CN105687209A - Application of radix salvia monomer compound to preparation of products for enhancing iPS cell biological characteristics - Google Patents
Application of radix salvia monomer compound to preparation of products for enhancing iPS cell biological characteristics Download PDFInfo
- Publication number
- CN105687209A CN105687209A CN201610104767.8A CN201610104767A CN105687209A CN 105687209 A CN105687209 A CN 105687209A CN 201610104767 A CN201610104767 A CN 201610104767A CN 105687209 A CN105687209 A CN 105687209A
- Authority
- CN
- China
- Prior art keywords
- ips
- cell biology
- monomer compound
- salvianolic acid
- salvia miltiorrhiza
- 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.)
- Granted
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- 239000000178 monomer Substances 0.000 title claims abstract description 23
- 150000001875 compounds Chemical class 0.000 title claims abstract description 22
- 230000002708 enhancing effect Effects 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 235000017276 Salvia Nutrition 0.000 title abstract 5
- 240000007164 Salvia officinalis Species 0.000 title 1
- 241000304195 Salvia miltiorrhiza Species 0.000 claims abstract description 21
- 235000011135 Salvia miltiorrhiza Nutrition 0.000 claims abstract description 21
- 239000011734 sodium Substances 0.000 claims abstract description 19
- 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 claims abstract description 18
- HYXITZLLTYIPOF-UHFFFAOYSA-N Tanshinone II Natural products O=C1C(=O)C2=C3CCCC(C)(C)C3=CC=C2C2=C1C(C)=CO2 HYXITZLLTYIPOF-UHFFFAOYSA-N 0.000 claims abstract description 18
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 18
- AZEZEAABTDXEHR-UHFFFAOYSA-M sodium;1,6,6-trimethyl-10,11-dioxo-8,9-dihydro-7h-naphtho[1,2-g][1]benzofuran-2-sulfonate Chemical compound [Na+].C12=CC=C(C(CCC3)(C)C)C3=C2C(=O)C(=O)C2=C1OC(S([O-])(=O)=O)=C2C AZEZEAABTDXEHR-UHFFFAOYSA-M 0.000 claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 17
- AIGAZQPHXLWMOJ-UHFFFAOYSA-N tanshinone IIA Natural products C1=CC2=C(C)C=CC=C2C(C(=O)C2=O)=C1C1=C2C(C)=CO1 AIGAZQPHXLWMOJ-UHFFFAOYSA-N 0.000 claims abstract description 17
- SNKFFCBZYFGCQN-UHFFFAOYSA-N 2-[3-[3-[1-carboxy-2-(3,4-dihydroxyphenyl)ethoxy]carbonyl-2-(3,4-dihydroxyphenyl)-7-hydroxy-2,3-dihydro-1-benzofuran-4-yl]prop-2-enoyloxy]-3-(3,4-dihydroxyphenyl)propanoic acid Chemical compound C=1C=C(O)C=2OC(C=3C=C(O)C(O)=CC=3)C(C(=O)OC(CC=3C=C(O)C(O)=CC=3)C(O)=O)C=2C=1C=CC(=O)OC(C(=O)O)CC1=CC=C(O)C(O)=C1 SNKFFCBZYFGCQN-UHFFFAOYSA-N 0.000 claims description 26
- SNKFFCBZYFGCQN-VWUOOIFGSA-N Lithospermic acid B Natural products C([C@H](C(=O)O)OC(=O)\C=C\C=1C=2[C@H](C(=O)O[C@H](CC=3C=C(O)C(O)=CC=3)C(O)=O)[C@H](OC=2C(O)=CC=1)C=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 SNKFFCBZYFGCQN-VWUOOIFGSA-N 0.000 claims description 24
- STCJJTBMWHMRCD-UHFFFAOYSA-N salvianolic acid B Natural products OC(=O)C(Cc1ccc(O)c(O)c1)OC(=O)C=Cc2cc(O)c(O)c3OC(C(C(=O)OC(Cc4ccc(O)c(O)c4)C(=O)O)c23)c5ccc(O)c(O)c5 STCJJTBMWHMRCD-UHFFFAOYSA-N 0.000 claims description 24
- 238000002347 injection Methods 0.000 claims description 14
- 239000007924 injection Substances 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 13
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 4
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- 239000011230 binding agent Substances 0.000 claims description 2
- 239000003086 colorant Substances 0.000 claims description 2
- 238000013270 controlled release Methods 0.000 claims description 2
- -1 correctives Substances 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 239000002502 liposome Substances 0.000 claims description 2
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- 239000002904 solvent Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 210000004027 cell Anatomy 0.000 abstract description 47
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 210000002242 embryoid body Anatomy 0.000 description 6
- 230000014509 gene expression Effects 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- NOTFZGFABLVTIG-UHFFFAOYSA-N Cyclohexylethyl acetate Chemical compound CC(=O)OCCC1CCCCC1 NOTFZGFABLVTIG-UHFFFAOYSA-N 0.000 description 3
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 241000699660 Mus musculus Species 0.000 description 2
- 208000012902 Nervous system disease Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 206010043276 Teratoma Diseases 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
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- 208000026106 cerebrovascular disease Diseases 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 210000001671 embryonic stem cell Anatomy 0.000 description 2
- 239000002038 ethyl acetate fraction Substances 0.000 description 2
- 210000002950 fibroblast Anatomy 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 2
- 230000000302 ischemic effect Effects 0.000 description 2
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- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000011580 nude mouse model Methods 0.000 description 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- 210000001778 pluripotent stem cell Anatomy 0.000 description 2
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- 238000011729 BALB/c nude mouse Methods 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 1
- 241000628997 Flos Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 241000207923 Lamiaceae Species 0.000 description 1
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
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- 108010019160 Pancreatin Proteins 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 108010087230 Sincalide Proteins 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 206010047295 Ventricular hypertrophy Diseases 0.000 description 1
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- 229910001425 magnesium ion Inorganic materials 0.000 description 1
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- 229960001412 pentobarbital Drugs 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
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- 238000004393 prognosis Methods 0.000 description 1
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- 108090000623 proteins and genes Proteins 0.000 description 1
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- 230000008672 reprogramming Effects 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
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- 238000004611 spectroscopical analysis Methods 0.000 description 1
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- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- 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
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0696—Artificially induced pluripotent stem cells, e.g. iPS
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/999—Small molecules not provided for elsewhere
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Genetics & Genomics (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Chemistry (AREA)
- Zoology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Biotechnology (AREA)
- Wood Science & Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Microbiology (AREA)
- Cell Biology (AREA)
- Transplantation (AREA)
- Biochemistry (AREA)
- General Engineering & Computer Science (AREA)
- Developmental Biology & Embryology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Plant Substances (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to pharmaceutical technology fields, and in particular to a kind of application of Salvia Miltiorrhiza Monomer compound in preparation enhancing iPS characteristics of cell biology product. The Salvia Miltiorrhiza Monomer compound is at least one of root of red-rooted salvia phenolic acid B and tanshinone IIA sodium sulfonate, and the structural formula of the root of red-rooted salvia phenolic acid B and tanshinone IIA is as shown in formula I and formula II: the present invention also provides a kind of enhancing iPS characteristics of cell biology drugs. IPS is pre-processed by the Salvia Miltiorrhiza Monomer ingredient of various concentration in the present invention, the results show that sodium tanshinon Ⅱa silate and root of red-rooted salvia phenolic acid B can promote multipotency to induce stem cells hyperplasia, and root of red-rooted salvia phenolic acid B is more significant in the ability of this aspect.
Description
Technical field
The invention belongs to pharmaceutical technology field, be specifically related to a kind of Salvia Miltiorrhiza Monomer compound and strengthen the application in iPS characteristics of cell biology product in preparation。
Background technology
Radix Salviae Miltiorrhizae system Labiatae herbaceos perennial, Radix Salviae Miltiorrhizae Chang Peiwu is in the prescription for the treatment of cardiovascular and cerebrovascular disease such as coronary heart disease, cerebral infarction。Secretion function of blood vessel endothelial cells is had protective effect, significantly inhibits arteriosclerosis by it, reduces the effects such as serum total cholesterol, anti-ventricular hypertrophy, antioxidation, arrhythmia。And cardiovascular patient often merges other diseases, and Radix Salviae Miltiorrhizae also has antiinflammatory, antiplatelet, anticoagulant, antithrombotic effect, can be effectively improved the prognosis of patient。Therefore, Radix Salviae Miltiorrhizae has broad application prospects in Prevention of cardiovascular disease。
Studying confirmation at present, inductive pluripotent stem cells (iPS) is by reprogramming a kind of pluripotent stem cell with the hyperproliferation similar to embryonic stem cell and Multidirectional Differentiation potentiality that somatic cell obtains, and is the important candidate stem cells repairing necrotic myocardium。Can not regenerate after cardiac muscle of mammal cell damage (such as ischemic heart desease, atherosclerosis, hypertension etc.), limit the self-regeneration function of cardiac muscle, and the similar embryonic stem cell of iPS cell, successfully it is divided into neuronal cell, neurogliocyte, cardiovascular cell and primordial germ cell etc. in vitro, therefore, iPS cell will be a kind of effective intervention means that may be used for the human diseasess such as treatment nervous system disease, cardiovascular disease, reproductive disease future。
Summary of the invention
In order to overcome the deficiencies in the prior art, the primary and foremost purpose of the present invention is in that to provide a kind of Salvia Miltiorrhiza Monomer compound to strengthen the application in iPS characteristics of cell biology product in preparation。
Another object of the present invention is to provide a kind of and strengthen iPS characteristics of cell biology medicine。
The purpose of the present invention is achieved through the following technical solutions:
A kind of Salvia Miltiorrhiza Monomer compound strengthens the application in iPS characteristics of cell biology product in preparation, described Salvia Miltiorrhiza Monomer compound is at least one in salvianolic acid B and sodium tanshinone IIA sulfate, described salvianolic acid B and shown in the structural formula of tanshinone ⅡA such as formula I and formula II:
The valid density of described salvianolic acid B is preferably 2.5 × 10-5Mol/L；
The valid density of described sodium tanshinon IIA silate injection is preferably 150 μm of ol/L；
Described Salvia Miltiorrhiza Monomer compound is preferably salvianolic acid B；
A kind of enhancing iPS characteristics of cell biology medicine, comprise above-mentioned salvianolic acid B, sodium tanshinone IIA sulfate or its pharmaceutically acceptable salt, and the mixture of the solvated compounds of salvianolic acid B, tanshinone ⅡA or its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer or its arbitrary proportion, including racemic mixture；
Described enhancing iPS characteristics of cell biology medicine also comprises pharmaceutic adjuvant or other compatible medicine；
Described pharmaceutic adjuvant refers to the pharmaceutical excipient of routine, such as solvent, disintegrating agent, correctives, preservative, coloring agent and binding agent etc.；
Described enhancing iPS characteristics of cell biology medicine includes various clinical pharmaceutical dosage form, such as tablet, injection, liposome nano granule, controlled release agent etc.；
Principles of the invention: the present invention is by after suitable iPS subcutaneous injection nude mice, visible iPS cell can break up three germinal layers, then with the Salvia Miltiorrhiza Monomer composition pretreatment iPS of variable concentrations, observe the biological effect of the Salvia Miltiorrhiza Monomer composition of variable concentrations, expression by OCT-4, C-myc after the different Salvia Miltiorrhiza Monomer composition pretreatment iPS cell of QPCR method detection, result shows, salvianolic acid B and sodium tanshinone IIA sulfate all can significantly improve the differentiation and proliferation ability of iPS, and salvianolic acid B is more notable in the effect of this aspect。
The present invention has such advantages as relative to prior art and effect:
(1) by the Salvia Miltiorrhiza Monomer composition pretreatment iPS of variable concentrations in the present invention, compare the Salvia Miltiorrhiza Monomer composition bioactive impact on iPS of each concentration, result shows, sodium tanshinon IIA silate injection and salvianolic acid B all can promote multipotency induction stem cells hyperplasia；Wherein, salvianolic acid B can promote the propagation of the iPS cell of In vitro culture, reduces its apoptosis, and can improve the expression of stem cell multi-lineage potential related gene (Oct4 and c-myc gene), thus improving iPS cell differentiation。
(2) the invention provides a kind of enhancing iPS characteristics of cell biology medicine, this medicine can promote the propagation of the iPS cell of In vitro culture, reduce its apoptosis, improve iPS cell differentiation, it is possible to be used for treating the human diseasess such as nervous system disease, cardiovascular disease (such as ischemic heart desease, atherosclerosis, hypertension etc.), reproductive disease。
Accompanying drawing explanation
Fig. 1 is the aspect graph of iPS cell colony；Wherein, A: the normal iPS cell colony (40 ×) cultivated under optical microscope；B: the normal iPS cell colony (40 ×) under fluorescence microscope；C: the iPS cellular morphology (40 ×) of differentiation。
Fig. 2 is the aspect graph of embryoid body；Wherein, A: the embryoid body (40 ×) under optical microscope；B；Embryoid body (40 ×) under fluorescence microscope。
Fig. 3 is the aspect graph after three embryonic tissue HE dyeing in teratoma；Wherein, A: the ciliated columnar epithelium of endoderm origin；B: the Flos Chrysanthemi group original neurocele of sample in ectodermal histological source；C: the cartilage islands in mesoderm tissues source。
Fig. 4 is the time growth curve figure of sodium tanshinon IIA silate injection pretreatment iPS cell。
Fig. 5 is the time growth curve figure after tanshinone IIA pretreatment iPS cell。
Fig. 6 is the time growth curve figure after salvianolic acid B pretreatment iPS cell。
Fig. 7 is OCT-4, C-myc gene expression results analysis chart after salvianolic acid B pretreatment iPS cell。
Detailed description of the invention
Below in conjunction with embodiment and accompanying drawing, the present invention is described in further detail, but embodiments of the present invention are not limited to this。
In embodiments of the invention, raw material Radix Salviae Miltiorrhizae is that Nanjing Ke Fei Pharmaceuticals Ltd gifts, and other reagent is commercial reagent, analytical pure, non-purification；Adopt the differentiation situation of HE dyeing dyeing detection iPS；The expression of westernblot method detection OCT-4, C-myc；
Embodiment 1 prepares iPS cell
(1) preparation of trophoderm (MEF): the gelatin of 0.1% (volume fraction) adds T25 culture bottle, shake up and cover, absorbed after 37 DEG C of cell culture incubators stand 20min, add 5～6mL and preheat the MEF culture fluid of 37 DEG C, meanwhile mouse embryo fibroblasts (purchased from Shanghai Chinese Academy of Sciences cell bank) is quickly removed from liquid nitrogen, it is placed in 37 DEG C of water-baths fast melt and immediately with taking in super-clean bench after the alcohol wipe cryopreservation tube that volume fraction is 75%, cell suspension in cryopreservation tube is transferred in the 15mL centrifuge tube containing MEF culture fluid, with the centrifugal 5min of 1000rpm, abandon supernatant resuspended after join in T25 culture bottle, it is placed into CO2In constant incubator, obtain trophoderm after cultivating 24h and can add iPS cell；
(2) cultivation of iPS cell and going down to posterity: the trophoderm obtained after cultivating 24h in step (1), T25 culture bottle uniformly it has been paved with as seen under 4 power microscopes, now can take out rapidly iPS cell (purchased from OEG cell institute of Shanghai Sheng Ke institute of the Chinese Academy of Sciences and OEG cell institute of Shanghai Sheng Ke institute of Chinese Academy of Sciences stem cell platform) cryopreservation tube from liquid nitrogen, the similar mouse embryo fibroblasts of resuscitation process, T25 culture bottle by the direct incoming MEF bed board of iPS cell of recovery, it is placed in 37 DEG C of cell culture incubators, change the change (Fig. 1) of liquid and observation of cell colony form every day。Treat that cell colony grows to suitable size and goes down to posterity in time, PBS (without calcium ions and magnesium ions) adds 0.25% (volume fraction) pancreatin (containing EDTA) digestion after rinsing one time gently, mice iPS cell culture fluid terminates digestion, with the centrifugal 5min of 1000rpm, abandon and reset and add culture fluid piping and druming and prepare into single cell suspension。
Embodiment 2 prepares Salvia Miltiorrhiza Monomer composition
(1) the ethanol extraction Radix Salviae Miltiorrhizae (1kg) adopting volume fraction to be 95%, it is thus achieved that total extract 76g；Total extract is suspended in 500mL water, by hexamethylene 100mL extracting twice, discards hexamethylene layer。Followed by ethyl acetate 100mL extracting twice, use Rotary Evaporators concentrating under reduced pressure, it is thus achieved that Ethyl acetate fraction；By the method for silica gel column chromatography, Ethyl acetate fraction is easily separated further, adopt cyclohexane-ethyl acetate gradient elution, collect cyclohexane-ethyl acetate 20:1 eluting position, monomeric compound tanshinone IIA (1.1g) is obtained after concentrating under reduced pressure, collect cyclohexane-ethyl acetate 2:1 eluting position, obtain monomeric compound salvianolic acid B (1.3g) after concentrating under reduced pressure, and identify the molecular structure of monomeric compound with method of spectroscopy。
Tanshinone IIA: C19H18O3, LSIMS, m/z=295 [M+H]+；1H-NMR (CDCl3, 300MHz): δ=1.31 (6H, s, H3-18andH3-18A),1.66(2H,m,H2-3),1.81(2H,m,H2-2),2.26(3H,s,H3-17), 3.29 (2H, t, J=6.6Hz, H2-1), 7.22 (1H, s, H-16), 7.55 (1H, d, J=8.3Hz, H-6), 7.63 (1H, d, J=8.3Hz, H-5). by above spectral data and and standard control, it can be determined that this compound is tanshinone IIA, and structure is such as shown in formula III:
Salvianolic acid B: C36H30O16, ESIMS, m/z=717 [M-H]-；1H-NMR(DMSO-d6, 300MHz): δ=2.96,2.76 (4H, m, H2-7andH2-7a '), 4.29 (1H, d, J=5.1Hz, H-8a), 5.11 (2H, m, H-8 ' andH-8a '), 5.80 (1H, d, J=5.1Hz, H-7a), 6.13 (1H, d, J=15.9Hz, H-8), 6.24 (1H, dd, J=1.8, 8.1Hz, H-6a), 6.45 (1H, d, J=1.8Hz, H-2a), 6.48 (1H, d, J=8.1Hz, H-5a), 6.54-6.72 (6H, m, H-2 ', H-5 ', H-6 ', H-2a ', H-5a ', H-6a '), 6.77 (1H, d, J=8.4Hz, H-5), 7.08 (1H, d, J=8.4Hz, H-6), 7.44 (1H, d, J=15.9Hz, H-7). by above spectral data and and standard control, may determine that this compound is salvianolic acid B (shown in formula I)。
(2) synthesis of sodium tanshinon IIA silate injection
0.523g tanshinone ⅡA, 25mL glacial acetic acid, 40mL acetic anhydride are placed in there-necked flask, and under the stirring of limit, while be gradually added into the mixed liquor of 20mL concentrated sulphuric acid-glacial acetic acid (1:1V/V), temperature controls, at 10～15 DEG C, 2h to be stirred at room temperature after dropwising。The mixture of reaction is slowly injected in isopyknic cold water, places 3 hours, add 20mL sodium chloride saturated solution after filtration, filter to obtain red precipitate。Being suspended in water, then extract with chloroform and remove unreacted tanshinone ⅡA, be evaporated, use recrystallizing methanol secondary, obtain red acicular crystal, survey fusing point 193～195 DEG C through fully dried, yield is 79%。Synthetic route is as follows:
Sodium tanshinon IIA silate injection is red acicular crystal (methanol), and Rhizoma et radix valerianae-concentrated sulphuric acid colour developing is for orange-yellow。ESI-MSm/z:373.0 [M-Na]-。1H-NMR(CD3OD, 300MHz): δ=1.32 (6H, s, H3-18andH3-18A),1.68(2H,m,H2-3),1.80(2H,m,H2-2),2.46(3H,s,H3-17), 3.16 (2H, t, J=6.3Hz, H2-1), 7.71 (1H, d, J=8.1Hz, H-6), 7.79 (1H, d, J=8.1Hz, H-5). by above spectral data and and standard control, it can be determined that this compound is sodium tanshinon IIA silate injection (formula II shown in)。
Embodiment 3 prepares embryoid body
Selecting the culture dish of 8cm, after being covered upset, within it the iPS cell hanging drop (embodiment 1 prepares) of 4～6 200 μ L is dripped in face, and culture dish adds 1mLPBS, then is overturn by lid lightly。CO2Constant incubator is cultivated 2～3 days, it was observed that cell mass, draw with dropper in the T25 culture bottle of incoming agar pretreatment and carry out cultivation 4～5 days, obtain embryoid body；The formation of embryoid body demonstrates iPS cell and has Multidirectional Differentiation ability (Fig. 2)。
Embodiment 4 prepares iPS differentiation model
IPS single cell clone strain (embodiment 1 prepares) is centrifugal after amplification digestion, and counted under microscope takes 1 × 105Cell melt and prepare into cell suspension in the PBS buffer solution of 200 μ L；By subcutaneous for BALB/c nude mice (purchased from Guangdong Medical Lab Animal Center) oxter big for this cell suspension inoculation to 4 week, observe teratomatous growing state, after 4～5 weeks, excessive pentobarbital is injected on nude mice abdominal cavity place after death super-clean bench and takes out teratoma, mass fraction be 4% paraformaldehyde fixing after specimens paraffin embedding slices carry out HE dyeing and observe, result is shown in Fig. 3, it is seen that iPS cell can break up three germinal layers。
The comparison on the impact that iPS breeds of the embodiment 5 different monomers composition
Take the logarithm the iPS cell (embodiment 1 prepares) of trophophase, with 1 × 106/ mL cell density is inoculated in 96 orifice plates, every hole 100 μ L；After cell attachment, liquid in hole is abandoned in suction, the tanshinone IIA (0.15625,0.3125,0.625,1.25,2.5,5,10 μ g/mL, embodiment 2 prepares) of variable concentrations, sodium tanshinon IIA silate injection (1.5 × 10 is added by every hole 100 μ L-4、1.5×10-3、1.5×10-2、1.5×10-1, 1.5,15,150 μm of ol/L, embodiment 2 prepares), salvianolic acid B group (1 × 10-4、5×10-5、2.5×10-5、1.25×10-5、6.25×10-6、3.125×10-6、1.5625×10-6Mol/L, embodiment 2 prepares) and blank group only add iPS cell culture fluid, often group 8 is parallel。Process respectively (4,8,12,24,48h) after, lucifuge adds CCK-8 (Japan colleague's chemistry institute) 10 μ L/ holes, places 2h, measure each hole optical density value D (450) by microplate reader at 450nm in incubator。Result is shown in Fig. 4～6。Result illustrates that salvianolic acid B and sodium tanshinon IIA silate injection can promote the propagation of iPS cell, reduces its apoptosis, and the optimization process concentration of salvianolic acid B is 2.5 × 10-5Mol/L, the valid density of sodium tanshinon IIA silate injection is preferably 150 μm of ol/L。
The impact on iPS differentiation potential gene OCT-4 and C-myc of the embodiment 6 Salvia Miltiorrhiza Monomer composition
Packet: by 1 × 106Individual iPS cell (embodiment 1 prepares) is planted and is reached 85～90% into 6cm culture dish 2 days cell densities of cultivation, and cell non-serum cultivates synchronization 6～12h, is randomly divided into 3 groups, it may be assumed that 1. Normal group；2. salvianolic acid B group (final concentration 2.5 × 10-5Mol/L)；3. sodium tanshinon IIA silate injection (150 μm of ol/L) group；Each group add adopt after 48h cultivated by medicine QPCR method detection OCT-4 and C-myc express (primer 5 '-3 ' OCT-4:AGGATGTGGTTCGAGTATGGTT；3 '-5 ' AAGGGACTGAGTAGAGTGTGGTG；C-myc:5 '-3 ' GGAAACGACGAGAACAGTTG；3 '-5 ' GCCAAGGTTGTGAGGTTAGG)。Result (Fig. 7) shows, salvianolic acid B significantly improves the expression of OCT-4 and C-myc compared with sodium tanshinon IIA silate injection, is obviously enhanced the differentiation capability of iPS。
Above-described embodiment is the present invention preferably embodiment; but embodiments of the present invention are also not restricted to the described embodiments; the change made under other any spirit without departing from the present invention and principle, modification, replacement, combination, simplification; all should be the substitute mode of equivalence, be included within protection scope of the present invention。
Claims (7)
1. a Salvia Miltiorrhiza Monomer compound strengthens the application in iPS characteristics of cell biology product in preparation, it is characterized in that: described Salvia Miltiorrhiza Monomer compound is at least one in salvianolic acid B and sodium tanshinone IIA sulfate, described salvianolic acid B and shown in the structural formula of tanshinone ⅡA such as formula I and formula II:
2. Salvia Miltiorrhiza Monomer compound according to claim 1 strengthens the application in iPS characteristics of cell biology product in preparation, it is characterised in that:
The valid density of described salvianolic acid B is 2.5 × 10-5Mol/L；
The valid density of described sodium tanshinon IIA silate injection is 150 μm of ol/L。
3. Salvia Miltiorrhiza Monomer compound according to claim 1 and 2 strengthens the application in iPS characteristics of cell biology product in preparation, it is characterised in that:
Described Salvia Miltiorrhiza Monomer compound is salvianolic acid B。
4. one kind strengthens iPS characteristics of cell biology medicine, it is characterized in that: comprise the salvianolic acid B described in any one of claims 1 to 3, sodium tanshinone IIA sulfate or its pharmaceutically acceptable salt, and the mixture of the solvated compounds of salvianolic acid B, tanshinone ⅡA or its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer or its arbitrary proportion, including racemic mixture。
5. enhancing iPS characteristics of cell biology medicine according to claim 4, it is characterised in that:
Described enhancing iPS characteristics of cell biology medicine also comprises pharmaceutic adjuvant or other compatible medicine。
6. enhancing iPS characteristics of cell biology medicine according to claim 5, it is characterised in that:
Described pharmaceutic adjuvant is solvent, disintegrating agent, correctives, preservative, coloring agent or binding agent。
7. the enhancing iPS characteristics of cell biology medicine according to any one of claim 4～6, it is characterised in that:
Described enhancing iPS characteristics of cell biology medicine is tablet, injection, liposome nano granule or controlled release agent。
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