CN109453367A - Application of the fibroblast growth factor 21 in the damage of acute liver damage ileal mucous membrane - Google Patents
Application of the fibroblast growth factor 21 in the damage of acute liver damage ileal mucous membrane Download PDFInfo
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Abstract
The present invention provides purposes of the fibroblast growth factor 21 in the case where acute liver damage is treated in preparation in intestinal mucosal injury drug.When FGF21 treats the intestinal mucosal injury under acute liver damage, the intestinal mucosa of damage is not only repaired, microbial flora in enteron aisle is reduced and hepatic injury is further aggravated, plays the role of controlling acute liver damage exacerbation；In addition, hepatic injury can also be repaired since FGF21 has therapeutic effect to the liver cell in hepatic injury.Using FGF21 can under acute liver damage intestinal mucosal injury and hepatic injury play therapeutic effect simultaneously.
Description
Technical field
The present invention relates to the new medical use of fibroblast growth factor 21 (FGF21), in particular to FGF21 is for controlling
The new opplication for treating the damage of acute liver damage ileal mucous membrane, belongs to biomedicine technical field.
Background technique
Acute liver damage is a kind of clinical syndrome, shows as occurring apparent hepatocellular damage suddenly and deteriorate rapidly,
Lead to hepatic encephalopathy and coagulation disorders, case fatality rate is high.There are many reason of clinically causing acute liver damage, mainly has
Virus infection, ethyl alcohol excess intake, wrongly takes poisonous food, radiation damage etc. at the improper, food additive of medication.
In recent years, it with the raising of quality of the life, takes Chinese herbal medicine and carries out health care, to the pursuit of game food and arbitrarily
The crowd for increasing clinical dosage gradually increases, so that the disease incidence of acute liver damage is stepped up.
Microbial flora containing substantial amounts in the enteron aisle of body (human body and animal body), intestinal colony can also be seen as
One bacterium organ of body, under normal circumstances, intestinal flora keep a kind of dynamic equilibrium state and mutual with host
Effect, the deep ability for influencing host versus infection.
However, in many diseases, such as hepatopathy, hemorrhagic shock, severe burn, fracture and multiple organ failure, intestines
The balance of road flora is often broken, so that intestinal flora ingredient changes, is become the source of organism infection, is generated serious
Clinical symptoms.
In various clinical diseases, especially in hepatopathy, due to the presence of intestines-liver axis, pass through bile secretion and liver blood
The variation of stream, so that the structure and composition of intestinal flora changes.The study found that Escherichia coli can not damage on enteron aisle
Expand the permeability of colon in the case where chrotoplast.In acute liver damage, the cellular immunity and humoral immune function of body are lost
It adjusts, inflammatory factor and stress hormone largely discharge, while intestinal mucosal barrier is impaired, and bacterium dystopy easily occurs for intestinal flora,
Hepatic injury is aggravated, the generation of multiple organ dysfunction or systemic inflammatory response is even resulted in.
Therefore, in treatment hepatopathy especially acute liver damage, intestinal mucosa reparation or the control of intestinal colony are to treatment
The effect of hepatopathy often be can not ignore.
Actively control infection is needed when clinical treatment acute liver damage, at present to prevent infection diffusion from aggravating the state of an illness；And
Combination other drugs are treated and are controlled.
However, anti-infectives are due to different antimicrobial spectrum and bacterial drug resistance, it may be for certain patients simultaneously
It is not applicable；Also, anti-infectives only control the breeding of bacterium colony, but have no effect for repairing intestinal mucosa damage, to liver
Damage also has no therapeutic effect.
Fibroblast growth factor 21 (FGF21) is a kind of specific effect in the new of liver, pancreas islet and adipose tissue
The type metabolic regulation factor.FGF21 has reduction body blood pressure and blood lipoid, improves a variety of sugar such as insulin resistance, protection beta Cell of islet
The function of lipid metaboli regulation.
FGF21 is also a kind of endogenous regulation factor, can be combined with the growth factor receptors of cell surface, and junket ammonia is activated
Acid kinase starts a series of changes of function so as to cause downstream signal activation.
FGF21 is current research hotspot, also to be developed there are many acting on；And research and develop the new clinical work of FGF21
With being the eternal pursuit of scientific research personnel.
In view of the above technical problems, the present inventor improves on the basis of existing technology, has investigated a kind of at fibre
Tie up new application of the Porcine HGF 21 in preparation treatment acute liver damage ileal mucous membrane damage medicine.
Summary of the invention
To solve the above-mentioned problems, present inventor has performed sharp studies, as a result, it has been found that: FGF21 treats acute liver damage
Under intestinal mucosal injury when, not only repair the intestinal mucosa of damage, reduce microbial flora in enteron aisle to hepatic injury further plus
Weight plays the role of controlling acute liver damage exacerbation；In addition, since FGF21 has treatment to the liver cell in hepatic injury
Effect, can also repair hepatic injury.Using FGF21 can under acute liver damage intestinal mucosal injury and hepatic injury play simultaneously
Therapeutic effect, so as to complete the present invention.
The purpose of the present invention is to provide following aspect:
The present invention provides a kind of pharmaceutical composition for treating acute liver damage, the composition includes fibroblast
Growth factor-2 1.
It is damaged with when intestinal mucosal injury, preferably acute liver damage with ileal mucous membrane when the acute liver damage.
The fibroblast growth factor 21 is used alone, or is used in conjunction with as active constituent and other auxiliary materials.
The fibroblast growth factor 21 is used with the solution form for being dissolved or dispersed in solvent；
Described pharmaceutical composition is powder-injection or injection solution；
The dosage of fibroblast growth factor 21 be 0-0.5mg/kg, preferably 0.01-0.35mg/ml, more preferably
0.01-0.3mg/ml。
Fibroblast growth factor 21 is dissolved/is suspended in solvent as active constituent and auxiliary material；
One of the preferred osmotic pressure regulator of the auxiliary material, pH adjusting agent, freeze drying protectant, complexing agent and antioxidant
Or it is a variety of；
The dosage of fibroblast growth factor 21 and auxiliary material is 0.1%-30%, preferably 0.1%-25%, more preferably
For 0.1%-20%, by weight.
It is acute in preparation treatment that the present invention provides a kind of fibroblast growth factor 21 (FGF21) or pharmaceutical composition
Purposes in liver injury medicament；
Wherein, fibroblast growth factor 21 improves the expression of SIRT1 in liver when treating acute liver damage；
Further, fibroblast growth factor 21 is in the case where acute liver damage is treated in preparation in intestinal mucosal injury drug
Purposes；
Especially use of the fibroblast growth factor 21 in preparation treatment acute liver damage ileal mucous membrane damage medicine
On the way.
The fibroblast growth factor 21 provided according to the present invention, has the advantages that
Fibroblast growth factor 21 or pharmaceutical composition can be used for treating acute liver damage；
(2) ileal mucous membrane when fibroblast growth factor 21 or pharmaceutical composition can be used for treating acute liver damage
Damage；
(3) fibroblast growth factor 21 or pharmaceutical composition do not promote the ability of cell Proliferation, will not antagonism
The function of other members of FGF family, safety in utilization are very high.
Detailed description of the invention
Fig. 1 shows the hematoxylin eosin staining figure of mouse liver in experimental example 1: A is blank control group；B is model group；C
For FGF21 low dose group；D is FGF21 middle dose group；E is FGF21 high dose group；F is diammonium glycyrrhizinate positive controls；
Fig. 2 shows the hematoxylin eosin staining figures of mouse ileal mucous membrane in experimental example 2: A is blank control group；B is model
Group；C is FGF21 low dose group；D is FGF21 middle dose group；E is FGF21 high dose group；F is diammonium glycyrrhizinate positive control
Group；
Fig. 3 shows the transmission electron microscope picture of mouse ileal mucous membrane in experimental example 3: A is blank control group；B is model group；C is
FGF21 low dose group；D is FGF21 middle dose group；E is FGF21 high dose group；F is diammonium glycyrrhizinate positive controls；
A shows the variation of FGF21 content in mice serum in experimental example 4 in Fig. 4；Western- in experimental example 4 is shown in B
The FGF21 of blot method measurement and the variation of the autophagy factor；
The expression of the SIRT1 and FGF21 of the mouse liver that western-blot method measures in experimental example 5 are shown in Fig. 5
Result figure.
Specific embodiment
Present invention will now be described in detail, and the features and advantages of the invention will become more with these explanations
It is clear, clear.
Dedicated word " exemplary " means " being used as example, embodiment or illustrative " herein.Here as " exemplary "
Illustrated any embodiment should not necessarily be construed as preferred or advantageous over other embodiments.Although each of embodiment is shown in the attached drawings
In terms of kind, but unless otherwise indicated, it is not necessary to attached drawing drawn to scale.
The present invention described below.
FGF21 is a kind of endocrine type fibroblast growth factor, has anti-oxidation stress, anti-inflammatory, improvement energy generation
It thanks, inhibit the cardiovascular protective effects such as cardiomyocyte apoptosis.
It in the present invention, is found by the internal in vitro study to FGF21, FGF21 damages hepatic injury especially Acute Hepatic
Liver cell has therapeutic effect in wound, reduces cell infiltration in liver cell, reduces vacuolar degeneration of hepatic cell and/or necrosis；
When using FGF21 treatment acute liver damage, it can be improved SIRT1's in liver (silent message regulatory factor 1)
Expression, also, the expression of SIRT1 increases with the increase of FGF21 dosage.
The III class histone that Sirt1 (silent message regulatory protein 1) belongs to (nicotinamide adenine dinucleotides) dependence is gone
Acetylase is a kind of multi-functional protein, research shows that Sirt1 can make relying on 310 of NF- κ B (RelA/p65)
The deacetylated transcriptional activity to inhibit NF- κ B of histidine residue, the expression for reducing gene downstream promote the apoptosis of cell,
In, NF- κ B is a kind of transcription factor, in the Codocyte factor and with inflammation, cell Proliferation, apoptosis, angiogenesis and transfer etc.
Crucial adjustment effect is played in the gene expression of related protein.Studies have shown that NF- κ B signal access is inflammatory reaction and urgency
Property hepatic injury connection one of important access, its activation can lead to the release of downstream inflammatory factor, and induction generates leucocyte Jie
Element -1 (IL-1), IL-6 and tumor necrosis factor-alpha (TNF-α), this infiltrates inflammatory factor large area, to induce acute
The hepatic injury even development of liver cancer.
P53 is the tumor suppressor gene for participating in cell cycle regulating, in numerous Cell cycle regulatory proteins, determines cell point
Change, growth retardation and Apoptosis.The study found that in CCl4, lipopolysaccharides (LPS) joint D-Gal (D-GalN) etc. lures
In the liver injury model led, model group p53 expression is all significantly increased, and after giving relative medicine treatment, p53 can be significantly reduced
Expression, this explanation, during hepar damnification and treatment, the expression of p53 plays crucial biology and makees
With Sirt1 can make p53 deacetylated to inhibit the activity of p53 and treatment of the anti-apoptotic to performance to acute liver damage
Effect.
FGF21 can also treat the intestinal mucosal injury under acute liver damage, repair intestinal mucosal injury, mitigate degree of injury；
Particularly, FGF21 can treat the damage of the ileal mucous membrane under acute liver damage, make ileal mucous membrane villus is loose to expand, iuntercellular
It connects normal.
When FGF21 treats the intestinal mucosal injury under acute liver damage, the intestinal mucosa of damage is not only repaired, is reduced micro- in enteron aisle
Hepatic injury is further aggravated in biological flora, plays the role of controlling acute liver damage exacerbation；In addition, due to FGF21 pairs
Liver cell in hepatic injury has therapeutic effect, can also repair hepatic injury.Due to the presence of intestines-liver axis, Hepatic function improvement
Afterwards, it by the variation of bile secretion and liver blood flow, so that the structure and composition of intestinal flora further improves and balances, reduces
Stimulation to intestinal mucosa；And improved intestinal mucosa and enteric microorganism composition can also reduce the influence to hepatic injury.It uses
FGF21 can under acute liver damage intestinal mucosal injury and hepatic injury play therapeutic effect simultaneously.
Therefore, the present invention provides a kind of pharmaceutical composition for treating acute liver damage, the composition includes into fibre
Tie up Porcine HGF 21.
It is damaged with when intestinal mucosal injury, preferably acute liver damage with ileal mucous membrane when the acute liver damage.
The fibroblast growth factor 21 is used alone, or is used in conjunction with as active constituent and other auxiliary materials.
In a preferred embodiment, the fibroblast growth factor 21 is to be dissolved or dispersed in the molten of solvent
Liquid form uses, and the solvent is water.
Preferably, fibroblast growth factor 21 is dissolved/is mixed as active constituent and auxiliary material in described pharmaceutical composition
It is suspended from solvent, the auxiliary material is preferably in osmotic pressure regulator, pH adjusting agent, freeze drying protectant, complexing agent and antioxidant
It is one or more；It can be conventionally powder needle or solution obtained in described pharmaceutical composition.
Described pharmaceutical composition preferably injects use, including any in intramuscular injection, intravenous injection and subcutaneous injection.Institute
It states pharmaceutical composition sustained release preparation can also be made and subcutaneously bury and stay, lasting slow release FGF21.
In pharmaceutical composition, the freeze drying protectant includes any in mannitol and glutathione；The osmotic pressure
Regulator is sodium chloride or glucose；The pH adjusting agent includes sodium hydroxide, sodium chloride, phosphoric acid, sodium dihydrogen phosphate, phosphoric acid hydrogen
One of disodium, sodium acetate are a variety of；The complexing agent is sodium ethylene diamine tetracetate；The antioxidant is vitamin C, Asia
It is any in sodium sulphate, sodium pyrosulfite.
The dosage of fibroblast growth factor 21 and auxiliary material is 0.1%-30%, preferably 0.1%-25%, more preferably
For 0.1%-20%, by weight.
In the liver damage disease of described pharmaceutical composition treatment, the acute of alcohol, drug or harmful substance induction can be
Hepatic injury, particularly including the acute liver damage of tetrachloro-methane induction.
Using FGF21 treatment tetrachloro-methane induction mouse polarity hepatic injury ileal mucous membrane damage when, it is preferable to use
The dosage of 0.5mg/kg or 1.0mg/kg is treated.
It, can be according to this field when using FGF21 or the medicine composite for curing acute human hepatic injury containing FGF21
Well known method derives adult dosage from the dosage of experimental animal.
Preferably, the dosage of fibroblast growth factor 21 be 0-0.5mg/kg, preferably 0.01-0.35mg/ml, more
Preferably 0.01-0.3mg/ml.
When treating acute liver damage intestinal mucosal injury using the FGF21, FGF21 does not promote the ability of cell Proliferation,
Will not antagonism FGF family other members function, safety in utilization is very high.
Therefore, the present invention provides a kind of FGF21 or aforementioned pharmaceutical compositions in preparation treatment acute liver damage drug
Application；Application especially in the case where acute liver damage is treated in preparation in intestinal mucosal injury drug.
The fibroblast growth factor 21 or pharmaceutical composition can be improved in liver when treating acute liver damage
The expression of SIRT1；It is acute in preparation treatment that thus the present invention also provides fibroblast growth factor 21 or pharmaceutical composition
Purposes in hepatic injury ileal mucous membrane damage medicine.
Embodiment
Embodiment 1
Establish model mice:
Taking weight is the healthy mice of 20-25g, uses carbon tetrachloride (CCl4) inducing mouse generation acute liver damage
(ALI)。
Research method:
ALI model mice 30 are taken, is divided into 5 groups, every group 6.Wherein,
Model group (ALI group) is model mice, without drug treatment；
Experimental group is provided with 3 groups, and intraperitoneal injection gives low dosage FGF21 (0.25mg/kg), middle dosage respectively
FGF21 (0.5mg/kg), high dose FGF21 (1mg/kg)；
Positive controls give diammonium glycyrrhizinate (DG) through gastric infusion with the dosage of 55mg/kg；
Blank control group (Control group) is normal mouse, same amount of normal saline is injected intraperitoneally.
Treatment 3 days.
Experimental example
Experimental example 1
FGF21 alleviate acute hepatic injury mice hepar damnification (FGF21: Zhejiang Grostre Biotech Co., Ltd.,
Specification: 1mg/mL)
It by the mouse in embodiment 1, puts to death, takes liver organization, carry out H&E (hematoxylin eosin staining method) dyeing.
As a result as shown in Figure 1, arrow is directed toward vacuole, triangle mark cell infiltration in figure.It can by H&E dyeing observation
Know:
In blank control group (Control group), hepatic tissue structure is normal, liver plate queueing discipline；
In model group (ALI group), there is cell infiltration around hepatic tissue central vein, based on neutrophil leucocyte, largely
Vacuolar degeneration of hepatic cell or necrosis；
In low dosage FGF21 group (0.25mg/kg), the visible oedema of hepatic tissue and partial necrosis occur, but hepatic injury degree
Obviously mitigate compared with model group；Simultaneously it is also found that low dosage FGF21 group, middle dosage FGF21 group (0.5mg/kg), high dose
Hepatic injury degree in FGF21 group (1mg/kg) gradually mitigates, and high dose FGF21 group effect is best, few liver cell vacuoles
Denaturation or necrosis, rare cell infiltration.
In positive controls (ALI+DG), compared with ALI group, the liver organization degree of injury in diammonium glycyrrhizinate group is obvious
Mitigate, the FGF21 therapeutic equivalence of therapeutic effect and 1mg/kg dosage.
As it can be seen that in CCl4In the acute hepatic injury mice of induction, FGF21 can alleviate hepar damnification, and have centainly
Dose dependent.
Experimental example 2
FGF21 repairs the ileal mucous membrane damage of acute hepatic injury mice
Mouse in Example 1 is put to death, and intestinal submucosa tissue is fetched, and carries out H&E (hematoxylin eosin staining method) dyeing.
As a result as shown in Fig. 2, arrow shows small intestine erosion in figure, circle shows mucous epithelium oedema.Observation result is dyed by H&E
Known to:
In blank control group (Control group), i.e. in A, intestinal villus is in finger-like, visible goblet cell in epithelium, intestinal glands
In visible paneth's cell, small intestines structure is normal, has no lesion；
In model group (ALI group), i.e. in B, myxedema denaturation, part mucous epithelium is flat, and intestinal villi part is rotten to the corn,
The infiltration of affected area visible inflammatory cell and fibroplasia；
In positive controls (ALI+DG), i.e. in F, ileal epithelium villus is normal, has no obvious lesion；
Low dosage FGF21 group (C figure), middle dosage FGF21 group (D figure), ileal mucous membrane damage in high dose FGF21 group (E figure)
Hurt degree gradually to mitigate, wherein FGF21 middle dose group and the visible mucous epithelium Mild edema of low dose group part sample, but compared with
ALI group, degree of injury is substantially reduced, and high dose group ileal epithelium villus is normal, has no that obvious lesion, therapeutic effect are right with the positive
It is suitable according to group.
As it can be seen that in CCl4In the acute hepatic injury mice of induction, the ileum that FGF21 can repair acute hepatic injury mice is viscous
Membrane damage；And therapeutic effect has certain dose dependent.
Experimental example 3
FGF21 repairs the ileal mucous membrane damage of acute hepatic injury mice
Mouse in Example 1 is put to death, and intestinal submucosa tissue is fetched, and carries out transmission electron microscope observing.As a result as shown in figure 3,
Show regions in first-trimester villi in figure at a；Show that normal cell connects at b；Show that villus is sparse at c, falls off, expands；Show that cell connection is thick at d
It is big unclear.
As shown in Figure 3:
In blank control group (Control group), see that A schemes, visible surface epithelial cell covers microvillus, suede on the inside of ileum
Hair structure and arrangement are normal, and Cell tracking is clear, has no lesion；
In ALI group, see that B schemes, ileal epithelium villus is degraded on a large scale, and villus is sparse and different in size, cell boundary
It is unclear, it is seen that the coarse deep dye of part cell connection, karyopyknosis are even disintegrated；
In positive controls (ALI+DG group), see that F schemes, ileal epithelium is normal, and accidental small range villus is loose to be expanded,
Cell tracking is normal；
In low dosage FGF21 group, ileal epithelium villus is compared to be improved in ALI group；Low dosage FGF21 group (C
Figure), middle dosage FGF21 group (D figure), ileal mucous membrane degree of injury gradually mitigates in high dose FGF21 group (E figure), wherein high dose
Amount group ileal epithelium is normal, and accidental small range villus is loose to be expanded, and Cell tracking is normal, therapeutic effect and the positive
Control group is substantially suitable.
As it can be seen that in CCl4In the acute hepatic injury mice of induction, the ileum that FGF21 can repair acute hepatic injury mice is viscous
Membrane damage.
Experimental example 4
It is related to autophagy that FGF21 repairs the damage of acute hepatic injury mice ileal mucous membrane
CCl is utilized in Example 14The ALI model mice of induction is experimental group, and Normal healthy mice is as a control group.
After ALI model mice models successfully, respectively at 6h, 12h, mouse is put to death for 24 hours, takes blood and liver organization, is detected in serum
The level of FGF21；And change feelings using the autophagy factor (LC3 I and LC3 II) in western-blot method detection liver organization
Condition.
As a result as shown in figure 4, A is the detection statistics result figure of B in Fig. 4, ordinate is FGF21 in ALI mice serum
In concentration；Wherein, p < 0.05 *；**p<0.01；***p<0.001.
By B in Fig. 4 it is found that compared with the control group, CCl4FGF21, autophagy in the ALI mice serum and liver organization of induction
The expression of factor LC3 II increases, and the expression highest in selected time point 6h, hereafter, as trauma time extends, table
Restore up to level to normal level or so, this explanation, in CCl4In the ALI mouse model of induction, FGF21 and autophagy expression quilt
Activation, thereby increases and it is possible to important protective effect is played in course of liver damage.
Experimental example 5
FGF21 enhances CCl4The expression of SIRT1 in the ALI mouse liver of induction
Blank control group and experimental group in Example 1, put to death mouse after treatment end, western-blot method into
Row detection, as a result as shown in Figure 5.
By in Fig. 5 it is found that in liver the expression of SIRT1 (silent message regulatory factor 1) increase with the increase of FGF21 dosage
Greatly.
It is described the invention in detail above in conjunction with detailed description and exemplary example, but these explanations are simultaneously
It is not considered as limiting the invention.It will be appreciated by those skilled in the art that without departing from the spirit and scope of the invention,
Can be with various equivalent substitutions, modifications or improvements are made to the technical scheme of the invention and its embodiments, these each fall within the present invention
In the range of.Scope of protection of the present invention is subject to the appended claims.
Claims (9)
1. treating the pharmaceutical composition of acute liver damage, the composition includes fibroblast growth factor 21.
2. composition according to claim 1, which is characterized in that excellent with intestinal mucosal injury when the acute liver damage
It is damaged when selecting acute liver damage with ileal mucous membrane.
3. composition according to claim 1, which is characterized in that the fibroblast growth factor 21 is used alone,
Or it is used in conjunction with as active constituent and other auxiliary materials.
4. composition according to claim 1, which is characterized in that the fibroblast growth factor 21 is to be dissolved in or divide
Dissipate the solution form use in solvent；
Described pharmaceutical composition is powder-injection or injection solution；
The dosage of fibroblast growth factor 21 is 0-0.5mg/kg, preferably 0.01-0.35mg/ml, more preferably 0.01-
0.3mg/ml。
5. composition according to claim 3, which is characterized in that fibroblast growth factor 21 as active constituent with
Auxiliary material is dissolved/is suspended in solvent；
One of the preferred osmotic pressure regulator of the auxiliary material, pH adjusting agent, freeze drying protectant, complexing agent and antioxidant are more
Kind；
The dosage of fibroblast growth factor 21 and auxiliary material is 0.1%-30%, preferably 0.1%-25%, more preferably
0.1%-20%, by weight.
6. a kind of purposes of fibroblast growth factor 21 in preparation treatment acute liver damage drug.
7. purposes according to claim 6, which is characterized in that fibroblast growth factor 21 is in treatment acute liver damage
The expression of SIRT1 in Shi Tigao liver.
8. purposes according to claim 6, which is characterized in that fibroblast growth factor 21 treats Acute Hepatic in preparation
Damage the purposes in lower intestinal mucosal injury drug.
9. purposes according to claim 8, which is characterized in that fibroblast growth factor 21 treats Acute Hepatic in preparation
Damage the purposes in intestinal mucosal injury drug next time.
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| CN112655601A (en) * | 2020-12-02 | 2021-04-16 | 中国水产科学研究院淡水渔业研究中心 | Establishment and application of model for inducing freshwater fish acute liver and intestine combined injury by carbon tetrachloride |
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| 王春妍: "急性肝损伤肠源性内毒素血症的基础研究及药物干预", 《中国博士学位论文全文数据库医药卫生科技辑》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110170046A (en) * | 2019-05-21 | 2019-08-27 | 温州医科大学 | Application of the fibroblast growth factor 21 in preparation treatment acute pancreatitis drug |
| CN112655601A (en) * | 2020-12-02 | 2021-04-16 | 中国水产科学研究院淡水渔业研究中心 | Establishment and application of model for inducing freshwater fish acute liver and intestine combined injury by carbon tetrachloride |
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