CN111249295A - Application of astragaloside IV in inhibiting local inflammatory reaction and treating arterial restenosis - Google Patents
Application of astragaloside IV in inhibiting local inflammatory reaction and treating arterial restenosis Download PDFInfo
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- CN111249295A CN111249295A CN202010205003.4A CN202010205003A CN111249295A CN 111249295 A CN111249295 A CN 111249295A CN 202010205003 A CN202010205003 A CN 202010205003A CN 111249295 A CN111249295 A CN 111249295A
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Abstract
The invention provides application of astragaloside IV in inhibiting local inflammatory reaction and treating arterial restenosis, and relates to the technical field of new application of traditional Chinese medicines. The invention simulates vascular intimal injury after Percutaneous Coronary Intervention (PCI) operation by establishing a rat common carotid artery saccule injury model, defines the inhibition effect of AS-IV on VSMCs proliferation and inflammation in vivo, and further provides a new, safe and effective solution for preventing and treating restenosis after PCI operation.
Description
Technical Field
The invention belongs to the technical field of new application of traditional Chinese medicines, and particularly relates to application of astragaloside IV in inhibiting local inflammatory reaction and treating arterial restenosis.
Background
The number of cardiovascular Disease patients in China is 2.9 hundred million, wherein the number of Coronary Heart Disease (CHD) is about 1100 million. The prevalence of PCI technology is a major historical breakthrough in CHD treatment, and its prevalence significantly improves the prognosis of CHD patients. However, the accompanying complication of In-stent restenosis (ISR) severely limits the application of this technique. ISR is recognized at present, that the net loss rate of the lumen is more than or equal to 50% in coronary angiography within 6-9 months after the stent is implanted. The clinical incidence of ISR after bare metal stent implantation is 20% -35%, and despite the widespread use of drug eluting stents, the incidence of ISR is still as high as 10%. ISR is the most common cause of post-PCI failure, reducing the long-term effectiveness of stent implantation. At present, balloon angioplasty, drug-eluting stents for in-stent restenosis, brachytherapy, drug-coated balloon angioplasty, excimer laser angioplasty and other treatment methods are mainly adopted for ISR treatment, but these treatment methods are not very effective. A great deal of clinical and experimental research is carried out at home and abroad, but the generation mechanism of restenosis is not completely understood. It is currently believed that the major mechanisms of occurrence of ISR are hyperproliferation and migration of VSMCs, endothelial cell damage, vascular recoil, persistent inflammatory responses and vascular remodeling. Therefore, the search for novel medicaments capable of early controlling the proliferation and migration of VSMCs and inhibiting the generation of local inflammatory reaction of the stent has important significance for preventing or blocking the generation and development of ISR.
Disclosure of Invention
In view of the above, the present invention aims to provide an application of astragaloside IV in inhibition of local inflammatory reaction and treatment of arterial restenosis, wherein astragaloside IV can inhibit proliferation of Vascular Smooth Muscle Cells (VSMCs) induced by TNF- α to exert an anti-vascular restenosis effect, and AS-IV can inhibit myocardial fibrosis to improve cardiac function, so AS to clarify the inhibition effect of AS-IV on VSMCs proliferation and inflammation in vivo, and further provide a new, safe and effective solution for prevention and treatment of PCI postoperative restenosis.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides application of astragaloside IV in preparing a medicament for preventing and/or treating restenosis in an arterial stent.
The invention also provides application of the astragaloside in preparing a medicine for inhibiting local inflammatory reaction.
Preferably, the local inflammatory response is caused by IL-6, TGF- β 1, TGF- β 2, TNF- α and/or IL-1 β.
The invention also provides application of astragaloside in preparing a medicament for inhibiting the phenotype conversion and proliferation of Ang-II stimulated VSMCs.
The invention also provides application of the astragaloside IV in preparing a medicament for reversing the promotion effect of inflammatory factor TNF-a on VSMCs proliferation.
The invention also provides a medicament for preventing and/or treating restenosis in an arterial stent, which takes astragaloside IV as an effective component.
The invention also provides a medicine for improving the adhesion and proliferation effects induced by endothelial cells, wherein the medicine takes astragaloside IV as an effective component.
The invention provides application of astragaloside IV in inhibiting local inflammatory reaction and treating arterial restenosis, which simulates vascular intimal injury after Percutaneous Coronary Intervention (PCI) operation by establishing a rat common carotid artery balloon injury model, defines the inhibiting effect of AS-IV on VSMCs proliferation and inflammation in vivo, and further provides a new, safe and effective solution for preventing and treating PCI postoperative restenosis.
In the embodiment of the invention, inflammatory factors such AS IL-6, TGF- β 1, TGF- β 2, TNF- α, IL-1 β and the like in rat balloon injury animal model serum are obviously up-regulated, which shows that inflammation plays an important role in ISR, and meanwhile, the result of a cytokine chip shows that AS-IV can inhibit the release of proinflammatory cytokines such AS IL-6, TGF- β 1, TNF- α, IL-1 β and the like, which shows that AS-IV has a good inhibition effect on inflammation.
Drawings
FIG. 1 is a HE slice and Ki67 histochemical expression map of common carotid artery after balloon injury, wherein A is the HE slice map, B is the statistic map of the lumen area of the HE slice, C is the Ki67 immunohistochemical result, and D is the Ki67 immunohistochemical quantitative map;
FIG. 2 shows the effect of cytokine chip detection balloon injury construction and AS-IV treatment on the expression of various inflammatory factors in SD rat peripheral serum, wherein A is a sham operation group, B is a balloon injury model group, and C is an AS-IV single treatment group;
FIG. 3 is a graph showing the expression results of intima of common carotid arteries CD3 and CD68 after balloon injury, wherein A is CD3 common carotid artery HE section immunohistochemistry, B is CD3 immunohistochemistry quantification, and compared with the model group, P is less than 0.05, C is CD68 common carotid artery HE section immunohistochemistry, and D is CD68 immunohistochemistry quantification, and compared with the model group, P is less than 0.05;
FIG. 4 is a graph showing the results of expression of PCNA, ICAM-1, α -SMA in each group after a balloon injury operation.
Detailed Description
The invention provides application of astragaloside IV in preparing a medicament for preventing and/or treating restenosis in an arterial stent.
The astragaloside IV (AS-IV) is preferably a monomeric compound extracted and separated from traditional Chinese medicine astragalus, and the method for extracting and separating is not particularly limited, and can be realized by utilizing the common method for extracting and separating the astragaloside IV in the field. The source of AS-IV is not particularly limited in the present invention, and the AS-IV can be extracted by itself or purchased AS a commercially available product, preferably AS a commercially available product. The medicine takes AS-IV AS an effective component, and preferably also comprises pharmaceutically acceptable auxiliary materials. The invention has no special limitation on the types and the proportion relationship of the auxiliary materials. The rat bursa injury model is constructed, and the result shows that AS-IV can control the proliferation and migration of VSMCs and finally prevent the occurrence of ISR (insulin dependent receptor) by inhibiting the activation of inflammatory cells and the release of inflammatory factors after PCI (peripheral component interconnect) operation.
The invention also provides application of the astragaloside in preparing a medicine for inhibiting local inflammatory reaction.
In the invention, the mechanical injury to the vascular intima after PCI operation and the continuous stimulation of the postoperative stent AS a foreign body substance to the vascular wall inevitably cause the aggregation of platelets and inflammatory cells and the release of inflammatory mediators, while inflammatory factors are 'important mediators' for promoting the migration and proliferation of VSMCs and finally causing the restenosis in the stent, the inflammatory factors such AS IL-6, TGF- β 1, TGF- β 2, TNF- α and IL-1 β in the serum of a rat balloon injury animal model of the invention are also obviously up-regulated, which shows that the inflammation plays an important role in ISR, and the result of a cytokine chip shows that AS-IV can inhibit the release of proinflammatory cytokines such AS IL-6, TGF- β 1, TNF- α and IL-1 β, and shows that AS-IV has a good inhibition effect on the inflammation.
In the invention, AS-IV has no direct inhibition effect on the proliferation of VSMCs, but can reverse the promotion effect of inflammatory factor TNF-a on the proliferation of VSMCs; but AS-IV also inhibits the phenotypic switching and proliferation of Ang-II stimulated VSMCs. Therefore, the invention also provides the application of the astragaloside in preparing the medicine for inhibiting the phenotype conversion and proliferation of the Ang-II stimulated VSMCs and the application of the astragaloside in preparing the medicine for reversing the promotion effect of the inflammatory factor TNF-a on the proliferation of the VSMCs.
The invention also provides a medicament for preventing and/or treating restenosis in an arterial stent, which takes astragaloside IV as an effective component.
The invention also provides a medicine for improving the adhesion and proliferation effects induced by endothelial cells, wherein the medicine takes astragaloside IV as an effective component.
The use of astragaloside provided by the present invention for inhibiting local inflammatory reactions and treating arterial restenosis is described in detail below with reference to the examples, but they should not be construed as limiting the scope of the present invention.
The terms or abbreviations presented In the present invention are to be interpreted AS PCI (percutaneous Coronary intervention; percutaneous Coronary intervention), ISR (In-stent restenosis), AS-IV (Astragaside IV; Astragaloside IV), CHD (Coronary Disease), VSMCs (vascular Smooth muscle cells), PCNA (stimulating Cell Nuclear antigen; Proliferating Cell nuclear antigen), α -SMA (α Smooth muscle actin; α -smoothened muscle activity), ICAM-1 (interstitial Cell adhesion molecule-1; intercellular adhesion molecule-1), CD3(cluster of differentiation 3; CD 383; cluster of proliferation 3; CD68(cluster of differentiation; 68; TNF 2-Necrosis Factor kinase (PBS), TNF-alpha (387) phosphate buffer).
Example 1
1. Main instruments and consumables:
ultra-low temperature refrigerator at minus 80 ℃, liquid nitrogen, autoclave, Eppendorf micropipette, Image Quant LAS500 imager, microplate reader, electrophoresis apparatus, vortex mixer, high-speed cold centrifuge, super clean bench, electronic balance, balloon catheter
2. The main reagents are as follows:
AS-IV (Beijing Apreptiles scientific Co.), CD3 immunohistochemical kit, CD68 immunohistochemical kit, Ki67 immunohistochemical kit, chloral hydrate, sodium carboxymethylcellulose (Beijing Ding national Biotech Co.), PCNA, a-SMA (Abcam Biotech, USA), ICAM-1, β -actin, goat anti-rabbit secondary antibody, BSA (Bo Tak, Wuhan Egyuchi Biotech).
3. Test method
(1) Experimental animal feeding and grouping
20 SPF-grade male SD rats with the age of 8 weeks are purchased at the animal breeding center of the Jinan Pengyue experiment in Shandong province, the weight of each rat is about 280-300 g, and all animal experiments are approved by the ethical committee of the Jining medical college, and the license: SCXK 20140007. The cells were conditioned in a controlled environment (23. + -. 2 ℃ C., 45%. + -. 5% humidity, 12 hours of darkness/12 hours of light cycle) for 3 days. The rats were randomly divided into 4 groups, i.e., a sham operation group, a model group, a low-dose radix astragali group (LD-AS-IV) and a high-dose radix astragali group (HD-AS-IV).
(2) Building rat common carotid artery sacculus injury model
The anesthesia is performed by using 10% chloral hydrate for intraperitoneal injection, and no obvious corneal reflex proves that the anesthesia is successful. The right common carotid artery is searched beside the right trachea in the anterior triangular area of the neck, and the internal, external and common carotid arteries are fully exposed. The external carotid artery distal end is permanently tied up by a No. 5-0 line at the external carotid artery starting part, and the common carotid artery proximal end and the internal carotid artery starting part are temporarily closed by a hemostatic clamp. Injecting heparin into the tail vein of a rat to heparinize the whole body (100U/kg), cutting a V-shaped incision at the distance from the external carotid artery to the starting part, inserting a 2F Fogarty balloon catheter into the incision for about 3-4 cm, pumping into a PTCA pressure pump for about 4-5 atmospheres, pulling back the balloon to generate friction feeling, pulling the balloon to proper pressure, pulling out the balloon catheter after repeating pulling for three times, ligating the external carotid artery at the incision, and removing a common carotid artery and an internal carotid artery hemostatic clamp. The common carotid artery was observed to have obvious pulsation, indicating that the blood flow was smooth. 3 days of celomicin injection after operation can resist infection.
(3) Intervention and material drawing with medicine
The sham operation group and the model group rats are subjected to intragastric administration with 2% sodium carboxymethylcellulose in the same amount, LD-AS-IV is subjected to intragastric administration with 60mg/kgAS-IV, HD-AS-IV is subjected to intragastric administration with 120mg/kgAS-IV, and the administration is started 3 days before the model building and is performed 1 time per day for 4 weeks. After 4 weeks, the rats are fasted and are forbidden to drink for 12 hours, the rats are anesthetized by 10% chloral hydrate intraperitoneal injection, the injured side common carotid artery is taken, blood is washed out in precooled PBS buffer solution, the common carotid artery is divided into 2 parts, 1 part of the common carotid artery is put into 4% paraformaldehyde solution for fixing for 12 hours, and then wax blocks are prepared by steps of 70%, 80%, 95% and 100% ethanol dehydration step by step, xylene transparency, wax dipping and the like, and HE staining is carried out after slicing. And taking out 1 part of the protein, quickly freezing by using liquid nitrogen, and storing in an ultralow temperature refrigerator for subsequent protein detection. Blood is collected from rat heart, 4ml is collected, centrifuged by a high-speed refrigerated centrifuge at 3000g for 10min, and then supernatant is collected and frozen in an ultra-low temperature refrigerator.
(4) Observation of blood vessel morphology and measurement of lumen area
The proliferation of the vascular intima is observed under an optical microscope, the area of the lumen is determined by adopting CaseViewer image analysis software, and the expression level of Ki67 is determined by an immunohistochemical method. The results are shown in FIG. 1, and compared with the sham group, the intima of the model group was significantly increased and the lumen was significantly reduced compared to the former. After AS-IV treatment, the proliferating intima was inhibited and the lumen was more patent, see A and B in FIG. 1. The expression of blood vessel intima Ki67 is measured by an immunohistochemical method, compared with a sham operation group, the expression of intima Ki67 in a model group is obviously increased, and the expression is reduced after AS-IV stem prognosis, which is shown in a figure 1C and D.
(5) Cytokine chip for detecting influence of AS-IV treatment on expression of various inflammatory factors in peripheral serum of SD rat
According to the operation instruction of the Kangcheng KCTMBCA protein quantitative kit, the concentration of a sample is measured, an antibody chip is sealed in a sealing buffer solution for 30 minutes, then the antibody chip is incubated for 1-2 hours at room temperature with a protein sample, the antibody chip is washed by a washing buffer solution, a biotin-labeled antibody is added, the antibody chip is incubated for 1-2 hours at room temperature, the antibody chip is washed by the washing buffer solution, streptavidin coupled with HRP is added, the antibody chip is incubated for 2 hours at room temperature, after the antibody chip is thoroughly washed by the washing buffer solution, a chemiluminescence reagent is added, an X-ray film is used for exposure (attention is kept out of light), an X-ray film exposure picture is obtained through a scanner, the signal intensity of the protein is quantitatively obtained through gray values, the original signal value is corrected and is normalized with positive protein, and the differentially expressed protein is obtained through group comparison of normalized values, the result is shown in figure 2, compared with a sham operation group, the inflammation factors such AS a balloon injury group IL-6, a TGF- β 1 group, a TGF- β 2, a TNF- α, an IL-1 β group, a balloon injury related inflammation factor, a balloon.
(6) Immunohistochemical determination of CD3, CD68 expression
Immunohistochemical staining detection of Ki67, CD3 and CD68 expression of total carotid paraffin blocks was performed by cutting into 5um slices, placing into 50 deg.C water, taking out the anti-shedding glass slide, and baking in an oven at 70 deg.C for 30 min. Dewaxing in xylene I, II for 10min, adding 100%, 95%, 85%, and 75% ethanol, respectively, gradually dehydrating for 5min, and washing with PBS buffer for 3 times. The slices were heated in citrate buffer for 5min, cooled and washed 3 times with PBS buffer. Goat serum was blocked for 30min at room temperature, sections were washed with PBS, diluted to 1: 200 primary antibody, 4 ℃ overnight. The next day, 3 washes in PBS buffer. Adding the mixture diluted to 1: 400 secondary antibody, incubated at room temperature for 60min, washed 3 times with PBS buffer for 5min each. Adding SABC reagent dropwise at 37 deg.C, acting for 20min, washing with PBS buffer for 5min for 3 times. And (4) dropwise adding DAB color developing agent, controlling the reaction time and terminating the reaction under the optimal state. Counterstaining with hematoxylin, dehydrating, transparentizing, and sealing for observation under the mirror. The expression of Ki67, CD3, CD68 was observed under the mirror. Selecting 5 visual fields from each section under 400 times of visual fields, applying Image-plus software5.0 Image analysis software to count and analyze functions, calculating the proportion of the number of positive cells in the neointima to all the cells, selecting a positive area, converting the background into white, converting a new picture into an 8-gray picture, and recording the reading of the software, namely the cumulative absorbance value. The results are shown in fig. 3, and compared with the sham group, the expression of CD3 in the model group is obviously increased, which indicates that the inflammatory response is activated, and the expression of CD3 can be inhibited by AS-IV, and shown in a and B in fig. 3; compared with the sham operation group, the expression of CD68 in the model group is increased, which indicates that the inflammatory response is obvious, the expression of CD68 is reduced after AS-IV treatment, and the inflammatory response is inhibited, and is shown AS C and D in figure 3.
(7) WesternBlot method for detecting PCNA, a-SMA and ICAM-1 expression in common carotid artery blood vessel
Weighing 60mg of blood vessel tissue, shearing in an EP tube, mixing RIPA lysate and PMSF protease inhibitor according to a ratio of 1: 99, crushing for 10s by using an ultrasonic crusher, placing on ice for cracking for about 25min, then placing 14000r/min in a 4 ℃ centrifuge, sucking supernatant into another EP tube, marking, detecting the concentration of each histone by using a BCA protein concentration measuring kit, calculating the sample loading amount according to a standard curve, preparing 10% SDS-PAGE electrophoresis gel, adding the extracted protein into 1/4 volumes of 5 xSDS sample loading buffer solution, boiling for 7min, loading according to the total amount of 30mg of protein, transferring the protein onto a PVDF membrane by electrotransfer (350mA, 120min), sealing for 1h at room temperature by using TBS/T containing 5% degreased milk, reacting with PCNA, a-SMA and ICAM-1 at 4 ℃ overnight, washing for 3 times by using TBS/0.5% Tween 20, incubating with goat anti-rabbit IgG labeled, incubating with the goat IgG-rabbit IgG antibody at 37 ℃, washing with 0.5% of ICAM-1, after transferring with the TBS/0.5% Tween 20 times, after transferring to 3 times, after transferring to a cell growth inhibition group after a cell growth reaction, a cell growth inhibition group is added into a cell growth group after a cell growth reaction is added into a luminous gel, a luminous cell growth inhibition group is added into a luminous cell growth inhibition group, a luminous cell growth group after a luminous cell growth system, a cell growth group is added into a luminous cell growth system, a cell growth system is added into a cell growth system after a cell growth.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (7)
1. Application of astragaloside IV in preparing medicine for preventing and/or treating restenosis in artery stent is provided.
2. Application of astragaloside IV in preparing medicine for inhibiting local inflammatory reaction is provided.
3. Use according to claim 2, characterized in that the local inflammatory response is caused by IL-6, TGF- β 1, TGF- β 2, TNF- α and/or IL-1 β.
4. Use of astragaloside IV in the preparation of a medicament for inhibiting the phenotypic switch and proliferation of Ang-II stimulated VSMCs.
5. Application of astragaloside IV in preparing medicine for reversing inflammatory factor TNF-a promoting VSMCs proliferation is provided.
6. A medicament for preventing and/or treating restenosis in an arterial stent is characterized in that the medicament takes astragaloside IV as an effective component.
7. A medicament for improving endothelial cell-induced adhesion and proliferation effects, which comprises astragaloside IV as an active ingredient.
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| CN112656827A (en) * | 2021-01-11 | 2021-04-16 | 广西国际壮医医院 | Radix araliae armatae total saponin and application thereof in preparation of medicine for treating restenosis after vascular injury |
| CN114712379A (en) * | 2022-04-18 | 2022-07-08 | 复旦大学 | Application of astragaloside IV in preparation of medicine for preventing and treating peritoneal dialysis intestinal complications |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112656827A (en) * | 2021-01-11 | 2021-04-16 | 广西国际壮医医院 | Radix araliae armatae total saponin and application thereof in preparation of medicine for treating restenosis after vascular injury |
| CN114712379A (en) * | 2022-04-18 | 2022-07-08 | 复旦大学 | Application of astragaloside IV in preparation of medicine for preventing and treating peritoneal dialysis intestinal complications |
| CN114712379B (en) * | 2022-04-18 | 2024-04-09 | 复旦大学 | Application of astragaloside IV in preparing medicine for preventing and treating peritoneal dialysis intestinal complications |
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