Application of bitter receptor 38 / 138 agonist in preparation of medicine for preventing and treating radiation injury
By using bitter taste receptor 38/138 agonists, such as benzedamium, propylthiouracil and thiourea, a pharmaceutical composition for preventing and treating radioactive damage was prepared, which solved the problem that existing drugs could not effectively prevent and treat normal tissue radiation damage after radiotherapy, and achieved the effect of significantly improving cell viability and reducing radioactive damage.
Patent Information
- Application Number
- CN202510091016.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-01-20
- Publication Date
- 2025-06-03
AI Technical Summary
Existing radiation damage prevention and treatment drugs cannot effectively prevent and treat radiation damage to normal tissues after radiation therapy, and there are problems such as obvious side effects and not long-lasting treatment effects.
Pharmaceutical compositions for preventing and treating radioactive damage were prepared using agonists of bitter receptor 38/138, such as benzedarum, propylthiourea and phenylthiourea as active ingredients. These agonists exert their pharmacological effects by activating bitter taste receptors, improving cell viability and clonal proliferation ability, and reducing radioactive responses and radiation damage to normal tissues.
Experimental results show that TAS2R38/138 agonist can significantly improve the viability and clonal proliferation ability of cells after IR irradiation, reduce the percentage of weight loss in mice, shorten colon length and lung tissue damage, proving its potential application value in preventing and treating radioactive injuries.
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Figure CN120078892A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to a new use of a drug, and specifically to the use of a bitter taste receptor 38 / 138 (TAS2R38 / 138) agonist in the preparation of a drug for preventing and treating radiation injury. Background Art
[0002] Radiotherapy is an important means of local treatment for tumors, but it will inevitably damage the surrounding normal tissues or organs during local irradiation. In terms of the reason, ionizing radiation (IR) such as X-rays, γ-rays, etc. can trigger cytotoxic reactions through direct and indirect effects. Among them, the direct effect refers to that IR directly acts on the nuclear DNA of cells, resulting in cytological effects such as single-strand and double-strand breaks and base damage of DNA. The indirect effect refers to that IR acts on the water molecules around cells, triggering a series of biological effects such as DNA damage and lipid peroxidation, resulting in cell dysfunction and even death. Drugs for preventing and treating radiation injury are mainly used to prevent and treat personnel irradiated by IR, including cancer patients, in order to reduce radiation reactions and radiation damage to normal tissues.
[0003] Bitter taste receptor 38 / 138, also known as taste receptor type-2 member 38 / 138 (TAS2R38 / 138), is a G protein-coupled receptor related to taste perception, mainly responsible for perceiving bitter taste, and has been found to be widely present in multiple organs and tissues of the body, including the intestine, respiratory tract, etc. TAS2R38 / 138 can be activated by specific agonists and exert a variety of physiological and pharmacological effects, with powerful functions.
[0004] With the increasing incidence of cancer globally, the clinical treatment demand for post-radiotherapy injury is becoming increasingly urgent. At present, the existing clinical treatment drugs mainly include non-steroidal anti-inflammatory drugs, antibiotics, probiotic preparations, etc. Although they can relieve the disease symptoms to a certain extent, they often cannot effectively prevent and treat the injury, and there are problems such as obvious side effects and short-lasting treatment effects. Therefore, it is urgent to find new treatment strategies and develop new drugs accordingly to cope with various clinical manifestations and potential consequences before and after radiotherapy. Although TAS2R38 / 138 has shown good pharmacological activity in regulating cell function, so far, no relevant research and application reports on its agonist for preventing and treating radiation injury have been found. Summary of the Invention
[0005] Object of the Invention: The main technical problem to be solved by the present invention is to provide the application of a TAS2R38 / 138 agonist in the preparation of a drug for preventing and treating radiation injury, and the application of a pharmaceutical composition containing the TAS2R38 / 138 agonist as an active ingredient in preventing and treating radiation injury.
[0006] Technical solution: Use of a bitter taste receptor 38 / 138 agonist in the preparation of a drug for preventing and treating radiation injuries.
[0007] For the use described above, the bitter taste receptor 38 / 138 agonist includes denatonium benzoate or a pharmaceutically acceptable salt thereof, propylthiouracil or a pharmaceutically acceptable salt thereof, phenylthiourea or a pharmaceutically acceptable salt thereof, other substances proven to have the effect of activating bitter taste receptor 38 / 138 or a pharmaceutically acceptable salt thereof.
[0008] For the use described above, the bitter taste receptor 38 / 138 agonist includes denatonium benzoate, propylthiouracil, phenylthiourea, denatonium benzoate, other substances proven to have the effect of activating bitter taste receptor 38 / 138.
[0009] For the use described above, the bitter taste receptor 38 / 138 agonist is formulated into a preparation by adding pharmaceutically acceptable excipients.
[0010] For the use described above, the preparation includes nasal drops, eye drops, powders, pills, capsules, tablets, microcapsules, soft capsules, membranes, suppositories, injections, ointments, tinctures, granules and aerosols.
[0011] A pharmaceutical composition with a bitter taste receptor 38 / 138 agonist as the active ingredient.
[0012] For the pharmaceutical composition described above, the bitter taste receptor 38 / 138 agonist includes denatonium benzoate or a pharmaceutically acceptable salt thereof, propylthiouracil or a pharmaceutically acceptable salt thereof, phenylthiourea or a pharmaceutically acceptable salt thereof, other substances proven to have the effect of activating bitter taste receptor 38 / 138 or a pharmaceutically acceptable salt thereof.
[0013] Use of the pharmaceutical composition described above in the preparation of a drug for preventing and treating radiation injuries.
[0014] For the use described above, the drug for preventing and treating radiation injuries includes a drug for preventing and treating radiotherapy injuries in cancer patients.
[0015] For the use described above, the drug for preventing and treating radiation injuries can reduce radiation reactions and radiation injuries to normal tissues.
[0016] In this invention, multiple IR-induced cell and mouse tissue injury models were established, and were respectively treated with the TAS2R38 / 138 agonists denatonium benzoate (DB), propylthiouracil (PROP), and phenylthiourea (PTC). The experimental results showed that DB, PROP, and PTC could all increase the cell viability and clonal proliferation ability of rat intestinal crypt epithelial cells (intestinal epithelial cell line 6, IEC-6), mouse alveolar epithelial cells (murine lung epithelial-12, MLE-12), and human skin fibroblasts (human skin fibroblast, HSF) after IR irradiation. In addition, in the in vivo model of mouse radiation injury, DB, PROP, and PTC significantly reduced the percentage of mouse body weight loss, shortening of colon length, and lung tissue injury. These results indicate that TAS2R38 / 138 agonists have potential application value in preventing and treating radiation injury.
[0017] The key points of this invention are as follows:
[0018] 1. TAS2R38 / 138 agonists have obvious preventive and therapeutic effects on radiation injury;
[0019] 2. The use of TAS2R38 / 138 agonists in the preparation of drugs for preventing and treating radiation injury.
[0020] Beneficial effects: Compared with the prior art, this invention has the following advantages: (1) For the first time, the effects of TAS2R38 / 138 agonists on the damage of cell viability and clonal proliferation ability caused by IR and mouse tissue injury were investigated, and it was confirmed that TAS2R38 / 138 agonists can significantly counteract radiation injury; (2) It reveals the application prospect of TAS2R38 / 138 agonists in the preparation of drugs for preventing and treating radiation injury. Description of the Drawings
[0021] Figure 1 Effects of DB, PROP, and PTC on the viability of IEC-6, MLE-12, and HSF cells treated with ionizing radiation (IR) (Mean±S.D., n = 3). ## P < 0.01, compared with the Control group; ** P < 0.01, * P < 0.05, compared with the IR model group;
[0022] Figure 2Effects of DB, PROP, and PTC on the clonal proliferation ability of IEC-6, MLE-12, and HSF cells induced by ionizing radiation (IR) (Mean±SD., n = 3). ## P < 0.01, compared with the Control group; ** P < 0.01, * P < 0.05, compared with the IR model group;
[0023] Figure 3 Effects of DB, PROP, and PTC on tissue damage in mice caused by ionizing radiation (IR) (Mean±SD., n = 6). ## P < 0.01, compared with the Normal group; ** P < 0.01, * P < 0.05, compared with the IR model group. Detailed implementation manners
[0024] The compounds DB (HY-B1146), PROP (HY-B0346), and PTC (HY-Y0351) used were all purchased from MedChemexpress Biotechnology Company, USA.
[0025] Example 1
[0026] Effects on cell viability damage caused by IR
[0027] IEC-6, MLE-12, and HSF cells were respectively inoculated into 96-well plates at a density of 1×10 6 / mL and cultured in an incubator at 37°C and 5% CO 2 . When the cells were fused to 80%, the TAS2R38 / 138 agonists DB (1 mM), PROP (1 mM), and PTC (1 mM) were added respectively, and irradiated with 6 Gy X-rays. After 24 h, 20 μL of MTT solution (5 mg / mL) was added to each well. The supernatant was discarded, 150 μL of dimethyl sulfoxide was added, and it was shaken in the dark for 10 min. After the crystals were fully dissolved, the absorbance value at 570 nm was measured. The experimental results are shown in Figure 1 .
[0028] The experimental results showed that DB, PROP, and PTC could dose-dependently improve the reduction of cell viability in IEC-6 cells, MLE-12 cells, and HSF cells caused by IR irradiation.
[0029] Example 2
[0030] Effects on the loss of cell clonal proliferation ability caused by IR
[0031] IEC-6, MLE-12, and HSF cells were seeded into 6-well plates at a density of 500 cells per well, treated with DB, PROP, and PTC (0.1, 0.3, 1 mM) for 24 h, and irradiated with 6 Gy of X-rays. They were cultured for 10 days until the vast majority of monoclonal cells had colonies of more than 50 cells, washed with pre-cooled PBS solution, fixed with 75% ethanol for 5 min, and stained with crystal violet for 10 min. The number of colonies was calculated and analyzed using Image J software. The colony formation rate = the number of effective clones / the number of seeded cells * 100%. Finally, a clone survival rate graph was plotted using GraphPad Prism 8.0 software. The experimental results are shown in Figure 2 。
[0032] The experimental results showed that DB, PROP, and PTC could dose-dependently enhance the reduction of clonogenic proliferation ability of IEC-6 cells, MLE-12 cells, and HSF cells induced by IR irradiation.
[0033] Example 3
[0034] Effect of TAS2R138 agonist on IR-induced tissue damage in mice
[0035] An in vivo model of radiation injury in mice was established. Specifically, the mice were anesthetized with isoflurane gas in an anesthesia chamber and then irradiated abdominally using a biological X-ray irradiator (RS2000Pro, RADSOURCE, USA) at a rate of 184.6 cGy / min with a single dose of 13 Gy. DB, PROP, and PTC (5 mg / kg) were administered by gavage. During the experiment, the body weight loss of the mice was monitored daily. After the last administration, the mice were euthanized, the lung and colon tissues were taken, the colon length was measured, and the lung tissues were fixed in 4% paraformaldehyde solution for pathological examination and scoring. The experimental results are shown in Figure 3 。
[0036] The experimental results showed that DB, PROP, and PTC significantly reduced the percentage of body weight loss in mice induced by IR, inhibited the shortening of the colon length, and reduced the pathological score of lung tissues.
[0037] Example 4
[0038] The TAS2R38 / 138 agonist was prepared into a preparation by adding pharmaceutically acceptable excipients
[0039] 50 mg of DB, PROP, or PTC was mixed with 40 mg of sodium carboxymethyl starch and 60 mg of dextrin, and an appropriate amount of 25% ethanol was used as a wetting agent to make a soft material. It was granulated by a conventional method, mixed with magnesium stearate, and made into tablets.
[0040] 50 mg of DB, PROP or PTC is mixed with 70 mg of sodium carboxymethyl starch, 10 mg of microcrystalline cellulose and 10 mg of powdered sugar. 30% ethanol is used as a wetting agent to make soft materials, which are granulated by the wet granulation method, and then filled into capsules to make capsule preparations.
[0041] 50 mg of DB, PROP or PTC is mixed with 40 mg of sodium carboxymethyl starch and 10 mg of talcum powder and made into a powder by conventional techniques.
[0042] 50 mg of DB, PROP or PTC is made into a syrup with 15 mg of powdered sugar and 8 mL of water by conventional techniques, and then 70 mg of starch is added and made into pills by conventional techniques.
[0043] 50 mg of DB, PROP or PTC is mixed evenly with 10 mL of 0.9% sodium chloride solution, 10 mL of peppermint oil and 15 mL of glycerol by conventional techniques and then subpackaged to make nasal drops.
[0044] 50 mg of DB, PROP or PTC is mixed with 200 mg of trehalose (osmotic protectant), 60 mg of sodium chloride (osmotic regulator), 4 mg of sodium bicarbonate (pH regulator), 10 mg of sodium hyaluronate (viscosity agent), 3 mg of ethylparaben (bacteriostatic agent), dissolved in 100 mL of injection water, filtered and subpackaged by conventional techniques to make eye drops.
[0045] 50 mg of DB, PROP or PTC is mixed evenly with an ethanol solution of ethylcellulose (80 mg of ethylcellulose and 6 mL of ethanol), made into granules by spray drying, and the granules are mixed evenly with 100 mg of anhydrous lactose, 100 mg of microcrystalline cellulose, 1 mg of silicon dioxide, 60 mg of crospovidone and 1 mg of magnesium stearate, and made into tablets by conventional techniques to obtain microencapsulated tablets, which are microcapsule preparations.
[0046] 50 mg of DB, PROP or PTC is stirred and mixed evenly with 85 g of 1,2 - propanediol, 25 g of absolute ethanol, 100 g of sorbitan monooleate, 100 g of medium - chain triglyceride and 100 g of Cremophor RH40 in a 50℃ water bath at 50 r / min until a yellow, homogeneous and transparent liquid is formed, that is, the self - emulsifying microemulsion content of PTC is obtained; the content is made into soft capsule preparations by conventional techniques.
[0047] 50 mg of DB, PROP or PTC is ground and mixed evenly with 2 mL of sodium carboxymethyl cellulose solution (1:109) and 3 g of propylene glycol and made into a film preparation by conventional techniques.
[0048] 50 mg of DB, PROP or PTC was mixed evenly with 356 mg of melted PEG1000, 356 mg of PEG4000 and 1.7 mL of glycerol, and suppositories were prepared by conventional techniques.
[0049] 50 mg of DB, PROP or PTC was mixed with 10 mL of benzyl alcohol, 8 g of sodium chloride, and water for injection was added to 100 mL, and injections were prepared by conventional techniques.
[0050] 50 mg of DB, PROP or PTC was stirred evenly with 4 mg of sodium carboxymethylcellulose, 20 mL of liquid paraffin, and 5 mL of 75% ethanol in 38 g of melted petrolatum at room temperature, and ointments were prepared by conventional techniques.
[0051] 50 mg of DB, PROP or PTC was dissolved in 10 mL of double-distilled water and then mixed evenly with 90 mL of 65% ethanol to prepare tinctures.
[0052] 50 mg of DB, PROP or PTC was mixed evenly with 90 g of lactose and 1.5 g of magnesium stearate and pressed into large tablets. The pre-pressed tablets were crushed, granulated, and sieved through a No. 2-3 sieve to prepare granules.
[0053] 50 mg of DB, PROP or PTC was stirred and dissolved with 2.5 g of polysorbate 80, 2 g of disodium ethylenediaminetetraacetate, 13.7 g of citric acid, 10.1 g of sodium citrate, and 35 mL of pure water, and then quantitatively filled into a spray device, and aerosols were prepared by conventional techniques.
Claims
1. Use of bitter taste receptor 38 / 138 agonists in the preparation of drugs for the prevention and treatment of radiation damage.
2. The use according to claim 1, characterized in that The bitter taste receptor 38 / 138 agonist includes denatonium benzoate or a pharmaceutically acceptable salt thereof, propylthiouracil or a pharmaceutically acceptable salt thereof, phenylthiourea or a pharmaceutically acceptable salt thereof, and other substances proven to have bitter taste receptor 38 / 138 activation effects or pharmaceutically acceptable salts thereof.
3. The use according to claim 2, characterized in that: The bitter taste receptor 38 / 138 agonists include denatonium benzoate, propylthiouracil, phenylthiourea, and other substances that have been confirmed to have bitter taste receptor 38 / 138 activation effects.
4. The use according to claim 1, characterized in that The bitter taste receptor 38 / 138 agonist is added with pharmaceutically acceptable excipients to prepare a preparation.
5. The use according to claim 4, characterized in that The preparations include nasal drops, eye drops, powders, pills, capsules, tablets, microcapsules, soft capsules, films, suppositories, injections, ointments, tinctures, granules and aerosols.
6. A pharmaceutical composition, characterized in that The active ingredient is a bitter taste receptor 38 / 138 agonist.
7. The pharmaceutical composition according to claim 6, characterized in that The bitter taste receptor 38 / 138 agonists include denatonium benzoate or a pharmaceutically acceptable salt thereof, propylthiouracil or a pharmaceutically acceptable salt thereof, phenylthiourea or a pharmaceutically acceptable salt thereof, and other substances that have been confirmed to have bitter taste receptor 38 / 138 activation effects and their pharmaceutically acceptable salts.
8. Use of the pharmaceutical composition according to claim 6 in the preparation of drugs for preventing and treating radiation damage.
9. The use according to claim 1 or 8, characterized in that The radiation injury prevention and treatment drugs include drugs for preventing and treating radiotherapy injuries in cancer patients.
10. The use according to claim 1 or 8, characterized in that: The radiation damage prevention and treatment medicine can reduce radiation reaction and radiation damage to normal tissues.