸シンターゼ活性もまた、対照と比較してアペリン処置マウスの筋肉ホモジネートに見られた(2.62±0.02vs2.91±0.07μmol/分/mg(タンパク質)、n=7〜9;P<0.001)。ミトコンドリア生合成を媒介する転写コアクチベーターであるペルオキシソーム増殖剤活性化レセプターγコアクチベーター1−α(PGC1−α)の発現もまた、アペリン処置マウスの筋肉において有意に増加し、一方、PGC1−βの発現は改変されなかった(図5C)。さらに、ミトコンドリア酸化的リン酸化及びミトコンドリア生合成を増加させるように協奏して作用する、核呼吸因子1(NRF1)及びミトコンドリア転写因子A(TFAM)の発現もアップレギュレーションされた。総合すると、これらの結果は、アペリンによる処置に応答して、ミトコンドリア生合成は、インシュリン耐性マウスの骨格筋において増加したことを強く示唆する。この仮説を試験するために、本発明者らは、筋肉のmtDNA及び密度を測定した。mtDNAと核DNAの比は、PBS処置マウスよりもアペリン処置マウスのヒラメ筋において有意により高かった(図5D)。さらに、電子顕微鏡は、アペリンによる処置は、全ミトコンドリア含量の最大の画分である筋原線維内(IMF)ミトコンドリアの密度を有意に増加させたことを実証した(図5E)。ミトコンドリア超微細構造のより少ない逆の変化(マトリックスの減少した電子密度及びクリステの減少)がまた、アペリン処置マウスのヒラメ筋のIMFミトコンドリア及び筋細胞膜下(SS)ミトコンドリアの両方に観察され(図5E)、これはミトコンドリア機能及びミトコンドリア生合成に対するアペリンの効果を強化する。
アシルカルニチンは、不完全なFAOから生じる基質の異化反応の副産物を示す。上昇したアシルカルニチンレベルは、肥満及びインシュリン耐性に関連していることが示された。長鎖アシルカルニチンは、ND対照マウスと比較して、HFDインシュリン耐性マウスのヒラメ筋のホモジネートにおいて上昇していた(図7A)。HFDアペリン処置マウスにおいては、アシルカルニチンレベル、特にC16:1及びC18:1種は、HFD PBS処置マウスと比較した場合に減少していたことは興味深い。アペリンによる慢性的な処置は、ヒラメ筋において完全なFAOを増加させたが不完全なFAOは増加させなかったので、本発明者らは、得られた低レベルのアシルカルニチンは、筋肉における改善されたインシュリン感受性と相関すると仮定した。実際に、インシュリンにより刺激されたグルコース取り込みは、PBS処置マウスと比較して、アペリン処置マウス筋肉において有意に増加した(図7B)。
本発明者らは、アペリンによる慢性的な処置は、インシュリン耐性マウスの骨格筋において、完全なFAO、ミトコンドリア呼吸能及びミトコンドリア生合成を増加させることを示す。ミトコンドリアへの脂質の流入は、低下したアシルカルニチンレベルと関連し、このことはFAOとトリカルボン酸サイクルとの間のより強固な共役を示唆する。このようなより強固な共役は、インシュリン感受性を高めるために重要であるようである。なぜなら、アペリン処置マウスの筋肉において、インシュリンにより刺激されたグルコース輸送の増加が観察されるからである。筋肉において増加したFAO及びミトコンドリア生合成並びに全体的な脂肪症の減少は、アペリンによる慢性的な処置で観察されたインシュリン感受性の全体的な改善に寄与し得る。
本出願全体を通して、種々の参考文献が、本発明が属する当技術分野の最新技術を記載する。これらの参考文献の開示は、本開示への参照により本明細書に組み入れられる。
Claims (5)
- 筋肉減少症の処置又は予防に使用するためのAPJレセプターアゴニストを含む組成物。
- 前記アゴニストがアペリンである、請求項1記載の組成物。
- 患者から得られたサンプルにおけるアペリンの発現を検出することからなる工程を含む、患者の筋肉減少症に罹患する能力をエクスビボにおいて予測するための方法。
- 前記アペリン発現が閾値と比較される、請求項3記載のエクスビボにおける方法。
- 前記サンプルが血漿である、請求項3又は4記載のエクスビボにおける方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP11306573.4 | 2011-11-28 | ||
EP11306573 | 2011-11-28 | ||
PCT/EP2012/073743 WO2013079487A1 (en) | 2011-11-28 | 2012-11-27 | Pharmaceutical composition for use in the treatment of dysfunction associated with aging |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2014534255A JP2014534255A (ja) | 2014-12-18 |
JP6082402B2 true JP6082402B2 (ja) | 2017-02-15 |
Family
ID=47227807
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2014542884A Active JP6082402B2 (ja) | 2011-11-28 | 2012-11-27 | 加齢に伴う機能障害の処置に使用するための薬学的組成物 |
Country Status (5)
Country | Link |
---|---|
US (1) | US9381229B2 (ja) |
EP (1) | EP2785365B1 (ja) |
JP (1) | JP6082402B2 (ja) |
ES (1) | ES2638649T3 (ja) |
WO (1) | WO2013079487A1 (ja) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2931299C (en) * | 2013-11-20 | 2024-03-05 | Regeneron Pharmaceuticals, Inc. | Aplnr modulators and uses thereof |
ES2950789T3 (es) * | 2014-06-10 | 2023-10-13 | Amgen Inc | Polipéptidos de apelina |
US10426818B2 (en) | 2015-03-24 | 2019-10-01 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Method and pharmaceutical composition for use in the treatment of diabetes |
WO2022138936A1 (ja) * | 2020-12-25 | 2022-06-30 | 国立研究開発法人国立精神・神経医療研究センター | 髄鞘修復剤 |
WO2024072907A1 (en) * | 2022-09-27 | 2024-04-04 | BioAge Labs, Inc. | Apelin receptor agonists for treating muscle conditions |
Family Cites Families (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
US5225539A (en) | 1986-03-27 | 1993-07-06 | Medical Research Council | Recombinant altered antibodies and methods of making altered antibodies |
US5567610A (en) | 1986-09-04 | 1996-10-22 | Bioinvent International Ab | Method of producing human monoclonal antibodies and kit therefor |
GB8823869D0 (en) | 1988-10-12 | 1988-11-16 | Medical Res Council | Production of antibodies |
AU643427B2 (en) | 1988-10-31 | 1993-11-18 | Immunex Corporation | Interleukin-4 receptors |
US5175384A (en) | 1988-12-05 | 1992-12-29 | Genpharm International | Transgenic mice depleted in mature t-cells and methods for making transgenic mice |
IL162181A (en) | 1988-12-28 | 2006-04-10 | Pdl Biopharma Inc | A method of producing humanized immunoglubulin, and polynucleotides encoding the same |
US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
US5859205A (en) | 1989-12-21 | 1999-01-12 | Celltech Limited | Humanised antibodies |
US6150584A (en) | 1990-01-12 | 2000-11-21 | Abgenix, Inc. | Human antibodies derived from immunized xenomice |
US5229275A (en) | 1990-04-26 | 1993-07-20 | Akzo N.V. | In-vitro method for producing antigen-specific human monoclonal antibodies |
WO1991018982A1 (en) | 1990-06-05 | 1991-12-12 | Immunex Corporation | Type ii interleukin-1 receptors |
US5545806A (en) | 1990-08-29 | 1996-08-13 | Genpharm International, Inc. | Ransgenic non-human animals for producing heterologous antibodies |
ES2136092T3 (es) | 1991-09-23 | 1999-11-16 | Medical Res Council | Procedimientos para la produccion de anticuerpos humanizados. |
US5573905A (en) | 1992-03-30 | 1996-11-12 | The Scripps Research Institute | Encoded combinatorial chemical libraries |
EP0690452A3 (en) | 1994-06-28 | 1999-01-07 | Advanced Micro Devices, Inc. | Electrically erasable memory and method of erasure |
CA2313246A1 (en) | 1997-12-24 | 1999-07-08 | Takeda Chemical Industries, Ltd. | Polypeptide, their production and use |
CN1419563A (zh) | 2000-03-23 | 2003-05-21 | 武田药品工业株式会社 | 肽衍生物 |
DE10138569A1 (de) | 2001-08-06 | 2003-04-30 | Bayer Ag | Regulation des APJ-Rezeptors |
US7947280B2 (en) | 2003-05-22 | 2011-05-24 | The Board Of Trustees Of The Leland Stanford Junior University | Apelin and uses thereof |
US20050112701A1 (en) | 2003-09-11 | 2005-05-26 | Aventis Pharma Deutschland Gmbh | Test system for the identification of APJ receptor ligands |
EP1520861A1 (en) * | 2003-09-11 | 2005-04-06 | Aventis Pharma Deutschland GmbH | Test system for the identification of APJ receptor ligands |
CA2625674C (en) * | 2005-08-29 | 2015-04-14 | Healor Ltd. | Methods and compositions for prevention and treatment of diabetic and aged skin |
JPWO2007072980A1 (ja) * | 2005-12-20 | 2009-06-04 | 武田薬品工業株式会社 | アペリンの新規用途 |
EP1903005A1 (en) | 2006-09-22 | 2008-03-26 | Umicore | Production of Si by reduction of SiCI4 with liquid Zn, and purification process |
WO2009033819A2 (en) | 2007-09-11 | 2009-03-19 | Mondobiotech Laboratories Ag | Use of a peptide as a therapeutic agent |
CA2699083A1 (en) | 2007-09-11 | 2009-04-16 | Mondobiotech Laboratories Ag | Use of a peptide as a therapeutic agent |
US8946382B2 (en) * | 2009-02-27 | 2015-02-03 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Apelin peptides and methods of use |
-
2012
- 2012-11-27 ES ES12791484.4T patent/ES2638649T3/es active Active
- 2012-11-27 WO PCT/EP2012/073743 patent/WO2013079487A1/en active Application Filing
- 2012-11-27 JP JP2014542884A patent/JP6082402B2/ja active Active
- 2012-11-27 EP EP12791484.4A patent/EP2785365B1/en active Active
- 2012-11-27 US US14/360,958 patent/US9381229B2/en active Active
Also Published As
Publication number | Publication date |
---|---|
JP2014534255A (ja) | 2014-12-18 |
ES2638649T3 (es) | 2017-10-23 |
US20150290286A1 (en) | 2015-10-15 |
US9381229B2 (en) | 2016-07-05 |
EP2785365A1 (en) | 2014-10-08 |
WO2013079487A1 (en) | 2013-06-06 |
EP2785365B1 (en) | 2017-07-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6082402B2 (ja) | 加齢に伴う機能障害の処置に使用するための薬学的組成物 | |
RU2636820C2 (ru) | Способы и применения ингибиторов пропротеиновой конвертазы субтилизин кексин типа 9(pcsk9) | |
US20100144603A1 (en) | Methods and uses thereof of prosaposin | |
JP5242396B2 (ja) | 抗体、および、sod1異常と関連した疾患の治療、予防、および、診断における前記抗体の使用 | |
US20130315940A1 (en) | Treatment of liver cancer | |
WO2005029066A2 (en) | Diagnostic markers and pharmacological targets in heart failure and related reagents and methods of use thereof | |
JP7330174B2 (ja) | オートファジーをモジュレーションするための方法及び医薬組成物 | |
JP2019514875A (ja) | 肝病態を治療又は予防する方法 | |
EP2089433B1 (en) | Therapy targeting cathepsin s | |
US20100098715A1 (en) | Annexin ii compositions for treating or monitoring inflammation or immune-mediated disorders | |
JP5045992B2 (ja) | 腸管m細胞マーカーとしてのgp2の使用 | |
JP6442403B2 (ja) | 代謝調節のための方法および組成物 | |
JP2014095643A (ja) | 炎症性疾患治療薬のスクリーニング方法、並びに炎症性疾患の治療及び検査 | |
WO2020096046A1 (ja) | 老化関連t細胞を標的とした糖代謝異常の予防または治療用ワクチン | |
US20210379147A1 (en) | Method and system for treating cancer utilizing tinagl1 | |
EP2997383A1 (en) | Fgf23 as a biomarker for predicting the risk of mortality due to end stage liver disease | |
KR20160068742A (ko) | Dpp-4를 표적으로 하는 당뇨병 치료용 백신 | |
KR102536092B1 (ko) | Lrp5 발현 또는 활성 억제제를 포함하는 허혈성 심장질환의 예방 또는 치료용 약학적 조성물 | |
US10928391B2 (en) | CD318 as a marker for, and CD318 inhibition as a treatment for, autoimmune disease | |
Palmiotti | Bile acid signalling in type 2 diabetes and its co-morbidities | |
Li | Humanizing bile acid metabolism in mice: impact on (patho) physiology and responses to dietary and pharmacological interventions | |
AU2013203640B2 (en) | Methods and uses thereof of prosaposin | |
TW200827718A (en) | Alpha-enolase specific antibody and method of use | |
JP2016508606A (ja) | トリプルネガティブ乳ガンにおける転移を予測及び予防するための方法 | |
JP2015520373A (ja) | 巣状分節性糸球体硬化症を診断及び処置するための方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
RD04 | Notification of resignation of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7424 Effective date: 20150312 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20151030 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20160726 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20161025 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20161227 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20170120 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6082402 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |