CN113750086A - 去氧穿心莲内酯在制备过氧化物酶体增殖物激活受体拮抗剂中的应用 - Google Patents
去氧穿心莲内酯在制备过氧化物酶体增殖物激活受体拮抗剂中的应用 Download PDFInfo
- Publication number
- CN113750086A CN113750086A CN202111105761.XA CN202111105761A CN113750086A CN 113750086 A CN113750086 A CN 113750086A CN 202111105761 A CN202111105761 A CN 202111105761A CN 113750086 A CN113750086 A CN 113750086A
- Authority
- CN
- China
- Prior art keywords
- deoxyandrographolide
- ppar
- alpha
- peroxisome proliferator
- transcriptional activity
- 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
- GVRNTWSGBWPJGS-YSDSKTICSA-N 4-[2-[(1r,4as,5r,6r,8as)-6-hydroxy-5-(hydroxymethyl)-5,8a-dimethyl-2-methylidene-3,4,4a,6,7,8-hexahydro-1h-naphthalen-1-yl]ethyl]-2h-furan-5-one Chemical compound C([C@H]1[C@]2(C)CC[C@@H](O)[C@]([C@H]2CCC1=C)(CO)C)CC1=CCOC1=O GVRNTWSGBWPJGS-YSDSKTICSA-N 0.000 title claims abstract description 58
- GVRNTWSGBWPJGS-UHFFFAOYSA-N deoxyandrographolide Natural products C=C1CCC2C(C)(CO)C(O)CCC2(C)C1CCC1=CCOC1=O GVRNTWSGBWPJGS-UHFFFAOYSA-N 0.000 title claims abstract description 57
- 239000002508 peroxisome proliferator activated receptor antagonist Substances 0.000 title description 2
- 102000023984 PPAR alpha Human genes 0.000 claims abstract description 55
- 108091008725 peroxisome proliferator-activated receptors alpha Proteins 0.000 claims abstract description 53
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 claims abstract description 27
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 claims abstract description 27
- 230000002103 transcriptional effect Effects 0.000 claims abstract description 27
- 239000000556 agonist Substances 0.000 claims abstract description 16
- 239000005557 antagonist Substances 0.000 claims abstract description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 16
- 239000003112 inhibitor Substances 0.000 claims description 16
- 201000010099 disease Diseases 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 14
- 102000005962 receptors Human genes 0.000 claims description 9
- 108020003175 receptors Proteins 0.000 claims description 9
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 5
- 208000017759 head and neck paraganglioma Diseases 0.000 claims description 5
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 5
- 201000002528 pancreatic cancer Diseases 0.000 claims description 5
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 5
- 208000005017 glioblastoma Diseases 0.000 claims description 4
- 206010012601 diabetes mellitus Diseases 0.000 claims description 2
- 208000035475 disorder Diseases 0.000 claims description 2
- 230000008482 dysregulation Effects 0.000 claims description 2
- 208000032839 leukemia Diseases 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 34
- YMTINGFKWWXKFG-UHFFFAOYSA-N fenofibrate Chemical compound C1=CC(OC(C)(C)C(=O)OC(C)C)=CC=C1C(=O)C1=CC=C(Cl)C=C1 YMTINGFKWWXKFG-UHFFFAOYSA-N 0.000 abstract description 22
- 229960002297 fenofibrate Drugs 0.000 abstract description 21
- 230000002401 inhibitory effect Effects 0.000 abstract description 11
- 230000001419 dependent effect Effects 0.000 abstract description 6
- 230000007423 decrease Effects 0.000 abstract 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 30
- 210000004027 cell Anatomy 0.000 description 22
- 238000001890 transfection Methods 0.000 description 11
- 239000005089 Luciferase Substances 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- 108060001084 Luciferase Proteins 0.000 description 7
- 244000118350 Andrographis paniculata Species 0.000 description 6
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 6
- 239000001963 growth medium Substances 0.000 description 6
- 239000013612 plasmid Substances 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 5
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 4
- 102000007399 Nuclear hormone receptor Human genes 0.000 description 4
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 4
- 108010028924 PPAR alpha Proteins 0.000 description 4
- 230000006907 apoptotic process Effects 0.000 description 4
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 4
- 238000012258 culturing Methods 0.000 description 4
- 230000002708 enhancing effect Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 230000037361 pathway Effects 0.000 description 4
- 241000746375 Andrographis Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 241000411851 herbal medicine Species 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 230000003211 malignant effect Effects 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 230000005758 transcription activity Effects 0.000 description 3
- IGXWBGJHJZYPQS-SSDOTTSWSA-N D-Luciferin Chemical compound OC(=O)[C@H]1CSC(C=2SC3=CC=C(O)C=C3N=2)=N1 IGXWBGJHJZYPQS-SSDOTTSWSA-N 0.000 description 2
- 241000254158 Lampyridae Species 0.000 description 2
- 241000589902 Leptospira Species 0.000 description 2
- 108010057466 NF-kappa B Proteins 0.000 description 2
- 102000003945 NF-kappa B Human genes 0.000 description 2
- 102100022935 Nuclear receptor corepressor 1 Human genes 0.000 description 2
- 101710153661 Nuclear receptor corepressor 1 Proteins 0.000 description 2
- 102100030569 Nuclear receptor corepressor 2 Human genes 0.000 description 2
- 101710153660 Nuclear receptor corepressor 2 Proteins 0.000 description 2
- 206010061332 Paraganglion neoplasm Diseases 0.000 description 2
- 102100022364 Polyunsaturated fatty acid 5-lipoxygenase Human genes 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 241000242739 Renilla Species 0.000 description 2
- KAEGGIFPLJZUOZ-UHFFFAOYSA-N Renilla luciferin Chemical compound C1=CC(O)=CC=C1C(N1)=CN2C(=O)C(CC=3C=CC=CC=3)=NC2=C1CC1=CC=CC=C1 KAEGGIFPLJZUOZ-UHFFFAOYSA-N 0.000 description 2
- 108700008625 Reporter Genes Proteins 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000027455 binding Effects 0.000 description 2
- 210000001185 bone marrow Anatomy 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 150000002617 leukotrienes Chemical class 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 239000006166 lysate Substances 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 208000030159 metabolic disease Diseases 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 108020004017 nuclear receptors Proteins 0.000 description 2
- 201000008968 osteosarcoma Diseases 0.000 description 2
- 230000036542 oxidative stress Effects 0.000 description 2
- 208000007312 paraganglioma Diseases 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 230000002633 protecting effect Effects 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 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
- 102000010400 1-phosphatidylinositol-3-kinase activity proteins Human genes 0.000 description 1
- 102100036009 5'-AMP-activated protein kinase catalytic subunit alpha-2 Human genes 0.000 description 1
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- BOJKULTULYSRAS-OTESTREVSA-N Andrographolide Chemical compound C([C@H]1[C@]2(C)CC[C@@H](O)[C@]([C@H]2CCC1=C)(CO)C)\C=C1/[C@H](O)COC1=O BOJKULTULYSRAS-OTESTREVSA-N 0.000 description 1
- 206010002329 Aneurysm Diseases 0.000 description 1
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 1
- 108010093579 Arachidonate 5-lipoxygenase Proteins 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 208000004429 Bacillary Dysentery Diseases 0.000 description 1
- 108060000903 Beta-catenin Proteins 0.000 description 1
- 102000015735 Beta-catenin Human genes 0.000 description 1
- 208000018240 Bone Marrow Failure disease Diseases 0.000 description 1
- 206010065553 Bone marrow failure Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 102000008169 Co-Repressor Proteins Human genes 0.000 description 1
- 108010060434 Co-Repressor Proteins Proteins 0.000 description 1
- 230000004568 DNA-binding Effects 0.000 description 1
- 102000007665 Extracellular Signal-Regulated MAP Kinases Human genes 0.000 description 1
- 108010007457 Extracellular Signal-Regulated MAP Kinases Proteins 0.000 description 1
- 102000001267 GSK3 Human genes 0.000 description 1
- 108060006662 GSK3 Proteins 0.000 description 1
- 206010017915 Gastroenteritis shigella Diseases 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 206010018381 Glomus tumour Diseases 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 101000783681 Homo sapiens 5'-AMP-activated protein kinase catalytic subunit alpha-2 Proteins 0.000 description 1
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 1
- 101000801228 Homo sapiens Tumor necrosis factor receptor superfamily member 1A Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 1
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 241000204031 Mycoplasma Species 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 108091007960 PI3Ks Proteins 0.000 description 1
- 108010015181 PPAR delta Proteins 0.000 description 1
- 108010016731 PPAR gamma Proteins 0.000 description 1
- 102000000536 PPAR gamma Human genes 0.000 description 1
- 108010044210 PPAR-beta Proteins 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 101710156627 Polyunsaturated fatty acid 5-lipoxygenase Proteins 0.000 description 1
- 208000033826 Promyelocytic Acute Leukemia Diseases 0.000 description 1
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 1
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 108091006300 SLC2A4 Proteins 0.000 description 1
- 208000003721 Triple Negative Breast Neoplasms Diseases 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 102100033732 Tumor necrosis factor receptor superfamily member 1A Human genes 0.000 description 1
- 206010046306 Upper respiratory tract infection Diseases 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 210000004404 adrenal cortex Anatomy 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000008484 agonism Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- ASLUCFFROXVMFL-UHFFFAOYSA-N andrographolide Natural products CC1(CO)C(O)CCC2(C)C(CC=C3/C(O)OCC3=O)C(=C)CCC12 ASLUCFFROXVMFL-UHFFFAOYSA-N 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000002058 anti-hyperglycaemic effect Effects 0.000 description 1
- 230000000719 anti-leukaemic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000003524 antilipemic agent Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- BLUAFEHZUWYNDE-NNWCWBAJSA-N artemisinin Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2OC(=O)[C@@H]4C BLUAFEHZUWYNDE-NNWCWBAJSA-N 0.000 description 1
- 229960004191 artemisinin Drugs 0.000 description 1
- 229930101531 artemisinin Natural products 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 150000001840 cholesterol esters Chemical class 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 230000001010 compromised effect Effects 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 210000003792 cranial nerve Anatomy 0.000 description 1
- 229940117173 croton oil Drugs 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 238000010864 dual luciferase reporter gene assay Methods 0.000 description 1
- 229940125753 fibrate Drugs 0.000 description 1
- 210000000232 gallbladder Anatomy 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000004190 glucose uptake Effects 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 208000006575 hypertriglyceridemia Diseases 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 238000003468 luciferase reporter gene assay Methods 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- 210000005210 lymphoid organ Anatomy 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 210000003519 mature b lymphocyte Anatomy 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 244000000010 microbial pathogen Species 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- NFVJNJQRWPQVOA-UHFFFAOYSA-N n-[2-chloro-5-(trifluoromethyl)phenyl]-2-[3-(4-ethyl-5-ethylsulfanyl-1,2,4-triazol-3-yl)piperidin-1-yl]acetamide Chemical compound CCN1C(SCC)=NN=C1C1CN(CC(=O)NC=2C(=CC=C(C=2)C(F)(F)F)Cl)CCC1 NFVJNJQRWPQVOA-UHFFFAOYSA-N 0.000 description 1
- IRSFLNXJVJKMDT-UHFFFAOYSA-N n-[6-[4-[3-[1-[(4-tert-butylphenyl)methyl]-4-ethyl-5-oxo-1,2,4-triazol-3-yl]propyl]phenyl]pyridin-3-yl]benzenesulfonamide Chemical compound N=1N(CC=2C=CC(=CC=2)C(C)(C)C)C(=O)N(CC)C=1CCCC(C=C1)=CC=C1C(N=C1)=CC=C1NS(=O)(=O)C1=CC=CC=C1 IRSFLNXJVJKMDT-UHFFFAOYSA-N 0.000 description 1
- 208000020588 necrotizing soft tissue infection Diseases 0.000 description 1
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 1
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000002250 progressing effect Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 108091006082 receptor inhibitors Proteins 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000008844 regulatory mechanism Effects 0.000 description 1
- 201000005113 shigellosis Diseases 0.000 description 1
- 210000001154 skull base Anatomy 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 238000011301 standard therapy Methods 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 208000006234 thyroid hormone resistance syndrome Diseases 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 208000022679 triple-negative breast carcinoma Diseases 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/19—Acanthaceae (Acanthus family)
-
- 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
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Diabetes (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Hematology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Medical Informatics (AREA)
- Botany (AREA)
- Biotechnology (AREA)
- Oncology (AREA)
- Alternative & Traditional Medicine (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Obesity (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明公开了一种去氧穿心莲内酯在制备过氧化物酶体增殖物激活受体PPARs的拮抗剂中的应用,本发明中去氧穿心莲内酯抑制过氧化物酶体增殖物激活受体PPARs转录活性的效果显著,尤其是抑制PPAR‑α的转录活性。PPAR‑α的转录活性随去氧穿心莲内酯浓度增加而降低,去氧穿心莲内酯以浓度依赖的方式降低PPAR‑α的转录活性,并且还具有抑制PPAR‑α特异性激动剂非诺贝特的作用。
Description
技术领域
本发明涉及一种核激素受体家族中的配体激活受体抑制剂的应用,特别涉及一种过氧化物酶体增殖物激活受体转录活性抑制剂的应用。
背景技术
过氧化物酶体增殖物激活受体(peroxisome proliferators-activatedreceptors,PPARs)是核激素受体家族中的配体激活受体,在不同的物种中已经发现了它的3种亚型(PPARα,PPARβ/δ,PPARγ),控制许多细胞内的代谢过程,属于配体诱导核受体(ligand-inducible nuclear receptors)。
胰腺癌是恶性程度极高的消化道肿瘤之一,其总体5年生存率不足8%,它的特点是容易早期转移,快速浸润,并且对标准治疗容易产生耐药性。头颈部副神经节瘤主要包括颈静脉球体瘤和颈动脉体瘤,临床上少见,占全身肿瘤的0.03%,若任其生长可压迫邻近组织、累及脑神经及侵蚀颅底骨质而出现多种临床症状,甚至危及生命。胶质母细胞瘤是成人常见的恶性程度最高的脑肿瘤,预后差,且大部分患者常表现出对化疗药的原发性与继发性耐药。而慢性淋巴细胞白血病(chronic lymphocytic leukemia,CLL)也是一种进展缓慢的以成熟B淋巴细胞在外周血、骨髓、脾脏和淋巴结聚集为特征的恶性淋巴系统克隆增殖性疾病,骨髓的正常造血功能受到抑制,最终骨髓衰竭,病人出现贫血、出血、感染以及淋巴器官浸润肿大。以上疾病均对人类健康产生较大危害,对家庭经济产生沉重的负担。
有研究显示,PPAR-α拮抗剂可能对上述肿瘤有治疗作用。如对头颈部副神经节瘤,可通过抑制PI3K/GSK3β/β-catenin通路降低HNPGLs细胞的活力和增殖。减弱MMPs表达,增强AMPK磷酸化,抑制NF-κB及其DNA结合活性。对于胰腺癌,可损害胰腺癌细胞的活力。对胶质母细胞瘤,可降低胆固醇酯和脂滴,重新编程脂质代谢,调节MVA通路;抑制5-LO表达,阻断ERKs磷酸化和Bcl-2/Bax信号的激活;克服TRAIL抗性以增强胶质瘤细胞的凋亡。对慢性淋巴细胞白血病,PPAR-α拮抗剂NXT629(Pubchem CID号:71721539;分子量:609.8)可使增殖的CLL细胞进入免疫原性死亡途径,直接诱导循环CLL细胞凋亡;即使存在保护性微环境,也能诱导CLL细胞死亡。PPAR-α拮抗剂MK886(Pubchem CID号:3651377;分子量为472.1)可阻断完整活化白细胞中白三烯的合成,具有减轻炎症反应性疾病如哮喘、关节炎和银屑病的作用;可抑制5-脂氧合酶向膜组分易位从而抑制骨肉瘤细胞中白三烯的合成,抑制骨肉瘤的进展;拮抗剂GW6471(Pubchem CID号:446738;分子量为619.7)可通过加强核受体与共阻遏蛋白(如SMRT和N-CoR)的结合,具有抑制急性早幼粒细胞白血病和甲状腺激素抵抗综合征的作用;可抑制以PPARα依赖性方式激活PI3K/Akt/NF-κB通路导致的卵巢癌和头颈部副神经节瘤的进展;可降低癌症干细胞的活力、增殖和球体形成,导致三阴性乳腺癌癌细胞凋亡和代谢障碍。
PPAR-α激动剂对代谢异常疾病如高甘油三脂血症、胰岛素抵抗症;心血管疾病如动脉粥样硬化;炎症性疾病如非酒精性脂肪性肝炎均具有保护改善的有益作用,且目前对PPAR-α激动剂有大量研究报道,贝特类降血脂药也广泛应用于临床且有较好的疗效。
去氧穿心莲内酯(Deoxyandrographolide,DAG)是从天然植物药穿心莲中提取的成分,它可通过葡萄糖转运蛋白4易位至L6肌管质膜,促进葡萄糖摄取并在体内发挥抗高血糖作用。对RAW 264.7巨噬细胞中LPS诱导的NO产生抑制作用,减轻氧化应激所带来的各种机体损伤。
已知穿心莲也具有抗病原微生物及抗炎、增强免疫、保肝利胆、抗肿瘤等功效,穿心莲主要成分之一的穿心莲内酯具有PPAR-α激动作用。而我们发现穿心莲成分去氧穿心莲内酯对PPAR-α转录活性具有抑制作用,这种对PPAR-α的双重调节机制为研发不良反应较少的抗肿瘤、抗白血病穿心莲新药制剂提供了一种可能。我们认为有很大的研究意义和发展空间。
发明内容
本发明的目的是提供去氧穿心莲内酯在制备过氧化物酶体增殖物激活受体PPARs的拮抗剂中的应用。
其中,所述去氧穿心莲内酯(deoxyandrographolide)的分子式为:C20H30O4;分子量为:334.4;cas号为4176-97-0;化学结构式如下:
去氧穿心莲内酯是一种已知化合物,可购自市售产品,也可从药材穿心莲中提取分离得到,具体的获取手段为现有技术,本发明对此不作特别限定。
去氧穿心莲内酯为白色粉末,可溶于甲醇、乙醇、丙酮、吡啶和氯仿,可溶于苯和乙醚的无色针状结晶(乙醚-轻石油醚),无色片状结晶(丙酮、乙醇或氯仿),属于萜类物质,旋光度为-40(c=1,无水乙醇)。
去氧穿心莲内酯是穿心莲的生物活性成分,具有抗菌和钩端螺旋体作用。临床适用治疗钩端螺旋体、急性细菌性痢疾、上呼吸道感染、流行性感冒及原因不明的发热等病症均有一定疗效;毒性小,未见明显副作用;能减少二甲苯或H+刺激所致伊文思兰自毛细血管壁的渗出,有抑制巴豆油所致大鼠炎性渗出作用,对大鼠蛋清性足肿有显著抑制作用,对肾上腺皮质功能有不同程度的兴奋作用;具有保护肝脏的作用,其通过诱导TNFRSF1A的释放,逐渐使肝细胞对TNF-α介导的凋亡脱敏。
为实现本发明的目的,本发明一方面提供一种去氧穿心莲内酯在制备过氧化物酶体增殖物激活受体PPARs的拮抗剂中的应用;去氧穿心莲内酯对过氧化物酶体增殖物激活受体PPARs具有抑制作用,去氧穿心莲内酯抑制过氧化物酶体增殖物激活受体PPARs转录活性的用途。
其中,所述过氧化物酶体增殖物激活受体选择PPAR-α亚型受体。
特别是,所述PPARs拮抗剂为PPARs转录活性抑制剂。
尤其是,所述去氧穿心莲内酯抑制PPARs转录活性,优选为抑制PPAR-α亚型受体的转录活性。
本发明另一方面提供一种去氧穿心莲内酯在制备治疗过氧化物酶体增殖物激活受体PPARs失调疾病的药物中的应用。
其中,所述过氧化物酶体增殖物激活受体失调疾病为PPAR-α亚型受体失调疾病。
特别是,所述治疗过氧化物酶体增殖物激活受体PPARs失调疾病的药物以去氧穿心莲内酯为活性成分制备而成,具体为本领域技术人员所掌握。
尤其是,本发明提供的去氧穿心莲内酯主要针对由PPAR-α亚型受体失调所引起的疾病,包括头颈部副神经节瘤、胰腺癌、胶质母细胞瘤等恶性消耗性疾病、白血病或糖尿病等。
特别是,所述PPAR-α亚型受体失调是指PPAR-α的转录活性过度增强。
我们的实验可直接证明去氧穿心莲内酯抑制PPAR-α的转录活性,可能通过增强PPAR-α与共阻遏蛋白(如SMRT和N-CoR)的结合,防止PPAR-α的羧基末端激活螺旋(AF-2)呈现活性构象,达到抑制PPAR-α的转录活性。
与现有技术相比,本发明具有如下优点和好处:
中草药具有悠久的应用历史,是药物开发的重要来源,很多高活性药物都是从中草药中发现的,例如青蒿素、紫杉醇等。而穿心莲作为一味重要的中草药,在中医药领域中广泛使用,本发明在研究过程中,筛选得到穿心莲提取物中的单体化合物去氧穿心莲内酯可以高效抑制过氧化物酶体增殖物激活受体的转录活性,可以抗高血糖,抑制RAW 264.7巨噬细胞中LPS诱导的NO产生,抑制COX-2活性,减轻氧化应激与炎症损伤,是新型的PPAR-α亚型受体转录活性抑制剂,即PPAR-α亚型受体拮抗剂。
附图说明
图1为不同浓度GW6471对PPAR-α转录活性的影响结果图。
图2为不同浓度非诺贝特对PPAR-α转录活性的影响结果图。
图3为不同浓度去氧穿心莲内酯(DAG)对PPAR-α转录活性的影响结果图。
图4为去氧穿心莲内酯(DAG)对非诺贝特激动PPAR-α转录活性的影响结果图。
具体实施方式
下面结合具体实施例来进一步描述本发明,本发明的优点和特点将会随着描述而更为清楚。但这些实施例仅是范例性的,并不对本发明的范围构成任何限制。本领域技术人员应该理解的是,在不偏离本发明的精神和范围下可以对本发明技术方案的细节和形式进行修改或替换,但这些修改和替换均落入本发明的保护范围内。
以下通过试验例来进一步阐述本发明所述穿心莲成分去氧穿心莲内酯的有益效果,这些试验例包括了本发明药物的药效学试验。
试验例1
1材料与方法
1.1细胞与质粒
HEK293细胞系从北京协和医学院细胞资源中心(其为细胞系资源的国家基础设施,NSTI的总部)购得。通过PCR和培养检查细胞系没有支原体污染,用PCR鉴定其种源,用STR谱(FBI,CODIS)鉴定细胞系。
质粒:pZdonor-CMV-PPARα、pGL4.23-PPRE-luc及pRL-CMV由北京北因健康科技有限公司提供。
1.2药品及主要试剂
去氧穿心莲内酯(Deoxyandrographolide),上海源叶生物科技有限公司,货号:B21031-5mg;PPAR-α特异性激动剂非诺贝特,上海源叶生物科技有限公司,货号49562-28-9;PPAR-α特异性抑制剂GW6471,MCE公司,美国,货号HY-15372;Lipofectamine3000Transfection Kit(Lipo3000转染试剂盒,试剂盒包含试剂lipo 3000、P3000),赛默飞公司,美国,货号L3000015;双荧光素酶报告基因检测试剂盒,promega,美国,货号E1960;
1.3仪器
SynergyII酶标仪,bio-tek公司,美国。
1.4试验方法
1.4.1分组与给药
实验分别设空白对照组,PPAR-α特异性抑制剂组,PPAR-α特异性激动剂组,去氧穿心莲内酯实验组,去氧穿心莲内酯+非诺贝特试验组,其中,空白对照组为0.1%DMSO;PPAR-α特异性抑制剂组中抑制剂GW6471的浓度为0.1、1、10uM;PPAR-α特异性激动剂组中激动剂非诺贝特的浓度为10、20、30、40uM;去氧穿心莲内酯实验组中去氧穿心莲内酯的浓度分别为12.5、25、50、100uM;去氧穿心莲内酯+非诺贝特试验组中去氧穿心莲内酯浓度为100uM,非诺贝特浓度为30uM。激动剂、抑制剂、去氧穿心莲内酯用0.1%DMSO溶解,制成上述相应的浓度。
1.4.2质粒转染HEK293细胞、药物干预
1)将HEK293细胞培养在含10%FBS的DMEM培养基中,放入37℃,5%CO2培养箱内培养。取生长旺盛的HEK293细胞,配制成5×105个/ml的HEK293细胞悬液,在转染前24h按照每孔1ml接种于24孔板中,即每孔内接种细胞密度为5×105个/孔;
2)接种24小时后弃去原有培养基,换上新配置的含10%FBS的DMEM培养基,置于37℃,5%CO2细胞培养箱中培养30min-60min;
3)制备脂质体-DNA复合物,按每孔转染样品量描述:
3-1)将脂质体lipo3000加入到无血清无抗生素的DMEM培养基中,充分混匀,其中lipo3000与无血清无抗生素的DMEM培养基的体积之比为0.75:25,通常是按照lipo3000(0.75ul)加入至25ul无血清无抗生素的DMEM培养基中的比例,充分混匀,得到A液;
3-2)将质粒pZdonor-CMV-PPARα、pGL4.23-PPRE-luc、pRL-CMV和试剂P3000按每孔分别为0.2μg、0.2μg、0.03μg、1ul的比例加入至25ul无血清无抗生素的DMEM培养基中,充分混匀,得到B液;
3-3)将B液加入A液中,室温静置15min,得到脂质体-DNA复合物;
PPAR-α为目的基因,PPRE是能与PPARα特异性结合的元件,PPRE质粒上携带萤火虫荧光(F),pRL质粒上携带海肾荧光(R)。双荧光素检测这两种荧光,其中萤火虫荧光值代表目的基因PPARα的绝对值,海肾荧光值代表内在的变化因素(如:培养细胞的数目和活力的差别,细胞转染和裂解的效率等)对实验准确性的影响,提供转录活力的内对照。
4)转染
按每孔转染量将上述步骤3)中制备的脂质体-DNA复合物加入到上述步骤2)中的24孔板培养体系中,轻摇培养板使其混匀,37℃培养24h使目的基因PPAR-α充分转染入细胞,然后给药,进行药物干预。
5)加药干预
5-1)PPAR-α特异性抑制剂干预
PPAR-α抑制剂GW6471溶于DMSO中,分别配制成浓度为0.1uM、1uM、10uM的抑制剂GW6471溶液,备用;
经上述步骤4)转染24h后,吸弃培养基,然后向24孔板培养体系的每孔内加入不同浓度的PPAR-α抑制剂GW6471溶液,浓度设置为0uM(即向其中加入0.1%DMSO),0.1uM、1uM、10uM;每个浓度3个复孔,重复3次。
5-2)PPAR-α特异性激动剂干预
PPAR-α激动剂非诺贝特溶于DMSO中,分别配制成浓度为10uM、20uM、30uM、40uM的激动剂非诺贝特溶液,备用;
经上述步骤4)转染24h后,吸弃培养基,然后向24孔板培养体系的每孔内加入不同浓度的PPAR-α激动剂非诺贝特,设置浓度为0uM(即向其中加入0.1%DMSO),10uM、20uM、30uM、40uM;每个浓度3个复孔,重复3次。
5-3)去氧穿心莲内酯干预
将去氧穿心莲内酯溶于DMSO中,分别配制成浓度为12.5uM、25uM、50uM、100uM的去氧穿心莲内酯溶液,备用;
经上述步骤4)转染24h后,吸弃培养基,然后向24孔板每孔内加入不同浓度的去氧穿心莲内酯,设置浓度为0uM(即向其中加入0.1%DMSO),12.5uM、25uM、50uM、100uM;每个浓度3个复孔,重复3次。
5-4)去氧穿心莲内酯与PPAR-α特异性激动剂同时干预
经上述步骤4)转染24h后,吸弃培养基,然后向24孔板每孔内加入用DMSO溶解的去氧穿心莲内酯和非诺贝特的混合液,混合液中去氧穿心莲内酯的浓度为100uM,非诺贝特的浓度为30uM;以及0.1%的DMSO;3个复孔,重复3次。
加入药物后,置于37℃,5%CO2细胞培养箱中进行培养,即进行药物干预。
1.4.3荧光素酶报告基因检测:
加药干预48h后,除去培养基,用预冷(温度4℃)的1×PBS清洗2遍,不要接触贴壁细胞,尽可能多地将漂洗用PBS吸出,每孔加入100μl的1×被动裂解液,室温下震摇15min,将裂解液转移至96孔板中,每孔100ul。
应用双荧光素酶报告基因测定试剂盒测定荧光素酶活性,预先将100ul荧光素酶测定试剂(LARII)加入96孔板中,再使用酶标仪测定萤火虫荧光素活性(F),然后再加入100ul终止液,接着再测定海肾荧光素活性(R),萤火虫荧光素与海肾荧光素光强的比值(F/R)即为PPAR-α转录表达强度。
2试验结果
2.1GW6471与非诺贝特对PPAR-α转录活性的影响
药物干预48h后,GW6471以浓度依赖的方式降低HEK293细胞PPAR-α的转录活性,GW6471 1uM时荧光素酶活性达到最低效应值(如图1);其中与空白对照组(即GW6471 0uM)比较,*p<0.05;非诺贝特以浓度依赖的方式增加HEK293细胞PPAR-α的转录活性,非诺贝特30uM时荧光素酶活性达到峰值(如图2);其中与空白对照组(即非诺贝特0uM)比较,*p<0.05。
2.2去氧穿心莲内酯对PPAR-α活性的影响
药物干预48h后,去氧穿心莲内酯以浓度依赖的方式降低HEK293细胞PPAR-α的转录活性(如图3),去氧穿心莲内酯100uM时荧光素酶活性达到最低效应值(图3),其中与空白对照组(即去氧穿心莲内酯0uM)比较,*p<0.05;100uM去氧穿心莲内酯与非诺贝特共同孵育后可显著抑制荧光素酶活性(如图4),与30uM非诺贝特比较,*p<0.05。
该实验利用双萤光素酶报告基因分析方法,建立PPAR-α抑制剂体外筛选体系,采用不同浓度的PPAR-α抑制剂GW6471干预,PPAR-α的转录活性随浓度增加而降低。特异性激动剂非诺贝特与100uM去氧穿心莲内酯共同孵育后,转录活性降低,表明去氧穿心莲内酯以浓度依赖的方式降低PPAR-α的转录活性,并可抑制特异性激动剂非诺贝特的作用。以上结果表明,去氧穿心莲内酯具有抑制PPAR-α转录活性的作用。
本发明上述实施例仅是范例性的,并不对本发明的范围构成任何限制。本领域技术人员应该理解的是,在不偏离本发明的精神和范围下可以对本发明技术方案的细节和形式进行修改或替换,但这些修改和替换均落入本发明的保护范围内。
Claims (9)
1.去氧穿心莲内酯在制备过氧化物酶体增殖物激活受体PPARs的拮抗剂中的应用。
2.如权利要求1所述的应用,其特征是,所述过氧化物酶体增殖物激活受体选择PPAR-α亚型受体。
3.如权利要求1所述的应用,其特征是,所述PPARs拮抗剂为PPARs转录活性抑制剂。
4.如权利要求1所述的应用,其特征是,所述去氧穿心莲内酯抑制PPARs转录活性。
5.如权利要求1所述的应用,其特征是,所述去氧穿心莲内酯抑制PPAR-α亚型受体转录活性。
6.去氧穿心莲内酯作为过氧化物酶体增殖物激活受体PPAR-α的特异性激动剂的抑制剂的应用。
7.去氧穿心莲内酯在制备治疗过氧化物酶体增殖物激活受体失调所致疾病的药物中的应用。
8.如权利要求7所述的应用,其特征是,所述过氧化物酶体增殖物激活受体失调所致疾病为头颈部副神经节瘤、胰腺癌、胶质母细胞瘤、白血病或糖尿病等疾病。
9.去氧穿心莲内酯在制备治疗过氧化物酶体增殖物激活受体PPAR-α亚型失调所致疾病的药物中的应用。
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111105761.XA CN113750086A (zh) | 2021-09-22 | 2021-09-22 | 去氧穿心莲内酯在制备过氧化物酶体增殖物激活受体拮抗剂中的应用 |
PCT/CN2022/119746 WO2023045891A1 (zh) | 2021-09-22 | 2022-09-20 | 去氧穿心莲内酯在制备过氧化物酶体增殖物激活受体拮抗剂中的应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111105761.XA CN113750086A (zh) | 2021-09-22 | 2021-09-22 | 去氧穿心莲内酯在制备过氧化物酶体增殖物激活受体拮抗剂中的应用 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN113750086A true CN113750086A (zh) | 2021-12-07 |
Family
ID=78796618
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202111105761.XA Pending CN113750086A (zh) | 2021-09-22 | 2021-09-22 | 去氧穿心莲内酯在制备过氧化物酶体增殖物激活受体拮抗剂中的应用 |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN113750086A (zh) |
WO (1) | WO2023045891A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023045891A1 (zh) * | 2021-09-22 | 2023-03-30 | 中国中医科学院广安门医院 | 去氧穿心莲内酯在制备过氧化物酶体增殖物激活受体拮抗剂中的应用 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102397273A (zh) * | 2011-12-07 | 2012-04-04 | 沈阳药科大学 | 穿心莲内酯的医药新用途 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1666985A (zh) * | 2004-03-11 | 2005-09-14 | 和记黄埔医药企业有限公司 | 穿心莲内酯及其衍生物、类似物的医药用途 |
US20200054657A1 (en) * | 2018-08-20 | 2020-02-20 | Thomas E Adrian | Compositions of Matter and Methoods to Treat Cancer |
CN113750086A (zh) * | 2021-09-22 | 2021-12-07 | 中国中医科学院广安门医院 | 去氧穿心莲内酯在制备过氧化物酶体增殖物激活受体拮抗剂中的应用 |
-
2021
- 2021-09-22 CN CN202111105761.XA patent/CN113750086A/zh active Pending
-
2022
- 2022-09-20 WO PCT/CN2022/119746 patent/WO2023045891A1/zh unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102397273A (zh) * | 2011-12-07 | 2012-04-04 | 沈阳药科大学 | 穿心莲内酯的医药新用途 |
Non-Patent Citations (2)
Title |
---|
DEEPTI ARHA等: "Deoxyandrographolidepromotesglucoseuptakethroughglucose transporter-4translocationtoplasmamembraneinL6myotubes and exertsantihyperglycemiceffect in vivo", 《EUROPEAN JOURNALOFPHARMACOLOGY》 * |
张二锋: "14-去氧穿心莲内酯脂质体的研究", 《中国优秀硕士学位论文全文数据库医药卫生科技辑》 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023045891A1 (zh) * | 2021-09-22 | 2023-03-30 | 中国中医科学院广安门医院 | 去氧穿心莲内酯在制备过氧化物酶体增殖物激活受体拮抗剂中的应用 |
Also Published As
Publication number | Publication date |
---|---|
WO2023045891A1 (zh) | 2023-03-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Han et al. | Valeric acid suppresses liver cancer development by acting as a novel HDAC inhibitor | |
Huang et al. | Punicalagin inhibited inflammation and migration of fibroblast-like synoviocytes through NF-κB pathway in the experimental study of rheumatoid arthritis | |
Sun et al. | Anti-diabetic potential of Pueraria lobata root extract through promoting insulin signaling by PTP1B inhibition | |
Chen et al. | “Kidney Tea” and its bioactive secondary metabolites for treatment of gout | |
Wilson et al. | Breast cancer-associated skeletal muscle mitochondrial dysfunction and lipid accumulation is reversed by PPARG | |
Yang et al. | Combination therapy with miR34a and doxorubicin synergistically inhibits Dox-resistant breast cancer progression via down-regulation of Snail through suppressing Notch/NF-κB and RAS/RAF/MEK/ERK signaling pathway | |
Nandi et al. | Deregulation of the CD44-NANOG-MDR1 associated chemoresistance pathways of breast cancer stem cells potentiates the anti-cancer effect of Kaempferol in synergism with Verapamil | |
Lee et al. | Cordycerebroside a suppresses vcam-dependent monocyte adhesion in osteoarthritis synovial fibroblasts by inhibiting mek/erk/ap-1 signaling | |
Zhao et al. | The NK-1R antagonist aprepitant prevents LPS-induced oxidative stress and inflammation in RAW264. 7 macrophages | |
Pei et al. | α-Cyperone inhibits the proliferation of human cervical cancer HeLa cells via ROS-mediated PI3K/Akt/mTOR signaling pathway | |
Deng et al. | The interplay between fibroblast‐like synovial and vascular endothelial cells leads to angiogenesis via the sphingosine‐1‐phosphate‐induced RhoA‐F‐Actin and Ras‐Erk1/2 pathways and the intervention of geniposide | |
Yang et al. | Esculin protects against methionine choline-deficient diet-induced non-alcoholic steatohepatitis by regulating the Sirt1/NF-κ B p65 pathway | |
Wu et al. | Chrysoeriol suppresses hyperproliferation of rheumatoid arthritis fibroblast-like synoviocytes and inhibits JAK2/STAT3 signaling | |
WO2023045891A1 (zh) | 去氧穿心莲内酯在制备过氧化物酶体增殖物激活受体拮抗剂中的应用 | |
Zeng et al. | Puerarin ameliorates caerulein-induced chronic pancreatitis via inhibition of MAPK signaling pathway | |
Xiong et al. | Tectoridin inhibits the progression of colon cancer through downregulating PKC/p38 MAPK pathway | |
Li et al. | Pogostone attenuates adipose tissue inflammation by regulating the adipocyte–macrophage crosstalk via activating SIRT1 | |
Wu et al. | Hesperetin exhibits anti-inflammatory effects on chondrocytes via the AMPK pathway to attenuate anterior cruciate ligament transection-induced osteoarthritis | |
Li et al. | 8-Methoxypsoralen has anti-inflammatory and antioxidant roles in osteoarthritis through SIRT1/NF-κB pathway | |
Qu et al. | Urolithin B suppresses osteoclastogenesis via inhibiting RANKL‐induced signalling pathways and attenuating ROS activities | |
Jiang et al. | Protective role of berberine and Coptischinensis extract on T2MD rats and associated islet Rin‑5f cells | |
Wang et al. | Aloe Extracts Inhibit Skin Inflammatory Responses by Regulating NF-κB, ERK, and JNK Signaling Pathways in an LPS-Induced RAW264. 7 Macrophages Model | |
Gao et al. | Resibufogenin, one of bufadienolides in toad venom, suppresses LPS-induced inflammation via inhibiting NF-κB and AP-1 pathways | |
Huang et al. | Myc is involved in Genistein protecting against LPS-induced myocarditis in vitro through mediating MAPK/JNK signaling pathway | |
Ou et al. | Potential Therapeutic Role of Z‐Isochaihulactone in Lung Cancer through Induction of Apoptosis via Notch Signaling |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20211207 |
|
RJ01 | Rejection of invention patent application after publication |