CN111419856A - Use of compound C L429 in radioresistant therapy - Google Patents
Use of compound C L429 in radioresistant therapy Download PDFInfo
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- CN111419856A CN111419856A CN202010237272.9A CN202010237272A CN111419856A CN 111419856 A CN111419856 A CN 111419856A CN 202010237272 A CN202010237272 A CN 202010237272A CN 111419856 A CN111419856 A CN 111419856A
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
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Abstract
The invention relates to the field of biomedicine, in particular to application of a compound C L429 in preparation of a radiation-resistant medicament, and has the beneficial effects that the compound C L429 has a new radiation-resistant application for the first time, can obviously improve the survival time of a mouse after radiation, and has a remarkable effect on the aspects of radiation-resistant intestinal tissue damage and bone marrow hematopoietic system damage.
Description
Technical Field
The invention relates to the field of biomedicine, in particular to application of a compound C L429 in radiation-resistant treatment.
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. Radiation can cause significant damage to intestinal tissue, lung tissue, and bone marrow tissue.
C L429 is a chimeric compound that stimulates both T L R2 and NOD2, consisting of NOD2 ligands covalently linked to Pam2C (T L R2 ligand) via a spacer high expression of NOD2 induces the production and autophagy of pro-inflammatory cytokines at the mucosal level and its activation C L429 has disclosed the use to induce synergistic human DC maturation in vitro and significantly enhance both systemic and mucosal immunity.
Disclosure of Invention
The invention aims to solve the technical problem of providing a new application of a compound C L429.
In a first aspect of the present invention, there is provided the use of compound C L429 or a pharmaceutically acceptable salt thereof in radioresistant therapy.
Specifically, the compound C L429 or a pharmaceutically acceptable salt thereof is prepared into a radiation-resistant medicament and then is administered to a patient.
Further, the compound C L429 or the pharmaceutically acceptable salt thereof has outstanding effects on radiation-induced intestinal tissue damage and bone marrow hematopoietic system damage.
In a second aspect of the present invention, there is provided the use of compound C L429 or a pharmaceutically acceptable salt thereof in the treatment of intestinal injury caused by radiation.
Specifically, the compound C L429 or a pharmaceutically acceptable salt thereof is prepared into a medicament for resisting intestinal injury caused by radiation and is administered to a patient.
In a third aspect of the present invention, there is provided the use of compound C L429 or a pharmaceutically acceptable salt thereof in the treatment of bone marrow hematopoietic system injury caused by radiation.
Specifically, the compound C L429 or a pharmaceutically acceptable salt thereof is prepared into a medicament for resisting bone marrow hematopoietic system injury caused by radiation and is administered to a patient.
Preferably, the radiation comprises α radiation, β radiation, gamma radiation, or X-ray radiation.
Specific examples of the pharmaceutically acceptable salts of the compounds of the present invention include salts of the above compounds with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and nitric acid, salts with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid and p-toluenesulfonic acid, and salts with acids of acidic amino acids such as aspartic acid and glutamic acid.
In a fourth aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutic amount of compound C L429 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant.
The invention has the beneficial effects that the compound C L429 has a new application of resisting radiation for the first time, and has a prominent effect on resisting radiation-induced intestinal tissue damage and bone marrow hematopoietic system damage.
Drawings
FIG. 1A is a graph of mouse survival at 7.5Gy radiation dose administered prior to irradiation;
FIG. 1B is a graph of mouse survival at 7.5Gy radiation dose following post-irradiation;
FIG. 1C is a graph of mouse survival at 9.0Gy radiation dose administered prior to irradiation;
FIG. 1D is a graph of mouse survival at 9.0Gy irradiation dose following post-irradiation administration;
FIG. 2A is a graph of HE staining of bone marrow sections at indicated time points following 7.5Gy total body irradiation in mice;
FIG. 2B is a bar graph of BMC counts detected at designated time points after 7.5Gy total body irradiation in mice;
FIG. 2C is a scattergram of apoptosis of BMC analyzed by flow cytometry at 24 hours post systemic irradiation with 7.5Gy or 9.0Gy in mice;
FIG. 2D is a bar graph of BMC apoptosis analyzed by flow cytometry at 24 hours post systemic irradiation with either 7.5Gy or 9.0Gy mice;
FIG. 2E is a graph of the number of L KS + and L KS-cells by flow cytometry at 24 hours post total body irradiation of 7.5Gy in mice;
FIG. 2F is a bar graph of L KS + and L KS-cells by flow cytometry at 24 hours after 7.5Gy total body irradiation in mice;
FIG. 3A is a mouse intestinal section microscopic staining image at a specified time point under 9.0Gy irradiation dose and before administration of radiation;
FIG. 3B is a histogram of intestinal villus length of mice at a specified time point under 9.0Gy irradiation dose administered before irradiation;
FIG. 3C is a graph showing the staining of mouse intestinal pathological section Ki67 at a specific time point under 9.0Gy irradiation dose and before administration of radiation;
FIG. 3D is a bar graph of active area ratios of mouse intestinal pathological section Ki67 at a given time point under 9.0Gy irradiation dose administered before irradiation;
FIG. 3E is a graph of mouse intestinal tract TUNE L staining at specified time points with 9.0Gy radiation dose administered prior to irradiation;
FIG. 3F is a bar graph of the number of surviving crypts in the intestinal tract of mice at a given time point under 9.0Gy radiation dose administered prior to irradiation.
Detailed Description
The invention is illustrated but not limited by the following examples. The technical solutions protected by the present invention are all the simple replacements or modifications made by the skilled person in the art.
The C L429 used in the examples was purchased from InvivoGen, WR2721(Amifostine) was purchased from MedChemexpress, and L PS lipopolysaccharide was purchased from Beijing Solebao technologies, Inc.
Experimental example 1
Male wild type C57B L/6 mice (6-8 weeks) were purchased at the Chinese academy of sciences (Shanghai) all mice were housed at the second university of military medicine (Shanghai) animal center for Specific Pathogen Free (SPF) laboratories the mice were randomized into A, B, C, D four large groups, each of which was further randomized into four subgroups with a blank control group of irradiation + PBS buffer (200. mu.l), a test group of C L429 in PBS (5mg/kg), a control group of L PS in PBS (2.5mg/kg), and a control group of WR 1 in PBS (150mg/kg), with 10 mice per group, for a total of 160 mice.
Group a was administered intraperitoneally 24 hours and 2 hours prior to irradiation, respectively, and then exposed to 7.5Gy gamma irradiation systemically and the 30 day life cycle was recorded, the results of which are shown in fig. 1A;
group B was directly irradiated with 7.5Gy gamma rays systemically, immediately after irradiation, and administered by peritoneal injection and the lifetime of 30 days was recorded, respectively, and the results are shown in FIG. 1B;
group C was administered intraperitoneally 24 hours and 2 hours prior to irradiation, respectively, and then exposed to 9.0Gy gamma radiation systemically and the 30 day life cycle was recorded, the results of which are shown in fig. 1C;
group D was directly irradiated with 9.0Gy gamma rays systemically, and immediately after irradiation, each was administered by peritoneal injection and the lifetime of 30 days was recorded, and the results are shown in fig. 1D.
The experimental result shows that the survival rate of mice in a test group injected with C L429 at 24 hours and 2 hours before irradiation is 100% under the irradiation intensity of 7.5Gy or 9.0Gy, while the protective effect of C L429 is remarkably superior to that of lipopolysaccharide (L PS) and WR2721 which are positive control drugs when all the mice treated by PBS die for 14 days after 9.0Gy TBI, and in addition, the therapeutic effect of C L429 is also remarkably superior to that of the positive control drugs in a B/D group administered after the irradiation of the mice, which proves that C L429 has remarkable radiation prevention and treatment effects in vivo.
Experimental example 2C L429 protection against radiation-induced damage to the hematopoietic System
The mice are divided into a control group and an experimental group, wherein the control group is irradiated and injected with PBS buffer solution in the abdominal cavity, and the experimental group is irradiated and injected with C L429 (5mg/kg) in the abdominal cavity.
Intraperitoneal injection of PBS/C L429 is respectively carried out 24 hours before the irradiation of the mouse and 2 hours before the irradiation of the mouse, and then the mouse is exposed to a radiation source for whole-body irradiation, (A) the mouse is respectively carried out bone marrow slice HE staining at 1.0D, 3.5D and 5.0D after 7.5Gy whole-body irradiation, (B) the mouse is respectively carried out BMC quantity detection at 1.0D, 3.5D and 5.0D after 7.5Gy whole-body irradiation, (C/D) the apoptosis of BMC is analyzed by flow cytometry at 24 hours after 7.5Gy whole-body irradiation of the mouse, (E/F) the number of L KS + and L KS-cells is analyzed by flow cytometry at 24 hours after 7.5Gy whole-body irradiation of the mouse;
the radioprotective effect of C L429 on bone marrow hematopoietic tissues was examined by pathological section staining, and it was found that the bone marrow tissue structure damage was reduced in mice in the C L429 group and recovered faster (fig. 2A) compared to the PBS control group after 7.5Gy total body irradiation than in the PBS control group (fig. 2B) the relative number of bone marrow nucleated cells was also higher in mice in the C L429 group than in the PBS group (fig. 2B) the apoptosis was examined using flow cytometry, we found that the apoptosis rate in the C L429 group was significantly lower than in the PBS group (fig. 2C/D) by examining the number of hematopoietic stem cells, C L429 also increased the number of L SK cells in mice after 7.5Gy irradiation (fig. 2E/F).
Experimental example 3C L429 protection against radiation-induced intestinal injury
The mice are divided into a control group and an experimental group, wherein the control group is irradiated and injected with PBS buffer solution in the abdominal cavity, the experimental group is irradiated and injected with C L (5mg/kg) in the abdominal cavity, and the control group and the experimental group are respectively injected with PBS buffer solution or C L429 24h and 2h before irradiation.
The radioprotective effect of C L429 on the gut was examined by pathological section staining, and it was found that gut injury was reduced, villus destruction was reduced, and crypt survival was increased in the C L429 group relative to the PBS control group (fig. 3A/B). crypt proliferation was found to be increased by intestinal pathological section Ki67 staining, and at 5.0 days post-TBI, the gut crypt proliferation capacity of mice in the C L429 group almost doubled compared to the PBS group (fig. 3C/D). evaluation of crypt apoptosis by the TUNE L method showed that the number of TUNE L + cells was decreased in the crypt of the C L429 group compared to the PBS group (fig. 3E/F). these data demonstrate that C L429 can prevent radiation-induced gut injury by promoting crypt cell proliferation and inhibiting crypt apoptosis.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various changes and modifications can be made without departing from the inventive concept of the present invention, and these changes and modifications are all within the scope of the present invention.
Claims (5)
1. Use of compound C L429 or a pharmaceutically acceptable salt thereof in anti-radiation therapy.
2. Use of compound C L429 or a pharmaceutically acceptable salt thereof in the treatment of intestinal injury caused by radiation.
3. The use of compound C L429 or a pharmaceutically acceptable salt thereof in the treatment of bone marrow hematopoietic system injury caused by radiation.
4. Use according to any one of claims 1 to 3, wherein the radiation is α -, β -, gamma-or X-ray radiation.
5. A pharmaceutical composition characterized by comprising a therapeutic amount of compound C L429 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202010237272.9A CN111419856A (en) | 2020-03-30 | 2020-03-30 | Use of compound C L429 in radioresistant therapy |
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| CN202010237272.9A CN111419856A (en) | 2020-03-30 | 2020-03-30 | Use of compound C L429 in radioresistant therapy |
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| CN202010237272.9A Pending CN111419856A (en) | 2020-03-30 | 2020-03-30 | Use of compound C L429 in radioresistant therapy |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111419856A (en) |
-
2020
- 2020-03-30 CN CN202010237272.9A patent/CN111419856A/en active Pending
Non-Patent Citations (4)
| Title |
|---|
| CHANSU LEE 等: "NOD2 Supports Crypt Survival and Epithelial Regeneration after Radiation-Induced Injury", 《INT. J. MOL. SCI.》 * |
| TYLER A. RICE 等: "Signaling via pattern recognition receptors NOD2 and TLR2 contributes to immunomodulatory control of lethal pneumovirus infection", 《ANTIVIRAL RESEARCH》 * |
| 刘聪: "新型靶向配体CL429防治辐射损伤的作用及机制", 《国家自然科学基金委员会 HTTPS://ISISN.NSFC.GOV.CN/EGRANTINDEX/FUNCINDEX/PRJSEARCH-LIST》 * |
| 杜继聪: "新型TLR配体Zymosan-A的辐射防护作用及其初步机制研究", 《中国优秀硕士学位论文全文数据库医药卫生科技辑》 * |
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