Use of indole-3-carbinol in the manufacture of a product for preventing, alleviating or / and treating co-morbidity of asthma and sleep disorders

Abstract

The present application relates to the technical field of biological medicine, and more particularly to the use of indole-3-formaldehyde in the preparation of products for preventing, alleviating or / and treating asthma and sleep disorder comorbidity. The present application finds that indole-3-formaldehyde can be used for preventing, alleviating or / and treating asthma and sleep disorder comorbidity, and provides a new prevention, alleviation or / and treatment strategy for such asthma.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, and more particularly to the use of indole-3-carboxaldehyde in the preparation of products for the prevention, relief, and / or treatment of comorbid asthma and sleep disorders. Background Technology

[0002] Asthma is a heterogeneous respiratory disease characterized by chronic airway inflammation, airway hyperresponsiveness, increased mucus secretion, and airway remodeling. Its development is closely related to abnormal activation of type II immune responses, typically manifested as enhanced type 2 helper T cell (Th2) immune responses, activation of group 2 innate lymphoid cells (ILC2), elevated levels of type II inflammatory factors (interleukins IL-4, IL-5, IL-13, etc.), and increased eosinophil infiltration. These inflammatory changes can lead to symptoms such as recurrent wheezing, shortness of breath, chest tightness, cough, and decreased lung function.

[0003] Currently, clinical treatment for asthma mainly relies on inhaled corticosteroids, β2-receptor agonists, leukotriene receptor antagonists, and some biologics. While these treatments can improve symptoms and control inflammation to some extent, problems remain, including insufficient treatment response in some patients, poor long-term medication adherence, high relapse risk, and adverse reactions. For asthma patients with persistently active inflammation or complex comorbidities, existing treatments are still insufficient to fully meet clinical needs. Therefore, finding novel interventions that can regulate the immune-inflammatory response in asthma and improve airway inflammatory damage is of great significance.

[0004] Sleep disorders are a common comorbidity in asthma patients, mainly manifested as insufficient sleep duration, increased nighttime awakenings, disrupted sleep structure, and decreased sleep quality. Studies have shown that sleep disorders are closely related to poor asthma control, worsening nighttime symptoms, increased risk of acute exacerbations, and elevated inflammation levels. Insufficient sleep can further promote the body's inflammatory response, enhance airway immune cell activation, and may worsen type II airway inflammation. Therefore, asthma with sleep disorders is not simply a combination of asthma and sleep problems, but rather a more complex inflammatory state that is more difficult to treat.

[0005] Indole-3-carboxaldehyde (I3A) is a small indole metabolite produced by tryptophan metabolism in intestinal symbiotic bacteria. Previous studies have shown that I3A can act as an endogenous ligand for the aryl hydrocarbon receptor (AhR), participating in the regulation of mucosal immune homeostasis and possessing certain anti-inflammatory effects. However, current technologies mainly focus on the role of I3A in intestinal inflammation, immune homeostasis, or other inflammatory diseases. Whether I3A can be used to intervene in asthma complicated by sleep disorders, especially whether it can inhibit pulmonary ILC2 activation, reduce the secretion of type II inflammatory factors, decrease eosinophils in bronchoalveolar lavage fluid, and alleviate inflammatory damage in lung tissue, remains unclear.

[0006] Therefore, there is an urgent need to develop a new, safe and effective intervention program to address the issues of increased airway inflammation, enhanced type II immune response, and limitations of existing treatments in asthma patients or models with comorbid sleep disorders. Summary of the Invention

[0007] The purpose of this invention is to provide the use of indole-3-carboxaldehyde in the preparation of products for the prevention, relief, and / or treatment of comorbid asthma and sleep disorders. The technical problem to be solved by this invention is not limited to the described technical subject matter; other technical subject matter not mentioned herein will be clearly understood by those skilled in the art through the following description.

[0008] Based on animal experiments, this invention found that I3A can significantly reduce the proportion and proliferation of ILC2 in the lungs of an asthma model combined with sleep deprivation, reduce the secretion of ILC2-related cytokines, reduce the level of inflammatory factors and eosinophil infiltration in bronchoalveolar lavage fluid, and improve pathological inflammatory damage in lung tissue. This suggests that I3A can be used to prepare products for the treatment and / or relief of comorbid asthma and sleep disorders.

[0009] In a first aspect, the present invention provides the use of indole-3-carboxaldehyde in the preparation of products for the prevention, relief, and / or treatment of comorbid asthma and sleep disorders.

[0010] In one implementation, the asthma is type II inflammation-related asthma or eosinophilic asthma.

[0011] In another implementation, the prevention, relief, and / or treatment of comorbid asthma and sleep disorders manifests as any of the following: A1. Reduces the proportion and / or proliferative capacity of type II intrinsic lymphoid cells in lung tissue; A2. Reduces the level of type II inflammatory factors in lung tissue; A3. Reduce the level of inflammatory factors in bronchoalveolar lavage fluid; A4. Reduce the proportion and / or absolute count of eosinophils in bronchoalveolar lavage fluid; A5. Reduces inflammatory cell infiltration in lung tissue and / or improves pathological damage to lung tissue.

[0012] Specifically, the type II inflammatory factors include IL-5 and / or IL-13.

[0013] In one implementation, the sleep disorder includes at least one of: sleep deprivation, insufficient sleep duration, poor sleep quality, difficulty falling asleep, and sleep structure disorder.

[0014] In another embodiment, the product includes, but is not limited to, drugs, medical devices, drug-device combinations, etc.

[0015] In a second aspect, the present invention provides a pharmaceutical formulation comprising indole-3-carboxaldehyde and pharmaceutically acceptable excipients.

[0016] In one embodiment, the content of indole-3-carboxaldehyde is 0-100 mg, and the content is not 0.

[0017] In another embodiment, the excipients include, but are not limited to, water-soluble excipients (such as polyethylene glycol, polyvinylpyrrolidone, organic acids, etc.), poorly soluble excipients (such as ethyl cellulose, cholesterol stearate, etc.), and enteric excipients (such as cellulose acetate phthalate, carboxymethyl cellulose, carboxyethyl cellulose, etc.).

[0018] In one embodiment, the pharmaceutical formulation may be a conventional formulation, a sustained-release formulation, a controlled-release formulation, or various microparticle delivery systems.

[0019] In another embodiment, the dosage form of the pharmaceutical preparation includes an oral preparation or an injectable preparation.

[0020] Specifically, the oral preparations include tablets, capsules, granules, pills, syrups, oral solutions, oral suspensions, and oral emulsions.

[0021] Preferably, when the dosage form is tablets, a wide variety of excipients known in the art can be used. Examples of excipients include, for instance, diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, aluminum silicate, etc.; humectants and binders such as water, glycerin, polyethylene glycol, ethanol, propanol, starch paste, dextrin, syrup, honey, glucose solution, gum arabic paste, gelatin paste, sodium carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, etc.; and disintegrants. Examples of additives include dried starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene, sorbitol fatty acid esters, sodium dodecyl sulfate, methylcellulose, ethylcellulose, etc.; disintegration inhibitors, such as sucrose, tristearate, cocoa butter, hydrogenated oil, etc.; absorption promoters, such as quaternary ammonium salts, sodium dodecyl sulfate, etc.; lubricants, such as talc, silica, corn starch, stearates, boric acid, liquid paraffin, polyethylene glycol, etc.

[0022] Furthermore, the tablets are further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or bilayer and multilayer tablets.

[0023] Preferably, when the dosage form is a pill, a wide variety of excipients known in the art can be used. Examples of excipients include, for instance, diluents and absorbents such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, kaolin, talc, etc.; binders such as gum arabic, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste or flour paste, etc.; and disintegrants such as agar powder, dried starch, alginate, sodium dodecyl sulfate, methylcellulose, ethylcellulose, etc.

[0024] Specifically, the injectable preparations include injection solutions and powder injections.

[0025] Preferably, when the dosage form is an injection, such as a solution, emulsion, lyophilized powder for injection, or suspension, all diluents commonly used in the art can be used, such as water, ethanol, polyethylene glycol, 1,3-propanediol, ethoxylated isostearyl alcohol, polyoxyethylene isostearyl alcohol, polyoxyethylene sorbitan fatty acid ester, etc.

[0026] Furthermore, the injection solution can be further formulated into an isotonic injection solution by adding appropriate amounts of sodium chloride, glucose, or glycerol to the injectable formulation. In addition, conventional solubilizers, buffers, pH adjusters, etc., can also be added.

[0027] Preferably, pharmaceutically acceptable excipients also include colorants, preservatives, flavorings, sweeteners, or other materials.

[0028] Preferably, the administration method of the injectable preparation includes subcutaneous injection, intravenous injection, intramuscular injection, and intracavitary injection.

[0029] In a third aspect, the present invention provides the use of the above-described pharmaceutical preparation in the preparation of products for the prevention, relief, and / or treatment of comorbid asthma and sleep disorders.

[0030] In a fourth aspect, the present invention provides a method for inhibiting the proliferation of type II innate lymphoid cells in vitro, using indole-3-formaldehyde to culture or treat lung tissue cells in vitro.

[0031] In a fifth aspect, the present invention provides a method for preventing, alleviating, and / or treating comorbid asthma and sleep disorders by administering an effective amount of indole-3-carboxaldehyde or an effective amount of a pharmaceutical preparation to a patient with comorbid asthma and sleep disorders.

[0032] In one embodiment, the effective amount is a dose that enables prevention, relief, and / or treatment in comorbid asthma and sleep disorders. Specifically, the dosage of indole-3-carboxaldehyde is 10-300 mg / kg / day, preferably 100 mg / kg / day.

[0033] In another embodiment, the patient is a mammal, such as a rodent or primate.

[0034] Compared with the prior art, the present invention has the following beneficial effects: (1) The present invention discovers that indole-3-carboxaldehyde can be used to prevent, alleviate or / and treat comorbid asthma and sleep disorders, providing a new prevention, relief or / and treatment strategy for this type of asthma.

[0035] (2) This invention demonstrates that indole-3-carboxaldehyde can reduce the proportion and proliferation capacity of ILC2 in the lungs, reduce the secretion of ILC2-related type II inflammatory factors, and improve the pathological state of asthma from the perspective of immune inflammation.

[0036] (3) This invention demonstrates that indole-3-carboxaldehyde can reduce the content of inflammatory factors and eosinophil infiltration in bronchoalveolar lavage fluid and alleviate lung tissue inflammatory damage, showing a good anti-airway inflammation effect. Attached Figure Description

[0037] Figure 1 This is a schematic diagram illustrating the construction of an animal model of asthma with sleep deprivation and the intervention with indole-3-formaldehyde in Example 1.

[0038] Figure 2 The results show the effects of indole-3-carboxaldehyde on the proportion and proliferation capacity of ILC2 cells in the lungs of mice in the SD and SD+I3A groups.

[0039] Figure 3 The results show the effect of indole-3-carboxaldehyde on the secretion of inflammatory factors by ILC2 cells in SD and SD+I3A mice.

[0040] Figure 4 The results show the effects of indole-3-carboxaldehyde on the content of inflammatory factors, the proportion of eosinophils, and the absolute count in the bronchoalveolar lavage fluid of mice in the SD and SD+I3A groups.

[0041] Figure 5 The image shows the H&E staining results and histological scores comparing the effects of indole-3-carboxaldehyde on the pathological damage of lung tissue in mice in the SD and SD+I3A groups. Detailed Implementation

[0042] The present invention will now be described in further detail with reference to specific embodiments. The given embodiments are merely illustrative of the invention and not intended to limit its scope. The embodiments provided below can serve as a guide for further improvements by those skilled in the art and do not constitute a limitation on the invention in any way.

[0043] Unless otherwise specified, the experimental methods used in the following examples are conventional methods, performed according to the techniques or conditions described in the literature in this field or according to the product instructions. Unless otherwise specified, the materials and reagents used in the following examples are commercially available.

[0044] Example 1 This embodiment utilizes a sleep deprivation animal model (SD) to simulate the clinical phenomenon of insufficient sleep duration.

[0045] Four-week-old C57BL6 / J mice (Cyagen Biotech Co., Ltd.) were randomly divided into two groups: the asthma + sleep deprivation group (SD) and the asthma + sleep deprivation + I3A treatment group (SD+I3A).

[0046] Sleep deprivation models were established in all mice using a sleep deprivation device (Shanghai Xinrun Information Technology Co., Ltd., model XR-XS108) operating for 12 hours / day for two consecutive weeks. The asthma + sleep deprivation + I3A treatment group received I3A (100 mg / kg / day) via gavage during SD modeling. After sleep deprivation modeling, mice were anesthetized with 1% isoflurane, and papain (20 μg / day / mouse) was dissolved in 20 μL PBS and administered via intranasal drip for 5 consecutive days. The experimental endpoint was recorded 24 hours after the last administration.

[0047] like Figure 1 As shown, Figure 1This embodiment demonstrates the construction process of an asthma model incorporating sleep deprivation and the I3A intervention protocol. The experimental procedure includes initial continuous sleep deprivation treatment, I3A intervention, and subsequent intranasal papain instillation to induce an asthma inflammatory response. This design effectively simulates the pathological process of asthma inflammation exacerbation under sleep deprivation and can be used to evaluate the therapeutic or alleviating effects of I3A in this combined disease state.

[0048] After the asthma model was established and the mice were euthanized, bronchoalveolar lavage fluid was collected for the detection of eosinophils and cytokines. Tissue from the left lung was taken, and a single-cell suspension was prepared to detect immune cells and cytokines. Tissue from the right lung was taken, fixed in 4% paraformaldehyde solution, and stained with H&E.

[0049] like Figure 2 As shown, compared with the SD group, the proportion of ILC2 in the lung tissue of mice in the SD+I3A group was reduced, and the proliferation capacity of ILC2 was decreased. Since ILC2 is an important immune cell driving type II airway inflammation, Figure 2 The results precisely demonstrate that in an asthma model combined with sleep deprivation, I3A can inhibit the expansion and activation of ILC2 in the lungs; and the reduced proportion and proliferation capacity of ILC2 indicate that I3A can alleviate the inflammatory response of asthma from the upstream immune cell level.

[0050] like Figure 3 As shown, compared with the SD group, the SD+I3A group had significantly lower levels of cytokines secreted by ILC2. ILC2 can secrete type II inflammatory factors such as IL-5 and IL-13, among which IL-5 is closely related to eosinophil recruitment and survival, and IL-13 is closely related to airway mucus secretion, airway hyperresponsiveness, and tissue inflammatory damage; therefore... Figure 3 Further evidence indicates that I3A can not only reduce the number or proportion of ILC2s, but also reduce the inflammatory effect of ILC2s, thereby inhibiting type II airway inflammatory responses.

[0051] Because bronchoalveolar lavage fluid can directly reflect the inflammatory state within the airway, eosinophilic infiltration is an important characteristic of type II asthma inflammation. For example... Figure 4 As shown, compared with the SD group, the content of inflammatory factors in the bronchoalveolar lavage fluid of mice in the SD+I3A group was reduced, and the proportion and absolute count of eosinophils were also decreased. Figure 4 It was confirmed that I3A treatment can reduce the level of local airway inflammation, reduce eosinophil recruitment, and thus alleviate the airway inflammatory response in asthma under conditions of sleep deprivation.

[0052] like Figure 5As shown, H&E staining of lung tissue revealed significant inflammatory cell infiltration and aggravated peribronchial and perivascular inflammation in the lung tissue of SD group mice. After I3A treatment, inflammatory cell infiltration in the lung tissue decreased, the tissue inflammation score decreased, and the pathological damage of the lung tissue was improved. These results further confirm from a histopathological perspective that I3A can alleviate lung inflammatory damage in an asthma model with sleep deprivation.

[0053] comprehensive Figures 2 to 5 The results showed that I3A can exert therapeutic and / or alleviating effects on the comorbidity of asthma and sleep disorders by inhibiting the expansion and activation of ILC2 in the lungs, reducing the secretion of type II inflammatory factors, decreasing the levels of inflammatory factors and eosinophils in bronchoalveolar lavage fluid, and improving pathological inflammatory damage in lung tissue. These experimental results indicate that I3A can be used to prepare products for the treatment and / or alleviation of the comorbidity of asthma and sleep disorders.

[0054] The present invention has been described in detail above. Those skilled in the art will recognize that the invention can be practiced in a wide range of ways with equivalent parameters, concentrations, and conditions without departing from its spirit and scope, and without requiring unnecessary experiments. While specific embodiments have been provided, it should be understood that further modifications can be made to the invention. In summary, according to the principles of the invention, this application is intended to include any changes, uses, or improvements to the invention, including changes made using conventional techniques known in the art that depart from the scope disclosed herein.

Claims

1. Use of indole-3-carboxaldehyde in the preparation of products for the prevention, relief and / or treatment of comorbid asthma and sleep disorders.

2. The use according to claim 1, characterized in that, The prevention, relief, and / or treatment of comorbid asthma and sleep disorders is defined as any one of the following: A1. Reduces the proportion and / or proliferative capacity of type II intrinsic lymphoid cells in lung tissue; A2. Reduces the level of type II inflammatory factors in lung tissue; A3. Reduce the level of inflammatory factors in bronchoalveolar lavage fluid; A4. Reduce the proportion and / or absolute count of eosinophils in bronchoalveolar lavage fluid; A5. Reduces inflammatory cell infiltration in lung tissue and / or improves pathological damage to lung tissue.

3. The use according to claim 2, characterized in that, The type II inflammatory factors include IL-5 and / or IL-13.

4. The use according to claim 1, characterized in that, The sleep disorders include at least one of the following: sleep deprivation, insufficient sleep time, poor sleep quality, difficulty falling asleep, and sleep structure disorder.

5. The use according to claim 1, characterized in that, The product is a drug, a medical device, or / and a combination of drug and device.

6. A pharmaceutical preparation, characterized in that, It contains indole-3-carboxaldehyde and pharmaceutically acceptable excipients.

7. The pharmaceutical preparation according to claim 6, characterized in that, The dosage forms of the pharmaceutical preparations include oral preparations or injectable preparations.

8. The pharmaceutical preparation according to claim 7, characterized in that, The oral preparations include tablets, capsules, granules, pills, syrups, oral solutions, oral suspensions, and oral emulsions; The injectable preparations include injection solutions and powder injections.

9. Use of the pharmaceutical preparation according to any one of claims 6-8 in the preparation of a product for the prevention, relief, and / or treatment of comorbid asthma and sleep disorders.

10. A method for inhibiting the proliferation of type II innate lymphoid cells in vitro, characterized in that, Lung tissue cells were cultured or treated in vitro using indole-3-carboxaldehyde.

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