Application of APE1 inhibitor in preparation of medicine for treating allergic rhinitis

Abstract

The invention belongs to the field of compound medicines, and relates to application of an APE1 inhibitor in preparation of a medicine for treating allergic rhinitis. The invention finds that the APE1 inhibitor can effectively relieve and treat the allergic rhinitis for the first time, a new target and a new way are provided for prevention and treatment of the allergic rhinitis, and the APE1 inhibitor C10 compound and a small molecule compound represented by the APE1 inhibitor C10 compound show an excellent effect in treatment of the allergic rhinitis.

Description

Technical Field

[0001] The invention belongs to the field of compound medicine and relates to the application of an APE1 inhibitor in the preparation of a medicine for treating allergic rhinitis. Background Art

[0002] Apurinic apyrimidinic endonuclease / redox factor APE1 is an extremely important bifunctional protein. Its C-terminus is involved in base excision repair after DNA mismatch; its N-terminus contains redox activity, which can reduce low-activity oxidized transcription factors to high-activity reduced transcription factors. Reduced transcription factors can bind to the promoter sequences of a series of genes to initiate the expression of these genes. APE1-regulated transcription factors include HIF-1α, Egr-1, AP-1, NF-κB, CREB, p53, etc. Many of the genes regulated by APE1 are related to immune response, so APE1 has an important influence on the balance of immune function, inflammation, and the development of immune diseases.

[0003] APE1 is essential for maintaining cellular homeostasis. As a redox-dependent regulator of multiple transcription factors, these functions make APE1 essential for regulating cell signaling, aging, and inflammatory pathways. First, APE-1 substrates AP-1, NF-kB, STAT3, and HIF-1 regulate the secretion of inflammatory cytokines such as IL-6, IL-8, and VEGF, affecting the occurrence of inflammatory diseases by regulating the microenvironment. In addition, APE1 is also involved in other key processes in the immune response, including the generation of reactive oxygen species and class switch recombination. The multiple functions of APE1 make it an important regulator of the pathogenesis of multiple diseases.

[0004] Allergic rhinitis (AR) is a type of rhinitis, also known as allergic rhinitis. It is one of the common non-infectious diseases in otolaryngology. It is caused by the release of a large amount of histamine, the main inflammatory mediator mediated by IgE, under the stimulation of external antigens, thereby inducing a non-infectious inflammatory disease of the nasal mucosa in which a variety of immune active cells and cytokines participate. The clinical symptoms are mainly sudden and recurrent nasal itching, sneezing, runny nose and nasal congestion, which seriously affect people's work, study and life. Commonly used antihistamines can relieve some clinical symptoms, but they often have side effects such as drowsiness and liver and kidney toxicity, and cannot solve the essential problem. And relevant data show that the scope of allergic rhinitis is relatively wide. It has now spread all over the world, and the incidence rate in different regions is not the same. In some areas, the incidence rate is as high as 40%. Relatively speaking, developed countries are more industrialized. Affected by industrialization, the incidence rate of allergic rhinitis is relatively high, gradually developing into a global health problem and receiving widespread attention.

[0005] The main treatments for AR include drug therapy, i.e., symptomatic treatment with glucocorticoids, antihistamines, anti-leukotrienes and other drugs, which cannot be cured; surgical treatment, selectively cutting off the pterygoid nerve to relieve rhinitis symptoms, but with many complications and uncertain efficacy, such as intractable dry eyes; specific immunotherapy, using allergen desensitization therapy, with a long course of treatment (3 years), poor compliance and uncertain efficacy. Recent studies have reported that ganciclovir can effectively relieve AR symptoms, but it is only used as a last-line therapy after conventional antiallergic drugs are ineffective, and it is an oral systemic medication, which cannot be used as a first-line clinical medication and has limited clinical use. In addition, many clinical studies have found that the current conventional treatment of AR is often ineffective and can lead to adverse reactions. Therefore, it is necessary to find more effective and safer methods to treat AR.

[0006] Therefore, it is urgent to develop new safe and effective targets and develop targeted anti-allergic rhinitis drugs. Summary of the invention

[0007] In early large-scale drug screening, the inventors found that C10 compound and structural analogs of C10 compound have excellent ability to inhibit the redox end of APE1 without affecting the DNA repair function of APE1, and are characteristic inhibitors that selectively inhibit the redox end of APE1.

[0008] It is known that innate immune cells, such as type II innate lymphoid cells (ILC2) and specialized dendritic cell (DC) populations, are located at the epithelial barrier, where they are exposed to antigens from pathogens or allergens, providing molecular cues and alarms for the immune system and inflammatory responses. Innate immune cells also acquire antigens at these sites, which they present to T cells to elicit T helper 2 (TH2) cell responses. TH2 cells and ILC2 produce large amounts of type II cytokines IL-4, IL-5, IL-9, and IL-13, promoting pleiotropic type II immune mechanisms, including B cell secretion of immunoglobulin E (IgE), eosinophilia, mastocytosis, goblet cell secretion of mucus, and M2 macrophage polarization. IL-13 can also promote the migration of dendritic cells (DC) to lymph nodes, further stimulating TH2 cell activation.

[0009] Therefore, theoretically, APE1 should play an important role in type II immune response diseases.

[0010] Based on this, the present invention provides a therapeutic drug or pharmaceutical composition for allergic rhinitis with an APE1 inhibitor as an active ingredient, wherein small molecule compounds represented by C10 and its derivatives show excellent effects in the treatment of AR.

[0011] Specifically, the technical solution of the present invention is as follows:

[0012] Use of an APE1 inhibitor in the preparation of a drug for treating allergic rhinitis, wherein the APE1 inhibitor includes a C10 compound or E3330 (APX-3330, CAS No.: 136164-66-4). Further, the APE1 inhibitor is a C10 compound, and the C10 compound has a structure as shown in Formula 1 below:

[0013]

[0014] Wherein R is C, N, S or O element; R1, R2, R3, R4, R5 or R6 are hydrogen, or various saturated or unsaturated, cyclic or non-cyclic, substituted or unsubstituted alkyl compounds.

[0015] Furthermore, the C10 compound has a structure as shown in Formula 2 below:

[0016]

[0017] The structure of E3330 is as follows:

[0018]

[0019] Furthermore, the above-mentioned APE1 inhibitor is used as an active ingredient, and the specific mechanism of action is to inhibit the redox end of APE1. These compounds are made into any tablets, gels, capsules, dispersions, injections, sprays, oral liquids and other pharmaceutically acceptable carriers and / or excipients in the form of pharmaceutical preparations, which all fall within the scope of protection of the present invention. The administration of the APE1 inhibitor includes oral administration, intranasal administration, injection administration or external administration, preferably intranasal administration.

[0020] Furthermore, the drug for treating allergic rhinitis also includes pharmaceutically acceptable excipients or solvents.

[0021] The present invention also provides a pharmaceutical composition for treating allergic rhinitis, comprising a C10 compound or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, and a pharmaceutically acceptable excipient and / or adjuvant.

[0022] Optionally, the C10 compound is a pharmaceutically acceptable salt thereof, and the pharmaceutically acceptable salt is a salt commonly used in pharmacy. Further, the salt is selected from one or more of acetate, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, benzoate, fumarate, maleate, succinic acid, tartaric acid, citrate, oxalic acid, glyoxylic acid, aspartic acid, tartrate, 2,5-dihydroxybenzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, benzoylsulfonate, hydroquinonesulfonate and p-toluenesulfonate.

[0023] The beneficial effects of the present invention are: the C10 compound of the present invention has an excellent therapeutic effect on allergic rhinitis, can effectively alleviate clinical symptoms, and provides a new approach for the prevention and treatment of AR.

[0024] Secondly, the C10 of the present invention has a simple structure, excellent potential, is a small molecule drug, has a simple synthesis method, and has good industrialization prospects.

[0025] The research of the present invention shows that APE1 has the function of regulating the DNA binding activity of a series of transcription factors, inducing ILC2 and Th2 cells to secrete type II inflammatory response cytokines IL-4, IL-5, IL-9 and IL-13, and promoting the pleiotropic type II immune mechanism; it also has the function of inducing APE1 nuclear translocation through oxidative stress response and promoting the production of type II inflammatory cytokines.

[0026] Therefore, as an effective APE1 inhibitor, C10 compound can significantly inhibit the pathological symptoms of chronic sinusitis, including alleviating the symptoms of nasal hypersensitivity in AR mice, specifically alleviating Th2 and Th17 type inflammation, reducing eosinophil infiltration and oxidative damage, improving cell activity, and reducing the level of immunoglobulin E (IgE) in the serum of AR mice, and has an anti-allergic effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] The accompanying drawings in the specification, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0028] Figure 1 This is a comparison chart of AR symptoms in mice in the C10 treatment group and the AR model group in the example;

[0029] Figure 2 This is a comparison chart of the total cell count and inflammatory cell (eosinophil, neutrophil) count in the nasal lavage fluid of mice in the C10 treatment group and the AR mouse model group in the Example;

[0030] Figure 3 This is a comparison of HE staining of the nasal mucosa of mice in the C10 treatment group and the AR model group in the example;

[0031] Figure 4 This is a comparison of PAS staining of the nasal mucosa of mice in the C10 treatment group and the AR model group in the example;

[0032] Figure 5 This is a comparison chart of mouse serum IgE and OVA-sIgE in the C10 treatment group and AR model group in the example;

[0033] Figure 6This is a comparison chart of Th1, Th2 and Th17 inflammatory factors in the nasal lavage fluid of mice in the C10 treatment group and the AR model group in the example;

[0034] Figure 7 This is a comparison of TUNEL staining of mouse nasal mucosal tissues in the C10 treatment group and the AR model group in the example;

[0035] Figure 8 This is a comparison of ROS staining in the nasal mucosal tissue of mice in the C10 treatment group and the AR model group in the example;

[0036] Fig. 9 It is a transmission electron microscopic comparison of the mouse nasal mucosal tissues of the C10 treatment group and the AR model group in the example;

[0037] Fig.10 This is a comparison of apoptosis detected by flow cytometry of HNEPCs in the C10 treatment group and the AR model group in the example;

[0038] Fig.11 This is a comparison of ROS in HNEPCs in the C10 treatment group and the AR model group in the example;

[0039] Fig.12 2 is the histopathological test result of nasal concha mucosa in the embodiment. DETAILED DESCRIPTION

[0040] In order to enable those skilled in the art to better understand the present application, the present application is further explained in conjunction with specific implementation methods.

[0041] In some embodiments, the drug for treating allergic rhinitis or the pharmaceutical composition for treating allergic rhinitis can be used to treat mammals suffering from allergic rhinitis diseases, disorders or conditions, including but not limited to any members of the class Mammalia: humans, non-human primates (such as chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals, such as rabbits, dogs and cats; laboratory animals, including rodents, such as rats, mice and guinea pigs, etc.

[0042] In some embodiments, the C10 compound of the present invention will be provided as a pharmaceutical formulation in a single dose at a concentration of 1 mg / ml, 5 mg / ml, 10 mg / ml, 20 mg / ml, 50 mg / ml, depending on the therapeutic effect. In other embodiments, administration will be carried out at a ratio of the mass of the C10 compound to the mass of the individual being treated, so that the dose will be 1 mg / kg, 5 mg / kg, 10 mg / kg, 20 mg / kg, 50 mg / kg, 100 mg / kg or more, depending on the therapeutic effect. In multiple administration embodiments, the dosing schedule may be 1 dose / day, 2 doses / day, 3 doses / day or more, and may continue for the necessary time, so that administration may continue for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 10 weeks, 20 weeks, or permanently for the life of the individual.

[0043] The term "treatment" as used herein includes alleviating, alleviating or ameliorating symptoms of a disease or condition, preventing other symptoms, ameliorating or preventing potential metabolic causes of symptoms, inhibiting a disease or condition, such as preventing the development of a disease or condition, alleviating a disease or condition, making a disease or condition better, alleviating symptoms caused by a disease or condition, or stopping symptoms of a disease or condition, and in addition, the term includes the purpose of prevention. The term also includes obtaining a therapeutic effect and / or a preventive effect.

[0044] Unless otherwise specified, the raw materials or reagents used in the examples of the present invention are commercially available products.

[0045] The percentages used in the embodiments of the present invention are all by mass unless otherwise specified.

[0046] Example 1

[0047] Clinical study: Inpatients with cerebrospinal fluid rhinorrhoea / nasal septum deviation and AR in the Department of Otolaryngology, Qilu Hospital of Shandong University and some healthy volunteers were selected. Following ethical requirements and with informed consent from the patients, a small amount of inferior turbinate mucosal tissue was clamped after anesthesia on the mucosal surface and fixed or frozen for further pathological histological examination. Clinical sample analysis found that compared with normal nasal mucosal tissue, the expression of APE1 in the nasal mucosal tissue of AR patients was significantly upregulated, and this upregulation was accompanied by pathological changes in the nasal mucosal tissue ( Fig.12 ), suggesting that APE1 is a target for allergic rhinitis.

[0048] Experimental animals: BALB / C mice, female, 6-8 weeks old, weighing 18-20 g, were purchased from Beijing Weitonglihua Experimental Animal Technology Co., Ltd. The mice were housed in an SPF constant temperature animal room (temperature: 23+2°C, relative humidity: 55±10%, light-dark cycle 12 h), and the model was established after 1 week of isolation and adaptive feeding.

[0049] Experimental materials: ovalbumin (OVA, A5503, Sigma Aldrich), aluminum hydroxide adjuvant (239186, SigmaAldrich), phosphate buffered saline (PBS, B310KJ, source culture), C10 compound (Formula 2, synthesized by Biochemical Company), E3330 (49581, Novus Biologicals), bronchial epithelial cell culture medium (3211, ScienCell), IL-13 recombinant protein (HY-P7033, MCE), LPS from Escherichia coli (L4391, Sigma-Aldrich), rat tail collagen (A1142801, Gibco), dimethyl sulfoxide DMSO (D8371, Solarbio), corn oil (C7030, Solarbio).

[0050] Reagent preparation: Sensitization solution: weigh 1 mg OVA and 112.5 mg Al(OH)3, add them into 10 ml PBS, place in a 4°C constant temperature oscillator and shake thoroughly to mix; 1% OVA stimulation solution (10 mg / ml OVA): weigh 100 mg OVA, add it into 10 ml PBS, dissolve and mix thoroughly, the stimulation solution must be freshly prepared.

[0051] Experimental methods:

[0052] 1. Construction of animal model:

[0053] 1.1 Animal grouping: The animals were randomly divided into 7 groups, with 6 animals in each group. Group A was the blank control group; Group B was the AR model group (nasal drops control, OVAi.n.); Group C was the C10 nasal drops group (C10i.n.); Group D was the E3330 nasal drops group (E3330i.n.); Group E was the AR model group (oral gavage control, OVA po); Group F was the C10 oral gavage group (C10 po); and Group G was the E3330 oral gavage group (E3330 po).

[0054] 1.2 Establishment of animal model: OVA was used to establish AR mouse model. In the basic sensitization stage, groups B, C, D, E, F, and G were sensitized by intraperitoneal injection of 200 μL of sensitizing drugs on days 1, 8, and 15, respectively, and the blank control group was intraperitoneally injected with equal doses of PBS on days 1, 8, and 15. One week later, that is, from the 22nd day, groups B, C, D, E, F, and G were given nebulized inhalation of 1% OVA stimulating solution, 20 minutes each time, once a day, for 1 week. After each nebulization, the mice were observed for 30 minutes for symptoms of scratching their noses, sneezing, and runny nose. The total score was recorded by the superposition method. The recorded scores are shown in the following table. A score of more than 5 points indicates that the AR modeling is successful.

[0055] Table 1 AR symptom scoring table

[0056]

[0057] 1.3 Animal administration: After successful modeling, mice in groups C and D were given intranasal drops (10 mg / kg) 1 hour before OVA stimulation, 20 μl each time (10 μl each in the left and right nasal cavities), once a day, for 2 consecutive weeks; mice in group B (i.e., AR model intranasal control group) were given intranasal drops of equal volume of PBS + DMSO, once a day, for 2 consecutive weeks. Mice in groups F and G were given intragastric administration 1 hour before OVA stimulation (10 mg / kg in group F and 20 mg / kg in group G), 200 μl each time, once a day, for 2 consecutive weeks; mice in group E (i.e., AR model intragastric control group) were given intragastric administration of equal volume of DMSO + corn oil, once a day, for 2 consecutive weeks. Mice in the blank group were given intranasal drops and intragastric administration of equal volume of PBS at the same time. Among them, the preparation method of C10 nasal drops is as follows: 28.6mg C10 powder is dissolved in 0.286ml DMSO, and after complete dissolution, 2.574ml PBS is added to dilute, that is, the drug concentration is 10mg / ml; the preparation method of E3330 nasal drops is as follows: 28.6mg E3330 powder is dissolved in 1.83ml DMSO, and after complete dissolution, 1.03ml PBS is added to dilute, that is, the drug concentration is 10mg / ml. The preparation method of C10 intragastric solution is as follows: 30mg C10 powder is dissolved in 1.2ml DMSO, and after complete dissolution, 28.8ml corn oil is added to dilute, that is, the drug concentration is 1mg / ml; the preparation method of E3330 nasal drops is as follows: 57.2mg E3330 powder is dissolved in 0.572ml DMSO, and after complete dissolution, 28.028ml corn oil is added to dilute, that is, the drug concentration is 2mg / ml.

[0058] 2. Nasal symptom evaluation: On day 42, 30 minutes after the last OVA challenge, three observers counted the number of sneezes and nasal scratches within 10 minutes to evaluate the improvement of nasal symptoms in AR mice treated with C10.

[0059] 3. Mouse serum collection: After 24 hours of drug intervention, mice were anesthetized by intraperitoneal injection of 2% sodium pentobarbital. Eyeballs were removed and peripheral blood was collected in 1.5 ml EP tubes, stored at room temperature for 0.5 hours, and then centrifuged (3000 rpm / 15-30 min / 4°C) after chromatography, and the supernatant was frozen at -80°C.

[0060] 4. Acquisition and detection of nasal lavage fluid: Mice were killed by cervical dislocation and disinfected with 75% alcohol. The mouse mouth was split open to fully expose the posterior nasopharynx, and 1 mL of pre-cooled PBS was used to gently irrigate the nasal cavity from the posterior nasal cavity. The nasal lavage fluid was collected and centrifuged (1200 rpm / 5 min / 4 ° C), and the supernatant was frozen at -80 ° C for ELISA detection. 100 μl PBS was added to the cell pellet for resuspending, and the cells were counted using a cell counter and spun at 1000 rpm·5 min. The cells were fixed with paraformaldehyde for subsequent Dif staining to evaluate the state of nasal inflammation.

[0061] 5. Histopathological examination: The mice were fixed in a clean bench, the skin on the nasal dorsum was split open, and the entire nasal bone and maxillary bone of some mice were removed intact. They were immediately fixed in 4% neutral paraformaldehyde solution for 24 hours, and then decalcified with EDTA decalcifier, dehydrated, waxed, embedded, and sectioned. HE and PAS staining were performed to observe the structural integrity of the mouse nasal mucosa tissue and inflammatory infiltration.

[0062] 6. Transmission electron microscopy: Take out the mouse nasal mucosa and quickly put it into the transmission electron microscopy fixative.

[0063] Afterwards, the resin blocks were formed after PBS bleaching, 1% osmium acid fixation, gradient ethanol, infiltration, and embedding. After trimming the surface of the resin block, ultrathin sections with a thickness of 70 nm were made and the sections were picked up and placed on two aromatic film grids. The sections were stained with 2% uranyl acetate solution for 30 minutes, and then stained with lead citrate staining solution for 5 minutes, and then washed thoroughly with water. The sections were baked under infrared light for 10 minutes, and after drying, the ultrastructure was observed under a transmission electron microscope at 80KV, and photographed at different magnifications.

[0064] 7.ELISA test: Take out the mouse serum and nasal lavage fluid supernatant samples and thaw them on ice. According to the reagent instructions, add the standard and sample in sequence, and then detect the absorbance on the machine after adding enzyme, incubation, washing, color development, termination and other steps to calculate the sample concentration.

[0065] 8. Cell culture: Primary human nasal epithelial cells (HNEPCs) were derived from outpatients or inpatients, and epithelial cells of the inferior turbinate tissue were scraped with a nasal probe. The 6-well plate was coated with rat tail collagen in advance, and the primary human nasal epithelial cells were transferred into the 6-well plate and supplemented with bronchial epithelial cell culture medium to 2 ml, and cultured in an incubator at 37°C and 5% CO2. When the cells were fused to 50-60%, the cells were treated with C10 (20 μm) or E3330 (40 μm) for 1 hour, and then stimulated with 20 ng / mL IL-13 recombinant protein combined with 2 ug / ml LPS for 48 hours.

[0066] 9. Flow cytometry: Carefully dissect the mouse nasal tissue from back to front along the cranial suture, remove the mouse nasal mucosa and place it in 1640 culture medium containing collagenase D, DNaseⅠ and DSpaseⅡ, cut it into pieces and incubate it in a 37℃ water bath for 40-50min. The digested nasal mucosa was ground and filtered with a 70μm filter to obtain a single cell suspension. After 48 hours of HNEPCs intervention, the cell suspension was digested and stained according to the instructions of the apoptosis kit and tested on the machine.

[0067] 10. TUNEL assay: After dewaxing, the nasal tissue sections were incubated with 20 μg / ml DNase-free proteinase K (#ST532, Beyotime) at 37°C for 30 min, and then incubated with 50 μl of TUNEL assay solution at 37°C for 1 hour. The samples were examined using a fluorescence microscope.

[0068] 11. Statistical analysis: All experimental research data were analyzed by SPSS25.0 software, and the quantitative data in the data were expressed as (x±S). If the comparison between three or more groups of samples conformed to the normal distribution and the variance was homogeneous, one-way ANOVA was used; if the data did not conform to the normal distribution, the non-parametric Kruskal-Wallis test and Dunnetts's pairwise comparison were used. P<0.05 indicated that the difference was statistically significant, P<0.01 was considered to be significantly different, P<0.001 was considered to be significantly different, and NS indicated that the difference was not statistically significant. All statistical graphs were generated using GraphPad Prism 8.0.

[0069] The experimental results are as follows Figure 1-Figure 11 shown.

[0070] pass Figure 1 It can be seen that the AR mouse model was established using OVA, and the number of sneezing and nose scratching in the C10 nasal drops group was significantly lower than that in the AR model group, indicating that the C10 compound can significantly improve the symptoms of sneezing and nose scratching in the AR mouse model, indicating that the C10 compound reduces the severity of AR in mice.

[0071] pass Figure 2 It can be seen that compared with the AR model group, the number of eosinophils and neutrophils in the C10 nasal drops group was significantly reduced, and the C10 compound can effectively reduce the total number of exfoliated cells and the number of eosinophils and neutrophils in the nasal lavage fluid, indicating that the inflammatory state of the nasal cavity of AR mice has improved.

[0072] pass Figure 3It can be seen that compared with the AR model group, the C10 compound can effectively improve the structural integrity of the nasal mucosal tissue, relieve nasal mucosal edema, and reduce the local infiltration of eosinophils and neutrophils, indicating that the pathological changes in the nasal mucosa of AR mice were alleviated.

[0073] pass Figure 4 It can be seen that compared with the AR model group, C10 can effectively reduce the number of goblet cells and improve the proliferation and hypertrophy of goblet cells.

[0074] pass Figure 5 It can be seen that compared with the AR model group, C10 can effectively reduce the expression levels of IgE and OVA-sIgE in serum, indicating that C10 can improve the allergic reaction of AR mice.

[0075] pass Figure 6 It can be seen that compared with the AR model group, C10 can upregulate the expression levels of Th1 (IFN-γ) type and downregulate the expression levels of Th2 (IL-4, IL-5, IL-13) and Th17 (IL-17A) type inflammatory factors, indicating that C10 can regulate the local tissue immune balance.

[0076] pass Figure 7 It can be seen that compared with the AR model group, C10 inhibited the apoptosis of nasal mucosal epithelial cells in AR mice.

[0077] pass Figure 8 It can be seen that compared with the AR model group, C10 effectively reduced the production of ROS in the nasal mucosal tissue of AR mice, indicating that C10 reduced oxidative damage in the nasal mucosal tissue of AR mice.

[0078] pass Fig. 9 It can be seen that compared with the AR model group, C10 effectively improved the mitochondrial morphology in the nasal mucosal tissue of AR mice.

[0079] pass Fig.10 It can be seen that in the in vitro model of AR induced by HNEPCs stimulated by IL-13 recombinant protein combined with IL-1β, C10 inhibited epithelial cell apoptosis and improved cell activity.

[0080] pass Fig.11 It can be seen that in the in vitro model of AR induced by HNEPCs stimulated by IL-13 recombinant protein combined with IL-1β, C10 effectively reduced the production of ROS in epithelial cells.

Claims

1. Use of an APE1 inhibitor in the preparation of a drug for treating allergic rhinitis, characterized in that: The APE1 inhibitor includes a C10 compound; the C10 compound has a structure as shown in Formula 1 below: Wherein R is C, N, S or O element; R1, R2, R3, R4, R5 or R6 are hydrogen, or various saturated or unsaturated, cyclic or non-cyclic, substituted or unsubstituted alkyl compounds.

2. Use of the APE1 inhibitor according to claim 1 in the preparation of a drug for treating allergic rhinitis, characterized in that: The APE1 inhibitor is a C10 compound; the C10 compound has a structure as shown in Formula 2 below:

3. Use of the APE1 inhibitor according to claim 1 or 2 in the preparation of a drug for treating allergic rhinitis, characterized in that: The dosage form of the drug for treating allergic rhinitis is nasal drops, nasal sprays, aerosols or powder sprays.

4. Use of the APE1 inhibitor according to claim 1 or 2 in the preparation of a drug for treating allergic rhinitis, characterized in that: The administration method of the drug for treating allergic rhinitis is oral administration, intranasal administration, injection administration or external administration.

5. Use of the APE1 inhibitor according to claim 1 or 2 in the preparation of a drug for treating allergic rhinitis, characterized in that: The administration method of the drug for treating allergic rhinitis is intranasal administration.

6. Use of the APE1 inhibitor according to claim 1 or 2 in the preparation of a drug for treating allergic rhinitis, characterized in that: The drug for treating allergic rhinitis also includes pharmaceutically acceptable adjuvants or solvents.

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