Use of astragaloside in preparation of medicine for treating chronic obstructive pulmonary disease

Abstract

The application discloses application of astragaloside in preparation of a medicine for treating chronic obstructive pulmonary disease. Through animal experiments, the application proves for the first time that astragaloside has a potential treatment effect on COPD, the astragaloside can reduce the number of inflammatory cells in bronchoalveolar lavage fluid, reduce the level of proinflammatory factors in the lung, reduce the deposition of collagen around the airway, up-regulate the protein level of epithelial cell marker E-cadherin in lung tissue, down-regulate the protein level of interstitial cell marker alpha-SMA, inhibit the phosphorylation level of p38 MAPK and ERK1 / 2 protein in lung tissue, up-regulate the expression level of antioxidant-related protein, and does not cause obvious hepatorenal toxicity at a treatment dose, showing good safety. Therefore, the application provides a new medicine for treating chronic obstructive pulmonary disease, and has a good clinical application prospect.

Description

Technical Field

[0001] This application relates to the application of astragaloside A in the preparation of drugs for treating chronic obstructive pulmonary disease, and belongs to the field of biomedical technology. Background Technology

[0002] Chronic obstructive pulmonary disease (COPD) is a common, preventable, and treatable chronic airway disease characterized by persistent airflow limitation and respiratory symptoms. It is typically caused by airway and / or alveolar abnormalities, often resulting from prolonged exposure to harmful particles or gases (such as cigarette smoke, air pollution, and occupational dust), and is associated with an abnormal inflammatory response of the lungs to these particles or gases. The pathophysiological changes in COPD primarily include chronic bronchitis, small airway obstruction (such as obstructive bronchiolitis), and lung parenchymal destruction (such as emphysema), which collectively lead to air trapping and progressive expiratory airflow limitation.

[0003] Currently, COPD is one of the leading causes of morbidity and mortality worldwide. Existing COPD treatment strategies primarily focus on symptom relief, reducing the frequency and severity of acute exacerbations, and improving exercise tolerance and quality of life. Commonly used medications include bronchodilators (such as β2-receptor agonists and anticholinergics) and inhaled corticosteroids. While these medications can control symptoms and improve lung function to some extent, they cannot effectively prevent or reverse the long-term progression of the disease. Particularly for patients with moderate to severe COPD, the persistent inflammatory response and immune dysregulation lead to irreversible airway remodeling, limiting the effectiveness of existing treatments. Furthermore, long-term use of certain medications (especially systemic corticosteroids) can cause a range of systemic side effects, restricting their clinical application. Therefore, there is an urgent need to develop novel therapeutic drugs that can effectively intervene in COPD progression at the pathophysiological level and have good safety profiles.

[0004] In recent years, Traditional Chinese Medicine (TCM) has demonstrated unique advantages in the prevention and treatment of COPD, exerting comprehensive therapeutic effects such as anti-inflammation, anti-oxidation, and immunomodulation through multiple targets and pathways. Astragaloside IV (AS-IV) is one of the main active ingredients isolated and extracted from the traditional Chinese medicine Astragalus membranaceus. Modern pharmacological studies have shown that AS-IV possesses various biological activities, including anti-inflammatory, anti-oxidative, anti-apoptotic, and anti-fibrotic effects, showing potential application value in the treatment of cardiovascular, cerebrovascular, liver, and kidney diseases. However, there are currently no in-depth and systematic reports on the application of AS-IV in COPD treatment, especially in improving COPD pathological features, regulating specific inflammatory pathways, and inhibiting airway remodeling.

[0005] Based on the problems existing in the prior art, this application aims to provide a new use for AS-IV, namely its application in the preparation of drugs for treating COPD, in order to provide a safer and more effective drug option for the clinical treatment of COPD through a new mechanism of action. Summary of the Invention

[0006] This application aims to address the problems and shortcomings of the prior art by providing a new use of AS-IV in the preparation of drugs for treating COPD.

[0007] To achieve the above objectives, this application adopts the following technical solution:

[0008] This application provides the use of astragaloside A in the preparation of a medicament for treating chronic obstructive pulmonary disease.

[0009] Furthermore, the drug comprises a pharmacologically active ingredient and pharmaceutically acceptable excipients, wherein the pharmacologically active ingredient is astragaloside A.

[0010] Further, the pharmaceutically acceptable excipients are one or more of the following: diluents, binders, wetting agents, lubricants, disintegrants, solvents, emulsifiers, cosolvents, preservatives, pH adjusters, osmotic pressure adjusters, surfactants, coating materials, antioxidants, and buffers.

[0011] Furthermore, the dosage form of the drug is an oral formulation, an inhaled formulation, or an injectable formulation.

[0012] Compared with the prior art, this application has the following beneficial effects: This application discloses the application of astragaloside A in the preparation of drugs for treating COPD. For the first time, it systematically elucidates the potential therapeutic effects of astragaloside A on COPD and its related mechanisms. Specifically, in COPD mice induced by systemic cigarette smoke exposure, astragaloside A can reduce the total number of white blood cells and the number of inflammatory cells such as monocytes and neutrophils in bronchoalveolar lavage fluid, reduce the protein levels of pro-inflammatory factors TNF-α, IL-6 and IL-1β in the lungs, reduce collagen deposition around the airways, upregulate the protein level of E-cadherin, an epithelial cell marker in lung tissue, downregulate the protein level of α-SMA, an interstitial cell marker, inhibit the phosphorylation level of p38 MAPK and ERK1 / 2 proteins in lung tissue, and upregulate the expression levels of antioxidant-related proteins Nrf2, SOD, HO-1, CAT and NQO1. Moreover, it did not cause significant hepatotoxicity or nephrotoxicity at therapeutic doses. In summary, this application demonstrates that astragaloside A can effectively treat COPD by exerting its effects through multiple mechanisms, including anti-inflammatory, antioxidant, and epithelial-mesenchymal transition inhibition, and has good safety profile, providing a new drug preparation approach for the treatment of chronic obstructive pulmonary disease. Attached Figure Description

[0013] Figure 1 Results of the detection of inflammatory cells in the bronchoalveolar lavage fluid of mice in each group: number of white blood cells (WBC), neutrophils and monocytes.

[0014] Figure 2 Results of detecting the protein secretion levels of inflammatory cytokines TNF-α, IL-6, and IL-1β in bronchoalveolar lavage fluid using enzyme-linked immunosorbent assay (ELISA).

[0015] Figure 3 Results of detecting the protein expression levels of epithelial cell marker E-cadherin and interstitial cell markers α-SMA and Vimentin in lung tissue using Western blotting.

[0016] Figure 4 The results of Western blotting were obtained by detecting the phosphorylation levels of p38 (A) and ERK (B) in mouse lung tissue and the protein expression levels of Nrf2, SOD1, CAT, HO-1, and NQO1 (C).

[0017] Figure 5 The in vivo safety of AS-IV at this therapeutic dose was assessed by performing pathological examination of liver and kidney tissues. Detailed Implementation

[0018] To make the technical solution of this application clearer and easier to understand, preferred embodiments are described in detail below with reference to the accompanying drawings.

[0019] Unless otherwise specified, the experimental or testing methods described in the following examples are conventional methods; the reagents and materials described are obtained from conventional commercial sources unless otherwise specified. Astragaloside IV (AS-IV, CAS No.: 84687-43-4) used in the following examples was purchased from Shanghai Ronghe Pharmaceutical Technology Development Co., Ltd.

[0020] Example This embodiment provides the application of AS-IV in the preparation of drugs for treating COPD. The following experimental protocol verifies the therapeutic effect and potential molecular mechanism of AS-IV on COPD: 1. Animal model construction and dosing regimen: This application uses the whole-body cigarette smoke exposure method to construct an animal model of COPD. Specifically, male C57BL / 6J mice were selected and randomly divided into a normal control group, a model group, a control drug treatment group, and an AS-IV treatment group. Modeling method: Starting from day 0 of the experiment, except for the normal control group, the animals in the other groups were placed in a cigarette smoke exposure device and exposed to cigarette smoke for 5 days a week for 12 consecutive weeks to establish a stable COPD mouse model.

[0021] Administration method: Starting from week 13 of the experiment, animals in the AS-IV treatment group were administered AS-IV (20 mg / kg) by gavage, while the control group was administered dexamethasone (DEX, 1 mg / kg) by gavage. The model group and the normal control group received an equal volume of solvent as a control. Administration was once daily for two consecutive weeks. Sample collection: Animals were sacrificed the day after the last administration, and bronchoalveolar lavage fluid, serum, lung tissue, and liver and kidney tissue were collected for subsequent indicator detection.

[0022] 2. The inhibitory effect of astragaloside A on airway inflammation: Inflammatory cell count: Bronchoalveolar lavage fluid was collected, centrifuged, and the total white blood cell count and differential cell count (including lymphocytes, monocytes / macrophages, and neutrophils) were determined. The inhibitory effect of AS-IV on airway inflammatory cell infiltration in COPD was assessed by comparing the differences in inflammatory cell counts among the groups. Results are shown below. Figure 1 As shown, AS-IV can significantly reduce the number of inflammatory cells (WBCs), neutrophils, and monocytes) in the bronchoalveolar lavage fluid of COPD mice.

[0023] Detection of inflammatory factors: The protein secretion levels of inflammatory cytokines TNF-α, IL-6, and IL-1β in bronchoalveolar lavage fluid were detected using enzyme-linked immunosorbent assay (ELISA). The results are as follows: Figure 2 As shown, AS-IV significantly reduced the levels of inflammatory factors in the bronchoalveolar lavage fluid of COPD mice. These findings clarify the regulatory role of AS-IV in pro-inflammatory factors.

[0024] 3. The effect of AS-IV on improving pulmonary fibrosis: Histopathological staining: Left lung tissue was taken, fixed, embedded, and sectioned, and then Masson staining was performed to observe the collagen deposition in the lung tissue.

[0025] Detection of epithelial-mesenchymal transition markers: Western blotting was used to detect the protein expression levels of epithelial cell marker E-cadherin and mesenchymal cell markers α-SMA and Vimentin in lung tissue. Results are as follows: Figure 3As shown, AS-IV significantly reduced peri-airway collagen deposition in the lung tissue of COPD mice, increased the protein level of the epithelial cell marker E-cadherin, and decreased the protein levels of the mesenchymal cell markers α-SMA and Vimentin. By analyzing the changes in these indicators, we explored the intervention effect of AS-IV on the epithelial-mesenchymal transition process in COPD pathology.

[0026] 4. The regulatory effects of AS-IV on signaling pathways and oxidative stress: MAPK signaling pathway detection: Western blotting was used to detect the phosphorylation levels of p38 MAPK and ERK1 / 2 proteins in lung tissue to explore whether AS-IV exerts its anti-inflammatory effect by regulating the MAPK signaling pathway.

[0027] Antioxidant stress assay: Western blotting was used to detect the protein expression levels of nuclear factor E2-related factor 2 (Nrf2) and its downstream antioxidant enzymes—superoxide dismutase (SOD), heme oxygenase-1, catalase (CAT), and quinone oxidoreductase (NQO1)—in lung tissue to verify the activating effect of AS-IV on the body's antioxidant defense system. The results are as follows: Figure 4 As shown, AS-IV inhibited the phosphorylation levels of p38 and ERK in the lung tissue of COPD mice. Figure 4 AB) upregulated the protein levels of the antioxidant transcription factor Nrf2 and its downstream antioxidant proteases SOD1, CAT, HO-1, and NQO1. Figure 4 C).

[0028] 5. Safety evaluation of AS-IV: The in vivo safety of AS-IV at this therapeutic dose was assessed through pathological examination of liver and kidney tissues, and the results were as follows: Figure 5 As shown, HE staining of liver and kidney tissues from both the normal control group and the AS-IV treatment group mice revealed intact and clear tissue structures with no pathological changes.

[0029] Through the implementation of the above technical solutions, this application systematically elucidates the potential application value and mechanism of action of AS-IV in the treatment of COPD from multiple dimensions such as inflammation, fibrosis, signaling pathways, oxidative stress and safety.

[0030] The above description is merely a preferred embodiment of this application and is not intended to limit this application in any form or substance. It should be noted that those skilled in the art can make several improvements and additions without departing from this application, and these improvements and additions should also be considered within the scope of protection of this application.

Claims

1. Application of astragaloside A in the preparation of drugs for treating chronic obstructive pulmonary disease.

2. The application according to claim 1, characterized in that, The drug comprises a pharmacologically active ingredient and pharmaceutically acceptable excipients, wherein the pharmacologically active ingredient is astragaloside A.

3. The application according to claim 1, characterized in that, The pharmaceutically acceptable excipients are Diluents, adhesives, wetting agents, lubricants, disintegrants, solvents, emulsifiers, cosolvents, preservatives, One or more of the following: pH adjuster, osmotic pressure regulator, surfactant, coating material, antioxidant and buffer.

4. The application according to any one of claims 1 to 3, characterized in that, The drug is available in oral, inhaled, or injectable formulations.

Images