CN115737617A - Application of carnosic acid or derivatives thereof in preparing medicament for treating and/or preventing type I interferon - Google Patents
Application of carnosic acid or derivatives thereof in preparing medicament for treating and/or preventing type I interferon Download PDFInfo
- Publication number
- CN115737617A CN115737617A CN202211449124.9A CN202211449124A CN115737617A CN 115737617 A CN115737617 A CN 115737617A CN 202211449124 A CN202211449124 A CN 202211449124A CN 115737617 A CN115737617 A CN 115737617A
- Authority
- CN
- China
- Prior art keywords
- carnosic acid
- interferon
- agents
- type
- sting
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- QRYRORQUOLYVBU-VBKZILBWSA-N carnosic acid Chemical compound CC([C@@H]1CC2)(C)CCC[C@]1(C(O)=O)C1=C2C=C(C(C)C)C(O)=C1O QRYRORQUOLYVBU-VBKZILBWSA-N 0.000 title claims abstract description 174
- 108010014726 Interferon Type I Proteins 0.000 title claims abstract description 51
- 102000002227 Interferon Type I Human genes 0.000 title claims abstract description 50
- 239000003814 drug Substances 0.000 title claims abstract description 22
- 230000019491 signal transduction Effects 0.000 claims abstract description 30
- 230000004913 activation Effects 0.000 claims abstract description 22
- 201000010099 disease Diseases 0.000 claims abstract description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 21
- LCAZOMIGFDQMNC-FORWCCJISA-N rosmanol Chemical compound C1CCC(C)(C)[C@@H]2[C@H]3[C@@H](O)C(C=C(C(=C4O)O)C(C)C)=C4[C@]21C(=O)O3 LCAZOMIGFDQMNC-FORWCCJISA-N 0.000 claims description 14
- XUSYGBPHQBWGAD-PJSUUKDQSA-N Carnosol Chemical compound CC([C@@H]1C2)(C)CCC[C@@]11C(=O)O[C@@H]2C2=C1C(O)=C(O)C(C(C)C)=C2 XUSYGBPHQBWGAD-PJSUUKDQSA-N 0.000 claims description 13
- CEEMRWKKNNEQDT-UHFFFAOYSA-N Rosmanol Natural products CC(C)c1cc2C(OC(=O)C)C3OC(=O)C4(CCCC(C)(C)C34)c2c(OC(=O)C)c1OC(=O)C CEEMRWKKNNEQDT-UHFFFAOYSA-N 0.000 claims description 13
- MMFRMKXYTWBMOM-UHFFFAOYSA-N Carnosol Natural products CCc1cc2C3CC4C(C)(C)CCCC4(C(=O)O3)c2c(O)c1O MMFRMKXYTWBMOM-UHFFFAOYSA-N 0.000 claims description 12
- 235000004654 carnosol Nutrition 0.000 claims description 12
- 241000282414 Homo sapiens Species 0.000 claims description 11
- 208000033237 Aicardi-Goutières syndrome Diseases 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 9
- -1 elixir Substances 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 239000007924 injection Substances 0.000 claims description 6
- 238000002347 injection Methods 0.000 claims description 6
- 238000001802 infusion Methods 0.000 claims description 5
- 239000003112 inhibitor Substances 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 239000000463 material Substances 0.000 claims description 5
- 239000000843 powder Substances 0.000 claims description 5
- 208000011580 syndromic disease Diseases 0.000 claims description 5
- 230000001594 aberrant effect Effects 0.000 claims description 4
- 239000000443 aerosol Substances 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 4
- 239000002674 ointment Substances 0.000 claims description 4
- 239000006187 pill Substances 0.000 claims description 4
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 4
- 241000282326 Felis catus Species 0.000 claims description 3
- 241001494479 Pecora Species 0.000 claims description 3
- 230000005856 abnormality Effects 0.000 claims description 3
- 239000003963 antioxidant agent Substances 0.000 claims description 3
- 239000011248 coating agent Substances 0.000 claims description 3
- 239000002552 dosage form Substances 0.000 claims description 3
- 239000003995 emulsifying agent Substances 0.000 claims description 3
- 239000000839 emulsion Substances 0.000 claims description 3
- 239000008187 granular material Substances 0.000 claims description 3
- 239000006210 lotion Substances 0.000 claims description 3
- 206010025135 lupus erythematosus Diseases 0.000 claims description 3
- 239000000829 suppository Substances 0.000 claims description 3
- 239000000725 suspension Substances 0.000 claims description 3
- 239000003826 tablet Substances 0.000 claims description 3
- 208000022715 Autoinflammatory syndrome Diseases 0.000 claims description 2
- 241000282693 Cercopithecidae Species 0.000 claims description 2
- 208000010445 Chilblains Diseases 0.000 claims description 2
- 206010012735 Diarrhoea Diseases 0.000 claims description 2
- 206010058314 Dysplasia Diseases 0.000 claims description 2
- 241000283073 Equus caballus Species 0.000 claims description 2
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 claims description 2
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 claims description 2
- 239000004599 antimicrobial Substances 0.000 claims description 2
- 239000002216 antistatic agent Substances 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- 210000000845 cartilage Anatomy 0.000 claims description 2
- 238000000576 coating method Methods 0.000 claims description 2
- 239000003086 colorant Substances 0.000 claims description 2
- 239000007888 film coating Substances 0.000 claims description 2
- 238000009501 film coating Methods 0.000 claims description 2
- 239000000796 flavoring agent Substances 0.000 claims description 2
- 235000013355 food flavoring agent Nutrition 0.000 claims description 2
- 235000003599 food sweetener Nutrition 0.000 claims description 2
- 239000003979 granulating agent Substances 0.000 claims description 2
- 230000004957 immunoregulator effect Effects 0.000 claims description 2
- 208000036546 leukodystrophy Diseases 0.000 claims description 2
- 239000007937 lozenge Substances 0.000 claims description 2
- 239000000314 lubricant Substances 0.000 claims description 2
- 239000006072 paste Substances 0.000 claims description 2
- 239000008104 plant cellulose Substances 0.000 claims description 2
- 239000004014 plasticizer Substances 0.000 claims description 2
- 239000003755 preservative agent Substances 0.000 claims description 2
- 230000002207 retinal effect Effects 0.000 claims description 2
- 239000004094 surface-active agent Substances 0.000 claims description 2
- 239000000375 suspending agent Substances 0.000 claims description 2
- 239000003765 sweetening agent Substances 0.000 claims description 2
- 239000006188 syrup Substances 0.000 claims description 2
- 235000020357 syrup Nutrition 0.000 claims description 2
- 208000019553 vascular disease Diseases 0.000 claims description 2
- 208000010603 vasculitis due to ADA2 deficiency Diseases 0.000 claims description 2
- 241000124008 Mammalia Species 0.000 claims 2
- 206010003402 Arthropod sting Diseases 0.000 claims 1
- 208000003014 Bites and Stings Diseases 0.000 claims 1
- 230000000181 anti-adherent effect Effects 0.000 claims 1
- 239000003911 antiadherent Substances 0.000 claims 1
- 239000007884 disintegrant Substances 0.000 claims 1
- 239000004503 fine granule Substances 0.000 claims 1
- 239000011505 plaster Substances 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 18
- 108010050904 Interferons Proteins 0.000 abstract description 16
- 229940079322 interferon Drugs 0.000 abstract description 16
- 102000014150 Interferons Human genes 0.000 abstract description 15
- 230000000694 effects Effects 0.000 abstract description 14
- 108090000623 proteins and genes Proteins 0.000 abstract description 11
- 230000014509 gene expression Effects 0.000 abstract description 6
- 230000001404 mediated effect Effects 0.000 abstract description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 21
- 210000004979 bone marrow derived macrophage Anatomy 0.000 description 19
- 108020004999 messenger RNA Proteins 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 17
- 238000002474 experimental method Methods 0.000 description 16
- 102100035533 Stimulator of interferon genes protein Human genes 0.000 description 15
- 101000643024 Homo sapiens Stimulator of interferon genes protein Proteins 0.000 description 13
- 241000699670 Mus sp. Species 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 238000000034 method Methods 0.000 description 12
- XGOYIMQSIKSOBS-UHFFFAOYSA-N vadimezan Chemical compound C1=CC=C2C(=O)C3=CC=C(C)C(C)=C3OC2=C1CC(O)=O XGOYIMQSIKSOBS-UHFFFAOYSA-N 0.000 description 11
- RFCBNSCSPXMEBK-INFSMZHSSA-N c-GMP-AMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]3[C@@H](O)[C@H](N4C5=NC=NC(N)=C5N=C4)O[C@@H]3COP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 RFCBNSCSPXMEBK-INFSMZHSSA-N 0.000 description 10
- 229950008737 vadimezan Drugs 0.000 description 10
- 238000011282 treatment Methods 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 8
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 7
- 108020004414 DNA Proteins 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 239000006228 supernatant Substances 0.000 description 6
- 101001011382 Homo sapiens Interferon regulatory factor 3 Proteins 0.000 description 5
- 230000002159 abnormal effect Effects 0.000 description 5
- 239000006166 lysate Substances 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 208000023275 Autoimmune disease Diseases 0.000 description 4
- 101000858088 Homo sapiens C-X-C motif chemokine 10 Proteins 0.000 description 4
- 101001057508 Homo sapiens Ubiquitin-like protein ISG15 Proteins 0.000 description 4
- 102100029843 Interferon regulatory factor 3 Human genes 0.000 description 4
- 102000004889 Interleukin-6 Human genes 0.000 description 4
- 108090001005 Interleukin-6 Proteins 0.000 description 4
- 238000011529 RT qPCR Methods 0.000 description 4
- 101150061787 Trex1 gene Proteins 0.000 description 4
- 238000003119 immunoblot Methods 0.000 description 4
- 230000002757 inflammatory effect Effects 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 210000003205 muscle Anatomy 0.000 description 4
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 4
- 241000282472 Canis lupus familiaris Species 0.000 description 3
- 102100031256 Cyclic GMP-AMP synthase Human genes 0.000 description 3
- 108030002637 Cyclic GMP-AMP synthases Proteins 0.000 description 3
- 102100027266 Ubiquitin-like protein ISG15 Human genes 0.000 description 3
- 239000012190 activator Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 230000006698 induction Effects 0.000 description 3
- 208000027866 inflammatory disease Diseases 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- 102100022900 Actin, cytoplasmic 1 Human genes 0.000 description 2
- 108010085238 Actins Proteins 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical class N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 101000665442 Homo sapiens Serine/threonine-protein kinase TBK1 Proteins 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 102000015617 Janus Kinases Human genes 0.000 description 2
- 108010024121 Janus Kinases Proteins 0.000 description 2
- 102000007651 Macrophage Colony-Stimulating Factor Human genes 0.000 description 2
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 description 2
- 108010047956 Nucleosomes Proteins 0.000 description 2
- 239000012124 Opti-MEM Substances 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- 208000033273 Proteasome-associated autoinflammatory syndrome Diseases 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 102100038192 Serine/threonine-protein kinase TBK1 Human genes 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000013592 cell lysate Substances 0.000 description 2
- 230000033077 cellular process Effects 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 230000001086 cytosolic effect Effects 0.000 description 2
- 230000002074 deregulated effect Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 230000008482 dysregulation Effects 0.000 description 2
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 239000002799 interferon inducing agent Substances 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 210000001623 nucleosome Anatomy 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 230000035790 physiological processes and functions Effects 0.000 description 2
- 229940115272 polyinosinic:polycytidylic acid Drugs 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 208000017502 proteosome-associated autoinflammatory syndrome Diseases 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 210000000689 upper leg Anatomy 0.000 description 2
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 1
- 241000486679 Antitype Species 0.000 description 1
- 208000011594 Autoinflammatory disease Diseases 0.000 description 1
- 102100025248 C-X-C motif chemokine 10 Human genes 0.000 description 1
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000282994 Cervidae Species 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 108010069941 DNA receptor Proteins 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000283074 Equus asinus Species 0.000 description 1
- 241001658031 Eris Species 0.000 description 1
- 208000021655 Hereditary Autoinflammatory disease Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101150103227 IFN gene Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- 241000207923 Lamiaceae Species 0.000 description 1
- 206010049287 Lipodystrophy acquired Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 206010058105 Neutrophilic dermatosis Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 208000035977 Rare disease Diseases 0.000 description 1
- 208000037340 Rare genetic disease Diseases 0.000 description 1
- 241001529742 Rosmarinus Species 0.000 description 1
- 208000027066 STING-associated vasculopathy with onset in infancy Diseases 0.000 description 1
- 101710196623 Stimulator of interferon genes protein Proteins 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 108091021474 TMEM173 Proteins 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000010775 animal oil Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 210000002798 bone marrow cell Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000003759 clinical diagnosis Methods 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
- 230000016396 cytokine production Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940079360 enema for constipation Drugs 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000009760 functional impairment Effects 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 208000035474 group of disease Diseases 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 230000007124 immune defense Effects 0.000 description 1
- 230000008938 immune dysregulation Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 208000006132 lipodystrophy Diseases 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 244000000010 microbial pathogen Species 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- 235000014593 oils and fats Nutrition 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 230000008447 perception Effects 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 210000003200 peritoneal cavity Anatomy 0.000 description 1
- 239000003330 peritoneal dialysis fluid Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 230000001018 virulence Effects 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The application of carnosic acid or a derivative thereof in preparing a medicament for treating and/or preventing type I interferon, wherein the carnosic acid or the derivative thereof can inhibit the expression of type I interferon and the level of a downstream related gene by inhibiting the activation of a cGAS-STING signal pathway. And the carnosic acid or the derivatives thereof can be extracted from plants, have wide sources, high safety and obvious curative effect, and are very suitable for preparing the medicine for treating and/or preventing I-type interferon mediated diseases.
Description
Technical Field
The invention relates to the technical field of biomedicine, in particular to application of carnosic acid or a derivative thereof in preparing a medicament for treating and/or preventing type I interferon.
Background
The I-type interferon disease is a group of diseases with a new concept in recent decade, belongs to autoinflammatory diseases in immunodeficiency diseases, and is characterized by inflammatory injury caused by excessive activation expression of I-type interferon in vivo. I interferon diseases are a group of hereditary auto-inflammatory diseases characterized by dysregulation of the type I Interferon (IFN) pathway, resulting in functional impairment of various cells, tissues and organs.
STING (stimulator of interferon genes), also known as TMEM173, MITA, ERIS or MPYS, plays a critical role in the induction of interferon production in response to signals from cytoplasmic DNA receptors upon stimulation of cytoplasmic DNA. DNA recognition receptors of host cells recognize foreign or endogenous "non-self" DNA and transmit a signal to a node molecule STING on the endoplasmic reticulum, which then rapidly dimerizes and translocates from the endoplasmic reticulum to the nucleosome. In this process, the kinase TBK1 is also recruited and transferred to the nucleosome for activation, and the activated TBK1 phosphorylates the transcription factor IRF3, and then IRF3 dimerizes and enters the nucleus to activate the transcriptional expression of various target genes. Normally activated cGAS-STING signaling pathways help the body to recognize and eliminate invading DNA pathogenic microorganisms, but abnormally over-activated cGAS-STING signaling pathways cause inflammation and autoimmune diseases in the body, such as Aicardi-Goutieres syndrome, systemic lupus erythematosus or lupus-like diseases.
For the treatment of type I interferon diseases, it is of great significance to inhibit the production of type I interferon. Theoretically, the antibody of type I interferon is a potential treatment mode, in vitro tests show that the antibody of anti-type I interferon can prevent the over-expression of type I interferon and related genes thereof, and the interferon monoclonal antibody for treating systemic lupus erythematosus is currently shown to be in a phase II clinical experiment stage. In addition, studies have shown that treatment with Janus kinase (JAK) inhibitors and reverse transcriptase inhibitors can improve some of the related diseases mediated by type I interferon, such as AGS syndrome, but to date, the number of patients receiving treatment is very small, no data from clinical trials exist, and the effect of such drugs on central nervous system diseases is difficult to judge. Therefore, it is necessary to develop a highly effective and safe drug for treating type i interferon-related diseases.
Disclosure of Invention
The technical problem to be solved by the application is to find a medicine for treating I type interferon diseases with high efficiency, stability and good safety, and particularly, the application provides the application of carnosic acid or derivatives thereof in preparing medicines for treating and/or preventing I type interferon diseases.
In one aspect, carnosic acid or derivatives thereof herein include, but are not limited to, carnosic acid, carnosol, and rosmanol. Carnosic acid (CA; CAS No.: 3650-09-7; molecular formula: C20H28O4; molecular weight: 332.434; pale yellow powder; readily soluble in organic solvents such as DMSO; the structural formula I is shown below) and its derivative Carnosol (CAS No.: 5957-80-2; molecular formula: C20H26O4; molecular weight: 330.418; pale yellow powder; soluble in solvents such as methanol and DMSO; the structural formula II is shown below) and Rosmanol (Rosmanol; CAS No.: 80225-53-2; molecular formula: C20H26O5; molecular weight: 346.42; white powder soluble in solvents such as methanol and DMSO; the structural formula III is shown below) are components of rosemary belonging to the Labiatae family, and have good anti-inflammatory, antioxidant, antibacterial and antiviral activities.
Carnosic acid (formula i), carnosol (formula ii) and rosmanol (formula iii):
applicants found that carnosic acid specifically inhibits the abnormal activation of the cGAS-STING signaling pathway, significantly reducing the expression of downstream type i interferons and related genes such as CXCL10, ISG and IL-6. Meanwhile, carnosic acid significantly inhibited DMXAA-induced type i interferon levels in vivo studies, which provided a potential treatment regimen for patients with type i interferon-related diseases. In addition, carnosic acid can also effectively reduce Trex1 -/- Mouse-mediated levels of type i interferon and related genes. Notably, the inventors also found that carnosol, a downstream product of carnosic acid, and rosmanol act specifically on the cGAS-STING signaling pathway, inhibiting the production of type i interferon. The above results all suggest that carnosic acid or its derivatives may be a candidate for the treatment and/or prevention of type i interferon diseases.
The present application has the following gain effects:
the application provides an application of carnosic acid or a derivative thereof in preparing a medicament for treating and/or preventing type I interferon. A large number of experiments show that carnosic acid or a derivative thereof can inhibit the expression of type I interferon at a cellular level by inhibiting the activation of a cGAS-STING signaling pathway. Further research shows that in vivo experiment, carnosic acid can effectively inhibit the over-activation of type I interferon and improve Trex1 -/- Levels of mouse self type i interferon and downstream related genes. The carnosic acid or the derivatives thereof including carnosol and rosmanol can be extracted from plants, have wide sources, high safety and obvious curative effect, and are very suitable for preparing the medicine for treating and/or preventing I-type interferon mediated diseases.
Additional features and advantages of the application will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by the practice of the application. Other advantages of the present application may be realized and attained by the instrumentalities and combinations particularly pointed out in the specification and the drawings.
Drawings
The drawings are intended to provide an understanding of the present disclosure, and are to be considered as forming a part of the specification, and are to be used together with the embodiments of the present disclosure to explain the present disclosure without limiting the present disclosure.
FIG. 1 is a graph showing the results of the inhibitory effect of carnosic acid on cGAS-STING signaling pathway activity in mouse BMDM (bone marrow-derived macrophage) cells in one embodiment of the present application. Wherein HT-DNA, poly (I: C), cGAMP and DMXAA are activators of cGAS-STING signaling pathway, p-IRF3 is a phosphorylated form of IRF3 protein, and p-STING is a phosphorylated form of STING protein. An increase in p-IRF3 and p-STING represents an increased degree of activation of the cGAS-STING signaling pathway.
FIG. 2 is a graph showing the results of the inhibitory effect of carnosic acid on cGAS-STING signaling pathway activity in human PBMC (peripheral blood mononuclear cells) cells in one embodiment of the present application.
FIG. 3 is a graph showing the results of the inhibitory effect of carnosic acid on type I interferon mRNA levels in mouse BMDM cells in one embodiment of the present application. Wherein DMSO was blank control and CA was carnosic acid treated group.
FIG. 4 is a graph showing the results of the inhibitory effect of carnosic acid on type I interferon mRNA levels in human PBMC cells in one embodiment of the present application.
FIG. 5 is a graph showing the results of the inhibitory effect of carnosic acid or its derivatives carnosol and rosmanol on cGAS-STING signaling pathway activity in BMDM in one embodiment of the present application.
Figures 6A-6B are graphs showing the results of the inhibition of abnormal increases in interferon inducer, such as DMXAA, induced type i interferon levels by carnosic acid in mice, where figure 6A is the level of type i interferon in serum and figure 6B is the level of type i interferon in the abdominal cavity, in one embodiment of the present application.
FIGS. 7A-7B show carnosic acid versus Trex1 in an embodiment of the present application -/- Results of the inhibitory effect on the mRNA level of type I interferon (FIG. 7A) and downstream gene ISG15 (FIG. 7B) in cells are shown. Wherein WT is a wild typeMouse, KO is Trex1 -/- A mouse.
FIG. 8 shows the carnosic acid pair Trex1 in one embodiment of the present application -/- Results of the inhibitory effect of type I interferon and mRNA levels of the related genes CXCL10, ISG15, IL-6 and TNF-. Alpha.in the heart of mice.
FIG. 9 shows the carnosic acid pair Trex1 in one embodiment of the present application -/- Results of the inhibitory effect of type I interferon and mRNA levels of the related genes CXCL10, ISG15, IL-6 and TNF-. Alpha.in mouse muscle tissue are shown.
FIG. 10 shows the carnosic acid pair Trex1 in one embodiment of the present application -/- Results of the inhibition of type I interferon and mRNA levels of the related genes CXCL10, ISG15, IL-6 and TNF-alpha in the mouse tongue.
Detailed Description
In many organisms, detection of foreign DNA is a key factor in immunity. In mammalian cells, this task is largely performed by the cyclic GMP-AMP synthase (cGAS) -interferon gene Stimulator (STING) pathway, which has become a key mechanism coupling DNA sensing and induction of a powerful innate immune defense program. It is noteworthy, however, that dysregulation of this highly versatile innate immune perception system may trigger aberrant activation of the cGAS-STING pathway, with concomitant production of type i interferons in large quantities, thereby mediating a variety of inflammatory and autoimmune diseases.
Type I autoinflammatory interferon disease is a genetically defined (monogenic or bigenic) immune dysregulation disease characterized by the presence of type I interferon signaling and variable systemic inflammation in the peripheral blood. Of this expanding group of rare diseases, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated body temperature/proteasome associated autoinflammatory syndrome (CANDLE/PRAAS), interferon gene stimulating factor (STING) -associated infantile vasculopathy (SAVI) and Aicardi-Goutieres syndrome (AGS) are the most common. AGS often presents as a rare genetic disease with major nervous system and skin involvement, and with the understanding of disease, significant clinical and genetic heterogeneity is gradually discovered. To date, 7 AGS virulence genes have been discovered, with the Trex1 gene being significantly representative.
Accordingly, the present application provides the use of carnosic acid or a derivative thereof in the manufacture of a medicament for the treatment and/or prophylaxis of type i interferon. The carnosic acid or the derivatives thereof provided by the application can inhibit or prevent abnormal activation of a cGAS-STING signaling pathway to trigger the rise of type I interferon, so as to cause inflammatory or autoimmune diseases. Optionally an inflammatory or autoimmune disease caused by a Trex1 gene deficiency, such as AGS syndrome.
The term "derivative" may refer to any compound having the same or similar core structure as the compound, but having at least one structural difference (including substitution, deletion, and/or addition of one or more atoms or functional groups).
In some embodiments, the carnosic acid or derivative thereof is carnosic acid, carnosol, and rosmanol represented by the following structural formula:
in some embodiments, the medicament prepared herein may comprise a pharmaceutically acceptable salt of carnosic acid or a derivative thereof. In some embodiments, the prepared medicament may also comprise other carnosic acid derivatives and pharmaceutically acceptable salts thereof. A "pharmaceutically acceptable salt" is a salt of a compound that can be formulated for pharmaceutical use, including, for example, metal salts (sodium, potassium, magnesium, calcium, etc.) and salts of ammonia or organic amines.
In some embodiments, the type i interferon disease comprises Aicardi-Goutieres syndrome, adenosine deaminase 2 deficiency, systemic lupus erythematosus, STING-related infantile onset vascular disease, proteasome-related autoinflammatory syndrome, symptomatic diarrhea/trihaloentero syndrome, X-linked reticuloendodermia, spinal cartilage dysplasia with immunoregulatory abnormalities, familial lupus chilblain, and retinal vasculopathy with leukodystrophy.
In some embodiments, the agents prepared herein are inhibitors that inhibit aberrant activation of the cGAS-STING signaling pathway. The abnormal activation of the cGAS-STING signaling pathway includes Trex1 gene variation, such as Trex1 gene defect, and induction of interferon inducer. Aberrant activation of the cGAS-STING signaling pathway can induce a variety of diseases and complications, including but not limited to AGS syndrome. Inhibitors refer to compounds that inhibit, partially or totally block stimulation or activation, decrease, arrest, delay activation, inactivate, desensitize, or down regulate physiological/cellular processes. An activator refers to a compound that induces, activates, stimulates, increases, promotes, enhances activation, sensitizes, or upregulates at least one physiological/cellular process. The inhibitor prepared in the application can reduce the level of type I interferon by inhibiting the abnormal activation of a cGAS-STING signaling pathway.
In some embodiments, the medicament prepared in the present application is administered orally, intravenously, intradermally, transdermally, intrathecally, intraarterially, intraperitoneally, intranasally, intravaginally, intrarectally, intravesically, intratumorally, topically, intramuscularly, subcutaneously, mucosally, by inhalation, by injection, by infusion, or any combination of the foregoing.
In some embodiments, the dosage form of the medicament prepared herein includes capsules, tablets, pills, liquids, powders, granules, fine granules, film coatings, pills, lozenges, sublingual agents, peptizers, buccal preparations, pastes, syrups, suspensions, elixirs, emulsions, coatings, ointments, plasters, poultices, transdermal preparations, lotions, inhalants, aerosols, injections, or suppositories.
In some embodiments, the medicament prepared herein further comprises a pharmaceutically acceptable excipient. By "pharmaceutically acceptable excipient" is meant an excipient that is generally safe, non-toxic, and desirable for use in preparing a pharmaceutical composition, and includes excipients that are acceptable for veterinary use as well as for human pharmaceutical use. Such excipients may be solid, liquid, semi-solid, or in the case of aerosol compositions, gaseous. Pharmaceutically acceptable organic or inorganic carriers and/or diluents suitable for oral and topical use can be used to formulate compositions containing the therapeutically active compounds. Diluents known in the art include aqueous media, vegetable and animal oils and fats. Stabilizers, wetting and emulsifying agents, salts for varying the osmotic pressure or buffers for ensuring a suitable pH value, and skin penetration enhancers may be used as adjuvants. Non-limiting examples of excipients include granulating agents, binders, lubricants, disintegrating agents, sweetening agents, glidants, anti-sticking agents, antistatic agents, surfactants, antioxidants, gums, coating agents, coloring agents, flavoring agents, plasticizers, preservatives, suspending agents, emulsifying agents, antimicrobial agents, plant cellulose materials and spheronizing agents and any combination thereof.
In some embodiments, carnosic acid or a derivative or pharmaceutically acceptable salt thereof may be suitably prepared as pharmaceutical compositions and unit dosage forms for use as: solid (e.g., tablets or filled capsules) or liquid (e.g., solutions, suspensions, emulsions, elixirs or capsules filled therewith) for oral use, in the form of ointments, suppositories, or enemas for rectal administration, in the form of sterile injectable solutions for parenteral use (e.g., intramuscular, subcutaneous, intravenous, epidural, intraarticular, and intrathecal administration); or in the form of ointments, lotions, creams, gels, patches, sublingual strips or films, etc., for parenteral (e.g., topical, buccal, sublingual, vaginal) administration.
In some embodiments, the pharmaceutical formulations prepared in the present application can be administered intravenously, intradermally, transdermally, intrathecally, intraarterially, intraperitoneally, intranasally, intravaginally, intrarectally, intravesically (e.g., directly administered into the bladder, such as by injection or by intravesical instillation), intratumorally, topically, intramuscularly, subcutaneously, mucosally, orally, topically, by inhalation (e.g., aerosol inhalation), by injection, by infusion, by continuous infusion, via a catheter, via lavage in cream, by direct local infusion in a liquid composition (e.g., liposomes), or by other methods as known to one of ordinary skill in the art, or any combination of the foregoing.
In some embodiments, the carnosic acid or derivative thereof is administered to the subject at a dose of 1-50mg/kg/d. In some embodiments, the dose of carnosic acid or derivative thereof administered to the subject daily is selected from the group consisting of: about 1.0mg/kg, about 2.0mg/kg, about 3.0mg/kg, about 4.0mg/kg, about 5.0mg/kg, about 6.0mg/kg, about 7.0mg/kg, about 8.0mg/kg, about 9.0mg/kg, about 10.0mg/kg, about 11.0mg/kg, about 12.0mg/kg, about 13.0mg/kg, about 14.0mg/kg, about 15.0mg/kg, about 16.0mg/kg, about 17.0mg/kg, about 18.0mg/kg, about 19.0mg/kg, about 20.0mg/kg, about 22.5mg/kg, about 25.0mg/kg, about 27.5mg/kg, about 30.0mg/kg, about 32.5mg/kg, about 35.0mg/kg, about 37.5mg/kg, about 40.0mg/kg, about 5.42 mg/kg, about 50mg/kg, about 50.0mg/kg.
In some embodiments, the subject herein is a human, rat, mouse, cat, dog, horse, sheep, cow, monkey. In some embodiments, illustrative examples of subjects include primates, particularly humans, companion animals such as cats and dogs and the like, working animals such as horses, donkeys and the like, livestock animals such as sheep, cattle, goats, pigs and the like, laboratory test animals such as rabbits, mice, rats, guinea pigs, hamsters and the like, and captive wild animals such as captive wild animals in zoos and wilderness parks, deer, australian wild dogs and the like. In some embodiments, the subject is a human.
The following detailed description of embodiments of the present application will be described in detail with reference to the accompanying drawings and examples.
The present application describes embodiments, but the description is illustrative rather than limiting and it will be apparent to those of ordinary skill in the art that many more embodiments and implementations are possible within the scope of the embodiments described herein. Although many possible combinations of features are shown in the drawings and discussed in the detailed description, many other combinations of the disclosed features are possible. Any feature of any embodiment may be used in combination with, or instead of, any other feature in any other embodiment, unless expressly limited otherwise.
This application includes and contemplates combinations of features known to those of ordinary skill in the art. The embodiments and features disclosed in this application can also be combined with any conventional features to form a unique inventive concept as defined by the claims. Any feature of any embodiment may also be combined with features from other inventive aspects to form yet another unique inventive aspect, as defined by the claims. Thus, it should be understood that any of the features shown and/or discussed in this application may be implemented individually or in any suitable combination. Accordingly, the embodiments are not limited except as by the appended claims and their equivalents. Furthermore, various modifications and changes may be made within the scope of the appended claims.
Further, in describing representative embodiments, the specification may have presented the method and/or process as a particular sequence of steps. However, to the extent that the method or process does not rely on the particular order of steps set forth herein, the method or process should not be limited to the particular sequence of steps described. Other orders of steps are possible as will be understood by those of ordinary skill in the art. Therefore, the particular order of the steps set forth in the specification should not be construed as limitations on the claims. Further, the claims directed to the method and/or process should not be limited to the performance of their steps in the order written, and one skilled in the art can readily appreciate that the sequences may be varied and still remain within the spirit and scope of the embodiments of the present application.
The experimental methods of the following examples, which are not specified under specific conditions, are generally determined according to national standards. The experimental materials not shown in the following examples are all commercially available materials. The equipment used in the steps in the following examples is conventional. If there is no corresponding national standard, it is carried out according to the usual international standards, to the conventional conditions or to the conditions recommended by the manufacturer. Unless defined or indicated otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. Carnosic acid or its derivatives used in the examples of this application are all available from TargetMol.
Example 1: carnosic acid significantly inhibited cGAS-STING signaling pathway activity in mouse BMDM and human PBMC cells
1 experimental method:
bone marrow cells were isolated from mouse thigh femurs and cultured in DMEM (dulbecco's modified eagle medium) containing growth factor MCSF (macrophage colony stimulating factor) to completely differentiate into mouse bone marrow macrophages (BMDMs) (10% FBS,1% penicillin/streptomycin). Subsequently, BMDMs were seeded in 12-well plates at a density of 1.2X106/ml overnight. The following day, cells were treated with carnosic acid (10 uM) for 1 hour, and then stimulated with several different cGAS-STING signaling pathway activators such as HT-DNA, poly (I: C), cGAMP and DMXAA (Vadimezan) for 2 hours. Subsequently, the supernatant was discarded, washed 3 times with PBS, and then the cells were lysed with RIPA (Radio immunopropraction Assay) lysate, and the inhibition of cGAS-STING signaling pathway by carnosic acid was evaluated by immunoblotting.
Similarly, hPBMC cells isolated from healthy volunteers were resuspended in serum-free opti-MEM and seeded at a density of 3 × 106/ml in 12-well plates, starved for 2 hours, and allowed to adhere better. Subsequently, the medium was replaced with 1640 medium (10% FBS,1% penicillin/streptomycin) and incubated overnight. The following day, carnosic acid diluted in opti-MEM (2.5, 5,10 uM) was treated for 1 hour, then HT-DNA was added for stimulation for 2 hours, then, the supernatant was discarded, washed 3 times with PBS, then the cells were lysed with RIPA lysate, and inhibition of the cGAS-STING signaling pathway by carnosic acid was assessed by immunoblotting.
Immunoblotting detection of expression of cGAS/STING signal pathway related protein
Western blot assay: and (3) detecting the protein levels of phosphorylated IRF3, phosphorylated STING, STING and beta-Actin in the cell lysate.
2. The experimental results are as follows:
the results of the above experiments are shown in FIG. 1, and in BMDMs, carnosic acid has a significant inhibitory effect on HT-DNA, cGAMP and DMXAA or induced cGAS-STING signaling pathway activation. As shown in FIG. 2, in human PBMC cells, carnosic acid significantly inhibited the HT-DNA, cGAMP and DIABZI-induced activation of the cGAS-STING signaling pathway.
Example 2: carnosic acid has good inhibition effect on the increase of the mRNA level of I-type interferon accompanied with the activation of cGAS-STING signal pathway in mouse BMDM and human PBMC cells
The experimental method comprises the following steps:
the experimental procedure of example 2 was similar to that of example 1, and BMDMs cells were stimulated with HT-DNA, cGAMP and DMXAA for 2 hours after 1 hour of treatment with carnosic acid (10 uM). Subsequently, the supernatant was discarded, washed three times with PBS, and then the cells were lysed with Trizol, an RNA lysate, and inhibition of mRNA level of IFN after cGAS-STING signaling pathway activation by carnosic acid was evaluated by qPCR. Similarly, human hBMC cells were stimulated with HT-DNA, cGAMP and DIABZI for 2 hours after 1 hour of carnosic acid (10 uM) treatment. Subsequently, the supernatant was discarded, washed three times with PBS, and then the cells were lysed with Trizol, and the suppression of mRNA levels of type i interferon by carnosic acid after activation of cGAS-STING signaling pathway was evaluated by qPCR.
The experimental results are as follows:
the results of the above experiments are shown in FIG. 3, and carnosic acid significantly inhibited HT-DNA, cGAMP and DMXAA-induced IFN gene mRNA levels in BMDMs. In addition, as shown in FIG. 4, carnosic acid also had significant inhibitory effects on HT-DNA, cGAMP and DIABZI-induced type I interferon gene mRNA levels in human PBMC cells.
Example 3: carnosic acid or derivatives thereof, carnosol and rosmanol remarkably inhibit cGAS-STING signaling pathway activity in mouse BMDMs
1. The experimental method comprises the following steps:
BMDMs collected and fully differentiated from the mouse femur were seeded overnight in 12-well plates at a density of 1.2x106/ml. The following day, cells were treated with carnosic acid, carnosol and rosmanol for 1 hour, respectively, and then treated with HT-DNA and cGAMP for 2 hours. Subsequently, the supernatant was completely discarded, washed 3 times with PBS, and then the cells were lysed with RIPA lysate. Samples were collected and cell lysates were analyzed by immunoblotting for protein levels of phosphorylated IRF3, phosphorylated STING, β -Actin to assess the effect of carnosic acid or its derivatives carnosol and rosmanol on cGAS-STING signaling pathway activation.
The experimental results are as follows:
the results of the above experiments are shown in FIG. 5, and in BMDMs, carnosic acid or its derivatives, carnosol and rosmanol, can specifically inhibit the activities of HT-DNA and cGAMP-induced cGAS-STING signaling pathways.
Example 4: in mice, carnosic acid has remarkable inhibitory effect on the level of IFN induced by DMXAA
The experimental method comprises the following steps:
approximately 8 weeks of C57BL/6 mice were purchased from Steps Bei Fu Biotechnology, inc. and were acclimatized for one week in advance. Mice were randomly divided into blank, model and carnosic acid treated groups, 6 per group. Mice were pre-treated with different doses of carnosic acid (15 mg/kg, 30 mg/kg) by intraperitoneal injection for 1 hour. Subsequently, DMXAA was prepared at a concentration of 30mg/kg and the mice were treated by intraperitoneal injection for 5 hours. Mouse serum, peritoneal lavage fluid and peritoneal cells were collected. The inhibitory effect of carnosic acid on DMXAA-induced type i interferon levels was evaluated.
Results of the experiment
Experimental results as shown in part 6A, carnosic acid significantly inhibited DMXAA-induced IFN levels in serum. In addition, as shown in fig. 6B, carnosic acid also had a significant inhibitory effect on type i interferon levels in the peritoneal cavity.
Example 5: carnosic acid remarkably inhibits Trex1 -/- Type I interference in BMDMsmRNA level of hormone
The experimental method comprises the following steps:
wild type mouse (WT) BMDMs and Trex1 -/- BMDMs at 1.2x10 6 The cells were seeded in 12-well plates overnight at a density of one/ml. WT BMDMs were blanked. The next day, treatment with carnosic acid (10 uM) was performed for 10 hours. Subsequently, cells were lysed with Trizol, and after collecting samples, carnosic acid was evaluated for Trex1 by qPCR -/- Inhibition of type I interferon mRNA levels in BMDMs.
Results of the experiment
The experimental results are shown in fig. 7A-7B, and carnosic acid significantly inhibited Trex1 -/- mRNA levels of type I interferons in BMDMs.
Example 6: carnosic acid p-Trex 1 -/- The mRNA level of the type I interferon in tissues such as heart, muscle, tongue and the like of mice has obvious inhibiting effect
The experimental method comprises the following steps:
selecting WT mice and Trex1 with the size of 4 weeks -/- Mice, with WT mice as a blank, 3 mice per group. Trex1 -/- Mice were treated with carnosic acid (20 mg/kg), injected intraperitoneally, and treated continuously for 2 weeks. After dosing, the mouse heart, muscle, tongue, etc. tissues were removed and a small portion was lysed in Trizol, after tissue homogenization, the supernatant was aspirated as RNA lysate and evaluated for Trex1 by qPCR for carnosic acid -/- Inhibition of type I interferon mRNA levels in mouse tissues.
The experimental results are as follows:
the above results are shown in FIG. 8, trex1 -/- The mRNA levels of type i interferon in the mouse heart were significantly inhibited after carnosic acid treatment. Likewise, as shown in fig. 9, trex1 -/- The mRNA level of type I interferon in mouse muscle tissue was inhibited by carnosic acid. Similarly, as shown in fig. 10, trex1 -/- The mRNA levels of type i interferon in the mouse tongue were inhibited by carnosic acid.
As can be seen from the above examples, the application provides a potential therapeutic scheme for type I interferon-mediated diseases by carnosic acid or derivatives thereof, which provides important reference for clinical diagnosis and therapeutic scheme. However, the present application is not limited to the above detailed features and the enumerated types of diseases resulting from deregulated cGAS-STING activity. It will be apparent to those skilled in the art that any modification of the present application, as well as the increased detection of disease types resulting from deregulated cGAS-STING activity, and the like, are within the scope of the protection and disclosure of the present application.
Claims (10)
1. Application of carnosic acid or its derivatives in preparing medicine for treating and/or preventing type I interferon is provided.
3. use according to claim 1, wherein the carnosic acid or derivative thereof is present in the form of a pharmaceutically acceptable salt thereof.
4. The use according to claim 1, wherein the type i interferon disease is selected from one or more of Aicardi-Goutieres syndrome, adenosine deaminase 2 deficiency, systemic lupus erythematosus, STING-related infantile onset vascular disease, proteasome-related autoinflammatory syndrome, symptomatic diarrhea/trimaran syndrome, X-linked reticuloendochrome abnormality, spinal cartilage dysplasia with immunoregulatory abnormality, familial lupus chilblain, and retinal vasculopathy with leukodystrophy.
5. The use of claim 1, wherein the medicament is an inhibitor that inhibits aberrant activation of the cGAS-STING signaling pathway.
6. The use of any one of claims 1-5, wherein the medicament is administered orally, intravenously, intradermally, transdermally, intrathecally, intraarterially, intraperitoneally, intranasally, intravaginally, intrarectally, intravesically, intratumorally, topically, intramuscularly, subcutaneously, mucosally, by inhalation, by injection, by infusion, or any combination thereof.
7. The use of any one of claims 1-5, wherein the medicament is in a dosage form selected from one or more of a capsule, tablet, pill, liquid, powder, granule, fine granule, film coating, pill, lozenge, sublingual, peptizer, buccal, paste, syrup, suspension, elixir, emulsion, coating, ointment, plaster, poultice, transdermal, lotion, inhalant, aerosol, injection, or suppository.
8. The use according to any one of claims 1-5, wherein the medicament further comprises a pharmaceutically acceptable excipient selected from one or more of granulating agents, binders, lubricants, disintegrants, sweetening agents, glidants, anti-adherents, antistatic agents, surfactants, antioxidants, gums, coating agents, coloring agents, flavoring agents, plasticizers, preservatives, suspending agents, emulsifying agents, antimicrobial agents, plant cellulose materials or spheronizing agents and any combination thereof.
9. The use of any one of claims 1-5, wherein the carnosic acid or derivative thereof is administered at a dose of 1-50mg/kg/d in the subject.
10. The use of claim 9, wherein the subject is a mammal, optionally the mammal is a human, rat, mouse, cat, dog, horse, sheep, cow, or monkey.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202211449124.9A CN115737617A (en) | 2022-11-18 | 2022-11-18 | Application of carnosic acid or derivatives thereof in preparing medicament for treating and/or preventing type I interferon |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202211449124.9A CN115737617A (en) | 2022-11-18 | 2022-11-18 | Application of carnosic acid or derivatives thereof in preparing medicament for treating and/or preventing type I interferon |
Publications (1)
Publication Number | Publication Date |
---|---|
CN115737617A true CN115737617A (en) | 2023-03-07 |
Family
ID=85373709
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202211449124.9A Pending CN115737617A (en) | 2022-11-18 | 2022-11-18 | Application of carnosic acid or derivatives thereof in preparing medicament for treating and/or preventing type I interferon |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN115737617A (en) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102861003A (en) * | 2011-07-05 | 2013-01-09 | 周应军 | Application of carnosic acid and its pharmaceutically acceptable salts in preparing medicines for preventing or treating cerebral infarction |
CN105324114A (en) * | 2013-03-19 | 2016-02-10 | 乐康瑞德有限公司 | Astaxanthin anti-inflammatory synergistic combinations |
CN107823196A (en) * | 2017-11-24 | 2018-03-23 | 广西医科大学 | Application of the carnosic acid in terms for the treatment of medicine for treating rheumatoid arthritis is prepared |
CN110227075A (en) * | 2019-07-01 | 2019-09-13 | 中国人民解放军总医院第五医学中心 | Purposes of the carnosol as inflammation corpusculum inhibitor |
CN111437279A (en) * | 2020-05-18 | 2020-07-24 | 中国科学院昆明动物研究所 | Application of HUWE1 inhibitor BI8626 in preparation of medicines for inhibiting activation of inflammasome |
-
2022
- 2022-11-18 CN CN202211449124.9A patent/CN115737617A/en active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102861003A (en) * | 2011-07-05 | 2013-01-09 | 周应军 | Application of carnosic acid and its pharmaceutically acceptable salts in preparing medicines for preventing or treating cerebral infarction |
CN105324114A (en) * | 2013-03-19 | 2016-02-10 | 乐康瑞德有限公司 | Astaxanthin anti-inflammatory synergistic combinations |
CN107823196A (en) * | 2017-11-24 | 2018-03-23 | 广西医科大学 | Application of the carnosic acid in terms for the treatment of medicine for treating rheumatoid arthritis is prepared |
CN110227075A (en) * | 2019-07-01 | 2019-09-13 | 中国人民解放军总医院第五医学中心 | Purposes of the carnosol as inflammation corpusculum inhibitor |
CN111437279A (en) * | 2020-05-18 | 2020-07-24 | 中国科学院昆明动物研究所 | Application of HUWE1 inhibitor BI8626 in preparation of medicines for inhibiting activation of inflammasome |
Non-Patent Citations (4)
Title |
---|
QING CHEN等.: ""Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer"", NATURE, vol. 533, no. 7604, pages 493 - 498 * |
TIEJUN LI等.: ""Antitumor Activity of cGAMP via Stimulation of cGAS-cGAMP-STING-IRF3 Mediated Innate Immune Response"", SCIENTIFIC REPORTS, vol. 6, no. 19049, pages 1 - 11 * |
王威,宋洋.: ""鼠尾草酚抗肿瘤活性机制的研究进展"", 华西药学杂志, vol. 33, no. 4, pages 429 - 434 * |
罗成,等.: ""鼠尾草酸药理作用的研究进展"", 中药药理与临床, vol. 36, no. 2, pages 271 - 276 * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1484059B1 (en) | Antiviral compositions comprising phenylacetic acid derivatives | |
KR20080085839A (en) | Compounds having cytokine modulating properties | |
US20080300253A1 (en) | Treatment of inflammatory disorders with praziquantel | |
JP6453441B2 (en) | Protein phosphatase 2A inhibitor for the treatment of myelodysplastic syndrome | |
AU2022210132A1 (en) | Anti-viral agent | |
CN114599357A (en) | Treatment of arthritis | |
EP0878192B1 (en) | Treating protozoal infections | |
KR20070103456A (en) | USE OF ESTROGEN RECEPTOR-beta; SELECTIVE AGONISTS FOR RADIATION-OR CHEMOTHERAPY-INDUCED MUCOSITIS AND RADIATION CYSTITIS | |
CN115737617A (en) | Application of carnosic acid or derivatives thereof in preparing medicament for treating and/or preventing type I interferon | |
WO2009019473A1 (en) | Treatments for inflammatory arthritis | |
US3560619A (en) | Aminoquinazolines and quinazolones in treatment of coccidiosis | |
KR101247802B1 (en) | Composition for preventing and treating inflammatory disease comprising piperine or pharmaceutically acceptable salt thereof as an active ingredient | |
CN115645385A (en) | Application of licochalcone B in preparation of medicine for treating and/or preventing type I interferon | |
US11364256B2 (en) | Viral inhibition | |
US20220339233A1 (en) | Compositions and methods for preventing recurrence of cancer | |
EP0215200B1 (en) | Use of sulfanilamido quinoxalines in the treatment of neoplastic diseases | |
AU774981B2 (en) | Thiazolopyrimidines useful as TNFalpha inhibitors | |
CN115190800A (en) | Application of BRD4 inhibitor | |
CN114762694A (en) | Use of oligosaccharyl transferase inhibitors for the prevention and/or treatment of novel coronavirus infections | |
JP4781624B2 (en) | RANTES inducer | |
JPWO2020004404A1 (en) | IL-1β inhibitor | |
KR100457113B1 (en) | Radiosensitizer containing ceramides or derivatives thereof and dimethylsphingosine as the active ingredient | |
KR101606885B1 (en) | Pharmaceutical composition for preventing and treating allergic disease comprising adenine or pharmaceutically acceptable salt thereof as an active ingredient | |
CN113197887B (en) | Application of 5-hydroxymethylfurfural in preparation of antiviral drugs | |
RU2717246C1 (en) | Ethyl 4-(5-benzoyl-6-(4-(diethylamino)phenyl)-4-hydroxy-2-thioxohexahydropyrimidin-4-carboxamino)benzoate, exhibiting analgesic and anti-inflammatory action |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |