Application of aloe-emodin in preparation of medicine for treating pulmonary arterial hypertension

Abstract

The invention discloses application of aloe-emodin in preparation of a medicine for treating pulmonary arterial hypertension, and belongs to the technical field of biological medicine. The pulmonary arterial hypertension disease rat model is constructed through hypoxia (10%) induction. After aloe-emodin is injected into the intraperitoneal cavity, the conditions of fur, diet, activity, death and the like of the pulmonary arterial hypertension rat model are observed. Results show that the aloe-emodin (as shown in the formula I) has the effects of remarkably improving pulmonary vascular remodeling of animals with pulmonary hypertension, relieving right ventricular hypertrophy and right heart failure, improving the life quality of the animals with pulmonary hypertension (improving feeding and water inflow) and increasing the survival rate of the animals with pulmonary hypertension. The invention provides a new technical means for preventing and treating pulmonary arterial hypertension diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a new use of aloe emodin (1,8-dihydroxy-3-(hydroxymethyl) anthraquinone), and in particular to the use of aloe emodin in preparing a drug for treating pulmonary hypertension. The present invention belongs to the technical field of biomedicine. Background Art

[0002] Pulmonary arterial hypertension (PAH) is a syndrome caused by changes in pulmonary vascular structure and function due to a variety of unknown or known reasons, which leads to continuous increase in pulmonary vascular resistance and pulmonary artery pressure, and then develops into right heart failure and even causes death. It is characterized by an increase in the mean pulmonary artery pressure (>20 mmHg) at rest. PAH has various clinical manifestations. In the early stage, there may be no symptoms or only mild symptoms, such as decreased exercise tolerance, dyspnea, chest tightness or chest pain. As the disease progresses, symptoms of right heart failure such as syncope, lower limb edema, and palpitations may occur. In the past 20 years, the treatment of PAH has been continuously updated and great progress has been made. Targeted drug therapy has improved the prognosis and survival of patients. However, there is still no effective cure, and it can only delay or prevent the progression of the disease.

[0003] The pathogenesis of pulmonary hypertension is multifactorial and multipathway, involving a complex interaction of genes, molecules, cells and environmental factors, of which the most important cause is hypoxia. Hypoxia causes changes in pulmonary blood vessels, including imbalance of pulmonary vasoconstriction and relaxation, accumulation of fibroblasts in the pulmonary artery adventitia, proliferation and migration of pulmonary artery smooth muscle cells, and proliferation and migration of pulmonary artery endothelial cells, which leads to vascular remodeling and the formation of a new intima, resulting in blocked blood vessels, increased pulmonary artery pressure and pulmonary artery resistance. At present, the proliferation and anti-apoptosis of pulmonary artery smooth muscle cells are important mechanisms of pulmonary vascular remodeling. Pulmonary vascular remodeling is the pathological basis for the continued development of PAH disease and the main reason for its poor drug efficacy.

[0004] At present, in clinical practice, the drug treatment of PAH patients mainly adopts conventional drug therapy, targeted drug therapy and traditional Chinese medicine therapy. In terms of new drug development, a variety of new drugs for the treatment of PAH have entered the clinical trial stage, and treatment strategies for different subtypes of PAH have been developed. In terms of general drug treatment, conventional drugs such as diuretics, digoxin, calcium channel blockers, and anticoagulants are often used in clinical intervention and treatment of PAH patients. There are currently five main types of PAH targeted drugs in clinical practice, namely endothelin receptor antagonist (ERA), phosphodiesterase 5 (PDE5) inhibitors, soluble guanylate cyclase (sGC) agonists, prostacyclin analogs and prostacyclin receptor agonists. The mechanism of action of these five types of drugs is mainly generated around three signaling pathways: endothelin pathway, nitric oxide pathway and prostacyclin pathway. Traditional Chinese medicine has the advantages of multiple targets, multiple pathways, interactions among multiple active ingredients, safety and low price in the treatment of PAH, including Xuesetong injection, sodium tanshinone ⅡA sulfonate injection, breviscapine injection and ligustrazine injection.

[0005] Aloe emodin (1,8-dihydroxy-3-(hydroxymethyl)anthraquinone) is an anthraquinone derivative with the molecular formula C 15 H 10 O5, which is an isomer of aloe-emodin, exists in plants of the genus Aloe. Studies have shown that aloe-emodin has pharmacological properties such as antibacterial and antitumor. In terms of neuroprotection, aloe-emodin can improve the learning and memory ability of rats with Alzheimer's disease; in terms of anti-tumor, aloe-emodin exerts its effects through mechanisms such as inducing tumor cell apoptosis, inhibiting proliferation, inhibiting invasion and metastasis, inducing autophagy, anti-inflammation and immunomodulation; aloe-emodin has also been found to reduce endocrine resistance of breast cancer; at the same time, in the treatment of diabetes, aloe-emodin shows the potential to lower blood sugar by inhibiting α-glucosidase activity. However, there are no reports on its use in pulmonary arterial hypertension (PAH).

[0006] The present invention studies the effect of aloe-emodin on pulmonary hypertension and finds that the compound can effectively improve pulmonary vascular remodeling in animals with pulmonary hypertension, reduce right ventricular hypertrophy and right heart failure, improve the quality of life of animals with pulmonary hypertension (increase food and water intake), and improve the survival rate of animals with pulmonary hypertension. Therefore, the compound can be used as a new type of drug for preventing and treating pulmonary hypertension for the prevention and treatment of pulmonary hypertension. Summary of the invention

[0007] The purpose of the present invention is to provide application of aloe emodin (1,8-dihydroxy-3-(hydroxymethyl) anthraquinone) in preventing and treating pulmonary hypertension.

[0008] In order to achieve the above purpose, the present invention adopts the following technical means:

[0009] The present invention constructs a rat model of pulmonary hypertension by inducing hypoxia (10%). After aloe-emodin is administered by intraperitoneal injection, the fur, diet, activity, death and the like of the rat model of pulmonary hypertension are observed. The results show that aloe-emodin can significantly improve the pulmonary vascular remodeling of rats with pulmonary hypertension induced by hypoxia, reduce right ventricular hypertrophy and right heart failure, improve the quality of life of animals with pulmonary hypertension (increase the amount of food and water intake), and improve the survival rate of animals with pulmonary hypertension. That is, the present invention finds through research that aloe-emodin has the effect of preventing and treating pulmonary hypertension.

[0010] Therefore, based on the above research, the present invention proposes the use of aloe-emodin in the preparation of a drug for treating pulmonary hypertension. The chemical structural formula of the aloe-emodin (Aloeemodin) is shown in Formula I:

[0011]

[0012] Preferably, the aloe-emodin achieves the purpose of treating pulmonary hypertension by alleviating pulmonary vascular remodeling and alleviating right ventricular hypertrophy and right heart failure in patients with pulmonary hypertension.

[0013] Compared with the prior art, the present invention has the following beneficial effects:

[0014] The present invention proposes a new drug, aloe-emodin, which can be used to prevent and treat pulmonary hypertension. Aloe-emodin can significantly improve hypoxia-induced pulmonary vascular remodeling, reduce right ventricular hypertrophy and right heart failure, improve the quality of life of patients with pulmonary hypertension (increase food and water intake), and improve the survival rate of patients. Aloe-emodin is extracted from natural plants, is safe, has no side effects, and is suitable for long-term use. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 The survival rates of normoxia + solvent group, normoxia + aloe-emodin group, hypoxia + solvent group and hypoxia + aloe-emodin group on different days indicate that aloe-emodin can improve the survival rate of animals with pulmonary hypertension.

[0016] Figure 2The graphs of the changes in food intake, water intake and body weight of rats in the normoxia + solvent group, normoxia + aloe-emodin group, hypoxia + solvent group and hypoxia + aloe-emodin group on different days indicate that hypoxia causes a gradual decrease in the food and water intake of rats, and that aloe-emodin treatment can significantly inhibit the weight loss of rats with pulmonary hypertension and increase the food intake and water intake of rats with pulmonary hypertension.

[0017] Figure 3 These are typical cross-sectional photos of small pulmonary vessels in the normoxia + solvent group, normoxia + aloe-emodin group, hypoxia + solvent group, and hypoxia + aloe-emodin group, indicating that aloe-emodin can significantly improve pulmonary vascular remodeling in rats with pulmonary hypertension;

[0018] Figure 4 Comparison of right ventricular pressure in rats with pulmonary hypertension in normoxia + solvent group, normoxia + aloe-emodin group, hypoxia + solvent group and hypoxia + aloe-emodin group, indicating that aloe-emodin can reduce right ventricular pressure in rats with pulmonary hypertension;

[0019] Figure 5 The right ventricular hypertrophy of rats in the normoxia + solvent group, normoxia + aloe-emodin group, hypoxia + solvent group and hypoxia + aloe-emodin group on different days indicates that aloe-emodin can significantly improve right ventricular hypertrophy in rats with pulmonary hypertension; *P<0.05, **P<0.01. DETAILED DESCRIPTION

[0020] The present invention will be further described below in conjunction with specific examples, and the advantages and features of the present invention will become clearer as the description proceeds. However, these examples are exemplary only and do not constitute any limitation to the scope of the present invention. It should be understood by those skilled in the art that the details and forms of the technical solution of the present invention may be modified or replaced without departing from the spirit and scope of the present invention, but these modifications and replacements all fall within the scope of protection of the present invention.

[0021] Example 1 Application of aloe-emodin in treating pulmonary hypertension

[0022] 1. Animals and experimental reagents:

[0023] Rats (strain: Wistar rats, purchased from Liaoning Changsheng Biotechnology Co., Ltd.).

[0024] 2. Establishment of hypoxia-induced pulmonary hypertension model:

[0025] 24 healthy Wistar rats (weight 120-150 grams) were randomly divided into two groups according to the weight balance principle, namely the experimental group and the control group. The control group rats were raised in a standard sterile breeding environment and randomly divided into two groups according to the weight balance principle, namely the normoxia + solvent group (solvent with the same volume as the aloe-emodin group, intraperitoneal injection method) and the normoxia + aloe-emodin group (aloe-emodin 60mg / kg / 2 days, intraperitoneal injection method). The experimental group rats were placed in an oxygen box for adaptive hypoxia for one week (oxygen partial pressure 12%), and then randomly divided into two groups according to the weight balance principle, namely the oxygen + solvent group (solvent with the same volume as the aloe-emodin group, intraperitoneal injection method) and the oxygen + aloe-emodin group (aloe-emodin 60mg / kg / 2 days, intraperitoneal injection method). After being placed in an oxygen box for continuous hypoxia (oxygen partial pressure 10%) for 21 days, the fur, diet, activity, death and other conditions were observed.

[0026] The heart and left lung were fixed with 4% paraformaldehyde, and the remaining lung lobes were cryopreserved. The fixed heart and lung were subjected to pathological staining.

[0027] 3. Results

[0028] 3.1 Aloe-emodin improves the survival rate of animals with pulmonary hypertension

[0029] After 24 days of hypoxia, aloe-emodin was administered and this time point was recorded as day 0 for each group. Log-rank (Mantel-Cox) test showed the survival rate of pulmonary hypertension animals at different days after aloe-emodin administration (P=0.005).

[0030] Through research, it was found that animals with pulmonary hypertension induced by hypoxia began to die as the feeding time prolonged. After 40 days of hypoxia, the mortality rate of the hypoxia + solvent group reached 50%, while the mortality rate of the hypoxia + aloe-emodin group (aloe-emodin, 60 mg / kg body weight / day, intraperitoneal injection) was only 33%, indicating that aloe-emodin can improve the survival rate of animals with pulmonary hypertension. The results are as follows Figure 1 shown.

[0031] 3.2 Aloe-emodin can significantly improve the quality of life of rats with pulmonary hypertension

[0032] Studies have found that hypoxia induces pulmonary hypertension in rats. As the feeding time increases, not only do the rats die one after another, but their weight gradually decreases during the feeding process, and their food and water intake also gradually decreases. Treatment with aloe-emodin can significantly inhibit weight loss and significantly increase the food and water intake of rats. The results are as follows Figure 2 shown.

[0033] 3.3 Aloe-emodin can significantly improve pulmonary vascular remodeling in rats with pulmonary hypertension

[0034] Hypoxia-induced pulmonary hypertension model can lead to pulmonary vascular remodeling. Compared with the hypoxia + solvent group, the pulmonary vascular remodeling of pulmonary hypertension rats in the hypoxia + aloe-emodin group was significantly improved. Figure 3 shown.

[0035] 3.4 Aloe-emodin can effectively reduce right ventricular pressure in rats with pulmonary hypertension

[0036] The hypoxia-induced pulmonary hypertension model showed a significant increase in right ventricular pressure. Compared with the hypoxia + solvent group, the increase in right ventricular pressure in the hypoxia + aloe-emodin group was significantly reduced. Figure 4 shown.

[0037] 3.5 Aloe-emodin can significantly reduce right ventricular hypertrophy in rats with pulmonary hypertension

[0038] The study found that rats with pulmonary hypertension induced by hypoxia gradually died. The dead rats were sampled and the results showed that the animal phenotype was significantly enlarged in the right ventricle, and the right heart hypertrophy index (right heart weight / left heart weight + ventricular septum) increased significantly. However, the increased right heart hypertrophy index was significantly inhibited after treatment with aloe-emodin. The results are as follows Figure 5 This indicates that aloe-emodin can significantly reduce right ventricular hypertrophy in rats with pulmonary hypertension and correct right heart failure.

Claims

1. Application of aloe-emodin in the preparation of a drug for treating pulmonary hypertension, wherein the chemical structural formula of the aloe-emodin (Aloeemodin, 1,8-dihydroxy-3-(hydroxymethyl) anthraquinone) is as shown in Formula I:

2. The use according to claim 1, characterized in that: The aloe-emodin achieves the purpose of treating pulmonary hypertension by alleviating pulmonary vascular remodeling and alleviating right ventricular hypertrophy and right heart failure in patients with pulmonary hypertension.

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