Application of bioactive composition in preventing, treating and improving aortic dissection

Abstract

The invention belongs to the technical field of biological medicine, and particularly discloses application of a bioactive composition in prevention, treatment and improvement of aortic dissection. The invention provides application of a bioactive composition in preparation of a medicine for preventing, treating and improving aortic dissection. The bioactive composition comprises docosahexaenoic acid and resveratrol. The invention discloses application of a bioactive composition in prevention, treatment and improvement of aortic dissection, and the aortic dissection is treated by repairing damaged aortic wall, retarding aortic dilatation, protecting elastic structure of aortic smooth muscle layer and recovering elastic phenotype of smooth muscle cells.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to the application of bioactive compositions in the prevention, treatment and improvement of aortic dissection. Background Technology

[0002] Aortic dissection is a fatal cardiovascular emergency characterized by a tear in the intima of the aorta, allowing blood to flow into the aortic media and form a false lumen, ultimately leading to the separation of the vessel wall into layers. The pathogenesis of this disease is closely related to multiple factors, with hypertension accounting for 70%-80% of cases. Hereditary connective tissue diseases, atherosclerosis, and trauma can also cause the elastic fibers of the aortic wall to rupture due to prolonged high-pressure blood flow or vascular structural abnormalities, ultimately resulting in intimal tearing. Aortic dissection is extremely dangerous, with a very high mortality rate in the acute phase, reaching up to 50% within 48 hours. The main causes of death include aortic rupture, multiple organ ischemia, and cardiovascular complications, seriously threatening human life and health. Currently, there are no specific drugs for the prevention and treatment of aortic dissection. Clinical treatment mainly relies on surgical intervention, but surgery carries high risks and significant prognoses. Therefore, developing safe and effective preventive and therapeutic drugs is of significant clinical and social importance.

[0003] Docosahexaenoic acid (DHA), an important member of the Omega-3 polyunsaturated fatty acid family, is an essential fatty acid for the human body, possessing a unique molecular structure and biological activity. Existing research has confirmed that DHA significantly regulates blood lipid levels, lowers blood pressure, and improves vascular endothelial function, while also playing important roles in anti-inflammation, anti-oxidation, and maintaining nervous system function. However, to date, there are no reports on the use of DHA for the prevention or treatment of aortic dissection.

[0004] Resveratrol belongs to the stilbene class of polyphenolic phytochemicals. Recent studies have shown that it possesses various biological activities, including regulating lipid metabolism, antioxidation, free radical scavenging, vasodilation, anti-inflammation, and anti-platelet aggregation, demonstrating a clear protective effect on the cardiovascular system. However, there are currently no reports on the use of resveratrol alone or in combination with DHA for the prevention and treatment of aortic dissection, indicating a significant research gap in its application in this field. Summary of the Invention

[0005] The present invention aims to provide the application of a bioactive composition in the prevention, treatment and improvement of aortic dissection. The bioactive composition contains docosahexaenoic acid and resveratrol, which treat aortic dissection by repairing the damaged aortic wall, slowing aortic dilation, protecting the elastic structure of the aortic smooth muscle layer, and restoring the elastic phenotype of smooth muscle cells.

[0006] To solve the above-mentioned technical problems, the technical solution adopted by the present invention is as follows:

[0007] The use of a bioactive composition in the preparation of medicaments for the prevention, treatment and improvement of aortic dissection.

[0008] Preferably, the bioactive composition comprises docosahexaenoic acid and resveratrol.

[0009] Preferably, the mass ratio of docosahexaenoic acid to resveratrol is 3-5:1.

[0010] Preferably, the bioactive composition treats aortic dissection by repairing the damaged aortic wall, slowing aortic dilation, protecting the elastic structure of the aortic smooth muscle layer, and restoring the elastic phenotype of smooth muscle cells.

[0011] The present invention also provides a medicament for the prevention, treatment and improvement of aortic dissection, comprising the bioactive composition as an active ingredient.

[0012] Preferably, pharmaceutically acceptable carriers are also included.

[0013] Preferably, the pharmaceutically acceptable carrier is one or more of the following: diluent, binder, wetting agent, lubricant, disintegrant, solvent, emulsifier, cosolvent, preservative, pH adjuster, osmotic pressure adjuster, surfactant, coating material, antioxidant, or buffer.

[0014] Preferably, the drug dosage form is an oral preparation, an injectable preparation, or an inhaled preparation.

[0015] The present invention also provides the use of the bioactive composition as described in the preparation of a medicament for repairing damaged aortic walls.

[0016] The present invention also provides the use of the bioactive composition as described in the preparation of a medicament for restoring the elastic phenotype of smooth muscle cells.

[0017] Compared with the prior art, the present invention has the following advantages and technical effects:

[0018] This invention discloses the application of a bioactive composition containing docosahexaenoic acid (DHA) and resveratrol in the prevention, treatment, and improvement of aortic dissection. This bioactive composition significantly reduces the incidence and mortality of aortic dissection. In animal experiments, it inhibits abnormal dilation of the aortic wall, slows the progression of aortic dissection, and alleviates pathological changes in vascular structure. After intervention with the composition, the rupture of the smooth muscle layer's elastic lamina was significantly reduced, and the secretion of inelastic collagen fibers and mucin deposition were effectively inhibited, demonstrating that the bioactive composition can repair damaged aortic wall structures and protect the integrity of the smooth muscle layer's elastic structure. In aortic dissection models, smooth muscle cells exhibit a loss of elasticity due to pathological stimulation. The bioactive composition of this invention can improve the structural and functional damage of the smooth muscle layer, promote the restoration of normal elasticity in smooth muscle cells, thereby maintaining the normal elasticity and mechanical properties of the aortic wall and inhibiting the occurrence and development of aortic dissection from a pathological mechanism perspective.

[0019] The bioactive compositions and related drugs of the present invention can significantly improve aortic dissection, providing a solid pharmacodynamic basis for the clinical prevention and treatment of aortic dissection, and have significant clinical application value and market prospects.

[0020] The technical solution of the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. Attached Figure Description

[0021] Figure 1 It has the structural formula of docosahexaenoic acid (DHA);

[0022] Figure 2 The structural formula for resveratrol is shown below.

[0023] Figure 3 This is a schematic diagram of the survival curves of mice in each treatment group in Example 1;

[0024] Figure 4 These are schematic diagrams of echocardiography of mice in each treatment group in Example 1. Figure 4 In the diagram, A represents the ultrasound image of the Control group. Figure 4 B in the diagram is an ultrasound illustration of the BAPN-induced interstitial tissue. Figure 4 In the diagram, C represents the ultrasound image of the BAPN+treatment intervention group;

[0025] Figure 5 This is a schematic diagram showing the maximum diameter of the aorta in each treatment group of mice in Example 1;

[0026] Figure 6 This is a schematic diagram showing the incidence of aortic dissection in mice of each treatment group in Example 1;

[0027] Figure 7These are anatomical photographs of the aorta of mice in each treatment group in Example 1. Figure 7 In this context, A represents the Control group. Figure 7 B in the text represents the BAPN-induced interlayer group. Figure 7 C in the text represents the BAPN+treatment intervention group;

[0028] Figure 8 This is a schematic diagram of the pathological staining results of mice in each treatment group in Example 1. Detailed Implementation

[0029] The technical solution of the present invention will be further described below with reference to the accompanying drawings and embodiments.

[0030] Unless otherwise defined, the technical or scientific terms used in this invention shall have the ordinary meaning as understood by one of ordinary skill in the art to which this invention pertains.

[0031] Source of experimental materials:

[0032] In this invention, unless otherwise specified, all other test materials and instruments are conventional test materials in the field and can be purchased through commercial channels.

[0033] In this embodiment of the invention, the DHA structural formula is as follows: Figure 1 As shown; the structural formula of resveratrol is as follows: Figure 2 As shown.

[0034] Example 1

[0035] 1. Test materials

[0036] BAPN feed: The feed contains 0.4% BAPN (β-aminopropionitrile) powder by weight.

[0037] Experimental animals and grouping: 3-week-old C57BL / 6J mice were used, including 12 mice in the Control group, 12 mice in the BAPN+treatment intervention group, and 12 mice in the BAPN-induced interlayer group.

[0038] Preparation of treatment drugs: Weigh out DHA and resveratrol, and calculate the daily gavage volume based on 100 μL per mouse per day. Dissolve the weighed DHA and resveratrol in 50 μL of DMSO, sonicate until homogeneous, add an appropriate amount of PEG400 for dilution, and store at -20℃.

[0039] 2. The test plan is as follows:

[0040] An animal model of aortic dissection was used, in which 3-week-old C57BL / 6J mice were fed a diet containing 0.4% BAPN for 21 days to induce the cross-linking and destruction of elastic fibers in the aortic wall, leading to the formation of aortic dissection aneurysms. This model simulates clinical aortic dissection injury. The successful establishment of the model was verified by multiple indicators, including the pathological morphology of the aorta, pathological sections of the lesion site, and masson staining. This model can be used to verify the effectiveness of the DHA and resveratrol combination.

[0041] The control group was fed a normal diet for 21 consecutive days. The treatment group and the BAPN-induced dissection group were fed a diet containing 0.4% BAPN powder mixed into their feed. The treatment group was administered resveratrol and DHA algal oil dissolved in DMSO and then diluted with PEG400, according to the mice's body weight. The dosage for treatment group A was 20 mg / kg / day (resveratrol) and 80 mg / kg / day (DHA), and the dosage for treatment group B was 15 mg / kg / day (resveratrol) and 20 mg / kg / day (DHA). Each mouse was administered 100 μL via gavage daily for 21 days. During the administration period, mouse mortality was recorded. After administration, the aortic diameter of the mice was measured, and the formation of aortic dissection was observed after dissection. The morbidity rate was also recorded.

[0042] By statistically analyzing the time to death of mice in different groups after atrial dissection up to day 21, overall survival curves were plotted and statistical analysis was performed. * indicates p < 0.05, ** indicates p < 0.01, and *** indicates p < 0.001. The results are as follows: Figure 3 As shown.

[0043] Depend on Figure 3 It was found that the survival rate of mice in treatment A was significantly higher than that in the BAPN-induced aortic dissection group, demonstrating that the combined drug intervention significantly reduced the mortality rate of mice in the aortic dissection model. Although the survival curve of treatment B was significantly different from that of the model group, it was not statistically significant, indicating that the dosage combination of the drugs affects the treatment effect. Given that the survival curve of treatment B was not significantly different from that of the model group, treatment B will not be investigated further in the following mechanistic experiments; treatment A will be referred to as the treatment group.

[0044] At day 21 of the animal experiment, aortic ultrasound was performed on all surviving mice. The intervention effect of the combination drug was evaluated by measuring the maximum diameter of aortic dilation. * indicates p<0.05, ** indicates p<0.01, and *** indicates p<0.001. The results are as follows: Figures 4-5 As shown.

[0045] Depend on Figures 4-5 It can be seen that the maximum diameter of aortic dilation in the treatment group (1.643 mm) was significantly smaller than that in the BAPN-induced dissection group (1.988 mm) and the control group (1.508 mm). The combination drug treatment significantly reduced the aortic diameter dilation in the model mice.

[0046] Tissue samples were collected from surviving mice, and the number of mice with aortic dilation in different groups was counted to calculate the incidence of aortic dissection in each group. In the figure, red represents the number of mice that died from aortic dissection rupture, blue represents the number of mice that died from dissection without rupture, and black represents the number of mice that did not experience dissection. The results are as follows: Figure 6 As shown.

[0047] Depend on Figure 6 It can be seen that the probability of dissection and death due to dissection rupture in the treatment group mice was significantly lower than that in the BAPN-induced dissection group, and the combined drug intervention reduced the incidence of dissection in the model mice.

[0048] Anatomical photographs of the aorta of mice in each experimental group are shown below. Figure 7 As shown.

[0049] Depend on Figure 7 The results showed that the aorta of healthy mice was structurally intact, with a smooth and transparent aortic wall and no obvious dissection or hemorrhage. However, mice in the BAPN-induced dissection group exhibited significant dissection rupture and hemorrhage, with cloudy and distorted aortic wall, indicating significant damage. Compared to the BAPN-induced dissection group, the treatment group, after intervention with the combination drugs, showed a smooth and transparent aortic wall without significant distortion, dissection, or hemorrhage. These results indicate that the combination drug intervention can alleviate the progression of aortic dissection and reduce its incidence.

[0050] The pathological staining results of the aorta in each experimental group of mice are as follows: Figure 8 As shown, the staining methods include Masson staining, Alcian blue staining, and elastic fiber staining.

[0051] Depend on Figure 8 It was found that in the BAPN-induced aortic dissection group, elastic fiber staining revealed that the elastic plates of the smooth muscle layer were broken and disappeared at the breakage points; Masson staining showed that smooth muscle cells secreted more inelastic collagen fibers under the stimulation of dissection, which severely damaged the elasticity of the aorta; in Alixin blue staining, there was a large amount of mucin deposition in the smooth muscle layer. These pathological staining results indicate that in the aortic dissection model, the structure and function of the vascular smooth muscle layer are damaged, the elastic phenotype is lost, elastic fibers are broken, and the aortic wall undergoes degenerative remodeling.

[0052] Compared with the BAPN-induced aortic dissection group, the treatment group showed a significant reduction in collagen fiber and proteoglycan deposition in the smooth muscle layer and a significant decrease in elastic fiber lamina breakage after combination drug intervention. These results indicate that combination drug intervention can alleviate the progression of aortic dissection by improving the structural and functional damage of the smooth muscle layer and restoring the elastic phenotype of smooth muscle cells.

[0053] In summary, gavage intervention with the combined drugs in aortic dissection model mice significantly reduced the incidence and mortality of dissection. Ultrasound results showed that the combined intervention alleviated the dilation of the aortic diameter in the model mice. The aforementioned pathological indicators indicate that the combined drug intervention effectively alleviated the occurrence and development of aortic dissection in mice.

[0054] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can still be made to the technical solutions of the present invention, and these modifications or equivalent substitutions cannot cause the modified technical solutions to deviate from the spirit and scope of the technical solutions of the present invention.

Claims

1. The use of a bioactive composition in the preparation of a medicament for the prevention, treatment and improvement of aortic dissection.

2. The application according to claim 1, characterized in that, The bioactive composition comprises docosahexaenoic acid and resveratrol.

3. The application according to claim 2, characterized in that, The mass ratio of docosahexaenoic acid to resveratrol is 3-5:

1.

4. The application according to claim 1, characterized in that, The bioactive composition treats aortic dissection by repairing the damaged aortic wall, slowing aortic dilation, protecting the elastic structure of the aortic smooth muscle layer, and restoring the elastic phenotype of smooth muscle cells.

5. A drug for preventing, treating, and improving aortic dissection, characterized in that, The bioactive composition described in claim 1 is included as the active ingredient.

6. The drug according to claim 5, characterized in that, It also includes pharmaceutically acceptable excipients.

7. The drug according to claim 6, characterized in that, 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, or buffers.

8. The drug according to claim 5, characterized in that, The drug dosage form is an oral preparation, an injectable preparation, or an inhaled preparation.

9. The use of the bioactive composition as described in claim 1 in the preparation of a medicament for repairing damaged aortic walls.

10. Use of the bioactive composition of claim 1 in the preparation of a medicament for restoring the elastic phenotype of smooth muscle cells.

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