Application of triptolide in preparation of medicine for treating diabetic vascular obstruction complications

Abstract

The invention belongs to the field of new application of medicines, and particularly relates to application of triptolide in preparation of medicines for treating diabetic vascular obstruction complications. Diabetes vascular obstruction is a common serious complication of diabetes and can cause various tissue injuries such as cardiovascular diseases, nephropathy and retinopathy. Experiments prove that the triptolide can remarkably improve the problems of blood vessel blockage, blood flow slowing, abnormal neovascularization and the like caused in a high-glucose environment, and meanwhile, the expression of blood glucose related indexes (such as Glucose and HbA1c) and inflammatory factors (such as TNF-alpha and IL-1beta) is reduced. In addition, triptolide can also protect pancreas from high glucose damage and improve functions of pancreatic beta cells. According to the invention, the clinical application range of the triptolide is expanded, and a new candidate substance is provided for drug treatment of diabetic vascular complications.

Description

Technical Field

[0001] This invention belongs to the field of new uses of pharmaceuticals, and more specifically, relates to the application of triptolide in the preparation of drugs for treating diabetic vascular obstructive complications. Background Technology

[0002] Diabetes mellitus (DM) is one of the fastest-growing diseases globally, becoming a worldwide epidemic and projected to affect 693 million adults by 2045. One of the most serious consequences of diabetes is the development of diabetic vascular complications, including macrovascular and microvascular complications. Macrovascular complications are primarily due to atherosclerosis and narrowing, or even obstruction, of the large arteries and veins, leading to peripheral artery disease (PAD), cardiovascular disease (CVD), and cerebrovascular disease. Microvascular complications include diabetic nephropathy (DN), diabetic retinopathy (DR), and diabetic neuropathy. These vascular complications can all eventually lead to vascular obstruction. Diabetic vascular obstruction is one of the most serious diabetic vascular complications, resulting in increased mortality, blindness, kidney failure, and a decline in the overall quality of life for diabetic patients, as well as a heavier personal and socioeconomic burden. Currently, controlling clinical risk factors and blood glucose alone cannot inhibit the development of vascular obstructive complications. Treatment for diabetic vascular obstruction primarily relies on multi-drug regimens, such as using statins to stabilize plaques, antiplatelet drugs to prevent thrombosis, and combining them with SGLT2 inhibitors or GLP-1 receptor agonists, which have both hypoglycemic and cardioprotective and renal protective effects. While this strategy is effective, it still has limitations, including complex regimens, the need for multiple drug combinations, and insufficient targeting of the core disease mechanism of high glucose-driven abnormal angiogenesis and inflammation. Summary of the Invention

[0003] The purpose of this invention is to provide the application of triptolide in the preparation of drugs for treating diabetic vascular obstruction complications.

[0004] This invention provides the application of triptolide in the preparation of drugs for treating diabetic vascular obstruction complications.

[0005] This invention addresses the current lack of effective treatments for diabetic vascular obstruction by proposing the use of triptolide in the treatment of this disease. The idea stems from an in-depth analysis of the mechanisms of diabetic vascular complications, particularly the process by which abnormal capillary proliferation and exacerbated inflammation in a high-glucose environment lead to vascular stenosis and even blockage. This invention uses a zebrafish model to simulate a diabetic state, verifying the effect of triptolide on improving vascular patency, and further examining its regulatory effects on blood glucose levels and inflammatory factors. Experimental results show that triptolide not only alleviates vascular obstruction but also possesses multiple effects including hypoglycemic, anti-inflammatory, and pancreatic cell protection, thus systematically demonstrating its potential value in the treatment of diabetic vascular obstruction.

[0006] Furthermore, the drug is used for: Lower blood sugar; Inhibits capillary proliferation caused by high blood sugar and the resulting slowing of blood flow leading to obstruction; It can alleviate pancreatic damage caused by high blood sugar.

[0007] Furthermore, the triptolide is prepared into a drug by combining it with pharmaceutically acceptable excipients.

[0008] The present invention also provides a pharmaceutical composition for treating diabetic vascular obstruction complications, the pharmaceutical composition comprising triptolide or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers and / or excipients.

[0009] Furthermore, the pharmaceutical composition also contains one or more other drugs for treating diabetic vascular obstruction complications.

[0010] Furthermore, the content of triptolide in the pharmaceutical composition is 0.1wt% to 99wt%.

[0011] Furthermore, the pharmaceutical composition is administered orally or by injection.

[0012] Furthermore, the dosage form of the pharmaceutical composition is tablets, capsules, granules, dispersants, oral liquids, injections, sprays, or drops.

[0013] The beneficial effects of this invention are as follows: This invention provides a novel application of triptolide in the treatment of diabetic vascular obstruction, with multiple beneficial effects: First, it can significantly improve vascular blockage and blood flow obstruction caused by high blood sugar, and reduce the formation of abnormal new capillaries; second, it can lower blood glucose levels and related markers (such as HbA1c), contributing to overall blood glucose control; third, it can inhibit the expression of inflammatory factors and alleviate diabetes-related inflammatory damage; fourth, it has a protective effect on the pancreas, improving the morphology and function of pancreatic β cells. These effects indicate that triptolide has comprehensive regulatory advantages in the treatment of diabetic vascular obstruction, providing an important basis for the development of novel drugs against diabetic vascular complications, and has significant clinical application prospects and social value. Attached Figure Description

[0014] Figure 1 The images show how TPL alleviates vascular obstruction in diabetes. In the images, A is a confocal microscope image, B is an enzyme activity detection image of glucose, C is an enzyme activity detection image of HbA1c, and D is a graph showing the mRNA expression levels of TNF-α and IL-β.

[0015] Figure 2 Diagram illustrating how TPL protects the pancreas from damage caused by high glucose. Detailed Implementation

[0016] The present invention will now be described in detail with reference to the accompanying drawings and specific embodiments, but this should not be construed as limiting the invention. Unless otherwise specified, the technical means used in the following embodiments are conventional means well known to those skilled in the art, and the materials, reagents, etc. used in the following embodiments are commercially available unless otherwise specified.

[0017] Example 1 All the genetically modified zebrafish used were purchased from the National Zebrafish Resource Center.

[0018] Experimental Methods: A double transgenic zebrafish strain, Tg(flk1:GFP; gata1:DsRed), was obtained by crossing a green fluorescent transgenic zebrafish strain Tg (flk1:GFP) specifically labeled with vascular endothelial cells and a red fluorescent transgenic zebrafish strain Tg (gata1:DsRed) specifically labeled with blood cells. After spawning, embryos of adult zebrafish were collected and cultured in an incubator at 28.5 degrees Celsius for 3 days. The control group received no treatment. Fertilized embryos that developed well and showed fluorescent labeling after 3 days of development were selected and treated with zebrafish embryo nutrient solution containing 3.5% glucose and 3.5% sucrose (i.e., the 3.5% high glucose group) for 1.5 days. The rescue group was treated with zebrafish embryo nutrient solution containing 87.5 μg / L triptolide (TPL), 3.5% glucose, and 3.5% sucrose for 1.5 days (i.e., the 3.5% high glucose + TPL group). Finally, confocal imaging was used to assess the vascular obstruction.

[0019] Experimental results: such as Figure 1 As shown in Figure A, the control group had patent blood vessels and continuous blood flow, while the high-glucose group showed vascular obstruction in zebrafish branches, with numerous neovascularizations observed in the capillary plexus, and blood flow gradually slowed until it stopped. Compared to the high-glucose group, the TPL rescue group showed significant improvement in vascular obstruction, a significant reduction in neovascularization in the capillary plexus, and improved blood flow, indicating that TPL can significantly inhibit vascular obstruction caused by high glucose. To further verify that TPL can inhibit vascular obstruction caused by diabetes, ELISA was used to detect diabetes-related indicators, such as... Figure 1 The results for B and C indicate that 3.5% high glucose treatment significantly upregulated glucose and HbA1c levels, while the high glucose + TPL group downregulated glucose and HbA1c levels. qPCR was used to detect inflammation-related genes, such as... Figure 1 As shown in Figure D, TNF-α and IL-1β levels were significantly upregulated after treatment with 3.5% high glucose, while the high glucose + TPL group downregulated the expression of TNF-α and IL-1β. This further suggests that TPL can inhibit vascular obstruction caused by diabetes.

[0020] Example 2 Experimental Methods: Zebrafish strains using the pancreatic exocrine gland-specific green fluorescent transgenic line Tg (ela3l: EGFP) and the pancreatic β-cell-specific red fluorescent transgenic line Tg (insulin: mcherry) were used. Zebrafish embryos from the control group, the 3.5% high-glucose group, and the TPL rescue group were exposed to a zebrafish embryo nutrient solution containing 3.5% glucose and 3.5% sucrose for 30 hours. The pancreatic development and damage were observed under a confocal microscope. The experimental treatments for the control group, the 3.5% high-glucose group, and the rescue group were the same as in Example 1.

[0021] Experimental results: such as Figure 2 In the control group, the exocrine pancreatic glands and pancreatic β cells were well-developed. However, after high glucose treatment, the exocrine pancreatic glands decreased in size, and the number of pancreatic β cells was damaged and reduced, with blurred cell fluorescence. Compared with the high glucose group, the TPL rescue group showed an increase in the number of pancreatic islet cells, stronger fluorescence, and enlarged exocrine pancreatic glands. This indicates that TPL can protect the pancreas from damage caused by high glucose.

[0022] It should be noted that when numerical ranges are mentioned in the claims of this invention, it should be understood that the two endpoints of each numerical range and any value between the two endpoints can be selected. To avoid redundancy, the present invention describes preferred embodiments.

[0023] Although preferred embodiments of the invention have been described, those skilled in the art, upon learning the basic inventive concept, can make other changes and modifications to these embodiments. Therefore, the appended claims are intended to be interpreted as including both the preferred embodiments and all changes and modifications falling within the scope of the invention.

[0024] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, if these modifications and variations fall within the scope of the claims of this invention and their equivalents, this invention also intends to include these modifications and variations.

Claims

1. Application of triptolide in the preparation of drugs for treating diabetic vascular obstructive complications.

2. The application according to claim 1, characterized in that, The drug is used for: Lower blood sugar; Inhibits capillary proliferation caused by high blood sugar and the resulting slowing of blood flow leading to obstruction; It can alleviate pancreatic damage caused by high blood sugar.

3. The application according to claim 1, characterized in that, The drug is made from triptolide and a pharmaceutically acceptable carrier and / or excipient.

4. A pharmaceutical composition for treating diabetic vascular obstruction complications, characterized in that, The pharmaceutical composition for treating diabetic vascular obstruction complications comprises triptolide or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and / or excipients.

5. The pharmaceutical composition according to claim 4, characterized in that, The pharmaceutical composition also contains one or more other drugs for treating diabetic vascular obstruction complications.

6. The pharmaceutical composition according to claim 4, characterized in that, The content of triptolide in the pharmaceutical composition is 0.1wt% to 99wt%.

7. The pharmaceutical composition according to claim 4, characterized in that, The pharmaceutical composition is administered orally or by injection.

8. The pharmaceutical composition according to claim 4, characterized in that, The dosage form of the pharmaceutical composition is tablets, capsules, granules, dispersants, oral liquids, injections, sprays, or drops.

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