CN114712379B - Application of astragaloside IV in preparing medicine for preventing and treating peritoneal dialysis intestinal complications - Google Patents
Application of astragaloside IV in preparing medicine for preventing and treating peritoneal dialysis intestinal complications Download PDFInfo
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- CN114712379B CN114712379B CN202210406588.5A CN202210406588A CN114712379B CN 114712379 B CN114712379 B CN 114712379B CN 202210406588 A CN202210406588 A CN 202210406588A CN 114712379 B CN114712379 B CN 114712379B
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to a prevention and treatment effect of astragaloside IV on peritoneal dialysis intestinal complications. Astragaloside IV comprises the following applications: a1: preparing a medicament for preventing and/or treating peritoneal dialysis intestinal complications; a2: preventing and/or treating peritoneal dialysis intestinal complications; a3: establishing a peritoneal dialysis animal medical model; a4: and establishing a peritoneal dialysis cell medical model. The invention discloses a new application of astragaloside IV for the first time, and provides a theoretical basis for pharmacological action of astragaloside IV in treating peritoneal dialysis intestinal complications.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of astragaloside IV in preventing and treating peritoneal dialysis intestinal complications.
Background
Peritoneal dialysis is a treatment mode of kidney replacement treatment of patients with end-stage renal disease, and has the advantages of remaining kidney function, convenience in treatment, preferential medical policy and the like; and there is no significant difference compared to hemodialysis in terms of extending patient survival. However, long-term peritoneal dialysis can also cause a series of complications. Clinical studies have shown that about 50% of patients with continuous ambulatory peritoneal dialysis experience varying degrees of digestive tract symptoms such as constipation, diarrhea, and intestinal infections. These symptoms on the one hand can cause inconvenience to the patient's life, reducing his quality of life; on the other hand, there is also an increased risk of intestinal peritonitis, with concomitant abdominal infections, placing the patient in a dangerous setting. Although the incidence of these complications is not low, scientific research on intestinal dysfunction caused by long-term peritoneal dialysis is far from adequate, and the etiology and pathogenesis are not clear; and there is no specific therapeutic regimen for these complications clinically. Therefore, searching and developing ideal medicine capable of intervening in the complicated intestinal symptoms of peritoneal dialysis has important significance for improving the clinical application value of the peritoneal dialysis technology and prolonging the life cycle of patients with end-stage renal disease.
Astragaloside IV (AS IV) is one of the main active components of radix astragali, and its molecular formula is C 14 H 68 O 14 . Astragaloside IV is lanolin alcohol-shaped tetracyclic triterpene saponin extracted from radix astragali, has wide biological application such as antiinflammatory, antioxidant, antibacterial, antiviral and anti-fibrosis, and has protective effects on kidney, liver, nerve center, cardiovascular and gastrointestinal tract. In recent years, a few reports indicate that astragaloside IV can treat intestinal inflammation by accelerating intestinal epithelial cell proliferation, stimulating stem cell growth, promoting wound healing and recovering mucosal barrier proteins and other biological activities. Also, it has been shown that astragaloside IV can improve constipation symptoms in mice by inhibiting damage to intestinal stromal cells, and regulating the composition of intestinal microbial colonies. In addition, astragaloside IV plays a positive role in the treatment of various chronic kidney diseases. Astragaloside IV can protect chronic glomerulonephritis by regulating autophagy, regulating mesangial cell proliferation and inhibiting inflammatory infiltration. Clinically, the traditional Chinese medicine astragalus membranaceus also proves that the traditional Chinese medicine astragalus membranaceus can reduce proteinuria of chronic kidney disease patients and improve the total cholesterol and albumin level of plasma. However, no report on the use of astragaloside IV for treating peritoneal dialysis intestinal complications is currently seen.
Therefore, based on the complex pharmacological actions of multiple levels and multiple targets of the astragaloside IV, the invention applies the astragaloside IV to the treatment of the peritoneal dialysis complicated intestinal diseases and explores the curative effect of the astragaloside IV.
Disclosure of Invention
One of the purposes of the present invention is to provide an application of astragaloside IV, namely a1, a2, a3 and a4.
a1: preparing a medicament for preventing and/or treating peritoneal dialysis intestinal complications;
a2: preventing and/or treating peritoneal dialysis intestinal complications;
a3: establishing a peritoneal dialysis animal medical model;
a4: and establishing a peritoneal dialysis cell medical model.
Preferably, the active ingredient of the medicament comprises astragaloside IV.
Preferably, the medicament is a medicament for preventing and/or treating peritoneal dialysis intestinal complications.
Preferably, the method for establishing the peritoneal dialysis animal medical model comprises the following steps:
s1: modeling and constructing a mouse model of end-stage renal disease;
s2: modeling, and constructing a normal mouse peritoneal dialysis model and an end-stage renal disease mouse peritoneal dialysis model; the peritoneal dialysis model of the end-stage renal disease mice is constructed according to the end-stage renal disease mice model in the step S1;
s3: administration, of two groups of peritoneal dialysis mice models of astragaloside IV in S2;
s4: after 6 weeks of modeling and administration, colon tissues of mice were collected for pathological analysis.
Preferably, the end stage renal disease mouse model in S1 is constructed using a 5/6 kidney cut procedure and measuring serum urea nitrogen and creatinine levels before and after the procedure.
Preferably, the S2 peritoneal dialysis mouse model is constructed by intraperitoneal administration of 2mL of 4.25% glucose peritoneal dialysis solution daily for 6 weeks.
Preferably, the astragaloside IV in S3 is administered orally and by gastric lavage at a dose of 10mg/kg/d.
In some preferred embodiments of the invention, a 5/6 kidney-cut procedure is used to construct a mouse model of end-stage renal disease, a peritoneal dialysis mouse model is constructed using peritoneal perfusing 4.25% glucose peritoneal dialysis solution, and treatment is performed using IV intragastric administration of astragaloside. The experiments were divided into 6 groups: normal Control group (Control group), peritoneal dialysis group (PDF group), end-stage renal disease group (5/6 Nx group), end-stage renal disease peritoneal dialysis group (5/6nx+pdf group), peritoneal dialysis administration group (pdf+as IV group), end-stage renal disease peritoneal dialysis administration group (5/6Nx+PDF+AS IV group).
The pathological changes of the barrier of the colonic mucosa are detected by H & E staining, PAS staining and transmission electron microscopy, and the protein expression changes of the zonula occludens proteins Occlutin and ZO-1 in colonic tissues are detected by Western-blotting and RT-PCR.
Preferably, the method for establishing the peritoneal dialysis cell medical model comprises the following steps:
s1: modeling, and constructing a peritoneal dialysis cell model;
s2: administration, administration of astragaloside IV to a peritoneal dialysis cell model, and observation of drug effect.
Preferably, the method for constructing the peritoneal dialysis cell model in S1 is to construct the peritoneal dialysis solution: the culture medium was mixed at 1:1 and the colonic epithelial cells T84 were cultured.
Preferably, astragaloside IV in S2 is administered at doses of 1. Mu.M, 5. Mu.M, and 10. Mu.M.
In some preferred embodiments of the invention, changes in cell viability are detected by CCK-8 and changes in protein expression of the claudin Occludin and ZO-1 in T84 cells are detected by Western-blotting and RT-PCR.
It is a second object of the present invention to provide a medicament for preventing and/or treating complications of peritoneal dialysis intestinal tract, wherein the pharmaceutically active ingredient comprises astragaloside IV.
Preferably, the medicament also comprises traditional Chinese medicine astragalus or a compound thereof in the traditional Chinese medicine of the traditional Chinese medicine.
Preferably, the medicament further comprises a pharmaceutically acceptable excipient selected from one or any combination of binders, fillers, plasticizers, glidants, disintegrants and lubricants.
Preferably, the medicament can also be an oral or injection.
On the basis of the common general knowledge in the field, the above preferred conditions can be arbitrarily combined without exceeding the conception and the protection scope of the invention.
The invention discloses a new application of astragaloside IV for the first time, and provides a theoretical basis for improving pharmacological actions of peritoneal dialysis intestinal functions of astragaloside IV.
Drawings
Fig. 1: effect of astragaloside IV on colon structure in PDF group mice and 5/6nx+pdf group mice. (a) a mouse colon appearance; (B) Quantification of colon length in mice * Represents p<0.05, ** Represents p<0.01, compared to Control group; # represents p<0.05， ## Represents p<0.01, compared to PDF group; & represents p<0.05， && Represents p<0.01, compared to 5/6Nx+PDF group; n=6).
Fig. 2: influence of astragaloside IV on the pathological structure of colon in PDF group mice and 5/6Nx+PDF group mice. (A) H & E staining showed mouse colonic mucosal epithelium and crypt structure; (B) PAS staining showed the structure and distribution of mouse colon goblet cells (n=6).
Fig. 3: astragaloside IV effect on colonic mucosa ultrastructural effects in PDF group mice and 5/6Nx+PDF group mice. Observing the change of the ultrastructure of the colon mucosa of the mouse by means of a Transmission Electron Microscope (TEM), villi represents microvilli, yellow arrows represent the tight connection between cells, and white arrows represent desmosome structure; magnification was 6000× (n=3).
Fig. 4: effect of astragaloside IV on colon-tight junction protein expression in PDF group mice and 5/6nx+pdf group mice. (A) Western-blotting explored the effect of peritoneal dialysis solution and astragaloside IV on the expression levels of colon-specific adhesion proteins Occlutin and ZO-1; (B) Quantitative statistics and obvious difference analysis of protein expression level * Represents p<0.05, ** Represents p<0.01, compared to Control group; # represents p<0.05， ## Represents p<0.01, compared to PDF group; & represents p<0.05， && Represents p<0.01, compared to 5/6Nx+PDF group; n=6).
Fig. 5: astragaloside IV shadow of colon tight junction protein mRNA expression of PDF group mice and 5/6Nx+PDF group miceAnd (5) sounding. RT-PCR explored the influence of peritoneal dialysis solution and astragaloside IV on expression level of colon-specific adhesion proteins Occlutin and ZO-1mRNA * Represents p<0.05, ** Represents p<0.01, compared to Control group; # represents p<0.05， ## Represents p<0.01, compared to PDF group; & represents p<0.05， && Represents p<0.01, compared to 5/6Nx+PDF group; n=6).
Fig. 6: influence of astragaloside IV on the viability of peritoneal dialysis T84 cells. (A) CCK-8 detects the influence of astragaloside IV on the activity of T84 cells; (B) CCK-8 detection of influence of astragaloside IV on peritoneal dialysis T84 cell viability * Represents p<0.05， ** Represents p<0.01 for Control group; # represents p<0.05， ## Represents p<0.01, relative to PDF group; n=3).
Fig. 7: effect of astragaloside IV on peritoneal dialysis T84 cell-tight junction protein expression. (A)
Western-blotting explored the effect of astragaloside IV on expression of peritoneal dialysis T84 cell adhesion proteins Occludin and ZO-1; (B) Quantitative statistics and obvious difference analysis of protein expression level * Represents p<0.05，
** Represents p<0.01 for Control group; # represents p<0.05， ## Represents p<0.01, relative to PDF group; n=3).
Fig. 8: effect of astragaloside IV on peritoneal dialysis T84 cell-tight junction protein mRNA expression. RT-PCR (reverse transcription-polymerase chain reaction) researches on influence of astragaloside IV on expression level of peritoneal dialysis T84 cell tight junction proteins Occlutin and ZO-1mRNA * Represents p<0.05， ** Represents p<0.01 for Control group; # represents p<0.05， ## Represents p<0.01, relative to PDF group; n=3).
Detailed Description
The technical solution of the present invention will be described in detail below with reference to the drawings and examples, but the present invention is not limited to the scope of the examples.
The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications. The reagents and materials used in the present invention are commercially available.
Animal experiments and cell experiments are carried out, the constructed peritoneal dialysis animal model and cell model are subjected to astragaloside IV intervention, and the animal models and cell models are detected by utilizing experimental methods such as histopathological staining, transmission electron microscopy, protein immunoblotting, real-time fluorescence quantitative PCR and the like. In the embodiment of the invention, animal experiment results show that astragaloside IV can protect structures such as colon crypt, microvilli and desmosome, can up-regulate the expression of the tight junction protein, and can reduce the damage of peritoneal dialysis solution to colon tissues. Cell experiment results show that astragaloside IV can promote cell proliferation, improve cell activity and up-regulate the expression of the tight junction protein to relieve the damage of peritoneal dialysis solution to colon epithelial cells.
In the embodiment of the invention, the following steps of intervention experiments are specifically performed:
(1) 5/6 kidney cutting operation of mice; (2) constructing a mouse peritoneal dialysis model; (3) histomorphology analysis; (4) ex vivo cell studies; (5) Western blotting experiments; (6) real-time fluorescence quantitative PCR experiment; (7) cell viability detection; (8) data analysis: experimental results are expressed in mean+ -SD, all data were analyzed using GraphPad Prism software One-Way ANOVA method, P < 0.05 considered significant differences.
EXAMPLE 1 astragaloside IV improvement of colon tissue injury in peritoneal dialysis mice
1. Animals
C57BL/6 mice, females, purchased from Shanghai Ling laboratory animal Co., ltd, were bred in SPF grade animal laboratory at laboratory animal center, university of double denier pharmaceutical college.
2. Experimental materials
Astragaloside IV (Adamas), low-calcium peritoneal dialysis solution (lactate-G4.25%) (Baite medical supplies Co., ltd.), pentobarbital (national drug Co., ltd.), creatinine assay kit (Nanj Biotechnology institute), urea nitrogen assay kit (Nanj Biotechnology institute), paraformaldehyde (national drug Co., ltd.), DMEM/F-12 medium (BIOAGRIO), fetal bovine serum (BIOAGRIO), trypsin (BIOAGRIO), penicillin/streptomycin (BIOAGRIO), RIPA lysate (Biyun Biotechnology Co., ltd.), BCA method protein quantification kit (Biyun Biotechnology Co., ltd.), 5×loading buffer (Shanghai Santa Biotechnology Co., ltd.), DMSO (Sigma), chemiluminescent hypersensitivity ECL (Bio-42rad), pre-dye marker (ThermoFisher), labeled anti-rabbit IgG (H+L) (Shanghai Santa Biotechnology Co., ltd.), trizol (TAR), KAKAKA 84 (perfect Real Time; kara, kadson Kadsura (GmbH-37-56), and Abna-37-zoid (Abbe).
3. Experimental instrument
Biological safety cabinet (Thermo Fisher), CO2 cell incubator (Thermo Fisher), refrigerated centrifuge (Thermo Fisher), micropipette (Eppendorf), thermostatic water bath (Shanghai macrolaboratory equipment, inc.), gel electrophoresis device (Bio Rad), transfer device (Bio Rad), gel image processing system (BioRad), inverted microscope (Carl Zeiss), Q-RTPCR instrument (Bio-Rad, USA), tissue homogenizer (Shanghai Net communication technology), enzyme labelling instrument (Tecan Systems Inc.).
4. Experimental method
(1) Establishment of 5/6 kidney cut induced end stage renal disease mouse model
C57BL/6 female mice, about 20g in weight, were randomly divided into a normal group (Control group) and a 5/6 kidney group (5/6 Nx group) at 10 weeks of age. 5/6 kidney-resected mice were anesthetized with pentobarbital, fixed on the side, and sterilized with iodophor. Skin, subcutaneous tissue and muscle tissue are sequentially cut, the left kidney is exposed, the kidney envelope is peeled off, the hemostatic forceps clamp the renal artery, and after the kidney is engorged with blood and becomes purple, the upper electrode and the lower electrode of the kidney are cut at 1/3 of the upper and lower positions of the kidney. The sponge gelatin is used for compression hemostasis, the hemostatic forceps are slowly loosened, and after the blood of the residual kidney returns to red, the left kidney is returned, and the wound is sutured. One week after the operation, right nephrectomy was performed. The skin, subcutaneous tissue and muscle tissue of the right abdomen were cut sequentially as described above, exposing the right kidney. Ligature the renal pedicles with surgical threads, excise the right kidney after the right kidney is engorged with blood and blackened, and suture the wound. And (3) sterilizing the operation by using iodophor to prevent infection.
After 14 days of right nephrectomy, the orbit was bled and serum was isolated and the mice were tested for changes in serum urea nitrogen (BUN) and creatinine (Cre) concentrations both pre-and post-operatively. When the post-operative serum urea nitrogen and creatinine levels increased to 2-3 times the normal concentration, the 5/6 kidney cut induced end stage renal disease model was considered successful in construction.
(2) Establishment of peritoneal dialysis mouse model and administration treatment
Normal mice and mice with 5/6 kidney-resected models were divided into: normal Control group (Control group), 5/6 kidney cut Control group (5/6 Nx group), normal peritoneal dialysis group (PDF group), 5/6 kidney cut + peritoneal dialysis group (5/6nx + PDF group), normal peritoneal dialysis + astragaloside IV group (PDF + AS IV group), 5/6 kidney cut + peritoneal dialysis + astragaloside IV group (5/6Nx+PDF+AS IV group), 6 mice per group.
Peritoneal dialysis model group mice (containing PDF group and 5/6nx+pdf group) were intraperitoneally injected daily with 2ml of peritoneal dialysis solution containing 4.25% glucose; astragaloside IV administration mice (containing PDF+AS IV group and 5/6Nx+PDF+AS IV group) were intraperitoneally injected daily with 2mL of peritoneal dialysis solution containing 4.25% glucose and administered Astragaloside IV (10 mg/kg) by combined gavage. After 6 weeks of molding and administration, the colon of the mice was peeled off and examined.
(3) Colon pathology detection
Colon tissue was fixed with 4% paraformaldehyde, paraffin embedded, and HE and PAS stained, and the extent of colon injury was observed under an electron microscope.
(4) Colon ultrastructural detection
Colon tissues are fixed by an electron microscope liquid and 1% osmium acid in sequence, 812 embedding agents are used for embedding, slicing is carried out, lead citrate solution is used for dyeing, and an image is acquired by a transmission electron microscope.
(5) Protein and gene level detection of tight junction protein expression levels
Western-blotting and RT-PCR were used to detect changes in expression of the zonal and ZO-1 proteins and mRNA in the peritoneal dialysis and administration groups.
The experimental results are shown in fig. 1 to 5: astragaloside IV effectively relieves pathological damage of colon of mice in PDF group and 5/6Nx+PDF group, protects intercellular connection structure, regulates expression of tight junction protein, and reduces damage of peritoneal dialysis solution to colon tissue.
EXAMPLE 2 Astragaloside IV alleviating damage to colonic epithelial cells by peritoneal dialysis solution
The experimental method is as follows:
(1) Peritoneal dialysis cell model construction and astragaloside IV intervention
T84 cells with good growth state are inoculated into a 6-hole plate, and when the growth density of the cells is 40% -50%, the cells are starved by a culture medium containing 1% fetal bovine serum. Cells were divided into Control (Control), peritoneal Dialysis (PDF) and dosing (pdf+as IV). Control group cells were cultured in medium containing 1% fetal bovine serum, PDF group in medium containing 1% fetal bovine serum: peritoneal dialysis fluid = 1:1 mixed culture, PDF + AS IV groups were intervened by adding different doses of astragaloside IV (final concentrations of 1 μm, 5 μm and 10 μm) while the peritoneal dialysis fluid was stimulated.
(2) Cell viability assay
After plating, modeling and administration according to the above method, cell viability was detected using CCK-8 kit.
(3) Protein and gene level detection of tight junction protein expression levels
Western-blotting and RT-PCR were used to detect changes in expression of the cell-adhesion proteins Occlutin and ZO-1 and mRNA in the peritoneal dialysis and administration groups.
The experimental results are shown in fig. 6-8, astragaloside IV obviously promotes proliferation of T84 cells, promotes expression of protein and mRNA of the tight junction proteins Occlutin and ZO-1, and effectively relieves damage of peritoneal dialysis solution to colon epithelial cells.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.
Claims (12)
1. The application of astragaloside IV is as follows a1:
a1: preparing the medicine for preventing and/or treating the peritoneal dialysis intestinal complications.
2. The use according to claim 1, wherein the active ingredient of the medicament comprises astragaloside IV.
3. The use according to claim 1, wherein the method of constructing a peritoneal dialysis animal medical model comprises the steps of:
s1: modeling and constructing a mouse model of end-stage renal disease;
s2: modeling, and constructing a normal mouse peritoneal dialysis model and an end-stage renal disease mouse peritoneal dialysis model; the peritoneal dialysis model of the end-stage renal disease mice is constructed according to the end-stage renal disease mice model in the step S1;
s3: administration, of two groups of peritoneal dialysis mice models of astragaloside IV in S2;
s4: after 6 weeks of modeling and administration, colon tissues of mice were collected for pathological analysis.
4. The use according to claim 3, wherein in S1, the end stage renal disease mouse model is constructed using a 5/6 kidney surgery and serum urea nitrogen and creatinine levels before and after the surgery are detected.
5. Use according to claim 3, characterized in that in S2 the peritoneal dialysis mouse model is constructed in such a way that 2mL of peritoneal dialysis solution containing 4.25% glucose is administered intraperitoneally daily for 6 weeks.
6. Use according to claim 3, characterized in that in S3 the dose of astragaloside IV is 10mg/kg/d for 6 weeks.
7. The use according to claim 1, wherein the method of constructing a peritoneal dialysis cell medical model comprises the steps of:
s1: modeling, peritoneal dialysis cell model;
s2: administration, administration of astragaloside IV to a peritoneal dialysis cell model, and observation of drug effect.
8. The use according to claim 7, wherein in S1, the peritoneal dialysis cell model is constructed by combining peritoneal dialysis solution: the culture medium was mixed at 1:1 to culture T84 cells.
9. The use according to claim 7, wherein the doses of astragaloside IV administered in S2 are 1 μΜ,5 μΜ and 10 μΜ.
10. The use according to claim 1, wherein the medicament further comprises traditional Chinese medicine astragalus or a compound thereof in Chinese medicine.
11. The use according to claim 1, wherein the medicament further comprises a pharmaceutically acceptable excipient selected from one or any combination of binders, fillers, plasticizers, glidants, disintegrants and lubricants.
12. The use according to claim 1, wherein the medicament is also an oral or injectable formulation.
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