CN115671124B - Application of aucubin in preparation of anoxic pulmonary arterial high pressure vascular remodeling drugs - Google Patents
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Abstract
The invention discloses an application of aucubin in preparing a medicine for remodelling hypoxic pulmonary arterial hypertension vessels, and relates to the field of new application of medicines. The in vitro cell experiment result shows that aucubin can effectively inhibit proliferation of PASMCs, weaken migration ability of cells, and promote apoptosis increase; in vivo experiments show that aucubin can obviously reduce pulmonary artery pressure and right ventricle systolic pressure in a rat hypoxic pulmonary artery high pressure model induced by chronic hypoxia, reduce right ventricle hypertrophy index, improve right ventricle hypertrophy condition, and in addition, pulmonary artery pathological tissue results also prove that aucubin can effectively inhibit pulmonary artery vascular wall thickening, lumen narrowing and other lesions after intervention in an HPH rat model, promote vascular wall to obviously thin and lumen enlarging, which proves that the aucubin can obviously improve HPH rat model vascular remodeling.
Description
Technical Field
The invention relates to the field of new application of medicines, in particular to application of aucubin in preparation of a medicine for remodelling hypoxic pulmonary arterial hypertension blood vessels.
Background
Pulmonary hypertension (pulmonary artery hypertension, PAH) refers to pulmonary arterial pressure rise caused by various reasons (pulmonary artery average pressure measured by a right heart catheter is more than or equal to 25mmHg in a sea level resting state), and is a chronic cardiovascular and pulmonary vascular disease which is difficult to cure, and has complex pathogenesis and poor prognosis. Wherein hypoxia-induced pulmonary hypertension (Hypoxic pulmonary hypertension, HPH) belongs to the third class of PAH classification, which is a clinical syndrome mainly manifested by dyspnea and hypodynamia after activity, and the clinical characteristics of the syndrome are consistent with those of PAH. The disease is mainly characterized by long-term hypoxia leading to pulmonary vascular remodeling and progressive increases in cardiopulmonary circulatory resistance, ultimately leading to right heart failure. Epidemiological investigation of HPH is rare worldwide, but Chronic Obstructive Pulmonary Disease (COPD), restrictive pulmonary disease, and altitude heart disease, which are all common causes of HPH, are all the most common causes of HPH, with prevalence of HPH of about 20% -91%. Under long-term hypoxia stimulation, in vivo oxidation/antioxidant balance is broken, oxidative stress is enhanced, smooth muscle layer of pulmonary artery is thickened, pulmonary arterial stenosis remodeling is the most important pathophysiological change of HPH, however, key mechanism causing pulmonary arterial remodeling is not clear, and no drug treatment method is approved for the disease FDA (food and drug administration in United states). The national guidelines for diagnosis and treatment of pulmonary hypertension (2021 edition) use long-term oxygen therapy as the primary recommendation for HPH, but this approach is long-lasting, difficult for many patients to tolerate, and oxygen therapy can only ameliorate partial alveolar hypoxia, with limited reduction in pulmonary arterial pressure. Therefore, how to develop a drug for remodelling hypoxic pulmonary arterial hypertension is still a urgent problem to be solved.
Aucubin (Aucubin) is known as beta-D-glucopyranoside, which belongs to iridoid glycoside compounds, white powder or crystals, is easily dissolved in water, methanol, ethanol, and insoluble in diethyl ether, chloroform, benzene and petroleum ether. Because aucubin is present in traditional Chinese medicines such as eucommia ulmoides, plantain herb, rehmannia root and the like, the aucubin can be extracted from natural plants, has wide sources, is cheap and easy to obtain, is convenient for industrialized extraction, and has almost no toxic or side effect on cells and animals in therapeutic doses. The application of aucubin in preparing antithrombotic drugs or idiopathic pulmonary fibrosis drugs has been reported in the literature (application of CN 102068450B-aucubin in preparing antithrombotic drugs, and application of CN 104116753B-aucubin in preparing idiopathic pulmonary fibrosis drugs), so that the clinical research and development of new drugs by using aucubin are possible, but related application research on the preparation of hypoxia pulmonary arterial hypertension vascular remodeling drugs by aucubin has not been discovered yet.
Disclosure of Invention
In view of the above, the invention provides an application of aucubin in preparing a medicine for remodelling hypoxic pulmonary arterial hypertension blood vessel.
Preferably, aucubin is added with pharmaceutical auxiliary materials to prepare injection.
Preferably, the aucubin concentration in the injection is 1mg/mL.
By adopting the application of aucubin in preparing the anoxic pulmonary arterial high pressure vascular remodeling medicine, on one hand, the results of in vitro cell experiments prove that the aucubin effectively inhibits the proliferation of PASMCs, weakens the migration capacity of cells, and promotes the obvious increase of apoptosis; on the other hand, in vivo experiments show that aucubin can obviously reduce pulmonary artery pressure and right ventricular systolic pressure in a rat pulmonary artery high pressure model induced by chronic hypoxia, reduce right ventricular hypertrophy index and improve right ventricular hypertrophy condition. In addition, pathological tissue results also prove that aucubin can effectively inhibit pulmonary artery vascular wall thickening, narrow lumen and other lesions after being interfered with an HPH rat model, promote the vascular wall to be obviously thinned and the lumen to be enlarged, and show that the aucubin can obviously improve pulmonary vascular remodeling of the HPH rat model.
Drawings
FIG. 1 is a schematic representation of rat pulmonary arteriole pathology observed under a microscope after HE staining;
FIG. 2 shows the results of a scratch test for the proliferation and migration of aucubin on rat Pulmonary Artery Smooth Muscle Cells (PASMCs);
FIG. 3 shows the results of apoptosis test of aucubin on rat Pulmonary Artery Smooth Muscle Cells (PASMCs) using flow apoptosis;
FIG. 4 is a graph showing the effect of aucubin on rat Pulmonary Artery Smooth Muscle Cells (PASMCs) cell activity using CCK8 kit;
FIG. 5 shows the results of measuring antioxidant enzyme content and oxidative stress index in alveolar lavage fluid using SOD, CAT, LDH and MDA kits.
Detailed Description
The principles and features of the present invention are described below with reference to the drawings, the examples are illustrated for the purpose of illustrating the invention and are not to be construed as limiting the scope of the invention.
The aucubin related by the invention is purchased from Shanghai source leaf biotechnology limited company, and the injection taking the aucubin as a main active ingredient: 20mg aucubin is dissolved in 20mL of sterile water for injection to prepare a solution with the concentration of 1mg/mL for later use; SD adult male rats were purchased from Hunan Tiansu Biotechnology Co.
Embodiment one: the injection taking aucubin as a main active ingredient is applied to the treatment process and effect verification of pulmonary arterial hypertension vascular remodeling of hypoxic rats, and comprises the following steps:
s101, placing 18 SD adult male rats in a normal pressure hypoxia chamber for feeding and molding, controlling the oxygen concentration to be 10+/-0.5%, controlling the temperature in the chamber to be 22-24 ℃, and carrying out hypoxia for 12 h/day, and continuously feeding for 4 weeks under hypoxia.
S102, detecting pulmonary artery pressure (mPAP) and Right Ventricular Systolic Pressure (RVSP) by using a Medlab-U biological signal acquisition and processing system through a right jugular vein catheterization after 4 weeks; and (3) determining a lung function index by using a small animal lung function detection system, and acquiring index data of the anoxic pulmonary arterial hypertension rat model to evaluate whether the model meets the standard, wherein if the rat mPAP is more than or equal to 25mmHg, RVSP is more than or equal to 28mmHg, and the lung function index is obviously reduced, the model can meet the anoxic pulmonary arterial hypertension rat model.
S103, dividing the evaluated standard-reaching HPH rats into 2 groups, wherein 6 rats are respectively a model group (HPH group) and a treatment group (HPH+AU), and then selecting 6 normal pressure cabin-fed SD adult male rats as a control group (CONT group); the treatment groups were intraperitoneally injected with an amount of 10mg/kg (1 mg/mL of the injection solution) based on the actual weight of the rats, and the model group and the control group were administered with an equal amount of physiological saline twice a day for 2 weeks.
And S104, measuring relevant indexes after 2 weeks of administration, and evaluating the treatment effect.
(1) Effects of aucubin on Right Ventricular Hypertrophy Index (RVHI), right Ventricular Systolic Pressure (RVSP), and pulmonary arterial pressure (mPAP) in hypoxic pulmonary hypertension rats
Rats in the control group (CONT group), the model group (HPH group) and the treatment group (hph+au) were sacrificed respectively, and hearts were taken to determine the right ventricular hypertrophy index [ RV/(lv+s) ]. Compared with the model group, RVHI is obviously reduced after the administration treatment of aucubin, RVSP and mPAP are obviously reduced, and the aucubin has good treatment effect on hypoxic pulmonary arterial hypertension rats.
TABLE 1 Effect of aucubin on right ventricular hypertrophy index, right ventricular systolic pressure and pulmonary artery pressure in hypoxic pulmonary hypertension rats before and after administration
| Group of | RVHI(％) | RVSP(mmHg) | mPAP(mmHg) |
| Control group | 22 | 19 | 16 |
| Model group | 31 | 35 | 27 |
| Treatment group | 24 | 24 | 20 |
(2) Influence of aucubin on pulmonary artery histopathology in rats with pulmonary hypertension
Rat lung tissue of control, model and treatment groups were taken and stained with hematoxylin-eosin (HE) to observe the histopathological changes of the pulmonary artery to determine pulmonary artery remodeling and measure pulmonary artery remodeling related indicators, respectively: the ratio (WT%) of pulmonary artery wall thickness to pulmonary artery outer diameter (WT%) and the ratio (WA%) of pulmonary artery wall area to pulmonary artery cross-sectional area (WA%) are shown in the results of fig. 1 and table 2, and the pulmonary artery wall of the model group rat is obviously thickened, and the pulmonary artery middle layer myogenic hypertrophy and lumen stenosis are seen, and the pulmonary artery intimal fibrosis thickening and cell abnormal hyperplasia are accompanied, so that the successful construction of the hypoxic pulmonary artery high pressure rat model is proved. The aucubin administration can obviously reduce the wall thickness of pulmonary artery blood vessels, lighten the myogenesis of pulmonary arteries and enlarge pulmonary artery blood vessel cavities, which shows that the aucubin has obvious treatment effect on pulmonary vascular remodeling of pulmonary artery high-pressure rats.
TABLE 2 results of influence of aucubin on pulmonary artery histopathology in rats with pulmonary hypertension
Embodiment two: proliferation, migration and apoptosis of aucubin on rat pulmonary artery smooth muscle cells (pulmonary arterial smooth muscle cells, PASMCs)
PASMCs culture: inoculating cells to the cell suspension according to experimental requirement, dripping in the center of glass sheet in cell culture dish, standing for 30min, adding F12 cell culture solution 2mL, adding CO 2 Culturing CONT cells (control group) in incubator at 37deg.C for 48 hr, or 3% concentration of O 2 HPH cells (model group) were cultured in a three-gas incubator at 37℃for 48 hours. Can be inoculated in a culture bottle for subculture and used for subsequent experiments of cell proliferation, migration, apoptosis and the like.
(1) Test of proliferation and migration of aucubin on rat pulmonary smooth muscle cells (PASMCs) by scratch test
Scratch experiment:
(1) Uniformly scribing lines across each well with a marker pen behind the 6-well plate, at least 3 lines;
(2) About 5X 10 each of the wells was seeded with 5 A plurality of test cells;
(3) After the cells are full, a trace is marked in the hole by using a 200 mu L gun head perpendicular to the back transverse line;
(4) Washing the cells with PBS for 3 times, removing the scraped cells, and culturing for 48 hours;
(5) Scratches (same mark position) at 0 and 48 were taken respectively;
(6) Calculating the area covered before and after migration of the scratched cells, i.e
Scratch migration area = initial scratch area-healing scratch area
The in vitro cell experiments are divided into a control group (CONT group), a model group (HPH group) and a treatment group (HPH+AU group), wherein aucubin is added to the HPH cell model which is evaluated to reach the standard according to the concentration of 250 mug/mL in the step (2). The results as shown in fig. 2 and table 3 show: compared with the model group, the migration healing area of the normal group is normalized to 1, and the healing area of the treatment group is about 0.8 times of that of the normal group, which indicates that the treatment group remarkably promotes the proliferation of cells and plays a good healing role.
(2) Apoptosis of aucubin on rat Pulmonary Artery Smooth Muscle Cells (PASMCs) using flow apoptosis
The experiment uses Annexin V to dye the nucleus of a cell red through cells in the middle and late stages of apoptosis and dead cells, so that the Annexin V is matched with PI for use, and the cells in different apoptosis periods can be distinguished by a flow cytometer. Taking PASMCs in logarithmic growth phase, fully digesting with 0.25% pancreatin, counting, taking 10×10 4 The individual cells were centrifuged at 1000rpm X5 min and the supernatant discarded. The pre-chilled PBS was washed 2 times and centrifuged at 1000rpm X5 min. With 100. Mu.L of 1 Xbinding Buffer (stock solution 10 Xbinding Buffer, ddH) 2 O diluted to 1 x BindingBuffer). 5 mu L of Annexin V-FITC is added, and after being uniformly mixed, 5 mu L Propidium lodide is added, and the mixture is uniformly mixed and reacted for 15min at room temperature in a dark place. 400. Mu.L of 1 Xbinding Buffer was added before detection, and apoptosis was detected by flow cytometry (Ex=488nm; em=530 nm).
The results as shown in fig. 3 and table 3 show: compared with the model group, aucubin can obviously inhibit proliferation and migration of PASMCs cells, obviously increase apoptosis, thin pulmonary artery vessel wall, enlarged lumen and improved pulmonary vessel remodeling.
TABLE 3 testing of the Effect of aucubin on proliferation and apoptosis Rate of rat pulmonary smooth muscle cells (PASMCs) Using flow apoptosis
| Group of | Proliferation Rate (%) | Apoptosis rate (%) |
| Control group | 62 | 8.44 |
| Model group | 91 | 4.64 |
| Treatment group | 37 | 28.70 |
(3) Determination of the Effect of aucubin on the Activity of rat pulmonary smooth muscle cells (PASMCs) Using CCK8 kit
Detection of STS cytotoxicity to PASMCs using CCK 8: after passing to 3 rd generation PASMCs and digesting with pancreatin, centrifuging, adding 4mL DMEM/F2 medium heavy suspension containing 1% diabody and 10% foetal calf serum, and adding 6×10 3 The wells were inoculated into 96-well plates, and when PASMCs were fused at 60%, the DMEM/F2 medium containing 1% diabody and 10% fetal calf serum was replaced with DMEM/F2 medium containing 1% diabody and no fetal calf serum, and PASMCs were synchronized for 12h, and DMEM/F2 medium containing 0. Mu.g/mL, 5. Mu.g/mL, 10. Mu.g/mL, 20. Mu.g/mL, 40. Mu.g/mL, 60. Mu.g/mL, 80. Mu.g/mL of 1% diabody of aucubin, and 1% fetal calf serum was added, respectively. 24h after the administration, PBS was rinsed 2 times, 100. Mu.l of DMEM/F2 medium containing 10% CCK8 was added and incubated at 37℃for 30 minutes, and the absorbance at 450nm was set with a microplate reader to detect OD. The results in FIG. 4 show that the cell viability of the 80 μg/mL aucubin dose group remained at 50% after 24h of drug intervention, indicating minimal toxicity of aucubin to PASMCs.
(4) Detection of antioxidant enzyme content and oxidative stress index in alveolar lavage fluid by using SOD, CAT, LDH and MDA kit
3mL of sterile physiological saline is used for repeatedly lavaging the main bronchus of the rats in the control group (CONT group), the model group (HPH group) and the treatment group (HPH+AU) for 3 times respectively, cleaning liquid is collected in the sterile tube, supernatant is collected after centrifugation, the operation is carried out according to the instruction of a detection kit of Catalase (CAT), superoxide dismutase (SOD), lactate Dehydrogenase (LDH) and Malondialdehyde (MDA), the OD value of each sample hole is measured, and the actual content of CAT, SOD, MDA, LDH in the control group and the alveolar lavage liquid is counted according to the absorbance value.
As shown in Table 4 and FIG. 5, aucubin increased the antioxidant enzyme (SOD, CAT) content in alveolar lavage fluid and decreased oxidative stress index (LDH, MDA) compared to HPH group. The aucubin plays an antioxidant role in an anoxic pulmonary arterial hypertension rat model, the proliferation and migration capacity of PASMCs cells is obviously reduced, apoptosis is obviously increased, vascular remodeling is improved, and the aucubin plays an important role in oxidative stress reaction in the occurrence and development of anoxic pulmonary arterial hypertension.
TABLE 4 detection of index changes of CAT, SOD, MDA and LDH in rat alveolar lavage fluid before and after aucubin treatment using kit
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather to enable any modification, equivalent replacement, improvement or the like to be made within the spirit and principles of the invention.
Claims (3)
1. The application of aucubin in preparing medicine for treating anoxia pulmonary arterial hypertension vascular remodeling is provided.
2. The use according to claim 1, wherein the aucubin is formulated into an injection by adding pharmaceutically acceptable excipients.
3. The use according to claim 2, wherein the aucubin concentration in the injection is 1mg/mL.
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| CN104116753A (en) * | 2014-08-01 | 2014-10-29 | 欧阳冬生 | Application of aucubin to preparation of medicines for treating idiopathic pulmonary fibrosis |
| WO2016119220A1 (en) * | 2015-01-30 | 2016-08-04 | 四川九章生物科技有限公司 | Eucommia leaf extract, and preparation method and use thereof |
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