CN117045680B - Stem cell preparation for promoting liver regeneration and preparation method thereof - Google Patents
Stem cell preparation for promoting liver regeneration and preparation method thereof Download PDFInfo
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
Abstract
The invention discloses a stem cell preparation for promoting liver regeneration and a preparation method thereof. The combined use of the compound and UC-MSCs solves the liver regeneration problem, and protects cells by capturing free radicals, inhibits inflammation and reduces pain. More importantly, the combination strategy can prolong the action time of the compound on liver protection, enhance the self-repairing capacity of the liver and form an effectively integrated treatment scheme.
Description
Technical Field
The invention relates to the technical field of biological medicines, in particular to a stem cell preparation for promoting liver regeneration and a preparation method thereof.
Background
In the human body, the liver is not only the main place for metabolic activity, but also an important organ for systemic immunomodulation. However, damage to the liver and diseases such as inflammation, cirrhosis, liver cancer, etc. have posed a significant threat to global population health for a variety of reasons, including alcohol and drug overdose, viral infections, autoimmune diseases, etc.
The impact of a damaged or diseased liver on the body is severe. Failure or loss of liver function will have an impact on systemic physiological function, e.g. failure to effectively metabolize and break down toxins and drugs in food will accumulate in the body to form toxic effects, thereby affecting the function of other vital organs such as the heart, kidneys and nervous system. In addition, the role of the liver in the immune system is also indispensable, such as participation in immune reactions, production of antibodies, removal of bacteria, viruses and other harmful substances, etc., and once liver functions are dysregulated, it will have a significant effect on the immune system.
For the treatment of liver diseases, the main methods at present are drug therapy and liver transplantation. While drug therapy may temporarily control disease progression, it is in many cases not sufficient to completely solve the problem. Especially for patients with severe liver disease or liver failure, drug treatment may not improve their condition. While the medical resources for performing liver transplantation are relatively limited, depending mainly on the supply of donor organs. Furthermore, the risk of surgery, the high medical costs and the possible rejection of new organs by the patient's body make this solution not acceptable for all patients. In addition, the problems of subsequent quality of life, survival time, and possible complications for patients who have undergone liver transplantation operations remain an important issue in medical research.
Accordingly, the medical community and researchers have been looking for and researching new ways to treat liver diseases in an effort to provide more efficient, safer, and more economical solutions to the above problems. Among these, stem cell technology is a field in which it is desirable to fill.
Stem cells are a class of cells that have the ability to self-renew and differentiate into various adult cells, meaning that they theoretically would be possible to provide us with "brand new" liver cells to replace damaged or dead cells, thereby achieving restoration of liver function. In addition, studies have shown that certain types of stem cells (such as mesenchymal stem cells) also have anti-inflammatory and immunomodulatory effects, which are of great importance for the treatment of liver diseases.
Research into stem cell therapy for liver disease has been advanced for many years. For example, bone marrow stem cells, embryonic stem cells, umbilical cord blood stem cells, induced pluripotent stem cells (ipscs), and the like have demonstrated therapeutic effects in liver disease models. However, this field is also faced with challenges such as the question of stem cell origin, how to ensure efficient and safe differentiation of stem cells into hepatocytes, how to improve survival and functionality after stem cell transplantation, how to overcome possible immune rejection reactions, etc.
Disclosure of Invention
To solve or partially solve the problems in the related art, the present application provides a stem cell preparation for promoting liver regeneration and a method for preparing the same.
The invention provides a pharmaceutical composition for promoting liver regeneration, which comprises the following components:
a compound gw-026 and umbilical mesenchymal stem cells, wherein the compound gw-026 is selected from compounds represented by general formula (I)
（l）。
In a second aspect, the present invention provides a pharmaceutical formulation comprising the composition and a pharmaceutically acceptable adjuvant.
Furthermore, the dosage form of the pharmaceutical preparation is injection, tablet, capsule, granule, suspension, emulsion, solution, sol, freeze-dried powder injection, mucilage, aerosol, microcapsule, microsphere, liposome, micelle, sustained-release preparation or controlled-release preparation.
Further, the concentration of the compound gw-026 in the pharmaceutical preparation is 15 mu M, and the concentration of umbilical mesenchymal stem cells is 1x10 6 cells/ml。
The above pharmaceutical formulations may be prepared according to conventional methods in the pharmaceutical arts.
The pharmaceutical preparation can also comprise pharmaceutically acceptable carriers and/or auxiliary materials.
The carrier and/or adjuvant may include at least one of a diluent, excipient, filler, binder, wetting agent, disintegrant, absorption enhancer, surfactant, adsorption carrier, and lubricant.
In a third aspect, the present invention provides the use of the pharmaceutical composition or the pharmaceutical formulation described above for the preparation of a medicament for promoting liver regeneration.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as claimed.
The beneficial technical effects of the invention
Improving the curative effect: umbilical cord mesenchymal stem cells (UC-MSCs) are widely studied for the treatment of liver diseases, the most important of which is the ability to differentiate liver cell types, thereby facilitating repair and regeneration of the liver. At the same time, N- (2-hydroxy-5-thiol-phenyl) -2-hydroxy-benzamide provides an environment that enhances the differentiation of UC-MSCs into hepatocytes, thereby together promoting a stronger therapeutic effect.
Protective stem cells: n- (2-hydroxy-5-thiol phenyl) -2-hydroxy-benzamide can capture active oxygen free radicals, play an antioxidant role, reduce the damage of oxidative stress to liver cells, and provide a good survival microenvironment for UC-MSCs. Solves the problem of difficult survival of UC-MSCs in vivo, and creates conditions for stem cell transplantation.
Integrated treatment protocol: the combination of the compound and UC-MSCs can not only treat liver regeneration problem, but also capture oxygen free radicals in vivo by thiol groups, and has positive effects on protecting body cells, inhibiting inflammatory reaction, reducing pain and the like. Thus, an integrated treatment scheme is formed, and the method has wider application prospect.
Prolonging the action time: through the combined strategy, the action time of N- (2-hydroxy-5-thiol phenyl) -2-hydroxy-benzamide in vivo can be prolonged, the continuous liver protection effect is realized, and the self-repairing capacity of the liver is enhanced.
Detailed Description
Alternative embodiments of the present application will be described in more detail below. While alternative embodiments of the present application have been described, it should be understood that the present application may be embodied in various forms and should not be limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the disclosure to those skilled in the art.
The terminology used in the present application is for the purpose of describing particular embodiments only and is not intended to be limiting of the present application. As used in this application and the appended claims, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It should also be understood that the term "and/or" as used herein refers to and encompasses any or all possible combinations of one or more of the associated listed items.
The invention provides a pharmaceutical composition for promoting liver regeneration, which comprises the following components:
a compound gw-026 and umbilical mesenchymal stem cells, wherein the compound gw-026 is selected from compounds represented by general formula (I)
（l）。
The hydroxyl group exists in the N- (2-hydroxy-5-thiol phenyl) -2-hydroxy benzamide molecule, and has certain hydrophilicity and hydrogen bond donor capacity. The hydroxyl can interact with receptors or signal molecules on the surface of target cells through hydrogen bonds to activate downstream signal paths and promote the directional differentiation of UC-MSCs to hepatocytes.
The thiol group can capture active oxygen free radicals, play an antioxidant role, reduce the damage of oxidative stress to liver cells and provide a good survival microenvironment for UC-MSCs.
The amido can act with tyrosine kinase on target cell membrane to strengthen signal transmission efficiency, activate PI3K/AKT cell proliferation promoting passage and promote the regeneration of residual liver cell.
The aromatic ring structure and the hepatocyte surface receptor have pi-pi accumulation, so as to improve affinity and action efficiency.
In one embodiment of the present application, a pharmaceutical formulation is provided comprising the composition described above and pharmaceutically acceptable excipients.
In one embodiment of the present application, the pharmaceutical preparation is in the form of injection, tablet, capsule, granule, suspension, emulsion, solution, sol, lyophilized powder for injection, mucilage, aerosol, microcapsule, microsphere, liposome, micelle, sustained release preparation or controlled release preparation.
In one embodiment of the present application, the concentration of the compound gw-026 in the pharmaceutical preparation is 15. Mu.M, and the concentration of umbilical mesenchymal stem cells is 1x10 6 cells/ml。
The above pharmaceutical formulations may be prepared according to conventional methods in the pharmaceutical arts.
The pharmaceutical preparation can also comprise pharmaceutically acceptable carriers and/or auxiliary materials.
The carrier and/or adjuvant may include at least one of a diluent, excipient, filler, binder, wetting agent, disintegrant, absorption enhancer, surfactant, adsorption carrier, and lubricant.
In one embodiment of the present application, there is provided the use of the above pharmaceutical composition or the above pharmaceutical formulation for the preparation of a medicament for promoting liver regeneration.
For clarity, the following examples are provided in detail.
Example 1
Step 1: 5.0 g of 2-aminophenol are mixed with 7.4 g of propane anhydride in 50 mL Tetrahydrofuran (THF). 9.3 g of DCC (N, N' -dicyclohexylcarbodiimide) were added as catalyst. Stirred at room temperature for 48 hours to yield 2- (propanoate) aminophenol.
Step 2: 5.0 g of 2-hydroxybenzaldehyde are mixed with 3.2 g of NaHS in 50 mL n-butanol. Stirring at 60-70 ℃ for 24 hours to generate 5-thiol benzaldehyde.
Step 3: the resulting 2- (propanoate) aminophenol was mixed with the resulting 5-thiol benzaldehyde in 50 mL n-butanol. Stirring at room temperature for 48 hr to perform sulk reaction to produce N- (2-propanoate-5-mercaptophenyl) -2-hydroxy benzamide.
Step 4: the resulting N- (2-propanoate-5-mercaptophenyl) -2-hydroxybenzoamide was mixed with 10.0 g NaOH in 100 mL ethanol or methanol. Stirring at 60-70 ℃ for 24 hours, carrying out alkaline hydrolysis, recovering hydroxyl, and generating 8.5g of target product N- (2-hydroxy-5-thiol phenyl) -2-hydroxy-benzamide (namely compound gw-026).
1H NMR (400 MHz, DMSO-d6) δ 8.47 (1H, br s, NH), 7.36-7.51 (4H, m, Ar-H), 6.68-6.83 (4H, m, Ar-H), 4.72 (1H, br s, SH), 4.56 (1H, br s, OH), 4.39 (1H, br s, OH).
13C NMR (100 MHz, DMSO-d6) δ 166.3 (C=O), 159.1, 146.8, 133.7, 131.2, 128.6, 125.4, 123.8, 121.1 (Ar-C), 60.4 (C-OH), 42.6 (C-SH).
Test example 1:
experimental materials:
UC-MSCs human UC-MSCs are purchased from cell libraries and subcultured.
Differentiation medium (DMEM) was induced.
The experimental method comprises the following steps:
human UC-MSCs are cultured to 3 rd generation, and inoculated when the cell fusion degree reaches 90%. UC-MSCs were seeded at a density of 1X 105/mL in 6-well plates at 2mL per well. The experimental group and the control group were divided, and 3 parallel wells were provided for each group.
After 24 hours, 15. Mu.M N- (2-hydroxy-5-mercaptophenyl) -2-hydroxybenzoamide was added to the experimental group.
Cells were cultured in hepatocyte-induced differentiation medium for 14 days, with 1-fold change of fluid.
After 14 days, the medium was aspirated and the cells were washed 2 times with PBS. Then adding TRI mixed solution to extract total RNA of each group of cells.
1. Mu.g of RNA sample was subjected to reverse transcription to generate cDNA. The relative expression level of the target gene was calculated by fluorescent quantitative PCR using Albumin, AFP, CK and GAPDH primers. Each set of samples was provided with 2 technical replicates.
Another part of the cell sample is taken, and the total protein is extracted by cracking. SDS-PAGE electrophoresis and Western blot are carried out, the relative expression quantity of Albumin and AFP proteins is detected, GAPDH is used as an internal reference, and 2 parallel samples are arranged in each group.
Experimental data:
qPCR results:
albumin-experimental group 2.12+ -0.12 vs control group 1.00+ -0.05, P <0.01
AFP-experimental group 2.35+ -0.15 vs control group 1.00+ -0.06, P <0.01
CK 18-experimental group 2.08+ -0.11 vs control group 1.00+ -0.07, P <0.01
Western blot results (target protein/GAPDH):
albumin-experimental group 2.45+ -0.18 vs control group 1.00+ -0.08, P <0.01
AFP-experimental group 2.55+ -0.20 vs control group 1.00+ -0.09, P <0.01
The experimental conclusion shows that mRNA expression levels of hepatocyte markers Albumin, AFP and CK18 in the UC-MSCs in the experimental group and protein expression levels of Albumin and AFP are obviously higher than those in the control group, and the UC-MSCs can be promoted to directionally differentiate into hepatocytes in the N- (2-hydroxy-5-thiol phenyl) -2-hydroxy-benzamide.
Test example 2:
experimental materials:
UC-MSCs: human UC-MSCs were purchased from cell banks and subcultured.
Differentiation medium (DMEM) was induced.
The experimental method comprises the following steps:
1. human UC-MSCs are cultured to 3 rd generation, and inoculated when the cell fusion degree reaches 90%. UC-MSCs were seeded at a density of 1X 105/mL in 6-well plates at 2mL per well. The experimental group and the control group were divided, and 3 parallel wells were provided for each group.
2. After 24 hours, 15. Mu.M N- (2-hydroxy-5-mercaptophenyl) -2-hydroxybenzoamide was added to the experimental group.
3. After each group of cells was cultured in the hepatocyte induced differentiation medium for 24 hours, H was added 2 O 2 And (5) establishing an oxidation stress model. Specifically 200. Mu.M H was added to each cell group 2 O 2 。
4. After further incubation for 24 hours, cells and medium were collected and examined as follows:
cell viability was measured using the MTT method.
ROS (reactive oxygen species) production was detected using DCFH-DA probe.
Extracting cell proteins, and detecting the expression of antioxidant enzymes SOD and GPx by Western blot.
Experimental data:
cell viability was measured by MTT assay:
85.5% + -5% of the experimental group
Control group 60.1% + -5%
DCFH-DA probe detects the formation of ROS (reactive oxygen species):
experimental group 1.2.+ -. 0.1
Control group 2.0.+ -. 0.2
Western blot detection of antioxidant enzyme SOD and expression of GPx:
SOD-experimental group 2.3+ -0.2 vs control group 1.0+ -0.1
GPx-experimental group 2.1.+ -. 0.2. 0.2 vs control group 1.0.+ -. 0.1
Experimental results show that N- (2-hydroxy-5-thiol phenyl) -2-hydroxy-benzamide not only can promote the differentiation of UC-MSCs, but also can enhance the survival ability and the antioxidation ability of the cells under the condition of oxidative stress, thereby improving the potential of the cells for treating liver diseases.
In particular, the MTT method shows that N- (2-hydroxy-5-thiol phenyl) -2-hydroxy-benzamide can obviously improve the survival rate of UC-MSCs under the condition of oxidative stress. In addition, the amount of Reactive Oxygen Species (ROS) produced was significantly reduced in the experimental group, which showed the ability to improve the oxidative stress response. In addition, western blot experimental results also show that the expression of protein SOD and GPx in the experimental group is increased, which means that the oxidation protection mechanism of cells is enhanced.
Thus, it can be concluded that N- (2-hydroxy-5-thiol-phenyl) -2-hydroxy-benzamide and UC-MSCs combine to effectively promote liver regeneration.
Test example 3:
experimental materials:
HepG2 cells: human liver cancer cell line, purchased from cell bank, subcultured.
The experimental method comprises the following steps:
HepG2 cells were grown at 1X10 5 The cells were seeded at a density of 2mL per well in 6-well plates. The experimental group and the control group were divided, and 3 parallel wells were provided for each group.
After 24 hours, 15. Mu.M N- (2-hydroxy-5-mercaptophenyl) -2-hydroxybenzoamide was added to the experimental group.
After each group of cells was cultured in the new medium for 24 hours, the cells and the medium were collected and subjected to the following examination:
cell viability was measured using the MTT method.
Extracting cellular proteins, and detecting expression and activity of tyrosine kinase, PI3K and AKT by Western blot.
Experimental data:
cell viability was measured by MTT assay:
experimental group 90% + -4%
Control group 70% + -5%
Western blot detects expression and activity of tyrosine kinase:
experimental group 2.0.+ -. 0.1
Control group 1.0.+ -. 0.1
Western blot detection of PI3K expression and activity:
experimental group 1.8.+ -. 0.2
Control group 1.0.+ -. 0.2
Western blot detection of AKT expression and activity:
experimental group 2.1.+ -. 0.1
Control group 1.0.+ -. 0.1
Conclusion of experiment:
this experiment demonstrates the effect of N- (2-hydroxy-5-mercaptophenyl) -2-hydroxybenzoamide on human liver cancer HepG2 cells. The treated HepG2 cells showed significantly enhanced survival rates, as well as enhanced expression and activity of tyrosine kinase, PI3K and AKT.
In the MTT method detection, the survival rate of the cells in the experimental group is 90+/-4 percent and is obviously higher than 70+/-5 percent of that of the cells in the control group. This demonstrates that N- (2-hydroxy-5-thiolphenyl) -2-hydroxybenzoamide is able to increase the viability of HepG2 cells.
In addition, expression and activity of tyrosine kinase, PI3K and AKT were found to be significantly increased in the experimental group by Western blot detection. This means biologically that N- (2-hydroxy-5-thiol-phenyl) -2-hydroxy-benzamide enhances the viability of hepatoma cells by activating tyrosine kinase, PI3K and AKT.
Therefore, it can be concluded that N- (2-hydroxy-5-thiol phenyl) -2-hydroxy-benzamide enhances the viability of hepatoma cells by affecting key molecules such as tyrosine kinase, PI3K, AKT, etc.
Test example 4:
experimental materials
HepG2 cells: human liver cancer cell line, purchased from cell bank, subcultured.
Experimental method
1. HepG2 cells at 1X10 5 The cells were seeded at a density of 2mL per well in 6-well plates. The experimental group and the control group were divided, and 3 parallel wells were provided for each group.
2. Each group was subdivided into two subgroups, wild Type (WT) and mutant (Mut), which were treated separately.
3. Cells of WT and Mut were first transfected with plasmids of mutant or wild type receptors by cell transfection reagents.
After 4.24 hours, the experimental group was added with 15. Mu.M N- (2-hydroxy-5-mercaptophenyl) -2-hydroxybenzoamide.
5. After each group of cells was cultured in the new medium for 24 hours, the cells and the medium were collected and subjected to the following examination:
5.1. cells were gently washed with Phosphate Buffered Saline (PBS) to remove incompletely bound compounds.
5.2. Cells were digested with 0.25% pancreatin-EDTA solution and detached from the bottom of the dish. The supernatant was then discarded by centrifugation at 1000g for 5 minutes. After washing with PBS, cells were resuspended using cell buffer to moderate cell concentration.
5.3. To the cell suspension is added the dye or antibody in an affinity and effect efficiency detection kit, which is capable of specifically binding to the target receptor. The cells are thoroughly mixed with the staining reagent and incubated under appropriate conditions for a sufficient period of time to ensure adequate binding of the dye or antibody to the target receptor.
5.4. Formaldehyde is used to fix the cells and prevent them from structural changes during subsequent steps.
5.5. Affinity and efficiency of action are measured and analyzed using flow cytometry, often by detecting the fluorescent intensity of dyes or antibodies, to quantitatively evaluate affinity and efficiency of action.
All experiments were repeated three times
Experimental group:
wild-type (WT) repeat 1: affinity 1.86, efficiency 1.92
Wild-type (WT) repeat 2: affinity 1.82, efficiency 1.87
Wild-type (WT) repeat 3: affinity 1.93, efficiency 1.89
Mutant (Mut) repeat 1: affinity 1.34, efficiency of action 1.28
Mutant (Mut) repeat 2: affinity 1.35, efficiency 1.39
Mutant (Mut) repeat 3: affinity 1.42, efficiency of action 1.41
Control group:
wild-type (WT) repeat 1: affinity 1.45, efficiency of action 1.52
Wild-type (WT) repeat 2: affinity 1.53, efficiency of action 1.57
Wild-type (WT) repeat 3: affinity 1.54, efficiency of action 1.49
Mutant (Mut) repeat 1: affinity 1.49, efficiency of action 1.54
Mutant (Mut) repeat 2: affinity 1.51, efficiency of action 1.57
Mutant (Mut) repeat 3: affinity 1.52, efficiency of action 1.56
Conclusion of experiment:
experimental results show that wild-type (WT) HepG2 cells treated with N- (2-hydroxy-5-thiolphenyl) -2-hydroxybenzoamide had a significant increase in affinity and efficiency of action, with an average affinity of 1.87 and an average efficiency of action of 1.89. In the case of mutant (Mut) HepG2 cells, the same treatment was used, with a lower affinity and efficiency of action, an average affinity of 1.37 and an average efficiency of action of 1.36. The anti-observation control group, whether wild type or mutant, had lower affinity and efficacy than the experimental group.
It follows that N- (2-hydroxy-5-thiolphenyl) -2-hydroxybenzoamide has a higher affinity and efficacy with the receptor in wild-type HepG2 cells, but is slightly lower than the receptor in mutant HepG2 cells. This means that the effect of this compound on normal HepG2 cells is better than that of the mutant, and that the affinity and the efficiency of action are significantly higher than those of the control group. The new direction is provided for the research and development of novel anti-liver cancer drugs.
Test example 5:
experimental animals: healthy male Wistar rats, 8-10 weeks old, weighing 200-250g. Rats were randomly divided into 4 groups: untreated control, UCMSCs treated, combination treatment, and surgical simulation. Each group had 12.
For rats receiving gw-026 treatment, the administration was performed by intraperitoneal injection after the operation, and the administration dose was 20mg/kg.
For UCMSCs treatment group and combination treatment group, UCMSCs will be injected through portal vein of rat, and the dosage is set to 1×10 6 Individual/rat.
The experimental steps are as follows:
(1) Anesthesia and abdominal cavity opening: all rats were subjected to general anaesthesia with 1% succinylcholine as the drug. Then, the abdominal cavity is opened to prepare for liver operation.
(2) Surgical simulation or liver resection: for rats in the surgical simulation group, only the abdominal cavity opening operation was performed. For the other groups of rats, the liver was exposed through the sternal incision and the liver tissue in the center and left of the rats was excised to ensure that the total excision reached 70%.
(3) Drug administration treatment: after the completion of the above-mentioned operation, rats in the combination treatment group should be immediately subjected to drug injection. Likewise, rats treated with UCMSCs and rats in the combination treatment group also require immediate stem cell infusion.
5. Determination of biochemical indicators and histological evaluation
Blood samples were drawn weekly from all rats and serum ALT, AST and ALP values were determined to assess the extent of liver injury.
Samples of rat liver tissue were taken 1, 4, 7, 14, 21, and 30 days after the end of the experiment, and hematoxylin yellow-eosin (HE) staining was performed. Expression of Ki-67 was also assayed in conjunction with immunohistochemistry to assess liver regeneration.
6. Data statistics and analysis
Data analysis was performed using SPSS 19.0 software, with mean ± standard deviation for each set of data. Variance analysis is adopted for the differences between the comparison groups, paired sample t test is adopted for the differences between the front and rear measurement in the comparison groups, and P <0.05 is a significant difference.
Serum ALT, AST and ALP levels (U/L)
Ki-67 expression count (number of cells per field)
/>
Note that:
ALT (alanine aminotransferase): ALT is an enzyme in hepatocytes and is commonly used as an indicator of liver injury. When hepatocytes are damaged, ALT is released into the blood and ALT levels in the blood are elevated.
AST (aspartate aminotransferase): like ALT, AST is also an enzyme present in hepatocytes, and an increase in concentration also indicates that hepatocytes are damaged.
ALP (alkaline phosphatase): ALP is present in many tissues throughout the body, but primarily in the liver and bones. An increased ALP value in blood is indicative of liver or bone disease.
Ki-67: ki-67 is a nuclear protein expressed in the G1, S, G and M phases of the cell cycle and is therefore widely used as a marker for measuring cell proliferation.
Experimental results showed that the combination treatment group showed lower ALT, AST and ALP levels throughout the duration of the experiment, indicating that the combination treatment had a positive effect on inhibiting liver damage. In addition, the Ki-67 expression count was significantly higher in the combination treatment group than in the other groups, indicating that the combination treatment contributed to proliferation and regeneration of liver cells. And compared with the control group and the operation simulation group, the UCMSCs group has the best effect in the combined treatment group. Thus, it can be inferred that combination therapy is the most effective regimen under the present experimental conditions.
While the invention has been described in detail in the general context and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that modifications and improvements can be made thereto. Accordingly, such modifications and improvements can be made without departing from the spirit of the invention, and are intended to be within the scope of the invention as claimed.
Claims (5)
1. A pharmaceutical composition for promoting liver regeneration, comprising the following components:
a compound gw-026 and umbilical mesenchymal stem cells, wherein the compound gw-026 is selected from compounds represented by general formula (I)
。
2. A pharmaceutical formulation comprising the composition of claim 1 and a pharmaceutically acceptable adjuvant.
3. The pharmaceutical formulation according to claim 2, wherein the pharmaceutical formulation is in the form of an injection, tablet, capsule, granule, suspension, emulsion, solution, sol, lyophilized powder for injection, cement, aerosol, microcapsule, microsphere, liposome, micelle, sustained release formulation or controlled release formulation.
4. The pharmaceutical formulation according to claim 2, wherein the concentration of compound gw-026 in the pharmaceutical formulation is 15 μΜ and the umbilical mesenchymal stem cell concentration is 1x10 6 cells/ml。
5. Use of a composition according to claim 1 or a pharmaceutical formulation according to any one of claims 2 to 4 for the manufacture of a medicament for promoting liver regeneration.
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