CN113209076A - 大豆苷元在制备减轻铂类药物毒性的药物中的应用 - Google Patents
大豆苷元在制备减轻铂类药物毒性的药物中的应用 Download PDFInfo
- Publication number
- CN113209076A CN113209076A CN202110448883.2A CN202110448883A CN113209076A CN 113209076 A CN113209076 A CN 113209076A CN 202110448883 A CN202110448883 A CN 202110448883A CN 113209076 A CN113209076 A CN 113209076A
- Authority
- CN
- China
- Prior art keywords
- daidzein
- platinum
- preparing
- pharmaceutically acceptable
- medicines
- 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
- ZQSIJRDFPHDXIC-UHFFFAOYSA-N daidzein Chemical compound C1=CC(O)=CC=C1C1=COC2=CC(O)=CC=C2C1=O ZQSIJRDFPHDXIC-UHFFFAOYSA-N 0.000 title claims abstract description 254
- 235000007240 daidzein Nutrition 0.000 title claims abstract description 127
- 239000003814 drug Substances 0.000 title claims abstract description 94
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 title claims abstract description 90
- 229940079593 drug Drugs 0.000 title claims abstract description 47
- 229910052697 platinum Inorganic materials 0.000 title claims abstract description 45
- 231100000419 toxicity Toxicity 0.000 title claims abstract description 17
- 230000001988 toxicity Effects 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 239000002243 precursor Substances 0.000 claims abstract description 13
- 239000004480 active ingredient Substances 0.000 claims abstract description 11
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 27
- 229960004316 cisplatin Drugs 0.000 claims description 27
- 102100025014 E3 ubiquitin-protein ligase TRIM63 Human genes 0.000 claims description 16
- 101710164910 E3 ubiquitin-protein ligase TRIM63 Proteins 0.000 claims description 16
- 102100040669 F-box only protein 32 Human genes 0.000 claims description 16
- 101710191029 F-box only protein 32 Proteins 0.000 claims description 16
- 210000004369 blood Anatomy 0.000 claims description 12
- 239000008280 blood Substances 0.000 claims description 12
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 claims description 12
- 101150094019 MYOG gene Proteins 0.000 claims description 10
- 210000000107 myocyte Anatomy 0.000 claims description 8
- 230000001105 regulatory effect Effects 0.000 claims description 7
- PNNCWTXUWKENPE-UHFFFAOYSA-N [N].NC(N)=O Chemical compound [N].NC(N)=O PNNCWTXUWKENPE-UHFFFAOYSA-N 0.000 claims description 6
- 229940109239 creatinine Drugs 0.000 claims description 6
- 206010003694 Atrophy Diseases 0.000 claims description 5
- 230000037444 atrophy Effects 0.000 claims description 5
- 239000000843 powder Substances 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000008187 granular material Substances 0.000 claims description 3
- 238000002347 injection Methods 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- 230000010024 tubular injury Effects 0.000 claims description 3
- 208000037978 tubular injury Diseases 0.000 claims description 3
- 230000001276 controlling effect Effects 0.000 claims description 2
- 239000006071 cream Substances 0.000 claims description 2
- 239000006196 drop Substances 0.000 claims description 2
- 238000010255 intramuscular injection Methods 0.000 claims description 2
- 238000010253 intravenous injection Methods 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 239000002674 ointment Substances 0.000 claims description 2
- 239000008188 pellet Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000006187 pill Substances 0.000 claims description 2
- 230000000630 rising effect Effects 0.000 claims description 2
- 239000000243 solution Substances 0.000 claims description 2
- 239000007921 spray Substances 0.000 claims description 2
- 238000010254 subcutaneous injection Methods 0.000 claims description 2
- 239000000829 suppository Substances 0.000 claims description 2
- 239000000725 suspension Substances 0.000 claims description 2
- 150000001949 daidzein Chemical class 0.000 claims 4
- -1 buccal preparations Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 25
- 210000002027 skeletal muscle Anatomy 0.000 abstract description 14
- 108090000623 proteins and genes Proteins 0.000 abstract description 12
- 102000004169 proteins and genes Human genes 0.000 abstract description 11
- 210000003734 kidney Anatomy 0.000 abstract description 8
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 abstract description 5
- 206010070863 Toxicity to various agents Diseases 0.000 abstract description 5
- 230000015556 catabolic process Effects 0.000 abstract description 5
- 238000006731 degradation reaction Methods 0.000 abstract description 5
- 230000004069 differentiation Effects 0.000 abstract description 5
- 230000005764 inhibitory process Effects 0.000 abstract description 5
- 230000006378 damage Effects 0.000 abstract description 4
- 238000002474 experimental method Methods 0.000 abstract description 2
- 206010028980 Neoplasm Diseases 0.000 description 28
- 241000699670 Mus sp. Species 0.000 description 19
- 210000004027 cell Anatomy 0.000 description 13
- 241000699666 Mus <mouse, genus> Species 0.000 description 11
- 238000011282 treatment Methods 0.000 description 10
- 239000000835 fiber Substances 0.000 description 9
- 238000000034 method Methods 0.000 description 8
- 230000037396 body weight Effects 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 235000012631 food intake Nutrition 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 210000003205 muscle Anatomy 0.000 description 4
- 210000003098 myoblast Anatomy 0.000 description 4
- 210000004940 nucleus Anatomy 0.000 description 4
- 238000010186 staining Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 101150113392 MYH4 gene Proteins 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 201000010063 epididymitis Diseases 0.000 description 3
- 230000037406 food intake Effects 0.000 description 3
- 230000004927 fusion Effects 0.000 description 3
- 230000001434 glomerular Effects 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 238000001262 western blot Methods 0.000 description 3
- 241000208340 Araliaceae Species 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 206010028289 Muscle atrophy Diseases 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 2
- 235000003140 Panax quinquefolius Nutrition 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 229940044683 chemotherapy drug Drugs 0.000 description 2
- 238000011284 combination treatment Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 210000003194 forelimb Anatomy 0.000 description 2
- 235000008434 ginseng Nutrition 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000020763 muscle atrophy Effects 0.000 description 2
- 231100000483 muscle toxicity Toxicity 0.000 description 2
- 201000000585 muscular atrophy Diseases 0.000 description 2
- 210000001087 myotubule Anatomy 0.000 description 2
- XTEGVFVZDVNBPF-UHFFFAOYSA-N naphthalene-1,5-disulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1S(O)(=O)=O XTEGVFVZDVNBPF-UHFFFAOYSA-N 0.000 description 2
- 231100000417 nephrotoxicity Toxicity 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- WLJVNTCWHIRURA-UHFFFAOYSA-N pimelic acid Chemical compound OC(=O)CCCCCC(O)=O WLJVNTCWHIRURA-UHFFFAOYSA-N 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- OXQGTIUCKGYOAA-UHFFFAOYSA-N 2-Ethylbutanoic acid Chemical compound CCC(CC)C(O)=O OXQGTIUCKGYOAA-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 241000173529 Aconitum napellus Species 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Natural products OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- 241000132012 Atractylodes Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- OMFXVFTZEKFJBZ-UHFFFAOYSA-N Corticosterone Natural products O=C1CCC2(C)C3C(O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 OMFXVFTZEKFJBZ-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 101710088172 HTH-type transcriptional regulator RipA Proteins 0.000 description 1
- 239000009636 Huang Qi Substances 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 208000013901 Nephropathies and tubular disease Diseases 0.000 description 1
- 206010029240 Neuritis Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-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
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 244000197580 Poria cocos Species 0.000 description 1
- 235000008599 Poria cocos Nutrition 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 208000032023 Signs and Symptoms Diseases 0.000 description 1
- 208000026214 Skeletal muscle atrophy Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical group [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 229940023019 aconite Drugs 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 208000022531 anorexia Diseases 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 230000004900 autophagic degradation Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- YBHILYKTIRIUTE-UHFFFAOYSA-N berberine Chemical compound C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 YBHILYKTIRIUTE-UHFFFAOYSA-N 0.000 description 1
- 229940093265 berberine Drugs 0.000 description 1
- QISXPYZVZJBNDM-UHFFFAOYSA-N berberine Natural products COc1ccc2C=C3N(Cc2c1OC)C=Cc4cc5OCOc5cc34 QISXPYZVZJBNDM-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 210000003855 cell nucleus Anatomy 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000009104 chemotherapy regimen Methods 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000003501 co-culture Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- OMFXVFTZEKFJBZ-HJTSIMOOSA-N corticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OMFXVFTZEKFJBZ-HJTSIMOOSA-N 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- 210000000918 epididymis Anatomy 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229950006191 gluconic acid Drugs 0.000 description 1
- 150000002333 glycines Chemical class 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 238000010874 in vitro model Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- TYQCGQRIZGCHNB-JLAZNSOCSA-N l-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 238000006241 metabolic reaction Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000006676 mitochondrial damage Effects 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000010814 radioimmunoprecipitation assay Methods 0.000 description 1
- 230000007076 release of cytoplasmic sequestered NF-kappaB Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000025185 skeletal muscle atrophy Effects 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- BUUPQKDIAURBJP-UHFFFAOYSA-N sulfinic acid Chemical compound OS=O BUUPQKDIAURBJP-UHFFFAOYSA-N 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 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
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 210000003854 type 2 muscle cell Anatomy 0.000 description 1
- 230000006663 ubiquitin-proteasome pathway Effects 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent 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
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/243—Platinum; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Inorganic Chemistry (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Neurology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Toxicology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了大豆苷元在制备减轻铂类药物毒性的药物中的应用,该药物的有效成分为大豆苷元、大豆苷元的水合物、大豆苷元药学上可接受的盐、大豆苷元的互变异构体、大豆苷元的立体异构体、大豆苷元的前体化合物中的一种或几种。本发明通过实验验证了大豆苷元可以减轻铂类药物对骨骼肌分化的抑制作用,并且可以下调骨骼肌降解相关蛋白,减轻铂类药物对肾脏的损伤,为制备减轻铂类药物毒性的药物提供了策略;此外,大豆苷元来源广泛,成本低廉,可被大量使用于制备减轻铂类药物毒性的药物中。
Description
技术领域
本发明涉及生物医药领域,尤其涉及大豆苷元在制备减轻铂类药物毒性的药物中的应用。
背景技术
铂类药物是当前在肿瘤治疗中应用非常广泛的一类化疗药物,适用于肺癌、卵巢癌、膀胱癌、头颈部肿瘤、多种消化道肿瘤等。铂类药物主要通过作用于肿瘤细胞DNA,与DNA形成加合物影响肿瘤细胞增殖、阻滞细胞周期,并诱导肿瘤细胞凋亡或坏死从而发挥抗癌作用。但是,铂类药物也存在很多毒副作用,如肾毒性、骨骼肌毒性等。这些毒副作用严重限制了铂类药物的临床应用,降低肿瘤病人对铂类药物的耐受,大大削弱了铂类药物的临床疗效。当前仅有采取水化的方法预防铂类药物导致的机体损伤,尚无特效干预手段。寻求减轻铂类药物毒性的方法或者治疗药物对于提高基于铂类药物的化疗方案的疗效具有重要意义。
中医药的临床应用历史悠久,在针对肿瘤及相关并发症的治疗中以中药汤药的应用更为广泛。然而中药汤药存在质控困难、变换频繁的缺点,致使难以实现大规模的推广。中药天然产物是一个待开发的药物资源库,紫杉醇、小檗碱等化学药物都源自植物药。养正消积胶囊、参附注射液、参苓白术散等中药复方在治疗癌症及减轻化疗药物毒副作用中已出现了很多正向的报道。从中药中筛查出减轻铂类药物毒性的小分子化合物,并且将其转化为化学药物对于开发减轻铂类药物毒性的治疗方案具有重要意义。
当前已存在很多铂类药物毒性的体内外模型可用于开发减轻铂类药物毒性的药物。奥沙利铂作用于C26荷瘤小鼠确实可以抑制肿瘤生长,但也导致肌肉萎缩。这一过程与自噬的启动、线粒体损伤和蛋白质合成被抑制有关。顺铂(DDP)在多种癌症模型中可以引起厌食、骨骼肌萎缩等症状,并且显著上调血浆皮质酮水平,顺铂相关的肌肉萎缩与激活NF-kappa B信号通路诱导炎症有关。DDP作用于大鼠和小鼠可以导致肾脏出现肾小球、肾小管的炎性改变,提升血尿素氮、血肌酐的水平。顺铂与小鼠C2C12肌管细胞共培养会使得C2C12肌管细胞发生萎缩,这一过程与泛素-蛋白酶体通路的激活有关。将中药相关小分子化合物作用于以上体内外模型可以对该小分子化合物的减轻铂类药物毒性的药理作用进行初步评价。
大豆苷元(daidzein,DAI,分子式:C15H10O4,分子量:254.24g/mol)可来源于大豆、中药黄芪、女贞子、牛膝等。许多体内外实验研究表明大豆苷元具有抗神经炎症、抗肿瘤、止吐等药理活性,具备一定的药用潜力,但目前未有将其应用于减轻铂类药物毒性的相关报道。
发明内容
本发明针对现有技术的不足,提供了大豆苷元在制备减轻铂类药物毒性的药物中的应用。
为实现上述目的,本发明采用以下技术方案:
本发明的第一方面是提供大豆苷元在制备减轻铂类药物毒性的药物中的应用,该药物的有效成分为大豆苷元、大豆苷元的水合物、大豆苷元药学上可接受的盐、大豆苷元的互变异构体、大豆苷元的立体异构体、大豆苷元的前体化合物中的一种或几种。
进一步地,上述铂类药物包括顺铂。
本发明的第二方面是提供大豆苷元在制备减轻铂类药物诱导的肌管细胞萎缩的药物中的应用,该药物的有效成分为大豆苷元、大豆苷元的水合物、大豆苷元药学上可接受的盐、大豆苷元的互变异构体、大豆苷元的立体异构体、大豆苷元的前体化合物中的一种或几种。
本发明的第三方面是提供大豆苷元在制备调控铂类药物对肌管细胞中MyHC、Atrogin1、MuRF1、MyoG蛋白表达的药物中的应用,该药物的有效成分为大豆苷元、大豆苷元的水合物、大豆苷元药学上可接受的盐、大豆苷元的互变异构体、大豆苷元的立体异构体、大豆苷元的前体化合物中的一种或几种。
进一步,MyHC、MyoG蛋白表达水平被上调,而Atrogin1、MuRF1蛋白的表达水平被显著下调。
本发明的第四方面是提供大豆苷元在制备缓解铂类药物导致的肾小球、肾小管损伤的药物中的应用,该药物的有效成分为大豆苷元、大豆苷元的水合物、大豆苷元药学上可接受的盐、大豆苷元的互变异构体、大豆苷元的立体异构体、大豆苷元的前体化合物中的一种或几种。
本发明的第五方面是提供大豆苷元在制备缓解铂类药物干预导致的血尿素氮、血肌酐的水平上升的药物中的应用,该药物的有效成分为大豆苷元、大豆苷元的水合物、大豆苷元药学上可接受的盐、大豆苷元的互变异构体、大豆苷元的立体异构体、大豆苷元的前体化合物中的一种或几种。
进一步地,上述药物还包括药学上可接受的载体或赋形剂。
进一步地,上述药物的给药途径为口服、透皮、肌肉、皮下或静脉注射。
进一步地,药物的剂型可以为片剂、胶囊剂、口服液、口含剂、颗粒剂、冲剂、丸剂、散剂、膏剂、丹剂、混悬剂、粉剂、溶液剂、注射剂、栓剂、霜剂、喷雾剂、滴剂或贴剂。
本发明的第六方面是提供一种药物组合物,包括铂类药物和大豆苷元。
本发明采用以上技术方案,与现有技术相比,具有如下技术效果:
本发明通过实验验证了大豆苷元可以减轻铂类药物对骨骼肌分化的抑制作用,并且可以下调骨骼肌降解相关蛋白,减轻铂类药物对肾脏的损伤,为制备减轻铂类药物毒性的药物提供了策略;此外,大豆苷元来源广泛,成本低廉,可被大量使用于制备减轻铂类药物毒性的药物中。
附图说明
图1为本发明一实施例中大豆苷元对经顺铂刺激的小鼠C2C12肌管细胞分化的影响结果图;其中,图A为不同处理组的肌管细胞的荧光显微镜结果,图B为对图A荧光区域MyHC荧光阳性面积进行统计的结果,图C为对图A肌管内外细胞核数量进行统计的结果;
图2为本发明一实施例中大豆苷元对经顺铂刺激的小鼠C2C12肌管细胞MyHC、Atrogin1、MuRF1、MyoG蛋白表达的影响结果图;其中,图A为大豆苷元对MyHC、Atrogin1、MuRF1、MyoG蛋白表达的影响的WB结果图;图B为不同处理组中,MyHC蛋白相对表达的柱状统计图;图C为不同处理组中,Atrogin1蛋白相对表达的柱状统计图;图D为不同处理组中,MuRF1蛋白相对表达的柱状统计图;图E为不同处理组中,MyoG蛋白相对表达的柱状统计图;
图3为本发明一实施例中大豆苷元对顺铂治疗下的LLC荷瘤小鼠的体重(图A)、瘤块体积(图B)、摄食量(图C)的影响结果图;
图4为本发明一实施例中大豆苷元对顺铂治疗下的LLC荷瘤小鼠的肿瘤重量(图A)、摄食量(图B)、腓肠肌重量(图C)、胫骨前肌重量(图D)、肾脏重量(图E)、附睾脂肪重量(图F)的影响结果图;
图5为本发明一实施例中大豆苷元对顺铂治疗下的LLC荷瘤小鼠的腓肠肌肌纤维横截面积的影响结果图,图A为大豆苷元对顺铂治疗下的LLC荷瘤小鼠的腓肠肌肌纤维横截面HE染色结果,图B为腓肠肌肌纤维横截面面积分布结果,图C为腓肠肌肌纤维横截面面积的柱状统计图;
图6为发明一实施例中大豆苷元对顺铂治疗下的LLC荷瘤小鼠的腓肠肌肌纤维类型的影响结果图,图A为大豆苷元对顺铂治疗下的LLC荷瘤小鼠的腓肠肌肌纤维横截面SDH染色结果,图B为腓肠肌肌纤维类型分布结果,图C为腓肠肌肌纤维类型基因Myh2、Myh4、Myh7的mRNA表达水平柱状统计图;
图7为本发明一实施例中大豆苷元对顺铂治疗下的LLC荷瘤小鼠的腓肠肌中MyHC、Atrogin1、MuRF1蛋白表达的影响结果图;其中,图A为腓肠肌中MyHC、Atrogin1、MuRF1蛋白表达的影响westernblot结果,图B为MyHC蛋白相对表达的柱状统计图,图C为Atrogin1蛋白相对表达的柱状统计图,图D为MuRF1蛋白相对表达的柱状统计图;
图8为本发明一实施例中大豆苷元对顺铂治疗下的LLC荷瘤小鼠的肾脏损伤的影响结果图;
图9为本发明一实施例中大豆苷元对顺铂治疗下的LLC荷瘤小鼠血尿素氮(图A)和血肌酐(图B)表达的影响柱状统计图。
具体实施方式
本发明提供了大豆苷元在制备减轻铂类药物毒性的药物中的应用,该药物的有效成分为大豆苷元、大豆苷元的水合物、大豆苷元药学上可接受的盐、大豆苷元的互变异构体、大豆苷元的立体异构体、大豆苷元的前体化合物中的一种或几种;该药物还包括药学上可接受的载体或赋形剂。其中:
术语“药学上可接受的盐”是指所述化合物与药学上可接受的无机酸或有机酸所形成的盐,所述的无机酸包括但不限于:盐酸、氢溴酸、磷酸、硝酸、硫酸;所述的有机酸包括但不限于:甲酸、乙酸、丙酸、丁二酸、1,5-萘二磺酸、亚细亚酸、草酸、酒石酸、乳酸、水杨酸、苯甲酸、戊酸、二乙基乙酸、丙二酸、琥珀酸、富马酸、庚二酸、己二酸、马来酸、苹果酸、氨基磺酸、苯丙酸、葡糖酸、抗坏血酸、烟酸、异烟酸、甲磺酸、对甲苯磺酸、柠檬酸,以及氨基酸;所述“药学上可接受的”是指适用于人而无过度不良副反应(如毒性、刺激和变态反应),即有合理的效益/风险比的物质。
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体,例如:烯醇与相应的酮。
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体,例如:顺反异构体、对映异构体、构象异构体等。
术语“前体化合物”是指在体外无活性,但能够在生物体内进行代谢或化学反应转化为本发明的活性成分,从而发挥其药理作用的化合物。
术语“药学上可接受的”是指适用于人而无过度不良副反应(如毒性、刺激和变态反应),即有合理的效益/风险比的物质。“载体或赋形剂”包括粘合剂、填充剂、稀释剂、压片剂、润滑剂、崩解剂、着色剂、调味剂、湿润剂中的一种或几种。
在本发明一优选的实施方式中,填充剂为纤维素、甘露糖醇、乳糖中的一种或几种;崩解剂包括淀粉、聚乙烯吡咯烷酮、淀粉衍生物中的一种或几种;润滑剂为硬脂酸镁;润湿剂为十二烷基硫酸钠。
下面通过具体实施例和附图对本发明进行详细和具体的介绍,以使更好的理解本发明,但是下述实施例并不限制本发明范围。
实施例中方法如无特殊说明的采用常规方法,使用的试剂如无特殊说明的使用常规市售试剂或按常规方法配制的试剂。
实施例1
本实施例验证大豆苷元对经顺铂刺激的小鼠C2C12肌管细胞分化的抑制作用,具体的实验内容和结果如下:
小鼠C2C12成肌细胞经2%马血清诱导分化为肌管细胞,用25μM大豆苷元及40μM顺铂(DDP)单用或同时使用与C2C12肌管细胞共培育24h,经固定、透膜、封闭后,孵育MyHC一抗4℃过夜,一抗孵育后经清洗孵育同型荧光二抗2小时,二抗孵育完成并清洗后孵育DAPI进行细胞核染色,孵育10min,清洗后加入抗荧光淬灭剂覆盖,最后荧光显微镜拍照,结果如图1A所示,对图1A荧光区域MyHC荧光阳性面积进行统计结果如图1B所示(*P<0.05,**P<0.01,***P<0.001,下同),对图1A肌管内外细胞核数量进行统计,计算融合指数(肌管内细胞核数量与总细胞核数量的比值),统计结果如图1C所示。由图1可知,C2C12肌管细胞经DDP处理24h后,肌管面积明显减小,发生萎缩,融合指数也出现下降。随大豆苷元浓度增大,MyHC标记的肌管细胞面积逐渐增大,融合指数上升,反映了大豆苷元可以减轻DDP诱导的C2C12肌管细胞萎缩。
实施例2
本实施例验证大豆苷元对经顺铂刺激的小鼠C2C12肌管细胞MyHC、Atrogin1、MuRF1、MyoG蛋白表达的调控作用,具体的实验内容和结果如下:
小鼠C2C12成肌细胞经2%马血清诱导分化为肌管细胞,用25μM大豆苷元及40μM顺铂(DDP)单用或同时使用与C2C12肌管细胞共培育24h,RIPA裂解液提取总蛋白,BCA法测定蛋白浓度后调平各样本蛋白浓度,western blot法检测肌分化与降解相关蛋白MyHC、Atrogin1、MuRF1、MyoG的表达,结果如图2所示。
由图2可知,C2C12肌管细胞经DDP处理24h后,MyHC、MyoG蛋白表达水平明显下降,肌蛋白降解相关的Atrogin1、MuRF1蛋白表达水平显著上升,在大豆苷元的干预下,MyHC、MyoG的蛋白表达水平被上调,而Atrogin1、MuRF1蛋白的表达水平被显著下调。
实施例3
本实施例验证大豆苷元对顺铂治疗下的LLC荷瘤小鼠的肌肉与肾脏毒性相关症状体征的减轻作用,具体的实验内容和结果如下:
第一天,将LLC细胞(2×106个细胞/只)皮下接种于20只C57BL/6小鼠的右上侧背部,20只荷瘤鼠分为四组,每组5只,分别是荷瘤对照组(LLC组)、顺铂治疗组(LLC+DDP组)、顺铂低剂量大豆苷元联合治疗组(LLC+DDP+DAI(L)组)、顺铂高剂量大豆苷元联合治疗组(LLC+DDP+DAI(H)组),另有同批次5只C57小鼠作为正常对照组(NC组)。待肿瘤长径达5mm后(约第5天)开始给药,顺铂给药方式为腹腔注射,大豆苷元给药方式为灌胃。给药方案:NC组(生理盐水)、LLC组(生理盐水)、LLC+DDP组(DDP 4mg/kg)、LLC+DDP+DAI(L)组(DDP 4mg/kg+DAI 20mg/kg)、LLC+DDP+DAI(H)组(DDP 4mg/kg+DAI 80mg/kg),顺铂给药周期均为3天1次,大豆苷元为每天1次。每次给药前检测体重、瘤块大小,体重、瘤块与摄食量趋势如图3A-C所示。由图3可知,DDP可以明显减轻小鼠体重、抑制肿瘤生长、降低摄食量,大豆苷元的干预可以减轻顺铂对体重和摄食量的影响,而对DDP的抑瘤作用没有影响。
第18天所有小鼠处死取材,检测瘤重、腓肠肌重量、胫骨前肌重量、肾脏重量、附睾脂肪重量以及前肢抓力,结果如图4A-F所示。经大豆苷元干预后,小鼠腓肠肌重量、胫骨前肌重量、肾脏重量、附睾脂肪重量以及前肢抓力显著提升。经大豆苷元干预后小鼠腓肠肌肌纤维横截面面积显著提升,如图5所示。SDH染色结果显示,DDP的干预使得小鼠骨骼肌中II型肌纤维比重下降,而大豆苷元的干预使得II型肌纤维比重上调,如图6A、B所示。腓肠肌中与II型肌纤维相关的Myh2和Myh4 mRNA的表达水平也被DDP显著下调,大豆苷元的干预也部分恢复了Myh2和Myh4 mRNA的表达水平,如图6C所示。取腓肠肌提取总蛋白,western blot法检测MyHC、Atrogin1、MuRF1蛋白的表达,DDP的干预使得MyHC的表达下调,Atrogin1、MuRF1的表达上调,而大豆苷元上调了MyHC的表达,下调了Atrogin1、MuRF1的表达,如图7所示。DDP的干预使得小鼠肾脏肾小球部分血管扩张充血,上皮细胞边界模糊,肾小管组织水肿,且出现蛋白管型,而大豆苷元的干预缓解了肾小球和肾小管的病变,如图8所示。取小鼠血清,检测血尿素氮、血肌酐的水平,大豆苷元的干预缓解了顺铂干预导致的血尿素氮、血肌酐的水平上升,如图9所示。
由上述实施例可知,大豆苷元可以减轻铂类药物对骨骼肌分化的抑制作用,并且可以下调骨骼肌降解相关蛋白的表达,对顺铂导致的肾小球、肾小管损伤也有缓解作用,这为制备减轻铂类药物毒性的药物提供了策略。
以上对本发明的具体实施例进行了详细描述,但其只是作为范例,本发明并不限制于以上描述的具体实施例。对于本领域技术人员而言,任何对本发明进行的等同修改和替代也都在本发明的范畴之中。因此,在不脱离本发明的精神和范围下所作的均等变换和修改,都应涵盖在本发明的范围内。
Claims (10)
1.大豆苷元在制备减轻铂类药物毒性的药物中的应用,其特征在于,所述药物的有效成分为大豆苷元、大豆苷元的水合物、大豆苷元药学上可接受的盐、大豆苷元的互变异构体、大豆苷元的立体异构体、大豆苷元的前体化合物中的一种或几种。
2.大豆苷元在制备减轻铂类药物诱导的肌管细胞萎缩的药物中的应用,其特征在于,所述药物的有效成分为大豆苷元、大豆苷元的水合物、大豆苷元药学上可接受的盐、大豆苷元的互变异构体、大豆苷元的立体异构体、大豆苷元的前体化合物中的一种或几种。
3.大豆苷元在制备调控铂类药物对肌管细胞中MyHC、Atrogin1、MuRF1、MyoG蛋白表达的药物中的应用,其特征在于,所述药物的有效成分为大豆苷元、大豆苷元的水合物、大豆苷元药学上可接受的盐、大豆苷元的互变异构体、大豆苷元的立体异构体、大豆苷元的前体化合物中的一种或几种。
4.大豆苷元在制备缓解铂类药物导致的肾小球、肾小管损伤的药物中的应用,其特征在于,所述药物的有效成分为大豆苷元、大豆苷元的水合物、大豆苷元药学上可接受的盐、大豆苷元的互变异构体、大豆苷元的立体异构体、大豆苷元的前体化合物中的一种或几种。
5.大豆苷元在制备缓解铂类药物干预导致的血尿素氮、血肌酐的水平上升的药物中的应用,其特征在于,所述药物的有效成分为大豆苷元、大豆苷元的水合物、大豆苷元药学上可接受的盐、大豆苷元的互变异构体、大豆苷元的立体异构体、大豆苷元的前体化合物中的一种或几种。
6.根据权利要求1-5任一项所述的应用,其特征在于,所述铂类药物包括顺铂。
7.根据权利要求1-5任一项所述的应用,其特征在于,所述药物还包括药学上可接受的载体或赋形剂。
8.根据权利要求1-5任一项所述的应用,其特征在于,所述药物的给药途径为口服、透皮、肌肉、皮下或静脉注射。
9.根据权利要求1-5任一项所述的应用,其特征在于,所述药物的剂型可以为片剂、胶囊剂、口服液、口含剂、颗粒剂、冲剂、丸剂、散剂、膏剂、丹剂、混悬剂、粉剂、溶液剂、注射剂、栓剂、霜剂、喷雾剂、滴剂或贴剂。
10.一种药物组合物,其特征在于,包括铂类药物和大豆苷元。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110448883.2A CN113209076A (zh) | 2021-04-25 | 2021-04-25 | 大豆苷元在制备减轻铂类药物毒性的药物中的应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110448883.2A CN113209076A (zh) | 2021-04-25 | 2021-04-25 | 大豆苷元在制备减轻铂类药物毒性的药物中的应用 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN113209076A true CN113209076A (zh) | 2021-08-06 |
Family
ID=77088857
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202110448883.2A Pending CN113209076A (zh) | 2021-04-25 | 2021-04-25 | 大豆苷元在制备减轻铂类药物毒性的药物中的应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN113209076A (zh) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060167037A1 (en) * | 2003-11-19 | 2006-07-27 | Kelly Graham E | Combinational radiotherapy and chemotherapy compositions and methods |
WO2006091187A1 (en) * | 2005-02-22 | 2006-08-31 | Landauer Michael R | Isoflavonoids for preventing radiation- and chemotherapy- induced weight loss |
CN105395567A (zh) * | 2014-09-10 | 2016-03-16 | 宝耕生技股份有限公司 | 减缓化疗药物副作用的组合物 |
-
2021
- 2021-04-25 CN CN202110448883.2A patent/CN113209076A/zh active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060167037A1 (en) * | 2003-11-19 | 2006-07-27 | Kelly Graham E | Combinational radiotherapy and chemotherapy compositions and methods |
WO2006091187A1 (en) * | 2005-02-22 | 2006-08-31 | Landauer Michael R | Isoflavonoids for preventing radiation- and chemotherapy- induced weight loss |
CN105395567A (zh) * | 2014-09-10 | 2016-03-16 | 宝耕生技股份有限公司 | 减缓化疗药物副作用的组合物 |
Non-Patent Citations (2)
Title |
---|
TOMAR A.等: "The dietary isoflavone daidzein mitigates oxidative stress, apoptosis, and inflammation in CDDP-induced kidney injury in rats: Impact of the MAPK signaling pathway", 《JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY》 * |
ZHANG H.等: "Daidzein alleviates cisplatin-induced muscle atrophy by regulating Glut4/AMPK/FoxO pathway", 《PHYTOTHERAPY RESEARCH》 * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN101935334A (zh) | 小檗碱甘草次酸对映体盐及其制备方法和用途 | |
CN109912600A (zh) | 一种防治肺纤维化的咪唑并嘧啶类衍生物及其应用 | |
CN100998648A (zh) | 复方丹参肠溶片的制备方法 | |
CN111803488B (zh) | 白术内酯ⅱ在制备抗肾纤维化药物中的应用及抗肾纤维化药物 | |
CN113209076A (zh) | 大豆苷元在制备减轻铂类药物毒性的药物中的应用 | |
CN112245415A (zh) | 6-姜烯酚在制备治疗癌症恶病质药物中的应用 | |
CN111700889A (zh) | 柚皮素在制备治疗癌症恶病质药物中的应用 | |
CN1923228B (zh) | 三七提取物、丹参提取物和川芎嗪的药物组合物 | |
CN100502867C (zh) | 青藤碱用于抗肿瘤药物的制备 | |
CN109260205B (zh) | 一种汉防己甲素在制备抗糖尿病合并高血压药物中的应用 | |
CN110302221B (zh) | 臭椿根皮总生物碱及制备方法和应用 | |
CN108358947B (zh) | 一种笼状呫吨酮类化合物及其制备方法和用途 | |
CN110179804B (zh) | Reversan在制备预防和治疗心脏病药物中应用 | |
CN109350620B (zh) | 一种治疗卵巢癌的药物及其用途 | |
CN110496131B (zh) | 人参总次苷组合物、人参皂苷Rg5、人参皂苷Rk1以及人参皂苷ck的应用 | |
CN109470788A (zh) | 一种妇科千金片的质量控制方法 | |
CN115721722B (zh) | 一种治疗egfr-tki耐药的非小细胞肺癌的药物组合物 | |
CN114712427B (zh) | 一种桃树根药物的应用 | |
CN110731962A (zh) | 小檗碱、黄连碱或其活性代谢产物、及其盐在预防和/或治疗尿酸性肾病药物中的应用 | |
CN108159041B (zh) | 一种占吨酮类化合物c的药物用途 | |
CN111265665B (zh) | 一种治疗宫颈癌的药物组合物及其制药用途 | |
CN108743654B (zh) | 一种用于治疗缺血性心脏病的中药组合物及其制备方法和应用 | |
CN114949184A (zh) | Glp-1代谢物在制备减轻急性肾损伤药物中的用途 | |
CN110215469B (zh) | 一种治疗胆管癌的药物组合物 | |
CN106581027B (zh) | 一种化合物及其药物用途、组合物与制剂 |
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: 20210806 |
|
RJ01 | Rejection of invention patent application after publication |