CN114732912A - Application of Zym-Dep in preparation of anti-radiation medicine or medicine for treating ionizing radiation injury - Google Patents
Application of Zym-Dep in preparation of anti-radiation medicine or medicine for treating ionizing radiation injury Download PDFInfo
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Abstract
The invention relates to the field of biomedicine, in particular to application of Zym-Dep in preparing an anti-radiation medicine or a medicine for treating ionizing radiation injury. The invention discovers and proves the new application of Zym-Dep in preparing anti-radiation medicines or medicines for treating ionizing radiation injury for the first time, and has outstanding effect in relieving radiation injury of peripheral blood leucocytes, bone marrow or intestinal tracts; meanwhile, the generation mechanism of the application is preliminarily researched, namely, Zym-Dep can realize the radiation resistance effect by up-regulating an NF-kB signal channel. The invention provides a new prevention strategy for radiation protection.
Description
Technical Field
The invention relates to the field of biomedicine, in particular to application of Zym-Dep in preparing an anti-radiation medicine or a medicine for treating ionizing radiation injury.
Background
At present, with the aggravation of nuclear threat and the more obvious toxic and side effects of the traditional protective agents such as amifostine (WR-2721), the search for novel radioprotectants has become an urgent task. The major component of Zymosan is β -glucan, Dectin-1 is a phagocytic receptor expressed on macrophages and dendritic cells, and is a specific receptor for β -glucan 3, which binds to and internalizes β -glucan, leading to the production of reactive oxygen species, the activation of NF- κ B, and the subsequent secretion of cytokines. Zym-Dep was obtained by treating zymosan with hot alkali to remove its Toll-like receptor (TLR) stimulating properties. Thus, Zym-Dep activates the C-type lectin receptor Dectin-1 but not TLR 2. In the process of researching the drug action of the Zym-Dep, the inventor unexpectedly discovers the radiation-resistant effect of the Zym-Dep, so that the research on the action and the preliminary mechanism of preventing and treating the ionizing radiation damage of the Zym-Dep is carried out.
The invention firstly confirms the radiation damage protection effect of the Zym-Dep from the whole animal level and the cell level and determines the optimal cell administration dosage of the Zym-Dep; on the premise of definite radiation protection effect, a signal path on which the Zym-Dep plays a radiation damage protection role is further researched.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: provides a new application of Zym-Dep in preparing anti-radiation drugs or drugs for treating ionizing radiation injury.
In a first aspect of the invention, there is provided the use of Zym-Dep in the manufacture of a medicament for the treatment of radiation damage;
further, the radiation injury comprises radiation injury of peripheral blood leukocytes, bone marrow or intestinal tract;
further, the radiation is gamma ray or X-ray radiation;
further, the daily dose of the drug administered to the subject is 0.01-100 mg/kg body weight, preferably 2.5mg/kg, in terms of Zym-Dep;
further, the Zym-Dep is obtained by treating zymosan with hot alkali to remove its Toll-like receptor stimulating properties;
in a second aspect of the invention, there is provided a pharmaceutical composition for the treatment of radiation damage, comprising a therapeutic amount of Zym-Dep and one or more pharmaceutically acceptable carriers or excipients;
further, the content of the Zym-Dep is 1-99%, preferably 99%, based on the total weight of the pharmaceutical composition; the Zym-Dep is obtained by treating zymosan with hot alkali to remove its Toll-like receptor stimulating properties;
further, the pharmaceutically acceptable carrier or excipient is selected from one or more of a solvent, a solubilizer, a cosolvent, an emulsifier, a flavoring agent, a smell correcting agent, a coloring agent, a binding agent, a disintegrating agent, a filling agent, a lubricating agent, a wetting agent, an osmotic pressure regulator, a pH regulator, a stabilizing agent, a surfactant or a preservative;
further, the dosage form is a solid preparation, a semi-solid preparation or a liquid preparation;
preferably, the solid preparation comprises tablets, capsules, granules and/or pills; the semisolid preparation comprises gel, suppository and/or ointment; the liquid formulations include emulsions, cocktails, suspensions and/or solutions.
The invention has the beneficial effects that the new application of the Zym-Dep in preparing the anti-radiation medicine or the medicine for treating the ionizing radiation injury is discovered and proved for the first time, and the Zym-Dep has the outstanding effect of relieving the radiation injury of peripheral blood leucocytes, bone marrow or intestinal tracts; meanwhile, the generation mechanism of the application is preliminarily researched, namely Zym-Dep can play a role in radiation protection by up-regulating NF-kB signal paths. The invention provides a new prevention strategy for radiation protection.
Drawings
FIG. 1: histogram effect of Zym-Dep on peripheral blood leukocyte counts in illuminated mice;
FIG. 2 is a schematic diagram: a map of changes in pathological morphology of mouse bone marrow;
FIG. 3: plot of the effect of Zym-Dep on MODE-K apoptosis after irradiation;
FIG. 4: plot of the effect of Zym-Dep on MODE-K cell viability after irradiation;
FIG. 5: Zym-Dep stimulates the change of expression level of cell-associated protein.
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.
Example 1: effect of Zym-Dep on the number of peripheral blood leukocytes in mice
1. Materials and methods
(1) Laboratory animals and cells
20 male mice with the SPF grade of C56BL/6 are 6-8 weeks old and 19-21 g in weight, purchased from the experimental animal center of naval military medical university and are daily raised in the animal house special for the radiation medical protection teaching and research room of naval medical department of naval medical university of China people liberation army naval medical university. Mouse intestinal epithelial cell line mode-K was purchased from American Type Culture Collection (ATCC) and cultured in RPMI1640 medium supplemented with 10% fetal bovine serum and a diabody at 5% CO2And cultured in a cell culture box at 37 ℃.
(2) Instruments and primary reagents
Zym-Dep was purchased from invivo Gen; GAPDH antibodies (murine) were purchased from Cell signaling; NF-. kappa.B antibodies (rabbit source) were purchased from Affinity; MYD88 antibody (rabbit source) was purchased from Proteitech; RPMI1640 medium was purchased from Gibco, USA; cell culture fetal bovine serum was purchased from PAA, germany; pancreatin cells purchased from Gibco, usa; CCK-8 cell counting reagents were purchased from the institute of Homon chemistry, Japan. The animal blood analyzer is purchased from Hissemcang medical electronics (Shanghai) Co., Ltd., model XN-1000V; flow cytometry was purchased from beckmann coulter co ltd, model Cytoflex; western blot electrophoresis system purchased from Bio-Rad; the apoptosis kit is purchased from Beijing Quanji Biotechnology, Inc.; cell culture chambers were purchased from REVCO, usa.
(3) Conditions of irradiation
The radiation center of army and military medical university is used in the research60And (3) carrying out gamma-ray irradiation by using a Co irradiation source, wherein the irradiation is carried out under the normal temperature condition, and the dose rate is 1 Gy/min.
(4) Grouping and dosing regimens for experimental animals:
the random number table method is divided into a normal control group, an 8Gy irradiation group and an 8Gy irradiation + Zym-Dep group; the 8Gy irradiation group receives whole body irradiation until the absorbed dose is 8Gy, and physiological saline is injected into the abdominal cavity 24h and 2h before irradiation; the 8Gy irradiation + Zym-Dep group received whole body irradiation until the absorbed dose was 8Gy, and ZYM-DEP was intraperitoneally injected 24h and 2h before irradiation.
2. Mouse peripheral blood leukocyte quantity detection
24h after irradiation, 100. mu.L of blood was collected from the mouse eyeballs, and the number of peripheral blood leukocytes (WBC) was measured by a hemocytometer.
The results showed a slight increase in WBC number in the 8Gy + Zym-Dep group compared to the 8Gy irradiated group, as shown in FIG. 1. It is shown that Zym-Dep can slow down the decrease of peripheral blood leukocyte number of the irradiated mice.
Example 2: effect of Zym-Dep on bone marrow tissue Damage in irradiated mice
The mice in example 1 were irradiated for 1, 3.5, and 7d, and their femurs were harvested after sacrifice, bone marrow pathological sections were prepared, routinely HE stained, observed under a microscope, and photographed.
The results show that bone marrow is highly sensitive to radiation and significant damage can occur after irradiation. As shown in FIG. 2, bone marrow of normal control mice was abundant in hematopoietic cells; bone marrow of mice in the 8Gy irradiation group can be obviously damaged, hematopoietic cells are degenerated and necrosed, and blood vessels are dilated and bleed; compared with the 8Gy irradiation group, the 8Gy irradiation plus Zym-Dep group reduced degeneration and necrosis of hematopoietic cells, and reduced vasodilation and hemorrhage.
Example 3: effect of Zym-Dep on the apoptosis Rate of mode-K cells in irradiated mice
After the mice in example 1 were irradiated, the mice were digested and centrifuged to collect MODE-K cells, washed twice with PBS, resuspended by adding Annexin V Binding Buffer, reacted for 15min by adding Annexin V-FITC and PI at room temperature in a dark place, the cells were mixed by adding Annexin V Binding Buffer, and the cells were detected by a flow cytometer within 1 h.
As shown in FIG. 3, the apoptosis rate of MODE-K cells was increased in the 8 Gy-irradiated group and decreased in the 8 Gy-administered Zym-Dep-irradiated group as compared with the normal control group.
Example 4: effect of Zym-Dep on MODE-K cell viability in irradiated mice
The mice in example 1 were inoculated with the irradiated MODE-K cell suspension in a 96-well plate, and after a certain period of culture in a cell incubator, CCK solution was added to each well to continue the culture for 1 hour, and the absorbance at 450nm was measured with a microplate reader.
The results showed that, as shown in FIG. 4, the MODE-K cell viability was decreased in both the 8Gy irradiation group and the 16Gy irradiation group as compared with the normal control group; after the Zym-Dep is administrated, the activity of the irradiated MODE-K cells is improved compared with that of a group without the Zym-Dep, and the effect of improving the activity of the irradiated MODE-K cells is most obvious when the concentration of the Zym-Dep is 25 ug/ml.
Example 5: effect of Zym-Dep on MODE-K cell protein expression
The control group, the group irradiated with 8Gy alone, and the group irradiated with 8Gy + ZYM-DEP in example 1 were washed with PBS, added with cell lysate on ice and left for 10min, the cells were scraped with a spatula and transferred to a 1.5ml centrifuge tube, disrupted by ultrasonication, centrifuged at 13500rpm in a 4 ℃ centrifuge for 15min, the supernatant was collected, and treated with 100 ℃ protein loading buffer for 10 min. And (3) performing electrophoretic separation on the extracted protein by adopting 10% polyacrylamide gel, and transferring the separated protein to a nitrocellulose membrane. L h was blocked with 5% skimmed milk powder in triethanolamine Tween Buffered Saline (TBST), and incubated overnight at 4 deg.C; TBST washing for 3 times, 10 min/time; incubating the secondary antibody for 1h, washing for 3 times by TBST, and washing for 10 min/time; adding an ultrasensitive chemiluminescence detection reagent, and collecting a chemiluminescence signal in a chemiluminescence imaging system. Wherein, the primary anti-GAPDH antibody (1:1000), NF-kB antibody (1:1000), Myd88 antibody (1: 1000); the secondary antibody horseradish enzyme is used for marking goat anti-mouse (1:5000), and the horseradish enzyme is used for marking goat anti-rabbit (1: 5000).
The results show that the expression level of NF-kB of the administration group is obviously increased along with time after 2h, 4h and 8h of western blot experiments after irradiation, as shown in figure 5, which indicates that the Zym-Dep can play a role in radioprotection by up-regulating an NF-kB signal channel.
In conclusion, the invention discovers for the first time that Zym-dep has obvious protective effect on peripheral blood leucocytes and bone marrow of mice after being irradiated and also has obvious protective effect on intestinal epithelial cells of the mice, and the invention is suggested to have high value in the aspect of radiation protection. Therefore, the Zym-dep has wide prospect in the development and utilization of the radiation damage protection field.
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 (10)
- Use of Zym-Dep in the manufacture of a medicament for the treatment of radiation-resistant or ionizing radiation injury.
- 2. The use of claim 1, wherein the radiation injury comprises radiation injury of peripheral blood leukocytes, bone marrow, or the intestinal tract.
- 3. Use according to claim 1, characterized in that the radiation is gamma-ray or X-ray radiation.
- 4. The use according to claim 1, wherein the medicament is administered to the subject at a daily dose of 0.01 to 100mg/kg body weight in Zym-Dep.
- 5. Use according to any one of claims 1 to 4, wherein the Zym-Dep is obtained by treating zymosan with hot alkali to remove its Toll-like receptor stimulating properties.
- 6. A pharmaceutical composition for the treatment of radiation damage or ionizing radiation damage comprising a therapeutic amount of Zym-Dep and one or more pharmaceutically acceptable carriers or excipients.
- 7. The pharmaceutical composition of claim 6, wherein the Zym-Dep is present in an amount of 1% to 99% based on the total weight of the pharmaceutical composition; the Zym-Dep is obtained by treating zymosan with hot alkali to remove its Toll-like receptor stimulating properties.
- 8. The pharmaceutical composition according to any one of claims 6 or 7, wherein the pharmaceutically acceptable carrier or excipient is selected from one or more of solvents, solubilizers, emulsifiers, flavors, corrigents, colorants, binders, disintegrants, fillers, lubricants, wetting agents, tonicity adjusting agents, pH adjusting agents, stabilizers, surfactants, or preservatives.
- 9. The pharmaceutical composition according to any one of claims 6 or 7, wherein the dosage form is a solid formulation, a semi-solid formulation or a liquid formulation.
- 10. The pharmaceutical composition of claim 9, wherein the solid formulation comprises a tablet, capsule, granule and/or pill; the semisolid preparation comprises gel, suppository and/or ointment; the liquid formulations include emulsions, cocktails, suspensions and/or solutions.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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