阅读说明：本技术 唾液酸在制备电离辐射致肠道或dna损伤防护药物中的应用 (Application of sialic acid in preparation of medicine for preventing intestinal tract or DNA (deoxyribonucleic acid) injury caused by ionizing radiation ) 是由 尚增甫 郎月 周平坤 周俊东 俞岚 于 2019-10-17 设计创作，主要内容包括：本发明涉及一种唾液酸在制备电离辐射致肠道或DNA损伤防护药物中的应用,并公开了药剂形式和给药方式。本发明所提供的以唾液酸为活性成分的电离辐射致肠道损伤防护药物具有毒副作用小、疗效显著、用药方便安全等优势,对于急性放射病患者、涉核从业人员、官兵、宇航员、放疗病人等不同人员均适用,在治疗前或执行任务、工作中均可用药。同时本发明提供了唾液酸作为DNA损伤修复蛋白DNA-PKcs激活剂的新应用和处理浓度、处理方式,在生物医学领域具有广泛的潜在应用前景。(The invention relates to an application of sialic acid in preparing a medicine for protecting intestinal tract or DNA injury caused by ionizing radiation, and discloses a medicament form and a medicament administration mode. The protective medicine for the intestinal injury caused by the ionizing radiation with the sialic acid as the active ingredient has the advantages of small toxic and side effects, obvious curative effect, convenience and safety in administration and the like, is suitable for different people such as patients with acute radiation, nuclear-involved workers, officers and soldiers, astronauts, patients with radiotherapy and the like, and can be used before treatment or during task execution and work. Meanwhile, the invention provides a new application of sialic acid as a DNA damage repair protein DNA-PKcs activator, a treatment concentration and a treatment mode, and the sialic acid has a wide potential application prospect in the field of biomedicine.)

1. Application of sialic acid in preparing medicine for preventing intestinal injury caused by ionizing radiation is disclosed.

2. Use according to claim 1, characterized in that: the drug is a water-soluble drug and contains one or more pharmaceutically acceptable carriers.

3. Use according to claim 2, characterized in that: the pharmaceutically acceptable carrier is selected from one or more of diluent, excipient, filler, adhesive, wetting agent, disintegrant, absorption enhancer, surfactant, adsorption carrier and lubricant.

4. Use according to any one of claims 1-3, characterized in that: the drug is administered via gavage or orally.

5. Use according to any one of claims 1-3, characterized in that: the dosage form of the medicine is injection, suspending agent, powder, tablet or granule.

6. The use according to claims 1-3, wherein the medicament is an injectable formulation comprising an aqueous solution of sialic acid and phosphate.

7. Use according to claim 1, characterized in that: the administration dose of the medicine is 50-100 mg/kg/day, the medicine is respectively administered 1 hour before the ionizing radiation, and the medicine is administered once more each day, two days and three days after the ionizing radiation.

8. Use of sialic acid in the preparation of a medicament for the protection against DNA damage induced by ionizing radiation.

9. Use according to claim 1 or 2, characterized in that: the ionizing radiation is alpha-ray, beta-ray, gamma-ray, X-ray or radioactive substance radiation.

10. Application of sialic acid in preparation of DNA damage repair protein DNA-PKcs kinase activator is provided.

Technical Field

The invention relates to the field of medicines related to radioactive intestinal injury treatment, in particular to application of sialic acid in preparation of medicines for protecting intestinal tract or DNA (deoxyribonucleic acid) injury caused by ionizing radiation.

Background

With the extensive development and utilization of nuclear energy and the rapid development of nuclear medicine in China, the chances of people exposed to ionizing radiation are increasing day by day. The fukushima nuclear power plant accident in 2011 and the recent nuclear crisis again alert us that a nuclear threat still exists.

The small intestine is very sensitive to ionizing radiation because of its extremely rapid renewal of epithelial cells, and is the most important target organ for ionizing radiation, and intestinal injury caused by ionizing radiation is one of the important causes of early death in patients with acute radiation. In addition, malignant tumor patients are another special population exposed to ionizing radiation, radiotherapy is an important treatment means for malignant tumors, more than 70% of malignant tumor patients are reported to need radiotherapy, intestinal injury is a common side effect of radiotherapy of tumors in the abdomen and pelvis, the life quality of the patients is greatly reduced, and even the patients are forced to stop treatment due to serious radiation injury. Therefore, the development of the ionizing radiation induced intestinal injury protection medicament is very important for the construction of a nuclear safety guarantee system and the clinical auxiliary treatment of tumors. CN 104023560 a discloses human milk oligosaccharides for preventing gastrointestinal damage and/or promoting gastrointestinal healing, but the damage of small intestine tissue caused by ionizing radiation is greatly different from the damage of gastrointestinal tract caused by other causes in the occurrence and development mechanisms, and there is no effective means or medicine for treating radioactive intestinal damage at present.

Pure sialic acid is N-acetylneuraminic acid (also known as cubilose acid), which accounts for around 10% of natural cubilose and is therefore also known as cubilose acid. Sialic acid is an essential polysaccharide for human body, and plays an important role in mediating various vital activities such as cellular immune response, cellular metabolism, cellular movement and the like. Sialic acid is also an essential component of the structure of Human Milk Oligosaccharides (HMOs). Sialic acid is approved by the FDA and the European food safety administration in the United states as a raw material of infant milk powder and common food, and is also listed in a new food raw material catalog in 5 months in 2017 and Weijian Wei of China. At present, sialic acid is widely used as a main functional component in various products in the fields of medicine, cosmetics and food nutrition fortification.

At present, the research on the medicines for protecting the intestinal injury caused by ionizing radiation is mostly in the preclinical stage, and although part of the medicines have a protective effect, the medicines have significant defects and mainly comprise: the medicine has high action concentration, low activity and obvious toxic and side effects, thereby limiting clinical application, and finding nontoxic or low-toxic and efficient ionizing radiation-induced intestinal injury protective medicines is always a pursuit hotspot of the medical community.

Disclosure of Invention

In order to solve the technical problems, the invention aims to provide the application of sialic acid in preparing medicines for protecting intestinal tracts or DNA (deoxyribonucleic acid) damage caused by ionizing radiation, wherein the sialic acid has small toxic and side effects and obvious curative effect.

the invention discloses application of sialic acid in preparing a medicament for preventing intestinal injury caused by ionizing radiation.

Further, the drug is a water-soluble drug and contains one or more pharmaceutically acceptable carriers.

Further, the pharmaceutically acceptable carrier is selected from one or more of diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption enhancers, surfactants, adsorption carriers and lubricants.

Further, the drug is administered via gavage or orally.

Furthermore, the medicament can be prepared into injection, suspending agent, powder, tablet or granule.

Further, the drug uses phosphate buffer as a diluent carrier.

Further, the medicament is an injection, and the injection comprises sialic acid and phosphate buffer solution.

Further, the concentration of the phosphate buffer is 0.01M, wherein the mass concentration of the sialic acid in the phosphate buffer is 5-10 mg/mL.

Further, the dose of the drug administered is 50-100 mg/kg/day, and is administered 1 hour before the ionizing radiation and once more each for one, two and three days after the ionizing radiation, respectively.

Further, the protective medicine is used for treating small intestine injury caused by ionizing radiation.

Further, small intestine epithelial cells were treated with 50-100. mu.g/mL sialic acid and administered 2 hours prior to irradiation.

Further, the intestinal injury by ionizing radiation is intestinal injury by alpha-ray, beta-ray, gamma-ray or X-ray radiation, or intestinal injury by radioactive substance radiation.

The second purpose of the invention is to disclose the application of sialic acid in preparing the medicine for preventing DNA damage induced by ionizing radiation.

Further, the ionizing radiation is alpha-ray, beta-ray, gamma-ray, X-ray, or radioactive substance radiation.

The third purpose of the invention is to disclose the application of sialic acid in preparing DNA damage repair protein DNA-PKcs kinase activator.

Further, the concentration of sialic acid is 25-100. mu.g/mL.

Unless otherwise specified, "sialic acid" in the context of the present invention refers to pure sialic acid.

By the scheme, the invention at least has the following advantages:

The medicine for preventing the intestinal injury caused by the ionizing radiation, which takes the sialic acid as the active ingredient, has the following advantages: (1) the toxic and side effects are small, and no obvious adverse reaction is caused when the mouse is treated under the body weight concentration of 100 mg/kg; (2) the curative effect is remarkable, the survival time of the mouse after the radiation of 10Gy rays can be remarkably prolonged by respectively administering the medicine once in the dosage of 50mg/kg body weight concentration 1 hour before the radiation, 1 day after the radiation, 2 days after the radiation and 3 days after the radiation; protecting the intestinal villus structure of a mouse receiving ionizing radiation to be complete and promoting the intestinal crypt cell proliferation of the mouse; (3) cellular results show that sialic acid at a concentration of 100 μ g/mL modulates ionizing radiation-induced DNA damage and promotes DNA damage repair protein activation; (4) in vitro results show that 25-100 mu g/mL sialic acid remarkably promotes the activity of DNA damage repair protein DNA-PKcs kinase; (5) the main administration route is oral administration, the medicine is convenient and safe to take, is suitable for different personnel such as acute radiation patients, nuclear workers, officers and soldiers, astronauts, radiotherapy patients and the like, and can be taken before treatment or during task execution and work. The properties show that sialic acid is unique in protecting intestines from being damaged by ionizing radiation, and has wide application prospect in the medical field of China.

The foregoing description is only an overview of the technical solutions of the present invention, and in order to make the technical solutions of the present invention more clearly understood and to implement them in accordance with the contents of the description, the following detailed description is given with reference to the preferred embodiments of the present invention and the accompanying drawings.

Drawings

FIG. 1 is a graph showing the comparison of survival curves of mice irradiated with 10Gy X-ray, a control group and a sialic acid-administered group;

FIG. 2 is a schematic diagram showing the structure of villi and crypts in the intestinal tract of a mouse after 10Gy X-ray irradiation for sialic acid protection according to the invention;

FIG. 3 is a schematic representation of proliferation of crypts in the intestinal tract of a mouse following X-ray exposure to 10Gy of sialic acid in accordance with the invention;

FIG. 4 shows the results of the test of inhibition of DNA damage of human small intestine epithelial cells (HIEC) by sialic acid in vitro after 2Gy X-ray irradiation;

FIG. 5 shows the result of the immunoblot assay of the autophosphorylation of DNA injury repair protein DNA-PKcs and phosphorylation of its target protein Chk2 in human intestinal epithelial cells after 4Gy X-ray irradiation in vitro with sialic acid according to the present invention;

FIG. 6 shows the results of in vitro tests for the activation of DNA-PKcs by sialic acid using the DNA-PKcs in vitro test system of Promega corporation in accordance with the present invention.

Detailed Description

The following detailed description of embodiments of the present invention is provided in connection with the accompanying drawings and examples. The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.