Use of hesperetin or sr1078 in the preparation of a medicament for improving salivary gland function

Abstract

This invention discloses the application of citrus flavonoids (NOB) or SR1078 in the preparation of drugs to improve salivary gland function, particularly in improving the circadian rhythm of salivary glands damaged by ionizing radiation. Oral administration of a specific dose of NOB or SR1078 can significantly promote salivary gland function. Furthermore, it does not interact with other drugs with anti-inflammatory or regenerative functions. It can be administered as a single dose or multiple times consecutively; it can be administered after injury, and this flexible administration method does not affect the tumor radiotherapy process.

Description

Technical Field

[0001] This invention belongs to the field of small molecule drug technology, specifically relating to the application of citrus flavonoids or SR1078 in the preparation of drugs to improve salivary gland function damaged by ionizing radiation. Background Technology

[0002] Radiation-induced xerostomia is a common complication after radiotherapy for head and neck tumors, severely impacting patients' quality of life. It primarily results from damage to the salivary glands caused by ionizing radiation after radiotherapy, leading to a significant decrease in the rate and quantity of saliva secretion and changes in its composition, mainly manifesting as dry mouth. Insufficient saliva prevents it from fully mixing with food, causing difficulty chewing and swallowing, often accompanied by oral infections, sometimes resulting in a burning sensation, decreased taste, and ulcers. Clinically, other complex factors can also cause xerostomia, including age, climate change, and medication use, which may also lead to decreased salivary gland function and insufficient saliva secretion.

[0003] Mild to moderate cases can use sugar-free chewing gum or lozenges to stimulate the salivary glands and promote saliva production. Severe cases require artificial saliva. While commercially available artificial saliva can mimic and replace natural saliva to alleviate dry mouth, it doesn't address the root cause. Furthermore, research on stem cell therapy and regenerative medicine is still in the laboratory stage.

[0004] Therefore, the existing technology still needs further improvement and enhancement. Summary of the Invention

[0005] To address the aforementioned problems, this invention aims to provide the application of citrus flavonoids or SR1078 in the preparation of drugs that improve circadian rhythms. This aims to solve the problem of dry mouth caused by salivary gland tissue damage due to ionizing radiation, which leads to a significant decrease in the rate and quantity of saliva secretion and changes in its composition. The invention seeks to increase the rate of saliva secretion and alleviate symptoms of dry mouth.

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

[0007] The first aspect is the application of citrus flavonoids or SR1078 in the preparation of drugs to improve salivary gland function damaged by ionizing radiation.

[0008] The following are preferred technical solutions of the present invention, but are not intended to limit the technical solutions provided by the present invention. The purpose and beneficial effects of the present invention can be better achieved and realized through the following preferred technical solutions.

[0009] Secondly, the application of a pharmaceutical preparation in the preparation of a drug for improving salivary gland function damaged by ionizing radiation, wherein the pharmaceutical preparation is citrus flavonoids or SR1078.

[0010] As a preferred technical solution, the pharmaceutical preparation is used in the preparation of a drug for improving salivary gland function damaged by ionizing radiation, wherein the dosage of the pharmaceutical preparation is 30-150 mg / kg.

[0011] As a preferred technical solution, the application of the pharmaceutical preparation in the preparation of a drug for improving salivary gland function damaged by ionizing radiation, wherein the administration is a single administration or multiple consecutive administrations.

[0012] Beneficial effects: Compared with the prior art, the present invention uses citrus flavonoids or SR1078 as active ingredients to treat salivary glands after radiation damage. It can improve the function of salivary glands after radiation damage, increase the amount of saliva secreted by the damaged salivary glands, increase the secretion speed of saliva, and relieve the symptoms of dry mouth. Attached Figure Description

[0013] Figure 1A To analyze gene expression in C57BL / 6 mice, the head and neck were irradiated with 5 Gy X-rays, and the submandibular glands were collected. Differential gene expression pathway analysis (RNA-seq; 6 hours) showed changes in circadian rhythms (indicated by arrows).

[0014] Figure 1B Changes in the expression of key genes related to the biological clock (qRT-PCR);

[0015] Figure 1C The expression of key functional genes of salivary glands was decreased (qRT-PCR). The x-axis represents light and dark time, with ZT0-ZT12 being light time and ZT12-ZT24 being dark time.

[0016] Figure 2 A schematic diagram illustrating the role of small molecule drugs that regulate circadian rhythms in rescuing salivary gland function. A. Oral administration of 150 mg / kg citrus flavonoids (Nob) rescued salivary gland function, showing a significant difference on day three (N=5); B. Oral administration of 50 mg / kg Nob for seven consecutive days rescued salivary gland function, showing significant differences on both day three and day seven (N=5); C. Oral administration of 75 mg / kg SR1078 rescued salivary gland function, showing significant differences on both day three and day seven (N=5).

[0017] Figure 3The results of experiments showed that the small molecule drug soy isoflavones (antioxidant / anti-radiation) and two other circadian rhythm regulators could not salvage salivary gland radiation damage. Specifically, A. Oral administration of 100 mg / kg Genistein (Gen) could not salvage salivary gland function (N=5); B. Oral administration of 50 mg / kg Gen for seven consecutive days could not salvage salivary gland function (N=5); C. Oral administration of 100 mg / kg SR9009 could not salvage salivary gland function (N=3); D. Oral administration of 50 mg / kg SR8278 could not salvage salivary gland function (N=3).

[0018] Figure 4A This study aimed to rescue the expression of key circadian rhythm genes by Nob (qRT-PCR).

[0019] Figure 4B Rescue of key salivary gland function gene expression by Nob (qRT-PCR);

[0020] Figure 4C Nob does not affect the expression of the cytokine IL-6, nor does it affect the expression of p21, a key downstream gene of p53 signaling (qRT-PCR);

[0021] Figure 4D Nob cannot salvage salivary gland cell senescence induced by ionizing radiation (b-Gal staining). Scale bar, 100 μm. Detailed Implementation

[0022] The present invention will be further described in detail below with reference to specific embodiments, but the implementation of the present invention is not limited thereto. For process parameters not specifically noted, conventional techniques can be referred to.

[0023] Those skilled in the art will understand that, unless specifically stated otherwise, the singular forms “a,” “an,” “the,” and “the” used herein may also include the plural forms. It should be further understood that the word “comprising” as used in this specification means the presence of the stated features, integers, or steps, but does not exclude the presence or addition of one or more other features.

[0024] It will be understood by those skilled in the art that, unless otherwise defined, all terms used herein (including technical and scientific terms) have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. It should also be understood that terms such as those defined in general dictionaries should be understood to have the meaning consistent with their meaning in the context of the prior art, and should not be interpreted in an idealized or overly formal sense unless specifically defined as herein. Other raw materials and reagents not specifically mentioned in this invention refer to those commonly used in the art.

[0025] This invention addresses the problem that, in existing radiotherapy for head and neck tumors, ionizing radiation causes damage to salivary gland tissue, resulting in a significant decrease in the rate and quantity of saliva secretion, for which there is no corresponding therapeutic drug.

[0026] To address the aforementioned technical problems, the inventors of this invention discovered in their research that ionizing radiation affects the circadian rhythm of the salivary glands in mice, leading to a decline in their salivary secretion function (e.g., Figure 1A , Figure 1B , Figure 1C (As shown). Using small molecule chemical drugs that enhance circadian rhythms, including nobiletin (NOB) / SR1078, but excluding soy isoflavones (Genistein (GEN) / SR8278 / SR9009), can salvage salivary gland function. Specifically... Figures 2 to 3 As shown; this effect is unrelated to cytokine secretion, tissue inflammation, and cell senescence induced by ionizing radiation, and is an independent, novel factor affecting salivary gland function (e.g. Figure 4A , Figure 4B , Figure 4C , Figure 4D (As shown). In other words, the inventors of this application have discovered a new factor affecting salivary gland function that is unaffected by other factors. Using this new factor, a new technical solution is provided to address the problem of salivary gland dysfunction following radiation damage, which leads to reduced saliva secretion and dry mouth.

[0027] Specifically, citrus flavonoid NOB is a polymethoxyflavonoid compound with the following molecular structure: It can improve sleep in mice, delay skeletal muscle aging, and extend the average lifespan of mice (PMID31462679). However, there is no record in the current technology of its effect on improving radiation-induced damage to salivary glands. Since the mechanism by which citrus flavonoid NOB improves salivary gland function impaired by ionizing radiation is a novel molecular mechanism, it does not conflict with other drugs with anti-inflammatory or regenerative functions. It can be administered as a single dose or multiple times consecutively; it can be administered after injury, providing flexible administration methods that do not interfere with the process of tumor radiotherapy.

[0028] Soy isoflavones (GEN) are alkaloids with antioxidant and anti-inflammatory properties, and have been reported to be effective in rescuing tissue damage caused by ionizing radiation (PMID 34093188; 14635262). However, studies have found that soy isoflavones (GEN) are ineffective against radiation-induced damage to salivary glands.

[0029] SR1078 is also a ROR activator, and its molecular structure is as follows: Although structurally similar to another circadian rhythm regulator molecule, T1317, SR1078 exhibits significantly different biological functions (PMID: 33781946; 20735016). SR1078 is effective in improving the circadian rhythm of salivary glands damaged by ionizing radiation. In contrast, SR8278 and SR9009, small molecule drugs with circadian rhythm regulation functions (PMID 33781946) and used in cancer treatment (PMID 29320480), are ineffective in improving the circadian rhythm of salivary glands damaged by ionizing radiation. This demonstrates that even structurally similar substances do not necessarily have the same effects. Structural similarity does not equate to identical function.

[0030] The present invention will be further explained and illustrated below by listing specific embodiments.

[0031] Example 1.

[0032] Mice were subjected to 5 Gy ionizing radiation to damage their salivary glands, followed by administration of NOB via gavage. Changes in salivary gland flow were measured. A single dose of 150 mg / kg showed significant effects. Figure 2 As shown in A in the diagram.

[0033] Example 2.

[0034] Mice were subjected to 5 Gy ionizing radiation to damage their salivary glands, followed by administration of NOB 50 mg / kg via gavage for 7 consecutive days. Changes in salivary gland flow were measured. A significant improvement in salivary gland function was observed, such as… Figure 2 As shown in B in the diagram.

[0035] Example 3.

[0036] Mice were subjected to 5 Gy ionizing radiation to damage their salivary glands, followed by administration of SR1078 (50 mg / kg) via gavage for 7 consecutive days. Salivary gland flow was measured. A significant improvement in salivary gland function was observed, such as… Figure 2 As shown in C.

[0037] In summary, this invention provides the application of citrus flavonoids or SR1078 in the preparation of drugs that improve circadian rhythms. Oral administration of a certain dose of citrus flavonoids or SR1078 can significantly promote salivary gland function and does not conflict with other drugs with anti-inflammatory or regenerative functions. It can be administered as a single dose or multiple times consecutively; it can be administered after injury, and this flexible administration method will not affect the tumor radiotherapy process.

[0038] The above description outlines the basic principles, main features, and performance advantages of this invention. It should be understood that the performance and applications of this invention are not limited to the examples described above. Those skilled in the art can make improvements or modifications based on the above description, and all such improvements and modifications should fall within the protection scope of the appended claims.

Claims

1. Application of citrus flavonoids or SR1078 in the preparation of drugs to improve salivary gland function in response to ionizing radiation damage; The molecular structural formula of the citrus flavonoid is as follows: The molecular structural formula of SR1078 is as follows: .

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