CN118615277A - New application of honokiol and genistein in compatibility - Google Patents
New application of honokiol and genistein in compatibility Download PDFInfo
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- CN118615277A CN118615277A CN202410844764.2A CN202410844764A CN118615277A CN 118615277 A CN118615277 A CN 118615277A CN 202410844764 A CN202410844764 A CN 202410844764A CN 118615277 A CN118615277 A CN 118615277A
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- genistein
- honokiol
- irradiation
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Abstract
The invention belongs to the technical field of biological medicines, and particularly discloses an application of honokiol and genistein in preparing a medicine for preventing and treating radioactive intestinal injury and a medicine for preventing and treating radioactive intestinal injury. According to the invention, cell experiments prove that the compatibility of honokiol and genistein shows a radiation protection effect in Human Intestinal Epithelial Cells (HIEC), and oxidative stress injury after cell irradiation is reduced by reducing radiation-induced apoptosis, ROS (reactive oxygen species) generation and DNA (deoxyribonucleic acid) injury. Meanwhile, the compatibility of honokiol and genistein also shows radiation protection effect in vivo experiments, and the compatibility treatment of honokiol and genistein can prolong the survival time of irradiated mice, resist the shortening of small intestine villi after irradiation, improve the intestinal tract structure of small intestine and promote the restoration of the epithelial injury of RIII. Therefore, the preparation of the medicine for preventing and treating the radioactive intestinal injury by combining honokiol and genistein is an effective strategy for preventing and treating the intestinal injury induced by IR.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to application of compatibility of honokiol and genistein in preparation of a medicine for preventing and treating radioactive intestinal injury, and a medicine for preventing and treating radioactive intestinal injury.
Background
With the rapid development and wide application of nuclear medicine and radiomedical diagnosis and treatment technologies, the chances of people contacting with radioactive rays are increased, and the probability of suffering radiation damage is also increased. The mechanism of human body injury caused by ionizing radiation mainly comprises direct injury and indirect injury, wherein the direct injury comprises ionization of biological macromolecules caused by high-energy rays of ionizing radiation and particles penetrating through a human body, and DNA fracture, protein denaturation, phospholipid molecule denaturation and the like are caused. Indirect damage is mainly generated by high-energy rays of ionizing radiation and water molecules in the body ionized by particles to generate free electrons, so that the level of active oxygen (Reactive oxygen species, ROS) in the body is increased, such as hydrogen peroxide (H 2O2) and hydroxyl radicals (OH) and the like, and excessive ROS in the body attack bases and ribose in DNA, and simultaneously break redox balance in cells to cause oxidative damage of the cells, so that mitochondrial respiratory chain breakage is caused, and the changes finally cause apoptosis of the cells.
Studies have shown that ionizing radiation-induced radiation damage to the body is a systemic response and that almost all organs and systems of the body undergo pathological changes. The intestinal tract is particularly sensitive to ionizing Radiation, and radioactive intestinal injury (Radiation-induced intestinal injury, RIII) caused by ionizing Radiation can cause side effects such as vomiting, weight loss, anorexia, dehydration, diarrhea, infection and the like, and in severe cases, can also cause death due to septic shock. The basic mechanism of RIII development is very complex and can be divided into two phases: mucosal disruption and subsequent inflammation. In the acute phase, inflammation is triggered by decreased expression of the fibronectin and mucosal rupture due to epithelial cell death, while impaired vascular endothelial stimulates secretion of cytokines, chemokines and growth factors and expression of adhesion molecules, and the additional recruitment of monocytes and activation of resident mast cells stimulates production of pro-inflammatory and pro-fibrotic mediators IL-1 beta, IL-6, TGF-beta and TNF-alpha. In addition, excessive and sustained ROS production can also damage cells. In summary, the response of intestinal tissue to radiation is mediated by cell death and activation of oxidative and inflammatory factors.
Radiation damage protection drugs refer to protective drugs that are capable of reducing radiation damage that are pre-used prior to the threat of radiation exposure. Despite some progress in the past, the exact mechanism of radiation damage has not been fully elucidated, and there is no comprehensive therapeutic strategy clinically available to address radiation damage, and no single, effective radioprotectors have heretofore been available. The existing radiation injury protective drugs mainly play roles in promoting DNA injury repair, inhibiting apoptosis, removing free radicals in vivo and the like, for example, a radiation protective agent amifostine (Amifostine). However, it has problems of lowering blood pressure, causing adverse reactions such as nausea, vomiting, etc., so that its application is limited.
Currently, the search for radiopharmaceuticals with fewer side effects has become a hotspot for research. The natural substances have the advantages of low toxicity, wide effect, multi-organ targeting and multi-target reduction of radiation damage. Therefore, the search for efficient and low-toxicity medicaments from natural Chinese herbal medicines has important significance. Compared with single active ingredient, the Chinese herbal compound has the advantages of multiple ingredients, multiple ways, multiple layers and multiple targets to exert pharmacological actions. Clinical verification shows that the compatibility and combination of the medicines can produce synergistic effect, enhance the curative effect of each other, reduce the drug resistance of diseases to single medicines, and enable the treatment not to be the effect of single medicines only for medicines with different mechanisms. In addition, the compatibility of medicines with synergistic effect can reduce the dosage and toxicity of the medicines, and the effects of reducing the dosage of each medicine and reducing toxic and side effects are achieved, which is particularly important for patients with long-term treatment. In addition, under the condition that multiple etiologies or disease mechanisms exist simultaneously, most single medicaments cannot be fully used, and the medicament combination can intervene aiming at the multiple etiologies or mechanisms, so that the success rate of treatment is improved. Studies have shown that oxidative damage following exposure to ionizing radiation is a key cause of sustained injury, while free radicals are triggers of sustained oxidative stress. At present, no report of using a medicine compatibility combination with an anti-radiation effect for preventing and treating the radioactive intestinal injury caused by the ionizing radiation exists, and no medicine combination is used for preparing a medicine preparation for preventing and treating the radioactive intestinal injury caused by the ionizing radiation.
Disclosure of Invention
The invention mainly solves the technical problem of providing a medicine for preventing and treating the radioactive intestinal injury and application of compatibility of honokiol and genistein in preparing the medicine for preventing and treating the radioactive intestinal injury.
In order to solve the technical problems, the invention adopts the following technical scheme:
New use of honokiol and genistein in compatibility is as follows: application of honokiol and genistein in preparing medicine for preventing and treating radioactive intestinal injury is provided.
Honokiol (Honokiol, HK) is a natural compound and is mainly extracted from the traditional Chinese medicine magnolia officinalis. Honokiol has various biomedical effects including anti-inflammatory, antioxidant, antitumor, sedative, neuroprotective, etc. Studies have suggested that honokiol may have a certain anti-radiation effect, and presumably can reduce cell damage and tissue damage caused by radiation by reducing the generation of free radicals, reducing oxidative stress damage, inflammation and the like.
Genistein (Genistein, gen) is a natural plant compound, belongs to flavonoid compounds, and mainly exists in plants such as soybeans, red beans, black beans and the like. Studies have shown that genistein has antioxidant, antiinflammatory, and antitumor effects. In addition, the genistein has a certain radiation-resistant effect, can reduce the damage of radiation to body tissues, and can protect cells from direct damage of DNA caused by radiation and damage caused by oxidative stress.
As a preferred embodiment of the invention, the mass ratio of honokiol to genistein is 1-2:1-4.
As a preferred embodiment of the invention, the application is: the application of honokiol and genistein in preparing medicine for reducing oxidative stress injury of intestinal cells after irradiation is provided.
In particular, the applications include, but are not limited to, one or more of the following:
(1) Application of honokiol and genistein in preparing medicine for inhibiting apoptosis of intestinal cells after irradiation;
(2) Application of honokiol and genistein in preparing medicine for reducing active oxygen level in intestinal cells after irradiation;
(3) The application of honokiol and genistein in preparing medicine for reducing DNA damage of intestinal cells after irradiation is provided.
As a preferred embodiment of the invention, the application is: the application of honokiol and genistein in preparing medicine for promoting intestinal injury repair after irradiation is provided.
In particular, the applications include, but are not limited to, one or more of the following:
(1) Application of honokiol and genistein in preparing medicine for improving intestinal tract shortening after irradiation;
(2) Application of honokiol and genistein in preparing medicine for improving intestinal tract structure damage after irradiation is provided.
Such intestinal structural impairment includes, but is not limited to, impairment of villi (e.g., shortening of small intestinal villi), reduced crypt number, etc.
As a preferred embodiment of the invention, the application is: the application of honokiol and genistein in preparing medicine for improving individual survival condition after irradiation is provided.
In particular, the applications include, but are not limited to, one or more of the following:
(1) Application of honokiol and genistein in preparing medicine for improving individual survival rate after irradiation;
(2) The application of honokiol and genistein in preparing medicine for prolonging individual life after irradiation is provided.
A medicine for preventing and treating radioactive intestinal injury comprises honokiol and genistein as effective components.
As a preferred embodiment of the invention, the mass ratio of the medicine neutralization magnolol to the genistein is 1-2:1-4.
As a preferred embodiment of the invention, the total content of the medicine-neutralized magnolol and genistein is a pharmacodynamic amount, and is valued in the range of 0.01wt% to 99.99 wt%.
As a preferred embodiment of the present invention, other active ingredients are also included in the medicament, including but not limited to active ingredients for preventing and treating radiation intestinal injury, active ingredients for eliminating or reducing toxic side effects of the medicament, and the like.
As a preferred embodiment of the present invention, pharmaceutically acceptable carriers are also included in the medicament, including but not limited to solvents, excipients, preservatives, stabilizers, wetting agents, emulsifiers, salts for regulating osmotic pressure, buffers, and the like.
As a preferred embodiment of the invention, the dosage form of the medicament is a pharmaceutically acceptable dosage form, including but not limited to powder injection, tablet, pill, capsule, spray, dispersion and the like.
As a preferred embodiment of the present invention, the route of administration of the drug is a pharmaceutically acceptable route, including but not limited to oral, intradermal, subcutaneous, intramuscular, intraperitoneal, intravenous, and transdermal, intranasal or buccal inhalation, and the like.
As a preferred embodiment of the invention, the dosage of the medicament is a pharmaceutically acceptable dosage.
The invention has the beneficial effects that:
The invention provides a medicine for preventing and treating radioactive intestinal injury and application of compatibility of honokiol and genistein in preparing medicine for preventing and treating radioactive intestinal injury. The invention has proved by cell experiments that the compatibility of honokiol HK and genistein in Human Intestinal Epithelial Cells (HIEC) shows radiation protection effect, and reduces oxidative stress injury after cell irradiation by reducing radiation-induced apoptosis, ROS generation and DNA injury. Meanwhile, the compatibility of honokiol HK and genistein Gen also shows radiation protection effect in vivo experiments, and the compatibility treatment of honokiol HK and genistein Gen can prolong the survival time of irradiated mice, resist the shortening of small intestine villi after irradiation, improve the small intestine intestinal tract structure and promote the restoration of the epithelial injury of RIII. Therefore, the compatibility of honokiol HK and genistein Gen can prepare the medicine for preventing and/or treating the radioactive intestinal injury, and compared with the prior method, the method is a strategy for actively and effectively preventing and treating the IR-induced intestinal injury.
Drawings
FIG. 1 shows the protective effect of the combination of honokiol and genistein on cells damaged by irradiation HIEC in experimental examples.
FIG. 2 shows the protective effect of the compatibility of honokiol and genistein on intestinal injury of radiation injury mice model in experimental examples.
The drawings in the examples and/or experimental examples are briefly described above in order to more clearly illustrate the technical solutions to be protected by the present invention. It should be understood that the above-described drawings are not to be construed as limiting the scope of the present invention in any way. Other relevant drawings may be made by those of ordinary skill in the art without undue burden from these drawings.
Detailed Description
The technical scheme of the present invention will be clearly and completely described in the following in connection with specific examples and experimental examples. It should be understood by those skilled in the art that the following examples and experimental examples are only for illustrating the technical scheme and effect of the present invention, and should not be construed as limiting the scope of the present invention. Based on the following examples, other technical solutions, such as modified, deformed or simply replaced technical solutions, obtained by a person skilled in the art without performing any inventive task, are all within the scope of the present invention.
The raw materials, reagents, equipment, etc. used in examples and experimental examples were commercially available products unless otherwise specified. Honokiol and genistein are all commercially available.
The methods used in examples and experimental examples are conventional methods unless otherwise specified.
The terms and abbreviations used in the examples and experimental examples are all conventional in the art, e.g., PBS is phosphate buffered saline.
Example 1
The embodiment provides a new application of honokiol and genistein, which is specifically as follows: application of honokiol and genistein in preparing medicine for preventing and treating radioactive intestinal injury is provided.
Example 2
The embodiment provides an application of compatibility of honokiol and genistein in preparing a medicament for preventing and treating radioactive intestinal injury, which comprises the following specific steps: use of honokiol in combination with genistein for the manufacture of a medicament for reducing oxidative stress damage of intestinal cells after irradiation, including but not limited to one or more of the following:
(1) Application of honokiol and genistein in preparing medicine for inhibiting apoptosis of intestinal cells after irradiation;
(2) Application of honokiol and genistein in preparing medicine for reducing active oxygen level in intestinal cells after irradiation;
(3) The application of honokiol and genistein in preparing medicine for reducing DNA damage of intestinal cells after irradiation is provided.
Example 3
The embodiment provides an application of compatibility of honokiol and genistein in preparing a medicament for preventing and treating radioactive intestinal injury, which comprises the following specific steps: use of honokiol in combination with genistein for the manufacture of a medicament for promoting repair of intestinal lesions after irradiation, including but not limited to one or more of the following:
(1) Application of honokiol and genistein in preparing medicine for improving intestinal tract shortening after irradiation;
(2) Application of honokiol and genistein in preparing medicine for improving intestinal structure damage (including intestinal villus Mao Bianduan and reduction of crypt number) after irradiation is provided.
Example 4
The embodiment provides an application of compatibility of honokiol and genistein in preparing a medicament for preventing and treating radioactive intestinal injury, which comprises the following specific steps: use of honokiol in combination with genistein for the manufacture of a medicament for improving survival of an individual after irradiation, including but not limited to one or more of the following:
(1) Application of honokiol and genistein in preparing medicine for improving individual survival rate after irradiation;
(2) The application of honokiol and genistein in preparing medicine for prolonging individual life after irradiation is provided.
Example 5
The embodiment provides a medicine for preventing and treating radioactive intestinal injury, which comprises the following medicinal components of honokiol and genistein, wherein the mass ratio of honokiol to genistein is 2:1, a step of; the total content of the two is the drug effect amount, and the pharmaceutical composition also comprises pharmaceutically acceptable oily solvent corn oil which is used for preparing the drug into a solution formulation.
In other embodiments of the invention, the mass ratio of drug neutralized magnolol to genistein is 1: 1. 1: 2. 1:4, at 1-2: the value can be in the range of 1-4. The medicine can also comprise other medicinal components, such as other medicinal components for preventing and treating the radioactive intestinal injury, medicinal components for eliminating or reducing toxic and side effects of the medicine, and pharmaceutically acceptable carriers, so that the medicine can be conveniently prepared into other pharmaceutically acceptable dosage forms.
Experimental example
1. Protection effect of honokiol HK and genistein Gen on irradiation injury HIEC cells
Normal human intestinal epithelial cells (HEALTHY INTESTINAL EPITHELIAL CELL, HIEC) were purchased from the Ji Ni euro organism, guangzhou; cell culture in DMEM medium containing 1% penicillin/streptomycin and 10% fetal bovine serum, and placed in a 5% CO 2 cell incubator at 37℃for culture. Experiments were performed with cells passaged less than 15 passages.
1. Influence of the compatibility of honokiol HK and genistein Gen on apoptosis of radiation injury HIEC cells
HIEC cells in the logarithmic growth phase were inoculated into 6-well plates at a rate of 8X 10 4 cells/mL, the loading volume per well was 2mL, and 3 wells were set per group. The experiments were divided into 6 groups, normal Control (Control), single Irradiation (IR), drug treatment: HK (2. Mu.g/mL), HK (1. Mu.g/mL), gen (0.5. Mu.g/mL), HK (2. Mu.g/mL) +Gen (1. Mu.g/mL), HK (1. Mu.g/mL) +Gen (0.5. Mu.g/mL).
The specific operation is as follows:
(1) And (3) drug treatment: HIEC cells with good growth state 1×10 6 cells/well are evenly spread in a 6-well plate, and after overnight cell adhesion, DMEM culture medium containing corresponding concentration of Gen and/or HK is added for co-incubation for 24 hours.
(2) And (3) radiation treatment: the single irradiation group (IR) and the drug treatment group were each subjected to X-ray irradiation at a dose of 4.0Gy (dose rate: 100.0 cGy/min), and the culture was continued in a CO 2 incubator for 48 hours after the irradiation.
(3) Collecting cells: cells in the supernatant were collected, the adherent cells were washed once with pre-chilled PBS buffer, the cells were digested with 0.5% pancreatin, the digestion was stopped with DMEM medium containing 10% FBS, centrifuged at 3500rpm at 4℃for 5 minutes, and the digested adherent cells and cells in the supernatant were collected.
(4) Sample preparation: the cells were washed once with pre-chilled PBS buffer, diluted 5X BindingBuffer with double distilled water to 1X working solution, and 500. Mu.L of 1X Biindingbuffer resuspended cells were taken.
(5) Dyeing: each sample was added with 5 μ LAnnexinV and 10 μLPI, vortexed gently with a vortexing device, and incubated at room temperature for 5 minutes in the dark.
(6) And (3) flow detection: the sample was analyzed by flow cytometry and the results are shown in FIG. 1.
2. Effect of Honokiol HK and genistein Gen compatibility on the level of Reactive Oxygen Species (ROS) in radiation damaged HIEC cells
(1) Cell plating: cells in the logarithmic growth phase were inoculated into 6-well plates at a rate of 8X 10 4 cells/mL, the loading volume per well was 2mL, and 3 wells were set per group.
(2) And (3) drug treatment: after the HIEC cells were attached overnight, each group was incubated with DMEM medium containing the corresponding concentrations of Gen and/or HK for 24 hours.
(3) And (3) radiation treatment: the individual irradiation group (IR) and the drug treatment group were subjected to X-ray irradiation at a total dose of 4.0Gy (dose rate of 100.0 cGy/min), and the cells were returned to the CO 2 incubator after the irradiation for continuous cultivation for 48 hours.
(4) Collecting cells: after the incubation, HIEC cells were collected by digestion centrifugation and cell count was performed by a hemocytometer, 2X 10 5 cells were collected from each sample, and centrifuged at 2000rpm at 4℃for 5 minutes.
(5) Washing the cells: the cells were washed once with PBS buffer.
(6) Probe staining: the DCFH-DA was diluted with serum-free DMEM medium at a ratio of 1:1000, the cells were resuspended in diluted DCFH-DA after collection, incubated at 37℃in a CO 2 incubator for 20 minutes, and the cells were mixed upside down every 4 minutes during incubation to allow sufficient contact between the probe and the cells.
(7) And (3) flow detection: after the incubation, the cells were washed 3 times with serum-free DMEM medium, centrifuged at 2000rpm at 4 ℃ for 5 minutes, and collected, and after the cells were resuspended in serum-free DMEM medium, fluorescence of FITC channels was detected by a flow on-machine, and the results are shown in fig. 1.
3. Influence of the compatibility of honokiol HK and genistein Gen on irradiation damage HIEC cell DNA
Severe DNA damage often occurs as a DNA double strand break, H2Ahistone familymemberX (h2a.x) is one of the variants of chromosomal histone H2A. When the cellular DNA double strand breaks, the H2AX undergoes phosphorylation modification to form gamma-H2 AX. The gamma-H2 AX content level can reflect the degree and repair condition of DNA damage, and is often applied to the research of cell DNA damage and apoptosis as an important DNA damage marker.
(1) Cell climbing tablet: coverslips were placed in 6-well plates, sterilized with 75% alcohol and irradiated with ultraviolet light overnight in a super clean bench. HIEC cells in the logarithmic growth phase were counted after pancreatin digestion and inoculated into 6-well plates with coverslips at a cell density of 1X 10 6 cells/mL and cultured overnight to allow the cells to adhere to the coverslips at the bottom of the well plates.
(2) And (3) drug treatment: the cells were grouped according to the above experimental method, and after overnight cell attachment, DMEM medium containing corresponding concentrations of Gen and/or HK was added for co-incubation for 24 hours.
(3) And (3) radiation treatment: the single irradiation group (IR) and the drug treatment group were each subjected to X-ray irradiation at a dose of 4.0Gy (dose rate: 100.0 cGy/min), and after the irradiation, the culture was continued in a CO 2 incubator for 48 hours, and after the treatment was completed, the old medium was aspirated and washed once with PBS buffer.
(4) Fixing: 1mL of fixative solution was added to each well, and after fixation for 15min, the fixative solution was aspirated off and washed 3 times with wash solution for 5min each.
(5) Closing: 1mL of immunostaining blocking solution was added, and after 15 minutes (10-20 minutes) of blocking at room temperature, the immunostaining blocking solution was aspirated and discarded.
(6) Antibody incubation: adding gamma-H2 AX mouse monoclonal antibody capable of fully covering a cell sample, incubating for 1 hour at room temperature, carefully sucking out the gamma-H2 AX mouse monoclonal antibody into a 15mL centrifuge tube after incubation, preserving at 4 ℃ in a refrigerator, recycling and reusing, and washing the pore plate with a washing liquid for 3 times for 10 minutes each time.
(7) Fluorescent labeling: and adding the anti-mouse Cy3, fully covering the sample, incubating for 1 hour at room temperature, carefully sucking out the anti-mouse Cy3 after the incubation is finished, sucking out the anti-mouse Cy3 into a 15mL centrifuge tube, preserving the anti-mouse Cy3 in a refrigerator at the temperature of 4 ℃, recycling the anti-mouse Cy3, and washing the pore plate with washing liquid for 2 times for 10 minutes each time.
(8) Nuclear staining: 1mL of nuclear staining solution (DAPI) was added and stained at room temperature for about 5 minutes, and after the staining was completed, the nuclear staining solution was aspirated, and the cells were washed 3 times with washing solution for 5 minutes each time.
(9) And (3) sealing piece observation: an appropriate amount of anti-fluorescence quenching sealing liquid was added dropwise, and after sealing the cover glass, the cover glass was observed under a fluorescence microscope, and analysis was performed using Image J software, and the results are shown in fig. 1.
2. Protection effect of honokiol HK and genistein Gen compatibility on small intestine injury of radiation injury mouse model
Healthy clean grade male C57BL/6 mice (SPF grade) were purchased from Henan Siebeskies biotechnology Co., ltd, bred in the SPF grade animal experiment center of Zhengzhou university, and bred in strict compliance with the SPF grade standard. Mice used to construct the model of systemic radiation injury are 7-8 weeks old and weigh approximately 18-22g. Mice were kept with sterilized drinking water and sterile feed at about 60% ambient humidity, about 25 ℃,12 hours of alternating brightness. Mice were acclimatized for one week and experiments were started after no abnormalities were observed.
1. Experimental grouping
Mice were randomly divided into 6 groups as follows:
a: normal Control group (Control);
b: an individual illumination group (IR);
Drug treatment group:
c: honokiol group HK (50 mg/kg);
d: genistein group Gen (160 mg/kg);
e: combination high dose group HK (50 mg/kg) +Gen (160 mg/kg);
F: combination low dose group HK (25 mg/kg) +Gen (80 mg/kg).
2. Administration mode
The normal Control group (Control) and the single irradiation group (IR) are used for pouring the gastric solvent corn oil according to the body weight of the mice for 7 continuous days, the HK and/or Gen are/is added to each administration group according to the corresponding administration dosage, the administration volume of the two medicines is 0.1mL/10g, the two medicines are respectively dissolved in the corn oil according to the administration concentration, and the two medicines are uniformly mixed before administration and then poured into the stomach.
3. Establishment of mouse whole body radiation injury model
C57BL/6 male mice are placed in a plastic glass box, 5 mice in each group are irradiated by X rays once, the total dose is 7.0Gy, and the dose rate is 100.0cGy/min.
4. HE staining of small intestine
The mice were sacrificed by neck-drawing 3 days after irradiation, dissected and rapidly removed from the whole intestinal tract, the intestinal tract was split longitudinally after the PBS buffer was aspirated by syringe to flush the intestinal contents, the small intestine was rolled into a "Swiss coil" intestine, which was then immersed in 4% paraformaldehyde tissue fixative for tissue fixation, embedding and H & E staining, and the tissue morphology of the small intestine was observed and the villus length was measured, as shown in FIG. 2.
5. Study of survival of mice 30 days after irradiation
60C 57BL/6 male mice were grouped and dosed according to the above experimental method, 10 mice per group were first placed in a plexiglass box and subjected to a total X-ray irradiation (Total body irradiation, TBI) at a dose of 7.0Gy (dose rate 100.0 cGy/min) which is a medium dose capable of causing significant radiation damage, whereas normal control mice were not subjected to irradiation. Mice death was recorded daily for 30 days post irradiation, a 30 day survival curve and a weight change curve were plotted, and the average number of days of survival for each group of mice was calculated, and the results are shown in fig. 2.
3. Experimental results
1. Protection effect of honokiol and genistein on irradiation injury HIEC cells
As shown in FIG. 1-A, after HIEC cells were irradiated with 4Gy X-rays for 48 hours, the early apoptosis rate and the late apoptosis rate of HIEC cells of the control group were significantly increased. Compared with IR (4 Gy), the early apoptosis rate and the late apoptosis rate of HIEC cells are obviously reduced after 2 mug/mLHK, 1 mug/mLGen or 0.5 mug/mL Gen treatment. In contrast, in the combination group of honokiol HK and genistein Gen, no matter 2 mug/mL and honokiol HK are combined with 1 mug/mL genistein Gen or 1 mug/mL and honokiol HK are combined with 0.5 mug/mL genistein Gen, the early apoptosis rate and the late apoptosis rate of HIEC cells are obviously reduced compared with the single use of HK or Gen, and the effect of the combination low-dose group is better than that of the combination high-dose group (P < 0.05). Wherein P <0.001 for # # compared to the blank; * P <0.05 compared to IR (4 Gy) group; * P <0.01 compared to IR (4 Gy) group; * P <0.001 compared to IR (4 Gy) group.
As shown in FIG. 1-B, 4Gy of X-ray irradiation can obviously induce the generation of ROS in HIEC cells, and different concentrations of honokiol HK and genistein Gen can obviously remove ROS in the irradiated cells, so that the honokiol HK and genistein Gen can improve oxidative stress injury caused by irradiation. After the combination of magnolol HK and genistein Gen, CI index of the combination of the two medicines was analyzed, which indicated that 2. Mu.g/mL of honokiol HK was compatible with 1. Mu.g/mL of genistein Gen, 1. Mu.g/mL of honokiol HK was compatible with 0.5. Mu.g/mL of genistein Gen, and both concentrations had synergistic inhibition effect on the ROS induced by irradiation. The CI value of the combined high-dose group is 0.76447, the combined low-dose group is 0.35196, and the combined high-dose group is strong in synergism. Wherein P <0.001 for # # compared to the blank; * P <0.05 compared to IR (4 Gy) group; * P <0.001 compared to IR (4 Gy) group.
As shown in the figure 1-C, the result of the cell immunofluorescence experiment shows that the DNA damage of HIEC cells can be obviously caused after 4Gy irradiation, compared with an IR (4 Gy) group, the pretreatment of honokiol HK and genistein Gen can reduce the generation of gamma-H2 AX caused by X rays, and the results prove that the honokiol HK and genistein Gen can improve the damage degree of cell DNA after irradiation, and the effect of compatibility of honokiol HK and genistein Gen on reducing the DNA damage is better than that of a single administration group (P < 0.001). P <0.001 compared to the blank, #; * P <0.001 compared to IR (4 Gy) group.
2. Protection effect of honokiol and genistein compatibility on small intestine injury of radiation injury mouse model
FIG. 2-A is a schematic diagram of the construction of a model of systemic radiation damage with mice dosing.
FIG. 2-B shows that honokiol HK, genistein, and both honokiol HK and genistein were able to improve irradiation-induced shortening of colon length in mice. Wherein P <0.001 for # # compared to the blank; * P <0.05 compared to IR (4 Gy) group; * P <0.01 compared to IR (4 Gy) group.
FIG. 2-C is a graph showing the survival curve of mice after irradiation and a statistical graph showing the average survival days. The single administration of genistein and the compatibility of high-dose honokiol HK and genistein Gen can improve the survival condition of mice and the survival rate of mice. The survival rate of the mice in the high-dose combined administration group is obviously improved compared with that of the mice in the irradiation group. Wherein P <0.01 compared to the IR (4 Gy) group; * P <0.001 compared to IR (4 Gy) group.
FIG. 2-D shows that honokiol HK, genistein Gen, and compatibility of honokiol HK and genistein Gen all improved intestinal structure of mice after irradiation. The morphological change of the small intestine is observed through the HE staining experiment, and the result shows that obvious small intestine structural damage can be observed 3 days after 7Gy irradiation, which is shown by small intestine villus damage and reduction of crypt number. The statistics of the lengths of small intestine villi shows that compared with an IR (7 Gy) group, the pretreatment of honokiol HK and genistein Gen can reduce the shortening of small intestine villi of mice caused by X rays, and proves that honokiol HK and genistein Gen can improve the damage degree of small intestine of mice after irradiation, and the effect of reducing the damage of small intestine of mice by the compatibility of honokiol HK and genistein Gen is better than that of a single administration group (P < 0.001). Wherein P <0.001 for # # compared to the blank; * P <0.05 compared to IR (7 Gy) group; * P <0.01 compared to IR (7 Gy) group; * P <0.001 compared to IR (7 Gy) group.
4. Conclusion(s)
In conclusion, experiments show that the compatibility of honokiol HK and genistein Gen shows radiation protection effect in Human Intestinal Epithelial Cells (HIEC), and oxidative stress injury after cell irradiation is reduced by reducing radiation-induced apoptosis, ROS generation and DNA injury. Meanwhile, the compatibility of honokiol HK and genistein Gen also shows radiation protection effect in vivo experiments, and the compatibility treatment of honokiol HK and genistein Gen prolongs the survival time of irradiated mice, resists the shortening of small intestine villi after irradiation, improves the small intestine intestinal tract structure and promotes the restoration of the epithelial injury of RIII. Thus, the compatibility of honokiol HK with genistein Gen is an effective strategy for preventing and treating IR-induced intestinal injury.
Although the technical solution and effects of the present invention have been described in detail with general description, specific embodiments and experimental examples, it should be understood that modifications, substitutions or improvements may be made by those skilled in the art without departing from the spirit and scope of the present invention.
Claims (10)
1. The new application of honokiol and genistein is characterized in that: the application is as follows: application of honokiol and genistein in preparing medicine for preventing and treating radioactive intestinal injury is provided.
2. The new use according to claim 1, characterized in that: the application is as follows: use of honokiol in combination with genistein for the manufacture of a medicament for reducing oxidative stress damage of intestinal cells after irradiation, including but not limited to one or more of the following:
(1) Application of honokiol and genistein in preparing medicine for inhibiting apoptosis of intestinal cells after irradiation;
(2) Application of honokiol and genistein in preparing medicine for reducing active oxygen level in intestinal cells after irradiation;
(3) The application of honokiol and genistein in preparing medicine for reducing DNA damage of intestinal cells after irradiation is provided.
3. The new use according to claim 1, characterized in that: the application is as follows: use of honokiol in combination with genistein for the manufacture of a medicament for promoting repair of intestinal lesions after irradiation, including but not limited to one or more of the following:
(1) Application of honokiol and genistein in preparing medicine for improving intestinal tract shortening after irradiation;
(2) Application of honokiol and genistein in preparing medicine for improving intestinal tract structure damage after irradiation is provided.
4. The new use according to claim 1, characterized in that: the application is as follows: use of honokiol in combination with genistein for the manufacture of a medicament for improving survival of an individual after irradiation, including but not limited to one or more of the following:
(1) Application of honokiol and genistein in preparing medicine for improving individual survival rate after irradiation;
(2) The application of honokiol and genistein in preparing medicine for prolonging individual life after irradiation is provided.
5. A medicament for preventing and treating radiation intestinal injury, characterized in that: the medicinal components of the medicine comprise honokiol and genistein.
6. A medicament according to claim 5, characterized in that: the mass ratio of the medicine neutralization magnolol to the genistein is 1-2:1-4.
7. A medicament according to claim 5, characterized in that: the total content of the medicine neutralized magnolol and genistein is the medicine effect amount, and the medicine effect amount is valued within the range of 0.01wt percent to 99.99wt percent.
8. A medicament according to claim 5, characterized in that: other medicinal components are also included in the medicament, including but not limited to medicinal components for preventing and treating the radioactive intestinal injury and medicinal components for eliminating or reducing toxic and side effects of the medicament.
9. A medicament according to claim 5, characterized in that: pharmaceutically acceptable carriers are also included in the medicament, including but not limited to solvents, excipients, preservatives, stabilizers, wetting agents, emulsifiers, salts for regulating osmotic pressure, buffers.
10. A medicament according to claim 5, characterized in that: the dosage form of the medicine is pharmaceutically acceptable dosage form, including but not limited to powder injection, tablet, pill, capsule, spray and dispersion liquid;
And/or the route of administration of the drug is a pharmaceutically acceptable route including, but not limited to, oral, intradermal, subcutaneous, intramuscular, intraperitoneal, intravenous, and transdermal, intranasal or buccal inhalation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410844764.2A CN118615277A (en) | 2024-06-27 | 2024-06-27 | New application of honokiol and genistein in compatibility |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410844764.2A CN118615277A (en) | 2024-06-27 | 2024-06-27 | New application of honokiol and genistein in compatibility |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN118615277A true CN118615277A (en) | 2024-09-10 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202410844764.2A Pending CN118615277A (en) | 2024-06-27 | 2024-06-27 | New application of honokiol and genistein in compatibility |
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| Country | Link |
|---|---|
| CN (1) | CN118615277A (en) |
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