CN105456481A - Application of fructus schisandrae sphenantherae extract in preparation of liver regeneration medicine - Google Patents
Application of fructus schisandrae sphenantherae extract in preparation of liver regeneration medicine Download PDFInfo
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- CN105456481A CN105456481A CN201510891109.3A CN201510891109A CN105456481A CN 105456481 A CN105456481 A CN 105456481A CN 201510891109 A CN201510891109 A CN 201510891109A CN 105456481 A CN105456481 A CN 105456481A
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- fructus schisandrae
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- schisandrae sphenantherae
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Abstract
The invention discloses application of a fructus schisandrae sphenantherae extract in preparation of a liver regeneration medicine. The fructus schisandrae sphenantherae extract is an alcohol extract of dried fruits of schisandrae sphenantherae, and the main effective ingredients of the fructus schisandrae sphenantherae extract comprise schisantherin and deoxyschizandrin. A partial hepatectomy mouse model is utilized, the fructus schisandrae sphenantherae extract is cooperatively applied, a result shows that the fructus schisandrae sphenantherae extract has the characteristics of being capable of significantly improving the quick recovering capacity of the liver-weight ratio and improving the quick proliferation capacity of liver cells, the mechanism relates to significant activation of protein expression of a related cell cycle, the manifestation is that cyclin D1 and PCNA proteins are significantly up-regulated, and meanwhile obvious improvement on liver tissue inflammatory infiltration and liver cell swelling is achieved. Experimental results show that the fructus schisandrae sphenantherae extract supplies a novel method and treatment means to liver regeneration after hepatectomy.
Description
Technical field
The invention belongs to medical art.More specifically, the application of Fructus Schisandrae Sphenantherae extract in preparation liver regeneration medicine is related to.
Background technology
Hepatectomy and Living Donor Liver Transplantation are the methods of the most effective Hepatoma therapy and End-stage liver disease in current world wide.In clinical practice, hepatectomy and the why feasible reason of Living Donor Liver Transplantation are unique, the powerful regeneration capacity of hepatocyte.But, after patient undergos surgery, if residue liver lacks regeneration capacity, delays regeneration capacity or regeneration capacity is weak, multiple bad syndrome can be caused, as Post operation acute hepatic failure, septic infection, ascites, hemorrhage, renal failure or hepatic encephalopathy.Wherein, the acute hepatic failure that Post operation occurs remains the main cause causing postoperative death rate, and is directly connected to the quality of patient's prognosis.
Liver regeneration mechanism is extremely complicated, in recent decades, very fast to relevant liver regeneration Recent Advances in Mechanism both at home and abroad, but still lacks the effective means of regulation and control liver regeneration in doctor trained in Western medicine field.At present, only be confined to the liver regeneration promoter in infrastest level, the multiplicaiton factor such as such as transforminggrowthfactor-α, hepatocyte growth factor, epidermal growth factor, or the aminoacid such as leucine, glutamic acid, valine, stem cell, platelet, anti-angiogenic antibody of releiving, thrombosis element etc.Therefore, how selectivity makes residue tranquillization hepatocyte effectively excite remaining hepatocellular regeneration potential and suppress hepatoma cell proliferation to be the key that postoperative patient is survived simultaneously, also has important theory significance and clinical value to the treatment of hepatic disease.
Fructus Schisandrae Sphenantherae SchisandrasphenantheraRehd.etWils. is people's conventional Chinese medicine, warm in nature, abnormal smells from the patient is sour, there is nourishing kidney of astringing the lung, effect of the hidroschesis that promotes the production of body fluid, mind tranquilizing and the heart calming, be mainly used in treatment chronic cough dyspnea due to deficiency, incessant chronic diarrhea, Tianjin few xerostomia, night sweat, breathe hard deficient pulse, forgetful insomnia etc.Along with pharmacological deeply development, find that Fructus Schisandrae Sphenantherae has antiinflammatory, improves immunologic function, blood vessel dilating, defying age, calmness, the pharmacological action such as anticancer, and liver protection effect.But have no the relevant report of Fructus Schisandrae Sphenantherae extract in Hepatectomy promotion liver regeneration at present.
Summary of the invention
The technical problem to be solved in the present invention is the deficiency overcoming liver regeneration technology after existing hepatectomy and Living Donor Liver Transplantation, and object is to provide the application of Fructus Schisandrae Sphenantherae extract in preparation liver regeneration medicine.The present inventor studies display, and Fructus Schisandrae Sphenantherae extract the regeneration capacity of selectivity to Hepatectomy liver can have significant facilitation, for the liver regeneration after clinical regulation and control hepatectomy or liver transplantation provides new ways and means.
Above-mentioned purpose of the present invention is achieved through the following technical solutions:
The application of Fructus Schisandrae Sphenantherae extract in preparation liver regeneration medicine, described Fructus Schisandrae Sphenantherae extract is the alcohol extract extractum of the dry fruit of Fructus Schisandrae Sphenantherae.
As the enforceable preferred version of one, the preparation method of upper described Fructus Schisandrae Sphenantherae extract is as follows:
S1. take the dry fruit of Fructus Schisandrae Sphenantherae, add the soak by water 0.5 ~ 2h of 6 ~ 10 times amount, filter and remove filtrate, obtain medicinal residues;
S2. medicinal residues are pulverized after drying, and with 70% alcohol reflux 2 ~ 3 times of 6 ~ 10 times amount, each 1 ~ 2h, filters, merging filtrate, concentrates, obtains Fructus Schisandrae Sphenantherae extract extractum.
Preferably, the amount of water described in step S1 is 8 times of Fructus Schisandrae Sphenantherae dry fruit.
Preferably, the time decocted described in step S1 is 1h.
Preferably, the amount of 70% ethanol described in step S2 is 8 times of medicinal residues.
Preferably, reflux, extract, described in step S2 2 times, each 1.5h.
Further preferably, in described Fructus Schisandrae Sphenantherae extract, the mass fraction of schisantherin A and deoxyschizandrin is all not less than 2.5%.
In addition, above-mentioned liver regeneration medicine refers to the medicine that can promote hepatectomy or the postoperative liver regeneration of major liver resection.
Further, above-mentioned liver regeneration medicine refers to the medicine that can improve liver/weight ratio recovery capability.
Specifically preferably, described liver regeneration medicine refers to the medicine that can improve hepatectomy or major liver resection postoperative liver/weight ratio recovery capability.
Further, described liver regeneration medicine refers to the medicine that can improve hepatocyte growth ability.
Specifically preferably, described liver regeneration medicine refers to the medicine that can improve hepatectomy or the postoperative hepatocyte competence for added value of major liver resection.
More specifically, above-mentioned liver regeneration medicine can make residue tranquillization hepatocyte effectively excite remaining hepatocellular regeneration potential and suppress hepatoma cell proliferation simultaneously by selectivity.
The above-mentioned liver regeneration medicine of the present invention can be used in treating the patient having accepted hepatectomy/or partial liver transplantation.
The mechanism of above-mentioned liver regeneration medicine relates to fast upregulation cyclin cyclinD1 and PCNA and expresses, thus promotes hepatocyte growth.
A kind of liver regeneration medicine, comprises above-mentioned Fructus Schisandrae Sphenantherae extract and pharmaceutical carrier.
Preferably, described pharmaceutical carrier is one or more in filler, binding agent, wetting agent, disintegrating agent, correctives, lubricant or antiseptic.
More preferably, described filler is starch, dextrin, Icing Sugar, lactose, microcrystalline Cellulose, calcium hydrogen phosphate or sugar alcohols.
Preferably, described binding agent is starch slurry, gelatin, polyvidone or cellulose derivative.
Preferably, described wetting agent is water and ethanol.
Preferably, described disintegrating agent is dried starch, carboxymethylstach sodium, carmethose, sodium bicarbonate or polyvidone.
Preferably, described correctives is stevioside, saccharin sodium, protein sugar or cyclamate.
Preferably, described lubricant is magnesium stearate, calcium stearate, micropowder silica gel, Pulvis Talci, Polyethylene Glycol or Stepanol MG.
Preferably, described antiseptic is benzoic acid, sorbic acid or nipalgin.
In addition, preferably, the dosage form of described liver regeneration medicine comprises tablet, powder, granule, capsule, solution, Emulsion etc.
Preferably, the dosage form of described medicine can also be slow releasing agent or controlled release agent.
In prior art before result of study of the present invention, although there is report one of Fructus Schisandrae Chinensis extrat and effective ingredient thereof schisantherin B prevention and therapy acetaminophen or the hepatotoxic Partial Mechanism caused by lithocholic acid to be significantly promote hepatocyte growth correlative protein expression.But, there is essential distinction in the liver toxicity symptom that one side acetaminophen or cholestasis cause and the acute liver damage that hepatectomy causes, there are some researches show, acetaminophen liver toxicity is started by its N-acetyl-p-benzoquinonimine, it can make liver endogenous glutathione exhaust, thus cause mitochondrial function confusion and nuclear dna damage, finally cause hepatocellular damage and hepatic necrosis; Lithocholic acid liver toxicity causes due to the retention of overdosage toxicity bile acid, and it can cause toxicant to be accumulated as bilirubin, cholesterol and bile acid thus adjoint liver function generation obstacle, hepatic fibrosis even liver cirrhosis.And hepatectomy is by the focal part excision in liver, remaining normal hepatic tissue can start tranquillization hepatocyte growth immediately, can improve hepatic injury situation very soon, reaches the behavior of original liver heavy then termination propagation.The Fructus Schisandrae Chinensis extrat effective ingredient of its report is different from the effective ingredient of Fructus Schisandrae Sphenantherae dry fruit alcohol extract of the present invention on the other hand.
Fructus Schisandrae Sphenantherae extract of the present invention (the dry fruit extract of Fructus Schisandrae Sphenantherae, principle active component is schisantherin A and deoxyschizandrin) significantly can promote the fast quick-recovery of liver/weight ratio and promotion hepatocyte fast breeding, and it promotes that after hepatectomy the mechanism of liver regeneration relates to fast upregulation cyclin CyclinD1 and PCNA and expresses, thus promote hepatocyte growth.
The present invention has following beneficial effect:
The present invention tests and utilizes 2/3 classical hepatectomy model, after giving Fructus Schisandrae Sphenantherae extract, effectively can accelerate the recovery of the heavy and function of liver, and be embodied in Hepatectomy 2 days, 3 days and 5 days, the liver weight ratio of mice significantly raises; Hepatectomy 1 day, 1.5 days, the hepatocyte that mice is in propagation was significantly increased, and reduces gradually subsequently; Inflammatory infiltration simultaneously in hepatic tissue and cellular edema situation are obviously improved.
In addition, the present invention also observes the impact that Fructus Schisandrae Sphenantherae grows normal hepatocytes, found that Fructus Schisandrae Sphenantherae does not affect normal liver growth.
Result shows in sum, and Fructus Schisandrae Sphenantherae extract the regeneration capacity of selectivity to Hepatectomy liver can have significant facilitation, for the liver regeneration after clinical regulation and control hepatectomy or liver transplantation provides new ways and means.
Accompanying drawing explanation
What Fig. 1 was Fructus Schisandrae Sphenantherae extract on the mice of partially hepatectomized and Mice normal liver/weight ratio affects result figure.
What Fig. 2 was Fructus Schisandrae Sphenantherae extract on the mouse liver cell inflammatory infiltration of partially hepatectomized and edema affects result figure (H & E dye hepatic pathology section).
To be Fructus Schisandrae Sphenantherae extract breed the mouse liver cell of partially hepatectomized Fig. 3 affects result figure (the hepatic pathology section of Ki67 SABC).
Fig. 4 is that Fructus Schisandrae Sphenantherae extract affects result figure to the protein expression of mouse liver CylinD1 and PCNA of Partial Resection.
In Fig. 1 ~ 4, A is hepatectomy group, and B is hepatectomy/Fructus Schisandrae Sphenantherae extract group, and C is sham operated rats, and D is sham-operation/Fructus Schisandrae Sphenantherae extract group.
Detailed description of the invention
Further illustrate the present invention below in conjunction with Figure of description and specific embodiment, but embodiment does not limit in any form to the present invention.Unless stated otherwise, the present invention adopts reagent, method and apparatus are the art conventional reagent, method and apparatus.
Unless stated otherwise, agents useful for same of the present invention and material are commercial.
The preparation of embodiment 1 Fructus Schisandrae Sphenantherae extract
Get Fructus Schisandrae Sphenantherae 100g, add the soak by water lh of 8 times amount, filter and remove filtrate, medicinal residues are pulverized after drying, and with 70% alcohol reflux 2 times of 8 times amount, each 1.5h, filters, merging filtrate, concentrates, obtains Fructus Schisandrae Sphenantherae extract extractum.
The preparation of embodiment 2 Fructus Schisandrae Sphenantherae extract
Get Fructus Schisandrae Sphenantherae 100g, add the soak by water 0.5h of 6 times amount, filter and remove filtrate, medicinal residues are pulverized after drying, and with 70% alcohol reflux 2 times of 6 times amount, each 1h, filters, merging filtrate, concentrates, obtains Fructus Schisandrae Sphenantherae extract extractum.
The preparation of embodiment 3 Fructus Schisandrae Sphenantherae extract
Get Fructus Schisandrae Sphenantherae 100g, add the soak by water 2h of 10 times amount, filter and remove filtrate, medicinal residues are pulverized after drying, and with 70% alcohol reflux 3 times of 10 times amount, each 2h, filters, merging filtrate, concentrates, obtains Fructus Schisandrae Sphenantherae extract extractum.
Embodiment 4 Fructus Schisandrae Sphenantherae extract is to the Effect study of Hepatectomy liver regeneration
This experiment, for the Fructus Schisandrae Sphenantherae extract prepared by embodiment 1, studies its effect to Hepatectomy liver regeneration.
1, experiment process
(1) animal model: C57BL/6 mice, male, 8-10 age in week, provided by Guangdong Medical Lab Animal Center, animal quality certification card number is SYXK (Guangdong) 2011-0112.
(2) rearing conditions: raise under standard laboratory conditions: temperature (23 ± 2 DEG C), humidity (55 ± 10%), 12 h light-12 h dark cycle, freely absorb water and food.
(2) experiment grouping: mice is divided into 4 groups at random:
A group: hepatectomy group;
B group: hepatectomy/Fructus Schisandrae Sphenantherae extract group (in schisantherin A, 9.2mg/kg, p.o.);
C group: sham operated rats;
D group: sham-operation/Fructus Schisandrae Sphenantherae extract group (in schisantherin A, 9.2mg/kg, p.o.).
And after reviving after surgery, start the Fructus Schisandrae Sphenantherae extract of the schisantherin A given containing 9.2mg/kg.Wherein sham operated rats and sham-operation/Fructus Schisandrae Sphenantherae extract group, sew up after opening mouse peritoneal, but do not carry out hepatectomy in process of the test.
Mice gives Fructus Schisandrae Sphenantherae extract and puts to death after 1 day, 1.5 days, 2 days, 3 days, 5 days, 7 days, 10 days.The liver gathered carries out histopathological examination and Study on Molecular Mechanism.
2, the mensuration of liver recondition index
Liver/weight ratio the formula of generally acknowledging according to academia weighs liver recondition:
。
Result as shown in Figure 1, can find out, after hepatectomy, liver/the weight ratio of mice increases gradually along with the prolongation of time, Fructus Schisandrae Sphenantherae extract then can accelerate the recovery of the liver/weight ratio of hepatectomy mice significantly in advance, 2 days, 3 days, 5 day time-division did not improve 16%, 21%, 20%, almost reached normal liver/weight ratio when 10 days.But giving separately the liver growth of Fructus Schisandrae Sphenantherae extract on normal mouse (sham-operation) does not affect.
The above results shows that Fructus Schisandrae Sphenantherae extract optionally can promote the recovery that Hepatectomy liver is heavy.
3, Liver Histology
(1) liver organization H & E dyes and observes liver damage situations
Hepatic tissue is fixed through 10% neutral formalin, organize repair cut, distilled water flushing, dehydration, paraffin embedding, conventional section obtain 4 μm of sections.Again section is dewaxed, dyeing, dehydration, transparent, mounting carry out observation by light microscope hepatocyte inflammatory infiltration and edema situation.Result as shown in Figure 2.
As can be seen from Figure 2, hepatectomy is after 1 day, and obvious inflammatory infiltration and edema appear in mice residue lobe of the liver central vein.Compare hepatectomy group, the cellular inflammation that Fructus Schisandrae Sphenantherae extract then significantly improves Hepatectomy mice infiltrates and edema situation.The above results has pointed out Fructus Schisandrae Sphenantherae extract to have certain therapeutical effect to liver organization damage after hepatectomy.
(2) liver organization Ki67 Immunohistochemical study hepatocyte growth situation
Ki-67 be a kind of nucleoprotein by MKI-67 gene code, be referred to as MKI-67 again, in each phase (G1, S, G2 and M) of cell proliferation, all have expression, but do not express in G0 phase cells quiescent phase, for pointing out the propagation active degree of cell.
Paraffin section closed through dewaxing aquation, antigen retrieval, serum, drips Ki67 primary antibodie, PBS rinses, drip that rabbit two is anti-, PBS flushing, DAB colour developing, haematoxylin dyeing, dehydration, mounting obtain Ki67 pathological immune group and cut.Result as shown in Figure 3.
As can be seen from Figure 3, after hepatectomy, mouse liver cell propagation along with time increase, and reached propagation peak value, subsequently along with the prolongation of time reduces gradually 2 days time.Compare hepatectomy group, Fructus Schisandrae Sphenantherae extract then significantly improves the hepatocellular propagation peak value of Hepatectomy in advance, and according to psychological need premature termination hepatocyte growth.The above results has pointed out Fructus Schisandrae Sphenantherae extract to have remarkable facilitation to liver cell regeneration after hepatectomy.
4, CyclinD1 and PCNA protein expression level detects
Adopt the total protein in total protein extraction agent box extraction liver organization, adopt BCA method to measure protein content and also carry out sodium lauryl sulphate-polyacrylamide gel electrophoresis.After transferring film, close 60 minutes by 5% defatted milk powder room temperature, CyclinD1 rabbit monoclonal antibodies and PCNA rabbit monoclonal antibodies 4 DEG C of overnight incubation; Adding rabbit two next day resists in incubated at room 65 minutes, Electrochemiluminescince development, fixing.Use the same method and carry out the protein expression analysis of internal reference GAPDH.Evaluate the expression whether Fructus Schisandrae Sphenantherae extract promotes CyclinD1 and PCNA, thus promote hepatocyte growth.Result as shown in Figure 4.
As can be seen from Figure 4, after hepatectomy, in mouse liver, CyclinD1 and PCNA protein expression increased along with the time, and 2 days time, reached propagation peak value, subsequently along with the prolongation of time reduces gradually.Compare hepatectomy group, Fructus Schisandrae Sphenantherae extract then significantly increases CyclinD1 and the PCNA protein expression of Hepatectomy mouse liver cell in advance.
The above results has pointed out Fructus Schisandrae Sphenantherae extract to relate to the remarkable facilitation of cell cycle associated protein CyclinD1 and PCNA expression to the mechanism of liver cell regeneration facilitation after hepatectomy.
Embodiment 5 Hepatectomy liver regeneration medicine
1, confirm through experiment, comprise the medicine of Fructus Schisandrae Sphenantherae extract, there is the characteristic well improving liver/weight ratio fast restoration capabilities and improve hepatocyte fast breeding ability, mechanism relates to remarkable active cell cycle correlative protein expression, show as and significantly raise cyclin CylinD1 and PCNA albumen, regulating liver-QI cellular edema is infiltrated to liver tissues inflammatory simultaneously and have clear improvement.Therefore this medicine is a kind of liver regeneration medicine of new Hepatectomy.
2, the above-mentioned liver regeneration medicine comprising Fructus Schisandrae Sphenantherae extract, can also comprise pharmaceutical carrier.
Described pharmaceutical carrier can be one or more in filler, binding agent, wetting agent, disintegrating agent, correctives, lubricant or antiseptic.
Wherein, described filler can be starch, dextrin, Icing Sugar, lactose, microcrystalline Cellulose, calcium hydrogen phosphate or sugar alcohols.
Described binding agent can be starch slurry, gelatin, polyvidone or cellulose derivative.
Described wetting agent can be water and ethanol.
Described disintegrating agent can be dried starch, carboxymethylstach sodium, carmethose, sodium bicarbonate or polyvidone.
Described correctives can be stevioside, saccharin sodium, protein sugar or cyclamate.
Described lubricant can be magnesium stearate, calcium stearate, micropowder silica gel, Pulvis Talci, Polyethylene Glycol or Stepanol MG.
Described antiseptic can be benzoic acid, sorbic acid or nipalgin.
In addition, the dosage form of described liver regeneration medicine can be tablet, powder, granule, capsule, solution, Emulsion etc., can also be slow releasing agent or controlled release agent.
Above-mentioned various types of liver regeneration medicine can prepare according to this area conventional method, and has significant facilitation to the liver regeneration that hepatectomy/Partial Resection is postoperative, may be used for treating the patient having accepted hepatectomy/or partial liver transplantation.
Claims (10)
1. the application of Fructus Schisandrae Sphenantherae extract in preparation liver regeneration medicine, it is characterized in that, described Fructus Schisandrae Sphenantherae extract is the alcohol extract extractum of the dry fruit of Fructus Schisandrae Sphenantherae.
2. apply according to claim 1, it is characterized in that, described Fructus Schisandrae Sphenantherae extract prepares by the following method:
S1. take the dry fruit of Fructus Schisandrae Sphenantherae, add the soak by water 0.5 ~ 2h of 6 ~ 10 times amount, filter and remove filtrate, obtain medicinal residues;
S2. medicinal residues are pulverized after drying, and with 70% alcohol reflux 2 ~ 3 times of 6 ~ 10 times amount, each 1 ~ 2h, filters, merging filtrate, concentrates, obtains Fructus Schisandrae Sphenantherae extract extractum.
3. apply according to claim 1, it is characterized in that, in described Fructus Schisandrae Sphenantherae extract, the mass fraction of schisantherin A and deoxyschizandrin is all not less than 2.5%.
4. apply according to claim 1, it is characterized in that, described liver regeneration medicine refers to the medicine that can promote hepatectomy or the postoperative liver regeneration of major liver resection.
5. apply according to claim 1, it is characterized in that, described liver regeneration medicine refers to the medicine that can improve liver/weight ratio recovery capability.
6. apply according to claim 1, it is characterized in that, described liver regeneration medicine refers to the medicine that can improve hepatocyte growth ability.
7. apply according to claim 6, it is characterized in that, described liver regeneration medicine refers to and residue tranquillization hepatocyte can be made effectively to excite remaining hepatocellular regeneration potential and suppress the medicine of hepatoma cell proliferation simultaneously by selectivity.
8. apply according to claim 6, it is characterized in that, described liver regeneration medicine refers to that can raise cyclin cyclinD1 and PCNA expresses thus the medicine promoting hepatocyte growth.
9. a liver regeneration medicine, is characterized in that, comprises Fructus Schisandrae Sphenantherae extract described in claim 1 or 2 and pharmaceutical carrier.
10. liver regeneration medicine according to claim 9, is characterized in that, described pharmaceutical carrier is one or more in filler, binding agent, wetting agent, disintegrating agent, correctives, lubricant or antiseptic.
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| CN108685885A (en) * | 2017-07-11 | 2018-10-23 | 南华大学 | Medical composition and its use containing schizandrin A |
| CN113604420A (en) * | 2021-07-07 | 2021-11-05 | 南方医科大学珠江医院 | Method for inducing human placental mesenchymal stem cells to differentiate into liver cells in vitro and composition containing schisandrin B |
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| CN103751173A (en) * | 2014-01-06 | 2014-04-30 | 广东医学院附属医院 | Application of dihydromyricetin in preparation of liver regeneration medicine |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108685885A (en) * | 2017-07-11 | 2018-10-23 | 南华大学 | Medical composition and its use containing schizandrin A |
| CN108685885B (en) * | 2017-07-11 | 2023-11-17 | 南华大学 | Pharmaceutical composition containing schizandrin A and application thereof |
| CN113604420A (en) * | 2021-07-07 | 2021-11-05 | 南方医科大学珠江医院 | Method for inducing human placental mesenchymal stem cells to differentiate into liver cells in vitro and composition containing schisandrin B |
| CN113604420B (en) * | 2021-07-07 | 2022-07-08 | 南方医科大学珠江医院 | Method for inducing human placental mesenchymal stem cells to differentiate into liver cells in vitro and composition containing schisandrin B |
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