CN113995749A - Application of pseudolaric acid B in preparing medicine for treating pulmonary hypertension - Google Patents
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Abstract
The invention discloses application of pseudolaric acid B in preparing a medicament for treating pulmonary hypertension. The invention belongs to the technical field of biological medicines. The invention constructs a pulmonary hypertension disease mouse model through hypoxia (10%) induction. After the pseudolaric acid B is injected into the abdominal cavity, the conditions of fur, diet, activity, death and the like of the pulmonary hypertension mouse model are observed. KnotThe pseudolaric acid B (shown in 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 living quality (improving food intake and water intake) of the pulmonary hypertension animals and improving the survival rate of the pulmonary hypertension animals. Therefore, the invention provides the pseudolaric acid B which has wide application prospect in the aspect of preventing and treating pulmonary hypertension disease.
Description
Technical Field
The invention relates to a new application of pseudolaric acid B (1R,7S,8R,9R) -7-Acetoxy-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-carboxy-penta-1,3-dienyl) -9-methyl-11-oxo-1), in particular to an application of the pseudolaric acid in preparing a medicine for treating pulmonary hypertension, which belongs to the technical field of biological medicines.
Background
Pulmonary Hypertension (PAH) is a progressive malignant cardiovascular disease caused by a variety of causes, the causes of which are complex but with similar pathophysiological changes, and is characterized by muscular hypertrophy in the middle layer of the small Pulmonary Artery and the small Pulmonary Artery, myomyelination of the small Pulmonary Artery, fibroplasia of the blood vessel intima, and luminal stenosis and occlusion with in situ thrombosis. The main symptoms are dyspnea, decreased motor ability and gradual progression to right heart failure, leading to death. Clinically, the death rate of pulmonary hypertension is high, prognosis is poor, huge medical resources are consumed, the pulmonary hypertension cannot be cured up to now, the existing treatment medicines are mainly used for symptomatic treatment, the disease progress of most of PAH patients cannot be avoided, and the development of new medicines is urgently needed.
Hypoxia is an important factor causing the onset of pulmonary hypertension, and long-term hypoxia can cause the tissue structure of the blood vessel wall and the functional change thereof, such as the increase of vascular resistance caused by hypoxic pulmonary vasoconstriction; irreversible pulmonary vascular remodeling due to proliferation and hypertrophy of pulmonary vascular endothelial cells, smooth muscle cells, and extracellular matrix further leads to increased vascular resistance and worsening of PAH. However, most of the current drugs for treating PAH have pulmonary vessel dilatation as the main treatment target, and few evidences show that the drugs have direct antiproliferative and vascular remodeling reversing effects. Therefore, the further search of new anti-proliferative and hypertrophic PAH medicines has important scientific value and clinical application prospect.
PAH progresses rapidly and has a poor prognosis with a 1-year survival rate of only 69% and a 5-year survival rate of only 38% without treatment, and in the last 20 years, with knowledge of the pathophysiological processes of pulmonary hypertension, several drugs have been developed clinically for treating patients with chronic pulmonary hypertension, including single or combined use of the following drugs: calcium Channel Blockers (CCBs), Prostacyclin Analogs (PAs), endothelin receptor antagonists (ETRAs), phosphodiesterase inhibitors (PDE5i) and soluble guanylate cyclase (sGC) stimulators. Despite the current use of these drugs, the prognosis of PAH remains poor, with 1-year mortality rates as high as 15% and 3-year survival rates as low as 35% in patients with PAH, and the potential for systemic side effects such as liver damage, dyspnea, diarrhea, nausea and pain from drug use, the long-term outcome of drug-treated patients remains uncertain. Poor treatment effect, more adverse reactions and urgent need for drugs with better curative effect and higher safety.
Pseudolaric acid B is a diterpenoid compound isolated from the root of pseudolaric acid B, and has anticancer, antifungal, and anti-fertilization effects, and immunosuppressive activity on T lymphocyte. Pseudolaric acid B has been reported to inhibit the secretion of Hepatitis B Virus (HBV) by apoptosis and cell cycle arrest, and also to induce autophagy. Furthermore, pseudolaric acid B is reported to have cytotoxic activity on tumor cells in the anti-tumor process, but has no obvious cytotoxicity on normal cells. However, no research report on the application of the drug to Pulmonary Arterial Hypertension (PAH) has been found.
The invention researches the effect of pseudolaric acid B on pulmonary hypertension, and the result shows that the compound can effectively improve pulmonary vascular remodeling of pulmonary hypertension animals, relieve right ventricular hypertrophy and right heart failure, improve the living quality (improve food intake and water intake) of the pulmonary hypertension animals and improve the survival rate of the pulmonary hypertension animals, so the compound can be used as a novel medicine for preventing and treating the pulmonary hypertension and is used for preventing and treating the pulmonary hypertension.
Disclosure of Invention
The invention aims to provide application of pseudolaric acid B (1R,7S,8R,9R) -7-Acetoxy-9- ((1E,3E) -4-methoxy-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 preventing and treating pulmonary hypertension.
In order to achieve the purpose, the invention adopts the following technical means:
the invention constructs a pulmonary hypertension disease mouse model through hypoxia induction. After the pseudolaric acid B is given through intraperitoneal injection, the conditions of fur, diet, activity, death and the like of the pulmonary hypertension mouse model are observed. The result shows that the pseudolaric acid B can obviously improve the pulmonary vascular remodeling of the hypoxia-induced pulmonary hypertension mice, relieve right ventricular hypertrophy and right heart failure, improve the living quality (improve the food intake and water intake) of the pulmonary hypertension animals and improve the survival rate of the pulmonary hypertension animals, namely the pseudolaric acid B has the function of preventing and treating the pulmonary hypertension diseases through research.
Therefore, on the basis of the research, the invention provides the application of pseudolaric acid B in preparing the medicine for treating pulmonary hypertension, wherein the chemical structural formula of the pseudolaric acid B is shown as the formula I:
preferably, the pseudolaric acid B achieves the purpose of treating the pulmonary hypertension by relieving pulmonary vascular remodeling of the patient with the pulmonary hypertension and relieving right ventricular hypertrophy and right heart failure of the patient with the pulmonary hypertension.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides a novel medicine for preventing and treating pulmonary hypertension, namely golden larch bark acetic acid, which is used for preventing and treating pulmonary hypertension, and the golden larch bark acetic acid is a diterpenoid compound separated from the root of golden larch bark, so the medicine has the characteristics of nature and high safety and is suitable for long-term administration. The pseudolaric acid B can achieve the purpose of treating the pulmonary hypertension by relieving the pulmonary vascular remodeling of the patient with the pulmonary hypertension and relieving the right ventricular hypertrophy and the right heart failure of the patient with the pulmonary hypertension. Therefore, the invention provides a new technical means for preventing and treating pulmonary hypertension, and the pseudolaric acid B also has wide application prospect in the aspect of preventing and treating pulmonary hypertension diseases.
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FIG. 1 shows the survival rates of normoxic + solvent group, normoxic + pseudolaric acid B group, hypoxia + solvent group and hypoxia + pseudolaric acid B group at different days, which indicates that pseudolaric acid B can increase the survival rate of pulmonary hypertension animals;
fig. 2 shows the right ventricular hypertrophy of mice in the normoxic and solvent group, the normoxic and pseudolaric acid acetic acid group, the hypoxia and solvent group and the hypoxia and pseudolaric acid acetic acid group on different days, which indicates that the pseudolaric acid acetic acid can significantly improve the right ventricular hypertrophy of the pulmonary hypertension mice;
fig. 3 is a graph of the food intake, water intake and body weight changes of mice in different days in the normoxic and solvent group, the normoxic and pseudolaric acid acetic acid group, the hypoxia and solvent group and the hypoxia and pseudolaric acid acetic acid group, which illustrates that the food intake and water intake of the mice are gradually reduced due to hypoxia, and the weight reduction of the mice with pulmonary hypertension can be remarkably inhibited and the food intake and water intake of the mice with pulmonary hypertension can be increased after the pseudolaric acid acetic acid is treated by medication;
fig. 4 compares the right ventricular pressure of the pulmonary hypertension mouse in the normoxic + solvent group, the normoxic + pseudolaric acid group, the hypoxia + solvent group and the hypoxia + pseudolaric acid group, which shows that the pseudolaric acid can reduce the right ventricular pressure of the pulmonary hypertension mouse;
p <0.01vs blank group; # P <0.01vs hypoxia model group;
fig. 5 is a cross-sectional photograph of a lung small blood vessel of a mouse in a normoxic and solvent group, a normoxic and pseudolaric acid B group, an anoxia and solvent group and a hypoxia and pseudolaric acid B group, which shows that the pseudolaric acid B can significantly improve the pulmonary vascular remodeling of the mouse with pulmonary hypertension.
Detailed Description
The present invention is further described below in conjunction with specific examples, and the advantages and features of the present invention will become more apparent as the description proceeds. These examples are merely illustrative and do not limit the scope of the invention in any way. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention, and that such changes and modifications may be made without departing from the spirit and scope of the invention.
Example 1 use of pseudolaric acid B in the treatment of pulmonary hypertension
1. Animal and experimental reagents:
mice (strain: Kunming mice, purchased from the SPF animal laboratories center of the institute of genome engineering model of major disease, university of Copticaceae),
2. establishing a hypoxia-induced pulmonary hypertension model:
healthy Kunming male mice 24 (with a weight of 20-25 g) were randomly divided into two groups, namely an experimental group and a control group, according to the weight balance principle. 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 a normoxic + solvent group (solvent with the same volume as the pseudolaric acid group, i.e. intraperitoneal injection method) and a normoxic + pseudolaric acid group (pseudolaric acid 10mg/kg/2 days, intraperitoneal injection method). The experimental group mice are placed in an anoxic box for adaptive hypoxia for one week (the oxygen partial pressure is 12%), then are randomly divided into 2 groups according to the weight balance principle, namely an anoxic + solvent group (a solvent with the same volume as a pseudolaric acid group and an intraperitoneal injection method) and an anoxic + pseudolaric acid group (the pseudolaric acid group and an intraperitoneal injection method) respectively, and are placed in the anoxic box for continuous hypoxia (the oxygen partial pressure is 10%), and after 21 days, the conditions of fur, diet, activity, death and the like are observed.
The heart and the left lung were taken for 4% fixation of paraformaldehyde, and the remaining lung lobes were frozen. Fixed hearts and lungs were pathologically stained.
3. Results
3.1 Dermastegia pseudolaricis acetic acid for increasing survival rate of pulmonary hypertension animals
The treatment with the administration of pseudolaric acid in hypoxia was carried out, with the time point being recorded as 0 day for each group, and the Log-rank (Mantel-Cox) test showed the survival of pulmonary hypertension animals on different days after the administration of pseudolaric acid (P ═ 0.005).
Through researches, the animals with pulmonary hypertension induced by hypoxia are died in succession along with the prolongation of the raising time, the mortality rate of the hypoxia model group reaches 58 percent, and the mortality rate of the hypoxia + pseudolaric acid group (10 mg/kg/2 days of pseudolaric acid, an intraperitoneal injection method) is only 17 percent, which shows that the pseudolaric acid can improve the survival rate of the animals with pulmonary hypertension, and the results are shown in figure 1.
3.2 Thesidachin A can remarkably reduce the hypertrophy of the right ventricle of the pulmonary hypertension mouse
The study finds that the hypoxia-induced pulmonary hypertension mice die gradually, the dead mice are obtained, and the results show that the phenotype of the obtained animals is remarkable in right ventricular hypertrophy, the right ventricular hypertrophy index (right ventricular weight/left ventricular weight + ventricular septum) is remarkably increased, and the right ventricular hypertrophy index increased after the pseudolaric acid is treated by the drug is remarkably inhibited, and the results are shown in fig. 2. The pseudolaric acid B can obviously relieve the right ventricular hypertrophy of the pulmonary hypertension mouse and correct right heart failure.
3.3 Dermata pseudolaricis acetic acid can obviously improve the living quality of the pulmonary hypertension mice
Research shows that hypoxia induces pulmonary hypertension of mice, the mice die continuously along with the increase of feeding time, and the weight of the mice is gradually reduced in the feeding process, and the food intake and the water intake are also gradually reduced. The pseudolaric acid treatment can obviously inhibit the weight loss and obviously increase the food intake and water intake of the mice, and the result is shown in figure 3.
3.4 Dermastegia chinensis acetic acid can effectively reduce the pressure of the right ventricle of a pulmonary hypertension mouse
A significant increase in right ventricular pressure was seen in the hypoxia-induced pulmonary hypertension model. The elevated pressure in the right ventricle was significantly reduced in the hypoxic + pseudolaric acid group compared to the hypoxic + solvent group, with the results shown in fig. 4.
3.5 Dermata chinensis acetic acid can obviously improve pulmonary hypertension mouse pulmonary vascular remodeling
Hypoxia-induced pulmonary hypertension models can lead to pulmonary vascular remodeling. Compared with the hypoxia and solvent group, the pulmonary hypertension mice pulmonary vascular remodeling condition is obviously improved in the hypoxia and pseudolaric acid B group, and the result is shown in figure 5.
Claims (2)
1. The application of pseudolaric acid B (1R,7S,8R,9R) -7-Acetoxy-9- ((1E,3E) -4-carboxy-penta-1,3-dienyl) -9-methyl-11-oxo-1) in the preparation of the medicine for treating pulmonary hypertension is shown as the formula I:
2. the use of claim 1, wherein: the pseudolaric acid B achieves the purpose of treating the pulmonary hypertension by relieving the pulmonary vascular remodeling of the patient with the pulmonary hypertension and relieving the right ventricular hypertrophy and the right heart failure of the patient with the pulmonary hypertension.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021216754A1 (en) * | 2020-04-21 | 2021-10-28 | Spring Discovery, Inc. | Use of p38 mapk inhibitors for prevention and treatment of aging and aging-related disorders and for boosting an immune system |
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| WO2021216754A1 (en) * | 2020-04-21 | 2021-10-28 | Spring Discovery, Inc. | Use of p38 mapk inhibitors for prevention and treatment of aging and aging-related disorders and for boosting an immune system |
Non-Patent Citations (2)
| Title |
|---|
| FANG-FANG YU等: "Pseudolaric Acid B Attenuates High Salt Intake-Induced Hypertensive Left Ventricular Remodeling by Modulating Monocyte/Macrophage Phenotypes", 《MEDICAL SCIENCE MONITOR》 * |
| 余芳芳: "土槿乙酸对高盐诱导的高血压性左心室重塑的影响及机制探讨", 《天津中医药大学硕士学位论文》 * |
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