阅读说明：本技术 一种Ferrostatin-1及其衍生物在制备治疗或预防电离辐射损伤药物中的应用 (Application of Ferrostatin-1 and derivatives thereof in preparation of medicines for treating or preventing ionizing radiation injury ) 是由 李德冠 董辉 樊赛军 董银萍 王梅芳 张远洋 吴静 张俊伶 路璐 于 2020-07-06 设计创作，主要内容包括：本发明公开了一种Ferrostatin-1及其衍生物在治疗或预防电离辐射损伤药物中的应用,涉及医药技术领域,具体公开了Ferrostatin-1及其衍生物在制备预防/治疗电离辐射引起的放射性肠损伤、放射性骨髓损伤和肌体DNA损伤药物中的应用。本发明提供的Ferrostatin-1及其衍生物对自然电离辐射、人工辐射有防护作用,可以作为放射性物质辐射、核物质泄露、空间电离辐射以及肿瘤放疗引起的生命体损伤防护方面的药物。本发明为Ferrostatin-1的应用提供了新的思路,为治疗或预防电离辐射损伤药物提供了新的参考。(The invention discloses application of Ferrostatin-1 and derivatives thereof in medicines for treating or preventing ionizing radiation damage, relates to the technical field of medicines, and particularly discloses application of Ferrostatin-1 and derivatives thereof in preparing medicines for preventing/treating radioactive intestinal damage, radioactive bone marrow damage and body DNA damage caused by ionizing radiation. The Ferrostatin-1 and the derivatives thereof provided by the invention have protective effects on natural ionizing radiation and artificial radiation, and can be used as medicines for protecting living body damage caused by radioactive substance radiation, nuclear substance leakage, space ionizing radiation and tumor radiotherapy. The invention provides a new idea for the application of Ferrostatin-1 and a new reference for the medicine for treating or preventing ionizing radiation injury.)

1. Application of Ferrostatin-1 and derivatives thereof in preparing medicines for treating or preventing ionizing radiation injury is provided.

2. The use of Ferrostatin-1 and its derivatives in the preparation of a medicament for treating or preventing ionizing radiation injury according to claim 1, wherein the medicament comprises a medicament for preventing/treating radioactive intestinal injury caused by ionizing radiation.

3. The use of Ferrostatin-1 and its derivatives in the preparation of a medicament for treating or preventing ionizing radiation injury according to claim 1, wherein the medicament comprises a medicament for preventing/treating ionizing radiation-induced radioactive bone marrow injury.

4. The use of Ferrostatin-1 and its derivatives in the preparation of a medicament for treating or preventing ionizing radiation damage according to claim 1, wherein the medicament comprises a medicament for preventing/treating body DNA damage caused by ionizing radiation.

5. The use of Ferrostatin-1 and its derivatives in the preparation of a medicament for the treatment or prevention of ionizing radiation injury as claimed in claim 1, wherein the medicament comprises a tumor radiotherapy adjuvant.

6. The use of Ferrostatin-1 and its derivatives in the preparation of a medicament for the treatment or prevention of ionizing radiation damage according to claim 5, wherein the tumor comprises intestinal tumor, hematopoietic tumor, myeloma.

7. The use of Ferrostatin-1 and its derivatives as claimed in any of claims 1 to 6 in the preparation of a medicament for treating or preventing ionizing radiation damage, wherein the ionizing radiation comprises natural ionizing radiation and artificial radiation; and the radiation of the ionizing radiation comprises at least one of X-ray and gamma ray.

Technical Field

The invention relates to the technical field of medicines, in particular to application of Ferrostatin-1 and derivatives thereof in preparing medicines for treating or preventing ionizing radiation injury.

Background

Radiation can be divided into non-ionizing radiation and ionizing radiation. Wherein, the energy of the ionizing radiation is stronger than that of the non-ionizing radiation, which can cause great harm to the health of human bodies. Ionizing radiation includes natural ionizing radiation including cosmic rays, earth's primary radionuclides, decay products of radon in the air, and various naturally occurring radionuclides, and artificial radiation; the artificial radiation includes medical X-ray, radioactive dust from atmospheric nuclear weapons test, radioactive waste discharged from nuclear industry, industrial gamma ray, 60Co ray, heavy ion radiation, radiation in tumor radiotherapy treatment, etc. In recent years, due to the deep utilization of nuclear energy (such as nuclear power plants, medical diagnosis and the like), human beings face more risks of ionizing radiation pollution.

However, the current drugs for the treatment of ionizing radiation damage are very limited. The application develops relevant research based on the reason, and finally discovers the compound Ferrostatin-1 with obvious radiation protection effect through long-term screening research, simultaneously discusses the application of the Ferrostatin-1 and derivatives thereof in preparing medicines for treating or preventing ionizing radiation injury, and fills the blank of the field by developing new application of the Ferrostatin-1.

Disclosure of Invention

In view of the above, the invention provides an application of Ferrostatin-1 and derivatives thereof in a medicine for treating or preventing ionizing radiation damage, and the Ferrostatin-1 and derivatives thereof can effectively prevent or treat the damage of ionizing radiation to organisms, so that the invention provides a new idea for the application of Ferrostatin-1 and provides a new reference for the medicine for treating or preventing ionizing radiation damage.

In order to achieve the purpose, the invention adopts the following technical scheme:

application of Ferrostatin-1 and derivatives thereof in preparing medicines for treating or preventing ionizing radiation injury is provided.

The invention applies the Ferrostatin-1 and the derivatives thereof to the medicine for treating or preventing the ionizing radiation damage, and can effectively prevent and treat the damage of the ionizing radiation to organisms;

specifically, the molecular structure and action effect of Ferrostatin-1 are as follows:

ferrostatin-1(Fer-1), CAS number: 347174-05-4, are potent and selective inhibitors of ferroptosis, scavenging lipid ROS.

The existing research shows that Ferrostatin-1(2 muM) acts on cancer cells to inhibit Erastin-induced Ferroptosis, which is iron-dependent non-apoptotic cell death, and Ferrostatin-1 acts on neonatal rat brain tablets to inhibit glutamate-induced cell death.

Ferrostatin-1 is not only a lipid ROS scavenger, has N-cyclohexyl moiety, can be used as a lipophilic anchor in biomembranes, and Ferrostatin-1 does not inhibit extracellular signal-regulated kinase (ERK) phosphorylation or HT-1080 cell proliferation arrest, so as to show that Ferrostatin-1 does not inhibit MEK/ERK pathway, can chelate iron or inhibit protein synthesis; and the Ferrostatin-1 inhibits Erastin-induced cytoplasm and lipid ROS accumulation, and under the cell-free condition, the Ferrostatin-1 is easy to oxidize and stabilize free radical 2, 2-diphenyl-1-picrazino (DPPH).

Preferably, the medicament comprises a medicament for preventing/treating radiation-induced intestinal injury caused by ionizing radiation.

Preferably, the medicament comprises a medicament for preventing/treating ionizing radiation-induced radioactive bone marrow damage.

Preferably, the medicament comprises a medicament for preventing/treating the DNA damage of the body caused by ionizing radiation.

The invention has certain prevention and treatment effects on various radioactive organ injuries, has wide application range and is convenient for popularization and use of medicines.

Preferably, the medicament comprises a tumor radiotherapy adjuvant.

Preferably, the tumor comprises an intestinal tumor, a hematopoietic tumor, a myeloma.

The Ferrostatin-1 and the derivatives thereof in the invention have obvious prevention or treatment effect on organ injury generated in the process of radiotherapy of various tumors, and can reduce the side effect of rays on human bodies in the process of radiotherapy of tumors.

Wherein the ionizing radiation comprises natural ionizing radiation and artificial radiation; and the rays of the ionizing radiation include X-rays, gamma rays, and the like.

Compared with the prior art, the invention discloses an application of Ferrostatin-1 and derivatives thereof serving as a scavenger of cell lipid ROS in preparation of a medicament for treating or preventing ionizing radiation damage, and the application has the following excellent effects:

(1) the Ferrostatin-1 and the derivatives thereof disclosed by the invention have certain prevention and treatment effects on various radioactive organ injuries, have wide application range and are convenient for popularization and use of medicaments;

(2) the Ferrostatin-1 and the derivatives thereof disclosed by the invention have certain effects of preventing and treating various ionizing radiation injuries, and have wide application range and obvious effect;

the analysis proves that the Ferrostatin-1 and the derivatives thereof provided by the invention have protective effects on natural ionizing radiation and artificial radiation, and can be used as medicines for protecting living body damage caused by radioactive substance radiation, nuclear substance leakage, space ionizing radiation and tumor radiotherapy; the invention provides a new idea for the application of Ferrostatin-1 and simultaneously provides a new reference for the medicine for treating or preventing ionizing radiation injury.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the provided drawings without creative efforts.

FIG. 1 is a graph of Ferrostatin-1 increasing survival rate of a treated mouse for 30 days.

FIG. 2 is a diagram showing that Ferrostatin-1 enhances the activity of bone marrow cells in the mice.

FIG. 3 is a graph of Ferrostatin-1 reducing ROS levels and DNA damage in bone marrow cells of irradiated mice.

FIG. 4 is a graph showing the results of HE staining of intestinal tissues of the irradiated mice.

FIG. 5 is a graph showing the results of tunel staining of intestinal tissues in the irradiated mice.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

The embodiment of the invention discloses application of Ferrostatin-1 and derivatives thereof in preparing a medicament for treating or preventing ionizing radiation injury.

Wherein the medicine comprises a medicine for preventing/treating radioactive intestinal injury caused by ionizing radiation.

Further, the medicament includes a preventive/therapeutic agent for radioactive bone marrow damage caused by ionizing radiation.

Further, the medicament comprises a medicament for preventing/treating the DNA damage of the body caused by ionizing radiation.

Further, the medicine comprises an auxiliary medicine for tumor radiotherapy.

Further, the tumor includes intestinal tumor, hematopoietic tumor, myeloma.

In order to further improve the technical scheme of the invention, the ionizing radiation comprises natural ionizing radiation and artificial radiation; and the rays of the ionizing radiation include X-rays, gamma rays, and the like.

The technical solution of the present invention is further illustrated by specific experiments.

The irradiation source used in the experiment of the invention is 137 Cs-gamma irradiation source or X-ray irradiation instrument, 160KV, which is provided by the institute of radiology of Chinese medical academy of sciences; the experimental animal is a C57BL/6 mouse purchased from Beijing Huafukang company; ferrostatin-1 reagent was purchased from Aladdin, and DCFH probe was purchased from Byunyan; h2AX antibody was purchased from CST corporation, usa; the instruments used include flow cytometers, microplate readers, cytometers, centrifuges, ultraclean benches, and the like.

Experiment 1: whole body irradiation mouse survival assay

After the mice were irradiated with total body radiation, they were weighed periodically and observed for death every day.

After injecting 5,10 and 20mg/kg Ferrostatin-1 into the abdominal cavity of the mouse respectively, the whole body of the mouse is irradiated with 9.0Gy which is 137 Cs-gamma irradiation source, and the survival rate of the mouse is observed for 30 days. Ferrostatin-1 of 20mg/kg was found to improve the survival rate of the mice (see figure 1 of the specification).

The result shows that Ferrostatin-1 has obvious protective effect on radiation injury.

Experiment 2: protective effect on bone marrow cells of irradiated mice

The bone marrow cells of the mice are extracted aseptically, the irradiation dose is 1Gy, and 160KV and X-ray irradiation are adopted. Ferrostatin-1(0.5, 1, 5,10,20 mu M) with different concentrations was added 0.5h before irradiation. After 18h of irradiation, a bioluminescent reagent is added to detect the activity of bone marrow cells. The result is shown in the attached figure 2 of the specification, 1Gy irradiation has obvious inhibition effect on the vitality of the bone marrow cells of the mice, 5 mu M Ferrostatin-1 has obvious protection effect on the bone marrow cells, and compared with a control group, P is less than 0.01.

Experiment 3: effect on ROS levels and DNA Damage in bone marrow cells of irradiated mice

The bone marrow cells of the mice are extracted aseptically, the irradiation dose is 1Gy, and 160KV and X-ray irradiation are adopted. Ferrostatin-1 was added at 5. mu.M 0.5h before irradiation. After 18h of irradiation, bone marrow cells were harvested and a portion was stained with DCFH probe to detect ROS levels. After the other part is fixed and broken, H2AX antibody is added, flow analysis is carried out, the result is shown in the attached figure 3 of the specification, and Ferrostatin-1 can obviously reduce the ROS level and the expression of H2AX in the bone marrow cells of the irradiated mice. H2AX is a marker of DNA damage, and the expression level can indicate the degree of DNA damage to some extent.

Experiment 4: has effect of protecting intestinal tract of irradiated mice

The mice are divided into 5 mice per group according to irradiation dose of 0Gy and 9Gy, and whole body irradiation and 137 Cs-gamma irradiation source are adopted. Ferrostatin-20mg/kg is injected into the abdominal cavity once 1h before irradiation and 1d after irradiation respectively, and each treatment group has 5 animals. After 3 days of irradiation, intestinal tissues are taken and subjected to histochemical staining, the results are shown in the attached figure 4 and the attached figure 5 of the specification, and the results show that Ferrostatin-1 has a remarkable protection effect on intestinal radiation injury and can inhibit apoptosis of intestinal cells of mice.

Wherein, in the attached figure 4 of the specification, A is HE staining of intestinal tissues of normal mice; b, HE staining of intestinal tissues of the irradiated mice; c: HE staining of intestinal tissues of mice administered with Ferrostatin-1; the figure shows that Ferrostatin-1 has a protective effect on the intestinal tract structure of mice.

In the attached figure 5 of the specification, A is normal mouse intestinal tissue tunel staining; staining the intestinal tissue tunel of the irradiated mice; c: the intestinal tissue tunel of the mice administered with Ferrostatin-1 was stained. The figure shows that Ferrostatin-1 can inhibit apoptosis of intestinal tract cells of mice.

The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.