Application of suramin sodium in prevention and / or treatment of radioactive intestinal injury

Abstract

The invention relates to the field of biology and medicine, and discloses application of suramin sodium in prevention and / or treatment of radioactive intestinal injury. The inventor of the invention discovers that suramin sodium is used for treating radioactive intestinal injury induced by ionizing radiation local irradiation, including improvement of intestinal tissue injury, promotion of intestinal crypt cell regeneration, inhibition of intestinal cell apoptosis and reduction of serum inflammatory factor level, so suramin sodium can be used as a potential medicine for treating radioactive intestinal injury.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine, and in particular to application of suramin sodium in preventing and / or treating radiation intestinal injury. Background Art

[0002] Radiation-induced intestinal injury refers to the damage to intestinal tissue caused by radiation, usually due to intestinal damage caused during radiotherapy of abdominal tumors (kidney, adrenal gland, bladder, prostate, uterus, ovary, etc.). After high-dose radiation, a large number of intestinal stem cells are exhausted, thereby blocking epithelial renewal and destroying epithelial integrity. The destruction of the mucosal barrier further leads to fluid loss, electrolyte imbalance, sepsis and even death in the human body. There are currently no approved drugs to prevent or alleviate radiation-induced intestinal injury. Despite advances in medical technology today, abdominal and pelvic radiotherapy still inevitably causes intestinal damage and leads to acute and chronic gastrointestinal complications, thereby limiting the treatment effect and reducing the patient's quality of life. Therefore, there is an urgent need for radioprotectants with few side effects and good therapeutic effects to alleviate radiation-induced intestinal injury.

[0003] Suramin sodium salt is a reversible competitive protein tyrosine phosphatase (PTPases) inhibitor, SIRTUINS inhibitor, competitive reverse transcriptase inhibitor, and SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) inhibitor. Suramin sodium can effectively inhibit IP5K and is an antiparasitic, antitumor and antiangiogenic agent. However, the role of suramin sodium in radiation-induced intestinal injury is still unclear. Summary of the invention

[0004] In order to overcome the above problems in the prior art, the present invention provides the use of suramin sodium in preventing and / or treating radiation intestinal injury.

[0005] The first aspect of the present invention provides the use of suramin sodium in the preparation of a medicament for preventing and / or treating radiation-induced intestinal injury.

[0006] Suramin sodium, the structure is shown below:

[0007]

[0008] In the present invention, the radiation intestinal injury refers to intestinal tissue damage caused by high-dose radiation exposure, which usually occurs within a few days after high-dose radiation exposure, and is mainly manifested by symptoms such as abdominal pain, diarrhea, anal pain, mucus stool, and blood in the stool. The radiation intestinal injury is preferably intestinal injury caused by local irradiation with ionizing radiation. The radiation intestinal injury is a complication caused by radiotherapy of malignant tumors in the abdomen and / or pelvis, that is, the object of prevention and / or treatment is a patient with a malignant tumor. Generally, malignant tumors that require radiotherapy are ovarian malignant tumors, endometrial cancer, cervical cancer, pelvic malignant lymphoma and other types. The ionizing radiation energy absorption dose that is prone to radiation ovarian malignant tumors, endometrial cancer, cervical cancer, and pelvic malignant lymphoma damage is 12-16Gy / time (time is 1).

[0009] The second aspect of the present invention provides the use of suramin sodium in the preparation of a medicament for improving intestinal tissue pathological damage (intestinal tissue pathological damage in radiation-induced intestinal damage).

[0010] The third aspect of the present invention provides the use of suramin sodium in the preparation of a medicament for promoting the regeneration of intestinal crypt cells (in radiation-induced intestinal injury).

[0011] The fourth aspect of the present invention provides the use of suramin sodium in the preparation of a medicament for inhibiting apoptosis of intestinal cells (in radiation-induced intestinal injury).

[0012] A fifth aspect of the present invention provides the use of suramin sodium in the preparation of a medicament for reducing the secretion of serum inflammatory factors (particularly the secretion of serum inflammatory factors in patients with radiation-induced intestinal injury).

[0013] In a preferred embodiment of the present invention, the inflammatory factor is selected from at least one of TNF-α, IL-6, MCP-1, IL-10 and IL-12p70.

[0014] The "prevention and / or treatment" in the present invention includes: relief of symptoms related to intestinal damage, including: relief of inflammation and edema symptoms.

[0015] In the present invention, there is no particular requirement for the administration method of suramin sodium, but it is preferably at least one of intravenous injection, intramuscular injection and subcutaneous injection. Those skilled in the art can prepare suramin sodium into a specific dosage form, such as an injection, according to the administration method.

[0016] In the present invention, the patient may include a mammal, such as a mouse or a human.

[0017] In the present invention, the dosage of suramin sodium can be determined according to the patient's condition. Taking mice as an example, the dosage of suramin sodium can be 10-50 mg / kg body weight / day.

[0018] Suramin sodium can improve tissue pathological damage, promote intestinal crypt cell regeneration, inhibit intestinal cell apoptosis, and reduce serum inflammatory factor levels. Therefore, suramin sodium can be used as a potential drug for the prevention and / or treatment of radiation-induced intestinal injury. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 Shown is the result of suramin sodium improving intestinal tissue damage in radiation-induced intestinal injury;

[0020] Figure 2 Shown is the result of suramin sodium promoting the regeneration of intestinal crypt cells in radiation-damaged intestine;

[0021] Figure 3 Shown is the result of suramin sodium inhibiting intestinal cell apoptosis in radiation-induced intestinal injury;

[0022] Figure 4 The figure shows the results of suramin sodium reducing the secretion of serum inflammatory factors in radiation-induced intestinal injury. DETAILED DESCRIPTION

[0023] The present invention will be described in detail below by way of examples. In the following examples, the number of mice in each treatment group is 6.

[0024] Example 1

[0025] C57BL / 6J male mice aged about 8-10 weeks were placed in the abdomen 60 The radiation intestinal injury model was established by Co irradiation with 14Gy. Specifically, 16 hours before and 6 hours after Co irradiation, the mice injected with Suramin sodium solution (Suramin) and the mice injected with Suramin sodium after irradiation (IR+Suramin) were intraperitoneally injected with 20mg / kg of Suramin sodium solution, and the control group (NC) and the irradiation group (IR+NC) were injected with the same dose of solvent, followed by intraperitoneal injection once every other day at the same time, and the modeling time was 4 days. The mice were then treated as follows:

[0026] (1) Suramin sodium improves intestinal tissue damage in radiation-induced intestinal injury

[0027] Radiation causes a significant decrease in the length of intestinal villi and the depth of crypts, leading to the loss of intestinal absorption and barrier function. After the intestinal barrier function is destroyed, a large number of intestinal bacteria invade the body, which in turn causes multiple organ failure. Therefore, the length of intestinal villi and the depth of crypts are one of the most direct detection indicators for evaluating radiation-induced intestinal injury. In order to evaluate the protective effect of suramin sodium on radiation-induced intestinal injury, intestinal tissues were collected 4 days after radiation, and HE staining (Solabol hematoxylin and eosin (HE) staining kit, G1120) was performed on them, and they were observed and images were collected under an optical microscope. The results showed that the intestinal structure of mice in the NC group and the Suramin group was intact, the intestinal villi were neatly arranged and complete in morphology, and the crypt size outlines were clearly identifiable and there was no obvious loss. 4 days after irradiation, the intestinal mucosal structure of mice in the IR group was obviously damaged, the intestinal villi fell off, and the crypts were unevenly arranged. Compared with the IR group, the intestinal villi structure of mice in the IR+Suramin group was relatively complete, and the difference in intestinal villi length was statistically significant ( Figure 1 , "*" indicates p<0.05). The above results indicate that suramin sodium can improve the intestinal tissue structure damage in radiation-induced intestinal injury.

[0028] (2) Suramin sodium promotes the regeneration of intestinal crypt cells in radiation-induced intestinal injury

[0029] Under normal circumstances, intestinal stem cells at the bottom of the intestinal crypts continue to proliferate and differentiate to ensure the normal replacement of intestinal tissue. After the intestine is damaged, intestinal stem cells are stimulated to proliferate in large numbers, promoting the regeneration and repair of the intestinal mucosa. 5-bromodeoxyuridine (BrdU) is a nucleoside analog that can compete with thymidine for incorporation into DNA and is often used to detect proliferating cells. By developing color with BrdU-specific antibody labeling, the proliferation of cells can be accurately reflected and the proliferation ability of cells can be judged. After 4 days of radiation, BrdU 100 mg / kg was injected intraperitoneally, and intestinal tissue was collected 1 hour later. BrdU immunohistochemical staining (MedChemExpress, #HY-15910) was performed on it, and the images were observed and collected under an optical microscope. The results showed that on the 4th day after irradiation, the number of BrdU-positive crypt cells in the IR group decreased significantly, while the number of BrdU-positive crypt cells in the IR+Suramin group increased significantly, and the differences were statistically significant ( Figure 2 "**" indicates p<0.01).

[0030] (3) Suramin sodium inhibits intestinal cell apoptosis in radiation-induced intestinal injury

[0031] Radiation causes the body to produce a large amount of reactive oxygen species, which rapidly induces apoptosis of intestinal cells. Therefore, the apoptosis of crypt cells was observed 6 hours after irradiation. Terminal deoxynucleotidyl transferase dUTP nick end (TUNEL) marks apoptotic cell nuclei and has been widely used in the study of apoptosis. After 6 hours of irradiation, intestinal tissues were collected, and TUNEL immunohistochemistry staining (Boster Biological TUNEL Apoptosis Two-Step Detection Kit (POD)) was observed under an optical microscope and images were collected. The results showed that after 6 hours of irradiation, the apoptosis rate of intestinal cells in the IR group increased significantly, while the apoptosis rate of IR+Suramin decreased significantly, and the difference was statistically significant ( Figure 3 "**" indicates p<0.01).

[0032] (4) Suramin sodium reduces the secretion of serum inflammatory factors in radiation-induced intestinal injury

[0033] Radiation causes the body to produce a large amount of PAMPs and DAMPs, activating the immune system and producing an inflammatory response, thereby causing a significant increase in the level of inflammatory factors in the serum. Before collecting the mouse intestinal tissue in step (1), the mouse serum samples were collected, and the micro-sample multi-index flow protein quantitative technology (Cytometric Bead Array, CBA) was used to detect the effect of suramin sodium on the secretion of inflammatory factors in the mouse systemic serum. The results showed that the levels of TNF-α, IL-6, MCP-1, IL-10, and IL-12p70 in the serum of the IR group were significantly increased compared with those of the NC group (P<0.0001), and the levels of TNF-α, IL-6, MCP-1, IL-10, and IL-12p70 in the serum of the IR+Suramin group were significantly decreased compared with those of the IR group, and the difference was statistically significant ( Figure 4 “*” indicates P < 0.05, “**” indicates P < 0.01, and “****” indicates P < 0.0001).

[0034] The preferred embodiments of the present invention are described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of simple modifications, including the combination of various technical features in any other suitable manner, and these simple modifications and combinations should also be regarded as the contents disclosed by the present invention and belong to the protection scope of the present invention.

Claims

1. Use of suramin sodium in the preparation of a drug for preventing and / or treating radiation-induced intestinal injury induced by a local irradiation model of ionizing radiation.

2. The use according to claim 1, wherein: The radiation intestinal injury is intestinal injury caused by local irradiation of ionizing radiation.

3. The use according to claim 1, wherein: The radiation-induced intestinal injury is a complication caused by radiotherapy for malignant tumors in the abdomen and / or pelvis.

4. The use according to claim 3, wherein: The malignant tumor is at least one of ovarian malignant tumor, endometrial cancer, cervical cancer and pelvic malignant lymphoma.

5. The use according to claim 3 or 4, wherein: The ionizing radiation energy absorption dose of the radiotherapy is 12-16Gy / time.

6. Application of suramin sodium in the preparation of drugs for improving pathological damage of intestinal tissue.

7. Use of suramin sodium in the preparation of a drug for promoting the regeneration of intestinal crypt cells.

8. Use of suramin sodium in the preparation of drugs for inhibiting intestinal cell apoptosis.

9. Use of suramin sodium in the preparation of a drug for reducing the secretion of serum inflammatory factors.

10. The use according to claim 9, wherein: The inflammatory factor is selected from at least one of TNF-α, IL-6, MCP-1, IL-10 and IL-12p70.

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