CN113995749B - Application of pseudolaric acid B in preparing medicine for treating pulmonary arterial hypertension - Google Patents
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Abstract
The invention discloses application of pseudolaric acid B in preparing a medicine for treating pulmonary arterial hypertension. The invention belongs to the technical field of biological medicine. The invention constructs a pulmonary artery high pressure disease mouse model through hypoxia (10%) induction. After injecting the pseudolaric acid B into the abdominal cavity, the skin, diet, activity, death and other conditions of the pulmonary artery high pressure mouse model are observed. As a result, the pseudolaric acid B (shown in the formula I) has the effects of remarkably improving pulmonary vascular remodeling of the pulmonary hypertension animals, relieving right ventricular hypertrophy and right heart failure, improving the survival quality of the pulmonary hypertension animals (improving feeding and water intake) and improving the survival rate of the pulmonary hypertension animals. Therefore, the invention provides that the golden larch bark acetic acid has wide application prospect in the aspect of preventing and treating pulmonary arterial hypertension diseases.
Description
Technical Field
The invention relates to a new application of pseudolaric acid B (pseudolaric acid B) (1R, 7S,8R, 9R) -7-acetic acid B-9- ((1E, 3E) -4-carboxy-penta-1, 3-dienyl) -9-methyl-11-oxo-1 (pseudolaric acid B) (1R, 7S,8R, 9R) -7-Acetoxy-9- ((1E, 3E) -4-carboxyl-penta-1, 3-dienyl) -9-methyl-11-oxo-1), in particular to an application of pseudolaric acid B in preparing a medicament for treating pulmonary arterial hypertension.
Background
Pulmonary hypertension (Pulmonary Artery Hypertension, PAH) is a progressive malignant cardiovascular disease caused by a number of causes, the cause of which is complex, but has similar pathophysiological changes, characterized by myogenic hypertrophy of the middle and fine pulmonary arteries, fibrotic hyperplasia of the intima of the blood vessels, and lumen stenosis occlusion with in situ thrombosis. The main symptoms are dyspnea, reduced exercise capacity and progressive right heart failure leading to death. Clinically, the death rate of pulmonary arterial hypertension is high, prognosis is poor, huge medical resources are consumed, and the pulmonary arterial hypertension can not be cured until now, the current therapeutic drugs mainly treat symptoms, the disease progression of most PAH patients is unavoidable, and development of new drugs is urgently needed.
Hypoxia is an important factor causing pulmonary hypertension, and long-term hypoxia can cause vascular wall tissue structure and functional changes thereof such as vascular resistance increase caused by hypoxia pulmonary vasoconstriction; irreversible pulmonary vascular remodeling by proliferation and hypertrophy of pulmonary vascular endothelial cells, smooth muscle cells and extracellular matrix further leads to increased vascular resistance and exacerbation of PAH. However, most of the current drugs for treating PAH will dilate pulmonary vessels as the main therapeutic target, and there is little evidence that these drugs have direct antiproliferative and inverse vascular remodeling effects. Therefore, the further search of new PAH drugs for resisting proliferation and hypertrophy has important scientific value and clinical application prospect.
PAH, if untreated, progresses rapidly, has a poor prognosis, with a survival rate of only 69% in 1 year and only 38% in 5 years, and in the last 20 years, with knowledge of the pathophysiological processes of pulmonary hypertension, several drugs have been developed clinically for treating chronic pulmonary hypertension patients, including single or combined use of: calcium Channel Blockers (CCBs), prostacyclin Analogs (PA), endothelin receptor antagonists (ETRA), phosphodiesterase inhibitors (PDE 5 i), and soluble guanylate cyclase (sGC) stimulators. Despite the current use of the above drugs, the prognosis for PAH remains poor, with patient mortality rates of PAH of up to 15% in 1 year and survival rates of up to 35% in 3 years, and with the possibility of systemic side effects such as liver injury, dyspnea, diarrhea, nausea and pain, long-term outcome for patients receiving drug therapy remains uncertain. Poor treatment effect and more adverse reactions, and medicines with better curative effects and safer effects are urgently needed.
The golden larch bark acetic acid (pseudolaric acid B) is diterpenoid compounds separated from the root of golden larch bark, has the largest proportion in golden larch bark, has the functions of resisting cancer, fungi, fertilization, and the like, and also has immunosuppressive activity on T lymphocytes. Pseudolaric acid B has been reported to inhibit secretion of Hepatitis B Virus (HBV) by apoptosis and cell cycle arrest, and also to induce autophagy. In addition, pseudolaric acid B has been reported to have cytotoxic activity against tumor cells in anti-tumor cells, but no significant cytotoxicity against normal cells. But no research report for pulmonary arterial hypertension (Pulmonary Arterial Hypertension, PAH) is currently seen.
The results of researching the effect of the pseudolaric acid B on pulmonary hypertension show that the compound can effectively improve pulmonary vascular remodeling of pulmonary hypertension animals, relieve right ventricular hypertrophy and right heart failure, improve the survival quality of pulmonary hypertension animals (improve feeding and water intake) and improve the survival rate of pulmonary hypertension animals, so the compound can be used as a novel medicine for preventing and treating pulmonary hypertension and is used for preventing and treating pulmonary hypertension.
Disclosure of Invention
The invention aims to provide application of (1R, 7S,8R, 9R) -7-acetic acid-9- ((1E, 3E) -4-carboxy-penta-1, 3-dienyl) -9-methyl-11-oxo-1 (pseudolaric acid B) and (1R, 7S,8R, 9R) -7-Acetoxy-9- ((1E, 3E) -4-carboxyl-penta-1, 3-dienyl) -9-methyl-11-oxo-1) in preventing and treating pulmonary arterial hypertension.
In order to achieve the above purpose, the invention adopts the following technical means:
the invention constructs a pulmonary artery high pressure disease mouse model through hypoxia induction. After administration of pseudolaric acid by intraperitoneal injection, the skin, diet, activity, death, etc. of the pulmonary arterial hypertension mouse model were observed. The results show that the golden larch bark acetic acid can obviously improve the pulmonary vascular remodeling of mice with hypoxia induced pulmonary hypertension, relieve the right ventricular hypertrophy and right heart failure, improve the life quality of the pulmonary hypertension animals (improve feeding and water intake) and improve the survival rate of the pulmonary hypertension animals, namely the golden larch bark acetic acid (pseudolaric acid B) has the effect of preventing and treating the pulmonary hypertension diseases through researches.
Therefore, on the basis of the research, the invention provides application of the golden larch bark acetic acid in preparing a medicine for treating pulmonary arterial hypertension, wherein the chemical structural formula of the golden larch bark acetic acid is shown as a formula I:
wherein, the preferred golden larch bark acetic acid achieves the aim of treating pulmonary arterial hypertension by reducing pulmonary vascular remodeling of patients with pulmonary arterial hypertension and reducing right ventricular hypertrophy and right heart failure of patients with pulmonary arterial hypertension.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides a novel medicine for preventing and treating pulmonary arterial hypertension, namely, pseudolaric acid B, which is used for preventing and treating pulmonary arterial hypertension, and the pseudolaric acid B is diterpenoid compounds separated from root parts of pseudolaric acid B, so that the medicine has the characteristics of naturalness and high safety, and is suitable for long-term administration. The pseudolaric acid can achieve the aim of treating the pulmonary arterial hypertension by relieving pulmonary vascular remodeling of the pulmonary arterial hypertension patient and relieving right ventricular hypertrophy and right heart failure of the pulmonary arterial hypertension patient. Therefore, the invention provides a new technical means for preventing and treating pulmonary hypertension, and also ensures that the golden larch bark acetic acid has wide application prospect in preventing and treating pulmonary hypertension diseases.
Drawings
FIG. 1 shows survival rates of normoxic + solvent, normoxic + pseudolaric acid B, anoxic + solvent and anoxic + pseudolaric acid B on different days, illustrating that pseudolaric acid B can increase survival rate in animals with pulmonary hypertension;
FIG. 2 is a graph showing that normoxic + solvent group, normoxic + pseudolaric acid group, anoxic + solvent group, and anoxic + pseudolaric acid group are shown to significantly improve pulmonary arterial hypertension mice right ventricular hypertrophy;
fig. 3 is a graph showing the feeding amount, water inflow and weight change of mice in normoxic + solvent group, normoxic + pseudolaric acid group, anoxic + solvent group and anoxic + pseudolaric acid group on different days, illustrating that hypoxia causes the feeding amount and water inflow of mice to gradually decrease, and the pseudolaric acid group can significantly inhibit the weight decrease of pulmonary artery high pressure mice and increase the feeding amount and water inflow of pulmonary artery high pressure mice after medication;
FIG. 4 shows a comparison of pulmonary artery hypertension mice right ventricular pressure in normoxic + solvent group, normoxic + pseudolaric acid group, anoxic + solvent group, and anoxic + pseudolaric acid group, demonstrating that pseudolaric acid can reduce pulmonary artery hypertension mice right ventricular pressure;
* P <0.01vs blank; # P <0.01vs hypoxia model group;
fig. 5 is a photograph of a typical pulmonary small vessel cross section of mice in normoxic + solvent group, normoxic + pseudolaric acid group, anoxic + solvent group, and anoxic + pseudolaric acid group, showing that pseudolaric acid can significantly improve pulmonary arterial hypertension mice pulmonary vessel remodeling.
Detailed Description
The invention will be further described with reference to specific examples, and advantages and features of the invention will become apparent from the description. These examples are merely exemplary and are not intended to limit the scope of the invention in any way. It will be understood by those skilled in the art that various changes and substitutions of details and forms of the technical solution of the present invention may be made without departing from the spirit and scope of the present invention, but these changes and substitutions fall within the scope of the present invention.
Example 1 use of pseudolaric acid B in the treatment of pulmonary hypertension
1. Animal and experimental reagent:
mice (strain: kunming mice, purchased from the SPF animal laboratory center of the animal institute of great disease genome engineering model of university of Dalian medical university),
2. establishing a hypoxia-induced pulmonary arterial hypertension model:
healthy Kunming male mice 24 (weight 20-25 g) were randomly divided into two groups according to the weight balance principle, namely an experimental group and a control group. Mice in the control group were bred in a standard sterile breeding environment and were randomly divided into two groups according to the weight balance principle, namely, normoxic+solvent group (solvent of the same volume as that of the golden larch bark acetic acid group, intraperitoneal injection method) and normoxic+golden larch bark acetic acid group (golden larch bark acetic acid 10mg/kg/2 days, intraperitoneal injection method). Mice in the experimental group are put into an anoxic tank for adaptive hypoxia for one week (oxygen partial pressure is 12%), then are randomly divided into 2 groups according to the weight balance principle, and are respectively an anoxic + solvent group (solvent with the same volume as that of the golden larch bark acetic acid group, i.e. an intraperitoneal injection method) and an anoxic + golden larch bark acetic acid group (golden larch bark acetic acid of 10mg/kg/2 days, i.e. an intraperitoneal injection method), and are put into the anoxic tank for continuous hypoxia (oxygen partial pressure of 10%), and after 21 days, the conditions of fur, diet, activity, death and the like are observed.
Taking heart and left lung, fixing polyformaldehyde by 4%, and freezing the rest lung lobes. The fixed heart and lungs were pathologically stained.
3. Results
3.1 Equisetum AcOEt for increasing survival rate of pulmonary arterial hypertension animals
Treatment with pseudolaric acid B was performed in the absence of hypoxia, each group was scored at this point for 0 days and Log-rank (Mantel-Cox) test showed survival of pulmonary hypertension animals on different days after pseudolaric acid B administration (P=0.005).
Through researches, the death rate of the hypoxia-induced pulmonary artery hypertension animals is 58% in the hypoxia model group and 17% in the hypoxia+golden larch bark acetic acid group (golden larch bark acetic acid 10mg/kg/2 days, intraperitoneal injection method) after the feeding time is prolonged, which shows that golden larch bark acetic acid can improve the survival rate of the pulmonary artery hypertension animals, and the result is shown in figure 1.
3.2 the golden larch bark acetic acid can obviously relieve the right ventricular hypertrophy of the mice with pulmonary arterial hypertension
The study found that hypoxia-induced pulmonary hypertension mice die gradually, and the dead mice were sampled, and as a result, the sampled mice were found to have a significantly increased right ventricular hypertrophy phenotype, right cardiac hypertrophy index (right heart weight/left heart weight + ventricular septum), and the increased right cardiac hypertrophy index after treatment with pseudolaric acid is significantly inhibited, and the results are shown in fig. 2. The golden larch bark acetic acid can obviously relieve the right ventricular hypertrophy of mice with pulmonary arterial hypertension and correct right heart failure.
3.3 the pseudolaric acid B can obviously improve the life quality of the pulmonary artery high pressure mice
The study shows that the mice die continuously along with the prolongation of the feeding time, the weight of the mice gradually decreases in the feeding process, and the feeding and water inflow of the mice also gradually decrease. The pseudolaric acid B treatment can significantly inhibit weight loss and significantly increase the feeding and water intake of mice, and the results are shown in figure 3.
3.4 golden larch bark acetic acid can effectively reduce the right ventricle pressure of the pulmonary artery high pressure mouse
The hypoxia-induced pulmonary hypertension model can see a significant increase in right ventricular pressure. The increased right ventricular pressure was significantly reduced in the anoxic + golden larch bark acetic acid group compared to the anoxic + solvent group, as shown in figure 4.
3.5 golden larch bark acetic acid can obviously improve pulmonary vascular remodeling of mice with pulmonary arterial hypertension
Hypoxia-induced pulmonary hypertension models can lead to pulmonary vascular remodeling. Compared with the anoxic + solvent group, the anoxic + soil-pseudolaric acid group has significantly improved pulmonary vascular remodeling condition of the pulmonary arterial hypertension mice, and the result is shown in fig. 5.
Claims (2)
1. Use of pseudolaric acid B in the manufacture of a medicament for the treatment of pulmonary hypertension, wherein the chemical structural formula of pseudolaric acid B (pseudolaric acid B) (1R, 7S,8R, 9R) -7-acetic acid B-9- ((1E, 3E) -4-carboxy-pent-1, 3-dienyl) -9-methyl-11-oxo-1 (1R, 7S,8R, 9R) -7-Acetoxy-9- ((1E, 3E) -4-carboxy-penta-1, 3-dienyl) -9-methyl-11-oxo-1) is as shown in formula I:
2. the use according to claim 1, wherein: the pseudolaric acid B can treat pulmonary hypertension by relieving pulmonary vascular remodeling of patients with pulmonary hypertension and relieving right ventricular hypertrophy and right heart failure of patients with pulmonary hypertension.
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